Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome often characterized by elevated left ventricular (LV) filling pressures (1). Hypertension is a well-known major risk factor in HFpEF pathogenesis, contributing also to increased LV chamber stiffness. However, elevated filling pressures are frequently observed even in patients with well-controlled blood pressure and no overt structural abnormalities, such as LV hypertrophy. This phenomenon also occurs in some elderly individuals without a formal HFpEF diagnosis. In this context, myocardial fibrosis has been shown to be one of the main pathological lesions of the cardiac tissue contributing to HFpEF and to chamber stiffness (2,3).

In their current study, Weil and colleagues investigate the short-term reversibility of LV fibrosis and chamber stiffness developed following repetitive brief pressure overload induction (4), highlighting the potential long-term consequences of transient hypertensive episodes.

Building on previous findings (5), the authors demonstrate that short duration increases in preload and afterload can rapidly induce myocardial stiffness in otherwise normal swine hearts. Specifically, two hours of daily phenylephrine (PE) infusion over two weeks led to elevated LV chamber stiffness, accompanied by increased interstitial fibrosis and capillary rarefaction.

Interestingly, although hemodynamics normalized after cessation of PE, and were stable 2 weeks and 4 weeks after, both fibrosis and chamber stiffness remained elevated. In fact, fibrosis not only persisted but tended to worsen at 2 weeks and remained elevated at 4 weeks. Proteomic profiling revealed a delayed increase in multiple collagen subtypes and basement membrane proteins, suggesting sustained extracellular matrix (ECM) remodeling independent of hemodynamic load. This phenotype, a stiff, fibrotic, yet structurally normal heart, mirrors a clinically relevant HFpEF subgroup, particularly among older adults who exhibit diastolic dysfunction despite controlled blood pressure and absence of hypertrophy.

Importantly, although the animals did not develop LV hypertrophy, cardiomyocyte size increased and cell density decreased, which may reflect myocardial injury, as supported by the observed decrease in ejection fraction and rise in troponin levels. Moreover, non-ECM contributors to myocardial stiffness, such as titin alterations (6), may also play a role and warrant further investigation.
From a clinical standpoint, these findings suggest that even brief episodes of pressure overload, such as those associated with transient hypertension or age-related reductions in aortic compliance, may induce lasting myocardial alterations. However, further studies are needed to determine whether fibrosis and chamber stiffness persist in the long term.

Notably, the persistence of fibrosis despite normalization of hemodynamic stress underscores the central role of ECM remodeling in HFpEF pathophysiology. This finding highlights the need for the development of antifibrotic therapeutic strategies that go beyond hemodynamic control, aiming instead to directly target fibroblast activation and reduce the synthesis of profibrotic molecules (3), with the objective of reversing established interstitial fibrosis and restoring normal chamber compliance.

Furthermore, the impact of brief, intermittent pressure overload emphasizes the importance of early detection, management, and monitoring of at-risk individuals (HFpEF stage B), to prevent myocardial damage and progression to symptomatic HFpEF (stage C).