Diet to Stop Hypertension: Should Fats be Included?

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. 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.

Dairy Foods: Beneficial Effects of Fermented Products on Cardiometabolic Health.

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. 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.

A Review of Low-Density Lipoprotein-Lowering Diets in the Age of Anti-Sense Technology.

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.

Australian Atherosclerosis Society Position Statement on Lipoprotein(a): Clinical and Implementation Recommendations.

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.

Dairy Foods: Is Its Cardiovascular Risk Profile Changing?

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. 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.

Dietary patterns, dietary nutrients and cardiovascular disease.

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.

Shark liver oil supplementation enriches endogenous plasmalogens and reduces markers of dyslipidemia and inflammation.

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 metabolized 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 randomized, 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 dyslipidemia and inflammation.

Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Practical Guidance for Food Consumption to Prevent Cardiovascular Disease.

This dietary guidance, informed by best contemporary evidence, aims to assist medical practitioners and allied health professionals in advising patients for the primary and secondary prevention of cardiovascular disease (CVD). While differing in some details from other current guidelines, the core messages accord with those published in 2019 by the American College of Cardiology/American Heart Association and the European Society of Cardiology/European Atherosclerosis Society; the National Lipid Association in 2014 and the NH&MRC Australian Dietary Guidelines in 2013. These were assessed through the Appraisal of Guidelines for Research and Evaluation (AGREE II) and the levels of evidence and classes of a recommendation developed using the GRADE system. Recommendations with high levels of evidence include increased consumption of plant based foods comprising mainly complex, fibre enriched carbohydrates (wholegrains, fruits and vegetables) while limiting intake of refined starches; partial replacement of saturated fats with monounsaturated or polyunsaturated fats and oils; reduced salt intake; achievement and maintenance of healthy weight; and low-to-moderate consumption of alcohol. Additional guidance but with moderate levels of evidence includes increased consumption of fish (and fish oils where indicated); reduction in sugar-sweetened beverages and added sugars; avoidance of butter and cream especially in those at increased CVD risk but encouragement of yoghurt; allow moderate consumption of lean meat but limit intake of processed meats; and limit cholesterol-rich foods such as eggs and crustaceans for those at increased CVD risk. Guidance has been formulated qualitatively on food categories of commonly eaten foods while avoiding prescriptive quantitative measures that are less readily translatable. This approach accords with current guidelines such as the American College of Cardiology/American Heart Association 2019 guidelines and is understandable and readily implemented.

Dietary management of cardiovascular risk including type 2 diabetes.

PURPOSE OF REVIEW: Recent changes or confirmations linking patterns of eating and specific dietary interventions in the management of cardiovascular risk factors including associations with prevalent and incident type 2 diabetes. RECENT FINDINGS: Recently published guidance for dietary management of cardiovascular risk and type 2 diabetes have mostly common features. Major findings include a trend to replace strict quantitative advice on nutrients with qualitative advice on food consumption with exceptions for diabetes, global advice to increase intake of plant foods, confirmation to substitute mono and polyunsaturated oils for saturated and trans fats, new advisory on supplemental omega-3 intake, less limitation on dairy foods and fermented dairy foods encouraged, reduced emphasis on specific cholesterol-rich foods allowing greater consumption of eggs except for people with diabetes, processed meat consumption limited allowing modest intake of lean red meat, distinguishing between 'healthy' and 'unhealthy' carbohydrates including sugars, and maintaining advice on healthy bodyweight, reducing salt intake and encouraging water as preferred beverage. SUMMARY: The new guidance for healthier patterns of food consumption supported by evidence is more readily understood by health practitioners and translatable to consumers and patients.

Changing dietary approaches to prevent cardiovascular disease.

PURPOSE OF REVIEW: We have focused on recent research relevant to effects of dietary patterns and major food groups on cardiovascular outcomes, taking into account guidelines and position statements from expert authorities, with an emphasis on important changes in recommendations, some of which remain controversial. RECENT FINDINGS: Major findings include: refocusing on qualitative patterns of food consumption replacing quantitative prescriptive advice on nutrients; increasing intake of plant foods; substituting saturated fats with polyunsaturated and monounsaturated oils; reducing salt intake; regular consumption of fish with a focus on omega-3 enrichment; not restricting dairy foods, other than butter and cream, with encouragement of some fermented products; reducing cholesterol intake for those at increased cardiovascular risk and diabetes, allowing 7-eggs weekly; restricting processed meats and allowing moderate lean meat consumption; preference for fiber-rich complex carbohydrates and reduced sugar intake; maintaining healthy bodyweight; and although water is the preferred beverage, allowing moderate alcohol consumption to national guidelines and avoiding alcohol in specific cardiovascular disorders. SUMMARY: The new approach that focuses on healthier patterns of food intake is more readily understood by health practitioners and translatable to consumers and patients.

Changes in plasma lipids predict pravastatin efficacy in secondary prevention.

BACKGROUNDStatins have pleiotropic effects on lipid metabolism. The relationship between these effects and future cardiovascular events is unknown. We characterized the changes in lipids upon pravastatin treatment and defined the relationship with risk reduction for future cardiovascular events.METHODSPlasma lipids (n = 342) were measured in baseline and 1-year follow-up samples from a Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study subcohort (n = 4991). The associations of changes in lipids with treatment and cardiovascular outcomes were investigated using linear and Cox regression. The effect of treatment on future cardiovascular outcomes was examined by the relative risk reduction (RRR).RESULTSPravastatin treatment was associated with changes in 206 lipids. Species containing arachidonic acid were positively associated while phosphatidylinositol species were negatively associated with pravastatin treatment. The RRR from pravastatin treatment for cardiovascular events decreased from 23.5% to 16.6% after adjustment for clinical risk factors and change in LDL-cholesterol (LDL-C) and to 3.0% after further adjustment for the change in the lipid ratio PI(36:2)/PC(38:4). Change in PI(36:2)/PC(38:4) mediated 58% of the treatment effect. Stratification of patients into quartiles of change in PI(36:2)/PC(38:4) indicated no benefit of pravastatin in the fourth quartile.CONCLUSIONThe change in PI(36:2)/PC(38:4) predicted benefit from pravastatin, independent of change in LDL-C, demonstrating its potential as a biomarker for monitoring the clinical benefit of statin treatment in secondary prevention.TRIAL REGISTRATIONAustralian New Zealand Clinical Trials Registry identifier ACTRN12616000535471.FUNDINGBristol-Myers Squibb; NHMRC grants 211086, 358395, and 1029754; NHMRC program grant 1149987; NHMRC fellowship 108026; and the Operational Infrastructure Support Program of the Victorian government of Australia.

Dietary Fat and Blood Pressure.

PURPOSE OF REVIEW: Do dietary fats lower blood pressure? This review covers total fats, individual fatty acids and foods that provide specific fats. RECENT FINDINGS: Evidence for blood pressure lowering is stronger for supplements providing individual marine fatty acids than for fish intake since data on fish consumption are scarce. Such effects are more readily apparent in hypertensive than normal subjects. Biological mechanisms to support linkage between dietary fish oils and blood pressure are plausible. Information on other dietary fatty acids (saturates, linoleic acid, alpha-linolenic acid) is mostly less robust and therefore inconclusive. However, findings with respect to consumption of dairy foods especially of the low-fat variety do suggest association with lower blood pressures. Apart from marine fatty acids which have mostly been significantly associated with clinically modest blood pressure-lowering, the effects of other dietary fatty acids are inconsistent or clinically minor. Consumption of dairy especially of yoghurt has been linked with lower blood pressure despite the relatively high saturated fat content but the mechanism is unclear.

Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.

Large-scale plasma lipidomic profiling identifies lipids that predict cardiovascular events in secondary prevention.

BACKGROUND: Plasma lipidomic measures may enable improved prediction of cardiovascular outcomes in secondary prevention. The aim of this study is to determine the association of plasma lipidomic measurements with cardiovascular events and assess their potential to predict such events. METHODS: Plasma lipids (n = 342) were measured in a retrospective subcohort (n = 5,991) of the LIPID study. Proportional hazards regression was used to identify lipids associated with future cardiovascular events (nonfatal myocardial infarction, nonfatal stroke, or cardiovascular death) and cardiovascular death. Multivariable models adding lipid species to traditional risk factors were created using lipid ranking established from the Akaike information criterion within a 5-fold cross-validation framework. The results were tested on a diabetic case cohort from the ADVANCE study (n = 3,779). RESULTS: Specific ceramide species, sphingolipids, phospholipids, and neutral lipids containing omega-6 fatty acids or odd-chain fatty acids were associated with future cardiovascular events (106 species) and cardiovascular death (139 species). The addition of 7 lipid species to a base model (11 conventional risk factors) resulted in an increase in the C-statistics from 0.629 (95% CI, 0.628-0.630) to 0.654 (95% CI, 0.653-0.656) for prediction of cardiovascular events and from 0.673 (95% CI, 0.671-0.675) to 0.727 (95% CI, 0.725-0.728) for prediction of cardiovascular death. Categorical net reclassification improvements for cardiovascular events and cardiovascular death were 0.083 (95% CI, 0.081-0.086) and 0.166 (95% CI, 0.162-0.170), respectively. Evaluation on the ADVANCE case cohort demonstrated significant improvement on the base models. CONCLUSIONS: The improvement in the prediction of cardiovascular outcomes, above conventional risk factors, demonstrates the potential of plasma lipidomic profiles as biomarkers for cardiovascular risk stratification in secondary prevention. FUNDING: Bristol-Myers Squibb, the National Health and Medical Research Council of Australia (grants 211086, 358395, and 1029754), and the Operational Infrastructure Support Program of the Victorian government of Australia.

D-Dimer Predicts Long-Term Cause-Specific Mortality, Cardiovascular Events, and Cancer in Patients With Stable Coronary Heart Disease: LIPID Study.

BACKGROUND: D-dimer, a degradation product of cross-linked fibrin, is a marker for hypercoagulability and thrombotic events. Moderately elevated levels of D-dimer are associated with the risk of venous and arterial events in patients with vascular disease. We assessed the role of D-dimer levels in predicting long-term vascular outcomes, cause-specific mortality, and new cancers in the LIPID trial (Long-Term Intervention with Pravastatin in Ischaemic Disease) in the context of other risk factors. METHODS: LIPID randomized patients to placebo or pravastatin 40 mg/d 5 to 38 months after myocardial infarction or unstable angina. D-dimer levels were measured at baseline and at 1 year. Median follow-up was 6.0 years during the trial and 16 years in total. RESULTS: Baseline D-dimer levels for 7863 patients were grouped by quartile (≤112, 112-173, 173-273, >273 ng/mL). Higher levels were associated with older age, female sex, history of hypertension, poor renal function, and elevated levels of B-natriuretic peptide, high-sensitivity C-reactive protein, and sensitive troponin I (each P<0.001). During the first 6 years, after adjustment for up to 30 additional risk factors, higher D-dimer was associated with a significantly increased risk of a major coronary event (quartile 4 versus 1: hazard ratio [HR], 1.45; 95% confidence interval, 1.21-1.74), major cardiovascular disease (CVD) event (HR, 1.45; 95% confidence interval, 1.23-1.71) and venous thromboembolism (HR, 4.03; 95% confidence interval, 2.31-7.03; each P<0.001). During the 16 years overall, higher D-dimer was an independent predictor of all-cause mortality (HR, 1.59), CVD mortality (HR, 1.61), cancer mortality (HR, 1.54), and non-CVD noncancer mortality (HR, 1.57; each P<0.001), remaining significant for deaths resulting from each cause occurring beyond 10 years of follow-up (each P≤0.01). Higher D-dimer also independently predicted an increase in cancer incidence (HR, 1.16; P=0.02).The D-dimer level increased the net reclassification index for all-cause mortality by 4.0 and venous thromboembolism by 13.6. CONCLUSIONS: D-dimer levels predict long-term risk of arterial and venous events, CVD mortality, and non-CVD noncancer mortality independent of other risk factors. D-dimer is also a significant predictor of cancer incidence and mortality. These results support an association of D-dimer with fatal events across multiple diseases and demonstrate that this link extends beyond 10 years' follow-up.

Weight Loss and Exercise Alter the High-Density Lipoprotein Lipidome and Improve High-Density Lipoprotein Functionality in Metabolic Syndrome.

OBJECTIVE: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. APPROACH AND RESULTS: Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. CONCLUSIONS: WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.

Predictors of incident heart failure in patients after an acute coronary syndrome: The LIPID heart failure risk-prediction model.

BACKGROUND: Coronary heart disease is a major cause of heart failure. Availability of risk-prediction models that include both clinical parameters and biomarkers is limited. We aimed to develop such a model for prediction of incident heart failure. METHODS: A multivariable risk-factor model was developed for prediction of first occurrence of heart failure death or hospitalization. A simplified risk score was derived that enabled subjects to be grouped into categories of 5-year risk varying from <5% to >20%. RESULTS: Among 7101 patients from the LIPID study (84% male), with median age 61years (interquartile range 55-67years), 558 (8%) died or were hospitalized because of heart failure. Older age, history of claudication or diabetes mellitus, body mass index>30kg/m2, LDL-cholesterol >2.5mmol/L, heart rate>70 beats/min, white blood cell count, and the nature of the qualifying acute coronary syndrome (myocardial infarction or unstable angina) were associated with an increase in heart failure events. Coronary revascularization was associated with a lower event rate. Incident heart failure increased with higher concentrations of B-type natriuretic peptide >50ng/L, cystatin C>0.93nmol/L, D-dimer >273nmol/L, high-sensitivity C-reactive protein >4.8nmol/L, and sensitive troponin I>0.018µg/L. Addition of biomarkers to the clinical risk model improved the model's C statistic from 0.73 to 0.77. The net reclassification improvement incorporating biomarkers into the clinical model using categories of 5-year risk was 23%. CONCLUSION: Adding a multibiomarker panel to conventional parameters markedly improved discrimination and risk classification for future heart failure events.

Persistent psychological distress and mortality in patients with stable coronary artery disease.

BACKGROUND: A single assessment of psychological distress, which includes depression and anxiety, has been associated with increased mortality in patients with coronary heart disease, but the prognostic importance of persistence of distress symptoms is less certain. AIM: To determine whether intermittent and/or persistent psychological distress is associated with long-term cardiovascular (CV) and total mortality in patients with stable coronary artery disease. METHODS: 950 participants in the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial completed at least four General Health Questionnaires (GHQ-30) at baseline and after ½, 1, 2 and 4 years. In a landmark analysis from 4 years, Cox proportional hazards models evaluated the risk of CV and total mortality by increasing levels of psychological distress: never distressed, sometimes any severity (GHQ score >5), persistent mild (GHQ score >5 on three or more occasions) and persistent moderate distress (GHQ score >10) on three or more occasions, over a median of 12.1 (IQR 8.6-12.5) years. The models were both unadjusted and adjusted for known baseline risk factors. RESULTS: Persistent moderate or greater psychological stress was reported on three or more assessments by 35 (3.7%) subjects. These patients had a higher risk of both CV death (adjusted HR 3.94, 95% CI 2.05 to 7.56, p<0.001) and all-cause mortality (adjusted HR 2.85, 95% CI 1.74 to 4.66, p<0.001) compared with patients with no distress. In contrast, patients who reported persistent mild distress (n=73, 7.7%) on three or more visits, and those who met criteria for distress on only one or two assessments (n=255, 26.8%), did not have an increased risk of CV or all-cause mortality during follow-up. CONCLUSION: In patients with stable coronary artery disease, persistent psychological distress of at least moderate severity is associated with a substantial increase in CV and all-cause mortality.

Neck Circumference Is Associated with Muscle Sympathetic Nerve Activity in Overweight and Obese Men but Not Women.

Background: Neck circumference (NC) is a predictor of cardiometabolic risk. The objective of this study was to explore the relationship of NC to muscle sympathetic nerve activity (MSNA) within an overweight and obese population. Methods: The study design was a retrospective cross-sectional analysis. Un-medicated persons (72 men, 53 postmenopausal women) aged 56 ± 1 years (mean ± SEM) with body mass index (BMI) 32.8 ± 0.4 kg/m2, were studied. NC was measured together with traditional anthropometric measures, supine blood pressure, fasting blood lipids, insulin, and glucose. Insulin sensitivity was assessed by homeostasis model (HOMA-IR) and Matsuda Insulin Sensitivity Index (ISI) derived from 75-g oral glucose tolerance test. Resting multiunit MSNA was recorded by microneurography in the peroneal nerve and expressed as burst frequency and burst incidence. Results: Men within the highest tertile of NC had significantly higher fasting and post-glucose plasma insulin levels (insulin AUC0-120), HOMA-IR, non-esterified fatty acids, MSNA (45 ± 2 vs. 36 ± 2 bursts per min; 69 ± 3 vs. 58 ± 3 bursts per 100 hb) and heart rate, and lower Matsuda ISI compared to men in the lowest tertile (P all <0.05). In stepwise regression analyses, NC alone explained 12%, and together with insulin AUC0-120 it accounted for 22%, of the variance in MSNA in men. In women, NC was associated with anthropometric measures but not with MSNA or metabolic indices. Conclusions: Among overweight and obese men, NC was independently associated with elevated MSNA and hyperinsulinemia, and thus may be relevant to cardiometabolic risk prediction. The biological basis of gender differences merits further elucidation.