Ties A. Mulders

Platelets in Patients with Premature Coronary Artery Disease Exhibit Upregulation of miRNA340* and miRNA624*

Background Coronary 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 Findings In 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/Significance Two 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.

Asymptomatic Individuals With a Positive Family History for Premature Coronary Artery Disease and Elevated Coronary Calcium Scores Benefit From Statin Treatment A Post Hoc Analysis From the St. Francis Heart Study

OBJECTIVES 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. BACKGROUND 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. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Arterial stiffness is increased in families with premature coronary artery disease

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±1.96 m/s and 7.38±1.08 m/s; p<0.05 patients vs all groups). Linear regression showed all groups related to PWV, with patients having the highest PWV and controls the lowest (p<0.0001). Furthermore, PWV was associated with first-degree relatives (OR 1.32, 95% CI 1.02 to 1.72; p<0.05) and premature CAD (OR 1.72, 95% CI 1.32 to 2.24; p<0.05) compared with controls. These findings were independent of blood pressure and other traditional risk factors. Conclusions Patients with premature CAD and their first-degree relatives had higher PWV compared with controls, independent of other risk factors. This holds promise for the future, in which arterial stiffness might play a role in risk prediction within families with premature CAD.

Non-invasive assessment of microvascular dysfunction in families with premature coronary artery disease

premature coronary artery disease Ties A. Mulders , Max Nieuwdorp , Erik S. Stroes , Hans Vink , Sara-Joan Pinto-Sietsma a,c,⁎ a Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands b Department of Physiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands c Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, Amsterdam, The Netherlands

Patients with premature cardiovascular disease and a positive family history for cardiovascular disease are prone to recurrent events.

BACKGROUND Premature cardiovascular disease (CVD) is treated in the same way as CVD of advanced age. However, in patients with premature CVD and a family history of CVD, different -possibly genetic- mechanisms may underlie this disease, which current medical treatment is not targeted to. This suggests that subjects with a genetic predisposition to CVD are more likely to have recurrent cardiovascular events. METHODS We retrospectively investigated 291 patients with premature CVD and assessed the amount of recurrent events according to family history in a follow-up period of 31 years. Premature CVD was defined as an event <51 years for men or <56 for women. We used a Cox proportional hazards model to estimate the relationship between a positive family history and recurrence of cardiovascular events. RESULTS Patients with recurrent events had more often a positive family history (60.0% vs. 47.1%; p<0.05), were more often smokers (85.2% vs. 70.7%; p<0.05), had more often hypertension (36.3% vs. 23.6%; p<0.05) and had a longer follow-up period (10.0 years vs. 5.4 years; p<0.001) than patients without recurrent events. After adjusting for these differences and modelling time to events, a positive family history was independently associated with recurrent events (Hazard ratio 1.31 (95% confidence intervals (CI) 1.01-1.72; p<0.05)). CONCLUSIONS Patients with a genetic predisposition for CVD are at risk for recurrent events, after adjusting for risk factors and other confounders. This might imply that in subjects with a genetic predisposition for CVD different pathophysiological mechanisms are active, leading to recurrent events.

Arterial stiffness in periodontitis patients and controls: A case-control and pilot intervention study

Increased arterial stiffness (AS) is an important indicator for atherosclerotic cardiovascular disease (ACVD). Epidemiologically, periodontitis and ACVD are associated. Therefore, we aimed to investigate AS in periodontitis patients and controls. In addition, we explored the effect of periodontal therapy on AS in a sub-group of cases. Pulse-wave velocity (PWV), a non-invasive chair-side function test for AS, was measured in periodontitis patients (n=57; mean age 46.6 years) and compared with a reference group (n=48; mean age 45.5 years). In addition, 45 cases (mean age 46.9 years) were 6 months followed after periodontal treatment, to explore a possible effect on arterial function. Periodontitis patients showed a significantly increased PWV compared with the reference group (8.01±0.20 vs 7.36±0.22 m s−1 respectively; P=0.029) and this remained significant after adjustments for ACVD risk factors (P=0.019). After periodontal therapy, no significant reduction in PWV was seen (8.00±1.8 to 7.82±1.6 m s−1; P=0.13), but systolic blood pressure (SBP) was significantly reduced (119.8±14.6 to 116.9±15.1 mm Hg; P=0.040). It can be concluded that periodontitis is associated with increased AS. This confirms with a new parameter the association of periodontitis with ACVD. Although periodontal treatment did not lower AS significantly, a modest reduction of SBP after 6 months was observed.

A positive family history for premature cardiovascular disease identifies patients prone to recurrent arterial thrombotic events.

Background: Cardiovascular disease (CVD) is characterized by slow progressive atherosclerosis and arterial thrombotic events, leading to occlusions. Whether either of these presentations is more likely in patients with a genetic predisposition for CVD is still unknown. We suggest that a genetic predisposition for CVD is related to recurrent events of the same nature. Methods: We retrospectively investigated 275 patients with premature CVD and divided them in two groups according to their first event: an arterial thrombotic event or stable atherosclerosis. We used a Cox proportional-hazards model to estimate the effect of a positive family history for CVD on recurrent events of the same nature. This was tested in the entire cohort and in patients with coronary artery disease only. Results: Patients with a first arterial thrombotic event and a positive family history had a threefold increased risk for a recurrent event of the same nature, compared to patients with a negative family history (hazard ratio 3.00, 95% confidence interval 1.32–6.81); p < 0.05). In contrast, a positive family history was not associated with an increased risk for a recurrent stable atherosclerosis (hazard ratio 0.98 (95% confidence interval 0.59–1.63). These findings were similar analysing the patients with coronary artery disease only. Additional adjustments for other risk factors did not change these associations. Conclusions: Patients with a first premature arterial thrombotic event and a positive family history for CVD have an increased risk for a second event of the same nature. This might be due to unknown hereditary mechanisms leading to recurrent acute events.

Coronary artery calcification score as tool for risk assessment among families with premature coronary artery disease.

INTRODUCTION There is discussion about incorporating a family history (FamHis) of premature coronary artery disease (CAD) in risk score algorithms. However, FamHis provides information on individual risk. Coronary artery calcification score (CACS) is a metric of atherosclerosis that may determine the individual risk within families at high risk of premature CAD. METHODS In asymptomatic individuals (n = 704), we assessed the association between FamHis of CAD and elevated CACS. To assess the predictive value of CACS in individuals with a FamHis of CAD, we performed a post-hoc analysis on the St. Francis Heart Study (n = 834). We assessed, in a case control design, the risk of future CAD in individuals with a FamHis of CAD and either CACS >80th percentile or no CACS at all. RESULTS Individuals with a FamHis for CAD had an increased risk for elevated CACS (adjusted odds ratio (OR) 2.23 (95% CI 1.48-3.36); p < 0.05), compared to those without a FamHis. In the prospective study (3.5 years follow-up), the event rate equally low in those with a positive FamHis and a negative FamHis (0% vs. 1%), if they had a CAC of 0. However, in those with CACS >80(th) percentile, a FamHis of CAD doubled the CAD event rate (positive FamHis 12.5% vs. negative FamHis 6.8%; adjusted HR 2.08 (95% CI 1.09-3.87; p < 0.05). CONCLUSION CAC scoring leads to risk discrimination among those with a positive FamHis for premature CAD. These results support testing CAC score in asymptomatic individuals with a positive FamHis to identify a high risk population.