Leaders in Pharmaceutical Business Intelligence (LPBI) Group

The ejection fraction (EF) is an important measurement in determining how well your heart is pumping out blood and in diagnosing and tracking heart failure.

A significant proportion of patients with heart failure happen to have a normal ventricular ejection fraction at echocardiography during examination. Previously called diastolic heart failure, it is nowadays referred to as heart failure with normal ejection fraction (HFNEF) or HF with preserved ejection fraction.

1. Perserved ejection fraction (HFpEF) – also referred to as diastolic heart failure.  The heart muscle contracts normally but the ventricles do not relax as they should during ventricular filling (or when the ventricles relax).
2. Reduced ejection fraction (HFREF) – also referred to as systolic heart failure.  The heart muscle does not contract effectively and less oxygen-rich blood is pumped out to the body.

What it is?
A measurement of how much blood the left ventricle pumps out with each contraction.

What it means.
An ejection fraction of 60 percent means that 60 percent of the total amount of blood in the left ventricle is pushed out with each heartbeat.

What’s normal?

• A normal heart’s ejection fraction may be between 55 and 70.
• You can have a normal ejection fraction reading and still have heart failure. If the heart muscle has become so thick and stiff that the ventricle holds a smaller-than-usual volume of blood, it might still seem to pump out a normal percentage of the blood that enters it. In reality, though, the total amount of blood pumped isn’t enough to meet your body’s needs.

What’s too low?

• A measurement under 40 may be evidence of heart failure or cardiomyopathy.
• An EF between 40 and 55 indicates damage, perhaps from a previous heart attack, but it may not indicate heart failure.
• In severe cases, EF can be very low.

What’s too high?
EF higher than 75 percent may indicate a heart condition like hypertrophic cardiomyopathy.

Tests for measuring EF:

• Echocardiogram (Echo)
• MUGA scan
• CAT scan
• Cardiac catheterization
• Nuclear stress test

SOURCE
http://www.heart.org/HEARTORG/Conditions/HeartFailure/SymptomsDiagnosisofHeartFailure/Ejection-Fraction-Heart-Failure-Measurement_UCM_306339_Article.jsp

Pathophysiology

Controversy continues regarding the prevalence of true abnormities of myocardial diastolic function in the syndrome of HFpEF. In a comprehensive invasive and noninvasive hemodynamic study in a group of highly selected patients with hemodynamically confirmed HFpEF, Prasad et al⁷ reported that compared with age-matched referent controls, increased static ventricular stiffness was not a universal finding in patients with HFpEF, although LV relaxation as assessed by tissue Doppler was consistently abnormal.

Substantial and growing attention has been given to the role of the cardiac interstitium in the pathophysiology of HFpEF. Zile and colleagues⁸ examined a panel of biomarkers for ability to discriminate symptomatic HFpEF from those with asymptomatic LV hypertrophy. This study showed that a panel of plasma biomarkers reflecting changes in extracellular matrix fibrillar collagen synthesis and degradation predicted the presence of HFpEF with an area under the curve of 0.79 and was more powerful than using N-terminal pro–B-type natriuretic peptide or clinical variables. Consistent with these findings, investigators from the Cardiovascular Health Study reported that biomarkers reflecting myocardial fibrosis, including carboxyl-terminal peptide of procollagen type I, carboxyl-terminal telopeptide of collagen type I, and amino-terminal peptide of procollagen type III, are significantly elevated in elderly patients with HFpEF and indeed are also elevated in those with systolic HF.⁹ Krum et al¹⁰ reported on a substudy from I-PRESERVE showing that increased baseline plasma levels of all collagen markers were associated with the I-PRESERVE primary outcome end point, although the relationship was not significant in a multivariable model. In a comprehensive human study, Westermann and colleagues¹¹ interrogated the influence of cardiac inflammation on extracellular matrix remodeling in patients with HFpEF. Using endomyocardial biopsy samples to isolate primary human cardiac fibroblasts, the authors interrogated the gene expression of extracellular matrix proteins after stimulation with transforming growth factor-β. They reported an increase of cardiac collagen accompanied by a decrease in the collagenase system of the heart, as well as a correlation between cardiac collagen, inflammatory cells, and diastolic dysfunction. They concluded that inflammation contributes to diastolic abnormalities in HFpEF by stimulating extracellular matrix accumulation. All of these data suggest that the interstitium may be a promising therapeutic target if specific therapies can be deployed.

Although abnormalities in myocardial diastolic properties have been the focus of pathophysiological studies in patients with HFpEF in the past, many recent investigations have examined other structural and functional contributors. Kurt and colleagues¹²reported that HFpEF patients have similar LV mass and left atrial volume in comparison with patients with LV hypertrophy who are not in HF, although a measure of left atrial strain was reduced, and left atrial stiffness was useful in discriminating patients with HFpEF from those with LV hypertrophy without HF symptoms.

Several studies examined pathophysiology in HFpEF patients during exercise stress, which is when most patients have symptoms. Phan and colleagues¹³ reported that chronotropic incompetence, as measured by the percentage of the heart rate reserve used during maximal exercise, was more commonly present in patients with HFpEF compared with referent controls, as was abnormal heart rate recovery. Using dobutamine stress echocardiography with color tissue Doppler imaging, Chattopadhyay et al¹⁴ reported evidence of impaired diastolic reserve during stress, as well as stress-induced increase in the LV end-diastolic pressure, likely resulting in exercise intolerance because 6-minute walk distance was inversely correlated with the measures of diastolic function at rest and stress. Borlaug and colleagues¹⁵ examined hemodynamic responses to stress as a potential diagnostic approach in patients with exertional dyspnea, in whom making a specific diagnosis may be challenging. The investigators studied patients with exertional dyspnea, preserved EF, normal brain natriuretic peptide levels, and normal resting hemodynamics. Exercise-induced elevation in pulmonary capillary wedge pressure was used to define HFpEF and was associated with blunted increases in heart rate and cardiac output and blunted systemic vasodilation. An exercise pulmonary artery systolic pressure ≥45 mm Hg identified HFpEF with 96% sensitivity and 95% specificity. These data suggest that patients who present a challenge for specific diagnosis should undergo an exercise hemodynamic study.

Two studies examined clinical or echocardiographic variables that might be useful in estimating LV filling pressures in patients with HFpEF. Drazner et al¹⁶ reported that right atrial pressures often reflected left-sided filling pressures in HFpEF, suggesting that estimation of jugular venous pressure could be used to assess volume status. However, the echocardiographic indexes E/e′ and E/Vp did not appear to reliably track changes in left-sided filling pressures in patients with HFpEF.¹⁷

Studies using translational models explored the underlying mechanism of the transition from compensated LV hypertrophy to a state of HF. In a transverse aortic constriction model adding mineralocorticoid (deoxycorticosterone acetate) excess, Mohammed et al¹⁸reported that mice treated with deoxycorticosterone acetate showed progressive activation of markers of oxidative stress but no evidence of mineralocorticoid receptor–dependent gene transcription. They concluded that pressure-overload hypertrophy sensitizes the heart to mineralocorticoid excess and that the transition to HF with preserved EF is associated with mechanisms independent of mineralocorticoid receptor–dependent gene transcription. In a study of cardiac energy metabolism in which Dahl salt-sensitive rats fed a high-salt diet were used to drive a transition from compensated LV hypertrophy to HF, Kato and colleagues¹⁹ reported that glucose uptake increased with LV hypertrophy and further increased at the HF stage, with decreased fatty acid uptake and corresponding changes in gene expression related to the metabolic pathways as well as mitochondrial function with the onset of HF. Dichloroacetate, which enhances glucose oxidation, attenuated the transition to HF, associated with increased energy reserves and reduced oxidative stress. The data from these models suggest potential therapeutic directions for the future, although mineralocorticoid receptor antagonism is already under comprehensive study.

Therapeutics

As noted, large randomized trials in broad populations of patients with HFpEF in which agents such as angiotensin receptor blockers were used have generally shown neutral results. Smaller trials continue to explore potential therapeutic directions for this challenging-to-manage syndrome. Kitzman and colleagues²⁰ randomized 71 elderly HFpEF patients with compensated symptoms and controlled blood pressure into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo.

There was no effect of the angiotensin-converting enzyme inhibitor on

• the primary end point of peak exercise oxygen consumption and
• no effect on multiple secondary end points including 6-minute walk distance,
• aortic distensibility,
• LV mass, or
• neurohormones.

The findings are consistent with the longer-term natural history outcomes of angiotensin receptor blocker trials.

Many of the same authors examined a nonpharmacological approach in a 16-week randomized study of supervised exercise training in 53 elderly patients with HFpEF.²¹The primary outcome was peak exercise oxygen uptake, which increased significantly in the exercise group compared with the control group (2.3±2.2 versus −0.3±2.1 mL/kg per meter; P=0.0002). Many secondary end points were also improved, including exercise time, 6-minute walk distance, and ventilatory anaerobic threshold. In contrast to some trials of exercise training, a key to the favorable results of this study may have been the good compliance with the exercise training regimen among the enrolled patients. These important data suggest an important therapeutic direction.

Favorable results were also seen in a small study involving an important subgroup of HFpEF patients, those with pulmonary hypertension. Guazzi and coworkers²² randomized 44 such patients to sildenafil at a dose of 50 mg 3 times per day or to placebo for 6 months. At the end of the trial, sildenafil was associated with decreased mean pulmonary artery and reduced right atrial pressure and improved right ventricular function. They also reported reduced lung water content and improved alveolar-capillary gas conductance, as well as improved measure of left-sided systolic and diastolic cardiac function. Results were maintained at 12 months.

Hence, although large trials using neurohormonal antagonists that have been favorable in HF with reduced EF have not shown favorable results in HFpEF, these early studies suggest promising therapeutic directions to explore. Such studies also enhance our understanding of pathophysiology and point the way to larger and more definitive investigations.