DR. MASSIE: I’m pleased to welcome you today to a discussion of one of the most perplexing problems in cardiology, namely, the management of patients presenting with symptoms and signs of congestive heart failure (HF) but who actually have normal or near-normal ejection fraction (EF). This syndrome is often termed HF with preserved ejection fraction (HFpEF).
I’m Barry Massie, Professor of Medicine at the University of California in San Francisco, and I’ll be moderating the call. I’m delighted to be joined by 2 colleagues who have devoted a great deal of effort to the pathophysiology of this syndrome and potential approaches to its treatment: Michael Zile, Professor of Medicine at the Medical University of South Carolina, Principal Investigator at the Gazes Cardiac Research Institute, and Director of the Medical Intensive Care Unit at the Ralph H. Johnson Department of Veterans Affairs Medical Center, and Sanjiv Shah, Associate Professor of Medicine–Cardiology at Northwestern University.
Dr. Zile, our first presenter, will discuss the epidemiology and pathophysiology of HFpEF. I’m sure you will quickly recognize his extensive knowledge and passion for the problem. After that, Dr. Shah, a former chief resident and cardiology fellow from our program at the University of California in San Francisco, who’s established a large program devoted to the study and treatment of HFpEF patients, will discuss his approach to the diagnosis and management of these patients.
DR. ZILE: I would like to start with a very short historical perspective that puts into context some of the terminology that’s already been used by Dr. Massie. Before 2006, EF < 35% was an inclusion criterion in virtually all the HF studies conducted. Therefore, all new medical and device-based management strategies were originally applied selectively to patients with clinical HF with a reduced EF (HFrEF), which was then called systolic HF.
However, as early as the 1970s, it was recognized that there were, in fact, a group of patients who had HF but an EF substantially higher than the 35% cutoff, ie, an EF > 50%. Kenneth Kessler was the first to publish the term “diastolic heart failure” in 1988 to describe such a group of patients.1
Until 2006, almost no reports of large randomized clinical trials that had examined this group of patients were published. Fortunately, between 2006 and 2009, the results of 5 studies that had examined patients with variable EF cutoffs—35%, 40%, or 45%—were published. Therefore, the term “heart failure with preserved EF” was suggested. For symmetry, a complementary term “heart failure with reduced ejection fraction” was proposed.
The diagnostic criteria commonly used for patients with HFpEF were recently published in a comprehensive review published by the Heart Failure Society of America in Journal of Cardiac Failure.2 Diagnosis requires clinical evidence of HF, meaning evidence of both symptoms and signs of HF, often supported by findings on chest radiography, cardiopulmonary exercise testing, or assessment of natriuretic peptides.
In addition to the signs and symptoms of HF, there’s a required EF cutoff or partition value. For the sake this presentation, let’s say that cutoff value is 50%. In addition, patients should have a normal left ventricular (LV) end-diastolic volume.
Supportive evidence for the presence of this clinical syndrome is found echocardiographically in structural or functional changes. One should be cognizant of ruling out nonmyocardial disease.
Patients with HFpEF have clinical characteristics that differ from those of patients with HFrEF. Patients with HFpEF tend to be older. The average age of patients approaches 70 to 75 years. They’re typically women and more often have hypertension and less often coronary artery disease (CAD).
The prevalence of this clinical syndrome exceeds 50% and appears to be increasing over time.3,4 While the rate of HF hospitalization of HFpEF patients continues to increase, the rate of HF hospitalization for HFrEF patients is actually decreasing. Data from epidemiological studies suggest that the survival rate of both HFrEF patients and HFpEF patients at 5 years posthospitalization was approximately 60%.5 In contrast, data from randomized clinical trials suggest significant differences in both morbidity and mortality between these 2 groups of patients. In a recent study by Campbell and McMurray, the clinical trials that randomized both HFrEF and HFpEF patients found different rates of overall mortality and overall hospitalization for these 2 groups, specifically higher rates for patients with HFrEF.6 However, they found that the functional impairment experienced by HFrEF and HFpEF patients in terms of exercise intolerance is basically equivalent. One example to support this finding is that cardiopulmonary exercise data and peak oxygen consumption (VO2) values are roughly equivalent in both groups7,8 of patients and approach the peak VO2 value of ≤14 mL/kg/min, a criterion for HF transplantation.9
HFpEF is commonly associated with clear abnormalities in both structure and function at the organ and ultrastructure levels. In at least one study published in Circulation, it was demonstrated that even patients with chronic compensated HFpEF have elevated pulmonary artery diastolic pressure or pulmonary capillary wedge pressure (PCWP).10 Those who then go on to develop decompensated HFpEF have further increases in diastolic pressure. The overall relationship between LV diastolic pressure and volume in patients with HFpEF is pushed up and to the left to a steeper curve such that the LV diastolic pressure is higher in HFpEF patients as compared to normal patients at any common volume.
Echocardiographic findings demonstrate that long-term increases in diastolic pressure are evidenced by an increase in the left atrial volume. In 2 recent echocardiographic substudies of Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE) and Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARM-Preserved), 60% to 70% of these patients experienced increase in left atrial volume.11,12 This increase in left atrial volume predicted a marked increase in cumulative event rates in terms of primary both end points and HF end points in both studies.
HFpEF patients have significant increases in fibrillar collagen, which are under the control of the cardiac fibroblast. Abnormalities can be seen in at least 4 specific mechanisms controlling collagen homeostasis, including synthesis, postsynthetic processing, posttranslational modification, and degradation.
In one exemplary study by Westermann and colleagues published in 2011, LV biopsy of patients with HFpEF revealed a 3-fold increase in collagen volume fraction and a 4-fold increase in collagen type 1 volume fraction compared to that in the control subjects.13
If you look at the evidence of abnormalities and extracellular matrix homeostasis in the plasma, you will find changes in collagen pro-peptides such as the N-terminal pro-peptide of collagen 3; in matrix metalloproteinases (MMPs), specifically MMP2 and MMP8; and in the tissue inhibitors of MMP (TIMPs), specifically TIMP4. Abnormalities in these 4 plasma biomarkers taken in aggregate as a biomarker panel are evidence of abnormalities in extracellular matrix homeostasis and can be used diagnostically to detect the presence of HFpEF.
There are, however, some issues that have been raised regarding the natural history and the underlying pathophysiologic mechanisms in HFpEF. I’ll give you 2 examples.
Some scientists and clinicians have argued that HFpEF is not a clinical syndrome, but rather a group of symptoms and signs caused by comorbidities and associated with specific epidemiologic factors such as advanced age, female sex, CAD, diabetes, and hypertension. However, if this were true, then the morbidity and mortality rates should be comparable between patients who have only these underlying comorbidities and patients who have these comorbidities and HFpEF.
Campbell and McMurray compared the overall mortality and HF hospitalization rates of studies that examined patients with underlying comorbidities such as diabetes, hypertension, or CAD and no HFpEF, versus those patients studied in trials with HFpEF.14 For example, in studies patients with hypertension, diabetes, or CAD but no HF, the HF hospitalization rate was <12/100 patient-years, whereas in patients with these comorbidities and HFpEF, the rate was >40/100 patient-years.
The second challenge put forth by some scientists and clinicians is that HF is a continuum and HFpEF and HFrEF are, in fact, expressions of one disease process.15 However, there are clear structural and functional differences between these 2 clinical syndromes and that patients with HFpEF do not, in fact, progress to become patients with HFrEF. I’ll give you 2 sets of evidence to support that.
Patients with HFpEF, in general, have a normal ventricular volume but experience increases in LV mass, which supports the existence of a type of structural abnormality summarized by the term “concentric remodeling” or “concentric hypertrophy.” In contrast, patients with HFrEF experience marked increases in volumes without a proportional increase in LV mass, and thus experience eccentric remodeling or eccentric hypertrophy. These chamber abnormalities are mirrored by ultrastructural abnormalities such as those seen in the cardiomyocyte length, width, and area in animal models of eccentric versus concentric hypertrophy. In addition, there are significant differences in extracellular matrix remodeling.16
Finally, at least 4 studies demonstrate that over variable periods of time and in the absence of an intercurrent myocardial infarction, patients with concentric remodeling, a common structural manifestation of HFpEF, do not frequently progress to eccentric remodeling, a common structural manifestation of HFrEF. This conversion rate is less than 1% per year.17–20
I think I’ll stop my comments there and let Dr. Massie talk about the clinical trials that have been performed over the past 5 years.
DR. MASSIE: In terms of treating these patients, I think Dr. Zile already alluded to the fact that it’s challenging, but we’re learning more and getting better at it. Compared with HFrEF, the most commonly studied variety of HF, we have fewer data for HFpEF, but our knowledge is growing. This subject is currently gaining importance.
Among the relatively few randomized trials, I’ll review and comment on 4 of them. Guidelines don’t have much to say because, frankly, we haven’t found much for them to say. Treatment remains relatively empiric, and different clinicians have different biases that affect the treatment that they provide; some, for instance, simply treat HFpEF patients with diuretics when they become edematous.
Several small studies have shown that some agents seem to work. Certainly, diuretics, while not truly addressing the underlying mechanism of HFpEF, make patients feel better when they are volume overloaded. Some have tried calcium blockers, although I don’t think they have much clinical benefit. Beta blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptor blockers, and now aldosterone blockers. Most recent trials have focused on inhibitors of the renin angiotensin system. Frankly, there hasn’t been a lot of beneficial evidence.
It’s sort of paradoxical, but the first trial of HFpEF ever conducted on a moderate scale was with digoxin in the Digitalis Investigation Group (DIG) trial.21 Given digoxin’s utility as an inotropic agent, studying it in patients with HFpEF is, of course, somewhat counterintuitive. Nevertheless, I think studying these patients was a wonderful idea by Richard Gorlin, who was running the large DIG trial of HFrEF and thought it was about time to look at HFpEF as well.
The DIG study enrolled patients aged 67 years and older and included a larger proportion of women than you’d generally see in trials of HFrEF. The criterion for enrollment was an EF > 45%. The average EF was 55%, but 27% of patients had an EF < 50%. I will talk about that in more detail further, but this is where the 2 types of HF sometimes overlap in these trials.
Only half of the patients had a history of myocardial infarction, which is not surprising given the physiology and pathophysiology that Dr. Zile talked about, but hypertension was the dominant finding. When asked to speculate on the cause, the investigators stated hypertension for 23% of the patients, but we’ll see in other trials that hypertension is much more prevalent. In the Digitalis Investigation Group-Preserved Ejection Fraction (DIG-PEF), 56% of the patients were deemed to have an ischemic etiology.
The CHARM study,22 an angiotensin receptor blocker trial, that also conducted parallel examination of groups of HFrEF and HFpEF patients, observed the same phenomenon observed in the DIG trial: When you examine heterogeneous populations, you ultimately examine people who are more likely to reflect a dominant population, which in this case were HFrEF patients.
The Perindopril in Elderly Persons (PEP) trial,23 in which the mean age was 75 years and included more women than men, reported a higher mean EF than the previous 2 trials. We don’t know how many patients had EF < 50% because the PEP trial used a wall motion score index rather than the more typical EF value. As in the previous trials, relatively low rates of prior myocardial infarction were observed, and hypertension was thought to be the major player for a very large number of patients.
The last of the 4 investigations is the I-PRESERVE trial,24 the largest of these trials. As in the previous studies, the trial included patients of advanced age with a normal EF and a high percentage of women. Among the 88% of patients who had hypertension, the investigators indicated that the hypertension was responsible for the HFpEF in about two-thirds of the population, although it’s not entirely clear how they could make that judgment. Ischemic etiology was less common.
In the DIG-Preserved trial, there was early separation in the event-free survival curves for digoxin and placebo, which is perhaps a little difficult to explain, but probably one of the few positive findings at any point in any of these trials.
I wanted to elaborate a little more on I-PRESERVE, a trial that included 360 centers in 29 countries, for several reasons. One is that many of us were involved in it, and we believe that it probably provided more data than any other single trial. It used an angiotensin receptor blocker like CHARM did, but clearly separated the HFrEF and HFpEF patients. Over 4000 HFpEF patients developed 140 events.
The inclusion criteria for I-PRESERVE were EF < 45% with symptomatic HF and either recent hospitalization for HF or findings that fit the profile of diastolic HF or HFpEF. Use of an ACE inhibitor was not a contraindication, largely because ACE inhibitors were becoming the standard therapy for diabetics who comprised a fair number of these patients. We also didn’t feel that we could ethically withhold an ACE inhibitor from them.
The primary end point was a composite outcome of all-cause mortality or cardiovascular hospitalization. An echocardiography substudy that Dr. Zile published gives much insight, more than we had in the past, on the pathophysiology of HFpEF.25
There were no patients in whom EF was <45%. In the 2 trials that did not allow patients with EF < 45% (PEP and I-PRESERVE), the Kaplan–Meier event curves did not separate much (ie, there were no major differences in outcomes).
Those are the trials that have been completed, and from which we’ve derived most of our current data. Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure (TOPCAT), a National Institute of Health-sponsored randomized controlled trial of spironolactone versus placebo in HFpEF,26 has clearly finished enrollment, but the results are not yet available. TOPCAT was originally designed to enroll 4500 patients, but could not reach that total because of challenges in the identification and recruitment of patients with HFpEF. The criteria for TOPCAT enrollment were age ≥50 years; EF ≥45%, as measured within 6 months of enrollment; signs and symptoms of HF; control of blood pressure at the time of study enrollment, despite the fact that the vast majority of patients had a history of hypertension and most other trials did not share this inclusion criterion; and, to ensure adequate event rates, at least one other high-risk HF feature, including hospitalization for HF within the past year and/or elevated levels of brain natriuretic peptides, either B-type natriuretic peptide (BNP) or N-terminal BNP.
Many of us thought that spironolactone might be an ideal drug because fibrosis, which spironolactone can at least reduce, if not prevent, is a major problem in some HFpEF patients.27 The composite primary end point in TOPCAT was cardiovascular death, aborted cardiac arrest, and hospitalization for HF management. The TOPCAT results are projected to be available in mid-2013.
So, what’s the conclusion? Do we know how to treat this entity? The answer in my mind is not yet, but we can prevent it, which would be my approach until we come up with a magic bullet to treat it. Most of these patients have hypertension, and many binge on salt, which is one of the reasons they have hypertension; obesity and diabetes seem to play a role to some degree as well. At this point, we don’t have any definitive answers about therapy.
DR. SHAH: I would like to first comment on something alluded to earlier: prevention of HFpEF is key. This concept cannot be overemphasized. Two trials worth mentioning with regard to prevention of HFpEF are the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) and the Hypertension in the Very Elderly Trial (HYVET). Using data from ALLHAT, Davis and colleagues found that in terms of preventing HFpEF in hypertensive patients, chlorthalidone was superior to other antihypertensive medications, including ACE inhibitors and calcium channel blockers.28
In HYVET, indapamide, a thiazide-like diuretic, either with or without perindopril was found to be very effective in preventing HF hospitalization in patients aged >80 years. Although EF was not documented in HYVET, HFpEF is the predominant form of HF in the elderly; thus, it is likely that indapamide reduced hospitalization for HFpEF in that trial.29
Both ALLHAT and HYVET are important because they show that HFpEF can be prevented in hypertensive individuals. Some may argue that diuretics had an unfair advantage in both trials; namely, that HF hospitalization diagnosis was in part due to fluid overload, which diuretics treat and prevent. However, regardless of the mechanism of benefit, the results of these trials clearly show that HFpEF hospitalization can be prevented. Given the high rates of morbidity and mortality after HFpEF hospitalization, prevention by any means is critical.3,30
Although HFpEF can be prevented, we still have the challenge of managing the millions of patients suffering from HFpEF syndrome. In 2007, we founded a dedicated HFpEF program here at Northwestern University. Our reasons for doing so included the heterogeneity and diverse etiology and pathophysiology of the patient population; the lack of both a classification system and treatments for HFpEF; and as Dr. Zile mentioned, the difficulty in diagnosing HFpEF. Unlike HFrEF, we can’t use a simple EF indicator (ie, low EF) to make a diagnosis. Therefore, we need to be more systematic about identifying these patients and recruiting them into our clinical and research HFpEF program.
Between 2007 and 2012 we enrolled >750 patients into our program and have since been able to collect comprehensive data on 430 of these patients. We created a systematic algorithm for patient identification, focusing on inpatients because, as stated earlier, these are the patients at highest risk. We perform a daily query of the inpatient electronic medical records using one or more of the following criteria: the word “heart failure” in the hospital notes, or BNP > 100 pg/mL, or administration of 2 or more doses of intravenous diuretics. This gives us a long list of patients on a daily basis that we trim down by excluding all those with EF < 50%. We then have a study coordinator review all the remaining charts to identify patients who meet the Framingham criteria for HF and then offer these patients postdischarge follow-up in the HFpEF clinic.
For those who decide to come to our clinic after hospitalization, we confirm the HFpEF diagnosis based on much of the criteria that Dr. Zile mentioned. We also exclude some patients, such as those with a prior history of reduced EF (<40%), severe valvular disease, or prior history of cardiac transplant. We then enroll the remaining patients into our registry. We perform physical examination, electrocardiography, laboratory testing, and echocardiography in all patients, and arterial tonometry, pulmonary function testing, and cardiopulmonary exercise testing, as well as overnight polysomnography in a subset of patients. We try to have all patients undergo cardiac catheterization because we want to exclude CAD and invasively confirm elevated LV filling pressures. This is especially important in patients who have signs and symptoms of HF but whose echocardiography results are equivocal for diastolic dysfunction and BNP < 100 pg/mL.
Importantly, we try to enroll every patient in a clinical trial. We were quite successful with that regard with the current TOPCAT, for which, as the leading enroller in the United States, we enrolled 77 patients. Clinical trial enrollment for HFpEF has been very challenging, and we believe that dedicated HFpEF programs will be critical for enhancing enrollment in HFpEF studies. Finally, after conducting initial confirmation of HFpEF diagnosis, baseline testing, and consideration for clinical trial enrollment, we follow patients every 3 to 6 months (or sooner as needed) to manage their HFpEF.
Our patients are younger by about 10 years as compared to those who have participated in the observational studies and clinical trials, such as I-PRESERVE, likely because elderly patients tend to not want to change doctors or have to see a new cardiologist, so elect not to enroll in our program. However, I also think that we identify patients at a younger age. We’re seeing younger patients with morbid obesity and diabetes and/or metabolic syndrome who are developing HFpEF. In our urban Chicago area, we have a diverse mix of ethnicity and races, and approximately 40% of the patient population is African-American, which is much higher than that in prior observational studies and clinical trials. Finally, as expected, comorbidities are quite common in patients in our HFpEF program, and the body mass index of our patients is much higher than that of patients in prior studies (mean body mass index, 33 kg/m2).
Analysis of data collected from patients enrolled in our HFpEF program confirmed that they met the objective criteria for HFpEF syndrome.31 Despite enrolling after HF hospitalization, during which they underwent intensive diuresis, they have remained quite symptomatic, with 49% continuing to have New York Heart Association Functional Classification (NYHA) Class III or IV symptoms. Furthermore, EF in our cohort is preserved (mean EF 61±7%), LV end-diastolic volume index is normal (41±12 mL/m2), and the majority have evidence of moderate or greater diastolic dysfunction (72% with grade 2 or 3 diastolic dysfunction and 79% with echocardiographic evidence of elevated LV end-diastolic pressure or PCWP). On invasive hemodynamic testing, mean PCWP was 23 mm Hg, which is quite high, considering that they had already undergone intravenous diuresis in the hospital. Thus, patients enrolled in our HFpEF program meet the objective criteria for HFpEF and despite treatment, remain quite symptomatic and fluid overloaded.
Drs. Zile and Massie described how we diagnose these patients and the lack of clinical trial data that we can refer to when treating these patients. These facts are important to know, but clinicians who treat these patients still need a roadmap for the major steps in diagnosis and treatment of HFpEF. The first step is to accurately diagnose the HFpEF syndrome (given its high prevalence, clinicians should have a low threshold to suspect the diagnosis in the dyspneic patient). Despite the limited data regarding BNP levels in diagnosis of HFpEF, clinicians often use levels of natriuretic peptides in diagnosis. When we systematically analyzed BNP levels in the patients in our program, we found that in up to 30% with confirmed HFpEF (ie, elevated PCWP and preserved EF), BNP level was normal (<100 pg/mL).32 Thus, a normal BNP level does not exclude a diagnosis of HFpEF syndrome.
When in doubt about HFpEF diagnosis, we perform cardiac catheterization for confirmation. While invasive hemodynamic testing is not necessary for all patients, it’s preferable to identify and diagnose HFpEF than miss it. We also routinely and systematically evaluate patients for CAD through stress testing and coronary angiography when possible, because multi-vessel CAD can mimic HFpEF, and treatment of CAD can provide symptomatic benefit.
The second step is to identify, target, and treat the underlying cause of HFpEF, an important part of our therapeutic strategy for the individual patient. Although HFpEF is very common and most commonly caused by standard comorbidities like hypertension, obesity, diabetes, CAD, and chronic kidney disease, we approach each patient as a unique case until proven otherwise. We must ensure that we don’t fail to detect constrictive pericarditis or infiltrative cardiomyopathy, which, although rarely causes HFpEF, requires treatment that differs significantly from that provided for HFpEF caused by more common conditions. Here, close examination of the echocardiogram can be very helpful. For example, on tissue Doppler imaging of the lateral mitral annulus, severe reduction in longitudinal systolic velocity (s′) and early diastolic velocity (e′) with preserved global EF suggests the possibility of infiltrative cardiomyopathy, especially in the setting of increased wall thickness and a low voltage electrocardiogram. On the other hand, a normal or exaggerated e′ velocity, despite a mitral inflow pattern, suggestive of significant diastolic dysfunction, can be a sign of constrictive pericarditis, especially if there are additional echocardiographic signs such as increased respiratory variation in the mitral inflow, diastolic septal bounce, or increased hepatic vein diastolic flow reversal during expiration.
Step 3 is, as stated in the HF guidelines, to treat HF by controlling blood pressure and treat fluid overload using diuretics. In terms of pharmacotherapy, I like to prescribe carvedilol, bumetanide, chlorthalidone, lisinopril, and spironolactone. As Dr. Massie just mentioned, we don’t have great data for any of these medications, but given the wide availability of generic forms of these agents and the use of many in the treatment of comorbidities common in HFpEF patients, they are affordable and effective options for the treatment of hypertension and fluid overload in these patients.
Step 4 is to aggressively treat comorbidities, which is a major reason for the high rate of morbidity of mortality in HFpEF patients. More than 90% of patients with HFpEF have hypertension, CAD, diabetes, and/or chronic kidney disease, and many have sleep-disordered breathing and chronic pulmonary obstructive disease.33,34 Thus, HFpEF patients are not treated just by treating their HF; we really need to treat the whole patient and work with our colleagues in internal medicine, geriatrics, and other subspecialties to provide holistic care.
Step 5 is to provide a structured program of exercise training. A recent meta-analysis on and several high-quality smaller studies have found that exercise training is beneficial in HFpEF.35–39
Step 6 is to provide HF education to our patients. In an analysis of data from the Mid-Michigan Guidelines Applied in Practice–Heart Failure (GAP-HF) trial, Hummel and colleagues found that HFpEF patients are less likely to receive appropriate discharge instructions than patients with HFrEF.40 Although the Get with the Guidelines–Heart Failure (GWTG-HF) study found that while discharge instructions for HFpEF patients have improved over time, they are still inadequate.4 Thus, HFpEF patients need better education at discharge regarding salt restriction and fluid management.
Step 7 is to group HFpEF patients into categories, given the heterogeneity of HFpEF syndrome. The first category is what we call "garden-variety" HFpEF patients, who are typically hypertensive and obese, may or may not have diabetes, and often have chronic kidney disease. In these patients, we treat the underlying hypertension and focus on weight loss and control of diabetes, if present.
The next subgroup is HFpEF patients in whom CAD is the primary driver of HFpEF. While we need better data on how to treat these patients, based on their pathophysiology (worse biventricular longitudinal systolic function) and my anecdotal experience, I treat them like HFrEF patients, with beta blockers, renin-angiotensin-aldosterone system (RAAS) antagonists, statins, and revascularization, which are often indicated for the treatment of CAD.
The next subgroup is HFpEF patients with atrial arrhythmia and few other comorbidities. These patients, who often have normal or easily controlled blood pressure and experience episodes of tachyarrhythmia that exacerbate HF, appear to be suffering from HFpEF due to the underlying atrial arrhythmia. In these patients, I attempt to maintain normal sinus rhythm, especially if they are less symptomatic and less fluid overloaded when in a normal sinus rhythm.
Some patients with HFpEF have predominantly right ventricular (RV) HF symptoms. These are patients with high pulmonary artery pressure and RV dysfunction on echocardiography in the setting of elevated LV end-diastolic pressure and clear LV diastolic dysfunction. The management of these patients is often challenging. As RV dysfunction worsens, significant tricuspid regurgitation occurs often, cardiac output decreases, and systemic pressures decline. The resultant severe central venous congestion can lead to “congestive nephropathy,” while renal function worsens, leading to even more fluid overload. In these patients, intensive diuresis (or ultrafiltration when needed), spironolactone, and digoxin can be helpful. If systemic hypotension limits adequate diuresis, we treat patients with midodrine. In patients with HFpEF with significant RV dysfunction and elevated pulmonary artery pressure, especially those with pulmonary arterial hypertension superimposed on pulmonary venous hypertension (defined as a PA diastolic pressure-PCWP gradient > 5 mmHg), sildenafil may be beneficial.41
Another group of patients includes those with HFpEF in the setting of cardiac structural and functional changes that mimic hypertrophic cardiomyopathy. These are elderly patients with long-standing hypertension whose echocardiographic findings are indistinguishable from hypertrophic cardiomyopathy. I therefore treat them by focusing on negative inotropes such as long-acting metoprolol, diltiazem, or verapamil and avoiding aggressive diuresis, which can result in LV outflow tract or intracavitary obstruction.
There are a few additional subgroups of HFpEF patients. Some patients have HFpEF associated with a high-output state, such as those with end-stage liver disease, hyperthyroidism, arteriovenous fistulas, or severe anemia. Enlargement of all 4 cardiac chambers is a clue to this diagnosis. In these cases, we treat the underlying cause and use diuretics as a mainstay. Some patients have multivalvular HFpEF, and in such patients, having moderate disease of multiple valves presents a treatment challenge. These patients often do not meet the criteria for valve replacement or repair, but develop moderate valvular lesions, which, combined with other risk factors for HFpEF, lead to symptomatic HF. Finally, there are patients with HFpEF caused by rare conditions such as infiltrative cardiomyopathies and constrictive pericarditis. I treat the underlying cause in these patients and enroll them in a clinical trial, if possible.
I’ll conclude by touching on beta-blocker therapy in HFpEF. There have been multiple observational studies and some clinical trials of this topic, including the Study of Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure (SENIORS),42 which studied nebivolol, a vasodilating beta blocker. When considering beta-blocker use in HFpEF, there are several key points to remember. We know that some patients with HFpEF have chronotropic incompetence, which underlies their inability to increase cardiac output with exercise.43,44 In these patients, beta-blocker therapy could be harmful. However, observational studies of HFpEF have shown that beta blockers are associated with better outcomes in HFpEF patients.
What’s key here is that if a beta blocker is going to be used, it should be a vasodilating beta blocker, and that’s why I like carvedilol; it acts as a potent blood pressure-lowering agent due to its vasodilating properties. In the Coreg Heart Failure Registry (COHERE), registry led by Dr. Massie, carvedilol was found to be associated with better outcomes in HF, regardless of the underlying EF.45 This study was limited by its observational design, but nevertheless indicates some potential benefit.
The last point I’ll mention on beta blockers in HFpEF is that it is important to differentiate not only the patients with chronotropic incompetence but also those with severe diastolic dysfunction and restricted filling on echocardiography—patients who have evidence of a restrictive cardiomyopathy. These patients are typically very sensitive to any rate-controlling agents because stroke volume is fixed, and they rely on increasing heart rate with exercise in order to augment cardiac output. In these patients, in particular, I am very hesitant about using beta blockers unless they have an atrial arrhythmia that results in high heart rates and worsening HF. In patients with a hypertrophic cardiomyopathy-like phenotype, on the other hand, who need adequate diastolic filling time and atrial kick, I find beta blockers very helpful. These are just anecdotal observations, but I’ve found them to be helpful.
I’ll conclude by stating that right now I agree with Dr. Massie that we don’t have good clinical trial data, but it’s clear that the next 5 to 10 years will be an exciting time in which we’re likely to reinvent our knowledge about HFpEF and the clinical management of this syndrome.
DR. MASSIE: Dr. Shah, have you had to send anybody with HFpEF for transplantation?
DR. SHAH: In my practice, we have considered cardiac transplantation in cases of severe restrictive cardiomyopathy.
DR. MASSIE: What about patients with amyloid-type cardiomyopathy?
DR. SHAH: Yes, cardiac amyloidosis, and those with idiopathic restrictive cardiomyopathy. Typically, these are the patients with restrictive cardiomyopathy that develop end-stage HF. Patients with “garden-variety” HFpEF typically don’t develop severe enough end-stage HF to warrant cardiac transplantation, and their advanced age and multiple comorbidities often preclude consideration for transplant. Patients with restrictive cardiomyopathy represent a difficult challenge in the current era of cardiac transplantation. These patients typically have small ventricular volumes and are therefore not good candidates for mechanical circulatory support. However, because of a preserved EF, inotropes are not helpful in most of these patients. Thus, they often wait on the transplant list for quite some time and get bypassed by HFrEF patients who have a 1B or 1A status in the setting of ventricular assist devices. Finally, in patients with primary (AL) cardiac amyloidosis some advocate cardiac transplant,46 but it has been our practice to use chemotherapy followed by autologous stem-cell transplantation for these types of patients, provided that we can get patients close to euvolemia and control their HF symptoms.
DR. ZILE: I have had patients with hypertrophic cardiomyopathy with a normal EF who have had very low myocardial peak VO2 values, ie, myocardial VO2 values significantly less than 14 mL/kg/min, who have gone in for transplantation. I suppose that there are some patients with valvular heart disease for whom, if they’re young enough, one could consider transplantation as well, if they’re not candidates for surgical replacement.
I’d like to talk about a couple of other issues that Dr. Shah’s comments have raised. One is the use of implantable hemodynamic monitors in this group of patients. The second is the use of device therapy for the treatment of hypertension, particularly resistant hypertension. Dr. Shah’s comment regarding the variety of diuretics that he uses in his incredibly well-developed clinic brings to mind 2 concepts. One is that the reason why diuretics reduce HF hospitalization is, in fact, the judicious use of small changes in dose. Small but judicious increases and decreases can not only acutely but chronically lower filling pressure. This has been demonstrated in at least 3 studies—Chronicle Offers Management to Patients With Advanced Signs and Symptoms of Heart Failure (COMPASS-HF),47 CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Patients (CHAMPION),48 and Home Self-Therapy in Severe Heart Failure Patients (HOMEOSTASIS).49
In addition, HOMEOSTASIS and its ongoing follow-up study, Left Atrial Pressure Monitoring to Optimize Heart Failure Therapy (LAPTOP-HF),50 not only demonstrated that it is important to lower pressure by making small and judicious changes in diuretic dose but also showed that every time we increase diuretic dose, we also increase activation of the sympathetic nervous system or the RAAS. When the diuretic dosage is increased, it should be accompanied by uptitration of sympathetic antagonist beta blockers and RAAS antagonists, if possible.
The only clinical trial that I know that demonstrated a clear statistically significant reduction in HF hospitalizations in this group of patients is CHAMPION, which achieved a very large reduction in HF hospitalization—one virtually unheard of in any other trial—by maintaining low filling pressures by the therapeutic interventions that I’ve just mentioned.
DR. SHAH: I was very impressed by CHAMPION—it’s exactly what we see clinically with these patients. For example, I’m continually amazed at the close relationship between dietary indiscretion and worsening HF. Another such example is that fact that around the Thanksgiving holiday, many of my patients with HFpEF will develop significant volume overload, often necessitating hospitalization for HF exacerbation. Dietary indiscretion and medication noncompliance inevitably lead to a sudden rise in filling pressures. If we could implant an implantable monitor in these patients, we would have the ability to preemptively strike and give them an increased dose, thereby improving their outcomes.
I also agree with being judicious, especially with loop diuretics, so that we don’t trigger the intense sympathetic response. I teach our cardiology fellows that while we treat with diuretics because they’re very effective in controlling symptoms, we try to find the minimal dose to keep patients euvolemic and thereby limit the degree of sympathetic discharge.
DR. ZILE: To follow-up on your comments, in CHAMPION and HOMEOSTASIS, in an average 7-day week, changes in medications for diuretics—and I should also mention long-acting nitrates—were made on about 5 of the 7 days, but the changes were very small. For example, small changes were made in furosemide dose, from 20 to 30 mg or from 30 to 40 mg (eg, ±10 mg/day), but produced significant long-term falls in filling pressure.
The other topic that I think we should mention is that new devices that are being used to treat resistant hypertension, which is important from the point of view of prevention and the treatment of hypertension. There’s no question that if you could achieve regression of LV hypertrophy in hypertensive HFpEF patients with LV hypertrophy, you could markedly decrease both morbidity and mortality.
This can be accomplished with renal artery denervation (RAD) through a transcatheter approach. The Renal Denervation in Patients With Uncontrolled Hypertension (Symplicity HTN-2) study showed that RAD could markedly decrease LV mass, as evidenced by a 13% reduction in LV mass 1 month and a 17% decrease in LV mass 6 months after RAD,51 and significantly increase percentages higher than those obtained with the pharmacologic interventions we’ve used in hypertension trials to cause regression of LV hypertrophy.
In addition to RAD, there’s also carotid sinus stimulation, vagal nerve stimulation, and spinal cord stimulation, which are being examined.
DR. MASSIE: I’m certainly impressed with the renal sympathetic nerve ablation data, which I think a group in London is acting upon by doing a trial on HFpEF patients. I think hypertension is at the core of this. Frankly, it’s people’s behavioral patterns that make that the case. So, if you ablate the renal sympathetic nerves, the patient probably can’t overcome that and consequently benefit from it.
I think renal sympathetic nerve ablation is something that’s probably here to stay. I haven’t been as impressed with carotid sinus stimulation, compared with the renal sympathetic nerve denervation. I think it’s time to have a laboratory to gather a working group to study HFpEF and probably take on some further trials with some of the promising therapies.
DR. SHAH: I’d like to mention a few additional aspects of HFpEF. One is the role of pulmonary hypertension in HFpEF and the use of phosphodiesterase type 5 (PDE5) inhibitors, and the other is the utility of ranolazine in HFpEF.
Data from Olmsted County, Minnesota, indicate that pulmonary hypertension, defined as elevated pulmonary artery systolic pressure on echocardiography, is very common in HFpEF.52 In addition, elevated pulmonary artery systolic pressure was found to be the best echocardiographic sign differentiating patients with HFpEF from patients with hypertension without HF.52 The high prevalence of pulmonary hypertension in HFpEF makes sense—high left atrial pressure at rest or with exercise, which is nearly universal in HFpEF, leads to passive elevation of pulmonary venous pressures and thus, pulmonary hypertension. In addition, akin to systolic systemic hypertension of the elderly, patients with HFpEF have systolic pulmonary hypertension, ie, they have disproportionate elevation of pulmonary artery systolic pressure and high pulmonary artery pulse pressure.
What’s not clear, as I stated earlier, is why some patients with HFpEF further develop an elevated pulmonary vascular resistance or a more reactive form of pulmonary hypertension. Whether the presence of superimposed pulmonary arterial hypertension or pulmonary arterial remodeling is due to comorbidities that cause pulmonary arterial hypertension, HF duration and severity of left atrial pressure elevation, or genetic factors is also unknown.
Regardless of the cause of superimposed (reactive) pulmonary arterial hypertension in HFpEF, it seems to be relatively uncommon in this patient population. RV dysfunction, however, is relatively common,53 and PDE5 inhibitors may have a role in either reactive pulmonary arterial hypertension or RV dysfunction in HFpEF, as demonstrated by Guazzi et al. in the aforementioned small clinical trial of sildenafil in such patients.41
The Evaluating the Effectiveness of Sildenafil at Improving Health Outcomes and Exercise Ability in People With Diastolic Heart Failure (RELAX) trial is a National Heart, Lung, and Blood Institute study that did not look at pulmonary hypertension specifically in HFpEF but rather, a broad spectrum of HFpEF patients. The idea behind RELAX was that PDE5 inhibitors have lusitropic myocardial effects that may improve diastolic function and are therefore useful simply on the basis of their action as vasodilators in HFpEF. However, the RELAX trial did not show any benefit to PDE5 inhibition in HFpEF patients without superimposed pulmonary arterial hypertension.54
Along with the PDE5 inhibitors, ranolazine, a late inward sodium channel (I[Na+]) inhibitor that seems to exert anti-ischemic effects in chronic stable angina by increasing myocardial relaxation, may be beneficial in patients with HFpEF. By blocking the late I[Na+] current, which is augmented in HF, there is less sodium in the myocyte, which results in less calcium in the myocyte during systole. Therefore, there is less postsystolic contraction of the myocyte, improved calcium handling, and better myocyte relaxation. Unfortunately, ranolazine did not demonstrate significant benefit in the Ranolazine for the Treatment of Diastolic Heart Failure (RALI-DHF) study, which was a small proof-of-concept HFpEF trial.55,56
DR. MASSIE: I think this has been a great discussion. The two of you come at HFpEF from somewhat different perspectives, but the consensus is that it’s a big problem and remains one of the most challenging problems in clinical cardiology. We need to continue to work to identify HFpEF patients and enroll them in clinical trials so that we can advance our knowledge in this patient population and find new targeted therapies for this patient population. Let’s hope some of these things that people are beginning to work with are successful.
UPDATE
The baseline clinical and echocardiographic characteristics of the TOPCAT trial have been published,57,58 providing insight into the 3445 patients with symptomatic heart failure with preserved ejection fraction (HFpEF) who were enrolled. Patients enrolled in the TOPCAT trial were similar to those in other HFpEF clinical trials and registries: the patients were older, more often female, and had a high prevalence of hypertension (91%). Baseline blood pressure, however, was well controlled (129/76 mm Hg; 7–16 mm Hg lower than that in other HFpEF clinical trials). Comorbidities were common, and quality life was poor (similar to end-stage renal disease). Structural heart disease was common in the TOPCAT trial, with a high prevalence of concentric left ventricular remodeling or hypertrophy and frequent left atrial enlargement. In November 2013, the results of the TOPCAT trial were presented at the American Heart Association Scientific Sessions. The TOPCAT trial failed to meet the primary combined endpoint of reducing cardiovascular mortality, aborted cardiac arrest, or HF hospitalization (hazard ratio [HR], 0.89; 95% confidence interval [CI], 0.77–1.04]; P = 0.14). Although spironolactone treatment did decrease HF hospitalization (HR, 0.83; 95% CI, 0.69–0.99; P = 0.042), all-cause hospitalizations did not differ among the treatment groups.
In a prespecified subgroup analysis based on the enrollment criteria, there was a statistically significant reduction in the primary endpoint in patients who entered the trial based on elevated natriuretic peptide levels (brain natriuretic peptide or N-terminal pro-brain natriuretic peptide). There was no difference in the primary endpoint for those patients who entered the trial based on prior history of HF hospitalization. Further exploration into the apparent dichotomy in the results, based on the enrollment criteria, revealed that there were major differences in the event rates in the Americas (United States, Canada, Brazil, and Argentina, where event rates were high [31.8%], similar to prior epidemiologic and observational studies) compared to Eastern Europe (Russia and the Republic of Georgia, where event rates were very low [8.4%]). A post-hoc analysis demonstrated that spironolactone treatment was beneficial in the Americas (HR, 0.82; 95% CI, 0.69–0.98 for the primary endpoint), but not in Eastern Europe. Furthermore, the majority of patients who entered the study based on the more objective natriuretic peptide criteria were from the Americas. These data demonstrate the importance of diagnosing HFpEF accurately (patients in Eastern Europe may not have had the HFpEF syndrome), and show that there may be patients with HFpEF, especially those with elevated natriuretic peptide levels, who would truly benefit from mineralocorticoid receptor antagonism.
Importantly, while hyperkalemia was more common in the TOPCAT trial patients treated with spironolactone (18.7% vs. 9.1%, respectively; P < 0.001), hypokalemia was less common in the spironolactone arm (16.2% vs. 22.9%, respectively), and there were no hyperkalemia-related deaths. Thus, if clinicians choose to use spironolactone to treat HFpEF, they should follow the TOPCAT trial guidelines for checking potassium levels and renal function at 1 week as well as at 30 days after starting spironolactone treatment, to prevent adverse events due to hyperkalemia. —Sanjiv J. Shah, MD, Northwestern University Feinberg School of Medicine, Chicago, IL
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