Nontraditional Risk Markers for Incident Coronary Artery Calcium Among Persons ≥65 Years of Age.

Background: The initiation of coronary artery calcium (CAC) is an important physiologic milestone associated with increased cardiovascular disease risk. However, traditional risk factors (RF) do not perform well for predicting incident CAC among the 54 million older U.S. adults. Objectives: The authors sought to assess the association between nontraditional cardiovascular disease RF and incident CAC in older persons. Methods: There were 815 MESA (Multi-Ethnic Study of Atherosclerosis) participants ≥65 years of age who had CAC = 0 at Visit 1 and a follow-up CAC scan. Multivariable adjusted Cox hazards ratios (aHR) and C-statistics were calculated to examine the association of nontraditional RF with incident CAC. Results: The mean age was 70.2 years and 67% were women. The median follow-up time to repeat CAC scan was 3.6 years (IQR: 2.6-9.2 years) and 45% of participants developed incident CAC. Albuminuria (aHR: 1.50, 95% CI: 1.07-2.09), carotid plaque (aHR: 1.32, 95% CI: 1.04-1.66), and thoracic aortic calcification (TAC) (aHR: 1.38, 95% CI: 1.10-1.75) were significantly associated with incident CAC, while higher levels of nontraditional RF including apolipoprotein-B, lipoprotein(a), high-sensitivity troponin T, and N-terminal pro-brain natriuretic peptide were not. When added to demographics, albuminuria, carotid plaque, and TAC provided a greater C-statistic improvement (+0.047, P = 0.004) vs all traditional RF combined (+0.033, P = 0.05). Conclusions: Among nontraditional RF and measures of subclinical atherosclerosis, only albuminuria, carotid plaque, and TAC were significantly associated with incident CAC in persons ≥65 years of age. Identification of albuminuria or extracoronary atherosclerosis may help guide the timing of repeat CAC scoring in older persons with baseline CAC = 0.

Aspirin use for primary prevention among US adults with and without elevated Lipoprotein(a).

Objective: Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein associated with atherosclerotic cardiovascular disease (ASCVD). We assessed the association between regular aspirin use and ASCVD mortality among individuals with versus without elevated Lp(a) in a nationally representative US cohort. Methods: Eligible participants were aged 40-70 years without clinical ASCVD, reported on aspirin use, and had Lp(a) measurements from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994), the only cycle of this nationally representative US cohort to measure Lp(a). Regular aspirin use was defined as taking aspirin ≥30 times in the previous month. Using NHANES III linked mortality records and weighted Cox proportional hazards regression, the association between regular aspirin use and ASCVD mortality was observed in those with and without elevated Lp(a) (≥50 versus <50 mg/dL) over a median 26-year follow-up. Results: Among 2,990 persons meeting inclusion criteria (∼73 million US adults), the mean age was 50 years, 86% were non-Hispanic White, 9% were non-Hispanic Black, 53% were female, and 7% reported regular aspirin use. The median Lp(a) was 14 mg/dL and the proportion with elevated Lp(a) was similar among those with versus without regular aspirin use (15.1% versus 21.9%, p = 0.16). Among individuals with elevated Lp(a), the incidence of ASCVD mortality per 1,000 person-years was lower for those with versus without regular aspirin use (1.2, 95% CI: 0.1-2.3 versus 3.9, 95% CI: 2.8-4.9). In multivariable modeling, regular aspirin use was associated with a 52% lower risk of ASCVD mortality among individuals with elevated Lp(a) (HR=0.48, 95% CI: 0.28-0.83), but not for those without elevated Lp(a) (HR=1.01, 95% CI: 0.81-1.25; p-interaction=0.001). Conclusion: Regular aspirin use was associated with significantly lower ASCVD mortality in adults without clinical ASCVD who had elevated Lp(a). These findings may have clinical and public health implications for aspirin utilization in primary prevention.

Temporal trends and racial/ethnic- and sex-differences in LDL cholesterol control among US adults with self-reported atherosclerotic cardiovascular disease.

Objective: Current guidelines for secondary prevention of atherosclerotic cardiovascular disease (ASCVD) recommend targeting a low-density lipoprotein cholesterol (LDL-C) of < 70 mg/dL. However, temporal trends and racial/ethnic- and sex-differences in achievement of LDL-C targets are not well described. We assessed trends and racial/ethnic- and sex-differences in achievement of LDL-C < 70 mg/dL using data from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2008 to 2017-March 2020. Methods: We combined NHANES cycles into 4 periods: 2005-2008, 2009-2012, 2013-2016, and 2017-March 2020 and included participants ≥ 40 years with self-reported ASCVD. We estimated LDL-C < 70 mg/dL prevalence over time and further stratified by sex and race/ethnicity. We used multivariable logistic regression adjusted for social determinants of health and clinical covariates to model LDL-C target attainment. Results: Among 1,826 NHANES participants representing 7,161,221 US adults with self-reported ASCVD (59.6% ≥ 65 years, 56.4% male, 74.8% White), LDL-C target attainment increased from 19.0% (95% CI, 15.3%-23.3%) in 2005-2008 to 26.3% (95% CI, 20.4%-33.1%) in 2017-March 2020 (P = 0.012 for trend). Achievement of LDL-C < 70 mg/dL significantly rose among men from19.5% (95% CI, 15.1%-24.8%) to 29.4% (95% CI, 20.7%-29.9%) without significant change in women (from 18.3% [95% CI, 13.6%-24.2%] to 22.5% [95% CI, 13.0%-35.9%]; P = 0.241 for trend). Improvement in LDL-C target attainment was similar among White, Black, and Hispanic individuals (∼5-7% increase) and was greatest among individuals of other (non-White, Hispanic, or Black) race/ethnicity (23.1% increase). In our multivariable analysis, comorbid diabetes and ages 65-75 and > 75 years were associated with LDL-C target attainment. Conclusion: LDL-C control modestly improved between 2005 and 2008 and 2017-March 2020; however, only ∼1/4 of individuals met guideline-directed LDL-C treatment targets by 2017-March 2020. Women had lower LDL-C control and lesser magnitude of improvement in LDL-C control than men, highlighting a need for targeted interventions to improve lipid-lowering therapy utilization in this population.

Supravalvular Aortic Stenosis in Homozygous Familial Hypercholesterolemia: Contemporary Management.

We report a case of a patient diagnosed with homozygous familial hypercholesterolemia and progressive supravalvular aortic stenosis. Treatment with long-term low-density lipoprotein apheresis and management with novel lipid-lowering agents including an angiopoetin-like protein inhibitor led to significant low-density lipoprotein reduction. The case highlights the challenges in managing the manifestations of homozygous familial hypercholesterolemia.

Liver and cardiovascular disease outcomes in metabolic syndrome and diabetic populations: Bi-directional opportunities to multiply preventive strategies.

The incidence and prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are rising globally. MetS and T2DM are associated with significant morbidity and mortality, which is partly related to liver and cardiovascular disease. Insulin resistance is central to MetS and T2DM pathophysiology, and drives ectopic fat deposition in the liver, also known as metabolic dysfunction-associated steatotic liver disease (MASLD). MetS and T2DM are not only risk factors for developing MASLD but are also independently associated with disease progression to steatohepatitis, cirrhosis, and hepatocellular carcinoma. In addition to the risk of liver disease, MetS and T2DM are independent risk factors for cardiovascular disease (CVD), including coronary artery disease (CAD) and heart failure (HF). Importantly, there is a bidirectional relationship between liver and CVD due to shared disease pathophysiology in patients with MetS and T2DM. In this review, we have described studies exploring the relationship of MetS and T2DM with MASLD and CVD, independently. Following this we discuss studies evaluating the interplay between liver and cardiovascular risk as well as pragmatic risk mitigation strategies in this patient population.

Acute Cardiac Events in Hospitalized Older Adults With Respiratory Syncytial Virus Infection.

Importance: Respiratory syncytial virus (RSV) infection can cause severe respiratory illness in older adults. Less is known about the cardiac complications of RSV disease compared with those of influenza and SARS-CoV-2 infection. Objective: To describe the prevalence and severity of acute cardiac events during hospitalizations among adults aged 50 years or older with RSV infection. Design, Setting, and Participants: This cross-sectional study analyzed surveillance data from the RSV Hospitalization Surveillance Network, which conducts detailed medical record abstraction among hospitalized patients with RSV infection detected through clinician-directed laboratory testing. Cases of RSV infection in adults aged 50 years or older within 12 states over 5 RSV seasons (annually from 2014-2015 through 2017-2018 and 2022-2023) were examined to estimate the weighted period prevalence and 95% CIs of acute cardiac events. Exposures: Acute cardiac events, identified by International Classification of Diseases, 9th Revision, Clinical Modification or International Statistical Classification of Diseases, Tenth Revision, Clinical Modification discharge codes, and discharge summary review. Main Outcomes and Measures: Severe disease outcomes, including intensive care unit (ICU) admission, receipt of invasive mechanical ventilation, or in-hospital death. Adjusted risk ratios (ARR) were calculated to compare severe outcomes among patients with and without acute cardiac events. Results: The study included 6248 hospitalized adults (median [IQR] age, 72.7 [63.0-82.3] years; 59.6% female; 56.4% with underlying cardiovascular disease) with laboratory-confirmed RSV infection. The weighted estimated prevalence of experiencing a cardiac event was 22.4% (95% CI, 21.0%-23.7%). The weighted estimated prevalence was 15.8% (95% CI, 14.6%-17.0%) for acute heart failure, 7.5% (95% CI, 6.8%-8.3%) for acute ischemic heart disease, 1.3% (95% CI, 1.0%-1.7%) for hypertensive crisis, 1.1% (95% CI, 0.8%-1.4%) for ventricular tachycardia, and 0.6% (95% CI, 0.4%-0.8%) for cardiogenic shock. Adults with underlying cardiovascular disease had a greater risk of experiencing an acute cardiac event relative to those who did not (33.0% vs 8.5%; ARR, 3.51; 95% CI, 2.85-4.32). Among all hospitalized adults with RSV infection, 18.6% required ICU admission and 4.9% died during hospitalization. Compared with patients without an acute cardiac event, those who experienced an acute cardiac event had a greater risk of ICU admission (25.8% vs 16.5%; ARR, 1.54; 95% CI, 1.23-1.93) and in-hospital death (8.1% vs 4.0%; ARR, 1.77; 95% CI, 1.36-2.31). Conclusions and Relevance: In this cross-sectional study over 5 RSV seasons, nearly one-quarter of hospitalized adults aged 50 years or older with RSV infection experienced an acute cardiac event (most frequently acute heart failure), including 1 in 12 adults (8.5%) with no documented underlying cardiovascular disease. The risk of severe outcomes was nearly twice as high in patients with acute cardiac events compared with patients who did not experience an acute cardiac event. These findings clarify the baseline epidemiology of potential cardiac complications of RSV infection prior to RSV vaccine availability.

Left Main Coronary Artery Calcium and Diabetes Confer Very-High-Risk Equivalence in Coronary Artery Calcium >1,000.

BACKGROUND: Although a coronary artery calcium (CAC) of ≥1,000 is a subclinical atherosclerosis threshold to consider combination lipid-lowering therapy, differentiating very high from high atherosclerotic cardiovascular disease (ASCVD) risk in this patient population is not well-defined. OBJECTIVES: Among persons with a CAC of ≥1,000, the authors sought to identify risk factors equating with very high-risk ASCVD mortality rates. METHODS: The authors studied 2,246 asymptomatic patients with a CAC of ≥1,000 from the CAC Consortium without a prior ASCVD event. Cox proportional hazards regression modelling was performed for ASCVD mortality during a median follow-up of 11.3 years. Crude ASCVD mortality rates were compared with those reported for secondary prevention trial patients classified as very high risk, defined by ≥2 major ASCVD events or 1 major event and ≥2 high-risk conditions (1.4 per 100 person-years). RESULTS: The mean age was 66.6 years, 14% were female, and 10% were non-White. The median CAC score was 1,592 and 6% had severe left main (LM) CAC (vessel-specific CAC ≥300). Diabetes (HR: 2.04 [95% CI: 1.47-2.83]) and severe LM CAC (HR: 2.32 [95% CI: 1.51-3.55]) were associated with ASCVD mortality. The ASCVD mortality per 100 person-years for all patients was 0.8 (95% CI: 0.7-0.9), although higher rates were observed for diabetes (1.4 [95% CI: 0.8-1.9]), severe LM CAC (1.3 [95% CI: 0.6-2.0]), and both diabetes and severe LM CAC (7.1 [95% CI: 3.4-10.8]). CONCLUSIONS: Among asymptomatic patients with a CAC of ≥1,000 without a prior index event, diabetes, and severe LM CAC define very high risk ASCVD, identifying individuals who may benefit from more intensive prevention therapies across several domains, including low-density lipoprotein-cholesterol lowering.

Does Elevated High-Density Lipoprotein Cholesterol Protect Against Cardiovascular Disease?

High-density lipoprotein (HDL) contributes to reverse cholesterol transport, which is 1 of the main explanations for the described inverse association between HDL-cholesterol (HDL-C) and atherosclerotic cardiovascular disease (ASCVD) risk. However, efforts to therapeutically raise HDL-C levels with niacin, fibrates, or cholesteryl ester transfer protein inhibitors have not demonstrated a reduction in ASCVD events when compared with placebo among individuals treated with statins. Furthermore, mendelian randomization studies suggest that HDL-C is unlikely to be a direct biologic variable impacting ASCVD risk. More recently, observations from well-conducted epidemiologic studies have indicated a nonlinear U-shaped relationship between HDL-C and subclinical atherosclerosis, and that very high HDL-C (≥80 mg/dL in men, ≥100 mg/dL in women) is paradoxically associated with higher all-cause and ASCVD-related mortality. These observations suggest that HDL-C is not a universal protective factor for atherosclerosis. Thus, there are several opportunities for reframing the contribution of HDL-C to ASCVD risk and related clinical calculators. Here, we examine our growing understanding of HDL-C and its role in ASCVD risk assessment, treatment, and prevention. We discuss the biological functions of HDL-C and its normative values in relation to demographics and lifestyle markers. We then summarize original studies that observed a protective association between HDL-C and ASCVD risk and more recent evidence indicating an elevated ASCVD risk at very high HDL-C levels. Through this process, we advance the discussion regarding the future role of HDL-C in ASCVD risk assessment and identify knowledge gaps pertaining to the precise role of HDL-C in atherosclerosis and clinical ASCVD.

Development and Validation of the American Heart Association's PREVENT Equations.

BACKGROUND: Multivariable equations are recommended by primary prevention guidelines to assess absolute risk of cardiovascular disease (CVD). However, current equations have several limitations. Therefore, we developed and validated the American Heart Association Predicting Risk of CVD EVENTs (PREVENT) equations among US adults 30 to 79 years of age without known CVD. METHODS: The derivation sample included individual-level participant data from 25 data sets (N=3 281 919) between 1992 and 2017. The primary outcome was CVD (atherosclerotic CVD and heart failure). Predictors included traditional risk factors (smoking status, systolic blood pressure, cholesterol, antihypertensive or statin use, and diabetes) and estimated glomerular filtration rate. Models were sex-specific, race-free, developed on the age scale, and adjusted for competing risk of non-CVD death. Analyses were conducted in each data set and meta-analyzed. Discrimination was assessed using the Harrell C-statistic. Calibration was calculated as the slope of the observed versus predicted risk by decile. Additional equations to predict each CVD subtype (atherosclerotic CVD and heart failure) and include optional predictors (urine albumin-to-creatinine ratio and hemoglobin A1c), and social deprivation index were also developed. External validation was performed in 3 330 085 participants from 21 additional data sets. RESULTS: Among 6 612 004 adults included, mean±SD age was 53±12 years, and 56% were women. Over a mean±SD follow-up of 4.8±3.1 years, there were 211 515 incident total CVD events. The median C-statistics in external validation for CVD were 0.794 (interquartile interval, 0.763-0.809) in female and 0.757 (0.727-0.778) in male participants. The calibration slopes were 1.03 (interquartile interval, 0.81-1.16) and 0.94 (0.81-1.13) among female and male participants, respectively. Similar estimates for discrimination and calibration were observed for atherosclerotic CVD- and heart failure-specific models. The improvement in discrimination was small but statistically significant when urine albumin-to-creatinine ratio, hemoglobin A1c, and social deprivation index were added together to the base model to total CVD (ΔC-statistic [interquartile interval] 0.004 [0.004-0.005] and 0.005 [0.004-0.007] among female and male participants, respectively). Calibration improved significantly when the urine albumin-to-creatinine ratio was added to the base model among those with marked albuminuria (>300 mg/g; 1.05 [0.84-1.20] versus 1.39 [1.14-1.65]; P=0.01). CONCLUSIONS: PREVENT equations accurately and precisely predicted risk for incident CVD and CVD subtypes in a large, diverse, and contemporary sample of US adults by using routinely available clinical variables.

Soluble urokinase Plasminogen Activator Receptor (suPAR) mediates the effect of a lower education level on adverse outcomes in patients with coronary artery disease.

AIMS: To investigate whether the adverse impact of lower educational attainment on mortality risk in patients with coronary artery disease (CAD) is mediated by the activation of inflammatory and immune pathways, estimated as elevated soluble urokinase plasminogen activator receptor levels. METHODS AND RESULTS: In 3164 patients undergoing coronary angiography, we investigated multivariable associations between suPAR and educational attainment and assessed the relationship between a lower educational level (defined as a high-school degree or less as the highest educational qualification) and outcomes using Cox proportional hazard and Fine and Gray's subdistribution competing risk models. The potential mediating effect through suPAR and high-sensitivity C-reactive protein (hs-CRP) was assessed using mediation analysis. A total of 1814 patients (57.3%) had achieved a higher (≥college) education level and 1350 patients (42.7%) a lower (≤high school) education level. Soluble urokinase plasminogen activator receptor levels were 9.0% [95% confidence interval (CI) 6.3-11.8, P ≤ 0.0001] higher in patients with lower educational qualifications than in those with higher educational qualifications after covariate adjustment. Lower educational attainment was associated with a higher risk of cardiovascular death after adjustment for demographic, clinical, and behavioural covariates, including CAD severity and heart failure history, medication use, and hs-CRP levels [hazard ratio 1.26 (95% CI 1.02-1.55, P = 0.03)]. However, after adjustment for suPAR levels, the effect of a lower educational level on cardiovascular death became insignificant. Values were similar for all-cause death. Soluble urokinase plasminogen activator receptor levels mediated 49% and hs-CRP levels 17% of the cardiovascular death risk attributable to lower educational attainment. CONCLUSION: Circulating suPAR levels importantly mediate the effects of lower educational attainment on mortality, indicating the importance of systemic inflammation and immune dysregulation as biologic mediators of adverse social determinants of health.

In patients with coronary artery disease (CAD), we demonstrate that nearly half of the higher risk of all-cause and cardiovascular mortality associated with lower educational attainment as a measure of socioeconomic status is mediated by systemic inflammation and immune dysregulation, which can be estimated by measuring the circulating soluble urokinase plasminogen activator receptor (suPAR) levels. Even after accounting for differences in cardiovascular risk factors, lower educational attainment is associated with higher mortality risk in patients with CAD and there is activation of inflammatory pathways and immune dysregulation in those with lower (≤high school) educational attainment than in those with higher (≥college) educational attainment, estimated as higher circulating suPAR levels.Almost half of the higher risk for adverse outcomes observed in those with lower educational attainment appears to be due to systemic inflammation and immune dysregulation and can be estimated from measuring suPAR levels.

Trends in sleep apnea and heart failure related mortality in the United States from 1999 to 2019.

National estimates of deaths related to both heart failure (HF) and sleep apnea (SA) are not known. We evaluated the trends in HF and SA related mortality using the CDC-WONDER database in adults aged ≥25 years in the US. All deaths related to HF and SA as contributing or underlying causes of death were queried. Between 1999 and 2019, there were a total of 6,484,486 deaths related to HF, 204,824 deaths related to SA, and 53,957 deaths related to both. There was a statistically significant increase in the age-adjusted mortality rate (AAMR) for both SA-related (average annual percent change [AAPC] 8.2%) and combined HF and SA- related (AAPC 10.1 %) deaths. Men had consistently higher AAMRs compared with women, and both groups had a similar increasing trend in AAMR. Non-Hispanic (NH) Black individuals had the highest HF and SA-related AAMR, followed by NH White and Hispanic/Latino individuals. Adults aged >75 years consistently had the highest AAMR with the steepest increase (AAPC 11.1%). In conclusion, HF and SA-related mortality has significantly risen over the past two decades with the elderly, men, and NH Black at disproportionately higher risk.

Thoracic Aortic Calcium Density and Area in Long-Term Atherosclerotic Cardiovascular Disease Risk Among Men Versus Women.

BACKGROUND: The development of thoracic aortic calcium (TAC) temporally precedes coronary artery calcium more often in women versus men. Whether TAC density and area confer sex-specific differences in atherosclerotic cardiovascular disease (ASCVD) risk is unknown. METHODS: We studied 5317 primary prevention patients who underwent coronary artery calcium scoring on noncontrast cardiac gated computed tomography with TAC >0. The Agatston TAC score (Agatston units), density (Hounsfield units), and area (mm2) were compared between men and women. Cox proportional hazards regression calculated adjusted hazard ratios for TAC density-area groups with ASCVD mortality, adjusting for traditional risk factors, coronary artery calcium, and TAC. Multinomial logistic regression calculated adjusted odds ratios for the association between traditional risk factors and TAC density-area groups. RESULTS: The mean age was 60.7 years, 38% were women, and 163 ASCVD deaths occurred over a median of 11.7-year follow-up. Women had higher median TAC scores (97 versus 84 Agatston units; P=0.004), density (223 versus 210 Hounsfield units; P<0.001), and area (37 versus 32 mm2; P=0.006) compared with men. There was a stepwise higher incidence of ASCVD deaths across increasing TAC density-area groups in men though women with low TAC density relative to TAC area (3.6 per 1000 person-years) had survival probability commensurate with the high-density-high-area group (4.8 per 1000 person-years). Compared with low TAC density-area, low TAC density/high TAC area conferred a 3.75-fold higher risk of ASCVD mortality in women (adjusted hazard ratio, 3.75 [95% CI, 1.13-12.44]) but not in men (adjusted hazard ratio, 1.16 [95% CI, 0.48-2.84]). Risk factors most strongly associated with low TAC density/high TAC area differed in women (diabetes: adjusted odds ratio, 2.61 [95% CI, 1.34-5.07]) versus men (hypertension: adjusted odds ratio, 1.45 [95% CI, 1.11-1.90]). CONCLUSIONS: TAC density-area phenotypes do not consistently associate with ASCVD mortality though low TAC density relative to area may be a marker of increased ASCVD risk in women.

Immune Activation Mediates the Association of Advanced Hepatic Fibrosis With Adverse Outcomes in Patients With Coronary Artery Disease.

BACKGROUND: Literature suggests a bidirectional association between advanced hepatic fibrosis (AHF) and coronary artery disease (CAD). We evaluated the association of AHF with immune activation, systemic inflammation, and adverse outcomes in patients with CAD. METHODS AND RESULTS: A fibrosis-4 index cutoff value ≥2.67 was used to define AHF. Circulating levels of soluble urokinase plasminogen activator receptor and hsCRP (high-sensitivity C-reactive protein) were measured as markers for immune activation and systemic inflammation, respectively. The relationship of AHF with soluble urokinase plasminogen activator receptor, hsCRP, and adverse cardiovascular outcomes was evaluated. Among 3406 participants with CAD, 479 had AHF. Participants with AHF were older; were less likely to be Black individuals; and had a lower body mass index, worse renal function, and a prior history of heart failure. In multivariable linear regression models adjusted for clinical and demographic confounders, participants with AHF had 15.6% higher soluble urokinase plasminogen activator receptor and 24.0% higher hsCRP levels. They were more likely to experience the following adverse outcomes: all-cause death (adjusted hazard ratio [HR], 1.57 ([95% CI, 1.29-1.92]; P<0.001) and cardiovascular death: (subdistribution HR, 1.50 [95% CI, 1.14-1.95]; P=0.003). Mediation analysis showed that 47.0% (95% CI, 13.6%-81.2%]; P=0.006) of the indirect effect of AHF on cardiovascular death was mediated by circulating soluble urokinase plasminogen activator receptor levels. CONCLUSIONS: AHF is independently associated with immune activation, systemic inflammation, and adverse cardiovascular outcomes in patients with CAD. The association of AHF with adverse outcomes is partly mediated by immune activation, and targeting this pathway may help reduce the residual risk in patients with CAD.

High-Density Lipoprotein Cholesterol in Atherosclerotic Cardiovascular Disease Risk Assessment: Exploring and Explaining the "U"-Shaped Curve.

PURPOSE OF REVIEW: Review updates for the association of HDL-cholesterol with atherosclerotic cardiovascular disease (ASCVD) and discuss the approach to incorporating HDL-cholesterol within risk assessment. RECENT FINDINGS: There is a U-shaped relationship between HDL-cholesterol and ASCVD. Both low HDL-cholesterol (< 40 mg/dL in men, < 50 mg/dL in women) and very-high HDL-cholesterol (≥ 80 mg/dL in men) are associated with a higher risk of all-cause and ASCVD mortality, independent from traditional risk factors. There has been inconsistency for the association between very-high HDL-cholesterol and mortality outcomes in women. It is uncertain whether HDL-cholesterol is a causal ASCVD risk factor, especially due to mixed results from Mendelian randomization studies and the collinearity of HDL-cholesterol with established risk factors, lifestyle behaviors, and socioeconomic status. HDL-cholesterol is a risk factor or risk enhancer in primary prevention and high-risk condition in secondary prevention when either low (men and women) or very-high (men). The contribution of HDL-cholesterol to ASCVD risk calculators should reflect its observed U-shaped association with all-cause and ASCVD mortality.

Novel Prediction Equations for Absolute Risk Assessment of Total Cardiovascular Disease Incorporating Cardiovascular-Kidney-Metabolic Health: A Scientific Statement From the American Heart Association.

Cardiovascular-kidney-metabolic (CKM) syndrome is a novel construct recently defined by the American Heart Association in response to the high prevalence of metabolic and kidney disease. Epidemiological data demonstrate higher absolute risk of both atherosclerotic cardiovascular disease (CVD) and heart failure as an individual progresses from CKM stage 0 to stage 3, but optimal strategies for risk assessment need to be refined. Absolute risk assessment with the goal to match type and intensity of interventions with predicted risk and expected treatment benefit remains the cornerstone of primary prevention. Given the growing number of therapies in our armamentarium that simultaneously address all 3 CKM axes, novel risk prediction equations are needed that incorporate predictors and outcomes relevant to the CKM context. This should also include social determinants of health, which are key upstream drivers of CVD, to more equitably estimate and address risk. This scientific statement summarizes the background, rationale, and clinical implications for the newly developed sex-specific, race-free risk equations: PREVENT (AHA Predicting Risk of CVD Events). The PREVENT equations enable 10- and 30-year risk estimates for total CVD (composite of atherosclerotic CVD and heart failure), include estimated glomerular filtration rate as a predictor, and adjust for competing risk of non-CVD death among adults 30 to 79 years of age. Additional models accommodate enhanced predictive utility with the addition of CKM factors when clinically indicated for measurement (urine albumin-to-creatinine ratio and hemoglobin A1c) or social determinants of health (social deprivation index) when available. Approaches to implement risk-based prevention using PREVENT across various settings are discussed.

A Synopsis of the Evidence for the Science and Clinical Management of Cardiovascular-Kidney-Metabolic (CKM) Syndrome: A Scientific Statement From the American Heart Association.

A growing appreciation of the pathophysiological interrelatedness of metabolic risk factors such as obesity and diabetes, chronic kidney disease, and cardiovascular disease has led to the conceptualization of cardiovascular-kidney-metabolic syndrome. The confluence of metabolic risk factors and chronic kidney disease within cardiovascular-kidney-metabolic syndrome is strongly linked to risk for adverse cardiovascular and kidney outcomes. In addition, there are unique management considerations for individuals with established cardiovascular disease and coexisting metabolic risk factors, chronic kidney disease, or both. An extensive body of literature supports our scientific understanding of, and approach to, prevention and management for individuals with cardiovascular-kidney-metabolic syndrome. However, there are critical gaps in knowledge related to cardiovascular-kidney-metabolic syndrome in terms of mechanisms of disease development, heterogeneity within clinical phenotypes, interplay between social determinants of health and biological risk factors, and accurate assessments of disease incidence in the context of competing risks. There are also key limitations in the data supporting the clinical care for cardiovascular-kidney-metabolic syndrome, particularly in terms of early-life prevention, screening for risk factors, interdisciplinary care models, optimal strategies for supporting lifestyle modification and weight loss, targeting of emerging cardioprotective and kidney-protective therapies, management of patients with both cardiovascular disease and chronic kidney disease, and the impact of systematically assessing and addressing social determinants of health. This scientific statement uses a crosswalk of major guidelines, in addition to a review of the scientific literature, to summarize the evidence and fundamental gaps related to the science, screening, prevention, and management of cardiovascular-kidney-metabolic syndrome.

Cardiovascular-Kidney-Metabolic Health: A Presidential Advisory From the American Heart Association.

Cardiovascular-kidney-metabolic health reflects the interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system and has profound impacts on morbidity and mortality. There are multisystem consequences of poor cardiovascular-kidney-metabolic health, with the most significant clinical impact being the high associated incidence of cardiovascular disease events and cardiovascular mortality. There is a high prevalence of poor cardiovascular-kidney-metabolic health in the population, with a disproportionate burden seen among those with adverse social determinants of health. However, there is also a growing number of therapeutic options that favorably affect metabolic risk factors, kidney function, or both that also have cardioprotective effects. To improve cardiovascular-kidney-metabolic health and related outcomes in the population, there is a critical need for (1) more clarity on the definition of cardiovascular-kidney-metabolic syndrome; (2) an approach to cardiovascular-kidney-metabolic staging that promotes prevention across the life course; (3) prediction algorithms that include the exposures and outcomes most relevant to cardiovascular-kidney-metabolic health; and (4) strategies for the prevention and management of cardiovascular disease in relation to cardiovascular-kidney-metabolic health that reflect harmonization across major subspecialty guidelines and emerging scientific evidence. It is also critical to incorporate considerations of social determinants of health into care models for cardiovascular-kidney-metabolic syndrome and to reduce care fragmentation by facilitating approaches for patient-centered interdisciplinary care. This presidential advisory provides guidance on the definition, staging, prediction paradigms, and holistic approaches to care for patients with cardiovascular-kidney-metabolic syndrome and details a multicomponent vision for effectively and equitably enhancing cardiovascular-kidney-metabolic health in the population.