Reducing saturated fat intake lowers LDL-C but increases Lp(a) levels in African Americans: the GET-READI feeding trial.

Reducing dietary saturated fatty acids (SFA) intake results in a clinically significant lowering of low-density lipoprotein cholesterol (LDL-C) across ethnicities. In contrast, dietary SFA's role in modulating emerging cardiovascular risk factors in different ethnicities remains poorly understood. Elevated levels of lipoprotein(a) [Lp(a)], an independent cardiovascular risk factor, disproportionally affect individuals of African descent. Here, we assessed the responses in Lp(a) levels to dietary SFA reduction in 166 African Americans enrolled in GET-READI (The Gene-Environment Trial on Response in African Americans to Dietary Intervention), a randomized controlled feeding trial. Participants were fed two diets in random order for 5 weeks each: 1) an average American diet (AAD) (37% total fat: 16% SFA), and 2) a diet similar to the Dietary Approaches to Stop Hypertension (DASH) diet (25% total fat: 6% SFA). The participants' mean age was 35 years, 70% were women, the mean BMI was 28 kg/m2, and the mean LDL-C was 116 mg/dl. Compared to the AAD diet, LDL-C was reduced by the DASH-type diet (mean change: -12 mg/dl) as were total cholesterol (-16 mg/dl), HDL-C (-5 mg/dl), apoA-1 (-9 mg/dl) and apoB-100 (-5 mg/dl) (all P < 0.0001). In contrast, Lp(a) levels increased following the DASH-type diet compared with AAD (median: 58 vs. 44 mg/dl, P < 0.0001). In conclusion, in a large cohort of African Americans, reductions in SFA intake significantly increased Lp(a) levels while reducing LDL-C. Future studies are warranted to elucidate the mechanism(s) underlying the SFA reduction-induced increase in Lp(a) levels and its role in cardiovascular risk across populations.

Cardiovascular Disease Mortality in Mississippi, 2000-2018.

INTRODUCTION: Cardiovascular disease (CVD) is the leading of cause of death in Mississippi. We explored trends in CVD death rates among adults in Mississippi aged 35 years or older to assess changes from 2000 through 2018. METHODS: We extracted data from Mississippi Vital Statistics from 2000 through 2018. We used underlying cause-of-death codes from the International Classification of Diseases, Tenth Revision (ICD-10) to identify CVD deaths; we included all cases with codes I00-I09, I11, I13, I20-I51, I60-I69, and I70. We calculated age-adjusted CVD death rates for the overall population by age, race, sex, and race-by-sex groups. RESULTS: Overall, the age-adjusted CVD death rate declined from 832.3 deaths per 100,000 population in 2000 to 550.5 deaths per 100,000 in 2018, a relative decline of 33.9% and an average annual decline of -2.3% (95% CI, -2.7% to -1.8%). Age-adjusted CVD death rates declined from 2000 through 2018 for all groups, but the magnitude of decline varied by subgroup (men, -2.0%; women, -2.6%; non-Hispanic Black, -2.4%; non-Hispanic White, -2.2%; non-Hispanic Black women, -3.0%; non-Hispanic White women, -2.5%; non-Hispanic Black men -2.1%; non-Hispanic White men -2.0%). Age-specific analysis indicated a significant average annual increase of 1.7% (95% CI, 0.6%-2.9%) from 2011 through 2018 for the group aged 55 to 64 years. CONCLUSION: From 2000 through 2018, age-adjusted CVD death rates in Mississippi declined for all age/race/sex groups. However, the magnitude of decline varied by subgroup. Targeted interventions for CVD risk reduction are needed for adults aged 55 to 64 years in Mississippi, the only age group in which we observed a significant annual increase in CVD death rates.

Heritability of apolipoprotein (a) traits in two-generational African-American and Caucasian families.

Heritability of LPA allele, apo(a) isoform sizes, and isoform-associated lipoprotein(a) [Lp(a)] levels was studied in 82 Caucasian and African-American families with two parents and two children (age: 6-74 years). We determined: 1) Lp(a) levels; 2) LPA allele sizes; 3) apo(a) isoform sizes; and 4) isoform-specific apo(a) levels (ISLs), the amount of Lp(a) carried by an individual apo(a) isoform. Trait heritability was estimated by mid-parent-offspring analysis. The ethnicity-adjusted heritability estimate for Lp(a) level was 0.95. Heritability for ISLs corresponding to the smaller LPA allele in a given allele-pair was higher than that corresponding to the larger LPA allele (0.91 vs. 0.59, P = 0.017). Although not statistically different, heritability for both apo(a) isoforms (0.90 vs. 0.70) and LPA alleles (0.98 vs. 0.82) was higher for the smaller versus larger sizes. Heritability was generally lower in African-Americans versus Caucasians with a 4-fold difference for the larger LPA allele (0.25 vs. 0.94, P = 0.001). In Caucasians, an overall higher heritability pattern was noted for the older (≥47 years) versus younger (<47 years) families. In conclusion, Lp(a) level and traits associated with the smaller LPA alleles were strongly determined by genetics, although with a varying ethnic influence. Ethnic differences in heritability of the larger LPA allele warrant further investigations.

Effect of antiretroviral therapy on allele-associated Lp(a) level in women with HIV in the Women's Interagency HIV Study.

We previously demonstrated an association between lipoprotein (a) [Lp(a)] levels and atherosclerosis in human immunodeficiency virus (HIV)-seropositive women. The effects of antiretroviral therapy (ART) on Lp(a) levels in relation to apo(a) size polymorphism remain unclear. ART effects on allele-specific apo(a) level (ASL), an Lp(a) level associated with individual apo(a) alleles within each allele-pair, were determined in 126 HIV-seropositive women. ART effects were tested by a mixed-effects model across pre-ART and post-ART first and third visits. Data from 120 HIV-seronegative women were used. The mean age was 38 years; most were African-American (∼70%). Pre-ART ASLs associated with the larger (4.6 mg/dl vs. 8.0 mg/dl, P = 0.024) or smaller (13 mg/dl vs. 19 mg/dl, P = 0.041) apo(a) sizes were lower in the HIV-seropositive versus HIV-seronegative group, as was the prevalence of a high Lp(a) level (P = 0.013). Post-ART ASL and prevalence of high Lp(a) or apo(a) sizes and frequency of small size apo(a) (22 kringles) did not differ between the two groups. ART increased Lp(a) level (from 18 to 24 mg/dl, P < 0.0001) and both ASLs (P < 0.001). In conclusion, regardless of genetic control, Lp(a) can be modulated by HIV and its treatment. ART initiation abrogates HIV-induced suppression of Lp(a) levels and ASLs, contributing to promote CVD risk in HIV-seropositive individuals.

Lipoprotein(a) and HIV: Allele-Specific Apolipoprotein(a) Levels Predict Carotid Intima-Media Thickness in HIV-Infected Young Women in the Women's Interagency HIV Study.

OBJECTIVE: In the general population, lipoprotein(a) [Lp(a)] has been established as an independent causal risk factor for cardiovascular disease. Lp(a) levels are to a major extent regulated by a size polymorphism in the apolipoprotein(a) [apo(a)] gene. The roles of Lp(a)/apo(a) in human immunodeficiency virus (HIV)-related elevated cardiovascular disease risk remain unclear. APPROACH AND RESULTS: The associations between total plasma Lp(a) level, allele-specific apo(a) level, an Lp(a) level carried by individual apo(a) alleles, and common carotid artery intima-media thickness were assessed in 150 HIV-infected and 100 HIV-uninfected women in the WIHS (Women's Interagency HIV Study). Linear regression analyses with and without adjustments were used. The cohort was young (mean age, ≈31 years), with the majority being Blacks (≈70%). The prevalence of a small size apo(a) (≤22 Kringle repeats) or a high Lp(a) level (≥30 mg/dL) was similar by HIV status. Total plasma Lp(a) level (P=0.029) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.022) were significantly associated with carotid artery intima-media thickness in the HIV-infected women only. After accounting for confounders (age, race, smoking, body mass index, blood pressure, hepatitis C virus coinfection, menopause, plasma lipids, treatment status, CD4+ T cell count, and HIV/RNA viral load), the association remained significant for both Lp(a) (P=0.035) and allele-specific apo(a) level carried by the smaller apo(a) sizes (P=0.010) in the HIV-infected women. Notably, none of the other lipids/lipoproteins was associated with carotid artery intima-media thickness. CONCLUSIONS: Lp(a) and allele-specific apo(a) levels predict carotid artery intima-media thickness in HIV-infected young women. Further research is needed to identify underlying mechanisms of an increased Lp(a) atherogenicity in HIV infection.

The roles of apo(a) size, phenotype, and dominance pattern in PCSK9-inhibition-induced reduction in Lp(a) with alirocumab.

An elevated level of lipoprotein (a) [Lp(a)] is a risk factor for CVD. Alirocumab, a monoclonal antibody to proprotein convertase subtilisin/kexin type 9, is reported to reduce Lp(a) levels. The relationship of Lp(a) reduction with apo(a) size polymorphism, phenotype, and dominance pattern and LDL cholesterol (LDL-C) reduction was evaluated in a pooled analysis of 155 hypercholesterolemic patients (75 with heterozygous familial hypercholesterolemia) from two clinical trials. Alirocumab significantly reduced total Lp(a) (pooled median: -21%, P = 0.0001) and allele-specific apo(a), an Lp(a) level carried by the smaller (median: -18%, P = 0.002) or the larger (median: -37%, P = 0.0005) apo(a) isoform, at week 8 versus baseline. The percent reduction in Lp(a) level with alirocumab was similar across apo(a) phenotypes (single vs. double bands) and carriers and noncarriers of a small size apo(a) (≤22 kringles). The percent reduction in LDL-C correlated significantly with the percent reduction in Lp(a) level (r = 0.407, P < 0.0001) and allele-specific apo(a) level associated with the smaller (r = 0.390, P < 0.0001) or larger (r = 0.270, P = 0.0183) apo(a) sizes. In conclusion, alirocumab-induced Lp(a) reduction was independent of apo(a) phenotypes and the presence or absence of a small size apo(a).

Lipoprotein (a): impact by ethnicity and environmental and medical conditions.

Levels of lipoprotein (a) [Lp(a)], a complex between an LDL-like lipid moiety containing one copy of apoB, and apo(a), a plasminogen-derived carbohydrate-rich hydrophilic protein, are primarily genetically regulated. Although stable intra-individually, Lp(a) levels have a skewed distribution inter-individually and are strongly impacted by a size polymorphism of the LPA gene, resulting in a variable number of kringle IV (KIV) units, a key motif of apo(a). The variation in KIV units is a strong predictor of plasma Lp(a) levels resulting in stable plasma levels across the lifespan. Studies have demonstrated pronounced differences across ethnicities with regard to Lp(a) levels and some of this difference, but not all of it, can be explained by genetic variations across ethnic groups. Increasing evidence suggests that age, sex, and hormonal impact may have a modest modulatory influence on Lp(a) levels. Among clinical conditions, Lp(a) levels are reported to be affected by kidney and liver diseases.

Lipoprotein(a) and apolipoprotein(a) in polycystic ovary syndrome.

OBJECTIVE: Levels of lipoprotein(a), Lp(a), an independent risk factor for cardiovascular disease (CVD), are affected by sex hormones. Women with polycystic ovary syndrome (PCOS) have elevated androgen levels and are at increased CVD risk. We investigated the impact of PCOS-related hormonal imbalance on Lp(a) levels in relation to apo(a) gene size polymorphism, a major regulator of Lp(a) level. DESIGN: Cross-sectional. PATIENTS: Forty-one Caucasian women with PCOS based on the NIH criteria. MEASUREMENTS: (1) Apo(a) gene size polymorphism measured as Kringle (K) 4 repeat number; (2) total plasma Lp(a) level; (3) allele-specific apo(a) level assessing the amount of Lp(a) carried by an individual apo(a) allele/isoform; and (4) sex hormone levels. RESULTS: The mean age was 32 ± 6 years, and the mean BMI was 35 ± 8 with 66% of women classified as obese (BMI >30 kg/m2 ). LDL cholesterol was borderline high (3·37 mmol/l), and HDL cholesterol was low (1·06 mmol/l). The distribution of Lp(a) level was skewed towards lower levels with a median level of 22·1 nmol/l (IQR: 6·2-66·5 nmol/l). Lp(a) levels were not correlated with age, body weight or BMI. The median allele-specific apo(a) level was 10·6 nmol/l (IQR: 3·1-31·2 nmol/l), and the median apo(a) size was 27 (IQR: 23-30) K4 repeats. Allele-specific apo(a) levels were significantly and inversely correlated with K4 repeats (r = -0·298, P = 0·007). Neither Lp(a) nor allele-specific apo(a) levels were significantly associated with testosterone or dehydroepiandrosterone sulphate levels. CONCLUSIONS: The apo(a) genetic variability remains the major regulator of plasma Lp(a) levels in women with PCOS.

Lipid Lowering with Soluble Dietary Fiber.

Consumption of dietary soluble fibers has been associated with health benefits such as reduced lipid levels, lower blood pressure, improved blood glucose control, weight loss, improved immune function, and reduced inflammation. Many of these health benefits relate to a reduced risk of developing cardiovascular disease. In this paper, we have reviewed recent studies on the hypocholesterolemic effects of dietary soluble fibers as well as fiber-rich foods. Findings include the following: (a) consumption of water-soluble, viscous-forming fibers can reduce total and low-density lipoprotein cholesterol levels by about 5-10 %; (b) minimal changes of high-density lipoprotein cholesterol or triglyceride levels were observed; (c) cholesterol-lowering properties of soluble fibers depend on their physical and chemical properties; and (d) medium to high molecular weight fibers are more effective in reducing lipid levels. Hypocholesterolemic benefits were also observed with some fiber-rich foods, such as whole oats, whole barley, legumes, peas, beans, flax seeds, apples, and citrus foods.

Rhesus monkey (Macaca mulatta) lipoprotein(a) and apolipoprotein(a): high frequency of small size apolipoprotein(a) isoforms.

BACKGROUND: Levels of lipoprotein(a), Lp(a), a genetically regulated independent cardiovascular risk factor present in humans and Old World monkeys, are impacted by the apolipoprotein(a), apo(a), gene. Allele-specific apo(a) levels, taking both the apo(a) genotypic and phenotypic characteristics into account, are useful markers to determine atherosclerotic cardiovascular risk. METHODS: We determined (i) the genetic variability of apo(a), (ii) Lp(a) levels, and (iii) allele-specific apo(a) levels in rhesus monkeys (n = 95). RESULTS: Lp(a) levels differed substantially between animals (range: 4-247 nmol/l) with a skewed distribution toward lower levels. Lp(a) and allele-specific apo(a) levels were inversely related to the number of apo(a) Kringle 4 (K4) repeats. The median apo(a) size was 23 K4 repeats, and the prevalence of a small size apo(a) (≤22 K4) was 43%. CONCLUSIONS: Distribution of Lp(a) and allele-specific apo(a) levels in rhesus monkeys reflected the corresponding human patterns, but with a high prevalence of smaller apo(a) sizes.

HIV disease activity as a modulator of lipoprotein(a) and allele-specific apolipoprotein(a) levels.

OBJECTIVE: Mechanisms underlying the cardiovascular risk of lipoprotein(a) are poorly understood. We investigated the relationship of apolipoprotein(a) (apo(a)) size, lipoprotein(a), and allele-specific apo(a) levels with HIV disease activity parameters in a biethnic population. METHODS AND RESULTS: Lipoprotein(a) and allele-specific apo(a) levels were determined in 139 white and 168 black HIV-positive patients. Plasma HIV RNA viral load and CD4+ T-cell count were used as surrogates for disease activity. Lipoprotein(a) and allele-specific apo(a) levels were higher in blacks than whites (for both P<0.001). Apo(a) allele size distribution was similar between the 2 ethnic groups, with a median apo(a) size of 28 kringle 4 repeats. Allele-specific apo(a) levels were positively associated with CD4+ T-cell count (P=0.027) and negatively with plasma HIV RNA viral load (P<0.001). Further, allele-specific apo(a) levels associated with smaller (<28 kringle 4) atherogenic apo(a) sizes were higher in subjects with CD4+ T-cell counts of ≥350 (P=0.002). CONCLUSIONS: Allele-specific apo(a) levels were higher in subjects with high CD4+ T-cell count or low plasma HIV RNA viral load. The findings suggest that HIV disease activity reduced allele-specific apo(a) levels. Higher allele-specific apo(a) levels associated with atherogenic small apo(a) sizes might contribute to increased cardiovascular risk in HIV-positive subjects with improved disease status.

Safety profile of proprotein convertase subtilisin/kexin type 9 inhibitors alirocumab and evolocumab: an updated meta-analysis and meta-regression.

BACKGROUND: The use of alirocumab and evolocumab is generally safe and well-tolerated. However, concerns remain about their long-term safety, especially with regard to new-onset or worsening diabetes mellitus (DM). We aim to assess the safety profile of alirocumab and evolocumab compared to comparator. METHODS: Studies were retrieved comparing the safety of PCSK9i vs. comparator (placebo or statin with or without ezetimibe). The primary outcome was adverse events leading to death. Secondary outcomes included serious adverse events, new onset diabetes mellitus (DM), worsening of DM, neurocognitive dysfunction, creatine kinase (CK) elevation, elevation of liver enzymes and local injection site reaction. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on PCSK9i type and treatment duration. RESULTS: We identified 56 studies with 85,123 adults (29.14% females). PCSK9i was not associated with adverse events that lead to death (OR 0.94, 95% CI 0.84 to 1.04, p = 0.22). Between the two PCSK9i, alirocumab decreased adverse events leading to death (OR 0.79, 95% CI, 0.67 to 0.94, p = 0.008). PCSK9i was associated with less serious events compared to the comparator (OR 0.93, 95% CI 0.89 to 0.98, p < 0.001). This reduction was driven mainly by alirocumab (OR 0.89, 95% CI, 0.85 to 0.93, p < 0.001). Evolocumab worsened DM (OR 2.3, 95% CI 1.26 to 4.2, p = 0.041). Subgroup analysis showed worsening of DM in the first 24 weeks of treatment with odds being highest in the first 12 weeks of treatment (<12 weeks: OR 3.82, 95% CI 1.13 to 12.99, p = 0.03; 12-24 weeks OR 2.12, 95% CI 1.20 to 3.73, p = 0.01. On the other hand, therapy >24 weeks reduced the odds of worsening DM (OR 0.89, 95% CI 0.79 to 0.99, p = 0.04). PCSK9i did not increase cognitive dysfunction, (OR 1.02, 95% CI 0.88 to 1.18, p = 0.76), or cause elevations in liver enzyme (OR 0.91, 95% CI 0.81 to 1.03, p = 0.14), or CK (OR 0.82, 95% CI 0.65 to 1.04, p = 0.10). However, PCSK9i was associated with local injection site reaction (OR 1.54, 95% CI 1.37 to 1.73, p < 0.01). CONCLUSION: Alirocumab decreased adverse events leading to death. Alirocumab and Evolocumab both decreased serious adverse events. PCSK9i did not increase new onset DM however evolocumab worsened DM in the first 24 weeks of treatment. PCSK9i did not increase neurologic dysfunction, and did not elevate liver enzymes and CK, however it was associated with local injection site reaction.

Lipoprotein(a) and diet-a challenge for a role of saturated fat in cardiovascular disease risk reduction?

In this perspective, we discuss new evidence relating to current dietary recommendations to reduce SFA intake to modulate an individual's global risk of CVD. Although it is well established that lowering dietary SFA intake has a beneficial effect on LDL cholesterol concentrations, findings increasingly indicate an opposite effect on lipoprotein(a) [Lp(a)] concentrations. In recent years, many studies have firmly established a role for an elevated Lp(a) concentration as a genetically regulated, causal, and prevalent risk factor for CVD. However, there is less awareness of the effect of dietary SFA intake on Lp(a) concentrations. This study discusses this issue and highlights the contrasting effect of reducing dietary SFA intake on LDL cholesterol and Lp(a), 2 highly atherogenic lipoproteins. This calls attention to the need for precision nutrition approaches that move beyond a "one-size-fits-all" approach. To illustrate the contrast, we describe the dynamic contributions of Lp(a) and LDL cholesterol concentrations to CVD risk during interventions with a low-SFA diet, with the hope that this will stimulate further studies and discussions regarding dietary management of CVD risk.

Sex Differences in Cardiovascular Outcomes and Cholesterol-Lowering Efficacy of PCSK9 Inhibitors: Systematic Review and Meta-Analysis.

Background: Guideline-recommended low-density lipoprotein cholesterol (LDL-C) thresholds are often not achieved in women. The proprotein convertase subtilisin/kexin type-9 inhibitor (PCSK9i) monoclonal antibodies can help further reduce LDL-C and major adverse cardiovascular events (MACE) although differences in efficacy by sex and type are less understood. Objectives: The authors sought to determine if there are differences in the efficacy of LDL-C lowering and reduction in the risk of MACE by sex and type of PCSK9i. Methods: A comprehensive literature search was done through October 17, 2022, for published trials comparing PCSK9i vs control. Outcomes assessed were LDL-C reduction and incidence of MACE following the use of PCSK9i vs placebo, stratified by sex and type of PCSK9i used. Results: We identified 16 trials with 54,996 adults, and 15,143 (27.5%) of them were female. PCSK9i significantly reduced MACE compared to placebo in both women (HR: 0.86, 95% CI: 0.74-0.97, P < 0.001) and men (HR: 0.85, 95% CI: 0.79-0.91, P < 0.001) with no significant sex difference (MD -0.01, 95% CI: -0.14 to -0.13, P = 0.930). PCSK9i also significantly reduced LDL-C levels in both sexes at 12 weeks (females: MD -62.57, 95% CI: -70.24 to -54.91, P < 0.001; males: MD -66.19, 95% CI: -72.03 to -60.34, P < 0.001) and 24 weeks (females: MD -47.52, 95% CI: -52.94 to -42.09, P < 0.001; males: MD -54.07, 95% CI: -59.46 to -48.68, P < 0.001). Significant sex difference was seen in the LDL reduction of PCSK9i for both 12 weeks (males vs females: MD -4.55, 95% CI: -7.34 to -1.75, P < 0.01) and 24 weeks (males vs females: MD -7.11, 95% CI: -9.99 to -4.23, P < 0.001). Conclusions: The use of PCSK9i results in significant LDL-C and MACE reduction in both males and females. While there is no significant sex difference in MACE reduction, LDL-C reduction is greater in males than in females. Our data support the equal use of PCSK9i in all eligible patients, regardless of sex.

Impaired incretin homeostasis in non-diabetic moderate-severe CKD.

Background: Incretins are regulators of insulin secretion and glucose homeostasis that are metabolized by dipeptidyl peptidase-4 (DPP-4). Moderate-severe CKD may modify incretin release, metabolism, or response. Methods: We performed 2-hour oral glucose tolerance testing (OGTT) in 59 people with non-diabetic CKD (eGFR<60 ml/min per 1.73 m2) and 39 matched controls. We measured total (tAUC) and incremental (iAUC) area under the curve of plasma total glucagon-like peptide-1 (GLP-1) and total glucose-dependent insulinotropic polypeptide (GIP). Fasting DPP-4 levels and activity were measured. Linear regression was used to adjust for demographic, body composition, and lifestyle factors. Results: Mean eGFR was 38 ±13 and 89 ±17ml/min per 1.73 m2 in CKD and controls. GLP-1 iAUC and GIP iAUC were higher in CKD than controls with a mean of 1531 ±1452 versus 1364 ±1484 pMxmin, and 62370 ±33453 versus 42365 ±25061 pgxmin/ml, respectively. After adjustment, CKD was associated with 15271 pMxmin/ml greater GIP iAUC (95% CI 387, 30154) compared to controls. Adjustment for covariates attenuated associations of CKD with higher GLP-1 iAUC (adjusted difference, 122, 95% CI -619, 864). Plasma glucagon levels were higher at 30 minutes (mean difference, 1.6, 95% CI 0.3, 2.8 mg/dl) and 120 minutes (mean difference, 0.84, 95% CI 0.2, 1.5 mg/dl) in CKD compared to controls. There were no differences in insulin levels or plasma DPP-4 activity or levels between groups. Conclusion: Incretin response to oral glucose is preserved or augmented in moderate-severe CKD, without apparent differences in circulating DPP-4 concentration or activity. However, neither insulin secretion nor glucagon suppression are enhanced.

Age as a modulator of inflammatory cardiovascular risk factors.

OBJECTIVE: Levels of acute phase reactants are affected by age. The extent to which cardiovascular risk associated with aging is due to an increase in the inflammatory burden is not known. We assessed the relationship with age of inflammatory markers, representing (1) systemic (C-reactive protein, fibrinogen, and serum amyloid-A) and (2) vascular (lipoprotein-associated phospholipase A(2) and pentraxin-3) inflammation. METHODS AND RESULTS: We determined lipoprotein-associated phospholipase A(2) mass and activity, C-reactive protein, fibrinogen, serum amyloid-A, and pentraxin-3 levels and other cardiovascular disease risk factors in 336 whites and 224 African Americans. Levels of systemic inflammatory markers increased significantly with age in both ethnic groups (P<0.05 for all), whereas trend patterns of vascular inflammatory markers did not change significantly with age for either group. In multivariate regression models adjusting for confounding variables, age remained independently associated with a composite Z score for systemic but not vascular inflammation (ß=0.250, P<0.001, and ß=0.276, P<0.001, for whites and African Americans, respectively). CONCLUSIONS: We report an increase in the systemic but not vascular inflammatory burden with age. Levels of both categories of inflammatory markers with age were similar across ethnicity after adjustment for confounders. Our results underscore the importance of age in evaluating inflammatory markers to assess cardiovascular risk.

Non-genetic influences on lipoprotein(a) concentrations.

An elevated level of lipoprotein(a) [Lp(a)] is a genetically regulated, independent, causal risk factor for cardiovascular disease. However, the extensive variability in Lp(a) levels between individuals and population groups cannot be fully explained by genetic factors, emphasizing a potential role for non-genetic factors. In this review, we provide an overview of current evidence on non-genetic factors influencing Lp(a) levels with a particular focus on diet, physical activity, hormones and certain pathological conditions. Findings from randomized controlled clinical trials show that diets lower in saturated fats modestly influence Lp(a) levels and often in the opposing direction to LDL cholesterol. Results from studies on physical activity/exercise have been inconsistent, ranging from no to minimal or moderate change in Lp(a) levels, potentially modulated by age and the type, intensity, and duration of exercise modality. Hormone replacement therapy (HRT) in postmenopausal women lowers Lp(a) levels with oral being more effective than transdermal estradiol; the type of HRT, dose of estrogen and addition of progestogen do not modify the Lp(a)-lowering effect of HRT. Kidney diseases result in marked elevations in Lp(a) levels, albeit dependent on disease stages, dialysis modalities and apolipoprotein(a) phenotypes. In contrast, Lp(a) levels are reduced in liver diseases in parallel with the disease progression, although population studies have yielded conflicting results on the associations between Lp(a) levels and non-alcoholic fatty liver disease. Overall, current evidence supports a role for diet, hormones and related conditions, and liver and kidney diseases in modifying Lp(a) levels.

Dietary Management of Heart Failure: DASH Diet and Precision Nutrition Perspectives.

Heart failure (HF) is a major health care burden increasing in prevalence over time. Effective, evidence-based interventions for HF prevention and management are needed to improve patient longevity, symptom control, and quality of life. Dietary Approaches to Stop Hypertension (DASH) diet interventions can have a positive impact for HF patients. However, the absence of a consensus for comprehensive dietary guidelines and for pragmatic evidence limits the ability of health care providers to implement clinical recommendations. The refinement of medical nutrition therapy through precision nutrition approaches has the potential to reduce the burden of HF, improve clinical care, and meet the needs of diverse patients. The aim of this review is to summarize current evidence related to HF dietary recommendations including DASH diet nutritional interventions and to develop initial recommendations for DASH diet implementation in outpatient HF management. Articles involving human studies were obtained using the following search terms: Dietary Approaches to Stop Hypertension (DASH diet), diet pattern, diet, metabolism, and heart failure. Only full-text articles written in English were included in this review. As DASH nutritional interventions have been proposed, limitations of these studies are the small sample size and non-randomization of interventions, leading to less reliable evidence. Randomized controlled interventions are needed to offer definitive evidence related to the use of the DASH diet in HF management.

Lp(a)-Associated Oxidized Phospholipids in Healthy Black and White Participants in Relation to apo(a) Size, Age, and Family Structure.

Background Lp(a) (lipoprotein(a)) is the major lipoprotein carrier of oxidized phospholipids (OxPL) and this function mediates Lp(a) atherogenicity. However, the relationship between OxPL, Lp(a), and genetic and biological characteristics remains poorly understood. We assessed the relationship between Lp(a)-bound OxPL, apolipoprotein(a) (apo(a)) size, age, and family structure in 2 racial groups. Methods and Results Healthy Black and White families were recruited from the general population (age: 6-74 years, n=267). OxPL and Lp(a) levels were assayed enzymatically; apo(a) isoform, LPA allele sizes, and allele-specific Lp(a) levels were determined. Lp(a)-OxPL levels did not differ significantly by racial and age groups. Lp(a)-OxPL levels were associated with total plasma Lp(a) in all participants and in race-specific analyses. Further, OxPL levels were significantly associated with allele-specific Lp(a) levels carried by the smaller apo(a) size in all participants (ß=0.33, P=0.0003) as well as separately for Black (ß=0.50, P=0.0032) and White (ß=0.26, P=0.0181) participants. A significant association of OxPL with allele-specific Lp(a) levels for larger apo(a) sizes was seen only in Black participants (ß=0.53, P=0.0076). In this group, Lp(a)-OxPL levels were also heritable (h2=0.29, P=0.0235), resulting in a significant interracial difference in heritability between Black and White people (P=0.0352). Conclusions Lp(a)-OxPL levels were associated with allele-specific Lp(a) level carried on smaller apo(a) sizes and among Black participants also for larger apo(a) sizes. The heritability estimates for Lp(a)-bound OxPL differed by race.