Heart Failure With Normal Ejection Fraction

A Growing Pandemic

Satnam Singh; Michael Frenneaux

Future Cardiol. 2012;8(3):383-392.

Etiology & Prevalence of HFNEF

HFNEF is a complex disease with increasing prevalence.^[8] Typically HFNEF patients are elderly females often suffering from one or more of the following diseases: hypertension, diabetes, obesity and, even more frequently observed, coronary artery disease.

Due to the lack of standardization of diagnostic criteria, HFNEF still remains underdiagnosed but recent studies provide a more accurate estimate of the prevalence of HFNEF among patients with HF, which averages approximately 54%, with a range from 40 to 70%.^[8] Owen et al. estimated the true prevalence of HFNEF in the community to be in the range of 1.1–5.5% of the general population.^[8] HFNEF patients have increased myocardial stiffness and impaired relaxation in diastole resulting in higher left atrial pressures.^[9] These high left atrial pressures predispose the patients to pulmonary venous congestion and dyspnea especially on exertion.^[10] Invasive studies in chronic HF with preserved ejection function (HFPEF) and hospitalized HFPEF patients have shown a leftward and upward shift of the LV end-diastolic pressure–volume relationship.^[10–12] HFPEF patients have raised LV end-diastolic pressure, end-systolic pressure, diastolic dysfunction, pulmonary capillary wedge pressure and pulmonary artery systolic pressure.^[13]

Penicka et al. demonstrated that dynamic mitral regurgitation may contribute to the pathophysiology of HFNEF, and that dys-synchrony may also play a role.^[12]

Ha et al.^[14] and lam et al.^[15] have independently demonstrated that pulmonary hypertension is common and often severe in patients with HFNEF syndrome. The prognosis of HFNEF worsens with pulmonary hypertension and right ventricular failure development.^[16]

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Abstract and Introduction
Definition of Heart Failure Normal Ejection Fraction
Scale of the Problem
Etiology & Prevalence of HFNEF
Pathophysiology of HFNEF
Diagnosis: What Do Current Guidelines Say?
Management of HFNEF
Conclusion
Future Perspective
References
Sidebar

Table 1. Major randomized control trials on heart failure with normal ejection fraction.
Study (year)	n	Inclusion criteria	Outcome	Follow-up	Results	Ref.
Setaro et al. (1990) Verapamil	20	EF >45%; males; mean age: 68; abnormal PFR 2.5 EDV/s	Exercise capacity	3 months	Significant improvement in exercise	[37]
Aronow et al. (1993) Enalapril	21	EF >50%; mean age: 79; prior MI; NYHA class III; frusemide 2 weeks before	NYHA class and exercise tolerance	3 months	Improved exercise capacity and improvement in NYHA class	[48]
Lang et al. (1995) Lisinopril	12	EF >50%; mean age: 72; angina/MI; NYHA class I–III; Normal CXR; diastolic dysfunction on Doppler echocardiography	Breathlessness and fatigue		No significant benefit in terms of echo parameters (E/A ratio) or in visual analog scales of symptoms	[49]
Aronow et al. (1997) Propranolol	158	EF >40%; mean age: 81; NYHA class II–III; prior MI; on ACE inhibitors and diuretics	All-cause mortality and nonfatal MI	32 months	35% significant reduction in total mortality and a 37% significant decrease in total mortality plus nonfatal myocardial infarction; improved LVEF by 6%; significantly greater reduction in left ventricular mass	[50]
Warner et al. (1999) Losartan	20	EF >50%; mean age: 64; diastolic dysfunction on echocardiography; normotensive at rest with hypertensive response to exercise; mitral flow velocity E/A <1; normal stress echocardiography	Quality of life and exercise tolerance	2 weeks for each arm, crossed over to other arm with 2-week washout period	Exercise time increased; quality of life improved with losartan; peak SBP during exercise decreased; resting BP unaltered	[51]
Hung et al. (2002) verapamil	30	EF >50%; NYHA class II–III	CHF score, treadmill exercise test, Doppler echocardiography	3 months	NYHA class improved exercise tolerance, significant benefit in terms of echocardiogram parameters (E/A ratio)	[52]
Zi et al. (2003) Quinapril	74	EF >40% mean age: 77; NYHA class II–III	Quality of life, NYHA class, exercise duration	6 months	Neutral results	[53]
Yusuf et al. (2003) Candesartan (CHARM-P)	3023	EF >40%; mean age: 67; NYHA class II–IV; prior hospitalization	Primary: cardiovascular death; HF-related hospitalization Secondary: composites of primary outcome (cardiovascular death, HF-related hospital admission) and MI, nonfatal stroke and coronary revascularization	36.6 months	Less hospitalization due to HF decompensation; relative risk reduction in CVS death by 11%; reduction in new onset DM	[54]
Nodari et al. (2003) Nebivolol	26 (30)^†	EF >50%; NYHA class II–III; mild hypertension; peak VO₂ 25 ml/kg/min; EDD <32 mm/m²	Primary: pulmonary wedge pressure at peak exercise Secondary: hemodynamic parameters and maximum exercise tolerance	6 months	Increase in peak VO₂ and VO₂ at AT; decrease in VE:VCO₂ ratio	[55]
Takeda et al. (2004) Carvedilol	40	EF >45%; mean age: 71; NYHA class II–III; Stage c HF	NYHA class; exercise tolerance plasma BNP levels	12 months	NYHA class improved, exercise tolerance, improved, reduction in plasma BNP levels	[56]
Flather (2005) Nebivolol (SENIORS) subgroup	752 (2128)^‡	EF >35%; mean age: 76	All-cause mortality, HF-related hospitalization	21 months	Reduction in all-cause mortality and hospitalization	[34]
Ahmed (2006) Digoxin DIG ancillary	988	EF >45%; mean age: 67; NYHA class I–IV; NSR	HF hospitalization and HF mortality	37 months	No difference in mortality due to cardiovascular causes; no difference in all-cause hospitalizations	[33]
Cleland (2006) Perindopril (PEP-CHF)	850	EF >40%; median age 75; diastolic dysfunction on echocardiography; prior hospitalization due to cardiac causes; serum creatinine <200 µmol/l	Composite all-cause mortality, hospitalization for HF	26 months	Reduced hospitalizations, improved exercise tolerance; improved NYHA class; neutral results for all-cause mortality	[57]
Massie (2008) Irbesartan (I-PRESERVE)	4128	EF >45%; mean age: 72; NYHA class II–IV; prior hospitalization with HF	Primary: all-cause death or hospitalization from cardiovascular cause Secondary: death from HF or hospitalization for HF, death from any cause and from cardiovascular causes, and quality of life	49.5 months	No significant difference	[58]
Yip (2008) Ramipril (Hong kong DHF)	151	EF >45%; mean age: 74; NYHA class II–IV; on diuretics; recent HF	Quality of life, exercise tolerance and hospital admissions	52 weeks	No significant difference	[59]

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A Growing Pandemic

Etiology & Prevalence of HFNEF

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