Assessment of novel cardiovascular biomarkers in women with a history of recurrent miscarriage.

OBJECTIVES: A history of recurrent miscarriage is associated with future cardiovascular disease. The aim of this study was to determine novel cardiovascular biomarkers in women with a history of recurrent miscarriage as this might lead to a better understanding of the association. STUDY DESIGN: Women who visited the recurrent miscarriage clinic at Leiden University Medical Centre (between 2000 and 2010), and had three consecutive miscarriages ≤30 years were invited to participate in this follow-up study (between 2012 and 2014). The reference group consisted of women with at least one uncomplicated pregnancy and a history of no miscarriage, matched on zip code, age, and date of pregnancy. MAIN OUTCOME MEASURES: Cardiovascular biomarkers were determined, classified into; inflammation (HsCRP, lipoprotein-associated phospholipase A2), thrombosis (homocysteine, folate, anti-cardiolipin antibodies and anti-ß-2-glycoprotein antibodies), lipid metabolism (lipoprotein(a)), renal function (creatinine, microalbuminuria), myocardial damage (N-terminal pro-brain natriuretic peptide, high sensitive TroponineT) and multiple mechanisms (albumin, vitamin D). RESULTS: In both groups, 36 women were included. Women with recurrent miscarriage had a significantly higher median HsCRP (1.49 mg/L) compared to women with no miscarriage (1.01 mg/L, p = 0.03) and a significantly lower mean albumin (46.0 vs 47.6g/L, p = 0.004) and vitamin D (55.6 vs 75.4nmol/L, p = 0.007), respectively. Differences remained after adjustments for classic cardiovascular risk factors (BMI, smoking, diabetes mellitus, and hypertension). CONCLUSIONS: Our findings suggest a proinflammatory state in women with a history of recurrent miscarriage, which suggests a less optimal health, compared to women with no miscarriage. More research (observational and intervention) is warranted to investigate the association with vitamin D.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Bramwell-Hill modeling for local aortic pulse wave velocity estimation: a validation study with velocity-encoded cardiovascular magnetic resonance and invasive pressure assessment.

BACKGROUND: The Bramwell-Hill model describes the relation between vascular wall stiffness expressed in aortic distensibility and the pulse wave velocity (PWV), which is the propagation speed of the systolic pressure wave through the aorta. The main objective of this study was to test the validity of this model locally in the aorta by using PWV-assessments based on in-plane velocity-encoded cardiovascular magnetic resonance (CMR), with invasive pressure measurements serving as the gold standard. METHODS: Seventeen patients (14 male, 3 female, mean age ± standard deviation = 57 ± 9 years) awaiting cardiac catheterization were prospectively included. During catheterization, intra-arterial pressure measurements were obtained in the aorta at multiple locations 5.8 cm apart. PWV was determined regionally over the aortic arch and locally in the proximal descending aorta. Subsequently, patients underwent a CMR examination to measure aortic PWV and aortic distention. Distensibility was determined locally from the aortic distension at the proximal descending aorta and the pulse pressure measured invasively during catheterization and non-invasively from brachial cuff-assessment. PWV was determined regionally in the aortic arch using through-plane and in-plane velocity-encoded CMR, and locally at the proximal descending aorta using in-plane velocity-encoded CMR. Validity of the Bramwell-Hill model was tested by evaluating associations between distensibility and PWV. Also, theoretical PWV was calculated from distensibility measurements and compared with pressure-assessed PWV. RESULTS: In-plane velocity-encoded CMR provides stronger correlation (p = 0.02) between CMR and pressure-assessed PWV than through-plane velocity-encoded CMR (r = 0.69 versus r = 0.26), with a non-significant mean error of 0.2 ± 1.6 m/s for in-plane versus a significant (p = 0.006) error of 1.3 ± 1.7 m/s for through-plane velocity-encoded CMR. The Bramwell-Hill model shows a significantly (p = 0.01) stronger association between distensibility and PWV for local assessment (r = 0.8) than for regional assessment (r = 0.7), both for CMR and for pressure-assessed PWV. Theoretical PWV is strongly correlated (r = 0.8) with pressure-assessed PWV, with a statistically significant (p = 0.04) mean underestimation of 0.6 ± 1.1 m/s. This theoretical PWV-estimation is more accurate when invasively-assessed pulse pressure is used instead of brachial cuff-assessment (p = 0.03). CONCLUSIONS: CMR with in-plane velocity-encoding is the optimal approach for studying Bramwell-Hill associations between local PWV and aortic distensibility. This approach enables non-invasive estimation of local pulse pressure and distensibility.

Non-invasive assessment of atherosclerotic coronary lesion length using multidetector computed tomography angiography: comparison to quantitative coronary angiography.

Multidetector computed tomography angiography (CTA) provides information on plaque extent and stenosis in the coronary wall. More accurate lesion assessment may be feasible with CTA as compared to invasive coronary angiography (ICA). Accordingly, lesion length assessment was compared between ICA and CTA in patients referred for CTA who underwent subsequent percutaneous coronary intervention (PCI). 89 patients clinically referred for CTA were subsequently referred for ICA and PCI. On CTA, lesion length was measured from the proximal to the distal shoulder of the plaque. Quantitative coronary angiography (QCA) was performed to analyze lesion length. Stent length was recorded for each lesion. In total, 119 lesions were retrospectively identified. Mean lesion length on CTA was 21.4 ± 8.4 mm and on QCA 12.6 ± 6.1 mm. Mean stent length deployed was 17.4 ± 5.3 mm. Lesion length on CTA was significantly longer than on QCA (difference 8.8 ± 6.7 mm, P < 0.001). Moreover, lesion length visualized on CTA was also significantly longer than mean stent length (CTA lesion length-stent length was 4.2 ± 8.7 mm, P < 0.001). Lesion length assessed by CTA is longer than that assessed by ICA. Possibly, CTA provides more accurate lesion length assessment than ICA and may facilitate improved guidance of percutaneous treatment of coronary lesions.

Economic evaluation of ezetimibe combined with simvastatin for the treatment of primary hypercholesterolaemia.

OBJECTIVE: This study aims to assess the cost-effectiveness of ezetimibe plus simvastatin (E/S) versus atorvastatin or simvastatin monotherapy as second-line treatment of primary hypercholesterolaemia from the Dutch healthcare perspective. METHODS: The evaluation used a Markov model and patient data from the Dutch EASEGO study in which patients failing to reach goal low-density lipoprotein cholesterol levels on atorvastatin 10 mg or simvastatin 20 mg had their dose doubled or switched to ezetimibe 10 mg plus generic simvastatin 20 mg (E10/S20). The second scenario, based on Dutch guidelines, switched patients from simvastatin 40 mg to atorvastatin 40 mg, or ezetimibe 10 mg was added to simvastatin 40 mg (E10/S40). The key effectiveness input measure was change in total cholesterol/high-density lipoprotein ratio obtained from the EASEGO study. In conformity with published studies linking reduced lipid levels to reduced risk of cardiovascular events, the present model assumed that a lipid decrease with ezetimibe may be a signal for reduced risk of cardiovascular events. Model parameters were derived from published literature. Sensitivity analyses were performed for the key parameters. RESULTS: In the EASEGO scenario, incremental cost-effectiveness ratio for E10/S20 was 3497/quality-adjusted life-years (QALY) vs atorvastatin 20 mg and 26,417/QALY vs simvastatin 40 mg. In the Dutch guidelines scenario, E10/S40 was dominant (more effective and cost-saving) vs atorvastatin 40 mg. Varying model inputs had limited impact on the cost-effectiveness of E/S. CONCLUSIONS: The analysis showed the cost-effectiveness of E/S versus atorvastatin 20 mg or simvastatin 40 mg (EASEGO scenario) at a threshold of 30,000/QALY and vs atorvastatin 40 mg was dominant (Dutch guidelines). Thus, E/S seems a valuable cost-effective second-line treatment option for patients not attaining lipid treatment goals.

Matrix metalloproteinases 2 and 3 gene polymorphisms and the risk of target vessel revascularization after percutaneous coronary intervention: Is there still room for determining genetic variation of MMPs for assessment of an increased risk of restenosis?

OBJECTIVE: Mixed results have been reported of matrix metalloproteinases (MMP) and their association with restenosis after percutaneous coronary intervention (PCI). The current study examines whether multiple single nucleotide polymorphisms (SNPs), covering the full genomic region of MMP2 and MMP3, were associated with restenosis in the GENDER study population. METHODS AND RESULTS: The GENetic DEterminants of Restenosis (GENDER) study enrolled 3104 consecutive patients after successful PCI. The primary endpoint was clinical restenosis, defined as target vessel revascularization (TVR), occurring in 9.8% of the patients. From the Hapmap database, 19 polymorphisms of MMP2 and 11 of MMP3 were selected. Furthermore, in a subpopulation, a genome-wide association analysis (GWA) was performed. No significant association was found with any of the investigated SNPs, including the previously reported 5A/6A polymorphism (rs3025058), with regard to TVR using single SNP analysis or haplotype analysis. CONCLUSION: We found no significant association of MMP2 or MMP3 with TVR with this SNP-broad gene approach. Although we did not test all the known polymorphisms of these genes, using tagging analyses we examined those SNPs covering all known haplotypes of MMP2 and MMP3 to conclude that these genes do not correlate with a genetic risk of coronary restenosis after successful PCI.

Non-invasive cardiac imaging techniques and vascular tools for the assessment of cardiovascular disease in type 2 diabetes mellitus.

Cardiovascular disease is the major cause of mortality in type 2 diabetes mellitus. The criteria for the selection of those asymptomatic patients with type 2 diabetes who should undergo cardiac screening and the therapeutic consequences of screening remain controversial. Non-invasive techniques as markers of atherosclerosis and myocardial ischaemia may aid risk stratification and the implementation of tailored therapy for the patient with type 2 diabetes. In the present article we review the literature on the implementation of non-invasive vascular tools and cardiac imaging techniques in this patient group. The value of these techniques as endpoints in clinical trials and as risk estimators in asymptomatic diabetic patients is discussed. Carotid intima-media thickness, arterial stiffness and flow-mediated dilation are abnormal long before the onset of type 2 diabetes. These vascular tools are therefore most likely to be useful for the identification of 'at risk' patients during the early stages of atherosclerotic disease. The additional value of these tools in risk stratification and tailored therapy in type 2 diabetes remains to be proven. Cardiac imaging techniques are more justified in individuals with a strong clinical suspicion of advanced coronary heart disease (CHD). Asymptomatic myocardial ischaemia can be detected by stress echocardiography and myocardial perfusion imaging. The more recently developed non-invasive multi-slice computed tomography angiography is recommended for exclusion of CHD, and can therefore be used to screen asymptomatic patients with type 2 diabetes, but has the associated disadvantages of high radiation exposure and costs. Therefore, we propose an algorithm for the screening of asymptomatic diabetic patients, the first step of which consists of coronary artery calcium score assessment and exercise ECG.

Multi-slice computed tomography coronary angiography: anatomic vs functional assessment in clinical practice.

Non-invasive imaging plays an increasingly important role in the diagnosis and risk stratification of coronary artery disease (CAD). Several techniques such as stress echocardiography and myocardial perfusion imaging have become available to assess cardiac function and myocardial perfusion. With the arrival of multi-slice computed tomography coronary angiography (CTA), non-invasive imaging of coronary anatomy has also become possible. Studies concerning the diagnostic accuracy have demonstrated a good agreement with conventional coronary angiography resulting in a sensitivity and specificity of approximately 86% and 96%, respectively. The high negative predictive value of 97% renders it particularly useful to rule out the presence of CAD in patients with an intermediate pretest likelihood. Moreover, comparative studies have demonstrated that anatomic imaging with CTA may provide information complementary to the traditionally used techniques for functional assessment. From these studies can be derived that only approximately 50% of significant stenoses on CTA are functionally relevant; a large proportion of significant (>50%) lesions on CTA does not result in perfusion abnormalities. Alternatively, many patients with a normal perfusion CTA show considerable atherosclerosis on CTA. Therefore, the combined use of these techniques may enhance the assessment of the presence and extent of CAD. In the future diagnostic algorithms, combining non-invasive anatomic and functional imaging need to be evaluated in large patient populations to establish their efficacy, safety, and cost effectiveness. Importantly, these investigations should result in the development of comprehensive guidelines on the use of CTA in clinical practice as well.

Assessment of left ventricular volumes and ejection fraction with 16-slice multi-slice computed tomography; comparison with 2D-echocardiography.

BACKGROUND: In recent years, multi-slice computed tomography (MSCT) has emerged as a rapidly expanding modality for non-invasive assessment of coronary artery disease. Simultaneously, left ventricular (LV) function can be evaluated although this is not yet a routine component of an MSCT examination. Accordingly, the purpose of the present study was to validate assessment of LV function with MSCT using 2D-echocardiography in a large cohort of patients. METHODS: In 70 patients (57 male, 13 female), 16-slice MSCT was performed (Toshiba Aquilion 16, Japan) followed by retrospective analysis of global LV function. For these measurements, 2D-echocardiography served as the standard of reference. RESULTS: For LV volumes, excellent correlations for both end-diastolic volume (EDV) (r=0.97) and end-systolic volume (ESV) (r=0.98) were obtained by linear regression analysis. At Bland-Altman analysis, mean differences (+/-standard deviations) of -1.4 ml+/-11.3 ml and -3.0 ml+/-7.7 ml were observed between MSCT and 2D-echocardiography for LV EDV and LV ESV respectively. As a result, LV EF was slightly overestimated with MSCT (1.7%+/-4.9%, P<0.05). Correlation between the two techniques was excellent (r=0.91). CONCLUSION: In a large cohort of patients, an excellent correlation was observed between 16-slice MSCT and 2D-echocardiography in the evaluation of LV volumes and EF. The addition of LV function analysis to the anatomical MSCT data may potentially enhance the diagnostic and prognostic value of the technique.

Comprehensive cardiac assessment with multislice computed tomography: evaluation of left ventricular function and perfusion in addition to coronary anatomy in patients with previous myocardial infarction.

OBJECTIVE: To evaluate a comprehensive multislice computed tomography (MSCT) protocol in patients with previous infarction, including assessment of coronary artery stenoses, left ventricular (LV) function and perfusion. PATIENTS AND METHODS: 16-slice MSCT was performed in 21 patients with previous infarction; from the MSCT data, coronary artery stenoses, (regional and global) LV function and perfusion were assessed. Invasive coronary angiography and gated single-photon emission computed tomography (SPECT) served as the reference standards for coronary artery stenoses and LV function/perfusion, respectively. RESULTS: 236 of 241 (98%) coronary artery segments were interpretable on MSCT. The sensitivity and specificity for detection of stenoses were 91% and 97%. Pearson's correlation showed excellent agreement for assessment of LV ejection fraction between MSCT and SPECT (49 (13)% v 53 (12)%, respectively, r = 0.85). Agreement for assessment of regional wall motion was excellent (92%, kappa = 0.77). In 68 of 73 (93%) segments, MSCT correctly identified a perfusion defect as compared with SPECT, whereas the absence of perfusion defects was correctly detected in 277 of 284 (98%) segments. CONCLUSIONS: MSCT permits accurate, non-invasive assessment of coronary artery stenoses, LV function and perfusion in patients with previous infarction. All parameters can be assessed from a single dataset.

B-mode ultrasound assessment of pravastatin treatment effect on carotid and femoral artery walls and its correlations with coronary arteriographic findings: a report of the Regression Growth Evaluation Statin Study (REGRESS).

OBJECTIVES: In this B-mode ultrasound study we assessed pravastatin treatment effects on carotid and femoral artery walls and investigated the correlations between the state and evolution of peripheral and coronary atherosclerosis. BACKGROUND: The Regression Growth Evaluation Statin Study (REGRESS) was an 11-center, 2-year, double-blind, placebo-controlled, prospective study of 885 men with coronary artery disease (CAD) (total cholesterol 4 to 8 mmol/liter). The study primarily investigated pravastatin treatment effects on the coronary lumen. This report focuses on the 255 patients who participated in the REGRESS ultrasound study. METHODS: Carotid and femoral artery walls were imaged at baseline and at 6, 12, 18 and 24 months. Pravastatin treatment effect was defined as the difference in progression of the combined intima-media thicknesses (IMT) between treatment groups. RESULTS: Pravastatin treatment effects were highly significant (combined IMT: p = 0.0085; combined far wall IMT: p < 0.0001; common femoral artery far wall IMT: p = 0.004). Correlations between the IMTs of the arterial wall segments ranged from -0.17 to 0.81. Baseline correlations between IMT and percent coronary lumen stenoses ranged from 0.23 to 0.36. Baseline IMT correlated with the mean coronary segment diameter (r = -0.32, p = 0.001) and minimal coronary obstruction diameter (r = -0.27, p = 0.005). There were no individual correlations between IMT and coronary lumen variables (p > 0.30). CONCLUSIONS: Pravastatin treatment effects on carotid and femoral artery walls were observed. B-mode ultrasound imaging studies of peripheral arterial walls could not describe the state and evolution of the coronary lumen in the individual patient, but proved to be a highly suitable tool for the assessment of antiatherosclerotic properties of agents.