Dietary Strategies to Improve Cardiovascular Health: Focus on Increasing High-Density Lipoprotein Functionality

Cardiovascular disease is one of the leading causes of morbidity and mortality worldwide, with increasing incidence. A cornerstone of cardiovascular disease prevention is lifestyle modification through dietary changes to influence various risk factors such as obesity, hypertension and diabetes. The effects of diet on cardiovascular health are complex. Some dietary components and metabolites directly affect the composition and structure of high-density lipoproteins (HDL) and increase anti-inflammatory and vasoprotective properties. HDLs are composed of distinct subpopulations of particles of varying size and composition that have several dynamic and context-dependent functions. The identification of potential dietary components that improve HDL functionality is currently an important research goal. One of the best-studied diets for cardiovascular health is the Mediterranean diet, consisting of fish, olive oil, fruits, vegetables, whole grains, legumes/nuts, and moderate consumption of alcohol, most commonly red wine. The Mediterranean diet, especially when supplemented with extra virgin olive oil rich in phenolic compounds, has been shown to markedly improve metrics of HDL functionality and reduce the burden, or even prevent the development of cardiovascular disease. Particularly, the phenolic compounds of extra virgin olive oil seem to exert the significant positive effects on HDL function. Moreover, supplementation of anthocyanins as well as antioxidants such as lycopene or the omega−3 fatty acid eicosapentaenoic acid improve parameters of HDL function. In this review, we aim to highlight recent discoveries on beneficial dietary patterns as well as nutritional components and their effects on cardiovascular health, focusing on HDL function.

High-density lipoprotein functionality in patients with hyperbaric oxygen therapy

High-density lipoprotein (HDL) cholesterol levels are associated with decreased risk of atherosclerotic disease, but also not all HDL are functionally equivalent. The functional status of HDL is closely linked to its primary protein component, apolipoprotein A-1 (ApoA-I) levels and paraoxonase 1 (PON1) enzyme. Functional changes of HDL may arise from hyperbaric oxygen therapy (HBO) induced posttranslational modification of ApoA-1 and PON1 levels. A total of 41 patients who met the research criteria were included in the study. On average, 30 sessions of HBO therapy were performed (range: 20-39). Laboratory measurements were performed at the beginning and at the end of HBO treatment in two groups of the same patients. We measured serum levels of Apo A-1, PON1, oxidized LDL (OxLDL) and routine lipid laboratory parameters to determine possible changes in HDL function with HBO therapy. As unexpected, long term HBO treatment have no effect on OxLDL and also on PON1 enzyme. However, the mean ApoA-1 values in the second group were statistically significantly increased than their pre-treatment values (P < 0.003). This preliminary study showed that HBO therapy increased the amount of serum ApoA-1. Actually, it can be assumed that the treatment of HBO does not have a negative effect on HDL functionality. The increase in ApoA-1 with HBO therapy is probably aimed at protecting against oxidative stress in patients. As a result, there is a need for larger clinical trials to determine the possible effects of HBO therapy on HDL functionality.

Environmental Factors Modifying HDL Functionality

Background: Currently, it has been recognized that High-Density Lipoproteins (HDL) functionality plays a much more essential role in protection from atherosclerosis than circulating HDL-cholesterol (HDL-C) levels per se. Cholesterol efflux from macrophages to HDL, cholesterol efflux capacity (CEC) has been shown to be a key metric of HDL functionality. Thus, quantitative assessment of CEC may be an important tool for the evaluation of HDL functionality, as improvement of HDL function may lead to a reduction of the risk for Cardiovascular disease (CVD). Introduction: Although the cardioprotective action of HDLs is exerted mainly through their involvement in the reverse cholesterol transport (RCT) pathway, HDLs also have important anti-inflammatory, antioxidant, antiaggregatory and anticoagulant properties that contribute to their favorable cardiovascular effects. Certain genetic, pathophysiologic, disease states and environmental conditions may influence the cardioprotective effects of HDL either by inducing modifications in lipidome and/or protein composition or in the enzymes responsible for HDL metabolism. On the other hand, certain healthy habits or pharmacologic interventions may actually favorably affect HDL functionality. Method: The present review discusses the effects of environmental factors, including obesity, smoking, alcohol consumption, dietary habits, various pharmacologic interventions, as well as aerobic exercise, on HDL functionality. Result: Experimental and clinical studies or pharmacological interventions support the impact of these environmental factors in the modification of HDL functionality, although the mechanisms that are mediated are poorly understood. Conclusion: Further research should be conducted to unreal the underlying mechanisms of these environmental factors and to identify new pharmacologic interventions, capable of enhancing CEC, improving HDL functionality and potentially improving cardiovascular risk.

The role of abnormalities of lipoproteins and HDL functionality in small fibre dysfunction in people with severe obesity

Obesity and associated dyslipidemia may contribute to increased cardiovascular disease. Obesity has also been associated with neuropathy. We have investigated presence of peripheral nerve damage in patients with severe obesity without type 2 diabetes and the status of metabolic syndrome and lipoprotein abnormalities. 47participants with severe obesity and 30 age-matched healthy controls underwent detailed phenotyping of neuropathy and an assessment of lipoproteins and HDL-functionality. Participants with severe obesity had a higher neuropathy symptom profile, lower sural and peroneal nerve amplitudes, abnormal thermal thresholds, heart rate variability with deep breathing and corneal nerve parameters compared to healthy controls. Circulating apolipoprotein A1 (P = 0.009), HDL cholesterol (HDL-C) (P < 0.0001), cholesterol efflux (P = 0.002) and paroxonase-1 (PON-1) activity (P < 0.0001) were lower, and serum amyloid A (SAA) (P < 0.0001) was higher in participants with obesity compared to controls. Obese participants with small nerve fibre damage had higher serum triglycerides (P = 0.02), lower PON-1 activity (P = 0.002) and higher prevalence of metabolic syndrome (58% vs. 23%, P = 0.02) compared to those without. However, HDL-C (P = 0.8), cholesterol efflux (P = 0.08), apoA1 (P = 0.8) and SAA (P = 0.8) did not differ significantly between obese participants with and without small nerve fibre damage. Small nerve fibre damage occurs in people with severe obesity. Patients with obesity have deranged lipoproteins and compromised HDL functionality compared to controls. Obese patients with evidence of small nerve fibre damage, compared to those without, had significantly higher serum triglycerides, lower PON-1 activity and a higher prevalence of metabolic syndrome.

Associations between High-Density Lipoprotein Functionality and Major Adverse Cardiovascular Events in Patients Who Have Undergone Coronary Computed Tomography Angiography

The present study aimed to investigate the associations between high-density lipoprotein (HDL) functionality and major adverse cardiovascular events (MACE) in patients who have undergone coronary computed tomography angiography (CCTA). We performed a prospective cohort study and enrolled 151 patients who underwent CCTA and had a follow-up of up to 5 years. We measured cholesterol efflux capacity (CEC), caspase-3/7 activity and monocyte chemoattractant protein-1 (MCP-1) secretion as bioassays of HDL functionality. The patients were divided into MACE(−) (n = 138) and MACE(+) (n = 13) groups. While there was no significant difference in %CEC, caspase-3/7 activity or MCP-1 secretion between the MACE(−) and MACE(+) groups, total CEC and HDL cholesterol (HDL-C) in the MACE(+) group were significantly lower than those in the MACE(−) group. Total CEC was correlated with HDL-C. A receiver-operating characteristic curve analysis showed that there was no significant difference between the areas under the curves for total CEC and HDL-C. In conclusion, total CEC in addition to HDL-C, but not %CEC, was associated with the presence of MACE. On the other hand, HDL functionality with regard to anti-inflammatory and anti-apoptosis effects was not associated with MACE.

Insulin Resistance Is Associated With Impaired HDL Function and Atherogenic Modification of LDL in Polycystic Ovarian Syndrome

Background and Aims: Polycystic ovarian syndrome (PCOS) is associated with increased risk of cardiovascular disease (CVD). The aim of this study was to assess the association between PCOS and markers of HDL functionality and atherogenic LDL modification. Methods: This is a cross-sectional study of 104 women with PCOS [median (IQR); age 29 (24–36) years, and BMI 32.9 (25.7–38.5) kg/m2] and 103 BMI-matched healthy participants (age 34 (27–37) years, and BMI 31.1 (27.6–35.5) kg/m2). PCOS was defined using the NIH criteria. Measurement of lipid profile and glycaemic blood parameters were undertaken. Patients with PCOS were divided into tertiles of insulin resistance assessed using the homeostatic model assessment (HOMA-IR). Cholesterol efflux capacity (CEC), and paraoxonase-1 (PON1) activity were measured as markers of HDL functionality. Oxidized LDL (OxLDL), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized phoshopholipids on apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) (OxPL-apo(a)), and glycated apoB were used as markers of atherogenic modification of LDL. Results: Patients with PCOS in the upper tertile of insulin resistance had impaired HDL functionality compared to the lower tertile and controls, with lower CEC [13.7 (12.4–14.6) vs 14.9 (13.6–17.0), P=0.003; and 14.5 (13.0–16.0) %, P=0.063 respectively] and PON1 activity [77.2 (48.2–129.2) vs 112.9 (54.0–175.4), P=0.043; and 131.6 (89.5–195.1) nmol/ml/min, P&lt;0.001 respectively]. Markers of atherogenic modification of LDL were also increased in the upper tertile compared to the lower tertile and controls, with higher levels of OxLDL [91.6 (58.8–120.9) vs 67.2 (20.1–86.3), P=0.016; and 74.8 (47.6–89.5) ng/ml, P=0.013 respectively], LpPLA2 [1.66 (1.48–1.84) vs 1.48 (1.39–1.60), P=0.004; and 1.53 (1.37–1.70) µg/ml, P=0.015 respectively], small-dense LDL cholesterol (sdLDL) [24.8 (16.8–35.0) vs 15.3 (11.3–20.1), P&lt;0.001; and 20.9 (14.6–29.0) mg/dl, P&lt;0.001 respectively], and glycated apoB [4.02 (3.63–4.33) vs 3.51 (3.27–3.70), P&lt;0.001; and 3.48 (3.20–3.96), P&lt;0.001 respectively]. Both BMI and insulin resistance were associated with adverse lipoprotein modification, correlating positively with OxLDL, LpPLA2, sdLDL, and glycated apoB (Spearman’s ρ=0.244–0.325 and Spearman’s ρ=0.254–0.377 respectively, all P&lt;0.050); and negatively with CEC (Spearman’s ρ=-0.244 and Spearman’s ρ=0.254 respectively, both P&lt;0.050). OxPL-apoB, OxPL-apo(a), and lipoprotein(a) did not differ between PCOS and controls. Conclusions: Insulin resistance is a key determinant of decreased HDL functionality and increased oxidative modification and glycation of LDL in PCOS, which is likely to contribute to the increased CVD risk.

Impaired High‐Density Lipoprotein Function in Patients With Heart Failure

Background We recently showed that, in patients with heart failure, lower high‐density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow‐up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti‐inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT‐CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti‐inflammatory capacity declined (both P <0.001). In contrast, antioxidative capacity increased ( P <0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT‐CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71–0.92; P =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow‐up, independent of HDL cholesterol. HDL cholesterol efflux and anti‐inflammatory capacity declined during follow‐up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.