P J Nestel’s research while affiliated with Baker Heart and Diabetes Institute and other places

BACKGROUND Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) (Lp[a]) levels are independently associated with atherosclerotic cardiovascular disease (ASCVD). However, the relationship between Lp(a) level, LDL-C level, and ASCVD risk at different thresholds is not well defined. METHODS A participant-level meta-analysis of 27 658 participants enrolled in 6 placebo-controlled statin trials was performed to assess the association of LDL-C and Lp(a) levels with risk of fatal or nonfatal coronary heart disease events, stroke, or any coronary or carotid revascularization (ASCVD). The multivariable-adjusted association between baseline Lp(a) level and ASCVD risk was modeled continuously using generalized additive models, and the association between baseline LDL-C level and ASCVD risk by baseline Lp(a) level by Cox proportional hazards models with random effects. The joint association between Lp(a) level and statin-achieved LDL-C level with ASCVD risk was evaluated using Cox proportional hazards models. RESULTS Compared with an Lp(a) level of 5 mg/dL, increasing levels of Lp(a) were log-linearly associated with ASCVD risk in statin- and placebo-treated patients. Among statin-treated individuals, those with Lp(a) level >50 mg/dL (≈125 nmol/L) had increased risk across all quartiles of achieved LDL-C level and absolute change in LDL-C level. Even among those with the lowest quartile of achieved LDL-C level (3.1–77.0 mg/dL), those with Lp(a) level >50 mg/dL had greater ASCVD risk (hazard ratio, 1.38 [95% CI, 1.06–1.79]) than those with Lp(a) level ≤50 mg/dL. The greatest risk was observed with both Lp(a) level >50 mg/dL and LDL-C level in the fourth quartile (hazard ratio, 1.90 [95% CI, 1.46–2.48]). CONCLUSIONS These findings demonstrate the independent and additive nature of Lp(a) and LDL-C levels for ASCVD risk, and that LDL-C lowering does not fully offset Lp(a)-mediated risk.

Purpose of Review International guidelines emphasize advice to incorporate dietary measures for the prevention and in the management of hypertension. Current data show that modest reductions in weight can have an impact on blood pressure. Reducing salt and marine oils have also shown consistent benefit in reducing blood pressure. Whether other dietary constituents, in particular the amount and type of fat that play important roles in cardiovascular prevention, influence blood pressure sufficiently to be included in the management of hypertension is less certain. In this review, we provide a summary of the most recent findings, with a focus on dietary patterns, fats and other nutrients and their impact on blood pressure and hypertension. Recent Findings Since reducing salt consumption is an established recommendation only corollary dietary advice is subject to the current review. Population studies that have included reliable evaluation of fat intake have indicated almost consistently blood pressure lowering with consumption of marine oils and fats. Results with vegetable oils are inconclusive. However dietary patterns that included total fat reduction and changes in the nature of vegetable fats/oils have suggested beneficial effects on blood pressure. Plant-based foods, dairy foods and yoghurt particularly, may also lower blood pressure irrespective of fat content. Summary Total fat consumption is not directly associated with blood pressure except when it is part of a weight loss diet. Consumption of marine oils has mostly shown moderate blood pressure lowering and possibly greatest effect with docosahexaenoic acid-rich oil.

Purpose of Review This review of recent observational studies and understanding of the complex nature of dairy foods is intended to reappraise the effects of different types of dairy foods on cardiovascular disease (CVD). Recent Findings Recent guidelines from major cardiovascular societies suggest that apart from the adverse effect of butter, consumption of more complex dairy products notably fermented varieties and yogurt in particular, appear to be inversely associated with outcomes of CVD and type 2 diabetes (T2D). Reduced fat in dairy food remains preferred for people at increased CVD risk. Summary Changed evidence has led to new advice regarding consumption of some dairy foods. The apparent beneficial effects of fermented milk products, particularly yogurt, allow for increased consumption of nutritious staple foods. Recent national guidelines reflect this view.

This narrative review discusses an important issue, the primary role of diet in reducing low-density lipoprotein cholesterol (LDLc) concentrations in polygenic hypercholesterolemia. Two effective drugs, statins, and ezetimibe, that lower LDLc > 20% are relatively inexpensive and potential competitors to strict dieting. Biochemical and genomic studies have shown that proprotein convertase subtilisin kexin type 9 (PCSK9) plays an important role in low-density lipoprotein (LDL) and lipid metabolism. Clinical trials have demonstrated that inhibitory monoclonal antibodies of PCSK9 dose-dependently lower LDLc up to 60%, with evidence of both regression and stabilization of coronary atherosclerosis and a reduction in cardiovascular risk. Recent approaches using RNA interference to achieve PCSK9 inhibition are currently undergoing clinical evaluation. The latter presents an attractive option of twice-yearly injections. They are, however, currently expensive and unsuitable for moderate hypercholesterolemia, which is largely due to inappropriate patterns of eating. The best dietary approach, the substitution of saturated fatty acids by polyunsaturated fatty acids at 5% energy, yields > 10% lowering of LDLc. Foods such as nuts and brans, especially within a prudent, plant-based diet low in saturates complemented by supplements such as phytosterols, have the potential to reduce LDLc further. A combination of such foods has been shown to lower LDLc by 20%. A nutritional approach requires backing from industry to develop and market LDLc-lowering products before pharmacology replaces the diet option. Energetic support from health professionals is vital.

This position statement provides guidance to cardiologists and related specialists on the management of adult patients with elevated lipoprotein(a) [Lp(a)]. Elevated Lp(a) is an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease (CAVD). While circulating Lp(a) levels are largely determined by ancestry, they are also influenced by ethnicity, hormones, renal function, and acute inflammatory events, such that measurement should be done after accounting for these factors. Further, circulating Lp(a) concentrations should be estimated using an apo(a)-isoform independent assay that employs appropriate calibrators and reports the results in molar units (nmol/L). Selective screening strategies of high-risk patients are recommended, but universal screening of the population is currently not advised. Testing for elevated Lp(a) is recommended in all patients with premature ASCVD and those considered to be at intermediate-to-high risk of ASCVD. Elevated Lp(a) should be employed to assess and stratify risk and to enable a decision on initiation or intensification of preventative treatments, such as cholesterol lowering therapy. In adult patients with elevated Lp(a) at intermediate-to-high risk of ASCVD, absolute risk should be reduced by addressing all modifiable behavioural, lifestyle, psychosocial and clinical risk factors, including maximising cholesterol-lowering with statin and ezetimibe and, where appropriate, PCSK9 inhibitors. Apheresis should be considered in patients with progressive ASCVD. New ribonucleic acid (RNA)-based therapies which directly lower Lp(a) are undergoing clinical trials.

The status of Lp(a) as a cardiovascular risk factor has been resurrected by advances in genetics. Mendelian randomisation studies show a causal link of Lp(a) with coronary artery disease (CAD), peripheral artery disease (PAD) and calcific aortic valve stenosis (CAVS). The genetics of Lp(a) is complex and extends beyond the kringle-IV type 2, being also dependent on ancestry. The plasma concentration of Lp(a) is determined by the hepatic production of apo(a) component of Lp(a), supporting the use of nucleic acids that inhibit the mRNA gene transcript for apo(a). Analytical barriers to measurement of Lp(a) are being addressed using isoform independent assays and a traceable standard. The association of Lp(a) and atherosclerotic cardiovascular disease is highest for myocardial infarction than PAD and CAVS. Increased risk of type 2 diabetes mellitus associated with low Lp(a) levels is perplexing and requires further investigations. The greatest advancement in Lp(a) lowering therapies is based on using RNA therapeutics that are now being investigated in clinical trials. PCSK9 inhibition lowers Lp(a) modestly, but whether cardiovascular benefit is independent of LDL lowering remains unclear. Opportunistic and selective testing for Lp(a) is supported by moderate evidence, the case for universal screening being premature. Modification of behavioural and clinical risk factors may be targeted to mitigate Lp(a) mediated risk of cardiovascular disease. Clinical practice guidelines have been developed to address gaps in care of high Lp(a), but full implementation awaits the findings of clinical outcome trials using RNA-directed therapies currently underway.

Background Elevated plasma cystatin C levels reflect reduced renal function and increased cardiovascular risk. Less is known about whether the increased risk persists long‐term or is independent of renal function and other important biomarkers. Methods and Results Cystatin C and other biomarkers were measured at baseline (in 7863 patients) and 1 year later (in 6106 patients) in participants in the LIPID (Long‐Term Intervention with Pravastatin in Ischemic Disease) study, who had a previous acute coronary syndrome. Outcomes were ascertained during the study (median follow‐up, 6 years) and long‐term (median follow‐up, 16 years). Glomerular filtration rate (GFR) was estimated using Chronic Kidney Disease Epidemiology Collaboration equations (first GFR‐creatinine, then GFR‐creatinine‐cystatin C). Over 6 years, in fully adjusted multivariable time‐to‐event models, with respect to the primary end point of coronary heart disease mortality or nonfatal myocardial infarction, for comparison of Quartile 4 versus 1 of baseline cystatin C, the hazard ratio was 1.37 (95% CI, 1.07–1.74; P =0.01), and for major cardiovascular events was 1.47 (95% CI, 1.19–1.82; P <0.001). Over 16 years, the association of baseline cystatin C with coronary heart disease, cardiovascular, and all‐cause mortality persisted (each P <0.001) and remained significant after adjustment for estimated GFR‐creatinine‐cystatin C. Cystatin C also predicted the development of chronic kidney disease for 6 years (odds ratio, 6.61; 95% CI, 4.28–10.20) independently of estimated GFR‐creatinine and other risk factors. However, this association was no longer significant after adjustment for estimated GFR‐creatinine‐cystatin C. Conclusions Cystatin C independently predicted major cardiovascular events, development of chronic kidney disease, and cardiovascular and all‐cause mortality. Prediction of long‐term mortality was independent of improved estimation of GFR. Registration URL: https://anzctr.org.au ; Unique identifier: ACTRN12616000535471.

Purpose of Review The majority of international guidelines for cardiovascular disease (CVD) prevention recommend moderate intake of low fat or fat-free products, and limiting full fat dairy food because of its high saturated fatty acid content. Recent equivocal observational studies and greater understanding of the complex nature of dairy foods has led to reappraisal for some types of dairy foods. Recent Findings Current guidelines from major cardiovascular societies have differed; interpretation of major observational studies has been inconsistent. Apart from the adverse effect of butter, consumption of more complex dairy products notably fermented varieties, yogurt in particular, appears to be inversely associated with outcomes of CVD and type 2 diabetes (T2D). Reduced fat in dairy food appears advantageous but is no longer a unanimous view although is preferred for people at increased CVD risk and dyslipidemia. Summary Changed evidence has led to new advice regarding consumption of some dairy foods. The apparent beneficial effects of cheese, fermented milk, and yogurt allow for increased consumption of nutritious staple foods. Reduced fat yogurt may be desirable as part of diets for individuals with CVD or T2D.

A healthy dietary pattern can benefit multiple cardiovascular disease (CVD) risk factors. In conjunction with current standard-of-care pharmaceutical interventions it can provide an effective strategy for the prevention of CVD. Previous dietary recommendations have focused on targeting macronutrients. However, most of the recent international dietary guidelines now recommend a whole food, dietary pattern approach, whilst avoiding quantitative nutrient advice. The guidelines recommend: (1) increased intake of plant-based foods including complex, fibre-rich carbohydrates such as wholegrains, fruits and vegetables, but restricting the intake of refined starches; (2) substituting saturated fats with polyunsaturated and monounsaturated oils; (3) reducing salt intake; (4) increased fish consumption (or fish oils where applicable); (5) reducing sugar-sweetened drinks and added sugars; (6) avoiding butter and cream particularly in individuals at increased risk of CVD, but encouraging fermented products such as yoghurt; there is no specific advice on cheese and milk; (7) allowing consumption of lean meat in moderation but restricting processed meats; and (8) reducing cholesterol intake and foods rich in cholesterol (e.g., eggs and crustaceans) for those with diabetes and at increased CVD risk. The dietary guidelines should be adhered to in conjunction with low-to-moderate alcohol consumption, regular physical activity, avoiding tobacco and maintaining a healthy weight. This review summarises recently published research, international guidelines and position statements for minimizing CVD risk.

Plasmalogens are membrane glycerophospholipids with diverse biological functions. Reduced plasmalogen levels have been observed in metabolic diseases, hence increasing their levels might be beneficial in ameliorating these conditions. Shark liver oil (SLO) is a rich source of alkylglycerols that can be metabolised into plasmalogens. This study was designed to evaluate the impact of SLO supplementation on endogenous plasmalogen levels in individuals with features of metabolic disease. In this randomised, double-blind, placebo-controlled cross-over study, the participants (10 overweight or obese males) received 4 g Alkyrol® (purified SLO) or placebo (methylcellulose) per day for 3 weeks followed by a 3-week washout phase and were then crossed over to 3 weeks of the alternate placebo/Alkyrol® treatment. SLO supplementation led to significant changes in plasma and circulatory white blood cell lipidomes, notably increased levels of plasmalogens and other ether lipids. In addition, SLO supplementation significantly decreased the plasma levels of total free cholesterol, triglycerides and C-reactive protein. These findings suggest that SLO supplementation can enrich plasma and cellular plasmalogens, and this enrichment may provide protection against obesity-related dyslipidaemia and inflammation.