Transitioning from Preclinical to Clinical Heart Failure with Preserved Ejection Fraction: A Mechanistic Approach

Abstract

To better understand heart failure with preserved ejection fraction (HFpEF), we need to better characterize the transition from asymptomatic pre-HFpEF to symptomatic HFpEF. The current emphasis on left ventricular diastolic dysfunction must be redirected to microvascular inflammation and endothelial dysfunction that leads to cardiomyocyte remodeling and enhanced interstitial collagen deposition. A pre-HFpEF patient lacks signs or symptoms of heart failure (HF), has preserved left ventricular ejection fraction (LVEF) with incipient structural changes similar to HFpEF, and possesses elevated biomarkers of cardiac dysfunction. The transition from pre-HFpEF to symptomatic HFpEF also involves left atrial failure, pulmonary hypertension and right ventricular dysfunction, and renal failure. This review focuses on the non-left ventricular mechanisms in this transition, involving the atria, right heart cavities, kidneys, and ultimately the currently accepted driver-systemic inflammation. Impaired atrial function may decrease ventricular hemodynamics and significantly increase left atrial and pulmonary pressure, leading to HF symptoms, irrespective of left ventricle (LV) systolic function. Pulmonary hypertension and low right-ventricular function are associated with the incidence of HF. Interstitial fibrosis in the heart, large arteries, and kidneys is key to the pathophysiology of the cardiorenal syndrome continuum. By understanding each of these processes, we may be able to halt disease progression and eventually extend the time a patient remains in the asymptomatic pre-HFpEF stage.

Keywords: atrial failure; heart failure with preserved ejection fraction; inflammation; pulmonary artery; renal function; right ventricle.

Figure 1

Mechanisms involved in transitioning from the pre-HFpEF stage to symptomatic HFpEF.

Figure 2

Interaction between atrial failure and the pre-HFpEF stage. Atrial failure is a main driver in transforming the pre-HFpEF stage into clinical HFpEF and is mainly driven by an impaired left atrial (LA) function and structure leading to increase LA and pulmonary artery (PA) pressure. The presence of atrial fibrillation (AF) and mitral regurgitation (MR) represent the rhythm and valvular manifestations of atrial failure syndrome, which further exacerbates the functional impairment of the LA and its hemodynamic consequences with adverse synergy. HFpEF, heart failure with preserved ejection fraction.

Figure 3

Pathophysiological pathways involved in right heart dysfunction (RHD) in heart failure with preserved ejection fraction (HFpEF). The passive backward transmission of left-sided pressure, comorbidities, systemic inflammation, neurohormonal pathways, genetic predisposition, and intrinsic lung and pulmonary vascular abnormalities are all factors interrelated in the pathogenesis of RHD in patients with HFpEF. Pulmonary vascular remodeling and the development of a pre-capillary component of pulmonary hypertension are key factors in developing RHD in HFpEF. Because of this pathophysiological pathways, right ventricular dysfunction, pulmonary hypertension, and functional tricuspid regurgitation are the main drivers of exercise intolerance, systemic congestion, and prognosis in HFpEF. RV: right ventricular.

Figure 4

Revisited cardiorenal syndrome (modified with permission from Ref. 69). This figure depicts a proposed new paradigm in which common risk factors lead to cardiorenal syndrome that may have either a cardiovascular (CV) or a renal clinical presentation. Bioprofiling with clinical and biomarker information will enable precision medicine optimized to a specific profile. CKD indicates chronic kidney disease. HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; KDIGO, Kidney Disease Improving Global Outcomes; LVH, left ventricular hypertrophy; and RIFLE (Risk, Injury, Failure, Loss, End-Stage).

Figure 5

Pathophysiological mechanisms linking systemic inflammation to diastolic LV stiffness. (A): Systemic inflammation causes the endothelial expression of adhesion molecules (VCAM: vascular cell adhesion molecule). They attract monocytes that become macrophages secreting transforming growth factor β (TGF β), which stimulates myofibroblasts to deposit collagen. (B): Systemic inflammation lowers the endothelial production of nitric oxide (NO), soluble guanylate cyclase (sGC) activity, protein kinase G (PKG) activity, and titin phosphorylation (P). Systemic inflammation also causes the endothelial production of reactive oxygen species (ROS) with the formation of disulfide bonds (S-S) within titin. Both hypophosphorylation and S-S bonds increase titin stiffness. (C): Systemic inflammation boosts the expression of inducible NO synthase (iNOS). This lowers X-box binding protein 1 spliced (XBP1s) and the activation of UPR genes, which can potentially lead to the accumulation of destabilized proteins similar to transthyretin-induced amyloid deposits.