Cardiovascular disease is a leading cause of morbidity and mortality among people with and without HIV. Among PWoH, cannabis has been associated with cardiovascular outcomes, including coronary artery disease, myocardial infarction (MI), and stroke. However, data on subclinical changes and other cardiovascular outcomes are limited among PWH. In this study, we examined the association of cannabis use and HIV with electrocardiogram (ECG) findings-evidence of MI, other abnormalities, and normal findings. Data from study visits between 2007 and 2017 from the MACS/WIHS Combined Cohort Study (N = 3610) were used. Descriptive statistics were derived, and unadjusted and adjusted odds ratios were estimated via baseline logistic regression. Most participants were PWH (n = 2272, 63%), and 28% reported cannabis use, with no significant difference in prevalence between PWH (27%) and PWoH (28%). Overall, 59% of participants had normal ECG findings. Cannabis use was not significantly associated with evidence of ECG abnormalities in unadjusted or adjusted analyses (aOR for MI: 1.02, 95% CI: 0.82 to 1.26, P = 0.85; aOR for other abnormalities: 1.02, 95% CI: 0.80 to 1.32, P = 0.86). Abnormal findings were more common in female participants than male participants (41% vs. 35%, P = 0.0002). Among male participants, PWH had higher odds of evidence of non-MI abnormalities compared with PWoH (aOR = 1.35, 95% CI: 1.01 to 1.81, P = 0.0464). Although cannabis use was not independently associated with evidence of ECG abnormalities, sex and HIV status are important determinants. Future studies should explore the role of cannabis metabolites and usage patterns in cardiovascular outcomes among PWH.

Background: The recent PREVENT-HF risk equations were developed to estimate 10-year risk of overall HF. While HF with preserved vs reduced ejection fraction (HFpEF; HFrEF) have common risk factors, distinct differences in risk conferred by older age, obesity, and coronary artery disease are known. In this context, we sought to evaluate the performance of PREVENT-HF equations relative to HFpEF vs HFrEF. Methods: We examined participants from 4 pooled community-based cohort studies: the Multi-Ethnic Study of Atherosclerosis (MESA), Framingham Heart Study (FHS) offspring exam 6, Cardiovascular Heart Study (CHS), and Prevention of Renal and Vascular End-stage Disease (PREVEND) study. We excluded those with ages <30 and >79 years, prevalent HF, prevalent CVD, and missing key clinical information. We compared the performance of the PREVENT-HF equation in predicting incident HFpEF vs HFrEF at 10 years using Uno’s C-statistics and area under receiver operating characteristic (AUROC). Results: Among 22,061 participants (age 59 ± 14 years, 54% women, BMI 27 ± 5 kg/m 2 ), 322 developed HFpEF and 464 HFrEF during a median follow-up of 10 years. The PREVENT-HF risk equation performed well for both HFpEF (c-statistic 0.81, 95% CI 0.80-0.83) and HFrEF (c-statistic 0.78 (95% CI 0.76-0.80), with similar improvement compared with age and sex alone (HFpEF: c-statistic 0.78, 95% CI 0.76-0.80; HFrEF: c-statistic 0.75, 95% CI 0.73-0.76, P<0.001 for delta for both). The AUROC remained stable across 1-10 years demonstrating consistently strong discrimination for both HFpEF and HFrEF. Time-dependent AUCs were generally higher for HFpEF compared with HFrEF, indicating slightly better discrimination for HFpEF across all time horizons ( Figure ). Conclusions: Our findings demonstrate overall similar performance of the PREVENT-HF risk model with respect to HFpEF and HFrEF. Future studies on subtype-specific risk models may improve upon current risk prediction tools for overall HF.

INTRODUCTION:Observational studies provide a signal that phosphodiesterase-5 inhibitors such as sildenafil are associated with lower mortality and ischaemic stroke during durable left ventricular assist device (LVAD) support. This study aims to determine the causal effects of sildenafil on platelet activation and circulating mediators of vascular remodelling during LVAD support. METHODS:We conducted a double-blind, randomized, placebo-controlled study to determine the effect of sildenafil on platelet activation and circulating mediators of vascular remodelling. Stable participants on LVAD support were assigned to sildenafil or placebo every 8 h for a 15-day period. Three primary endpoints were percent change in platelet activation by collagen, thromboxane (Tx) A2, and adenosine diphosphate (ADP). Secondary endpoints included changes in circulating mediators of vascular remodelling. RESULTS:Twenty participants were randomized. On day 15, those on sildenafil had lower collagen (-41%, -60 to -24, vs. -7%, -18 to 79, P = .038), but not TxA2 (-24%, -45 to -14 vs. 3%, -15 to 87, P = .112), and ADP (-5%, -70 to 25 vs. 31%, -29 to 242, P = .122) induced platelet activation compared to placebo. Endothelin-1 changed by -30% (-53 to 4) in the sildenafil group vs. -3% (-18 to 22) with placebo (P = .041). Angiopoietin (ang)-2 changed by -5% (-11 to -4) with sildenafil compared to 3% (-5 to 15) with placebo (P = .039), while ang-1 increased by 24% (17-54) with sildenafil and was -4% (-19 to -2) with placebo (P = .001), leading to a change in the ang-2/ang-1 ratio by -23% (-45 to -15) with sildenafil compared to 8% (-3 to 24) with placebo (P = .001). Hs-CRP and fibrinogen were unchanged between the groups. CONCLUSION:Fifteen days of sildenafil exposure modifies platelet activation and lowers mediators of vascular remodelling on LVAD support.

People with HIV (PWH) have an increased risk of developing cardiovascular disease (CVD). Our recent data demonstrated that the multi-isoform proinflammatory cytokine IL-32 is upregulated in PWH and is associated with arterial stiffness and subclinical atherosclerosis. However, the mechanisms by which IL-32 contributes to the pathogenesis of these diseases remain unclear. Here, we show that while the less expressed IL-32α isoform induces the differentiation of human classical monocytes into the calcium-resorbing osteoclast cells, the dominantly expressed isoforms IL-32β and IL-32γ suppress this function through the inhibition of TGF-β and induce the differentiation of monocytes into the calcium-depositing osteocalcin+ osteoblasts. These results aligned with the increase in plasma levels of osteoprotegerin, a biomarker of vascular calcification, and its association with the presence of coronary artery subclinical atherosclerosis and calcium score in PWH. These findings support a novel role for the proinflammatory cytokine IL-32 in the pathophysiology of CVD by increasing vascular calcification in PWH.

Background Calcific aortic valve disease (CAVD), and ensuing severe aortic stenosis (AS), is the foremost valvular disorder of aging, yet preventive therapies are lacking. A better understanding of the molecular underpinnings of aortic valve calcification (AVC) is necessary to develop pharmacologic interventions. Methods and Results We undertook large‐scale plasma proteomics in a cohort study of adults ≥65 years old, the CHS (Cardiovascular Health Study), to identify individual proteins associated with echocardiographic AVC and incident moderate/severe AS. Proteomics measurements were performed with the aptamer‐based SomaLogic platform of ~5000 proteins. Significant proteins were validated in a second cohort, the AGES‐RS (Age, Gene/Environment Susceptibility‐Reykjavik Study), which assessed AVC and AS by computed tomography. The potential causal associations of replicated proteins were tested in 2‐sample Mendelian randomization using identified cis protein quantitative trait loci in consortia having computed tomography‐quantified AVC or AS as outcomes. Six proteins showed Bonferroni‐corrected significant relationships with AVC in CHS. Three of these, CXCL‐12 (C‐X‐C chemokine ligand 12), KLKB1 (kallikrein), and leptin, replicated in AGES‐RS, of which the former 2 are novel. Only 1 protein, CXCL6, which showed a near‐significant association with AS in the replication cohort, was significantly (positively) associated with incident AS. Mendelian randomization analysis was conducted for KLKB1, CXCL12, and CXCL6, which supported a causal relationship for higher KLKB1 with lower AVC (beta=−0.25, P=0.009). Conclusions This study of older adults newly identified and largely replicated associations of 3 circulating proteins with calcific aortic valve disease, of which the relationship of plasma KLKB1 may have a causal basis. Additional investigation is necessary to determine if KLKB1 could be harnessed for calcific aortic valve disease therapeutics.

Introduction: The relationships among gut microbial alterations, host inflammation, and cardiac dysfunction remain understudied, particularly in the context of HIV. Hypothesis: We hypothesized that higher abundance of pro-inflammatory gut bacteria is associated with higher levels of host circulating inflammatory makers and cardiac dysfunction. Methods: We examined associations of gut microbial features (16S rRNA sequencing) with cardiac dysfunction (Echocardiography) in 973 women from the MACS/WIHS Combined Cohort Study. Cardiac dysfunction was defined as the presence of left ventricular systolic (LV ejection fraction<54%) or diastolic (ASE 2016 criteria) dysfunction. In a subset (n=397), we further integrated cardiac dysfunction-associated microbial features (Shotgun metagenomics sequencing) with serum proteomic inflammatory markers (Olink platform inflammation panel) in relation to cardiac dysfunction. Results: The potentially pathogenic bacteria Streptococcus, Eggerthella and Anaeroglobus , were positively associated with cardiac dysfunction, while the beneficial genera Roseburia and Alistipes were linked to lower odds of cardiac dysfunction ( Fig. 1A ). Results were consistent in women with and without HIV. These cardiac dysfunction-associated bacteria were associated with a number of circulating proteomic inflammatory markers ( Fig. 1B ). For example, the pathogenic Streptococcus was positively associated with the pro-inflammatory cytokines IL-8 and IL-6, the chemokine MCP-3 (linked to immune response and atherosclerosis), and the inflammatory mediator OSM (associated with vascular inflammation and heart failure). Proteomic inflammatory scores were generated for each genus based on their specific inflammatory marker profiles. The inflammatory score for Streptococcus was significantly associated with cardiac dysfunction ( Fig. 1C ). Associations between bacterial genera and cardiac dysfunction were attenuated after further adjustment for specific microbial associated inflammatory markers ( Fig. 1D ). Conclusion: Among women living with or at risk of HIV, we identified gut microbial features associated with cardiac dysfunction, with certain microbiota-related inflammatory markers partially explaining these associations.

BACKGROUND:The 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines introduced elevated natriuretic peptide (NP) levels as a criterion for defining stage B heart failure (HF), or pre-HF, to identify individuals at greatest risk for future HF. Given the known NP deficiency in obesity, we aimed to assess whether a single NP cut point would disproportionately up-classify individuals with versus without obesity to stage B HF. METHODS:Participants free of HF from 5 community-based cohorts were included. We examined the reclassification of individuals to stage B HF using the 2022 versus 2013 guidelines, stratified by obesity class. Cox proportional hazards models were used to assess the association of NPs with incident HF across obesity classes. RESULTS:Among 32 735 participants, 35% had normal weight, 40% were overweight, 17% had obesity class 1, and 8% had obesity class 2/3. When applying the 2022 versus 2013 criteria, the proportion of individuals up-classified to stage B HF using the NP criterion was 62% among those with normal weight, 51% for those overweight, 47% for individuals with obesity class 1, and 42% for individuals with obesity class 2/3. Over a median follow-up of 13 years, 3077 HF events occurred. Both higher NP and body mass index were associated with greater HF risk, as expected (P<0.0001 for both). Importantly, body mass index modified the association of NP with HF risk, such that higher NP concentration was associated with greater HF risk among individuals with lower body mass index. The optimal NT-proBNP (N-terminal pro-B-type natriuretic peptide) cut point to predict future HF risk was lower among individuals with obesity (80 pg/mL; 95% CI, 53-121) compared with normal-weight individuals (109 pg/mL; 95% CI, 80-157). CONCLUSIONS:The application of a single NP cut point resulted in fewer individuals with obesity being up-classified to stage B HF compared with normal-weight individuals. Adjusting NP cut points for individuals with obesity may improve the accuracy of HF risk stratification.

AIMS:Circulating ketone bodies (KB) are an important source of metabolic fuel for the myocardium under physiological and pathological conditions. Prior studies have linked KB levels with adverse cardiovascular outcomes. However, their relationship with atrial fibrillation (AF) risk remains unknown. The objective is to evaluate the association of KB levels with the risk of incident AF. METHODS AND RESULTS:This prospective, multicentre cohort study recruited patients without baseline AF from the Multi-Ethnic Study of Atherosclerosis (MESA) and the UK Biobank (UKB), respectively. Total KB levels were measured by nuclear magnetic resonance spectroscopy in both studies. The associations between total and individual KB and incident AF were evaluated using multivariable-adjusted Cox proportional hazard models. Prespecified interaction analyses were performed for smoking status, history of diabetes mellitus, history of hypertension, body mass index, and self-reported race/ethnicity (to represent a social construct). A total of 6783 participants [mean (standard deviation, SD) age 62 (10) years, 52% women, 38% White, 27.5% Black, 21.8% Hispanic, and 11.6% Chinese American] from MESA and 116 480 participants [mean (SD) age 56.5 (8) years, 54% women, 94% White] from the UKB were included. Over a median follow-up of 16.5 (10.3-17.4) years in MESA and 13.6 (12.8-14.4) years in the UKB, higher levels of total KB were associated with a higher risk of incident AF. In MESA, each doubling of baseline total KB levels was associated with a 1.08-fold increased hazard of incident AF on follow-up [95% confidence interval (CI): 1.00-1.16] after adjustment for confounding factors. Consistent results were obtained in a subgroup analysis stratified by different types of KB (β-hydroxybutyrate, acetoacetate, and acetone). There was a significant interaction with current smoking, such that per doubling of total KB levels was associated with a 1.32-fold increased hazard for incident AF in current smokers (95% CI: 1.08-1.61), but this association was not seen among former/never smokers [hazard ratio (95% CI): 1.05 (0.95-1.13)]. These results were replicated in the UKB. CONCLUSION:Higher concentrations of KB are associated with an increased risk of AF in predominantly healthy, community-based cohorts, acknowledging that many participants also had comorbidities such as hypertension and diabetes, particularly among smokers. Ketone bodies could serve as a potential biomarker for identifying populations at risk for AF.

Background MGP (matrix Gla protein) inhibits arterial calcification. Higher inactive MGP, in its dephosphorylated‐uncarboxylated (dp‐uc) form, is positively associated with vascular calcification, possibly portending adverse cardiovascular events. The objective of this study was to determine the association of dp‐ucMGP with incident cardiovascular disease (CVD) events and mortality in MESA (Multi‐Ethnic Study of Atherosclerosis). Methods MESA is a prospective cohort study of 45‐ to 84‐year‐old individuals enrolled between 2000 and 2002 with adjudicated outcomes through 2019. Dp‐ucMGP was measured at baseline in n=2663 participants with cardiac computed tomography at Exams 1 (2000–2002) and 5 (2010–2012). Age‐stratified Cox proportional hazard models were used to assess dp‐ucMGP with risk of all CVD (mean follow‐up 16±4 years), hard CVD (17±3 years), hard coronary heart disease (17±3 years), and all‐cause mortality (18±2 years). Results The youngest age quartile (45‐ to 53‐years‐old) with higher dp‐ucMGP levels (520–2934 pmol/L) had an increased risk of all CVD (hazard ratio [HR], 3.05 [95% CI, 1.58–5.90], P=0.001), hard CVD (HR, 2.85 [95% CI, 1.30–6.23], P=0.009), hard coronary heart disease (HR, 3.79 [95% CI, 1.31–10.95], P=0.014), and all‐cause mortality (HR, 2.73 [95% CI, 1.19–6.30], P=0.018) compared with those with dp‐ucMGP levels between 150 and 519 pmol/L in maximally adjusted models. Conclusions Younger individuals 45 to 53 years old with elevated dp‐ucMGP levels (≥520 pmol/L) had an increased risk of incident CVD, coronary heart disease, and all‐cause mortality. No association was seen in older adults. Additional studies are needed to better delineate the relationship of inactive MGP with incident CVD, coronary heart disease, and all‐cause mortality.

Background: Health disparities regarding heart failure (HF) incidence by age, race, sex at birth, socioeconomic status (SES) and their intersections remain under-researched. Methods: We harmonized data from nine cohorts (WHI, FOHS, ARIC, Health ABC, REGARDS, CARDIA, JHS, CHS, and MESA). We performed a descriptive study of the cohort calculating incidence rates (IR) and incidence rate ratios (IRR). Age was defined at time zero for each cohort. Participants who identified as Black or white were included. SES was categorized as low or high based on both an educational attainment of some college/vocational training or less and an income, using household size and Official Poverty Measure (OPM) less than 200%. We stratified by age (≤65 vs. >65 years) and evaluated IRs and IRRs, standardized by age (using 10-year intervals), sex, and race, depending on the comparison. Results: A total of 9700 incident HF cases occurred among 96000 participants free of HF at baseline followed up for a median of 13.7 years. Black participants had a slightly lower overall incidence of HF than Whites (IRR: 0.93, 95% CI: 0.89-0.97). We observed a higher risk of HF among Black participants≤65 years of age (IRR: 1.22, 95% CI: 1.14-1.31) compared to Whites. Conversely, Black individuals >65 years of age had a lower incidence than Whites (IRR: 0.75, 95% CI: 0.71-0.80). Women had a lower incidence of HF than men (IRR: 0.66, 95% CI: 0.63-0.68), overall and in age strata. Low, as compared to high SES individuals had a higher incidence of HF (IRR: 1.67, 95% CI: 1.60-1.74. Among those ≤65, low SES Black men (IRR: 2.16, 95% CI: 1.81, 2.56) and low SES White men (IRR: 1.60, 95% CI: 1.35,1.91) had the highest incidence rate of HF compared to high SES White men. Conclusion: Both Black and White low SES groups are at the highest HF risk. Effect modification by age is apparent for race differences but a limitation of present descriptive analysis is that competing risk of death is not accounted for. 10-year cumulative incidence risk and its differences based on race, sex, and/or SES by accounting for competing risk of death are planned.

Background: Resilience to aging diseases is observed in families with a history of extreme longevity. They may be protected by 3 potential genetic mechanisms: 1) carrying a lower disease risk burden as reflected in polygenic risk scores (PRS), 2) carrying rare disease-resilience genetic variants that are not included in the PRS, or 3) carrying protective genotypes that buffer the effect of common genetic risk factors in PRS. We investigated genetic resilience to CVD by comparing specific PRS in the offspring of parents with extreme longevity (OPEL) to offspring of usual survival (OPUS) in the UK Biobank. Methods: OPEL (n=9,584) was defined as having at least one parent in the top percentile of survival; father ≥ 95 years, mother ≥ 97 years. OPUS (n=180,042) was defined as both parents with usual survival; father < 84 years and mother < 87 years. PRS of cardiovascular outcomes were available from the UK Biobank. We considered time to cardiovascular events of myocardial infarction, stroke, and Ischemic Stroke (ISS) from the time of enrollment. Cox proportional hazards models were used to assess the effect of PRS and family history on men and women separately, with deprivation index as a covariate. Results: OPUS on average had higher cardiovascular PRS than OPEL. The difference was moderate in size (0.20 to 0.24) but statistically significant. However, PRS did not fully explain the significantly lower cardiovascular disease risk among OPEL. The hazard ratio (HR) of OPUS over OPEL remained highly elevated after we adjusted for PRS in the model (Table). Furthermore, we found no evidence that the effect of PRS was reduced in OPEL. Conclusions: Exceptional parental longevity is associated with reduced risk of cardiovascular disease in offspring of long-lived parents, independent of known polygenic risk scores. PRS explained only a small fraction of the protective effect observed in OPEL individuals. These findings suggest that rare or undiscovered genetic variants may underlie familial longevity and disease resilience, offering potential targets for future research on healthy aging and disease prevention.

Study Objectives:Circulating non-esterified fatty acids (NEFAs) have been associated with impaired glucose metabolism but their modifiable determinants remain uncertain. We sought to determine the association between objectively-measured sleep disordered breathing (SDB), which is also associated with dysglycemia, and NEFA levels among community-dwelling older adults. Methods:We analyzed 787 older adults who had total fasting and post-load NEFAs measured in 1996-1997 in the Cardiovascular Health Study and underwent polysomnography between 1995 and 1997 in the Sleep Heart Health Study. We used multivariable linear regression to model NEFAs as a function of four SDB parameters: apnea-hypopnea index, arousal index, hypoxemia, and slow-wave sleep, and tested formal mediating effects by insulin sensitivity estimated with the Gutt index. Results:The mean age of study participants was 77.5 ± 4.3 years. The proportion of females and non-Hispanic whites was 58.7 per cent and 84.2 per cent, respectively. We did not find statistically significant associations between any of the SDB parameters and fasting NEFAs, but higher amounts of slow-wave sleep were significantly associated in a linear fashion with lower total post-load NEFAs in unadjusted and adjusted models [adjusted: β = -0.004, SE = 0.001, p = .02]. In mediation analyzes, 10 per cent of the slow wave sleep-NEFA association was mediated by Gutt-estimated insulin sensitivity (p = .45 for the indirect effect). Conclusions:Among the SDB measures studied, only higher levels of objectively measured slow-wave sleep were significantly associated with lower levels of post-load NEFAs, although the underlying mechanism is uncertain. Establishing a causal link would make SDB interventions a promising target for NEFA regulation.

Circulating non-esterified fatty acids (NEFAs) have toxic effects on a variety of organs central to cardiometabolic disease and can cross the blood-brain barrier. Whether NEFAs associate with cognitive decline or dementia remains unknown.Circulating total NEFA levels were measured in 3,242 participants without dementia among older adults of the Cardiovascular Health Study (CHS) and related to adjudicated dementia over 6 years (n=456 cases) and annually assessed cognitive decline. For confirmation, we related circulating NEFAs to cognition assessed 10 years later among 4,361 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).In CHS participants, each SD higher NEFA levels were associated with a hazard ratio (HR) for all-cause dementia of 1.11 (95% CI: 1.01; 1.22). Baseline NEFA levels were also associated with more rapid decline in cognition over 6 years of follow-up. In MESA, circulating NEFA measurements were associated with lower cognitive scores measured 10 years later.’

OBJECTIVE:To evaluate the prevalence of pathogenic/likely pathogenic inherited cardiomyopathy variants and their association with heart failure in the (TOPMed) TransOmic for Precision of Medicine cohorts. METHODS:A retrospective cohort study using the TOPMed cohorts, including multi-ancestry US adults (≥18 years of age) with sequencing data, was conducted. Pathogenic/likely pathogenic inherited cardiomyopathy variant carrier status was determined based on ClinVar variants classified with two or more stars of evidence. Individuals without pathogenic/likely pathogenic variants were used as the reference group. The primary outcome was heart failure , adjudicated by an expert panel. Cox proportional hazards models assessed the association between carrier status and heart failure risk, adjusting for sex, study cohort, coronary artery disease, and genetic ancestry. Age was used as the timescale to account for the effect of variants since birth, and interval censoring was used to handle the uncertainty in the timing of heart failure events. RESULTS:Among 30,977 individuals (median age, 61.0 years; 71.3% female; 37.0% non-European ancestry), 229 (0.7%) were identified as pathogenic/likely pathogenic inherited cardiomyopathy variant carriers. There were 3,298 events of heart failure (35 in carriers and 3,263 in non-carriers). The heart failure incidence rate was higher in variant carriers (2.06 per 1000 person-years) compared with noncarriers (1.40 per 1000 person-years), with an adjusted hazard ratio of 1.68 (95% CI, 1.29-2.22). CONCLUSION:Approximately 1 in 140 US adults carry a cardiomyopathy variant, which increases heart failure risk. Targeted genetic screening may facilitate early identification and preventive interventions to reduce heart failure risk in carriers.

Purpose: We designed a study investigating the cardioprotective role of sleep apnea (SA) in patients with acute myocardial infarction (AMI), focusing on its association with infarct size and coronary collateral circulation. Methods: We recruited adults with AMI, who underwent Level-III SA testing during hospitalization. Delayed-enhancement cardiac magnetic resonance (CMR) imaging was performed to quantify AMI size (percent-infarcted myocardium). Rentrop Score quantified coronary collateralization (scores 0-3, higher scores indicating augmented collaterals). Group differences in Rentrop grade and infarct size were compared using the Wilcoxon Rank-Sum test and Fisher's Exact test as appropriate, with a significance threshold set at p <0.05. Results: Among 33 adults, mean age was 54.4 +/- 11.5 and mean BMI was 28.4 +/- 5.9. 8 patients (24%) had no SA, and 25 (76%) had SA (mild n=10, moderate n=8, severe n=7). 66% (n=22) underwent CMR, and all patients had Rentrop scores. Median infarct size in the no-SA group was 22% versus 28% in the SA group (p=0.79). While we did not find statistically significant differences, moderate SA had a trend toward a smaller infarct size (median 15.5%; IQR 9.23) compared to the other groups (no SA [22.0%; 16.8,31.8], mild SA [27%; 23.8,32.5], and severe SA [34%; 31.53], p=0.12). A higher proportion of moderate SA patients had a Rentrop grade >0, with a trend toward significance (moderate SA versus other groups: 62.5% versus 28%, p=0.08). Conclusion: Our study did not find statistically significant differences in cardiac infarct size and the presence of coronary collaterals by sleep apnea severity among patients with AMI. However, our results are hypothesis-generating, and suggest that moderate SA may potentially offer cardioprotective benefits through enhanced coronary collaterals. These insights call for future research to explore the heterogeneity in ischemic preconditioning by SA severity and hypoxic burden to guide tailored clinical strategies for SA management in patients with AMI.

BACKGROUND:Elevated levels of fibroblast growth factor 23 (FGF23) are associated with left ventricular hypertrophy and heart failure (HF) in individuals with and without kidney disease. Prior studies investigated the association of FGF23 and structural cardiac changes using conventional echocardiography, which is limited in its ability to detect early cardiac dysfunction. We investigated the relationship between FGF23 levels and cardiac dynamics using two-dimensional speckle tracking echocardiography (2D-STE), a novel imaging modality. METHODS:This was a cross-sectional analysis of data from the Cardiovascular Health Study, an ongoing prospective, population-based cohort study. The study population included 506 participants from CHS with available c-terminal (cFGF23) and intact FGF23 (iFGF23) measurements from 1996-1997 and 2D-STE images from 1994-1995. Forty two percent of the study population had CKD, defined as an eGFR < 60 ml/min/1.73m2, and the mean eGFR was 63 ml/min/1.73m2. The primary exposures were cFGF23 and iFGF23. The primary outcomes were six 2D-STE parameters performed at the 1994-1995 study visit. Linear regression models were used to examine the independent associations of FGF23 with six cardiac 2D-STE indices adjusting for demographics, cardiovascular risk factors, markers of kidney disease severity, and inflammation. RESULTS:cFGF23 levels were moderately correlated with iFGF23 levels in the CHS population. In fully adjusted models, cFGF23 was associated with left atrial dysfunction, but no other cardiac imaging parameter (β estimate -2.47; 95% Confidence Interval -4.68, -0.25; Table 2 ). iFGF23 was not associated with any of the six 2D-STE indices. Limitations include small sample size and noncurrent FGF23 measurements and 2D-STE imaging. CONCLUSIONS:In a limited sample of individuals enrolled in the CHS with c- and i-FGF23 measurements, we did not find consistent associations between FGF23 levels and 2D-STE parameters. Further investigations in a larger population with concurrent 2D-STE are needed to better understand the associations of FGF23 with early changes in cardiac mechanics.

Heart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment.