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HDL over 74 mg/dL associated with drastically higher mortality


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Very high HDL is a risk factor:


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

European Heart Journal, Volume 38, Issue 32, 21 August 2017, Pages 2478–2486,https://doi.org/10.1093/eurheartj/ehx163






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).



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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A couple of papers that discuss the current  emphasis on HDL functionality  vs concentration:


Current and future therapies for addressing the effects of inflammation on HDL cholesterol metabolism




There have been several sharp turns in the evidence trailmarking the atheroprotective role of high density lipoproteins (HDLs). Very early studies on dyslipidaemia highlighted the positive correlation between total triglycerides (TGs) with the risk of developing cardiovascular disease (CVD). Since themid-1970s, numerous epidemiological and animal studies,including the Framingham Study (Gordon et al., 1977), reported that HDL cholesterol (HDL-C) has the strongest inverse relationship with the development of CVD of the known serum lipid factors (Badimon et al., 1990; Rubinet al., 1991; Liu et al., 1994; Plump et al., 1994). This association is underpinned by reverse cholesterol transport (RCT) a process by which HDL-C transfers the cholesterol from peripheral cells, for example, lipid-laden foam cells, to the liver for secretion into bile and faeces. The promotion of RCT is considered a major anti-atherogenic function of HDL-C(Gofman et al., 1966; Miller and Miller, 1975; Rhoads et al.,1976).
Based on these ndings, interventions to increase the levels of HDL-C were developed but found to be ineffective for preventing cardiovascular outcomes in several large clinical trials (Brousseau et al., 2004; McKenney et al., 2006; Barteret al., 2007; Boden et al., 2011; Lüscher et al., 2012; Schwartzet al., 2012). Given these results, the importance of HDL-C   for preventing CVD has been questioned and revisited. An expert panel from the National Lipid Association concluded that although HDL-C is not a therapeutic target at the present time,rigorous research into the biology and clinical signicance of low HDL-C should continue and that the development of novel drugs designed to modulate the serum levels and functionality of HDL particles should also continue(Toth et al., 2013), a recommendation which has been echoed by other experts in the eld (Brown et al., 2014; Toth et al., 2014).
In our opinion, the key issue in this matter is the functionality of HDL-C, which can be affected by adipose tissue (AT) and low-grade systemic inammation (Brewer, 2007;Rader and Daugherty, 2008; Rosenson, 2010; Zhang et al.,2010; Chung et al., 2011). Here, we discuss the data available illustrating the effect of inammation on the functionality of  HDL particles and potential therapeutic interventions that can help reverse these effects and, thus, prevent the development of metabolic abnormalities leading to the progression of CVD and associated co-morbidities.

Small HDL Promotes Cholesterol Efflux by the ABCA1 Pathway in Macrophages: Implications for Therapies Targeted to HDL



PMCID: PMC4380245
Recent clinical and genetic studies clearly demonstrate that elevating HDL-C does not necessarily reduce CVD risk (1). Therefore, it is time to end the clinical focus on HDL-C and to understand—at the mechanistic level—how HDL's functional properties contribute to that risk. It will also be important to link changes in HDL's size and function to genetics and HDL-targeted therapies. The development of new metrics for quantifying HDL function, based on a better understanding of macrophage reverse cholesterol transport, is essential for achieving these goals.



See also:


Adv Nutr. 2017 Mar 15;8(2):226-239. doi: 10.3945/an.116.014050. Print 2017 Mar. PMID:28298268

Effects of Dietary Flavonoids on Reverse Cholesterol Transport, HDL Metabolism, and HDL Function





Strong experimental evidence confirms that HDL directly alleviates atherosclerosis. HDL particles display diverse atheroprotective functions in reverse cholesterol transport (RCT), antioxidant, anti-inflammatory, and antiapoptotic processes. In certain inflammatory disease states, however, HDL particles may become dysfunctional and proatherogenic. Flavonoids show the potential to improve HDL function through their well-documented effects on cellular antioxidant status and inflammation. The aim of this review is to summarize the basic science and clinical research examining the effects of dietary flavonoids on RCT and HDL function.


Based on preclinical studies that used cell culture and rodent models, it appears that many flavonoids (e.g., anthocyanidins, flavonols, and flavone subclasses) influence RCT and HDL function beyond simple HDL cholesterol concentration by regulating cellular cholesterol efflux from macrophages and hepatic paraoxonase 1 expression and activity. In clinical studies, dietary anthocyanin intake is associated with beneficial changes in serum biomarkers related to HDL function in a variety of human populations (e.g., in those who are hyperlipidemic, hypertensive, or diabetic), including increased HDL cholesterol concentration, as well as HDL antioxidant and cholesterol efflux capacities. However, clinical research on HDL functionality is lacking for some flavonoid subclasses (e.g., flavanols, flavones, flavanones, and isoflavones). Although there has been a tremendous effort to develop HDL-targeted drug therapies, more research is warranted on how the intake of foods or specific nutrients affects HDL function.



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