In HFpEF, the rise in end-diastolic pressure is caused by a complex interaction between diastolic dysfunction, underlying although not overt systolic dysfunction, atrial and LV stiffness, and reduced arterial compliance.¹⁷ There is an elevation of LV filling pressures either only with exercise or also at rest with worsening during exercise.¹⁸ In a significant proportion of patients, elevation in LV filling pressure is contributed by diastolic dysfunction with impaired active relaxation and increased LV passive chamber stiffness leading to the LV diastolic pressure-volume relationship shifted up and to the left.¹⁹ In these patients, during exercise or with other increases in heart rate, the baseline abnormalities may be accentuated leading to increases in LV diastolic pressure.¹⁸ Although there has been significant progress in noninvasive measurement of diastolic function, it is not possible to accurately assess a significant proportion of patients, especially in light of differing methods and uncertain abnormal thresholds in aging populations using echocardiography. For example, in an older Olmsted County epidemiologic study of HF patients, 78% of those with HFpEF had diastolic dysfunction, 10% had normal diastolic function, and the remainder were indeterminate.²⁰ More recently, in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial, diastolic function was measured using the ratio between transmitral E wave velocity and tissue Doppler e’ velocities, and graded based on the ratio of E/e’, transmitral E/A, and deceleration time of transmitral E velocity. Owing to the presence of atrial fibrillation, missing tissue Doppler, or transmitral E velocity, only 52% of patients with HFpEF could have diastology assessed. In these patients, diastolic dysfunction was present in only 66%; 44% had moderate to severe dysfunction. Nonetheless, regardless of the method of noninvasive diastolic assessment, studies have shown that worse diastolic function is associated with adverse outcomes in patients with HFpEF, including mortality and HF hospitalization.²¹

Other cardiac mechanisms are likely to contribute to HFpEF but are less easily assessed and not well studied in epidemiologic studies or clinical trials. These include extrinsic LV restraint by the pericardium and the right heart causing an elevation of LV filling pressures, especially during exercise. For example, HFpEF patients with severe obesity may have increased pericardial restraint owing to increased mediastinal, chest wall, and abdominal fat.²² LV systolic dysfunction may also be present as measured by strain and without necessarily impacting LVEF.²³ In the TOPCAT trial, longitudinal strain was abnormal in over half the patients and was associated with a higher risk of CV death or HF hospitalization. Thus, in the setting of HFpEF, impaired longitudinal strain predicts a worse prognosis.²⁴

Furthermore, elevated filling pressure in HFpEF results in left atrial remodeling and dysfunction, which may lead to pulmonary hypertension (PH) and eventually right ventricular failure. When atrial fibrillation is present, as it is in many patients with HFpEF, PH and subsequent right HF can ensue more quickly, sometimes irreversibly. In fact, left atrial dysfunction has been associated with worse exercise capacity, more advanced pulmonary vascular disease, and higher mortality.²⁵

Left heart-related or Group 2 PH is defined as an increase in mean pulmonary artery pressure (PAP) greater than 20 to 25 mm Hg with a pulmonary capillary wedge pressure (PCWP) ≥15 mm Hg.²⁶ Some epidemiologic studies suggest that HFpEF may be a more common cause of PH than other forms of PH²⁷ and may occur in up to 36% to 53% of patients with HFpEF.²¹ This group of patients are often older, have more CV comorbidities, worse exercise capacity, and more impaired renal function compared to patients with idiopathic PH.²⁸ With long-standing PH, the right ventricle (RV) can hypertrophy, dilate, and eventually fail especially if significant tricuspid regurgitation develops and there is concomitant renal failure.²⁸ Importantly, the development of RV dysfunction predicts a worse prognosis and a marked increased risk of death in patients with HFpEF.²⁹

In addition to cardiac abnormalities, systemic vasculature, endothelium, adipocytes, and skeletal muscle play a role in HFpEF.¹⁸,²²,³⁰ Clinically, these abnormalities may be latent at rest and only reveal themselves during stress; thus, symptoms may only occur during exercise or other stress.¹⁸ A major contributor to HFpEF is the systemic circulation whereby the aortic and conduit stiffness result in excessive blood pressure
variability and greater arterial afterload mismatch, especially during exercise. Endothelial dysfunction and abnormal nitric oxide-mediated vasodilation are found in almost half of patients with HFpEF¹⁸ and are associated with a worse prognosis compared to those with normal vasodilator response.³¹ Skeletal muscle alterations have also been observed in HFpEF, with increased fatty infiltration and reduced sarcomeres, along with an impaired ability to extract oxygen, contributing to exercise intolerance.³⁰ Similar underlying mechanisms contribute to both chronic kidney disease and HFpEF, and subsequent sodium and volume overload further contribute to both kidney and heart dysfunction in a vicious cycle. In chronic kidney disease, CV events are more likely in those with modest degrees of volume overload with or without concomitant hypertension.³²

The comorbidity-inflammation paradigm proposed by Paulus and Tschöpe suggests that HFpEF may be the result of a comorbidity-induced systemic pro-inflammatory state, which leads to endothelial dysfunction, coronary microvascular dysfunction, and abnormal cardiac structure and function.¹⁶ Comorbidities including diabetes, obesity, and hypertension may induce a systemic pro-inflammatory state, which causes coronary microvascular endothelial inflammation. The endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes, which in turn induces hypertrophy and increases resting tension from hypophosphorylation of titin. Both the stiff cardiomyocytes and interstitial fibrosis then contribute to high diastolic LV stiffness and HF. A recent study undertook a comprehensive proteomic evaluation of this inflammatory paradigm.³³ The investigators found that the comorbidity burden was associated with heightened systemic inflammation, which in turn was associated with worse cardiac function and hemodynamic stress. Thus, anti-inflammatory strategies may hold promise in the treatment of this HFpEF phenotype.

Inflammation from visceral and epicardial fat is a contributor to the higher incidence of HFpEF with obesity. However, other mechanisms such as abnormal sodium retention leading to increased plasma volume and LV and RV dilation, alterations in energy substrate metabolism, PH leading to RV failure, and mechanical epi/pericardial, chest wall or abdominal restraint leading to diastolic ventricular interactions may all play a role.²²,³⁴