Left ventricular dysfunction in heart failure with preserved ejection fraction-molecular mechanisms and impact on right ventricular function

Abstract

The current classification of heart failure (HF) based on left ventricular (LV) ejection fraction (EF) identifies a large group of patients with preserved ejection fraction (HFpEF) with significant morbidity and mortality but without prognostic benefit from current HF therapy. Co-morbidities and conditions such as arterial hypertension, diabetes mellitus, chronic kidney disease, adiposity and aging shape the clinical phenotype and contribute to mortality. LV diastolic dysfunction and LV structural remodeling are hallmarks of HFpEF, and are linked to remodeling of the cardiomyocyte and extracellular matrix. Pulmonary hypertension (PH) and right ventricular dysfunction (RVD) are particularly common in HFpEF, and mortality is up to 10-fold higher in HFpEF patients with vs. without RV dysfunction. Here, we review alterations in cardiomyocyte function (i.e., ion homeostasis, sarcomere function and cellular metabolism) associated with diastolic dysfunction and summarize the main underlying cellular pathways. The contribution and interaction of systemic and regional upstream signaling such as chronic inflammation, neurohumoral activation, and NO-cGMP-related pathways are outlined in detail, and their diagnostic and therapeutic potential is discussed in the context of preclinical and clinical studies. In addition, we summarize prevalence and pathomechanisms of RV dysfunction in the context of HFpEF and discuss mechanisms connecting LV and RV dysfunction in HFpEF. Dissecting the molecular mechanisms of LV and RV dysfunction in HFpEF may provide a basis for an improved classification of HFpEF and for therapeutic approaches tailored to the molecular phenotype.

Keywords: Heart failure (HF); calcium; cardiomyocytes; metabolism; pulmonary hypertension (PH); right ventricle; sodium.

Figure 1

Mechanisms of cardiomyocyte dysfunction in HFpEF. Cardiomyocyte phenotypes include altered ion homeostasis (increased cytosolic Ca²⁺ and Na⁺ load), increased myofilament Ca²⁺ sensitivity, slower sarcomere relaxation and increased passive stiffness linked to reduced cGMP-PKG-mediated signaling. Mitochondrial oxidative capacity is reduced due to dysregulated intracellular metabolic processing despite an increased external supply with energy substrates. ROS (from mitochondria and external sources) and reduced NO availability contribute to increased oxidative and nitrosative stress and metabolic toxicity. HFpEF, heart failure with preserved ejection fraction; ROS, reactive oxygen species; NO, nitric oxide.

Figure 2

Myocardial remodeling in HFrEF and HFpEF. HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction.

Figure 3

RVD in HFpEF vs. HFrEF. HFpEF is characterized by concentric LV hypertrophy. In turn, LV cavity size, EDV, and ultimately SV decrease. The resulting ventricular output imbalance between LV and RV increases the prevalence of PH-LHD and hence, the probability of RVD. Conversely, HFrEF causes LV dilatation, increasing LV cavity size and EDV. This enables the LV to transiently maintain a stable SV despite a reduced EF. As a consequence, ventricular output imbalance, PH-LHD and ultimately RVD are less common in HFrEF. RVD, right ventricular dysfunction; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LV, left ventricular; EDV, end-diastolic volume; SV, stroke volume; PH-LHD, pulmonary hypertension associated with left heart disease.