Myocardial hypertrophy and its role in heart failure with preserved ejection fraction

Abstract

Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, increased mechanical load, and cytokines associated with arterial hypertension, chronic kidney disease, diabetes, and other comorbidities. Here we discuss the experimental and clinical evidence that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. Mechanisms leading to diastolic dysfunction in LVH are incompletely understood, but may include extracellular matrix changes, vascular dysfunction, as well as altered cardiomyocyte mechano-elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we and others have shown increased Ca(2+) turnover and impaired relaxation in cardiomyocytes from hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical setting of patients with compound comorbidities, diastolic dysfunction may occur independently of LVH. This may be one explanation why current approaches to reduce LVH have not been effective to improve symptoms and prognosis in HFpEF. Exercise training, on the other hand, in clinical trials improved exercise tolerance and diastolic function, but did not reduce LVH. Thus current clinical evidence does not support regression of LVH as a surrogate marker for (short-term) improvement of HFpEF.

Keywords: HFpEF; cardiac myocytes; diastolic dysfunction; left ventricular hypertrophy; remodeling.

Figure 1

Role of left ventricular hypertrophy in heart failure. Based on (89), heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction are driven by different pathomechanisms (blue and red arrows). While both share some degree of neurohumoral activation (middle), the proposed paradigm suggests systemic low-grade inflammation and oxidative stress are more prominent mediators of HFpEF whereas cardiomyocyte injury is pivotal in HFrEF. Downstream signaling activates some protective (green circular arrow) but overwhelmingly maladaptive (red circular arrows) pathways (5). Left ventricular hypertrophic remodeling is common but not inevitable (thin arrows), however, the cellular phenotype differs in HFpEF vs HFrEF. See text for more details.

Figure 2

Cellular pathomechanisms linking left ventricular hypertrophy to diastolic dysfunction. See text for details.

Figure 3

Upper left: Example [Ca2+]i transients from healthy (N=3) and remodeled hearts (N=2, ejection fraction ⍰ 45%; 1 with concentric remodeling and 1 with eccentric hypertrophy). Ca2+ transient amplitude (upper right) was significantly increased, changes in time to half maximal release (TF50, lower left) and relaxation (RT50, lower right) did not reach significance (number in bars indicate number of cells, error bars=S.E.M.).