Cardiovascular disease (CVD) is the leading global cause of death, accounting for 17.3 million deaths per year. Preventive treatment that reduces CVD by even a small percentage can substantially reduce, nationally and globally, the number of people who develop CVD and the costs of caring for them. This American Heart Association presidential advisory on dietary fats and CVD reviews and discusses the scientific evidence, including the most recent studies, on the effects of dietary saturated fat intake and its replacement by other types of fats and carbohydrates on CVD. In summary, randomized controlled trials that lowered intake of dietary saturated fat and replaced it with polyunsaturated vegetable oil reduced CVD by ≈30%, similar to the reduction achieved by statin treatment. Prospective observational studies in many populations showed that lower intake of saturated fat coupled with higher intake of polyunsaturated and monounsaturated fat is associated with lower rates of CVD and of other major causes of death and all-cause mortality. In contrast, replacement of saturated fat with mostly refined carbohydrates and sugars is not associated with lower rates of CVD and did not reduce CVD in clinical trials. Replacement of saturated with unsaturated fats lowers low-density lipoprotein cholesterol, a cause of atherosclerosis, linking biological evidence with incidence of CVD in populations and in clinical trials. Taking into consideration the totality of the scientific evidence, satisfying rigorous criteria for causality, we conclude strongly that lowering intake of saturated fat and replacing it with unsaturated fats, especially polyunsaturated fats, will lower the incidence of CVD. This recommended shift from saturated to unsaturated fats should occur simultaneously in an overall healthful dietary pattern such as DASH (Dietary Approaches to Stop Hypertension) or the Mediterranean diet as emphasized by the 2013 American Heart Association/American College of Cardiology lifestyle guidelines and the 2015 to 2020 Dietary Guidelines for Americans.

Dietary Fats and Cardiovascular Disease: A Presidential Advisory From the American Heart Association

http://jultika.oulu.fi/files/nbnfi-fe2019071022988.pdf

Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies

Mendelian randomization (MR) is a burgeoning field that involves the use of genetic variants to assess causal relationships between exposures and outcomes MR studies can be straightforward; for example, genetic variants within or near the encoding locus that is associated with protein concentrations can help to assess their causal role in disease However, a more complex relationship between the genetic variants and an exposure can make findings from MR more difficult to interpret In this Review, we describe some of these challenges in interpreting MR analyses, including those from studies using genetic variants to assess causality of multiple traits (such as branched-chain amino acids and risk of diabetes mellitus); studies describing pleiotropic variants (for example, C-reactive protein and its contribution to coronary heart disease); and those investigating variants that disrupt normal function of an exposure (for example, HDL cholesterol or IL-6 and coronary heart disease) Furthermore, MR studies on variants that encode enzymes responsible for the metabolism of an exposure (such as alcohol) are discussed, in addition to those assessing the effects of variants on time-dependent exposures (extracellular superoxide dismutase), cumulative exposures (LDL cholesterol), and overlapping exposures (triglycerides and non-HDL cholesterol) We elaborate on the molecular features of each relationship, and provide explanations for the likely causal associations In doing so, we hope to contribute towards more reliable evaluations of MR findings

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Mendelian randomization in cardiometabolic disease: challenges in evaluating causality

Aims High-density lipoprotein (HDL) cholesterol concentrations are inversely associated with cardiovascular disease and mortality across a range of concentrations, but genetic evidence suggest that extreme high concentrations may paradoxically lead to more cardiovascular disease. We tested the hypothesis that extreme high concentrations of HDL cholesterol are associated with high all-cause mortality in men and women. Methods and results A total of 52 268 men and 64 240 women were included from the two prospective population-based studies, the Copenhagen City Heart Study and the Copenhagen General Population Study. During 745 452 person-years of follow-up, number of deaths from any cause were 5619 (mortality rate, 17.1/1000 person-years (95% confidence interval (CI): 16.7-17.6)) in men and 5059 (mortality rate, 12.1/1000 person-years (11.8-12.4)) in women. The association between HDL cholesterol concentrations and all-cause mortality was U-shaped for both men and women, with both extreme high and low concentrations being associated with high all-cause mortality risk. The concentration of HDL cholesterol associated with the lowest all-cause mortality was 1.9 mmol/L (95% CI: 1.4-2.0) (73 mg/dL (54-77)) in men and 2.4 mmol/L (1.8-2.5) (93 mg/dL (69-97)) in women. When compared with the groups with the lowest risk, the multifactorially adjusted hazard ratios for all-cause mortality were 1.36 (95% CI: 1.09-1.70) for men with HDL cholesterol of 2.5-2.99 mmol/L (97-115 mg/dL) and 2.06 (1.44-2.95) for men with HDL cholesterol ≥3.0 mmol/L (116 mg/dL). For women, corresponding hazard ratios were 1.10 (0.83-1.46) for HDL cholesterol of 3.0-3.49 mmol/L (116-134 mg/dL) and 1.68 (1.09-2.58) for HDL cholesterol ≥3.5 mmol/L (135 mg/dL). Conclusion Men and women in the general population with extreme high HDL cholesterol paradoxically have high all-cause mortality. These findings need confirmation in other studies.

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Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies.

Cardiovascular disease, with atherosclerosis as the major underlying factor, remains the leading cause of death worldwide. It is well established that cholesterol ester-enriched foam cells are the ...

HDL and Reverse Cholesterol Transport.

Scavenger receptor BI (SR-BI) is the major receptor for high-density lipoprotein (HDL) cholesterol (HDL-C). In humans, high amounts of HDL-C in plasma are associated with a lower risk of coronary heart disease (CHD). Mice that have depleted Scarb1 (SR-BI knockout mice) have markedly elevated HDL-C levels but, paradoxically, increased atherosclerosis. The impact of SR-BI on HDL metabolism and CHD risk in humans remains unclear. Through targeted sequencing of coding regions of lipid-modifying genes in 328 individuals with extremely high plasma HDL-C levels, we identified a homozygote for a loss-of-function variant, in which leucine replaces proline 376 (P376L), in SCARB1, the gene encoding SR-BI. The P376L variant impairs posttranslational processing of SR-BI and abrogates selective HDL cholesterol uptake in transfected cells, in hepatocyte-like cells derived from induced pluripotent stem cells from the homozygous subject, and in mice. Large population-based studies revealed that subjects who are heterozygous carriers of the P376L variant have significantly increased levels of plasma HDL-C. P376L carriers have a profound HDL-related phenotype and an increased risk of CHD (odds ratio = 1.79, which is statistically significant).

/pdf/rare-variant-in-scavenger-receptor-bi-raises-hdl-cholesterol-4mm94sme8k.pdf

Hancock-Cerutti Wf

Papers

Rare variant in scavenger receptor BI raises HDL cholesterol and increases risk of coronary heart disease