When assessing the causal effect of an exposure on two or more outcomes in an observational study, a linear combination of outcomes may lessen the sensitivity of a test of the global null hypothesis to potential unmeasured biases. While all linear combinations of scored outcomes can be considered using Scheffe projections or constrained variants thereof, finding the combination that minimizes sensitivity to unmeasured biases requires corrections for multiple testing, which can erode power, especially when many outcomes are of interest. To mitigate this issue, we propose splitting the sample into a planning sample to identify an optimal linear combination and an analysis sample to conduct inference. We provide a novel characterization of the set of linear combinations for which this approach is guaranteed to achieve the same asymptotic power as full-sample alternatives and conduct extensive simulation studies that demonstrate enhanced power in finite samples. Finally, we apply our method to investigate the effects of poverty on the emergence of cardiovascular disease risk factors in children and adolescents. We discover adverse consequences on outcomes related to body composition, physical activity, and tobacco exposure. Although the impact of poverty on elevated tobacco exposure shows some robustness to unmeasured confounding, the other findings remain sensitive to potential biases.

Lipoprotein(a) [Lp(a)] remains a well-established, genetically determined predictor of cardiovascular risk due to its pro-atherogenic and pro-thrombotic effects. This review examines the paradoxical relationship between Lp(a) and metabolic dysfunction-associated steatotic liver disease (MASLD), where Lp(a) levels decline with advanced fibrosis despite persistently elevated cardiovascular disease (CVD) risk. Studies consistently show an inverse association between Lp(a) and MASLD severity. Evidence suggests that lower Lp(a) levels are a consequence of hepatic dysfunction rather than protective against cardiovascular disease. Additionally, selective hepatic insulin resistance increases VLDL production, diverting apoB100 from Lp(a) assembly, while insulin directly suppresses apolipoprotein(a) synthesis. Genetic variants linked to MASLD may further impair hepatic lipid secretion and reduce Lp(a). Lower Lp(a) levels in MASLD likely reflect impaired hepatic synthetic function rather than reduced cardiovascular risk. Recognizing this paradox may improve risk stratification and interpretation of Lp(a) in patients with MASLD

Objective Although body mass index (BMI)-defined non-obesity metabolic dysfunction-associated steatotic liver disease (MASLD) predicts poor prognosis, the role of visceral adiposity and weight-based phenotypes is unclear. This study aimed to examine the clinical correlates of four unique MASLD phenotypes based on BMI and waist-to-height ratio (WHtR) and to assess the prognostic value of this classification with respect to mortality. Design Population-based cross-sectional study with prospective mortality follow-up. Setting Nationally representative US population derived from the National Health and Nutrition Examination Survey (NHANES), 2007–2018. Participants 6300 adults with MASLD, sampled from NHANES 2007 to 2018. Methods Participants were allocated into four phenotypes based on obesity/lean and central adiposity status. Obesity was defined as BMI≥30 kg/m², while those without obesity were determined as lean. High central adiposity was defined as WHtR≥0.6. Primary outcome measure The primary outcome was all-cause mortality. This was ascertained through National Death Index linkage with follow-up censored at 31 December 2019. Results Among adults with MASLD, 72.1% had obesity with high central adiposity (mean follow-up: 6.9±3.5 years). The non-obesity, high central adiposity phenotype (9.6%) exhibited the highest rates of hypertension (60.2%), type 2 diabetes (31.8%) and chronic kidney disease (23.3%). This phenotype portended the poorest 6-year survival (p<0.001) and was independently associated with higher all-cause mortality (adjusted HR (aHR) 3.1, 95% CI 1.3 to 7.7). A J-shaped association was observed between BMI and mortality, with increasing WHtR linked to elevated risk. Conclusion Non-obesity MASLD with high central adiposity confers the poorest survival and cardiometabolic burden.

Background: Cardiovascular disease remains the leading cause of death worldwide. Primary prevention focuses on lowering the risk of a first cardiovascular event in individuals without established disease. Despite its widespread use, uncertainty persists on how different drug-based strategies compare in preventing major adverse cardiovascular events. This analysis aims to synthesize current evidence to address these gaps. Methods: A systematic review of randomised controlled trials was performed in primary prevention populations. Eligible trials evaluated cardiovascular pharmacotherapies, reported clinical cardiovascular outcomes (2-, 3-, or 4-point MACE), and excluded participants with prior myocardial infarction. Study-level hazard ratios with 95% confidence intervals were synthesised using a random-effects frequentist network meta-analysis. Treatment effects were estimated relative to placebo, ranked using SUCRA values and P-scores, and assessed robustness through sensitivity analyses addressing heterogeneity in outcome definitions. Results: Across outcomes, pharmacological treatments were compared with historical standard-of-care (SOC) to access effectiveness. For overall 3-point MACE, PCSK9 inhibitors ranked highest (HR: 0.511, 95%CI: 0.342-0.765, p<0.01), followed by statin-fibrate combination therapy (HR: 0.627, 95%CI: 0.417-0.945, p=0.026) and bempedoic acid (HR: 0.640, 95%CI: 0.413-0.991, p=0.045). Current SOC and omega-3 fatty acids (FA) showed modest effects. When 3-point MACE outcomes were stratified by ASCVD risk, omega 3 FA exhibited a stronger risk reduction than statin-fibrate combination, bempedoic acid and current SOC in the high-risk cohort. For 2-point MACE, current SOC was the only therapy associated with a significant risk reduction (HR: 0.75, 95%CI: 0.598-0.941, p=0.013). For 4-point MACE, PCSK9 inhibitors demonstrated the largest relative benefit with ezetimibe, current SOC and bempedoic acids also showing significant effects. Conclusion: Across all three MACE definitions, PCSK9 inhibitors demonstrate consistent and significant benefit, reinforcing their central role in primary cardiovascular prevention. Overall, these findings support a targeted, risk-based approach to primary prevention, informing the rational selection of lipid-lowering therapies to optimize cardiovascular risk reduction.

AIMS:Chronic inflammation has been implicated in renal decline, but long-term population-based data are limited. We aimed to evaluate the associations between baseline inflammatory markers [interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP)] and long-term renal function decline and incident chronic kidney disease (CKD). METHODS AND RESULTS:This prospective cohort study included participants of the Multi-Ethnic Study of Atherosclerosis (MESA) with estimated glomerular function (eGFR) > 60 mL/min/1.73 m2 and available IL-6 and hsCRP measurements at visit 1. Outcomes included longitudinal changes in eGFR and log-transformed urinary albumin-creatinine ratio [log(UACR)] through visit 5, and incident CKD through 2018. Mixed-effect linear regression models assessed renal function decline. Fine-Gray regression was used to model incident CKD, accounting for competing mortality. Among 4680 (hsCRP) and 4580 (IL-6) participants (median follow-up for incident CKD: 16.8 years), higher IL-6 was consistently associated with faster eGFR decline [tertile 3 (T3; vs. T1): -0.32 mL/min/1.73m2/year (95% CI: 0.23-0.42 mL/min/1.73m2/year), P < 0.001] greater log[UACR] increase [T3: 6.67 × 10-3 unit/year (2.95 × 10-3-10.39 × 10-3 unit/year), P < 0.001], and higher CKD incidence [T3: sub-hazard ratio 1.65 (1.23-2.20), P = 0.001]. Contrastingly, hsCRP exhibited weaker and inconsistent associations. CONCLUSION:Elevated IL-6 predicts greater long-term eGFR decline, worsening albuminuria, and higher CKD risk. These results highlight IL-6's potential as a renal risk biomarker, meriting further study in cardiovascular-kidney-metabolic (CKM) syndromes. LAY SUMMARY:This study investigated how inflammation is related to deteriorations in kidney function and the occurrence of chronic (long-term) kidney disease (CKD), both of which are critical components of the cardiovascular-kidney-metabolic (CKM) syndrome. Using data from the Multi-Ethnic Study of Atherosclerosis, over 4500 volunteers had inflammation markers measured and were followed for almost 17 years. We found that higher levels of inflammation were correlated with worse deterioration in kidney function and higher risks of developing CKD. These findings reaffirmed the pivotal role of inflammation in the long-term development of kidney disease. This study highlights the need for further investigation of how inflammatory markers can be used to predict future heart and kidney disease, especially as new drugs to treat inflammation are being developed.

Background: The Pooled Cohort Equation (PCE), a central tool in preventive cardiology, was developed without representation of Hispanic/Latino adults, a diverse and heterogenous group. We leveraged HCHS/SOL, the largest population-based study of Hispanic/Latinos, to evaluate performance of the PCE, stratified by genetic ancestry, self-reported background group and race. Methods: We included 5416 participants aged 44–74 years without prior ASCVD, statin use, diabetes, or LDL-C ≥190 mg/dL. Ten-year atherosclerotic cardiovascular disease (ASCVD) risk (2008–2019) was calculated using race-specific (non-Hispanic Black [NHB] and non-Hispanic White [NHW]) PCEs, with ASCVD events (myocardial infarction and stroke) adjudicated using hospital records. Genetic ancestry (European, African, and Amerindian) was estimated using ADMIXTURE. Kaplan-Meier estimates determined observed ASCVD event probabilities. Calibration was assessed using predicted-to-observed (P/O) ratios and C-statistics provided model discrimination. All analyses were weighted and accounted for HCHS/SOL complex survey design. Results: Mean age (SE) was 53.6 (0.2) years, 53.2% were female. Over a 10-year mean follow-up, 1.5% developed ASCVD. Both PCEs overestimated risk (predicted: 6.9% [NHB], 6.0% [NHW]), with P/O >1 across all Hispanic background groups (Table) . Miscalibration was most pronounced in Hispanics of Dominican background (P/O: 6.43 [NHB], 5.11 [NHW]) and participants with greater-than-median Amerindian Ancestry (P/O: 6.89 [NHB], 5.89 [NHW]). Calibration was more accurate among people who reported Black/African American race (P/O: 1.52 [NHB], 1.24 [NHW]), and Puerto Rican background (P/O: 2.96 [NHB], 2.49 [NHW]). Discrimination was moderate overall (C=0.70 [NHB], 0.71 [NHW]), varied by Hispanic background (Table 1), and was highest among individuals with greater-than-median African Ancestry (0.77 [NHB], 0.77 [NHW]) (Table) . Conclusions: While both the NHB and NHW PCEs overestimated ASCVD risk across all Hispanic background groups, calibration was more accurate in Hispanic/Latino individuals self-identified as Black, and discrimination was strongest with the NHW PCE. These findings highlight the need for more inclusive and tailored risk prediction tools in diverse populations.

This review characterizes atherosclerotic cardiovascular disease (ASCVD) risk associated with Lipoprotein(a) [Lp(a)], with a focus on current and emerging therapeutic strategies for individuals with elevated Lp(a). Though Lp(a) is predominantly genetically inherited, optimization of risk factors, healthy lifestyle, and statin therapy are associated with a lower risk of ASCVD in those with elevated Lp(a). Observational research and post-hoc analyses suggest that aspirin use may be associated with lower ASCVD risk among individuals with elevated Lp(a), supporting an individualized, shared decision-making approach that considers bleeding risk, overall cardiovascular risk profile, and additional markers of cardiovascular risk. Post-hoc analyses of randomized controlled trials demonstrate that individuals with elevated Lp(a) are more likely to benefit from PCSK9 inhibitors compared to those with normal Lp(a), as PCSK9 inhibitors lead to an approximate 20–25

South Asians (SAs) experience a disproportionately high burden of premature atherosclerotic cardiovascular disease, yet conventional risk assessment algorithms often underestimate their cardiovascular risk. This review highlights the evolving role of atherosclerosis imaging, namely, coronary artery calcium scoring and coronary computed tomographic angiography (CTA), as complementary tools for earlier detection and refined risk stratification in SAs. The authors review evidence demonstrating earlier appearance and greater coronary plaque burden in SAs, often accompanied by higher risk plaque features and inflammation, even in the setting of a zero or low coronary artery calcium score. Advances in coronary CTA, including artificial intelligence-enabled plaque quantification, perivascular fat attenuation index, and computed tomography-derived fractional flow reserve, enable the characterization of high-risk vascular biology and may guide targeted preventive therapies. Coronary artery calcium scoring can refine risk in SAs as broadly as in other ethnic groups. However, in younger SAs who may not yet have developed calcified plaque, the selective and judicious application of coronary CTA to visualize noncalcified plaque in targeted high-risk individuals offers an evolving strategy for earlier and personalized initiation of aggressive preventive therapies.

Cardiovascular-kidney-metabolic (CKM) syndrome is associated with increased risks of cardiovascular disease (CVD) and all-cause mortality, but its relationship with body composition phenotypes remains unclear. This population-based cohort study utilized data from the National Health and Nutrition Examination Survey (NHANES) 2007–2018, linked to the National Death Index through December 31, 2019. Participants were stratified on body mass index (BMI) and waist-to-height ratio (WHtR): (1) obesity with central adiposity (high BMI, high WHtR), (2) obesity without central adiposity (high BMI, low WHtR), (3) normal weight with central adiposity (normal BMI, high WHtR), and (4) normal weight without central adiposity (normal BMI, low WHtR). CKM multimorbidity was defined as ≥ 2 of hypertension, hyperlipidemia, diabetes, chronic kidney disease, and/or CVD. Primary and secondary outcomes were all-cause and cardiovascular mortality. Associations were assessed using survey-weighted Cox proportional hazards models. The weighted cohort represented 106.9 million US adults (mean age 47.2). Majority were normal weight without central adiposity (53.3

Background:Cardiovascular-kidney-liver-metabolic (CKLM) diseases constitute the presence of MASLD, T2D, CKD, obesity and/or CVD, that often co-exist and synergistically increase cardiovascular risk. However, the prevalence, extent and outcomes of the CKLM burden remain poorly understood. Methods:This population-based study utilised National Health and Nutrition Examination Survey (NHANES) 2007-2018 database, examining individuals' number (0-4) and permutations of CKLM diseases, namely: type 2 diabetes (T2D), obesity, metabolic dysfunction-associated steatotic liver disease (MASLD), chronic kidney disease (CKD). The primary outcome was all-cause mortality. Cox regression models were constructed to evaluate the relationship between CKLM phenotypes and all-cause mortality, adjusting for age, sex, race, socioeconomic status, and physical activity. Results:The weighted cohort represented 97.8 million US adults (mean age 47.7 ± 16.7 years). 54.16% of the cohort had ≥1 CKLM diseases. From 2007 to 2018, the proportion of individuals with ≥2 CKLM diseases increased from 32.4% to 55.6% of the population, with the largest increase in proportion of individuals with 4 diseases. The most common CKLM phenotype was MASLD-obesity (23.0%), followed by MASLD-obesity-T2D (5.1%). The highest mortality rates were observed in individuals with 4 CKLM diseases (21.4%), followed by 3 diseases (12.2%). Cox regression revealed that 4 diseases predicted the highest mortality risk (aHR 2.24, 95%CI: 1.66-3.02, p < 0.001), followed by 3 diseases (aHR 1.52, 95%CI: 1.25-1.85, p < 0.001). The MASLD-T2D-CKD phenotype (aHR 3.13, 95%CI: 1.80-5.42, p < 0.001) and T2D-CKD phenotype (aHR 3.26, 95%CI: 2.33-4.55, p < 0.001) predicted the highest mortality risk. Conclusions:The CKLM multimorbidity burden is rising in the US population. Higher CKLM burden (≥3 CKLM diseases) and CKD-centric phenotypes (MASLD-T2D-CKD or T2D-CKD) independently predict the highest mortality risk.

BACKGROUND:Insulin resistance (IR) and lipoprotein(a), Lp(a), are established contributors to cardiovascular disease (CVD) risk. Whether IR modifies the association between Lp(a) and CVD in primary prevention remains uncertain. METHODS:This prospective cohort study included UK Biobank participants without baseline CVD. IR at enrollment was assessed using the triglyceride-glucose index (TyG). The primary outcome was first major adverse cardiovascular event, defined as peripheral arterial disease, coronary artery disease, myocardial infarction, ischemic stroke, or cardiovascular death. Cox models estimated adjusted hazard ratios (aHRs) with 95% CIs for log-transformed Lp(a) and TyG, adjusting for each other. Lp(a) was categorized as <125 or ≥125 nmol/L; high IR was TyG ≥75th cohort percentile. Participants were stratified into 4 joint Lp(a)/IR groups using low Lp(a)/low IR as reference. RESULTS:Among 328 031 participants (mean age 56.4 years; 54.7% women), 26 865 CVD events occurred over 14.6 years median follow-up (interquartile range 13.7-15.4). Per 1-SD increase, aHRs were 1.08 (95% CI, 1.06-1.09) for log-Lp(a) and 1.06 (95% CI, 1.04-1.07) for TyG, each adjusted for the other. The P-value for the multiplicative interaction between TyG and Lp(a) was 0.07. Relative to reference, aHRs (95% CI) were 1.15 (1.10-1.20) for ≥125/low IR, 1.09 (1.06-1.12) for <125/high IR, and 1.32 (1.24-1.41) for ≥125/high IR. CONCLUSIONS:Lp(a) and IR each independently contribute to cardiovascular risk, with a combination offering improved risk stratification. This suggests that accounting for IR may enhance the assessment of Lp(a)-associated risk in the context of primary CVD prevention setting.

Background Elevated plasma concentrations of Lp(a) have been established as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD), including coronary artery disease, myocardial infarction, and calcific aortic valve disease. In this paper we performed a systematic review to evaluate the efficacy and safety of emerging Lp(a)-lowering therapies. Methods A systematic search of PubMed, Embase, and ClinicalTrials.gov was conducted to identify clinical trials evaluating targeted Lp(a)-lowering agents. Studies reporting changes in circulating Lp(a) levels and safety outcomes were included. Therapies were categorized based on their mechanism of action, including antisense oligonucleotides, small interfering RNA (siRNA), and small-molecule inhibitors. Results Targeted therapies demonstrated substantial reductions in circulating Lp(a) concentrations across early- and mid-phase clinical trials. Antisense oligonucleotide therapy with pelacarsen reduced Lp(a) levels by up to 80%, while siRNA-based therapies including olpasiran, lepodisiran, and zerlasiran achieved reductions of up to 80–95%. These agents generally demonstrated favorable safety and tolerability profiles, with most reported adverse events being mild and primarily related to injection-site reactions. In addition, muvalaplin, an oral small-molecule inhibitor targeting Lp(a) assembly, has shown promising reductions in Lp(a) levels in early-phase studies. Conclusions Emerging Lp(a)-targeted therapies achieve significant reductions in circulating Lp(a) concentrations and represent a promising strategy for addressing residual cardiovascular risk associated with elevated Lp(a). Ongoing large-scale cardiovascular outcome trials will determine whether pharmacologic lowering of Lp(a) translates into reductions in cardiovascular events.

Chronic kidney disease (CKD) and metabolic dysfunction–associated steatotic liver disease (MASLD) have been associated with an increased risk of cardiovascular disease. This study seeks to examine the prognostic value of the coexistence of CKD and MASLD in patients presenting with acute myocardial infarction (AMI). This cohort study describes the clinical characteristics and long-term outcomes of patients following AMI, stratified by the presence of CKD and MASLD. A Kaplan–Meier curve was constructed for 30-day mortality. Cox regression analysis was used to investigate independent predictors of long-term all-cause mortality, adjusted for age, sex, ethnicity, previous AMI, AMI type, and left ventricular ejection fraction (LVEF). A total of 6757 patients with AMI were examined. Those with coexisting CKD and MASLD (CKD(+)/MASLD(+)) had the highest rates of obesity (97.7

Health care professionals are increasingly required to address the burden of cardiovascular disease (CVD) as the adult population ages. Primary prevention, or interventions targeted at delaying the onset of clinical CVD, is critical to improving outcomes in this demographic. A unique challenge in this population is applying standardized guidelines to a population that requires individualized care and patient-centered medical management.

AIM The “2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Dyslipidemia” retires and replaces the “2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol.” METHODS A comprehensive literature search was conducted from October 2024 to December 2024 to identify clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human participants that were published in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. STRUCTURE The focus of this clinical practice guideline is to address the evaluation, management, and monitoring of individuals with dyslipidemias, including high blood cholesterol, hypertriglyceridemia, and elevated lipoprotein(a).