Circulation

BackgroundElevated lipoprotein(a) [Lp(a)] is causally implicated in atherosclerotic cardiovascular disease, but its prospective association with incident ischemic stroke in real-world clinical populations remains incompletely characterized. Observational data are complicated by testing-indication bias and aggressive preventive management in identified high-Lp(a) patients. MethodsWe conducted a retrospective cohort study using the TriNetX US Collaborative Network (66-67 healthcare organizations). Adults with Lp(a) measurements (LOINC 10835-7; January 2015-December 2025) were categorized as C-HIGH (Lp(a) [&ge;]50 mg/dL) or C-LOW (<50 mg/dL) and balanced by 1:1 propensity score matching on cardiovascular diagnoses, medications, tobacco history, and four laboratory variables. Pre-specified analyses included an alternative cutoff ([&ge;]30 mg/dL), dose-response evaluation across three strata, and a 2-year landmark analysis. ResultsAfter expanded propensity score matching, the primary analysis included 97,882 matched adults (48,941 per arm). Incident ischemic stroke/TIA occurred in 2.45% vs 2.69% (Cox HR 0.956, 95% CI 0.878-1.041; log-rank p=0.299). The Lp(a) [&ge;]30 mg/dL sensitivity analysis (121,076 matched) yielded HR 0.947 (0.878-1.023; p=0.168). Dose-response analysis showed no significant association at any stratum. A 2-year landmark analysis confirmed a null late-period effect (HR 1.071, 0.905-1.268; p=0.427). A post-hoc composite (stroke/TIA, cardiac arrest, heart failure) was null (HR 0.979; p=0.512). A broader MACE-like composite including MI yielded a nominally significant Cox HR of 1.058 (1.004- 1.116; p=0.034), with entirely null crude estimates, attributable to differential follow-up time. ConclusionsElevated Lp(a) was not associated with incident ischemic stroke or TIA across multiple thresholds and follow-up windows in this large federated cohort. These real-world findings are consistent with testing-indication bias and treatment attenuation in clinically identified high-Lp(a) populations.

Background. Septal reduction therapy (SRT) is recommended in drug-refractory, symptomatic obstructive hypertrophic cardiomyopathy (oHCM). We evaluated whether aficamten, a novel cardiac myosin inhibitor, can reliably transition guideline-eligible SRT candidates to ineligibility, and the associated safety profile of aficamten in this group. Methods. We analyzed participants with oHCM enrolled in FOREST-HCM (NCT04848506), the long-term open-label extension study of aficamten, from 28 May 2021 to 9 May 2025. Results. Three hundred and fifteen patients were included, of whom 104 met 2024 ACC/AHA guideline criteria for SRT eligibility at baseline. The SRT-eligible cohort was predominantly female (57%), with mean resting and Valsalva left ventricular outflow tract (LVOT) gradients of 63 {+/-} 39 and 109 {+/-} 42 mmHg, and all were in New York Heart Association (NYHA) class III. All baseline SRT-eligible patients became SRT-ineligible with aficamten therapy during study follow-up over a median of 42 days (IQR: 17, 49), except for one participant who withdrew from the study to pursue SRT (total of 3 participants withdrew). After dose titration, 3/104 (2.9%) remained guideline-eligible; by week 72 no patients met eligibility criteria. At maintenance, resting and Valsalva LVOT gradients improved by a least-squares mean of ?41 mmHg ([95% CI ?44 to ?37]; P<0.0001) and ?56 mmHg ([95% CI ?62 to ?51]; P<0.0001), respectively. Relative to baseline, NT-proBNP improved by 77% (95% CI 74 ? 80%), high-sensitivity cardiac troponin I decreased by 38% (95% CI 30 ? 46%), KCCQ-CSS improved by a mean of 20.2 (SD 19.3) points, and 95.2% of SRT-eligible patients had improved by ?1 NYHA class. Overall, the safety profile was favorable, with 2 occurrences of left ventricular ejection fraction (LVEF) < 50% over 193.7 patient-years of follow-up (1 event per 100 patient-years), managed by down-titration. There were no baseline SRT-eligible patients who died or developed LVEF <40%. Conclusions. Aficamten resolved guideline eligibility for SRT in nearly all baseline-eligible patients, with rapid and durable improvements in hemodynamics, symptoms, biomarkers and health status sustained for up to 3.5 years. Instances of LVEF <50% were rare and without clinical sequelae. These data support aficamten as a safe and effective alternative to SRT in oHCM.

BACKGROUNDAficamten is a next-in-class, oral, selective cardiac myosin inhibitor approved for the treatment of obstructive hypertrophic cardiomyopathy (oHCM). A comprehensive understanding of long-term safety is essential to inform clinical use. OBJECTIVETo assess the integrated safety profile of aficamten across phase 2/3 clinical trials in patients with oHCM. METHODSThis integrated safety analysis pooled data from patients with oHCM who received [&ge;]1 dose of aficamten or placebo/metoprolol in REDWOOD-HCM, SEQUOIA-HCM, MAPLE-HCM, and FOREST-HCM. Safety outcomes included treatment-emergent adverse events (TEAEs), serious TEAEs, adverse events of special interest, occurrences of site-read left ventricular ejection fraction (LVEF) <50%, and echocardiography-guided treatment modifications. Events were summarized descriptively and using exposure-adjusted incidence rates (EAIRs) per 100-patient-years. RESULTSThe cumulative aficamten-treated pool included 463 unique patients, representing 697 patient-years of exposure. Aficamten was well tolerated, with permanent treatment discontinuation occurring in 4 (0.9%) aficamten-treated patients (EAIR 0.6). In the control group pool, rates of TEAEs were comparable between aficamten and placebo/metoprolol, except hypertension was more common in aficamten-treated patients. In the cumulative aficamten-treated pool, LVEF <50% occurred in 19 (4.1%) patients (EAIR 2.8). There were no cases of LVEF <50% associated with clinical heart failure that were attributable to aficamten, and no excursions of LVEF <40%. New-onset atrial fibrillation was uncommon (EAIR 2.4). CONCLUSIONSOver nearly 700 patient-years of exposure, aficamten was well tolerated with a favorable safety profile in patients with oHCM. The rates of clinically relevant systolic dysfunction, atrial fibrillation, and other major cardiovascular events were low and similar to placebo or metoprolol. Clinical trial registrationREDWOOD-HCM (NCT04219826); SEQUOIA-HCM (NCT05186818); MAPLE-HCM (NCT05767346); FOREST-HCM (NCT04848506)

Background/PurposeDesmoplakin (DSP) mutations are linked to familial cardiomyopathies with a very high arrhythmogenic propensity. While autosomal recessive inheritance forms manifest in the cardio-cutaneous Carvajal syndrome, the dominant-inheritance variants associate to DSP-cardiomyopathy (DSP-CM). This latter is a subtype of Arrhythmogenic Cardiomyopathy characterized by frequent myocarditis-like episodes, dominant left ventricular (LV) remodeling, recurrent premature ventricular contractions and life-threatening arrhythmias, frequently preceding LV dysfunction and dilation. Notably, DSP-CM evades the diagnostic identifiers of Arrhythmogenic Cardiomyopathy, further complicating risk-stratification and prediction. At the time being, the pathogenetic mechanisms underlying DSP-related cardiomyopathies are largely obscure and their elucidation is urgently required. MethodsTo this end, we employed CRISPR-Cas9 to generate a novel knock-in mouse model harboring a point mutation at the murine ortholog of human Serine-299, a mutation site previously identified in a family affected by left dominant-Arrhythmogenic Cardiomyopathy. In both heterozygotes and homozygotes, cardiac function was assessed by echocardiography and telemetry-ECG, at different ages. Results were correlated with heart structure, which was assessed by ultrastructural, histopathological and molecular/biochemical assays. The effects of moderate exercise on disease manifestations were tested. ResultsThe homo- and hetero-zygous expression of mutant DspS311A allele replicated the human cardiac phenotypes of Carvajal syndrome and DSP-CM, respectively. Indeed, DspS311A/S311A mice featured precocious dilated cardiomyopathy with biventricular fibrotic remodeling, aneurisms, systolic dysfunction, increased arrhythmic vulnerability, sudden death and, remarkably, cutaneous defects. Differently, DspWT/S311A mice did not show evident cutaneous alterations, and myocardial remodeling and contractile dysfunction developed later and were associated to increased cell death, inflammatory response and patchy fibrosis predominantly in the LV. Notably, as observed in certain patient subgroups, DspWT/S311A mice had electrophysiological alterations (i.e. QRS prolongation, distal conduction defects and sustained ventricular arrhythmias) prior to developing contractile dysfunction. Furthermore, in both genotypes, exercise accelerated myocardial remodeling and increased the incidence of arrhythmic mortality. ConclusionsOur novel DspS311A mice recapitulate the clinical and pathological features of the respective dominant (i.e. DSP-CM) and recessive (i.e. Carvajal syndrome) forms of DSP-related cardiomyopathies. Thus, DspS311A mice are a novel experimental model of human diseases, suited to test therapeutic interventions aimed at reducing the burden of stress-dependent SD.

BackgroundMaintaining low levels of low-density lipoproteins (LDL) over time has the potential to substantially reduce the lifetime risk of atherosclerotic cardiovascular disease. However, the optimal timing of lowering LDL to prevent atherosclerotic cardiovascular events is unknown. MethodsWe combined evidence from Mendelian randomization studies and randomized trials to develop a causal AI algorithm to estimate the benefit of lowering LDL on the risk of major cardiovascular events (MCVE) in discrete time-units of exposure. We tested the accuracy of this algorithm among 440,371 participants randomized by nature to a partial loss-of-function (LOF) variant in the PCSK9 gene, and 46,488 participants in two large randomized trials of PCSK9 inhibitors. We then used this algorithm to estimate the benefit of lowering LDL using a once-yearly dose of an siRNA directed against PCSK9 beginning at different ages among 2.3 million men and women. ResultsThe causal AI algorithm accurately estimated the benefit of lifelong lower LDL due to partial loss-of-function of the PCSK9 gene, and the benefit of lowering LDL with a PCSK9 inhibitor starting at a mean age of 61 years, with nearly superimposable observed and predicted event curves. Lowering LDL by 36% was estimated to reduce the lifetime risk of MCVE by 57% (HR: 0.43, 95%CI: 0.39-0.47) if started at age 30, by 48% (HR: 0.52, 95%CI: 0.50-0.54) if started at age 40, by 38% (HR: 0.62, 95%CI: 0.60-0.65) if started at age 50, and by 26% (HR: 0.74, 95%CI: 0.71-0.77) if started at age 60 years. Moderate LDL lowering starting at age 40 years was estimated to have a greater benefit than more aggressively LDL lowering beginning at age 55 years, with a lower residual risk at all ages. In addition, the benefit of earlier LDL lowering persisted throughout life leading to a quantifiable legacy benefit. ConclusionsThe benefit of lowering LDL is determined by the magnitude, duration, and timing of LDL lowering. Modest sustained LDL lowering beginning in early to middle adulthood, which can be achieved with a once-yearly dose of a PCSK9 siRNA, may be the optimal strategy to prevent atherosclerotic cardiovascular events by slowing the progression of atherosclerosis.

Background: Andersen-Tawil syndrome type 1 (ATS1) is caused by loss-of-function mutations in KCNJ2, which encodes the inward rectifier K+ channel Kir2.1, a key determinant of IK1. Impaired Kir2.1 destabilizes membrane excitability and predisposes to ventricular arrhythmias. Most ATS1 variants disrupt channel regulation by phosphatidylinositol 4,5-bisphosphate (PIP2), but whether specific mutations confer differential arrhythmic risk remains unclear. Objective: To determine whether ATS1 variants disrupting Kir2.1-PIP2 interactions define distinct arrhythmic risk profiles and establish a mechanistically informed framework for risk stratification. Methods: We performed a pooled patient-level analysis of 225 ATS1 patients carrying KCNJ2 variants impairing Kir2.1-PIP2 interaction. Inclusion of 22 clinical and electrocardiographic variables were used to identify mutation-specific risk profiles and predictors for arrhythmia risk. The approach was validated in a multicenter cohort of 20 ATS1 patients. Functional validation was performed using patient-derived iPSC-CMs, cardiac-targeted mouse models, and structural in silico analyses. Results: ATS1 variants segregated into three discrete clusters corresponding to high-, intermediate-, and low-risk arrhythmic phenotypes, establishing a mutation-dependent hierarchy of arrhythmic risk. Regression analyses identified six variables independently associated with severe arrhythmic outcomes. Patient-derived iPSC-CM demonstrated graded impairment of electrical propagation and arrhythmia susceptibility, with a hierarchy in conduction velocity, CV:Control > R82W > R218W > G215D). Cardiac-targeted ATS1 mouse models reproduced the clinical risk stratification. Structural modeling showed that high-risk variants localize near the channel pore and disrupt Kir2.1-PIP2 interactions through mutation-specific mechanisms. Conclusions: ATS1 caused by Kir2.1-PIP2-disrupting variants is not a uniform disorder but comprises biologically distinct subgroups with predictable differences in arrhythmic severity. Integrating genetics, functional phenotyping, and structural modeling provides a mechanistically grounded framework for ATS1 risk stratification and precision therapy development.

The ISCHEMIA trial reported no reduction in cardiovascular death or myocardial infarction (MI) with an initial invasive strategy. However, this neutrality depends on the design of the primary composite endpoint, which combined spontaneous type-1 and type-3 MI (plaque rupture or sudden death) with procedural type-4a/5 MI defined by permissive biomarker thresholds and minimal prognostic significance. In addition, {approx}20% crossover in the conservative arm diluted the intention-to-treat (ITT) contrast. Using only published aggregate data, we conducted design-based reanalyses. We separated spontaneous from procedural MI and repeated analyses after excluding patients censored by procedural events ("restricted" analysis). We corrected for misattribution by reallocating the 20 first procedural MIs reported in the conservative arm--events that necessarily occurred after revascularization--to the invasive arm. We estimated the causal effect of early revascularization among compliers using an instrumental-variable Wald estimator. We derived the threshold weight w\*w^\*w\* at which procedural MI would neutralize the composite, calculated fragility, and estimated numbers needed to treat/harm (NNT/NNH). Finally, we reconstructed parametric pseudo-Kaplan-Meier curves by calibrating Weibull models to the published 4-year risks. Across 5,179 patients, spontaneous MI were halved by invasive therapy (2.9% vs 5.8%; relative risk 0.51), confirmed in restricted analysis (RR 0.52). Procedural MI were more frequent in the invasive arm (2.7% vs 0.8%; RR 3.45). After reallocation of the 20 misattributed events, the all-MI composite reversed (RR 1.08). Instrumental-variable analysis indicated that early revascularization among compliers reduced spontaneous MI by -4.8 percentage points (NNT {approx}21) while increasing procedural MI by +3.2 points (NNH {approx}31). The threshold was w*=0.81: unless a procedural MI is valued at [&ge;]81% of a spontaneous MI, invasive therapy is favorable. Fragility analysis showed that only 20 events (0.4% of the cohort) sufficed to reverse the composite. Weibull curves illustrated early procedural hazard and late spontaneous benefit. Neutrality in ISCHEMIA is thus an artifact of endpoint construction and misattribution. Invasive therapy consistently reduces clinically meaningful spontaneous MI, while procedural events are prognostically trivial.

Although Lp(a) is an established risk factor for ASCVD, our analysis indicates its importance remains substantially underestimated. Reanalyzing cardiovascular outcomes trial (CVOT) data for the PCSK9 antibody alirocumab stratified by Lp(a) quartiles, we find that approximately 70% of the observed benefit is attributable to absolute reductions in Lp(a), rather than to lowering of LDL-C. This result aligns with a prior post hoc analysis of the PCSK9 antibody evolocumab, which attributed 57% of the benefit to Lp(a) reduction. These findings challenge the prevailing assumption that the benefits of PCSK9 therapy are mediated primarily through LDL-C lowering. Based on the observed relationship, we project that late-stage, Lp(a)-targeted therapies could reduce the risk of major adverse cardiovascular events (MACE) by roughly 50[~]60% in phase 3 trials, which would be unprecedented in prior CVOT trials. Our projection also suggests that setting a therapeutic goal of a 15[~]20% reduction in MACE would confer benefit to roughly 40% of secondary-prevention patients with elevated Lp(a), well beyond the current eligibility range (13[~]21%). Further health-economic modeling suggests these therapies would have would have favorable health-economic value, as numbers-needed-to-treat would substantially lower than PCSK9 agents.

Clonal hematopoiesis of indeterminate potential (CHIP) occurs as a result of acquired mutations in bone marrow progenitor cells. CHIP confers a twofold risk of atherosclerotic cardiovascular disease (ASCVD). However, there is limited data regarding specific cardiovascular phenotypes in this population. We recruited patients from the Vanderbilt University Medical Center cardiac catheterization laboratory and performed next generation sequencing to determine CHIP status. Multivariable logistic regression models and proportional odds models were used to assess the association between CHIP status and coronary angiography. We find nearly 1 in 5 patients undergoing coronary angiography have a CHIP mutation. Those with CHIP had a higher risk of having left main coronary artery disease compared to non-CHIP carriers. We additionally find that those with a specific CHIP mutation, ten eleven translocase 2 (TET2) has a larger effect size on left main stenosis compared with other CHIP mutations. This is the first description of a specific atherosclerotic phenotype in CHIP and serves as a basis for understanding enhanced morbidity and mortality in CHIP.

Truncating variants in the Alpha Kinase 3 (ALPK3) gene have recently emerged as an important cause of genetic cardiomyopathy globally and here we demonstrate the efficacy and safety of a viral-based gene replacement therapy for ALPK3. Given the loss-of-function nature of these variants, we reasoned that a gene replacement approach would improve heart function in this patient population. We demonstrate that the delivery of full length ALPK3 via adeno-associated virus could restore contractile function in human cardiac organoids and in vivo mouse models carrying clinically relevant mutations in ALPK3. The role of disrupted proteostasis networks in multiple forms of genetic cardiomyopathy suggest that delivery this novel AAV-ALPK3 may provide functional benefit outside of cardiomyopathy induced by ALPK3. Titin truncating variants (TTNtv) are the most common cause of dilated cardiomyopathy, and interestingly also contributes to the M-Band protein quality control network coordinated by ALPK3. Notably, in human cardiac organoids carrying a TTNtv we observed that the ALPK3 gene therapy could completely restore contractile deficits. This opens the exciting prospect for indication expansion of AAV-ALPK3 into other forms of cardiomyopathy that currently have no therapeutic options.

Abstract Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have demonstrated cardiovascular benefit in type 2 diabetes and obesity, with recent observational data suggesting favorable associations after transcatheter aortic valve replacement. Whether similar associations exist after surgical aortic valve replacement (SAVR) is unknown. Methods: Retrospective propensity-matched cohort analysis using the TriNetX U.S. Collaborative Network. Adults with type 2 diabetes or obesity (BMI [&ge;]30 kg/m2) undergoing SAVR were categorized by GLP-1 RA exposure (any use within 3 months before through 1 year after SAVR) versus no use. One-to-one matching was performed on 44 covariates. Primary outcomes were 1-year all-cause mortality, heart failure, acute kidney injury, acute myocardial infarction, cerebral infarction, and atrial fibrillation. Sensitivity analyses included 30-day landmark restriction and falsification outcomes. Results: After matching, 1,984 patients were retained per cohort. GLP-1 RA use was associated with lower 1-year risks of all-cause mortality (4.8% vs 10.4%; HR, 0.44; 95% CI, 0.34-0.56), acute kidney injury (6.9% vs 10.1%; HR, 0.65; 95% CI, 0.49-0.85), myocardial infarction (3.0% vs 5.1%; HR, 0.57; 95% CI, (0.40-0.82), heart failure (11.3% vs 15.7%; HR, 0.68; 95% CI, (0.51-0.90), and atrial fibrillation or flutter (10.1% vs 13.9%; HR, 0.69; 95% CI, 0.54-0.90; all P[&le;]006). Cerebral infarction did not differ. In landmark analysis, mortality, heart failure, and acute kidney injury associations persisted; myocardial infarction and atrial fibrillation associations were attenuated. Falsification outcomes were null. Conclusions: Perioperative GLP-1 RA use was associated with lower 1-year cardiovascular event rates after SAVR. These hypothesis-generating findings support prospective randomized investigation.

Background Targeted pharmacologic therapies for transthyretin amyloid cardiomyopathy (ATTR-CM) improve survival; however, their effects on cardiac structural parameters remain incompletely defined. Objectives To evaluate the pooled effects of disease-modifying therapies for ATTR-CM on echocardiographic structural parameters. Methods In accordance with PRISMA guidelines, we performed a systematic review and meta-analysis of randomized controlled trials and observational studies published through March 2025 assessing transthyretin stabilizers and RNA-silencing therapies in adults with cardiac amyloidosis. Outcomes included changes in global longitudinal strain (GLS), left ventricular ejection fraction (LVEF), interventricular septal (IVS) thickness, left ventricular mass, stroke volume, E/e? ratio, and LV end-diastolic volume. Pooled between-group mean differences were calculated using random-effects models. Sensitivity analyses were performed. Results Eighteen studies (11 randomized, 7 observational) encompassing 3,646 patients were included. Compared with control, drug therapy was associated with attenuation of GLS decline (mean difference [MD] -0.69%; 95% CI -1.10 to -0.29; P<0.001) and preservation of LVEF (MD 1.62%; 95% CI 0.73 to 2.51; P<0.001). Treatment was also associated with reduced worsening of E/e? ratio, and preservation of stroke volume. No significant between-group differences were observed for IVS thickness, LV mass and LV end-diastolic volume. Within-group analyses showed no change in echocardiographic parameters between baseline and follow-up in treated patients, in contrast to significant worsening in the control cohort. Conclusions Disease-modifying therapies for ATTR-CM are associated with stabilization and attenuated progression of cardiac remodeling rather than reversal of structural abnormalities.

BackgroundThe I-bar protein MTSS1 is a known modifier of heart failure and contractile phenotypes but its role in modulating contractile dysfunction in genetic forms of Mendelian dilated cardiomyopathy (DCM) is not known. MethodsThe potential role of cardiac MTSS1 in TTN DCM was explored using time-to-event models in longitudinal human datasets. Using induced siRNA and mutant forms of pluripotent stem cell cardiomyocytes (iPSC-CMs) the impact of siRNA knockdown of MTSS upon sarcomere and Cardiomyocyte biology was assessed via quantitative high-content microscopy, and the impact and mechanism of MTSS1 knockdown upon contractility was assessed using engineered heart tissues (EHTs). ResultsAmongst individuals affected with TTN DCM, a variant conferring lower cardiac levels of MTSS1 was associated with significantly improved event-free survival from cardiovascular death or heart transplant (HR 0.29, p=0.0016). Knockdown of MTSS1 by siRNA significantly improved the appearance of iPSC-CM models of TTN (p=2.9e-06), CSRP3 (p=3.1e-14), and RBM20 (p=4.4e-04) DCM as assessed by quantitative microscopy. Correspondingly, siRNA knockdown of MTSS1 increased contractility in EHT models of TTN DCM (p=0.003), CSRP3 DCM (p=0.008), and RBM20 DCM (p<2e-16). Across all genetic backgrounds, knockdown of MTSS1 was observed to increase the number of sarcomeres (p<0.0001), and in co-immunoprecipitation experiments MTSS1 physically interacts with MYO18A a key determinant of early sarcomere formation. Knockdown of MTSS1 resulted in increased transcription of MYH7 (0.29 log2FC, p=2.9e-06) along with other sarcomere genes. ConclusionsIn iPSC-CMs Knockdown of MTSS1 by siRNA increased number of sarcomeres and was observed to increase twitch force in select in vitro models, and may suggest MTSS1 plays a previously unrecognized role in modulating sarcomere production. Human observational and iPSC-CM experimental data supports the hypothesis that reduced expression of MTSS1 may be beneficial in Mendelian DCM caused by TTN, RBM20, and CSRP3.

BackgroundThe MI-GENES clinical trial (NCT01936675), in which participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (FRSg, n=103), or an integrated risk score (IRSg, n=104) that additionally included a polygenic risk score (PRS), demonstrated that after 6 months, participants randomized to IRSg had higher statin initiation and lower low-density lipoprotein cholesterol (LDL-C). ObjectivesIn a post hoc 10-year follow-up analysis of the MI-GENES trial, we investigated whether disclosure of a PRS for CHD was associated with a reduction in adverse cardiovascular events. MethodsParticipants were followed from randomization beginning in October 2013 until September 2023 to ascertain adverse cardiovascular events, testing for CHD, and changes in risk factors, by blinded review of electronic health records. The primary outcome was the time from randomization to the occurrence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Statistical analyses were conducted using Cox proportional hazards regression and linear mixed-effects models. ResultsWe followed all 203 participants who completed the MI-GENES trial, 100 in FRSg and 103 in IRSg (mean age at the end of follow-up: 68.2{+/-}5.2, 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in FRSg and 2 in IRSg (hazard ratio (HR), 0.20; 95% confidence interval (CI), 0.04 to 0.94; P=0.042). In FRSg, 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRSg (HR, 0.51; 95% CI, 0.32 to 0.81; P=0.004). IRSg participants had a longer duration of statin therapy during the first four years post-randomization and a greater reduction in LDL-C for up to 3 years post-randomization. No significant differences between the two groups were observed for hemoglobin A1C, systolic and diastolic blood pressures, weight, and smoking cessation rate during follow-up. ConclusionsThe disclosure of an IRS that included a PRS to individuals at intermediate risk for CHD was associated with a lower incidence of MACE after a decade of follow-up, likely due to a higher rate of initiation and longer duration of statin therapy, leading to lower LDL-C levels.

Myocardial infarction (MI) is associated with an inflammatory process mainly attributed to innate immune components. Very recently, the role of T-cells in both inflammation and healing has been suggested through various human and mouse studies. Previous studies showed that CD4+ and CD8+ T cells affect post-MI repair but did not investigate how to leverage T cell biology to predict post-MI outcomes in patients. For instance, the antigenic trigger of T-cells is still unknown in human. Indeed, others and we identified T-cell specific for myosin infiltrating the myocardium in mouse models of MI, recent studies identified expanded clones in human myocardium, altogether suggesting a tissue-specific T-cell activation. However, it is still unclear how acute post-MI immune responses shape long-term cardiac functional outcomes in individual patients. In this study, we analyzed the role of T-cell in predicting post-MI repair by analyzing the T-cell receptor (TCR) repertoire. Indeed, the TCR repertoire is now considered as a marker of the clinical status of individuals. Previous studies in infectious but also autoimmune contexts showed the potential of the TCR repertoire to predict the disease. Therefore, assessing the dynamic changes in global TCR repertoires may provide valuable information about the antigen-specific immune responses underlying post-MI healing. In our study, we carefully selected patients that suffered from MI on a prospective cohort. The TCR repertoire has been analyzed by next generation sequencing at the index hospitalization with the aim to identify features predict of their healing outcome assessed at 12 months post-MI. While no major variations have been found in diversity of TCR gene usage, we identified unique TCR signatures predicting one-year cardiac functional outcomes. Our result enables early immune-based risk stratification of MI patients and calls for larger studies to develop novel predictive biomarkers and possibly new therapeutics.

IntroductionPreterm pre-eclampsia is associated with increased risk of later cardiovascular disease. This study examines cardiometabolic health 3-6 years post-preterm pre-eclampsia and explores whether early postnatal cardiovascular phenotypes relate to later cardiovascular morbidity. MethodsPICk-UP trial participants who experienced preterm pre-eclampsia underwent assessments including anthropometry, blood pressure (BP), arteriography, echocardiography, biomarkers and cardiac magnetic resonance (CMR) imaging 3-6 years postpartum. The primary outcome was hypertension prevalence, with secondary outcomes including cardiac fibrosis, remodelling, and function, obesity, and lipid abnormalities. Associations between baseline, pregnancy and postnatal characteristics with the primary and secondary outcomes were explored. ResultsForty-five women were included; 37 underwent echocardiography and 20 had CMR. At 3-6 years, 53% had hypertension, 32% developed de novo hypertension, 30% had adverse left ventricular (LV) remodelling, 49% had diastolic dysfunction, and 27% were obese. Myocardial fibrosis was detected in 35% of CMR participants. No cardiovascular measures changed from 6 months postpartum to 3-6 years. Women who developed hypertension demonstrated higher BP and LV mass index, from 6 weeks postpartum, with distinct postnatal BP trajectories. Women with myocardial fibrosis exhibited higher sFlt and CRP concentrations from 6 weeks postpartum, with sFlt correlating with native T1 at 3-6 years. DiscussionWomen with prior preterm pre-eclampsia show significant cardiometabolic morbidity 3-6 years postpartum. Early postnatal phenotypes indicate long-term cardiovascular risk. Persistent anti-angiogenic imbalance and inflammation may contribute to myocardial fibrosis. Early BP, weight, and biomarker measurement may help identify at-risk women, warranting further studies on optimising postnatal care to mitigate cardiovascular risk after preterm pre-eclampsia.

BackgroundCardiovascular and cerebrovascular risks of SARS-CoV-2 infection and mRNA vaccination remain incompletely defined and lacking comparative outcomes such as sex-specific vulnerabilities. MethodsUsing the TriNetX Research Network (December 2020-December 2024), we identified four mutually exclusive cohorts: uninfected/unvaccinated (naive), infected/unvaccinated, vaccinated-only, and infected/vaccinated (hybrid immunity). We compared 50 prespecified cardiovascular, cerebrovascular, and mortality outcomes across four pairwise cohort comparisons, with analyses stratified by sex and time of event windows (0-3, 3- 6, 6-9, and >9months). Different vaccine dosing strategies were analyzed. ResultsAmong 30.3 million individuals, infection was associated with a 4.5-fold increased mortality in males and 4.0-fold in females (p<0.001) as well as marked increases in myocarditis, myocardial infarction, and pulmonary embolism. Inflammatory cardiac complications occurred four times more often after infection than vaccination. Vaccination alone conferred a 76% reduction in major adverse cardiovascular events (MACE) in males and 69% in females, with no detectable cardiovascular toxicity. Post-infection vaccination provided an additional 36-38% MACE reduction, though males with hybrid immunity had a late increased risk of pericarditis. Completing the two-dose vaccine series maximally reduced mortality (by 77%) and myocarditis (by 62%) versus single dosing; further doses gave minimal additional benefit but sustained the benefit of the primary vaccination series. Females had higher infection-linked myocarditis risk despite lower mortality. ConclusionsSARS-CoV-2 infection confers substantially greater and sustained cardiovascular and cerebrovascular risk than mRNA vaccination, confirming a highly favorable benefit-risk profile for vaccination. These findings support extended cardiovascular surveillance after infection and targeted, risk-based vaccination strategies.

BackgroundGenetic diagnosis has become increasingly important to guide clinical decision making for patients with dilated cardiomyopathy (DCM). Disease-causing (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic dilated cardiomyopathy (DCM), but the role of truncating RBM20 variants (RBM20tvs) is unclear. ObjectiveAssess the contribution of RBM20tvs to DCM. MethodsWe assembled an international cohort of DCM patients with RBM20 variants and used data from the genome-first UK Biobank (UKB) to assess the etiologic fraction, natural history and penetrance of RBM20tvs. ResultsThe etiologic fraction of RBM20tvs in arrhythmogenic DCM was modest (0.53[0.32,0.67], p=7.5x10-5). RBM20tv DCM patients presented to referral centers later in life than RBM20 P/LP DCM patients (53{+/-}10 vs. 34{+/-}18 years, p=4x10-3), and were less likely to have a family history of sudden cardiac arrest (20% vs. 65%, p= 0.046) or cardiomyopathy (20% vs. 78% p=5.4x10-3). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between RBM20tv and RBM20 P/LP DCM patients, though sex-adjusted lifetime hazard was reduced in RBM20tv DCM (HR 0.15[0.03,0.66],p=0.009). In UKB, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20tvs than in those with TTNtvs (HR 0.55 [0.36,0.84], p=5.9x10-3). ConclusionsRBM20tvs contribute to arrhythmogenic DCM phenotypes, but confer milder disease severity alone than RBM20 P/LP variants, and reduced lifetime disease penetrance compared to TTNtvs. Their potential for additive interactions with other damaging variants should be considered in DCM patients and families.

BackgroundCalcineurin in a pleiotropic signaling enzyme that promotes pathological cardiac remodeling but also cardioprotection in ischemia-reperfusion injury. In addition, calcineurin inhibitors are immunosuppressants. This pleiotropy has precluded the use of calcineurin inhibitors as treatments for heart failure. Cdc42-interacting protein 4 (CIP4/TRIP10) is an endosomal scaffold protein that organizes a calcium and calcineurin A{beta}2 (CaNA{beta}2) signaling compartment activated by G-protein coupled receptors independently of contractile calcium. CIP4 binds CaNA{beta}2 via the CaNA{beta}-specific N-terminal polyproline (PP) domain. We previously showed that targeting of CIP4-CaNA{beta}2 signalosomes inhibited pathological cardiac hypertrophy and the development of heart failure induced by chronic pressure overload in mice. It is unknown whether CIP4-CaNA{beta}2 signalosomes contribute to cardioprotection and/or cardiac remodeling in ischemic heart disease. MethodsCIP4 conditional knock-out (CKO) mice were studied by echocardiography with strain analysis and histology following ischemia-reperfusion (I/R) injury and permanent left coronary artery (LCA) ligation to induce myocardial infarction. Wildtype C57BL/6NJ mice were transduced with adeno-associated virus (AAV) engineered for cardiomyocyte-specific expression of either a CaNA{beta}2 shRNA to inhibit CaNA{beta}2 expression, a VIVIT peptide to inhibit CaN-NFAT signaling, or a CaNA{beta}2 PP peptide to block CIP4-CaNA{beta}2 binding. AAV-transduced mice were studied by I/R injury. Additional mice were subjected to permanent LCA ligation and subsequently treated with AAV to test the effects of CaN inhibition in chronic ischemic cardiomyopathy. The effects of CaNA{beta}2 PP-GFP expression on primary T-cell activation were studied in vitro. ResultsCIP4 CKO mice and mice expressing the PP anchoring disruptor peptide exhibited preserved cardiac function after I/R injury and decreased infarct size and preserved cardiac function 8 weeks after myocardial infarction by permanent LCA ligation. In contrast, cardiomyocyte-specific depletion of CaNA{beta}2 and VIVIT peptide expression worsened outcome after I/R injury and in chronic ischemic cardiomyopathy. In addition, in contrast to cardiomyocytes, PP-mediated CaNA{beta} anchoring inhibition had no effect on T-cell activation and cytokine expression in vitro. ConclusionsCIP4-CaNA{beta}2 signalosomes promote adverse cardiac remodeling and are not cardioprotective. Proof-of-concept is provided for the treatment of ischemic cardiomyopathy by a PP anchoring disruptor gene therapy. Targeting these complexes may be beneficial in cardiovascular diseases, including ischemic cardiomyopathy and acute myocardial infarction. Clinical PerspectiveO_ST_ABSWhat is New?C_ST_ABSO_LITargeting CIP4, which is a scaffold protein for the phosphatase calcineurin, improves cardiac function in mice after acute myocardial infarction due to ischemia-reperfusion injury and in chronic ischemic cardiomyopathy. C_LIO_LIGene therapy-based expression of a calcineurin A{beta}-derived polyproline peptide, which can compete CIP4-calcineurin binding, is beneficial in acute and chronic myocardial infarction. C_LI What Are the Clinical Implications?O_LIThis study establishes CIP4 signalosomes as a new drug target for the treatment of ischemia-reperfusion injury and chronic pathological cardiac remodeling. C_LIO_LIThis study provides proof-of-concept for a new gene therapy approach to treating acute myocardial infarction and chronic ischemic cardiomyopathy. C_LI

Background and AimsThe diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM) requires advanced imaging, precluding large-scale pre-clinical testing. Artificial intelligence (AI)-enabled transthoracic echocardiography (TTE) and electrocardiography (ECG) may provide a scalable strategy for pre-clinical monitoring. MethodsThis was a retrospective analysis of individuals referred for nuclear cardiac amyloid testing at Yale-New Haven Health System (YNHHS, internal cohort) and Houston Methodist Hospitals (HMH, external cohort). Deep learning models trained to discriminate ATTR-CM from age/sex-matched controls on TTE videos (AI-Echo) and ECG images (AI-ECG) were deployed to generate study-level ATTR-CM probabilities (0-100%). Longitudinal trends in AI-derived probabilities were examined using age/sex-adjusted linear mixed models, and their discrimination of future disease was evaluated across preclinical stages. ResultsAmong 984 participants at YNHHS (median age 74 years, 44.3% female) and 806 at HMH (69 years, 34.5% female), 112 (11.4%) and 174 (21.6%) tested positive for ATTR-CM, respectively. Across cohorts and modalities, AI-derived ATTR-CM probabilities from 7,352 TTEs and 32,205 ECGs diverged as early as 3 years before diagnosis in cases versus controls (ptime(x)group interaction[&le;]0.004). Among those with both AI-Echo and AI-ECG available one-to-three years before nuclear testing (n=433 [YNHHS] and 174 [HMH]), a double-negative screen at a 0.05 threshold (164 [37.9%] and 66 [37.9%], vs all else) had 90.9% and 85.7% sensitivity (specificity of 40.3% and 41.2%), whereas a double-positive screen (78 [18.0%] and 26 [14.9%], vs all else) had 85.5% and 88.9% specificity (sensitivity of 60.6% and 42.9%). ConclusionsAI-enabled echocardiography and electrocardiography may enable scalable risk stratification of ATTR-CM during its pre-clinical course. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=112 SRC="FIGDIR/small/24312556v3_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@a9e7acorg.highwire.dtl.DTLVardef@a8defborg.highwire.dtl.DTLVardef@c751e7org.highwire.dtl.DTLVardef@1d21c45_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOStructured Graphical Abstract.C_FLOATNO Artificial intelligence (AI)-enhanced interpretation of standard echocardiographic videos and electrocardiographic (ECG) images may serve as digital biomarkers of disease progression during the early pre-clinical and clinical stages of transthyretin amyloid cardiomyopathy. We show that across two geographically distinct cohorts of individuals referred for nuclear cardiac amyloid testing, cases exhibit significantly faster progression in their AI-defined probabilities in the years before nuclear cardiac amyloid testing, compared with controls, a finding that was consistent across cohorts and modalities. These findings suggest that AI-enabled echocardiography and ECG may be able to identify those at risk for ATTR-CM up to 3 years before clinical diagnosis through standard clinical pathways. AI: artificial intelligence; ATTR-CM: transthyretin amyloid cardiomyopathy; ECG: electrocardiography; TTE: transthoracic echocardiography. C_FIG