Primary and Secondary Diastolic Dysfunction in Heart Failure With Preserved Ejection Fraction

Abstract

Approximately 50% of patients with symptoms and signs of heart failure have a left ventricular ejection fraction (LVEF) ≥50% and are often simply referred to as 'heart failure with preserved EF', 'HFpEF'. Many of such patients have HF secondary to specific cardiac conditions (i.e., valvular or pericardial disease) in which the symptoms and signs occur despite the LVEF being preserved due to diastolic dysfunction secondary to the underlying disease (secondary HFpEF), differently from those HFpEF patients in which the impaired LV filling is due to a primary diastolic dysfunction (primary HFpEF). When primary HFpEF patients are properly diagnosed, they appear to have a milder form of HF with a lower cardiovascular mortality compared with HFrEF and secondary HFpEF population, but a risk of HF hospitalization that is significantly higher than patients with similar cardiovascular risk factors but without the diagnosis of HFpEF. We herein review the diagnostic approach to HFpEF and present a differential diagnosis of HFpEF in a primary and secondary form.

Figure 1.

Primary and secondary HFpEF. The exact prevalence of HFpEF is unknown. It is estimated at approximately 40% of patients with heart failure (HF) have reduced EF% (LVEF ≤40%), 20% have LVEF between 40% and 49%, and the remaining have preserved left ventricular ejection fraction (LVEF ≥50%) or HFpEF. Patients with HFpEF can be distinguished in 2 subgroups based on whether a specific cause can be identified or not. Secondary causes of HFpEF include valvular heart disease, hypertrophic cardiomyopathy, restrictive/infiltrative cardiomyopathies, constrictive pericarditis and other conditions. Primary HFpEF refers to a condition in which a primary impairment in myocardial relaxation or compliance exists. The prevalence of HFpEF in its primary and secondary forms is not represented in epidemiological scale. HF = heart failure; HFmEF: HE with mid-range ejection fraction; HFpEF = HF with preserved ejection fraction; HFrEF = HF with reduced ejection fraction.

Figure 2.

Diagnostic algorithm for HFpEF. The diagnosis of HFpEF begins with the elicitation of symptoms and signs of heart failure, associated with the documentation of risk factors and co-morbid conditions. The diagnosis requires validation of the diagnosis of heart failure using data derived from either echocardio-Doppler study or invasive hemodynamics, or elevation of natriuretic peptides. Cardiac imaging is central to assessment as it allows to investigate the presence of the secondary causes HFpEF such as valvular heart disease, cardiomyopathies, pericardial disease, or other. In selected patients, additional tests may be necessary to further investigate the differential diagnosis of primary and secondary HFpEF, and to evaluate the role of concomitant non-cardiac disease that may present with similar symptoms and signs. AF = atrial fibrillation; AV = arteriovenous; BNP = brain natriuretic peptide; CKD = chronic kidney disease; COPD = chronic obstructive pulmonary disease; CTEPH = chronic thromboembolic pulmonary hypertension; DM = diabetes mellitus; EF = ejection fraction; F = Female; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HTN = hypertension; JVD = jugular vein distension; LAVI = left atrial volume index; LV = left ventricle; LVEF = left ventricular ejection fraction; LVMI = left ventricular mass index; M = Male; MI = myocardial infarction; NT-proBNP = N-terminal pro brain natriuretic peptide; PAH = pulmonary arterial hypertension; PASP = pulmonary artery systolic pressure; PH = pulmonary hypertension.

Figure 3.

Pathophysiology of primary HFpEF. Several risk factors (obesity, hypertension, aging, and physical inactivity) contribute to create a systemic proinflammatory status and/or haemodynamic stress that promote a primary myocardial diastolic dysfunction (impaired myocardial relaxation and compliance) leading to concentric remodeling/hypertrophy, and elevated LV filling pressures and/or impaired cardiac output. Moreover, co-morbid conditions and contributing factors (obesity, abnormal ventriculoarterial coupling, deconditioning, ventilatory inefficiency, pulmonary diseases, diabetes mellitus, and malnutrition) further contribute to exercise intolerance and clinical symptoms in patients with primary HFpEF. HFpEF = heart failure with preserved ejection fraction; LV = left ventricle; NO = nitrogen oxygen SVR = systemic vascular resistance; V/Q = ventilation/perfusion ratio.

Figure 4.

Risk of CV death and CV death or HF hospitalization in high-risk patients with HTN without HF, patients with primary HFpEF and patients with HFrEF. The incidence of CV death at mid-term follow-up from randomized clinical trials appears to be lower in primary HFpEF compared with HFrEF, while not different than those with high-risk HTN without HF. The risk of HF hospitalization, in contrast, differs substantially between hypertensive patients without HF and those with HFpEF: patients with HFpEF have a much higher risk of HF hospitalization than patients with asymptomatic HTN. CV = cardiovascular; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reduced ejection fraction; HTN = hypertension; RCT = randomized control trials.