The role of diastolic dysfunction in heart failure with reduced ejection fraction (HFrEF)

Abstract Background Heart Failure (HF) is traditionally categorized as HF with reduced (HFrEF) and preserved (HFpEF) Ejection Fraction (EF), depending on whether this parameter is ≤40% or ≥50%, respectively. According to this classification, HFrEF is defined by systolic dysfunction and contraction problems, whereas HFpEF is characterized by diastolic dysfunction and filling problems. Even with the introduction of a third category, Heart Failure with mildly reduced EF, this classification still overlooks that diastolic dysfunction may also occur in HFrEF, and systolic impairment in HFpEF. To better address the complexity of clinical presentations, we aim to investigate the role of diastolic function in the prognosis and clinical course of HFrEF. Methods Based on left atrial volume index (LAVI) and E/e′ ratio, 700 patients with dilatedcardiomyopathy (DCM) were stratified into three groups reflecting normal, mild, and severe diastolic dysfunction. Within this DCM cohort, we performed an integrative survival analysis incorporating echocardiographic and clinical information (such as heart failure-related hospitalizations, life-threatening arrhythmic events, and cardiac mortality) to assess the impact of diastolic dysfunction on patient outcomes. In parallel, we analysed bulk RNA sequencing of right septal biopsies in a subset of 200 DCM patients to determine differences in gene expression and pathway activation between the previously characterized diastolic dysfunction groups. Results An exploratory analysis of the clinical dataset revealed that both primary and secondary DCM cases were included in the study: 83 out of 700 patients tested positive for a likely pathogenic (LP) mutation, of whom 40 carry a titin truncating variant (TTV). While age does not differ significantly among groups, patients with severe diastolic dysfunction are also more likely to exhibit systolic impairment (reflected by lower EF), and to carry a LP genetic mutation. Differential gene expression analysis of the 200-patient RNA-seq dataset subset, normalized for age, sex, and EF, identified 6 upregulated genes in patients with severe diastolic dysfunction relative to those with mild dysfunction and normal function. The corresponding proteins are primarily associated with immune response mechanisms, whereas one candidate gene is predicted to participate in the Notch signaling pathway, a key regulator of cardiac development, disease, and regeneration. Conclusions In addition to systolic impairment, DCM patients can also exhibit varying degree of diastolic dysfunction, suggesting that the traditional classification of HF into HFrEF and HFpEF is an oversimplified picture of a much more complex disease spectrum. More severe diastolic dysfunction in DCM patients is not only associated with higher likelihood of carrying a LP genetic mutation but also with key differences in gene expression, which suggest a role for both immune response and Notch signalling.