Toro V, Mougin M, Brossat C
… +17 more, Jambon-Barbara C, Hlavaty A, Guay CA, El Kabbout R, Bilodeau C, Grobs Y, Martineau S, Breuils-Bonnet S, Abi-Sleimen A, Ruffenach G, Boucherat O, Bisserier M, Provencher S, Bonnet S, Montani D, Khouri C, Potus F
Circulation
· 2026 May · PMID 42189958
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Hou Y, Li Q, Wei TW
… +27 more, Lin X, Guo J, Yuan P, Shen H, Gao Y, Pan Q, Xu C, Biasin V, Li Y, He Y, Wu J, Li L, Jin J, Wei X, Lin J, Ma S, Jiang N, Ma J, Zhi X, Jiang Q, Qu L, Liang Q, Jiang L, Osto E, Shyy JY, Wang X, Meng D
Circulation
· 2026 May · PMID 42186808
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BACKGROUND: Vascular remodeling is a central characteristic of pulmonary hypertension (PH), yet the precise mechanisms underlying this process remain poorly understood. METHODS: The coimmunoprecipitation assay was used t...BACKGROUND: Vascular remodeling is a central characteristic of pulmonary hypertension (PH), yet the precise mechanisms underlying this process remain poorly understood. METHODS: The coimmunoprecipitation assay was used to explore prolyl hydroxylase that modifies BACH1 (BTB and CNC homology 1). Cultured pulmonary artery smooth muscle cells, rodent models with PH, specimens from patients with idiopathic pulmonary arterial hypertension, and single-nucleus RNA sequencing were used to study the role of BACH1 in the regulation of PH and the underlying mechanisms. RESULTS: In this study, we found that the transcription factor BACH1 was upregulated in lung tissues and pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension and animals with experimental PH. Under normoxia, the prolyl hydroxylation of BACH1, mediated by PHD (prolyl hydroxylase) 2, facilitated BACH1 degradation by VHL (von Hippel-Lindau) protein. Hypoxic exposure decreased this prolyl hydroxylation with subsequent increased BACH1 protein stability. The deficiency or overexpression of BACH1 in smooth muscle cells in mice alleviated or exacerbated pulmonary vascular remodeling and hypoxia-induced PH. Hypoxia triggered the accumulation of BACH1 and its recruitment to the promoter region of TGFBR2 (transforming growth factor β receptor type II) in smooth muscle cells. This recrui tment activated TGFBR2 transcription, thereby promoting vascular remodeling by upregulating SMAD (suppressor of mothers against decapentaplegic) signaling and extracellular matrix deposition. Decreased TGFBR2 expression or inhibited kinase activity significantly attenuated the BACH1-induced extracellular matrix genes. Furthermore, the BACH1-enhanced PH development was blunted by a TGFBR2 kinase inhibitor. CONCLUSIONS: Our study illustrates that BACH1 is prolyl-hydroxylated in an oxygen/PHD-dependent manner, affecting its stability through VHL. BACH1 is crucial for hypoxia-induced PH by activating TGFBR2/SMAD in smooth muscle cells. Thus, BACH1 inhibition may be a potential therapeutic strategy for PH.
Osmancik P, Neuzil P, Hozmanova J
… +19 more, Petru J, Herman D, Kralovec S, Hozman M, Tichy M, Waldauf P, Karel T, Sediva L, Fischer J, Stepanek L, Mala I, Lekesova V, Hala P, Funasako M, Vesela J, Filipcova V, Karch J, Whang W, Reddy VY
Circulation
· 2026 Jun · PMID 42186803
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BACKGROUND: Catheter ablation for atrial fibrillation (AF) is one of the most common cardiovascular procedures being performed worldwide. Despite the large body of evidence of its effectiveness, with a single exception,...BACKGROUND: Catheter ablation for atrial fibrillation (AF) is one of the most common cardiovascular procedures being performed worldwide. Despite the large body of evidence of its effectiveness, with a single exception, prior ablation studies were largely unblinded trials. Accordingly, residual concerns remained about placebo effects, both for AF recurrence and, in particular, on subjective outcomes such as quality of life or anxiety. Here, we compared pulsed field ablation (PFA) with a sham procedure to treat patients with symptomatic AF. METHODS: This prospective, sham-controlled, single-blind, randomized clinical trial with blinded end-point assessment enrolled patients with AF that was highly symptomatic (Atrial Fibrillation Effect on Quality-of-Life score <50). Patients were assigned 1:1 to PFA or a sham procedure. All participants received implantable cardiac monitors for continuous rhythm monitoring during follow-up. The 6-month co-primary outcomes were (1) time to first recurrence of atrial tachyarrhythmia and (2) changes from baseline in Atrial Fibrillation Effect on Quality-of-Life scores compared between groups. Secondary outcomes were AF burden and psychological distress (assessed by the Hospital Anxiety and Depression Scale [HADS]). RESULTS: Patients (n=60) were randomized to PFA or sham. At 6 months, the first co-primary end point of AF recurrence was met in 2 patients (6.7%) who underwent PFA and 25 patients (83.3%) who underwent sham (posterior hazard ratio, 19.6 [95% bayesian credible intervals, 6.7-76.9]; posterior probability of superiority >0.99). For the second co-primary end point, Atrial Fibrillation Effect on Quality-of-Life scores showed greater improvement from baseline with PFA than sham (improved by 43.9+18.1 points versus 11.3+27.9 points; posterior median difference, 32.6 [95% bayesian credible interval, 20.2-44.9]; posterior probability of superiority >0.99). AF burden at 6 months was significantly lower in the PFA than the sham group (0 [0-0] versus 0.43 [0.04-3.47]; between group median difference, -0.39 [95% credible interval, -2.5 to -0.1], posterior probability of superiority >0.99). The Hospital Anxiety and Depression Scale score changed by -4 points (-7.8 to -2.0) with PFA and by -0.5 (-4.5 to 1.0) with sham (group median difference, -3.5 [95% credible interval, -6.0 to -1.0]; posterior probability of superiority >0.99). CONCLUSIONS: In patients with AF, PFA was superior to sham in reducing arrhythmia recurrences and burden and improving quality of life and AF-associated psychological distress. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05717725.
Monguillon V, Marston NA, Bohula EA
… +17 more, Park JG, Kuder JF, Murphy SA, De Ferrari GM, Leiter LA, Nicolau JC, Ebenbichler C, Sinnaeve P, Goudev A, Budaj A, Averkov O, Tokgözoğlu L, Blankstein R, Vinereanu D, Giugliano RP, Sabatine MS, O'Donoghue ML
Circulation
· 2026 Jun · PMID 42183757
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BACKGROUND: Lp(a) (lipoprotein[a]) is a risk factor for coronary heart disease. Whether baseline Lp(a) identifies higher-risk patients who derive more benefit from evolocumab is not established in a population without pr...BACKGROUND: Lp(a) (lipoprotein[a]) is a risk factor for coronary heart disease. Whether baseline Lp(a) identifies higher-risk patients who derive more benefit from evolocumab is not established in a population without previous myocardial infarction (MI) or stroke. METHODS: From June 2019 to November 2021, the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk Without Prior Myocardial Infarctions or Stroke) enrolled patients with qualifying atherosclerosis or high-risk diabetes without previous MI or stroke and randomized them to evolocumab or placebo (median follow-up 4.6 years). In a prespecified analysis, Lp(a) was assessed at baseline in 7557 patients. Cox models were used to assess the adjusted risk of cardiovascular events by baseline Lp(a) in the placebo arm, and the efficacy of evolocumab by baseline Lp(a). The primary outcome of interest was the composite of major coronary events (coronary heart disease death, MI, or urgent coronary revascularization). RESULTS: Median age was 66 [interquartile range, 60-71] years, and 42.8% were women; median Lp(a) was 28 [interquartile range, 9-132] nmol/L. Higher baseline Lp(a) was associated with an increased risk of major coronary events (adjusted hazard ratio [HR] per 100 nmol/L increase in Lp(a), 1.15 [95% CI, 1.05-1.26]; =0.004), particularly for MI (HR, 1.23 [95% CI, 1.10-1.38]; <0.001). There was no association between Lp(a) and ischemic stroke (HR, 1.00 [95% CI, 0.84-1.19]; =0.99). After 48 weeks, evolocumab reduced LDL-C (low-density lipoprotein cholesterol) by 66.8 mg/dL and Lp(a) by 38.0 nmol/L in patients with baseline Lp(a) >105 nmol/L versus 61.1 mg/dL and 6.0 nmol/L in those with baseline Lp(a) ≤105 nmol/L. The relative reductions in the rate of major coronary events were 41% (HR, 0.59 [95% CI, 0.41-0.83]) in those with Lp(a) >105 nmol/L compared with 35% (HR, 0.65 [95% CI, 0.51-0.82]) in those below (-interaction=0.45 for Lp[a] modeled as continuous variable). The corresponding absolute reductions were 3.7% versus 2.5% (-interaction=0.09), corresponding to a number needed to treat of 28 versus 40 to prevent 1 major coronary event at 5 years. CONCLUSIONS: In patients with atherosclerosis or high-risk diabetes but without previous MI or stroke, Lp(a) was independently associated with an increased risk of major coronary events but not ischemic stroke. Evolocumab reduced the relative risk of major coronary events to a similar degree irrespective of baseline Lp(a), with a numerically greater absolute risk reduction in patients with elevated Lp(a). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.
Gu H, Wen J, Liu Y
… +19 more, Xue Y, Zhao M, Zhao Y, Bi L, Cui H, Zhang W, Wenli X, Wang K, Deng Y, Yu X, Wang H, Hu J, Liu W, Guo Y, Chen C, Dong E, Zhang Y, Shyy JY, Xiao H
Circulation
· 2026 May · PMID 42170742
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BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na/H and Ca) cycling underlies reduced cardiac contr...BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and high mortality. Dysregulation of intracellular ion (ie, Na/H and Ca) cycling underlies reduced cardiac contractility. The mechanisms linking myocardial stress to this ion dysregulation remain incompletely understood. Although the metabolic transcription factor SREBP1 (sterol regulatory element-binding protein 1) remodels cardiac metabolism, its role in HFrEF without metabolic comorbidities, particularly regarding ion handling, remains undefined. METHODS: Cardiac tissues from HFrEF patients and mice subjected to transverse aortic constriction (TAC) were analyzed for SREBP1 transactivation of sodium-hydrogen exchanger 3 (NHE3). Cardiomyocyte-specific SREBP1 transgenic (Srebp1a-Tg) and knockdown (Cre-Srebp1) mice were generated. AAV9 vectors carrying (encoding NHE3), Srebp1a or shRNA against , driven by the cardiomyocyte-specific cTnT promoter, were used to validate the role of the SREBP1-NHE3 in HFrEF. RESULTS: SREBP1 was activated in human hearts with HFrEF because of dilated cardiomyopathy, but without diabetes or hyperlipidemia, and in TAC-induced HFrEF mouse hearts. Srebp1a-Tg mice exhibited impaired cardiac contractility with dysregulated calcium handling in cardiomyocytes without apparent lipid accumulation. Transcriptomics analysis identified increased NHE3 expression in Srebp1a-Tg mice, confirmed by NHE3 upregulation in TAC hearts and human failing hearts. ChIP-seq, ChIP, and promoter reporter assay demonstrated direct transcriptional regulation of (encoding NHE3) by SREBP1. NHE3 activity was enhanced in cardiomyocytes isolated from Srebp1a-Tg mice or those underwent TAC, whereas cardiomyocyte-specific knockdown in TAC mice reduced NHE3 activity. Cardiomyocyte-specific knockdown of or restored calcium handling and improved cardiac function in TAC mice. In Srebp1a-Tg mice, NHE3 knockdown alleviated Na and Ca overload and rescued cardiac systolic dysfunction. Conversely, NHE3 overexpression caused contractile impairment in both Cre-Srebp1 mice and controls, which offset the protective effect because of SREBP1 loss in the context of Na and Ca overload. CONCLUSIONS: SREBP1 directly transactivates cardiac NHE3 during the progression of HFrEF, leading to dysregulated calcium handling and impaired contractility, revealing a novel, noncanonical role for SREBP1 in the pathophysiology of heart failure and offering a potential new therapeutic target.
An J, Han C, Jiang Y
… +11 more, Shi J, Li H, Wang C, Huang J, Xu S, Ni J, Cao Y, Feng Y, Lyu Q, Dong N, Qin G
Circulation
· 2026 Jun · PMID 42170739
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BACKGROUND: Metabolic remodeling, marked by maladaptive shifts in substrate use and energy production, is a hallmark of pathologic cardiac hypertrophy. Yet the mechanisms linking stress signaling to impaired myocardial g...BACKGROUND: Metabolic remodeling, marked by maladaptive shifts in substrate use and energy production, is a hallmark of pathologic cardiac hypertrophy. Yet the mechanisms linking stress signaling to impaired myocardial glucose oxidation remain incompletely defined. Sam68 (Src-associated in mitosis, 68 kDa; also known as [KH domain-containing, RNA-binding, signal transduction-associated protein 1]), a STAR (signal transduction and activation of RNA) family RNA-binding protein, has not previously been implicated in cardiac metabolic control. METHODS: SAM68 expression was examined in failing human hearts and transcriptomic data sets. Cardiomyocyte-specific Sam68 knockout mice (Sam68cKO) and AAV9 (adeno-associated virus serotype 9)-cTnT (cardiac troponin T)-mediated cardiomyocyte Sam68 overexpression (Sam68OE) were studied in transverse aortic constriction and angiotensin II models. Mechanistic studies included RNA sequencing, targeted metabolomics, in vivo [U-C]-glucose tracing, coimmunoprecipitation, and protein-protein docking. Therapeutic relevance was tested with a PDK4 (pyruvate dehydrogenase kinase 4) inhibitor and the Sam68-Src interface blocker YB-0158, including pharmacokinetics, target engagement, and validation in Sam68cKO mice. RESULTS: Sam68 was increased in failing human cardiomyocytes and in murine hypertrophic hearts. Sam68cKO markedly attenuated angiotensin II- and transverse aortic constriction-induced hypertrophy, whereas Sam68OE aggravated remodeling and dysfunction. In vivo [U-C]-glucose flux analysis showed that transverse aortic constriction caused sustained uncoupling of glycolysis from glucose oxidation, with increased glycolytic labeling but reduced C incorporation into tricarboxylic acid cycle intermediates at 3 days and 4 weeks. Sam68 deletion restored glucose-derived carbon entry into the tricarboxylic acid cycle, enhanced PDH (pyruvate dehydrogenase)-dependent M+2 labeling, and improved oxidative-anaplerotic balance during pressure overload. Mechanistically, Sam68 served as a stress-activated scaffold that promoted Src-dependent STAT3 (signal transducer and activator of transcription 3) Tyr705 phosphorylation, nuclear accumulation, and transcriptional induction of PDK4, leading to PDH Ser293 phosphorylation and suppression of PDH activity. The PDK4 inhibitor blunted Sam68OE-driven remodeling while preserving PDH activity and mitochondrial respiratory programs. YB-0158 achieved cardiac exposure, disrupted Sam68-Src engagement in vivo, suppressed STAT3-PDK4-PDH signaling, and improved transverse aortic constriction remodeling; these effects were lost in Sam68cKO mice, supporting on-target dependence. In failing human hearts, the Src-SAM68-STAT3-PDK4 axis was activated, and SAM68 abundance increased in parallel with PDK4 and reduced left ventricular ejection fraction. CONCLUSIONS: Sam68 is a stress-activated cardiomyocyte scaffold that drives pathologic hypertrophy through a Src-STAT3-PDK4 program that inhibits PDH and suppresses glucose oxidation. Genetic or pharmacologic disruption of this axis restores PDH-dependent pyruvate oxidation and limits pressure-overload remodeling, identifying Sam68 as a druggable metabolic control node in heart failure.
BACKGROUND: End-stage hypertrophic cardiomyopathy (HCM) is a distinct and advanced form of HCM, defined by a left ventricular ejection fraction <50% and associated with a markedly poor prognosis. Evidence on the prognost...BACKGROUND: End-stage hypertrophic cardiomyopathy (HCM) is a distinct and advanced form of HCM, defined by a left ventricular ejection fraction <50% and associated with a markedly poor prognosis. Evidence on the prognostic relevance of late gadolinium enhancement (LGE) and its key features in end-stage HCM remains limited. The aim of our study was to evaluate the prognostic value of the LGE granularity model, including its location, extent, and pattern in patients with end-stage HCM. METHODS: All patients referred for cardiovascular magnetic resonance assessment of HCM at 3 French tertiary university hospitals between 2008 and 2024 were retrospectively screened, and all patients with a left ventricular ejection fraction <50% were included. The LGE granularity model was defined as a model combining LGE extent (unique versus multiple involvement), location (septal versus other), and pattern (subepicardial versus midwall). The primary end point was all-cause mortality. RESULTS: Among 2873 patients with HCM, 691 (24%) with end-stage HCM were included (52±7 years, 54% male). After a median follow-up of 9 years (interquartile range, 6-11), 226 patients died (33%). LGE was observed in 259 (37%) patients and was associated with mortality, even after adjustment for classical prognostic factors (hazard ratio, 1.52 [95% CI, 1.07-2.18]; =0.02). Each LGE granularity component was independently associated with mortality after adjustment: LGE extent (hazard ratio, 2.85 [95% CI, 1.03-7.85]; =0.02), septal location (hazard ratio, 1.73 [95% CI, 1.10-2.73]; <0.001), and midwall pattern (hazard ratio, 4.15 [95% CI, 1.79-9.61]; <0.001). CONCLUSIONS: In this large multicenter cohort of patients with end-stage HCM, the LGE granularity model integrating LGE extent, location, and pattern provided strong and independent prognostic value.
Ballin M, Carlsson AC, Wändell P
… +5 more, Ahlqvist VH, Brunström M, Henriksson P, Nordström A, Nordström P
Circulation
· 2026 May · PMID 42165142
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BACKGROUND: Young athletes and adolescents with high cardiorespiratory fitness appear to have a higher risk of atrial fibrillation (AF), but the extent to which this reflects causal effects or shared genetic, behavioral,...BACKGROUND: Young athletes and adolescents with high cardiorespiratory fitness appear to have a higher risk of atrial fibrillation (AF), but the extent to which this reflects causal effects or shared genetic, behavioral, and environmental factors remains uncertain. METHODS: This cohort study with sibling control analysis comprised Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 and completed cardiorespiratory fitness testing. The outcomes were AF and non-AF cardiovascular disease (CVD; eg, stroke and ischemic heart disease), defined as a composite end point of diagnosis or death in the National Patient Register and the Cause of Death Register, until December 31, 2023. Flexible parametric regressions estimated standardized cumulative risk differences (RDs) by deciles of fitness. RESULTS: Among 1 124 049 men (mean age, 18.3 years), 45 179 (4.0%) experienced an AF event and 96 404 (8.6%) had a non-AF CVD event at a median age of 54.8 and 54.4 years. In population-wide analysis controlling for measured confounders, compared with the lowest decile of fitness, the highest decile had a small excess in AF that exceeded the reduction in non-AF CVD during early adulthood, whereas the reduction in non-AF CVD became larger from 45 years of age onwards. In full-sibling comparisons controlling for shared familial factors, the age-dependent trade-off disappeared entirely, leaving no age window with a net cardiovascular disadvantage. Already from 35 years of age, the reduction in non-AF CVD was larger (RD, -0.11% [95% CI, -0.21% to -0.01%]) than the excess in AF (RD, 0.06% [95% CI, -0.01% to 0.12%]). By 65 years of age, the gap further widened, with an even larger reduction in non-AF CVD (RD, -3.91% [95% CI, -5.40% to -2.42%]) compared with the excess in AF (RD, 2.30% [95% CI, 1.15%-3.45%]). CONCLUSIONS: High adolescent cardiorespiratory fitness is associated with a small excess in AF risk during early adulthood that is outweighed by larger reductions in non-AF CVD after controlling for familial confounders. These findings support population-level efforts to improve youth cardiorespiratory fitness and provide reassurance about the safety and benefits of high fitness levels.
van Diepen S, Rampersad P, Luk A
… +13 more, Dahiya G, Zern EK, Alviar CL, Barnett CF, Bohula EA, Bartos JA, Slater TM, Tavazzi G, Gage A, American Heart Association Council on Cardiopulmonary, Critical Care, Perioperative and Resuscitation (3CPR), Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia
Circulation
· 2026 Jun · PMID 42165141
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Cardiac intensive care units are specialized, high-acuity, and resource-intensive environments for the care of critically ill patients with cardiovascular disease. Over the past 60 years, medical and interventional thera...Cardiac intensive care units are specialized, high-acuity, and resource-intensive environments for the care of critically ill patients with cardiovascular disease. Over the past 60 years, medical and interventional therapeutic advances have improved survival and reduced the risk of life-threatening arrythmias in many common cardiovascular conditions. Nonetheless, some hospitals have maintained historical cardiac intensive care admission practices, resulting in admissions of low-acuity patients who could otherwise be cared for in a telemetry-equipped hospital ward environment. These triage practices may be partially attributable to a lack of guidance from international societies on contemporary cardiac intensive care admission standards. In this scientific statement, we propose cardiac intensive care triage practice standards for common cardiovascular conditions, summarize available prediction scores, and outline priorities for future health services research in this field.