European Heart Journal

Published by Oxford University Press (OUP)
Online ISSN: 1522-9645
Publications
Amplification of the pressure waveform moving from the aorta to the radial artery. 
Indirect, non-invasive methods for estimating central pressure
Difference between brachial and aortic systolic blood pressure (SphygmoCor) in healthy men (dark blue bars; n 1⁄4 2779) and women (light blue bars; n 1⁄4 2869). The data repre- sent means + SD. 
Article
Pressure measured with a cuff and sphygmomanometer in the brachial artery is accepted as an important predictor of future cardiovascular risk. However, systolic pressure varies throughout the arterial tree, such that aortic (central) systolic pressure is actually lower than corresponding brachial values, although this difference is highly variable between individuals. Emerging evidence now suggests that central pressure is better related to future cardiovascular events than is brachial pressure. Moreover, anti-hypertensive drugs can exert differential effects on brachial and central pressure. Therefore, basing treatment decisions on central, rather than brachial pressure, is likely to have important implications for the future diagnosis and management of hypertension. Such a paradigm shift will, however, require further, direct evidence that selectively targeting central pressure, brings added benefit, over and above that already provided by brachial artery pressure.
 
Article
Insufficient spatial and temporal resolutions have limited image quality and accuracy of multi-detector CT (MDCT) for coronary artery visualization and detection of stenoses. We assessed the accuracy of a new 16-slice scanner with 370 ms rotation and 0.75 mm collimation for detection of coronary stenoses using an analysis approach based on coronary artery segments. Fifty consecutive patients scheduled for diagnostic coronary angiography in stable clinical condition and sinus rhythm were enrolled. All patients with a heart rate > 60 b.p.m. received 100 mg atenolol p.o. and up to four doses of 5 mg metoprolol i.v. before the scan. MDCT was performed using 16 x 0.75 mm collimation, 120 kV, and ECG-gated tube current modulation. Ninety millilitres of contrast agent was injected intravenously. MDCT images were visually analysed using the 16-segment coronary artery model of the American Heart Association and compared with invasive, quantitative coronary angiography in a blinded fashion. A significant stenosis was assumed if the diameter reduction was > or = 50%. Mean heart rate was 58 b.p.m. during MDCT. After exclusion of two patients with not fully evaluable data sets, MDCT correctly identified at least one coronary stenosis in all 25 patients with significant coronary lesions in angiography and correctly demonstrated the absence of stenoses in 19/23 patients (sensitivity 100%, specificity 83%). Sensitivity and specificity for all 50 patients were 93 and 83%, respectively. On a per-segment basis, nine coronary segments distal of total occlusions and 128 coronary segments with a reference diameter < 1.5 mm were excluded from the analysis. Twenty-eight of the included 663 segments (4%) were unevaluable due to calcification or motion artefact. In the remaining 635 segments, 50/53 stenoses were detected by MDCT (sensitivity 94%, specificity 96%, negative predictive value 99%, positive predictive value 69%). Increasing temporal and spatial resolutions of MDCT lead to improved evaluation and diagnostic accuracy for detection of coronary stenoses.
 
Article
Aims The importance of coronary heart disease risk factors may differ between individuals and community and by sex and age. Methods and Results The Copenhagen City Heart Study followed for 21 years a random sample of 5599 men and 6478 women aged 30 to 79 years at baseline. The importance of risk factors in individuals and the community were evaluated as relative- and population-attributable risks. We traced 2180 coronary events. In Cox regression analysis with ten risk factors entered simultaneously, relative risks for coronary heart disease in men ranged from 1·69 to 1·20 with the highest risks for diabetes, hypertension, smoking, and physical inactivity. In women, relative risks ranged from 2·74 to 1·19 with the highest risks for diabetes, smoking, hypertension, and physical inactivity. Population-attributable risks in men ranged from 22% to 3% with the highest risks for smoking, hypertension, and no daily alcohol intake. In women, attributable risks ranged from 37% to 3% with the highest risks for smoking, hypertension, and hypercholesterolaemia. Several of these rankings differed by age. Conclusions The importance of coronary heart disease risk factors may differ for individuals, the community, and by sex and age. Consequently, prevention strategies should be tailored accordingly.
 
Characteristics of the parents in the cohort (F1), their offspring (F2), and grandparents (F0) by quintiles of birth weight adjusted for gestational age (n 5 1 004 255) 
Hazard ratios (95% confidence interval) of death by cardiovascular causes in grandparents and small for gestational age in offspring before and after adjusting for maternal smoking during pregnancy among births from 1998 to 2009 (n ¼ 345 624). Model 1: adjusted for grandparental age, birth order, and year of birth. 
Article
Aims: Cardiovascular diseases (CVDs) have been related to low birth weight, suggesting the foetal environment may program future risk. Alternatively, common genetic factors for both low birth weight and CVD could explain such associations. We investigated associations between offspring birth weight and paternal and maternal cardiovascular mortality and offspring birth weight and cardiovascular mortality among all four grandparents, and further assessed the mediating role of maternal smoking during pregnancy. Methods and results: All births from 1967 to 2008 that could be linked to parents and grandparents comprised the population (n = 1,004,255). The mortality follow-up among parents was from 1970 to 2008 and among grandparents from 1960 to 2008. The association of grandparental mortality with maternal smoking during pregnancy was analysed in a subpopulation of those born after 1997 (n = 345,624). Per quintile higher in birth weight was related to 0.82 (0.75-0.89) hazard ratio from coronary heart disease in mothers and 0.94 (0.92-0.97) in fathers. For stroke, these were 0.85 (0.78-0.92) and 0.94 (0.89-1.00), respectively. In grandparents for cardiovascular causes, the effects were 0.95 (0.93-0.96) (maternal grandmother), 0.97 (0.96-0.98) (maternal grandfather), 0.96 (0.94-0.98) (paternal grandmother), and 0.98 (0.98-1.00) (paternal grandfather). Adjusting for maternal smoking in pregnancy in the subpopulation accounted for much of the effect on grandparental cardiovascular mortality in all categories of birth weight. For grandparental diabetes mortality, U-shaped associations were seen with grandchild birth weight for the maternal grandmother and inverse associations for all other grandparents. Conclusion: Associations between CVD mortality in all four grandparents and grandchild birth weight exist, and while genetic and environmental factors may contribute to these, it appears that there is an important role for maternal smoking during pregnancy (and associated paternal smoking) in generating these associations. For diabetes, however, it appears that intrauterine environmental influences and genetic factors contribute to the transgenerational associations.
 
Article
The aim of this study was to assess the association between maximum daily atrial fibrillation (AF) burden and risk of ischaemic stroke. Cardiac implanted electronic devices (CIEDs) enhance detection of AF, providing a comprehensive measure of AF burden. A pooled analysis of individual patient data from five prospective studies was performed. Patients without permanent AF, previously implanted with CIEDs, were included if they had at least 3 months of follow-up. A total of 10 016 patients (median age 70 years) met these criteria. The risk of ischaemic stroke associated with pre-specified cut-off points of AF burden (5 min, 1, 6, 12, and 23 h, respectively) was assessed. During a median follow-up of 24 months, 43% of 10 016 patients experienced at least 1 day with at least 5 min of AF burden and for them the median time to the maximum AF burden was 6 months (inter-quartile range: 1.3-14). A Cox regression analysis adjusted for the CHADS2 score and anticoagulants at baseline demonstrated that AF burden was an independent predictor of ischaemic stroke. Among the thresholds of AF burden that we evaluated, 1 h was associated with the highest hazard ratio (HR) for ischaemic stroke, i.e. 2.11 (95% CI: 1.22-3.64, P = 0.008). Device-detected AF burden is associated with an increased risk of ischaemic stroke in a relatively unselected population of CIEDs patients. This finding may add to the basis for timely and clinically appropriate decision-making on anticoagulation treatment.
 
Article
Single coronary artery is a rare congenital anomaly of the coronary arteries where only one coronary artery arises from the aortic trunk by a single coronary ostium, supplying the entire heart. A database consisting of the angiographic reports of 50000 consecutive coronary angiographies performed in adult patients in the University Hospital of Leuven between March 1973 and August 1991 was searched for the diagnosis of single coronary artery. All films concerned were reviewed and classified according to their anatomical type. Thirty-three cases of single coronary artery were retrieved, yielding an incidence of 0·066%. Patient characteristics and clinical data are described, with a discussion on the pathological importance of this finding.
 
Article
Blood pressure is a major cause of cardiovascular disease (CVD) and both may increase as outdoor temperatures fall. However, there are still limited data about seasonal variation in blood pressure and CVD mortality among patients with prior-CVD. We analysed data on 23 000 individuals with prior-CVD who were recruited from 10 diverse regions into the China Kadoorie Biobank during 2004-8. After 7 years of follow-up, 1484 CVD deaths were recorded. Baseline survey data were used to assess seasonal variation in systolic blood pressure (SBP) and its association with outdoor temperature. Cox regression was used to examine the association of usual SBP with subsequent CVD mortality, and seasonal variation in CVD mortality was assessed by Poisson regression. All analyses were adjusted for age, sex, and region. Mean SBP was significantly higher in winter than in summer (145 vs. 136 mmHg, P < 0.001), especially among those without central heating. Above 5°C, each 10°C lower outdoor temperature was associated with 6.2 mmHg higher SBP. Systolic blood pressure predicted subsequent CVD mortality, with each 10 mmHg higher usual SBP associated with 21% (95% confidence interval: 16-27%) increased risk. Cardiovascular disease mortality varied by season, with 41% (21-63%) higher risk in winter compared with summer. Among adult Chinese with prior-CVD, there is both increased blood pressure and CVD mortality in winter. Careful monitoring and more aggressive blood pressure lowering treatment in the cold months are needed to help reduce the winter excess CVD mortality in high-risk individuals. © The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
 
Article
To determine the strength of evidence for preoperative statin use for prevention of adverse postoperative outcomes in patients undergoing cardiac surgery. After literature search in major databases, 19 studies were identified [three RCT (randomized prospective clinical trials), 16 observational] that reported outcomes of 31 725 cardiac surgery patients with (n = 17 201; 54%) or without (n = 14 524; 46%) preoperative statin therapy. Outcomes that were analysed included early all-cause mortality (30-day mortality), myocardial infarction (MI), atrial fibrillation (AF), stroke and renal failure. Odds ratio (OR) with 95% confidence intervals (95%CI) were reported using fixed or random effect models and publication bias was assessed. Preoperative statin therapy resulted in a 1.5% absolute risk reduction (2.2 vs. 3.7%; P < 0.0001) and 43% odds reduction for early all-cause mortality (OR 0.57; 95%CI: 0.49-0.67). A significant reduction (P < 0.01) in statin pretreated patients was also observed for AF (24.9 vs. 29.3%; OR 0.67, 95%CI: 0.51-0.88), stroke (2.1 vs. 2.9%, OR 0.74, 95%CI: 0.60-0.91), but not for MI (OR 1.11; 95%CI: 0.93-1.33) or renal failure (OR 0.78, 95%CI: 0.46-1.31). Funnel plot and Egger's regression analysis (P = 0.60) excluded relevant publication bias. Our meta-analysis provides evidence that preoperative statin therapy exerts substantial clinical benefit on early postoperative adverse outcomes in cardiac surgery patients, but underscores the need for RCT trials.
 
Prevalence of cardiovascular risk factors by educational level (adjusted for age in 10 year categories). Netherlands Monitoring Project on Cardiovascular Disease Risk Factors, 1987-1991 A 8 e Risk factors Level of education 
of men and women with none, one, two and three risk factors and the percentage of men and women with specific combinations of the three major risk factors (adjusted for age) 
Article
The study objective was to describe the associations between socioeconomic status and (concurrence of) cardiovascular risk factors. The Netherlands Monitoring Project on Cardiovascular Risk Factors is a screening project that was carried out from 1987-1991 in three cities. Cross-sectional data were obtained on educational level and on the prevalence of smoking, alcohol intake, physical inactivity, obesity, hypertension, hypercholesterolaemia and low HDL-cholesterol. A total of 36 000 men and women, aged 20-59 years participated. For all risk factors, except alcohol intake, a significant inverse association was found with educational level. Concurrence of risk factors was more prevalent in lower educated groups than in higher educated groups, but not more than can be expected under the condition of independence of the risk factors (no clustering). In conclusion, in the lower educated groups the prevalence of individual risk factors and of concurrence of risk factors was higher than in the higher educated groups. Concurrence of risk factors can have a synergistic effect on the risk for cardiovascular disease. Therefore socioeconomic differences in risk factors may explain a greater part of the socioeconomic differences in cardiovascular morbidity and mortality than is generally assumed.
 
Study characteristics 
Flow diagram of included studies.  
Forest plot of all-cause mortality.  
Forest plot of cardiovascular death mortality.  
Forest plot of coronary heart disease death plus non-fatal MI. Yu et al. reported zero events in both arms and therefore did not contribute to this analysis.  
Article
Statin therapy is associated with important benefits for patients at risk of, and with, established cardiovascular disease. There is widespread interest in whether intensive dosing of statins yields larger treatment effects. We aimed to determine if intensive dosing is clinically important using a meta-analysis of randomized clinical trials (RCTs). We conducted comprehensive searches of electronic databases from inception to December 2010. We included any RCT evaluating a larger dose with a clinically common dose. Two reviewers independently extracted data, in duplicate. We performed random-effects meta-analysis and a trial sequential analysis. We identified 10 RCTs enrolling a total of 41 778 participants. Trials followed patients for a mean of 2.5 years. We did not find statistically significant effects on all-cause mortality [relative risk (RR) 0.92, 95% confidence interval (CI), 0.83-1.03, P = 0.14, I(2) = 38%] or cardiovascular disease (CVD) deaths (RR 0.89, 95% CI, 0.78-1.01, P = 0.07, I(2) = 34%). When we pooled the composite endpoint of coronary heart disease (CHD) death plus non-fatal myocardial infarction (MI), we found a significant protective effect of intensive statin dosing (RR 0.90, 95% CI, 0.84-0.96, P ≤ 0.0001, I(2) = 0%). We also found a significant effect on non-fatal MIs (RR 0.82, 95% CI, 0.76-0.89, P ≤ 0.0001, I(2) = 0%) and a significant reduction in the composite of fatal and non-fatal strokes (excluding transient ischaemic attacks) reported in 10 RCTs (RR 0.86, 95% CI, 0.77-0.96, P = 0.006, I(2) = 0%). A subgroup analysis of three trials examining acute coronary syndrome patients found significant effects on all-cause (RR 0.75, 95% CI, 0.61-0.91, P = 0.005, I(2) = 0%) and CVD mortality (RR 0.74, 95% CI, 0.59-0.94, P = 0.013, I(2) = 0%) with intensive dosing. Applying an analysis of optimal information size on the primary analysis, we found that the evidence for CHD death plus non-fatal MIs is conclusive. The evidence for CVD deaths alone is not yet conclusive. Available evidence suggests that intensive statin therapy reduces the risk of non-fatal events and may have a role in reducing mortality.
 
Disposition of patients in the trial. 
Primary intravascular ultrasonography results
Article
High-density lipoproteins (HDLs) have several potentially protective vascular effects. Most clinical studies of therapies targeting HDL have failed to show benefits vs. placebo. To investigate the effects of an HDL-mimetic agent on atherosclerosis by intravascular ultrasonography (IVUS) and quantitative coronary angiography (QCA). A prospective, double-blinded, randomized trial was conducted at 51 centres in the USA, the Netherlands, Canada, and France. Intravascular ultrasonography and QCA were performed to assess coronary atherosclerosis at baseline and 3 (2-5) weeks after the last study infusion. Five hundred and seven patients were randomized; 417 and 461 had paired IVUS and QCA measurements, respectively. Patients were randomized to receive 6 weekly infusions of placebo, 3 mg/kg, 6 mg/kg, or 12 mg/kg CER-001. The primary efficacy parameter was the nominal change in the total atheroma volume. Nominal changes in per cent atheroma volume on IVUS and coronary scores on QCA were also pre-specified endpoints. The nominal change in the total atheroma volume (adjusted means) was -2.71, -3.13, -1.50, and -3.05 mm(3) with placebo, CER-001 3 mg/kg, 6 mg/kg, and 12 mg/kg, respectively (primary analysis of 12 mg/kg vs. placebo: P = 0.81). There was also no difference among groups for the nominal change in per cent atheroma volume (0.02, -0.02, 0.01, and 0.19%; nominal P = 0.53 for 12 mg/kg vs. placebo). Change in the coronary artery score was -0.022, -0.036, -0.022, and -0.015 mm (nominal P = 0.25, 0.99, 0.55), and change in the cumulative coronary stenosis score was -0.51, 2.65, 0.71, and -0.77% (compared with placebo, nominal P = 0.85 for 12 mg/kg and nominal P = 0.01 for 3 mg/kg). The number of patients with major cardiovascular events was 10 (8.3%), 16 (13.3%), 17 (13.7%), and 12 (9.8%) in the four groups. CER-001 infusions did not reduce coronary atherosclerosis on IVUS and QCA when compared with placebo. Whether CER-001 administered in other regimens or to other populations could favourably affect atherosclerosis must await further study.Name of the trial registry: Clinicaltrials.gov; Registry's URL: http://clinicaltrials.gov/ct2/show/NCT01201837?term=cer-001&rank=2; Trial registration number: NCT01201837.
 
Article
To evaluate the efficacy and safety of hirudin, a direct thrombin inhibitor, in patients with acute myocardial infarction, a dose-finding, angiography study was carried out. After a pilot phase in 10 patients treated with a bolus of 0.1 mg.kg-1 and a continuous infusion of 0.06 mg.kg-1.h-1 (dose group I), two doses of hirudin, bolus 0.2 mg.kg-1.h-1 (DG II), and bolus 0.4 mg.kg-1 with 0.15 mg.kg-1.h-1 (DG III) were tested and compared with heparin as an adjunct to streptokinase and aspirin. This interim analysis was mandatory due to puncture-site related bleedings. Early and complete patency was achieved in 30% of 35 heparin patients, in 40% of 10 DG I, in 47% of 58 DG II and in 62% of 14 DG III patients. A dose-response relationship particularly between DG I and DG II, was also observed in the anti-thrombotic activity monitored by the aPTT. Apart from the catheter-related bleedings, there were low rates of serious adverse events.
 
aPTT levels in sec during hirudin infusion at the four pre-defined periods of the day 
Article
Circadian variations have been described for a number of haemostatic and physiological factors, all of which might predispose towards clotting in the late morning. The anticoagulation effect of heparin has been shown to respond in a circadian manner, resulting in minimal prolongation of the activated partial thromboplastin time (aPTT) in the morning. Recombinant hirudin (HBW 023) given as a bolus of 0.07, 0.1, 0.2 or 0.4 mg.kg-1 followed by an infusion of 0.05, 0.06, 0.1 or 0.15 mg.kg-1 over 48 h was used as conjunctive therapy to thrombolysis with front-loaded recombinant tissue-type plasminogen activator (100 mg.90 min-1) in 40 patients with acute myocardial infarction. APTT, activated clotting time and free hirudin plasma levels were determined at baseline and at 8, 12, 16, 20, 24, 32, 40 and 48 h. The prolongation of aPTT and activated clotting time was dose-dependent and stable. In 82.5% of the patients, aPTT values were ranged between the highest and the lowest aPTT of < 30 s. When the results were divided into four time intervals (0000-0600, 0600-1200, 1200-1800, 1800-2400) neither in the individual patients nor in the mean values of the four different dose groups was any significant circadian variation in aPTT or activated clotting time prolongation observed. The pharmacokinetic studies of free hirudin plasma levels revealed no circadian rhythm either. All but one patient (97.5%) had a patent vessel (TIMI grade 2/3) at the end of the hirudin infusion. Recombinant hirudin, in contrast to heparin, does not show any circadian variation in its anticoagulation effect. This might, in part, explain the more stable and predictable anticoagulation achieved by hirudin, which is associated with a reduced rate of reocclusions after thrombolysis.
 
Study flow diagram.
Observed (Kaplan–Meier) risk of all cause-mortality and non-fatal MI or coronary death for stable angina patients and stable patients 6 months after ACS. The numbers of patients at risk per unit time are shown below each plot.
The contribution of each variable included in the CALIBER model for predicting all-cause mortality in SCAD, assessed by the decrease in the C-index upon its removal from the complete model.
Evaluation of prediction performance upon incremental addition of different sets of predictors, using sociodemographics as the reference model. *Based on guideline definition of low (<1%), intermediate (1–3%), and high (>3%) annual risk. **Assuming that management is associated with hazard ratio 0.8 and is cost-effective at high risk.
Article
The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD. Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan-Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13-16 life years or 15-18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation. These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.
 
Article
Coronary bifurcations account for up to 15% of all percutaneous coronary interventions (PCIs) and are one of the most challenging lesions in interventional cardiology.1 The treatment strategy has rapidly improved over the years. Initially, bifurcation lesion treatment used to be associated with a high risk of complications and restenosis.2,3 The use of drug-eluting stents (DES) and introduction of different bifurcation stenting strategies and techniques resulted in marked improvements.4–6 Thus, the ARTS II study had comparable event rates in bifurcation and non-bifurcation lesions.7 The optimal stenting technique with DES is still a matter of considerable debate where one of the concerns is the potential increased risk of late stent thrombosis associated with treatment complexity. Based on the randomized studies on one- vs. two-stent techniques available today, and based on the KISSS principle (Keep It Simple Swift and Safe), the generally accepted approach to bifurcation stenting is the provisional stenting technique. In this technique, the main vessel (MV) is stented first and the side branch (SB) is only stented in the case of severe stenosis or flow problems after MV stenting.8 The approach has been found to be safe and efficient in registries and randomized trials. … *Corresponding author: Tel: +45 89496248. Fax: +45 89496002. Email: jens.lassen{at}ki.au.dk
 
Article
Prolonged sedentary time is ubiquitous in developed economies and is associated with an adverse cardio-metabolic risk profile and premature mortality. This study examined the associations of objectively assessed sedentary time and breaks (interruptions) in sedentary time with continuous cardio-metabolic and inflammatory risk biomarkers, and whether these associations varied by sex, age, and/or race/ethnicity. Cross-sectional analyses with 4757 participants (≥ 20 years) from the 2003/04 and 2005/06 US National Health and Nutrition Examination Survey (NHANES). An Actigraph accelerometer was used to derive sedentary time [< 100 counts per minute (cpm)] and breaks in sedentary time. Independent of potential confounders, including moderate-to-vigorous exercise, detrimental linear associations (P for trends < 0.05) of sedentary time with waist circumference, HDL-cholesterol, C-reactive protein, triglycerides, insulin, HOMA-%B, and HOMA-%S were observed. Independent of potential confounders and sedentary time, breaks were beneficially associated with waist circumference and C-reactive protein (P for trends <0.05). There was limited evidence of meaningful differences in associations with biomarkers by age, sex, or race/ethnicity. Notable exceptions were sex-differences in the associations of sedentary time and breaks with HDL-cholesterol, and race/ethnicity differences in the association of sedentary time with waist circumference with associations detrimental in non-Hispanic whites, null in Mexican Americans, and beneficial in non-Hispanic blacks. These are the first population-representative findings on the deleterious associations of prolonged sedentary time with cardio-metabolic and inflammatory biomarkers. The findings suggest that clinical communications and preventive health messages on reducing and breaking up sedentary time may be beneficial for cardiovascular disease risk.
 
Article
To analyse the vasoreactivity of a coronary segment, previously scaffolded by the ABSORB bioresorbable vascular scaffold (BVS) device, in relationship to its intravascular ultrasound-virtual histology (IVUS-VH) composition and reduction in greyscale echogenicity of the struts. Coronary segments, transiently scaffolded by a polymeric device, may in the long-term recover a normal vasomotor tone. Recovery of a normal endothelial-dependent vasomotion may be enabled by scaffold bioresorption, composition of the underlying tissue, or a combination of both mechanisms. All patients from the ABSORB Cohort A and B trials, who underwent a vasomotion test and IVUS-VH investigation at 12 and 24 months, were included. Acetylcholine (Ach) and nitroglycerin were used to test either the endothelial-dependent or -independent vasomotion of the treated segment. Changes in polymeric strut echogenicity-a surrogate for bioresorption-IVUS-VH composition of the tissue underneath the scaffold and their relationship with the pharmacologically induced vasomotion were all evaluated. Overall, 26 patients underwent the vasomotion test (18 at 12 and 8 at 24 months). Vasodilatory response to Ach was quantitatively associated with larger reductions over time in polymeric strut echogenicity (y= -0.159x- 6.85; r= -0.781, P< 0.001). Scaffolded segments with vasoconstriction to Ach had larger vessel areas (14.37 ± 2.50 vs. 11.85 ± 2.54 mm(2), P= 0.030), larger plaque burden (57.31 ± 5.96 vs. 49.09 ± 9.10%, P= 0.018), and larger necrotic core (NC) areas [1.39 (+1.14, +1.74) vs. 0.78 mm(2) (+0.20, +0.98), P= 0.006] compared with those with vasodilation. Vasodilatory response to Ach, in coronary segments scaffolded by the ABSORB BVS device, is associated with a reduction in echogenicity of the scaffold over time, and a low amount of NC. In particular, the latter finding resembles the behaviour of a native coronary artery not caged by an intracoronary device.
 
Article
PY-108-068 (PY) has calcium antagonist and coronary dilatory activity in animals, suggesting that it may be useful for the treatment of angina pectoris. We have studied its effects in 19 patients with stable exertional angina. After a 2-week single-blind placebo run-in phase, patients were randomised double-blind to either 75 mg or 150 mg of the drug (in three divided doses) daily for 2 weeks, crossing over to the alternate dose for a further 2 weeks. Maximal treadmill tests with computer-assisted electrocardiographic analysis were used to evaluate efficacy. The mean +/- SEM exercise time to onset of angina increased from 6.1 +/- 0.5 min on placebo to 9.3 +/- 0.8 min on PY 75 mg (P less than 0.001) and to 9.2 +/- 0.8 min on PY 150 mg (P less than 0.001) vs placebo; NS vs 75 mg). The time to development of 1 mm ST-segment depression in lead CC5 also increased from 5.0 +/- 0.7 min on placebo to 6.4 +/- 0.9 min on PY 75 mg (P less than 0.01) and to 7.0 +/- 0.8 min on PY 150 mg (P less than 0.01 vs placebo; NS vs 75 mg). Unlike other calcium antagonists, treatment with PY-108-068 did not significantly alter the resting or maximal heart rates or the heart rate gain during exercise. Resting blood pressure was reduced at the higher dose level but peak blood pressure during exercise and peak double product were unaltered by PY-108-068 treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
 
Article
At present, 0.2–4% of all pregnancies in western industrialised countries are complicated by cardiovascular diseases (CVD), and the number of the patients who develop cardiac problems during pregnancy is increasing. Nevertheless, the number of such patients presenting to the individual physician is small. However, knowledge of the risks associated with CVD during pregnancy and their management are of pivotal importance for advising patients before pregnancy. Therefore, guidelines on disease management in pregnancy are of great relevance. Such guidelines have to give special consideration to the fact that all measures concern not only the mother, but the fetus as well. Therefore, the optimum treatment of both must be targeted. A therapy favourable for the mother can be associated with an impairment of the child, and in extreme cases treatment measures which protect the survival of the mother can cause the death of the fetus. On the other hand, therapies to protect the child may lead to a suboptimal outcome for the mother. Because prospective or randomised studies are absent, with few exceptions, recommendations in this guideline mostly correspond to the evidence level C. Some general conclusions have arisen from these guidelines: counselling and management of women of childbearing age with suspected cardiac disease should start before pregnancy occurs; they should be managed by interdisciplinary teams; high risk patients should be treated in specialized centres; and diagnostic procedures and interventions should be performed by specialists with great expertise in the individual techniques and experience in treating pregnant patients. Registries and prospective studies are urgently needed to improve the state of knowledge. The spectrum of CVD in pregnancy is changing and differs between countries. In the western world, the risk of CVD in pregnancy has increased due to increasing age at first pregnancy and increasing prevalence of cardiovascular risk factors- diabetes, hypertension and obesity. Also the treatment of congenital heart disease has improved resulting in an increased number of women with heart disease reaching childbearing age. In western countries maternal heart disease is now the major cause of maternal death during pregnancy. Hypertensive disorders are the most frequent cardiovascular events during pregnancy, occurring in 6–8% of all pregnancies. In the western world, congenital heart disease is the most frequent cardiovascular disease present during pregnancy (75–82%), with shunt lesions predominating (20-65%). Congenital heart disease just represents 9–19% outside Europe and North America. Rheumatic valvular disease dominates in non-western countries comprising 56–89% of all cardiovascular diseases in pregnancy. Cardiomyopathies are rare, but represent severe causes of cardiovascular complications in pregnancy. Peripartum cardiomyopathy (PPCM) is the most common cause of severe complications.
 
Article
Benefits and complications of postoperative implantable cardioverter-defibrillator tests are controversial matters. This study sought to assess the necessity of defibrillation function tests after implantation. We retrospectively analysed 1007 implantable cardioverter-defibrillator tests in 587 systems and 556 patients. Nine hundred and thirty implantable cardioverter-defibrillator tests (89.4%) were routinely performed. Seventy-one tests (7%) were performed after a change in the antiarrhythmic drug regimen and six tests (0.60%) because of a suspected dysfunction of the implantable cardioverter-defibrillator. During routine tests, four systems (0.4%) failed to defibrillate the patient. However, in all but one test, abnormalities of the system had been observed before the test. After the addition of antiarrhythmic drugs, two of 71 implantable cardioverter-defibrillator systems (2.8%) failed to defibrillate the patient. One of six systems tested due to a suspected dysfunction failed to defibrillate the patient. During 16 tests (1.6%), complications occurred. Our experience demonstrates that postoperative tests of the defibrillation function of implantable cardioverter-defibrillators rarely reveal dysfunctions. As testing is unpleasant for the patient and not free of complications, tests might be restricted to those patients in whom a dysfunction is suspected and to those patients in whom class I or class III antiarrhythmic drugs have been added to the antiarrhythmic drug regimen.
 
Article
To determine the safety of high-dose dobutamine-atropine stress cardiovascular magnetic resonance (stress-CMR), which recently emerged as a highly accurate modality for diagnosis of inducible myocardial ischaemia. From 1997 to 2002, 1000 consecutive stress-CMR examinations were performed. Images were acquired at rest and during a high-dose dobutamine-atropine protocol in 3 short-axis, a 4- and a 2-chamber view. Stress testing was discontinued when > or =85% of age-predicted heart rate was reached, on patient request, maximum pharmacologic infusion, or when new or worsening wall motion abnormalities, severe angina, dyspnoea, increase or decrease in blood pressure, or severe arrhythmias occurred. Stress-CMR was successfully performed in all but four patients (0.4%; insufficient ECG-triggering). Target heart rate was not reached in 95 cases (9.5%), due to maximum pharmacologic infusion in submaximal negative examinations in 21 cases (2.1%), and limiting side effects in 74 (7.4%). Side effects included one case (0.1%) of sustained and four cases (0.4%) of non-sustained ventricular tachycardia, 16 cases (1.6%) of atrial fibrillation, and two cases (0.2%) of transient second degree AV block. The safety profile of stress-CMR is similar to other methodologies using dobutamine infusions. Patients must be closely monitored, and resuscitation equipment and trained personnel must be available.
 
Article
To determine the circadian rhythm of paroxysmal atrial fibrillation in a very large outpatient population. METHODS and We reviewed all emergency telephone calls received in Shahal (a medical service covering 44 000 subscribers), from 1987 to 1997. Patients were included if new-onset atrial fibrillation was recorded. During this study period, 9989 episodes of paroxysmal atrial fibrillation were recorded. The time of onset was not uniformly distributed throughout the 24 h period. Instead, the distribution of arrhythmic episodes showed a double peak, with a significant increase in the number of episodes in the morning and a second rise in the evening (P<0.001). A non-uniform weekly distribution of events was also noted, with substantially fewer episodes on Saturdays (P<0.001). Finally, more arrhythmias occurred during the last months of each year (P<0.001). The onset of paroxysmal atrial fibrillation does not occur randomly. The large patient population in the present study suggests that the circadian rhythm of paroxysmal atrial fibrillation is similar to that described for other cardiovascular diseases, with clustering of events in the morning and (to a lesser degree) late in the evening. Weekly and yearly circadian patterns are also prominent.
 
Article
Long-term follow-up of 101 healthy elderly subjects living independently in the community has been undertaken by means of clinical examination, resting ECG and 24-hour ambulatory cardiac monitoring. It appears that the finding of ventricular premature complexes at the rate of 10 per hour or greater is associated with a significant increase in mortality. The prevalence of atrial fibrillation, initially found to be 11% rises with age to 17% by the age of 84 years. Long-term ambulatory monitoring is essential in the proper documentation of paroxysmal atrial fibrillation. Bundle branch block also occurs in over 10% of elderly people and the prevalence rises steeply with age, so that at the end of this study more than one quarter of the survivors had evidence of His–Purkinje disease. Over 5% of our subjects had definite indications for pacing during the period of follow-up and lends support to the opinion that the current pacemaker implantation rate in the United Kingdom is below the optimal level.
 
Article
A new generation of multidetector-row CT (MDCT) scanners allows complete coronary coverage using retrospective ECG gating and 1mm slices. The purpose of this study was to investigate the potential of high resolution MDCT angiography with retrospective gating for detection of coronary artery stenoses. A total of 102 patients underwent both conventional and MDCT coronary angiography. After intravenous injection of a non-ionic contrast medium the entire heart was scanned within a single breath hold using 1mm slices. All MDCT data sets were reconstructed with retrospective gating at 20% to 80% in increments of 10% relative to the cardiac cycle. Two blinded independent reviewers analysed image quality for segments 1-4 (right coronary artery), 5-8 (left main, left anterior descending), and 11, 12 (left circumflex). These segments were evaluated for the presence or absence of significant (>or=50%) stenoses. The results were compared with those of invasive coronary angiography in a blinded fashion. Overall sensitivity for the detection of significant stenoses (>or=50%) were 0.86 (reader 1) and 0.93 (reader 2), specificity 0.96 (reader 1) and 0.97 (reader 2), negative predictive value 0.98 (reader 1) and 0.99 (reader 2). High resolution MDCT angiography with retrospective gating permits the non-invasive detection of coronary artery stenoses with high accuracy if image quality is optimized for each of the three major coronary arteries.
 
Article
Few date are available about cardiac involvement in AIDS. We examined 102 consecutive patients with AIDS diagnosed clinically and serologically (Walter Reed Stage 5 and 6), by means to TM and cross-sectional echocardiography with the aim of detecting cardiac abnormalities. None of the patients had overt clinical signs of heart failure. Fifty-five (54%) patients showed persistent tachycardia, diminished left ventricular (LV) wall thickness (mean 7.6±0.2 mm) and decreased percentage LV fractional shortening (27±5). In 42 (41%) there was a globular and poorly contracting LV. Thirty-nine (38%) patients had pericardial effusion which was moderate in 30 and small in nine. In four patients, valvular endocarditic vegetation was shown—on the tricuspid valve in three, on the aortic valve in one: all of them were drug addicts; in three (2.9%) patients a cardiac mass was found which proved to be a localization of Kaposi's sarcoma in two. Twenty-five (24.5%) patients died; necropsy showed cardiac dilation, and thin LV walls in 18. On microscopic examination, myocardial fibrosis and lymphocyte infiltration with cell necrosis were observed. We conclude that cardiac abnormalities are common in AIDS. Impairment in LV contractility as assessed from fractional shortening appears to be the most common echocardiographic finding, followed by LV wall thinning, pericardial effusion and eventually by LV cavity dilation. This evolution is suggestive of myocardial damage and supports the hypothesis that dilated cardiomyopathy may be a cardiac complications of AIDS.
 
Article
The role of programmed ventricular stimulation (PVS) in patients at high risk of sudden death related to idiopathic dilated cardiomyopathy (DCM) is still controversial The possible reason is that most study series have been too small or that only a few patients had documented sustained ventricular tachyarrhythmias. This study therefore, looked at PVS performed in 102 patients with DCM and documented sustained ventricular tachycardia (VT; n=63) or ventricular fibrillation (VF; n=39). Sustained VT was induced in 27 of 63 patients (43%) with documented sustained VT and in 14 of 39 patients (36%) with documented VF (ns). VF was induced in nine patients (14%) with a history of sustained VT and in seven (18%) with a history of VF (ns). At a mean follow-up of 32±15 months, sudden death occurred in 14 (14%) patients, a rate similar in both patients with documented VT and VF (ns). Incidence of sudden death at 36 months was 6% in patients with inducible sustained VT/VF compared to 29% in patients without inducible VT/VF (P<0·05) A favourable drug regimen (response to drug and no intolerable side effects) was obtained by serial drug testing in 25 of all 102 patients (25%). A cardioverter defibrillator (ICD) was implanted in 32 patients, in 63% of whom discharges were observed during 18±11 months of follow-up; only one patient (3%) died suddenly. Thus, in patients with DCM, there was no relationship between documented and inducible ventricular tachzyarrhythmias, and initiation of sustained VT or VF had little prognostic value for the prediction of subsequent sudden death. Wherever antiarrhythmic drug therapy was of limited value, implantation of an ICD may improve the prognosis of these high risk patients.
 
Article
Since 1979 we have carried out symptom limited exercise stress tests for the diagnosis of chest pain in 104 patients, 61 male, 43 female, over 65 years of age, mean age 68±3 years. An upright bicycle ergometer was used for 64 tests, a treadmill for 38 tests and a supervised walk for 2 patients unable to undergo formal exercise testing. A positive result of ≥ 1 mm of ST depression was recorded in 45% of patients; males 57%, females 28% (P<0·01). Bicycle and treadmill tests were equally likely to produce a positive result; bicycle 43%, treadmill 50% (NS). The limiting symptom was chest pain in 43%, dyspnoea in 26% and fatigue in 30% of patients. No serious arrhythmias or collapses occurred. During a mean follow up to 24±18 months 13 patients died. A positive exercise test was associated with a significantly increased risk of cardiac death, 8 of 47 patients with positive tests died compared with 1 of 57 patients with negative or equivocal tests (P <0·02). The remaining 4 deaths were due to malignancy. Exercise testing can thus be safely performed in elderly subjects with the expectation of a high diagnostic yield. A positive result confers a poor prognosis.
 
Article
To determine very long-term survival and incidence of recurrent interventions following aorto-coronary bypass surgery using venous grafts. A group of 1041 consecutive patients operated upon between 1971 and 1980 were followed for a median of 19 years (range 13-26). Peri-operative mortality was 1.2%. Survival probability at 5, 10, 15, and 20 years was 92%, 77%, 57%, and 40%, respectively. After 5 or more years following operation the mortality was higher than in the matched Dutch population. Age, extent of coronary artery disease, and ejection fraction are independent predictors of mortality. Of the 593 deceased patients at least 63% died of a probable cardiac cause, while cardiovascular mortality is 40% in the general Dutch population. Repeat revascularization procedures (aorto-coronary bypass surgery or percutaneous transluminal coronary angioplasty) were performed in 343 patients (33%), with an increasing incidence after 7 years. Aorto-coronary bypass surgery using vein grafts is safe and has a reasonable long-term prognosis for survival, although less than a matched population. After approximately 7 years both mortality and the need for repeated revascularizations increased. Since a majority of patients died of a cardiac cause and a substantial number of patients required repeated revascularization, aorto-coronary bypass surgery is a palliative treatment of a progressive disease.
 
Article
The first 1041 patients who underwent an isolated aorto-coronary bypass operation in the same institution since it opened in 1971, were followed for up to 10 years to determine their prognosis. The mean follow-up time was 3.5 years. The probability of survival at five years was 94 +/- 2% (95% confidence limits). This was similar to the survival of the general Dutch population matched for age and sex. Multivariate survival analysis with the proportional hazards model did reveal a relationship of the rate of death with sex and age at operation; however this was not significant. There was a trend to a higher death rate with more vascular involvement (rate ratio of 3 vessel-versus 1 vessel disease of 1.9, N.S.) and a significant association with a low ejection fraction (EF) (ratio EF less than or equal to 0.30 v. EF greater than or equal to 0.55 of 2.7. P less than 0.05). Though surgery seems to eradicate the poor longterm outlook for patients with more serious vascular disease, the adverse influence of decreased left ventricular function on survival is not changed.
 
Article
To evaluate longterm survival, 1041 consecutive patients with aorto-coronary bypass operations were followed for a mean of 7.5 years (range 5 to 14.5). The peri-operative mortality was 12 (1.2%). Of the 131 late deaths, 97 (74%) were cardiac in origin. The survival probability at 5 years was 92 ±2% and at 10 years 79 ±4%. Figures for a matched general Dutch population are 94% and 87%, respectively. Stepwise multivariate analysis revealed an association between death rate and impaired left ventricular function (rate ratio impaired function versus normal: 1.82, P =0.0007) and extent of vascular disease (rate ratio 3 vessel-versus 1 vessel disease: 1.80, P = 0.01) while no relation was found with sex or age at operation. Surgery seems to provide a good probability of survival, although in patients with extensive vascular involvement and/or a decreased left ventricular function at the time of operation, the longterm outlook is less favourable than for those without these characteristics.
 
Article
Atrioventricular synchronous pacing exerts beneficial effects, including reduction of left ventricular outflow tract gradients, in patients with hypertrophic obstructive cardiomyopathy. The Pacing in Cardiomyopathy study was initiated to explore the effects of pacing in a double-blind randomized crossover fashion. The aims were to ascertain the beneficial effects of pacing in a controlled study and to rule out a placebo effect by pacing. This paper deals with the outcome of pacing on quality of life during 1 year of follow-up. Quality of life was evaluated with the Karolinska questionnaire, validated for patients paced for bradyarrhythmias and ischaemic heart disease. Drug-refractory patients with hypertrophic obstructive cardiomyopathy were recruited for the study and after a temporary pacing procedure implanted with permanent pacemakers. Patients were randomized to two study arms defining the sequence of pacemaker programming. In one arm the pacemaker was inactive, in the other active. After 3 months the pacemaker was reprogrammed to the alternate mode and a further 3 months followed. After this period subsequent pacemaker programming corresponded to the mode preferred by the patient. A last assessment was made 1 year after baseline examinations. Eighty patients completed the first crossover period and 75 completed the full 1 year of follow-up. Active pacing induced significant quality of life improvements, in the order of 9-44%, regardless of programming sequence. Discontinuation of pacing after a first active period resulted in the return of symptoms. Fourteen patients requested early reprogramming after having been programmed to inactive pacing after a first period of active pacing. Seventy-six patients preferred active pacing after the crossover period. A further 6 months of pacing induced progressive improvement in symptoms already favourably influenced. Atrioventricular synchronous pacing has a profound beneficial effect on most domains of quality of life in patients with hypertrophic obstructive cardiomyopathy refractory to drug treatment.
 
Article
Mortality from cardiac surgery is an essential indicator of quality and forms the basis of treatment strategy decisions in eligible patients. No contemporary complete data on unselected adult cardiac surgery patients are available in Germany. A registry was started in June 1997 of all patients referred to surgery from 85 cardiology centres in Germany. The registry was intended to include 10 000 patients and this number was reached in March 1998. Follow-up of the patients was by simple questionnaire, reporting the date of surgery, major complications, and symptomatic improvement. If the questionnaire was not returned, a reminder letter was sent and, if necessary, further telephone investigations were performed. This resulted in 99.9% complete data. Of 10 525 patients operated on, 3.91% had died by 30 days after surgery. The overall operative mortality was 4.57%, which included 69 patients who died after more than 30 days from complications related to surgery. By multivariate analysis, the following predictors of mortality were identified: previous surgery, emergency or complex operation; age >75 years, female gender, cardiac failure, angina CCS class IV, and three-vessel coronary disease. An integral part of the registry was a pre-operative prediction of surgical risk in five categories. This risk estimate revealed a surprisingly correct prediction of the mortality observed. In a representative unselected group of cardiac surgery patients, operative mortality was 4.57%. Several procedural and clinical parameters were significantly correlated with mortality, but the risk increment by each of these factors was small. Unstructured clinical judgement reliably predicted the operative risk.
 
Article
This study was designed to assess the functional effects of a transvenous coronary sinus technique of skeletal myoblast delivery in infarcted myocardium. An anterior myocardial infarction was created percutaneously in 14 sheep. Simultaneously, a muscle biopsy was harvested and expanded. Two weeks later, sheep were instrumented percutaneously with a dedicated catheter incorporating an extendable needle for puncture of the venous wall and, under endovascular ultrasound guidance, a microcatheter was advanced through the needle into the target scar for cell delivery. Following the baseline echocardiographic assessment of left ventricular (LV) function, sheep were randomly allocated to receive four-staged in-scar injections of either autologous cells (n=7) or culture medium (n=7). Two months later, LV function was reassessed blindly and hearts were explanted for subsequent histological and immunohistochemical analysis. There were no acute procedural complications. Baseline LV ejection fraction (EF) was significantly lower in transplanted sheep than in controls [38% (35-48) vs. 51% (38-55), respectively, P=0.03; median (range)]. Two months later, LVEF was significantly higher in the transplanted group than in controls [50% (47-56) vs. 39% (36-47), respectively, P=0.002]. Clusters of myoblasts were identified by histology and immunohistochemistry in three of the seven transplanted sheep. These data suggest the functional efficacy of the transvenous coronary sinus technique as a less invasive means of cell delivery to infarcted myocardium.
 
Article
DPI201-106 is a new positive inotropic agent. The cardiac electrophysiology of 16 patients was studied before and during DPI 201-106 administration (loading dose of intravenous DPI 201-106, 1.8 mg kg-1 h-1 administered over 10 min, followed by a maintenance dose of 0.2 mg kg-1 h-1). DPI 201-106 had no effect on the sinus node. The AH interval during fixed-rate atrial pacing became prolonged during DPI 201-106 infusion. There was a significant prolongation of the QT interval [QT (corrected), 417 +/- 22 to 502 +/- 35 ms, P less than 0.05; QT (atrial pacing at 600 ms), 374 +/- 17 to 419 +/- 23 ms, P less than 0.05; QT (ventricular pacing at 600 ms), 409 +/- 37 to 449 +/- 30 ms, P less than 0.05]. The ventricular effective refractory period significantly prolonged during DPI 201-106 administration (242 +/- 21 to 287 +/- 56 ms, P less than 0.05), but the supernormal-period duration decreased. The atrial effective refractory period was shortened in four patients and prolonged in one (261 +/- 67 to 240 +/- 53 ms, NS). The corrected atrial repolarization time (PTac) shortened significantly during DPI 210-106 infusion (479 +/- 26 to 445 +/- 22 ms at 20 min of the maintenance dose, P less than 0.05). Atrial fibrillation was initiated in five patients during DPI infusion, but no ventricular arrhythmia was provoked. These findings suggest that DPI 201-106 has novel differential electrophysiological effects on atria and ventricles.
 
Article
DPI 201-106 is a novel compound unrelated to other cardioactive agents and has been shown to have an inotropic effect in animal preparations. The drug was given by intravenous infusion (20 mg over 10 min) to 10 patients with moderate cardiac failure and the haemodynamic effects measured at intervals up to 1 h following infusion. Maximal effects were seen immediately following the infusion of DPI 201-106. Cardiac index showed an increase from baseline 2.72 (0.16) 1 min-1 m-2 to 3.18 (0.21) 1 min-1 m-2 at the end of infusion (P less than 0.001). Subsequent values were not significantly raised. Pulmonary capillary wedge pressure and pulmonary artery pressure fell from 27.6 (3.2) and 36.9 (4.4) to 15.3 (3.6) and 24.2 (4.9) mmHg, respectively (P less than 0.001 in both cases). A statistically significant effect on cardiac index was not seen at 1 h. However, pulmonary pressures remained reduced at this point. Radionuclide ejection fraction showed a significant increase from 15.4 (1.5) to 21.9 (2.2)% (P less than 0.005) at the end of infusion, and maintained a significant increase at 1 h. Having demonstrated beneficial, acute haemodynamic effects in this study, further work should be undertaken with DPI 201-106 to investigate the effect of chronic treatment in patients with cardiac failure.
 
Article
AimsMicroRNAs (miRNAs, miR) are endogenous short RNA sequences that regulate a wide range of physiological and pathophysiological processes. Several miRNAs control the formation of new blood vessels either by increasing or by inhibiting angiogenesis. Here, we investigated the possible role of the miR-106b∼25 cluster in postnatal neovascularization and in regulation of the angiogenic properties of adult bone marrow-derived stromal cells.Methods and resultsTo study the effect of miR-106b∼25 deletion on neovascularization, we used a miR-106b∼25 knockout (KO) mouse model. After inducing hindlimb ischaemia, we showed that vascularization in ischaemic mice devoid of miR-106b∼25 is impaired, as evident from the reduced blood flow on laser Doppler perfusion imaging. The miR-106b∼25 cluster was also shown here to be an essential player in the proper functioning of bone marrow-derived stromal cells through its regulation of apoptosis, matrigel tube formation capacity, cytokine secretion, and expression of the stem-cell marker Sca-1. In addition, we showed that capillary sprouting from miR-106b∼25 KO aortic rings is diminished.Conclusion These results show that the miR-106b∼25 cluster regulates post-ischaemic neovascularization in mice, and that it does so in part by regulating the function of angiogenic bone marrow-derived stromal cells and of endothelial cells.
 
Clinical and baseline echocardiographic findings for the positive and the negative population SE+ (n=284) SE (n=798) P value 
Univariate predictors of cardiac death OR (95% CI) P value 
Cumulative survival rates free of any cardiac events (including cardiac death, non-fatal myocardial infarction, and revascularization procedures) in patients with negative (continuous line) and positive (broken line) stress testing result. 
Article
In this study we sought to determine the safety, feasibility and prognostic value of pharmacological stress echocardiography performed in a primary care cardiology centre, populated by unselected patients evaluated with the aid of limited financial and technological resources. The study population was 1082 patients undergoing pharmacological stress echocardiography with either dipyridamole (n=714) or dobutamine (n=368) for the evaluation of known or suspected coronary artery disease. The echocardiogram was positive in 284 (26%) patients. Two sustained ventricular tachycardias, reversible by antidote, occurred during stress testing. Limiting ischaemia-independent side effects occurred in 1.5% dipyridamole and in 2.4% dobutamine stress echocardiograms. During follow-up (33+/-18 months), 17 cardiac deaths and 27 non-fatal myocardial infarctions occurred. One hundred and twenty-seven patients underwent coronary revascularization, of whom 105 (37%) had a positive and 22 (3%) a negative stress testing result (P<0.0001). At Cox analysis, allowing for 14 clinical and stress-echo variables. the independent predictors of cardiac death were, in decreasing order, a positive stress testing result (Odds ratio [OR]=6.0), resting wall motion score index (OR=5.7), age greater than 65 years (OR=4.9), previous Q-wave myocardial infarction (OR=3.5), and hypercolesterolaemia (OR=2.7). The 4-year survival rate was 99.2% for patients with a negative and 89.8% for patients with a positive stress testing result (P=0.0000). When cardiac hard events (cardiac death and non-fatal myocardial infarction) were considered as end-points, the following variables were independently associated with prognosis: positive result of stress testing (OR=3.1), hypercolesterolaemia (OR=2.4), and resting wall motion score index (OR=2.7). The 4-year infarction-free survival rate was 97.0% for patients with a negative and 81.4% for patients with a positive stress testing result (P=0.0000). Pharmacological stress echocardiography with either dipyridamole or dobutamine was safe and feasible, providing an excellent tool for prognostic assessment of coronary artery disease in a primary care cardiology centre.
 
Description of patients and controls from the genome-wide association studies 
Description of patients and controls from the wet-lab replication phase 
Association results from Stages I to III for SNP rs7595264 located on 2p24.3 and SNP rs3739998 located on 10p11.23 
Results of association analysis of traditional risk factors with rs3739998 in a total of 3458 population-based controls from the MONICA/KORA Augsburg F3/F4 cohort 
Article
Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]. Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.
 
Histology of excised tissue of ventricular septal aneurysm of Patient IV-1. (A) Haematoxylin/eosin stain of surgical specimen at ×100 magnification. Arrows depict the thickened endocardium and arrowheads the invasion of myocardium with fibroblastic material. (B) Verhoeff Van Gieson staining for elastic fibres, ×100 magnification (blue-black). Arrows indicate the thickened endocardium and arrowheads the increase in elastic fibres and fibrotic material.
Genome-wide LOD scores of for all three linkage scenarios. X-axis: concatenated chromosomes, drawn to scale. Y-axis: parametric multipoint LOD scores. Top, middle, and bottom: linkage scenarios 1, 2, and 3, respectively. Asterisk indicates the maximal LOD score in models 1 and 2.
Haplotype pedigree of the family described. Disease haplotypes are boxed. Filled symbols indicate affected clinical status; open symbols, unaffected clinical status. Circles indicate females; squares, males; slash, deceased. III-5, IV-1, and IV-3 are recombinant for disease allele. No DNA samples were available in individuals without haplotypes. Haplotypes were inferred for Individuals I-1, I-2, I-5, I-6, II-9, and III-7 (grey symbols).
Two-dimensional echocardiography in family members recruited in addition to those included in our previous report. 10 Arrowheads depict septal thinning/aneurysm. (A) Parasternal short-axis view in Individual II-2 showing marked septal thinning at mid-septal/apical level, with slight bulging of the thinned interventricular septum into the right ventricular cavity. (B) Apical four-chamber view in Individual II-8 of a marked apical aneurysm.  
Article
Although ventricular septal defects (VSD) are the most common congenital heart lesion, familial clustering has been described only in rare instances. The aim of this study was to identify genetic factors and chromosomal regions contributing to VSD. A unique, large kindred segregating various forms of septal pathologies-including VSD, ventricular septal aneurysms, and atrial septal defects (ASD)-was ascertained and characterized clinically and genetically. Eighteen family members in three generations could be studied, out of whom 10 are affected (2 ASD, 3 septal aneurysm, 4 VSD, and 1 tetralogy of Fallot). Parametric multipoint LOD scores reach significance on chromosome 10p15.3-10p15.2 (max. 3.29). The LOD score support interval is in a gene-poor region where deletions have been reported to associate with septal defects, but that is distinct from the DiGeorge syndrome 2 region on 10p. Multiple linkage analysis scenarios suggest that tetralogy of Fallot is a phenocopy and genetically distinct from the autosomal dominant form of septal pathologies observed in this family. This study maps a rare familial form of VSD/septal aneurysms to chromosome 10p15 and extends the spectrum of the genetic heterogeneity of septal pathologies. Fine mapping, haplotype construction, and resequencing will provide a unique opportunity to study the pathogenesis of septal defects and shed light on molecular mechanisms of septal development.
 
The genomic region analysed surrounding the CXCL12 region. (A) Linkage disequilibrium in PennCath in the CXCL12 region, with arrows demarcating the region from around CXCL12 to the genome-wide association studies region. The asterisk denotes the haplotype block which contains rs1746048 and rs501120. (B) A magnified view of the haplotype block containing rs1746048 and rs501120 from the HapMap CEU population. The asterisk corresponds to the same position as the PennCath linkage disequilibrium plot, and the green arrowhead denotes rs1746048.  
Characteristics of PennCath study sample
Characteristics of PennCAC study sample
The genome-wide association studies coronary artery disease risk allele at rs1746048 is associated with higher CXCL12 transcript levels in human tissue: strongest individual probe associations 
Two published coronary artery disease single-nucleotide polymorphisms and surrounding regions, including two recombinant hotspots around CXCL12. Each single-nucleotide polymorphism is shown with linkage disequilibrium (r 2 ) and recombination rates at these loci using HapMap CEU data; vertical dashed lines demarcate a linkage disequilibrium block in which r 2 . 0.8.  
Article
Two single-nucleotide polymorphisms (SNPs), rs1746048 and rs501120, from genome wide association studies of coronary artery disease (CAD) map to chromosome 10q11 ∼80 kb downstream of chemokine CXCL12. Therefore, we examined the relationship between these two SNPs and plasma CXCL12 levels. We tested the association of two SNPs with plasma CXCL12 levels in a two-stage study (n= 2939): first in PennCath (n= 1182), a Caucasian, angiographic CAD case-control study, and second in PennCAC (n= 1757), a community-based study of CAD risk factors. Plasma CXCL12 levels increased with age and did not vary by gender. There was no linkage disequilibrium between these two SNPs and SNPs within CXCL12 gene. However, CAD risk alleles at rs1746048 (C allele, P= 0.034; CC 2.33 ± 0.49, CT 2.27 ± 0.46, and TT 2.21 ± 0.52 ng/mL) and rs501120 (T allele, P= 0.041; TT 2.34 ± 0.49, CT 2.28 ± 0.46, and CC 2.23 ± 0.53 ng/mL) were associated with higher plasma levels of CXCL12 in age and gender adjusted models. In Stage 2, we confirmed this association (rs501120, T allele, P= 0.007), and meta-analysis strengthened this finding (n= 2939, P= 6.0 × 10(-4)). Finally, in exploratory analysis, the rs1746048 risk allele tended to have higher transcript levels of CXCL12 in human natural killer cells and the liver. Coronary artery disease risk alleles downstream of CXCL12 are associated with plasma protein levels of CXCL12 and appear to be related to CXCL12 transcript levels in two human cell lines. This implicates CXCL12 as potentially causal and supports CXCL12 as a potential therapeutic target for CAD.
 
Top-cited authors
Paulus Kirchhof
  • University Heart and Vascular Center Hamburg
Juhani M Knuuti
  • Turku University Hospital
Philippe Kolh
  • University of Liège
Adam Torbicki
  • Centrum Medyczne Ksztalcenia Podyplomowego
Zeljko Reiner
  • University Hospital Centre Zagreb