European Heart Journal

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems in sub-Saharan Africa is limited. We assessed the prevalence and correlates of multidomain HMOD in a geographically diverse population in Ghanaian adult. Methods: This cross-sectional secondary analysis of the Ghana Heart Study, which included 1,106 adults aged [&ge;]18 years from four Ghanaian regions between September 2016 and March 2017. Multidomain HMOD was determined using a pre-specified 9-domain composite score [&ge;]2, using an ESH/ESC 2018 guideline-informed selection of HMOD domain with baPWV instead of carotid-femoral PWV (cfPWV), due to device unavailability, and a threshold of [&ge;]14 m/s which was derived from analysis within the cohort. LODO sensitivity analyses were used to address issues of predictor-outcome circularity. We used logistic regression models to examine association between each predictor and multidomain HMOD, adjusted for age, systolic blood pressure, body mass index, presence of dyslipidaemia and smoking status. We also performed receiver operating characteristic (ROC) analysis to determine correlates of multidomain HMOD and compare the discriminative ability of each predictor against the others. Results: The mean age of participants was 46.9{+/-}17.2 years of which 58% were females. Multidomain HMOD was observed in 21.3% (235/1,106; zero-imputation lower bound 21.2%) of participants studied. There was a marked increase in the prevalence of multidomain HMOD with advancing age. Thus, while 8.6% (44/ 511) of adults<45years had multidomain HMOD, 20.6% (63/306) of 45- to 59-yr-olds and 44.4% (128/ 288) of individuals [&ge;]60 years had multidomain HMOD. HMOD-positive adults were older (59.1{+/-}8.4 vs 43.6{+/-}13.4y, p<0.001), had higher systolic BP (147{+/-}22 vs 123{+/-}21 mmHg, p<0.001), and had higher prevalence of hypertension (73% vs 28%, p<0.001) than their HMOD-negative counterparts. Using the primary (circular) specification, the strongest co-occurrence among all domains of HMOD was observed between peripheral artery disease and other HMOD (OR 41.2, 95% CI 20.7-81.6; p<0.001) followed by valvular burden and other HMOD (OR 14.4, 95% CI 4.8-43.8; p<0.001) and between ECG-LVH and other HMOD (OR 9.0, 95% CI 5.9-13.8; p<0.001) (S2 Table). After LODO correction to remove the self-inclusive co-occurrence between each predictor domain and the outcome (all p-values calculated in S2 Table), there was no significant association between the remaining 8 HMOD domains and the prevalence of multidomain HMOD (all p-values>0.05; S2 Table). This was not the case for baPWV, however. Thus, whereas the AUC of the best performing non-self-inclusive HMOD domain (ECG-CMD) only reached 0.688{+/-}0.016 (vs 0.827{+/-}0.008 for self-inclusive AUC calculated for the sake of interest only and provided as supplementary material), baPWV demonstrated good discriminative capacity (LODO-adjusted AUC = 0.702, 95% CI 0.654-0.751; S3 Fig). However, this AUC did not significantly exceed that for age alone (AUC = 0.752; {Delta}AUC = -0.050, 95% CI ?0.103 to 0.03; p=0.106; S3 Fig). Most importantly, after adjustment for SBP (a direct mediator in this pathway), the LODO AUC for baPWV did not exceed that for the single variable age (S3 Fig), indicating that baPWV does not possess independent discriminative power for multidomain HMOD above and beyond the information provided by SBP and age. Importantly, however, the adjusted OR for baPWV did not reach statistical significance (OR 1.094, 95% CI 0.986-1.213; p=0.091), suggesting that while circularity prevented validation of biological association, it did not prove the absence of association altogether. Sensitivity analysis (estimating total as opposed to direct effect) in which SBP was excluded from the regression model to estimate the total effect of baPWV on the prevalence of HMOD showed that, indeed, the OR for baPWV was significantly elevated (OR 1.261; 95% CI 1.150-1.382; p<0.001) in this specification. The effect of SBP, a direct mediator in this pathway, therefore apparently accounted for the non-significance in the original model entirely. Formal mediation analysis using the aforementioned specification yielded that SBP indeed mediated 69.9% (95% CI 41.3-128.8%) of the effect of baPWV on the prevalence of HMOD. Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in multiple HMOD domains. baPWV has good discriminative power for HMOD risk prediction in a Ghanaian adult population under the non-circular LODO estimand (LODO- adjusted AUC = 0.702; 95% CI: 0.654, 0.751) than the PCE (AUC = 0.496; 95% CI: 0.438, 0.555; {Delta}AUC = +0.206; p < 0.001). However, baPWV LODO AUC (0.702) was not statistically significantly greater than age alone (AUC = 0.752; 95% CI: 0.730, 0.774; {Delta}AUC = -0.050, p = 0.106). AUC for self- inclusive model was provided in supplementary materials for the reader's perusal, and that AUC (0.827; 95% CI: 0.794, 0.860) is circular. The prevalence of ECG-LVH was substantially higher (42%) than that of echocardiographic- LVH (5.9%) in this Black African population. These findings support further research on the role of baPWV for HMOD risk prediction in a Ghanaian adult population. Prospective validation of baPWV would be needed before clinical use.

Background: Echocardiographic assessment of tricuspid regurgitation (TR) remains valve-centric, and right-heart remodeling is not captured. Strain parameters carry prognostic value but are evaluated in isolation. Objectives: To develop integrated right atrial (RA) and right ventricular (RV) remodeling indices using automated echocardiography and assess their utility for TR severity grading, phenotyping, and prognostic stratification. Methods: We analyzed 8,231 patients with functional TR (mild-or-greater) from two tertiary centers (2023-2024) using an automated AI-based echocardiographic solution. The RA remodeling index (RA reservoir strain/RA volume index) and RV remodeling index (RV free wall strain/RV end-diastolic area) were derived automatically; patients were classified into four RA-RV remodeling phenotypes. The primary outcome was all-cause death or heart failure (HF) hospitalization. Results: During median follow-up of 19.3 months, the primary outcome occurred in 574 patients (7.0%). Both indices outperformed individual components for severe TR discrimination (RA: AUC 0.857 vs. 0.757; RV: 0.710 vs. 0.601; both P<0.05). After multivariate adjustment, the RA (HR per unit decrease, 1.27; 95% CI, 1.09-1.49; P=0.002) and RV remodeling indices (2.32; 1.76-3.06; P<0.001) were independently associated with the primary outcome; on mutual adjustment, only the RV index retained significance and provided incremental prognostic value ({Delta}C-index +0.010; NRI +0.237; both P<0.05). The four phenotypes showed progressively divergent risk (log-rank P<0.001), with combined remodeling (Low RA/Low RV) carrying the highest risk. Conclusions: Automated integrated RA and RV remodeling indices improved TR severity discrimination and enabled clinically meaningful right-heart phenotyping. The RV index conferred incremental prognostic value, whereas the RA index better reflected atrial-stage remodeling and disease burden.

Diastolic heart failure (HF) in primary cardiomyopathy is under-recognized and often diagnosed late, particularly in children. While recent studies have advanced understanding of HF with preserved ejection fraction in older adults, the prevalence, outcomes and molecular drivers of diastolic HF in pediatric and young adult cardiomyopathy remain poorly defined, where disease is typically driven by primary myocardial disease rather than acquired co-morbidities. The Canadian Cardiomyopathy Collaborative (C3) was assembled to leverage three of Canadas leading pediatric and adult cardiomyopathy biobank registries. Its flagship initiative, Artificial Intelligence to Model Diastolic Heart Failure (AID-HF), aims to integrate deep phenotyping - including comprehensive diastolic function assessment - with genomics, lipidomics and proteomics and apply machine learning to identify biological and clinical signatures that drive cardiac function and outcomes in cardiomyopathy. Harmonized phenotyping and multiomics protocols across registries will create a uniquely integrated national data resource and enable the goals of AID-HF i.e., earlier diagnosis and new therapeutic targets for diastolic HF in cardiomyopathy.

Background: Cardiovascular-kidney-metabolic (CKM) syndrome is a leading driver of cardiovascular morbidity and mortality. Whole-body molecular imaging is well-positioned to phenotype such syndromes, yet no imaging biomarker quantifies cumulative CKM burden. Bone scintigraphy with 99mTc-labeled bisphosphonates is widely performed and expanding with transthyretin amyloidosis assessment, under which Perugini grade 0 (absent cardiac uptake) is considered clinically benign. Objective: We hypothesized that the soft tissue-to-bone ratio (STBR) on these scans captures CKM burden and is an independent prognostic biomarker. Methods: We retrospectively analyzed 8,769 consecutive patients without cardiac uptake on 99mTc-DPD whole-body planar scintigraphy. The primary endpoint was all-cause mortality. Secondary endpoints were major adverse cardiovascular events (MACE) and heart failure hospitalization. Cox models were adjusted for ten established cardiovascular risk factors. Imaging-phenotype association (IPA) analysis mapped STBR to 1,210 clinical traits. STBR distribution across CKM stages was assessed in four prespecified analyses, including a non-cancer subgroup. Results: During a median follow-up of 5.1 years (IQR 2.5-8.2), 2,418 deaths occurred. Patients with prespecified STBR >0.5 (n=772, 8.8%) had significantly higher mortality (adjHR 1.73, 95% CI 1.54-1.94, p<0.0001) with an adjHR of up to 3.42 at higher thresholds (95% CI 2.05-5.42, p<0.0001). Hazard increased monotonically with STBR. STBR >0.5 was independently associated with MACE (adjHR 1.51, 95% CI 1.11-2.05, p=0.008) and heart failure hospitalization (adjHR 1.31, 95% CI 1.02-1.67, p=0.03). The association was robust across all prespecified subgroups and sensitivity analyses, including continuous STBR and patients without renal insufficiency. IPA analysis identified significant associations with type 2 diabetes, chronic kidney disease, chronic ischaemic heart disease, heart failure, atrial fibrillation, liver disease, amyloidosis, and hypertension among binary traits, as well as with CRP, NT-proBNP, BUN, cholesterol (inverse), and hemoglobin (inverse) among continuous parameters. STBR increased monotonically across CKM stages in all sensitivity analyses (all p<0.0001). Conclusions: STBR derived from routine 99mTc-DPD bone scintigraphy in patients without cardiac uptake is an independent prognostic imaging biomarker associated with cumulative cardiovascular-kidney-metabolic burden. As an opportunistic measure from scans already acquired at scale, STBR could refine CKM risk stratification at no additional cost, radiation, or acquisition time.

Background: Treatment response in heart failure with reduced ejection fraction (HFrEF) is assessed predominantly through left ventricular (LV) functional recovery, while longitudinal changes in left atrial (LA) hemodynamic burden remain underexplored. The LA stiffness index (LASI), derived from E/e' and LA reservoir strain, integrates LV filling pressure and LA compliance. Objectives: We investigated longitudinal trajectories of LASI and their prognostic implications in HFrEF treated with angiotensin receptor-neprilysin inhibitor (ARNI)-based therapy. Methods: From the multicenter STRATS-HF-ARNI registry, 1,039 patients with HFrEF who underwent serial echocardiography at baseline and one-year follow-up were classified into four LASI trajectory patterns dichotomized at the cohort median (1.22): persistently compliant (Group A, 46.8%), reverse remodeling (B, 28.5%), progressive stiffening (C, 3.2%), and persistently stiff (D, 21.6%). Results: On multivariable Cox regression, Group D was independently associated with elevated risks of all-cause mortality (adjusted hazard ratio [aHR] 2.68, 95% CI 1.57-4.59), cardiovascular mortality (aHR 4.36, 1.97-9.64), and HF hospitalization (aHR 3.83, 2.22-6.60), whereas Group B showed outcomes comparable to Group A. One-year LASI progression independently predicted all three outcomes. LASI elevation at one year predicted adverse outcomes even among patients with recovered LV function, and LASI trajectory classification provided incremental prognostic discrimination beyond conventional diastolic and strain parameters. Among sinus-rhythm patients (n=786), Group C exhibited the highest risk of new-onset atrial fibrillation. Conclusions: In HFrEF treated with ARNI-based therapy, LASI trajectories identify distinct prognostic phenotypes. Persistent LA stiffness confers adverse outcomes independent of LV recovery, and serial LASI assessment may enhance risk stratification beyond LV-centric metrics.

Rheumatic heart disease (RHD) is a leading preventable cause of cardiac death in children in low and middle-income countries. Nepals epidemiological data come mainly from auscultation surveys that miss subclinical disease, and no echocardiographic screening study had been conducted in Dhanusha district, a densely populated, low-income region in southern Nepal. We aimed to determine the prevalence of borderline and definite RHD among school children (6-16 years) in Dhanusha using the 2012 World Heart Federation (WHF) echocardiographic criteria, identify independent predictors, and quantify school-level clustering via the intraclass correlation coefficient (ICC). In a cross-sectional study (January 2023-December 2024), we screened 4,536 children from 8 public schools selected by four-stage cluster sampling. RHD was classified by WHF 2012 criteria; predictors were identified using random-effects logistic regression with school as random intercept. Ethical approval was from the Nepal Health Research Council (Protocol No. 155/2023). Overall prevalence of borderline or definite RHD was 18.7 per 1,000 (95% CI 15.1-23.0); definite RHD was 6.8 per 1,000 (95% CI 4.7-9.7) and borderline RHD 11.9 per 1,000 (95% CI 9.0-15.5). Prevalence was higher in girls (23.3 per 1,000) than boys (13.6 per 1,000; P=0.02), with the peak in girls aged 10-14 years (26.0 per 1,000). Subclinical disease accounted for 64.7% of cases; auscultation sensitivity was 35.3%. Mitral valve involvement predominated. Female sex was the sole independent predictor (OR 1.60, 95% CI 1.02-2.53; P=0.043). The school-level ICC was 0.19 (95% CI 0.07-0.44; P<0.001), giving a design effect of {approx}109. The echocardiographic RHD burden in Dhanusha (18.7 per 1,000) is the highest documented in Nepal. Two-thirds of cases are subclinical. Female sex and school attended explain a similar amount of variance in RHD risk, supporting school-targeted screening and informing sample size planning for future cluster-based surveillance.

IntroductionWith improved life expectancy, mitral annular calcification and calcific mitral stenosis (CMS) are increasing in prevalence. Echocardiographic evaluation of CMS is challenging due to acoustic shadowing and lack of CMS specific data on assessment of severity and outcomes. MethodsWe retrospectively identified patients with isolated CMS between the years 1/1/2010 and 4/5/2022. Severe CMS was defined as MVAcont [&le;]1.5 cm2. The primary outcome was a composite of all-cause mortality, mitral valve replacement (MVR) and ischemic stroke. Outcomes were collected through electronic health records with follow up through 8/15/2025. ResultsOur cohort included a total of n=717 patients with CMS of which n=140 had severe CMS. The mean age was 74{+/-}13 years and cohort was predominantly female. We found that MVAPHT consistently overestimates the MVA and is a poor predictor of severe CMS. Mean gradient >5 mm Hg had 81% specificity and 57% sensitivity for severe CMS. Over a median follow up of 36 (IQR 10.5-49.7) months, a total of n=331 (46.2%) patients died, and the primary composite outcome occurred in n=370 (51.6%). Although MVAcont [&le;]1.5 cm2 [aHR 1.3 (95% CI 0.9-1.8),p=0.29] was not an independent predictor of the primary outcome we found that mTMG was a significant independent predictor primary outcome [aHR 1.5 (95% CI 1.1-2), p<0.01]. Patients with MVAcont [&le;]1.5 cm2 and mean gradient [&ge;] 5 mmHg had the highest risk for the primary outcome [aHR 2 (95% CI 1.1-3.7),p=.02]. ConclusionPatients with severe CMS are older, female with a high burden of comorbidities and carry an overall poor prognosis. mTMG is an independent prognostic marker in these patients. Patients with MVA [&le;]1.5 cm2 and mTMG [&ge;]5 mmHg have the worst prognosis.

Importance Dilated cardiomyopathy (DCM) is a major cause of heart failure that disproportionately affects individuals of African genetic ancestry (AFR), among whom familial clustering of disease is also more pronounced relative to those of European ancestry (EUR). However, established monogenic DCM genes, identified primarily in EUR populations, explain a smaller proportion of DCM cases in AFR populations. A recent study identified a common AFR-specific nonsense variant in CD36 that accounts for a substantial burden of DCM in AFR. How the risk and population impact of this variant compare with those of established genetic causes of DCM is unknown. Objective To compare the contribution of a CD36 nonsense variant to DCM risk with that of truncating variants in TTN and pathogenic or likely pathogenic (P/LP) variants in other established DCM genes. Design, Setting, and Participants Multicohort genetic association study including AFR and EUR participants with exome or genome sequence and DCM case status from four datasets: All of Us, Million Veteran Program, Penn Medicine Biobank, and the DCM Precision Medicine Study. Exposure Carrier status for TTN truncating variants, P/LP variants in 11 high confidence DCM genes, and the CD36 nonsense variant (Y325*; 0, 1, or 2 copies). Main Outcomes and Measures Odds of DCM; prevalence of risk-variant carriers among DCM cases; and population attributable fraction (PAF) for DCM. Results Among 82,623 AFR individuals across four studies, the mean age was 53.4 years and 1,625 had DCM. CD36 Y325* risk-allele homozygotes had 4.8-fold (95% CI, 3.1-7.3) increased odds of DCM, and CD36 Y325* heterozygotes had 1.4-fold (95% CI, 1.2-1.7) increased odds. TTN truncating variants also conferred elevated risk of DCM in AFR participants (OR, 8.46; 95% CI, 5.3-12.3). Among AFR DCM cases, 2.5% were CD36 homozygotes, second only to TTN truncating variants (4.3%) and exceeding all other high-confidence DCM genes combined (1.5%). In population-level analyses incorporating both heterozygous and homozygous CD36 Y325* carriers, the population-attributable fraction for CD36 (9.0%) surpassed that of TTN truncating variants (3.6%). Conclusions and Relevance An ancestry-specific CD36 variant contributes more to DCM burden in AFR ancestry than established DCM genes, including TTN truncating variants, typically considered the most common genetic cause of DCM. These findings reshape the known genetic architecture of DCM in individuals of African ancestry and highlight the importance of representation in genomic research.

Background: Comprehensive assessment of hypertension-mediated organ damage (HMOD) across multiple organ systems remains limited in sub-Saharan Africa. We aimed to determine the prevalence and predictors of multidomain HMOD in a geographically diverse Ghanaian adult population. Methods: This secondary analysis of the Ghana Heart Study included 1,106 adults from four regions. Multidomain HMOD was defined as a pre-specified 9-domain TOD composite score ?2, based on the ESH/ESC 2018 guidelines framework. Logistic regression and ROC analysis were used to identify predictors and compare discriminative performance. Results: Mean age was 46.9 (17.2) years and 58% were female. Multidomain HMOD prevalence was 21.2% (235/1,106) and increased steeply with age: 8.6% (<45 years), 20.6% (45?59 years), and 44.4% (?60 years). Hypertension prevalence was 73% in the HMOD group versus 28% in those without HMOD (p < 0.001). The strongest independent associations were peripheral artery disease (OR 41.2), valvular burden (OR 14.4), and ECG-LVH (OR 9.0). baPWV showed superior discriminative performance (AUC 0.827, 95% CI 0.794?0.860) compared with the ASCVD Pooled Cohort Equations (AUC 0.466; ?AUC +0.351, DeLong test p < 0.001). Conclusions: One in five Ghanaian adults has hypertension-mediated organ damage in ?2 organ systems. baPWV is the strongest predictor and substantially improves risk stratification beyond conventional scores. These findings support the use of baPWV to guide hypertension management and HMOD assessment in West Africa.

Background: Left atrial (LA) stiffness index is a non-invasive echocardiographic parameter reflecting left ventricular filling pressure; however, its prognostic significance in hypertension remains unclear. We aimed to assess the prognostic value of the longitudinal change in LA stiffness index in patients with hypertension. Methods: We analyzed 1,442 hypertensive patients from the STRATS-HHD registry who underwent echocardiography including LA and left ventricular (LV) strain at baseline and 6-18 months. Patients were categorized into four groups according to longitudinal changes in LA stiffness index: normal-normal, improved, aggravated, and persistently stiff. The primary outcome was a composite of hospitalization for heart failure (HHF) and cardiovascular death, and secondary outcomes included HHF and incident atrial fibrillation. Results: Among 1,442 patients, 996 (69.1%) were classified as normal-normal, 173 (12.0%) as improved, 91 (6.3%) as aggravated, and 182 (12.6%) as persistently stiff. Over 5 years, aggravated (adjusted hazard ratio [aHR] 2.175, 95% confidence interval [CI] 1.048-4.515, P=0.037) and persistently stiff (aHR 2.935, 95% CI 1.697-5.076, P<0.001) groups were associated with a higher risk of the primary outcome, whereas the improved group showed a similar risk to the normal-normal group. Similar trends were observed for HHF and for incident atrial fibrillation. Adding LA stiffness index into a model including clinical factors and LV mass index improved risk prediction for composite outcomes. Conclusions: LA stiffness index was associated with clinical outcomes in hypertensive patients, with longitudinal changes providing additional prognostic information. Assessment of its trajectory may further refine risk stratification in patients with hypertension.

Background: Concomitant arrhythmogenic right ventricular cardiomyopathy (ARVC) and mitral valve prolapse (MVP) has only been described in case reports. Little is known about genetic and phenotypic characteristics of these patients. Objective: To describe the prevalence, genetics, and imaging characteristics of MVP in ARVC patients. Methods: We identified 111 definite ARVC cases through medical record review, arrhythmia/cardiomyopathy targeted gene panels, and contrast cardiac magnetic resonance data. MVP was diagnosed on echocardiography as mitral leaflet displacement greater than 2 mm above the annular plane in systole, with borderline MVP defined as less than or equal to 2 mm. Results: We found MVP/borderline MVP in 14% of ARVC patients. Cardiac arrest occurred in 20% of those with MVP/borderline MVP compared to 16% without valve abnormalities. Among 69 ARVC patients with identified genetic variants, PKP2 mutations were highly prevalent (64%), particularly in those with MVP (83%). Most MVPs had posterior prolapse (73%) and trace/mild mitral regurgitation (87%). None had mitral annular disjunction. ARVCs with MVP had higher LV mass (93 vs. 75 g/m2, p = 0.02) and a higher prevalence of LV wall motion abnormalities (27% vs. 5%, p = 0.02) compared to ARVCs without valve abnormalities. Conclusions: MVP is prevalent in ARVC and characterized by PKP2 variants in most cases. Typical features of arrhythmic MVP like bileaflet involvement and annular disjunction are rare in ARVC with MVP; features of arrhythmogenic left-sided cardiomyopathy (increased LV mass index and wall motion abnormalities) are more common. Further studies are needed to understand the role of MVP in arrhythmic risk stratification of ARVC.

Background: Traditional heart rate (HR) adjusted QT correction (QTc) formulae often fail to eliminate the inverse HR-QT interval relationship, particularly in pediatric patients. In this study, we optimized our previously published adaptive QTc (QTcAd) formula by including additional demographic variables and broadening the pediatric age range. We tested the hypothesis that QTcAd improves congenital long QT syndrome (congenital LQTS) detection performance and reduces erroneous classifications across pediatric cohorts. Methods: We retrospectively analyzed 8,306 ECGs from 4,556 cardiovascular disease (CVD)-free pediatric patients. For neonatal patients (1-30 days old), we derived daily QTcAd parameter values. For older patients, we developed regression models to estimate QTcAd parameters (mean Heart Rate (HR) = -15.9ln(days) + 219; |m| = 0.0001(days) + 1, where |m|=absolute HR-QT regression slope). To support LQTS screening, we constructed dynamic QTcAd thresholds by estimating age-specific reference limits. Diagnostic performance was tested in a clinically confirmed LQTS cohort (n=137), and further evaluated in the Pediatric Heart Network (PHN; n=2,394) and Emergency Department (ED; n=2,002) cohorts. Results: Using the confirmed LQTS cohort as the event population and the CVD-free cohort as the non-event population, QTcAd demonstrated higher sensitivity than QTcB (92% vs 46.7%). QTcAd maintained high specificity (96.9% vs 98.9%), which resulted in a higher Youden index (0.889 vs 0.456). In the PHN healthy cohort, both QTc formulae classified the majority of individuals as normal (QTcAd 95%; QTcB 98.2%) indicating few false-positives. In the ED cohort, QTcAd reduced borderline/prolonged QTc classifications requiring follow-up, yielding 270 fewer repeat-testing triggers than QTcB. We developed a publicly accessible calculator to compute QTcAd and classify congenital LQTS risk. Conclusion: We developed and validated an enhanced QTcAd formula for pediatric patients. QTcAd-based-age-adjusted dynamic thresholding improved performance for congenital LQTS screening, while maintaining high specificity. This reduces false-positive LQTS classifications and repeat ECGs, thereby decreasing unnecessary downstream clinical evaluation.

Background: Primary aldosteronism (PA) testing is recommended for patients with resistant hypertension but remains underused, and evidence linking aldosterone-targeted therapy to improved cardiovascular and renal outcomes is limited. Methods: In a nationwide cohort of patients with resistant hypertension between 2001 and 2022, we assessed PA testing and subsequent mineralocorticoid receptor antagonist (MRA) use and adrenalectomy. Among tested patients, time-dependent Cox models were used to assess associations between treatment exposure and mortality, major adverse cardiovascular events (MACE) and renal outcomes. Results: Among 254,338 patients, only 2.0% were tested for PA. Tested patients had a higher prevalence of hypokalemia and cardiometabolic comorbidities. In the overall tested population, MRA use was not associated with lower risks of cardiovascular or renal outcomes. However, when testing resulted in an established PA diagnosis, the use of both MRA (hazard ratio [HR] 0.60, 95% CI 0.42-0.86) and adrenalectomy (HR 0.33, 95% CI 0.20-0.54) were associated with a reduced risk of MACE compared with no aldosterone-targeted therapy. Similar results were observed regarding mortality. Adrenalectomy was associated with lower risk of MACE (HR 0.55, 95% CI 0.30-0.99), all-cause mortality (HR 0.52, 95% CI 0.29-0.93) and renal outcomes (HR 0.37, 95% CI 0.17-0.80) compared with MRA in patients with a diagnosis of PA. Conclusions: PA remains markedly underrecognized in resistant hypertension. Among patients with resistant hypertension who did undergo PA testing with establishment of a PA diagnosis, aldosterone-targeted therapy resulted in lower risk of adverse cardiorenal outcomes and death when compared to conventional antihypertensive therapy.

BackgroundImpaired myocardial metabolism is a defining feature of heart failure, but many defective pathways and mechanisms remain to be identified. Prior studies find phosphoglycerate kinase and its synthesized product 3-phospho-glycerate required for the serine synthetic pathway (SSP) are reduced in human HFpEF myocardium. As serine is also provided exogenously, the impact of SSP reduction is uncertain. Here, we tested if and how SSP decline coupled to phosphoglycerate dehydrogenase (PHGDH) impacts cardiomyocyte (CM) and whole heart metabolic remodeling and stress responses. MethodsStudies were performed in isolated CMs and mice with CM-selective knock-down of PHGDH. Using pharmacological inhibition or genetic silencing of PHGDH, we tested their impact on CM one-carbon metabolism pathways, cell hypertrophic responses, mitochondrial respiration, and in vivo functional, structural, and metabolic adaptations to pressure-overload stress. ResultsIn CMs, PHGDH inhibition caused dose-dependent serine depletion linearly coupled with cytotoxicity, accompanied by NAD/NADH and GSH/GSSG imbalance, reduced ATP, and disruption of one-carbon and nucleotide metabolites. Stable-isotope tracing revealed distinct metabolic fates of glucose-derived (SSP) versus exogenous serine. Exogenous serine did not rescue PHGDH-deficient CMs, whereas combined ribose and an anti-oxidant (DTT) attenuated injury and reduced nucleotide pools. PHGDH suppression reduced amino acid abundance, impaired nascent protein synthesis, and blunted endothelin-1-induced hypertrophic and mitochondrial respiration. In vivo, cardiomyocyte-specific PHGDH heterozygous mice (PHGDH+/-) had no basal phenotype, but amplified chamber dilation, dysfunction, fibrosis, and mortality 4 weeks after transverse aortic constriction (TAC). Corresponding increases in amino acids, one-carbon metabolites, nucleotides, and TCA-cycle intermediates in wild-type TAC hearts were significantly blunted in PHGDH+/- hearts. ConclusionsCardiomyocyte SSP is a critical regulator of redox balance, one-carbon metabolism, purine synthesis, amino acid homeostasis, and growth-related pathways required for cardiac adaptation to pressure overload. It is non-redundant with exogenous serine by providing distinct influences on key metabolic pathways and is a potential therapeutic target.

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.

Patients with Fontan circulation face evolving risk for cardiovascular morbidity and mortality, yet the interplay between cardiac function, vascular properties, and circulating proteins is incompletely defined. We hypothesized that biochemical biomarkers and multimodal cardiovascular profile differ significantly between Fontan patients and controls, and that selected markers may serve as predictors of reduced single ventricle function. We conducted a prospective observational study at a tertiary pediatric heart center including 31 individuals with Fontan circulation and 52 matched controls. Cardiac function was assessed by echocardiography; vascular phenotyping included carotid intima-media thickness, central and peripheral blood pressure, augmentation index corrected for heart rate, carotid-femoral pulse wave velocity, aging index, and reactive hyperemia index. Compared to controls, the Fontan group had increased pulse wave reflection and central systolic pressure as well as decreased echocardiographic markers of systolic and diastolic function, while pulse wave velocity and other vascular parameters were not significantly different between the groups. Levels of 92 circulating cardiovascular biomarkers were quantified in a subset of 25 of the Fontan cohort and 81 controls using a proximity extension assay. Twenty-two biomarkers differed significantly in the Fontan group compared to controls, including FGF23, REN, HAOX1, and IL17D. Levels of several of these biomarkers correlated with patient age. Most importantly, HAOX1 (a peroxisomal oxidase linked to redox metabolism) and FGF23 (a bone-derived hormone regulating phosphate and vitamin D homeostasis) correlated negatively with ejection fraction within the Fontan group. By contrast, BNP was not associated with cardiac function in the Fontan group. None of the biomarkers correlated with central arterial parameters. In summary, central arterial hemodynamics and biomarkers such as FGF23 and HOAX1 may improve monitoring of cardiovascular function in single ventricle patients with Fontan circulation.

Background World Symposium on Pulmonary Hypertension (WSPH) Group 2 pulmonary hypertension (PH) is a clinically integrated phenotype attributed to left heart disease, whereas pre- versus post-capillary classification is operationalized primarily by pulmonary capillary wedge pressure (PCWP). Although current recommendations emphasize contextual interpretation and provocative testing for intermediate PCWP values, the relationship between PCWP-based classification and underlying phenotype has not been systematically evaluated. We aim to quantify phenotype-hemodynamic discordance across the PCWP spectrum and evaluate a staged physiology-guided framework incorporating inhaled nitric oxide (iNO), ventricular geometry, and provocative testing. Methods We studied 1,032 participants from the NHLBI-sponsored PVDOMICS cohort with multidisciplinary adjudicated phenotypes integrating clinical, imaging, physiologic, and hemodynamic data. Stage-specific PCWP thresholds classified pre- versus post-capillary physiology at rest, during iNO, and during provocation (fluid challenge or invasive cardiopulmonary exercise testing [iCPET]). Echocardiographic right ventricular-to-left ventricular (RV/LV) ratio was evaluated as a marker of ventricular interdependence. Restricted cubic spline and staged concordance analyses defined certainty-based PCWP ranges and incremental diagnostic yield. Results Adjudicated Group 2 phenotype was present in 37.0% of participants. Resting PCWP demonstrated good discrimination (AUC 0.86), but substantial bidirectional phenotype-hemodynamic discordance persisted across intermediate PCWP ranges. At a resting PCWP of 12 mmHg, 25% of participants classified as pre-capillary had adjudicated Group 2 PH, whereas at 18 mmHg, 35% classified as post-capillary remained discordant non-Group 2. Concordance did not approach 90% until PCWP values were <9 mmHg or >24 mmHg. Dynamic testing incrementally improved concordance within these overlap zones. Nearly half of adjudicated Group 2 PH participants (46.5%) were not identified by resting PCWP alone; incorporation of iNO and provocative testing increased cumulative Group 2 identification by 63.4% and improved sensitivity from 79.9% to 83.7%. Model discrimination improved from an AUC of 0.863 to 0.908 (likelihood-ratio P<0.001). iNO increased PCWP in discordant Pre/G2 participants, unmasking latent left-sided limitation, while lowering PCWP in discordant Post/NonG2 participants, consistent with ventricular interdependence. RV/LV ratio [&ge;]0.94 reduced discordant Post/NonG2 classification by 70.5%, and incorporation of PCWP/cardiac output slope improved physiologic specificity during exercise. Conclusions Group 2 PH is a dynamic, load-dependent phenotype inadequately characterized by resting PCWP alone. Intermediate PCWP values represent continuous probabilities of bidirectional discordance rather than discrete diagnostic states. A staged physiology-guided approach integrating iNO, ventricular geometry, and provocative testing improves concordance between hemodynamic classification and clinically integrated phenotype assignment.

Background: Aortic stenosis (AS) is a progressive valvular disease associated with poor prognosis once symptoms develop, yet routine echocardiographic screening is impractical. While artificial intelligence (AI)-based electrocardiogram (ECG) models have shown promise for AS detection, it remains unclear whether they primarily reflect conventional left ventricular hypertrophy (LVH) voltage criteria or capture additional ECG features. Methods and Results: We developed a deep learning model using 244,816 ECGs from 51,713 patients across six academic institutions in Japan (CLIDAS database). AS labels were derived from inpatient Diagnosis Procedure Combination (DPC) codes. The model achieved an area under the receiver operating characteristic curve (AUC) of 0.849 (95% confidence interval 0.832-0.865) in the independent test cohort, with consistent performance across institutions, sex, and age. At a threshold of 0.1, sensitivity was 79.1%, specificity was 73.9%, and negative predictive value (NPV) was 98.0%. Conventional LVH voltage criteria (Sokolow-Lyon AUC 0.706; Cornell AUC 0.692) showed lower performance, and adding them to the AI model conferred no incremental benefit (AUC 0.849 vs. 0.847). Gradient-weighted class activation mapping (Grad-CAM) revealed predominant attention around QRS complexes in limb leads, beyond regions typically assessed in LVH evaluation. Conclusions: This multicenter AI-ECG model demonstrated strong discrimination for AS and captured ECG features beyond conventional LVH voltage criteria. The high NPV supports its use as a rule-out pre-screening tool.

Introduction: Calcific aortic stenosis (CAS) is a progressive valvular disease characterized by lipid accumulation, inflammation, and osteogenic remodeling. Emerging evidence implicates gut microbiota-derived metabolites in cardiovascular pathology, yet their contribution to valvular disease remains poorly defined. The aim of this study was to investigate gut microbiota and metabolite signatures in patients with CAS and explore causal relationships using Mendelian randomization (MR). Methods: In a prospective cohort of 54 patients with CAS and 41 age, sex, BMI-balanced non-CAS controls, we performed integrated microbiome and metabolomic profiling. Gut microbial composition was assessed by 16S rRNA sequencing, and circulating levels of tryptophan derivatives, short-chain fatty acids, bile acids, and TMA/TMAO-related metabolites were quantified. MR analyses were performed to assess causal contributions of key metabolic and inflammatory markers to CAS. Results: Baseline characteristics were comparable between groups. CAS patients exhibited a distinct tryptophan metabolic profile, characterized by higher concentrations of inflammatory kynurenine-pathway metabolites and lower indole-3-sulfate. With consistent effect sizes despite modest statistical significance after multiple testing correction. Pathway-level analyses supported preferential routing of tryptophan toward inflammatory host metabolism. In contrast, global microbiota diversity and overall community structure were preserved. However, CAS was associated with depletion of specific Firmicutes taxa, including Eubacterium coprostanoligenes, a key cholesterol-converting bacterium mediating intestinal cholesterol-to-coprostanol transformation. MR analyses suggested LDL cholesterol and lipoprotein(a) as upstream triggers of CAS, whereas ALPL and tryptophan/kynurenine metabolites appear downstream and might reflect systemic inflammation and local metabolic consumption. Sex-stratified analyses revealed enhanced kynurenine pathway activation in males, whereas females exhibited relatively higher TMAO and indole-related metabolites. Conclusion: CAS is characterized by a focused gut-host metabolic reprogramming defined by inflammatory tryptophan catabolism and loss of cholesterol-transforming microbial functions, rather than global dysbiosis. These findings identify a potential gut, valve metabolic axis contributing to valvular calcification, with potential sex-specific effects.

Background Myocardial remodeling precedes symptomatic heart failure, which is important to detect early. We assessed feasibility and clinical correlates of a novel integrated assessment of myocardial remodeling in a large rural cohort in the Southeastern United States. Methods Echoes were obtained with AI assistance (Caption guidance) in 3100 adults in the NHLBI-funded RURAL cohort study. Of those, 1895 had quantifiable global longitudinal strain (GLS), left ventricular mass (LVM), and left atrial volume (LAV). LV-LA Health was based on a simple count of sex-specific abnormalities (0-3), indexed to body surface area (BSA) or height (Table 1). Relationships with demographics and risk factors were compared with Spearman correlation and Mantel-Haenszel tests, with moderate and severe results combined. Results Median (IQR) age was 49 (40-58). Impaired LV-LA Health is common even in a low PREVENT cardiovascular (CV) risk population (median 10-year risk 3.3%; 25th, 75th 1.2,7.2) with preserved ejection fraction (EF; 60%; 57,62). The prevalence of abnormalities differed greatly by indexing method: 18.2% with BSA (15.1% mild; 3.1% mod/severe) vs 51% with height (38.3% mild; 12.7% mod/severe) (Figure 1). LV-LA impairment increased with age, PREVENT CV risk score and cardiovascular risk factors (hypertension, diabetes, dyslipidemia, obesity); all p<0.001. Impairment was more common in Black vs White people (p<0.001) and differed by sex only with height indexation. Conclusions A novel LV-LA health composite of routinely acquired echocardiographic measures identifies substantial subclinical cardiac remodeling in a middle-aged rural community cohort, not detected by PREVENT score or ejection fraction. This is the first application of this framework in a large, unselected community sample. Indexation method affects prevalence, with BSA likely underestimating risk in adiposity-enriched populations. Findings suggest a high rural burden and longitudinal evaluation with future CV events is ongoing.