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Background: Approximately 50% of patients with signs and symptoms of heart failure (HF) are suffering from diastolic dysfunction, termed heart failure with preserved ejection fraction (HFpEF). Right ventricular (RV) dysfunction (RVD) is seen frequently (30%) in these patients and associated with poor clinical outcomes and increased mortality. Currently, there are no specific therapeutic options available addressing RVD in HF. On this account, we studied a well described small animal model of HFpEF, the ZSF-1 obese rat, to investigate a potential RV involvement and underlying pathomechanisms. Results: Echocardiographic and hemodynamic examinations confirmed the previously described HFpEF phenotype of the ZSF-1 obese rat with preserved left ventricular (LV) ejection fraction (LVEF), LV hypertrophy (increased LV mass) and diastolic dysfunction as evident by increased E/e’ ratio and LV end-diastolic filling pressures. Assessment of the RV revealed distinct changes in structure, such as an increased ventricular diameter and thickening of the free wall, and function, i.e. decreased RVEF. Analysis of Ca2+ handling and contractility in isolated RV cardiomyocytes showed distinct changes. Ca2+ transient amplitude was drastically reduced while diastolic [Ca2+]i remained normal. In addition, the frequency-dependent increase of systolic [Ca2+]i was lost. However, RV cardiomyocyte cell shortening amplitude was preserved. RV myofilament Ca2+ sensitivity was increased, which was associated with a hyperphosphorylation of S-282 of the cardiac myosin binding protein C (cMyBP-C) – a known regulator of myofilament Ca2+ sensitivity. Conclusion: RVD is present in this established rat metabolic HFpEF model in-vivo, associated with profound changes in RV cardiomyocyte Ca2+ homeostasis and increased myofilament Ca2+ sensitivity, likely due to hyperphosphorylation of the sarcomeric protein cMyBP-C., Hintergrund: Etwa 50% aller Patienten mit klinischen Zeichen einer Herzinsuffizienz leiden an der sogenannten diastolischen Herzinsuffizienz bzw. Herzinsuffizienz mit erhaltener Ejektionsfraktion (HFpEF). Im Rahmen dieser Erkrankung leiden etwa 30% der Patienten ebenfalls unter einer rechtsventrikulären Dysfunktion (RVD), die mit erhöhter Mortalität in dieser Patientengruppe assoziiert ist. Aktuell sind keine spezifischen Therapeutika für die RVD bei Herzinsuffizienz verfügbar. Aus diesem Grund haben wir ein gängiges Kleintiermodell für HFpEF, die ZSF-1 obese Ratte, auf eine potentielle RVD untersucht, um im Weiteren die zu Grunde liegenden Pathomechanismen zu evaluieren. Ergebnisse: Echokardiographische und hämodynamische Untersuchungen bestätigten den zuvor beschriebenen HFpEF Phänotyp in der ZSF-1 obese Ratte. Es zeigten sich eine erhaltene linksventrikuläre Ejektionsfraktion (LVEF), LV Hypertrophie im Sinne einer gesteigerten LV Masse, sowie eine diastolische Dysfunktion, manifestiert als erhöhte E/e’ Ratio und gesteigerte LV end-diastolische Druckverhältnisse. Die Analyse des RV fand relevante, strukturelle Veränderungen im Sinne einer vergrößerten rechten Herzkammer, sowie einer verdickten freien Wand des RV, als auch funktional eine erniedrigte RVEF vor. In isolierten RV Kardiomyozyten konnten wir signifikante Änderungen in der Ca2+ Homöostase beobachten. Hierzu zählen eine stark verringerte Ca2+ Transienten-Amplitude bei erhaltener diastolischer [Ca2+]i. Die frequenzabhängige Zunahme der systolischen [Ca2+]i-Amplitude ging verloren, wobei die Kontraktilität der Kardiomyozyten erhalten blieb, woraus sich eine gesteigerte Myofilament-Ca2+-Sensitivität in den RV Kardiomyozyten der ZSF-1 obese Tiere ableitete. Dies war assoziiert mit einer Hyperphosphorylierung des kardialen Myosin-bindenden Proteins C (cMyBP-C), einem zuvor beschriebenen Regulator der Myofilament-Ca2+-Sensitiv. Schlussfolgerung: Im etablierten ZSF-1 Ratten HFpEF Model besteht eine RVD, welche mit fundamentalen Änderungen in der kardiomyozytären Ca2+-Homöostase und gesteigerte Myofilament-Ca2+-Sensitivität assoziiert ist und vermutlich durch eine Hypersphosphorylierung des cMyBP-C vermittelt wird.

Aims: Heart failure with preserved ejection fraction (HFpEF) is an increasingly prevalent disease. Physical exercise has been shown to alter disease progression in HFpEF. We examined cardiomyocyte Ca2+ homeostasis and left ventricular function in a metabolic HFpEF model in sedentary and trained rats following 8 weeks of moderate-intensity continuous training (MICT) or high-intensity interval training (HIIT). Methods and results: Left ventricular in vivo function (echocardiography) and cardiomyocyte Ca2+ transients (CaTs) (Fluo-4, confocal) were compared in ZSF-1 obese (metabolic syndrome, HFpEF) and ZSF-1 lean (control) 21- and 28-week-old rats. At 21 weeks, cardiomyocytes from HFpEF rats showed prolonged Ca-2(+) reuptake in cytosolic and nuclear CaTs and impaired Ca2+ release kinetics in nuclear CaTs. At 28 weeks, HFpEF cardiomyocytes had depressed CaT amplitudes, decreased sarcoplasmic reticulum (SR) Ca2+ content, increased SR Ca2+ leak, and elevated diastolic [Ca2+] following increased pacing rate (5 Hz). In trained HFpEF rats (HIIT or MICT), cardiomyocyte SR Ca2+ leak was significantly reduced. While HIIT had no effects on the CaTs (1-5 Hz), MICT accelerated early Ca-2(+) release, reduced the amplitude, and prolonged the CaT without increasing diastolic [Ca2+] or cytosolic Ca2+ load at basal or increased pacing rate (1-5 Hz). MICT lowered pro-arrhythmogenic Ca2+ sparks and attenuated Ca2+-wave propagation in cardiomyocytes. MICT was associated with increased stroke volume in HFpEF. Conclusions: In this metabolic rat model of HFpEF at an advanced stage, Ca2+ release was impaired under baseline conditions. HIIT and MICT differentially affected Ca2+ homeostasis with positive effects of MICT on stroke volume, end-diastolic volume, and cellular arrhythmogenicity.

Aims Heart failure with preserved ejection fraction (HFpEF) is frequently (30%) associated with right ventricular (RV) dysfunction, which increases morbidity and mortality in these patients. Yet cellular mechanisms of RV remodelling and RV dysfunction in HFpEF are not well understood. Here, we evaluated RV cardiomyocyte function in a rat model of metabolically induced HFpEF. Methods and results Heart failure with preserved ejection fraction‐prone animals (ZSF‐1 obese) and control rats (Wistar Kyoto) were fed a high‐caloric diet for 13 weeks. Haemodynamic characterization by echocardiography and invasive catheterization was performed at 22 and 23 weeks of age, respectively. After sacrifice, organ morphometry, RV histology, isolated RV cardiomyocyte function, and calcium (Ca2+) transients were assessed. ZSF‐1 obese rats showed a HFpEF phenotype with left ventricular (LV) hypertrophy, LV diastolic dysfunction (including increased LV end‐diastolic pressures and E/e′ ratio), and preserved LV ejection fraction. ZSF‐1 obese animals developed RV dilatation (50% increased end‐diastolic area) and mildly impaired RV ejection fraction (42%) with evidence of RV hypertrophy. In isolated RV cardiomyocytes from ZSF‐1 obese rats, cell shortening amplitude was preserved, but cytosolic Ca2+ transient amplitude was reduced. In addition, augmentation of cytosolic Ca2+ release with increased stimulation frequency was lost in ZSF‐1 obese rats. Myofilament sensitivity was increased, while contractile kinetics were largely unaffected in intact isolated RV cardiomyocytes from ZSF‐1 obese rats. Western blot analysis revealed significantly increased phosphorylation of cardiac myosin‐binding protein C (Ser282 cMyBP‐C) but no change in phosphorylation of troponin I (Ser23, 24 TnI) in RV myocardium from ZSF‐1 obese rats. Conclusions Right ventricular dysfunction in obese ZSF‐1 rats with HFpEF is associated with intrinsic RV cardiomyocyte remodelling including reduced cytosolic Ca2+ amplitudes, loss of frequency‐dependent augmentation of Ca2+ release, and increased myofilament Ca2+ sensitivity.

Additional file 1: Figure S1. (A) Longitudinal and (B) transversal LV fractional shortening as observed in echocardiography (parasternal long axis view). (C) Correlation of longitudinal and (D) transversal LV fractional shortening with LA volume. (E) Exemplary electrocardiogram to monitor atrial fibrillation (excerpt of 30 min continuous recording). (F) Total occurrence of atrial fibrillation during screened time intervals. (G) Serum concentration of creatinine and (H) urea. Statistical analysis: Two-way ANOVA followed by post-hoc Bonferroni (G, H). n = animals. 10.016, 2

Metabolic syndrome-mediated heart failure with preserved ejection fraction (HFpEF) is commonly accompanied by left atrial (LA) cardiomyopathy, significantly affecting morbidity and mortality. We evaluate the role of reactive oxygen species (ROS) and intrinsic inflammation (TNF-&alpha, IL-10) related to dysfunctional Ca2+ homeostasis of LA cardiomyocytes in a rat model of metabolic HFpEF. ZFS-1 obese rats showed features of HFpEF and atrial cardiomyopathy in vivo: increased left ventricular (LV) mass, E/e&rsquo, and LA size and preserved LV ejection fraction. In vitro, LA cardiomyocytes exhibited more mitochondrial-fission (MitoTracker) and ROS-production (H2DCF). In wildtype (WT), pro-inflammatory TNF-&alpha, impaired cellular Ca2+ homeostasis, while anti-inflammatory IL-10 had no notable effect (confocal microscopy, Fluo-4). In HFpEF, TNF-&alpha, had no effect on Ca2+ homeostasis associated with decreased TNF-&alpha, receptor expression (western blot). In addition, IL-10 substantially improved Ca2+ release and reuptake, while IL-10 receptor-1 expression was unaltered. Oxidative stress in metabolic syndrome mediated LA cardiomyopathy was increased and anti-inflammatory treatment positively affected dysfunctional Ca2+ homeostasis. Our data indicates, that patients with HFpEF-related LA dysfunction might profit from IL-10 targeted therapy, which should be further explored in preclinical trials.