Search

Background/Introduction Atrial fibrillation (AF) is a common heart rhythm disturbance, associated with an increased risk of stroke, hospital admissions and mortality, especially in patients with reduced ejection fraction. Among the oldest medications used for heart-rate control is digitalis, but largely due to observational studies showing an increased risk of death it has fallen out of favour. Recently newer clinical trials reported that the treatment with digitalis in permanent AF might be superior to beta blocker therapy in regard to functional status and symptom burden. Given this diverging results we attempt to analysis a large cohort of patients facilitating a propensity score matching algorithm. Purpose To assess the associations of digitalis treatment with mortality in patients with increased cardiovascular risk. Methods Patients were derived from a large cohort study including participants from a tertiary care centre who were referred to coronary angiography. The propensity score matching is based on a predefined list of variables, with digitalis as treatment. Matching strategy is nearest neighbour matching and to prove consistency, radius matching (radius = 0.1). For survival analysis we used a Cox proportional hazard regression comparing patients with and without digitalis for all-cause mortality. The analysis is conducted using STATA 13 MP. All patients provided written informed consent and the study was approved by the ethics committee. Results A total of 2457 patients (median age: 63.5 [IQR = 56.3–70.6] years, 30.1% women) referred to coronary angiography, with a median follow up of 9.9 (IQR = 8.5–10.7) years were included. The matching process and the resulting propensity score fulfilled all statistical assumptions and resulted in a balanced cohort. The risk for all-cause mortality was higher among propensity score matched participants not treated with digitalis compared to patients on treatment (n=514) HR 3.03 (95% CI 2.5 to 3.7). Total mortality in patients with AF on digitalis after a median follow-up of 9.9 years was 27.6%. At baseline, only 42.4% of patients with AF were on oral anticoagulation. Conclusions In the present cohort treatment with digitalis was associated with a lower risk of all-cause mortality after long-term follow-up. The patient population has a clinically significant 10-year mortality risk. The results may not apply to other cohorts but may help inform future clinical trials. Funding Acknowledgement Type of funding sources: None.

Background/Introduction The rate corrected QT time (QTc) is the most commonly used ECG derived parameter to identify and risk-stratify inherited and acquired arrhythmia risk. Among the many potentially influencing factors, the female menstrual cycle has been described to lead to minor intra-individual changes, but the overall influence of sexual hormones on the QTc is incompletely understood. We therefore aimed to elucidate this relationship in hypertensive subjects. Purpose To identify confounding factors in QTc determination and elucidate potential endocrine causes of variable QTc time. Methods The Styrian Hypertension study is a cohort study aiming to identify novel cardiovascular risk factors. Subjects were recruited from a tertiary care center outpatient clinic. QTc was calculated according to Framingham and linear regression formulas adhering to the AHA/ACCF/HRS 2009 guideline for surface ECG interpretation. Plasma concentrations of estrone (E1), estradiol (E2), 17α-Hydroxyprogesterone and progesterone were measured by Biocrates AbsoluteIDQ Stero17 Kit. Patients on QTc altering medication were excluded from the present analyses. Results A total of 142 participants (mean [SD] age, 59.4 [11.7] years; 52% women, 80,1% post-menopause) were eligible for the present analyses. Linear regression analyses adjusted for potassium, HbA1c, NTproBNP and mean systolic blood pressure revealed only an association of QTc with progesterone (beta coefficient [95% CI]) of 0.38 [0.14 – 0.62] (P=0.002) in males. Detailed analyses revealed an U-shaped association. The other hormones showed no significant association in the present cohort of patients. Subgroups of premenopausal women and of patients without elevated blood pressure revealed no statistically significant results. Conclusions Contrary to previous evidence we found no sign. association between female sexual hormones and QTc time. We observed increased QTc time in males depending on their progesterone plasma concentrations, but the isolated finding may be a statistical outlier. Funding Acknowledgement Type of funding sources: None.

Introduction and aim Vitamin D deficiency is associated with an adverse prognosis in patients with coronary artery disease (CAD). Decreased levels of vitamin D are associated with low sunshine exposure, resulting in seasonal variations of vitamin D. The aims of this study were to investigate the influence of different specific weather conditions on vitamin D levels and to explore a possible improvement of risk stratification by vitamin D levels in stable patients with CAD using meteorological data. Methods The study population consists of two independent cohorts of stable patients undergoing coronary angiography with suspected or known CAD: as derivation cohort, the ongoing biomarker registry BioPROSPECTIVE with n=1,766 enrolled patients between 2010 and 2013 (median age 70.1 yrs; 30.8% females); and as validation cohort, the Ludwigshafen Risk and Cardiovascular Health (LURIC) Study with n=3,299 patients (median age 63.5 yrs; 30.3% females). In the derivation cohort 235 (13.3%) patients were known to be deceased by 08/2018. In the validation cohort 760 (23.0%) patients died within a median follow-up time of 7.75 years. 25-OH vitamin D levels were measured by commercial assays. Vitamin D deficiency was defined as 25-OH vitamin D levels ≤20 ng/mL. Daily averaged data on six weather conditions of the 180 days prior to enrolment were collected for each patient from the weather station located closest to the respective study centre. Using air pressure, precipitation height, sunshine duration, temperature, relative humidity, and vapour pressure a weather model was constructed that significantly correlated with vitamin D levels (r=0.37; p Results In the derivation cohort, median vitamin D levels were lower in non-survivors (13.3 [9.65–19.65] ng/mL) than in survivors (15.70 [10.7–22.65] ng/mL; p Conclusions Different weather conditions show a significant impact on vitamin D levels in stable patients. Adding data on weather conditions improve the risk stratification by vitamin D for predicting mortality in stable CAD patients. Acknowledgement/Funding The study is financially supported by the Kerckhoff Heart Research Institute (KHFI) and the German Center for Cardiovascular Research (DZHK).

Aims: Both elevated inflammatory activity and sustained tachycardia reflect unfavourable cardiovascular risk profiles, and there is evidence to suggest the deleterious effects of inflammation are amplified by increased heart rate. The purpose of this study was to assess the interaction between resting heart rate and inflammation in cardiovascular mortality.Methods and results: A total of 3267 patients (2283 men), aged 18-95 years, scheduled for coronary angiography, were followed prospectively. By principle component analysis, we developed an overall multi-marker index of inflammation weighting the respective coefficients of five inflammatory markers including: interleukin-6, C-reactive protein, serum amyloid A, neutrophils, and fibrinogen. Cox proportional hazard regression models were employed to evaluate the relationship between inflammation and heart rate with cardiovascular mortality. Across 29 940 person years of follow-up, there were 546 (17%) deaths due to cardiovascular disease (CVD). Significantly, we observed a strong synergistic effect of inflammatory activity and concurrent elevated heart rate. For CVD mortality, patients in the highest quartile of inflammation had an adjusted hazard ratio (95% confidence interval) of 1.84 (1.31-2.57), P < 0.0001 if their resting heart rate was Conclusion: The present analyses underline elevated inflammation as a risk factor for cardiovascular mortality. The effects of inflammation appeared to be strongly amplified by a faster resting heart rate. If confirmed by additional studies, this association may prove a useful adjunct for therapeutic approaches to alleviate symptoms and prolong survival.

Aims Cardiac remodelling might be an important mechanism for aldosterone-mediated cardiovascular (CV) morbidity and mortality. Previous studies relating aldosterone to left ventricular (LV) structure however revealed conflicting results. Methods and results We aimed to evaluate the relationship of serum aldosterone concentration (SAC) and aldosterone-to-renin ratio (ARR) with echocardiographic parameters of LV remodelling in CV risk patients with preserved left ventricular ejection fraction (LVEF). We studied 1575 participants (54.1% female) with CV risk factors and LVEF >50% (61.7 ± 6.1%). Of the total, 94.7% of patients had no overt heart failure. All patients underwent measurement of SAC, ARR, and comprehensive echocardiographic analysis. Overall, multivariate adjusted analysis of covariance (ANCOVA) showed a significant increase in LV mass ( P = 0.001), LV mass index ( P = 0.001), relative wall thickness ( P = 0.011), and LV posterior wall thickness ( P < 0.001) with increasing SAC. This overall association of SAC and LV remodelling was driven by a statistic significant effect exclusively in women. In multivariate logistic regression analysis higher SAC levels were independently related to concentric LV hypertrophy [odds ratio (OR; with 95% CI) by comparing SAC levels in the third gender-specific tertile with the first tertile: 1.87; 95% CI: 1.31–2.68; P = 0.001]. Higher SAC levels were positively related to concentric LVH in either sex. We observed no significant associations between the ARR and echocardiographic parameters of LV remodelling. Conclusion Circulating aldosterone but not ARR levels are independently related to echocardiographic parameters of LV structure, particularly in women. Higher SAC however was related to concentric LVH in either sex. Our findings in a large CV risk cohort with preserved LVEF indicate aldosterone-mediated pro-hypertrophic effects as a potential pathway for structural alterations of the left ventricular myocardium.

Aims Dialysis patients experience an excess mortality, predominantly of sudden cardiac death (SCD). Accumulating evidence suggests a role of vitamin D for myocardial and overall health. This study investigated the impact of vitamin D status on cardiovascular outcomes and fatal infections in haemodialysis patients. Methods and results 25-hydroxyvitamin D [25(OH)D] was measured in 1108 diabetic haemodialysis patients who participated in the German Diabetes and Dialysis Study and were followed up for a median of 4 years. By Cox regression analyses, we determined hazard ratios (HR) for pre-specified, adjudicated endpoints according to baseline 25(OH)D levels: SCD ( n = 146), myocardial infarction (MI, n = 174), stroke ( n = 89), cardiovascular events (CVE, n = 414), death due to heart failure ( n = 37), fatal infection ( n = 111), and all-cause mortality ( n = 545). Patients had a mean age of 66 ± 8 years (54% male) and median 25(OH)D of 39 nmol/L (interquartile range: 28–55). Patients with severe vitamin D deficiency [25(OH)D of≤ 25 nmol/L] had a 3-fold higher risk of SCD compared with those with sufficient 25(OH)D levels >75 nmol/L [HR: 2.99, 95% confidence interval (CI): 1.39–6.40]. Furthermore, CVE and all-cause mortality were strongly increased (HR: 1.78, 95% CI: 1.18–2.69, and HR: 1.74, 95% CI: 1.22–2.47, respectively), all persisting in multivariate models. There were borderline non-significant associations with stroke and fatal infection while MI and deaths due to heart failure were not meaningfully affected. Conclusion Severe vitamin D deficiency was strongly associated with SCD, CVE, and mortality, and there were borderline associations with stroke and fatal infection. Whether vitamin D supplementation decreases adverse outcomes requires further evaluation.

Aims Sudden cardiac death (SCD) is the most common fatal cardiovascular event. Free fatty acids (FFAs) exert several harmful effects on the myocardium and may therefore contribute to SCD. We examined whether fasting FFA predict SCD in patients who had undergone coronary angiography. Methods and results FFAs were measured at baseline (1997–2000) in 3315 patients scheduled for coronary angiography. Angiographic coronary artery disease was found in 2231 study participants. After a median time of follow-up of 6.85 years, 165 SCD occurred in the entire study population. In a Cox proportional hazards model, the unadjusted hazard ratio (HR) for SCD in the fourth when compared with the first FFA quartile was 2.95 (95% CI 1.84–4.73; P < 0.001). After adjustment for common and emerging cardiovascular risk factors, the HR remained significant at 1.76 (1.03–3.00; P = 0.038). High FFA levels were also significantly associated with all-cause and cardiovascular mortality, even after exclusion of patients with SCD. Conclusion Our study shows that elevated plasma FFAs are an independent risk factor for future SCD in patients referred to coronary angiography. These results may suggest that modulation of myocardial fatty acid uptake and/or metabolism are a possible target of treatment, but it still remains to be clarified whether high FFA levels are a cause or a consequence of pathological processes that underlie the association between FFA and SCD.

Aims The genetic polymorphism of apolipoprotein E ( APOE ) has been suggested to modify the effect of smoking on the development of coronary artery disease (CAD) in apparently healthy persons. The interaction of these factors in persons undergoing coronary angiography is not known. Methods and results We analysed the association between the APOE-genotype , smoking, angiographic CAD, and mortality in 3263 participants of the LUdwigshafen RIsk and Cardiovascular Health study. APOE-genotype s were associated with CAD [ɛ22 or ɛ23: odds ratio (OR) 0.56, 95% confidence interval (CI) 0.43–0.71; ɛ24 or ɛ34 or ɛ44: OR 1.10, 95% CI 0.89–1.37 compared with ɛ33] and moderately with cardiovascular mortality [ɛ22 or ɛ23: hazard ratio (HR) 0.71, 95% CI 0.51–0.99; ɛ33: HR 0.92, 95% CI 0.75–1.14 compared with ɛ24 or ɛ34 or ɛ44]. HRs for total mortality were 1.39 (95% CI 0.39–0.1.67), 2.29 (95% CI 1.85–2.83), 2.07 (95% CI 1.64–2.62), and 2.95 (95% CI 2.10–4.17) in ex-smokers, current smokers, current smokers without, or current smokers with one ɛ4 allele, respectively, compared with never-smokers. Carrying ɛ4 increased mortality in current, but not in ex-smokers (HR 1.66, 95% CI 1.04–2.64 for interaction). These findings applied to cardiovascular mortality, were robust against adjustment for cardiovascular risk factors, and consistent across subgroups. No interaction of smoking and ɛ4 was seen regarding non-cardiovascular mortality. Smokers with ɛ4 had reduced average low-density lipoprotein (LDL) diameters, elevated oxidized LDL, and lipoprotein-associated phospholipase A2. Conclusion In persons undergoing coronary angiography, there is a significant interaction between APOE-genotype and smoking. The presence of the ɛ4 allele in current smokers increases cardiovascular and all-cause mortality. The original version of this article was incorrect. In the present version of the sentence ‘Smokers with ɛ4...’, the phrase ‘elevated average low-density lipoprotein’ has been replaced with ‘reduced average low-density lipoprotein (LDL)’, and the word ‘elevated’ has been added to ‘oxidized LDL’.

Aims Previous risk assessment scores for patients with coronary artery disease (CAD) have focused on primary prevention and patients with acute coronary syndrome. However, especially in stable CAD patients improved long-term risk prediction is crucial to efficiently apply measures of secondary prevention. We aimed to create a clinically applicable mortality prediction score for stable CAD patients based on routinely determined laboratory biomarkers and clinical determinants of secondary prevention. Methods and results We prospectively included 547 patients with stable CAD and a median follow-up of 11.3 years. Independent risk factors were selected using bootstrapping based on Cox regression analysis. Age, left ventricular function, serum cholinesterase, creatinine, heart rate, and HbA1c were selected as significant mortality predictors for the final multivariable model. The Vienna and Ludwigshafen Coronary Artery Disease (VILCAD) risk score based on the aforementioned variables demonstrated an excellent discriminatory power for 10-year survival with a C-statistic of 0.77 ( P < 0.001), which was significantly better than an established risk score based on conventional cardiovascular risk factors (C-statistic = 0.61, P < 0.001). Net reclassification confirmed a significant improvement in individual risk prediction by 34.8% (95% confidence interval: 21.7–48.0%) compared with the conventional risk score ( P < 0.001). External validation of the risk score in 1275 participants of the Ludwigshafen Risk and Cardiovascular Health study (median follow-up of 9.8 years) achieved similar results (C-statistic = 0.73, P < 0.001). Conclusion The VILCAD score based on a routinely available set of risk factors, measures of cardiac function, and comorbidities outperforms established risk prediction algorithms and might improve the identification of high-risk patients for a more intensive treatment.

Aims Elevated parathyroid hormone (PTH) levels have been associated with increased cardiovascular risk in the general population. We aimed to elucidate whether PTH levels are associated with mortality and fatal cardiovascular events in patients referred for coronary angiography. Methods and results Intact PTH was measured in 3232 Caucasian patients from the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study, who underwent coronary angiography at baseline (1997–2000). During a median follow-up time of 7.7 years, 742 patients died including 467 deaths due to cardiovascular causes. Unadjusted Cox proportional hazard ratios (HRs) (with 95% confidence intervals) in the fourth when compared to the first PTH quartile were 2.13 (1.75–2.60) for all-cause and 2.47 (1.92–3.17) for cardiovascular mortality. After adjustments for common cardiovascular risk factors, these HRs remained significant with 1.71 (1.39–2.10) for all-cause and 2.02 (1.55–2.63) for cardiovascular mortality. Among specific cardiovascular events we observed a particularly strong association of PTH with sudden cardiac death (SCD). The adjusted HR for SCD in the first vs. the fourth PTH quartile was 2.68 (1.71–4.22). Conclusion Our results among patients undergoing coronary angiography show that PTH levels are an independent risk factor for mortality and cardiovascular events warranting further studies to evaluate whether PTH modifying treatments reduce cardiovascular risk.

Aims Evidence has accumulated that elevated aldosterone levels are associated with increased risks of fatal cardiovascular (CV) events. With the present analysis, we aimed at evaluating prospectively whether plasma aldosterone correlates with all-cause and CV disease (CVD) mortality in a large cohort of patients. Methods and results Median plasma aldosterone concentration (PAC) was 79.0 (48.0–124.0) pg/mL (normal range: 30–160) in 3153 patients [median age: 63.5 (56.3–70.6) years; 30.1% women] who had undergone coronary angiography. After a median follow-up of 7.7 (7.2–8.5) years, a total of 716 participants died [22.7%; 454 (14.4%) due to CV causes and 262 (8.3%) due to non-CV causes]. In multivariable Cox proportional hazard analysis, adjusted for age, gender, antihypertensive treatment, and established CV risk factors, PAC levels stratified in quartiles were significantly associated with all-cause and CVD mortality. Compared with the reference (first) PAC quartile, hazard ratios (confidence interval 95%) for the fourth, third, and second PAC quartiles were 1.30 (1.02–1.65, P = 0.033), 1.32 (1.04–1.68, P = 0.021), and 1.20 (0.93–1.54, P = 0.155) for total mortality and 1.58 (1.15–2.16, P = 0.004), 1.39 (1.01–1.90, P = 0.041), and 1.63 (1.20–2.20, P = 0.002) for CVD mortality, respectively. Analyses for specific causes of CV death revealed strong associations between PAC levels and higher risk for fatal stroke and sudden cardiac death. Conclusion In a large cohort of patients scheduled for coronary angiography, variation in PAC levels within the normal range is associated with increased all-cause and CVD mortality independent of major established CV risk factors.

Purpose: The aldosterone to renin ratio (ARR) is a screening tool for primary aldosteronism (PA). Accumulating evidence suggests that ARR may be significantly associated with blood pressure (BP) even below the threshold for PA. We therefore aimed to evaluate the relationship between the ARR and 24 hour ambulatory BP monitoring measurements (ABPM). Methods: We recruited essential hypertensive patients derived from the outpatient clinic at the department of internal medicine of the local medical university hospital. ABPM measurements were obtained every 15min during the day (06:00-24:00 o'clock) and every 30 min during the night (00:00–06:00). Plasma aldosterone and plasma renin concentrations were measured by means of a RadioImmunoAssay (RIA). Results: We examined 172 hypertensive patients (age: 59.6±11.3years; 51.2% females) with a mean systolic/diastolic 24-hour ABPM value of 129/77mmHg. In linear regression analyses adjusted for age, sex, 24-hour urinary sodium and body mass index, ARR was significantly associated with night-time systolic (beta coefficient:0.19; p=0.017) and diastolic ABPM (beta coefficient:0.28; p