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DR. GIVERTZ: I’m Michael Givertz. I am the Medical Director of the Heart Transplant and Mechanical Circulatory Support Program at the Brigham and Women’s Hospital in Boston, Massachusetts. I am interested in the management of patients with advanced heart disease and those with heart failure with preserved ejection fraction (HFpEF) as well as those with reduced ejection fraction (EF). In particular, I focus on patients with comorbidities, including pulmonary hypertension (PH) and chronic kidney disease.
DR. LEWIS: I’m Greg Lewis from Massachusetts General Hospital (MGH), Boston. I am a member of the Heart Failure and Transplant Unit, and I direct the cardiopulmonary exercise labs at MGH. Like Dr. Givertz, I am interested in heart failure (HF) with both preserved EF and reduced EF and in patients who have PH complicating both the abovementioned conditions.
DR. PRITZKER: I’m Marc Pritzker. I’m a professor of Cardiovascular Medicine and Surgery at the University of Minnesota and a part of the Advanced Heart Failure Group here. I’m also the Director of the Pulmonary Hypertension Center, and I have a special interest in diastolic dysfunction, which is going to be the leading cause of PH in Western society,1 if it isn’t already.
DR. FRANCIS: Let’s begin with a case and then proceed from there. It’s a short vignette.
An 83-year-old woman is suffering from long-standing diabetes, coronary disease, and hypertension. She’s admitted to the hospital with acute HF. An echocardiogram was performed, which indicates a normal EF of 65%. She has left ventricular (LV) hypertrophy, a small LV cavity, and a large left atrium.
Doppler studies indicate that the left atrial pressure is probably slightly elevated. There is clear diastolic dysfunction, as shown by echocardiography, and enough tricuspid regurgitation to suggest that the pulmonary artery (PA) pressure is approximately 70/30 mm Hg.
She has been given intravenous furosemide, her condition improves, and she is subsequently discharged. She then visits the outpatient clinic where follow-up echocardiogray indicates the persistence of PH. Her estimated PA pressure by echocardiogram is slightly lower (60/30 mm Hg), although her LV filling pressures are probably lower.
Although I’m not exactly sure of the situation at the Brigham or MGH, I suspect that it’s similar to the situation here and around the country: We are now seeing many such patients. They’re often elderly women with many comorbid conditions, and they’re sometimes admitted with atrial fibrillation, which makes the estimation of diastolic function problematic. They’re treated conventionally with diuretics and antihypertensive therapies, but they tend to fare poorly. Often, they return to the hospital and pose a recurrent problem.
Dr. Pritzker, let’s start with you. The patient’s PA pressure is quite high, at least based on the estimation by an echocardiogram. It’s fairly common for these patients to have PH, but this patient’s PA pressure is probably disproportionately high relative to her slightly elevated left atrial pressure.
Granted that we don’t have the hemodynamic data from the catheterization lab; nonetheless, am I right? Are we seeing more of these patients with so-called reactive or disproportionate PH or hypertension that is higher than what you would expect, given the clinical context?
DR. PRITZKER: I agree. We probably encounter 3 or 4 new patients a week who are referred to us because of certain observations during echocardiographic screening. In reality, these patients have diastolic dysfunction, and probably half of the patients in our clinic have PH that appears to be higher than the classical expectation that the PA pressure follows the left atrial pressure.
This situation could be viewed in 2 ways. One is the eyeball method, which many people do and just say, “Well, that seems high to me compared to what the wedge pressure is.” The transpulmonary gradient, which is the mean PA pressure minus the wedge pressure, or, sometimes, the pulmonary diastolic pressure minus the wedge pressure, is above 15 mm Hg.
Based on the information given in this case, the patient’s mean PA pressure is above 40 mm Hg. I’m assuming that modestly elevated pulmonary capillary wedge pressure is approximately 15 to 20 mm Hg, which indicates an elevated transpulmonary gradient by any measurement.
DR. FRANCIS: Dr. Givertz, what is the scope of this problem in your hospital?
DR. GIVERTZ: As Dr. Pritzker was alluding to, we are seeing many such patients. I’m not sure if we’re actually looking for them or if we are looking more closely at the estimates of PA pressure by echocardiogram, which we may have been less attuned to previously.
The problem of HFpEF, which is a broad definition for this patient’s condition, is that it’s not something new: It’s something that we’ve been struggling with for many years, particularly in older patients. As Dr. Francis mentioned, these patients are typically women with a history of hypertension and often, other comorbidities.
This case would seem unusual, mostly due to the estimated PA pressure. I think that’s probably what caught the eye of the clinicians here.
We probably wouldn’t have given it a second thought if the estimated PA pressure was in the 40s or, maybe, 50s. It is only once the pressure increases above 60 mm Hg that we begin to realize that some other factor could be involved or that something was overlooked, which we now need to look at a little more closely.
Since you didn’t mention anything about the mitral valve, let’s assume that there isn’t any mitral valve disease here and we’re not missing significant mitral regurgitation at rest or ischemic mitral regurgitation, which is something you would want to rule out. This is a common problem, and I think we’re seeing it more often because we’re more closely looking for it.
DR. FRANCIS: I agree, Dr. Givertz. But, it turns out that this patient has minimal mitral regurgitation.
Dr. Lewis, as you have a focused laboratory interest in this problem, what do you think of this case, particularly with regard to the scope of the problem?
DR. LEWIS: I think that it is clearly a major problem. I would like to add that these patients can come to subspecialty care through different routes. It’s not uncommon for a patient like the one in question to be hospitalized through the general medical service or to be assessed by a pulmonary specialist or general cardiologist.
Unlike patients who have advanced LV systolic dysfunction and are often routed into the well-oiled machine of an advanced cardiomyopathy clinic, these patients are identified through providers with different scopes of practice. For example, I believe that these patients are often initially referred to a pulmonary physician.
This makes the problem more challenging because there’s a less-inherent ownership within a predefined group of clinicians. Additionally, this case has features that are clearly suggestive of a pre-capillary PH as well as provide evidence of increased left-sided filling pressures. These patients may be directed through different routes of care in the hospital.
It does present a slight problem, particularly when the house staff is presenting the case and people have their own ideas about what we should call it. Dr. Givertz, what should we call this syndrome? What do you refer to it as at the Brigham?
DR. GIVERTZ: That’s an excellent question. We have moved away from the older terminology of diastolic HF, as probably, most have, although there are some strong proponents of this terminology, which assumes that there is some abnormality in diastolic function.
In an 83-year-old woman with long-standing hypertension, I think LV hypertrophy, a small cavity on her echocardiogram report, and a large left atrium are certainly markers of diastolic dysfunction. So, calling this diastolic HF might be justified.
We probably overstep that terminology in patients who have the clinical syndrome of HF, as this patient does, with dyspnea on exertion, volume overload, and a normal or near-normal EF. So, this meets the basic definition of HFpEF, and there are echocardiographic indicators of abnormal diastolic function. So, you could call it diastolic HF.
The key indicator here is the breadth. Although it is just a descriptive term, I would prefer using a term like HFpEF, and we generally use this term on rounds in the hospital or in an ambulatory setting.
The terminology is important because we don’t assume that this is just a problem of diastole or relaxation. There may be other comorbidities and aspects related to the pathophysiology,2 which may have a larger role to play than only causing a simple abnormality in diastolic function.
DR. FRANCIS: I agree, Dr. Givertz, although I have found that there are certain experts and authors who are accustomed to a specific terminology, which is unfortunate because some patients don’t really have diastolic dysfunction, and I don’t think we understand the underlying pathophysiology very well.
DR. PRITZKER: Drs. Givertz and Lewis, is there a certain trigger in echocardiogram reports such that when an elevation in PA pressure is evident, as in this case, the examiners make the diastology a little bit more manifest or look at tricuspid annular plane systolic excursion or PA acceleration time?
I think we all have difficulties with that. I have looked at reports from several different hospitals, and nobody provides a consistent report once an increase in PA pressure has been identified.
DR. GIVERTZ: I think that’s an excellent point. We get comprehensive echocardiogram reports; it’s the way that our laboratory runs. But we don’t have a trigger that leads to the reporting of additional indices of diastolic function. With high PA pressures, a focus on the right ventricle (RV) (in terms of tricuspid annular plane systolic excursion measurements or RV dimensions) would be particularly helpful in terms of having additional information about the etiology of PH.
DR. LEWIS: In our institution, there is no dedicated report type for this constellation of findings. The conclusion of the interpretation would indicate that findings were consistent with diastolic dysfunction.
Dr. Francis, you mentioned in the description that there was some indication of left atrial pressure elevation in the Doppler studies. I know our echocardiographers at MGH generally avoid reporting Doppler measurements such as E/A ratios or estimates of left atrial pressure based on E/E' values.Ultimately, for patient management, it will be important to establish widely accepted echocardiographic criteria that differentiate precapillary PH, postcapillary PH, and mixed PH.
DR. FRANCIS: That’s a good point. As you know, some hospitals, like my former institution the Cleveland Clinic, did attempt to carry out the calculations, but in most places, these calculations are really not done. I personally assessed the echocardiogram as a consequence of my obsessive behavior. I have also talked to the echocardiographers about it and gathered an intuitive sense of impaired filling.
If you were to guess, you would say that the left atrial pressure is somewhat higher than normal. This is a really subjective phrase. It wasn’t actually measured, of course, and it wasn’t calculated.
DR. PRITZKER: I think it would be helpful if each institution could, at least, have a trigger, so that when the patient goes back to a family practitioner, a pulmonologist or another specialist, there is some comprehensive information that can give the practitioner some direction.
As echocardiograms become more capable of calculating these derived values (E/E prime, E to A, etc.), even general cardiologists begin feeling confused. So I like Dr. Lewis’ idea about inserting a comment at the end to at least point people in some direction.
DR. FRANCIS: Let’s focus a little on what’s different about this particular patient, which is something that I’m personally interested in. Dr. Lewis, why is it that some of these patients have higher PA pressures than what you would expect, given the clinical context? Is there something unusual about them? Is there something relevant that we can discuss, which might help identify such a patient?
DR. LEWIS: I think that’s a key question regarding the evaluation of patients like this one. For me, the first thing to do when I see a patient like this is to make sure that there aren’t other factors, other than left heart disease, that may be mediating the PH.
Even if there is a suggestion of elevated left atrial pressure, it’s important to think beyond the left heart, in terms of additional direct insults that may have been sustained by the pulmonary circulation. For example, does the patient have chronic obstructive pulmonary disease that may be contributing to the high pulmonary arterial pressures? Does the patient have sleep apnea or a history of chronic thromboembolic disease in the lung? Even an overlapping syndrome such as scleroderma or sarcoidosis can cause LV dysfunction as well as pulmonary arterial hypertension but would be unusual to detect at an advanced age in terms of relevance to this case.
Epidemiologic studies can also provide clues regarding the type of patients who tend to have higher pulmonary arterial pressures (eg, older individuals or people with higher systolic blood pressure).
I have been surprised by our relative lack of ability to predict who’s going to have a higher transpulmonary gradient, based on the clinical features alone. For a given left atrial pressure, why do some patients have higher transpulmonary gradients than others?
Elevation of transpulmonary gradients is not simply related to degree of elevation in left-sided pressure alone. That is clear from the relatively weak correlation between PA systolic pressure and left-sided filling pressure.3 I don’t think it is related to the duration of HF alone either.
In our patient population, we’ve recorded the time when patients were diagnosed with HF because I commonly hear, “Well, if the patient has HF for a sufficient amount of time, he/she will gradually develop increases in transpulmonary gradient because of high pressure on the left side of the heart.” The duration of HF was not significantly related to the transpulmonary gradient. Therefore, I believe we need to look at new ways of understanding which patients will develop high transpulmonary gradients.
There’s some work being conducted in this area. Investigators at Dr. Francis’s former institution recently published a study about arginine metabolism dysregulation and some circulating markers that were high in patients who had a high burden of precapillary PH and HF.4
Dr. Givertz has been involved in studies evaluating endothelin levels or cyclic guanosine monophosphate-adenosine monophosphate release through the pulmonary circulation as potential indicators of dysregulation in signaling systems within pulmonary circulation. There may also be permissive genotypes that predispose patients to develop precapillary PH in the setting of left heart dysfunction.
So, I think that the question is a good one, but for me, it raises many more questions about why these patients are different. I don’t think we can explain it on the basis of clinical characteristics alone.
DR. FRANCIS: Dr. Lewis has had extensive experience in studying these patients in the laboratory and performing exercise tests on them. Dr. Lewis, from a clinical rather than research standpoint, when would you actually consider conducting more invasive studies like you are currently doing in the research laboratory?
DR. LEWIS: We haven’t talked about invasive phenotyping of patients yet, but to address Dr. Givertz’s point, the question pertains to when we need to carefully study the conditions in the pulmonary circulation. I believe that knowing the left atrial pressure is important for truly understanding the transpulmonary gradient, and I’d like to know whether it’s greater than 15 mm Hg, as Dr. Pritzker indicated; this level serves as a trigger for looking carefully into the pulmonary circulation.
Dr. Francis, I find the exercise status to be particularly informative in patients who exhibit shortness of breath with exertion. However, it’s not entirely clear whether their symptoms are being mediated by left-heart disease or a primary insult to the pulmonary circulation.
Often, even when patients have a resting right-heart catheterization, we see borderline elevations in pulmonary arterial pressure, say, a mean pressure of 20 to 25 mm Hg, and a pulmonary capillary wedge pressure of 10 to 15 mm Hg, but symptoms are present.
In such cases, instead of looking at hemodynamic measurements during a single moment in time, I find it quite helpful to make serial measurements under different loading conditions that are introduced by the very highly relevant physiologic state of exercise. We often encounter patients who have shortness of breath with exertion, which is not entirely explained by the initial diagnostic testing results.
I find it particularly useful to characterize the changes in the pulmonary capillary wedge pressure and transpulmonary gradient when patients are subjected to exercise. We can begin to classify patients based on whether their burden of precapillary PH is high or there is truly a left-sided predominance to their symptoms.
DR. FRANCIS: This gives rise to question of whether therapeutic targets exist. We all know that they exist, but what is the therapy? Perhaps, we’re not so sure about that.
DR. PRITZKER: We’re predominantly using sildenafil because it’s easily available in the hospital and doesn’t require cumbersome pre-approval for acute use like in the case of endothelin antagonists. We have a good experience of using it, and we follow it up with 6-min walks, which perhaps, in this population, is slightly easier to do.
DR. FRANCIS: Dr. Pritzker, what is your threshold for administering sildenafil? Is it lower?
DR. PRITZKER: Yes, because I think there’s more relevant evidence, including the provocative work of an Italian group and Dr. Lewis’ work. We don’t necessarily know why we’re making them better yet, but clearly, people are having fewer symptoms. This is more anecdotal than longitudinal, but patients have fewer symptoms, feel better, and seem to have better function. We also see fewer hospital admissions. I think a previous paper published at the end of last year presented similar findings.
DR. FRANCIS: Dr. Givertz, can you comment about the therapy?
DR. GIVERTZ: I think we’re all gaining experience with using sildenafil or longer-acting phosphodiesterase type 5 (PDE5) inhibitors in this patient population, but that might not be the first thing I would reach for.
This patient was admitted with acute HF. Presumably, there was a fluid problem here as well. I might be initially inclined to make sure I have optimized diuretic therapy. If this patient wasn’t already on nitrates, given the underlying coronary disease and hypertension, I think administering nitrates would be a reasonable next step.
Although there are certainly patients who cannot tolerate nitrate therapy due to its side effects such as headache or light-headedness, I might try administering nitrates before opting for a PDE5 inhibitor.
DR. PRITZKER: I assumed that the patient had been stabilized, and we still had a therapeutic gap after conventional therapy.
DR. FRANCIS: That’s a good point because it is related to the timing of initiation of such therapy; I am quite conservative about it. I don’t have as much experience as the other physicians on the panel, but my tendency would be to go with conventional medical therapy, as bad as it is, and if the patient didn’t improve thereafter, I would think about sending the patient to Dr. Pritzker or beginning sildenafil treatment myself.
Dr. Lewis, you’re actually involved in a National Institute of Health study, a consortium study. Is that right?
DR. LEWIS: That’s right; it’s the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)trial.5 Michael and Maggie Redfield from the Mayo Clinic are involved as well, and Dr. Redfield is the principal architect of the trial. But, we are adjudicating the primary end point here, which is a cardiopulmonary exercise endpoint.
Dr. Francis, I agree with Drs. Pritzker and Givertz in terms of the therapeutic approach. There certainly have been some cautionary accounts from other pulmonary vasodilators that have been tried in patients who have left heart disease, predominantly those with systolic dysfunction and have not resulted in improved outcomes.6 Therefore, I tend to refrain from using endothelin antagonists as well as the prostacyclins.
There has been some promising work done with PDE5 inhibitors in left-heart disease, and we will know the results from the RELAX trial soon. We completed enrollment of just over 200 patients, and we’re trying to determine whether we can improve exercise capacity over a period of 24 weeks with sildenafil in patients with HFpEF.
The results of PDE5 inhibition in HF with preserved LVEF from the Guazzi group demonstrated that patients with a significant burden of right-heart disease may derive significant improvement in precapillary PH with sildenafil.7 I believe if there is right-heart dysfunction that is largely attributed to high pulmonary vascular resistance or a high transpulmonary gradient, then pulmonary vasodilators like PDE5 inhibitors will have a promising role to play. Potentially, there are also some novel therapies involving the use of some of the soluble guanylate cyclase stimulators and activators in trials.
If patients have a predominant left-heart dysfunction with a modest transpulmonary gradient, I think they are much better served by trying to optimize the diuretic therapy and treat the systemic hypertension.
DR. FRANCIS: Thank you, Dr. Lewis. I think we agree that this is clearly an emerging problem, and it’s prevalence is increasing, partly because of the aging population. It is true that these patients are often admitted to general medicine wards and are sometimes transferred to the cardiology groups when they are faring poorly, and I don’t know what we can do about that.
There does seem to be a subset of patients with disproportionate PH, and there’s a lot of interest in that particular subset. I don’t know if they’re clearly identifiable from the phenoclinical phenotype, but I think that they pose more difficult problems.
Lastly, I’m delighted to know that the RELAX trial is on the verge of completion, and we will probably have some results soon. Management of patients with HFpEF and PH has been a problem for all of us, and as yet, we do not have good, randomized, controlled trials to help us understand how to manage them.
On that note, I’d like to thank the discussants for their participation.
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DR. GIVERTZ: I’m Michael Givertz. I am the Medical Director of the Heart Transplant and Mechanical Circulatory Support Program at the Brigham and Women’s Hospital in Boston, Massachusetts. I am interested in the management of patients with advanced heart disease and those with heart failure with preserved ejection fraction (HFpEF) as well as those with reduced ejection fraction (EF). In particular, I focus on patients with comorbidities, including pulmonary hypertension (PH) and chronic kidney disease.
DR. LEWIS: I’m Greg Lewis from Massachusetts General Hospital (MGH), Boston. I am a member of the Heart Failure and Transplant Unit, and I direct the cardiopulmonary exercise labs at MGH. Like Dr. Givertz, I am interested in heart failure (HF) with both preserved EF and reduced EF and in patients who have PH complicating both the abovementioned conditions.
DR. PRITZKER: I’m Marc Pritzker. I’m a professor of Cardiovascular Medicine and Surgery at the University of Minnesota and a part of the Advanced Heart Failure Group here. I’m also the Director of the Pulmonary Hypertension Center, and I have a special interest in diastolic dysfunction, which is going to be the leading cause of PH in Western society,1 if it isn’t already.
DR. FRANCIS: Let’s begin with a case and then proceed from there. It’s a short vignette.
An 83-year-old woman is suffering from long-standing diabetes, coronary disease, and hypertension. She’s admitted to the hospital with acute HF. An echocardiogram was performed, which indicates a normal EF of 65%. She has left ventricular (LV) hypertrophy, a small LV cavity, and a large left atrium.
Doppler studies indicate that the left atrial pressure is probably slightly elevated. There is clear diastolic dysfunction, as shown by echocardiography, and enough tricuspid regurgitation to suggest that the pulmonary artery (PA) pressure is approximately 70/30 mm Hg.
She has been given intravenous furosemide, her condition improves, and she is subsequently discharged. She then visits the outpatient clinic where follow-up echocardiogray indicates the persistence of PH. Her estimated PA pressure by echocardiogram is slightly lower (60/30 mm Hg), although her LV filling pressures are probably lower.
Although I’m not exactly sure of the situation at the Brigham or MGH, I suspect that it’s similar to the situation here and around the country: We are now seeing many such patients. They’re often elderly women with many comorbid conditions, and they’re sometimes admitted with atrial fibrillation, which makes the estimation of diastolic function problematic. They’re treated conventionally with diuretics and antihypertensive therapies, but they tend to fare poorly. Often, they return to the hospital and pose a recurrent problem.
Dr. Pritzker, let’s start with you. The patient’s PA pressure is quite high, at least based on the estimation by an echocardiogram. It’s fairly common for these patients to have PH, but this patient’s PA pressure is probably disproportionately high relative to her slightly elevated left atrial pressure.
Granted that we don’t have the hemodynamic data from the catheterization lab; nonetheless, am I right? Are we seeing more of these patients with so-called reactive or disproportionate PH or hypertension that is higher than what you would expect, given the clinical context?
DR. PRITZKER: I agree. We probably encounter 3 or 4 new patients a week who are referred to us because of certain observations during echocardiographic screening. In reality, these patients have diastolic dysfunction, and probably half of the patients in our clinic have PH that appears to be higher than the classical expectation that the PA pressure follows the left atrial pressure.
This situation could be viewed in 2 ways. One is the eyeball method, which many people do and just say, “Well, that seems high to me compared to what the wedge pressure is.” The transpulmonary gradient, which is the mean PA pressure minus the wedge pressure, or, sometimes, the pulmonary diastolic pressure minus the wedge pressure, is above 15 mm Hg.
Based on the information given in this case, the patient’s mean PA pressure is above 40 mm Hg. I’m assuming that modestly elevated pulmonary capillary wedge pressure is approximately 15 to 20 mm Hg, which indicates an elevated transpulmonary gradient by any measurement.
DR. FRANCIS: Dr. Givertz, what is the scope of this problem in your hospital?
DR. GIVERTZ: As Dr. Pritzker was alluding to, we are seeing many such patients. I’m not sure if we’re actually looking for them or if we are looking more closely at the estimates of PA pressure by echocardiogram, which we may have been less attuned to previously.
The problem of HFpEF, which is a broad definition for this patient’s condition, is that it’s not something new: It’s something that we’ve been struggling with for many years, particularly in older patients. As Dr. Francis mentioned, these patients are typically women with a history of hypertension and often, other comorbidities.
This case would seem unusual, mostly due to the estimated PA pressure. I think that’s probably what caught the eye of the clinicians here.
We probably wouldn’t have given it a second thought if the estimated PA pressure was in the 40s or, maybe, 50s. It is only once the pressure increases above 60 mm Hg that we begin to realize that some other factor could be involved or that something was overlooked, which we now need to look at a little more closely.
Since you didn’t mention anything about the mitral valve, let’s assume that there isn’t any mitral valve disease here and we’re not missing significant mitral regurgitation at rest or ischemic mitral regurgitation, which is something you would want to rule out. This is a common problem, and I think we’re seeing it more often because we’re more closely looking for it.
DR. FRANCIS: I agree, Dr. Givertz. But, it turns out that this patient has minimal mitral regurgitation.
Dr. Lewis, as you have a focused laboratory interest in this problem, what do you think of this case, particularly with regard to the scope of the problem?
DR. LEWIS: I think that it is clearly a major problem. I would like to add that these patients can come to subspecialty care through different routes. It’s not uncommon for a patient like the one in question to be hospitalized through the general medical service or to be assessed by a pulmonary specialist or general cardiologist.
Unlike patients who have advanced LV systolic dysfunction and are often routed into the well-oiled machine of an advanced cardiomyopathy clinic, these patients are identified through providers with different scopes of practice. For example, I believe that these patients are often initially referred to a pulmonary physician.
This makes the problem more challenging because there’s a less-inherent ownership within a predefined group of clinicians. Additionally, this case has features that are clearly suggestive of a pre-capillary PH as well as provide evidence of increased left-sided filling pressures. These patients may be directed through different routes of care in the hospital.
It does present a slight problem, particularly when the house staff is presenting the case and people have their own ideas about what we should call it. Dr. Givertz, what should we call this syndrome? What do you refer to it as at the Brigham?
DR. GIVERTZ: That’s an excellent question. We have moved away from the older terminology of diastolic HF, as probably, most have, although there are some strong proponents of this terminology, which assumes that there is some abnormality in diastolic function.
In an 83-year-old woman with long-standing hypertension, I think LV hypertrophy, a small cavity on her echocardiogram report, and a large left atrium are certainly markers of diastolic dysfunction. So, calling this diastolic HF might be justified.
We probably overstep that terminology in patients who have the clinical syndrome of HF, as this patient does, with dyspnea on exertion, volume overload, and a normal or near-normal EF. So, this meets the basic definition of HFpEF, and there are echocardiographic indicators of abnormal diastolic function. So, you could call it diastolic HF.
The key indicator here is the breadth. Although it is just a descriptive term, I would prefer using a term like HFpEF, and we generally use this term on rounds in the hospital or in an ambulatory setting.
The terminology is important because we don’t assume that this is just a problem of diastole or relaxation. There may be other comorbidities and aspects related to the pathophysiology,2 which may have a larger role to play than only causing a simple abnormality in diastolic function.
DR. FRANCIS: I agree, Dr. Givertz, although I have found that there are certain experts and authors who are accustomed to a specific terminology, which is unfortunate because some patients don’t really have diastolic dysfunction, and I don’t think we understand the underlying pathophysiology very well.
DR. PRITZKER: Drs. Givertz and Lewis, is there a certain trigger in echocardiogram reports such that when an elevation in PA pressure is evident, as in this case, the examiners make the diastology a little bit more manifest or look at tricuspid annular plane systolic excursion or PA acceleration time?
I think we all have difficulties with that. I have looked at reports from several different hospitals, and nobody provides a consistent report once an increase in PA pressure has been identified.
DR. GIVERTZ: I think that’s an excellent point. We get comprehensive echocardiogram reports; it’s the way that our laboratory runs. But we don’t have a trigger that leads to the reporting of additional indices of diastolic function. With high PA pressures, a focus on the right ventricle (RV) (in terms of tricuspid annular plane systolic excursion measurements or RV dimensions) would be particularly helpful in terms of having additional information about the etiology of PH.
DR. LEWIS: In our institution, there is no dedicated report type for this constellation of findings. The conclusion of the interpretation would indicate that findings were consistent with diastolic dysfunction.
Dr. Francis, you mentioned in the description that there was some indication of left atrial pressure elevation in the Doppler studies. I know our echocardiographers at MGH generally avoid reporting Doppler measurements such as E/A ratios or estimates of left atrial pressure based on E/E' values.Ultimately, for patient management, it will be important to establish widely accepted echocardiographic criteria that differentiate precapillary PH, postcapillary PH, and mixed PH.
DR. FRANCIS: That’s a good point. As you know, some hospitals, like my former institution the Cleveland Clinic, did attempt to carry out the calculations, but in most places, these calculations are really not done. I personally assessed the echocardiogram as a consequence of my obsessive behavior. I have also talked to the echocardiographers about it and gathered an intuitive sense of impaired filling.
If you were to guess, you would say that the left atrial pressure is somewhat higher than normal. This is a really subjective phrase. It wasn’t actually measured, of course, and it wasn’t calculated.
DR. PRITZKER: I think it would be helpful if each institution could, at least, have a trigger, so that when the patient goes back to a family practitioner, a pulmonologist or another specialist, there is some comprehensive information that can give the practitioner some direction.
As echocardiograms become more capable of calculating these derived values (E/E prime, E to A, etc.), even general cardiologists begin feeling confused. So I like Dr. Lewis’ idea about inserting a comment at the end to at least point people in some direction.
DR. FRANCIS: Let’s focus a little on what’s different about this particular patient, which is something that I’m personally interested in. Dr. Lewis, why is it that some of these patients have higher PA pressures than what you would expect, given the clinical context? Is there something unusual about them? Is there something relevant that we can discuss, which might help identify such a patient?
DR. LEWIS: I think that’s a key question regarding the evaluation of patients like this one. For me, the first thing to do when I see a patient like this is to make sure that there aren’t other factors, other than left heart disease, that may be mediating the PH.
Even if there is a suggestion of elevated left atrial pressure, it’s important to think beyond the left heart, in terms of additional direct insults that may have been sustained by the pulmonary circulation. For example, does the patient have chronic obstructive pulmonary disease that may be contributing to the high pulmonary arterial pressures? Does the patient have sleep apnea or a history of chronic thromboembolic disease in the lung? Even an overlapping syndrome such as scleroderma or sarcoidosis can cause LV dysfunction as well as pulmonary arterial hypertension but would be unusual to detect at an advanced age in terms of relevance to this case.
Epidemiologic studies can also provide clues regarding the type of patients who tend to have higher pulmonary arterial pressures (eg, older individuals or people with higher systolic blood pressure).
I have been surprised by our relative lack of ability to predict who’s going to have a higher transpulmonary gradient, based on the clinical features alone. For a given left atrial pressure, why do some patients have higher transpulmonary gradients than others?
Elevation of transpulmonary gradients is not simply related to degree of elevation in left-sided pressure alone. That is clear from the relatively weak correlation between PA systolic pressure and left-sided filling pressure.3 I don’t think it is related to the duration of HF alone either.
In our patient population, we’ve recorded the time when patients were diagnosed with HF because I commonly hear, “Well, if the patient has HF for a sufficient amount of time, he/she will gradually develop increases in transpulmonary gradient because of high pressure on the left side of the heart.” The duration of HF was not significantly related to the transpulmonary gradient. Therefore, I believe we need to look at new ways of understanding which patients will develop high transpulmonary gradients.
There’s some work being conducted in this area. Investigators at Dr. Francis’s former institution recently published a study about arginine metabolism dysregulation and some circulating markers that were high in patients who had a high burden of precapillary PH and HF.4
Dr. Givertz has been involved in studies evaluating endothelin levels or cyclic guanosine monophosphate-adenosine monophosphate release through the pulmonary circulation as potential indicators of dysregulation in signaling systems within pulmonary circulation. There may also be permissive genotypes that predispose patients to develop precapillary PH in the setting of left heart dysfunction.
So, I think that the question is a good one, but for me, it raises many more questions about why these patients are different. I don’t think we can explain it on the basis of clinical characteristics alone.
DR. FRANCIS: Dr. Lewis has had extensive experience in studying these patients in the laboratory and performing exercise tests on them. Dr. Lewis, from a clinical rather than research standpoint, when would you actually consider conducting more invasive studies like you are currently doing in the research laboratory?
DR. LEWIS: We haven’t talked about invasive phenotyping of patients yet, but to address Dr. Givertz’s point, the question pertains to when we need to carefully study the conditions in the pulmonary circulation. I believe that knowing the left atrial pressure is important for truly understanding the transpulmonary gradient, and I’d like to know whether it’s greater than 15 mm Hg, as Dr. Pritzker indicated; this level serves as a trigger for looking carefully into the pulmonary circulation.
Dr. Francis, I find the exercise status to be particularly informative in patients who exhibit shortness of breath with exertion. However, it’s not entirely clear whether their symptoms are being mediated by left-heart disease or a primary insult to the pulmonary circulation.
Often, even when patients have a resting right-heart catheterization, we see borderline elevations in pulmonary arterial pressure, say, a mean pressure of 20 to 25 mm Hg, and a pulmonary capillary wedge pressure of 10 to 15 mm Hg, but symptoms are present.
In such cases, instead of looking at hemodynamic measurements during a single moment in time, I find it quite helpful to make serial measurements under different loading conditions that are introduced by the very highly relevant physiologic state of exercise. We often encounter patients who have shortness of breath with exertion, which is not entirely explained by the initial diagnostic testing results.
I find it particularly useful to characterize the changes in the pulmonary capillary wedge pressure and transpulmonary gradient when patients are subjected to exercise. We can begin to classify patients based on whether their burden of precapillary PH is high or there is truly a left-sided predominance to their symptoms.
DR. FRANCIS: This gives rise to question of whether therapeutic targets exist. We all know that they exist, but what is the therapy? Perhaps, we’re not so sure about that.
DR. PRITZKER: We’re predominantly using sildenafil because it’s easily available in the hospital and doesn’t require cumbersome pre-approval for acute use like in the case of endothelin antagonists. We have a good experience of using it, and we follow it up with 6-min walks, which perhaps, in this population, is slightly easier to do.
DR. FRANCIS: Dr. Pritzker, what is your threshold for administering sildenafil? Is it lower?
DR. PRITZKER: Yes, because I think there’s more relevant evidence, including the provocative work of an Italian group and Dr. Lewis’ work. We don’t necessarily know why we’re making them better yet, but clearly, people are having fewer symptoms. This is more anecdotal than longitudinal, but patients have fewer symptoms, feel better, and seem to have better function. We also see fewer hospital admissions. I think a previous paper published at the end of last year presented similar findings.
DR. FRANCIS: Dr. Givertz, can you comment about the therapy?
DR. GIVERTZ: I think we’re all gaining experience with using sildenafil or longer-acting phosphodiesterase type 5 (PDE5) inhibitors in this patient population, but that might not be the first thing I would reach for.
This patient was admitted with acute HF. Presumably, there was a fluid problem here as well. I might be initially inclined to make sure I have optimized diuretic therapy. If this patient wasn’t already on nitrates, given the underlying coronary disease and hypertension, I think administering nitrates would be a reasonable next step.
Although there are certainly patients who cannot tolerate nitrate therapy due to its side effects such as headache or light-headedness, I might try administering nitrates before opting for a PDE5 inhibitor.
DR. PRITZKER: I assumed that the patient had been stabilized, and we still had a therapeutic gap after conventional therapy.
DR. FRANCIS: That’s a good point because it is related to the timing of initiation of such therapy; I am quite conservative about it. I don’t have as much experience as the other physicians on the panel, but my tendency would be to go with conventional medical therapy, as bad as it is, and if the patient didn’t improve thereafter, I would think about sending the patient to Dr. Pritzker or beginning sildenafil treatment myself.
Dr. Lewis, you’re actually involved in a National Institute of Health study, a consortium study. Is that right?
DR. LEWIS: That’s right; it’s the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)trial.5 Michael and Maggie Redfield from the Mayo Clinic are involved as well, and Dr. Redfield is the principal architect of the trial. But, we are adjudicating the primary end point here, which is a cardiopulmonary exercise endpoint.
Dr. Francis, I agree with Drs. Pritzker and Givertz in terms of the therapeutic approach. There certainly have been some cautionary accounts from other pulmonary vasodilators that have been tried in patients who have left heart disease, predominantly those with systolic dysfunction and have not resulted in improved outcomes.6 Therefore, I tend to refrain from using endothelin antagonists as well as the prostacyclins.
There has been some promising work done with PDE5 inhibitors in left-heart disease, and we will know the results from the RELAX trial soon. We completed enrollment of just over 200 patients, and we’re trying to determine whether we can improve exercise capacity over a period of 24 weeks with sildenafil in patients with HFpEF.
The results of PDE5 inhibition in HF with preserved LVEF from the Guazzi group demonstrated that patients with a significant burden of right-heart disease may derive significant improvement in precapillary PH with sildenafil.7 I believe if there is right-heart dysfunction that is largely attributed to high pulmonary vascular resistance or a high transpulmonary gradient, then pulmonary vasodilators like PDE5 inhibitors will have a promising role to play. Potentially, there are also some novel therapies involving the use of some of the soluble guanylate cyclase stimulators and activators in trials.
If patients have a predominant left-heart dysfunction with a modest transpulmonary gradient, I think they are much better served by trying to optimize the diuretic therapy and treat the systemic hypertension.
DR. FRANCIS: Thank you, Dr. Lewis. I think we agree that this is clearly an emerging problem, and it’s prevalence is increasing, partly because of the aging population. It is true that these patients are often admitted to general medicine wards and are sometimes transferred to the cardiology groups when they are faring poorly, and I don’t know what we can do about that.
There does seem to be a subset of patients with disproportionate PH, and there’s a lot of interest in that particular subset. I don’t know if they’re clearly identifiable from the phenoclinical phenotype, but I think that they pose more difficult problems.
Lastly, I’m delighted to know that the RELAX trial is on the verge of completion, and we will probably have some results soon. Management of patients with HFpEF and PH has been a problem for all of us, and as yet, we do not have good, randomized, controlled trials to help us understand how to manage them.
On that note, I’d like to thank the discussants for their participation.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
DR. GIVERTZ: I’m Michael Givertz. I am the Medical Director of the Heart Transplant and Mechanical Circulatory Support Program at the Brigham and Women’s Hospital in Boston, Massachusetts. I am interested in the management of patients with advanced heart disease and those with heart failure with preserved ejection fraction (HFpEF) as well as those with reduced ejection fraction (EF). In particular, I focus on patients with comorbidities, including pulmonary hypertension (PH) and chronic kidney disease.
DR. LEWIS: I’m Greg Lewis from Massachusetts General Hospital (MGH), Boston. I am a member of the Heart Failure and Transplant Unit, and I direct the cardiopulmonary exercise labs at MGH. Like Dr. Givertz, I am interested in heart failure (HF) with both preserved EF and reduced EF and in patients who have PH complicating both the abovementioned conditions.
DR. PRITZKER: I’m Marc Pritzker. I’m a professor of Cardiovascular Medicine and Surgery at the University of Minnesota and a part of the Advanced Heart Failure Group here. I’m also the Director of the Pulmonary Hypertension Center, and I have a special interest in diastolic dysfunction, which is going to be the leading cause of PH in Western society,1 if it isn’t already.
DR. FRANCIS: Let’s begin with a case and then proceed from there. It’s a short vignette.
An 83-year-old woman is suffering from long-standing diabetes, coronary disease, and hypertension. She’s admitted to the hospital with acute HF. An echocardiogram was performed, which indicates a normal EF of 65%. She has left ventricular (LV) hypertrophy, a small LV cavity, and a large left atrium.
Doppler studies indicate that the left atrial pressure is probably slightly elevated. There is clear diastolic dysfunction, as shown by echocardiography, and enough tricuspid regurgitation to suggest that the pulmonary artery (PA) pressure is approximately 70/30 mm Hg.
She has been given intravenous furosemide, her condition improves, and she is subsequently discharged. She then visits the outpatient clinic where follow-up echocardiogray indicates the persistence of PH. Her estimated PA pressure by echocardiogram is slightly lower (60/30 mm Hg), although her LV filling pressures are probably lower.
Although I’m not exactly sure of the situation at the Brigham or MGH, I suspect that it’s similar to the situation here and around the country: We are now seeing many such patients. They’re often elderly women with many comorbid conditions, and they’re sometimes admitted with atrial fibrillation, which makes the estimation of diastolic function problematic. They’re treated conventionally with diuretics and antihypertensive therapies, but they tend to fare poorly. Often, they return to the hospital and pose a recurrent problem.
Dr. Pritzker, let’s start with you. The patient’s PA pressure is quite high, at least based on the estimation by an echocardiogram. It’s fairly common for these patients to have PH, but this patient’s PA pressure is probably disproportionately high relative to her slightly elevated left atrial pressure.
Granted that we don’t have the hemodynamic data from the catheterization lab; nonetheless, am I right? Are we seeing more of these patients with so-called reactive or disproportionate PH or hypertension that is higher than what you would expect, given the clinical context?
DR. PRITZKER: I agree. We probably encounter 3 or 4 new patients a week who are referred to us because of certain observations during echocardiographic screening. In reality, these patients have diastolic dysfunction, and probably half of the patients in our clinic have PH that appears to be higher than the classical expectation that the PA pressure follows the left atrial pressure.
This situation could be viewed in 2 ways. One is the eyeball method, which many people do and just say, “Well, that seems high to me compared to what the wedge pressure is.” The transpulmonary gradient, which is the mean PA pressure minus the wedge pressure, or, sometimes, the pulmonary diastolic pressure minus the wedge pressure, is above 15 mm Hg.
Based on the information given in this case, the patient’s mean PA pressure is above 40 mm Hg. I’m assuming that modestly elevated pulmonary capillary wedge pressure is approximately 15 to 20 mm Hg, which indicates an elevated transpulmonary gradient by any measurement.
DR. FRANCIS: Dr. Givertz, what is the scope of this problem in your hospital?
DR. GIVERTZ: As Dr. Pritzker was alluding to, we are seeing many such patients. I’m not sure if we’re actually looking for them or if we are looking more closely at the estimates of PA pressure by echocardiogram, which we may have been less attuned to previously.
The problem of HFpEF, which is a broad definition for this patient’s condition, is that it’s not something new: It’s something that we’ve been struggling with for many years, particularly in older patients. As Dr. Francis mentioned, these patients are typically women with a history of hypertension and often, other comorbidities.
This case would seem unusual, mostly due to the estimated PA pressure. I think that’s probably what caught the eye of the clinicians here.
We probably wouldn’t have given it a second thought if the estimated PA pressure was in the 40s or, maybe, 50s. It is only once the pressure increases above 60 mm Hg that we begin to realize that some other factor could be involved or that something was overlooked, which we now need to look at a little more closely.
Since you didn’t mention anything about the mitral valve, let’s assume that there isn’t any mitral valve disease here and we’re not missing significant mitral regurgitation at rest or ischemic mitral regurgitation, which is something you would want to rule out. This is a common problem, and I think we’re seeing it more often because we’re more closely looking for it.
DR. FRANCIS: I agree, Dr. Givertz. But, it turns out that this patient has minimal mitral regurgitation.
Dr. Lewis, as you have a focused laboratory interest in this problem, what do you think of this case, particularly with regard to the scope of the problem?
DR. LEWIS: I think that it is clearly a major problem. I would like to add that these patients can come to subspecialty care through different routes. It’s not uncommon for a patient like the one in question to be hospitalized through the general medical service or to be assessed by a pulmonary specialist or general cardiologist.
Unlike patients who have advanced LV systolic dysfunction and are often routed into the well-oiled machine of an advanced cardiomyopathy clinic, these patients are identified through providers with different scopes of practice. For example, I believe that these patients are often initially referred to a pulmonary physician.
This makes the problem more challenging because there’s a less-inherent ownership within a predefined group of clinicians. Additionally, this case has features that are clearly suggestive of a pre-capillary PH as well as provide evidence of increased left-sided filling pressures. These patients may be directed through different routes of care in the hospital.
It does present a slight problem, particularly when the house staff is presenting the case and people have their own ideas about what we should call it. Dr. Givertz, what should we call this syndrome? What do you refer to it as at the Brigham?
DR. GIVERTZ: That’s an excellent question. We have moved away from the older terminology of diastolic HF, as probably, most have, although there are some strong proponents of this terminology, which assumes that there is some abnormality in diastolic function.
In an 83-year-old woman with long-standing hypertension, I think LV hypertrophy, a small cavity on her echocardiogram report, and a large left atrium are certainly markers of diastolic dysfunction. So, calling this diastolic HF might be justified.
We probably overstep that terminology in patients who have the clinical syndrome of HF, as this patient does, with dyspnea on exertion, volume overload, and a normal or near-normal EF. So, this meets the basic definition of HFpEF, and there are echocardiographic indicators of abnormal diastolic function. So, you could call it diastolic HF.
The key indicator here is the breadth. Although it is just a descriptive term, I would prefer using a term like HFpEF, and we generally use this term on rounds in the hospital or in an ambulatory setting.
The terminology is important because we don’t assume that this is just a problem of diastole or relaxation. There may be other comorbidities and aspects related to the pathophysiology,2 which may have a larger role to play than only causing a simple abnormality in diastolic function.
DR. FRANCIS: I agree, Dr. Givertz, although I have found that there are certain experts and authors who are accustomed to a specific terminology, which is unfortunate because some patients don’t really have diastolic dysfunction, and I don’t think we understand the underlying pathophysiology very well.
DR. PRITZKER: Drs. Givertz and Lewis, is there a certain trigger in echocardiogram reports such that when an elevation in PA pressure is evident, as in this case, the examiners make the diastology a little bit more manifest or look at tricuspid annular plane systolic excursion or PA acceleration time?
I think we all have difficulties with that. I have looked at reports from several different hospitals, and nobody provides a consistent report once an increase in PA pressure has been identified.
DR. GIVERTZ: I think that’s an excellent point. We get comprehensive echocardiogram reports; it’s the way that our laboratory runs. But we don’t have a trigger that leads to the reporting of additional indices of diastolic function. With high PA pressures, a focus on the right ventricle (RV) (in terms of tricuspid annular plane systolic excursion measurements or RV dimensions) would be particularly helpful in terms of having additional information about the etiology of PH.
DR. LEWIS: In our institution, there is no dedicated report type for this constellation of findings. The conclusion of the interpretation would indicate that findings were consistent with diastolic dysfunction.
Dr. Francis, you mentioned in the description that there was some indication of left atrial pressure elevation in the Doppler studies. I know our echocardiographers at MGH generally avoid reporting Doppler measurements such as E/A ratios or estimates of left atrial pressure based on E/E' values.Ultimately, for patient management, it will be important to establish widely accepted echocardiographic criteria that differentiate precapillary PH, postcapillary PH, and mixed PH.
DR. FRANCIS: That’s a good point. As you know, some hospitals, like my former institution the Cleveland Clinic, did attempt to carry out the calculations, but in most places, these calculations are really not done. I personally assessed the echocardiogram as a consequence of my obsessive behavior. I have also talked to the echocardiographers about it and gathered an intuitive sense of impaired filling.
If you were to guess, you would say that the left atrial pressure is somewhat higher than normal. This is a really subjective phrase. It wasn’t actually measured, of course, and it wasn’t calculated.
DR. PRITZKER: I think it would be helpful if each institution could, at least, have a trigger, so that when the patient goes back to a family practitioner, a pulmonologist or another specialist, there is some comprehensive information that can give the practitioner some direction.
As echocardiograms become more capable of calculating these derived values (E/E prime, E to A, etc.), even general cardiologists begin feeling confused. So I like Dr. Lewis’ idea about inserting a comment at the end to at least point people in some direction.
DR. FRANCIS: Let’s focus a little on what’s different about this particular patient, which is something that I’m personally interested in. Dr. Lewis, why is it that some of these patients have higher PA pressures than what you would expect, given the clinical context? Is there something unusual about them? Is there something relevant that we can discuss, which might help identify such a patient?
DR. LEWIS: I think that’s a key question regarding the evaluation of patients like this one. For me, the first thing to do when I see a patient like this is to make sure that there aren’t other factors, other than left heart disease, that may be mediating the PH.
Even if there is a suggestion of elevated left atrial pressure, it’s important to think beyond the left heart, in terms of additional direct insults that may have been sustained by the pulmonary circulation. For example, does the patient have chronic obstructive pulmonary disease that may be contributing to the high pulmonary arterial pressures? Does the patient have sleep apnea or a history of chronic thromboembolic disease in the lung? Even an overlapping syndrome such as scleroderma or sarcoidosis can cause LV dysfunction as well as pulmonary arterial hypertension but would be unusual to detect at an advanced age in terms of relevance to this case.
Epidemiologic studies can also provide clues regarding the type of patients who tend to have higher pulmonary arterial pressures (eg, older individuals or people with higher systolic blood pressure).
I have been surprised by our relative lack of ability to predict who’s going to have a higher transpulmonary gradient, based on the clinical features alone. For a given left atrial pressure, why do some patients have higher transpulmonary gradients than others?
Elevation of transpulmonary gradients is not simply related to degree of elevation in left-sided pressure alone. That is clear from the relatively weak correlation between PA systolic pressure and left-sided filling pressure.3 I don’t think it is related to the duration of HF alone either.
In our patient population, we’ve recorded the time when patients were diagnosed with HF because I commonly hear, “Well, if the patient has HF for a sufficient amount of time, he/she will gradually develop increases in transpulmonary gradient because of high pressure on the left side of the heart.” The duration of HF was not significantly related to the transpulmonary gradient. Therefore, I believe we need to look at new ways of understanding which patients will develop high transpulmonary gradients.
There’s some work being conducted in this area. Investigators at Dr. Francis’s former institution recently published a study about arginine metabolism dysregulation and some circulating markers that were high in patients who had a high burden of precapillary PH and HF.4
Dr. Givertz has been involved in studies evaluating endothelin levels or cyclic guanosine monophosphate-adenosine monophosphate release through the pulmonary circulation as potential indicators of dysregulation in signaling systems within pulmonary circulation. There may also be permissive genotypes that predispose patients to develop precapillary PH in the setting of left heart dysfunction.
So, I think that the question is a good one, but for me, it raises many more questions about why these patients are different. I don’t think we can explain it on the basis of clinical characteristics alone.
DR. FRANCIS: Dr. Lewis has had extensive experience in studying these patients in the laboratory and performing exercise tests on them. Dr. Lewis, from a clinical rather than research standpoint, when would you actually consider conducting more invasive studies like you are currently doing in the research laboratory?
DR. LEWIS: We haven’t talked about invasive phenotyping of patients yet, but to address Dr. Givertz’s point, the question pertains to when we need to carefully study the conditions in the pulmonary circulation. I believe that knowing the left atrial pressure is important for truly understanding the transpulmonary gradient, and I’d like to know whether it’s greater than 15 mm Hg, as Dr. Pritzker indicated; this level serves as a trigger for looking carefully into the pulmonary circulation.
Dr. Francis, I find the exercise status to be particularly informative in patients who exhibit shortness of breath with exertion. However, it’s not entirely clear whether their symptoms are being mediated by left-heart disease or a primary insult to the pulmonary circulation.
Often, even when patients have a resting right-heart catheterization, we see borderline elevations in pulmonary arterial pressure, say, a mean pressure of 20 to 25 mm Hg, and a pulmonary capillary wedge pressure of 10 to 15 mm Hg, but symptoms are present.
In such cases, instead of looking at hemodynamic measurements during a single moment in time, I find it quite helpful to make serial measurements under different loading conditions that are introduced by the very highly relevant physiologic state of exercise. We often encounter patients who have shortness of breath with exertion, which is not entirely explained by the initial diagnostic testing results.
I find it particularly useful to characterize the changes in the pulmonary capillary wedge pressure and transpulmonary gradient when patients are subjected to exercise. We can begin to classify patients based on whether their burden of precapillary PH is high or there is truly a left-sided predominance to their symptoms.
DR. FRANCIS: This gives rise to question of whether therapeutic targets exist. We all know that they exist, but what is the therapy? Perhaps, we’re not so sure about that.
DR. PRITZKER: We’re predominantly using sildenafil because it’s easily available in the hospital and doesn’t require cumbersome pre-approval for acute use like in the case of endothelin antagonists. We have a good experience of using it, and we follow it up with 6-min walks, which perhaps, in this population, is slightly easier to do.
DR. FRANCIS: Dr. Pritzker, what is your threshold for administering sildenafil? Is it lower?
DR. PRITZKER: Yes, because I think there’s more relevant evidence, including the provocative work of an Italian group and Dr. Lewis’ work. We don’t necessarily know why we’re making them better yet, but clearly, people are having fewer symptoms. This is more anecdotal than longitudinal, but patients have fewer symptoms, feel better, and seem to have better function. We also see fewer hospital admissions. I think a previous paper published at the end of last year presented similar findings.
DR. FRANCIS: Dr. Givertz, can you comment about the therapy?
DR. GIVERTZ: I think we’re all gaining experience with using sildenafil or longer-acting phosphodiesterase type 5 (PDE5) inhibitors in this patient population, but that might not be the first thing I would reach for.
This patient was admitted with acute HF. Presumably, there was a fluid problem here as well. I might be initially inclined to make sure I have optimized diuretic therapy. If this patient wasn’t already on nitrates, given the underlying coronary disease and hypertension, I think administering nitrates would be a reasonable next step.
Although there are certainly patients who cannot tolerate nitrate therapy due to its side effects such as headache or light-headedness, I might try administering nitrates before opting for a PDE5 inhibitor.
DR. PRITZKER: I assumed that the patient had been stabilized, and we still had a therapeutic gap after conventional therapy.
DR. FRANCIS: That’s a good point because it is related to the timing of initiation of such therapy; I am quite conservative about it. I don’t have as much experience as the other physicians on the panel, but my tendency would be to go with conventional medical therapy, as bad as it is, and if the patient didn’t improve thereafter, I would think about sending the patient to Dr. Pritzker or beginning sildenafil treatment myself.
Dr. Lewis, you’re actually involved in a National Institute of Health study, a consortium study. Is that right?
DR. LEWIS: That’s right; it’s the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Diastolic Heart Failure (RELAX)trial.5 Michael and Maggie Redfield from the Mayo Clinic are involved as well, and Dr. Redfield is the principal architect of the trial. But, we are adjudicating the primary end point here, which is a cardiopulmonary exercise endpoint.
Dr. Francis, I agree with Drs. Pritzker and Givertz in terms of the therapeutic approach. There certainly have been some cautionary accounts from other pulmonary vasodilators that have been tried in patients who have left heart disease, predominantly those with systolic dysfunction and have not resulted in improved outcomes.6 Therefore, I tend to refrain from using endothelin antagonists as well as the prostacyclins.
There has been some promising work done with PDE5 inhibitors in left-heart disease, and we will know the results from the RELAX trial soon. We completed enrollment of just over 200 patients, and we’re trying to determine whether we can improve exercise capacity over a period of 24 weeks with sildenafil in patients with HFpEF.
The results of PDE5 inhibition in HF with preserved LVEF from the Guazzi group demonstrated that patients with a significant burden of right-heart disease may derive significant improvement in precapillary PH with sildenafil.7 I believe if there is right-heart dysfunction that is largely attributed to high pulmonary vascular resistance or a high transpulmonary gradient, then pulmonary vasodilators like PDE5 inhibitors will have a promising role to play. Potentially, there are also some novel therapies involving the use of some of the soluble guanylate cyclase stimulators and activators in trials.
If patients have a predominant left-heart dysfunction with a modest transpulmonary gradient, I think they are much better served by trying to optimize the diuretic therapy and treat the systemic hypertension.
DR. FRANCIS: Thank you, Dr. Lewis. I think we agree that this is clearly an emerging problem, and it’s prevalence is increasing, partly because of the aging population. It is true that these patients are often admitted to general medicine wards and are sometimes transferred to the cardiology groups when they are faring poorly, and I don’t know what we can do about that.
There does seem to be a subset of patients with disproportionate PH, and there’s a lot of interest in that particular subset. I don’t know if they’re clearly identifiable from the phenoclinical phenotype, but I think that they pose more difficult problems.
Lastly, I’m delighted to know that the RELAX trial is on the verge of completion, and we will probably have some results soon. Management of patients with HFpEF and PH has been a problem for all of us, and as yet, we do not have good, randomized, controlled trials to help us understand how to manage them.
On that note, I’d like to thank the discussants for their participation.
FoxP2 Media LLC is the publisher of The Medical Roundtable.
FoxP2 Media LLC
