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Cardiac healing following acute myocardial infarction (MI) involves the mobilization and activation of immune cells, including macrophages. In the early phase after MI, macrophages adopt a proinflammatory phenotype, while polarizing toward a reparative one in the late stage. Although metabolic reprogramming has been observed during this transition, the mechanistic links to macrophage differentiation are still poorly understood. In this issue of the JCI, Cai, Zhao and colleagues demonstrate that mitochondrial function in macrophages governed the resolution of inflammation and tissue repair by modulating the phagocytic removal of apoptotic cells (so-called efferocytosis) as well as myofibroblast activation. These findings provide important mechanistic insights into the potential relevance of metabolic modulation of macrophage functions following MI, which might lead to alternative therapeutic strategies for MI. [ABSTRACT FROM AUTHOR]

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First, because the sample size did not allow robust conclusions regarding different types and aetiologies of HF, the differential impact of CHIP on the risk of HFpEF versus HFrEF and ischaemic versus non-ischaemic HF remains to be clarified. B This article refers to 'Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers' by C. Shi I et al i ., published in this issue on pages 4-13. b The accumulation of somatic mutations is an age-related process that normally involves all proliferating tissues. However, CHIP mutations were significantly associated with incident HF when considering individuals younger than 65 years, a difference apparently driven by the increased risk of HF with preserved ejection fraction (HFpEF). [Extracted from the article]

Heart failure is a growing health burden worldwide characterized by alterations in excitation-contraction coupling, cardiac energetic deficit and oxidative stress. While current treatments are mostly limited to antagonization of neuroendocrine activation, more recent data suggest that also targeting metabolism may provide substantial prognostic benefit. However, although in a broad spectrum of preclinical models, oxidative stress plays a causal role for the development and progression of heart failure, no treatment that targets reactive oxygen species (ROS) directly has entered the clinical arena yet. In the heart, ROS derive from various sources, such as NADPH oxidases, xanthine oxidase, uncoupled nitric oxide synthase and mitochondria. While mitochondria are the primary source of ROS in the heart, communication between different ROS sources may be relevant for physiological signalling events as well as pathologically elevated ROS that deteriorate excitation-contraction coupling, induce hypertrophy and/or trigger cell death. Here, we review the sources of ROS in the heart, the modes of pathological activation of ROS formation as well as therapeutic approaches that may target ROS specifically in mitochondria. [Display omitted] • Oxidative stress is a hallmark of heart failure. • Mitochondria are the main source of reactive oxygen species (ROS) in heart. • Mitochondrial redox state is governed by excitation-contraction coupling. • Mitochondrial ROS exert crosstalk with ROS from other cellular sources. • Targeting mitochondrial ROS or ion handling may improve the course of heart failure. [ABSTRACT FROM AUTHOR]

A Perspective on "ATP synthase K SP + sp - and H SP + sp -fluxes drive ATP synthesis and enable mitochondrial K SP + sp -"uniporter" function: I. Characterization of ion fluxes" & "ATP synthase K SP + sp - and H SP + sp -fluxes drive ATP synthesis and enable mitochondrial K SP + sp -"uniporter" function: II. First, these observations identify K SP + sp import via the F SB 1 sb F SB o sb -ATP synthase as one central mechanism by which the rate of ATP turnover in the cytosol is matched by ADP phosphorylation in mitochondria. [Extracted from the article]

Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission. This editorial refers to 'Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission' by S.B. Kalkhoran I et al i . pp. 282-294. [Extracted from the article]

The article offers information on mitochondrial transplantation, a therapeutic approach developed by J.D. McCully and colleagues that entails the injection of healthy mitochondria harvested from unaffected tissue into an ischemic organ of the same subject. Topics discussed include process through mitochondria enter cardiac myocytes; and ways in which extracellular mitochondria supply ATP for myofilament contraction.

The heart consumes large amounts of energy in the form of ATP that is continuously replenished by oxidative phosphorylation in mitochondria and, to a lesser extent, by glycolysis. To adapt the ATP supply efficiently to the constantly varying demand of cardiac myocytes, a complex network of enzymatic and signalling pathways controls the metabolic flux of substrates towards their oxidation in mitochondria. In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and the progression of the disease. In this Review, we give an overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus. Although the energetic deficit in failing hearts - discovered >2 decades ago - might account for contractile dysfunction during maximal exertion, we suggest that the alterations of intermediate substrate metabolism and oxidative stress rather than an ATP deficit per se account for maladaptive cardiac remodelling and dysfunction under resting conditions. Treatments targeting substrate utilization and/or oxidative stress in mitochondria are currently being tested in patients with heart failure and might be promising tools to improve cardiac function beyond that achieved with neuroendocrine inhibition. [ABSTRACT FROM AUTHOR]

Barth syndrome (BTHS) is an inherited form of cardiomyopathy, caused by a mutation within the gene encoding the mitochondrial transacylase tafazzin. Tafazzin is involved in the biosynthesis of the unique phospholipid cardiolipin (CL), which is almost exclusively found in mitochondrial membranes. CL directly interacts with a number of essential protein complexes in the mitochondrial membranes including the respiratory chain, mitochondrial metabolite carriers, and proteins, involved in shaping mitochondrial morphology. Here we describe, how in BTHS CL deficiency causes changes in the morphology of mitochondria, structural changes in the respiratory chain, decreased respiration, and increased generation of reactive oxygen species. A large number of cellular and animal models for BTHS have been established to elucidate how mitochondrial dysfunction induces sarcomere disorganization and reduced contractility, resulting in dilated cardiomyopathy in vivo. [ABSTRACT FROM AUTHOR]

The processes of excitation–contraction (EC) coupling consume large amounts of energy that need to be replenished by oxidative phosphorylation in the mitochondria. Since Ca2+ activates key enzymes of the Krebs cycle in the mitochondrial matrix, it is important to understand the mechanisms and kinetics of mitochondrial Ca2+ uptake to delineate how in cardiac myocytes, energy supply is efficiently matched to demand. In recent years, the identification of various proteins involved in mitochondrial Ca2+ signalling and the tethering of mitochondria to the sarcoplasmic reticulum (SR) has considerably advanced the field and supported the concept of a mitochondrial Ca2+ microdomain, in which Ca2+ concentrations are high enough to overcome the low Ca2+ affinity of the principal mitochondrial Ca2+ uptake mechanism, the Ca2+ uniporter. Furthermore, defects in EC coupling that occur in heart failure disrupt SR-mitochondrial Ca2+ crosstalk and may cause energetic deficit and oxidative stress, both factors that are thought to be causally involved in the initiation and progression of the disease. [ABSTRACT FROM AUTHOR]

Abstract: The processes of excitation–contraction coupling in cardiac myocytes require enormous amounts of energy in the form of ATP, which is produced by oxidative phosphorylation in mitochondria. Due to the constantly varying workloads of the heart, efficient matching of energy supply to demand is a requisite for proper heart function. Ca2+ is taken up by mitochondria via the mitochondrial Ca2+ uniporter (MCU) where it stimulates key dehydrogenases of the Krebs cycle to match regeneration of NADH to its oxidation by the respiratory chain. The kinetics of mitochondrial Ca2+ uptake, however, remain controversial due to the low Ca2+ sensitivity of the MCU. Here, we review the evidence for the existence of a “mitochondrial Ca2+ microdomain”, in which the close association of the sarcoplasmic reticulum (SR) to mitochondria provides “hot spots” of very high Ca2+ concentrations in the vicinity of mitochondria, sufficient to overcome the low Ca2+ affinity of the MCU. Mitofusins 1 and 2 play redundant roles in regulating mitochondrial dynamics by controlling fusion of mitochondria with each other. Recent work revealed a unique role for mitofusin 2 in tethering mitochondria to the sarco-/endoplasmic reticulum in various cell types, including cardiac myocytes. Disruption of SR–mitochondrial Ca2+ cross talk in heart failure through spatial and ionic alterations may give rise to energetic deficit and oxidative stress, two factors believed to play causal roles in the progression of the disease. On the other hand, excessive mitochondrial Ca2+ uptake can trigger programmed necrosis, substantiating the ambiguity of the close interplay between these cousin organelles in health and disease. This article is part of a Special Issue entitled "Focus on Cardiac Metabolism". [Copyright &y& Elsevier]

In chronic heart failure, maladaptive remodeling of the left ventricle (LV) with systolic and diastolic dysfunction underlies the inability of the heart to pump sufficient blood to supply the body with blood and oxygen. Three integral aspects of this maladaptive LV remodeling are (1) defects in excitation-contraction (EC) coupling, particularly of cellular Ca2+ and Na+ homeostasis; (2) an energetic deficit; and (3) oxidative stress. Although these three aspects are often investigated separately from each other, their close and dynamic interplay are increasingly recognized. Central to this novel approach are mitochondria, which are the main source for cellular ATP, but also for reactive oxygen species, and their function is critically regulated by Ca2+ and Na+. Here, we review recent advances in our understanding of how maladaptive changes of EC coupling can contribute to the energetic deficit and oxidative stress, which may initiate a vicious cycle leading to progressive cardiac dysfunction. [ABSTRACT FROM AUTHOR]

Cardiac excitation-contraction (EC) coupling consumes vast amounts of cellular energy, most of which is produced in mitochondria by oxidative phosphorylation. In order to adapt the constantly varying workload of the heart to energy supply, tight coupling mechanisms are essential to maintain cellular pools of ATP, phosphocreatine and NADH. To our current knowledge, the most important regulators of oxidative phosphorylation are ADP, Pi, and Ca2+. However, the kinetics of mitochondrial Ca2+-uptake during EC coupling are currently a matter of intense debate. Recent experimental findings suggest the existence of a mitochondrial Ca2+ microdomain in cardiac myocytes, justified by the close proximity of mitochondria to the sites of cellular Ca2+ release, i. e., the ryanodine receptors of the sarcoplasmic reticulum. Such a Ca2+ microdomain could explain seemingly controversial results on mitochondrial Ca2+ uptake kinetics in isolated mitochondria versus whole cardiac myocytes. Another important consideration is that rapid mitochondrial Ca2+ uptake facilitated by microdomains may shape cytosolic Ca2+ signals in cardiac myocytes and have an impact on energy supply and demand matching. Defects in EC coupling in chronic heart failure may adversely affect mitochondrial Ca2+ uptake and energetics, initiating a vicious cycle of contractile dysfunction and energy depletion. Future therapeutic approaches in the treatment of heart failure could be aimed at interrupting this vicious cycle. [ABSTRACT FROM AUTHOR]

The treatment of chronic heart failure with most β-adrenergic receptor (β-AR) antagonists leads to an improvement of symptoms and left ventricular function. However, only metoprolol, bisoprolol and carvedilol have been shown to reduce mortality in these patients. Bucindolol did not reduce mortality and xamoterol even increased it. These differences may be related to different inverse agonist or partial agonist activity of β-AR antagonists. This review focusses on the determination of different intrinsic activity of the mentioned β-AR antagonists in the human myocardium. Furthermore, the clinical impact of these differences is examined. In this regard, the effect of the different β-AR antagonists on β-AR regulation, minimum heart rate and exercise tolerance, as well as prognosis, is highlighted. It is concluded that the degree of inverse agonism of a β-AR antagonist determines the degree of β-AR resensitization, reduction of minimum heart rate, improvement of exercise tolerance and possibly also improvement of prognosis of patients with chronic heart failure. [Copyright &y& Elsevier]

In LCAD KO mice, defective FA oxidation increases systemic glucose consumption during fasting, thus rapidly draining hepatic glycogen stores ( I Figure 1 i ). This editorial refers to 'A mitochondrial long-chain fatty acid oxidation defect leads to transfer RNA uncharging and activation of the integrated stress response in the mouse heart', by P. Ranea-Robles I et al. i , https://doi.org/10.1093/cvr/cvac050. Impaired amino acid metabolism contributes to fasting-induced hypoglycemia in fatty acid oxidation defects. [Extracted from the article]

The article provides information related to a research conducted to determine the role of G-protein-coupled receptor kinase 2 (GRK2) in the case of heart failure. Heart failure occurs due to the failure of left ventricle to pump blood to body parts. GRK2-regulation of excitation-contraction coupling has been characterized to ameliorate the development of heart stress.

B This article refers to 'Haemodynamic effects of the nitroxyl donor cimlanod (BMS-986231) in chronic heart failure: a randomized trial' by N.N. Lang I et al i ., published in this issue on pages 1147-1155. b Heart failure (HF) is a leading cause for hospital admissions in developed countries, and its incidence further increases with the prolonged average life expectancy. The authors conclude that in patients with chronic HFrEF, the haemodynamic effects of cimlanod and NTG are similar, and that therefore the effects of cimlanod are best explained by venodilatation and preload reduction without additional inotropic or lusitropic effects. In fact, the redox reactivity of HNO that accounts for its inotropic effects can be both a blessing and a curse, since by its capacity to react with reactive oxygen species to form NO, the HNO molecule is rather unstable in oxidizing conditions5,9 ( I Figure i 1). [Extracted from the article]

Hypertrophic cardiomyopathy (HCM) is the most common form of hereditary cardiomyopathy and is mainly caused by mutations of genes encoding cardiac sarcomeric proteins. HCM is characterized by hypertrophy of the left ventricle, frequently involving the septum, that is not explained solely by loading conditions. HCM has a heterogeneous clinical profile, but diastolic dysfunction and ventricular arrhythmias represent two dominant features of the disease. Preclinical evidence indicates that the enhanced Calcium (Ca2+) sensitivity of the myofilaments plays a key role in the pathophysiology of HCM. Notably, this is not always a direct consequence of sarcomeric mutations, but can also result from secondary mutation‐driven alterations. Here, we review experimental and clinical evidence indicating that increased myofilament Ca2+ sensitivity lies upstream of numerous cellular derangements which potentially contribute to the progression of HCM toward heart failure and sudden cardiac death. [ABSTRACT FROM AUTHOR]

Recent epidemiological analyses suggest that incident cancer may be more common among patients with preexisting heart failure (HF) than in patients without HF. Arguments against this notion have been the increased chance of co-occurrence of 2 high-prevalence conditions and increased tumor detection in patients with HF because of intensified medical observation. However, biological data lend support to the hypothesis that HF is an oncogenic condition. Neurohormonal activation has been related to cancer initiation, progression, and dissemination by studies not specifically focusing on HF, which are now reappraised in the light of the emerging evidence that tumors are diagnosed more often in HF than control cohorts. Furthermore, a thought-provoking scenario to be considered is that a systemically perturbed milieu, where low-grade inflammation plays a primary role, leads to both HF and malignancy, thus connecting 1 disease to another. Postischemic HF has been shown to promote tumor growth in an animal model. Exploring these and other pathways potentially linking HF to malignancy is a new and exciting field of research, with the ultimate goal of answering the question of whether HF does promote cancer. [ABSTRACT FROM AUTHOR]

Vascular disease and heart failure impart an enormous burden in terms of global morbidity and mortality. Although there are many different causes of cardiac and vascular disease, most causes share an important pathological mechanism: oxidative stress. In the failing heart, oxidative stress occurs in the myocardium and correlates with left ventricular dysfunction. Reactive oxygen species (ROS) negatively affect myocardial calcium handling, cause arrhythmia, and contribute to cardiac remodeling by inducing hypertrophic signaling, apoptosis, and necrosis. Similarly, oxidative balance in the vasculature is tightly regulated by a wealth of pro- and antioxidant systems that orchestrate region-specific ROS production and removal. Reactive oxygen species also regulate multiple vascular cell functions, including endothelial and smooth muscle cell growth, proliferation, and migration; angiogenesis; apoptosis; vascular tone; host defenses; and genomic stability. However, excessive levels of ROS promote vascular disease through direct and irreversible oxidative damage to macromolecules, as well as disruption of redox-dependent vascular wall signaling processes. [ABSTRACT FROM AUTHOR]

Contraction and relaxation of the heart consume large amounts of energy that need to be replenished by oxidative phosphorylation in mitochondria, and matching energy supply to demand involves the complimentary control of respiration through ADP and Ca2+. In heart failure, an imbalance between ADP and Ca2+ leads to oxidation of mitochondrial pyridine nucleotides, where NADH oxidation may limit ATP production and contractile function, while NADPH oxidation can induce oxidative stress with consecutive maladaptive remodelling. Understanding the complex mechanisms that disturb this finely tuned equilibrium may aid the development of drugs that could ameliorate the progression of heart failure beyond the classical neuroendocrine inhibition. [ABSTRACT FROM AUTHOR]

Mitochondria are central organelles in the homeostasis of the cardiovascular system via the integration of several physiological processes, such as ATP generation via oxidative phosphorylation, synthesis/exchange of metabolites, calcium sequestration, reactive oxygen species (ROS) production/buffering and control of cellular survival/death. Mitochondrial impairment has been widely recognized as a central pathomechanism of almost all cardiovascular diseases, rendering these organelles important therapeutic targets. Mitochondrial dysfunction has been reported to occur in the setting of drug-induced toxicity in several tissues and organs, including the heart. Members of the drug classes currently used in the therapeutics of cardiovascular pathologies have been reported to both support and undermine mitochondrial function. For the latter case, mitochondrial toxicity is the consequence of drug interference (direct or off-target effects) with mitochondrial respiration/energy conversion, DNA replication, ROS production and detoxification, cell death signaling and mitochondrial dynamics. The present narrative review aims to summarize the beneficial and deleterious mitochondrial effects of common cardiovascular medications as described in various experimental models and identify those for which evidence for both types of effects is available in the literature. [ABSTRACT FROM AUTHOR]

Mutations in mitochondrial aminoacyl-tRNA synthetases (mtARSs) have been reported in patients with mitochondriopathies: most commonly encephalopathy, but also cardiomyopathy. Through a GWAS, we showed possible associations between mitochondrial valyl-tRNA synthetase (VARS2) dysregulations and non-ischemic cardiomyopathy. We aimed to investigate the possible consequences of VARS2 depletion in zebrafish and cultured HEK293A cells. Transient VARS2 loss-of-function was induced in zebrafish embryos using Morpholinos. The enzymatic activity of VARS2 was measured in VARS2-depleted cells via northern blot. Heterozygous VARS2 knockout was established in HEK293A cells using CRISPR/Cas9 technology. BN-PAGE and SDS-PAGE were used to investigate electron transport chain (ETC) complexes, and the oxygen consumption rate and extracellular acidification rate were measured using a Seahorse XFe96 Analyzer. The activation of the integrated stress response (ISR) and possible disruptions in mitochondrial fatty acid oxidation (FAO) were explored using RT-qPCR and western blot. Zebrafish embryos with transient VARS2 loss-of-function showed features of heart failure as well as indications of CNS and skeletal muscle involvements. The enzymatic activity of VARS2 was significantly reduced in VARS2-depleted cells. Heterozygous VARS2-knockout cells showed a rearrangement of ETC complexes in favor of complexes III2, III2 + IV, and supercomplexes without significant respiratory chain deficiencies. These cells also showed the enhanced activation of the ISR, as indicated by increased eIF-2α phosphorylation and a significant increase in the transcript levels of ATF4, ATF5, and DDIT3 (CHOP), as well as disruptions in FAO. The activation of the ISR and disruptions in mitochondrial FAO may underlie the adaptive changes in VARS2-depleted cells. [ABSTRACT FROM AUTHOR]

Aims Cardiac energetic impairment is a major finding in takotsubo patients. We investigate specific metabolic adaptations to direct future therapies. Methods and results An isoprenaline-injection female rat model (vs. sham) was studied at Day 3; recovery assessed at Day 7. Substrate uptake, metabolism, inflammation, and remodelling were investigated by 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography, metabolomics, quantitative PCR, and western blot (WB). Isolated cardiomyocytes were patch-clamped during stress protocols for redox states of NAD(P)H/FAD or [Ca2+]c, [Ca2+]m, and sarcomere length. Mitochondrial respiration was assessed by seahorse/Clark electrode (glycolytic and β-oxidation substrates). Cardiac 18F-FDG metabolic rate was increased in takotsubo (P  = 0.006), as was the expression of GLUT4-RNA/GLUT1/HK2-RNA and HK activity (all P  < 0.05), with concomitant accumulation of glucose- and fructose-6-phosphates (P  > 0.0001). Both lactate and pyruvate were lower (P  < 0.05) despite increases in LDH-RNA and PDH (P  < 0.05 both). β-Oxidation enzymes CPT1b-RNA and 3-ketoacyl-CoA thiolase were increased (P  < 0.01) but malonyl-CoA (CPT-1 regulator) was upregulated (P  = 0.01) with decreased fatty acids and acyl-carnitines levels (P  = 0.0001–0.02). Krebs cycle intermediates α-ketoglutarate and succinyl-carnitine were reduced (P  < 0.05) as was cellular ATP reporter dihydroorotate (P  = 0.003). Mitochondrial Ca2+ uptake during high workload was impaired on Day 3 (P  < 0.0001), inducing the oxidation of NAD(P)H and FAD (P  = 0.03) but resolved by Day 7. There were no differences in mitochondrial respiratory function, sarcomere shortening, or [Ca2+] transients of isolated cardiomyocytes, implying preserved integrity of both mitochondria and cardiomyocyte. Inflammation and remodelling were upregulated—increased CD68-RNA, collagen RNA/protein, and skeletal actin RNA (all P  < 0.05). Conclusion Dysregulation of glucose and lipid metabolic pathways with decreases in final glycolytic and β-oxidation metabolites and reduced availability of Krebs intermediates characterizes takotsubo myocardium. The energetic deficit accompanies defective Ca2+ handling, inflammation, and upregulation of remodelling pathways, with the preservation of sarcomeric and mitochondrial integrity. [ABSTRACT FROM AUTHOR]

Aims Autophagy protects against the development of cardiac hypertrophy and failure. While aberrant Ca2+ handling promotes myocardial remodelling and contributes to contractile dysfunction, the role of autophagy in maintaining Ca2+ homeostasis remains elusive. Here, we examined whether Atg5 deficiency-mediated autophagy promotes early changes in subcellular Ca2+ handling in ventricular cardiomyocytes, and whether those alterations associate with compromised cardiac reserve capacity, which commonly precedes the onset of heart failure. Methods and results RT–qPCR and immunoblotting demonstrated reduced Atg5 gene and protein expression and decreased abundancy of autophagy markers in hypertrophied and failing human hearts. The function of ATG5 was examined using cardiomyocyte-specific Atg5 -knockout mice (Atg5−/−). Before manifesting cardiac dysfunction, Atg5−/− mice showed compromised cardiac reserve in response to β-adrenergic stimulation. Consequently, effort intolerance and maximal oxygen consumption were reduced during treadmill-based exercise tolerance testing. Mechanistically, cellular imaging revealed that Atg5 deprivation did not alter spatial and functional organization of intracellular Ca2+ stores or affect Ca2+ cycling in response to slow pacing or upon acute isoprenaline administration. However, high-frequency stimulation exposed stunted amplitude of Ca2+ transients, augmented nucleoplasmic Ca2+ load, and increased CaMKII activity, especially in the nuclear region of hypertrophied Atg5−/− cardiomyocytes. These changes in Ca2+ cycling were recapitulated in hypertrophied human cardiomyocytes. Finally, ultrastructural analysis revealed accumulation of mitochondria with reduced volume and size distribution, meanwhile functional measurements showed impaired redox balance in Atg5−/− cardiomyocytes, implying energetic unsustainability due to overcompensation of single mitochondria, particularly under increased workload. Conclusion Loss of cardiac Atg5 -dependent autophagy reduces mitochondrial abundance and causes subtle alterations in subcellular Ca2+ cycling upon increased workload in mice. Autophagy-related impairment of Ca2+ handling is progressively worsened by β-adrenergic signalling in ventricular cardiomyocytes, thereby leading to energetic exhaustion and compromised cardiac reserve. [ABSTRACT FROM AUTHOR]

Abstract: Reactive oxygen species (ROS) play an important role in cardiovascular diseases, and one important source for ROS are mitochondria. Emission of ROS from mitochondria is the net result of ROS production at the electron transport chain (ETC) and their elimination by antioxidative enzymes. Both of these processes are highly dependent on the mitochondrial redox state, which is dynamically altered under different physiological and pathological conditions. The concept of “redox-optimized ROS balance” integrates these aspects and implies that oxidative stress occurs when the optimal equilibrium of an intermediate redox state is disturbed towards either strong oxidation or reduction. Furthermore, mitochondria integrate ROS signals from other cellular sources, presumably through a process termed “ROS-induced ROS release” that involves mitochondrial ion channels. Here, we attempt to integrate these recent advances in our understanding of the control of mitochondrial ROS emission and develop a concept of how in heart failure, defects in ion handling can lead to mitochondrial oxidative stress. This article is part of a Special Issue entitled “Redox Signalling in the Cardiovascular System”. [Copyright &y& Elsevier]

Tachycardiomyopathy is characterised by reversible left ventricular dysfunction, provoked by rapid ventricular rate. While the knowledge of mitochondria advanced in most cardiomyopathies, mitochondrial functions await elucidation in tachycardiomyopathy. Pacemakers were implanted in 61 rabbits. Tachypacing was performed with 330 bpm for 10 days (n = 11, early left ventricular dysfunction) or with up to 380 bpm over 30 days (n = 24, tachycardiomyopathy, TCM). In n = 26, pacemakers remained inactive (SHAM). Left ventricular tissue was subjected to respirometry, metabolomics and acetylomics. Results were assessed for translational relevance using a human-based model: induced pluripotent stem cell derived cardiomyocytes underwent field stimulation for 7 days (TACH–iPSC–CM). TCM animals showed systolic dysfunction compared to SHAM (fractional shortening 37.8 ± 1.0% vs. 21.9 ± 1.2%, SHAM vs. TCM, p < 0.0001). Histology revealed cardiomyocyte hypertrophy (cross-sectional area 393.2 ± 14.5 µm2 vs. 538.9 ± 23.8 µm2, p < 0.001) without fibrosis. Mitochondria were shifted to the intercalated discs and enlarged. Mitochondrial membrane potential remained stable in TCM. The metabolite profiles of ELVD and TCM were characterised by profound depletion of tricarboxylic acid cycle intermediates. Redox balance was shifted towards a more oxidised state (ratio of reduced to oxidised nicotinamide adenine dinucleotide 10.5 ± 2.1 vs. 4.0 ± 0.8, p < 0.01). The mitochondrial acetylome remained largely unchanged. Neither TCM nor TACH–iPSC–CM showed relevantly increased levels of reactive oxygen species. Oxidative phosphorylation capacity of TCM decreased modestly in skinned fibres (168.9 ± 11.2 vs. 124.6 ± 11.45 pmol·O2·s−1·mg−1 tissue, p < 0.05), but it did not in isolated mitochondria. The pattern of mitochondrial dysfunctions detected in two models of tachycardiomyopathy diverges from previously published characteristic signs of other heart failure aetiologies. [ABSTRACT FROM AUTHOR]

The interplay between the cardiovascular system, metabolism, and inflammation plays a central role in the pathophysiology of a wide spectrum of cardiovascular diseases, including heart failure. Here, we provide an overview of the fundamental aspects of the interrelation between inflammation and metabolism, ranging from the role of metabolism in immune cell function to the processes how inflammation modulates systemic and cardiac metabolism. Furthermore, we discuss how disruption of this immuno-metabolic interface is involved in the development and progression of cardiovascular disease, with a special focus on heart failure. Finally, we present new technologies and therapeutic approaches that have recently emerged and hold promise for the future of cardiovascular medicine. [ABSTRACT FROM AUTHOR]

Abstract: In heart failure, alterations of excitation–contraction underlie contractile dysfunction. One important defect is an elevation of the intracellular Na+ concentration in cardiac myocytes ([Na+]i), which has an important impact on cytosolic and mitochondrial Ca2+ homeostasis. While elevated [Na+]i is thought to compensate for decreased Ca2+ load of the sarcoplasmic reticulum (SR), it yet negatively affects energy supply-and-demand matching and can even induce mitochondrial oxidative stress. Here, we review the mechanisms underlying these pathophysiological changes. The chain of events may constitute a vicious cycle of ion dysregulation, oxidative stress and energetic deficit, resembling characteristic cellular deficits that are considered key hallmarks of the failing heart. This article is part of a Special Issue entitled “Na+ Regulation in Cardiac Myocytes”. [Copyright &y& Elsevier]

It has become common sense that the failing heart is an 'engine out of fuel'. However, undisputable evidence that, indeed, the failing heart is limited by insufficient ATP supply is currently lacking. Over the last couple of years, an increasingly complex picture of mechanisms evolved that suggests that potentially metabolic intermediates and redox state could play the more dominant roles for signaling that eventually results in left ventricular remodeling and contractile dysfunction. In the pathophysiology of heart failure, mitochondria emerge in the crossfire of defective excitation-contraction coupling and increased energetic demand, which may provoke oxidative stress as an important upstream mediator of cardiac remodeling and cell death. Thus, future therapies may be guided towards restoring defective ion homeostasis and mitochondrial redox shifts rather than aiming solely at improving the generation of ATP. [ABSTRACT FROM AUTHOR]

The role of the Na+/K+-ATPase (NKA) in heart failure associated with myocardial infarction (MI) is poorly understood. The elucidation of its precise function is hampered by the existence of two catalytic NKA isoforms (NKA-α1 and NKA-α2). Our aim was to analyze the effects of an increased NKA-α2 expression on functional deterioration and remodeling during long-term MI treatment in mice and its impact on Ca2+ handling and inotropy of the failing heart. Wild-type (WT) and NKA-α2 transgenic (TG) mice (TGα2) with a cardiac-specific overexpression of NKA-α2 were subjected to MI injury for 8 wk. As examined by echocardiography, gravimetry, and histology, TG-α2 mice were protected from functional deterioration and adverse cardiac remodeling. Contractility and Ca2+ transients (Fura 2-AM) in cardiomyocytes from MI-treated TG-α2 animals showed reduced Ca2+ amplitudes during pacing or after caffeine application. Ca2+ efflux in cardiomyocytes from TG-α2 mice was accelerated and diastolic Ca2+ levels were decreased. Based on these alterations, sarcomeres exhibited an enhanced sensitization and thus increased contractility. After the acute stimulation with the β-adrenergic agonist isoproterenol (ISO), cardiomyocytes from MI-treated TG-α2 mice responded with increased sarcomere shortenings and Ca2+ peak amplitudes. This positive inotropic response was absent in cardiomyocytes from WT-MI animals. Cardiomyocytes with NKA-α2 as predominant isoform minimize Ca2+ cycling but respond to b-adrenergic stimulation more efficiently during chronic cardiac stress. These mechanisms might improve the b-adrenergic reserve and contribute to functional preservation in heart failure. [ABSTRACT FROM AUTHOR]

Diastolic dysfunction is a major feature of hypertrophic cardiomyopathy (HCM). Data from patient tissue and animal models associate increased Ca2+ sensitivity of myofilaments with altered Na+ and Ca2+ ion homeostasis in cardiomyocytes with diastolic dysfunction. In this study, we tested the acute effects of ouabain on ventricular myocytes of an HCM mouse model. The effects of ouabain on contractility and Ca2+ transients were tested in intact adult mouse ventricular myocytes (AMVMs) of Mybpc3 -targeted knock-in (KI) and wild-type (WT) mice. Concentration-response assessment of contractile function revealed low sensitivity of AMVMs to ouabain (10 μM) compared to literature data on human cardiomyocytes (100 nM). Three hundred μM ouabain increased contraction amplitude (WT ~1.8-fold; KI ~1.5-fold) and diastolic intracellular Ca2+ in both WT and KI (+12–18%), but further decreased diastolic sarcomere length in KI cardiomyocytes (−5%). Western Blot analysis of whole heart protein extracts revealed 50% lower amounts of Na+/K+ ATPase (NKA) in KI than in WT. Ouabain worsened the diastolic phenotype of KI cardiomyocytes at concentrations which did not impair WT diastolic function. Ouabain led to an elevation of intracellular Ca2+, which was poorly tolerated in KI showing already high cytosolic Ca2+ at baseline due to increased myofilament Ca2+ sensitivity. Lower amounts of NKA in KI could amplify the need to exchange excessive intracellular Na+ for Ca2+ and thereby explain the general tendency to higher diastolic Ca2+ in KI. [ABSTRACT FROM AUTHOR]

[Display omitted] Myocardial infarction (MI) is one of the major contributors to cardiovascular morbidity and mortality. Excess inflammation significantly contributes to cardiac remodeling and heart failure after MI. Accumulating evidence has shown the central role of cellular metabolism in regulating the differentiation and function of cells. Metabolic rewiring is particularly relevant for proinflammatory responses induced by ischemia. Hypoxia reduces mitochondrial oxidative phosphorylation (OXPHOS) and induces increased reliance on glycolysis. Moreover, activation of a proinflammatory transcriptional program is associated with preferential glucose metabolism in leukocytes. An improved understanding of the mechanisms that regulate metabolic adaptations holds the potential to identify new metabolic targets and strategies to reduce ischemic cardiac damage, attenuate excess local inflammation and ultimately prevent the development of heart failure. Among possible drug targets, glucose transporter 1 (GLUT1) gained considerable interest considering its pivotal role in regulating glucose availability in activated leukocytes and the availability of small molecules that selectively inhibit it. Therefore, we summarize current evidence on the role of GLUT1 in leukocytes (focusing on macrophages and T cells) and non-leukocytes, including cardiomyocytes, endothelial cells and fibroblasts regarding ischemic heart disease. Beyond myocardial infarction, we can foresee the role of GLUT1 blockers as a possible pharmacological approach to limit pathogenic inflammation in other conditions driven by excess sterile inflammation. [ABSTRACT FROM AUTHOR]

Mitochondrial membrane potential (ΔΨm) depolarization contributes to cell death and electrical and contractile dysfunction in the post-ischemic heart. An imbalance between mitochondrial reactive oxygen species production and scavenging was previously implicated in the activation of an inner membrane anion channel (IMAC), distinct from the permeability transition pore (PTP), as the first response to metabolic stress in cardiomyocytes. The glutathione redox couple, GSH/GSSG, oscillated in parallel with ΔΨm and the NADH/NAD+ redox state. Here we show that depletion of reduced glutathione is an alternative trigger of synchronized mitochondrial oscillation in cardiomyocytes and that intermediate GSH/GSSG ratios cause reversible ΔΨm depolarization, although irreversible PTP activation is induced by extensive thiol oxidation. Mitochondrial dysfunction in response to diamide occurred in stages, progressing from oscillations in ΔΨm to sustained depolarization, in association with depletion of GSH. Mitochondrial oscillations were abrogated by 4′-chlorodiazepam, an IMAC inhibitor, whereas cyclosporin A was ineffective. In saponin-permeabilized cardiomyocytes, the thiol redox status was systematically clamped at GSH/GSSG ratios ranging from 300:1 to 20:1. At ratios of 150:1-100:1, ΔΨm depolarized reversibly, and a matrix-localized fluorescent marker was retained; however, decreasing the GSH/GSSG to 50:1 irreversibly depolarized ΔΨm and induced maximal rates of reactive oxygen species production, NAD(P)H oxidation, and loss of matrix constituents. Mitochondrial GSH sensitivity was altered by inhibiting either GSH uptake, the NADPH-dependent glutathione reductase, or the NADH/NADPH transhydrogenase, indicating that matrix GSH regeneration or replenishment was crucial. The results indicate that GSH/GSSG redox status governs the sequential opening of mitochondrial ion channels (IMAC before PTP) triggered by thiol oxidation in cardiomyocytes. [ABSTRACT FROM AUTHOR]

Keywords: Diabetes mellitus; Metabolism; Mitochondria; Heart; Fatty acids EN Diabetes mellitus Metabolism Mitochondria Heart Fatty acids 1283 1284 2 04/06/20 20200401 NES 200401 Diabetic patients carry the risk of developing a specific form of cardiac dysfunction, termed diabetic cardiomyopathy, which is not accounted for by coronary artery disease or hypertension, but likely stems from hormonal and metabolic derangements associated with diabetes. Altogether, these findings suggest that in addition to ATP production, FA metabolism impacts on contractile performance by modulating cellular redox balance of the diabetic heart. [Extracted from the article]

Abstract: The α1c subunit of the cardiac L-type Ca2+ channel, which contains the channel pore, voltage- and Ca2+-dependent gating structures, and drug binding sites, has been well studied in heterologous expression systems, but many aspects of L-type Ca2+ channel behavior in intact cardiomyocytes remain poorly characterized. Here, we develop adenoviral constructs with E1, E3 and fiber gene deletions, to allow incorporation of full-length α1c gene cassettes into the adenovirus backbone. Wild-type (α1c-wt) and mutant (α1c-D-) Ca2+ channel adenoviruses were constructed. The α1c-D- contained four point substitutions at amino acid residues known to be critical for dihydropyridine binding. Both α1c-wt and α1c-D- expressed robustly in A549 cells (peak L-type Ca2+ current (ICaL) at 0mV: α1c-wt −9.94±1.00pA/pF, n=9; α1c-D- −10.30pA/pF, n=12). ICaL carried by α1c-D- was markedly less sensitive to nitrendipine (IC50 17.1μM) than α1c-wt (IC50 88nM); a feature exploited to discriminate between engineered and native currents in transduced guinea-pig myocytes. 10μM nitrendipine blocked only 51±5% (n=9) of ICaL in α1c-D--expressing myocytes, in comparison to 86±8% (n=9) of ICaL in control myocytes. Moreover, in 20μM nitrendipine, calcium transients could still be evoked in α1c-D--transduced cells, but were largely blocked in control myocytes, indicating that the engineered channels were coupled to sarcoplasmic reticular Ca2+ release. These α1c adenoviruses provide an unprecedented tool for structure–function studies of cardiac excitation–contraction coupling and L-type Ca2+ channel regulation in the native myocyte background. [Copyright &y& Elsevier]

While classical cannabinoid receptors are known to crucially impact on myocardial infarction (MI) repair, a function of the cannabinoid-sensitive receptor GPR55 herein is poorly understood. We investigated the role of GPR55 in cardiac physiology and post-MI inflammation and remodelling. Global GPR55−/− and wildtype (WT) mice were basally characterized or assigned to 1, 3 or 28 days permanent MI and subsequently analysed via pro-inflammatory and pro-hypertrophic parameters. GPR55−/− deficiency was basally associated with bradycardia, increased diastolic LV volume and sarcomere length and a subtle inflammatory phenotype. While infarct size and myeloid cell infiltration were unaffected by GPR55 depletion, acute cardiac chemokine production was prolonged post-MI. Concurrently, GPR55−/− hearts exhibited a premature expansion of pro-reparative and phagocytic macrophages paralleled by early up-regulation of extracellular matrix (ECM) factors 3 days post-MI, which could be mimicked by sole haematopoietic GPR55 depletion. Moreover, global GPR55 deficiency mitigated MI-induced foetal gene re-programming and cardiomyocyte hypertrophy, culminating in aggravated LV dilatation and infarct expansion. GPR55 regulates cardiac homeostasis and ischaemia responses by maintaining adequate LV filling and modulating three crucial processes post-MI: wound healing kinetics, cardiomyocyte hypertrophy and maladaptive remodelling. [ABSTRACT FROM AUTHOR]

Excessive mitochondrial ROS production has been causally linked to the pathophysiology of aging in the heart and other organs, and plays a deleterious role in several age-related cardiac pathologies, including myocardial ischemia-reperfusion injury and heart failure, the two worldwide leading causes of death and disability in the elderly. However, ROS generation is also a fundamental mitochondrial function that orchestrates several signaling pathways, some of them exerting cardioprotective effects. In cardiac myocytes, mitochondria are particularly abundant and are specialized in subcellular populations, in part determined by their relationships with other organelles and their cyclic calcium handling activity necessary for adequate myocardial contraction/relaxation and redox balance. Depending on their subcellular location, mitochondria can themselves be differentially targeted by ROS and display distinct age-dependent functional decline. Thus, precise mitochondria-targeted therapies aimed at counteracting unregulated ROS production are expected to have therapeutic benefits in certain aging-related heart conditions. However, for an adequate design of such therapies, it is necessary to unravel the complex and dynamic interactions between mitochondria and other cellular processes. [Display omitted] [ABSTRACT FROM AUTHOR]