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Cardiovascular disease (CVD) is the leading cause of morbimortality in Europe and worldwide. CVD imposes a heterogeneous spectrum of cardiac remodelling, depending on the insult nature, that is, pressure or volume overload, ischaemia, arrhythmias, infection, pathogenic gene variant, or cardiotoxicity. Moreover, the progression of CVD‐induced remodelling is influenced by sex, age, genetic background and comorbidities, impacting patients' outcomes and prognosis. Cardiac reverse remodelling (RR) is defined as any normative improvement in cardiac geometry and function, driven by therapeutic interventions and rarely occurring spontaneously. While RR is the outcome desired for most CVD treatments, they often only slow/halt its progression or modify risk factors, calling for novel and more timely RR approaches. Interventions triggering RR depend on the myocardial insult and include drugs (renin–angiotensin–aldosterone system inhibitors, beta‐blockers, diuretics and sodium–glucose cotransporter 2 inhibitors), devices (cardiac resynchronization therapy, ventricular assist devices), surgeries (valve replacement, coronary artery bypass graft), or physiological responses (deconditioning, postpartum). Subsequently, cardiac RR is inferred from the degree of normalization of left ventricular mass, ejection fraction and end‐diastolic/end‐systolic volumes, whose extent often correlates with patients' prognosis. However, strategies aimed at achieving sustained cardiac improvement, predictive models assessing the extent of RR, or even clinical endpoints that allow for distinguishing complete from incomplete RR or adverse remodelling objectively, remain limited and controversial. This scientific statement aims to define RR, clarify its underlying (patho)physiologic mechanisms and address (non)pharmacological options and promising strategies to promote RR, focusing on the left heart. We highlight the predictors of the extent of RR and review the prognostic significance/impact of incomplete RR/adverse remodelling. Lastly, we present an overview of RR animal models and potential future strategies under pre‐clinical evaluation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: We have previously shown that treatment with recombinant human neuregulin‐1 (rhNRG‐1) improves pulmonary arterial hypertension (PAH) in a monocrotaline (MCT)‐induced animal model, by decreasing pulmonary arterial remodelling and endothelial dysfunction, as well as by restoring right ventricular (RV) function. Additionally, rhNRG‐1 treatment showed direct myocardial anti‐remodelling effects in a model of pressure loading of the RV without PAH. This work aimed to study the intrinsic cardiac effects of rhNRG‐1 on experimental PAH and RV pressure overload, and more specifically on diastolic stiffness, at both the ventricular and cardiomyocyte level. We studied the effects of chronic rhNRG‐1 treatment on ventricular passive stiffness in RV and LV samples from MCT‐induced PAH animals and in the RV from animals with compensated and decompensated RV hypertrophy, through a mild and severe pulmonary artery banding (PAB). We also measured passive tension in isolated cardiomyocytes and quantified the expression of myocardial remodelling‐associated genes and calcium handling proteins. Chronic rhNRG‐1 treatment decreased passive tension development in RV and LV isolated from animals with MCT‐induced PAH. This decrease was associated with increased phospholamban phosphorylation, and with attenuation of the expression of cardiac maladaptive remodelling markers. Finally, we showed that rhNRG‐1 therapy decreased RV remodelling and cardiomyocyte passive tension development in PAB‐induced RV hypertrophy animals, without compromising cardiac function, pointing to cardiac‐specific effects in both hypertrophy stages. In conclusion, we demonstrated that rhNRG‐1 treatment decreased RV intrinsic diastolic stiffness, through the improvement of calcium handling and cardiac remodelling signalling. [ABSTRACT FROM AUTHOR]

As heart failure with preserved ejection fraction (HFpEF) rises to epidemic proportions, major steps in patient management and therapeutic development are badly needed. With the current position paper we seek to update our view on HFpEF as a highly complex systemic syndrome, from risk factors and mechanisms to long-term clinical manifestations. We will revise recent advances in animal model development, experimental set-ups and basic and translational science approaches to HFpEF research, highlighting their drawbacks and advantages. Directions are provided for proper model selection as well as for integrative functional evaluation from the in vivo setting to in vitro cell function testing. Additionally, we address new research challenges that require integration of higher-order inter-organ and inter-cell communication to achieve a full systems biology perspective of HFpEF. [ABSTRACT FROM AUTHOR]

Key points This paper describes a novel model that allows exploration of matrix-induced cardiomyocyte adaptations independent of the passive effect of matrix rigidity on cardiomyocyte function., Detachment of adult cardiomyocytes from the matrix enables the study of matrix effects on cell shortening, Ca2+ handling and myofilament function., Cell shortening and Ca2+ handling are altered in cardiomyocytes cultured for 24 h on a stiff matrix., Matrix stiffness-impaired cardiomyocyte contractility is reversed upon normalization of extracellular stiffness., Matrix stiffness-induced reduction in unloaded shortening is more pronounced in cardiomyocytes isolated from obese ZSF1 rats with heart failure with preserved ejection fraction compared to lean ZSF1 rats., Abstract Extracellular matrix (ECM) stiffening is a key element of cardiac disease. Increased rigidity of the ECM passively inhibits cardiac contraction, but if and how matrix stiffening also actively alters cardiomyocyte contractility is incompletely understood. In vitro models designed to study cardiomyocyte-matrix interaction lack the possibility to separate passive inhibition by a stiff matrix from active matrix-induced alterations of cardiomyocyte properties. Here we introduce a novel experimental model that allows exploration of cardiomyocyte functional alterations in response to matrix stiffening. Adult rat cardiomyocytes were cultured for 24 h on matrices of tuneable stiffness representing the healthy and the diseased heart and detached from their matrix before functional measurements. We demonstrate that matrix stiffening, independent of passive inhibition, reduces cell shortening and Ca2+ handling but does not alter myofilament-generated force. Additionally, detachment of adult cultured cardiomyocytes allowed the transfer of cells from one matrix to another. This revealed that stiffness-induced cardiomyocyte changes are reversed when matrix stiffness is normalized. These matrix stiffness-induced changes in cardiomyocyte function could not be explained by adaptation in the microtubules. Additionally, cardiomyocytes isolated from stiff hearts of the obese ZSF1 rat model of heart failure with preserved ejection fraction show more pronounced reduction in unloaded shortening in response to matrix stiffening. Taken together, we introduce a method that allows evaluation of the influence of ECM properties on cardiomyocyte function separate from the passive inhibitory component of a stiff matrix. As such, it adds an important and physiologically relevant tool to investigate the functional consequences of cardiomyocyte-matrix interactions. [ABSTRACT FROM AUTHOR]

The aim of the present study was to investigate how early the onset of ischaemia-induced changes in gene expression is in remote myocardium, and whether these changes would be different for left and right ventricles. Wistar rats (n=27) were randomly assigned to left coronary artery (LCA) ligation for 30 or 120 min and sham groups. Evans Blue infusion revealed antero-apical left ventricle (LV) and left intraventricular (IV) septal ischaemia (35.5+/-0.6% of LV mass). LCA ligation induced transient LV systolic dysfunction and sustained biventricular slowing of relaxation. Regarding mRNA levels, type B natriuretic peptide (BNP) was upregulated in the LV at 30 (+370+/-191%) and 120 min (+221+/-112%), whilst in the right ventricle (RV) this was only significant at 120 min (+128+/-39%). Hipoxia-inducible factor 1alpha and interleukin 6 overexpression positively correlated with BNP. Inducible NO synthase upregulation was present in both ventricles at 120 min (LV, +327+/-195%; RV, +311+/-122%), but only in the RV at 30 min (+256+/-88%). Insulin-like growth factor 1 increased in both ventricles at 30 (RV, +59+/-18%; LV, +567+/-192%) and 120 min (RV, +69+/-33%; LV, +120+/-24%). Prepro-endothelin-1 was upregulated in the RV at 120 min (+77+/-25%). Ca2+-handling proteins were selectively changed in the LV at 120 min (sarcoplasmic reticulum Ca2+ ATPase, 53+/-7%; phospholamban, +31+/-4%; Na+-Ca2+ exchanger, 31+/-6%), while Na+-H+ exchanger was altered only in the RV (-79+/-5%, 30 min; +155+/-70%, 120 min). Tumour necrosis factor-alpha and angiotensin converting enzyme were not significantly altered. A very rapid modulation of remote myocardium gene expression takes place during myocardial ischaemia, involving not only the LV but also the RV. These changes are different in the two ventricles and in the same direction as those observed in heart failure.