Impact of Systemic Atherosclerosis on Clinical Characteristics and Short-Term Outcomes in Patients with Deep Venous Thrombosis or Thrombophlebitis.

BACKGROUND: Venous thromboembolism (VTE) and atherosclerosis are accompanied by substantial cardiovascular mortality; links between both disease entities were reported. We aimed to investigate the impact of systemic atherosclerosis on adverse outcomes in patients with deep venous thrombosis or thrombophlebitis (DVT) and to identify differences in DVT patients with and without systemic atherosclerosis. METHODS: The German nationwide inpatient sample was used for this analysis. Patients admitted for DVT were included in this study and stratified by systemic atherosclerosis (composite of coronary artery disease, myocardial infarction, ischemic stroke, and/or atherosclerotic arterial diseases). We compared DVT patients with (DVT+Athero) and without (DVT-Athero) systemic atherosclerosis and analysed the impact of systemic atherosclerosis on adverse outcomes. RESULTS: Overall, 489,679 patients with DVT (55.7% females) were included in this analysis. Among these, 53,309 (10.9%) were coded with concomitant systemic atherosclerosis with age-dependent incline. Concomitant PE (4.1% vs.3.8%, P=0.001) was more frequently in DVT-Athero and risk for PE in DVT patients was independently associated with absence of systemic atherosclerosis (OR 0.87 [95%CI 0.83-0.91], P<0.001). In-hospital mortality (3.4% vs.1.4%, P<0.001) and adverse in-hospital events (2.2% vs.0.8%, P<0.001) were more prevalent in DVT+Athero compared to DVT-Athero; both, in-hospital mortality (OR 1.52 [95%CI 1.41-1.63], P<0.001) and adverse in-hospital events (OR 1.49 [95%CI 1.40-1.58], P<0.001) were affected independently of sex, age and comorbidities by systemic atherosclerosis. CONCLUSIONS: Systemic atherosclerosis in DVT patients was accompanied by poorer outcomes. Systemic atherosclerosis was associated with higher bleeding rate and with isolated DVT (without concomitant PE).

The impact of aircraft noise on vascular and cardiac function in relation to noise event number: a randomized trial.

AIMS: Nighttime aircraft noise exposure has been associated with increased risk of hypertension and myocardial infarction, mechanistically linked to sleep disturbance, stress, and endothelial dysfunction. It is unclear, whether the most widely used metric to determine noise exposure, equivalent continuous sound level (Leq), is an adequate indicator of the cardiovascular impact induced by different noise patterns. METHODS AND RESULTS: In a randomized crossover study, we exposed 70 individuals with established cardiovascular disease or increased cardiovascular risk to two aircraft noise scenarios and one control scenario. Polygraphic recordings, echocardiography, and flow-mediated dilation (FMD) were determined for three study nights. The noise patterns consisted of 60 (Noise60) and 120 (Noise120) noise events, respectively, but with comparable Leq, corresponding to a mean value of 45 dB. Mean value of noise during control nights was 37 dB. During the control night, FMD was 10.02 ± 3.75%, compared to 7.27 ± 3.21% for Noise60 nights and 7.21 ± 3.58% for Noise120 nights (P < 0.001). Sleep quality was impaired after noise exposure in both noise scenario nights (P < 0.001). Serial echocardiographic assessment demonstrated an increase in the E/E' ratio, a measure of diastolic function, within the three exposure nights, with a ratio of 6.83 ± 2.26 for the control night, 7.21 ± 2.33 for Noise60 and 7.83 ± 3.07 for Noise120 (P = 0.043). CONCLUSIONS: Nighttime exposure to aircraft noise with similar Leq, but different number of noise events, results in a comparable worsening of vascular function. Adverse effects of nighttime aircraft noise exposure on cardiac function (diastolic dysfunction) seemed stronger the higher number of noise events.

Impact of pulmonary embolism on in-hospital mortality of patients with ischemic stroke.

BACKGROUND: Pulmonary embolism (PE) is a frequent complication in immobile stroke patients and an important cause of death in stroke patients. We aimed to investigate predictors of PE and the impact of PE on survival of ischemic stroke patients. METHODS: Patients were selected by screening the German nationwide inpatient sample (2005-2017) for ischemic stroke (ICD-code I63) and stratified for occurrence of PE (ICD-code I26). Impact of PE on mortality and predictors for PE in ischemic stroke patients were analysed. RESULTS: Overall, 2,914,546 patients were hospitalized due to ischemic stroke (50.5% females; 69.3% aged ≥70 years) in Germany 2005-2017. Among these, 0.4% had PE and 7.2% died during hospitalization. In-hospital mortality rate of ischemic stroke patients with PE was substantially higher compared to those patients without PE (28.4% vs. 7.1%, P < 0.001). PE was strongly associated with in-hospital death (OR 5.786, 95%CI 5.515-6.070, P < 0.001). Important predictors of PE were cancer (OR 3.165, 95%CI 2.969-3.374, P < 0.001), coagulation abnormalities (OR 2.672, 95CI 2.481-2.878, P < 0.001), heart failure (OR 1.553, 95%CI 1.472-1.639, P < 0.001) and obesity (OR 1.559, 95%CI 1.453-1.672, P < 0.001). Systemic thrombolysis was not beneficial regarding survival in unselected ischemic stroke patients. In contrast, systemic thrombolysis was beneficial in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation (OR 0.866, 95%CI 0.782-0.960, P = 0.006). CONCLUSIONS: Patients with ischemic stroke revealed still a high in-hospital mortality of 7.2% in Germany. While only a minority of 0.4% of the ischemic stroke patients suffered from occurrence of PE, PE was accompanied by a substantial increase regarding in-hospital mortality. Systemic thrombolysis was beneficial regarding short-term survival in ischemic stroke patients without PE, who had to undergo cardio-pulmonary resuscitation.

Sex-specific differences regarding seasonal variations of incidence and mortality in patients with myocardial infarction in Germany.

BACKGROUND: Seasonal variation regarding the incidence and the short-term mortality of acute myocardial infarction (MI) was frequently reported, but data about sex-specific differences are sparse. METHODS: We analysed the impact of seasons and temperature on incidence and in-hospital mortality of patients with acute MI in Germany between 2005 and 2015. RESULTS: The nationwide sample comprised 3,008,188 hospitalizations of MI patients (2005-2015). The incidence was 334.7/100,000 citizens/year. Incidence inclined from 316.3 to 341.6/100,000 citizens/year (ß 0.17 [0.10 to 0.24], P < 0.001), while in-hospital mortality rate decreased from 14.1% to 11.3% (ß -0.29 [-0.30 to -0.28], P < 0.001). Overall, 377,028 (12.5%) patients died in-hospital. Seasonal variation of both incidence and in-hospital mortality was of substantial magnitude. Seasonal incidence (86.1 vs. 79.0/100,000 citizens/year, P < 0.001) and in-hospital mortality (13.2% vs. 12.1%, P < 0.001) were higher in winter than in summer. Risk to die in winter was elevated (OR 1.080 (95% CI 1.069-1.091), P < 0.001) compared to summer season independently of sex, age and comorbidities. Reperfusion treatment with drug eluting stents and coronary artery bypass graft were more often used in summer. We observed sex-specific differences regarding the seasonal variation of in-hospital mortality: males showed lowest mortality in summer, while females during fall. Low temperature dependency of mortality seems more pronounced in males. CONCLUSION: Incidence of acute MI increased 2005-2015, while in-hospital mortality rate decreased. Seasonal variation of incidence and in-hospital mortality were of substantial magnitude with lowest incidence and lowest mortality in the summer season. Additionally, we observed sex-specific differences regarding the seasonal variation of the in-hospital mortality.

Syncope in the German Nationwide inpatient sample - Syncope in atrial fibrillation/flutter is related to pulmonary embolism and is accompanied by higher in-hospital mortality.

AIMS: Syncope is a common phenomenon in the general population. Although most of the causes are of benign origin, some comorbidities are accompanied by high mortality. We aimed to compare the in-hospital mortality of patients with syncope related to different comorbities and investigate the impact of syncope in patients with atrial fibrillation/flutter (AF). METHODS: The nationwide inpatient sample of Germany of the years 2011-2014 was used for this analysis. Patients with syncope (ICD-code R55) were stratified by presence of selected comorbidities. Additionally, AF patients with and without syncope were compared. Incidence of syncope and in-hospital mortality were calculated. Syncope as a predictor of adverse outcome in AF patients was investigated. RESULTS: In total, 1,628,859 hospitalizations of patients with syncope were identified; incidence was 504.6/100,000 citizens/year with case-fatality rate of 1.6%. Patients with syncope revealed frequently comorbidities as AF, heart failure and pneumonia. In-hospital mortality was high in syncope patients with pulmonary embolism (PE, 13.0%), pneumonia (12.8%), myocardial infarction (MI, 9.7%) and stroke (8.5%). We analysed 1,106,019 hospitalizations (52.9% females, 54.9% aged > 70 years) of patients with AF (2011-2014). Among these, 23,694 (2.1%) were coded with syncope and 0.7% died. Syncope had no significant impact on in-hospital mortality (OR 1.04, 95%CI 0.92-1.17, P = .503) independently of age, sex and comorbidities, but was associated with PE (OR 1.83, 95%CI 1.42-2.36, P < .001), MI (OR 1.68, 95%CI 1.48-1.90, P < .001), stroke (OR 1.66, 95%CI 1.42-1.94, P < .001) and pneumonia (OR 1.26, 95%CI 1.16-1.37, P < .001). CONCLUSIONS: Syncope is a frequent cause for referrals in hospitals. While the overall in-hospital mortality rate is low (<2%), syncope in coprevalence with PE, pneumonia, MI and stroke showed a mortality rate > 8%. Syncope in AF patients had no independent impact on in-hospital mortality.

Impact of chronic obstructive pulmonary disease on the outcomes of patients with peripheral artery disease.

BACKGROUND: Peripheral artery disease (PAD) and chronic obstructive pulmonary disease (COPD) are both related with high in-hospital mortality. We aimed to investigate the impact of COPD on the in-hospital outcomes in PAD. METHODS: PAD patients were selected based on ICD-code I70.2 of the German nationwide database, stratified for COPD and compared regarding adverse in-hospital outcomes. RESULTS: Between 01/2005-12/2015, 5,611,827 inpatients (64.8% males) were diagnosed with PAD; of those, 13.6% were coded additionally with COPD. Overall, 277,894 PAD patients (5.0%) died during in-hospital course. Prevalence of cardiovascular diseases as well as cancer (12.1% vs. 7.0%, P < 0.001) was higher in PAD patients with COPD compared to PAD patients without COPD. PAD patients with COPD showed more often lower PAD stages according to Fontaine classification (PAD stage I: 27.1% vs. 19.3%, P < 0.001; PAD stage IIa: 34.9% vs. 35.5%, P < 0.001; PAD stage IIb: 14.5% vs. 13.6%, P < 0.001; PAD stage III: 11.8% vs. 14.8%, P < 0.001; PAD stage IV: 13.8% vs. 19.6%, P < 0.001). The all-cause in-hospital mortality was significantly higher in PAD patients with COPD compared to those without COPD (6.5% vs. 4.7%, P < 0.001). Cardiovascular events comprising pulmonary embolism and myocardial infarction occurred more often in coprevalence with PAD and COPD. COPD was an independent predictor of in-hospital death (OR 1.16 (95%CI 1.15-1.17) P < 0.001) and an independent predictor for pulmonary embolism (PE, OR 1.44 (1.40-1.49), P < 0.001) in PAD patients. CONCLUSION: COPD was associated with a high in-hospital mortality in PAD patients probably driven by higher frequencies of PE and cancer.

Impact of atrial fibrillation on in-hospital mortality of ischemic stroke patients and identification of promoting factors of atrial thrombi - Results from the German nationwide inpatient sample and a single-center retrospective cohort.

Ischemic stroke is one of the leading causes of death and disability. Atrial fibrillation (AF) is a well-recognized risk factor for ischemic stroke.We aimed to investigate the impact of AF on in-hospital mortality of ischemic stroke patients and to identify parameters associated with intra-cardiac thrombogenic material.Patients were selected by screening the nationwide sample for ischemic stroke by ICD-Code (I63), stratified for AF. In this cohort, the association between in-hospital deaths and AF was investigated.In a second study, we performed a retrospective analysis of patients who underwent transesophageal echocardiography (TEE) for various reasons, assigned these to 2 groups based on the heart-rhythm (sinus-rhythm [SR] vs AF) and examined associations between clinical and echocardiographic parameters and intra-cardiac thrombogenic material.The Nationwide sample comprised 292,401 inpatients (48.5% females) with ischemic stroke. Incidence was 360 per 100,000 citizens, with an age-dependent increase. In-hospital mortality rate was 8.2%; AF patients had 1.85-fold higher mortality rate (12.1% vs 6.5%).In the retrospective study, 219 patients (median age 67 [59.1-77.3] years, 39.3% females) were included: 115 patients with AF (median age 71 [59.0-78.0] years, 41.7% females) and 104 patients (median age 68 [56.3-76.8] years, 36.5% females) with SR. Solid thrombus or spontaneous-echo-contrast) was detected in 16 TEEs. Atrial dimensions were significantly enlarged in AF patients. Age, blood-flow velocity in LAA, LAA diameters, atrial areas, AF, and CHA2DS2-VASc-score were associated with thrombogenic material.Incidence of ischemic stroke increased with age. AF was connected with higher stroke mortality. Presence of intra-cardiac thrombogenic material was associated with AF and most CHA2DS2-VASc-score factors. AF was associated with larger atrial dimensions and larger cavities favored thrombogenic material.

Obesity paradox in peripheral artery disease.

BACKGROUND & AIMS: Previous studies have suggested an obesity survival paradox in patients with peripheral artery disease (PAD). We investigated the influence of obesity and underweight on adverse in-hospital outcomes in PAD. METHODS: Patients diagnosed with PAD based on ICD-code I70.2 of the German nationwide database were stratified for obesity, underweight and a reference group with normal-weight/over-weight and compared regarding adverse in-hospital outcomes. RESULTS: Between 01/2005-12/2015, 5,611,484 inpatients (64.8% males) were diagnosed with PAD; of those, 8.9% were coded with obesity and 0.3% with underweight. Obese patients were younger (70 (IQR 63/76) vs. 73 (66/80) years, P < 0.001), more frequently female (36.7% vs. 35.1%, P < 0.001), had less cancer (4.9% vs. 7.9%, P < 0.001) and had less treatment with major amputation (2.6% vs. 3.2%, P < 0.001) compared to the reference group. Overall, 277 876 (5.0%) patients died in-hospital. Obese patients showed lower mortality rate (3.2% vs. 5.1%, P < 0.001) compared to the reference group and reduced risk of in-hospital mortality (OR, 0.617 [95%CI 0.607-0.627], P < 0.001). This "obesity paradox" was demonstrated in obesity classes I (OR, 0.475 [95%CI 0.461-0.490], P < 0.001), II (OR, 0.580 [95%CI 0.557-0.605], P < 0.001), and III (OR, 0.895 [95%CI 0.857-0.934], P < 0.001) and was independent of age, sex and comorbidities. Underweight patients revealed higher in-hospital mortality (6.0% vs. 5.1%, P < 0.001) compared to the reference group (OR, 1.179 [95%CI 1.106-1.257], P < 0.001) and showed higher prevalence of cancer (22.0% vs. 7.9%, P < 0.001). CONCLUSIONS: Coding for obesity is associated with lower in-hospital mortality in PAD patients relative to those with normal-weight/over-weight. This obesity survival paradox was independent of age, gender and comorbidities and observed for all obesity classes.

Impact of symptomatic atherosclerosis in patients with pulmonary embolism.

BACKGROUND: Atherosclerosis is associated with increased cardiovascular mortality. Associations between venous thromboembolism and atherosclerosis were recently reported. We aimed to investigate the impact of symptomatic atherosclerosis on adverse outcomes in patients with pulmonary embolism (PE) and to identify significant differences among patients with PE stratified by symptomatic atherosclerosis. METHODS: Patients were selected by screening the nationwide inpatients sample for PE (ICD-code I26) stratified by symptomatic atherosclerosis (composite of coronary artery disease [ICD-code I25], myocardial infarction [ICD-code I21], ischemic stroke [ICD-code I63], and/or atherosclerotic arterial diseases [ICD-code I70]). We compared PE patients with (PE + Athero) and without (PE - Athero) symptomatic atherosclerosis and analysed the impact of symptomatic atherosclerosis on adverse outcomes. RESULTS: Overall, 213,995 patients with PE (54.2% females) were included in this analysis. Of these, 30,157 (14.1%) had symptomatic atherosclerosis with age-dependent incline. Deep vein thrombosis or thrombophlebitis (45.1% vs. 36.9%, P < 0.001) was more commonly observed in the PE - Athero group (Odds Ratio (OR) 0.713 [95% CI 0.695-0.731], P < 0.001). In-hospital mortality (12.1% vs. 9.6%, P < 0.001) and adverse in-hospital events (16.8% vs. 12.6%, P < 0.001) were affected by symptomatic atherosclerosis; both in-hospital mortality (OR 1.107 [95% CI 1.061-1.155], P < 0.001) and adverse in-hospital outcomes (OR 1.143 [95%CI 1.102-1.186], P < 0.001) were affected independently of age, gender, comorbidities, and reperfusion treatments. CONCLUSIONS: Symptomatic atherosclerosis in patients with PE increased with age and was associated with a poorer outcome. Cardiovascular-atherosclerotic diseases might play a major role in thrombus formation in isolated PE.

Syncope in haemodynamically stable and unstable patients with acute pulmonary embolism - Results of the German nationwide inpatient sample.

Syncope in pulmonary embolism (PE) could be the first sign of haemodynamic compromise. We aimed to investigate pathomechanisms of syncope and its impact on mortality. For this study, patients (aged ≥ 18years) were selected by screening the German nationwide inpatient sample for PE and stratified included patients by syncope (2011-2014). We analysed predictors of syncope in haemodynamically stable PE. Impact of syncope on in-hospital mortality in haemodynamically stable and unstable PE and benefit of systemic thrombolysis in haemodynamically stable PE with syncope (PE + Syncope) were analyzed. The German nationwide inpatient sample comprised 293,640 (84.9%) haemodynamically stable and 52,249 (15.1%) unstable PE patients; among them 2.3% had syncope. Right ventricular dysfunction (RVD) was a key predictor for syncope. In-hospital mortality-rate was lower in haemodynamically stable (6.4% vs. 7.6%, P < 0.001) and unstable PE + Syncope than in PE-Syncope (48.4% vs. 55.5%, P < 0.001) with reduced risk for in-hospital death in stable (OR 0.68 (95%CI 0.61-0.75), P < 0.001) and unstable (OR 0.69 (95% CI 0.62-0.78), P < 0.001) inpatients independent of age and sex. Haemodynamically stable PE + Syncope patients were more often treated with systemic thrombolysis (3.1% vs. 2.1%, P < 0.001). Systemic thrombolysis was associated with reduced in-hospital mortality in haemodynamically stable PE + Syncope (1.9% vs. 6.6%, P = 0.004) independently of age, RVD and tachycardia (OR 0.30 (95%CI 0.11-0.82), P = 0.019). In conclusion, in-hospital mortality was 6.4% in haemodynamically stable PE + Syncope. Haemodynamically stable PE + Syncope patients were more often treated with systemic thrombolysis and showed a trend to improved survial.

Interferon- and ribavirin-free therapy with new direct acting antivirals (DAA) for chronic hepatitis C improves vascular endothelial function.

INTRODUCTION: Chronic Hepatitis C virus infection (HCV) is associated with extrahepatic manifestations and an increased prevalence in cardiovascular disease. New direct acting antivirals (DAA) have revolutionized HCV treatment with high rates of sustained virological response (SVR). Recently it was demonstrated, that SVR reduces morbidity and overall mortality more than can be solely explained by hepatic effects, suggesting that treatment with DAA also affects cardiovascular disease. The aim of this pilot study was to identify possible underlying mechanisms behind the HCV-associated cardiovascular mortality reported by others. METHODS AND RESULTS: 20 HCV patients (10 genotype GT1, 10 GT3) were treated with interferon (IFN)- and ribavirin (RBV)-free DAA regimens for 12 weeks (SVR12). Primary endpoint was an improvement in endothelial function (flow-mediated dilation, FMD) at SVR12 compared to baseline. Patient demographics, FMD, markers for endothelial function and inflammation, coagulation and oxidative stress were measured at baseline, end of treatment and SVR12. All patients achieved SVR12. There was a significant increase in FMD from 9.4 ±â€¯5.2% at baseline to 11.9 ±â€¯4.5% at SVR12 (p = 0.04). Concomitantly, there were significant reductions in levels of endothelium-derived adhesion molecules E-selectin, VCAM-1 and ICAM-1. While APRI values were also significantly lower, liver stiffness did not change significantly. There were no relevant changes in systemic inflammation, oxidative stress, insulin resistance or coagulation pathways. CONCLUSIONS: Successful DAA therapy was associated with improvements in endothelial function and a reduction of soluble adhesion molecules. Our findings indicate that HCV infection affects the endothelium and that DAA-treatment reverses these effects and enhances endothelial function.

Sex-specific differences in mortality and the obesity paradox of patients with myocardial infarction ages >70 y.

OBJECTIVES: Recent studies suggest an obesity survival paradox in patients with acute myocardial infarction (MI). The aim of this study was to investigate the in-hospital mortality of patients aged ≥70 y with acute MI relative to sex and obesity. METHODS: We selected patients ≥70 y of age with a diagnosis of acute MI based on the International Classification of Diseases (ICD) code I21 in the nationwide database of the Federal Statistical Office of Germany in 2014. We stratified the patients for sex and obesity versus nonobesity, and obesity classes I, II, and III. We compared the in-hospital mortality of these groups. RESULTS: In 2014, 122 607 patients ≥70 y of age were diagnosed with acute MI in Germany. Among these inpatients 14 342 (11.7%) died during their in-hospital stay. The calculated incidence was 938.46 per 100 000 citizens. Overall, 7874 MI patients (6.4%) had an additional coded diagnosis of obesity; 513 of these patients (6.5%) died while in the hospital. The number of MI events was higher in men than in women (56.2 versus 43.8%), whereas mortality rate of the women exceeded that of the men (12.7 versus 10.9%). Obesity mitigated sex differences in mortality after MI. Overall mortality after acute MI was distinctly lower in all obesity classes relative to MI patients without coded obesity. Relative mortality risk was 0.45, 0.62, and 0.75 in obesity classes I, II, and III, respectively. The present results point to a pronounced obesity paradox in women. CONCLUSIONS: Obesity is associated with lower in-hospital mortality in patients ≥70 y with MI relative to MI patients without coded obesity. Although women showed higher in-hospital mortality, sex differences were significantly attenuated by obesity. Women showed a pronounced obesity paradox in the higher obesity classes.

Impact of exaggerated blood pressure response in normotensive individuals on future hypertension and prognosis: Systematic review according to PRISMA guideline.

PURPOSE: Arterial hypertension (aHT) is the leading risk factor for morbidity and mortality worldwide. Blood pressure (BP) deviation at rest is well defined and accompanies risk for cardiovascular events and cardiovascular mortality. A growing body of evidence emphasises that an exaggerated blood pressure response (EBPR) in cardiopulmonary exercise testing (CPET) could help to identify seemingly cardiovascular healthy and normotensive subjects, who have an increased risk of developing aHT and cardiovascular events in the future. MATERIALS AND METHODS: The PubMed online database was searched for published studies reporting exercise-related BP and both the risk of aHT and cardiovascular events in the future. RESULTS: We identified 18 original studies about EBPR in CPET, which included a total of 35,151 normotensive individuals for prediction of new onset of aHT in the future and 11 original studies with 43,012 enrolled subjects with the endpoint of cardiovascular events in the future. Although an EBPR under CPET is not well defined, a large number of studies emphasise that EBPR in CPET is associated with both new-onset aHT and cardiovascular events in the future. CONCLUSIONS: A growing number of studies support the hypothesis that EBPR in CPET may be a diagnostic tool to identify subjects with an elevated risk of developing aHT and cardiovascular events in the future.

Hypertension is strongly associated with false-positive bicycle exercise stress echocardiography testing results.

INTRODUCTION: Exercise echocardiography is a reliable routine test in patients with known or suspected coronary artery disease. However, in ∼15% of all patients, stress echocardiography leads to false-positive stress echocardiography results. We aimed to investigate the impact of hypertension on stress echocardiographic results. METHODS: We performed a retrospective study of patients with suspected or known stable coronary artery disease who underwent a bicycle exercise stress echocardiography. Patients with false-positive stress results were compared with those with appropriate results. RESULTS: 126 patients with suspected or known coronary artery disease were included in this retrospective study. 23 patients showed false-positive stress echocardiography results. Beside comparable age, gender distribution and coronary artery status, hypertension was more prevalent in patients with false-positive stress results (95.7% vs. 67.0%, p = 0.0410). Exercise peak load revealed a borderline-significance with lower loads in patients with false-positive results (100.0 (IQR 75.0/137.5) vs. 125.0 (100.0/150.0) W, p = 0.0601). Patients with false-positive stress results showed higher systolic (2.05 ± 0.69 vs. 1.67 ± 0.39 mmHg/W, p = 0.0193) and diastolic (1.03 ± 0.38 vs. 0.80 ± 0.28 mmHg/W, p = 0.0165) peak blood pressure (BP) per wattage. In a multivariate logistic regression test, hypertension (OR 17.6 [CI 95% 1.9-162.2], p = 0.0115), and systolic (OR 4.12 [1.56-10.89], p = 0.00430) and diastolic (OR 13.74 [2.46-76.83], p = 0.00285) peak BP per wattage, were associated with false-positive exercise results. ROC analysis for systolic and diastolic peak BP levels per wattage showed optimal cut-off values of 1.935mmHg/W and 0.823mmHg/W, indicating false-positive exercise echocardiographic results with AUCs of 0.660 and 0.664, respectively. CONCLUSIONS: Hypertension is a risk factor for false-positive stress exercise echocardiographic results in patients with known or suspected coronary artery disease. Presence of hypertension was associated with 17.6-fold elevated risk of false-positive results.

Predictive value of brachial reactive hyperemia and flow-mediated dilation in stable coronary artery disease.

BACKGROUND: The purpose of this study was to determine the predictive value of a single measurement of reactive hyperemia (RH) and brachial flow-mediated dilation (FMD) in patients with established stable coronary artery disease (CAD). METHODS: RH and brachial artery FMD were ultrasonographically measured in 325 patients with stable CAD. Patients were followed for cerebro-cardiovascular events. The median follow-up was 3.7 years (range 0.01-5.7 years). RESULTS: Sixty-seven patients (20.6%) had an cerebro-cardiovascular event. Patients with subsequent events had lower FMD (4.9 ± 3.3% versus 6.3 ± 3.5%, p = 0.003), higher brachial artery resting diameter (5.1 ± 0.7 mm versus 4.8 ± 0.7 mm, p = 0.002) and lower NMD (11.2 ± 5.1% versus 12.8 ± 5.4%, p = 0.02), while the mean hyperemic flow velocity and shear stress did not differ from patients without cerebro-cardiovascular events. Cox proportional hazard model adjusted for sex, age, BMI, and traditional cardiovascular risk factors revealed a hazard ratio of 0.84 for lower FMD (p = 0.01). CONCLUSIONS: We conclude that single spot measurements of peak RH do not provide long-term prognostic information, but evaluation of conduit artery FMD predicts long-term cerebro-cardiovascular events in patients with stable CAD. The prognostic value of FMD is incremental to traditional cardiovascular risk factors and may therefore be of clinical importance.

ß-Blockers in patients with intermittent claudication and arterial hypertension: results from the nebivolol or metoprolol in arterial occlusive disease trial.

The use of ß-receptor blockers in peripheral arterial disease is controversial for their impact on vasomotor tone. The ß-blocker nebivolol possesses vasodilating, endothelium-dependent, NO-releasing properties that might be beneficial in peripheral arterial disease. The aim of the study was to evaluate the effects and tolerability of nebivolol in comparison with metoprolol in these patients. A total of 128 patients with intermittent claudication and essential hypertension were included and double-blind randomized to receive 5 mg of nebivolol (N=65) or 95 mg of metoprolol (N=63) once daily. End points were changes in ankle-brachial index, initial and absolute claudication distance, endothelial function assessed by flow-mediated dilatation of the brachial artery, blood pressure, and quality of life using the claudication scale questionnaire. End point analysis was possible in 109 patients (85.2%). After the 48-week treatment period, ankle-brachial index and absolute claudication distance improved significantly in both patient groups (P<0.05 for both), with no difference across treatments. A significant increase of initial claudication distance was found in the nebivolol group. Adjusted mean change of initial claudication distance was 33.9% after nebivolol (P=0.003) and 16.6% after metoprolol (P=0.12) treatment. Quality of life was not influenced by either treatment, and there was no relevant change in flow-mediated dilatation in patients treated with nebivolol or metoprolol (P=0.16). Both drugs were equally effective in lowering blood pressure. In conclusion, ß-blocker therapy was well tolerated in patients with intermittent claudication and arterial hypertension during a treatment period of ≈1 year. In the direct comparison, there was no significant difference between nebivolol and metoprolol.

Lack of evidence for pleiotropic effects of clopidogrel on endothelial function and inflammation in patients with stable coronary artery disease: results of the double-blind, randomized CASSANDRA study.

BACKGROUND: Recently we have demonstrated a dose-dependent improvement of endothelial function after administration of a single loading dose of clopidogrel in patients with coronary artery disease (CAD). We therefore hypothesized that chronic therapy with clopidogrel may improve endothelial function in patients with CAD. METHODS: In a double-blind, randomized, monocentric study 120 patients with established CAD were randomized to one of the following treatment arms: clopidogrel 75 mg q.d., acetylsalicylic acid (ASA) 100 mg q.d., or a combination of ASA and clopidogrel. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent nitroglycerin-mediated dilation (NMD) of the brachial artery were determined before and after 28 days of treatment. The effect of clopidogrel was monitored in vitro by ADP-induced platelet aggregation in platelet-rich plasma. Effects of treatment on platelet superoxide production were measured by lucigenin-enhanced chemiluminescence in washed platelets. C-reactive protein, RANTES and monocyte chemoattractant protein-1 were determined as inflammatory markers. The study was registered as ISRCTN34097747. RESULTS: Treatment groups were comparable regarding age, gender, cardiovascular risk factor distribution and concomitant medication. FMD [median (IQR) ASA, +0.8 (-2.0; 2.7); ASA + clopidogrel, ±0 (-2.0; 2.9); clopidogrel, +1.0 (-1.1; 2.4); P = n.s.], NMD, platelet superoxide production or inflammatory markers remained unchanged in all treatment groups. CONCLUSION: We conclude that the beneficial effects of short-term effects of clopidogrel on endothelial function of patients with CAD are abolished after long-term clopidogrel treatment.

Effects of pentaerythritol tetranitrate on endothelial function in coronary artery disease: results of the PENTA study.

BACKGROUND: Pentaerythritol tetranitrate (PETN) differs from other organic nitrates by the lack of tolerance induction and by antioxidative properties. The purpose of this study was to determine the effect of PETN on endothelial function in patients with coronary artery disease (CAD). We hypothesized that the treatment with PETN improves endothelial function in patients with CAD. METHODS: In a prospective, double-blind study, we randomly assigned 80 patients to treatment for 8 weeks with oral PETN 80 mg t.i.d. (PETN) or placebo (C). The primary endpoint was the absolute change in brachial artery flow-mediated dilation (FMD) from baseline to follow-up. Furthermore, changes in nitroglycerin-mediated dilation (NMD), digital peripheral arterial tonometry (PAT) index, vascular shear stress, mean flow velocity, plasma bilirubin, C-reactive protein (CRP) and thiobarbituric acid reactive substances (TBARS), serum ferritin, and the activity of the PETN bioactivating enzyme aldehyde dehydrogenase-2 (ALDH-2) in peripheral blood mononuclear cells were analyzed. Raw data entry, data monitoring and statistical analysis were performed independently. RESULTS: The treatment groups were comparable regarding demographics, cardiovascular risk and concomitant medication. There was no difference in the change in FMD between the two treatment groups (mean +/- SD: PETN: +1.6 +/- 3.3% vs. C: +1.4 +/- 4.1%; P = 0.7). NMD increased after treatment with PETN and was higher compared with C (PETN: +3.8 +/- 5.5% vs. C: +0.6 +/- 4.2%; P = 0.004). Mean PAT index and ALDH-2 activity remained unchanged. Relative changes in mean flow volume (P = 0.04) and mean flow velocity (P = 0.01) upon ischemia increased in the PETN group versus C. Changes in bilirubin, ferritin, TBARS and CRP did not differ between the groups. CONCLUSIONS: We conclude that chronic PETN therapy in patients with CAD may be established for symptomatic treatment without adverse effects on endothelial function and with beneficial effects on the microcirculation.

Flow-mediated dilation in patients with coronary artery disease is enhanced by high dose atorvastatin compared to combined low dose atorvastatin and ezetimibe: results of the CEZAR study.

BACKGROUND: Effects independent from cholesterol reduction on vascular function are considered to importantly contribute to the beneficial effects of statin therapy in cardiovascular disease. We aimed to evaluate the effect of high versus low dose atorvastatin on endothelial dysfunction in patients with coronary artery disease (CAD) in a setting of comparable cholesterol reduction. METHODS AND RESULTS: Fifty-eight patients with CAD were randomly assigned to double-blind treatment for 8 weeks with atorvastatin 80 mg per day (A80) or atorvastatin 10mg+ezetimibe 10mg per day (A10E10), respectively. Flow-mediated vasodilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent vasodilation (NMD), lipid, C-reactive protein (CRP) plasma concentrations and urinary 8-iso-prostaglandin F2alpha excretion were measured before and after treatment. Total cholesterol, triglycerides and LDL-cholesterol levels were significantly reduced with no difference between A80 and A10E10. A80 caused significantly stronger improvement of FMD compared to A10E10 (absolute change FMD: A80+2.7+/-3.0% (post vs. pre p<0.001), A10E10+0.6+/-2.9% (post vs. pre p=0.25), A80 vs. A10E10 p=0.018). NMD was improved by A80 but not by A10E10 (absolute change NMD: A80+2.7+/-4.6%, A10E10+0.7+/-3.5%, p=0.12). Both treatment groups caused a comparable reduction of CRP and did not effect urinary 8-iso-prostaglandin F2alpha excretion. There was no correlation between FMD or NMD change and LDL-cholesterol change in either treatment group. CONCLUSIONS: The present findings clearly suggest that in the presence of comparable LDL-lowering effects of both treatment forms, LDL-cholesterol independent effects of high dose atorvastatin therapy account for the improvement of endothelium-dependent vasodilation in patients with stable CAD.

Effects of oral niacin on endothelial dysfunction in patients with coronary artery disease: results of the randomized, double-blind, placebo-controlled INEF study.

High-density-lipoproteins-cholesterol (HDL-C) is invertedly related to the incidence of cardiovascular events. Recent studies suggest that HDL-C directly improves endothelial function. Nicotinic acid (niacin) effectively raises serum HDL-C. We therefore hypothesized that treatment with niacin improves endothelial dysfunction in patients with coronary artery disease (CAD). One hundred seven patients with CAD were randomly assigned to double-blinded treatment for 12 weeks with extended-release (ER)-niacin 1000 mg/day (N) or placebo (C), respectively. Flow-mediated dilation (FMD) of the brachial artery, nitroglycerin-mediated endothelium-independent dilation (NMD) and serum lipid concentrations were measured before and after treatment. Triglycerides (P=0.013), low-density-lipoprotein-cholesterol (LDL-C) (P=0.013) and HDL-C (P<0.0001) were altered by N compared to C. Niacin treatment was without effect on FMD or NMD, respectively, compared to placebo. However, post-hoc subgroup analysis revealed an improvement in FMD in patients with low HDL-C at baseline (absolute change in FMD (mean+/-S.D.) N: +3.25+/-3.88%, C: +1.03+/-2.71% in low tertile HDL-C