Diagnosis and treatment of heart failure with preserved left ventricular ejection fraction

Table 1 Conditions that contribute to heart failure with preserved ejection fraction

Obesity

Hypertension

Coronary artery disease

Atrial fibrillation

Diabetes mellitus

Chronic obstructive pulmonary disease

Obstructive sleep apnea

Anemia

Table 2 Clinical characteristics of patients with heart failure with preserved ejection fraction and heart failure and reduced ejection fraction

	HFpEF	HFrEF
Sex	Women (62%)	Men (60%)
Age (yr)	74	70
Obesity	41.4%	35.5%
Diabetes mellitus	45%	40%
Hypertension	77%	69%
Chronic kidney disease	56%	45%
Coronary artery disease	50%`	59%
Prior myocardial infarction	24%	36%
LV remodeling	Concentric	Eccentric
LV ejection fraction	≥ 50%	< 40%
Atrial fibrillation in hospitalized patients	65%	53%
Ventricular dysrhythmias	3%	11%
Hospitalizations for heart failure	Increasing	Decreasing
Therapies that decrease mortality	None at present time	Beta-Blockers, ACE inhibitors, biventricular pacemakers, coronary revascularization

HFpEF: Heart failure with preserved ejection fraction; HFrEF: Heart failure and reduced ejection fraction; LV: Left ventricular.

Table 3 Echocardiographic indices of diastolic dysfunction

1. The ratio of the mitral blood flow velocity into the LV in early diastole (the E wave) to peak blood flow velocity in late diastole caused by atrial contraction (the A wave), or the E/A ratio, ≥ 2. The normal E/A is approximately 0.8. However, tachycardia, atrioventricular block, and left bundle branch block can lead to fusion of E and A waves, and ambiguity in diastolic function assessment.

2. Increased left atrial pressure measured by early mitral blood flow velocity across the mitral valve (E wave) to the early diastolic velocity (e’) of the lateral mitral annulus, or E/e’ ratio. An E/e’ ratio 10 = mild and E/e’ ratio > 14 = significant LV dysfunction. If the lateral mitral annulus e' velocity is not quantifiable, the septal mitral annular e' velocity can be used. In this case, the E/e’ is increased if the ratio is > 15.

3. Lateral mitral annular e’ velocity < 10 cm/s or septal e’ mitral annular velocity < 7 cm/s.

4. Pulmonary artery systolic pressure > 35 mmHg indicative of pulmonary arterial hypertension. Pulmonary artery systolic pressure = 4 × (peak tricuspid regurgitation velocity)2 + estimated right atrial pressure. These criteria should not be used in patients with significant pulmonary disease.

5. An echocardiographic determination of global longitudinal strain of -16.05 ± 2.16. This measurement can separate patients with HFpEF from patients with hypertension and normal controls in whom the global longitudinal strain measurements are -18.58 ± 2.84 and -19.59 ± 1.49, respectively.

HFpEF: Heart failure with preserved ejection fraction.

Table 4 Heart failure preserved ejection fraction scoring system: Heart failure with preserved ejection fraction

Clinical characteristic	Clinical measurement	Points awarded
Heavy	Body mass index > 30 kg/m2	Two
Hypertension	Two or more hypertensive medications	One
Atrial fibrillation	Paroxysmal or persistent	Three
Pulmonary hypertension by echocardiogram	Pulmonary artery systolic pressure > 35 mmhg	One
Elderly	Age > 60 yr	One
LV filling pressure by echocardiogram	Echocardiographic e/e’ > 9	One

Table 5 Survival after cardiac magnetic resonance determined extracellular volume determination

CMR ECV	Year one	Year two	Year three	Year four
ECV < 25%	95.8%	95.8%	95.8%	82.1%
25% ≤ ECV < 30%	95.5%	90.5%	87.6%	81.1%
30% ≤ ECV < 35%	88.0%	77.3%	69.6%	65%
35% > ECV < 40%	82.2%	74.3%	69.4%	61.7%
ECV ≤ 40%	40.0%	40.0%	40.0%	40.0%
Cardiac amyloid	47.1%	23.5%	0%	0%

CMR: Cardiac magnetic resonance; ECV: Extracellular volume.

Table 6 Pharmacologic studies in heart failure with preserved ejection fraction

Ref.	Drug vs control	Drug half-life hours	Number patients	Duration	LVEF	Results
Beta-blockers
Swedish Heart Failure Registry[81]	All BBs (prescribed at discharge	6-h Atenolol; 12-19 h Nevibolol	8244	755 d	LVEF 49%-50% and LVEF > 50%	β-blockers decreased mortality but not combined all-cause mortality or hospitalizations
SWEDIC Trial[82]	Carvedilol	6-10 h	97	6 mo	LVEF ≥ 40%	E/A ratio improved but no other measures of diastolic function
J-DHF Trial[83]	Carvedilol	6-10 h	245	38 mo	LVEF ≥ 40%	Standard dose, but not low dose, carvedilol reduced; CV mortality and hospitalizations
COHERE Registry[84]	Carvedilol	6-10 h	4280	12 mo	LVEF > 40%	Carvedilol had no mortality benefit but decreased hospitalization
SENIORS[85,86]	Nebivolol	2.5-20 h	643	21 mo	LVEF > 35%	Nebivolol did not decrease CV hospitalizations or mortality
ELANDD Trial[87]	Nebivolol	2.5-20 h	116	21 mo	LVEF ≥ 45%	Nebivolol did not increase exercise capacity
CIBIS-ELD Trial[88]	Bisoprolol vs Carvedilol	9-12 vs 6-10 h	250	3 mo	LVEF ≥ 45%	Bisoprolol and carvedilol had no effect on established and prognostic markers of diastolic function
El-Refai et al[89]	Beta Blocker (bisoprolol, carvedilol, metoprolol, labetalol, and atenolol)	6-7 h (Atenolol); 9-12 h (Bisoprolol)	741	25 mo	LVEF ≥ 50%	Beta blockers decreased mortality and HF rehospitalizations
β-PRESERVE[90]	Metoprolol succinate vs control	3-9 h	1200	24 mo	LVEF ≥ 50%	Trial Results not available
OPTIMIZE-HF[91]	All BBs (prescribed at discharge)	6-7 h Atenolol 12-19 h Nebivolol	21149	3 mo	LVEF 40%-49% and ≥ 50%	Beta blockers had no effect on mortality and rehospitalization
Calcium channel blockers
Setaro et al[92]	Verapamil vs placebo	4.5-12 h	20	1 mo	LVEF ≥ 45%	Verapamil increased exercise capacity clinicoradio-graphic score. No change in LVEF.
Hung et al[93]	Verapamil vs placebo	4.5-12 h	15	3 mo	Normal LVEF	Verapamil increased exercise time and LV diastolic function
ACE inhibitors
Aronow et al[94]	Enalapril vs control (diuretics alone)	11 h	21	3 mo	LVEF ≥ 50%	Enalapril increased exercise time and LVEF
PEP-CHF trial[95]	ACE inhibitor (perindopril) vs placebo	3-10 h with prolonged terminal elimination	207	12 mo	LVEF ≥ 45%	Perindopril increased 6 min walk distance but did not decrease mortality
Angiotensin II receptor blockers
I-PRESERVE[96]	Irbesartan vs placebo	11-15 h	4563	24 mo	LVEF ≥ 45%	No decrease in hospitalization or mortality
CHARM-Preserved[97]	Candesartan vs control medication (ACE Inhibitor, BB, CCB)	9 h	3023	37 mo	LVEF ≥ 40%	Candesartan slightly decreased hospitalizations but did not decrease mortality
Angiotensin receptor blocker/nephrilysin inhibitors
PARAMOUNT Trial[98]	Sacubitril/valsartan vs valsartan	11.5 h	301	3 and 8-9 mo	LVEF ≥ 45%	Sacubiril Valsartan reduced NT-proBNP
PARAGON-HF Governmental Trial NCT01920711	Sacubitril/valsartan vs valsartan	11.5	4300	57 mo	LVEF ≥ 45%	Sacubitril/valsartan not superior to valsartan alone in decreasing hospitalization or cardiovascular mortality
Ivabradine
Kosmala et al[99]	Ivabradine vs placebo	11 h	61	7 d	LVEF ≥ 50%	Ivabradine increased exercise time, peak oxygen uptake, and decreased E/e’
EDIFY trial[100]	Ivabradine vs placebo	11 h	179	8 mo	LVEF ≥ 45%	No improvement in 6 min walk, E/e’, or NT-proBNP
Statins
Fukuta et al[101]	Standard HF therapy with a statin vs without a statin	2 h (lovastatin)-19 h (rosuvastatin)	137	21 mo	LVEF ≥ 50%	Statin therapy associated with reduced mortality
Ouzounian et al[102]	Standard HF therapy with a statin vs without a statin	2 h (lovastatin)-19 h (rosuvastatin)	6451	38 mo	LVEF ≥ 50%	Statins did not decrease morbidity or mortality in patients with HF without CAD
Animal model of heart ailure (rats)[103]	Standard HF therapy with rosuvastatin vs without rosuvastatin	19 h	46	19 mo	Preserved EF	Statins had no benefit
Digoxin
(DIG) trial[104]	Digoxin vs placebo	36-48 h	988	37 mo	LVEF ≥ 45%	Digoxin had no effect on all-cause and CV mortality, heart failure hospitalizations
Phosphodiesterase-5 inhibitors
RELAX trial[105]	Sildenafil vs placebo	3-4 h	216	24 mo	LVEF ≥ 50%	No improvement in 6 min walk distance, clinical status, or peak O2 consumption
Nitrates
NEAT-HFpEF trial[106]	Isosorbide mononitrate vs placebo	2.5-5.1 h	110	22 mo	LVEF ≥ 50%	No improvement in 6 min walk distance or NT-proBNP
INDIE-HFpEF[107,108]	Inhaled inorganic nitrite vs placebo	0.7 h	105	4 wk	LVEF ≥ 50%	No significant improvement in exercise tolerance, NY Heart Association Class, E/e’, NT-proBNP
Governmental trial NCT02840799	Oral KNO3 vs KCL	1.2 h	26	1 mo	LVEF ≥ 50%	KNO3 trial is in progress

LVEF: Left ventricular ejection fractions; HF: Heart failure; EF: Ejection fraction.