Does Adopting Western Low-density Lipoprotein Cholesterol Targets Expose Indians to a Higher Risk of Cardiovascular Events? Expert Opinion From the Lipid Association of India.

Adverse cardiovascular (CV) events have declined in Western countries due at least in part to aggressive risk factor control, including dyslipidemia management. The American and European (Western) dyslipidemia treatment guidelines have contributed significantly to the reduction in atherosclerotic cardiovascular disease (ASCVD) incidence in the respective populations. However, their direct extrapolation to Indian patients does not seem appropriate for the reasons described below. In the US, mean low-density lipoprotein cholesterol (LDL-C) levels have markedly declined over the last 2 decades, correlating with a proportional reduction in CV events. Conversely, poor risk factor control and dyslipidemia management have led to increased CV and coronary artery disease (CAD) mortality rates in India. The population-attributable risk of dyslipidemia is about 50% for myocardial infarction, signifying its major role in CV events. In addition, the pattern of dyslipidemia in Indians differs considerably from that in Western populations, requiring unique strategies for lipid management in Indians and modified treatment targets. The Lipid Association of India (LAI) recognized the need for tailored LDL-C targets for Indians and recommended lower targets compared to Western guidelines. For individuals with established ASCVD or diabetes with additional risk factors, an LDL-C target of <50 mg/dL was recommended, with an optional target of ≤30 mg/dL for individuals at extremely high risk. There are several reasons that necessitate these lower targets. In Indian subjects, CAD develops 10 years earlier than in Western populations and is more malignant. Additionally, Indians experience higher CAD mortality despite having lower basal LDL-C levels, requiring greater LDL-C reduction to achieve a comparable CV event reduction. The Indian Council for Medical Research-India Diabetes study described a high prevalence of dyslipidemia among Indians, characterized by relatively lower LDL-C levels, higher triglyceride levels, and lower high-density lipoprotein cholesterol (HDL-C) levels compared to Western populations. About 30% of Indians have hypertriglyceridemia, aggravating ASCVD risk and complicating dyslipidemia management. The levels of atherogenic triglyceride-rich lipoproteins, including remnant lipoproteins, are increased in hypertriglyceridemia and are predictive of CV events. Hypertriglyceridemia is also associated with higher levels of small, dense LDL particles, which are more atherogenic, and higher levels of apolipoprotein B (Apo B), reflecting a higher burden of circulating atherogenic lipoprotein particles. A high prevalence of low HDL-C, which is often dysfunctional, and elevated lipoprotein(a) [Lp(a)] levels further contribute to the heightened atherogenicity and premature CAD in Indians. Considering the unique characteristics of atherogenic dyslipidemia in Indians, lower LDL-C, non-HDL-C, and Apo B goals compared to Western guidelines are required for effective control of ASCVD risk in Indians. South Asian ancestry is identified as a risk enhancer in the American lipid management guidelines, highlighting the elevated ASCVD risk of Indian and other South Asian individuals, suggesting a need for more aggressive LDL-C lowering in such individuals. Hence, the LDL-C goals recommended by the Western guidelines may be excessively high for Indians and could result in significant residual ASCVD risk attributable to inadequate LDL-C lowering. Further, the results of Mendelian randomization studies have shown that lowering LDL-C by 5-10 mg/dL reduces CV risk by 8-18%. The lower LDL-C targets proposed by LAI can yield these incremental benefits. In conclusion, Western LDL-C targets may not be suitable for Indian subjects, given the earlier presentation of ASCVD at lower LDL-C levels. They may result in greater CV events that could otherwise be prevented with lower LDL-C targets. The atherogenic dyslipidemia in Indian individuals necessitates more aggressive LDL-C and non-HDL-C lowering, as recommended by the LAI, in order to stem the epidemic of ASCVD in India.

Liver fibrosis according to diabetes status and relation to cardiovascular risk and mortality in US adults.

Study objective: Liver fibrosis is associated with increased cardiovascular disease (CVD) risk and mortality. However, it is unknown how these risks compare in those with pre-diabetes (pre-DM) or diabetes (DM). We examined the association of FIB-4 levels, an indicator of liver fibrosis, with CVD risk and mortality according to DM status. Design and setting: Prospective, longitudinal cohort study. Participants: We examined 13,326 U.S. adults (6.7 % with DM) with FIB-4 measures classified as low (<1.30), intermediate (1.30- < 2.67), high (2.67- < 3.25), and very high (≥3.25). National Death Index linkage provided mortality status for CVD, liver-related, and all causes over 17.5 years. Main outcomes: We calculated 10-year ASCVD risk in persons without known ASCVD. Cox regression examined the relation of FIB-4 with mortality by DM status. Results: High/very high FIB-4 levels were greater in those with (2.2 %) vs. without (0.4 %) DM (p < 0.0001). Higher FIB-4 scores and DM were associated with greater estimated ASCVD risks (p < 0.0001); 44.5 % of those at high /very high FIB-4 levels had ≥20 % estimated ASCVD risk. CVD mortality hazard ratios (HRs) (95 % CI) associated with high/very high FIB-4 in those with pre-DM and DM were 8.76 (3.66-20.95), and 0.89 (0.22-3.53), respectively, and for total mortality were 5.46 (3.16-9.43), and 2.07 (0.90-4.74), respectively, which were attenuated after adjustment. Conclusions: Our findings indicate the need for increased efforts to identify those at risk of liver fibrosis in adults with pre-DM or DM to prevent CVD and total mortality.

Association of Energy Intake and Dietary Glycemic Load in Different Time Periods With Cardiovascular Disease Mortality Among U.S. Adults With Type 2 Diabetes.

OBJECTIVE: To examine the associations of energy intake and glycemic load (GL) in different time periods during the day with cardiovascular disease (CVD) mortality risk in adults with type 2 diabetes. RESEARCH DESIGN AND METHODS: This cohort study included 2,911 adults with diabetes from who were part of the U.S. National Health and Nutrition Examination Survey 2003-2014 (baseline), and CVD mortality data obtained by linkage to the National Death Index through 2019. Energy intake and GL in early morning (6:00-7:59 a.m.), late morning (8:00-10:59 a.m.), afternoon (11:00 a.m.-5:59 p.m.), evening (6:00-11:59 p.m.), and night (0:00-5:59 a.m.) were derived from two 24-h dietary recalls at baseline. Cox models were used to estimate hazard ratios (HRs) for CVD mortality, adjusted for total energy intake, diet quality, sociodemographic and lifestyle characteristics, and medical conditions. RESULTS: At baseline, the study population (51.8% female, 62.3% non-Hispanic White) had a mean age of 57.4 (SE, 0.4) years. Over a median follow-up of 9.3 (interquartile range = 6.8, 12.1) years, 190 CVD deaths were documented. Energy intake and GL in late morning were inversely associated with CVD mortality risk (per 100-kcal energy intake increment, HR 0.90 [95% CI 0.83-0.98]; per 10-unit GL increment, HR 0.86 [95% CI 0.77-0.95]). In contrast, energy intake and GL at night were positively associated with CVD mortality risk (per 100-kcal energy intake increment, HR 1.22 [95% CI 1.07-1.40]; per 10-unit GL increment, HR 1.44 [95% CI 1.17-1.77]). CONCLUSIONS: For adults with type 2 diabetes, late morning may be a protective eating time against CVD mortality, whereas night may be a detrimental eating time.

Rapid achievement of low-density lipoprotein cholesterol goals within 1 month after acute coronary syndrome during combination therapy with rosuvastatin, ezetimibe and bempedoic acid: Initial experience from the LAI-REACT study.

Rapid reduction of low-density lipoprotein cholesterol (LDL-C) to target levels immediately following acute coronary syndrome (ACS) event is critical to prevent future events. High-dose statins alone often fail to achieve LDL-C goals. Proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK9i) combined with high-dose statins improves LDL-C goal attainment, but is unaffordable for many patients in India and worldwide. In a real-world open-label study, we demonstrated in a cohort of 122 patients with ACS, concurrent triple therapy with rosuvastatin 40 mg/d, ezetimibe 10 mg/d, and bempedoic acid 180 mg/d (REB) started at the time of hospital admission was associated with 57.7%, 61.7%, 61.9% and 60.6% reductions in LDL-C from 115.6 mg/dL at baseline to 48.9 mg/dL at week 1, 44.3 mg/dL at week 2, 44.1 mg/dL at week 4, and 45.6 mg/dL at week 6, respectively (each p < 0.001 compared to baseline; p < 0.001 across repeated measures). REB provided significant reductions in LDL-C within as early as one week and enabled 76.3% and 92.2% of patients to achieve the Lipid Association of India and American College of Cardiology recommended LDL-C targets of <50 mg/dl and <70 mg/dl within 2-weeks, respectively, which were sustained at 4-6 weeks. REB was generally well tolerated. Our study demonstrates the capacity to rapidly achieve LDL-C goals after ACS with triple REB therapy, an affordable regimen in India.

Immunogenicity of mRNA vs. BBV152 vaccine boosters against Omicron subvariants: Final results from Phase B of the PRIBIVAC study, a randomized clinical trial.

BACKGROUND: BBV152 (Covaxin™) is a whole-virion inactivated SARS-CoV-2 vaccine mixed with an immune adjuvant. We aimed to compare immune responses after booster vaccination with heterologous BBV152 versus homologous mRNA vaccine. METHODS: We conducted a randomized, participant-blinded, controlled trial. Fifty mRNA-vaccinated participants were enrolled and randomized to receive an mRNA booster (n = 26) or BBV152 (n = 24). Blood samples were collected pre-vaccination, and at Day 7, 28, 180 and 360 post-booster for analysis of humoral and cellular immune responses. Primary end point was the SARS-CoV-2 anti-spike antibody titer at day 28. RESULTS: Recruitment began in January 2022 and was terminated early due to the BBV152 group meeting pre-specified criteria for futility. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBV152 (2004 IU/mL; 95 % confidence interval [CI], 1132-3548) vs mRNA (26,669 IU/mL; 95 % CI, 21,330-33,266; p < 0.0001), but comparable levels of spike-specific CD4 and cytotoxic T-cells were observed. Anti-spike antibody titers remained significantly different at Day 180: BBV152 4467 IU/mL (95 % CI, 1959-10,186) vs mRNA 20,749 IU/mL (95 % CI, 12,303-35,075; p = 0.0017). Levels of surrogate virus neutralizing antibodies against ancestral and Omicron subvariants BA.1 and BA.2 were significantly higher among mRNA recipients at Day 180, including after adjusting for intercurrent infection. By Day 360, anti-spike antibody titers and neutralizing antibody levels against Omicron subvariants became similar between vaccine groups. By the end of the study, 16 in each arm (mRNA 64 % and BBV152 69.6 %) had breakthrough infections and time to COVID-19 infection between vaccine groups were similar (p = 0.63). CONCLUSIONS: Wild-type SARS-CoV-2 anti-spike antibody titer and surrogate virus neutralizing test levels against wild-type SARS-CoV-2 and Omicron subvariants BA.1/BA.2/BA.5 were significantly higher at Day 28 and 180 in individuals who received booster vaccination with an mRNA vaccine compared with BBV152. CLINICAL TRIAL REGISTRATION NUMBER: NCT05142319.

Global Challenges After a Global Challenge: Lessons Learned from the COVID-19 Pandemic.

Coronavirus disease 2019 (COVID-19) has affected not only individual lives but also the world and global systems, both natural and human-made. Besides millions of deaths and environmental challenges, the rapid spread of the infection and its very high socioeconomic impact have affected healthcare, economic status and wealth, and mental health across the globe. To better appreciate the pandemic's influence, multidisciplinary and interdisciplinary approaches are needed. In this chapter, world-leading scientists from different backgrounds share collectively their views about the pandemic's footprint and discuss challenges that face the international community.

Coronary Artery Calcium for Risk Stratification Among Persons With Very High HDL Cholesterol.

Background: Compared to normal high-density lipoprotein (HDL) cholesterol values, very high HDL cholesterol is associated with a higher incidence of mortality and atherosclerotic cardiovascular disease (ASCVD). As such, clinical risk stratification among persons with very high HDL cholesterol is challenging. Objectives: Among persons with very high HDL cholesterol, the purpose was to determine the prevalence of coronary artery calcium (CAC) and compare the association between traditional risk factors vs CAC for all-cause mortality and ASCVD. Methods: The primary analysis was completed among 446 participants from the Cedars-Sinai Medical Center of the CAC Consortium with very high HDL cholesterol (≥77 mg/dL in men, ≥97 mg/dL in women). Cox proportional hazards regression assessed the association of CAC and traditional risk factors with all-cause mortality during a median follow-up of 10.7 years. Replication and validation analyses were performed for all-cause mortality among 119 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with very high HDL cholesterol, who also had information on incident ASCVD. Results: The mean age was 57.9 years old, 49% were women, and the median HDL cholesterol was 98 mg/dL. One-half of participants (50%) had prevalent CAC, in whom the median CAC score was 118. Prevalent CAC conferred a 3.6-fold higher risk of all-cause mortality (HR: 3.64; 95% CI: 1.21-11.01), which appeared to be a more robust predictor than individual traditional risk factors beyond age. In the validation sample, prevalent CAC but not individual traditional risk factors were associated with all-cause mortality (HR: 2.39; 95% CI: 1.07-5.34) and a 4.0-fold higher risk of ASCVD (HR: 4.06; 95% CI: 1.11-14.84). Conclusions: Measurement of CAC may facilitate clinical risk assessment among individuals with very high HDL cholesterol.

TNFR1 signaling promotes pancreatic tumor growth by limiting dendritic cell number and function.

Pancreatic adenocarcinoma (PDAC) is one the most intractable cancers, in part due to its highly inflammatory microenvironment and paucity of infiltrating dendritic cells (DCs). Here, we find that genetic ablation or antibody blockade of tumor necrosis factor receptor 1 (TNFR1) enhanced intratumor T cell activation and slowed PDAC growth. While anti-PD-1 checkpoint inhibition alone had little effect, it further enhanced intratumor T cell activation in combination with anti-TNFR1. The major cellular alteration in the tumor microenvironment in the absence of TNFR1 signaling was a large increase in DC number and immunostimulatory phenotype. This may reflect a direct effect on DCs, because TNF induced TNFR1-dependent apoptosis of bone-marrow-derived DCs. The therapeutic response to anti-TNFR1 alone was superior to the combination of DC-activating agonistic anti-CD40 and Flt3 ligand (Flt3L). These observations suggest that targeting TNFR1, perhaps in concert with other strategies that promote DC generation and mobilization, may have therapeutic benefits.

First SARS-CoV-2 Omicron infection as an effective immune booster among mRNA vaccinated individuals: final results from the first phase of the PRIBIVAC randomised clinical trial.

BACKGROUND: Understanding how SARS-CoV-2 breakthrough infections impacts the breadth of immune responses against existing and pre-emergent SARS-CoV-2 strains is needed to develop an evidence-based long-term immunisation strategy. METHODS: We performed a randomised, controlled trial to assess the immunogenicity of homologous (BNT162b2) versus heterologous (mRNA-1273) booster vaccination in 100 BNT162b2-vaccinated infection-naïve individuals enrolled from October 2021. Post hoc analysis was performed to assess the impact of SARS-CoV-2 infection on humoral and cellular immune responses against wild-type SARS-CoV-2 and/or Omicron subvariants. FINDINGS: 93 participants completed the study at day 360. 71% (66/93) of participants reported first SARS-CoV-2 Omicron infection by the end of the study with similar proportions of infections between homologous and heterologous booster groups (72.3% [34/47] vs 69.6% [32/46]; p = 0.82). Mean wildtype SARS-CoV-2 anti-S-RBD antibody level was significantly higher in heterologous booster group compared with homologous group at day 180 (14,588 IU/mL; 95% CI, 10,186-20,893 vs 7447 IU/mL; 4646-11,912; p = 0.025). Participants who experienced breakthrough infections during the Omicron BA.1/2 wave had significantly higher anti-S-RBD antibody levels against wildtype SARS-CoV-2 and antibody neutralisation against BA.1 and pre-emergent BA.5 compared with infection-naïve participants. Regardless of hybrid immunity status, wildtype SARS-CoV-2 anti-S-RBD antibody level declined significantly after six months post-booster or post-SARS-CoV-2 infection. INTERPRETATION: Booster vaccination with mRNA-1273 was associated with significantly higher antibody levels compared with BNT162b2. Antibody responses are narrower and decline faster among uninfected, vaccinated individuals. Boosters may be more effective if administered shortly before infection outbreaks and at least six months after last infection or booster. FUNDING: Singapore NMRC, USFDA, MRC.

AI-enabled Cardiac Chambers Volumetry and Calcified Plaque Characterization in Coronary Artery Calcium (CAC) Scans (AI-CAC) Significantly Improves on Agatston CAC Score for Predicting All Cardiovascular Events: The Multi-Ethnic Study of Atherosclerosis.

Background: Coronary artery calcium (CAC) scans contain valuable information beyond the Agatston Score which is currently reported for predicting coronary heart disease (CHD) only. We examined whether new artificial intelligence (AI) algorithms applied to CAC scans may provide significant improvement in prediction of all cardiovascular disease (CVD) events in addition to CHD, including heart failure, atrial fibrillation, stroke, resuscitated cardiac arrest, and all CVD-related deaths. Methods: We applied AI-enabled automated cardiac chambers volumetry and automated calcified plaque characterization to CAC scans (AI-CAC) of 5830 individuals (52.2% women, age 61.7±10.2 years) without known CVD that were previously obtained for CAC scoring at the baseline examination of the Multi-Ethnic Study of Atherosclerosis (MESA). We used 15-year outcomes data and assessed discrimination using the time-dependent area under the curve (AUC) for AI-CAC versus the Agatston Score. Results: During 15 years of follow-up, 1773 CVD events accrued. The AUC at 1-, 5-, 10-, and 15-year follow up for AI-CAC vs Agatston Score was (0.784 vs 0.701), (0.771 vs. 0.709), (0.789 vs.0.712) and (0.816 vs. 0.729) (p<0.0001 for all), respectively. The category-free Net Reclassification Index of AI-CAC vs. Agatston Score at 1-, 5-, 10-, and 15-year follow up was 0.31, 0.24, 0.29 and 0.29 (p<.0001 for all), respectively. AI-CAC plaque characteristics including number, location, and density of plaque plus number of vessels significantly improved NRI for CAC 1-100 cohort vs. Agatston Score (0.342). Conclusion: In this multi-ethnic longitudinal population study, AI-CAC significantly and consistently improved the prediction of all CVD events over 15 years compared with the Agatston score.

Energy Intake and Dietary Glycemic Load in Late Morning and Risk of Type 2 Diabetes: The Hispanic Community Health Study/Study of Latinos-A Multicenter Prospective Cohort Study.

OBJECTIVE: To evaluate the association between meal timing and type 2 diabetes risk in U.S. Hispanic/Latino adults. RESEARCH DESIGN AND METHODS: The Hispanic Community Health Study/Study of Latinos (HCHS/SOL) is a multicenter, community-based, prospective cohort study. This study included 8,868 HCHS/SOL adults without diabetes at baseline (2008-2011) and attending the visit 2 examination (2014-2017). Energy intake and glycemic load (GL) in each meal timing were assessed at baseline using two 24-h dietary recalls. Incident diabetes was identified through annual follow-up calls or at visit 2. Hazard ratios (HRs) for incident diabetes were estimated using Cox models, accounting for the complex survey design. RESULTS: The study population (50.9% female) had a baseline mean age of 39.0 (95% CI, 38.4-39.5) years. Over a median (range) follow-up of 5.8 (0.8-9.6) years, 1,262 incident diabetes cases were documented. Greater energy intake and GL in late morning (9:00-11:59 a.m.) were associated with a lower diabetes risk, whereas greater energy intake and GL in other meal timings were not. After accounting for diet quantity and quality, sociodemographic characteristics, lifestyle factors, and chronic conditions, the HRs were 0.94 (95% CI, 0.91-0.97) per 100-kcal energy intake increment and 0.93 (0.89-0.97) per 10-unit GL increment in late morning. Replacing energy intake or GL from early morning (6:00-8:59 a.m.), afternoon (12:00-5:59 p.m.), or evening (6:00-11:59 p.m.) with late-morning equivalents was associated with a comparably lower diabetes risk. CONCLUSIONS: This study identified late morning as a favorable meal timing in Hispanic/Latino adults, providing a novel perspective on type 2 diabetes prevention that warrants confirmation.

Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune suppression.

Low response rate, treatment relapse, and resistance remain key challenges for cancer treatment with immune checkpoint blockade (ICB). Here we report that loss of specific tumor suppressors (TS) induces an inflammatory response and promotes an immune suppressive tumor microenvironment. Importantly, low expression of these TSs is associated with a higher expression of immune checkpoint inhibitory mediators. Here we identify, by using in vivo CRISPR/Cas9 based loss-of-function screening, that NF1, TSC1, and TGF-ß RII as TSs regulating immune composition. Loss of each of these three TSs leads to alterations in chromatin accessibility and enhances IL6-JAK3-STAT3/6 inflammatory pathways. This results in an immune suppressive landscape, characterized by increased numbers of LAG3+ CD8 and CD4 T cells. ICB targeting LAG3 and PD-L1 simultaneously inhibits metastatic progression in preclinical triple negative breast cancer (TNBC) mouse models of NF1-, TSC1- or TGF-ß RII- deficient tumors. Our study thus reveals a role of TSs in regulating metastasis via non-cell-autonomous modulation of the immune compartment and provides proof-of-principle for ICB targeting LAG3 for patients with NF1-, TSC1- or TGF-ß RII-inactivated cancers.

US Population Eligibility and Estimated Impact of Tirzepatide Treatment on Obesity Prevalence and Cardiovascular Disease Events.

PURPOSE: Tirzepatide promotes weight loss and reduces risk factors for cardiovascular disease (CVD) in adults with overweight and obesity. We examined the number of US adults eligible for tirzepatide and its impact on obesity and CVD events. METHODS: We identified US adults aged ≥ 18 years from the cross-sectional US National Health and Nutrition Examination Survey (NHANES) 2015-2018 eligible for tirzepatide based on SURMOUNT-1 trial eligibility criteria. Weight changes in SURMOUNT-1 from tirzepatide 15 mg treatment were used to project the impact on weight change and obesity prevalence in the population assuming titration to this dosage. We estimated 10-year CVD risks from BMI-based Framingham CVD risk scores before and after applying tirzepatide 15 mg treatment BMI and risk factor effects from SURMOUNT-1, the differences in estimated risks multiplied by the eligible NHANES weighted population representing the estimated "preventable" CVD events. RESULTS: We identified 4015 US adults (estimated population size of 93.4 million [M]) to fit SURMOUNT-1 eligibility criteria, representing 38% of US adults. When the effects of 15 mg tirzepatide were applied, we estimated 70.6% (65.9 M) and 56.7% (53.0 M) of adults to show ≥ 15% and ≥ 20% reductions in weight, respectively, translating to 58.8% (55.0 M) fewer persons with obesity. Among those without CVD, estimated 10-year CVD risks were 10.1% "before" and 7.7% "after" tirzepatide "treatment" reflecting a 2.4% absolute (and 23.6% relative) risk reduction translating to 2.0 million preventable CVD events over 10 years. CONCLUSION: Tirzepatide treatment in appropriate US adults may substantially reduce obesity prevalence and CVD events, impacting beneficially on associated healthcare costs.

Effects of omega-3 fatty acids on coronary revascularization and cardiovascular events: a meta-analysis.

AIMS: Benefits of pharmacologic omega-3 fatty acid administration in cardiovascular prevention are controversial. Particularly, effects on coronary revascularization are unclear; also debated are specific benefits of eicosapentaenoic acid (EPA). We investigated incident coronary revascularizations, myocardial infarction (MI), stroke, heart failure (HF), unstable angina, and cardiovascular death, in subjects randomized to receive EPA or EPA + docosahexaenoic acid (EPA + DHA) vs. control. METHODS AND RESULTS: Meta-analysis of randomized controlled trials (RCTs) was conducted after MEDLINE, Embase, Scopus, Web of Science, and Cochrane Library search. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed for abstracting data and assessing data quality and validity. Data were pooled using a random effects model. Eighteen RCTs with 134 144 participants (primary and secondary cardiovascular prevention) receiving DHA + EPA (n = 52 498), EPA alone (n = 14 640), or control/placebo (n = 67 006) were included. Follow-up ranged from 4.5 months to 7.4 years. Overall, compared with controls, omega-3 supplementation reduced the risk of revascularization [0.90, 95% confidence interval (CI) 0.84-0.98; P = 0.001; P-heterogeneity = 0.0002; I2 = 68%], MI (0.89, 95% CI 0.81-0.98; P = 0.02; P-heterogeneity = 0.06; I2 = 41%), and cardiovascular death (0.92, 95% CI 0.85-0.99; P = 0.02; P-heterogeneity = 0.13; I2 = 33%). Lower risk was still observed in trials where most participants (≥60%) were on statin therapy. Compared with DHA + EPA, EPA alone showed a further significant risk reduction of revascularizations (0.76, 95% CI 0.65-0.88; P = 0.0002; P-interaction = 0.005) and all outcomes except HF. CONCLUSION: Omega-3 fatty acid supplementation reduced the risk of cardiovascular events and coronary revascularization, regardless of background statin use. Eicosapentaenoic acid alone produced greater benefits. The role of specific omega-3 molecules in primary vs. secondary prevention and the potential benefits of reduced revascularizations on overall health status and cost savings warrant further research.

It is debated whether pharmacologic administration of omega-3 fatty acids reduces cardiac events. In particular, it is unclear whether benefits are actually restricted to the use of eicosapentaenoic acid (EPA), or whether combined administration of EPA + docosahexaenoic acid (DHA) is needed; furthermore, little is known about possible benefits of omega-3 fatty acids in reducing incidence of coronary revascularization procedures. In this meta-analysis of all published evidence of clinical trials comparing EPA alone or EPA + DHA vs. control (134 144 participants), we demonstrate the following: In the overall analysis of all trials, omega-3 supplementation reduced the risk of myocardial infarction and cardiovascular death, to a modest extent. However, when trials administering EPA alone were separately analysed, a further significant risk reduction for cardiovascular outcomes was demonstrated. Importantly, these benefits were also observed in subjects who were already taking statins as part of their chronic therapy.Administration of omega-3 fatty acids, particularly EPA alone, was also associated with a substantial decrease in the risk for subsequent coronary revascularizations. Reduction of revascularization procedures may induce additional benefits on overall health status and associated cost savings.

Impact of Aging on Cardiovascular Diseases: From Chronological Observation to Biological Insights: JACC Family Series.

Cardiovascular disease (CVD) has increasing challenges for human health with an increasingly aging population worldwide, imposing a significant obstacle to the goal of healthy aging. Rapid advancements in our understanding of biological aging process have shed new light on some important insights to aging-related diseases. Although numerous reviews delved into the mechanisms through which biological aging affects CVD and age-related diseases, most of these reviews relied heavily on research related to cellular and molecular processes often observed from animal experiments. Few reviews have provided insights that connect hypotheses regarding the biological aging process with the observed patterns of chronological aging-related impacts on CVD in human populations. The purpose of this review is to highlight some of the major questions in studies of aging-related CVD and provide our perspectives in the context of real-world patterns of CVD with multidimensional information and potential biological insights.

Impact of cardiorespiratory fitness and diabetes status on cardiovascular disease and all-cause mortality: An NHANES retrospective cohort study.

High cardiorespiratory fitness (CRF) is associated with decreased mortality in people with pre-diabetes (pre-DM) and diabetes mellitus (DM); however, the degree to which CRF attenuates the risk of cardiovascular disease (CVD)-related and all-cause mortality is unclear. Study objective: We examined the impact of CRF status on CVD-related morbidity and all-cause mortality in non-DM, Pre-DM, and DM populations. Design and setting: 13,968 adults from the Third US National Health and Nutrition Examination Survey (NHANES III) were stratified into non-DM, pre-DM, or DM groups based on HbA1c levels. VO2Max was calculated using the Fitness Registry and Importance of Exercise: A National Database (FRIEND) equation. Participants: Participants were categorized into tertiles of VO2Max; first VO2Max tertile was the lowest VO2Max and third VO2Max tertile was the highest. Main outcome measures: Cox regression was used to analyze the relationship between glycemic levels, VO2Max, and CVD-related and all-cause mortality. Results: Those with DM in the highest fitness tertile had CVD (HR 0.13; 95 % CI 0.06, 0.27; p < 0.0001) and all cause (HR 0.28; 95 % CI 0.21, 0.38; p < 0.0001) mortality rates as low or lower than those with pre-DM (CVD HR 1.02; 95 % CI 0.78, 1.33 p < 0.892; all cause HR 0.96; 95 % CI 0.83, 1.12; p < 0.5496) or non-DM (CVD HR 0.65; 95 % CI 0.52, 0.80; p < 0.0001; all cause HR 0.61; 95 % CI 0.55, 0.68; p < 0.0001) at lower fitness levels. Regardless of DM status, there was lower all-cause mortality with higher CRF levels. Conclusions: Higher fitness levels in DM individuals are associated with total and CVD mortality rates as low or lower than those without DM with lower fitness.

Polygenic risk and incident coronary heart disease in a large multiethnic cohort.

Objective: Many studies support the notion that polygenic risk scores (PRS) improve risk prediction for coronary heart disease (CHD) beyond conventional risk factors. However, PRS are not yet considered risk-enhancing factor in guidelines. Our objective was to determine the predictive performance of a commercially available PRS (CARDIO inCode-Score®) compared with the Pooled Cohorts Equations (PCE) in a contemporary, multi-ethnic cohort. Methods: Participants (n = 63,070; 67 % female; 18 % non-European) without prior CHD were followed from 2007 through 12/31/2022. The association between the PRS and incident CHD was assessed using Cox regression adjusting for genetic ancestry and risk factors. Event rates were estimated by categories of PCE and by low/intermediate/high genetic risk within PCE categories; risk discrimination and net reclassification improvement (NRI) were also assessed. Results: There were 3,289 incident CHD events during 14 years of follow-up. Adjusted hazard ratio (aHR) for incident CHD per 1 SD increase in PRS was 1.18 (95 % CI:1.14-1.22), and the aHR for the upper vs lower quintile of the PRS was 1.66 (95 % CI:1.49-1.86). The association was consistent in both sexes, in European participants compared with all minority groups combined and was strongest in the first 5 years of follow-up. The increase in the C-statistic was 0.004 (0.747 vs. 0.751; p < 0.0001); the NRI was 2.4 (0.9-3.8) for the entire cohort and 9.7 (7.5-12.0) for intermediate PCE risk individuals. After incorporating high genetic risk, a further 10 percent of participants at borderline/intermediate PCE risk would be candidates for statin therapy. Conclusion: Inclusion of polygenic risk improved identification of primary prevention individuals who may benefit from more intensive risk factor modification.