We investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway.
Forty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan–GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and PPARG.
Angiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P < 0.05, all). Accumulation of polymorphonuclear neutrophils was significantly lower, while microvessel cross-sectional area was significantly higher in the telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P < 0.05). ICAM-1 and VCAM-1 levels were also significantly lower, and correlated with lower NF-κB expression in these groups. The effects were the most significant in the telmisartan group compared with the telmisartan–GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P < 0.05, all).
Except for the typical effects of angiotensin II-receptor blocker, telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway.
Ischemia/reperfusion; Microvascular dysfunction; Telmisartan; Peroxisome proliferator-activated receptor gamma
Cardiovascular disease is a major cause of mortality and morbidity and its prevalence is set to increase. While the benefits of medical and lifestyle interventions are established, the effectiveness of interventions which seek to improve the way preventive care is delivered in general practice is less so. The aim was to study and to compare the effectiveness of 2 intervention programmes for reducing cardiovascular risk factors within general practice.
A randomised controlled trial was conducted in Belgium between 2007-2010 with 314 highly educated and mainly healthy professionals allocated to a medical (MP) or a medical + lifestyle (MLP) programme. The MP consisted of medical assessments (screening and follow-up) and the MLP added a tailored lifestyle change programme (web-based and individual coaching) to the MP. Primary outcomes were total cholesterol, blood pressure, and body mass index (BMI). The secondary outcomes were smoking status, fitness-score, and total cardiovascular risk.
The mean age was 41 years, 95 (32%) participants were female, 7 had a personal cardiovascular event in their medical history and 3 had diabetes. There were no significant differences found between MP and MLP in primary or secondary outcomes. In both study conditions decreases of cholesterol, systolic blood pressure, and diastolic blood pressure were found. Unfavourable increases were found for BMI (p < .05). A significant decrease of the overall cardiovascular risk was reported (p < .001).
Both interventions are effective in reducing cardiovascular risk. In our population the combined medical and lifestyle programme was not superior to the medical programme.
Cardiovascular diseases; Prevention; General practice; Lifestyle programmes
We report on the prospective association between smoking and depression and health-related quality of life (HRQOL) in patients with coronary artery disease (CAD).
Prospective study of 193 patients with assessment of depression occurring 3-, 6- and 9- months (T1, 2, and 3, respectively) following discharge from hospital for a cardiac event. HRQOL was assessed at T3. T1 depression was assessed by clinical interview; T2 and T3 depression was assessed by self-report. Smoking at time of cardiac event was assessed by self-report. Multivariate analyses controlled for known demographic, psychosocial and clinical correlates of depression.
Smoking at the time of index cardiac event increased the likelihood of being diagnosed with Major Depressive Disorder (MDD) at T1 by 4.30 [95% CI, 1.12-16.46; p < .05]. The likelihood of receiving a diagnosis of minor depression, dysthymia or MDD as a combined group was increased by 8.03 [95% CI, 2.35-27.46; p < .01]. Smoking did not reliably predict depression at T2 or T3 and did not reliably predict persistent depression. Smoking increased the likelihood of being classified as depressed according to study criteria at least once during the study period by 5.19 [95% CI, 1.51-17.82; p < .01]. Smoking independently predicted worse mental HRQOL.
The findings support a role for smoking as an independent predictor of depression in CAD patients, particularly in the first 3 months post-cardiac event. The well-established imperative to encourage smoking cessation in these patients is augmented and the findings may add to the evidence for smoking cessation campaigns in the primary prevention of depression.
Coronary artery disease; Depression; Smoking; Quality of life
Ambulatory blood pressure monitoring is regarded as the gold standard for monitoring nocturnal blood pressure (NBP) and is usually performed out of office. Currently, a novel method for monitoring NBP is indispensible in the inpatient setting. The widely used manual BP monitoring procedure has the potential to monitor NBP in the hospital setting. The feasibility and accuracy of manual sphygmomanometer to monitor NBP has not been explored widely.
A cross-sectional study was conducted at the cardiology department of a university-affiliated hospital to study patients with mild-to-moderate essential hypertension. One hundred and fifty-five patients were recruited to compare BP derived from a manual device and ambulatory BP monitoring (ABPM). The manual BP measurement was performed six times at 22:00, 02:00, 06:00, 10:00, 14:00 and 18:00 h. The measurements at 22:00, 02:00 and 06:00 h were defined as night-time and the others as daytime. ABPM was programmed to measure at 30-min intervals between measurements.
All-day, daytime and night-time BP did not differ significantly from 24-h ambulatory systolic BP [all-day mean difference −0.52±4.67 mmHg, 95% confidence interval (CI) –1.26 to 0.22, P=0.168; daytime mean difference 0.24±5.45 mmHg, 95% CI −0.62 to 1.11, P=0.580; night-time mean difference 0.30±7.22 mmHg, 95% CI −0.84 to 1.45, P=0.601) rather than diastolic BP. There was a strong correlation between clinical and ambulatory BP for both systolic and diastolic BP. On the basis of ABPM, 101 (65%) patients were classified as non-dippers, compared with 106 (68%) by manual sphygmomanometer (P<0.001).
Traditional manual sphygmomanometer provides similar daytime and night-time systolic BP measurements in hospital. Moreover, the detection of non-dippers by manual methods is in good agreement with 24-h ABPM. Further studies are required to confirm the clinical relevance of these findings by comparing the association of NBP in the hospital ward assessed by manual monitoring with preclinical organ damage and cardiovascular and cerebrovascular outcomes.
Nocturnal blood pressure; Ambulatory blood pressure monitoring; Hypertension; Non-dipper
Palliative treatment with the Fontan procedure has greatly improved survival for children with functionally univentricular heart. Since Fontan performed the first successful operation, the procedure has evolved and is now performed as Total Cavo-Pulmonary Connection (TCPC).
An increasing prevalence and longer life expectancy of TCPC patients have raised new challenges. The survivors are often suffering complications such as arrhythmias, myocardial dysfunction, thromboembolic events, neuropsychological deficit, protein-losing enteropathy and reduced exercise capacity. Several causes for the reduced exercise capacity may be present e.g. impaired function of the single ventricle, valve dysfunction and chronotropic impairment, and perhaps also increased pulmonary vascular resistance. Thus, plasma endothelin-1 has been shown to correlate with increased pulmonary vascular resistance and the risk of failing Fontan circulation. This has raised the question of the role for pulmonary vasodilation therapy, especially endothelin receptor antagonist in the management of TCPC patients.
The TEMPO trial aims to investigate whether Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients. The trial design is randomized, double-blind and placebo-controlled. Bosentan/placebo is administered for 14 weeks with control visits every four weeks. The primary endpoint is change in maximal oxygen consumption as assessed on bicycle ergometer test. Secondary endpoints include changes in pulmonary blood flow during exercise test, pro brain natriuretic peptide and quality of life.
We hypothesize that treatment with Bosentan, an endothelin receptor antagonist, can be administered safely and improve exercise capacity in TCPC patients.
Univentricular heart; Fontan; Exercise capacity; Endothelin receptor antagonist; Randomized placebo-controlled trial
Aortic dissection(AD) is an acute process of large blood vessels characterized by dangerous pathogenic conditions and high disability and high mortality. The pathogenesis of AD remains debated. Matrix metalloproteinase-12 (MMP-12) participates in many pathological processes such as abdominal aortic aneurysm, atherosclerosis, emphysema and cancer. However, this elastase has rarely been assessed in the presence of AD. The aim of the present study was to investigate the expression of MMP-12 in aortic tissue so as to offer a better understanding of the possible mechanisms of AD.
The protein expression levels of MMP-12 were analyzed and compared in aorta tissue and the blood serum samples by reverse transcription polymerase chain reaction(RT-PCR), Western blotting, immuno-histochemistry, fluorescence resonance energy transfer ( FRET ) activity assay and enzyme-linked immuno sorbent assay ( ELISA ), respectively. Ascending aorta tissue specimens were obtained from 12 patients with an acute Stanford A-dissection at the time of aortic replacement, and from 4 patients with coronary artery disease (CAD) undergoing coronary artery bypass surgery. Meanwhile, serum samples were harvested from 15 patients with an acute Stanford A-dissection and 10 healthy individuals who served as the control group.
MMP-12 activity could be detected in both AD and CAD groups, but the level in the AD group was higher than those in the CAD group (P < 0.05). MMP-12 proteolysis existed in both serum samples of the AD and healthy groups, and the activity level in the AD group was clearly higher than in the healthy group (P < 0.05). For AD patients, MMP-12 activity in serum was higher than in the aorta wall (P < 0.05). MMP-12 activity in the aortic wall tissue can be inhibited by MMP inhibitor v (P < 0.05).
The present study directly demonstrates that MMP-12 proteolytic activity exists within the aorta specimens and blood samples from aortic dissection patients. MMP-12 might be of potential relevance as a clinically diagnostic tool and therapeutic target in vascular injury and repair.
Aortic dissection; MMP-12; Protein expression
The aim of this study was to investigate the association of sex hormone-binding globulin (SHBG) and hypertension in a Swedish population.
The study is based on a random sample of a Swedish population of men and women aged 30–74 years (n=2,816). Total testosterone, oestradiol and SHBG were measured in 2,782 participants. Free androgen index was then calculated according to the formula FAI=100 × (Total testosterone)/SHBG. Hypertension was diagnosed according to JNC7.
In men, but not in women, significant association between SHBG and both diastolic (diastolic blood pressure: β=−0.143 p<0.001) and systolic blood pressure (systolic blood pressure β=−0.114 p<0.001) was found. The association was still significant after adjusting for age, body mass index (BMI), homeostatic model assessment insulin resistance (HOMA-IR), triglycerides, high density lipoproteins (HDL) and C-reactive protein (CRP) (diastolic blood pressure: β=−0.113 p<0.001; systolic blood pressure β=−0.093 p=0.001). An inverse association was observed between SHBG and hypertension in both men (B=−0.024 p<0.001) and women (B=−0.022 p<0.001). The association was still significant in women older than 50 years after adjustments for age, BMI, physical activity, CRP and alcohol consumption (B=−0.014, p=0.008).
In conclusion, these results show a strong association between SHBG and blood pressure independent of major determinants of high blood pressure. This association might be addressed to direct effects of SHBG in endothelial cells through the receptor for SHBG. If this is confirmed by other observational and experimental studies, it might become a new field for the development of therapies for lowering blood pressure.
Sex hormone binding globulin (SHBG); Testosterone; Gender; Hypertension; BMI
Among adults with congenital heart diseases (CHD) evaluation of sudden cardiac death (SCD) risk remains a great challenge. Although microvolt T-wave alternans has been incorporated into SCD risk stratification algorithm, its role in adults with CHD still requires investigation. We sought to determine the incidence of MTWA in this specific group and its coincidence with ventricular arrhythmia (VA) and other clinical findings presumably associated with SCD.
A case–control study was performed in which 102 patients with CHD characterized by right ventricle pathology or single ventricle physiology (TGA, UVH, Ebstein’s anomaly, ccTGA, Eisenmenger syndrome, DORV, CAT, unoperated ToF) were compared to 45 age- and sex-matched controls. All subjects underwent spectral MTWA test, ambulatory ecg monitoring, cardiopulmonary test, BNP assessment. After excluding technically inadequate traces, the remaining MTWA results were classified as positive(+), negative(−) and indeterminate(ind). Due to similar prognostic significance MTWA(+) and (ind) were combined into a common group labeled ‘abnormal’.
Abnormal MTWA was present more often in the study group, compared to controls (39.2% vs 2.3%, p = 0.00001). Sustained ventricular tachycardia (sVT) was observed more often among subjects with abnormal MTWA compared to MTWA(−): 19.4% vs 3.6%, p = 0.026. The patients with abnormal MTWA had a lower blood saturation (p = 0.047), more often were males (p = 0.031), had higher NYHA class (p = 0.04), worse cardiopulmonary parameters: %PeakVO2 (p = 0.034), %HRmax (p = 0.003). Factors proven to increase probability of abnormal MTWA on multivariate linear regression analysis were: sVT (OR = 20.7, p = 0.037) and male gender (OR = 15.9, p = 0.001); on univariate analysis: male gender (OR = 2.7, p = 0.021), presence of VA (OR = 2.6, p = 0.049), NYHA > I (OR = 2.06, p = 0.033), %HRmax (OR = 0.94, p = 0.005), %PeakVO2 (OR = 0.97, p = 0.042), VE/VCO2slope (OR = 1.05, p = 0.037).
Abnormal MTWA occurs significantly more often in adults with the chosen forms of CHD than among healthy subjects. The probability of abnormal MTWA increases in patients with malignant VA, in males and among subjects with heart failure and cyanosis. MTWA might be of potential role in risk stratification for SCD in adults with CHD.
Excess accumulation of visceral fat is a prominent risk factor for cardiovascular and metabolic morbidity. While computed tomography (CT) is the gold standard to measure visceral adiposity, this is often not possible for large studies - thus valid, but less expensive and intrusive proxy measures of visceral fat are required such as dual-energy X-ray absorptiometry (DXA). Study aims were to a) identify a valid DXA-based measure of visceral adipose tissue (VAT), b) estimate VAT heritability and c) assess visceral fat association with morbidity in relation to body fat distribution.
A validation sample of 54 females measured for detailed body fat composition - assessed using CT, DXA and anthropometry – was used to evaluate previously published predictive models of CT-measured visceral fat. Based upon a validated model, we realised an out-of-sample estimate of abdominal VAT area for a study sample of 3457 female volunteer twins and estimated VAT area heritability using a classical twin study design. Regression and residuals analyses were used to assess the relationship between adiposity and morbidity.
Published models applied to the validation sample explained >80% of the variance in CT-measured visceral fat. While CT visceral fat was best estimated using a linear regression for waist circumference, CT body cavity area and total abdominal fat (R2 = 0.91), anthropometric measures alone predicted VAT almost equally well (CT body cavity area and waist circumference, R2 = 0.86). Narrow sense VAT area heritability for the study sample was estimated to be 58% (95% CI: 51-66%) with a shared familial component of 24% (17-30%). VAT area is strongly associated with type 2 diabetes (T2D), hypertension (HT), subclinical atherosclerosis and liver function tests. In particular, VAT area is associated with T2D, HT and liver function (alanine transaminase) independent of DXA total abdominal fat and body mass index (BMI).
DXA and anthropometric measures can be utilised to derive estimates of visceral fat as a reliable alternative to CT. Visceral fat is heritable and appears to mediate the association between body adiposity and morbidity. This observation is consistent with hypotheses that suggest excess visceral adiposity is causally related to cardiovascular and metabolic disease.
Visceral fat; Adiposity; DXA; Type 2 diabetes; Hypertension; Subclinical atherosclerosis; Liver function
Early detection of heart failure is essential to effectively reduce related mortality. The quantification of the mechanical properties of the myocardium, a primordial indicator of the viability of the cardiac tissue, is a key element in patient’s care. Despite an incremental utilization of multi-parametric magnetic resonance imaging (MRI) for cardiac tissue characteristics and function, the link between multi-parametric MRI and the mechanical properties of the heart has not been established. We sought to determine the parametric relationship between the myocardial mechanical properties and the MR parameters. The specific aim was to develop a reproducible evaluative quantitative tool of the mechanical properties of cardiac tissue using multi-parametric MRI associated to principal component analysis.
Samples from porcine hearts were submitted to a multi-parametric MRI acquisition followed by a uniaxial tensile test. Multi linear regressions were performed between dependent (Young’s modulus E) and independent (relaxation times T1, T2 and T2*, magnetization transfer ratio MTR, apparent diffusion coefficient ADC and fractional anisotropy FA) variables. A principal component analysis was used to convert the set of possibly correlated variables into a set of linearly uncorrelated variables.
Values of 46.1±12.7 MPa for E, 729±21 ms for T1, 61±6 ms for T2, 26±7 for T2*, 35±5% for MTRx100, 33.8±4.7 for FAx10-2, and 5.85±0.21 mm2/s for ADCx10-4 were measured. Multi linear regressions showed that only 45% of E can be explained by the MRI parameters. The principal component analysis reduced our seven variables to two principal components with a cumulative variability of 63%, which increased to 80% when considering the third principal component.
The proposed multi-parametric MRI protocol associated to principal component analysis is a promising tool for the evaluation of mechanical properties within the left ventricle in the in vitro porcine model. Our in vitro experiments will now allow us focused in vivo testing on healthy and infracted hearts in order to determine useful quantitative MR-based biomarkers.
Cardiac muscle; Myocardium; Ventricle; Mechanical properties; Multi-parametric MRI; Multiple regressions; Principal component analysis
Routine electrocardiograms (ECGs) are not recommended for asymptomatic patients because the potential harms are thought to outweigh any benefits. Assessment tools to identify high risk individuals may improve the harm versus benefit profile of screening ECGs. In particular, people with unrecognized myocardial infarction (UMI) have elevated risk for cardiovascular events and death.
Using logistic regression, we developed a basic assessment tool among 16,653 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study using demographics, self-reported medical history, blood pressure, and body mass index and an expanded assessment tool using information on 51 potential variables. UMI was defined as electrocardiogram evidence of myocardial infarction without a self-reported history (n = 740).
The basic assessment tool had a c-statistic of 0.638 (95% confidence interval 0.617 - 0.659) and included age, race, smoking status, body mass index, systolic blood pressure, and self-reported history of transient ischemic attack, deep vein thrombosis, falls, diabetes, and hypertension. A predicted probability of UMI > 3% provided a sensitivity of 80% and a specificity of 30%. The expanded assessment tool had a c-statistic of 0.654 (95% confidence interval 0.634-0.674). Because of the poor performance of these assessment tools, external validation was not pursued.
Despite examining a large number of potential correlates of UMI, the assessment tools did not provide a high level of discrimination. These data suggest defining groups with high prevalence of UMI for targeted screening will be difficult.
Myocardial infarction; Screening; Electrocardiography
Ischemic postconditioning (PostC), reperfusion in brief cycles, is known to induce short-term reduction in infarct size in patients with ST elevation myocardial infarction (STEMI), especially among those with large myocardium at risk (MaR). The aim of the present study was to investigate the long-term effect of PostC on infarct size and left ventricular ejection fraction (LVEF).
Sixty-eight patients with a first STEMI were randomised to primary percutaneous coronary intervention (PCI) (n = 35) or PCI followed by PostC (n = 33). MaR was determined as abnormally contracting segments on left ventricular angiogram. Cardiac magnetic resonance was performed at 3 and 12 months for the determination of infarct size and LVEF.
Overall there was no difference in infarct size expressed in percentage of MaR between patients randomised to the control (31%; 23, 41) and PostC (31%; 23, 43) groups at 12 months. Likewise there was no difference in LVEF between control (49%; 41, 55) and PostC (52%; 45, 55). In contrast, patients in the PostC group with MaR in the upper quartile had a significantly smaller infarct size (29%; 18, 38) than those in the control group (40%; 34, 48; p < 0.05) at 12 months. In these patients LVEF was higher in the PostC (47%; 43, 50) compared to the control group (38%; 34, 42; p < 0.01).
In this long-term follow-up study PostC did not reduce infarct size in relation to MaR or improved LVEF in the overall study population. However, the present data suggest that PostC exerts long-term beneficial effects in patients with large MaR thereby extending previously published short-term observations.
Karolinska Clinical Trial Registration (http://www.kctr.se). Unique identifier: CT20080014
Myocardial infarction; Infarct size; Postconditioning; CMR
Self-monitoring of hypertension with self-titration of antihypertensives (self-management) results in lower systolic blood pressure for at least one year. However, few people in high risk groups have been evaluated to date and previous work suggests a smaller effect size in these groups. This trial therefore aims to assess the added value of self-management in high risk groups over and above usual care.
The targets and self-management for the control of blood pressure in stroke and at risk groups (TASMIN-SR) trial will be a pragmatic primary care based, unblinded, randomised controlled trial of self-management of blood pressure (BP) compared to usual care. Eligible patients will have a history of stroke, coronary heart disease, diabetes or chronic kidney disease and will be recruited from primary care. Participants will be individually randomised to either usual care or self-management. The primary outcome of the trial will be difference in office SBP between intervention and control groups at 12 months adjusted for baseline SBP and covariates. 540 patients will be sufficient to detect a difference in SBP between self-management and usual care of 5 mmHg with 90% power. Secondary outcomes will include self-efficacy, lifestyle behaviours, health-related quality of life and adverse events. An economic analysis will consider both within trial costs and a model extrapolating the results thereafter. A qualitative analysis will gain insights into patients’ views, experiences and decision making processes.
The results of the trial will be directly applicable to primary care in the UK. If successful, self-management of blood pressure in people with stroke and other high risk conditions would be applicable to many hundreds of thousands of individuals in the UK and beyond.
Hypertension; Self-management; Stroke, Diabetes; Coronary heart disease; Chronic kidney disease; Primary care
The editors of BMC Cardiovascular Disorders would like to thank all our reviewers who have contributed to the journal in Volume 12 (2012).
The proceeding of blood pressure (BP) from normal level to the hypertension has been found to be associated with increased cardiovascular events and multiple vascular risk factors. However, whether the process is associated with increased carotid atherosclerotic plaque per se or not is still unclear.
Nine hundred and forty-two participants aged from 46 to 75 were enrolled from community population in Southern China. Their metabolic risk factors, carotid intima-media thickness (cIMT) and atherosclerotic plaque formation were analyzed and stratified by different blood pressure levels according to JNC-7 or ESH/ESC-2007 classification.
From low BP level to higher BP level, multiple metabolic risk factors increased linearly. Prehypertension in JNC-7 classification (or normal BP and high normal BP in ESH/ESC-2007 classification) was correlated with thicker cIMT and more plaque formation than normotension (or optimal BP) (p < 0.001). After adjusting multiple metabolic factors, the differences were still significant (p < 0.05). Furthermore, prehypertensive participants had a trend to be thicker carotid IMT (OR and its 95% CI: 1.65, 0.97-2.82, p = 0.067) and significantly higher carotid plaque occurrence (OR and its 95% CI: 2.36, 1.43-3.88, p = 0.001) than normotensive ones. However, there was no significant difference of cIMT and plaque formation between normal BP and high normal BP (p > 0.05). Plaque formation in prehypertension was as significant as that in hypertension.
Prehypertension is associated with significantly increased carotid atherosclerotic plaque and is a primary stratify risk factor for carotid atherosclerosis which could cause ischemic stroke in middle-aged and elderly population in Southern China.
Carotid atherosclerosis; cIMT; Plaque; Hypertension; Prehypertension; Blood pressure
We compared aortic stiffness, aortic impedance and pressure from wave reflections in the setting of bicuspid aortic valve (BAV) to the tricuspid aortic valve (TAV) in the absence of proximal aortic dilation. We hypothesized BAV is associated with abnormal arterial stiffness.
Ten BAV subjects (47 ± 4 years, 6 male) and 13 TAV subjects (46 ± 4 years, 10 male) without significant aortic valve disease were prospectively recruited. Characteristic impedance (Zc) was derived from echocardiographic images and pulse wave Doppler of the left ventricular outflow tract. Applanation tonometry was performed to obtain pulse wave velocity (PWV) at several sites as measures of arterial stiffness and augmentation index (AIx) as a measure of wave reflection.
There were no significant differences between BAV and TAV subjects with regard to heart rate or blood pressure. Zc was similar between BAV and TAV subjects (p=0.25) as was carotid-femoral pulse wave velocity (cf-PWV) and carotid-radial PWV (cr-PWV) between BAV and TAV subjects (p=0.99). Carotid AIx was significantly higher in BAV patients compared with TAV patients (14.3 ± 4.18% versus -3.02 ± 3.96%, p=0.007).
Aortic stiffness and impedance is similar between subjects with BAV and TAV with normal aortic dimensions. The significantly higher carotid AIx in BAV, a proxy of increased pressure from wave reflections, may reflect abnormal vascular function distal to the aorta.
Bicuspid aortic valve; Arterial stiffness; Augmentation index; Pulse wave velocity
Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals.
Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System.
Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (χ2 = 7.02; p = 0.0081) and another GGCGGAGT (χ2 = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (χ2 = 5.66; p = 0.017) and ATTGAGAC (χ2 = 5.93; p = 0.015), obesity with GGCGGAGT (χ2 = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (χ2 = 6.68; p = 0.010) and GGTGGGAT (χ2 = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD.
These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.
Angiotensinogen polymorphism; Primary hypertension; Type 2 diabetes mellitus; Obesity; Coronary artery disease; Gene-disease interactions; Pleiotropy
Neurofibromatosis type 1 (NF1) is a multi-systemic disease caused by neurofibromin deficiency. The reduced life expectancy of patients with NF1 has been attributed to NF1-associated malignant neoplasms. However, an analysis of death certificates in the USA suggests that vascular disease could be an important cause of early death among these patients. Endothelial dysfunction (ED) is related to vasculopathy and is an early marker of subclinical atherosclerosis. Since neurofibromin has already been demonstrated to affect endothelial cell function, ED may be associated with NF1. The purpose of this study was to assess endothelial function in patients with NF1 using a non-invasive method.
NF1 patients and healthy control subjects, aged 18 to 35 years, were included. Subjects were excluded if they had any risk factor for vascular disease or any other condition known to affect endothelial function. Endothelial function was assessed using reactive hyperemia-peripheral arterial tone (RH-PAT) technology. ED was defined as a reactive hyperemia index (RHI) lower than 1.35.
Four of the 29 (13.8%) NF1 patients and 1 of the 30 (3.3%) healthy volunteers had ED (p = 0.153). RHI medians and interquartile intervals were 1.8 (1.58-2.43) for the NF1 group and 2.02 (1.74 – 2.49) for the control group (p = 0.361).
The prevalence of ED was similar in NF1 patients and healthy controls.
Neurofibromatosis type 1; Endothelial dysfunction; Peripheral arterial tonometry; Reactive hyperemia
Venous thromboembolism comprising pulmonary embolism and deep vein thrombosis is a common condition with an incidence of approximately 1 per 1,000 per annum causing both mortality and serious morbidity. The principal aim of treatment of a venous thromboembolism with heparin and warfarin is to prevent extension or recurrence of clot. However, the recurrence rate following a deep vein thrombosis remains approximately 10% per annum following treatment cessation irrespective of the duration of anticoagulation therapy. Patients with raised D-dimer levels after discontinuing oral anticoagulation treatment have also been shown to be at high risk of recurrence.
Post thrombotic syndrome is a complication of a deep vein thrombosis which can lead to chronic venous insufficiency and ulceration. It has a cumulative incidence after 2 years of around 25% and it has been suggested that extended oral anticoagulation should be investigated as a possible preventative measure.
Patients with a first idiopathic venous thromboembolism will be recruited through anticoagulation clinics and randomly allocated to either continuing or discontinuing warfarin treatment for a further 2 years and followed up on a six monthly basis. At each visit D-dimer levels will be measured using a Roche Cobas h 232 POC device. In addition a venous sample will be taken for laboratory D-dimer analysis at the end of the study. Patients will be examined for signs and symptoms of PTS using the Villalta scale and complete VEINES and EQ5D quality of life questionnaires.
The primary aim of the study is to investigate whether extending oral anticoagulation treatment (prior to discontinuing treatment) beyond 3–6 months for patients with a first unprovoked proximal deep vein thrombosis or pulmonary embolism prevents recurrence. The study will also determine the role of extending anticoagulation for patients with elevated D-dimer levels prior to discontinuing treatment and identify the potential of D-dimer point of care testing for identification of high risk patients within a primary care setting.
Venous thromboembolism; Deep vein thrombosis; Pulmonary embolism; Extended warfarin; Post thrombotic syndrome; D-dimer
The removal of mercury sphygmomanometers from health centers requires the validation of other instruments to measure blood pressure in the limbs to calculate the ankle-brachial index (ABI).
Descriptive cross-sectional study of agreement between two measurement methods in type 2 diabetes patients from three urban primary healthcare centres in the Barcelonès Nord i Maresme area (Catalonia, Spain).
ABI was determined with Doppler and mercury sphygmomanometer and Doppler and the “hybrid” sphygmomanometer OMRON HEM-907 model. Agreement was evaluated using the weighted kappa index. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated using the mercury sphygmomanometer as the gold standard.
211 patients were included, from these, 421 limbs were available for study. The mean age of the participants was 67 years (SD = 10), 51.7% were women.
The index of agreement between ABI measured with a mercury sphygmomanometer and with the OMRON HEM-907 blood pressure monitor was good (weighted kappa index = 0.68; CI 95%: [0.55–0.79]) and improved when the ABI cut-off value was set at ≤0.70 (weighted kappa index = 0.92; CI 95%: [0.81–1.00]). Sensitivity and specificity were 77.5% and 98.2%, respectively. PPV was 83.8% and NPV was 97.3%. With the ABI cut-off value ≤0.70, sensitivity and specificity increased to 85.7% and 100%, respectively, PPV to 100% and NPV to 99.4%.
The combination of a Doppler device with the hybrid sphygmomanometer is a simple and reliable method to measure ABI showing that hybrid sphygmomanometer is a good alternative to the use of mercury sphygmomanometers.
Ankle brachial blood pressure index; Peripheral arterial disease; Blood pressure; Type 2 diabetes mellitus; Doppler; Sensitivity and specificity
Arterial media calcification (AMC) is highly prevalent and is a major cause of morbidity, mortality, stroke and amputation in patients with diabetes mellitus (DM). Previous research suggests that advanced glycation end products (AGEs) are responsible for vascular calcification in diabetic patients. The potential link between oxidative stress and AGEs-induced vascular calcification, however, has not been examined.
Male Wistar rats received a high fat diet for 8 weeks followed by a single dose of streptozotocin to induce DM (DM). Calcification was induced with Vitamin D3 and nicotine (VDN). We started VDN treatment at 1 week after the initial streptozotocin injection (DM+VDN). Age-matched rats were used as controls (CON). Metabolic parameters, aortic calcium content, alkaline phosphatase (ALP) protein, malondialdehyde (MDA) content, Cu/Zn superoxide dismutase (SOD) activity, aorta receptor for advanced glycation end products (RAGE) and aorta AGEs levels were measured. In vitro, vascular smooth muscle cells (VSMCs) were cultured with AGEs in DMEM containing 10 mmol·L-1 ß -glycerophosphate (ß-GP). Calcium content and ALP activity were used to identify osteoblastic differentiation and mineralization. Western blots were used to examine protein expression of Cu/Zn SOD, NADPH oxidase Nox1 and RAGE. In addition, the intracellular reactive oxygen species (ROS) generation was evaluated using fluorescent techniques with dihydroethidine (DHE) method.
The DM+VDN group showed a significant increase in aortic calcium content, levels of aorta AGEs, MDA content, ALP protein levels and RAGE expression, although Cu/Zn SOD activity decreased significantly. In vitro, enhanced Nox1, RAGE expression as well as the production of intracellular superoxide anions, and reduced expression of Cu/Zn SOD induced by AGEs were attenuated by the anti-RAGE antibody or a ROS inhibitor. Furthermore, the AGEs-stimulated ROS increase was also significantly inhibited by a SOD mimetic. Increased ALP activity and calcium deposition were also inhibited markedly by the ROS inhibitor and the anti-RAGE antibody.
These results suggest that AGEs enhance vascular calcification partly through a RAGE/oxidative stress pathway.
Diabetes mellitus; Advanced glycation end products; Vascular smooth muscle cells; Calcification; Oxidative stress
Increased levels of cardio-enriched microRNAs (miRNAs) have been described in patients with myocardial infarction (MI). We wanted to evaluate the diagnostic and prognostic potential of cardio-enriched miRNAs in patients presenting with a suspected acute coronary syndrome (ACS).
Cardio-enriched miRNAs (miR-1, miR-208b and miR-499-5p) were measured using real time PCR in plasma samples from 424 patients with suspected ACS treated in a coronary care unit. miRNAs were assessed for discrimination of a clinical diagnosis of myocardial infarction and for association with 30-day mortality and diagnosis of heart failure. Correlation with left ventricular systolic dysfunction as measured by the ejection fraction (LVEF) was also assessed. To confirm myocardial origin miRNA was measured during coronary artery bypass surgery.
miRNAs were higher in MI patients and correlated with LVEF (p < 0.001). Discrimination of MI was accurate for miR-208b (AUC = 0.82) and miR-499-5p (AUC = 0.79) but considerable lower than for Troponin T (AUC = 0.95). Increased miRNA levels were strongly associated with increased risk of mortality or heart failure within 30 days for miR-208b (OR 1.79, 95% CI = 1.38-2.23, p = 1 × 10-5) and miR-499-5p (OR 1.70, 95% CI = 1.31-2.20, p = 5 × 10-5) but the association was lost when adjusting for Troponin T. During surgery miR-208b and miR-499-5p was released in the coronary sinus after cardioplegia-reperfusion to markedly higher levels than in a peripheral vein.
Our findings confirm increased levels of cardio-enriched miRNAs in the blood of MI patients and establish association of increased miRNA levels with reduced systolic function after MI and risk of death or heart failure.
MiRNA; Myocardial infarction; Acute coronary syndrome; Biomarker; Prognosis
The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG).
The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a Lower 1,5-AG group (n = 36) and a Higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups.
The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT.
Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease.
1,5-anhydroglucitol; Pulsatility index; Postprandial glucose; Nondiabetic patients
Recent increases in cardiovascular risk-factor prevalences have led to new national policy recommendations of universal screening for primary prevention of cardiovascular disease in Malaysia. This study assessed whether the current national policy recommendation of universal screening was optimal, by comparing the effectiveness and impact of various cardiovascular screening strategies.
Data from a national population based survey of 24 270 participants aged 30 to 74 was used. Five screening strategies were modelled for the overall population and by gender; universal and targeted screening (four age cut-off points). Screening strategies were assessed based on the ability to detect high cardiovascular risk populations (effectiveness), incremental effectiveness, impact on cardiovascular event prevention and cost of screening.
26.7% (95% confidence limits 25.7, 27.7) were at high cardiovascular risk, men 34.7% (33.6, 35.8) and women 18.9% (17.8, 20). Universal screening identified all those at high-risk and resulted in one high-risk individual detected for every 3.7 people screened, with an estimated cost of USD60. However, universal screening resulted in screening an additional 7169 persons, with an incremental cost of USD115,033 for detection of one additional high-risk individual in comparison to targeted screening of those aged ≥35 years. The cost, incremental cost and impact of detection of high-risk individuals were more for women than men for all screening strategies. The impact of screening women aged ≥45 years was similar to universal screening in men.
Targeted gender- and age-specific screening strategies would ensure more optimal utilisation of scarce resources compared to the current policy recommendations of universal screening.
Cardiovascular risk; Cardiovascular disease; Policy; Screening
Adiponectin, paradoxically reduced in obesity and with lower levels in African Americans (AA), modulates several cardiometabolic risk factors. Because abdominal visceral adipose tissue (VAT), known to be reduced in AA, and subcutaneous adipose tissue (SAT) compartments may confer differential metabolic risk profiles, we investigated the associations of VAT and SAT with serum adiponectin, separately by gender, with the hypothesis that VAT is more strongly inversely associated with adiponectin than SAT.
Participants from the Jackson Heart Study, an ongoing cohort of AA (n = 2,799; 64% women; mean age, 55 ± 11 years) underwent computer tomography assessment of SAT and VAT volumes, and had stored serum specimens analyzed for adiponectin levels. These levels were examined by gender in relation to increments of VAT and SAT.
Compared to women, men had significantly lower mean levels of adiponectin (3.9 ± 3.0 μg/mL vs. 6.0 ± 4.4 μg/mL; p < 0.01) and mean volume of SAT (1,721 ± 803 cm3 vs. 2,668 ± 968 cm3; p < 0.01) but significantly higher mean volume of VAT (884 ± 416 cm3 vs. 801 ± 363 cm3; p < 0.01). Among women, a one standard deviation increment in VAT was inversely associated with adiponectin (β = − 0.13; p < 0.0001) after controlling for age, systolic blood pressure, fasting plasma glucose, high-density lipoprotein cholesterol, triglycerides, education, pack-years of smoking and daily intake of alcohol. The statistically significant inverse association of VAT and adiponectin persisted after additionally adjusting for SAT, body mass index (BMI) and waist circumference (WC), suggesting that VAT provides significant information above and beyond BMI and WC. Among men, after the same multivariable adjustment, there was a direct association of SAT and adiponectin (β = 0.18; p = 0.002) that persisted when controlling for BMI and WC, supporting a beneficial effect of SAT. Insulin resistance mediated the association of SAT with adiponectin in women.
In African Americans, abdominal visceral adipose tissue had an inverse association with serum adiponectin concentrations only among women. Abdominal subcutaneous adipose tissue appeared as a protective fat depot in men.