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

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.

Results

Based on left atrial volume index (LAVI) and E/e′ ratio, 700 patients with both primary and secondary dilated cardiomyopathy (DCM) were stratified into three groups reflecting normal, mild, and severe diastolic dysfunction. An exploratory analysis of the clinical dataset revealed that patients with severe diastolic dysfunction are also more likely to exhibit systolic impairment (reflected by lower EF), and to carry a likely pathogenic genetic mutation.

Differential gene expression analysis of a 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. Several differentially regulated genes corresponded to immune response mechanisms, however the involvement of Notch signaling pathway, a key regulator of cardiac development, disease, and regeneration was also identified.

Conclusions

In addition to systolic impairment, DCM patients can also exhibit varying degree of diastolic dysfunction. 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.