Aim: Calcium ions play a pivotal role in matching energy supply and demand in cardiac muscle. Mitochondrial calcium concentration is lower in animal models of heart failure with reduced ejection fraction (HFrEF), but limited information is available about mitochondrial calcium handling in heart failure with preserved ejection fraction (HFpEF).Methods: We assessed mitochondrial Ca²⁺ handling in intact cardiomyocytes from Zucker/fatty Spontaneously hypertensive F1 hybrid (ZSF1)‐lean (control) and ZSF1‐obese rats, a metabolic risk‐related model of HFpEF. A mitochondrially targeted Ca²⁺ indicator (MitoCam) was expressed in cultured adult rat cardiomyocytes. Cytosolic and mitochondrial Ca²⁺ transients were measured at different stimulation frequencies. Mitochondrial respiration and swelling, and expression of key proteins were determined ex vivo.Results: At rest, mitochondrial Ca²⁺ concentration in ZSF1‐obese was larger than in ZSF1‐lean. The diastolic and systolic mitochondrial Ca²⁺ concentrations increased with stimulation frequency, but the steady‐state levels were larger in ZSF1‐obese. The half‐widths of the contractile responses, the resting cytosolic Ca²⁺ concentration and the decay half‐times of the cytosolic Ca²⁺ transients were higher in ZSF1‐obese, likely because of a lower SERCA2a/phospholamban ratio. Mitochondrial respiration was lower, particularly with nicotinamide adenine dinucleotide (NADH) (complex I) substrates, and mitochondrial swelling was larger in ZSF1‐obese.Conclusion: The free mitochondrial calcium concentration is higher in HFpEF owing to alterations in mitochondrial and cytosolic Ca²⁺ handling. This coupling between cytosolic and mitochondrial Ca²⁺ levels may compensate for myocardial ATP supply in vivo under conditions of mild mitochondrial dysfunction. However, if mitochondrial Ca²⁺ concentration is sustainedly increased, it might trigger mitochondrial permeability transition pore opening.

Vast parts of mammalian genomes are actively transcribed, predominantly giving rise to non-coding RNA (ncRNA) transcripts including microRNAs, long ncRNAs, and circular RNAs among others. Contrary to previous opinions that most of these RNAs are non-functional molecules, they are now recognized as critical regulators of many physiological and pathological processes including those of the cardiovascular system. The discovery of functional ncRNAs has opened up new research avenues aiming at understanding ncRNA-related disease mechanisms as well as exploiting them as novel therapeutics in cardiovascular therapy. In this review, we give an update on the current progress in ncRNA research, particularly focusing on cardiovascular physiological and disease processes, which are under current investigation at the ESC Working Groups of Myocardial Function and Cellular Biology of the Heart. This includes a range of topics such as extracellular vesicle-mediated communication, neurohormonal regulation, inflammation, cardiac remodelling, cardio-oncology as well as cardiac development and regeneration, collectively highlighting the wide-spread involvement and importance of ncRNAs in the cardiovascular system.

Although increased oxidative stress is a major component of diabetic hypertensive cardiomyopathy, research into the effects of antioxidants on cardiac remodeling remains scarce. The actions of antioxidant apocynin include inhibiting reactive oxygen species (ROS) generation by nicotinamide adenine dinucleotide phosphate (NADPH) oxidases and ROS scavenging. We evaluated the effects of apocynin on cardiac remodeling in spontaneously hypertensive rats (SHR) with diabetes mellitus (DM). Male SHR were divided into four groups: control (SHR, n = 16); SHR treated with apocynin (SHR-APO; 16 mg/kg/day, added to drinking water; n = 16); diabetic SHR (SHR-DM, n = 13); and SHR-DM treated with apocynin (SHR-DM-APO, n = 14), for eight weeks. DM was induced by streptozotocin (40 mg/kg, single dose). Statistical analyzes: ANOVA and Tukey or Mann–Whitney. Echocardiogram in diabetic groups showed higher left ventricular and left atrium diameters indexed for body weight, and higher isovolumetric relaxation time than normoglycemic rats; systolic function did not differ between groups. Isolated papillary muscle showed impaired contractile and relaxation function in diabetic groups. Developed tension was lower in SHR-APO than SHR. Myocardial hydroxyproline concentration was higher in SHR-DM than SHR, interstitial collagen fraction was higher in SHR-DM-APO than SHR-APO, and type III collagen protein expression was lower in SHR-DM and SHR-DM-APO than their controls. Type I collagen and lysyl oxidase expression did not differ between groups. Apocynin did not change collagen tissue. Myocardial lipid hydroperoxide concentration was higher in SHR-DM than SHR and SHR-DM-APO. Glutathione peroxidase activity was lower and catalase higher in SHR-DM than SHR. Apocynin attenuated antioxidant enzyme activity changes in SHR-DM-APO. Advanced glycation end-products and NADPH oxidase activity did not differ between groups. Apocynin reduces oxidative stress independently of NADPH oxidase activity and does not change ventricular or myocardial function in spontaneously hypertensive rats with diabetes mellitus. The apocynin-induced myocardial functional impairment in SHR shows that apocynin actions need to be clarified during sustained chronic pressure overload.

Small extracellular vesicles (sEV) derived from various cell sources have been demonstrated to enhance cardiac function in preclinical models of myocardial infarction (MI). The aim of this study was to compare different sources of sEV for cardiac repair and determine the most effective one, which nowadays remains limited. We comprehensively assessed the efficacy of sEV obtained from human primary bone marrow mesenchymal stromal cells (BM‐MSC), human immortalized MSC (hTERT‐MSC), human embryonic stem cells (ESC), ESC‐derived cardiac progenitor cells (CPC), human ESC‐derived cardiomyocytes (CM), and human primary ventricular cardiac fibroblasts (VCF), in in vitro models of cardiac repair. ESC‐derived sEV (ESC‐sEV) exhibited the best pro‐angiogenic and anti‐fibrotic effects in vitro. Then, we evaluated the functionality of the sEV with the most promising performances in vitro, in a murine model of MI‐reperfusion injury (IRI) and analysed their RNA and protein compositions. In vivo, ESC‐sEV provided the most favourable outcome after MI by reducing adverse cardiac remodelling through down‐regulating fibrosis and increasing angiogenesis. Furthermore, transcriptomic, and proteomic characterizations of sEV derived from hTERT‐MSC, ESC, and CPC revealed factors in ESC‐sEV that potentially drove the observed functions. In conclusion, ESC‐sEV holds great promise as a cell‐free treatment for promoting cardiac repair following MI.

Heart failure (HF) is a systemic disease that can be divided into HF with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). HFpEF accounts for over 50% of all HF patients and is typically associated with high prevalence of several comorbidities, including hypertension, diabetes mellitus, pulmonary hypertension, obesity, and atrial fibrillation. Myocardial remodeling occurs both in HFrEF and HFpEF and it involves changes in cardiac structure, myocardial composition, and myocyte deformation and multiple biochemical and molecular alterations that impact heart function and its reserve capacity. Understanding the features of myocardial remodeling has become a major objective for limiting or reversing its progression, the latter known as reverse remodeling (RR). Research on HFrEF RR process is broader and has delivered effective therapeutic strategies, which have been employed for some decades. However, the RR process in HFpEF is less clear partly due to the lack of information on HFpEF pathophysiology and to the long list of failed standard HF therapeutics strategies in these patient's outcomes. Nevertheless, new proteins, protein-protein interactions, and signaling pathways are being explored as potential new targets for HFpEF remodeling and RR. Here, we review recent translational and clinical research in HFpEF myocardial remodeling to provide an overview on the most important features of RR, comparing HFpEF with HFrEF conditions.

“Obesity cardiomyopathy” effects have been widely described; however, the specific contribution of metabolic changes and altered adipokine secretion are still uncharacterized. Moreover, a diagnosis based on body mass index might not be the most accurate to identify increased adiposity and its outcomes. In this study, we aimed to determine the impact of a Western-type diet [hypercaloric diet (HCD)] ingestion on biventricular structure and function, as well as the metabolic and endocrine changes that occur before the establishment of overt obesity. Wistar rats were fed for 6 wk with a regular diet or HCD. At the end of the protocol, metabolic tests, cardiac structure, and functional evaluation were performed, and blood and tissue samples collected to perform histological, molecular biology, and functional studies. The animals that ingested the HCD presented increased adiposity and larger adipocyte cross-sectional area, but similar body weight compared with the regular diet group. At the cardiac level, HCD induced biventricular cardiomyocyte hypertrophy, fibrosis, increased stiffness, and impaired relaxation. Galectin-3 plasma expression was likewise elevated in the same animals. The nutritional modulation also altered the secretory pattern of the adipose tissue, originating a proinflammatory systemic environment. In this study, we observed that before “clinical” overweight or frank obesity is established, the ingestion of a HCD-induced cardiac remodeling manifests by increased biventricular stiffness and diastolic dysfunction. The mechanism triggering the cardiac alterations appears to be the proinflammatory environment promoted by the adipose tissue dysfunction. Furthermore, galectin-3, a profibrotic molecule, might be a potential biomarker for the myocardial alterations promoted by the HCD before overweight or obesity.