Journal of the American College of Cardiology Vol. 63, No. 5, 2014� 2014 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jacc.2013.10.007

EDITORIAL COMMENT

Heart Failure WithPreserved Ejection Fraction

A Heterogenous Disorder WithMultifactorial Pathophysiology*

Dalane W. Kitzman, MD, Bharathi Upadhya, MD

Winston-Salem, North Carolina

Heart failure (HF) with preserved ejection fraction(HFpEF) is the most common form of HF in the pop-ulation (1). Among elderly women living in the community,HFpEF comprises nearly 90% of incident HF cases (2).Furthermore, HFpEF is increasing out of proportion toHF with reduced EF (HFrEF), and its prognosis is wors-ening while that of HFrEF is improving (3). The healthand economic impact of HFpEF is at least as great as thatof HFrEF, with similar severity of chronic exercise intoler-ance (4), acute hospitalization rates (3,5), and substantialmortality (3).

See page 447

Despite the importance of HFpEF, our understanding ofits pathophysiology is incomplete, and optimal treatmentremains largely undefined. Originally thought to be purelydue to left ventricular (LV) diastolic dysfunction (hence thenow-discarded misnomer “diastolic HF”), it is now obviousthat HFpEF is much more complex. Findings to date in-dicate important contributions from aging (6,7), neuroendo-crine dysfunction (4,8), inflammation (9,10), LV systolicdysfunction (11,12) right ventricular dysfunction (13), chro-notropic incompetence (14), autonomic dysfunction (15),vascular dysfunction (15–17), pulmonary and renal dysfunction(1,2,18), skeletal muscle dysfunction (19–21), and multiplecomorbidities (22) including obesity, hypertension, atrialfibrillation, and anemia. Although this complexity presentschallenges, it also presents opportunities for advancing ourunderstanding and provides potentially novel therapeutic

*Editorials published in the Journal of the American College of Cardiology reflect the

views of the authors and do not necessarily represent the views of JACC or the

American College of Cardiology.

From the Sections on Cardiology and Geriatrics, Department of Internal Medicine,

Wake Forest School of Medicine, Winston-Salem, North Carolina. Supported in

part by National Institutes of Health grants R37AG18915 and P30AG021332.

Dr. Kitzman is a consultant for Relypsa Inc., Boston Scientific, Abbott, Servier,

AbbVie, Icon, Forest, and GlaxoSmithKline; has received grant support from

Novartis; and owns stock in Gilead Sciences. Dr. Upadhya has reported that she has

relationships relevant to the contents of this paper to disclose.

targets. Such should be welcomed because the agents tested intrials to date, which were based upon our previous, simplisticassumptions, have not been positive.

The results of the exemplary study by Kraigher-Kraineret al. (12) reported in this issue of the Journal provide addi-tional strong support for the concepts of phenotypic hetero-geneity and multifactorial contributions in the HFpEFsyndrome. Their well-designed, well-conducted ancillarystudy utilized a standardized protocol with state-of-the art,detailed echo-Doppler measures of cardiac structure andfunction, formal training of sonographers at 65 field sites,and expert, blinded quantitative image analysis, all orches-trated by a highly experienced echocardiographic core labo-ratory (12). Systolic function was assessed as longitudinaland circumferential strain by deformation analysis using2-dimensional digital echocardiography speckle-tracking.This method has advantages over tissue Doppler strainmethods and is more amenable to multisite trials involvingmultiple ultrasonographic instrument vendors. The investi-gators further enhanced the study by including 2 age-matched control groupsdnormal subjects and patients withhypertension.

Despite relatively preserved ejection fraction, both longi-tudinal and circumferential strain were significantly reducedin HFpEF patients compared to both control groups (12).Longitudinal strain was the most abnormal. Reduced lon-gitudinal strain was most common in the HFpEF patientswithin the lower EF range (45% to 54%) but was presentin 50% of patients within the normal EF range. Reducedstrain was present even after excluding patients withischemic heart disease. Reduced strain was associated withacute hospitalization and higher N-terminal pro-brainnatriuretic peptide (NT-proBNP) levels.

These data indicate that systolic dysfunction is commonin HFpEF and likely contributes to its pathophysiologyand poor outcomes. Kraigher-Krainer et al. (12) performedmeasurements only at rest and in stable outpatients. Previousstudies of exercise intolerance (23,24) and acute pulmonaryedema (25), the 2 key manifestations of HFpEF, have notfound contributions from traditional measures of systolicdysfunction. However, Henein et al. (26) found that failureto increase longitudinal strain during exercise contributes toexercise intolerance.

These findings should not be surprising. LV relaxationand contraction are intimately related; both are dependentupon availability of adenosine triphosphate and modulatedby adrenergic stimulation. Studies of HFrEF establishedlong ago that systolic dysfunction is rarely present withoutconcomitant diastolic dysfunction. The present study furtherpromotes the concept of generalized cardiac dysfunction inHF, even when EF is apparently preserved.

The therapeutic implications are confounded by trialexperience involving HFrEF patients, in whom inotropesimprove systolic function and exercise capacity but in-crease mortality. Beta-blockers, which are negative inotropes(and negative lusitropes), paradoxically reduce mortality.

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Manipulating LV systolic and diastolic function to improveoutcomes in HF patients has proved more challenging thananticipated.

The present study (12) had several other importantfindings: only 8% of patients had LV hypertrophy; only 15%had concentric remodeling; Doppler tissue diastolic veloci-ties were only mildly lower than normal subjects and similarto hypertensive subjects; end-diastolic volume was largerthan both normal and hypertension controls; systolic anddiastolic blood pressure were controlled; and left atrialpressure was frankly increased in <50% of patients. Thesefindings occurred despite stringent inclusion criteria,including severely increased NT-proBNP. Other studies,including population-based studies less influenced by trialselection criteria, have had similar findings (18,24,27). Thus,in stark contrast to earlier paradigms, many stable outpa-tients with HFpEF, in some cases the majority, do nothave LV hypertrophy, concentric remodeling, uncontrolledhypertension, elevated left atrial pressure, or abnormal dia-stolic filling, and do have LV dilation, reduced systolicfunction, and a variety of noncardiovascular abnormalities.

The presence of phenotypic heterogeneity, multifactorialpathophysiology, and multiorgan involvement in HFpEFshould not be surprising. These features are also seen inHFrEF, and reflect HF as a systemic disorder. They are alsotypical of other disorders common in the elderly. HFpEF isstrongly influenced by aging, a systemic process affecting allorgan systems (6,7). The impact of multiple comorbiditiestypical of older HFpEF patients further ensures phenotypicheterogeneity and multifactorial pathophysiology (22).

A broader, systemic view of HFpEF also helps explainobservations that nearly two-thirds of subsequent hospital-izations are non-HF related and approximately 50% arenoncardiac (5), that the majority of HFpEF patients die ofnoncardiovascular causes (28), and that the large HFpEFpharmacological trials to date, which were based on earliersimplistic paradigms, have not been positive.

Progress in HFpEF will be made by incorporating theseconcepts of heterogeneity and multifactorial contributions,and searching for the common threads and links with otherdebilitating disorders common among the elderly (29). Forexample, recent parabiosis studies show that signaling factorsin the circulation can reverse or accelerate key features ofcardiovascular aging related to HFpEF (30). Key findingssuch as this further support that HF in the elderly isa systemic process, and could increase understanding ofthe fundamental pathophysiology of HFpEF and lead todevelopment of novel strategies for its prevention andtreatment.

Reprint requests and correspondence: Dr. Dalane W. Kitzman,Department of Internal Medicine, Cardiology and Geriatrics,Wake Forest School of Medicine, Medical Center Boulevard,Winston-Salem, North Carolina 27157-1045. E-mail: dkitzman@wakehealth.edu.

REFERENCES

1. Kitzman DW, Gardin JM, Gottdiener JS, et al., for the CardiovascularHealth Study Group. Importance of heart failure with preservedsystolic function in patients > or ¼ 65 years of age. CHS ResearchGroup. Cardiovascular Health Study. Am J Cardiol 2001;87:413–9.

2. Gottdiener JS, Arnold AM, Aurigemma GP, et al. Predictors ofcongestive heart failure in the elderly: the Cardiovascular Health Study.J Am Coll Cardiol 2000;35:1628–37.

3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL,Redfield MM. Trends in prevalence and outcome of heart failure withpreserved ejection fraction. N Engl J Med 2006;355:251–9.

4. Kitzman DW, Little WC, Brubaker PH, et al. Pathophysiologicalcharacterization of isolated diastolic heart failure in comparison tosystolic heart failure. JAMA 2002;288:2144–50.

5. Dunlay SM, Redfield MM, Weston SA, et al. Hospitalizations afterheart failure diagnosis: a community perspective. J Am Coll Cardiol2009;54:1695–702.

6. Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders incardiovascular disease enterprises. Part II. The aging heart in health:links to heart disease. Circulation 2003;107:346–54.

7. Kitzman DW, Taffet G. Effects of aging on cardiovascular structureand function. In: Halter JB, Ouslander JG, Tinetti ME, et al., editors.Hazzard’s Geriatric Medicine and Gerontology. 6th ed. New York:McGraw Hill, 2009:883–95.

8. Clarkson PBM, Wheeldon NM, MacFadyen RJ, Pringle SD,MacDonald TM. Effects of brain natriuretic peptide on exercisehemodynamics and neurohormones in isolated diastolic heart failure.Circulation 1996;93:2037–42.

9. Westermann D, Lindner D, Kasner M, et al. Cardiac inflammationcontributes to changes in the extracellular matrix in patients with heartfailure and normal ejection fraction. Circ Heart Fail 2011;4:44–52.

10. Brinkley TE, Leng XY, Miller ME, et al. Chronic inflammation isassociated with low physical function in older adults across multiplecomorbidities. J Gerontol A Biol Sci Med Sci 2009;64A:455–61.

11. Yip GW-K, Zhang Q, Xie JM, et al. Resting global and regional leftventricular contractility in patients with heart failure and normal ejec-tion fraction: insights from speckle-tracking echocardiography. Heart2011;97:287–94.

12. Kraigher-Krainer E, Shah AM, Gupta DK, et al. Impaired systolicfunction by strain imaging in heart failure with preserved ejectionfraction. J Am Coll Cardiol 2014;63:447–56.

13. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertensionin heart failure with preserved ejection fraction. Circulation 2011;124:164–74.

14. Brubaker PH, Joo KC, Stewart KP, Fray B, Moore B, Kitzman DW.Chronotropic incompetence and its contribution to exercise intolerancein older heart failure patients. J Cardiopulm Rehabil 2006;26:86–9.

15. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropicand vasodilator reserves limit exercise capacity in patients with heartfailure and a preserved ejection fraction. Circulation 2006;114:2138–47.

16. Schwartzenberg S, Redfield MM, From AM, Sorajja P,Nishimura RA, Borlaug BA. Effects of vasodilation in heart failurewith preserved or reduced ejection fraction: implications of distinctpathophysiologies on response to therapy. J Am Coll Cardiol 2012;59:442–51.

17. Hundley WG, Kitzman DW, Morgan TM, et al. Cardiac cycledependent changes in aortic area and aortic distensibility are reduced inolder patients with isolated diastolic heart failure and correlate withexercise intolerance. J Am Coll Cardiol 2001;38:796–802.

18. Maurer MS, Burkhoff D, Fried LP, Gottdiener J, King DL,Kitzman DW. Ventricular structure and function in hypertensiveparticipants with heart failure and a normal ejection fraction: theCardiovascular Health Study. J Am Coll Cardiol 2007;49:972–81.

19. Bhella PS, Prasad A, Heinicke K, et al. Abnormal haemodynamicresponse to exercise in heart failure with preserved ejection fraction. EurJ Heart Fail 2011;13:1296–304.

20. Nicklas B, Leng I, Delbono O, et al. Relationship of physical functionto vastus lateralis capillary density and metabolic enzyme activity inelderly men and women. Aging Clin Exper Res 2008;20:302–9.

21. Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky SB,Eggebeen J, Kitzman DW. Impaired aerobic capacity and physicalfunctional performance in older heart failure patients with preserved

JACC Vol. 63, No. 5, 2014 Kitzman and UpadhyaFebruary 11, 2014:457–9 Heart Failure With Preserved EF: A Heterogeneous Disorder

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ejection fraction: role of lean body mass. J Gerontol A Biol Sci MedSci 2013;68:968–75.

22. Ather S, ChanW, Bozkurt B, et al. Impact of noncardiac comorbiditieson morbidity and mortality in a predominantly male population withheart failure and preserved versus reduced ejection fraction. J Am CollCardiol 2012;59:998–1005.

23. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM,Kitzman DW. Determinants of exercise intolerance in elderly heartfailure patients with preserved ejection fraction. J Am Coll Cardiol2011;58:265–74.

24. Maeder MT, Thompson BR, Brunner-La Rocca H-P, Kaye DM.Hemodynamic basis of exercise limitation in patients with heart failureand normal ejection fraction. J Am Coll Cardiol 2010;56:855–63.

25. Gandhi SK, Powers JE, Fowle KM, et al. The pathogenesis of acutepulmonary edema associated with hypertension. N Engl J Med 2001;344:17–22.

26. Henein M, Morner S, Lindmark K, Lindqvist P. Impaired leftventricular systolic function reserve limits cardiac output and exercise

capacity in HFpEF patients due to systemic hypertension. Int J Cardiol2013;168:1088–93.

27. Borlaug BA, Nishimura RA, Sorajja P, Lam CSP, Redfield MM.Exercise hemodynamics enhance diagnosis of early heart failure withpreserved ejection fraction. Circ Heart Fail 2010;3:588–95.

28. Lee DS, Gona P, Albano I, et al. A systematic assessment of causes ofdeath after heart failure onset in the community: clinical perspective.Circ Heart Fail 2011;4:36–43.

29. Cruz-Jentoft AJ, Landi F, Topinkova E, Michel JP. Understandingsarcopenia as a geriatric syndrome. Curr Opin Clin Nutr Metab Care2010;13:1–7.

30. Rando T, Finkel T. Cardiac aging and rejuvenationda sense ofhumors? N Engl J Med 2013;369:575–6.

Key Words: cardiac biomarkers - diastolic heart failure -

echocardiography - mechanics - systolic strain.