LDL-cholesterol concentrations: a genome-wide association study.

BACKGROUND: LDL cholesterol has a causal role in the development of cardiovascular disease. Improved understanding of the biological mechanisms that underlie the metabolism and regulation of LDL cholesterol might help to identify novel therapeutic targets. We therefore did a genome-wide association study of LDL-cholesterol concentrations. METHODS: We used genome-wide association data from up to 11,685 participants with measures of circulating LDL-cholesterol concentrations across five studies, including data for 293 461 autosomal single nucleotide polymorphisms (SNPs) with a minor allele frequency of 5% or more that passed our quality control criteria. We also used data from a second genome-wide array in up to 4337 participants from three of these five studies, with data for 290,140 SNPs. We did replication studies in two independent populations consisting of up to 4979 participants. Statistical approaches, including meta-analysis and linkage disequilibrium plots, were used to refine association signals; we analysed pooled data from all seven populations to determine the effect of each SNP on variations in circulating LDL-cholesterol concentrations. FINDINGS: In our initial scan, we found two SNPs (rs599839 [p=1.7x10(-15)] and rs4970834 [p=3.0x10(-11)]) that showed genome-wide statistical association with LDL cholesterol at chromosomal locus 1p13.3. The second genome screen found a third statistically associated SNP at the same locus (rs646776 [p=4.3x10(-9)]). Meta-analysis of data from all studies showed an association of SNPs rs599839 (combined p=1.2x10(-33)) and rs646776 (p=4.8x10(-20)) with LDL-cholesterol concentrations. SNPs rs599839 and rs646776 both explained around 1% of the variation in circulating LDL-cholesterol concentrations and were associated with about 15% of an SD change in LDL cholesterol per allele, assuming an SD of 1 mmol/L. INTERPRETATION: We found evidence for a novel locus for LDL cholesterol on chromosome 1p13.3. These results potentially provide insight into the biological mechanisms that underlie the regulation of LDL cholesterol and might help in the discovery of novel therapeutic targets for cardiovascular disease.

Pharmacist interventions to improve cardiovascular disease risk factors in diabetes: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: This systematic review and meta-analysis of randomized controlled trials (RCTs) assesses the effect of pharmacist care on cardiovascular disease (CVD) risk factors among outpatients with diabetes. RESEARCH DESIGN AND METHODS: MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched. Pharmacist interventions were classified, and a meta-analysis of mean changes of blood pressure (BP), total cholesterol (TC), LDL cholesterol, HDL cholesterol, and BMI was performed using random-effects models. RESULTS: The meta-analysis included 15 RCTs (9,111 outpatients) in which interventions were conducted exclusively by pharmacists in 8 studies and in collaboration with physicians, nurses, dietitians, or physical therapists in 7 studies. Pharmacist interventions included medication management, educational interventions, feedback to physicians, measurement of CVD risk factors, or patient-reminder systems. Compared with usual care, pharmacist care was associated with significant reductions for systolic BP (12 studies with 1,894 patients; -6.2 mmHg [95% CI -7.8 to -4.6]); diastolic BP (9 studies with 1,496 patients; -4.5 mmHg [-6.2 to -2.8]); TC (8 studies with 1,280 patients; -15.2 mg/dL [-24.7 to -5.7]); LDL cholesterol (9 studies with 8,084 patients; -11.7 mg/dL [-15.8 to -7.6]); and BMI (5 studies with 751 patients; -0.9 kg/m(2) [-1.7 to -0.1]). Pharmacist care was not associated with a significant change in HDL cholesterol (6 studies with 826 patients; 0.2 mg/dL [-1.9 to 2.4]). CONCLUSIONS: This meta-analysis supports pharmacist interventions-alone or in collaboration with other health care professionals-to improve major CVD risk factors among outpatients with diabetes.

Autophagosome maturation is impaired in Fabry disease.

Fabry disease is a lysosomal storage disorder (LSD) caused by a deficiency in alpha-galactosidase A. The disease is characterized by severe major organ involvement, but the pathologic mechanisms responsible have not been elucidated. Disruptions of autophagic processes have been reported for other LSDs, but have not yet been investigated in Fabry disease. Renal biopsies were obtained from five adult male Fabry disease patients before and after three years of enzyme replacement therapy (ERT) with agalsidase alfa. Vacuole accumulation was seen in renal biopsies from all patients compared with control biopsies. Decreases in the number of vacuoles were seen after three years of ERT primarily in renal endothelial cells and mesangial cells. Measurement of the levels of LC3, a specific autophagy marker, in cultured cells from Fabry patients revealed increased basal levels compared to cells from non-Fabry subjects and a larger increase in response to starvation than seen in non-Fabry cells. Starvation in the presence of protease inhibitors did not result in a significant increase in LC3 in Fabry cells, whereas a further increase in LC3 was observed in non-Fabry cells, an observation that is consistent with impaired autophagic flux in Fabry disease. Overexpression of LC3 mRNA in Fabry fibroblasts compared to control cells is consistent with an upregulation of autophagy. Furthermore, LC3 and p62/SQSTM1 (that binds to LC3) staining in renal tissues and in cultured fibroblasts from Fabry patients supports impairment of autophagic flux. These findings suggest that Fabry disease is linked to a deregulation of autophagy.

Randomized trial of a computerized coronary heart disease risk assessment tool in HIV-infected patients receiving combination antiretroviral therapy.

BACKGROUND: Exposure to combination antiretroviral therapy (cART) can lead to important metabolic changes and increased risk of coronary heart disease (CHD). Computerized clinical decision support systems have been advocated to improve the management of patients at risk for CHD but it is unclear whether such systems reduce patients' risk for CHD. METHODS: We conducted a cluster trial within the Swiss HIV Cohort Study (SHCS) of HIV-infected patients, aged 18 years or older, not pregnant and receiving cART for >3 months. We randomized 165 physicians to either guidelines for CHD risk factor management alone or guidelines plus CHD risk profiles. Risk profiles included the Framingham risk score, CHD drug prescriptions and CHD events based on biannual assessments, and were continuously updated by the SHCS data centre and integrated into patient charts by study nurses. Outcome measures were total cholesterol, systolic and diastolic blood pressure and Framingham risk score. RESULTS: A total of 3,266 patients (80% of those eligible) had a final assessment of the primary outcome at least 12 months after the start of the trial. Mean (95% confidence interval) patient differences where physicians received CHD risk profiles and guidelines, rather than guidelines alone, were total cholesterol -0.02 mmol/l (-0.09-0.06), systolic blood pressure -0.4 mmHg (-1.6-0.8), diastolic blood pressure -0.4 mmHg (-1.5-0.7) and Framingham 10-year risk score -0.2% (-0.5-0.1). CONCLUSIONS: Systemic computerized routine provision of CHD risk profiles in addition to guidelines does not significantly improve risk factors for CHD in patients on cART.

Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis.

PURPOSE: Subclinical hypothyroidism has been associated with elevated cholesterol and increased risk for atherosclerosis, but data on the risk of coronary heart disease (CHD) are conflicting. We performed a systematic review to determine whether subclinical hypothyroidism is associated with CHD in adults. METHODS: We searched MEDLINE from 1966 to April 2005, and the bibliographies of key articles to identify studies that provided risk estimates for CHD or cardiovascular mortality associated with subclinical hypothyroidism. Two authors independently reviewed each potential study for eligibility, assessed methodologic quality, and extracted the data. RESULTS: We identified 14 observational studies that met eligibility criteria. Subclinical hypothyroidism increased the risk of CHD (summary odds ratio [OR]: 1.65, 95% confidence interval [CI], 1.28-2.12). The summary OR for CHD was 1.81 (CI, 1.38-2.39) in 9 studies adjusted or matched for demographic characteristics, and 2.38 (CI, 1.53-3.69) after pooling the studies that adjusted for most cardiovascular risk factors. Sensitivity analyses including only population-based studies and those with formal outcome adjudication procedures yielded similar results. Subgroup analyses by type of study design showed a similar trend, but lower risk, in the 5 prospective cohort studies (OR 1.42, CI, 0.91-2.21), compared with the case-control and cross-sectional studies (OR 1.72, CI, 1.25-2.38). CONCLUSION: Our systematic review indicates that subclinical hypothyroidism is associated with an increased risk of CHD. Clinical trials are needed to assess whether thyroxine replacement reduces the risk of CHD in subjects with subclinical hypothyroidism.

Pulmonary involvement in Fabry disease: Overview and perspectives.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A, which leads to storage of sphingolipids in virtually all human cells and consequently to organ dysfunction. Pulmonary involvement is still debated. But, obstructive lung disease is up to ten times more prevalent in patients with FD compared to general public. Also, an accelerated decline in forced expiratory volume in one second (FEV1) over time was observed in these patients. Lysosomal storage of glycosphingolipids is considered leading to small airway disease via hyperplasia of the bronchiolar smooth muscle cells. Larger airways may become involved with ongoing disease process. There is no evidence for involvement of the lung interstitium in FD. The effect of enzyme replacement therapy on respiratory involvement remains to be determined in large, prospective controlled trials.

Genetic variants influencing circulating lipid levels and risk of coronary artery disease.

OBJECTIVE: Genetic studies might provide new insights into the biological mechanisms underlying lipid metabolism and risk of CAD. We therefore conducted a genome-wide association study to identify novel genetic determinants of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides. METHODS AND RESULTS: We combined genome-wide association data from 8 studies, comprising up to 17 723 participants with information on circulating lipid concentrations. We did independent replication studies in up to 37 774 participants from 8 populations and also in a population of Indian Asian descent. We also assessed the association between single-nucleotide polymorphisms (SNPs) at lipid loci and risk of CAD in up to 9 633 cases and 38 684 controls. We identified 4 novel genetic loci that showed reproducible associations with lipids (probability values, 1.6×10(-8) to 3.1×10(-10)). These include a potentially functional SNP in the SLC39A8 gene for HDL-C, an SNP near the MYLIP/GMPR and PPP1R3B genes for LDL-C, and at the AFF1 gene for triglycerides. SNPs showing strong statistical association with 1 or more lipid traits at the CELSR2, APOB, APOE-C1-C4-C2 cluster, LPL, ZNF259-APOA5-A4-C3-A1 cluster and TRIB1 loci were also associated with CAD risk (probability values, 1.1×10(-3) to 1.2×10(-9)). CONCLUSIONS: We have identified 4 novel loci associated with circulating lipids. We also show that in addition to those that are largely associated with LDL-C, genetic loci mainly associated with circulating triglycerides and HDL-C are also associated with risk of CAD. These findings potentially provide new insights into the biological mechanisms underlying lipid metabolism and CAD risk.

Impact of enhanced compliance initiatives on the efficacy of rosuvastatin in reducing low density lipoprotein cholesterol levels in patients with primary hypercholesterolaemia.

The effectiveness of lipid-lowering medication critically depends on the patients' compliance and the efficacy of the prescribed drug. The primary objective of this multicentre study was to compare the efficacy of rosuvastatin with or without access to compliance initiatives, in bringing patients to the Joint European Task Force's (1998) recommended low-density lipoprotein cholesterol (LDL-C) level goal (LDL-C, <3.0 mmol/L) at week 24. Secondary objectives were comparison of the number and percentage of patients achieving European goals (1998, 2003) for LDL-C and other lipid parameters. Patients with primary hypercholesterolaemia and a 10-year coronary heart disease risk of >20% received open label rosuvastatin treatment for 24 weeks with or without access to compliance enhancement tools. The initial daily dosage of 10 mg could be doubled at week 12. Compliance tools included: a) a starter pack for subjects containing a videotape, an educational leaflet, a passport/goal diary and details of the helpline and/or website; b) regular personalised letters to provide message reinforcement; c) a toll-free helpline and a website. The majority of patients (67%) achieved the 1998 European goal for LDL-C at week 24. 31% required an increase in dosage of rosuvastatin to 20 mg at week 12. Compliance enhancement tools did not increase the number of patients achieving either the 1998 or the 2003 European target for plasma lipids. Rosuvastatin was well tolerated during this study. The safety profile was comparable with other drugs of the same class. 63 patients in the 10 mg group and 58 in the 10 mg Plus group discontinued treatment. The main reasons for discontinuation were adverse events (39 patients in the 10 mg group; 35 patients in the 10 mg Plus group) and loss to follow-up (13 patients in the 10 mg group; 9 patients in the 10 mg Plus group). The two most frequently reported adverse events were myalgia (34 patients, 3% respectively) and back pain (23 patients, 2% respectively). The overall rate of temporary or permanent study discontinuation due to adverse events was 9% (n = 101) in patients receiving 10 mg rosuvastatin and 3% (n = 9) in patients titrated up to 20 mg rosuvastatin. Rosuvastatin was effective in lowering LDL-C values in patients with hypercholesterolaemia to the 1998 European target at week 24. However, compliance enhancement tools did not increase the number of patients achieving any European targets for plasma lipids.

La néphropathie ischémique par athérosclérose aortorénale : acquisitions thérapeutiques [Atherosclerotic renal artery disease management update]

In the case of atherosclerotic renal artery disease, the best conclusive results lie principally not in the degree of the stenosis but rather in the degree the renal parenchymal disease beyond the stenosis itself. These determining factors involve the controlling of the patients blood pressure, the improvement in the renal function and the beneficial results to the cardiovascular system. Besides the indispensable medical treatment, a revascularisation by angioplasty may be indicated. This procedure with or without vascular stent often allows satisfactory angiographic results. A treatment by surgical revascularisation is only recommended in the case of extensive atherosclerotic lesions of the aorta, complex lesions of the latter or an abdominal aortic aneurism. Although the frequency of restenosis of angioplasty with stent remains extremely low, the risk of cholesterol emboli due to the diffuse atherosclerotic lesions of the abdominal aorta, must be considered at the time of each aortic catheterization. The therapeutic approach of atherosclerotic renal artery disease must be dictated by the whole cardiovascular risk factors and by the threat of target organs. The control of the blood pressure and the maintenance of the renal function must be integrated in the decisional algorithm as well as the possible risks in carrying out an eventual revascularisation procedure. Finally, the renal angioplasty should in numerous situations be integrated in the overall assumption of responsibility of the atherosclerotic vascular diseases, and should be part of the medical treatment. Several questions still do exist; at what moment an atherosclerotic renal artery stenosis should and e considered critical, and which procedure should be considered for which patient? The purpose of this review is to propose a decisional tool for individualized treatments in the light of results from randomized and controlled studies.

When cholesterol is not cholesterol: a note on the enzymatic determination of its concentration in model systems containing vegetable extracts

Background: Experimental evidences demonstrate that vegetable derived extracts inhibit cholesterol absorption in the gastrointestinal tract. To further explore the mechanisms behind, we modeled duodenal contents with several vegetable extracts. Results: By employing a widely used cholesterol quantification method based on a cholesterol oxidase-peroxidase coupled reaction we analyzed the effects on cholesterol partition. Evidenced interferences were analyzed by studying specific and unspecific inhibitors of cholesterol oxidase-peroxidase coupled reaction. Cholesterol was also quantified by LC/MS. We found a significant interference of diverse (cocoa and tea-derived) extracts over this method. The interference was strongly dependent on model matrix: while as in phosphate buffered saline, the development of unspecific fluorescence was inhibitable by catalase (but not by heat denaturation), suggesting vegetable extract derived H2O2 production, in bile-containing model systems, this interference also comprised cholesterol-oxidase inhibition. Several strategies, such as cholesterol standard addition and use of suitable blanks containing vegetable extracts were tested. When those failed, the use of a mass-spectrometry based chromatographic assay allowed quantification of cholesterol in models of duodenal contents in the presence of vegetable extracts. Conclusions: We propose that the use of cholesterol-oxidase and/or peroxidase based systems for cholesterol analyses in foodstuffs should be accurately monitored, as important interferences in all the components of the enzymatic chain were evident. The use of adequate controls, standard addition and finally, chromatographic analyses solve these issues.

Prevalence of Ischemic Heart Disease and Management of Coronary Risk in Daily Clinical Practice: Results from a Mediterranean Cohort of HIV-Infected Patients

There are conflicting data on the prevalence of coronary events and the quality of the management of modifiable cardiovascular risk factors (CVRF) inHIV-infected patients. Methods.We performed a retrospective descriptive study to determine the prevalence of coronary events and to evaluate the management of CVRF in a Mediterranean cohort of 3760 HIV-1-infected patients from April 1983 through June 2011. Results.We identified 81 patients with a history of a coronary event (prevalence 2.15%); 83% of them suffered an acute myocardial infarction. At the time of the coronary event, CVRF were highly prevalent (60.5% hypertension, 48% dyslipidemia, and 16% diabetes mellitus).OtherCVRF, such as smoking, hypertension, lack of exercise, and body mass index, were not routinely assessed. After the coronary event, a significant decrease in total cholesterol ( � = 0.025) and LDLcholesterol ( � = 0.004) was observed. However, the percentage of patients whomaintained LDL-cholesterol > 100mg/dL remained stable (from 46% to 41%, � = 0.103). Patients using protease inhibitors associated with a favorable lipid profile increased over time ( � = 0.028). Conclusions.The prevalence of coronary events in our cohort is low. CVRF prevalence is high and theirmanagement is far from optimal. More aggressive interventions should be implemented to diminish cardiovascular risk in HIV-infected patients.

Screening for cardiovascular disease risk and subsequent management in low and middle income countries : challenges and opportunities

Background: Cardiovascular disease (CVD), mainly heart attack and stroke, is the leading cause of premature mortality in low and middle income countries (LMICs). Identifying and managing individuals at high risk of CVD is an important strategy to prevent and control CVD, in addition to multisectoral population-based interventions to reduce CVD risk factors in the entire population. Methods: We describe key public health considerations in identifying and managing individuals at high risk of CVD in LMICs. Results: A main objective of any strategy to identify individuals at high CVD risk is to maximize the number of CVD events averted while minimizing the numbers of individuals needing treatment. Scores estimating the total risk of CVD (e.g. ten-year risk of fatal and non-fatal CVD) are available for LMICs, and are based on the main CVD risk factors (history of CVD, age, sex, tobacco use, blood pressure, blood cholesterol and diabetes status). Opportunistic screening of CVD risk factors enables identification of persons with high CVD risk, but this strategy can be widely applied in low resource settings only if cost effective interventions are used (e.g. the WHO Package of Essential NCD interventions for primary health care in low resource settings package) and if treatment (generally for years) can be sustained, including continued availability of affordable medications and funding mechanisms that allow people to purchase medications without impoverishing them (e.g. universal access to health care). This also emphasises the need to re-orient health systems in LMICs towards chronic diseases management.

Association between parental history and genetic risk scores for coronary heart disease prediction: The population-based CoLaus study.

BACKGROUND AND AIMS: Parental history (PH) and genetic risk scores (GRSs) are separately associated with coronary heart disease (CHD), but evidence regarding their combined effects is lacking. We aimed to evaluate the joint associations and predictive ability of PH and GRSs for incident CHD. METHODS: Data for 4283 Caucasians were obtained from the population-based CoLaus Study, over median follow-up time of 5.6 years. CHD was defined as incident myocardial infarction, angina, percutaneous coronary revascularization or bypass grafting. Single nucleotide polymorphisms for CHD identified by genome-wide association studies were used to construct unweighted and weighted versions of three GRSs, comprising of 38, 53 and 153 SNPs respectively. RESULTS: PH was associated with higher values of all weighted GRSs. After adjustment for age, sex, smoking, diabetes, systolic blood pressure, low and high density lipoprotein cholesterol, PH was significantly associated with CHD [HR 2.61, 95% CI (1.47-4.66)] and further adjustment for GRSs did not change this estimate. Similarly, one standard deviation change of the weighted 153-SNPs GRS was significantly associated with CHD [HR 1.50, 95% CI (1.26-1.80)] and remained so, after further adjustment for PH. The weighted, 153-SNPs GRS, but not PH, modestly improved discrimination [(C-index improvement, 0.016), p = 0.048] and reclassification [(NRI improvement, 8.6%), p = 0.027] beyond cardiovascular risk factors. After including both the GRS and PH, model performance improved further [(C-index improvement, 0.022), p = 0.006]. CONCLUSION: After adjustment for cardiovascular risk factors, PH and a weighted, polygenic GRS were jointly associated with CHD and provided additive information for coronary events prediction.

Did Dumbo suffer a heart attack? independent association between earlobe crease and cardiovascular disease.

BACKGROUND: Earlobe crease (ELC) has been associated with cardiovascular diseases (CVD) or risk factors (CVRF) and could be a marker predisposing to CVD. However, most studies studied only a small number of CVRF and no complete assessment of the associations between ELC and CVRF has been performed in a single study. METHODS: Population-based study (n = 4635, 46.7 % men) conducted between 2009 and 2012 in Lausanne, Switzerland. RESULTS: Eight hundred six participants (17.4 %) had an ELC. Presence of ELC was associated with male gender and older age. After adjusting for age and gender (and medication whenever necessary), presence of ELC was significantly (p < 0.05) associated with higher levels of body mass index (BMI) [adjusted mean ± standard error: 27.0 ± 0.2 vs. 26.02 ± 0.07 kg/m(2)], triglycerides [1.40 ± 0.03 vs. 1.36 ± 0.01 mmol/L] and insulin [8.8 ± 0.2 vs. 8.3 ± 0.1 μIU/mL]; lower levels of HDL cholesterol [1.61 ± 0.02 vs. 1.64 ± 0.01 mmol/L]; higher frequency of abdominal obesity [odds ratio and (95 % confidence interval) 1.20 (1.02; 1.42)]; hypertension [1.41 (1.18; 1.67)]; diabetes [1.43 (1.15; 1.79)]; high HOMA-IR [1.19 (1.00; 1.42)]; metabolic syndrome [1.28 (1.08; 1.51)] and history of CVD [1.55 (1.21; 1.98)]. No associations were found between ELC and estimated cardiovascular risk, inflammatory or liver markers. After further adjustment on BMI, only the associations between ELC and hypertension [1.30 (1.08; 1.56)] and history of CVD [1.47 (1.14; 1.89)] remained significant. For history of CVD, further adjustment on diabetes, hypertension, total cholesterol and smoking led to similar results [1.36 (1.05; 1.77)]. CONCLUSION: In this community-based sample ELC was significantly and independently associated with hypertension and history of CVD.