A High Throughput Biochemical Fluorometric Method for Measuring Lipid Peroxidation in HDL

Current cell-based assays for determining the functional properties of high-density lipoproteins (HDL) have limitations. We report here the development of a new, robust fluorometric cell-free biochemical assay that measures HDL lipid peroxidation (HDLox) based on the oxidation of the fluorochrome Amplex Red. HDLox correlated with previously validated cell-based (r = 0.47, p<0.001) and cell-free assays (r = 0.46, p<0.001). HDLox distinguished dysfunctional HDL in established animal models of atherosclerosis and Human Immunodeficiency Virus (HIV) patients. Using an immunoaffinity method for capturing HDL, we demonstrate the utility of this novel assay for measuring HDLox in a high throughput format. Furthermore, HDLox correlated significantly with measures of cardiovascular diseases including carotid intima media thickness (r = 0.35, p<0.01) and subendocardial viability ratio (r = −0.21, p = 0.05) and physiological parameters such as metabolic and anthropometric parameters (p<0.05). In conclusion, we report the development of a new fluorometric method that offers a reproducible and rapid means for determining HDL function/quality that is suitable for high throughput implementation.     

Low concentrations of medium-sized HDL particles predict incident CVD in chronic kidney disease patients

Patients with chronic kidney disease (CKD) are at high risk for CVD. However, traditional CVD risk factors cannot completely explain the increased risk. Altered HDL proteome is linked with incident CVD in CKD patients, but it is unclear whether other HDL metrics are associated with incident CVD in this population. In the current study, we analyzed samples from two independent prospective case-control cohorts of CKD patients, the Clinical Phenotyping and Resource Biobank Core (CPROBE) and the Chronic Renal Insufficiency Cohort (CRIC). We measured HDL particle sizes and concentrations (HDL-P) by calibrated ion mobility analysis and HDL cholesterol efflux capacity (CEC) by cAMP-stimulated J774 macrophages in 92 subjects from the CPROBE cohort (46 CVD and 46 controls) and in 91 subjects from the CRIC cohort (34 CVD and 57 controls). We tested associations of HDL metrics with incident CVD using logistic regression analysis. No significant associations were found for HDL-C or HDL-CEC in either cohort. Total HDL-P was only negatively associated with incident CVD in the CRIC cohort in unadjusted analysis. Among the six sized HDL subspecies, only medium-sized HDL-P was significantly and negatively associated with incident CVD in both cohorts after adjusting for clinical confounders and lipid risk factors with odds ratios (per 1-SD) of 0.45 (0.22–0.93, P = 0.032) and 0.42 (0.20–0.87, P = 0.019) for CPROBE and CRIC cohorts, respectively. Our observations indicate that medium-sized HDL-P—but not other-sized HDL-P or total HDL-P, HDL-C, or HDL-CEC—may be a prognostic cardiovascular risk marker in CKD.     

Burden of Hospital Admission and Repeat Angiography in Angina Pectoris Patients with and without Coronary Artery Disease: A Registry-Based Cohort Study

Aims

To evaluate risk of hospitalization due to cardiovascular disease (CVD) and repeat coronary angiography (CAG) in stable angina pectoris (SAP) with no obstructive coronary artery disease (CAD) versus obstructive CAD, and asymptomatic reference individuals.

Methods and Results

We followed 11,223 patients with no prior CVD having a first-time CAG in 1998–2009 due to SAP symptoms and 5,695 asymptomatic reference individuals from the Copenhagen City Heart Study through registry linkage for 7.8 years (median). In recurrent event survival analysis, patients with SAP had 3–4-fold higher risk of hospitalization for CVD irrespective of CAG findings and cardiovascular comorbidity. Multivariable adjusted hazard ratios(95%CI) for patients with angiographically normal coronary arteries was 3.0(2.5–3.5), for angiographically diffuse non-obstructive CAD 3.9(3.3–4.6) and for 1–3-vessel disease 3.6–4.1(range)(all P<0.001). Mean accumulated hospitalization time was 3.5(3.0–4.0)(days/10 years follow-up) in reference individuals and 4.5(3.8–5.2)/7.0(5.4–8.6)/6.7(5.2–8.1)/6.1(5.2–7.4)/8.6(6.6–10.7) in patients with angiographically normal coronary arteries/angiographically diffuse non-obstructive CAD/1-, 2-, and 3-vessel disease, respectively (all P<0.05, age-adjusted). SAP symptoms predicted repeat CAG with multivariable adjusted hazard ratios for patients with angiographically normal coronary arteries being 2.3(1.9–2.9), for angiographically diffuse non-obstructive CAD 5.5(4.4–6.8) and for obstructive CAD 6.6–9.4(range)(all P<0.001).

Conclusions

Patients with SAP symptoms and angiographically normal coronary arteries or angiographically diffuse non-obstructive CAD suffer from considerably greater CVD burdens in terms of hospitalization for CVD and repeat CAG compared with asymptomatic reference individuals even after adjustment for cardiac risk factors and exclusion of cardiovascular comorbidity as cause. Contrary to common perception, excluding obstructive CAD by CAG in such patients does not ensure a benign cardiovascular prognosis.     

Mortality Associated with Diabetes and Cardiovascular Disease in Older Women

Background

Current guidelines for the prevention of cardiovascular disease (CVD) recommend diabetes as a CVD risk equivalent. However, reports that have examined the risk of diabetes in comparison to pre-existing CVD are lacking among older women. We aimed to assess whether diabetes was associated with a similar risk of total and cause-specific mortality as a history of CVD in older women.

Methodology/Principal Findings

We studied 9218 women aged 68 years or older enrolled in a prospective cohort study (Study of Osteoporotic Fracture) during a mean follow-up period of 11.7 years and compared all-cause, cardiovascular and coronary heart disease mortality among 4 groups: non-diabetic women with and without existing CVD, diabetic women with and without existing CVD. Mean (SD) age of the participants was 75.2 (5.3) years, 3.5% reported diabetes and 6.8% reported existing CVD. During follow-up, 5117 women died with 36% from CVD. The multivariate adjusted risk of cardiovascular mortality was increased among both non-diabetic women with CVD (hazard ratio (HR) 2.32, 95% CI: 1.97–2.74, P<0.001) and diabetic women without CVD (HR 2.06, CI: 1.62–2.64, P<0.001) compared to non-diabetic women without existing CVD. All-cause, cardiovascular and coronary mortality of non-diabetic women with CVD were not significantly different from diabetic women without CVD.

Conclusions/Significance

Older diabetic women without CVD have a similar risk of cardiovascular mortality compared to non-diabetic women with pre-existing CVD. The equivalence of diabetes and CVD seems to extend to older women, supporting current guidelines for cardiovascular prevention.     

Roles of maternal HDL during pregnancy

BackgroundHigh density lipoproteins (HDL) were first linked to cardiovascular disease (CVD) over 30 years ago when an inverse relationship was shown between CVD and HDL-cholesterol levels. It is now apparent that HDL composition and function, not cholesterol levels, are the pertinent measurements describing HDL's role in various disease processes, especially those with subclinical or overt inflammation.Scope of reviewPregnancy is also an inflammatory state. When inflammation becomes excessive during pregnancy, there is an increased risk for adverse outcomes that affect the health of the mother and fetus, including preterm birth and preeclampsia. Though studies on HDL during pregnancy are limited, recent evidence demonstrates that HDL composition and function change during pregnancy and in women with adverse outcomes.General significanceIn this review, we will discuss how HDL may play a role in maintaining a healthy pregnancy and how impairments in function could lead to pregnancies with adverse outcomes.     

Television viewing and incident cardiovascular disease: prospective associations and mediation analysis in the EPIC Norfolk Study

Background

Although television viewing time is detrimentally associated with intermediate cardiovascular risk factors, the relationship with incident total (i.e. combined fatal and non-fatal) cardiovascular disease (CVD), non-fatal CVD and coronary heart disease is largely unknown. This study examined whether television viewing time is associated with these three outcomes, independently of physical activity energy expenditure and other confounding variables.

Methodology/Principal Findings

A population-based cohort of 12,608 men and women (aged 61.4±9.0), free from stroke, myocardial infarction and cancer at baseline in 1998–2000 were followed up until 2007 (6.9±1.9 years). Participants self-reported education, smoking, alcohol use, antihypertensive, lipid lowering and antidepressant medication, disease history, total energy intake, sleep duration, physical activity and television viewing. BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol and glycated haemoglobin (HbA_1c) were measured by standardized procedures; a clustered metabolic risk score was constructed. Every one hour/day increase in television viewing was associated with an increased hazard for total (HR = 1.06, 95%CI = 1.03–1.08; 2,620 cases), non-fatal CVD (HR = 1.06, 95%CI = 1.03–1.09; 2,134 cases), and coronary heart disease (HR = 1.08, 95%CI = 1.03–1.13; 940 cases), independent of gender, age, education, smoking, alcohol, medication, diabetes status, CVD family history, sleep duration and physical activity energy expenditure. Energy intake, BMI, waist circumference, blood pressure, triglycerides, HDL cholesterol, HbA_1c and the clustered metabolic risk score only partially mediated these associations.

Conclusions

These results indicate that the most prevalent leisure time (sedentary) behaviour, television viewing, independently contributes to increased CVD risk. Recommendations on reducing television viewing time should be considered.     

Free Levels of Selected Organic Solutes and Cardiovascular Morbidity and Mortality in Hemodialysis Patients: Results from the Retained Organic Solutes and Clinical Outcomes (ROSCO) Investigators

Background and Objectives

Numerous substances accumulate in the body in uremia but those contributing to cardiovascular morbidity and mortality in dialysis patients are still undefined. We examined the association of baseline free levels of four organic solutes that are secreted in the native kidney — p-cresol sulfate, indoxyl sulfate, hippurate and phenylacetylglutamine — with outcomes in hemodialysis patients.

Design, Setting, Participants and Measurements

We measured these solutes in stored specimens from 394 participants of a US national prospective cohort study of incident dialysis patients. We examined the relation of each solute and a combined solute index to cardiovascular mortality and morbidity (first cardiovascular event) using Cox proportional hazards regression adjusted for demographics, comorbidities, clinical factors and laboratory tests including Kt/V_UREA.

Results

Mean age of the patients was 57 years, 65% were white and 55% were male. In fully adjusted models, a higher p-cresol sulfate level was associated with a greater risk (HR per SD increase; 95% CI) of cardiovascular mortality (1.62; 1.17–2.25; p=0.004) and first cardiovascular event (1.60; 1.23–2.08; p<0.001). A higher phenylacetylglutamine level was associated with a greater risk of first cardiovascular event (1.37; 1.18–1.58; p<0.001). Patients in the highest quintile of the combined solute index had a 96% greater risk of cardiovascular mortality (1.96; 1.05–3.68; p=0.04) and 62% greater risk of first cardiovascular event (1.62; 1.12–2.35; p=0.01) compared with patients in the lowest quintile. Results were robust in sensitivity analyses.

Conclusions

Free levels of uremic solutes that are secreted by the native kidney are associated with a higher risk of cardiovascular morbidity and mortality in incident hemodialysis patients.     

Differential Cardiovascular Outcomes after Dipeptidyl Peptidase-4 Inhibitor,Sulfonylurea, and Pioglitazone Therapy,All in Combination with Metformin,for Type 2 Diabetes: A Population-Based Cohort Study

Background/ObjectivesData on the comparative effectiveness of oral antidiabetics on cardiovascular outcomes in a clinical practice setting are limited. This study sought to determine whether a differential risk of cardiovascular disease (CVD) exists for the combination of a dipeptidyl peptidase-4 (DPP-4) inhibitor plus metformin versus a sulfonylurea derivative plus metformin or pioglitazone plus metformin.MethodsWe conducted a cohort study of 349,476 patients who received treatment with a DPP-4 inhibitor, sulfonylurea, or pioglitazone plus metformin for type 2 diabetes using the Korean national health insurance claims database. The incidence of total CVD and individual outcomes of myocardial infarction (MI), heart failure (HF), and ischemic stroke (IS) were assessed using the hazard ratios (HRs) estimated from a Cox proportional-hazards model weighted for a propensity score.ResultsDuring follow-up, 3,881 patients developed a CVD, including 428 MIs, 212 HFs, and 1,487 ISs. The adjusted HR with 95% confidence interval (CI) for a sulfonylurea derivative plus metformin compared with a DPP-4 inhibitor plus metformin was 1.20 (1.09-1.32) for total CVD; 1.14 (1.04-1.91) for MI; 1.07 (0.71-1.62) for HF; and 1.51 (1.28-1.79) for IS. The HRs with 95% CI for total CVD, MI, HF, and IS for pioglitazone plus metformin were 0.89 (0.81-0.99), 1.05 (0.76-1.46), 4.81 (3.53-6.56), and 0.81 (0.67-0.99), respectively.ConclusionsCompared with a DPP-4 inhibitor plus metformin, treatment with a sulfonylurea drug plus metformin was associated with increased risks of total CVD, MI, and IS, whereas the use of pioglitazone plus metformin was associated with decreased total CVD and IS risks.     

Impact of Cardiovascular Calcifications on the Detrimental Effect of Continued Smoking on Cardiovascular Risk in Male Lung Cancer Screening Participants

Background

Current smokers have an increased cardiovascular disease (CVD) risk compared to ex-smokers due to reversible as well as irreversible effects of smoking. We investigated if current smokers remain to have an increased CVD risk compared to ex-smokers in subjects with a long and intense smoking history. We in addition studied if the effect of smoking continuation on CVD risk is independent of or modified by the presence of cardiovascular calcifications.

Methods

The cohort used comprised a sample of 3559 male lung cancer screening trial participants. We conducted a case-cohort study using all CVD cases and a random sample of 10% (n = 341) from the baseline cohort (subcohort). A weighted Cox proportional hazards model was used to estimate the hazard ratios for current smoking status in relation to CVD events.

Results

During a median follow-up of 2.6 years (max. 3.7 years), 263 fatal and non-fatal cardiovascular events (cases) were identified. Age, packyears and cardiovascular calcification adjusted hazard ratio of current smokers compared to former smokers was 1.33 (95% confidence interval 1.00–1.77). In additional analyses that incorporated multiplicative interaction terms, neither coronary nor aortic calcifications modified the association between smoking status and cardiovascular risk (P = 0.08).

Conclusions

Current smokers have an increased CVD risk compared to former smokers even in subjects with a long and intense smoking history. Smoking exerts its hazardous effects on CVD risk by pathways partly independent of cardiovascular calcifications.     

Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: baseline characteristics and short-term effects of fenofibrate [ISRCTN64783481]

Objective

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study is examining the effects of long-term fibrate therapy on coronary heart disease (CHD) event rates in patients with diabetes mellitus. This article describes the trial's run-in phase and patients' baseline characteristics.

Research design and methods

FIELD is a double-blind, placebo-controlled trial in 63 centres in 3 countries evaluating the effects of fenofibrate versus placebo on CHD morbidity and mortality in 9795 patients with type 2 diabetes mellitus. Patients were to have no indication for lipid-lowering therapy on randomization, but could start these or other drugs at any time after randomization. Follow-up in the study was to be for a median duration of not less than 5 years and until 500 major coronary events (fatal coronary heart disease plus nonfatal myocardial infarction) had occurred.

Results

About 2100 patients (22%) had some manifestation of cardiovascular disease (CVD) at baseline and thus high risk status. Less than 25% of patients without CVD had a (UKPDS determined) calculated 5-year CHD risk of <5%, but nearly all had a 5-year stroke risk of <10%. Despite this, half of the cohort were obese (BMI > 30), most were men, two-thirds were aged over 60 years, and substantial proportions had NCEP ATP III features of the metabolic syndrome independent of their diabetes, including low HDL (60%), high blood pressure measurement or treatment for hypertension (84%), high waist measurement (68%), and raised triglycerides (52%). After a 6-week run-in period before randomisation with all participants receiving 200 mg comicronized fenofibrate, there were declines in total and LDL cholesterol (10%) and triglycerides (26%) and an increase in HDL cholesterol (6.5%).

Conclusion

The study will show the effect of PPAR-alpha agonist action on CHD and other vascular outcomes in patients with type 2 diabetes including substantial numbers with low to moderate CVD risk but with the various components of the metabolic syndrome. The main results of the study will be reported in late 2005.     

GlycA,a Pro-Inflammatory Glycoprotein Biomarker,and Incident Cardiovascular Disease: Relationship with C-Reactive Protein and Renal Function

Objective

GlycA is a novel nuclear magnetic resonance spectroscopy-measured biomarker of systemic inflammation. We determined whether GlycA is associated with incident cardiovascular disease (CVD) in men and women, examined whether this association with CVD is modified by renal function, and compared this association with high sensitivity C-reactive protein (hsCRP).

Research design and methods

A prospective cohort study was performed among 4,759 subjects (PREVEND study) without a history of CVD and cancer. Incident CVD was defined as the combined endpoint of cardiovascular morbidity and mortality. Cox regression analyses were used to examine associations of baseline GlycA and hsCRP with CVD.

Results

298 first CVD events occurred during a median follow-up of 8.5 years. After adjustment for clinical and lipid measures the hazard ratio (HR) for CVD risk in the highest GlycA quartile was 1.58 (95% CI, 1.05–2.37, P for trend = 0.004). This association was similar after further adjustment for renal function (estimated glomerular filtration rate and urinary albumin excretion). After additional adjustment for hsCRP, GlycA was still associated with incident CVD (HR: 1.16 per SD change (95% CI, 1.01–1.33), P = 0.04). Similar results were obtained for hsCRP (HR per SD change after adjustment for GlycA: 1.17 (95% CI 1.17 (95% CI, 1.01–3.60), P = 0.04). CVD risk was highest in subjects with simultaneously higher GlycA and hsCRP (fully adjusted HR: 1.79 (95% CI, 1.31–2.46), P<0.001).

Conclusion

GlycA is associated with CVD risk in men and women, independent of renal function. The association of GlycA with incident CVD is as strong as that of hsCRP.     

Relationships of BMI to Cardiovascular Risk Factors Differ by Ethnicity

The burden of cardiovascular risk associated with obesity disproportionately affects African Americans and little is known about ethnic/racial differences in the relationship of obesity to cardiometabolic risk. This report assesses whether obesity is similarly associated with cardiometabolic risk factors in African Americans and whites of European ancestry. Cross‐sectional observational data from the Jackson Heart Study (JHS) and the Framingham Heart Study (FHS) were compared. This analysis uses participants aged 35–74 years with BMI >18.5 kg/m², and free of prevalent cardiovascular disease (CVD), from the initial JHS clinical examination (2000–2004) and the FHS Offspring (1998–2001) and Third Generation (2002–2005) cohorts. Participants were evaluated for the presence of lipid abnormalities, hypertension, and diabetes. Overall, 4,030 JHS (mean age 54 years, 64% women) and 5,245 FHS (mean age 51 years, 54% women) participants were available for analysis. The prevalence of all risk factors except high triglycerides and low high‐density lipoprotein (HDL) was substantially higher in JHS (all P < 0.001) and BMI was associated with increasing prevalence of most CVD risk factors within each race. For diabetes mellitus, hypertension, and low HDL, steeper relationships to BMI were observed in FHS than in JHS (P values <0.001–0.016). There were larger proportional increases in risk factor prevalence with increasing BMI in whites than in African Americans. The higher prevalence rates of cardiometabolic risk factors at nearly all levels of BMI in African Americans, however, suggest that additional factors contribute to the burden of CVD risk in African Americans.     

Psychological stress and cardiovascular disease: empirical demonstration of bias in a prospective observational study of Scottish men

ObjectivesTo examine the association between self perceived psychological stress and cardiovascular disease in a population where stress was not associated with social disadvantage.DesignProspective observational study with follow up of 21 years and repeat screening of half the cohort 5 years from baseline. Measures included perceived psychological stress, coronary risk factors, self reported angina, and ischaemia detected by electrocardiography.Setting27 workplaces in Scotland.Participants5606 men (mean age 48 years) at first screening and 2623 men at second screening with complete data on all measuresResultsBoth prevalence and incidence of angina increased with increasing perceived stress (fully adjusted odds ratio for incident angina, high versus low stress 2.66, 95% confidence interval 1.61 to 4.41; P for trend <0.001). Prevalence and incidence of ischaemia showed weak trends in the opposite direction. High stress was associated with a higher rate of admissions to hospital generally and for admissions related to cardiovascular disease and psychiatric disorders (fully adjusted rate ratios for any general hospital admission 1.13, 1.01 to 1.27, cardiovascular disease 1.20, 1.00 to 1.45, and psychiatric disorders 2.34, 1.41 to 3.91). High stress was not associated with increased admission for coronary heart disease (1.00, 0.76-1.32) and showed an inverse relation with all cause mortality, mortality from cardiovascular disease, and mortality from coronary heart disease, that was attenuated by adjustment for occupational class (fully adjusted hazard ratio for all cause mortality 0.94, 0.81 to 1.11, cardiovascular mortality 0.91, 0.78 to 1.06, and mortality from coronary heart disease 0.98, 0.75 to 1.27).ConclusionsThe relation between higher stress, angina, and some categories of hospital admissions probably resulted from the tendency of participants reporting higher stress to also report more symptoms. The lack of a corresponding relation with objective indices of heart disease suggests that these symptoms did not reflect physical disease. The data suggest that associations between psychosocial measures and disease outcomes reported from some other studies may be spurious.

What is already known on this topic

Higher psychological stress has predicted coronary heart disease in several observational studiesExposure to stress and heart disease outcomes were often based on self report so that a general tendency to negative perceptions may have generated a spurious association between higher perceived stress and heart disease symptoms

What this study adds

Perceived stress was strongly related to subjective symptoms of heart disease, including those leading to hospital admissionHowever, stress showed a weakly inverse relation to all objective indices of heart disease: socially advantaged men perceived themselves to be most stressed, and the “protective” effect of stress was probably attributable to residual confoundingSuggestions that psychological stress is an important determinant of heart disease may be premature     

Lifetime Smoking History and Cause-Specific Mortality in a Cohort Study with 43 Years of Follow-Up

BackgroundIn general, smoking increases the risk of mortality. However, it is less clear how the relative risk varies by cause of death. The exact impact of changes in smoking habits throughout life on different mortality risks is less studied.MethodsWe studied the impact of baseline and lifetime smoking habits, and duration of smoking on the risk of all-cause mortality, mortality of cardiovascular diseases (CVD), chronic obstructive pulmonary disease (COPD), any cancer and of the four most common types of cancer (lung, colorectal, prostate, and breast cancer) in a cohort study (Vlagtwedde-Vlaardingen 1965–1990, with a follow-up on mortality status until 2009, n = 8,645). We used Cox regression models adjusted for age, BMI, sex, and place of residence. Since previous studies suggested a potential effect modification of sex, we additionally stratified by sex and tested for interactions. In addition, to determine which cause of death carried the highest risk we performed competing-risk analyses on mortality due to CVD, cancer, COPD and other causes.ResultsCurrent smoking (light, moderate, and heavy cigarette smoking) and lifetime persistent smoking were associated with an increased risk of all-cause, CVD, COPD, any cancer, and lung cancer mortality. Higher numbers of pack years at baseline were associated with an increased risk of all-cause, CVD, COPD, any cancer, lung, colorectal, and prostate cancer mortality. Males who were lifetime persistent pipe/cigar smokers had a higher risk of lung cancer [HR (95% CI) = 7.72 (1.72–34.75)] as well as all-cause and any cancer mortality. A longer duration of smoking was associated with a higher risk of COPD, any and lung cancer [HR (95% CI) = 1.06 (1.00–1.12), 1.03 (1.00–1.06) and 1.10 (1.03–1.17) respectively], but not with other mortality causes. The competing risk analyses showed that ex- and current smokers had a higher risk of cancer, CVD, and COPD mortality compared to all other mortality causes. In addition, heavy smokers had a higher risk for COPD mortality compared to cancer, and CVD mortality.ConclusionOur study indicates that lifetime numbers of cigarettes smoked and the duration of smoking have different impacts for different causes of mortality. Moreover, our findings emphasize the importance of smoking-related competing risks when studying the smoking-related cancer mortality in a general population and that smoking cessation immediately effectively reduces the risk of all-cause and any cancer mortality.     

Quantifying HDL proteins by mass spectrometry: how many proteins are there and what are their functions?

Introduction: Many lines of evidence indicate that low levels of HDL cholesterol increase the risk of cardiovascular disease (CVD). However, recent clinical studies of statin-treated subjects with established atherosclerosis cast doubt on the hypothesis that elevating HDL cholesterol levels reduces CVD risk.

Areas covered: It is critical to identify new HDL metrics that capture HDL’s proposed cardioprotective effects. One promising approach is quantitative MS/MS-based HDL proteomics. This article focuses on recent studies of the feasibility and challenges of using this strategy in translational studies. It also discusses how lipid-lowering therapy and renal disease alter HDL’s functions and proteome, and how HDL might serve as a platform for binding proteins with specific functional properties.

Expert commentary: It is clear that HDL has a diverse protein cargo and that its functions extend well beyond its classic role in lipid transport and reverse cholesterol transport. MS/MS analysis has demonstrated that HDL might contain >80 different proteins. Key challenges are demonstrating that these proteins truly associate with HDL, are functionally important, and that MS-based HDL proteomics can reproducibly detect biomarkers in translational studies of disease risk.     

Ten-Year Mortality and Cardiovascular Morbidity in the Finnish Diabetes Prevention Study—Secondary Analysis of the Randomized Trial

Background

The Finnish Diabetes Prevention Study (DPS) was a randomized controlled trial, which showed that it is possible to prevent type 2 diabetes by lifestyle changes. The aim of the present study was to examine whether the lifestyle intervention had an effect on the ten-year mortality and cardiovascular morbidity in the DPS participants originally randomized either into an intervention or control group. Furthermore, we compared these results with a population-based cohort comprising individuals of varying glucose tolerance states.

Methods and Findings

Middle-aged, overweight people with IGT (n = 522) were randomized into intensive intervention (including physical activity, weight reduction and dietary counseling), or control “mini-intervention” group. Median length of the intervention period was 4 years and the mean follow-up was 10.6 years. The population-based reference study cohort included 1881 individuals (1570 with normal glucose tolerance, 183 with IGT, 59 with screen-detected type 2 diabetes, 69 with previously known type 2 diabetes) with the mean follow-up of 13.8 years. Mortality and cardiovascular morbidity data were collected from the national Hospital Discharge Register and Causes of Death Register. Among the DPS participants who consented for register linkage (n = 505), total mortality (2.2 vs. 3.8 per 1000 person years, hazard ratio HR = 0.57, 95% CI 0.21–1.58) and cardiovascular morbidity (22.9 vs. 22.0 per 1000 person years, HR = 1.04, 95% CI 0.72–1.51) did not differ significantly between the intervention and control groups. Compared with the population-based cohort with impaired glucose tolerance, adjusted HRs were 0.21 (95% CI 0.09–0.52) and 0.39 (95% CI 0.20–0.79) for total mortality, and 0.89 (95% CI 0.62–1.27) and 0.87 (0.60–1.27) for cardiovascular morbidity in the intervention and control groups of the DPS, respectively. The risk of death in DPS combined cohort was markedly lower than in FINRISK IGT cohort (adjusted HR 0.30, 95% CI 0.17–0.54), but there was no significant difference in the risk of CVD (adjusted HR 0.88, 95% CI 0.64–1.21).

Conclusions

Lifestyle intervention among persons with IGT did not decrease cardiovascular morbidity during the first 10 years of follow-up. However, the statistical power may not be sufficient to detect small differences between the intervention and control groups. Low total mortality among participants of the DPS compared with individuals with IGT in the general population could be ascribed to a lower cardiovascular risk profile at baseline and regular follow-up.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00518167","term_id":"NCT00518167"}}NCT00518167     

Pulmonary surfactant protein B carried by HDL predicts incident CVD in patients with type 1 diabetes

Atherosclerotic CVD is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome have been shown to associate with prevalent CVD in T1DM. We therefore sought to determine which proteins carried by HDL might predict incident CVD in patients with T1DM. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study. We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). We found that only one HDL protein—SFTPB (pulmonary surfactant protein B)—predicted incident CVD in all the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12–4.21, P = 0.022). In addition, plasma fractionation demonstrated that SFTPB is nearly entirely bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status and a wide range of confounding factors, including HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost entirely bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker—and perhaps mediator—of CVD risk in patients with T1DM.     

Night work as a risk factor for future cause-specific disability pension: A prospective twin cohort study in Sweden

The objectives of the study were to investigate the associations between night work and disability pension (DP) due to all causes, cardiovascular (CVD), mental, and other diagnoses, adjusting for familial confounding. The material of the study included comprehensive survey data on 27 165 Swedish twins born in 1935–1958 that were linked with DP data for the survey period (1998–2003) to 2013. Night work was assessed as years of working nights at least every now and then, and categorized into not at all, 1–10 years and over 10 years. For statistical analyses, Cox proportional hazards regressions were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). The results of the study indicated that over 10 years duration of night work had an age- and sex-adjusted HR of 1.48 (95% CI 1.11–1.98) for DP due to CVD and 1–10 years of night work an HR of 1.28 (95% CI 1.06–1.55) for DP due to mental diagnoses, but attenuated when covariates were adjusted for. Both 1–10 years (HR 1.27, 95% CI 1.17–1.39) and >10 years of night work (HR 1.20, 95% CI 1.08–1.34) were associated with DP due to all causes and other diagnoses. These risks remained after adjusting for covariates. To conclude, even modest exposure in terms of duration of night work is a risk factor for all-cause DP, but also for DP due to mental and other diagnoses. The risk of DP due to CVD seems to be associated with longer (>10 years) periods of night work. All the associations between night work and DP seem to be influenced by various covariates.     

Diet‐induced Changes in Intra‐abdominal Adipose Tissue and CVD Risk in American Women

The aim of the study was to determine what effect weight loss had on intra‐abdominal adipose tissue (IAAT) and cardiovascular disease (CVD) risk in 135 premenopausal overweight African‐American (AA) and European‐American (EA) women matched for BMI. Blood lipids, systolic blood pressure (SBP), diastolic BP (DBP), and IAAT (computed tomography determined) were examined prior to and after an 800 kcal/day diet producing 12 kg‐weight loss. Significant decreases in IAAT (～38%), total cholesterol (TC; 3%), low‐density lipoproteins (LDLs: 6%), triglycerides (TGs: 27%), cholesterol/high‐density lipoprotein ratio (C/HDL ratio: 18%), SBP (3%), and DBP (3%) occurred while HDL increased (16%), following weight loss and 1 month energy balance. Significant interactions between time and race showed that AA women decreased TG and increased HDL proportionately less than EA women. After adjusting for ΔIAAT, none of the CVD variables significantly changed after weight loss with the exception of HDL and C/HDL ratio. After adjusting for ΔLF (leg fat), ΔTC, ΔTG, ΔLDL, and ΔC/HDL ratio were significantly different. Multiple regression showed that independent of each other, ΔIAAT was significantly and positively related to ΔTC (adjusted β = 0.24) and ΔTG (adjusted β = 0.47), and ΔLF was negatively related to ΔTC (adjusted β = ?0.19) and ΔTG (adjusted β = ?0.18). Overweight and premenopausal AA and EA women benefitted from weight loss by decreasing IAAT and improving CVD risk. The changes in IAAT were significantly related to blood lipids, but loss of LF seems to be related to reduced improvement in TC and TG. Based on these results, interventions should focus on changes on IAAT.