Frontiers in Cardiovascular Medicine

BackgroundThe adult mammalian heart lacks the regenerative potential required to replenish depleted cardiomyocytes and restore cardiac function after injury. Ischemic cardiac injury contributes to heart failure, a leading cause of death worldwide. Neonatal mice possess the capacity to regenerate injured myocardium and macrophages contribute to this process. The mechanisms contributing to the regenerative crosstalk between macrophages and cardiomyocytes remain incompletely elucidated and offer potential to inform future therapeutic strategies. MethodsTo test the immune contribution during cardiac regeneration, we studied the response to myocardial ischemia in neonatal mice after silencing myeloid hypoxia inducible factor 1 (Hif1) and reconstituting HIF-dependent mitogens. In parallel, we examined epigenetic and transcriptional signatures of the cardiac macrophage response and focused on intercellular crosstalk with cardiomyocytes. ResultsIn myeloid Hif1 deficient mice, cardiac regenerative function was lost after coronary ligation. This manifested through loss of ventricular systolic function and elevated myocardial scarring. HIF1 was found to be activated in resident-type cardiac macrophages after ischemic insult. Hypoxia stimulated macrophages to secrete insulin-like growth factor 1 (IGF-1), and this required Hif1. Parallel multiomic analysis revealed epigenetic regenerative signatures. ConclusionsThe data reveal an age-restricted requirement for myeloid Hif1 in neonatal cardiac regeneration, likely through IGF-1 signaling.

Background: Individuals with coronary artery disease (CAD) are at higher risk of cognitive decline and dementia, in which gray matter cerebral blood flow (CBF) plays a critical role. This study investigated the effects of High Intensity Interval Training (HIIT) and HIIT plus resistance training (RT) on CBF and other health outcomes in individuals with CAD. Methods: This trial included 105 participants with CAD (age 62.1 (SD 6.6) years, 21% women) randomly assigned to HIIT+RT (n=37), HIIT (n=35) or usual care (n=33). The primary outcome was the change in global CBF from baseline to 12-week follow-up. Secondary outcomes included: region-specific CBF (hippocampus, precuneus, and anterior/posterior cingulate cortex), cognitive function (general cognition, episodic memory, processing speed, working memory and executive function/attentional control), peak oxygen uptake (VO2peak), muscular fitness (30s sit-to-stand) and body composition [weight, body mass index (BMI), and fat and muscle mass). Data were analyzed using available-case intention-to-treat constrained (baseline-adjusted) linear mixed models. Predefined subgroup analyses were conducted for age, sex, education, and baseline level of the outcome studied. Results: No significant between-group differences were observed in CBF changes in the whole sample. However, participants with lower CBF at baseline showed greater CBF increases in the HIIT group compared to both usual care (+7.1 ml/100g/min, P=0.02) and HIIT+RT (+5.53 ml/100g/min, P=0.04). No effects were observed on regional CBF or cognition. Both exercise groups improved VO2peak compared to usual care (HIIT+RT: +2.6; HIIT: +2.5 mL/kg/min, both P<0.001). Only HIIT+RT increased muscular fitness (vs usual care: +3.3; vs HIIT: +3.1 repetitions, both P<0.001), and only HIIT decreased BMI (vs usual care: -0.47; vs HIIT+RT: -0.44 kg/m2, both P<0.03). No life-threatening events or deaths occurred during 1995 training sessions in the exercise groups, nor in the usual care group. Conclusion: Twelve weeks of HIIT+RT or HIIT did not increase CBF in the whole sample with CAD, but HIIT effectively increased CBF in those who had poorer CBF at baseline. While no cognitive benefits were observed, we found exercise-specific improvements in other clinically relevant outcomes, such as VO2peak, muscular fitness, and BMI.

IntroductionInadequately controlled inflammation is a key driver of adverse cardiac remodelling after acute myocardial infarction (AMI). Central to this process is activation of the NLRP3 inflammasome-gasdermin D (GSDMD) pathway, which promotes pyroptosis and the release of the pro-inflammatory cytokine interleukin-1{beta} (IL-1{beta}), a mediator strongly associated with infarct severity and poor clinical outcomes. This study investigates whether repurposing the FDA-approved therapeutic Disulfiram, recently shown to inhibit GSDMD pore formation, could reduce inflammation and thus improve cardiac injury after AMI. Methods and ResultsCardiac ischemia-reperfusion (I/R) injury was induced in C57BL/6 mice by 60-minute ligation of the left coronary artery followed by reperfusion. Disulfiram (25 or 50 mg/kg) was administered at reperfusion and daily thereafter. Cardiac function was assessed by echocardiography, while fibrosis and inflammation were evaluated by histology, RT-PCR, immunohistochemistry and immunoblotting. Leukocyte populations in blood, spleen, bone marrow and heart were analysed by flow cytometry. In vitro, mouse bone marrow-derived macrophages (BMDMs) and PMA-differentiated THP-1 cells were treated with Disulfiram. Cytokine secretion, inflammatory gene expression and changes in cell viability (propidium iodide (PI) staining and lactate dehydrogenase (LDH) release) were measured. Disulfiram (50 mg/kg) significantly improved cardiac function 7 days post-I/R. This was accompanied by a significant reduction in cardiac fibrosis and inflammation, as reflected by a lower abundance of inflammatory cells in circulation and cardiac tissue. In LPS- and ATP/Nigericin-stimulated BMDMs and THP-1 cells, Disulfiram dose-dependently (0.1-50 {micro}M) reduced IL-1{beta} and IL-6 secretion and attenuated membrane permeability and cell lysis. ConclusionsThis study demonstrates that Disulfiram improves cardiac function post-AMI by ameliorating inflammation and fibrosis, which was associated with reductions in cytokine release from inflammatory cells in vitro. Therefore, targeting GSDMD by "repurposing" the FDA-approved drug, Disulfiram, may represent a novel way to provide cardio-protection post-AMI. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=82 SRC="FIGDIR/small/710794v1_ufig1.gif" ALT="Figure 1"> View larger version (11K): org.highwire.dtl.DTLVardef@7fd82eorg.highwire.dtl.DTLVardef@149de52org.highwire.dtl.DTLVardef@a2fe0eorg.highwire.dtl.DTLVardef@d56b4f_HPS_FORMAT_FIGEXP M_FIG C_FIG

Hypertrophic cardiomyopathy (HCM) is a genetic heart disease characterized by left ventricular hypertrophy. Mutations in genes for sarcomere proteins, e.g. in cardiac myosin-binding protein C (cMyBPC), cause symptoms like heart failure and sudden cardiac death. In HCM, the heart utilizes high amounts of glucose. Increased glucose metabolism creates intermediates for hyaluronan (HA) synthesis, resulting in HA accumulation within the extracellular space, which could contribute to cardiomyocyte hypertrophy. We aimed to describe the connection between HA and cardiomyocyte hypertrophy using cMyBPC+/- mice treated with two different {beta}-blockers - either metoprolol or propranolol - for 11 months. The results showed that HA metabolism is altered in HCM, and consequently, HA is significantly more abundant in hearts of cMyBPC+/- mice compared to wild-type mice. High HA abundance correlated with increased cardiomyocyte size. Gene expression of HA synthase 2 was elevated in cMyBPC+/- mice. Treatment with propranolol significantly increased HA synthase 3 expression, while HA synthase 2 was maintained at wild-type level. Treatment with metoprolol or propranolol did not prevent HA accumulation nor decreased cardiomyocyte hypertrophy. These findings show a novel connection between high HA abundance and cardiomyocyte hypertrophy in cMyBPC+/- mice.

Backgound: Accurate assessment of diastolic function and left ventricular (LV) filling pressure is central to heart failure diagnosis and risk stratification. Contemporary guideline algorithms rely on complex parameters that are not consistently available in routine clinical practice. Objective: To compare the diagnostic and prognostic performance of the 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) and 2025 ASE guidelines with a deep learning model based on routinely acquired echocardiographic variables. Methods: This study evaluated the guideline-based algorithms and a deep learning model in participants from the Atherosclerosis Risk in Communities (ARIC) cohort (n=5450) for prognostication and two invasive hemodynamic validation cohorts from the United States (n=83) and Japan (n=130) for detection of elevated left ventricular filling pressure. Results: In the ARIC cohort, the deep learning model demonstrated superior prognostic performance compared with the 2016 and 2025 guidelines (C-index: 0.676 vs. 0.638 and 0.602, respectively; both p<0.001). Similar findings were observed among participants with preserved ejection fraction (C-index: 0.660 vs. 0.628 and 0.590; both p<0.001), with improved performance compared with the H2FPEF score (C-index: 0.660 vs. 0.607; p<0.001). In the US hemodynamic validation cohort, the deep learning model showed higher diagnostic performance than the 2025 guidelines (AUC: 0.879 vs. 0.822; p=0.041) and similar performance compared with the 2016 guidelines (AUC: 0.879 vs. 0.812; p=0.138). In the Japanese hemodynamic validation cohort, the deep learning model outperformed both guidelines (AUC: 0.816 vs. 0.634 and 0.694; both p<0.05). Conclusions: A deep learning model leveraging routinely available echocardiographic parameters demonstrated improved diagnostic and prognostic performance compared with contemporary guideline-based approaches, potentially offering a scalable alternative for assessing diastolic function and left ventricular filling pressures.

ObjectiveObesity is a major risk factor for coronary heart disease (CHD). This study aims to develop a metabolite signature of body mass index (BMI-MetSig) then assess its association with incident CHD and responsiveness to metabolic and bariatric surgery (MBS). Research Design and MethodsIn a case-control study of incident CHD nested within the Southern Community Cohort Study (SCCS) including 600 case-control pairs, we used elastic net regression with 10-fold cross-validation to derive the BMI-MetSig. Associations of BMI-MetSig with incident CHD was examined using conditional logistic regression in the nested case-control study. Further, in a cohort of 95 patients who received MBS, we evaluated this BMI-MetSig in association with estimated 30-year cardiovascular disease (CVD) risks, which was estimated by the American Heart Associations PREVENT equations, and examined changes of its constituent metabolites after surgery using linear mixed-effects models. ResultsIn the SCCS, the BMI-MetSig, comprising 94 metabolites, was significantly associated with incident CHD risk among all participants (OR per standard deviation [SD] increase: 1.48; 95% CI, 1.28-1.71) and across subgroups. Among MBS patients, the BMI-MetSig was significantly associated with increased estimated 30-year risks of CHD ({beta} per SD increase: 1.29; p<0.001) and other CVDs. Levels of 17 (20.0%) and 19 (22.4%) metabolites in the BMI-MetSig significantly changed 3- and 12-month post-surgery (FDR<0.10 and log2FC > 0.15), including choline and acetyl-2-aminoadipate. ConclusionsThe BMI-MetSig is associated with higher CHD incidence and estimated 30-year CVD risks and responds to MBS. BMI-MetSig may serve as a blood-based biomarker for cardiometabolic risk stratification and monitoring.

AimsHypoplastic left heart syndrome (HLHS) is a severe congenital heart disease characterized by ventricular hypoplasia and impaired cardiac function. Clinically, inhaled nitric oxide (NO) therapy is used to reduce pulmonary vascular resistance and improve cardiopulmonary stability in HLHS patients. However, whether NO signaling contributes to HLHS pathogenesis remains unknown. Cytoglobin (CYGB) is a heme protein traditionally thought to limit NO bioavailability. Unexpectedly, our recent work shows that CYGB/Cygb enhances NO signaling through activation of the nitric oxide synthase-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway. In zebrafish embryos, Cygb-dependent NO signaling is required for normal cilia motility and for the establishment of correct cardiac laterality. Here, our aim was to determine whether Cygb-dependent NO-sGC signaling linked to cilia function regulates cardiac morphogenesis and contributes to ventricular hypoplasia in HLHS. Methods and ResultsWe found that loss of Cygb (cygb2) in zebrafish disrupts NO-sGC signaling during cardiogenesis, altering cardiac progenitor organization and migration within the anterior lateral plate mesoderm (ALPM). Disruption of these processes impairs heart tube morphogenesis, thereby producing a compact ventricle with increased wall thickness despite preserved cardiomyocyte number, reduced ventricle size and decreased stroke volume, recapitulating key features of HLHS. Genetic disruption of the sGC -subunit (gucy1a1) and pharmacological NO scavenging phenocopy the cygb2 mutant phenotype, resulting in reduced cGMP levels, compact ventricular architecture and decreased stroke volume (SV). Consistently, restoration of NO-sGC signaling in cygb2 mutants rescues early cardiac progenitor patterning, ventricular morphology and SV. ConclusionsThese findings identify Cygb-dependent NO-sGC signaling as a critical developmental pathway for ventricular development and performance, temporally linking cardiac progenitor dynamics to cilia-dependent signaling associated with left-right patterning. This study further suggests that pharmacological activation of sGC may provide a therapeutic strategy for hypoplastic ventricular disease. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=187 HEIGHT=200 SRC="FIGDIR/small/711730v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@e266corg.highwire.dtl.DTLVardef@fca897org.highwire.dtl.DTLVardef@1a06fc2org.highwire.dtl.DTLVardef@93acd_HPS_FORMAT_FIGEXP M_FIG C_FIG

Purpose: Spatial distribution of coronary artery calcium (CAC) may provide additional prognostic value in patients undergoing SPECT and PET myocardial perfusion imaging (MPI). We aimed to automatically identify CAC in proximal segments from attenuation correction CT (CTAC) scans using artificial intelligence (AI) and to evaluate prognostic significance in two large international multicenter registries. Methods: From hybrid MPI/CT imaging (N=43,099) across 15 sites, we included 4,552 most relevant patients with 1) no prior coronary artery disease; 2) AI-derived mild CAC scores (1-99); and 3) normal perfusion (stress total perfusion deficit <5%). The independent associations between AI-identified proximal CAC and major adverse cardiovascular events (MACE) and all-cause mortality (ACM) were evaluated using multivariable Cox regression, likelihood ratio test (LRT), and continuous net reclassification index (NRI). Results: Among the patients with mild CAC and normal perfusion (mean age 65{+/-}12 years, 51% male), 1,730 (38%) had proximal CAC. Over 3.6 (inter-quartile interval 2.1, 5.2) years follow up, 599 (13%) and 444 (10%) patients had MACE or ACM, respectively. Proximal CAC was associated with an increased risk of MACE (adjusted hazard ratio [HR] 1.24, 95% CI 1.03-1.48, P=0.02) and ACM (adjusted HR 1.25, 95% CI 1.01-1.53, P=0.04) after the adjustment of CAC score and density, clinical risk factors, and perfusion deficit. Proximal CAC improved the risk stratification of MACE (LRT P=0.02; NRI 12%) and ACM (LRT P=0.04; NRI 12%). Conclusion: In patients with mild CAC and normal perfusion, AI detection of proximal CAC identified a higher-risk group for adverse outcomes, highlighting its prognostic utility.

IntroductionPatients with type 2 diabetes mellitus (T2DM) are at increased risk of coronary artery disease and frequently undergo coronary angiography or percutaneous coronary intervention. Although risk factors for post-contrast acute kidney injury (PC-AKI) are well defined, effective preventive strategies remain limited. MethodsThis multicenter observational cohort study included 975 patients aged 18-75 years who underwent coronary angiography and/or percutaneous coronary intervention with iodinated contrast between June 2023 and June 2024. All patients received standardized intravenous hydration. Participants were grouped according to chronic sodium-glucose co-transporter-2 (SGLT2) inhibitor use ([&ge;]3 months). PC-AKI was defined as a [&ge;]25% or [&ge;]0.5 mg/dL increase in serum creatinine within 48-72 hours after contrast exposure. ResultsThe mean age was 59.2 {+/-} 11.7 years, and 70.8% were male; 16.9% were using SGLT2 inhibitors. PC-AKI occurred in 7.3% of patients, and 0.7% required renal replacement therapy. In univariate analysis, advanced age, diabetes, hypertension, heart failure, diuretic use, and elevated urea, creatinine, potassium, and uric acid levels were associated with PC-AKI. Higher eGFR, albumin, sodium levels, and SGLT2 inhibitor use were inversely associated. In multivariate analysis, age [&ge;]65.5 years (OR 4.53), diabetes (OR 2.49), and uric acid >6.75 mg/dL (OR 2.34) remained independent risk factors, while eGFR >81.5 mL/min/1.73 m2 (OR 0.38), sodium >137.5 mmol/L (OR 0.36), and SGLT2 inhibitor use (OR 0.09) were independently protective. ConclusionBeyond established cardioprotective and renoprotective effects, SGLT2 inhibitors may reduce the risk of PC-AKI in patients with T2DM, potentially through decreased renal oxygen consumption and attenuation of contrast-induced hypoxic injury.

BackgroundQuantitative myocardial blood flow (MBF) and myocardial flow reserve (MFR) provide incremental diagnostic and prognostic value in cardiac PET, but their widespread use is limited by the technical demands of dynamic imaging protocols. We evaluated the feasibility of using artificial intelligence (AI) to predict MBF and MFR from static and gated PET images, without the need for dynamic acquisition. MethodsA machine learning (XGBoost) model was trained on 82Rb PET multi-center dataset using static perfusion imaging, injected dose, hemodynamic measures, clinical data and CT-derived features (including body composition) from the hybrid CT attenuation scan. Model performance was evaluated externally in an independent cohort. ResultsIn total, 10,566 (derivation-cohort) and 7,842 (external-cohort) patients were included in this multi-center study. On the external-cohort, AI approach achieved an Area under the curve (AUC) of 0.92 (0.92-0.93) for abnormal stress MBF and 0.91 (0.90-0.92) for abnormal MFR; Intra-class correlation (ICC) 0.80 (0.78-0.82) and 0.78 (0.76-0.79), respectively. AI MFR closely mirrored the prognostic performance of measured MFR, showing nearly identical Kaplan-Meier risk stratification (both p<0.0001) and maintaining strong, and independently significant associations with all-cause mortality (HR 3.4 [2.8-4.2] vs. 4.6 [3.6-5.8]; both p<0.001), and demonstrated similar added value to perfusion for mortality prediction. ConclusionAI-predicted virtual stress MBF and MFR assessment using static and gated PET data is feasible and generalizable across cohorts. By removing the dependency on dynamic acquisitions, this approach has the potential to broaden the clinical adoption of flow quantification. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=97 SRC="FIGDIR/small/26345376v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@ec2522org.highwire.dtl.DTLVardef@17a04aforg.highwire.dtl.DTLVardef@1c99db7org.highwire.dtl.DTLVardef@1918c8f_HPS_FORMAT_FIGEXP M_FIG STRUCTURED GRAPHICAL ABSTRACT PET: Positron Emission Tomography, CT: Computed Tomography, MFR: Myocardial Flow Reserve C_FIG Key Question: Can machine learning models trained on dynamic PET datasets accurately predict regional stress myocardial blood flow (MBF) and myocardial flow reserve (MFR) from static image features, physiological parameters, and CT-based anatomical measures? Key Finding: Artificial intelligence can accurately estimate MBF and MFR from non-dynamic PET data, with strong agreement to reference standards. Take-home Message: By eliminating reliance on dynamic PET acquisitions, machine-learning has the potential to broaden clinical adoption of quantitative flow assessment.

BackgroundCardiovascular disease (CVD) prevention is limited by the major challenge of low long-term adherence to effective lifestyle regimens. Arterial stiffness (measured by carotid-femoral pulse wave velocity, cfPWV) and maximal cardiorespiratory fitness (measured by VO2max), are modifiable risk factors for CVD but require sustained lifestyle change. Wearable technology provides continuous measurement and offers a scalable platform to deliver health interventions. A combination of continuous monitoring with a wearable device and an artificial intelligence (AI) -based coach personalized for individual data and preferences could be a powerful, low-barrier tool for achieving sustainable cardiovascular health benefits by directly addressing the adherence challenge. ObjectiveWe will study the comparative effectiveness of a wearable and an interactive app-based AI coaching intervention promoting moderate exercise on improving gold-standard cfPWV and VO2max. This will be compared to a supervised high-intensity interval training (HIIT) group (benchmark with known benefits for VO2max) and a control group using only Oura Ring (passive monitoring). We will also conduct a detailed Process Evaluation (structured interviews) to study the feasibility and experience of interacting with the AI coach. MethodsThis randomized controlled trial recruited 165 eligible sedentary participants aged 30-65 years. Co-primary outcomes cfPWV and VO2max were measured at baseline and will be repeated after 12 weeks. Participants were equally randomized into three groups: an AI-based coaching group (steady-state exercise), a HIIT group (supervised exercise) and a control group (usual low activity). The AI-based coaching group receives personalized guidance using large language model (LLM) technology. All participants wear Oura Ring and are blinded to cardiovascular health metrics provided by the ring. ResultsThe recruitment for the study began in October 2024 and will end when 165 men and women have been recruited. Data collection for the study is scheduled to conclude early 2026. Data collection is ongoing. ConclusionsThis study will evaluate if a highly scalable, AI-based coaching intervention can achieve comparable gains in CV structural health (cfPWV) and functional capacity VO2max relative to a resource-intensive supervised HIIT benchmark. The findings will provide essential evidence on the use of digital health tools to promote sustainable exercise adherence. ClinicalTrials.gov registration identifierNCT06644014 (Registered: 2024-10-15)

BackgroundAn elevated calcium-phosphate product (CPP), defined as a product of serum calcium and serum phosphate, is a hallmark of CKD-mineral and bone disorder and has been implicated in accelerated coronary artery calcification, arterial stiffness, and left ventricular hypertrophy. These pathological changes contribute to adverse cardiovascular outcomes. While prior studies have shown worse percutaneous coronary outcomes (PCI) outcomes in CKD patients overall, the prognostic impact of CPP levels remains underexplored. The objective is to evaluate post-PCI outcomes in CKD patients with and without hypercalcemia and hyperphosphatemia. MethodsA retrospective cohort analysis was conducted using the TriNetX U.S. Collaborative Network, focusing on adult patients with CKD undergoing PCI. Patients were grouped based on serum calcium and phosphorus levels, with those having hypercalcemia and hyperphosphatemia compared to those without. Diagnoses and procedures were identified using ICD-10 and CPT codes. Propensity score matching was applied to account for differences between groups. Post PCI outcomes were analyzed. Primary outcome was all-cause mortality. Secondary outcomes encompass coronary artery bypass grafting (CABG), myocardial infarction (MI), in-stent re-stenosis [redo PCI] and target vessel revascularization, heart failure (HF) exacerbations, and peri-/ post-procedural complications were assessed within a 5-year follow-up period. Kaplan-Meier analysis with log-rank was used for statistical comparisons, with significance set at p<0.05. ResultsThe elevated CPP group was significantly associated with increased post-PCI all-cause mortality [hazard ratio (HR) 1.428], in-stent restenosis [HR 1.589], heart failure exacerbations [HR 1.492], and recurrent angina or MI [HR 1.396]. No significant differences were found in rates of post PCI CABG, periprocedural complications (postprocedural cardiac insufficiency, postprocedural cardiac arrest, postprocedural heart failure, intraoperative cerebrovascular infarction, postprocedural cerebrovascular infarction, and intraoperative cardiac arrest), or redo PCI. ConclusionIn this propensity score-matched analysis, elevated CPP in CKD patients undergoing PCI was independently associated with worse outcomes, including higher mortality and cardiovascular event rates. These findings highlight the prognostic value of CPP and the need for closer metabolic monitoring and individualized risk stratification. O_FIG O_LINKSMALLFIG WIDTH=177 HEIGHT=200 SRC="FIGDIR/small/26347359v1_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@198df1forg.highwire.dtl.DTLVardef@160722borg.highwire.dtl.DTLVardef@e796fforg.highwire.dtl.DTLVardef@6a40d6_HPS_FORMAT_FIGEXP M_FIG C_FIG

BACKGROUNDDilated cardiomyopathy (DCM) presents a highly heterogeneous spectrum, including a familial subset with elevated arrhythmic risk. Traditional demographic and imaging markers, such as late gadolinium enhancement, have been inadequate for identifying high-risk patients before arrhythmic events. Remodelling of the interventricular septum--central to ventricular mechanics and conduction--may offer improved risk stratification. OBJECTIVESTo identify differences in left ventricular (LV) morphology between arrhythmic and idiopathic dilated cardiomyopathy (aDCM vs iDCM), and to identify LV remodeling patterns that link to adverse outcomes. METHODSThree-dimensional LV shape models were constructed from end diastolic cardiovascular magnetic resonance images of 102 individuals subdivided by their idiopathic or arrhythmic subgroup allocation. A statistical shape model was built using principal component analysis. A linear discriminant analysis determined shape features of the arrhythmic subgroup and increased composite arrhythmic outcome of sudden cardiac death, aborted sudden cardiac death, and sustained ventricular tachycardia. RESULTSThe idiopathic DCM group displayed larger mass, length, diameter, mass to volume ratio, and a mild spiral pattern of thicker septal walls (p=0.004). The arrhythmic DCM group displayed a more conical (wider basal and mid wall to apical diameter) LV, and the lack of the spiral septal morphology was the most significant feature (p=0.006) to identify subjects that had the composite arrhythmic outcome. CONCLUSIONThe LV morphology derived suggests a differentiation of arrhythmic DCM patients beyond size, function and LGE presence. This was distinctive and captured shape features that suggest alternate mechanisms for arrhythmic risk linked to a pattern of remodeling. Graphical AbstractAssessing LV morphology signature of arrhythmic DCM phenotype O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=114 SRC="FIGDIR/small/26346514v1_ufig1.gif" ALT="Figure 1"> View larger version (39K): org.highwire.dtl.DTLVardef@1f47f7aorg.highwire.dtl.DTLVardef@dd5d08org.highwire.dtl.DTLVardef@106ef07org.highwire.dtl.DTLVardef@36eb76_HPS_FORMAT_FIGEXP M_FIG C_FIG

Abstract Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathy constitute the principal phenotypes of primary cardiomyopathy, yet both lack sufficient therapeutic options. Integrating genetic insights with detailed cardiac phenotyping offers a promising strategy to prioritize targets and elucidate their mechanisms of action. Methods: We conducted an three-stage analysis. First, drug-target Mendelian randomization (MR) was performed using cis-acting protein (pQTL) and expression (eQTL) quantitative trait loci as genetic instruments for potential drug targets. Second, we examined causal associations between 82 cardiac magnetic resonance (CMR)-derived imaging traits and HCM/DCM risk in a CMR-based MR analysis. Third, mediation MR was employed to quantify the proportion of the genetic effect of prioritized drug targets on cardiomyopathy risk that was mediated through specific CMR phenotypes. Results: Our analyses identified 19 and 13 potential therapeutic targets for HCM and DCM, respectively. CMR-based MR revealed that HCM risk was causally associated with increased right ventricular ejection fraction (RVEF) and greater left ventricular wall thickness, whereas DCM risk was linked to ventricular dilation, impaired myocardial strain, and altered aortic dimensions. Critically, mediation analysis established that these CMR traits served as significant intermediate pathways. The protective effect of ALPK3 on HCM risk was mediated through a reduction in myocardial wall thickness. Conversely, the effects of PDLIM5, HSPA4, and FBXO32 on DCM risk were exerted in part via alterations in aortic dimensions. Conclusion: This integrative genetic and imaging study systematically identify candidate therapeutic targets for HCM and DCM and delineates the specific CMR phenotypes through which they likely exert their causal effects. Our findings advance the understanding of disease pathogenesis and highlight new possibilities for improving the diagnosis and management of cardiomyopathy.

ObjectiveTo investigate the effects of aerobic swimming exercise on blood pressure, cardiac function, and the myocardial AGEs/RAGE-p38 MAPK-NF-{kappa}B signaling pathway in spontaneously hypertensive rats (SHR). MethodsTwenty-four male Wistar-Kyoto (WKY) rats were randomly assigned to three control subgroups (C-0, C-4, C-8; n=8 each). Fifty-six SHRs were allocated into seven subgroups (S-0, S-4, S-8, SE-4, LE-4, SE-8, and LE-8; n=8each) to receive different swimming intervention protocols. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured via the tail-cuff method. Cardiac parameters, including ejection fraction (EF), fractional shortening (FS), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), and stroke volume (SV), were assessed using echocardiography. Myocardial morphological alterations were observed through hematoxylin-eosin (HE) staining, and myocardial hydroxyproline content was quantified using the alkaline hydrolysis method. Furthermore, the myocardial expressions of advanced glycation end products (AGEs), receptor for AGEs (RAGE), phosphorylated p38 mitogen-activated protein kinase (p-p38 MAPK), and nuclear factor-kappa B (NF-{kappa}) were detected by immunohistochemistry (IHC). ResultsAerobic exercise significantly reduced blood pressure in SHRs, partially improved cardiac function and myocardial architecture, and decreased hydroxyproline content (except in the SE-4 group). Furthermore, the exercise intervention downregulated the expressions of AGEs, RAGE (except in the SE-4 group), p-p38 MAPK, and NF-{kappa}, with efficacy varying according to exercise duration and intervention cycles. ConclusionAerobic exercise alleviates the progression of hypertension and mitigates the risk of cardiac dysfunction in SHRs by inhibiting myocardial glycation. This cardioprotective effect may be mediated by the suppression of p38 MAPK activation and the subsequent reduction of NF-{kappa} nuclear translocation.

Background and aimsIncreased levels of -tubulin and its post-translational modifications (PTMs) are found in human heart failure and could initiate diastolic dysfunction by modulating cardiomyocyte stiffness. How these modifications occur and how they may underlie cardiac dysfunction remains unknown. Upstream kinases may play a critical role, but this has not been explored. Methods and resultsHere we address this question by, for the first time ever, determining levels of the enzymes involved in microtubule (MT) detyrosination and acetylation (TAT1, HDAC6) in a well-characterized cohort of patients with hypertrophic cardiomyopathy (HCM). In HCM patients (N=10-11), protein levels of detyrosination enzymes remain unaltered, whilst levels of TAT1 and HDAC6 were decreased and increased, respectively. Phosphoproteomics in HCM (N=24) and control (N=8) myocardium identified significant differences in over 1900 serine/threonine and 160 tyrosine phosphosites, in addition to increased EGFR/IGF1R-MAPK signaling in HCM. We subsequently showed that MT repolymerization was increased in HCM MYBPC3Arg943X hiPSC-CMs. Isoprenaline-mediated PKA activation decreased MT repolymerization in hiPSC-CMs and revealed CLASP1, MAST4 and MAP1A as potential MT modifiers in HCM. ConclusionsWe show that the altered HCM MT code cannot be attributed to levels of key MT-modifying enzymes. By combining kinome analyses in human HCM hearts with hiPSC-CM studies on MT dynamics, PTMs and contractility we unveiled a regulatory role for MTs in the cardiomyocyte response to beta-adrenergic receptor stimulation. Disease-mediated changes in the MT code thereby exert both a direct, and indirect effect on cardiac function via mediating the response to adrenergic activation. Graphical Abstract created with BioRender.com O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=122 SRC="FIGDIR/small/706710v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1c58dc4org.highwire.dtl.DTLVardef@de502eorg.highwire.dtl.DTLVardef@1621512org.highwire.dtl.DTLVardef@557b82_HPS_FORMAT_FIGEXP M_FIG C_FIG

AimsWe aimed to develop and evaluate fully automated artificial intelligence (AI) system. for detection of mitral valve prolapse (MVP) and mitral regurgitation (MR) from echocardiographic studies. Methods and ResultsWe used a dataset of 24,869 echocardiographic studies from the University of California San Francisco (UCSF) to train a multi-view deep neural network (DNN) to detect MVP using apical 4-chamber, 2-chamber, and parasternal long-axis views. A separate dataset of 27,906 studies from UCSF was used to train a second multi-view DNN model to detect moderate-to-severe or severe MR using color Doppler in the same views. External validation was performed on echocardiographic MVP videos from Houston Methodist Hospital. The DNN model for MVP detection achieved an AUC of 0.917 (95% CI: 0.899-0.934), with stronger performance in those with mitral annular disjunction or bileaflet MVP. External validation for MVP detection in a geographically and demographically distinct population yielded an AUC of 0.835 (95% CI: 0.803-0.869). The DNN for detection of moderate-to-severe or severe MR in patients with concurrent MVP achieved an AUC of 0.877 (95% CI: (0.805-0.939). ConclusionsAI algorithms can perform automatic detection of MVP and clinically significant MR from echocardiogram studies with high performance. The MVP DNN performed particularly well for more severe MVP phenotypes such as mitral annular disjunction or bileaflet MVP. These algorithms could provide a novel approach for automated, accurate, and rapid diagnosis of MVP and its common clinical sequelae across institutions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/26347229v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1d78db8org.highwire.dtl.DTLVardef@995b29org.highwire.dtl.DTLVardef@301b86org.highwire.dtl.DTLVardef@5f1427_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundBoth acute myocardial infarction (AMI) and acute myocarditis are characterised by cardiac troponin release as a marker of cardiomyocyte injury. While peak troponin is widely accepted as a surrogate marker for infarct size in AMI, its relationship with myocardial injury in acute myocarditis is unclear. This study aimed to quantify and compare the association between peak high-sensitivity cardiac troponin and cardiovascular magnetic resonance (CMR) late gadolinium enhancement (LGE) extent in patients with AMI versus acute myocarditis. MethodsPatients undergoing CMR imaging and measurement of high-sensitivity cardiac troponin I during hospital admission were retrospectively included. LGE extent was quantified in grams using the semi-automated expectation-maximization weighted intensity algorithm (EWA). ResultsCompared to patients with acute myocarditis (n=47), patients with AMI (n=49) had higher peak troponin levels (median [interquartile range] 32,470 [3,109-104,699] vs 7,295 [1,857-22,550] ng/L, p=0.002), larger LGE extent (25 [13-56] vs 10 [6-17] g, p<0.001), and lower left ventricular ejection fraction (45 [36- 52] vs 55 [49-58] %, p<0.001). Peak troponin was moderately positively correlated with LGE extent in both AMI (rho=0.56, p<0.001) and acute myocarditis (rho=0.58, p<0.001). However, the ratio of peak troponin to LGE mass was higher in AMI compared to acute myocarditis (1,299 [419-3233] vs 909 [310-1446] ng/L/g, p=0.02). ConclusionsPeak cardiac troponin correlates positively with LGE extent in both AMI and acute myocarditis, but the magnitude of LGE and LV systolic dysfunction is greater in AMI. Also, AMI typically has an approximately 40% greater amount of troponin release per unit LGE mass compared to acute myocarditis. This suggest that troponin-based estimates of myocardial injury size estimated by LGE are not directly interchangeable between ischaemic and inflammatory myocardial diseases.

BACKGROUNDThe coronary vessel system is a dense and diverse network of arteries, veins and capillaries formed by endothelial cells from a variety of sources. While hypoxia is a known stimulus for angiogenic sprouting generally, the exact mechanisms by which hypoxia, and resultant increased VEGFA, influences vessel growth in the heart are not clearly delineated. METHODSWe used a genetic model to mimic hypoxia through ectopic stabilisation of myocardial HIF. This enabled us to study the consequences of hypoxia without vascular depletion. Changes in coronary ECs in these hearts relative to littermate controls were assessed by single cell RNA-sequencing, and by examining the activity of enhancer:reporter transgenes active in different coronary vessel beds downstream of distinct vascular regulatory pathways. RESULTSAnalysis of hypoxia-mimic hearts found increased angiogenic gene expression alongside expanded activity of the VEGFA-MEF2-driven angiogenic regulatory pathway in a pattern that indicated increased endocardial-derived angiogenic sprouting. Conversely, regulatory pathways specifically active in the sinus venosus (SV)-derived plexus showed little variance in response to stabilized HIF, and sprouting from the SV was not expanded. Although hypoxia and increased VEGFA levels have been previously linked to increased arterial differentiation, we saw little change in initial arterial EC differentiation in the experimental hearts. However, mature coronary arterial formation was delayed. CONCLUSIONSThese observations further emphasize a direct and specific link between hypoxia and endocardial coronary vessel sprouting and suggest a role of hypoxia/VEGFA in guiding coronary arterial coalescence.

BackgroundCoronary artery tortuosity (CAT) is often viewed as a benign angiographic finding; however, emerging evidence suggests its potential hemodynamic significance, particularly in non-atherosclerotic cardiomyopathies such as Takotsubo syndrome (TS). ObjectivesThis study aimed to investigate the prevalence and hemodynamic implications of CAT in patients diagnosed with Takotsubo cardiomyopathy (TCM) and to evaluate the association between the severity of tortuosity and myocardial injury markers, recovery of ventricular function, and other clinical variables. MethodsA retrospective review of 100 patients with TCM from the Baptist Memorial Hospital network (2015-2025) was conducted. Tortuosity severity was quantified using angiographic criteria per Eleid et al. (2014). Associations between CAT and biochemical or echocardiographic parameters were evaluated using multiple linear regression and non-parametric tests. ResultsCAT was highly prevalent (85.1%) in this TCM cohort, with a mean tortuosity index of 3.26--significantly higher than in general angiography populations. No significant correlations were found between tortuosity severity and peak troponin levels (p = .588) or ejection fraction (EF) at presentation (p = .820). Full EF recovery (55-65%) at [&ge;]3 months occurred in 70.7% of patients and was not significantly associated with prior cardiomyopathy, coronary artery tortuosity index or baseline troponin levels. ConclusionsCAT appears markedly more prevalent among patients with TCM, although its severity does not correlate with biomarker elevation or EF recovery. These findings suggest that coronary tortuosity may contribute to the hemodynamic environment predisposing to TS, without directly determining the extent of myocardial dysfunction or recovery.