Association of High-Density Lipoprotein Parameters and Risk of Heart Failure: A Multicohort Analysis.

BACKGROUND: High-density lipoprotein (HDL) is commonly characterized by its cholesterol concentration (HDL-C) and inverse association with atherosclerotic cardiovascular disease. OBJECTIVES: The authors sought to evaluate the association of HDL particle concentration (HDL-P), HDL particle size (HDL-size), HDL-C, and cholesterol content per particle (HDL-C/HDL-P) with risk of overall heart failure (HF) and subtypes. METHODS: Participants from the Atherosclerosis Risk In Communities Study, Dallas Heart Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-stage Disease studies without HF history were included. Associations of HDL-P, HDL-size, HDL-C, and HDL-C/HDL-P with risk of overall HF, HF with reduced and preserved ejection fraction were assessed using adjusted Cox models. RESULTS: Among 16,925 participants (53.5% women; 21.8% Black), there were 612 incident HF events (3.6%) (HF with reduced ejection fraction, 309 [50.5%]; HF preserved ejection fraction, 303 [49.5%]) over median follow-up of 11.4 years. In adjusted models, higher HDL-P was significantly associated with lower HF risk (HR of highest vs lowest tertile of HDL-P: 0.76 [95% CI: 0.62-0.93]). Larger HDL-size was significantly associated with higher overall HF risk (HR of largest vs smallest tertile of HDL-size: 1.27 [95% CI: 1.03-1.58]). HF risk associated with HDL-P and HDL-size was similar for HF subtypes. In adjusted analyses, there was no significant association between HDL-C and HF risk. Higher HDL-C/HDL-P was significantly associated with higher overall HF risk (HR of highest vs lowest tertile of HDL-C/HDL-P: 1.29 [95% CI: 1.04-1.60]). CONCLUSIONS: Higher HDL-P was associated with a lower risk of HF. In contrast, larger HDL-size was associated with higher risk of HF and there was no significant association observed between HDL-C and HF risk after accounting for cardiovascular risk factors.

Sarcopenic Obesity and Cardiovascular Disease: An Overlooked but High-Risk Syndrome.

PURPOSE OF REVIEW: Sarcopenic obesity (SO), defined as the coexistence of excess fat mass and reduced skeletal muscle mass and strength, has emerged as an important cardiovascular risk factor, particularly in older adults. This review summarizes recent findings on the diagnosis, prevalence, health impacts, and treatment of SO. RECENT FINDINGS: Growing evidence suggests SO exacerbates cardiometabolic risk and adverse health outcomes beyond either condition alone; however, the heterogeneity in diagnostic criteria and the observational nature of most studies prohibit the evaluation of a causal relationship. This is concerning given that SO is increasing with the aging population, although that is also difficult to assess accurately given wide-ranging prevalence estimates. A recent consensus definition proposed by the European Society for Clinical Nutrition and Metabolism and the European Association for the Study of Obesity provides a framework of standardized criteria to diagnose SO. Adopting uniform diagnostic criteria for SO will enable more accurate characterization of prevalence and cardiometabolic risk moving forward. Although current management revolves around diet for weight loss coupled with resistance training to mitigate further muscle loss, emerging pharmacologic therapies have shown promising results. As the global population ages, diagnosing and managing SO will become imperative to alleviate the cardiovascular burden.

The aryl hydrocarbon receptor (AHR) repressor limits expression of antimicrobial genes but not AHR-dependent genes in intestinal eosinophils.

Intestinal eosinophils express the aryl hydrocarbon receptor (AHR), an environmental sensor and ligand-activated transcription factor that responds to dietary or environmental ligands. AHR regulates tissue adaptation, survival, adhesion, and immune functions in intestinal eosinophils. The AHR repressor (AHRR) is itself induced by AHR and believed to limit AHR activity in a negative feedback loop. We analysed gene expression in intestinal eosinophils from WT and AHRR-KO mice and found that AHRR did not suppress most AHR-dependent genes. Instead, AHRR limited the expression of a distinct small set of genes involved in the innate immune response. These included S100 proteins, antimicrobial proteins and alpha-defensins. Using bone marrow-derived eosinophils we found that AHRR-KO eosinophils released more reactive oxygen species upon stimulation. This work shows that the paradigm of AHRR as a repressor of AHR transcriptional activity does not apply to intestinal eosinophils. Rather, AHRR limits the expression of innate immune response and antimicrobial genes, possibly to maintain an anti-inflammatory phenotype in eosinophils when exposed to microbial signals in the intestinal environment.

Personalized Intervention Based on Early Detection of Atherosclerosis: JACC State-of-the-Art Review.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide and challenges the capacity of health care systems globally. Atherosclerosis is the underlying pathophysiological entity in two-thirds of patients with CVD. When considering that atherosclerosis develops over decades, there is potentially great opportunity for prevention of associated events such as myocardial infarction and stroke. Subclinical atherosclerosis has been identified in its early stages in young individuals; however, there is no consensus on how to prevent progression to symptomatic disease. Given the growing burden of CVD, a paradigm shift is required-moving from late management of atherosclerotic CVD to earlier detection during the subclinical phase with the goal of potential cure or prevention of events. Studies must focus on how precision medicine using imaging and circulating biomarkers may identify atherosclerosis earlier and determine whether such a paradigm shift would lead to overall cost savings for global health.

Global burden of cardiovascular disease attributable to smoking, 1990-2019: an analysis of the 2019 Global Burden of Disease Study.

AIMS: This study aims to investigate the trends in the global cardiovascular disease (CVD) burden attributable to smoking from 1990 to 2019. METHODS AND RESULTS: Global Burden of Disease Study 2019 was used to analyse the burden of CVD attributable to smoking (i.e. ischaemic heart disease, peripheral artery disease, stroke, atrial fibrillation and flutter, and aortic aneurysm). Age-standardized mortality rates (ASMRs) per 100 000 and age-standardized disability-adjusted life year rates (ASDRs) per 100 000, as well as an estimated annual percentage change (EAPC) in ASMR and ASDR, were determined by age, sex, year, socio-demographic index (SDI), regions, and countries or territories. The global ASMR of smoking-attributed CVD decreased from 57.16/100 000 [95% uncertainty interval (UI) 54.46-59.97] in 1990 to 33.03/100 000 (95% UI 30.43-35.51) in 2019 [EAPC -0.42 (95% UI -0.47 to -0.38)]. Similarly, the ASDR of smoking-attributed CVD decreased between 1990 and 2019. All CVD subcategories showed a decline in death burden between 1990 and 2019. The burden of smoking-attributed CVD was higher in men than in women. Significant geographic and regional variations existed such that Eastern Europe had the highest ASMR and Andean Latin America had the lowest ASMR in 2019. In 2019, the ASMR of smoking-attributed CVD was lowest in high SDI regions. CONCLUSION: Smoking-attributed CVD morbidity and mortality are declining globally, but significant variation persists, indicating a need for targeted interventions to reduce smoking-related CVD burden.

The burden of cardiovascular disease (CVD) attributed to smoking declined worldwide between 1990 and 2019. The burden of smoking-attributed CVD was higher in men than in women in 2019. There were significant variations between different countries and regions such that Eastern Europe had the highest death rate and Andean Latin America had the lowest death rate in 2019. Also, countries with high socio-economic status had lower death rates from smoking-attributed CVD. This highlights the need for targeted interventions to reduce the burden of smoking-attributed CVD. The overall age-adjusted deaths from CVD attributed to smoking declined from 57.16/100 000 in 1990 to 33.03/100 000 in 2019.In 2019, ischaemic heart disease was the leading cause of smoking-attributed CVD deaths.

Impact of optimal cholesterol levels on subclinical atherosclerosis in the absence of risk factors in young adults.

BACKGROUND AND AIMS: We aimed to assess the association of blood lipids with the prevalence, incidence, and progression of subclinical atherosclerosis among young individuals without dyslipidemia and other traditional cardiovascular risk factors (CVRFs). METHODS: A total of 1270 participants from the Coronary Artery Risk Development in Young Adults (CARDIA) study aged 32-46 years free of cardiovascular disease, diabetes, hypertension, current smoking, and dyslipidemia (total cholesterol [TC] ≥ 240 mg/dL, triglycerides [TG] ≥ 150 mg/dL, low-density lipoprotein cholesterol [LDL-C] ≥ 160 mg/dL, high-density lipoprotein cholesterol [HDL-C] < 40 mg/dL, or taking lipid-lowering medications) were included. A subgroup with optimal lipids within the low-CVRF group was defined with TC < 200 mg/dL, LDL-C < 100 mg/dL, non-HDL-C < 130 mg/dL, and women with HDL-C ≥ 50 mg/dL. RESULTS: 1-SD higher TC (25.9 mg/dL), LDL-C (24.7 mg/dL), and non-HDL-C (26.6 mg/dL) were associated with a greater risk of presence (hazard ratios: 1.30-1.36), incidence (1.30-1.32), and progression (1.31-1.35) of coronary artery calcium (CAC) and a 42-44% greater odds of composite mean carotid intima-media thickness (CIMT) ≥ 75th percentile [780 µm] (p < 0.05). Repeating the analyses in a subset of participants with a CAC score of zero did not alter the association of TC, LDL-C, and non-HDL-C with CIMT. In the subgroup with optimal lipids, these lipid indices remained associated with an increased risk of presence and incidence of CAC and greater CIMT measures. CONCLUSIONS: Among adults aged 32-46 years, in the absence of traditional CVRFs, elevated cholesterol levels, even within what is considered optimal, are associated with atherosclerosis and arteriopathy.

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.

The desert woodrat (Neotoma lepida) induces a diversity of biotransformation genes in response to creosote bush resin.

Liver biotransformation enzymes have long been thought to enable animals to feed on diets rich in xenobiotic compounds. However, despite decades of pharmacological research in humans and rodents, little is known about hepatic gene expression in specialized mammalian herbivores feeding on toxic diets. Leveraging a recently identified population of the desert woodrat (Neotoma lepida) found to be highly tolerant to toxic creosote bush (Larrea tridentata), we explored the expression changes of suites of biotransformation genes in response to diets enriched with varying amounts of creosote resin. Analysis of hepatic RNA-seq data indicated a dose-dependent response to these compounds, including the upregulation of several genes encoding transcription factors and numerous phase I, II, and III biotransformation families. Notably, elevated expression of five biotransformation families - carboxylesterases, cytochromes P450, aldo-keto reductases, epoxide hydrolases, and UDP-glucuronosyltransferases - corresponded to species-specific duplication events in the genome, suggesting that these genes play a prominent role in N. lepida's adaptation to creosote bush. Building on pharmaceutical studies in model rodents, we propose a hypothesis for how the differentially expressed genes are involved in the biotransformation of creosote xenobiotics. Our results provide some of the first details about how these processes likely operate in the liver of a specialized mammalian herbivore.

Impact of coronary artery calcium on mortality and cardiovascular events in metabolic syndrome and diabetes among younger adults.

AIMS: Whether coronary artery calcium (CAC) testing in younger individuals with metabolic syndrome (MetS) and diabetes mellitus (DM) helps predict cardiovascular disease (CVD) and death independent of traditional risk factors (RFs) remains less clear. METHODS AND RESULTS: We pooled data obtained from 5174 individuals aged 38-55 years from the CARDIA (Coronary Artery Risk Development in Young Adults; n = 3047, year 20) and MESA (Multi-Ethnic Study of Atherosclerosis; n = 2127, Visit 1) studies who completed computed tomography of CAC. The mean age (SD) of participants (44.7% men) was 47.3 (4.2) years. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) of CVD, coronary heart disease (CHD), and all-cause death. There were 1085 participants (21.0%) with prevalent CAC at baseline. A total of 461 (8.9%) had DM, 1025 (19.8%) had MetS without DM, and 3688 (71.3%) had neither condition. Over a median follow-up of 14.2 years, 256 (5.0%) participants died, and 304 (5.9%) CVD and 188 (3.6%) CHD events occurred. The CAC score was independently associated with incident CVD in those with DM (HR: 95% CI; 1.22: 1.08-1.38), MetS (1.18: 1.08-1.31), and neither condition (1.36: 1.26-1.46). The corresponding HRs for CAC ≥ 100 were 2.70 (1.25-5.83), 3.29 (1.87-5.79), and 6.30 (4.02-9.86), respectively. Similar associations for CHD and death were found. The impact of CAC ≥ 100 on CVD and CHD was lower in the presence of DM (P interaction < 0.05). The association of CAC with all outcomes in individuals with DM remained significant after adjusting with haemoglobin A1c levels. CONCLUSION: Coronary artery calcium score is independently associated with cardiovascular events and death over nearly 15 years after screening at ages 38-55 years, with a less pronounced impact on CVD and CHD events in the presence of DM.

In this pooled cohort, we aimed to analyse the relationship between coronary artery calcium (CAC) and incidence of cardiovascular disease (CVD), coronary heart disease (CHD), and all-cause mortality among younger individuals with diabetes mellitus (DM), metabolic syndrome (MetS), and neither condition. The CAC score was independently associated with incident CVD, CHD, and all-cause mortality in those with DM, MetS, and neither condition. The impact of CAC ≥ 100 on CVD and CHD events was lower in the presence of DM. The association of CAC with all outcomes in individuals with DM remained significant after adjusting with haemoglobin A1c levels.

Small Dense Low-Density Lipoprotein Cholesterol and Coronary Artery Calcification in the Multi-Ethnic Study of Atherosclerosis.

AIM: Elevated small dense-LDL-cholesterol (sd-LDL-C) increases atherosclerotic cardiovascular disease (CVD) risk. Although coronary artery calcium (CAC) is widely used for predicting CVD events, few studies have examined the relationship between sd-LDL-C and CAC. METHODS: This study included 4672 individuals with directly-measured baseline sd-LDL-C and CAC from the Multi-Ethnic Study of Atherosclerosis (mean [SD] age: 61.9 [10.4] years; 52.5% women; 47.3% with baseline CAC [mean score >0]). We used multivariable general linear models and restricted cubic splines with goodness of fit testing to evaluate the association of sd-LDL-C with the presence of CAC. Odds ratios (OR [95% CI]) were adjusted for demographics and cardiovascular risk factors, including estimated total LDL-C. RESULTS: Higher quartiles of sd-LDL-C were associated with presence of CAC, even after accounting for total LDL-C. Compared to the lowest quartile of sd-LDL-C, participants in Quartiles 2, 3 and 4 had higher odds for the presence of baseline CAC (Quartile 2 OR: 1.24 [1.00, 1.53]; Quartile 3 OR: 1.51 [1.19, 1.93]; and Quartile 4 OR 1.59 [1.17, 2.16]). Splines suggested a quadratic curvilinear relationship of continuous sd-LDL-C with CAC after adjustment for demographics and CVD risk factors (quadratic vs. first-order sd-LDL-C terms likelihood ratio test: p=0.015), but not after accounting for total LDL-C (quadratic vs. first-order terms: p=0.156). CONCLUSIONS: In a large, multi-ethnic sample without known CVD, higher sd-LDL-C was associated with the presence of CAC, above and beyond total LDL-C. Whether selective direct measurement of sd-LDL-C is indicated to refine cardiovascular risk assessment in primary prevention warrants further investigation.

Higher levels of small dense particles of low-density lipoprotein (LDL) cholesterol, better known as the "bad cholesterol," are associated with greater risk for the presence of coronary artery calcium, a strong marker for heart disease, even when accounting for estimated total (small dense + large body particles) LDL cholesterol. This risk is stronger in older individuals. Peak risk seems to occur between 49 to 71 mg/dL and does not increase further at higher levels.

High-Sensitivity C-Reactive Protein Is Associated With Heart Failure Hospitalization in Patients With Metabolic Dysfunction-Associated Fatty Liver Disease and Normal Left Ventricular Ejection Fraction Undergoing Coronary Angiography.

BACKGROUND: Systemic chronic inflammation plays a role in the pathophysiology of both heart failure with preserved ejection fraction (HFpEF) and metabolic dysfunction-associated fatty liver disease. This study aimed to investigate whether serum hs-CRP (high-sensitivity C-reactive protein) levels were associated with the future risk of heart failure (HF) hospitalization in patients with metabolic dysfunction-associated fatty liver disease and a normal left ventricular ejection fraction. METHODS AND RESULTS: The study enrolled consecutive individuals with metabolic dysfunction-associated fatty liver disease and normal left ventricular ejection fraction who underwent coronary angiography for suspected coronary heart disease. The study population was subdivided into non-HF, pre-HFpEF, and HFpEF groups at baseline. The study outcome was time to the first hospitalization for HF. In 10 019 middle-aged individuals (mean age, 63.3±10.6 years; 38.5% women), the prevalence rates of HFpEF and pre-HFpEF were 34.2% and 34.5%, with a median serum hs-CRP level of 4.5 mg/L (interquartile range, 1.9-10 mg/L) and 5.0 mg/L (interquartile range, 2.1-10.1 mg/L), respectively. Serum hs-CRP levels were significantly higher in the pre-HFpEF and HFpEF groups than in the non-HF group. HF hospitalizations occurred in 1942 (19.4%) patients over a median of 3.2 years, with rates of 3.7% in non-HF, 20.8% in pre-HFpEF, and 32.1% in HFpEF, respectively. Cox regression analyses showed that patients in the highest hs-CRP quartile had a ≈4.5-fold increased risk of being hospitalized for HF compared with those in the lowest hs-CRP quartile (adjusted-hazard ratio, 4.42 [95% CI, 3.72-5.25]). CONCLUSIONS: There was a high prevalence of baseline pre-HFpEF and HFpEF in patients with metabolic dysfunction-associated fatty liver disease and suspected coronary heart disease. There was an increased risk of HF hospitalization in those with elevated hs-CRP levels.

Temporal Trends in Substance Use and Cardiovascular Disease-Related Mortality in the United States.

BACKGROUND: There are limited data on substance use (SU) and cardiovascular disease (CVD)-related mortality trends in the United States. We aimed to evaluate SU+CVD-related deaths in the United States using the Centers for Disease Control and Prevention Wide-Ranging, Online Data for Epidemiologic Research database. METHODS AND RESULTS: The Multiple Cause-of-Death Public Use record death certificates were used to identify deaths related to both SU and CVD. Crude, age-adjusted mortality rates, annual percent change, and average annual percent changes with a 95% CI were analyzed. Between 1999 and 2019, there were 636 572 SU+CVD-related deaths (75.6% men, 70.6% non-Hispanic White individuals, 65% related to alcohol). Age-adjusted mortality rates per 100 000 population were pronounced in men (22.5 [95% CI, 22.6-22.6]), American Indian or Alaska Native individuals (37.7 [95% CI, 37.0-38.4]), nonmetropolitan/rural areas (15.2 [95% CI, 15.1-15.3]), and alcohol-related death (9.09 [95% CI, 9.07 to 9.12]). The overall SU+CVD-related age-adjusted mortality rates increased from 9.9 (95% CI, 9.8-10.1) in 1999 to 21.4 (95% CI, 21.2-21.6) in 2019 with an average annual percent change of 4.0 (95% CI, 3.7-4.3). Increases in SU+CVD-related average annual percent change were noted across all subgroups and were pronounced among women (4.8% [95% CI, 4.5-5.1]), American Indian or Alaska Native individuals, younger individuals, nonmetropolitan areas, and cannabis and psychostimulant users. CONCLUSIONS: There was a prominent increase in SU+CVD-related mortality in the United States between 1999 and 2019. Women, non-Hispanic American Indian or Alaska Native individuals, younger individuals, nonmetropolitan area residents, and users of cannabis and psychostimulants had pronounced increases in SU+CVD mortality.

Treatment Prediction in the ICU Using a Partitioned, Sequential, Deep Time Series Analysis.

We have developed a time-oriented machine-learning tool to predict the binary decision of administering a medication and the quantitative decision regarding the specific dose. We evaluated our tool on the MIMIC-IV ICU database, for three common medical scenarios. We use an LSTM based neural network, and considerably extend its use by introducing several new concepts. We partition the common 12-hour prediction horizon into three sub-windows. Partitioning models the treatment dynamics better, and allows the use of previous sub-windows' data as additional training data with improved performance. We also introduce a sequential prediction process, composed of a binary treatment-decision model, followed, when relevant, by a quantitative dose-decision model, with improved accuracy. Finally, we examined two methods for including non-temporal features, such as age, within the temporal network. Our results provide additional treatment-prediction tools, and thus another step towards a reliable and trustworthy decision-support system that reduces the clinicians' cognitive load.

Assembly and annotation of 2 high-quality columbid reference genomes from sequencing of a Columba livia × Columba guinea F1 hybrid.

Pigeons and doves (family Columbidae) are one of the most diverse extant avian lineages, and many species have served as key models for evolutionary genomics, developmental biology, physiology, and behavioral studies. Building genomic resources for columbids is essential to further many of these studies. Here, we present high-quality genome assemblies and annotations for 2 columbid species, Columba livia and Columba guinea. We simultaneously assembled C. livia and C. guinea genomes from long-read sequencing of a single F1 hybrid individual. The new C. livia genome assembly (Cliv_3) shows improved completeness and contiguity relative to Cliv_2.1, with an annotation incorporating long-read IsoSeq data for more accurate gene models. Intensive selective breeding of C. livia has given rise to hundreds of breeds with diverse morphological and behavioral characteristics, and Cliv_3 offers improved tools for mapping the genomic architecture of interesting traits. The C. guinea genome assembly is the first for this species and is a new resource for avian comparative genomics. Together, these assemblies and annotations provide improved resources for functional studies of columbids and avian comparative genomics in general.