In heart failure, alterations of Na and Ca handling, energetic deficit, and oxidative stress in cardiac myocytes are important pathophysiological hallmarks. Mitochondria are central to these processes because they are the main source for ATP, but also reactive oxygen species (ROS), and their function is critically controlled by Ca During physiological variations of workload, mitochondrial Ca uptake is required to match energy supply to demand but also to keep the antioxidative capacity in a reduced state to prevent excessive emission of ROS. Mitochondria take up Ca via the mitochondrial Ca uniporter, which exists in a multiprotein complex whose molecular components were identified only recently. In heart failure, deterioration of cytosolic Ca and Na handling hampers mitochondrial Ca uptake and the ensuing Krebs cycle-induced regeneration of the reduced forms of NADH (nicotinamide adenine dinucleotide) and NADPH (nicotinamide adenine dinucleotide phosphate), giving rise to energetic deficit and oxidative stress. ROS emission from mitochondria can trigger further ROS release from neighboring mitochondria termed ROS-induced ROS release, and cross talk between different ROS sources provides a spatially confined cellular network of redox signaling. Although low levels of ROS may serve physiological roles, higher levels interfere with excitation-contraction coupling, induce maladaptive cardiac remodeling through redox-sensitive kinases, and cell death through mitochondrial permeability transition. Targeting the dysregulated interplay between excitation-contraction coupling and mitochondrial energetics may ameliorate the progression of heart failure.

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.

The effects of intense glycaemic control on macrovascular complications in patients with type 2 diabetes are incompletely resolved, and many glucose-lowering medications negatively affect cardiovascular outcomes. Recently, the EMPA-REG OUTCOME trial revealed that empagliflozin, an inhibitor of the sodium-glucose cotransporter 2 (SGLT2), substantially reduced the risk of hospitalization for heart failure, death from cardiovascular causes, and all-cause mortality in patients with type 2 diabetes mellitus at high cardiovascular risk. Although several mechanisms may explain this benefit, plasma volume contraction and a metabolic switch favouring cardiac ketone bodies oxidation have recently been proposed as the major drivers. Recent experimental work has prompted a novel and intriguing hypothesis, according to which empagliflozin may reduce intracellular sodium (Na+) load observed in failing cardiac myocytes by inhibiting the sarcolemmal Na+/H+ exchanger. Since elevated intracellular Na+ hampers mitochondrial Ca2+ handling and thereby, deteriorates energy supply and demand matching and the mitochondrial antioxidative defence systems, empagliflozin may positively affect cardiac function by restoring mitochondrial function, and redox state in the failing heart. Here, we review the current evidence for such a third mechanistic hypothesis, which may foster heart failure and diabetes research into a new direction which harbours several potential targets for therapeutic intervention.

The co‐occurrence of cancer and heart failure (HF) represents a significant clinical drawback as each disease interferes with the treatment of the other. In addition to shared risk factors, a growing body of experimental and clinical evidence reveals numerous commonalities in the biology underlying both pathologies. Inflammation emerges as a common hallmark for both diseases as it contributes to the initiation and progression of both HF and cancer. Under stress, malignant and cardiac cells change their metabolic preferences to survive, which makes these metabolic derangements a great basis to develop intersection strategies and therapies to combat both diseases. Furthermore, genetic predisposition and clonal haematopoiesis are common drivers for both conditions and they hold great clinical relevance in the context of personalized medicine. Additionally, altered angiogenesis is a common hallmark for failing hearts and tumours and represents a promising substrate to target in both diseases. Cardiac cells and malignant cells interact with their surrounding environment called stroma. This interaction mediates the progression of the two pathologies and understanding the structure and function of each stromal component may pave the way for innovative therapeutic strategies and improved outcomes in patients. The interdisciplinary collaboration between cardiologists and oncologists is essential to establish unified guidelines. To this aim, pre‐clinical models that mimic the human situation, where both pathologies coexist, are needed to understand all the aspects of the bidirectional relationship between cancer and HF. Finally, adequately powered clinical studies, including patients from all ages, and men and women, with proper adjudication of both cancer and cardiovascular endpoints, are essential to accurately study these two pathologies at the same time.

Background: Barth syndrome (BTHS) is caused by mutations of the gene encoding tafazzin, which catalyzes maturation of mitochondrial cardiolipin and often manifests with systolic dysfunction during early infancy. Beyond the first months of life, BTHS cardiomyopathy typically transitions to a phenotype of diastolic dysfunction with preserved ejection fraction, blunted contractile reserve during exercise and arrhythmic vulnerability. Previous studies traced BTHS cardiomyopathy to mitochondrial formation of reactive oxygen species (ROS). Since mitochondrial function and ROS formation are regulated by excitation-contraction (EC) coupling, integrated analysis of mechano-energetic coupling is required to delineate the pathomechanisms of BTHS cardiomyopathy. Methods: We analyzed cardiac function and structure in a mouse model with global knockdown of tafazzin ( Taz -KD) compared to wild-type (WT) littermates. Respiratory chain assembly and function, ROS emission, and Ca 2+ uptake were determined in isolated mitochondria. EC coupling was integrated with mitochondrial redox state, ROS, and Ca 2+ uptake in isolated, unloaded or preloaded cardiac myocytes, and cardiac hemodynamics analyzed in vivo . Results: Taz -KD mice develop heart failure with preserved ejection fraction (>50%) and age-dependent progression of diastolic dysfunction in the absence of fibrosis. Increased myofilament Ca 2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, partly compensated by accelerated diastolic Ca 2+ decay through preactivated sarcoplasmic reticulum Ca 2+ ATPase (SERCA). Taz deficiency provoked heart-specific loss of mitochondrial Ca 2+ uniporter (MCU) protein that prevented Ca 2+ -induced activation of the Krebs cycle during β-adrenergic stimulation, oxidizing pyridine nucleotides and triggering arrhythmias in cardiac myocytes. In vivo , Taz -KD mice displayed prolonged QRS duration as a substrate for arrhythmias, and a lack of inotropic response to β-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca 2+ export via the mitochondrial Na + /Ca 2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo . Conclusions: Downregulation of MCU, increased myofilament Ca 2+ affinity, and preactivated SERCA provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca 2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

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.

Mitochondrial transplantation is a therapeutic approach developed by McCully and colleagues that entails the injection of healthy mitochondria harvested from unaffected tissue into an ischemic organ of the same subject (1). It has recently been applied to human pediatric patients with myocardial ischemia (2), receiving widespread media attention accompanied by sensationalistic claims on its mechanism of action, e.g.: (a) after injection into the heart, "mitochondria moved like magnets to the proper places in the cells and began supplying energy;" and (b) after infusion into the coronary arteries, "somehow the organelles will gravitate almost magically to the injured cells that need them and take up residence" (3). According to the purported mechanism of action, the mitochondria must, seemingly, perform three "magic tricks." First, the mitochondria must survive transfer from an intracellular environment to an extracellular one with high Ca 2+ concentrations. Second, if they survive, mitochondria must produce ATP that is able to enter cardiac myocytes to support contraction. Third, enough mitochondria must pass through the cell membrane to contribute to ATP production by the host cell. A corollary to trick number three is a variation in which the mitochondria are injected into the bloodstream and somehow pass through the endothelial vascular permeability barrier, migrate into the interstitium, and are incorporated into the dysfunctional target tissue. Given the rapid translation of this method to the clinic, it behooves us to determine whether these extraordinary claims are convincingly supported.

The main focus of cardio-oncology has been the prevention and treatment of the cardiac toxicity of chemotherapy and radiotherapy. Furthermore, several targeted therapies have been associated with unexpected cardiotoxic side-effects. Recently, epidemiological studies reported a higher incidence of cancer in patients with heart failure (HF) compared with individuals without HF. On this basis, it has been proposed that HF might represent an oncogenic condition. This hypothesis is supported by preclinical studies demonstrating that hyperactivation of the sympathetic nervous system and renin-angiotensin-aldosterone system, which is a hallmark of HF, promotes cancer growth and dissemination. Another intriguing possibility is that the co-occurrence of HF and cancer is promoted by a common pathological milieu characterised by a state of chronic low-grade inflammation, which predisposes to both diseases. In this review, we provide an overview of the mechanisms underlying the bidirectional relationship between HF and cancer.