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Post-contrast acute kidney injury (AKI) is a dreaded complication of endovascular revascularization using iodinated contrast medium in patients with peripheral artery disease and concomitant chronic kidney disease (CKD). This study sought to evaluate the incidence of AKI in patients with peripheral artery disease and CKD undergoing endovascular revascularization and using carbon dioxide (CO2) as contrast medium. From 04/2015 to 07/2018, all consecutive peripheral artery disease patients with CKD stage ≥ 3 referred for endovascular revascularization of symptomatic peripheral artery disease were prospectively included. During endovascular revascularization, CO2 as contrast medium was manually injected and iodinated contrast medium was additionally used when needed. The reference group consisted of 211 cardiovascular risk factor-matched patients undergoing endovascular revascularization with iodinated contrast medium only. CO2-guided endovascular revascularization was performed in 102 patients, thereof 16 (15.7%) patients exclusively with CO2. Baseline CKD stage ≥ 4 and iodinated contrast medium volume > 50 ml were disproportionally associated with post-procedural post-contrast AKI. At CKD stage 4 the odds ratio for post-contrast AKI was 13.2 (95% CI 1.489–117.004; p = 0.02) for iodinated contrast medium volume 51-100 ml and 37.7 (95% CI 3.927–362.234; p = 0.002) for iodinated contrast medium volume > 100 ml. The corresponding values at CKD stage 5 were 23.7 (95% CI 2.666–210.583; p = 0.005) and 28.3 (95% CI 3.289–243.252; p = 0.002), respectively. Radiation (dose area product) was significantly higher in the CO2-endovascular revascularization group (6.025 ± 6.926 cGy*cm2 vs. 4.281 ± 4.722 cGy*cm2, p = 0.009). CO2 is an applicable and safe alternative to iodinated contrast medium for endovascular revascularization in peripheral artery disease patients with concomitant CKD. Patients with CKD stage 4 or 5, being at highest risk for post-contrast AKI, should primarily be treated by CO2-guided endovascular revascularization.

Zusammenfassung Hintergrund Die periphere arterielle Verschlusskrankheit (pAVK) ist eine atherosklerotische Gefäßerkrankung mit hoher Morbidität und Mortalität. Eine konsequente medikamentöse Sekundärprävention gehört zur essenziellen und evidenzbasierten Therapie der pAVK. Das Ziel der vorliegenden Studie war es, den Status quo der medikamentösen Sekundärprävention anhand von Rezepteinlösungen zu ermitteln. Methoden Basierend auf Sekundärdaten der Kassenärztlichen Vereinigung Westfalen-Lippe (KVWL), wurden im Zeitraum von 2014 bis 2017 Patienten mit einer gesicherten pAVK-Kodierung (I70.2-/I73.9-) identifiziert und deren Rezepteinlösung bezüglich Thrombozytenaggregationshemmern (TAH), oralen Antikoagulanzien, lipidmodifizierender Medikation (LLT) sowie ACE(„angiotensin-converting enzyme“)-Hemmer im 4. Quartal nach der Diagnosekodierung erfasst. Ergebnisse Im Diagnosezeitraum 2014/2015 hatten im Einzugsgebiet KVWL 238.397 Patienten eine pAVK. Der Anteil an eingelösten Rezepten betrug im 4. Quartal nach der Diagnosestellung 25,9 % für LLT, 13,6 % für Acetylsalicylsäure, 4,5 % für Clopidogrel, 5,5 % für Vitamin-K-Antagonisten (VKA), 3,5 % für nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAK) und 26,8 % für ACE-Hemmer. Im Verlauf von 3 Jahren (n = 241.375 Patienten mit pAVK 2016/2017) stieg der Anteil an eingelösten Rezepten bis auf VKA für alle anderen Substanzen an (p Schlussfolgerung Die leitliniengerechte medikamentöse Sekundärprävention bei pAVK-Patienten in Deutschland ist weiterhin verbesserungswürdig. Eine konsequente Umsetzung evidenzbasierter medikamentöser Sekundärprävention beherbergt ein großes Potenzial zur Verbesserung der Gesamtprognose der pAVK-Patienten.

Lower extremity artery disease (LEAD) affects millions of elderly patients and is associated with elevated cardiovascular morbidity and mortality. Risk factor modification, including the therapy of dyslipidaemia, is mandatory to reduce cardiovascular event rates and to improve survival rates. However, only a minority achieve the recommended low-density lipoprotein cholesterol (LDL-C) target level < 55 mg/dL, according to the current ESC/EAS guidelines on the treatment of dyslipidaemia. This study elucidated the implementation of the lipid-lowering guideline recommendations of 400 LEAD patients with LDL-C > 100 mg/dL and their adherence to treatment adjustment during follow-up. Despite a sustained statin prescription in 93% of the patients, including 77% with high-intensity statins at follow-up, only 18% achieved the target level. Ezetimibe appeared in 21% and LDL-C goals were reached significantly more often with combination therapy. Recurrent revascularization appeared more often (28%) than coronary artery or cerebrovascular disease progression (14%) and 7% died. Despite the frequent use of high-intensity statins and expandable rates of ezetimibe, the progression of cardiovascular events remained inevitable. Only 18% of the patients had received recommendations on lifestyle modification, including dietary adaptations, which is key for a holistic approach to risk factor control. Thus, efforts for both pharmacological and behavioral strategies are needed to improve clinical outcomes and survival rates.

Peripheral arterial occlusive disease (PAOD) is an atherosclerotic vascular disease with high morbidity and mortality. A consistent medication-based secondary prevention is part of the essential and evidence-based treatment of PAOD. The aim of this study was to ascertain the status quo of medicinal secondary prevention based on submitted prescriptions.In the time period from 2014 to 2017 patients with a confirmed PAOD coding (I70.2-/I73.9-) were identified based on secondary data of the Association of Statutory Health Insurance Physicians Westphalia-Lippe (KVWL). The prescriptions submitted with respect to platelet inhibitors, oral anticoagulants, lipid lowering therapy (LLT) and angiotensin-converting enzyme (ACE) inhibitors in the fourth quarter year after diagnosis coding were collated.In the diagnosis period 2014/2015 a total of 238,397 patients had PAOD in the catchment area of the KVWL. The proportion of submitted prescriptions in the fourth quarter year after diagnosis was 25.9% for LLT, 13.6% for acetylsalicylic acid, 4.5% for clopidogrel, 5.5% for vitamin K antagonists (VKA), 3.5% for non-vitamin K‑dependent oral anticoagulants (NOAC) and 26.8% for ACE inhibitors. Over the course of the 3 years (n = 241,375 patients with PAOD 2016/2017) the proportion of submitted prescriptions for all substances except VKA increased (p 0.001), whereby the largest relative increase was noted for NOAC (relative increase of 81.7%).The guideline-conform medicinal secondary prevention in patients with PAOD in Germany is still in need of improvement. A consistent implementation of evidence-based medicinal secondary prevention harbors a great potential for improvement of the overall prognosis in patients with PAOD.HINTERGRUND: Die periphere arterielle Verschlusskrankheit (pAVK) ist eine atherosklerotische Gefäßerkrankung mit hoher Morbidität und Mortalität. Eine konsequente medikamentöse Sekundärprävention gehört zur essenziellen und evidenzbasierten Therapie der pAVK. Das Ziel der vorliegenden Studie war es, den Status quo der medikamentösen Sekundärprävention anhand von Rezepteinlösungen zu ermitteln.Basierend auf Sekundärdaten der Kassenärztlichen Vereinigung Westfalen-Lippe (KVWL), wurden im Zeitraum von 2014 bis 2017 Patienten mit einer gesicherten pAVK-Kodierung (I70.2-/I73.9-) identifiziert und deren Rezepteinlösung bezüglich Thrombozytenaggregationshemmern (TAH), oralen Antikoagulanzien, lipidmodifizierender Medikation (LLT) sowie ACE(„angiotensin-converting enzyme“)-Hemmer im 4. Quartal nach der Diagnosekodierung erfasst.Im Diagnosezeitraum 2014/2015 hatten im Einzugsgebiet KVWL 238.397 Patienten eine pAVK. Der Anteil an eingelösten Rezepten betrug im 4. Quartal nach der Diagnosestellung 25,9 % für LLT, 13,6 % für Acetylsalicylsäure, 4,5 % für Clopidogrel, 5,5 % für Vitamin-K-Antagonisten (VKA), 3,5 % für nicht-Vitamin-K-abhängige orale Antikoagulanzien (NOAK) und 26,8 % für ACE-Hemmer. Im Verlauf von 3 Jahren (n = 241.375 Patienten mit pAVK 2016/2017) stieg der Anteil an eingelösten Rezepten bis auf VKA für alle anderen Substanzen an (p 0,001), wobei der größte relative Anstieg bei NOAK zu verzeichnen war (relativer Anstieg um 81,7 %).Die leitliniengerechte medikamentöse Sekundärprävention bei pAVK-Patienten in Deutschland ist weiterhin verbesserungswürdig. Eine konsequente Umsetzung evidenzbasierter medikamentöser Sekundärprävention beherbergt ein großes Potenzial zur Verbesserung der Gesamtprognose der pAVK-Patienten.

Background and objectives Despitethe multiple depicted associations of CKD with reduced cardiovascular and overall prognoses, the association of CKD with outcome of patients undergoing transcatheter aortic valve implantation has still not been well described. Design, setting, participants, & measurements Data from all hospitalized patients who underwent transcatheter aortic valve implantation procedures between January 1, 2010 and December 31, 2013 in Germany were evaluated regarding influence of CKD, even in the earlier stages, on morbidity, in-hospital outcomes, and costs. Results A total of 28,716 patients were treated with transcatheter aortic valve implantation. A total of 11,189 (39.0%) suffered from CKD. Patients with CKD were predominantly women; had higher rates of comorbidities, such as coronary artery disease, heart failure at New York Heart Association 3/4, peripheral artery disease, and diabetes; and had a 1.3-fold higher estimated logistic European System for Cardiac Operative Risk Evaluation value. In-hospital mortality was independently associated with CKD stage ≥3 (up to odds ratio, 1.71; 95% confidence interval, 1.35 to 2.17; P Conclusions This analysis illustrates for the first time on a nationwide basis the association of CKD with adverse outcomes in patients who underwent transcatheter aortic valve implantation. Thus, classification of CKD stages before transcatheter aortic valve implantation is important for appropriate risk stratification.

Summary: Background: Patients with chronic critical limb-threatening ischemia (CLTI) are at high risk of amputation and death. Despite the general recommendation for revascularization in CTLI in the guidelines, the underlying evidence for such a recommendation is limited. The aim of our study was to assess the outcome of patients with CLTI depending on the use of revascularization in a retrospective real-world cohort. Patients and methods: Administrative data of the largest German Health insurance (BARMER GEK) were provided for all patients that were hospitalized for the treatment of CLTI Rutherford category (RF) 5 and 6 between 2009 and 2011. Patients were followed-up until December 31st, 2012 for limb amputation and death in relation to whether patients did (Rx +) or did not have (Rx −) revascularization during index-hospitalization. Results: We identified 15,314 patients with CLTI at RF5 (n = 6,908 (45.1%)) and RF6 (n = 8,406 (54.9%)), thereof 7,651 (50.0%) underwent revascularization (Rx +) and 7,663 (50.0%) were treated conservatively (Rx −). During follow-up (mean 647 days; 95% CI 640–654 days) limb amputation (46.5% Rx− vs. 40.6% Rx+, P

The prevalence of diabetes mellitus (DM) and its associated complications such as peripheral artery disease (PAD) and diabetic foot syndrome (DFS) are increasing worldwide. We aimed to determine the contemporary acute and long-term outcome of patients with PAD and DFS in Germany.Nationwide, anonymized data of 40,335 patients hospitalized for PAD and/or DFS from the years 2009-2011 were analyzed and followed up until 2013. Patients were classified into 3 groups: DFS, PAD+DM and PAD without DM. In-hospital and long-term outcome (1156days, 95% CI 1.151-1.161) regarding major and minor amputation and mortality was assessed. Cumulative amputation-free survival and overall survival rates were calculated using Kaplan-Meier analysis.The proportion of DFS, PAD+DM and PAD only was 17.3%, 21.5% and 61.2%, respectively. At index-hospitalization, DFS patients had the highest amputation (31.9% vs. 11.1% vs. 6.0%), yet the lowest revascularization rate (18.2% vs. 67.8% vs. 71.6%) compared to patients with PAD only and PAD+DM (P0.001). Cumulative 4-year survival (57.4%, 60.8% and 70.0%) and amputation-free-survival (45.4%, 74.4% and 86.5%) were lowest for DFS followed by PAD+DM and PAD only (P0.001).Patients with diabetes, particularly those with DFS, have persistent high rates of limb amputation and of mortality in a real-world setting. Our data emphasize the need for further dedicated research to identify and target the underlying causes of the extraordinary poor outcome in this high risk population.

Background: To assess the nationwide contemporary burden of cardiovascular risk factors, comorbidities, and in-hospital mortality in patients with lower limb amputation (LLA) due to peripheral arterial disease and critical limb ischemia (CLI) in Germany. Methods: German nationwide data for 2005 and 2009 were analyzed regarding in-hospital rates of major and minor ischemic LLA, risk factors, comorbidities, surgical and endovascular revascularizations, and in-hospital mortality. Results: In 2005, a total of 22 479 major (7.8%) and 28 262 minor (9.8%) LLAs were performed with a relative decrease of −21.8% in major LLA, yet with a relative increase of +2% in minor LLA rate in 2009. The overall revascularization rate before amputation was 46% in 2005 and 57% in 2009. In-hospital mortality for non-CLI, minor, and major amputees was 3.3%, 4.6%, and 19.8%, respectively ( P < .001 for major vs minor LLA and non-CLI). Conclusion: The total number of ischemic LLA and amputation-related in-hospital mortality remains high in Germany in the 21st century. The poor outcome of patients with CLI might in part be due to underuse of revascularizations prior to amputation.

Evident data about the additive effect of "the fifth cardiovascular risk factor" (anemia) and peripheral arterial disease (PAD) focused on morbidity and outcome of patients with PAD are currently still missing.A total of 41,882 PAD patients were included. Of these, 5566 (13.3%) suffered from anemia. Patients with anemia were older (P0.001), suffered more often from chronic kidney disease (P0.001), coronary artery disease (P0.001), and more severe PAD (P0.001). However, they received significantly less endovascular revascularizations (P0.001), had higher amputation rates (acute anemia: 3.7-fold, P0.001; nutritional, aplastic, and anemia in chronic disease: 2.9-fold, P0.001), higher in-hospital mortality rates (acute anemia: 6.4-fold, P0.001; nutritional, aplastic, and anemia in chronic disease: 4.6-fold; P0.001), had significantly higher in-hospital complications (P0.001) compared to those without anemia. During a follow-up time up to 4years (until Dec. 31st, 2012, median 775days, 25th-75th percentiles 469-1120days) nutritional, aplastic, and anemia in chronic disease and acute anemia were high significant predictors of long-term mortality and amputation (each P0.001). Lengths of hospital stay and reimbursement costs were higher (nutritional, aplastic, and anemia in chronic disease: 2-fold higher (P0.001), acute anemia: 3-fold higher (P0.001)) than in patients without anemia.This study illustrates from a large, comprehensive database the association of acute, nutritional, aplastic, and anemia in chronic disease on morbidity, in-hospital treatment and complications, short- and long term outcome, and costs of patients with PAD.

Background: The prevalence of diabetes mellitus and its associated complications such as peripheral artery disease is increasing worldwide. We aimed to explore the distinct impact of type 1 diabetes mellitus and type 2 diabetes mellitus on treatment and on short- and long-term outcome in patients with peripheral artery disease. Methods: Retrospective analysis of anonymized data of hospitalized patients covered by a large German health insurance. Assessment of patient’s characteristics (comorbidities, complications, etc.) and outcome using multivariable Cox regression and Kaplan–Meier curves. Results: Among 41,702 patients with peripheral artery disease, 339 (0.8%) had type 1 diabetes mellitus and 13,151 (31.5%) had type 2 diabetes mellitus. Patients with diabetes mellitus had more comorbidities and complications than patients without diabetes mellitus ( p Conclusion: Although the fraction of type 1 diabetes mellitus among patients with peripheral artery disease and diabetes mellitus is low, it represents a subset of patients being at particular high risk for limb amputation. Research focused on elaborating the determinants of limb amputation and mortality in peripheral artery disease patients with diabetes mellitus is warranted to improve the poor prognosis of these patients.

Despite the many studies showing an association between CKD and a high risk of ischemic events and mortality, the association of CKD with peripheral arterial disease (PAD) still has not been well described.This large cohort study assessed the association of CKD, even in the earlier stages, with morbidity, short- and long-term outcome, and costs among patients with PAD.We identified 41,882 patients with PAD who had an index hospitalization between January 1, 2009, and December 31, 2011. Of these, 8470 (20.2%) also had CKD (CKD stage 2: n=2158 [26%]; stage 3: n=3941 [47%]; stage 4: n=935 [11%]; stage 5: n=1436 [17%]). The ratio of women to men was 1:1.2. Compared with patients without known CKD, those with CKD had higher frequencies of coronary artery disease (1.8-fold higher; P0.001), chronic heart failure (3.3-fold higher; P0.001), and Rutherford PAD categories 5 and 6 (1.8-fold higher; P0.001); underwent significantly fewer revascularizations (0.9-fold fewer; P0.001); had a nearly two-fold higher amputation rate (P0.001); had higher frequencies of in-hospital infections (2.1-fold higher; P0.001), acute renal failure (2.8-fold higher; P0.001), and sepsis (1.9-fold higher; P0.001); had a 2.5-fold higher frequency of myocardial infarction (P0.001); and had a nearly three-fold higher in-hospital mortality rate (P0.001). In an adjusted multivariable Cox regression model, CKD remained a significant predictor of long-term outcome of patients with PAD during follow-up for up to 4 years (until December 31, 2012; median, 775 days; 25th-75th percentiles, 469-1120 days); the hazard ratio was 2.59 (95% confidence interval, 2.21 to 2.78; P0.001). The projected mortality rates after 4 years were 27% in patients without known CKD and 46%, 52%, 72%, and 78% in those with CKD stages 2, 3, 4, and 5, respectively. Lengths of hospital stay and reimbursement costs were on average nearly 1.4-fold higher (P0.001) in patients who also had CKD.This analysis illustrates the significant and important association of CKD with in-hospital and long-term mortality, morbidity, amputation rates, duration and costs of hospitalization, in-hospital treatment, and complications in patients with PAD.

To investigate the relevance of atrial fibrillation or flutter (AF) for outcome of patients who are hospitalized for peripheral artery disease (PAD) and/or critical limb ischemia (CLI).We compared baseline data, co-morbidities, procedural data as well as in-hospital and long-term outcome of 41,882 patients who were hospitalized with PAD or CLI between 2009 and 2011 according to whether they did or did not have atrial fibrillation/flutter. Follow-up was available until December 2012. Of these, 5622 patients (13.4%) had AF. AF patients were significantly older (78±9 vs. 70±11years) and had significantly more comorbidities, such as diabetes (40.8 vs. 31.1%), chronic kidney disease (40.1 vs. 19.0%), coronary artery disease (38.0 vs. 23.0%) and chronic heart failure (26.9 vs. 7.2%, each p0.001). They had more advanced PAD as shown by higher Rutherford classes. In-hospital complications including acute renal failure, myocardial infarction, stroke sepsis and death occurred significantly more often (each p0.001). Duration of hospital stay was significantly longer and costs were markedly higher in patients with AF (each p0.001). Using multivariate Cox regression analyses regarding long-term outcomes, AF was an independent predictor for death (HRR 1.46; 95% CI 1.39-1.52, p0.001), ischemic stroke (HRR 1.63; 95% CI 1.44-1.85) and amputation (HRR 1.14; 95% CI 1.07-1.21).Presence of AF in patients admitted for PAD and CLI is associated with worse in-hospital and long-term outcome than in patients without AF. This effect was independent of numerous other comorbidities and stage of vascular disease.

Peripheral arterial disease (PAD) and chronic kidney disease (CKD) are associated with increased mortality rates. We assessed long-term outcomes of patients with PAD and CKD. Patients with PAD undergoing invasive angiography and/or endovascular revascularization between 2005 and 2010 were retrospectively classified into 5 CKD stages. A follow-up was performed and 572 patients were included, 116 patients (20%) had normal renal function, 245 were in CKD stage 2 (43%), 156 in CKD stage 3 (27%), and 55 in CKD stages 4 + 5 (10%). Diabetes mellitus, hypertension, and anemia were more frequent in higher CKD stages ( P < .03). During follow-up (mean 1135 days; 95% confidence interval 1159-1259), cumulative mortality was 21% and increased with advanced CKD stages (9%, 16%, 29%, and 47%, respectively, P < .001). In multivariate Cox regression models, higher CKD stages were significantly associated with poor survival. Medication adherence for secondary prevention was significantly lower than recommended but irrespective of CKD stages. Kidney function is an independent predictor of worse long-term survival in patients with PAD. While standard medications were used less often than recommended, no differences between CKD stages were noted.

Aims Only few and historic studies reported a bad prognosis of peripheral arterial disease (PAD) and critical limb ischaemia (CLI). The contemporary state of treatment and outcomes should be assessed. Methods and results From the largest public health insurance in Germany, all in- and outpatient diagnosis and procedural data were retrospectively obtained from a cohort of 41 882 patients hospitalized due to PAD during 2009–2011, including a follow-up until 2013. Patients were classified in Rutherford categories 1–3 ( n = 21 197), 4 ( n = 5353), 5 ( n = 6916), and 6 ( n = 8416). The proportions of patients with classical risk factors such as hypertension, dyslipidaemia, and smoking declined with higher Rutherford categories (each P < 0.001) while diabetes, chronic kidney disease, and chronic heart failure increased (each P < 0.001). Angiographies and revascularizations were performed less often in advanced PAD (each P < 0.001). In-hospital amputations increased continuously from 0.5% in Rutherford 1–3 to 42% in Rutherford 6, as also myocardial infarctions, strokes, and deaths (each P < 0.001). Among 4298 amputated patients with CLI, 37% had not received any angiography or revascularization neither during index hospitalization nor the 24 months before. During follow-up (mean 1144 days), 7825 patients were amputated and 10 880 died. Kaplan–Meier models projected 4-year mortality risks of 18.9, 37.7, 52.2, and 63.5% in Rutherford 1–3, 4, 5, and 6, and for amputation of 4.6, 12.1, 35.3, and 67.3%, respectively. In multivariable Cox regression models, PAD categories were significant predictors of death, amputation, myocardial infarction, and stroke (each P < 0.001). Length of in-hospital stay (5.8 ± 6.7 days, 10.7 ± 11.1days, 15.2 ± 13.8 days and 22.1 ± 20.3 days; P < 0.001) and mean case costs (3662 ± 3186 €, 5316 ± 6139 €, 6021 ± 4892 €, and 8461 ± 8515 €; P < 0.001) increased continuously in Rutherford 1–3, 4, 5, and 6. While only 49% of the patients suffered from CLI, these produced 65% of in-hospital costs (141 million €), and 56% during follow-up (336 million €). Conclusion Regardless of recent advances in PAD treatment, current outcomes remain poor especially in CLI. Despite overwhelming evidence for reduction of limb loss by revascularization, CLI patients still received significantly less angiographies and revascularizations.

Purpose. Glomerular filtration rate 2 is associated with increased all-cause mortality. Multiple studies have shown that serum cystatin C is more accurate than serum creatinine for detection of mild to moderate chronic kidney dysfunction. We examined the predictive value of the preinterventional cystatin C for all-cause mortality after contrast media exposition. Methods. The prognostic value of preinterventional cystatin C for all-cause mortality was retrospectively analysed in the prospective single-centre “Dialysis-versus-Diuresis” Trial (January 2001–July 2004). Associations during up to 1316 days of followup for all-cause mortality were assessed. The study population consisted of 373 patients (aged 35–89, mean 67 years, 16.4% female). Results. During followup, 65 deaths occurred. Multivariate cox regression confirmed the preinterventional CyC level to be an independent predictor of all-cause mortality (odds ratio 2.061, 95% confidence interval 1.054–4.031, P=0.035). Hazard rate ratio for all-cause mortality was increased in the third cystatin C quartile (>1.4 mg/L) compared with the lowest quartile (P=0.001), in the fourth cystatin C quartile (>1.6 mg/L) compared with the lowest quartile, 5.38, 95% confidence interval 2.329–12.427 (P<0.001). Conclusions. Cystatin C is significantly associated with all-cause mortality after coronarography, regardless of the age, gender, and glomerular filtration rate.

Background Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC. Methods During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns). Results Among the proteins analyzed, only tissue levels of norepinephrine (NE; P < 0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P < 0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls. Conclusions The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of β-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.

Peripheral arterial disease (PAD) and chronic kidney disease (CKD) are major public health problems worldwide. Evaluations of large-scale data on morbidity, outcome, and costs in patients having PAD with CKD are essential. Cross-sectional nationwide population-based analysis of all hospitalizations for PAD during 2009 in Germany focused on the stage-related impact of CKD on morbidity, in-hospital mortality, amputations, length of hospital stay, and health-related expenditure. The total number of hospitalizations was 483 961. Of those, 132 993 (27.5%) had CKD. Chronic kidney disease caused 1.8-fold higher amputation rate ( P < .001) with a stepwise increasing rate with higher CKD stage. Chronic kidney disease doubled in-hospital mortality of patients with PAD (7.8%; n = 10 421) versus 4.0% (n = 14 174, P < .001) with a stepwise increasing risk with higher CKD stage ( P < .001). The highest in-hospital mortality occurred in patients with coprevalence of CKD stage 4 and Fontaine stage IV (16.4%, n = 1176, P < .001). Chronic kidney disease caused 15% higher costs and 21% increased length of stay compared to the whole PAD cohort. This analysis demonstrates the stage-related influence of CKD on morbidity, in-hospital mortality, amputations, length of hospital stay, and reimbursement costs of hospitalized patients with PAD.

Background: In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS. Methods and Results: Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 ± 15 years) and five controls (three male; age 43 ± 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5′monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (Gi1,2α), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, Gi1,2α, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations. Conclusions: The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of β-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis. (PACE 2011; 34:1147–1153)

Aging of the population is one of the major challenges facing public health systems. The impact of aging on acute and long-term outcome of patients with peripheral artery disease (PAD) and critical limb ischemia (CLI) is currently not sufficiently clarified. This analysis consists of comprehensive, anonymized data obtained from the largest public health insurance in Germany.A total of 41,740 PAD patients with an index hospitalization between January 1, 2009, and December 31, 2011, and a follow-up time up to 4 years were included (40-49 years: n = 1179; 50-59 years: n = 5415; 60-69 years: n = 10,565; 70-79 years: n = 13,313; 80-89 years: n = 9714; and 90-100 years: n = 1554). Advanced age was associated with female gender (men-women ratio up to 1:3.3), less smoking, less frequent obesity, more often chronic heart failure (up to 9-fold), chronic kidney disease (up to 4-fold), fewer angiographies (up to 0.8-fold), fewer endovascular (up to 0.5-fold) and surgical revascularizations (up to 0.9-fold), higher rates of amputation (up to 2.5-fold), acute renal failure (up to 3.7-fold), in-hospital mortality (up to 12-fold), myocardial infarction (up to 2.8-fold), ischemic stroke (up to 1.5-fold), infection (up to 1.4-fold), and sepsis (up to 1.8-fold) (each P.001). During follow-up, advanced age was a highly significant independent predictor of long-term mortality, myocardial infarction, and stroke (each P.001). Lengths of hospital stay (up to 1.3-fold longer) and reimbursement costs (up to 1.1-fold higher) were clearly associated with advanced age (each P.001).This study demonstrates the impact of aging on morbidity, in-hospital treatment, complications, and acute and long-term outcome of PAD patients.

The aim of this study was to assess the long-term, all-cause mortality among PAD patients hospitalized for invasive diagnostics and/or endovascular revascularization (ER) and the applied secondary prevention management.From 2005 to 2009, at our center 582 consecutive patients underwent invasive peripheral angiography in part in combination with coronary angiography and/or ER. Patients were classified according to their Fontaine stage into 3 subgroups: Fontaine I/IIa, Fontaine IIb, and Fontaine stages III and IV (which were classified as critical limb ischemia, CLI). Demographic and clinical data were retrospectively obtained and patients followed up.Mean age increased with higher Fontaine stages (P=0.009). The proportion of patients with diabetes and anemia was lowest in Fontaine stage IIb and highest in CLI (each p0.001). The cumulative all-cause mortality during follow-up was 17% in Fontaine stage I/IIa, 22% in Fontaine stage IIb and 34% in CLI, respectively (P0.001). In multivariate cox regression models including diabetes mellitus, gender, age, creatinine and baseline hemoglobin, patients with Fontaine stage IIb had a 1.4-fold (95%CI 0.60-3.16) and those with CLI a 2.3-fold (95%CI 1.03-5.08) increased mortality compared to Fontaine stage I/IIa. At baseline, patients with CLI received significantly less beta blocker, statins, ACE or AT1 inhibitors and less anticoagulants; at follow-up only statins were significantly less often prescribed to CLI patients (all p0.05). Univariate analyses showed that a therapy with statins (HR 0.64; CI 0.43-0.96; P=0.03) and antiplatelet/anticoagulant agents (HR 0.5; CI 0.27-0.94; P=0.03) significantly reduced mortality.Long-term mortality in CLI patients doubles the rate in patients with Fontaine stage I/IIa. Non-adherence to evidence-based recommendations and guidelines such as inadequate use of cardioprotective drugs might contribute to the observed high mortality rates in patients with CLI.

OBJECTIVES In open heart surgery using cardiopulmonary bypass, perfusion of the lower extremities is markedly reduced which may induce critical ischaemia in patients with pre-existing peripheral artery disease. Whether these patients have an increased risk for amputation and should better undergo peripheral revascularization prior to surgery remains unclear. METHODS From 1 January 2009 to 31 December 2010, 785 consecutive patients undergoing open heart surgery were retrospectively included. In 443 of these patients, preoperative ankle brachial index (ABI) measurements were available. The cohort was divided into four groups: (i) ABI < 0.5, (ii) ABI 0.5-0.69, (iii) ABI 0.7-0.89 or (iv) ABI ≥ 0.9. Follow-up data of 413 (93.2%) patients were analysed with regard to mortality and amputations. RESULTS The groups differed significantly in terms of age, cardiac risk factors, performed cardiac surgery and renal function. Postoperative delayed wound healing was significantly associated with lower ABI (25.9, 15.2, 27.0 and 9.6% in Groups I-IV, respectively, P = 0.003), whereas 30-day mortality was not significantly higher in patients with lower ABI (0, 4.3, 8.1 and 3.9%, respectively, P = 0.4). Kaplan-Meier models showed a significantly lower long-term survival over 4 years in patients with reduced ABI (P = 0.001, long-rank test) while amputations occurred rarely with only one minor amputation in Group II (P = 0.023). CONCLUSIONS Patients with reduced ABIs undergoing heart surgery showed more wound-healing disturbances, and higher long-term mortality compared with those with normal ABIs. However, no perioperative ischaemia requiring amputation occurred. Thus, reduced ABIs were not associated with increased peripheral risks in open heart surgery but ABI may be helpful in selecting the site for saphenectomy to potentially avoid delayed healing of related wounds in legs with severely impaired arterial perfusion.

Inherited ventricular arrhythmias such as the long QT syndrome (LQTS), Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), idiopathic ventricular fibrillation (VF), and arrhythmogenic right ventricular cardiomyopathy (ARVC) account for a relevant proportion of sudden cardiac death cases in young patients cohorts. The detailed pathogenetic mechanisms of inherited ventricular arrhythmias are still poorly understood because systematic investigations are difficult to perform due to low patient numbers and the lack of appropriate experimental models. However, recent advances in research and science have identified a genetic background for many of these diseases. Present Knowledge: In LQTS, various mutations in different genes encoding for cardiac potassium and sodium channel proteins have been identified (“channelopathy”), and initial progress in genotype-phenotype correlation is made. Mutations in the cardiac sodium channel gene have also been identified in a subset of patients with Brugada syndrome, whereas a genetic background has not yet been demonstrated in idiopathic VF and right ventricular outflow-tract tachycardia (RVO-VT). Very recently, mutations in the cardiac ryanodine receptor gene have been identified in CPVT and in a subgroup of patients with ARVC. Although several chromosomal loci were suggested, no other responsible genes or mutations have been found in autosomal dominant forms of ARVC. However, in Naxos disease, a recessive form of ARVC with coexpression of palmoplantar keratoderma and woolly hair, a mutation in the plakoglobin gene has recently been discovered, thus underscoring the potential role of genetic alterations in cytoskeletal proteins in ARVC. Future Perspectives: In the next years, significant progress in the genetic diagnosis pathophysiologic understanding of disease mechanisms, genotype-phenotype correlation, and the development of gene- or target-directed treatment strategies can be expected in the field of inherited ventricular arrhythmias. Conclusion: This review summarizes the current knowledge of the molecular mechanisms, including aspects of pathoanatomy, autonomic innervation, genetics, and genotype-phenotype correlations with their potential implications for diagnosis and treatment of inherited ventricular arrhythmias.

Aims The prevalence of peripheral arterial disease (PAD) and especially of critical limb ischaemia (CLI) is announced to rise dramatically worldwide, with a considerable impact on the health care and socio-economic systems. We aimed to characterize the recent trends in morbidity and in-hospital outcome of PAD among all hospitalized patients in the entire German population between 2005 and 2009. Methods and results Nationwide data of all hospitalizations in Germany in 2005, 2007, and 2009 were analysed regarding the prevalence of PAD, comorbidities, endovascular (EVR) and surgical revascularizations (SR), major and minor amputations, in-hospital mortality, and associated costs. From 2005 to 2009, total PAD cases increased by 20.7% (from 400 928 to 483 961), with an increase of CLI subset from 40.6 to 43.5%. Total EVR increased by 46%, while thromb-embolectomy, endarterectomy, and patch plastic increased by 67, 42, and 21%, respectively. Peripheral bypasses decreased by 2%. Major amputation decreased from 4.6 to 3.5%, while minor amputation slightly increased from 4.98 to 5.11%. The crude overall in-hospital mortality remained unchanged in claudicants (2.2%), while it decreased from 9.8 to 8.4% in CLI patients. However, mortality rate according to the Poisson model ( n /1000 hospital residence days) increased significantly in claudicants ( P < 0.001). Total reimbursement costs for PAD in-patient care increased by 21% with an average per case costs in 2009 of €4506 in a claudicant and €6791 in a CLI patient. Conclusion This population-based analysis documents the significant rise of PAD, particularly of the CLI subset, and highlights the malign prognosis associated with PAD as indicated by high amputation and in-hospital mortality rates.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an important cause of sudden cardiac death especially in times of increased sympathetic tone, for example, during sports, which have been confirmed by nuclear imaging studies. However, the underlying biochemical pathways remain to be delineated. Therefore, we investigated the expression levels of proteins of the signaling cascade in patients with ARVC.During diagnostic work-up, right ventricular endomyocardial biopsies (EMBs) were sampled from 15 consecutive male ARVC patients (52 ± 14 years). Tissue levels of key proteins of the signaling cascade were analyzed. Results were compared to those obtained from EMBs of 10 patients with idiopathic right ventricular outflow-tract tachycardia (RVOT; 41 ± 14 years) and of five control subjects without identifiable structural heart disease (42 ± 13 years; P = ns).Among the proteins analyzed, only tissue levels of norepinephrine (NE; P0.04) and cyclic adenosine-3´,5´-monophospate (cAMP; P0.01) were significantly lower in ARVC when compared to RVOT patients. When compared to controls, mean cAMP levels were lower in patients with ARVC but did not reach statistical significance. No differences in cAMP were observed between RVOT and controls.The current findings confirm and expand the concept of adrenergic dysfunction in ARVC: the reduction of NE in ARVC could lead to an impaired stimulation of β-adrenoceptor subsequent signaling pathways with potential implication for cardiac fibrosis and arrhythmogenesis.

Background/Aims: Contrast medium-induced acute kidney injury (CI-AKI) is an important complication following the use of iodinated contrast media. It accounts for a significant number of hospital-acquired acute kidney injuries and is associated with increased in-hospital and long-term mortality and immense health care costs. We evaluated whether the presence of peripheral arterial occlusive disease (PAD) affects the incidence of CI-AKI following heart catheterization. Methods: The impact of PAD on the frequency of CI-AKI after heart catheterization was analysed in the prospective single-centre Dialysis-versus-Diuresis trial (January 2001 to July 2004). The patients were retrospectively divided into 3 subgroups: patients with coronary heart disease (CHD), patients with PAD and patients without PAD or CHD. Results: 412 patients were included (83.5% men, 29.1% diabetes mellitus, 4.9% ejection fraction Conclusion: Patients with PAD significantly more often develop a CI-AKI after heart catheterization than those without PAD.

In patients with Brugada syndrome (BrS), life-threatening ventricular tachyarrhythmias predominantly occur during vagal stimulation at rest or during sleep. Previous imaging studies displayed an impaired autonomic function in BrS patients. However, it remains unclear whether these alterations primarily stem from a reduction of synaptic release of norepinephrine (NE) or an enhanced presynaptic reuptake. Both conditions could lead to reduced NE concentrations in the synaptic cleft. Therefore, we analyzed key components of the sympathoadrenergic signaling pathways in patients with BrS.Endomyocardial biopsies were obtained from eight BrS patients (seven male; age 49 ± 15 years) and five controls (three male; age 43 ± 13 years; P = ns). The concentrations of NE, epinephrine (Epi), NE transport (NET) carrier protein, cyclic adenosine 5'monophosphate (cyclic adenosine monophosphate [cAMP]), inhibitory G-proteins (G(i1,2) α), troponin-I (TNI), and phosphorylated TNI were analyzed. Levels of NET, G(i1,2) α, TNI, Epi, and phosphorylated TNI were comparable between the groups. Compared to controls, patients with BrS showed reduced cAMP and NE concentrations.The current findings expand the concept of adrenergic dysfunction in BrS: the reduction of NE in BrS could lead to an impaired stimulation of β-adrenoceptors resulting in a reduction of cAMP and alterations of the subsequent signaling pathway with potential implication for arrhythmogenesis.

Dilated cardiomyopathy (DCM) is a major cause of heart failure with a high familial recurrence risk. So far, the genetics of DCM remains largely unresolved. We conducted the first genome-wide association study (GWAS) to identify loci contributing to sporadic DCM.One thousand one hundred and seventy-nine DCM patients and 1108 controls contributed to the discovery phase. Pools of DNA stratified on disease status, population, age, and gender were constituted and used for testing association of DCM with 517 382 single nucleotide polymorphisms (SNPs). Three DCM-associated SNPs were confirmed by individual genotyping (P5.0 10(-7)), and two of them, rs10927875 and rs2234962, were replicated in independent samples (1165 DCM patients and 1302 controls), with P-values of 0.002 and 0.009, respectively. rs10927875 maps to a region on chromosome 1p36.13 which encompasses several genes among which HSPB7 has been formerly suggested to be implicated in DCM. The second identified locus involves rs2234962, a non-synonymous SNP (c.T757C, p. C151R) located within the sequence of BAG3 on chromosome 10q26. To assess whether coding mutations of BAG3 might cause monogenic forms of the disease, we sequenced BAG3 exons in 168 independent index cases diagnosed with familial DCM and identified four truncating and two missense mutations. Each mutation was heterozygous, present in all genotyped relatives affected by the disease and absent in a control group of 347 healthy individuals, strongly suggesting that these mutations are causing the disease.This GWAS identified two loci involved in sporadic DCM, one of them probably implicates BAG3. Our results show that rare mutations in BAG3 contribute to monogenic forms of the disease, while common variant(s) in the same gene are implicated in sporadic DCM.