Infective endocarditis: Refer for expert team care as soon as possible

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Infective endocarditis: Refer for expert team care as soon as possible

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.1 When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.2

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.9 When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

References
  1. Soud M, Pacha HM, Alraies MC. How soon should patients with infective endocarditis be referred for valve surgery? Cleve Clin J Med 2018; 85(5):362–364. doi:10.3949/ccjm.85a:17052
  2. Pettersson GB, Coselli JS, Pettersson GB, et al. 2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary. J Thorac Cardiovasc Surg 2017; 153(6):1241–1258.e29. doi:10.1016/j.jtcvs.2016.09.093
  3. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132(15):1435–1486. doi:10.1161/CIR.0000000000000296
  4. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36(44):3075–3128. doi:10.1093/eurheartj/ehv319
  5. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease:executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(23):2440–2492. doi:10.1161/CIR.0000000000000029
  6. Byrne JG, Rezai K, Sanchez JA, et al. Surgical management of endocarditis: the Society of Thoracic Surgeons clinical practice guideline. Ann Thorac Surg 2011; 91(6):2012–2019. doi:10.1016/j.athoracsur.2011.01.106
  7. Yanagawa B, Pettersson GB, Habib G, et al. Surgical management of infective endocarditis complicated by embolic stroke: practical recommendations for clinicians. Circulation 2016; 134(17):1280–1292. doi:10.1161/CIRCULATIONAHA.116.024156
  8. Cahill TJ , Baddour LM, Habib G, et al. Challenges in infective endocarditis. J Am Coll Cardiol 2017; 69(3):325–344. doi:10.1016/j.jacc.2016.10.066
  9. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 2012; 366(26):2466–2473. doi:10.1056/NEJMoa1112843
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Author and Disclosure Information

Gösta B. Pettersson, MD, PhD
Surgical Director, Adult Congenital Heart Disease Center, Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Pediatric Institute, and Transplant Center, Cleveland Clinic

Brian Griffin, MD
Section Head, Department of Cardiovascular Medicine; Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Steven M. Gordon, MD
Chairman, Department of Infectious Disease, Medicine Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Eugene H. Blackstone, MD
Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, and Department of Quantitative Health Sciences, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Gösta B. Pettersson, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Desk J4-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; petterg@ccf.org

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infectious endocarditis, surgery, thromboembolism, valve, blood cultures, vegetations, multidisciplinary care, Gosta Pettersson, Brian Griffin, Steven Gordon, Eugene Blackstone
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Gösta B. Pettersson, MD, PhD
Surgical Director, Adult Congenital Heart Disease Center, Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Pediatric Institute, and Transplant Center, Cleveland Clinic

Brian Griffin, MD
Section Head, Department of Cardiovascular Medicine; Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Steven M. Gordon, MD
Chairman, Department of Infectious Disease, Medicine Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Eugene H. Blackstone, MD
Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, and Department of Quantitative Health Sciences, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Gösta B. Pettersson, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Desk J4-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; petterg@ccf.org

Author and Disclosure Information

Gösta B. Pettersson, MD, PhD
Surgical Director, Adult Congenital Heart Disease Center, Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, Pediatric Institute, and Transplant Center, Cleveland Clinic

Brian Griffin, MD
Section Head, Department of Cardiovascular Medicine; Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Steven M. Gordon, MD
Chairman, Department of Infectious Disease, Medicine Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Eugene H. Blackstone, MD
Department of Thoracic and Cardiovascular Surgery, Heart and Vascular Institute, and Department of Quantitative Health Sciences, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Address: Gösta B. Pettersson, MD, PhD, Department of Thoracic and Cardiovascular Surgery, Desk J4-1, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; petterg@ccf.org

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Related Articles

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.1 When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.2

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.9 When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

In this issue of the Journal, Soud et al discuss the timing of referral of patients with infective endocarditis to surgery.1 When having this discussion, it is important to understand the nature of the disease and the role of surgery in its treatment.

See related article

Unless successfully treated and cured, infective endocarditis is fatal. It is associated with septic embolism (systemic with left-sided infective endocarditis and pulmonary with right-sided infective endocarditis), destruction of valve tissue, and invasion outside the aortic root or into the atrioventricular groove. Antimicrobials kill sensitive and exposed organisms but cannot reach those hiding in vegetations or biofilm, on foreign material, or in invaded extravascular tissue.

The objectives of surgery are to eliminate the source of embolism, debride and remove infected tissue and foreign material, expose and make residual organisms vulnerable to antimicrobials, and restore functional valves and cardiac integrity. Surgery to treat infective endocarditis is difficult and high-risk and requires an experienced surgeon. But final cure of the infection is still by antimicrobial treatment.

INFECTIVE ENDOCARDITIS NEEDS MULTIDISCIPLINARY CARE

Every aspect of infective endocarditis—diagnosis, medical management, management of complications, and surgery—is difficult. Recent guidelines2–6 therefore favor care by a multidisciplinary team that includes an infectious disease specialist, cardiologist, and cardiac surgeon from the very beginning, with access to any other needed discipline, often including neurology, neurosurgery, nephrology, and dependence specialists. Patients with infective endocarditis should be referred early to a center with access to a full endocarditis treatment team. The need for surgery and the optimal timing of it are team decisions. The American Association for Thoracic Surgery infective endocarditis guidelines are question-based and address most aspects that surgeons must consider before, during, and after operation.2

IF SURGERY IS INDICATED, IT IS BEST DONE SOONER

Once there is an indication to operate, the operation should be expedited. Delays mean continued risk of disease progression, invasion, heart block, and embolic events. Determining the timing of surgery is difficult in patients who have suffered an embolic stroke—nonhemorrhagic or hemorrhagic—or who have suffered brain bleeding; management of these issues has recently triggered expert opinion and review articles.7,8 The recommendation for early surgery is based on the conviction that once the patient has been stabilized (or has overwhelming mechanical hemodynamic problems requiring emergency surgery) and adequate antimicrobial coverage is on board, there are no additional benefits to delaying surgery.9 When the indication to operate is large mobile vegetations associated with a high risk of stroke, surgery before another event can make all the difference.

In the operating room, the first aspect addressed is adequate debridement. There is wide agreement that repair is preferable to replacement for the mitral and tricuspid valves, but there is no agreement that an allograft (although favored by our team) is the best replacement alternative for a destroyed aortic root. The key is that surgeons and their surgical teams must have the experience and tools that work for them.

Our recommendation is to refer all patients with infective endocarditis to a center with access to a full team of experienced experts able to address all aspects of the disease and its complications.

References
  1. Soud M, Pacha HM, Alraies MC. How soon should patients with infective endocarditis be referred for valve surgery? Cleve Clin J Med 2018; 85(5):362–364. doi:10.3949/ccjm.85a:17052
  2. Pettersson GB, Coselli JS, Pettersson GB, et al. 2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary. J Thorac Cardiovasc Surg 2017; 153(6):1241–1258.e29. doi:10.1016/j.jtcvs.2016.09.093
  3. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132(15):1435–1486. doi:10.1161/CIR.0000000000000296
  4. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36(44):3075–3128. doi:10.1093/eurheartj/ehv319
  5. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease:executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(23):2440–2492. doi:10.1161/CIR.0000000000000029
  6. Byrne JG, Rezai K, Sanchez JA, et al. Surgical management of endocarditis: the Society of Thoracic Surgeons clinical practice guideline. Ann Thorac Surg 2011; 91(6):2012–2019. doi:10.1016/j.athoracsur.2011.01.106
  7. Yanagawa B, Pettersson GB, Habib G, et al. Surgical management of infective endocarditis complicated by embolic stroke: practical recommendations for clinicians. Circulation 2016; 134(17):1280–1292. doi:10.1161/CIRCULATIONAHA.116.024156
  8. Cahill TJ , Baddour LM, Habib G, et al. Challenges in infective endocarditis. J Am Coll Cardiol 2017; 69(3):325–344. doi:10.1016/j.jacc.2016.10.066
  9. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 2012; 366(26):2466–2473. doi:10.1056/NEJMoa1112843
References
  1. Soud M, Pacha HM, Alraies MC. How soon should patients with infective endocarditis be referred for valve surgery? Cleve Clin J Med 2018; 85(5):362–364. doi:10.3949/ccjm.85a:17052
  2. Pettersson GB, Coselli JS, Pettersson GB, et al. 2016 The American Association for Thoracic Surgery (AATS) consensus guidelines: surgical treatment of infective endocarditis: executive summary. J Thorac Cardiovasc Surg 2017; 153(6):1241–1258.e29. doi:10.1016/j.jtcvs.2016.09.093
  3. Baddour LM, Wilson WR, Bayer AS, et al. Infective endocarditis in adults: diagnosis, antimicrobial therapy, and management of complications: a scientific statement for healthcare professionals from the American Heart Association. Circulation 2015; 132(15):1435–1486. doi:10.1161/CIR.0000000000000296
  4. Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines for the management of infective endocarditis: the Task Force for the Management of Infective Endocarditis of the European Society of Cardiology (ESC). Endorsed by: European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Nuclear Medicine (EANM). Eur Heart J 2015; 36(44):3075–3128. doi:10.1093/eurheartj/ehv319
  5. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC guideline for the management of patients with valvular heart disease:executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(23):2440–2492. doi:10.1161/CIR.0000000000000029
  6. Byrne JG, Rezai K, Sanchez JA, et al. Surgical management of endocarditis: the Society of Thoracic Surgeons clinical practice guideline. Ann Thorac Surg 2011; 91(6):2012–2019. doi:10.1016/j.athoracsur.2011.01.106
  7. Yanagawa B, Pettersson GB, Habib G, et al. Surgical management of infective endocarditis complicated by embolic stroke: practical recommendations for clinicians. Circulation 2016; 134(17):1280–1292. doi:10.1161/CIRCULATIONAHA.116.024156
  8. Cahill TJ , Baddour LM, Habib G, et al. Challenges in infective endocarditis. J Am Coll Cardiol 2017; 69(3):325–344. doi:10.1016/j.jacc.2016.10.066
  9. Kang DH, Kim YJ, Kim SH, et al. Early surgery versus conventional treatment for infective endocarditis. N Engl J Med 2012; 366(26):2466–2473. doi:10.1056/NEJMoa1112843
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Infective endocarditis: Refer for expert team care as soon as possible
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Radiation-induced heart disease: A practical guide to diagnosis and management

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Radiation-induced heart disease: A practical guide to diagnosis and management

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.1

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.2

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.3

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.4 Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.5

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.6 A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.7

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.8

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.9

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).10

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.11

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.12

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).13

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.7

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.14

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.15 In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.16

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.17

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.18 Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,19 and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.20 Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.21

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.22

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.23 Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al24 revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Figure 1. Three-dimensional echocardiography in a patient with radiation-induced aortic stenosis demonstrates a typical pattern of thickening and calcification affecting the aortomitral curtain (arrows) and the anterior mitral valve leaflet.

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.25

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.27 Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.28

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.29

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,23 the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.23

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.30

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.31

 

 

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.32

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.33

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.34

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.35

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.35 Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.38

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.39 Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.40

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.41 Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.42

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.40 Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.43

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.44

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.45 However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.46 This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.47

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.48 In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.49

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.50

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation51:

  • Total radiation dose to the heart > 40 Gy
  • Delay of 10 years or more since therapy
  • Abnormal interval electrocardiographic changes such as bundle branch block
  • Prior pericardial involvement
  • Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).10 The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.10

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.52 The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).53

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.54 These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.55

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

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Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Cian P. McCarthy, MD
Department of Medicine, Massachusetts General Hospital, Boston, MA

Patrick Collier, MD, PhD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Milind Desai, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Head, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, and Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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radiation-induced heart disease, RIHD, radiotherapy, breast cancer, lymphoma, coronary artery disease, valvular disease, pericardial disease, Eoin Donnellan, Dermot Phelan, Cian McCarthy, Patrick Collier, Milind Desai, Brian Griffin
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Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Cian P. McCarthy, MD
Department of Medicine, Massachusetts General Hospital, Boston, MA

Patrick Collier, MD, PhD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Milind Desai, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Head, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, and Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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Eoin Donnellan, MD
Department of Internal Medicine, Cleveland Clinic; Clinical Instructor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Cian P. McCarthy, MD
Department of Medicine, Massachusetts General Hospital, Boston, MA

Patrick Collier, MD, PhD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Milind Desai, MD
Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Head, Section of Cardiovascular Imaging, Department of Cardiovascular Medicine, and Vice Chair, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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Related Articles

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.1

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.2

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.3

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.4 Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.5

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.6 A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.7

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.8

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.9

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).10

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.11

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.12

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).13

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.7

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.14

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.15 In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.16

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.17

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.18 Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,19 and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.20 Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.21

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.22

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.23 Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al24 revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Figure 1. Three-dimensional echocardiography in a patient with radiation-induced aortic stenosis demonstrates a typical pattern of thickening and calcification affecting the aortomitral curtain (arrows) and the anterior mitral valve leaflet.

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.25

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.27 Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.28

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.29

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,23 the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.23

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.30

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.31

 

 

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.32

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.33

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.34

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.35

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.35 Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.38

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.39 Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.40

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.41 Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.42

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.40 Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.43

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.44

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.45 However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.46 This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.47

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.48 In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.49

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.50

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation51:

  • Total radiation dose to the heart > 40 Gy
  • Delay of 10 years or more since therapy
  • Abnormal interval electrocardiographic changes such as bundle branch block
  • Prior pericardial involvement
  • Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).10 The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.10

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.52 The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).53

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.54 These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.55

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

Advances in radiotherapy over the past 50 years have dramatically improved outcomes in patients with malignancy. Five-year overall survival rates for Hodgkin lymphoma and non-Hodgkin lymphoma now stand at 80%, and breast cancer survival is 90%.1

Increased longevity, however, has come at the cost of late side effects such as radiation-induced heart disease (RIHD). Cardiac dysfunction due to radiation involves a spectrum of disease processes in patients who have undergone mediastinal, thoracic, or breast radiotherapy and may involve any cardiac structure, including the pericardium, myocardium, valves, conduction system, and coronary arteries.

Overall, compared with nonirradiated patients, patients who have undergone chest radiotherapy have a 2% higher absolute risk of cardiac morbidity and death at 5 years and a 23% increased absolute risk after 20 years.2

This article will review the pathophysiology and epidemiology of RIHD and will offer a practical approach to its diagnosis and management.

MOST DAMAGE IS ENDOTHELIAL 

Cardiac myocytes are relatively resistant to radiation damage because of their postmitotic state. But endothelial cells remain sensitive to radiation, and the pathophysiology of most forms of RIHD appears to be associated with damage to endothelial cells. Conventional cardiac risk factors such as hyperlipidemia and smoking have been shown to compound and accelerate radiation-induced endothelial damage in animal models.3

Radiation is believed to result in transient increases in oxidative stress, resulting in formation of reactive oxygen species and a subsequent inflammatory response that includes activation of nuclear factor-kappa B. Upregulation of proinflammatory pathways results in increased expression of matrix metalloproteinases, adhesion molecules, and proinflammatory cytokines and downregulation of vasculoprotective nitric oxide.4 Indirect evidence for radiation-induced vascular inflammation comes from numerous studies that demonstrated increased levels of the proinflammatory cytokines interleukin 6, tumor necrosis factor alpha, and interferon gamma in Japanese atomic bomb survivors.5

RISK FACTORS

Risk factors for RIHD are summarized in Table 1.

The volume of heart irradiated is a major determinant of the development of RIHD.6 A retrospective study of 960 breast cancer patients in Stockholm between 1971 and 1976 found that those who had received the highest doses and volumes of cardiac radiation had a threefold higher risk of cardiac death. By comparison, those with lesser volumes of the heart exposed to radiation had no increase in risk of cardiac death compared with the general population.7

Younger age at the time of radiotherapy is associated with an increased risk of RIHD in breast cancer and lymphoma patients. A retrospective analysis of 635 patients under age 21 with Hodgkin lymphoma treated with radiotherapy showed a relative risk of fatal myocardial infarction of 41.5 compared with a general population matched for age, sex, and race.8

Conventional cardiac risk factors such as smoking, hypertension, diabetes, and hyperlipidemia further increase the risk of RIHD, and radiation increases the cardiotoxicity of chemotherapeutic agents such as anthracyclines.9

In general, high-risk patients are defined as those with at least one risk factor for RIHD who underwent anterior or left-sided chest irradiation  (Table 1).10

CORONARY ARTERY DISEASE

Ischemic heart disease is the most common cause of cardiac death in patients who have undergone radiation therapy. Atherosclerotic lesions in RIHD are morphologically identical to those in nonirradiated vessels and are characterized by intimal proliferation, accumulation of lipid-rich macrophages, and plaque formation.11

A retrospective single-institution study of 415 patients with Hodgkin lymphoma who had undergone radiation therapy found the incidence of coronary artery disease 20 years later to be 10%. The mean time to development of coronary artery disease was 9 years, and all patients who developed it had at least one conventional cardiac risk factor.12

A meta-analysis of more than 20,000 breast cancer patients who received radiotherapy in 40 randomized controlled trials found an increase in the rate of non-breast-cancer deaths, primarily from vascular causes (annual event ratio 1.27, P <  .0001).13

A randomized controlled trial comparing breast cancer patients who underwent preoperative or postoperative radiotherapy vs those who had surgery alone revealed a significantly higher death rate from coronary artery disease in the postradiotherapy group.7

The risk of radiation-induced coronary artery disease is proportional to both the dose and the duration of radiation therapy. A retrospective study of more than 2,000 women undergoing radiotherapy for breast cancer found that the relative risk of coronary artery disease increased linearly by about 7.4% per Gy of radiation to the heart, with no apparent ceiling.14

The distribution of atherosclerotic coronary arteries correlates well with the areas exposed to the highest doses of radiation. For instance, in left-sided breast cancer, the apex and anterior wall of the heart typically receive the highest doses of radiation; consequently, the left anterior descending and distal diagonal branches are most prominently involved.15 In patients with lymphoma who undergo radiotherapy to mediastinal nodes and in breast cancer patients receiving radiotherapy to the internal mammary chain, basal structures may be exposed as well. Ostial lesions can also be seen in these patients.16

The clinical presentation of coronary artery disease in radiotherapy recipients does not differ significantly from that in the general population. Ischemia may be silent, may lead to classic anginal symptoms, or may cause sudden cardiac death. The incidence of silent myocardial infarction has been reported to be higher after mediastinal radiotherapy than it is in the general population, possibly from damage to nerve endings within the radiation field.17

Management of radiation-associated coronary artery disease

Managing patients with radiation-associated coronary artery disease is challenging, but the therapeutic options remain the same as those in nonirradiated patients and include medical therapy, percutaneous coronary intervention, and coronary artery bypass grafting, depending on the site and extent of disease.18 Although results are conflicting, there does not seem to be a significant difference in the rates of stent restenosis between patients with a history of radiation therapy and the general population.

Percutaneous coronary intervention is generally preferred to coronary artery bypass grafting in these patients for several reasons. Radiation-induced fibrosis of surrounding structures generally makes surgical procedures more difficult,19 and inclusion of the internal mammary artery or internal thoracic artery in the radiation field may result in stenosis of these vessels, rendering them unsuitable for harvesting.20 Moreover, many patients with RIHD have concurrent radiation-induced lung damage, which increases the risk of perioperative pulmonary complications.21

If the coronary lesions are not amenable to percutaneous intervention, a careful valvular evaluation should be performed preoperatively in view of the frequency of radiation-associated valvular disease. In a study of 72 patients with RIHD undergoing coronary artery bypass grafting, 40% required valvular surgery at the time of surgery or shortly thereafter.22

Results of studies of coronary artery bypass graft outcomes in patients with a history of thoracic radiation therapy have been conflicting, but success seems to depend on the status of the internal mammary and internal thoracic arteries.23 Therefore, the patency of these vessels should be elucidated preoperatively by angiography and intraoperatively by visual inspection of the vessels for fibrosis.

A large single-institution study by Wu et al24 revealed higher short-term and long-term mortality rates in patients with RIHD undergoing cardiac surgery than in control patients without RIHD undergoing similar procedures.

VALVULAR DISEASE

Figure 1. Three-dimensional echocardiography in a patient with radiation-induced aortic stenosis demonstrates a typical pattern of thickening and calcification affecting the aortomitral curtain (arrows) and the anterior mitral valve leaflet.

Radiation therapy may directly affect heart valves, and both stenotic (Figure 1) and regurgitant lesions have been described. Pathologic findings include leaflet retraction, fibrotic thickening, and late calcification.25

The precise mechanism of radiation-induced valvular disease is unknown but is thought to be a change in the phenotype of valvular interstitial cells from a myofibroblast to an osteoblast-like cell. Radiation results in significant expression of osteogenic factors such as bone morphogenic protein 2, osteopontin, alkaline phosphatase, and runt-related transcription factor 2 by valvular interstitial cells.26

Valvular heart disease is evident in as many as 81% of patients with RIHD, with the aortic and mitral valves affected more commonly than the tricuspid and pulmonic valves.27 Why there are more left-sided valve lesions than pulmonic valve lesions, despite the pulmonic valve’s anterior position in the heart, is unknown but may be due to higher pressures across the left-sided heart valves.

Although valvular disease is common in patients with RIHD, clinically significant disease is not; more than 70% of patients with radiation-induced valvular disease have no symptoms. A study of 38 cases of radiation-induced valvular disease reported a mean time to development of asymptomatic valvular lesions of 11.5 years and an average time to symptomatic valvular dysfunction of 16.5 years, indicating that 5 years seems to be the interval required for progression from asymptomatic to symptomatic valvular RIHD.28

The thickness of the aortomitral curtain (the junction between the base of the anterior mitral leaflet and the aortic root) is an independent predictor of the long-term risk of death in patients with valvular RIHD.29

Management of radiation-induced valvular disease

Management of patients with valvular RIHD poses a major clinical conundrum because of  the high rates of perioperative morbidity and death in patients with a history of chest radiotherapy. In one study,23 the long-term mortality rate was 45% in postradiotherapy patients undergoing single-valve surgery and 61% in those undergoing surgery on two or more valves, compared with 13% and 17% in patients with no history of chest radiotherapy.23

Furthermore, valve repair is an unattractive option in these patients because of high failure rates of mitral valve and tricuspid valve repair attributed to ongoing radiotherapy-induced valvular changes after repair.30

As a result, valve replacement is generally preferred in this group. Patients should be advised of the higher risk of perioperative and long-term morbidity and death associated with open heart surgery than in the general population, and that the risks are even higher with repeat open heart surgery.

This risk has implications for the choice of replacement valves in younger patients. Bioprosthetic valves, which deteriorate over time, may not be advisable. Transcatheter aortic valve replacement has been successful in radiation-induced valvular disease and may become the preferred method of aortic valve replacement.31

 

 

PERICARDIAL DISEASE

Pericardial disease is a frequent manifestation of RIHD and covers a spectrum of manifestations from acute pericarditis, pericardial effusion, and tamponade to constrictive pericarditis. In a necropsy study, 70% of patients with RIHD were found to have pericardial involvement.32

The mechanism is believed to be radiation-induced microvascular injury resulting in increased capillary permeability and the sometimes rapid development of a protein-rich exudate. Associated inflammation may cause acute pericarditis, which may eventually be complicated by chronic pericarditis. The parietal surface tends to be affected more severely than the epicardium.33

Perhaps as a result of recent advances such as lower radiation doses, equal weighting of the anterior and posterior fields, and subcarinal blocking, incidence rates of pericarditis as low as 2.5% have been reported.34

Pericardial RIHD may be divided into early acute pericarditis, delayed chronic pericardial effusion, and constrictive pericarditis.

Early acute pericarditis is rare and is thought to represent a reaction to tumor necrosis. It is defined as occurring during radiotherapy and occurs almost exclusively with high-dose radiotherapy for lymphoma. Due to the relatively benign course of acute pericarditis and fear of tumor recurrence, it is not an indication to withhold radiotherapy.35

Delayed chronic pericardial effusion occurs months to years after radiotherapy, is typically asymptomatic, and presents as an enlarged cardiac silhouette on chest imaging.35 Delayed pericardial effusion is followed with imaging. While in many cases it resolves within 2 years, it may also be long-standing. Pericardiocentesis or a pericardial window may be performed to treat symptomatic effusion or delayed effusion causing hemodynamic compromise.35–37 Hypothyroidism should be ruled out, as it can complicate mantle irradiation and result in chronic pericardial effusion.38

Constrictive pericarditis may occur as a late complication of radiotherapy and typically causes symptoms of congestive heart failure. Pericardial stripping in these patients is complicated by the possibility of coexisting RIHD of the valves, myocardium, or coronary arteries, as well as mediastinal fibrosis. A study of 163 patients who underwent pericardial stripping for chronic pericarditis found a 7-year overall survival rate of only 27%, far lower than the rate for those who had no history of radiation exposure.39 Therefore, these patients are often treated for symptom control with diuretics and a low-salt diet rather than with surgery.

MYOCARDIAL DISEASE

Microvascular injury in the myocardium results in chronic ischemia, which may lead to myocardial fibrosis, typically manifesting as diastolic dysfunction. Chest radiotherapy may result in both systolic and diastolic dysfunction, and dilated and restrictive cardiomyopathy are well-recognized complications.40

Historically, high radiation doses resulted in systolic dysfunction in more than half of patients who underwent thoracic radiotherapy.41 Now, however, fewer than 5% of patients develop reductions in left ventricular ejection fraction, and most cases of radiotherapy-induced cardiomyopathy have a restrictive pattern.42

In a single-institution study, diastolic dysfunction was reported in as many as 14% of patients who underwent thoracic radiotherapy for Hodgkin lymphoma.40 Systolic dysfunction is now seen almost exclusively in patients  treated concurrently with cardiotoxic chemotherapeutic agents such as anthracyclines in addition to radiotherapy.43

In a childhood cancer survival series, the hazard ratio of congestive heart failure in patients who had undergone radiotherapy for Wilms tumor was 6.6—almost identical to the occurrence in sibling controls. By contrast, the hazard ratio increased to 18.3 in those who received doxorubicin in addition to radiotherapy.44

Treatment of radiation-induced cardiomyopathy

Treatment of radiation-induced cardiomyopathy is similar to that for other forms of cardiomyopathy, with an emphasis on symptom management.

Heart transplant may be an option for highly selected patients with end-stage heart failure secondary to RIHD. In one report, a series of four RIHD patients received a heart transplant, and all four survived past 48 months.45 However, data from the United Network of Organ Sharing revealed an increase in the all-cause mortality rate in patients undergoing heart transplant for RIHD compared with those undergoing transplant for cardiomyopathy due to other causes.46 This trend may be confounded by a higher prevalence of prior cardiac surgery in the RIHD group—itself an established risk factor for poor posttransplant outcomes.

CONDUCTION SYSTEM DISEASE

Life-threatening arrhythmias have been reported that are distinct from the common, asymptomatic repolarization abnormalities that occur during radiotherapy. Atrioventricular nodal bradycardia, all degrees of heart block, and sick sinus syndrome have all been reported after chest radiotherapy. As conduction abnormalities do not typically manifest until years after radiotherapy, it is difficult to establish causation and, consequently, to define incidence.

Right bundle branch block is the most common conduction abnormality because of the proximity of the right bundle to the endocardium on the right side.47

Chest radiotherapy is also associated with prolongation of the corrected QT interval (QTc). A study in patients with a history of thoracic radiotherapy found that the QTc characteristically increased with exercise, a poor prognostic indicator.48 In a study of 134 survivors of childhood cancer, 12.5% of those who had undergone radiotherapy had a resting QTc of 0.44 msec or more.49

Furthermore, a study of 69 breast cancer survivors found a higher incidence of conduction abnormalities at 6 months and 10 years after radiotherapy compared with baseline. The characteristic electrocardiographic changes at 6 months were T-wave changes. At 10 years, the T-wave abnormalities had resolved and were replaced by ST depression.50

As mentioned above, establishing radiotherapy as a cause for these conduction abnormalities is challenging, given the lag between radiation therapy and electrocardiographic changes. The following criteria have been proposed for establishing a link between atrioventricular blockade and prior radiation51:

  • Total radiation dose to the heart > 40 Gy
  • Delay of 10 years or more since therapy
  • Abnormal interval electrocardiographic changes such as bundle branch block
  • Prior pericardial involvement
  • Associated cardiac or mediastinal lesions.

SCREENING GUIDELINES

Consensus guidelines for identifying and monitoring RIHD have been published by the European Association of Cardiovascular Imaging and the American Society of Echocardiography (Table 2).10 The European Society of Medical Oncology has also issued guidelines for the prevention, diagnosis, and management of cardiovascular disease associated with cancer therapy.

Briefly, the guidelines call for aggressive cardiac risk-factor modification through weight loss, exercise, blood pressure control, and smoking cessation, in addition to early detection of RIHD. Cardiovascular screening for risk factors and a careful clinical examination should be performed in all patients. Baseline comprehensive transthoracic echocardiography is advocated in all patients before starting radiotherapy to detect cardiac anomalies. Beyond this, an annual history and physical examination, paying close attention to the signs and symptoms of cardiopulmonary disease, is essential. The development of new cardiopulmonary symptoms or a new physical finding such as a murmur should prompt evaluation with transthoracic echocardiography.

In patients without symptoms, screening transthoracic echocardiography at 10 years after the start of radiotherapy is recommended in light of the high probability of diagnosing cardiac disease at this juncture. In patients with no preexisting cardiac disease, surveillance transthoracic echocardiography should be at 5-year intervals thereafter.

In high-risk patients without symptoms (those who have undergone anterior or left-sided radiotherapy and have at least one risk factor for RIHD), initial screening transthoracic echocardiography is recommended 5 years after radiotherapy. These patients have a heightened risk of coronary events as described above and, consequently, are recommended to undergo noninvasive imaging 5 to 10 years after radiation exposure. If this initial examination is negative, stress testing should be repeated at 5-year intervals. Stress echocardiography and stress cardiac magnetic resonance imaging have higher specificity than stress electrocardiography and therefore are generally preferred. Stress scintigraphy should be used with caution, as it adds to the cumulative radiation exposure.

The role of magnetic resonance imaging and computed tomography depends on the results of initial transthoracic echocardiography and the clinical indication, in addition to the center’s expertise and facilities. However, there are currently no data advocating their use as screening tools, except for early detection of porcelain aorta in high-risk patients.10

MODERN RADIOTHERAPY TECHNIQUES

In recent years, there has been emphasis on exposing the patient to as little radiation as possible without compromising cure.52 The three major strategies employed to decrease cardiac exposure include reducing the radiation dose, reducing the radiation field and volume, and using newer planning and delivery techniques.

Reducing the radiation dose. It is well recognized that the mean dose of radiation to the heart is a significant predictor of cardiovascular disease, with one study demonstrating a linear increase in the risk of coronary artery disease with increasing mean heart radiation dose (excess relative risk per Gy 7.4%, 95% confidence interval 3.3%–14.8%).53

Reducing the radiation field and volume. Modern strategies and computed tomography-based radiotherapy planning have enabled a transition from older techniques such as extended-field radiation therapy, mantle-field radiation therapy, and involved-field radiation therapy to new techniques such as involved-node and involved-site radiation therapy.54 These have shown promise. For instance, a study in patients with early Hodgkin lymphoma found a mean heart dose of 27.5 Gy with mantle-field therapy compared with 7.7 Gy with involved-node therapy. This decrease in mean heart dose was associated with a reduction in the 25-year absolute excess cardiac risk from 9.1% to 1.4% and a reduction in cardiac mortality from 2.1% to 1%.55

Employing newer planning and delivery systems has also demonstrated some promise in reducing rates of cardiac morbidity and mortality. Extended-field radiation therapy, mantle-field radiotherapy, and involved-field radiation therapy were traditionally based on two-dimensional planning and often resulted in large volumes of myocardium being unnecessarily exposed to large doses of radiation because of the uncertainty in targeting. Involved-site and involved-node radiotherapy are based on computed tomography, resulting in more accurate targeting and sparing of normal tissue.

In addition, newer techniques such as intensity-modulated radiotherapy and proton beam therapy have resulted in further improvements in conformality compared with three-dimensional conformal radiotherapy.56,57 Respiratory motion management, including deep inspiration breath-holding and end-inspiration breath-holding, have decreased the radiation dose to the heart in patients undergoing mediastinal radiotherapy.58,59

TOWARD THE GOALS OF PREVENTION AND EARLIER DETECTION

As survival from breast cancer and lymphoma has increased, we continue to see legacy or latent effects of therapy, such as RIHD. Radiation therapy can affect any cardiac structure and is a major cause of morbidity and death in cancer survivors.

Modern radiation techniques use a variety of mechanisms to decrease the radiation dose to the heart. A large body of evidence emanating from an era of higher radiation doses and a lack of knowledge of the cardiac effects of radiation highlight the perilous cardiac consequences of chest radiation. With advances in radiotherapy and the development and widespread implementation of consensus guidelines, we envision earlier detection and less frequent occurrence of RIHD, although the latter trend could be blunted by increased cardiovascular risk factors within the population. Given the lag between irradiation and the cardiac consequences, it may be a number of years before any comparisons can be drawn.

References
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  2. Galper SL, Yu JB, Mauch PM, et al. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011; 117:412–418.
  3. Amromin GD, Gildenhorn HL, Solomon RD, Nadkarni BB. The synergism of x-irradiation and cholesterol-fat feeding on the development of coronary artery lesions. J Atheroscler Res 1964; 4:325–334.
  4. Tribble DL, Barcellos-Hoff MH, Chu BM, Gong EL. Ionizing radiation accelerates aortic lesion formation in fat-fed mice via SOD-inhibitable processes. Arterioscler Thromb Vasc Biol 1999; 19:1387–1392.
  5. Hayashi T, Morishita Y, Kubo Y, et al. Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. Am J Med 2005; 118:83–86.
  6. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010; 76(suppl 3):S77–S85.
  7. Rutqvist LE, Lax I, Fornander T, Johansson H. Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 1992; 22:887–896.
  8. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol 1993; 11:1208–1215.
  9. Meyer RM, Gospodarowicz MK, Connors JM, et al; NCIC Clinical Trials Group; Eastern Cooperative Oncology Group. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 2012; 366:399–408.
  10. Lancellotti P, Nkomo VT, Badano LP, et al; European Society of Cardiology Working Groups on Nuclear Cardiology and Cardiac Computed Tomography and Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013; 26:1013–1032.
  11. Cheng RK, Lee MS, Seki A, et al. Radiation coronary arteritis refractory to surgical and percutaneous revascularization culminating in orthotopic heart transplantation. Cardiovasc Pathol 2013; 22:303–308.
  12. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 2003; 290:2831–2837.
  13. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087–2106.
  14. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368:987–998.
  15. Lind PA, Pagnanelli R, Marks LB, et al. Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution. Int J Radiat Oncol Biol Phys 2003; 55:914–920.
  16. Rademaker J, Schöder H, Ariaratnam NS, et al. Coronary artery disease after radiation therapy for Hodgkin’s lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients. AJR Am J Roentgenol 2008; 191:32–37.
  17. Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment. Br Heart J 1993; 69:496–500.
  18. Mousavi N, Nohria A. Radiation-induced cardiovascular disease. Curr Treat Options Cardiovasc Med 2013; 15:507–517.
  19. McEniery PT, Dorosti K, Schiavone WA, Pedrick TJ, Sheldon WC. Clinical and angiographic features of coronary artery disease after chest irradiation. Am J Cardiol 1987; 60:1020–1024.
  20. Renner SM, Massel D, Moon BC. Mediastinal irradiation: a risk factor for atherosclerosis of the internal thoracic arteries. Can J Cardiol 1999; 15:597–600.
  21. Chang AS, Smedira NG, Chang CL, et al. Cardiac surgery after mediastinal radiation: extent of exposure influences outcome. J Thorac Cardiovasc Surg 2007; 133:404–413.
  22. Handa N, McGregor CG, Danielson GK, et al. Coronary artery bypass grafting in patients with previous mediastinal radiation therapy. J Thorac Cardiovasc Surg 1999; 117:1136–1142.
  23. Gharagozloo F, Clements IP, Mullany CJ. Use of the internal mammary artery for myocardial revascularization in a patient with radiation-induced coronary artery disease. Mayo Clin Proc 1992; 67:1081–1084.
  24. Wu W, Masri A, Popovic ZB, et al. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study. Circulation 2013; 127:1476–1485.
  25. Brand MD, Abadi CA, Aurigemma GP, Dauerman HL, Meyer TE. Radiation-associated valvular heart disease in Hodgkin’s disease is associated with characteristic thickening and fibrosis of the aortic-mitral curtain. J Heart Valve Dis 2001; 10:681–685.
  26. Nadlonek NA, Weyant MJ, Yu JA, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg 2012; 144:1466–1470.
  27. Tamura A, Takahara Y, Mogi K, Katsumata M. Radiation-induced valvular disease is the logical consequence of irradiation. Gen Thorac Cardiovasc Surg 2007; 55:53–56.
  28. Carlson RG, Mayfield WR, Normann S, Alexander JA. Radiation-associated valvular disease. Chest 1991; 99:538–545.
  29. Desai MY, Wu W, Masri A, et al. Increased aorto-mitral curtain thickness independently predicts mortality in patients with radiation-associated cardiac disease undergoing cardiac surgery. Ann Thorac Surg 2014; 97:1348–1355.
  30. Crestanello JA, McGregor CG, Danielson GK, et al. Mitral and tricuspid valve repair in patients with previous mediastinal radiation therapy. Ann Thorac Surg 2004; 78:826–831.
  31. Latib A, Montorfano M, Figini F, et al. Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis. J Cardiovasc Med (Hagerstown) 2012; 13:397–398.
  32. Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol 1996; 27:766–773.
  33. Carver JR, Shapiro CL, Ng A, et al; ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25:3991–4008.
  34. Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin’s disease. An analysis of technique, tumor eradication, and complications. Cancer 1976; 37:2813–2825.
  35. Morton DL, Glancy DL, Joseph WL, Adkins PC. Management of patients with radiation-induced pericarditis with effusion: a note on the development of aortic regurgitation in two of them. Chest 1973; 64:291–297.
  36. Arsenian MA. Cardiovascular sequelae of therapeutic thoracic radiation. Prog Cardiovasc Dis 1991; 33:299–311.
  37. Imazio M, Brucato A, Mayosi BM, et al. Medical therapy of pericardial diseases: part II: Noninfectious pericarditis, pericardial effusion and constrictive pericarditis. J Cardiovasc Med (Hagerstown). 2010; 11:785–794.
  38. Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation 1993; 87:1435–1441.
  39. Bertog SC, Thambidorai SK, Parakh K, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol 2004; 43:1445–1452.
  40. Heidenreich PA, Hancock SL, Vagelos RH, Lee BK, Schnittger I. Diastolic dysfunction after mediastinal irradiation. Am Heart J 2005; 150:977–982.
  41. Burns RJ, Bar-Shlomo BZ, Druck MN, et al. Detection of radiation cardiomyopathy by gated radionuclide angiography. Am J Med 1983; 74:297–302.
  42. Constine LS, Schwartz RG, Savage DE, King V, Muhs A. Cardiac function, perfusion, and morbidity in irradiated long-term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1997; 39:897–906.
  43. Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Invest 1999; 17:408–422.
  44. Termuhlen AM, Tersak JM, Liu Q, et al. Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2011; 57:1210–1216.
  45. Handa N, McGregor CG, Daly RC, et al. Heart transplantation for radiation-associated end-stage heart failure. Transpl Int 2000; 13:162–165.
  46. DePasquale EC, Nasir K, Jacoby DL. Outcomes of adults with restrictive cardiomyopathy after heart transplantation. J Heart Lung Transplant 2012; 31:1269–1275.
  47. Adams MJ, Lipshultz SE, Schwartz C, Fajardo LF, Coen V, Constine LS. Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 2003; 13:346–356.
  48. Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993; 11:1906–1910.
  49. Orzan F, Brusca A, Gaita F, Giustetto C, Figliomeni MC, Libero L. Associated cardiac lesions in patients with radiation-induced complete heart block. Int J Cardiol 1993; 39:151–156.
  50. Larsen RL, Jakacki RI, Vetter VL, Meadows AT, Silber JH, Barber G. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. Am J Cardiol 1992; 70:73–77.
  51. Shapiro CL, Hardenbergh PH, Gelman R, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 1998; 16:3493–3501.
  52. Armstrong GT, Chen Y, Yasui Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med 2016; 374:833–842.
  53. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol 2016; 34:235–243.
  54. Maraldo MV, Ng AK. Minimizing cardiac risks with contemporary radiation therapy for Hodgkin lymphoma. J Clin Oncol 2016; 34:208–210.
  55. Maraldo MV, Brodin NP, Vogelius IR, et al. Risk of developing cardiovascular disease after involved node radiotherapy versus mantle field for Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2012; 83:1232–1237.
  56. Maraldo MV, Specht L. A decade of comparative dose planning studies for early-stage Hodgkin lymphoma: what can we learn? Int J Radiat Oncol Biol Phys 2014; 90:1126–1135.
  57. Hoppe BS, Flampouri S, Su Z, et al. Consolidative involved-node proton therapy for Stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a Phase II study. Int J Radiat Oncol Biol Phys 2012; 83:260–267.
  58. Petersen PM, Aznar MC, Berthelsen AK, et al. Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. Acta Oncol 2015; 54:60–66.
  59. Aznar MC, Maraldo MV, Schut DA, et al. Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92:169–174.
References
  1. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ. Cancer statistics, 2009. CA Cancer J Clin 2009; 59:225–249.
  2. Galper SL, Yu JB, Mauch PM, et al. Clinically significant cardiac disease in patients with Hodgkin lymphoma treated with mediastinal irradiation. Blood 2011; 117:412–418.
  3. Amromin GD, Gildenhorn HL, Solomon RD, Nadkarni BB. The synergism of x-irradiation and cholesterol-fat feeding on the development of coronary artery lesions. J Atheroscler Res 1964; 4:325–334.
  4. Tribble DL, Barcellos-Hoff MH, Chu BM, Gong EL. Ionizing radiation accelerates aortic lesion formation in fat-fed mice via SOD-inhibitable processes. Arterioscler Thromb Vasc Biol 1999; 19:1387–1392.
  5. Hayashi T, Morishita Y, Kubo Y, et al. Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. Am J Med 2005; 118:83–86.
  6. Gagliardi G, Constine LS, Moiseenko V, et al. Radiation dose-volume effects in the heart. Int J Radiat Oncol Biol Phys 2010; 76(suppl 3):S77–S85.
  7. Rutqvist LE, Lax I, Fornander T, Johansson H. Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Int J Radiat Oncol Biol Phys 1992; 22:887–896.
  8. Hancock SL, Donaldson SS, Hoppe RT. Cardiac disease following treatment of Hodgkin’s disease in children and adolescents. J Clin Oncol 1993; 11:1208–1215.
  9. Meyer RM, Gospodarowicz MK, Connors JM, et al; NCIC Clinical Trials Group; Eastern Cooperative Oncology Group. ABVD alone versus radiation-based therapy in limited-stage Hodgkin’s lymphoma. N Engl J Med 2012; 366:399–408.
  10. Lancellotti P, Nkomo VT, Badano LP, et al; European Society of Cardiology Working Groups on Nuclear Cardiology and Cardiac Computed Tomography and Cardiovascular Magnetic Resonance; American Society of Nuclear Cardiology, Society for Cardiovascular Magnetic Resonance, and Society of Cardiovascular Computed Tomography. Expert consensus for multi-modality imaging evaluation of cardiovascular complications of radiotherapy in adults: a report from the European Association of Cardiovascular Imaging and the American Society of Echocardiography. J Am Soc Echocardiogr 2013; 26:1013–1032.
  11. Cheng RK, Lee MS, Seki A, et al. Radiation coronary arteritis refractory to surgical and percutaneous revascularization culminating in orthotopic heart transplantation. Cardiovasc Pathol 2013; 22:303–308.
  12. Hull MC, Morris CG, Pepine CJ, Mendenhall NP. Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy. JAMA 2003; 290:2831–2837.
  13. Clarke M, Collins R, Darby S, et al; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 366:2087–2106.
  14. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med 2013; 368:987–998.
  15. Lind PA, Pagnanelli R, Marks LB, et al. Myocardial perfusion changes in patients irradiated for left-sided breast cancer and correlation with coronary artery distribution. Int J Radiat Oncol Biol Phys 2003; 55:914–920.
  16. Rademaker J, Schöder H, Ariaratnam NS, et al. Coronary artery disease after radiation therapy for Hodgkin’s lymphoma: coronary CT angiography findings and calcium scores in nine asymptomatic patients. AJR Am J Roentgenol 2008; 191:32–37.
  17. Orzan F, Brusca A, Conte MR, Presbitero P, Figliomeni MC. Severe coronary artery disease after radiation therapy of the chest and mediastinum: clinical presentation and treatment. Br Heart J 1993; 69:496–500.
  18. Mousavi N, Nohria A. Radiation-induced cardiovascular disease. Curr Treat Options Cardiovasc Med 2013; 15:507–517.
  19. McEniery PT, Dorosti K, Schiavone WA, Pedrick TJ, Sheldon WC. Clinical and angiographic features of coronary artery disease after chest irradiation. Am J Cardiol 1987; 60:1020–1024.
  20. Renner SM, Massel D, Moon BC. Mediastinal irradiation: a risk factor for atherosclerosis of the internal thoracic arteries. Can J Cardiol 1999; 15:597–600.
  21. Chang AS, Smedira NG, Chang CL, et al. Cardiac surgery after mediastinal radiation: extent of exposure influences outcome. J Thorac Cardiovasc Surg 2007; 133:404–413.
  22. Handa N, McGregor CG, Danielson GK, et al. Coronary artery bypass grafting in patients with previous mediastinal radiation therapy. J Thorac Cardiovasc Surg 1999; 117:1136–1142.
  23. Gharagozloo F, Clements IP, Mullany CJ. Use of the internal mammary artery for myocardial revascularization in a patient with radiation-induced coronary artery disease. Mayo Clin Proc 1992; 67:1081–1084.
  24. Wu W, Masri A, Popovic ZB, et al. Long-term survival of patients with radiation heart disease undergoing cardiac surgery: a cohort study. Circulation 2013; 127:1476–1485.
  25. Brand MD, Abadi CA, Aurigemma GP, Dauerman HL, Meyer TE. Radiation-associated valvular heart disease in Hodgkin’s disease is associated with characteristic thickening and fibrosis of the aortic-mitral curtain. J Heart Valve Dis 2001; 10:681–685.
  26. Nadlonek NA, Weyant MJ, Yu JA, et al. Radiation induces osteogenesis in human aortic valve interstitial cells. J Thorac Cardiovasc Surg 2012; 144:1466–1470.
  27. Tamura A, Takahara Y, Mogi K, Katsumata M. Radiation-induced valvular disease is the logical consequence of irradiation. Gen Thorac Cardiovasc Surg 2007; 55:53–56.
  28. Carlson RG, Mayfield WR, Normann S, Alexander JA. Radiation-associated valvular disease. Chest 1991; 99:538–545.
  29. Desai MY, Wu W, Masri A, et al. Increased aorto-mitral curtain thickness independently predicts mortality in patients with radiation-associated cardiac disease undergoing cardiac surgery. Ann Thorac Surg 2014; 97:1348–1355.
  30. Crestanello JA, McGregor CG, Danielson GK, et al. Mitral and tricuspid valve repair in patients with previous mediastinal radiation therapy. Ann Thorac Surg 2004; 78:826–831.
  31. Latib A, Montorfano M, Figini F, et al. Percutaneous valve replacement in a young adult for radiation-induced aortic stenosis. J Cardiovasc Med (Hagerstown) 2012; 13:397–398.
  32. Veinot JP, Edwards WD. Pathology of radiation-induced heart disease: a surgical and autopsy study of 27 cases. Hum Pathol 1996; 27:766–773.
  33. Carver JR, Shapiro CL, Ng A, et al; ASCO Cancer Survivorship Expert Panel. American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: cardiac and pulmonary late effects. J Clin Oncol 2007; 25:3991–4008.
  34. Carmel RJ, Kaplan HS. Mantle irradiation in Hodgkin’s disease. An analysis of technique, tumor eradication, and complications. Cancer 1976; 37:2813–2825.
  35. Morton DL, Glancy DL, Joseph WL, Adkins PC. Management of patients with radiation-induced pericarditis with effusion: a note on the development of aortic regurgitation in two of them. Chest 1973; 64:291–297.
  36. Arsenian MA. Cardiovascular sequelae of therapeutic thoracic radiation. Prog Cardiovasc Dis 1991; 33:299–311.
  37. Imazio M, Brucato A, Mayosi BM, et al. Medical therapy of pericardial diseases: part II: Noninfectious pericarditis, pericardial effusion and constrictive pericarditis. J Cardiovasc Med (Hagerstown). 2010; 11:785–794.
  38. Polikar R, Burger AG, Scherrer U, Nicod P. The thyroid and the heart. Circulation 1993; 87:1435–1441.
  39. Bertog SC, Thambidorai SK, Parakh K, et al. Constrictive pericarditis: etiology and cause-specific survival after pericardiectomy. J Am Coll Cardiol 2004; 43:1445–1452.
  40. Heidenreich PA, Hancock SL, Vagelos RH, Lee BK, Schnittger I. Diastolic dysfunction after mediastinal irradiation. Am Heart J 2005; 150:977–982.
  41. Burns RJ, Bar-Shlomo BZ, Druck MN, et al. Detection of radiation cardiomyopathy by gated radionuclide angiography. Am J Med 1983; 74:297–302.
  42. Constine LS, Schwartz RG, Savage DE, King V, Muhs A. Cardiac function, perfusion, and morbidity in irradiated long-term survivors of Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1997; 39:897–906.
  43. Tolba KA, Deliargyris EN. Cardiotoxicity of cancer therapy. Cancer Invest 1999; 17:408–422.
  44. Termuhlen AM, Tersak JM, Liu Q, et al. Twenty-five year follow-up of childhood Wilms tumor: a report from the Childhood Cancer Survivor Study. Pediatr Blood Cancer 2011; 57:1210–1216.
  45. Handa N, McGregor CG, Daly RC, et al. Heart transplantation for radiation-associated end-stage heart failure. Transpl Int 2000; 13:162–165.
  46. DePasquale EC, Nasir K, Jacoby DL. Outcomes of adults with restrictive cardiomyopathy after heart transplantation. J Heart Lung Transplant 2012; 31:1269–1275.
  47. Adams MJ, Lipshultz SE, Schwartz C, Fajardo LF, Coen V, Constine LS. Radiation-associated cardiovascular disease: manifestations and management. Semin Radiat Oncol 2003; 13:346–356.
  48. Schwartz CL, Hobbie WL, Truesdell S, Constine LC, Clark EB. Corrected QT interval prolongation in anthracycline-treated survivors of childhood cancer. J Clin Oncol 1993; 11:1906–1910.
  49. Orzan F, Brusca A, Gaita F, Giustetto C, Figliomeni MC, Libero L. Associated cardiac lesions in patients with radiation-induced complete heart block. Int J Cardiol 1993; 39:151–156.
  50. Larsen RL, Jakacki RI, Vetter VL, Meadows AT, Silber JH, Barber G. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. Am J Cardiol 1992; 70:73–77.
  51. Shapiro CL, Hardenbergh PH, Gelman R, et al. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. J Clin Oncol 1998; 16:3493–3501.
  52. Armstrong GT, Chen Y, Yasui Y, et al. Reduction in late mortality among 5-year survivors of childhood cancer. N Engl J Med 2016; 374:833–842.
  53. van Nimwegen FA, Schaapveld M, Cutter DJ, et al. Radiation dose-response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma. J Clin Oncol 2016; 34:235–243.
  54. Maraldo MV, Ng AK. Minimizing cardiac risks with contemporary radiation therapy for Hodgkin lymphoma. J Clin Oncol 2016; 34:208–210.
  55. Maraldo MV, Brodin NP, Vogelius IR, et al. Risk of developing cardiovascular disease after involved node radiotherapy versus mantle field for Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 2012; 83:1232–1237.
  56. Maraldo MV, Specht L. A decade of comparative dose planning studies for early-stage Hodgkin lymphoma: what can we learn? Int J Radiat Oncol Biol Phys 2014; 90:1126–1135.
  57. Hoppe BS, Flampouri S, Su Z, et al. Consolidative involved-node proton therapy for Stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a Phase II study. Int J Radiat Oncol Biol Phys 2012; 83:260–267.
  58. Petersen PM, Aznar MC, Berthelsen AK, et al. Prospective phase II trial of image-guided radiotherapy in Hodgkin lymphoma: benefit of deep inspiration breath-hold. Acta Oncol 2015; 54:60–66.
  59. Aznar MC, Maraldo MV, Schut DA, et al. Minimizing late effects for patients with mediastinal Hodgkin lymphoma: deep inspiration breath-hold, IMRT, or both? Int J Radiat Oncol Biol Phys 2015; 92:169–174.
Issue
Cleveland Clinic Journal of Medicine - 83(12)
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Cleveland Clinic Journal of Medicine - 83(12)
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914-922
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914-922
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Radiation-induced heart disease: A practical guide to diagnosis and management
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Radiation-induced heart disease: A practical guide to diagnosis and management
Legacy Keywords
radiation-induced heart disease, RIHD, radiotherapy, breast cancer, lymphoma, coronary artery disease, valvular disease, pericardial disease, Eoin Donnellan, Dermot Phelan, Cian McCarthy, Patrick Collier, Milind Desai, Brian Griffin
Legacy Keywords
radiation-induced heart disease, RIHD, radiotherapy, breast cancer, lymphoma, coronary artery disease, valvular disease, pericardial disease, Eoin Donnellan, Dermot Phelan, Cian McCarthy, Patrick Collier, Milind Desai, Brian Griffin
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KEY POINTS

  • Ischemic heart disease is the most common cause of cardiac death after radiotherapy. Valvular, pericardial, myocardial, and conduction system disease are also common.
  • Surgery may not be an attractive option because of radiation-induced fibrosis of surrounding structures. Consequently, conservative interventions are preferred.
  • The incidence of RIHD is expected to decline, as lower doses of radiation are being used in radiotherapy than in the past.
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When does asymptomatic aortic stenosis warrant surgery? Assessment techniques

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When does asymptomatic aortic stenosis warrant surgery? Assessment techniques

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 851 and 4% of people over age 85.2 Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.3 Under current guidelines,4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).10 Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers11 (and to less than 1% at some hospitals),12 arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).15

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

Figure 1.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

  • Mean pressure gradient > 40 mm Hg
  • Peak aortic jet velocity > 4.0 m/s
  • Aortic valve area < 1 cm2.

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

Figure 2.

The American College of Cardiology and American Heart Association (ACC/AHA)4 have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.3

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.3

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.4

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al13 examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.13 This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al18 found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).4

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,19 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm2 or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.20 A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).20

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis21,22 and a higher mortality rate after valve replacement,23 making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al24 in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.5 But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,14 and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.4

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

 

 

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,27 in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study14 of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m2, compared with 65% in patients whose left ventricular mass was less than 100 g/m2.

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al8 investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm2/m2 had a 77% 2-year probability of aortic valve replacement or death.

Beach et al28 examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,29 and atrial natriuretic peptide,30 with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al33 showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.35 A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al38 in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al8 in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient19 and systolic pulmonary artery pressure.21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

References
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  14. Mihaljevic T, Nowicki ER, Rajeswaran J, et al. Survival after valve replacement for aortic stenosis: implications for decision making. J Thorac Cardiovasc Surg 2008; 135:1270–1279.
  15. Kang DH, Park SJ, Rim JH, et al. Early surgery versus conventional treatment in asymptomatic very severe aortic stenosis. Circulation 2010; 121:1502–1509.
  16. Alborino D, Hoffmann JL, Fournet PC, Bloch A. Value of exercise testing to evaluate the indication for surgery in asymptomatic patients with valvular aortic stenosis. J Heart Valve Dis 2002; 11:204–209.
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  18. Rafique AM, Biner S, Ray I, Forrester JS, Tolstrup K, Siegel RJ. Meta-analysis of prognostic value of stress testing in patients with asymptomatic severe aortic stenosis. Am J Cardiol 2009; 104:972–977.
  19. Lancellotti P, Lebois F, Simon M, Tombeux C, Chauvel C, Pierard LA. Prognostic importance of quantitative exercise Doppler echocardiography in asymptomatic valvular aortic stenosis. Circulation 2005; 112(suppl I):I377–I382.
  20. Marechaux S, Hachicha Z, Bellouin A, et al. Usefulness of exercise-stress echocardiography for risk stratification of true asymptomatic patients with aortic valve stenosis. Eur Heart J 2010; 31:1390–1397.
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  28. Beach JM, Mihaljevic T, Rajeswaran J, et al. Ventricular hypertrophy and left atrial dilatation persist and are associated with reduced survival after valve replacement for aortic stenosis. J Thorac Cardiovasc Surg 2014; 147:362–369.e8.
  29. Vanderheyden M, Goethals M, Verstreken S, et al. Wall stress modulates brain natriuretic peptide production in pressure overload cardiomyopathy. J Am Coll Cardiol 2004; 44:2349–2354.
  30. Ikeda T, Matsuda K, Itoh H, et al. Plasma levels of brain and atrial natriuretic peptides elevate in proportion to left ventricular end-systolic wall stress in patients with aortic stenosis. Am Heart J 1997; 133:307–314.
  31. Qi W, Mathisen P, Kjekshus J, et al. Natriuretic peptides in patients with aortic stenosis. Am Heart J 2001; 142:725–732.
  32. Weber M, Arnold R, Rau M, et al. Relation of N-terminal pro-B-type natriuretic peptide to severity of valvular aortic stenosis. Am J Cardiol 2004; 94:740–745.
  33. Bergler-Klein J, Klaar U, Heger M, et al. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004; 109:2302–2308.
  34. Lim P, Monin JL, Monchi M, et al. Predictors of outcome in patients with severe aortic stenosis and normal left ventricular function: role of B-type natriuretic peptide. Eur Heart J 2004; 25:2048–2053.
  35. Holt B. Strain and strain rate echocardiography and coronary artery disease. Circ Cardiovasc Imaging 2011; 4:179–190.
  36. Ng AC, Delgado V, Bertini M, et al. Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis. Eur Heart J 2011; 32:1542–1550.
  37. Ng AC, Delgado V, Bertini M, et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2009; 104:1398–1401
  38. Kearney LG, Lu K, Ord M, et al. Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis. Eur Heart J Cardiovasc Imag 2012; 13:827–833.
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Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Section Head of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Section Head of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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School of Medicine, University College Cork, Cork, Ireland

Dermot Phelan, MD, PhD
Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic; Assistant Professor, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH

Brian Griffin, MD
Section Head of Cardiovascular Imaging, Department of Cardiovascular Medicine, Heart and Vascular Institute, Cleveland Clinic

Address: Dermot Phelan, MD, PhD, Director of Sports Cardiology, Department of Cardiovascular Medicine, Heart and Vascular Institute, J1-5, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; pheland@ccf.org

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Related Articles

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 851 and 4% of people over age 85.2 Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.3 Under current guidelines,4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).10 Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers11 (and to less than 1% at some hospitals),12 arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).15

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

Figure 1.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

  • Mean pressure gradient > 40 mm Hg
  • Peak aortic jet velocity > 4.0 m/s
  • Aortic valve area < 1 cm2.

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

Figure 2.

The American College of Cardiology and American Heart Association (ACC/AHA)4 have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.3

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.3

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.4

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al13 examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.13 This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al18 found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).4

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,19 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm2 or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.20 A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).20

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis21,22 and a higher mortality rate after valve replacement,23 making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al24 in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.5 But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,14 and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.4

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

 

 

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,27 in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study14 of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m2, compared with 65% in patients whose left ventricular mass was less than 100 g/m2.

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al8 investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm2/m2 had a 77% 2-year probability of aortic valve replacement or death.

Beach et al28 examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,29 and atrial natriuretic peptide,30 with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al33 showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.35 A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al38 in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al8 in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient19 and systolic pulmonary artery pressure.21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

Aortic stenosis is the most common valvular heart condition in the developed world, affecting 3% of people between ages 75 and 851 and 4% of people over age 85.2 Aortic valve replacement remains the only treatment proven to reduce the rates of mortality and morbidity in this condition.3 Under current guidelines,4,5 the onset of symptoms of exertional angina, syncope, or dyspnea in a patient who has severe aortic stenosis is a class I indication for surgery—ie, surgery should be performed.

However, high-gradient, severe aortic stenosis that is asymptomatic often poses a dilemma. The annual rate of sudden death in patients with this condition is estimated at 1% to 3%,6–9 but the surgical mortality rate in aortic valve replacement has been as high as 6% in Medicare patients (varying by center and comorbidities).10 Therefore, the traditional teaching was to not surgically replace the valve in asymptomatic patients, based on an adverse risk-benefit ratio. But with improvements in surgical techniques and prostheses, these rates have been reduced to 2.41% at high-volume centers11 (and to less than 1% at some hospitals),12 arguing in favor of earlier intervention.

Complicating the issue, transcatheter aortic valve replacement has become widely available, but further investigation into its use in this patient cohort is warranted.

Furthermore, many patients with severe but apparently asymptomatic aortic stenosis and normal left ventricular ejection fraction may actually have impaired exercise capacity, or they may have structural left ventricular changes such as severe hypertrophy or reduction in global strain, which may worsen the long-term survival rate.13,14

A prospective trial in patients with severe aortic stenosis found that mortality rates were significantly lower in those who underwent surgery early than in those who received conventional treatment, ie, watchful waiting (no specific medical treatment for aortic stenosis is available).15

Patients with asymptomatic severe aortic stenosis are a diverse group; some have a far worse prognosis than others, with or without surgery.

Figure 1.

This paper reviews the guidelines for valve replacement in this patient group and the factors useful in establishing who should be considered for early intervention even if they have no classic symptoms (Figure 1).

SIGNS AND SYMPTOMS OF STENOSIS

Aortic stenosis is often first suspected when a patient presents with angina, dyspnea, and syncope, or when an ejection systolic murmur is heard incidentally on physical examination—typically a high-pitched, crescendo-decrescendo, midsystolic ejection murmur that is best heard at the right upper sternal border and that radiates to the carotid arteries.

Several physical findings may help in assessing the severity of aortic stenosis. In mild stenosis, the murmur peaks in early systole, but as the disease progresses the peak moves later into systole. The corollary of this phenomenon is a weak and delayed carotid upstroke known as “pulsus parvus et tardus.” This can be assessed by palpating the carotid artery while auscultating the heart.

Aortic stenosis is often first suspected when a patient has angina, dyspnea, and syncope or an ejection systolic murmur

The second heart sound becomes progressively softer as the stenosis advances until it is no longer audible. If a fourth heart sound is present, it may be due to concentric left ventricular hypertrophy with reduced left ventricular compliance, and a third heart sound indicates severe left ventricular dysfunction. Both of these findings suggest severe aortic stenosis.

ECHOCARDIOGRAPHIC MEASURES OF SEVERITY

Echocardiography is the best established and most important initial investigation in the assessment of a patient with suspected aortic stenosis. It usually provides accurate information on the severity and the mechanism of stenosis. The following findings indicate severe aortic stenosis:

  • Mean pressure gradient > 40 mm Hg
  • Peak aortic jet velocity > 4.0 m/s
  • Aortic valve area < 1 cm2.

RECOMMENDATIONS FOR SURGERY BASED ON SEVERITY AND SYMPTOMS

Figure 2.

The American College of Cardiology and American Heart Association (ACC/AHA)4 have issued the following recommendations for aortic valve replacement, based on the severity of stenosis and on whether the patient has symptoms (Figure 2):

Severe stenosis, with symptoms: class I recommendation (surgery should be done). Without surgery, these patients have a very poor prognosis, with an overall mortality rate of 75% at 3 years.3

Severe stenosis, no symptoms, in patients undergoing cardiac surgery for another indication (eg, coronary artery bypass grafting, ascending aortic surgery, or surgery on other valves): class I recommendation for concomitant aortic valve replacement.

Moderate stenosis, no symptoms, in patients undergoing cardiac surgery for another indication: class IIa recommendation (ie, aortic valve replacement “is reasonable”).

Very severe stenosis (aortic peak velocity > 5.0 m/s or mean pressure gradient ≥ 60 mm Hg), no symptoms, and low risk of death during surgery: class IIa recommendation.

Severe stenosis, no symptoms, and an increase in transaortic velocity of 0.3 m/s or more per year on serial testing or in patients considered to be at high risk for rapid disease progression, such as elderly patients with severe calcification: class IIb recommendation (surgery “can be considered”). The threshold to replace the valve is lower for patients who cannot make serial follow-up appointments because they live far away or lack transportation, or because they have problems with compliance.

Surgery for those with left ventricular dysfunction

Echocardiography also provides information on left ventricular function, and patients with left ventricular dysfunction have significantly worse outcomes. Studies have shown substantial differences in survival in patients who had an ejection fraction of less than 50% before valve replacement compared with those with a normal ejection fraction.3

Thus, the ACC/AHA guidelines recommend immediate referral for aortic valve replacement in asymptomatic patients whose left ventricular ejection fraction is less than 50% (class I recommendation, level of evidence B) in the hope of preventing irreversible ventricular dysfunction.4

TREADMILL EXERCISE TESTING UNMASKS SYMPTOMS

Treadmill testing is absolutely contraindicated in patients with severe symptomatic aortic stenosis

In the past, severe aortic stenosis was considered a contraindication to stress testing because of concerns of precipitating severe, life-threatening complications. However, studies over the past 10 years have shown that a supervised modified Bruce protocol is safe in patients with severe asymptomatic aortic stenosis.16,17

However, treadmill exercise testing clearly is absolutely contraindicated in patients with severe symptomatic aortic stenosis because of the risk of syncope or of precipitating a malignant arrhythmia. Nevertheless, it may play an essential role in the workup of a physically active patient with no symptoms.

Symptoms can develop insidiously in patients with chronic valve disease and may often go unrecognized by patients and their physicians. Many patients who state they have no symptoms may actually be subconsciously limiting their exercise to avoid symptoms.

Amato et al13 examined the exercise capacity of 66 patients reported to have severe asymptomatic aortic stenosis. Treadmill exercise testing was considered positive in this study if the patient developed symptoms or complex ventricular arrhythmias, had blood pressure that failed to rise by 20 mm Hg, or developed horizontal or down-sloping ST depression (≥ 1 mm in men, ≥ 2 mm in women). Twenty (30.3%) of the 66 patients developed symptoms during exercise testing, and they had a significantly worse prognosis: the 2-year event-free survival rate was only 19% in those with a positive test compared with 85% in those with a negative test.13 This study highlights the problem of patients subconsciously reducing their level of activity, thereby masking their true symptoms.

A meta-analysis by Rafique et al18 found that asymptomatic patients with abnormal results on exercise testing had a risk of cardiac events during follow-up that was eight times higher than normal, and a risk of sudden death 5.5 times higher.

With trials demonstrating that exercise testing is safe and prognostically useful in patients with aortic stenosis, the ACC/AHA guidelines emphasize its role, giving a class I recommendation for aortic valve replacement in patients who develop symptoms on exercise testing, and a class IIa recommendation in asymp­tomatic patients with decreased exercise tolerance or an exercise-related fall in blood pressure (Figure 2).4

STRESS ECHOCARDIOGRAPHY

Stress echocardiography has been used since the 1980s to assess the hemodynamic consequences of valvular heart disease, and many studies highlight its prognostic usefulness in patients with asymptomatic aortic stenosis.

In a 2005 study by Lancellotti et al,19 69 patients with severe asymptomatic aortic stenosis underwent a symptom-limited bicycle exercise stress test using quantitative Doppler echocardiography both at rest and at peak exercise, and a number of independent predictors of poor outcome (ie, symptoms, aortic valve replacement, death) were identified. These predictors included an abnormal test result, defined as any of the following: angina, dyspnea, ST-segment depression of 2 mm Hg or more, a fall or a small (< 20 mm Hg) rise in systolic blood pressure during the test, an aortic valve area of 0.75 cm2 or less, or a mean increase in valve gradient of 18 mm Hg or more.

Subsequently, a multicenter prospective trial assessed the value of exercise stress echocardiography in 186 patients with asymptomatic moderate or severe aortic stenosis.20 A mean increase in the aortic valve gradient of 20 mm Hg or more after exercise was associated with a rate of cardiovascular events (death, aortic valve replacement) 3.8 times higher, independent of other risk factors and whether moderate or severe stenosis was present (Table 1).20

Exercise-induced changes in systolic pulmonary artery pressure, which can be assessed using stress echocardiography, also have prognostic utility. Elevated systolic pulmonary artery pressure (> 50 mm Hg) seems to portend a poorer prognosis21,22 and a higher mortality rate after valve replacement,23 making it an independent predictor of hospital mortality and postoperative major adverse cardiovascular and cerebrovascular events (Table 1).

Exercise echocardiography also can be used to assess the patient’s contractile reserve. Left ventricular contractile reserve can be defined as an exercise-induced increase in left ventricular ejection fraction. In a study by Maréchaux et al24 in 50 patients with asymptomatic aortic stenosis and a normal resting left ventricular ejection fraction (> 50%), 40% of patients did not have left ventricular contractile reserve. In fact, their left ventricular ejection fraction decreased with exercise (from 64 ± 10% to 53 ± 12%). The subgroup of patients without contractile reserve developed symptoms more frequently during exercise and had lower event-free survival (Table 1).

Stress echocardiography has recently been introduced into the European Society of Cardiology guidelines, which give a class IIb indication for aortic valve replacement in asymp­tomatic patients who have severe aortic stenosis, a normal ejection fraction, and a greater than 20-mm Hg increase in mean gradient on exercise.5 But it has yet to be introduced into the ACC/AHA guidelines as a consideration for surgery.

LEFT VENTRICULAR FUNCTION: BEYOND EJECTION FRACTION

Left ventricular dysfunction is a bad sign for patients with aortic stenosis. Struggling to empty its contents through the narrowed aortic valve, the left ventricle is subjected to increased wall stress and eventually develops hypertrophy. The hypertrophied heart muscle requires more oxygen but receives less perfusion. Eventually, myocardial fibrosis develops, leading to systolic dysfunction and a reduction in the ejection fraction. As described above, patients with asymptomatic aortic stenosis and a left ventricular ejection fraction less than 50% have a poor prognosis,14 and therefore the ACC/AHA guidelines give this condition a class I recommendation for surgery.4

The ejection fraction has limitations as a marker of left ventricular function

However, the ejection fraction has limitations as a marker of left ventricular function. It reflects changes in left ventricular cavity volume but not in the complex structure of the left ventricle. Several studies show that up to one-third of patients with severe aortic stenosis have considerable impairment of intrinsic myocardial systolic function despite a preserved ejection fraction.8,25,26

Thus, other variables such as left atrial size, left ventricular hypertrophy, myocardial deformation (assessed using strain imaging), and B-type natriuretic peptide (BNP) level may also be considered in assessing the effect of severe aortic stenosis on left ventricular function in the context of a normal ejection fraction (Table 2).

 

 

Left ventricular hypertrophy

The development of left ventricular hypertrophy is one of the earliest compensatory responses of the ventricle to the increase in afterload. This leads to impaired myocardial relaxation and reduced myocardial compliance, with resultant diastolic dysfunction with increased filling pressures.

Cioffi et al,27 in a study in 209 patients with severe but asymptomatic aortic stenosis, found that inappropriately high left ventricular mass (> 110% of that expected for body size, sex, and wall stress) portended a 4.5-times higher risk of death, independent of other risk factors.

Severe left ventricular hypertrophy may have a long-term effect on prognosis irrespective of valve replacement. An observational study14 of 3,049 patients who underwent aortic valve replacement for severe aortic stenosis showed that the 10-year survival rate was 45% in those whose left ventricular mass was greater than 185 g/m2, compared with 65% in patients whose left ventricular mass was less than 100 g/m2.

Thus, as surgical mortality and morbidity rates decrease, the impact of these structural changes in left ventricular wall thickness may affect the decision to intervene earlier in order to improve longer-term outcomes in select asymptomatic patients with high-risk features.

Left atrial size

Diastolic dysfunction is caused by increased afterload and results in elevated left ventricular end-diastolic pressure and elevated left atrial pressure. The left atrium responds by dilating, which increases the risk of atrial fibrillation.

Lancellotti et al8 investigated the negative prognostic implications of a large indexed left atrial area in asymptomatic patients with severe aortic stenosis. They found that patients with an indexed left atrial area greater than 12.2 cm2/m2 had a 77% 2-year probability of aortic valve replacement or death.

Beach et al28 examined cardiac remodeling after surgery and found that the left atrial diameter did not decrease after aortic valve replacement, even after left ventricular hypertrophy reversed. This observation has major prognostic implications. Patients with a severely enlarged left atrium (> 5.0 cm in diameter) had considerably lower survival rates than patients with a diameter less than 3.55 cm at 5 years (61% vs 85%) and at 10 years (28% vs 62%) after aortic valve replacement.

Therefore, left atrial size appears to have an important long-term impact on prognosis in patients with aortic stenosis even after aortic valve replacement and adds valuable information when assessing the effect of aortic stenosis on myocardial function.

B-type natriuretic peptide

Natriuretic peptides are cardiac hormones released in response to myocyte stretch. In aortic stenosis, increased afterload induces significant expression of BNP, N-terminal proBNP,29 and atrial natriuretic peptide,30 with numerous studies showing a good correlation between plasma natriuretic peptide levels and severity of aortic stenosis.31–34

Natriuretic peptides, though not specific, are an easy and low-cost way to assess left ventricular function

Bergler-Klein et al33 showed that patients with asymptomatic aortic stenosis who developed symptoms during follow-up had higher levels of these biomarkers than patients who remained asymptomatic. Of note, patients with BNP levels lower than 130 pg/mL had significantly better symptom-free survival than those with higher levels, 66% vs 34% at 12 months.

However, these biomarkers are not specific to aortic stenosis and can be elevated in any condition that increases left ventricular stress. Nevertheless, they offer an easy and low-cost way to assess left ventricular function and may give an indication of the total burden of disease on the left ventricle.

Global left ventricular longitudinal strain

In view of the limitations of the left ventricular ejection fraction in identifying changes in the structure of the heart and in early detection of myocardial dysfunction, assessment of myocardial deformation using strain imaging is proving an attractive alternative.

Strain is the normalized, dimensionless measure of deformation of a solid object (such as a segment of myocardium) in response to an applied force or stress.35 A novel echocardiographic technique allows assessment of segmental myocardial deformation and thereby overcomes the limitation of tethering, which limits other echocardiographic techniques in the assessment of systolic function. Strain can be circumferential, longitudinal, or radial and is generally assessed using either tissue Doppler velocities or 2D echocardiographic speckle-tracking techniques. Longitudinal strain has proven to be a more sensitive method than left ventricular ejection fraction in detecting subclinical myocardial dysfunction and is a superior prognosticator in a variety of clinical conditions.36,37

Abnormal strain develops very early in the disease process and can even be seen in patients with mild aortic stenosis.

A study by Kearney et al38 in 146 patients with various degrees of aortic stenosis (26% mild, 21% moderate, and 53% severe) and preserved left ventricular ejection fraction demonstrated that global longitudinal strain worsened with increasing severity of aortic stenosis. Furthermore, global longitudinal strain was a strong independent predictor of all-cause mortality (hazard ratio 1.38, P < .001).

Similarly, in a study by Lancellotti et al8 in 163 patients with at least moderate to severe asymptomatic aortic stenosis, impaired longitudinal myocardial strain was an independent predictor of survival. Patients with longitudinal strain greater than 15.9% had significantly better outcomes than patients with strain of 15.9% or less (4-year survival 63% vs 22%, P < .001).

Hence, left ventricular global longitudinal strain offers an alternative—perhaps a superior alternative—to left ventricular ejection fraction in detecting and quantifying left ventricular dysfunction in asymptomatic aortic stenosis. It is an exciting new marker for the future in aortic stenosis, with a threshold of strain below 15.9% as a possible cutoff for those at higher risk of poorer outcomes.

WHERE ARE WE NOW? WHERE ARE WE GOING?

Aortic valve replacement in patients with severe but asymptomatic aortic stenosis remains a topic of debate, but support is growing for earlier intervention.

Now that concerns over the safety of exercise stress testing in patients with severe asymptomatic aortic stenosis have subsided following multiple studies,16,17 exercise testing should be performed in patients with asymp­tomatic severe aortic stenosis suspected of having reduced exercise capacity, with stress echocardiography providing added prognostic information through its assessment of exercise-induced changes in mean pressure gradient19 and systolic pulmonary artery pressure.21–23

Further study of the newer evaluation techniques is needed to evaluate long-term

Assessing left ventricular function provides important information about prognosis, with left ventricular ejection fraction, left ventricular diameter, left atrial size, BNP, and global longitudinal strain all helping identify asymptomatic patients at higher risk of death. Surgical intervention in asymptomatic patients with severe aortic stenosis may be considered when there is evidence of higher longer-term mortality risk based on reduced functional capacity, excess left ventricular hypertrophy, and abnormal left ventricular function as detected by ancillary methods such as global longitudinal strain and BNP elevation despite a normal left ventricular ejection fraction.

Figure 3.

Figure 3 shows a possible algorithm to define which patients would benefit from earlier intervention. However, left ventricular hypertrophy, left atrial diameter, BNP, left ventricular longitudinal strain, and changes in systolic pulmonary artery pressure are not included in the current ACC/AHA guidelines for the management of asymptomatic patients with severe aortic stenosis. Further study is needed to determine whether earlier intervention in those with adverse risk profiles based on the newer evaluation techniques described above leads to better long-term outcomes.

Intervention should especially be considered in those in whom the measured surgical risk is low and in surgical centers at which the mortality rate is low.

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  36. Ng AC, Delgado V, Bertini M, et al. Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis. Eur Heart J 2011; 32:1542–1550.
  37. Ng AC, Delgado V, Bertini M, et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2009; 104:1398–1401
  38. Kearney LG, Lu K, Ord M, et al. Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis. Eur Heart J Cardiovasc Imag 2012; 13:827–833.
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  30. Ikeda T, Matsuda K, Itoh H, et al. Plasma levels of brain and atrial natriuretic peptides elevate in proportion to left ventricular end-systolic wall stress in patients with aortic stenosis. Am Heart J 1997; 133:307–314.
  31. Qi W, Mathisen P, Kjekshus J, et al. Natriuretic peptides in patients with aortic stenosis. Am Heart J 2001; 142:725–732.
  32. Weber M, Arnold R, Rau M, et al. Relation of N-terminal pro-B-type natriuretic peptide to severity of valvular aortic stenosis. Am J Cardiol 2004; 94:740–745.
  33. Bergler-Klein J, Klaar U, Heger M, et al. Natriuretic peptides predict symptom-free survival and postoperative outcome in severe aortic stenosis. Circulation 2004; 109:2302–2308.
  34. Lim P, Monin JL, Monchi M, et al. Predictors of outcome in patients with severe aortic stenosis and normal left ventricular function: role of B-type natriuretic peptide. Eur Heart J 2004; 25:2048–2053.
  35. Holt B. Strain and strain rate echocardiography and coronary artery disease. Circ Cardiovasc Imaging 2011; 4:179–190.
  36. Ng AC, Delgado V, Bertini M, et al. Alterations in multidirectional myocardial functions in patients with aortic stenosis and preserved ejection fraction: a two-dimensional speckle tracking analysis. Eur Heart J 2011; 32:1542–1550.
  37. Ng AC, Delgado V, Bertini M, et al. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Am J Cardiol 2009; 104:1398–1401
  38. Kearney LG, Lu K, Ord M, et al. Global longitudinal strain is a strong independent predictor of all-cause mortality in patients with aortic stenosis. Eur Heart J Cardiovasc Imag 2012; 13:827–833.
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When does asymptomatic aortic stenosis warrant surgery? Assessment techniques
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Aortic stenosis, echocardiography, aortic valve, ejection fraction, jet velocity, pressure gradient, valve area, BNP, valvuloplasty, valve replacement, left ventricular hypertrophy, LVH, strain, Cian McCarthy, Dermot Phelan, Brian Griffin
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Aortic stenosis, echocardiography, aortic valve, ejection fraction, jet velocity, pressure gradient, valve area, BNP, valvuloplasty, valve replacement, left ventricular hypertrophy, LVH, strain, Cian McCarthy, Dermot Phelan, Brian Griffin
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  • Echocardiography is the best established and most important initial test in patients with suspected aortic stenosis.
  • Traditional echocardiographic variables used in assessing aortic stenosis and the need for surgery are the pressure gradient across the valve, the velocity through the valve, the valve area, and the left ventricular ejection fraction.
  • Aortic valve replacement is recommended for severe aortic stenosis if the patient has symptoms. It is also recommended if the left ventricular ejection fraction is less than 50%, if the patient is undergoing other cardiac surgery, or if symptoms arise on exercise stress testing.
  • Novel assessment variables include left ventricular hypertrophy, left atrial size, B-type natriuretic peptide level, and global left ventricular longitudinal strain.
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Choosing the most appropriate valve operation and prosthesis

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