Hannes Alber

HMG-CoA Reductase Inhibitors Regulate Inflammatory Transcription Factors in Human Endothelial and Vascular Smooth Muscle Cells

Objective—Pleiotropic atheroprotective effects of HMG-CoA reductase inhibitors may be mediated on the level of vascular gene transcription. The aim of this study was to characterize the effects of statins on the activation of transcription factors known to regulate inflammation and cell proliferation/differentiation. Methods and Results—Simvastatin, atorvastatin, and lovastatin (0.1 to 10 &mgr;mol/L) inhibited the binding of nuclear proteins to both the nuclear factor-kappa B (NF-&kgr;B) and activator protein-1 (AP-1) DNA consensus oligonucleotides in human endothelial and vascular smooth muscle cells as assessed by electrophoretic mobility shift assay (EMSA). The inhibitory effects of statins on NF-&kgr;B or AP-1–dependent transcriptional activity were examined by transient transfection studies. HMG-CoA reductase inhibitors upregulated I&kgr;B-&agr; protein levels in endothelial cells and decreased c-Jun mRNA expression in smooth muscle cells as analyzed by Western and Northern blotting, respectively. Furthermore, statins inhibited DNA binding of hypoxia-inducible factor-1&agr;. Downstream effects of statins included inhibition of plasminogen activator inhibitor-1 and vascular endothelial growth factor-A mRNA levels in endothelial cells. Conclusions—HMG-CoA reductase inhibitors downregulate the activation of transcription factors NF-&kgr;B, AP-1, and hypoxia-inducible factor-1&agr;. These findings support the concept that statins have antiinflammatory and antiproliferative effects that are relevant in the treatment of atherosclerotic diseases.

Drug-Eluting versus Bare-Metal Stents in Large Coronary Arteries

BACKGROUND Recent data have suggested that patients with coronary disease in large arteries are at increased risk for late cardiac events after percutaneous intervention with first-generation drug-eluting stents, as compared with bare-metal stents. We sought to confirm this observation and to assess whether this increase in risk was also seen with second-generation drug-eluting stents. METHODS We randomly assigned 2314 patients needing stents that were 3.0 mm or more in diameter to receive sirolimus-eluting, everolimus-eluting, or bare-metal stents. The primary end point was the composite of death from cardiac causes or nonfatal myocardial infarction at 2 years. Late events (occurring during months 7 to 24) and target-vessel revascularization were the main secondary end points. RESULTS The rates of the primary end point were 2.6% among patients receiving sirolimus-eluting stents, 3.2% among those receiving everolimus-eluting stents, and 4.8% among those receiving bare-metal stents, with no significant differences between patients receiving either drug-eluting stent and those receiving bare-metal stents. There were also no significant between-group differences in the rate of late events or in the rate of death, myocardial infarction, or stent thrombosis. Rates of target-vessel revascularization for reasons unrelated to myocardial infarction were 3.7% among patients receiving sirolimus-eluting stents, 3.1% among those receiving everolimus-eluting stents, and 8.9% among those receiving bare-metal stents. The rate of target-vessel revascularization was significantly reduced among patients receiving either drug-eluting stent, as compared with a bare-metal stent, with no significant difference between the two types of drug-eluting stents. CONCLUSIONS In patients requiring stenting of large coronary arteries, no significant differences were found among sirolimus-eluting, everolimus-eluting, and bare-metal stents with respect to the rate of death or myocardial infarction. With the two drug-eluting stents, similar reductions in rates of target-vessel revascularization were seen. (Funded by the Basel Cardiovascular Research Foundation and the Swiss National Foundation for Research; Current Controlled Trials number, ISRCTN72444640.).

Second Internal Thoracic Artery Versus Radial Artery in Coronary Artery Bypass Grafting A Long-Term, Propensity Score–Matched Follow-Up Study

Background— The best second arterial conduit for multiple arterial revascularization (MAR) is still a matter of debate. Previous studies on the benefit of either using the radial artery (RA) or the right internal thoracic artery (RITA) in coronary artery bypass grafting are not conclusive. The aim of our study was to compare the perioperative and long-term outcome of either RA or RITA grafts as second conduits for MAR. Methods and Results— A consecutive series of 1001 patients undergoing first nonemergent coronary artery bypass grafting receiving either RA or RITA as second graft for MAR between 2001 and 2010 were studied. There were 277 patients receiving a RITA and 724 patients receiving a RA in addition to a left internal thoracic artery (LITA). Concomitant saphenous vein grafts (SVG) were grafted in addition as necessary. Propensity score–matched analysis was performed to compare the 2 groups, bilateral ITA±SVG (BITA±SVG group) and the LITA+RA±SVG group relative to overall survival and major adverse cardiac and cerebrovascular events–free survival. Hazard ratios and their 95% confidence intervals were estimated by COX regression stratified on matched pairs. The incidence of perioperative major adverse cardiac and cerebrovascular events was significantly lower in the BITA±SVG group (1.4% versus 7.6%, P <0.001). Overall survival (hazard ratio 0.23; 95% confidence interval 0.066–0.81; P =0.022) and major adverse cardiac and cerebrovascular events–free survival (hazard ratio 0.18; 95% confidence interval 0.08–0.42; P <0.001) were significantly better in the BITA±SVG group compared to the LITA+RA±SVG group. Conclusions— The results of our study provide strong evidence for the superiority of a RITA graft compared to RA as a second conduit in MAR. # Clinical Perspective {#article-title-34}Background— The best second arterial conduit for multiple arterial revascularization (MAR) is still a matter of debate. Previous studies on the benefit of either using the radial artery (RA) or the right internal thoracic artery (RITA) in coronary artery bypass grafting are not conclusive. The aim of our study was to compare the perioperative and long-term outcome of either RA or RITA grafts as second conduits for MAR. Methods and Results— A consecutive series of 1001 patients undergoing first nonemergent coronary artery bypass grafting receiving either RA or RITA as second graft for MAR between 2001 and 2010 were studied. There were 277 patients receiving a RITA and 724 patients receiving a RA in addition to a left internal thoracic artery (LITA). Concomitant saphenous vein grafts (SVG) were grafted in addition as necessary. Propensity score–matched analysis was performed to compare the 2 groups, bilateral ITA±SVG (BITA±SVG group) and the LITA+RA±SVG group relative to overall survival and major adverse cardiac and cerebrovascular events–free survival. Hazard ratios and their 95% confidence intervals were estimated by COX regression stratified on matched pairs. The incidence of perioperative major adverse cardiac and cerebrovascular events was significantly lower in the BITA±SVG group (1.4% versus 7.6%, P<0.001). Overall survival (hazard ratio 0.23; 95% confidence interval 0.066–0.81; P=0.022) and major adverse cardiac and cerebrovascular events–free survival (hazard ratio 0.18; 95% confidence interval 0.08–0.42; P<0.001) were significantly better in the BITA±SVG group compared to the LITA+RA±SVG group. Conclusions— The results of our study provide strong evidence for the superiority of a RITA graft compared to RA as a second conduit in MAR.

Atherosclerosis as a risk factor for benign prostatic hyperplasia

To evaluate the relationship between clinical benign prostatic hyperplasia (BPH) and atherosclerosis, using colour Doppler ultrasonography (CDUS) and symptom scores.

Valvular heart disease in Parkinson's disease vs. controls: An echocardiographic study

Restrictive valvulopathy has been reported in association with dopamine agonist therapy in parkinsonian patients. The majority of reports have been related to pergolide, but anecdotal cases following treatment with bromocriptine or cabergoline have also been presented. It is presently unclear whether the potential induction of restrictive cardiac valvulopathy is a class effect of all dopamine agonists or if there is a differential risk between ergot and nonergot compounds. In this study, the frequency of a valvular regurgitation as assessed by routine transthoracic echocardiography was compared between 75 patients with Parkinsons disease (PD) treated with pergolide (n = 29), cabergoline (n = 13), pramipexole or ropinirole (n = 33), and 49 age‐matched nonparkinsonian controls. The exposure to pergolide and cabergoline was associated with higher frequencies of valvular regurgitation grades 2 and 3 (31% and 47%) compared with age‐matched controls (13%), while there was no increase of valvular regurgitation grades 2 and 3 in patients treated with nonergot compounds (10%). Evidence for restrictive valvulopathy was found in one patient treated with pergolide and cabergoline each. While this study shows similarly increased frequencies of valvular regurgitation in patients treated with the ergot agonists pergolide and cabergoline in comparison to both normal controls and patients treated with nonergot agonists, evidence for restrictive valvulopathy was only found in two cases. These results highlight the need for further prospective studies of the prevalence and underlying mechanisms of cardiac valvulopathy in PD patients treated with different dopamine agonists.

Cardiac hepatopathy before and after heart transplantation

Chronic cardiac hepatopathy is a common entity in patients evaluated for heart transplantation (HTX). Hepatic injury is caused by severe heart failure resulting from prolonged recurrent congestion and/or impaired arterial perfusion. No data are available on the reversibility of cardiac hepatopathy in patients undergoing HTX. Data of 56 consecutive adult patients undergoing HTX during 2000–02 at the University Hospital of Innsbruck were analysed retrospectively. The following parameters were evaluated at the time of listing and 3, 6 and 12 months after HTX. Plasma levels of gamma‐glutamyl transferase (γ‐GT), alkaline phosphatase (AP), bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) and total plasma protein. When listed for HTX, only 12% of all patients analysed had physiological values throughout the seven laboratory parameters assessed. Elevated levels of γ‐GT, AP, bilirubin, AST, ALT, LDH and total plasma protein were detected in 66.6%, 29%, 50%, 16.7%, 10%, 40% and 18% of all patients respectively. Accordingly, median plasma levels of γ‐GT, bilirubin and LDH were elevated, whereas the mean plasma level of AP was at the upper normal range. In contrast, median plasma level of AST and mean plasma levels of ALT and total plasma protein were within the normal range: γ‐GT (median, 109.0; range, 634.0 U/l; n = 36), AP (mean, 120.2 ± 78.9 U/l; n = 29), bilirubin (median, 1.3; range, 16.1 mg/dl; n = 32), LDH (median, 226.0; range, 2355.0 U/l; n = 33), AST (median, 29.0; range, 145.0 U/l; n = 36), ALT (mean, 28.3 ± 20.8 U/l; n = 36) and total plasma protein (mean, 7.2 ± 1.1 g/dl; n = 25). Within 3 months after HTX, elevated parameters except LDH significantly ameliorated: γ‐GT (median, 59.0; range, 1160.0 U/l; P = 0.011), AP (92.2 ± 75.2 U/l; P = 0.016), bilirubin (median, 0.9; range, 8.1 mg/dl; P = 0.004), LDH slightly increased (median, 281.0; range, 543.0 U/l; P = 0.039), but there was a delayed improvement of this parameter after 6 and 12 months post‐HTX. End‐stage heart failure is characterized by a cholestatic liver enzyme profile with elevated plasma levels of γ‐GT and bilirubin. These parameters significantly improve within 3 months after HTX. Therefore, chronic cardiac hepatopathy seems to be a benign, potentially reversible disease.

Long-Term Efficacy and Safety of Biodegradable-Polymer Biolimus-Eluting Stents: Main Results of the Basel Stent Kosten-Effektivitäts Trial- PROspective Validation Examination II (BASKET-PROVE II), A Randomized, Controlled Noninferiority 2-Year Outcome Trial

Background— Biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and as safe >1 year as bare-metal stents (BMS). Thus, very late stent thrombosis (VLST) attributable to durable polymers should no longer appear. Methods and Results— To address these early and late aspects, 2291 patients presenting with acute or stable coronary disease needing stents ≥3.0 mm in diameter between April 2010 and May 2012 were randomly assigned to biolimus-A9–eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide–coated BMS in 8 European centers. All patients were treated with aspirin and risk-adjusted doses of prasugrel. The primary end point was combined cardiac death, myocardial infarction, and clinically indicated target-vessel revascularization within 2 years. The combined secondary safety end point was a composite of VLST, myocardial infarction, and cardiac death. The cumulative incidence of the primary end point was 7.6% with BP-DES, 6.8% with DP-DES, and 12.7% with BMS. By intention-to-treat BP-DES were noninferior (predefined margin, 3.80%) compared with DP-DES (absolute risk difference, 0.78%; −1.93% to 3.50%; P for noninferiority 0.042; per protocol P=0.09) and superior to BMS (absolute risk difference, −5.16; −8.32 to −2.01; P=0.0011). The 3 stent groups did not differ in the combined safety end point, with no decrease in events >1 year, particularly VLST with BP-DES. Conclusions— In large vessel stenting, BP-DES appeared barely noninferior compared with DP-DES and more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates >1 year. Findings challenge the concept that durable polymers are key in VLST formation. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT01166685.

Gender-related outcome following percutaneous coronary intervention for ST-elevation myocardial infarction: data from the Austrian acute PCI registry

AIMS Whether or not primary percutaneous coronary intervention (P-PCI) is equally effective and safe in women and men in a real world setting is still a matter of debate. The aim of this study was to evaluate the effect of gender on in-hospital outcome after P-PCI for ST-elevation myocardial infarction (STEMI) in a prospective national registry. METHODS AND RESULTS This registry includes in-hospital outcome data from 19 PCI-performing hospitals. During 12 months, 1087 patients with STEMI were registered (mean age 62 +/- 13 years; 27% women). Women were older than men (67 +/- 13 vs. 60 +/- 13 years; p < 0.001) and more often had diabetes mellitus (21% vs. 13%; p < 0.001) or cardiogenic shock (15% vs. 9%; p=0.004). PCI was performed in 1004 patients (92.4%) and more frequently in men than in women (93.9 vs. 88.3%, p=0.002), whereas conservative treatment was more often decided in women (9.3% vs 4.3%; p=0.002). No differences were found between women and men in primary success rate (TIMI 2+3 flow, 92.9% vs. 93%; p=0.96). On univariate analysis, in-hospital mortality was higher in women than in men (13.7% vs. 7.2%; p=0.001). On multivariable analysis age, shock, diabetes and TIMI flow before PCI remained associated with mortality. CONCLUSIONS Women have higher in-hospital mortality following PCI for STEMI. On multivariate analysis age, shock, diabetes and TIMI flow, but not gender, were associated with mortality in this national register. Older age and more comorbidity are likely to explain the higher mortality in female patients undergoing P-PCI.

Comparison of peripheral endothelial function in shift versus nonshift workers.

Shift working is related to increased cardiovascular morbidity. Peripheral endothelial dysfunction, an inherent feature of early atherosclerosis, has been suggested as a surrogate marker of cardiovascular risk. Whether shift working is associated with peripheral endothelial dysfunction has not been investigated to date. A total of 48 male shift workers (SWs) and 47 male nonshift workers (NSWs) (mean age 43 ± 5 years) were recruited from a glass manufactory. The SWs and NSWs were matched according to age, body mass index, smoking habits, family history of premature coronary artery disease, prevalence of hypercholesterolemia and hypertension, and work place. Their sport habits were also documented. Peripheral endothelial function was assessed using the EndoPAT technique to determine the peripheral arterial tone (PAT) index. According to the study design, no difference was found in the risk factor profiles between the SWs and NSWs. Despite a greater percentage of regular physical activity among the SWs (16.7 vs 4.3%, p = 0.05), shift working was associated with a reduced PAT index compared to working only on the day shift (PAT index 1.73 ± 0.4 vs 1.94 ± 0.5, p = 0.03). In the NSW group, the participants with regular physical training (n = 16) had a greater PAT index than those without regular physical activity (n = 12; PAT index 2.28 ± 0.45 vs 1.86 ± 0.51, p = 0.03). No such difference was found in the SWs. In conclusion, SWs had a reduced PAT index compared with NSWs, suggesting endothelial dysfunction. Therefore, the known increased cardiovascular risk in those shift working might be related to endothelial dysfunction.

Association of improvement of brachial artery flow-mediated vasodilation with cardiovascular events

The aim of this pilot study was to test the prognostic value of serial measurements of peripheral endothelial function, assessed by brachial artery flow-mediated dilation (FMD), in patients with angiographically proven coronary artery disease. In 68 patients, FMD was measured on the day after coronary angiography and again after a mean of 14 ± 12 months. Patients were divided into two groups: absolute improvement in FMD ≥ 3% (FMD-improver += FMD-i) and <3% (FMD-non-improver = FMD-ni). After a mean follow-up of 44 ± 12 months, cardiovascular events were recorded. Baseline characteristics were similar between groups, except the number of risk factors which was smaller in FMD-i (1.6 ± 0.7 vs 2.1 ± 0.9, p < 0.02). Cardiovascular events were more frequent in FMD-ni (9 vs 1 event; p < 0.05). In Kaplan–Meier analysis, a trend towards a better outcome in patients with improved FMD was found using the log-rank test (p = 0.08). The single baseline FMD showed no relationship with late cardiovascular events. Thus, ‘delta-FMD’ may be more closely related to prognosis than a single FMD measurement.