Association of inflammatory markers with incident heart failure or cancer in the HUNT3 and Health ABC population studies.

AIMS: To investigate the relationship between chronic low-grade inflammation, as measured by high-sensitivity C-reactive protein (hsCRP) levels, and incident heart failure (HF) or cancer. METHODS: We assessed the relationship between baseline hsCRP concentrations and subsequent HF or cancer in two community-based cohorts, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (ABC) study. In the latter, the analysis was replicated with interleukin (IL)-1, IL-6, or tumour necrosis factor (TNF)-α instead of hsCRP. RESULTS: In HUNT3, hsCRP was measured in 47,163 subjects (mean age 52.3 ± 15.8 years). During a median follow-up of 12.1 years, 2,034 (4.3%) individuals developed HF and 5,024 (10.7%) cancer, with 442 (0.9%) being diagnosed with both. After adjusting for age, male sex, diabetes, obesity, previous or current smoking, and comorbidities, elevated baseline hsCRP was associated with a higher risk of HF or cancer (HR 1.09; 95%CI, 1.07-1.10). In the Health ABC study, hsCRP levels were assessed in 2,803 participants, who had a mean age of 72.6 ± 2.9 years and a higher burden of comorbidities than in HUNT3. During a median follow-up of 8.2 years, HF and cancer were diagnosed in 346 (12.3%) and 776 (27.7%) subjects, respectively, with 77 (2.7%) having both conditions. After adjusting for the same variables used for the HUNT3 cohort, hsCRP remained significantly associated with incident HF or cancer (HR 1.11; 95%CI, 1.05-1.18), as were IL-1 (HR 1.15; 1.07-1.24), IL-6 (HR 1.09; 1.02-1.17), and TNF-α (HR 1.15; 1.07-1.24). CONCLUSIONS: A state of chronic, low-grade inflammation captured by an increase in hsCRP levels is associated with an increased risk of developing HF or cancer, with potential implications for clinical trials with anti-inflammatory therapies.

There is an increasing recognition that cardiovascular (CV) risk factors portend an increased risk of both heart failure (HF) and cancer. Chronic, low-grade inflammation might represent a shared pathogenic pathway underlying the association between these risk factors, HF, and malignancy. The biomarker high-sensitivity C-reactive protein (hsCRP) might add prognostic information on CV and cancer risk by capturing this inflammatory state. In this study we analysed the association of inflammation, as assessed by baseline measurement of hsCRP, and the risk of developing HF and cancer in two community-based prospective studies, the Trøndelag Health Study (HUNT3) and the Health, Aging and Body Composition (Health ABC) study.In these cohorts, comprising more than 50,000 individuals, inflammation at baseline was associated with an increased risk of incident HF or cancer during a median follow-up of 8-12 years, after adjusting for traditional risk factors and comorbidities.In the Health ABC study sample, three inflammatory markers other than hsCRP, namely interleukin (IL)-1, IL-6, or tumour necrosis factor α, performed similarly to hsCRP in predicting the risk of incident HF or cancer. These results provide insights into the interconnection between HF and cancer and reinforce the concept that low-grade, chronic inflammation promotes the development of both HF and cancer and, thereby, might be targeted for prevention of either condition. Furthermore, our findings confirm the reliability of hsCRP as a biomarker to select individuals who may benefit from anti-inflammatory treatments to reduce CV and cancer events.

Fabry Disease: Cardiac Implications and Molecular Mechanisms.

PURPOSE OF REVIEW: This review explores the interplay among metabolic dysfunction, oxidative stress, inflammation, and fibrosis in Fabry disease, focusing on their potential implications for cardiac involvement. We aim to discuss the biochemical processes that operate in parallel to sphingolipid accumulation and contribute to disease pathogenesis, emphasizing the importance of a comprehensive understanding of these processes. RECENT FINDINGS: Beyond sphingolipid accumulation, emerging studies have revealed that mitochondrial dysfunction, oxidative stress, and chronic inflammation could be significant contributors to Fabry disease and cardiac involvement. These factors promote cardiac remodeling and fibrosis and may predispose Fabry patients to conduction disturbances, ventricular arrhythmias, and heart failure. While current treatments, such as enzyme replacement therapy and pharmacological chaperones, address disease progression and symptoms, their effectiveness is limited. Our review uncovers the potential relationships among metabolic disturbances, oxidative stress, inflammation, and fibrosis in Fabry disease-related cardiac complications. Current findings suggest that beyond sphingolipid accumulation, other mechanisms may significantly contribute to disease pathogenesis. This prompts the exploration of innovative therapeutic strategies and underscores the importance of a holistic approach to understanding and managing Fabry disease.

Exploring the Connection Between Relaxed Myosin States and the Anrep Effect.

The Anrep effect is an adaptive response that increases left ventricular contractility following an acute rise in afterload. Although the mechanistic origin remains undefined, recent findings suggest a two-phase activation of resting myosin for contraction, involving strain-sensitive and posttranslational phases. We propose that this mobilization represents a transition among the relaxed states of myosin-specifically, from the super-relaxed (SRX) to the disordered-relaxed (DRX)-with DRX myosin ready to participate in force generation. This hypothesis offers a unified explanation that connects myosin's SRX-DRX equilibrium and the Anrep effect as parts of a singular phenomenon. We underscore the significance of this equilibrium in modulating contractility, primarily studied in the context of hypertrophic cardiomyopathy, the most common inherited cardiomyopathy associated with diastolic dysfunction, hypercontractility, and left ventricular hypertrophy. As we posit that the cellular basis of the Anrep effect relies on a two-phased transition of myosin from the SRX to the contraction-ready DRX configuration, any dysregulation in this equilibrium may result in the pathological manifestation of the Anrep phenomenon. For instance, in hypertrophic cardiomyopathy, hypercontractility is linked to a considerable shift of myosin to the DRX state, implying a persistent activation of the Anrep effect. These valuable insights call for additional research to uncover a clinical Anrep fingerprint in pathological states. Here, we demonstrate through noninvasive echocardiographic pressure-volume measurements that this fingerprint is evident in 12 patients with hypertrophic obstructive cardiomyopathy before septal myocardial ablation. This unique signature is characterized by enhanced contractility, indicated by a leftward shift and steepening of the end-systolic pressure-volume relationship, and a prolonged systolic ejection time adjusted for heart rate, which reverses post-procedure. The clinical application of this concept has potential implications beyond hypertrophic cardiomyopathy, extending to other genetic cardiomyopathies and even noncongenital heart diseases with complex etiologies across a broad spectrum of left ventricular ejection fractions.

Mutations in DNAJC19 cause altered mitochondrial structure and increased mitochondrial respiration in human iPSC-derived cardiomyocytes.

BACKGROUND: Dilated cardiomyopathy with ataxia (DCMA) is an autosomal recessive disorder arising from truncating mutations in DNAJC19, which encodes an inner mitochondrial membrane protein. Clinical features include an early onset, often life-threatening, cardiomyopathy associated with other metabolic features. Here, we aim to understand the metabolic and pathophysiological mechanisms of mutant DNAJC19 for the development of cardiomyopathy. METHODS: We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) of two affected siblings with DCMA and a gene-edited truncation variant (tv) of DNAJC19 which all lack the conserved DnaJ interaction domain. The mutant iPSC-CMs and their respective control cells were subjected to various analyses, including assessments of morphology, metabolic function, and physiological consequences such as Ca2+ kinetics, contractility, and arrhythmic potential. Validation of respiration analysis was done in a gene-edited HeLa cell line (DNAJC19tvHeLa). RESULTS: Structural analyses revealed mitochondrial fragmentation and abnormal cristae formation associated with an overall reduced mitochondrial protein expression in mutant iPSC-CMs. Morphological alterations were associated with higher oxygen consumption rates (OCRs) in all three mutant iPSC-CMs, indicating higher electron transport chain activity to meet cellular ATP demands. Additionally, increased extracellular acidification rates suggested an increase in overall metabolic flux, while radioactive tracer uptake studies revealed decreased fatty acid uptake and utilization of glucose. Mutant iPSC-CMs also showed increased reactive oxygen species (ROS) and an elevated mitochondrial membrane potential. Increased mitochondrial respiration with pyruvate and malate as substrates was observed in mutant DNAJC19tv HeLa cells in addition to an upregulation of respiratory chain complexes, while cellular ATP-levels remain the same. Moreover, mitochondrial alterations were associated with increased beating frequencies, elevated diastolic Ca2+ concentrations, reduced sarcomere shortening and an increased beat-to-beat rate variability in mutant cell lines in response to ß-adrenergic stimulation. CONCLUSIONS: Loss of the DnaJ domain disturbs cardiac mitochondrial structure with abnormal cristae formation and leads to mitochondrial dysfunction, suggesting that DNAJC19 plays an essential role in mitochondrial morphogenesis and biogenesis. Moreover, increased mitochondrial respiration, altered substrate utilization, increased ROS production and abnormal Ca2+ kinetics provide insights into the pathogenesis of DCMA-related cardiomyopathy.

Activation of the integrated stress response rewires cardiac metabolism in Barth syndrome.

Barth Syndrome (BTHS) is an inherited cardiomyopathy caused by defects in the mitochondrial transacylase TAFAZZIN (Taz), required for the synthesis of the phospholipid cardiolipin. BTHS is characterized by heart failure, increased propensity for arrhythmias and a blunted inotropic reserve. Defects in Ca2+-induced Krebs cycle activation contribute to these functional defects, but despite oxidation of pyridine nucleotides, no oxidative stress developed in the heart. Here, we investigated how retrograde signaling pathways orchestrate metabolic rewiring to compensate for mitochondrial defects. In mice with an inducible knockdown (KD) of TAFAZZIN, and in induced pluripotent stem cell-derived cardiac myocytes, mitochondrial uptake and oxidation of fatty acids was strongly decreased, while glucose uptake was increased. Unbiased transcriptomic analyses revealed that the activation of the eIF2α/ATF4 axis of the integrated stress response upregulates one-carbon metabolism, which diverts glycolytic intermediates towards the biosynthesis of serine and fuels the biosynthesis of glutathione. In addition, strong upregulation of the glutamate/cystine antiporter xCT increases cardiac cystine import required for glutathione synthesis. Increased glutamate uptake facilitates anaplerotic replenishment of the Krebs cycle, sustaining energy production and antioxidative pathways. These data indicate that ATF4-driven rewiring of metabolism compensates for defects in mitochondrial uptake of fatty acids to sustain energy production and antioxidation.

Health position paper and redox perspectives on reactive oxygen species as signals and targets of cardioprotection.

The present review summarizes the beneficial and detrimental roles of reactive oxygen species in myocardial ischemia/reperfusion injury and cardioprotection. In the first part, the continued need for cardioprotection beyond that by rapid reperfusion of acute myocardial infarction is emphasized. Then, pathomechanisms of myocardial ischemia/reperfusion to the myocardium and the coronary circulation and the different modes of cell death in myocardial infarction are characterized. Different mechanical and pharmacological interventions to protect the ischemic/reperfused myocardium in elective percutaneous coronary interventions and coronary artery bypass grafting, in acute myocardial infarction and in cardiotoxicity from cancer therapy are detailed. The second part keeps the focus on ROS providing a comprehensive overview of molecular and cellular mechanisms involved in ischemia/reperfusion injury. Starting from mitochondria as the main sources and targets of ROS in ischemic/reperfused myocardium, a complex network of cellular and extracellular processes is discussed, including relationships with Ca2+ homeostasis, thiol group redox balance, hydrogen sulfide modulation, cross-talk with NAPDH oxidases, exosomes, cytokines and growth factors. While mechanistic insights are needed to improve our current therapeutic approaches, advancements in knowledge of ROS-mediated processes indicate that detrimental facets of oxidative stress are opposed by ROS requirement for physiological and protective reactions. This inevitable contrast is likely to underlie unsuccessful clinical trials and limits the development of novel cardioprotective interventions simply based upon ROS removal.

Mitochondrial function in macrophages controls cardiac repair after myocardial infarction.

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.

Cancer Incidence and Mortality According to Pre-Existing Heart Failure in a Community-Based Cohort.

Background: Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results. Objectives: This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort. Methods: Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates. Results: The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those <70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53). Conclusions: HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states.

Mitochondria as Therapeutic Targets in Heart Failure.

PURPOSE OF REVIEW: We review therapeutic approaches aimed at restoring function of the failing heart by targeting mitochondrial reactive oxygen species (ROS), ion handling, and substrate utilization for adenosine triphosphate (ATP) production. RECENT FINDINGS: Mitochondria-targeted therapies have been tested in animal models of and humans with heart failure (HF). Cardiac benefits of sodium/glucose cotransporter 2 inhibitors might be partly explained by their effects on ion handling and metabolism of cardiac myocytes. The large energy requirements of the heart are met by oxidative phosphorylation in mitochondria, which is tightly regulated by the turnover of ATP that fuels cardiac contraction and relaxation. In heart failure (HF), this mechano-energetic coupling is disrupted, leading to bioenergetic mismatch and production of ROS that drive the progression of cardiac dysfunction. Furthermore, HF is accompanied by changes in substrate uptake and oxidation that are considered detrimental for mitochondrial oxidative metabolism and negatively affect cardiac efficiency. Mitochondria lie at the crossroads of metabolic and energetic dysfunction in HF and represent ideal therapeutic targets.

Loss of Mitochondrial Ca2+ Uniporter Limits Inotropic Reserve and Provides Trigger and Substrate for Arrhythmias in Barth Syndrome Cardiomyopathy.

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). Because mitochondrial function and ROS formation are regulated by excitation-contraction 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 with wild-type littermates. Respiratory chain assembly and function, ROS emission, and Ca2+ uptake were determined in isolated mitochondria. Excitation-contraction coupling was integrated with mitochondrial redox state, ROS, and Ca2+ 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 Ca2+ affinity and slowed cross-bridge cycling caused diastolic dysfunction, in part, compensated by accelerated diastolic Ca2+ decay through preactivated sarcoplasmic reticulum Ca2+-ATPase. Taz deficiency provoked heart-specific loss of mitochondrial Ca2+ uniporter protein that prevented Ca2+-induced activation of the Krebs cycle during ß-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 ß-adrenergic stimulation. Cellular arrhythmias and QRS prolongation, but not the defective inotropic reserve, were restored by inhibiting Ca2+ export through the mitochondrial Na+/Ca2+ exchanger. All alterations occurred in the absence of excess mitochondrial ROS in vitro or in vivo. CONCLUSIONS: Downregulation of mitochondrial Ca2+ uniporter, increased myofilament Ca2+ affinity, and preactivated sarcoplasmic reticulum Ca2+-ATPase provoke mechano-energetic uncoupling that explains diastolic dysfunction and the lack of inotropic reserve in BTHS cardiomyopathy. Furthermore, defective mitochondrial Ca2+ uptake provides a trigger and a substrate for ventricular arrhythmias. These insights can guide the ongoing search for a cure of this orphaned disease.

The α2-isoform of the Na+/K+-ATPase protects against pathological remodeling and ß-adrenergic desensitization after myocardial infarction.

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 (TG-α2) 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 ß-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 ß-adrenergic stimulation more efficiently during chronic cardiac stress. These mechanisms might improve the ß-adrenergic reserve and contribute to functional preservation in heart failure.NEW & NOTEWORTHY Reduced systolic and diastolic calcium levels in cardiomyocytes from NKA-α2 transgenic mice minimize the desensitization of the ß-adrenergic signaling system. These effects result in an improved ß-adrenergic reserve and prevent functional deterioration and cardiac remodeling.

Haematopoietic and cardiac GPR55 synchronize post-myocardial infarction remodelling.

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.

Pharmacological inhibition of GLUT1 as a new immunotherapeutic approach after myocardial infarction.

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.

Ouabain worsens diastolic sarcomere length in myocytes from a cardiomyopathy mouse model.

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.

Cellular and mitochondrial mechanisms of atrial fibrillation.

The molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation-contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Common mechanistic pathways in cancer and heart failure. A scientific roadmap on behalf of the Translational Research Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC).

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.

Role of serum biomarkers in cancer patients receiving cardiotoxic cancer therapies: a position statement from the Cardio-Oncology Study Group of the Heart Failure Association and the Cardio-Oncology Council of the European Society of Cardiology.

Serum biomarkers are an important tool in the baseline risk assessment and diagnosis of cardiovascular disease in cancer patients receiving cardiotoxic cancer treatments. Increases in cardiac biomarkers including cardiac troponin and natriuretic peptides can be used to guide initiation of cardioprotective treatments for cancer patients during treatment and to monitor the response to cardioprotective treatments, and they also offer prognostic value. This position statement examines the role of cardiac biomarkers in the management of cancer patients. The Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) in collaboration with the Cardio-Oncology Council of the ESC have evaluated the current evidence for the role of cardiovascular biomarkers in cancer patients before, during and after cardiotoxic cancer therapies. The characteristics of the main two biomarkers troponin and natriuretic peptides are discussed, the link to the mechanisms of cardiovascular toxicity, and the evidence for their clinical use in surveillance during and after anthracycline chemotherapy, trastuzumab and HER2-targeted therapies, vascular endothelial growth factor inhibitors, proteasome inhibitors, immune checkpoint inhibitors, cyclophosphamide and radiotherapy. Novel surveillance clinical pathways integrating cardiac biomarkers for cancer patients receiving anthracycline chemotherapy or trastuzumab biomarkers are presented and future direction in cardio-oncology biomarker research is discussed.