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  • The following are the supplementary data related to this


    The following are the supplementary data related to this article.
    Transparency document
    Acknowledgements We thank Angelika Keller and Kerstin Hadamek for excellent technical assistance, and Heinrich Blazyca and Drs. Dennis Klein and Rudolf Martini for generous help with grip strength measurements. Marjolein Bosma is thanked for the analysis of B6 vitamers. We acknowledge the assistance of Charlotte Auth and Gabriel Christmann with immunoblots. This work was supported by the Deutsche Forschungsgemeinschaft SFB728 and SFB688 (to AG) and the IZKF Würzburg (to LH). CW was supported by a predoctoral fellowship from the Medical Faculty of the University of Würzburg (Graduate School of Life Sciences) and by a Kaltenbach predoctoral fellowship from the German Heart Foundation.
    Introduction Heart failure (HF) has historically been defined by the inability of the myocardium to pump blood normally due to an impaired systolic contractile performance of the left ventricle (LV). Recently, cardiologists have identified a subtype of HF presenting clinical signs and symptoms of HF but with normal or nearly normal left ventricular ejection fraction (LVEF) [[1], [2], [3], [4]]. In fact, half of all patients with HF are classified as having diastolic dysfunction and a relatively preserved EF (HFpEF). The diagnosis of HFpEF underlines the quasi-normal systolic function (EF >50%) and allows the discrimination from HF patients with reduced EF (HFrEF) [2,3]. Patients with HFpEF are commonly older than HFrEF patients and often present co-morbidities such as hypertension, obesity, diabetes mellitus, anemia, and atrial fibrillation. Diastolic dysfunction in HFpEF has been frequently associated with LV hypertrophy in response to systemic A 61603 [5,6]. A specific, effective therapy has not yet been identified to treat HFpEF [[7], [8], [9]]. Management to delay disease progression is limited to diuretics, treatment of hypertension, and care of lung function abnormalities and other comorbidities [7,[10], [11], [12]]. Identification of targetable mechanisms involved in the pathogenesis and progression of HFpEF is still a major challenge [13]. The heart of HFpEF patients exhibits structural alterations including cardiac hypertrophy, interstitial fibrosis, and coronary capillary rarefaction [14]. These alterations may contribute to increased LV passive stiffness, impaired relaxation, elevated LV end-diastolic pressure, and enlarged left atrium (LA) due to increased filling pressures [3,4,15]. The underlying mechanisms are diverse and complex, involving systemic inflammation, oxidative stress, coronary microvascular endothelial dysfunction, infiltration by activated macrophages, reactive interstitial fibrosis, changes in the extracellular matrix, and modifications in the phenotype of cardiomyocytes resulting from the myocardial remodeling [9]. Changes in both collagen and titin organization/structure/isoform contribute to the development of passive stiffness [16]. Hypophosphorylation of myofilament proteins and increased Ca2+ sensitivity have also been reported, suggesting that functional impairment at the cardiomyocyte level is an early event [17]. Abnormal intracellular Ca2+ cycling, in relation with impaired intracellular Ca2+ decline following systole and diastolic Ca2+ overload, respectively, may also compromise relaxation and myocyte stiffness [18,19]. The purpose of this study was to investigate the cellular phenotype and Ca2+ handling mechanisms in an experimental model presenting common characteristics of HFpEF and relevant to systemic hypertension. This approach provided a unique access to cellular and molecular functions not accessible in human. Four weeks after surgery, a portion of rats submitted to chronic pressure overload induced by abdominal aortic banding (AAB), recapitulated criteria of preclinical models of HFpEF [20] including lung congestion, concentric hypertrophy, increased LV mass, impaired active relaxation, impaired passive filling, enlarged LA, and cardiomyocytes hypertrophy. The results show stronger contraction of LV myocytes associated with critical alterations in Ca2+ cycling and opposing effects on various Ca2+ handling proteins possibly to maintain normal contraction.