Frontiers in Cardiovascular Medicine

Introduction Percutaneous coronary intervention (PCI) is a widely adopted strategy for managing coronary artery disease (CAD), leading to improved survival rates, particularly in developing countries. However, the increased survival of these patients imposes a substantial burden on long-term management, especially at the primary healthcare level. Recently, the hemoglobin-to-red cell distribution width ratio (HRR) has emerged as a potentially valuable prognostic biomarker for post-PCI patients. Despite its accessibility and cost-effectiveness, HRR has not been extensively investigated in resource-limited settings. Aim This study aimed to evaluate the prognostic value of the HRR in predicting 3-year major adverse cardiovascular events (MACE) among patients undergoing PCI who were managed at the primary healthcare level. Methods We conducted a multicenter prospective cohort study in Vietnam. A total of 626 post-PCI patients were ultimately included in the final analysis. The study commenced in October 2019 and concluded in October 2025. The association between HRR and 3-year MACE was evaluated using Cox proportional hazards regression models. Results The MACE incidence decreased progressively across the ascending HRR quartiles (p < 0.001). According to the unadjusted Cox model, each unit increase in HRR was associated with a lower risk of MACE (HR = 0.756; 95% CI, 0.703-0.814; p < 0.001). This association persisted after adjustment for age, sex, comorbidities (Model I: HR = 0.810; 95%CI: 0.750-0.878; p < 0.001). HRR outperformed its individual components, hemoglobin and red cell distribution width. Subgroup analyses confirmed the consistency of the association across clinically relevant strata. Calibration and decision-curve analyses further suggested acceptable risk estimation and potential clinical utility of HRR for 3-year MACE risk stratification. In the discriminative analysis for predicting 3-year MACE, the HRR had the highest area under the curve outperforming other inflammation-based indices. Conclusion A lower HRR was independently associated with a greater 3-year MACE risk in post-PCI patients. HRR outperforms commonly used leukocyte- and platelet-derived indices, highlighting its potential utility as a simple, cost-effective prognostic marker in resource-constrained healthcare settings.

2-5% of pregnancies are complicated by chronic hypertension [1], increasing the risk of peripartum cardiomyopathy and maternal morbidity [2, 3]. Hypertension reduces stroke volume, whereas pregnancy increases stroke volume. The combined impact of these opposing loads on cardiac function and strain remains unclear. We used a mouse model of pregnancy with pre-existing hypertension to characterize cardiac remodeling. We hypothesized that pregnancy may counteract hypertension-related reductions in cardiac function. Nulliparous female C57Bl6/J mice (7-11 weeks old) were assigned into pregnant (PREG, n=11), angiotensin II-treated (ANGII, n=7), and ANGII+PREG (n=8) groups. Hypertension was induced with subcutaneous angII infusion (1000 ng/kg/min). Cardiac function was measured with high-frequency ultrasound. Ejection fraction (EF) was maintained in PREG animals at 65% but decreased significantly by day 36 in ANGII animals (44.85{+/-}3.27%). In ANGII+PREG mice, EF initially decreased but trended towards PREG values on postpartum day 1. Left ventricle strain was lower in ANGII and ANGII+PREG groups compared to PREG. ANGII and ANGII+PREG animals showed decreased early longitudinal diastolic strain rate at mid-pregnancy compared to baseline (0.82{+/-}0.09% ANGII; 0.73{+/-}0.09% ANGII+PREG), while increasing in PREG (1.76{+/-}0.14%). Minimal physiologically relevant fibrosis was noted across groups via immunohistochemistry. Heart mass-to-body mass was lowest in PREG (6.20{+/-}0.22 mg/g), greatest in ANGII (8.95{+/-}0.39 mg/g), and intermediate in ANGII+PREG (6.92{+/-}0.25 mg/g). Cardiomyocyte cross-sectional area was similar between groups. Overall, pregnancy altered the functional and hypertrophic response to elevated blood pressure. Findings from this work set the foundation for future efforts that may eventually improve cardiovascular care for pregnant patients.

BackgroundCardiovascular disease risk is higher in men than in women. Although sex differences in aortic wall adaptation following antihypertensive treatment have been reported in acute hypertension models, the response after gradually developing hypertension, which mimics human essential hypertension, remains unclear. This study investigated sex differences in aortic wall adaptation following acute blood pressure reduction after gradually developing hypertension. MethodSeventeen-week-old spontaneously hypertensive rats (SHRs) were assigned to the Hypertensive group or the antihypertensive (Reversal) group (N = 5/sex each). The Reversal group received the antihypertensive drug captopril for 4 weeks to maintain systolic blood pressure below 130 mmHg. Age-matched Wistar Kyoto rats (N = 3/sex) served as normotensive (Normal) group. After the experimental period, arterial wall thickness, circumferential wall stress, smooth muscle cell phenotype, and histological changes were evaluated. ResultsAntihypertensive treatment significantly reduced systolic blood pressure in both sexes. Both male and female SHRs exhibited elevated circumferential wall stress during the gradual development of hypertension. In females, antihypertensive treatment significantly reduced medial thickness compared with the Hypertensive group, whereas males showed no reduction. Circumferential wall stress in female Reversal group did not differ significantly from either the Hypertensive or Normal group, whereas males exhibited a significant reduction in circumferential wall stress compared with the Hypertensive group. Furthermore, the reduced collagen area fraction in the Hypertensive group returned to the normotensive levels only in females following antihypertensive treatment. ConclusionThese findings indicate that vascular remodeling induced by gradually developing hypertension is more effectively reversed by antihypertensive treatment in females than in males.

Background and Aims: Epicardial adipose tissue (EAT) has emerged as an important cardiovascular biomarker that reflects both inflammatory and cardiometabolic risk. EAT volume and density vary significantly across populations, yet there is a lack of multicenter studies investigating the predictive value of population-specific EAT percentiles. Methods: In this multicenter study, we retrospectively analyzed low-dose computed tomography correction scans from 42,842 patients undergoing myocardial perfusion imaging. A derivation cohort of 15,082 patients was used to establish sex- and age-specific nomograms for EAT density and EAT volume indexed to body surface area. Percentile-based thresholds were tested for outcome prediction in a validation cohort of 27,760 patients. For clinical implementation, we developed an online EAT percentile calculator. Results: Percentile curves demonstrated increased BSA-indexed EAT volume and decreasing EAT density with age. Over a median follow-up of 3.6 years (IQR: 1.83 - 5.14), 4,956 patients experienced a nonfatal myocardial infarction or death. In multivariable Cox models, patients above the 95th sex- and age-specific percentile had significantly worse outcomes for BSA- indexed EAT volume [adjusted hazard ratio 1.30, 95% CI: 1.14 - 1.49, p < 0.001] and EAT density [adjusted hazard ratio 1.7, 95% CI: 1.51 - 1.92, p<0.001] when compared to patients below the 50th percentile (p<0.001). Conclusion: Age- and sex-specific EAT percentiles provide a clinically interpretable framework for contextualizing automated EAT measurements and identifying patients at increased cardiovascular risk. EAT density was a stronger prognostic marker and identified elevated risk even among patients with normal BMI, supporting its potential to provide information beyond conventional anthropometric assessment.

HIV infection significantly elevated the odds of cardiovascular diseases, including myocardial fibrosis. We aimed to determine the difference of late gadolinium enhancement (LGE), extracellular volume (ECV), T1, and T2 using cardiac magnetic resonance imaging (CMR) in patients living with HIV (PLWH) and healthy controls. The databases Scopus, Web of Science, Embase, and PubMed were searched systematically using relevant keywords. STATA version 17 was used for meta-analysis using random effect and fixed effect models for heterogeneous and non-heterogeneous analyses. An overall number of 13 studies were included in the current analysis involving 1425 PLWH and 766 healthy controls. PLWH showed significantly higher LGE (OR: 5.47, 95% CI: 1.90-15.64, p<0.001) and ECV (mean difference: 1.46, 95% CI: 0.21-2.71, p=0.02) compared to controls. However, differences in Left Ventricular Ejection Fraction (LVEF) were not significant (mean difference: -1.41, 95% CI: -2.81- -0.01, p=0.05). There were no meaningful disparities in pro B-type natriuretic peptide (BNP) values (mean difference: 8.67, 95% CI: 0.04-17.29, p=0.05) or T2 values (mean difference: 0.91 ms, 95% CI: -1.04-2.86, p=0.36), but T1 values were significantly higher in PLWH (mean difference: 13.78 ms, 95% CI: 9.16-18.40, p<0.001). In meta regression, LGE was correlated with nadir CD4 (z=-3.41, p-value<0.001). In addition, ECV was correlated with white race (Z=-3.97, p-value<0.001), Hepatitis C (Z=-2.08, p-value=0.037), and smoking (Z=2.05, p-value=0.041). HIV is related to a significantly elevated rate of myocardial fibrosis, and factors such as lower nadir CD4, white race, hepatitis C, and smoking were correlated with hepatitis C. Keywords: Myocardial fibrosis, HIV, AIDS, Cardiovascular diseases, Heart failure

Introduction: In hypertrophic cardiomyopathy (HCM), wall stress and subclinical myocardial injury related in part to pathological hypercontractility, which in turn are associated with worse outcomes. Cell-free DNA (cfDNA) is released from cardiomyocytes (cfDNA-CM) through irreversible cellular injury and death. We investigated the feasibility of quantifying cfDNA-CM and its relationship to HCM patient characteristics. Methods: We analyzed 57 plasma samples from stable patients with HCM and 10 plasma samples from patients with acute myocardial infarction (AMI). Plasma cfDNA was isolated from both groups. Whole genome bisulfite sequencing (WGBS) libraries were generated and sequenced with short-read sequencing. Methylation patterns were used for tissue deconvolution analysis and cell-specific cfDNA quantification. Results: Yields of cfDNA (p = 0.003) and cfDNA-CM (p = 0.002) fractions were higher in AMI controls than HCM, supporting the validity of the assay. Within the HCM cohort, the median cfDNA yield was 12.22 ng [IQR: 7.77, 18.94]. The cfDNA-CM fraction in this cohort ranged from 0% to 6.4% of total cfDNA. Higher cfDNA-CM tertiles were associated with higher body mass index (BMI, p=0.001), a greater prevalence of BMI 30 kg/m2 (p<0.001), and a higher prevalence of obstructive sleep apnea (p=0.038). No significant differences were observed in other demographic, genetic, and laboratory characteristics. Higher cfDNA-CM tertile was numerically associated with higher New York Heart Association (NYHA) functional class and left ventricular outflow tract (LVOT) obstruction, while circulating biomarkers of wall stress (NT-proBNP) and myocardial injury (troponin) did not differ across tertiles (p=0.83 and p=0.29, respectively). Conclusion: Isolation and quantification of cfDNA as well as detection of cfDNA-CM in chronic stable patients with HCM are feasible. Higher cfDNA-CM fraction was associated with increasing BMI and cardiometabolic comorbidity burden. The absence of association with traditional circulating biomarkers suggests that cfDNA-CM may reflect a distinct domain of myocardial health, injury, and adverse remodeling.

Abstract Background The SYNTAX score (SS) quantifies the severity and complexity of coronary artery lesions and serves as an independent predictor of major adverse cardiovascular events and mortality in patients with acute coronary syndrome (ACS). However, few studies have examined the association between SS and in-hospital cardiac arrest (IHCA) in this population. Therefore, this study aims to elucidate the relationship between SS and the incidence of IHCA in patients with ACS. Methods This study consecutively enrolled 3,224 patients undergoing percutaneous coronary intervention (PCI). Logistic regression and restricted cubic spline (RCS) analyses were employed to examine the association between SS and the incidence of IHCA. Participants were stratified into three groups based on SS: Group T1 (SS ? 10, N = 1,097), Group T2 (10 < SS ? 18, N = 1,089), and Group T3 (SS > 18, N = 1,038). The primary endpoint was the incidence of IHCA. Results The overall incidence of IHCA was 4% (N=147). After adjusting for covariates, SS was significantly associated with the incidence of IHCA in ACS patients treated with PCI (OR = 1.0400; 95% confidence interval (CI) = 1.0200?1.0700; p < 0.001). Compared with the T1 group, the T3 group exhibited an increased risk of IHCA (OR = 2.1800; 95% CI = 1.2900?3.6900; p = 0.0040). Subgroup analyses revealed that, after covariate adjustment, patients with ST-segment elevation myocardial infarction (STEMI) had an increased risk of IHCA (OR = 1.0700; 95% CI = 1.0300?1.1100; p < 0.001). Similarly, both patients with diabetes mellitus (DM) (OR = 1.0400; 95% CI = 1.000?1.0700; p = 0.0270) and those without DM (OR = 1.0600; 95% CI = 1.0200?1.1000; p = 0.0020) showed an increased risk. Furthermore, elderly patients (?60 years) (OR = 1.0300; 95% CI = 1.0100?1.0700; p = 0.0210) and non-elderly patients (<60 years) (OR = 1.0500; 95% CI = 1.000?1.1000; p = 0.0470) had an increased risk, as did male patients (OR = 1.0500; 95% CI = 1.0200?1.0700; p = 0.0020). RCS analysis indicated a dose-response relationship between IHCA incidence and SS (nonlinear p-value = 0.906), with the risk of IHCA increasing when SS exceeded 23.975. Incorporating SS into the baseline risk model improved the predictive value for IHCA incidence in ACS patients undergoing PCI (Net reclassification improvement [NRI]: 0.3537 [0.1906?0.5167], p < 0.001; Integrated discriminant improvement [IDI]: 0.0104 [0.0025?0.0183], p = 0.0097). Conclusions Among patients with ACS undergoing PCI, SS is significantly associated with the incidence of IHCA. Consequently, SS may serve as an effective predictor of IHCA in this population.

Preeclampsia (PE) is a severe pregnancy-associated hypertensive disorder and a major contributor to maternal and perinatal morbidity and mortality. The mechanisms of PE pathogenesis are not yet understood. This paper aims to explore candidate PE-associated biomarkers and regulatory mechanisms using bioinformatics analysis of placental transcriptomic datasets. We downloaded placental transcriptomic datasetsGSE203507 and GSE148241 from GEO and investigated differentially expressed genes(DEGs) between PE and control samples. We performed Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Disease Ontology (DO), and protein-protein interaction (PPI) analyses to characterize the potential role, disease associations, and interaction networks of the DEGs. We validated the mRNA expression patterns of candidate hub genes using two independent placental transcriptomic datasets, GSE143966 and GSE114691.We identified 263 DEGs in the discovery analysis and further obtained 150 overlapping DEGs including80 upregulated genes and 70 downregulated genes, for downstream analysis. We then identified eight candidate hub genes: OPRK1, OXGR1, HCAR3, CCR5, HCAR2, CXCL1, FPR3, and SSTR1using Meta scape software(v3.5.20260201). In the validation phase, most candidate hub genes showed broadly consistent mRNA expression trends across GSE114691 and GSE143966, while FPR3 showed weaker cross-dataset consistency. These findings provide candidate PE-associated genes and regulatory pathways for further experimental and clinical validation..

ImportanceCardiovascular disease remains the leading cause of mortality worldwide. Although machine learning models have demonstrated strong predictive performance, limited attention has been given to uncertainty quantification and gender-specific risk factor identification, which are essential for clinically trustworthy artificial intelligence. ObjectiveTo develop and evaluate an interpretable and uncertainty-aware machine learning framework for cardiovascular disease prediction that integrates an association study on biomarkers, explainable artificial intelligence, and gender-stratified risk assessment. Design, Setting, and ParticipantsThis retrospective observational study utilized the UCI Heart Disease dataset comprising 918 participants, including 725 males and 193 females. Demographic, clinical, laboratory, and exercise-related variables were analyzed. Missing values were addressed using a hybrid imputation strategy combining MICE and supervised Random Forest imputation. MethodsAn ensemble machine learning imputation strategy was developed to address missingness. Then advanced machine learning models were developed and evaluated using stratified training/testing partitions and 5-fold cross-validation. Predictive performance was assessed using several evaluation metrics. Uncertainty was quantified through bootstrap resampling, predictive entropy, and mutual information. Linear Double machine learning and Causal Forest double machine learning were applied to estimate gender-specific averages and association studies for risk factors. ResultsRandom Forest achieved the strongest and most stable predictive performance across male and female cohorts, with ROC-AUC values exceeding 0.90 and robust cross-validation performance. Hybrid imputation improved classification performance, increasing the F1-score from 0.87 to 0.89 and ROC-AUC from 0.90 to 0.92. The causal association study analyzes identified the number of major vessels, ST-segment slope, thalassemia, and exercise-induced angina as the strongest determinants of heart disease, with notable differences observed between male and female subgroups. Conclusions and RelevanceIntegrating predictive modeling, uncertainty quantification, and association study machine learning provides a robust and clinically interpretable framework for cardiovascular disease risk assessment. The proposed approach improves prediction reliability while identifying gender-specific causally important risk factors, supporting precision cardiovascular medicine and trustworthy clinical artificial intelligence.

Klf9 is a cardiac-enriched transcription factor of the Kruppel-like factor (Klf) family. Klf9 levels decrease during cardiac hypertrophy; however, no studies have examined its transcriptional targets or role in the progression of hypertrophy. Here, we report genome-wide differential Klf9 occupancy during cardiac hypertrophy, with a predominant enrichment at the metabolic gene promoters. Further, using conditional Klf9 knock-in mice subjected to pressure overload for 1 or 2 weeks, we show that restoring Klf9 expression initially inhibits hypertrophy but later leads to early-onset heart failure. We conclude that a decrease in Klf9 is required for metabolic adaptations that support the development of compensatory hypertrophy.

Abstract Routine blood tests can be used to calculate several inflammation-related ratios, including the neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR). These indices are widely reported as markers of cardiovascular risk, but it is unclear whether they provide comparable information or whether SII, which is derived from platelet count and NLR, adds anything beyond NLR. We analyzed two independent samples from the National Health and Nutrition Examination Survey (NHANES): 15,141 adults from 2005-2010 (development cohort) and 15,392 adults from 2011-2016 (validation cohort), each with complete blood count data and linked mortality follow-up. Survey-weighted Cox models, restricted cubic splines, multiple imputation, and model comparison were used, and the development model was applied to the validation cohort. During a median follow-up of 11.4 years, 795 cardiovascular deaths occurred in the development cohort; the validation cohort recorded 364 cardiovascular deaths over 5.75 years. In the development cohort, hazard ratios per 1-SD increase were 1.32 (95% CI 1.21-1.44) for NLR, 1.21 (1.12-1.32) for SII, and 1.13 (1.04-1.22) for PLR. When NLR and SII were entered together, only NLR remained associated (HR 1.49, 1.23-1.81). The validation cohort showed the same pattern: NLR was strongest (HR 1.35, 1.22-1.49), and neither SII nor PLR remained significant after mutual adjustment. The frozen model showed good discrimination (C-index 0.8991 to 0.9023) and calibration (slope 0.96). Adding NLR produced only a small improvement in discrimination, and reclassification results were inconsistent between cohorts.

Importance: The immune mechanisms driving vascular disease remain incompletely understood. People with HIV (PWH), even during effective antiretroviral therapy (ART), exhibit persistent immune activation and inflammation, which may contribute to higher rates of vascular disease and mortality compared with people without HIV (PWoH). Leveraging a cohort of U.S. military personnel followed from HIV diagnosis through long-term ART suppression, we sought to identify immunologic pathways underlying increased vascular risk. Objective: To identify plasma biomarkers reflecting distinct immune mechanisms that predict incident vascular outcomes in ART-suppressed PWH. Design: Case-cohort study within the U.S. Military HIV Natural History Study. Setting: Longitudinal, multicenter observational cohort. Participants: A total of 1,002 ART-suppressed PWH (HIV RNA <50 copies/mL) were included, with N=135 vascular event (VE) cases and N=702 controls. Cases encompassed atherosclerotic cardiovascular disease (ASCVD) - coronary artery disease (CAD), myocardial infarction (MI), stroke (CVA), peripheral artery disease (PAD) - and venous thrombotic events (VTE) - deep vein thrombosis (DVT) and pulmonary embolism (PE). Exposures: Thirty-three soluble plasma analytes quantified using a high-sensitivity multiplex assay from samples collected [&ge;]1 year after ART suppression. Main Outcomes and Measures: The primary outcome was incident ASCVD. Associations between cytokine concentrations (individual and clustered) and vascular risk were evaluated using unsupervised clustering, Cox proportional hazards models, and causal inference (to estimate 5-year ASCVD risk under hypothetical cytokine alterations). Mediation analyses assessed direct and indirect effects of key inter-related cytokines. Secondary outcome included any VE (ASCVD plus VTE). Covariates included traditional cardiovascular risk factors, HIV clinical variables, and demographics. False discovery rate (FDR) adjustment was applied using the Benjamini-Hochberg method. Results: Cytokine clusters reflecting NLRP3 inflammasome activation and persistent inflammation (IL-18, IL-6) and individual markers (IL-18: HR=1.89, q=0.007; TGF-{beta}2: HR=0.74, q=0.026) were associated with increased ASCVD risk. IL-18 remained nominally significant after adjusting for traditional risk factors (p<0.05) but did not meet FDR significance (q<0.05). Conclusions and Relevance: NLRP3 inflammasome activation and reduced TGF-{beta}2, indicating loss of anti-inflammatory and repair mechanisms, may contribute to atherogenesis in ART-suppressed PWH. These findings highlight potential interventional targets for mitigating inflammation-driven vascular risk and warrant validation in larger cohorts to inform novel therapeutic strategies.

Background: Aortic stenosis (AS) is a valvular heart disease which imposes chronic pressure overload on the left ventricle (LV). Although LV remodelling may regress following aortic valve replacement, the molecular determinants of reverse remodelling remain poorly understood. This study develops a machine learning-based model using myocardial microRNA (miRNA) expression profiles to predict LV mass normalization one year after valve replacement. Methods: Consensus selection combining Random Forest and Bayesian Network analyses was applied to miRNA sequencing data from LV biopsies of 12 matched patient pairs with AS. Selected miRNAs were qPCR quantified in an extended cohort of 89 AS patients and incorporated into predictive models. Sex-stratified analyses were performed. Model robustness was assessed using bootstrap resampling and cross-validation. Candidate miRNAs and target genes were evaluated in LV from a murine model of pressure overload induced by transverse aortic constriction (TAC). Results: The combined Random Forest-Bayesian Network approach identified a three-miRNA signature (miR-517a-3p, miR-122b-5p, and miR-4683) associated with LV mass normalization after valve replacement. Validation in an extensive cohort demonstrated good overall discrimination and achieved its highest performance in women (AUC >0.80). Functional analyses identified drebrin (DBN1) as a putative target of miR-517a-3p and supported its potential involvement in pressure overload-induced cardiac remodelling. Conclusion: Random Forest and Bayesian Network integrated analyses enabled the identification of a myocardial miRNA signature with sex-dependent predictive value for reverse cardiac remodelling after aortic valve replacement. Functional validation supports the relevance of selected miRNAs and their downstream targets, highlighting their potential as biomarkers and candidate regulators of myocardial recovery.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome that predominantly affects women. It is not known why SCAD occurs in specific coronary artery segments. We aimed to identify anatomical and hemodynamic factors that lead to SCAD. Methods: We studied 36 women with angiographically-confirmed SCAD from more than 20 hospital sites and 75 sex- and ethnicity-matched control participants with normal coronary anatomy. Coronary arteries were reconstructed from computed tomography coronary angiography (CTCA) to quantify vessel geometry (curvature, diameter, torsion) and flow-derived metrics (time-averaged endothelial shear stress [TAESS], topological shear variation index [TSVI], oscillatory shear index [OSI], and relative residence time [RRT]) at the tree (left/right), territory (LAD, LCx, RCA), and lesion levels. Results: Compared with controls, SCAD-affected coronary arteries had greater curvature and higher TAESS and TSVI at the whole-tree level (all p?0.007). At the vessel (territory) level, SCAD-affected arteries were smaller in average diameter and showed higher curvature, TAESS, and TSVI than matched control vessels (all p?0.047). Within the same patient, SCAD lesion segments were characterized by smaller diameter, lower torsion, and higher TAESS and TSVI than non-affected segments from the same coronary tree (all p?0.001; curvature borderline). A model combining curvature, TAESS, and TSVI discriminated SCAD from controls with AUC 0.95 (left tree) and 0.97 (right tree); adding diameter yielded AUCs >0.91 at the territory level. Conclusions: SCAD was associated with a reproducible multi-scale signature of smaller vessel caliber and higher, more variable endothelial shear stress supporting a hemodynamic contribution to SCAD clustering in specific coronary arteries and segments.

Background This study presents reference ranges for cardiovascular magnetic resonance (CMR)-derived myocardial strain from the Healthy Hearts Consortium, while evaluating variations by demographic characteristics (age, sex, and ethnicity) and technical factors (scanner vendor, magnetic field strength). We derived reference ranges and centile-based categories for ventricular, atrial, and rapid strain parameters. The prognostic relevance of these categories was assessed by examining their associations with incident cardiovascular events. Methods The dataset included 9,088 CMR studies. Automated image analysis pipelines were established using suiteHEART (NeoSoft Inc.) and cvi42 (Circle Cardiovascular Imaging). A three-step quality control framework was applied including exclusion of incomplete data, visual assessment of image and segmentation quality, and statistical outlier removal. Ventricular strain and strain rate were measured using both software solutions. Additional cvi42 derived metrics included velocity and displacement, annular plane systolic excursion metrics, and rapid strain parameters. Age- and sex-specific reference ranges were generated using lambda-mu-sigma (LMS) modeling with penalized splines. Reference ranges were defined as values between the 2.5th and 97.5th percentiles. For lower-tail classification, values below the 2.5th percentile were considered mildly out-of-range and values below the 0.5th percentile at least moderately out-of-range. Differences across scanner vendors (Siemens, Philips, GE) and magnetic field strengths (1.5 T vs. 3 T) were evaluated using adjusted linear models. The prognostic relevance of selected cvi42-derived categories was evaluated in approximately 45,000 UK Biobank participants using Cox regression adjusted for age, sex, and body mass index. Results After quality control, 8,975 CMR examinations (cvi42) and 8,992 (suiteHEART) were available for analysis; these represent software-specific analytic cohorts. Most exclusions occurred during visual quality control. Women had higher absolute ventricular and atrial strain values than men across all age groups. Left ventricular (LV) longitudinal strain and strain rate were slightly lower in older ages, whereas circumferential and radial parameters remained largely stable. Left atrial strain was also lower in older age groups, while right atrial strain did not vary by age. Annular plane systolic excursion and rapid strain metrics showed similar sex-specific patterns, with modestly lower atrial and displacement values in older groups. Ethnicity-related differences were modest, heterogeneous, and substantially smaller in magnitude than age- and sex-related differences. Technical effects were parameter specific. While LV longitudinal and circumferential strains were largely unaffected, radial strain was higher at 3 T and showed vendor-related differences. LMS-derived reference ranges and centile thresholds were applied both across all ethnicities and within ethnicity-specific analyses, and are presented stratified by age and sex. In the prognostic analysis, centile categories were most consistently associated with incident heart failure. LV longitudinal, circumferential, and radial strain below the 0.5th centile were associated with significantly increased risk of incident heart failure (HRs: 9.9 to 12.4, 95% CIs 7.00-13.90 to 8.49-18.06). Conclusion This study provides age- and sex-specific reference ranges and centile-based categories for CMR-derived strain parameters in a large reference population. Age and sex represent the primary determinants of myocardial deformation, whereas scanner-related effects are parameter-specific. Values in the lower extremes of the healthy reference distribution, particularly for LV strain, are associated with increased risk of incident heart failure. These findings enable standardized, centile-based classification of myocardial strain, facilitating consistent interpretation and improving risk stratification in research and clinical practice.

Background The phosphocreatine-to-ATP ratio (PCr/ATP), measurable by 31P magnetic resonance spectroscopic imaging (31P-MRSI), is a sensitive marker of myocardial energetic reserve. Regional energetic-mechanical coupling, evaluable only per-segment to avoid confounding from spatially heterogeneous disease, represents an important target for cardiac metabolic trials. We extend our previously validated 7T regional 31P-MRSI approach to patients with cardiovascular disease. Methods Twenty-one participants underwent same-day 7T 31P-MRSI and 3T CMR: 9 healthy volunteers, 4 with type 2 diabetes, 5 with heart failure, and 3 with ischaemic cardiomyopathy. PCr/ATP was mapped across six mid-ventricular AHA segments. Ejection fraction, global longitudinal strain, peak filling rate, and regional circumferential and radial strain were derived from 3T CMR. Group differences were assessed by Kruskal-Wallis test with Bonferroni-corrected pairwise comparisons; segment-level associations by per-segment Spearman correlation and linear mixed effects models. Results PCr/ATP differed significantly across groups (p = 0.005, eta^2 = 0.58), ranging from 1.78 +/- 0.21 in healthy volunteers to 1.10 +/- 0.28 in heart failure. Mean PCr/ATP correlated with ejection fraction (rs = 0.65, p = 0.002), global longitudinal strain (rs = -0.63, p < 0.001), and peak filling rate (rs = 0.52, p = 0.023). Segment-level energetic-mechanical coupling was significant in the anteroseptal and inferoseptal segments (circumferential strain rs = -0.49 to -0.56; radial strain rs = 0.43 to 0.57, all p < 0.05), with no significant associations in other segments, consistent with a displacement-related measurement quality gradient. In ischaemic patients, PCr/ATP was significantly lower in infarct segments (0.79 +/- 0.20) than remote myocardium (1.33 +/- 0.22, p = 0.008, r = 0.62). All three ischaemic patients demonstrated remote PCr/ATP below the healthy volunteer median, with two below the 5th percentile (rank-sum p = 0.018; Fisher p = 0.045). Conclusions Regional 7T 31P-MRSI detects segment-level energetic differences across cardiovascular disease states and reveals spatially specific energetic-mechanical coupling confined to the septal segments in the current ungated acquisition. Energetic impairment in ischaemic cardiomyopathy extends into structurally preserved remote myocardium. These findings support larger studies using regional 31P-MRSI to investigate regional energetic-mechanical coupling as a target for metabolic cardiac therapies.

Background: This study aimed to determine the prevalence of BBB, characterize associated clinical and echocardiographic phenotypes, and evaluate associations with incident cardiovascular diseases and all-cause mortality in the general population. Methods: We analyzed 12-lead electrocardiograms from 14,212 subjects from the Hamburg City Health Study (45-74 years). BBBs were defined using Minnesota Code criteria. We applied elastic net regularization to identify clinical associations, and multivariable Cox models for outcome analyses. The total cardiovascular outcome included all-cause mortality, incident heart failure, myocardial infarction, atrial fibrillation, pulmonary embolism, and stroke. Results: Complete left (cLBBB) and right (cRBBB) bundle branch blocks were prevalent in 0.8% and 2.3% of subjects, respectively. Subjects with complete BBB were generally older with a higher burden of cardiovascular risk factors and comorbidities, cLBBB additionally showed higher N-terminal pro-hormone of brain natriuretic peptide levels. The main predictor of BBB was age. Male sex was an additional predictor for cRBBB, while hypertension, hypercholesterolemia, and reduced left ventricular ejection fraction predicted cLBBB. Both, cLBBB and cRBBB were associated with a reduced left ventricular ejection fraction, increased septal wall thickness, and left atrial enlargement. cRBBB demonstrated right ventricular dilation, whereas cLBBB showed markedly impaired left atrial strain. In adjusted analyses, both BBBs were associated with the total cardiovascular outcome (cLBBB: hazard ratio [HR], 2.71; 95% confidence interval [CI], 1.68-4.39; p<0.001; cRBBB: HR, 1.52; 95% CI, 1.09-2.12; p=0.01). Although both were significantly associated with incident heart failure, myocardial infarction, and atrial fibrillation, cLBBB uniquely was associated with all-cause mortality, whereas cRBBB distinctly was associated with incident stroke. Conclusion: In the general population, BBB is a high-risk phenotype characterized by subclinical cardiac alterations and a markedly worse long-term outcome. These findings underscore the importance of early risk stratification. Proactive clinical management in otherwise asymptomatic individuals presenting with these conduction disturbances should be considered.

Mitochondrial transplantation has recently emerged as an alternative treatment for cardiovascular disease (CVD), aimed at increasing mitochondrial number and improving mitochondrial function. Though mitochondrial dysfunction is a key factor in the development of right ventricular hypertrophy/failure, the effects of mitochondrial transplantation on disease mitigation have been largely unexplored. Therefore, this in vitro study aimed to determine whether the transplantation of exogenous L6 myotube mitochondria mitigates negative outcomes in H9C2 cardiomyocytes that were stimulated to hypertrophy with phenylephrine. Control (CTL), control with mitochondrial transplantation (MitoTx), Phenylephrine only (Phe-only), and phenylephrine with mitochondrial transplantation (Phe+MitoTx) treatments were evaluated. Pilot experiments indicated mitochondrial transplantation into healthy cardiomyocytes acutely increased Complex I-linked oxidative phosphorylation (OXPHOS) capacity (p=0.005) and maximal respiratory capacity (p=0.022) within 24 hours, and these data alongside microscopic evidence of fluorescently labeled L6 mitochondria in H9C2 cardiomyocytes suggested successful transplantation. Regarding treatment comparisons, Phe-only showed a significant increase in cell area (p<0.05), while Phe+MitoTx blunted the hypertrophic cardiomyocyte response. Consistent with these results, proteomic analysis of 4,806 proteins showed that transplantation enriched the mitochondrial proteome, impacting pathways including OXPHOS, respiration, fatty acid and amino acid metabolism, while suppressing extracellular matrix remodeling and de-differentiation signatures. This response was observed in healthy and phenylephrine-stressed cardiomyocytes. In conclusion, our in vitro data indicates that transplantation of L6 skeletal muscle mitochondria mitigates negative effects induced by phenylephrine in H9C2 cardiomyocytes. However, more rigorous in vivo studies are needed to determine if this is a suitable approach for disease mitigation.

Introduction: The femoropopliteal artery undergoes substantial axial compression, bending, torsion, and pinching during limb flexion. When an implanted stent does not accommodate these deformations, repetitive biomechanical mismatch may alter the vascular response to implantation and contribute to restenosis. We tested whether designing a peripheral stent to better accommodate physiologic limb-flexion deformation reduces the subsequent inflammatory and neointimal response. Methods: A nitinol stent was developed using multi-objective computational optimization to maintain arterial apposition while reducing wall stress and luminal pinching during physiologic deformation. Sixteen Yucatan minipigs were studied in independent 3- and 6-month cohorts (n=8 each). Each animal received the optimized stent in one limb and a commercial stent with representative biomechanical behavior contralaterally. CTA quantified in vivo limb-flexion deformation, while CT and histology assessed stenosis, neointimal accumulation, inflammatory-cell burden, SMA-positive tissue, and extracellular-matrix composition. Results: The optimized stent accommodated greater axial shortening than the commercial comparator at both 3 months (11.2{+/-}2.7% vs. 6.6{+/-}2.1%, p=0.003) and 6 months (13.7{+/-}4.4% vs. 6.8{+/-}2.3%, p=0.004). Intimal hyperplasia volume was lower with the optimized stent at 3 months (227.5{+/-}85.2 vs. 350.0{+/-}130.5 mm3, p=0.002) and 6 months (183.6{+/-}46.2 vs. 261.2{+/-}60.6 mm3, p=0.001), with significantly lower maximum, mean, and median stenosis at both timepoints. At 3 months, macrophage and total inflammatory-cell counts were 51% and 45% lower, respectively, with the optimized stent. Histologic tissue area was 28% lower at 3 months and 12% lower at 6 months. SMA-positive tissue fraction was higher with the optimized stent at both timepoints, whereas elastin, glycosaminoglycan, and collagen fractions were similar between devices. Discussion: Improved accommodation of limb-flexion deformation was associated with a smaller inflammatory and neointimal response to stent implantation through 6 months, while overall neointimal matrix composition remained largely unchanged. These findings provide in vivo evidence that biomechanical compatibility with the dynamic lower-limb environment can influence vascular healing and should be considered a mechanistic design criterion for peripheral artery stents.

Background: Pericoronary adipose tissue (PCAT) attenuation on coronary computed tomography angiography (CTCA) has emerged as a novel non-invasive biomarker of coronary inflammation and cardiovascular risk. The degree to which PCAT reflects local or systemic inflammation remains uncertain. We hypothesized that the presence, location and extent of PCAT would be associated with transcoronary or transcardiac cytokine gradient. Methods: This prospective cohort study involved 31 adults with stable coronary artery disease who underwent clinically indicated CTCA within 90 days of invasive coronary angiography. Patients with acute coronary syndromes or unstable angina were excluded. Blood samples were obtained from peripheral vein, coronary sinus, aortic root, and right coronary artery at time of cardiac catheterization. Plasma interleukin-6 (IL-6) and interleukin-1{beta} (IL-1{beta}) concentrations from each site were used to calculate transcardiac and transcoronary cytokine gradients. PCAT attenuation was measured using semi-automatic software by readers blinded to clinical and biochemical endpoints. Results: Participants were predominantly male (76%), aged 66.6 {+/-} 9.4 years, with a high prevalence of hypercholesterolemia (76%), hypertension (73%), and diabetes (36%). Mean PCAT attenuation was -74.8 HU (RCA), -70.3 HU (LCx), and -73.6 HU (LAD). Regression analyses showed no significant associations between PCAT attenuation and IL-6 gradients across any coronary territory (all p >0.40; R2 {approx} 0), including in plaque-free subgroup analyses. IL-1{beta} was below the assay detection limit in 81% of participants; analyses using non-parametric testing and logistic no association with PCAT attenuation. RCA (OR 0.96, 95% CI 0.88-1.06, p=0.46), LCx (OR 1.00, 95% CI 0.91-1.09, p=0.94), LAD (OR 0.99, 95% CI 0.90-1.08, p=0.81). Conclusion: In a cohort with predominantly stable coronary disease, PCAT attenuation was not associated with intracardiac or intracoronary IL-6 or IL-1{beta} gradients, including in plaque-free vessels. These findings suggest that PCAT attenuation may not reflect active cytokine-mediated coronary inflammation in stable disease.