Aetiology

Common risk factors and comorbidities of HFpEF include hypertension, coronary artery disease, diabetes, atrial fibrillation, obesity, and renal dysfunction.[2][4]

Other conditions can cause HF with a preserved EF and should be considered in the differential diagnosis of HFpEF. These are also known as HFpEF ‘mimics’ and include infiltrative cardiomyopathies (e.g., amyloidosis, haemochromatosis), hypertrophic cardiomyopathy, valvular disease, pericardial disease, or high-output heart failure.[2][11]

Amyloid cardiomyopathy is an underdiagnosed cause of HF and should be considered, especially when there are typical findings (low complexes on resting 12-lead ECG, speckled concentric hypertrophy on echo).[4]​ HFpEF mimics have specific management options that differ from HFpEF, and are not covered in this topic.

Pathophysiology

Diastole is a dynamic process that begins as contraction finishes and includes isovolumetric relaxation and early ventricular filling. Impaired relaxation and altered ventricular filling can result in diastolic dysfunction.

Ventricular relaxation is an active process mediated by ATP and controlled primarily by calcium uptake by the sarcoplasmic reticulum. The seminal studies on HFpEF described prolonged isovolumic left ventricular (LV) relaxation, increased diastolic LV stiffness, and slow LV filling.[20][21] LV diastolic dysfunction results from increased myocardial stiffness, in the absence of pericardial or endocardial disease. Both the extracellular matrix and the cardiomyocytes contribute to myocardial stiffness.

Ventricular filling is affected by elasticity, compliance, and stiffness, which are measured in end-diastole. An increase in chamber stiffness may occur secondary to any combination of the following:[22]

  • A rise in filling pressures due to volume overloaded states, such as valvular regurgitation and dilated cardiomyopathy

  • A steeper pressure-volume curve, whether from ventricular hypertrophy/concentric remodelling (from hypertension, aortic stenosis, etc.) or from increased extracellular matrix leading to myocardial restriction (amyloidosis, endomyocardial fibrosis, etc.)

  • A decrease in ventricular distensibility caused by extrinsic compression of the ventricles, as seen in tamponade or constrictive pericarditis.

The resulting elevation in LV filling pressures causes elevation in the pulmonary capillary pressures, causing symptoms of pulmonary congestion. Elevation of pressures in the left atrium may predispose to complications such as atrial arrhythmias.

In HFpEF, myocardial dysfunction and remodelling are driven by endothelial inflammation and oxidative stress.[23]​ Comorbidities such as obesity, diabetes mellitus, hypertension, chronic obstructive pulmonary disease, and renal insufficiency induce systemic inflammation and endothelial dysfunction with elevated plasma levels of inflammatory biomarkers, including soluble interleukin 1 receptor-like 1 (IL1RL1), C-reactive protein (CRP), growth differentiation factor 15 (GDF15), (IL)-6, tumour necrosis factor (TNF)-alpha, soluble ST2 (sST2), pentraxin 3, reactive oxygen species (ROS), vascular cell adhesion molecule (VCAM), and E-selectin.[23][24]​​

Endothelial inflammation and the presence of ROS leads to reduced bioavailability of nitric oxide and production of peroxynitrite, which lowers soluble guanylate cyclase (sGC) activity in adjacent cardiomyocytes. Lower sGC activity decreases cyclic guanosine monophosphate concentration and protein kinase G activity, which increases resting tension and promotes cardiomyocyte stiffness and hypertrophy.[23][24]​​ ROS also trigger cardiomyocyte death by autophagy, apoptosis, or necrosis, with the myocytes replaced with fibrous tissue.[23]

Myocardial fibrosis with collagen deposition causes diastolic LV dysfunction. The inflammatory markers VCAM and E-selectin attract leukocytes that release transforming growth factor β (TGF-β). TGF-β stimulates conversion of fibroblasts to myofibroblasts, which deposit collagen.[23][24]

Inflammatory biomarkers affect the lungs, myocardium, skeletal muscle, and kidneys, promoting pulmonary hypertension, myocardial remodelling, deficient skeletal muscle oxygen extraction during exercise, and renal sodium retention.[24]

Classification

Universal definition and classification of heart failure: classifications of heart failure according to ejection fraction[1]

  • Heart failure with reduced ejection fraction (HFrEF): heart failure with left ventricular ejection fraction (LVEF) ≤40%.

  • Heart failure with mildly reduced ejection fraction (HFmrEF): heart failure with LVEF 41% to 49%

  • Heart failure with preserved ejection fraction (HFpEF): heart failure with LVEF ≥50%

  • Heart failure with improved ejection fraction (HFimpEF): heart failure with a baseline LVEF of ≤40%, a ≥10-point increase from baseline LVEF, and a second measurement of LVEF of >40%.

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