Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high...Altered cardiac and systemic metabolism is a hallmark of heart failure (HF). In the failing heart, cardiomyocytes develop alterations in substrate preference, mitochondrial oxidative metabolism, and the shuttling of high-energy phosphates from mitochondria to the cytosol that compromise energetic efficiency and contribute to disease progression. At the systemic level, neurohormonal activation plays a dominant role in HF with reduced ejection fraction, whereas HF with preserved ejection fraction is shaped by the clustering of multiple comorbidities, such as diabetes, obesity and hypertension, which disrupt the physiological crosstalk between the heart and metabolically active organs. This review provides a perspective on cardiac metabolism in HF. We delineate the specific alterations in substrate metabolism that characterize HF with reduced ejection fraction versus HF with preserved ejection fraction, examine the impact of interorgan communication on myocardial function, and highlight how the benefits of emerging HF therapies, including sodium-glucose cotransporter 2 inhibitors and GLP-1 receptor agonists, may be mediated, at least in part, through the restoration of metabolic homeostasis.
De Gaspari M, Pilichou K, Zorzi A
… +13 more, Bueno Marinas M, Cason M, Celeghin R, Sarto P, Fedeli U, Rigato I, Cipriani A, Perazzolo Marra M, Bauce B, Corrado D, Thiene G, Rizzo S, Basso C
BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a major cause of sudden cardiac death (SCD) in competitive athletes. We aimed to evaluate the prevalence and characteristics of ACM with the increased awareness of the d...BACKGROUND: Arrhythmogenic cardiomyopathy (ACM) is a major cause of sudden cardiac death (SCD) in competitive athletes. We aimed to evaluate the prevalence and characteristics of ACM with the increased awareness of the disease at preparticipation screening after the introduction of the 1994 and 2010 diagnostic criteria. METHODS: The North-East Italy registry of juvenile SCD (≤40 years old) was searched for competitive athletes dying due to ACM in the time interval from 1985 to 2024. Cases referred from other regions were also included. Clinical and pathology data were analyzed according to guidelines. RESULTS: ACM was the cause of SCD in 29% of athletes. The incidence rate of SCD in athletes was 0.43 (0.27-0.65) versus 0.14 (0.05-0.33) per 100 000/y before and after 2010, respectively. Fifty-one athletes with ACM (50 male, 25±6.4 years) were enrolled. The pattern was right ventricular/biventricular in 74.5% and left ventricular in 25.5% (41% after 2010). Fibrofatty replacement was transmural in 63% of right ventricular/biventricular ACM and exclusively subepicardial-midmural in left ventricular ACM. First-line preparticipation screening revealed abnormalities in 62.7% (83.3% before 1994 and 40.9% after 2010). Twelve-lead ECG abnormalities were present in 50.9% (60.5% in right ventricular/biventricular ACM and 23% in left ventricular ACM), with negative T waves in 39.2% and low QRS voltage in 25.5%. Premature ventricular complexes/nonsustained ventricular tachycardia with left bundle-branch block or multiple morphologies were present on basal or limited exercise ECG in 35.3%. Maximal stress test, Holter, and 2-dimensional echocardiography were positive in 55%, 45.4%, and 5.8% of cases, respectively. In the only case who underwent contrast-enhanced cardiac magnetic resonance, late gadolinium enhancement was detected. CONCLUSIONS: ACM-related SCD incidence appeared lower in the post-2010 period. A phenotypic shift toward the left ventricular variant is observed, with ECG changes in a minority of cases and usually normal 2-dimensional echocardiography. If the index of suspicion is high, contrast-enhanced cardiac magnetic resonance is crucial for early identification and SCD prevention.
Barac A, Guha A, Fleming TR
… +10 more, Bonaca M, Thavendiranathan P, Deswal A, Amiri-Kordestani L, Bhatnagar V, Cordoba R, Hurvitz S, Adjei AA, Agarwal N, American Heart Association Cardio-Oncology Committee of the Council on Clinical Cardiology and Council on Genomic and Precision Medicine; Council on Cardiovascular and Stroke Nursing; and Council on Peripheral Vascular Disease
Circulation
· 2026 Jun · PMID 42296446
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The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular to...The unprecedented expansion of approved oncology therapies has prolonged survival and transformed the prognosis for many patients diagnosed with cancer. However, cancer treatments may be associated with cardiovascular toxicities that manifest through vascular, myocardial, or metabolic pathways, potentially limiting the use of cancer therapeutics and adversely affecting outcomes. Oncology clinical trials provide an important opportunity to evaluate cardiovascular safety signals by generating data on the incidence, timing, and spectrum of toxicities. However, progress has been limited by inconsistent definitions and variable approaches to event characterization. This scientific statement aligns the advances in cardiovascular medicine and cardiovascular clinical trials to provide criteria for systematic selection, rigorous characterization, and adjudication of cardiovascular endpoints in contemporary oncology trials. The proposed framework links drug-specific mechanisms to endpoint selection and standardizes the approach to definitions of adverse cardiovascular events, including heart failure, arrhythmias, myocarditis, and thrombotic events. Definitions of major adverse cardiac events, clinical events, and surrogate endpoints are discussed, along with strategies for alignment with the Common Terminology Criteria for Adverse Events and patient-reported outcomes. Practical guidance is provided for prospective surveillance, decentralized and hybrid clinical trial designs, independent endpoint adjudication, and statistical approaches to competing risks and late-emerging toxicities. By harmonizing cardiovascular endpoint assessment across oncology trials, this scientific statement aims to enhance risk stratification, facilitate regulatory acceptance, and inform clinical decision-making, ultimately improving patient safety while supporting innovation in cancer therapeutics.
Kato R, Takigawa M, Kawamura I
… +12 more, Toda M, Honda M, Negishi M, Tateishi R, Iwakawa H, Yamao K, Goto K, Nishimura T, Tao S, Miyazaki S, Watanabe H, Sasano T
Vahle B, Weidner S, Tomalka A
… +11 more, Schauer A, Augstein A, Männel A, Barthel P, Friedrich J, Beck G, Labeit S, Bowen TS, Siebert T, Linke A, Adams V
BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitoc...BACKGROUND: Exercise intolerance, promoted by skeletal muscle- and mitochondrial dysfunction, has been identified as a therapeutic target in heart failure with preserved ejection fraction (HFpEF). In the context of mitochondrial dysfunction, altered cardiolipin integrity has been reported in the myocardium of HFpEF, suggesting Elamipretide, a cardiolipin stabilizing agent, as potential therapeutic approach. The present study investigated cardiolipin dysregulation in the skeletal muscle of HFpEF rats and analyzed the effect of Elamipretide treatment. METHODS: Female zucker fatty spontaneously hypertensive heart failure F1 hybrid lean (n=10, control) and obese rats (n=24, HFpEF) were included. At 20 weeks of age, HFpEF rats were randomized into 2 groups receiving NaCl (n=12) or Elamipretide (n=12) for 12 weeks. Skeletal muscle tissue was collected for whole-muscle force, single-fiber mechanics, mitochondrial respiration, histology and molecular analyses. RESULTS: HFpEF rats exhibited reduced cardiolipin levels (-6.8%, =0.007) and maturation (shown via tafazzin expression), contractile dysfunction, titin hyperphosphorylation, fiber atrophy and increased oxidative stress markers. Elamipretide improved whole muscle (soleus: +8.2%, =0.041, extensor digitorum longus: +10.9%, =0.016) and single-fiber (soleus: +173.2%, <0.001, extensor digitorum longus: +66.0%, =ns) contractile function and titin phosphorylation (soleus: -35.4%, <0.001, extensor digitorum longus: -40.2%, <0.001), while preventing atrophy development (soleus: +49%, =0.001, extensor digitorum longus: +54.8%, <0.001). Improved mitochondrial function, presumably through cardiolipin-mediated improvements in oxidative phosphorylation, could be associated with muscle force and cardiolipin integrity. CONCLUSIONS: Our data highlight cardiolipin stabilization as a key modulator of mitochondrial and contractile function in HFpEF, identifying Elamipretide as a promising therapeutic approach for skeletal muscle dysfunction.
Kucera C, Ramalingam AR, Raph SM
… +6 more, Paily R, Srivastava S, Lorkiewicz PK, Bhatnagar A, Nystoriak MA, Carll AP
Circ Arrhythm Electrophysiol
· 2026 Jun · PMID 42290371
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BACKGROUND: Despite the growing popularity of electronic cigarettes, evidence is mounting that vaping induces autonomic nervous system imbalance, cardiac arrhythmia, and potentially even cardiac arrest. The ingredients m...BACKGROUND: Despite the growing popularity of electronic cigarettes, evidence is mounting that vaping induces autonomic nervous system imbalance, cardiac arrhythmia, and potentially even cardiac arrest. The ingredients menthol, WS-3, and WS-23 are cooling agents that enhance the appeal of electronic cigarettes (e-cigs) but bear unknown risks when inhaled. METHODS: We systematically evaluated how these coolants influence the impacts of e-cigs on cardiac and cellular electrophysiology in mice and human induced pluripotent stem cell-derived cardiomyocytes, respectively. Mice were exposed by inhalation to e-cig aerosols generated from standard e-liquid solvents and 2.5% nicotine benzoate (vehicle), or from vehicle plus menthol, WS-3, or WS-23, at increasing concentrations throughout exposure. Telemetry-derived electrocardiograms were analyzed for changes in heart rate, heart rate variability, morphology, and ventricular premature beat arrhythmias. Human induced pluripotent stem cell-derived cardiomyocytes were evaluated for the effects of serially increasing coolant concentrations on beat rate, electric field potential duration, and rate-corrected field potential duration from a newly validated formula, in the absence and presence of norepinephrine to simulate basal physiology and nicotine-evoked sympathoexcitation. RESULTS: Upon e-cig aerosol inhalation, all coolants acutely enhanced vehicle-induced autonomic imbalance, but only the synthetic coolants, WS-3 and WS-23, potentiated ventricular arrhythmogenesis. Ventricular premature beats during e-cig exposures correlated with sympathetic dominance and transient delays in ventricular repolarization measured by heart rate variability and rate-corrected QT interval, respectively; however, correlations were strongest for WS-23 despite no significant impact of coolants on nicotine intake. Conversely, in human induced pluripotent stem cell-derived cardiomyocytes, coolants did not affect basal physiology but slowed beat rate and shortened rate-corrected field potential duration during norepinephrine stimulation. CONCLUSIONS: Together, these data indicate that coolants dose-dependently enhance the arrhythmogenicity of e-cigs, likely through acute alterations in autonomic modulation and repolarization. Pending confirmation by human studies, these common non-nicotine additives may exacerbate e-cig cardiotoxicity and pose unique cardiovascular risks, particularly in those with arrhythmogenic susceptibility to sympathetic stimulation or slowed ventricular repolarization.
BACKGROUND: Cardiac acute rejection (AR) is a risk factor for poor outcomes; however, there are limited risk prediction models to stratify these patients for death or prolonged left ventricular (LV) dysfunction. We asses...BACKGROUND: Cardiac acute rejection (AR) is a risk factor for poor outcomes; however, there are limited risk prediction models to stratify these patients for death or prolonged left ventricular (LV) dysfunction. We assessed the prognostic utility of percent donor-derived cell-free DNA (%dd-cfDNA) measured at AR diagnosis for predicting adverse outcomes. METHODS: The prospective multicenter GRAFT study (Genomic Research Alliance for Transplantation) enrolled heart transplant recipients and collected serial plasma samples to quantitate %dd-cfDNA. AR was defined as acute cellular rejection, antibody-mediated rejection, as well as biopsy-negative antibody-mediated rejection (donor-specific antibody positivity with LV dysfunction). In the primary analyses, AR was stratified by %dd-cfDNA at diagnosis using a data-driven threshold of 0.15%. Cox regression models assessed the associations between the time-dependent covariates of AR and %dd-cfDNA levels at the AR diagnosis and the outcome of prolonged LV ejection fraction decline (≤50% for ≥90 days) and death. RESULTS: The study included 277 patients and 3218 %dd-cfDNA measurements. Over a median follow-up of 4.9 years (interquartile range, 2.5-5.0), 53 patients experienced the composite outcome of death or prolonged LV dysfunction, and 75 (27%) patients developed AR, including 43 (15%) patients with acute cellular rejection, 18 (7%) with pathological antibody-mediated rejection, and 14 (5%) with donor-specific antibody+/LV dysfunction. AR was associated with an increased risk of the primary composite outcome (hazard ratio, 4.47 [95% CI, 2.42-8.26]; <0.001). When AR was stratified by %dd-cfDNA at diagnosis, patients with %dd-cfDNA ≥0.15% had higher risks of prolonged LV dysfunction, death, and the composite outcome compared with patients who had not developed AR at the same follow-up time (hazard ratio, 6.28 [95% CI, 3.04-13.0]; <0.001 for the composite outcome). In contrast, the risks of death and prolonged LV ejection fraction reduction were not statistically significantly increased among patients who developed AR with %dd-cfDNA <0.15% at diagnosis. CONCLUSIONS: AR with elevated %dd-cfDNA levels at diagnosis is associated with an increased risk of adverse outcomes after heart transplant, offering novel prognostic utility.
Spaulding C, Krackhardt F, Bogaerts K
… +30 more, Abdelaal E, Alfonso F, Briguori C, Bruch L, Cruden N, Den Hartog AW, Garot P, Godin M, Hildick-Smith D, Johnson T, Ladwiniec A, Linke A, Maart CA, Mashayekhi K, Meier P, Meunier L, Morgan K, O'Kane P, Puymirat E, Rissanen TT, Sabaté M, Schmitz T, Toth GG, Trevelyan J, Wanczura P, Marcus W, Wykrzykowska JJ, Urban P, Eccleshall S, SELUTION DeNovo Investigators
Circulation
· 2026 Jun · PMID 42290366
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BACKGROUND: Implantation of drug eluting stents (DESs) is currently the default approach for percutaneous coronary interventions, but long-term adverse events still exist. An approach with minimal stenting deserves to be...BACKGROUND: Implantation of drug eluting stents (DESs) is currently the default approach for percutaneous coronary interventions, but long-term adverse events still exist. An approach with minimal stenting deserves to be assessed in a randomized trial. We studied a novel sirolimus-eluting balloon (SEB) that elutes sirolimus over a 90-day period using a biodegradable polymer microreservoir technology. METHODS: In a multicenter, open-label, randomized trial, we compared an SEB-based strategy with provisional DES with one of systematic DES for de novo lesions in coronary arteries between 2 and 5 mm in diameter. Subjects were randomized 1:1 before percutaneous coronary intervention. The primary end point was target vessel failure, a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. It was tested for noninferiority at 1 year with the use of an absolute margin equal to 50% of the combined event rate at a significance level of 0.025. The primary analysis population included all randomized subjects with completed or attempted percutaneous revascularization, analyzed according to the intention-to-treat principle. A sensitivity analysis was performed on the per-protocol population. RESULTS: Between August 27, 2021, and July 29, 2024, 3323 participants were randomized and treated in 62 sites. Among 1661 participants in the SEB strategy group, bailout stenting was performed in 343 (20.7%). Target vessel failure occurred over 365 days in 88 (5.3%) and 73 (4.4%) participants in the SEB and the systematic DES strategy groups, respectively (risk difference, 0.91% [95% CI -0.55% to 2.38%]; 1-sided =0.02 for noninferiority with a 2.44% noninferiority margin). Clinically driven target vessel revascularization occurred more frequently in the SEB strategy group (3.3% versus 2.1%; risk difference, 1.22% [95% CI, 0.11%-2.33%). Safety events, including lesion thrombosis, were low and similar in both groups. Although the results of the per-protocol population (3194 participants, 96%) did not confirm noninferiority (upper boundary of the 95% CI, 2.63; =0.04), they were similar to the intention-to-treat results in both magnitude and direction. CONCLUSIONS: At 1 year, in the primary intention-to-treat analysis population, a strategy of percutaneous coronary intervention with SEB and provisional DES was noninferior to the systematic use of DES for the primary end point of target vessel failure. The per-protocol population sensitivity analysis did not confirm noninferiority. Clinically driven target vessel revascularization occurred more frequently in the SEB strategy group. At 5 years, target vessel failure will be tested again for noninferiority and for superiority if noninferiority is achieved. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT04859985.
Loh KWZ, Zhou Y, Liu C
… +10 more, Zhai J, Jaladanki CK, Jia Yi Neo C, Yu D, Liang MC, Shen M, Fan H, Liao P, Hu Z, Soong TW
Circulation
· 2026 Jun · PMID 42290338
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BACKGROUND: Fine-tuning of Ca1.2 calcium channel activity by binding proteins represents a novel mechanism for regulating smooth muscle contraction and blood pressure (BP). This study aimed to elucidate the role of Gal-3...BACKGROUND: Fine-tuning of Ca1.2 calcium channel activity by binding proteins represents a novel mechanism for regulating smooth muscle contraction and blood pressure (BP). This study aimed to elucidate the role of Gal-3 (galectin-3), a newly identified Ca1.2-binding protein, in the pathogenesis of hypertension. METHODS: In vitro, ex vivo, and in vivo experiments involving molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements were used to evaluate the molecular mechanisms by which Gal-3 binds to and elevates membrane insertion of Ca1.2 channels. The experiments were performed in transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates; spontaneously hypertensive rats; or human patients. In vivo experiments involving delivery of the blocking iGal3BP (inhibitory galectin-3-binding peptide) into spontaneously hypertensive rats were performed to investigate its effect on BP. RESULTS: We identified Gal-3 as a novel binding partner and unexpected positive modulator of the Ca1.2 channel through binding to the intracellular II-III loop. Gal-3 increased total and surface expression, current density, and open probability of Ca1.2 channels. Both Ca1.2 and Gal-3 were upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle significantly lowered Ca1.2 protein and BP in mice. With specific binding sites identified within both Gal-3 and the Ca1.2 II-III loop, the peptide iGal3BP, designed to block Ca1.2-Gal-3 interaction, significantly reduced BP in spontaneously hypertensive rats by decreasing Ca1.2 protein expression. Repeated iGal3BP administration resulted in cumulative peptide accumulation in mesenteric arteries and produced a sustained reduction in BP, which demonstrated greater long-lasting antihypertensive efficacy compared with amlodipine and losartan. Administration of iGal3BP in combination with a negative modulatory Gal-1 mimetic peptide that mimics Gal-1-Ca1.2 interaction returned systolic BP to normotensive levels within 4 hours and lowered BP in hypertensive rats in a sustained manner for 35 days. CONCLUSIONS: These results provide strong evidence that Gal-based Ca1.2 channel modulators are novel therapeutic pathways for normalizing BP.