page 1 Myocardial Hypertrophy and Its Role in Heart Failure with Preserved Ejection 1 Fraction 2

Abstract 13 Left ventricular hypertrophy (LVH) is the most common myocardial structural abnormality associated 14 with heart failure with preserved ejection fraction (HFpEF). LVH is driven by neurohumoral activation, 15 increased mechanical load and cytokines associated with arterial hypertension, chronic kidney 16 disease, diabetes and other co-morbidities. Here we discuss the experimental and clinical evidence 17 that links LVH to diastolic dysfunction and qualifies LVH as one diagnostic marker for HFpEF. 18 Mechanisms leading to diastolic dysfunction in LVH are incompletely understood but may include 19 extracellular matrix changes, vascular dysfunction as well as altered cardiomyocyte mechano-20 elastical properties. Beating cardiomyocytes from HFpEF patients have not yet been studied, but we 21 and others have shown increased Ca2+ turnover and impaired relaxation in cardiomyocytes from 22 hypertrophied hearts. Structural myocardial remodeling can lead to heterogeneity in regional 23 myocardial contractile function, which contributes to diastolic dysfunction in HFpEF. In the clinical 24 setting of patients with compound co-morbidities, diastolic dysfunction may occur independently of 25 LVH. This may be one explanation why current approaches to reduce LVH have not been effective to 26 improve symptoms and prognosis in HFpEF. Exercise training on the other hand, in clinical trials 2