Heart failure with a normal ejection fraction

The typical image of a patient with heart failure is of a breathless person with a large flabby heart, which contracts poorly with a reduced left ventricular ejection fraction. However, many patients, mainly elderly women, have symptoms of heart failure but their hearts are not enlarged. Echocardiography shows a relatively normal left ventricular ejection fraction but usually with some left ventricular hypertrophy. Because systolic function was thought to be normal or near normal, the term “diastolic heart failure” was coined for this group of patients. However, we now know that systolic function is not entirely normal, and the problem is not only caused by diastolic dysfunction; hence the term “heart failure with a normal ejection fraction” is more appropriate.

Recent epidemiological studies have shown that heart failure with a normal ejection fraction is now a more common cause of hospital admission than systolic heart failure in many parts of the world.1 2 Mortality is also similar for both types of heart failure.1 Yet recognition of heart failure with a normal ejection fraction is poor and few trials of treatments exist.

In contrast to systolic heart failure, where an echocardiogram can easily show a dilated ventricle and reduced left ventricular ejection fraction, the lack of good non-invasive indices of diastolic function makes heart failure with a normal ejection fraction more difficult to diagnose. Recent European Society of Cardiology guidelines suggested a diagnostic algorithm for heart failure with a normal ejection fraction.3 In essence, if a breathless patient has left ventricular hypertrophy, left atrial enlargement, and evidence of a raised left atrial pressure either by B-type natiuretic peptide (which is especially useful in primary care) or newer echocardiographic indices then the diagnosis of heart failure with a normal ejection fraction is highly likely.

The pathophysiology behind the symptoms is complex, and not only diastolic abnormalities are involved. In the normal heart, left ventricular twist during systole (which stores energy), motion of the mitral annulus towards the apex during systole (which also helps suck blood into the atrium), and the corresponding untwisting process and recoil in early diastole when that energy is released to generate the negative intraventricular pressure gradient or suction in early diastole, are tightly coordinated both temporally and functionally. This process is followed by the rapid motion of the mitral annulus back towards the base of the heart, which also aids ventricular filling by moving the mitral annulus around the column of the incoming blood.4 5 All these aspects of ventricular function increase on exercise, not only to accelerate ventricular ejection, but more importantly to enable rapid filling of the ventricle during a shortened diastole while maintaining a low filling pressure. In patients with heart failure and a normal ejection fraction, this close relation between systole and diastole is disrupted, and recent studies have shown a variety of abnormalities of systolic and diastolic function—reduced myocardial systolic strain, reduced ventricular systolic rotation at rest (which fails to increase normally on exercise), reduced mitral annular motion in systole and diastole, and delayed ventricular untwisting associated with reduced left ventricular suction.6 7 Other factors are also involved, such as increased arterial stiffness, which affects ventricular function, and impaired heart rate responses to exercise, similar to patients with systolic heart failure.8

Thus, both systolic heart failure and heart failure with a normal ejection fraction have systolic and diastolic functional abnormalities to various degrees and differ mainly by ventricular size. This is probably because infarction—the most common cause of systolic heart failure—is a powerful remodelling stimulus, whereas with hypertension and diabetes—the main causes of heart failure with a normal ejection fraction—the remodelling process is slower and initially hypertrophy occurs without chamber dilatation. However, hypertension can eventually produce ventricular dilatation and typical systolic heart failure if poorly treated.2

Few large scale treatment trials have been conducted in heart failure with a normal ejection fraction because in the early trials of heart failure a reduced left ventricular ejection fraction was a prerequisite for entry. However, one trial found that the angiotensin receptor antagonist candesartan modestly reduced hospital admissions for heart failure but did not significantly affect mortality in patients with heart failure with a normal ejection fraction.9 However, a small randomised controlled trial found that diuretics alone reduced symptoms and improved quality of life significantly, but that adding ramipril or irbesartan was not more efficacious.10

Another recent study also evaluated the effect of the angiotensin receptor blocker irbesartan on mortality and cardiovascular morbidity in 4128 patients with heart failure with a normal ejection fraction. It found no benefit of irbesartan over placebo in reducing mortality or morbidity from cardiovascular disease.11 These negative results are surprising. Fibrosis of the left ventricle is increased with left ventricular hypertrophy and hypertension. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers can block the fibrogenic action of angiotensin experimentally and have been shown to reduce fibrosis in patients with hypertension.12 Fibrosis and altered collagen in left ventricular hypertrophy may have a deleterious effect on overall myocardial architecture, particularly ventricular twist and torsion. Nevertheless, the reduction of fibrosis may be an important therapeutic target, and the ongoing studies of spironolactone in heart failure with a normal ejection fraction will be interesting.

In summary, heart failure with a normal ejection fraction is a mixed bag of differing pathologies and aetiologies that in combination cause the elderly heart to fail. Despite being common, this type of heart failure is often not recognised, and evidence based treatment—apart from diuretics for symptoms—is lacking.