Heart failure is preceded by ventricular remodeling, changes in left ventricular mass, and myocardial volume after alterations in loading conditions. Concentric hypertrophy arises after pressure overload, involves wall thickening, and forms a substrate for diastolic dysfunction. Eccentric hypertrophy develops in volume overload conditions and leads wall thinning, chamber dilation, and reduced ejection fraction. The molecular events underlying these distinct forms of cardiac remodeling are poorly understood. Here, we demonstrate that miR-148a expression changes dynamically in distinct subtypes of heart failure: while it is elevated in concentric hypertrophy, it decreased in dilated cardiomyopathy. In line, antagomir-mediated silencing of miR-148a caused wall thinning, chamber dilation, increased left ventricle volume, and reduced ejection fraction. Additionally, adeno-associated viral delivery of miR-148a protected the mouse heart from pressure-overload-induced systolic dysfunction by preventing the transition of concentric hypertrophic remodeling toward dilation. Mechanistically, miR-148a targets the cytokine co-receptor glycoprotein 130 (gp130) and connects cardiomyocyte responsiveness to extracellular cytokines by modulating the Stat3 signaling. These findings show the ability of miR-148a to prevent the transition of pressure-overload induced concentric hypertrophic remodeling toward eccentric hypertrophy and dilated cardiomyopathy and provide evidence for the existence of separate molecular programs inducing distinct forms of myocardial remodeling.

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So far, opposing outcomes have been reported following neonatal apex resection in mice, questioning the validity of this injury model to investigate regenerative mechanisms. We performed a systematic evaluation, up to 180 days after surgery, of the pathophysiological events activated upon apex resection. In response to cardiac injury, we observed increased cardiomyocyte proliferation in remote and apex regions, neovascularization, and local fibrosis. In adulthood, resected hearts remain consistently shorter and display permanent fibrotic tissue deposition in the center of the resection plane, indicating limited apex regrowth. However, thickening of the left ventricle wall, explained by an upsurge in cardiomyocyte proliferation during the initial response to injury, compensated cardiomyocyte loss and supported normal systolic function. Thus, apex resection triggers both regenerative and reparative mechanisms, endorsing this injury model for studies aimed at promoting cardiomyocyte proliferation and/or downplaying fibrosis.

Worldwide, over 26 million patients suffer from heart failure (HF). One strategy aspiring to prevent or even to reverse HF is based on the transplantation of cardiac tissue‐engineered (cTE) constructs. These patient‐specific constructs aim to closely resemble the native myocardium and, upon implantation on the diseased tissue, support and restore cardiac function, thereby preventing the development of HF. However, cTE constructs off‐the‐shelf availability in the clinical arena critically depends on the development of efficient preservation methodologies. Short‐ and long‐term preservation of cTE constructs would enable transportation and direct availability. Herein, currently available methods, from normothermic‐ to hypothermic‐ to cryopreservation, for the preservation of cardiomyocytes, whole‐heart, and regenerative materials are reviewed. A theoretical foundation and recommendations for future research on developing cTE construct specific preservation methods are provided. Current research suggests that vitrification can be a promising procedure to ensure long‐term cryopreservation of cTE constructs, despite the need of high doses of cytotoxic cryoprotective agents. Instead, short‐term cTE construct preservation can be achieved at normothermic or hypothermic temperatures by administration of protective additives. With further tuning of these promising methods, it is anticipated that cTE construct therapy can be brought one step closer to the patient.

Background and Purpose: The increasing number of cancer survivors has caused growing concern over chemotherapy‐induced cardiotoxicity. This study aimed to investigate a novel human model of cardiotoxicity and explore cardioprotection.Experimental Approach: Living myocardial slices (LMS) were obtained from explanted end‐stage heart failure hearts, then exposed to doxorubicin (Dox) to investigate cardiotoxic effects and to dexrazoxane (Dex) to explore cardioprotection. We assessed contractile function and glucose consumption, followed by evaluation of calcium transients, structural integrity and transcriptomic changes. Additionally, electrocardiogram (ECG) alterations were analysed in patients treated with anthracyclines to corroborate the cardiotoxicity findings from LMS.Key Results: We observed distinct functional responses to Dox, with LMS derived from some patients exhibiting high susceptibility to Dox‐induced cardiotoxicity. LMS from susceptible patients displayed reduced contractile function and excitability, myofibre dyssynchrony, structural damage and decreased metabolic activity. Dex pretreatment partially mitigated these effects, preserving contractile function and preventing structural damage. Consistent with ex vivo findings, patients treated with anthracyclines exhibited acute and chronic alterations in T‐, P‐ and R‐wave morphology of the ECG, confirming variable susceptibility at the clinical level.Conclusions and Implications: We highlight the value of human LMS in studying Dox‐induced cardiotoxicity and the cardioprotective potential of Dex, even when sourced from end‐stage heart failure patients. Susceptible patients harboured cardiomyopathy‐associated genetic mutations, suggesting that genetic screening including cardiomyopathy‐associated genes, prior to anthracycline treatment, could enable improved patient risk stratification. We demonstrate the potential utility of ECG changes for early detection of subclinical cardiotoxicity.