Small left ventricular volume in HFpEF: from phenotype to clinical implications

Abstract

The conventional model of heart failure with preserved ejection fraction (HFpEF) attributes its main pathogenesis to cardio-renal-metabolic interactions that drive myocardial inflammation, fibrosis, concentric left ventricular (LV) hypertrophy, and increased diastolic stiffness, while relatively preserving systolic function. This prevailing paradigm assumes a uniform underlying mechanism across most HFpEF cases and relies on left ventricular ejection fraction (LVEF) as a categorical variable, thereby overlooking its continuous nature and the presence of distinct phenotypes within the preserved LVEF range. Several clinical and patho-physiological observations challenge this paradigm. First, diastolic dysfunction and LV hypertrophy alone do not fully explain the severity of symptoms or outcomes in many patients. 1 Second, epidemiological data indicate that the risk of adverse events remains high as LVEF exceeds 60%-65%, contradicting the assumption that higher EF is invariably protective. 2 Third, emerging evidence indicates distinct haemodynamic patterns between HF with normal and supranormal LVEF. In a cohort study, Rosch et al. reported that patients with LVEF 50%-60% displayed eccentric remodelling, myocardial fibrosis, and preserved stroke volume reserve, whereas those with LVEF >60%, predominantly older hypertensive women, had smaller LV volumes, increased ventricular stiffness, and impaired stroke volume augmentation. 3 Consistent with this concept, Popovic et al. recently provided detailed invasive and imaging evidence in a cohort of 621 patients with HF, showing that individuals with LVEF ≥65% manifest a distinct 'cardiac contracture' phenotype characterized by ventricular stiffening, small cavity dimensions, and limited cardiac output reserve. 4 Forth, a consistent lack of clinical benefit from neurohormonal antagonists , including renin-angiotensin system inhibitors and beta-blockers has been found in patients with HF and LVEF ≥60%-65% across multiple randomized trials and registries. 5 These discrepancies suggest that the prevailing HFpEF framework may fail to capture the full spectrum of phenotypic and mechanistic heterogeneity, particularly in patients at the upper end of the LVEF spectrum. Reframing HFpEF: the small LV engine as a novel pathophysiological framework We advance a novel, testable hypothesis that a small LV represents a central and primary determinant of a distinct HFpEF phenotype. From fundamental physiological principles, reduced LV dimensions confer an intrinsically lower preload reserve and a limited capacity to augment stroke volume during exercise or stress, accompanied by a leftward shift of the LV end-diastolic pressure-volume relationship, indicative of reduced diastolic capacitance (Figure 1). Nature provides striking examples of organisms with small LVs in which cardiac output is sustained primarily through chronotropic reserve. 6 Thereby, 'supra-normal' ejection fraction and tachycardia may be interpreted as compensatory adaptations, rather than primary pathophysiologic drivers, aiming to preserve forward output in the context of reduced preload reserve. Within this framework, LV hypertrophy and conventional indices of diastolic dysfunction would primarily exacerbate the underlying