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Objective A positive family history of premature coronary artery disease (CAD) is a risk factor for cardiovascular disease (CVD), independent of traditional risk factors. Therefore, currently used risk algorithms poorly predict risk in these individuals. Novel methods are thus needed to assess cardiovascular risk. Pulse-wave velocity (PWV) might be such a method, but it is unknown whether PWV is increased in first-degree relatives of patients with premature CAD. Design Observational case-control study. Setting Academic hospital. Patients Patients with premature CAD and a positive family history of premature CVD (n = 50), their first-degree relatives without CVD (n = 50) and unrelated controls (n = 50). Interventions None. Main Outcome Measures PWV was measured with using an Arteriograph system. Differences in PWV were assessed by a generalised linear model and multinomial logistic regression. Results Patients with premature CAD had a higher PWV compared with first-degree relatives and controls (9.69+/-2.90 m/s vs 8.15+/-61.96 m/s and 7.38+/-61.08 m/s; p

The goal of this study was to evaluate whether individuals with a positive family history for premature coronary artery disease (CAD) and coronary calcium scoring (CCS) above the 80th percentile might benefit from preventive treatment.First-degree relatives of patients with premature CAD have an increased risk for cardiovascular disease (CVD), whereas events are poorly predicted in these individuals. Surrogate markers, such as CCS, might refine risk scoring. Nevertheless, the outcome of the St. Francis Heart trial, which investigated the effect of atorvastatin 20 mg/day in asymptomatic individuals with CCS above the 80th percentile, did not reach statistical significance.We performed a post hoc analysis on the database of the St. Francis trial to assess efficacy of treatment with atorvastatin 20 mg/day in those with CCS above the 80th percentile and presence (n = 543) or absence (n = 462) of a positive family history for premature CAD. All participants received aspirin 81 mg/day. Primary outcome included coronary death, myocardial infarction, coronary revascularization, stroke, and arterial surgery.A total of 1,005 individuals, with a mean age of 59.0 ± 5.9 years and a median absolute CCS of 370 Agatston units (interquartile range: 183 to 662) participated in the trial. After a follow-up of 4.3 (interquartile range: 3.5 to 4.5) years, 7.2% of the treated individuals with a positive family history had a cardiovascular event versus 12.5% of the placebo group (hazard ratio [HR]: 0.55; 95% confidence intervals [CI]: 0.31 to 0.97; p = 0.040). This is comparable with a number needed to treat of 18.9. In individuals without a family history, events were minimally reduced: 6.6% in the treated versus 6.8% in the placebo group (HR: 1.04; 95% CI: 0.51 to 2.13; p = 0.912).The combination of a positive family history and CCS above the 80th percentile identifies a subgroup within the primary prevention population that receives greater benefit from statin treatment than the population at large. These results have important implications for future guidelines concerning individuals with a positive family history for premature CAD.

BackgroundCoronary artery disease (CAD) is the leading cause of human morbidity and mortality worldwide, underscoring the need to improve diagnostic strategies. Platelets play a major role, not only in the process of acute thrombosis during plaque rupture, but also in the formation of atherosclerosis itself. MicroRNAs are endogenous small non-coding RNAs that control gene expression and are expressed in a tissue and disease-specific manner. Therefore they have been proposed to be useful biomarkers. It remains unknown whether differences in miRNA expression levels in platelets can be found between patients with premature CAD and healthy controls.Methodology/principal findingsIn this case-control study we measured relative expression levels of platelet miRNAs using microarrays from 12 patients with premature CAD and 12 age- and sex-matched healthy controls. Six platelet microRNAs were significantly upregulated (miR340*, miR451, miR454*, miR545:9.1. miR615-5p and miR624*) and one miRNA (miR1280) was significantly downregulated in patients with CAD as compared to healthy controls. To validate these results, we measured the expression levels of these candidate miRNAs by qRT-PCR in platelets of individuals from two independent cohorts; validation cohort I consisted of 40 patients with premature CAD and 40 healthy controls and validation cohort II consisted of 27 patients with artery disease and 40 healthy relatives. MiR340* and miR624* were confirmed to be upregulated in patients with CAD as compared to healthy controls in both validation cohorts.Conclusion/significanceTwo miRNAs in platelets are significantly upregulated in patients with CAD as compared to healthy controls. Whether the two identified miRNAs can be used as biomarkers and whether they are cause or consequence of the disease remains to be elucidated in a larger prospective study.

Impaired coronary endothelial function in a rat model of spontaneous albuminuria.BackgroundAlbuminuria is an independent risk factor of coronary artery disease and has been proposed to reflect a general endothelial disorder. The Munich Wistar Frömter (MWF) rat strain develops spontaneous albuminuria and, therefore, may be an interesting experimental model to study alterations of endothelial function under conditions of increased albuminuria. Our aim was to investigate if the MWF strain shows generalized endothelial dysfunction or endothelial dysfunction localized to the coronary vascular bed, and if so, determine which endothelial dilative mediators are involved.MethodsCoronary and mesenteric arteries were investigated for endothelium-dependent relaxation and the contribution of prostacyclin, nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) in MWF rats compared to normal Wistar rats. In addition, as MWF rats show increased blood pressure, spontaneously hypertensive rats (SHR) with similar hypertension but without increased albuminuria also were studied.ResultsMaximal total endothelium-dependent relaxation of coronary arteries was strongly impaired in MWF rats (55 ± 3%) compared to Wistar (89 ± 5%) and SHR (89 ± 2%) P < 0.05, respectively. The NO-mediated relaxation as well as the relaxation mediated by EDH were significantly lower in coronary arteries from MWF compared to Wistar. In mesenteric arteries of MWF the endothelium-dependent relaxation was intact.ConclusionsThe strong impairment of coronary endothelium-dependent relaxation in the MWF model of spontaneous albuminuria may be due to defects in production or activity of NO and EDH. The intact mesenteric endothelium-dependent relaxation suggests that increased albuminuria may not be related to generalized endothelial vasodilator dysfunction in this model. Selective impairment of coronary endothelial function in a setting of spontaneous albuminuria may be a feature of the MWF that may be employed to further study cause–effect relations between albuminuria and coronary artery disease.

Microalbuminuria is associated with both an increased prevalence of cardiovascular risk factors and greater renal and cardiovascular morbidity. We questioned whether in the general population such associations can be found at lower levels of urinary albumin excretion than that of classically defined microalbuminuria. To that purpose urinary albumin concentration was measured in 40619 subjects aged 28 to 75 years. The subjects filled in a questionnaire on cardiovascular risk factors and events and were divided in deciles according to their urinary albumin concentration. Smoking was associated with albuminuria in the fifth or higher decile of urinary albumin concentration, that is with an albumin concentration of 5.1 mg/l and higher. The lower cut-off point for a positive association with hypertension was 8.8 mg/l, and for diabetes 11.2 mg/l. Family history for cardiovascular disease and hyperlipidaemia were not associated with albuminuria. We conclude that urinary albumin concentrations far below the microalbuminuric range are associated with increased prevalence of established cardiovascular risk factors. Family history for cardiovascular disease and hyperlipidaemia seems to behave differently. These data emphasize the need for more studies on the impact of albuminuria on the prediction of cardiovascular and renal disease in the general population.

Smoking induces albuminuria and accelerates progression to renal failure in persons with diabetes, but little is known about the relation between smoking and renal function in nondiabetic persons.To investigate whether smoking is related to albuminuria and abnormal renal function in nondiabetic persons.Cross-sectional study.Groningen, The Netherlands.7476 participants in the PREVEND (Prevention of REnal and Vascular ENd stage Disease) Study.Microalbuminuria and high normal albuminuria were defined as urinary albumin excretion of 30 to 300 mg/24 h and 15 to 30 mg/24 h, respectively. Elevated or decreased glomerular filtration rate (GFR) was defined as a creatinine clearance that exceeded or was less than two times the standard deviation of the mean value in nondiabetic, nonsmoking participants who had an albumin excretion of 0 to 15 mg/24 h, adjusted for age and sex.Current smokers had a higher median albumin excretion than nonsmokers and were more likely to have microalbuminuria and high normal albuminuria with elevated or decreased GFR. After adjustment for several potential confounding factors, persons who smoked 20 or fewer cigarettes/d and persons who smoked more than 20 cigarettes/d, respectively, showed a dose-dependent association between smoking and high normal albuminuria (relative risk, 1.33 [95% CI, 1.10 to 1.61] and 1.98 [CI, 1.49 to 2.64]), microalbuminuria (relative risk, 1.92 [CI, 1.54 to 2.39] and 2.15 [CI, 1.52 to 3.03]), elevated GFR (relative risk, 1. 82 [CI, 1.31 to 2.53] and 1.84 [CI, 1.12 to 3.02]), and decreased GFR (relative risk, 1.53 [CI, 1.04 to 2.24] and 1.83 [CI, 1.05 to 3. 20]), respectively. Quitting smoking was associated only with microalbuminuria.Smoking is associated with albuminuria and abnormal renal function. However, these associations are less pronounced or absent in former smokers.

Microalbuminuria (MA) is an important early sign of diabetic nephropathy. Hyperfiltration and impaired filtration in relation to albuminuria has been well investigated in diabetic subjects. This study tested the hypothesis that an increased urinary albumin excretion (UAE) is associated with renal functional abnormalities also in nondiabetic subjects. The relation between UAE and creatinine clearances (Ccr) in 7728 nondiabetic subjects was studied. Subjects were divided in four groups according to UAE (mg/24 h): 0 to 15 (control), 15 to 30 (high-normal albuminuria [HNA]), 30 to 300 (MA), >300 (macroalbuminuria). An elevated filtration and a diminished filtration were defined as a Ccr exceeding or below 2x the SD of the control group corrected for age and gender. Ccr followed a parabolic trend, with a higher Ccr in the HNA as compared with control and a lower Ccr in the MA and macroalbuminuria group as compared with HNA. With each increasing UAE level, male sex, age, body mass index, minimal waist circumference, systolic and diastolic BP, plasma glucose, and a positive family history for diabetes all followed a significant linear increasing trend (P < 0.001). After adjustment for age, gender, body mass index, plasma glucose, a positive family history for diabetes, systolic and diastolic BP, antihypertensive medication, and smoking in a multivariate analysis, HNA and MA were independently associated with an elevated filtration (RR 1.8 [95% confidence interval, 1.30 to 2.51] and 1.7 [1.17 to 2. 45]). Macroalbuminuria was independently associated with a diminished filtration (4.3 [range, 1.97 to 9.36]). In conclusion, an elevated UAE might be an important and early sign for progressive renal function loss in a nondiabetic population.

Background: MicroRNAs have been established as markers for cardiovascular disease in many studies. However, most of the patients included in these studies were treated with aspirin for secondary prevention reasons. It is known, that there are individual differences in the response of platelets to aspirin. Whether the response of platelets to aspirin shows differences in miRNA expression is not know. We therefore, studied the influence of aspirin on microRNA expression levels, in isolated platelets of healthy volunteers. Additionally we analyzed, whether the in vitro response of platelets to indometacine, a surrogate for aspirin, in ADP-mediated whole blood aggregation was related to differences in miRNA profiles. Methods and results: We measured relative expression levels of platelet microRNAs using microarrays before and after two weeks of aspirin use (100 mg, once daily) in 15 healthy individuals (age 45-65 years). Based on aspirin-induced changes in microRNA profile, two subgroups could be distinguished: a group of individuals (n=9) with similar and a group with different (n=6) miRNA profiles before and after aspirin use. Additionally, we performed in vitro whole blood aggregation studies to determine whether the observed difference in microRNA profile before and after aspirin use, could be linked to platelet function. Whole blood from the same individuals, in the absence of aspirin, was tested using Multiplate® aggregometry and was incubated with indometacine to mimic aspirin use. The subjects with a similar microRNA profile had significantly reduced ADP-mediated aggregation as compared to the group in which the microRNA profile was different before and after medication. Conclusion: Differences in platelet microRNA profiles after aspirin use are related to differences in ADP-mediated indometacine-treated whole blood aggregation. This could imply that differences in miRNA profiles might identify individuals with aspirin resistance.

Introduction: Patients with a genetic predisposition – as identified by a positive family history - for premature coronary artery disease (CAD) differ in phenotype and risk factor load compared to those without such predisposition. However, these groups receive the same preventive medical regimen. It is unclear whether this results in an increased risk for recurrent CAD in those with a genetic predisposition to premature CAD. Methods: We retrospectively investigated 2,756 patients with premature CAD (event

Introduction: Individuals with a family history of premature coronary artery disease (CAD) have an increased cardiovascular risk. Since current risk algorithms poorly predict risk, especially in younger individuals, novel methods are needed to assess cardiovascular risk in these families. Recently, microvascular function (using imaging of the sublingual microvasculature with videomicroscopy) was put forward as an indicator of vascular vulnerability in CAD. We set out to evaluate if microvascular dysfunction was present in premature CAD families. Methods: In 50 patients with premature CAD (men

The Authors' reply Recently, we reported a case-control study in which we found that both patients with premature coronary artery disease (CAD) and their ‘healthy’ asymptomatic first degree relatives had increased arterial stiffness compared with controls.1 Noteworthy, these patients and their first degree relatives had at least two prematurely affected relatives within their family. With interest we read the comment by Zaman2 who disputes that a family history of premature CAD is an important risk factor on a population base, for which he refers to the INTERHEART study.3 However, we have several arguments to oppose his statement. We agree that the INTERHEART study shows that a combination of nine risk …

The burden of cardiovascular disease (CVD) cannot be fully addressed by therapy targeting known pathophysiological pathways. Even with stringent control of all risk factors CVD events are only diminished by half. A number of additional pathways probably play a role in the development of CVD and might serve as novel therapeutic targets. Genome wide expression studies represent a powerful tool to identify such novel pathways. We compared the expression profiles in monocytes from twenty two young male patients with premature familial CAD with those from controls matched for age, sex and smoking status, without a family history of CVD. Since all patients were on statins and aspirin treatment, potentially affecting the expression of genes in monocytes, twelve controls were subsequently treated with simvastatin and aspirin for 6 and 2 weeks, respectively. By whole genome expression arrays six genes were identified to have differential expression in the monocytes of patients versus controls; ABCA1, ABCG1 and RGS1 were downregulated in patients, whereas ADRB2, FOLR3 and GSTM1 were upregulated. Differential expression of all genes, apart from GSTM1, was confirmed by qPCR. Aspirin and statins altered gene expression of ABCG1 and ADBR2. All finding were validated in a second group of twenty four patients and controls. Differential expression of ABCA1, RSG1 and ADBR2 was replicated. In conclusion, we identified these 3 genes to be expressed differently in CAD cases which might play a role in the pathogenesis of atherosclerotic vascular disease.