Journal of Cardiac Failure Vol. 20 No. 10 2014
Editorial Comment
Heart Failure With Normal Ejection Fraction, Heart Failure With Preserved Ejection Fraction, Diastolic Heart Failure, or Huff-Puff: Time for a New Taxonomy for Hypertensive-Metabolic Heart Failure ALANNA A. MORRIS, MD,1 JAVED BUTLER, MD, MPH,1 AND MARVIN A. KONSTAM, MD2 Atlanta, Georgia; and Boston, Massachusetts
with HFpEF, and the one often implied when the term HFpEF is used, actually has no name. It occurs predominantly in the elderly and more often in women, with variable degrees of left ventricular hypertrophy, interstitial fibrosis, and vascular stiffening, and is associated with a history of hypertension, diabetes, and/or metabolic syndrome. Studies investigating patients with HFpEF have used varying enrollment criteria, probably resulting in some variability in the mix of underlying disease states. There is not even consensus on the EF cutoff to be used for excluding the common substrates of HF with reduced EF (HFrEF), ie, ischemic or nonischemic dilated cardiomyopathy. As a result, generalization of results and the specific application of conclusions to a particular disease state are challenging. This issue of enrollment variability has most likely limited the ability to test the efficacy of therapeutic interventions and has likely contributed to the neutral findings of several clinical trials. It is troubling that despite observational evidence suggesting that mortality rates for patients with HFpEF are similar to those with HFrEF1,2 (although they undoubtedly differ in different disease states), the only pharmacologic agents designated as class I therapy for patients with HF in the absence of reduced EF are diuretics to improve symptoms. No therapies have been documented to impact morbidity, mortality, or even symptoms for these patients.3,4 Our inability to identify treatments for this condition is most probably related to our lack of focus on differentiating the various disease states that contribute to the broad description of HFpEF. It is worth noting that the success of treatments in altering the natural history of patients with ischemic or idiopathic dilated cardiomyopathies stems from the impact of these treatments on the underlying disease state, not on its hemodynamic characteristics. A similar approach should be considered in diseases that present with HFpEF. Several criteria have been proposed to identify patients with HFpEF, as distinct from those with ischemic or
The clinical syndrome of heart failure (HF) manifests as fluid retention and symptomatic dyspnea and fatigue, usually resulting in exercise intolerance. This clinical syndrome in the presence of normal ejection fraction (EF) has represented a challenge to diagnosis and management. The terminology regarding this constellation has evolved and varied, including the terms ‘‘diastolic HF,’’ ‘‘HF with normal systolic function,’’ ‘‘HF with preserved EF (HFpEF),’’ and ‘‘HF with normal EF.’’ The latter 2 terms are preferable to the others, because they are purely descriptive, and do not imply a specific functional condition, since the measured EF relates at least as much to the manner in which the left ventricle has remodeled (with or without chamber enlargement) as it does to the systolic or diastolic functional characteristics of the myocardium. Regardless of the terminology, the constellation of clinical HF and preserved EF does not define a specific disease. Rather, there are a variety of diseases with which this constellation of findings may be associated, each with its own etiology, pathology, pathophysiology, hemodynamic characteristics, and prognosis. Among these are restrictiveinfiltrative diseases (eg, amyloidosis), restrictive-fibrotic diseases (eg, scleroderma), constrictive pericardial disease, genetically mediated hypertrophic cardiomyopathy, valvular heart disease, and primary or secondary pulmonary vascular diseases (often with elevated left atrial pressure via ventricular interdependence). The most common disease associated From the 1Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia and 2Cardiovascular Center, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts. Manuscript received August 15, 2014; revised manuscript accepted August 18, 2014. Reprint requests: Javed Butler, MD, MPH, Cardiology Division, Emory University Hospital, 1365 Clifton Road, NE, Suite AT430, Atlanta, GA 30322. Tel: 404 778-5273; Fax: 404 778-5285. E-mail: javed.butler@ emory.edu See page 780 for disclosure information. 1071-9164/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2014.08.007
779
780 Journal of Cardiac Failure Vol. 20 No. 10 October 2014 nonischemic dilated cardiomyopathies, including a) clinical signs or symptoms, b) evidence of preserved left ventricular (LV) EF, and c) evidence of abnormal LV diastolic function.3,5 These criteria are problematic because they do not address the underlying etiology or pathobiology. Evidence on echocardiography of preserved EF mostly confirms that the LV has not remodeled with longitudinal hypertrophy and cavity enlargement, but it tells us little about the state of myocardial contractility, diastolic function, or the nature of the underlying disease state. Furthermore, ‘‘preserved EF’’ does not distinguish patients who had previous HFrEF with subsequent myocardial recovery. The presence of diastolic dysfunction, as defined by echo-Doppler measurements, is important as a physiologic contributor to HF. However, it is neither the sole contributor to the clinical syndrome nor specific, because these changes are present in many asymptomatic elderly and/or hypertensive patients. Other physiologic parameters are increasingly recognized to contribute to symptom burden,6 including resting and exercise-exacerbated systolic dysfunction,7,8 impaired ventricular-vascular coupling,8,9 abnormal exerciseinduced and flow-mediated vasodilation,8,10 and pulmonary arterial hypertension.11 In this issue of the Journal, Houstis and Lewis revisit the approach to diagnosis in HFpEF by placing a greater emphasis on the role of exercise testing and the hemodynamic source of exercise intolerance. The authors reviewed 15 studies of patients with preserved EF, exercise intolerance, and either clinical or physiologic criteria for HF. Because the ability to identify the mechanism of exercise intolerance depends on how patients are selected, the authors performed an exhaustive review of the physiologic parameters that can be used for this purpose. They organized the contributors to exercise intolerance into classes based on the Fick equation for cardiac output calculation, scrutinizing 1) peak heart rate (HR), 2) peak stroke volume (SV), and 3) peak arterial-venous oxygen difference (AVO2) as contributors to decreased functional capacity in HFpEF. In addition, the authors examined non-Fick mechanisms that influence peak exercise capacity, including elevated LV filling pressure. The authors recommend identifying subgroups of HFpEF patients with a common underlying mechanism of symptoms, such as HFpEF with a low HR response to exercise (HFpEF-HR) or HFpEF with impaired sSV during exercise (HFpEF-SV). Though this classification is cumbersome to implement in practice, we agree in principle that subclassification of patients by the mechanisms that contribute most to symptom burden adds valuable information. The failure of clinical trials to show improvements in exercise tolerance or outcomes in HFpEF warrants continued investigation to determine whether a select subgroup may preferentially benefit from a particular treatment. Such subgroups may be defined based on exercise hemodynamics in the manner suggested by Houstis and Lewis. However, we believe that the main goal should be to define the underlying disease state. For ischemic and nonischemic dilated
cardiomyopathies, we long ago realized that the greatest patient benefit is derived from agents directed at slowing or reversing the underlying pathobiology, particularly pathologic hypertrophy associated with cardiac remodeling, rather than those directed at abnormal hemodynamics. The same thinking should be applied to other conditions not associated with LV chamber enlargement or reduced EF. Exercise hemodynamics may aid in this process but represent only one approach toward determining the underlying disease state. To accomplish the latter goal, additional tools should be developed and tested, such as novel biomarkers and novel imaging modalities. Particular attention should be given to the unnamed disease mentioned above, for which we propose the term hypertensive-metabolic heart failure. This condition is the most prevalent, and its cardiovascular and noncardiovascular sequelae account for much of the morbidity and mortality associated with HFpEF.12,13 HF is a major and growing health problem, and approximately one-half of the HF population has preserved EF. Without modifications to our current diagnostic algorithms directed toward advancing and informing the pathophysiologic targets, our treatments will likely continue to fail while the overall condition reaches epidemic proportions. Houstis and Lewis recommend exercise testing as a valuable component that could be added to the HFpEF workup, both to quantify functional capacity and to identify the causal factors driving symptoms. We think that such testing should be incorporated into a broader approach, including advanced biomarkers and imaging modalities, designed to best define the underlying disease state. It is imperative that we identify means to better characterize the underlying pathobiology, regardless of EF, so that we can determine treatment targets that might reduce the substantial burden of HF. Disclosures None.
References 1. Somaratne JB, Berry C, McMurray JJ, Poppe KK, Doughty RN, Whalley GA. The prognostic significance of heart failure with preserved left ventricular ejection fraction: a literature-based meta-analysis. Eur J Heart Fail 2009;11:855e62. 2. Meta-analysis Global Group in Chronic Heart Failure. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750e7. 3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:e240e327. 4. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, et al. Developing therapies for heart failure with preserved ejection
Editorial Comment
5. 6.
7.
8.
9.
fraction: current state and future directions. J Am Coll Cardiol 2014;2: 97e112. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118e21. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011;32: 670e9. Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease: insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 2009;54:410e8. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010;56: 845e54. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved
10.
11.
12.
13.
Morris et al
781
ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 2003;107:714e20. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588e95. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53:1119e26. Campbell RT, McMurray JJ. Comorbidities and differential diagnosis in heart failure with preserved ejection fraction. Heart Fail Clin 2014; 10:481e501. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998e1005.
Editorial Comment
Heart Failure With Normal Ejection Fraction, Heart Failure With Preserved Ejection Fraction, Diastolic Heart Failure, or Huff-Puff: Time for a New Taxonomy for Hypertensive-Metabolic Heart Failure ALANNA A. MORRIS, MD,1 JAVED BUTLER, MD, MPH,1 AND MARVIN A. KONSTAM, MD2 Atlanta, Georgia; and Boston, Massachusetts
with HFpEF, and the one often implied when the term HFpEF is used, actually has no name. It occurs predominantly in the elderly and more often in women, with variable degrees of left ventricular hypertrophy, interstitial fibrosis, and vascular stiffening, and is associated with a history of hypertension, diabetes, and/or metabolic syndrome. Studies investigating patients with HFpEF have used varying enrollment criteria, probably resulting in some variability in the mix of underlying disease states. There is not even consensus on the EF cutoff to be used for excluding the common substrates of HF with reduced EF (HFrEF), ie, ischemic or nonischemic dilated cardiomyopathy. As a result, generalization of results and the specific application of conclusions to a particular disease state are challenging. This issue of enrollment variability has most likely limited the ability to test the efficacy of therapeutic interventions and has likely contributed to the neutral findings of several clinical trials. It is troubling that despite observational evidence suggesting that mortality rates for patients with HFpEF are similar to those with HFrEF1,2 (although they undoubtedly differ in different disease states), the only pharmacologic agents designated as class I therapy for patients with HF in the absence of reduced EF are diuretics to improve symptoms. No therapies have been documented to impact morbidity, mortality, or even symptoms for these patients.3,4 Our inability to identify treatments for this condition is most probably related to our lack of focus on differentiating the various disease states that contribute to the broad description of HFpEF. It is worth noting that the success of treatments in altering the natural history of patients with ischemic or idiopathic dilated cardiomyopathies stems from the impact of these treatments on the underlying disease state, not on its hemodynamic characteristics. A similar approach should be considered in diseases that present with HFpEF. Several criteria have been proposed to identify patients with HFpEF, as distinct from those with ischemic or
The clinical syndrome of heart failure (HF) manifests as fluid retention and symptomatic dyspnea and fatigue, usually resulting in exercise intolerance. This clinical syndrome in the presence of normal ejection fraction (EF) has represented a challenge to diagnosis and management. The terminology regarding this constellation has evolved and varied, including the terms ‘‘diastolic HF,’’ ‘‘HF with normal systolic function,’’ ‘‘HF with preserved EF (HFpEF),’’ and ‘‘HF with normal EF.’’ The latter 2 terms are preferable to the others, because they are purely descriptive, and do not imply a specific functional condition, since the measured EF relates at least as much to the manner in which the left ventricle has remodeled (with or without chamber enlargement) as it does to the systolic or diastolic functional characteristics of the myocardium. Regardless of the terminology, the constellation of clinical HF and preserved EF does not define a specific disease. Rather, there are a variety of diseases with which this constellation of findings may be associated, each with its own etiology, pathology, pathophysiology, hemodynamic characteristics, and prognosis. Among these are restrictiveinfiltrative diseases (eg, amyloidosis), restrictive-fibrotic diseases (eg, scleroderma), constrictive pericardial disease, genetically mediated hypertrophic cardiomyopathy, valvular heart disease, and primary or secondary pulmonary vascular diseases (often with elevated left atrial pressure via ventricular interdependence). The most common disease associated From the 1Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia and 2Cardiovascular Center, Tufts Medical Center, Tufts University School of Medicine, Boston, Massachusetts. Manuscript received August 15, 2014; revised manuscript accepted August 18, 2014. Reprint requests: Javed Butler, MD, MPH, Cardiology Division, Emory University Hospital, 1365 Clifton Road, NE, Suite AT430, Atlanta, GA 30322. Tel: 404 778-5273; Fax: 404 778-5285. E-mail: javed.butler@ emory.edu See page 780 for disclosure information. 1071-9164/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cardfail.2014.08.007
779
780 Journal of Cardiac Failure Vol. 20 No. 10 October 2014 nonischemic dilated cardiomyopathies, including a) clinical signs or symptoms, b) evidence of preserved left ventricular (LV) EF, and c) evidence of abnormal LV diastolic function.3,5 These criteria are problematic because they do not address the underlying etiology or pathobiology. Evidence on echocardiography of preserved EF mostly confirms that the LV has not remodeled with longitudinal hypertrophy and cavity enlargement, but it tells us little about the state of myocardial contractility, diastolic function, or the nature of the underlying disease state. Furthermore, ‘‘preserved EF’’ does not distinguish patients who had previous HFrEF with subsequent myocardial recovery. The presence of diastolic dysfunction, as defined by echo-Doppler measurements, is important as a physiologic contributor to HF. However, it is neither the sole contributor to the clinical syndrome nor specific, because these changes are present in many asymptomatic elderly and/or hypertensive patients. Other physiologic parameters are increasingly recognized to contribute to symptom burden,6 including resting and exercise-exacerbated systolic dysfunction,7,8 impaired ventricular-vascular coupling,8,9 abnormal exerciseinduced and flow-mediated vasodilation,8,10 and pulmonary arterial hypertension.11 In this issue of the Journal, Houstis and Lewis revisit the approach to diagnosis in HFpEF by placing a greater emphasis on the role of exercise testing and the hemodynamic source of exercise intolerance. The authors reviewed 15 studies of patients with preserved EF, exercise intolerance, and either clinical or physiologic criteria for HF. Because the ability to identify the mechanism of exercise intolerance depends on how patients are selected, the authors performed an exhaustive review of the physiologic parameters that can be used for this purpose. They organized the contributors to exercise intolerance into classes based on the Fick equation for cardiac output calculation, scrutinizing 1) peak heart rate (HR), 2) peak stroke volume (SV), and 3) peak arterial-venous oxygen difference (AVO2) as contributors to decreased functional capacity in HFpEF. In addition, the authors examined non-Fick mechanisms that influence peak exercise capacity, including elevated LV filling pressure. The authors recommend identifying subgroups of HFpEF patients with a common underlying mechanism of symptoms, such as HFpEF with a low HR response to exercise (HFpEF-HR) or HFpEF with impaired sSV during exercise (HFpEF-SV). Though this classification is cumbersome to implement in practice, we agree in principle that subclassification of patients by the mechanisms that contribute most to symptom burden adds valuable information. The failure of clinical trials to show improvements in exercise tolerance or outcomes in HFpEF warrants continued investigation to determine whether a select subgroup may preferentially benefit from a particular treatment. Such subgroups may be defined based on exercise hemodynamics in the manner suggested by Houstis and Lewis. However, we believe that the main goal should be to define the underlying disease state. For ischemic and nonischemic dilated
cardiomyopathies, we long ago realized that the greatest patient benefit is derived from agents directed at slowing or reversing the underlying pathobiology, particularly pathologic hypertrophy associated with cardiac remodeling, rather than those directed at abnormal hemodynamics. The same thinking should be applied to other conditions not associated with LV chamber enlargement or reduced EF. Exercise hemodynamics may aid in this process but represent only one approach toward determining the underlying disease state. To accomplish the latter goal, additional tools should be developed and tested, such as novel biomarkers and novel imaging modalities. Particular attention should be given to the unnamed disease mentioned above, for which we propose the term hypertensive-metabolic heart failure. This condition is the most prevalent, and its cardiovascular and noncardiovascular sequelae account for much of the morbidity and mortality associated with HFpEF.12,13 HF is a major and growing health problem, and approximately one-half of the HF population has preserved EF. Without modifications to our current diagnostic algorithms directed toward advancing and informing the pathophysiologic targets, our treatments will likely continue to fail while the overall condition reaches epidemic proportions. Houstis and Lewis recommend exercise testing as a valuable component that could be added to the HFpEF workup, both to quantify functional capacity and to identify the causal factors driving symptoms. We think that such testing should be incorporated into a broader approach, including advanced biomarkers and imaging modalities, designed to best define the underlying disease state. It is imperative that we identify means to better characterize the underlying pathobiology, regardless of EF, so that we can determine treatment targets that might reduce the substantial burden of HF. Disclosures None.
References 1. Somaratne JB, Berry C, McMurray JJ, Poppe KK, Doughty RN, Whalley GA. The prognostic significance of heart failure with preserved left ventricular ejection fraction: a literature-based meta-analysis. Eur J Heart Fail 2009;11:855e62. 2. Meta-analysis Global Group in Chronic Heart Failure. The survival of patients with heart failure with preserved or reduced left ventricular ejection fraction: an individual patient data meta-analysis. Eur Heart J 2012;33:1750e7. 3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2013;128:e240e327. 4. Butler J, Fonarow GC, Zile MR, Lam CS, Roessig L, Schelbert EB, et al. Developing therapies for heart failure with preserved ejection
Editorial Comment
5. 6.
7.
8.
9.
fraction: current state and future directions. J Am Coll Cardiol 2014;2: 97e112. Vasan RS, Levy D. Defining diastolic heart failure: a call for standardized diagnostic criteria. Circulation 2000;101:2118e21. Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment. Eur Heart J 2011;32: 670e9. Borlaug BA, Lam CS, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease: insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol 2009;54:410e8. Borlaug BA, Olson TP, Lam CS, Flood KS, Lerman A, Johnson BD, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010;56: 845e54. Kawaguchi M, Hay I, Fetics B, Kass DA. Combined ventricular systolic and arterial stiffening in patients with heart failure and preserved
10.
11.
12.
13.
Morris et al
781
ejection fraction: implications for systolic and diastolic reserve limitations. Circulation 2003;107:714e20. Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588e95. Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol 2009; 53:1119e26. Campbell RT, McMurray JJ. Comorbidities and differential diagnosis in heart failure with preserved ejection fraction. Heart Fail Clin 2014; 10:481e501. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, Zachariah AA, et al. Impact of noncardiac comorbidities on morbidity and mortality in a predominantly male population with heart failure and preserved versus reduced ejection fraction. J Am Coll Cardiol 2012;59:998e1005.
![[Heart failure with preserved ejection fraction (HFpEF)].](/assets/img/hold.png)
