Search

Lowering of low-density lipoprotein (LDL) cholesterol represents one of the most effective interventions in cardiovascular prevention. Besides the oral treatment with statins, ezetimibe and bempedoic acid, subcutaneously administered inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) have been established as further cornerstones of lipid-lowering treatment. The antibodies evolocumab and alirocumab are administered subcutaneously every 2-4 weeks and lower LDL cholesterol by around 60%, independent of pre-treatment with very good tolerability. Both drugs successfully reduced cardiovascular endpoints in large outcome trials. A novel principle of PCSK9 inhibition is RNA interference, which is exploited by the novel compound inclisiran. Inclisiran is a double-stranded modified RNA molecule, which neutralizes the mRNA of PCSK9 and thus inhibits PCSK9 protein synthesis intracellularly. Inclisiran only needs to be administered every 6 months. The cardiovascular outcome trial ORION‑4 is currently ongoing. In Germany, prescription of PCSK9 inhibitors is regulated by the decision of the Federal Joint Committee. Novel strategies to inhibit PCSK9 function are under development and include orally available drugs and animal experiment concepts on gene editing, which are in different states of evaluation.Die therapeutische Senkung des LDL(„low-density lipoprotein“)-Cholesterins ist einer der effektivsten Maßnahmen in der kardiovaskulären Prävention. Neben der oralen Therapie mit Statinen, Ezetimib und Bempedoinsäure haben sich subkutan applizierte Inhibitoren der Proproteinkonvertase Subtilisin/Kexin Typ 9 (PCSK9) als weitere Säule der lipidsenkenden Therapie etabliert. Die alle 2 bis 4 Wochen subkutan zu verabreichenden Antikörper Evolocumab und Alirocumab senken das LDL-Cholesterin unabhängig von der Vorbehandlung um rund 60 % bei sehr guter Verträglichkeit. Für beide Wirkstoffe liegen positive Endpunktstudien vor. Ein neues Prinzip zur PCSK9-Inhibition ist die RNA-Interferenz, welche mit dem Wirkstoff Inclisiran genutzt wird. Bei Inclisiran handelt es sich um ein doppelsträngiges modifiziertes RNA-Molekül, welches die mRNA von PCSK9 neutralisiert und damit die PCSK9-Proteinsynthese intrazellulär hemmt. Inclisiran muss nur halbjährlich appliziert werden. Die Endpunktstudie ORION‑4 läuft gegenwärtig. Die Verschreibung von PCSK9-Hemmern ist in Deutschland durch einen Beschluss des Gemeinsamen Bundesausschusses reglementiert. Neue Strategien zur PCSK9-Hemmung sind in Entwicklung und umfassen u. a. oral verfügbare Wirkstoffe und tierexperimentelle Konzepte zur Gentherapie, welche sich in unterschiedlichen Stadien der Prüfung befinden. more...

BackgroundThe persistence of the SARS-CoV2 pandemic, partly due to the appearance of highly infectious variants, has made booster vaccinations necessary for vulnerable groups. Questions remain as to which cohorts require SARS-CoV2 boosters. However, there is a critical lack of data on the dynamics of vaccine responses in patients with chronic inflammatory diseases (CID) undergoing immunosuppressive/disease modifying anti-rheumatic (DMARD) treatment. Here, we present the first data regarding the decline of the vaccine-induced humoral immune responses in patients with CID.Methods23 patients with CID were monitored clinically and for anti-spike IgG and IgA levels, neutralization efficacy and antigen-specific CD4+ T cell responses over the first 6 months after SARS-CoV2 vaccination. 24 healthy individuals were included as controls.ResultsWhile anti-spike IgG-levels declined in CID patients and healthy controls, patients receiving anti-TNF treatment showed significantly greater declines at 6 months post second vaccination in IgG and especially neutralizing antibodies. IgA levels were generally lower in CID patients, particularly during anti-TNF therapy. No differences in SARS-CoV2 spike-specific CD4+ T-cell frequencies were detected.ConclusionAlthough the long-term efficacy of SARS-CoV2 vaccination in CID patients undergoing disease-modifying therapy is still not known, the pronounced declines in humoral responses towards SARS-CoV2 6 months after mRNA vaccination in the context of TNF blockade should be considered when formulating booster regimens. These patients should be considered for early booster vaccinations. more...

Epidemiological and clinical studies have shown a relevant association between heart rate and cardiovascular mortality. Experimental studies identified vascular effects of heart rate reduction with the If channel inhibitor ivabradine. Therefore, the effects of heart rate reduction on endothelial function and indices of arterial stiffness were examined in patients with stable coronary artery disease in a prospective, placebo-controlled clinical crossover study.Twenty-three patients (18 men and 5 women) with a resting heart rate (HR) of at least 70 beats per minute (bpm) and stable coronary artery disease were enrolled in this study. In a cross-over design, all patients were treated with ivabradine (Iva, 7.5 mg b.i.d.) and placebo for 6 months each. Iva reduced heart rate by 11.4 bpm (Iva 58.8 ± 8.2 bpm vs. placebo 70.2 ± 8.3 bpm, P 0.0001). Augmentation index (AIx75), carotid-femoral pulse wave velocity (cfPWV) and central aortic blood pressure were measured using applanation tonometry (SphygmoCor). HRR by Iva increased AIx75 by 12.4% (Iva 24.3 ± 10.5% vs. placebo 21.3 ± 10.1%, P 0.05) and reduced cfPWV by 14.1% (Iva 6.3 ± 1.7 m/s vs. placebo 7.3 ± 1.4 m/s, P 0.01). Iva increased mean central blood pressure by 7.8% (Iva 107.5 ± 15.4 mmHg vs. placebo 99.1 ± 12.2 mmHg, P 0.001). Endothelial function was determined measuring the flow-mediated vasodilation (FMD) of the brachial artery. HRR by Iva increased FMD by 18.5% (Iva 7.3 ± 2.2% vs. placebo 6.0 ± 2.0%, P 0.001). Aortic distensibility was characterized by MRI. HRR by Iva increased aortic distensibility by 33.3% (Iva 0.003 ± 0.001/mmHg vs. placebo 0.002 ± 0.010/mmHg, P 0.01) and circumferential cyclic strain by 37.1% (Iva 0.062 ± 0.027 vs. placebo 0.039 ± 0.018, P 0.0001).Heart rate reduction with Iva increased endothelium-dependent vasodilation and reduced arterial stiffness in patients with stable CAD. These findings corroborate and expand the results collected in experimental studies and indicate the importance of heart rate as a determinant of vascular function. more...

Only fifteen months after the beginning of the COVID-19 pandemic, several vaccines are already available for clinical use. While the spike protein of SARS-CoV-2 constitutes the main target of all predominant SARS-CoV-2 vaccines, they work by different mechanisms (mRNA-based vaccines vs. vector-based vaccines vs. protein-based vaccines).Though there are slight differences regarding the level of protection against mild COVID-19, all five vaccines that have been through phase 3 trials were nearly 100 % effective in preventing severe or fatal cases of COVID-19. The side effects were of short duration.Patients with chronic kidney disease (or other significant comorbidities) were largely excluded from Phase 3 trials, which makes definite recommendations concerning their vaccination difficult. The vaccine's effectiveness may be reduced in that population due to a uremic immune defect and/or immunosuppressive medication. However, these patients have an increased risk for severe or fatal COVID-19, so that they may particularly benefit from the vaccine. Innerhalb von nur 15 Monaten nach Beginn der COVID-19-Pandemie stehen bereits mehrere SARS-CoV-2-Impfstoffe zum klinischen Einsatz bereit. Während das Zielmolekül aller prädominierenden Vakzine das Spike-Protein von SARS-CoV-2 ist, lassen sie sich anhand ihres Wirkprinzip in mRNA-basierte, Vektor-basierte und Protein-basierte Impfstoffe unterscheiden. BEDEUTUNG FüR CHRONISCH NIERENKRANKE MENSCHEN: Das Aussprechen von Empfehlungen für chronisch nierenkranke Menschen ist aufgrund deren geringer Repräsentation in den Zulassungsstudien erschwert – wie bei anderen Patienten mit schwerer Komorbidität. Aufgrund von urämischem Immundefekt und/oder medikamentöser Immunsuppression könnte die Effektivität der Impfung im Einzelfall relativ vermindert sein. Dennoch profitieren vermutlich gerade diese Patienten von einer Impfung, da sie ein erhöhtes Risiko für einen schweren oder gar tödlichen COVID-19-Verlauf aufweisen. more...

We aimed to explore whether interventional closure of patent foramen ovale (PFO) results in reduction of composite outcome [stroke/transitory ischemic attack (TIA), death, and thrombolysis in myocardial infarction—TIMI bleeding], stroke and stroke/TIA compared to medical treatment in patients with cryptogenic stroke. Searching the PUBMED and Cochrane library database, we performed meta-analysis from all randomized controlled studies that compared effects of interventional PFO closure with medical treatment on stroke prevention. 3560 patients from six randomized trials were included. Interventional PFO closure reduced composite outcome (RR of 0.47, 0.26–0.85, p = 0.01), stroke (RR of 0.38, 0.18–0.82, p = 0.01) and stroke/TIA (RR of 0.56, 0.43–0.74, p more...

IgG4-related disease (IgG4-RD) is an entity first described less than 20 years ago, characterized by tumorous swelling of affected organs. Differentiation from malignant disease, systemic infections and other systemic autoimmune diseases can be challenging. Typical histopathologic findings facilitate a diagnosis in a compatible clinical context. Because nearly every organ system can be affected, management of IgG4-RD is a challenging task requiring multidisciplinary work-up and treatment. Medical treatment usually consists of glucocorticoids, which may be combined with other immunosuppressives. Surgical or interventional treatment may be necessary if complications arise. Since high-quality evidence is lacking for most aspects of the management of IgG4-RD, international collaborative studies are urgently needed.ÜBERSICHT UND NOMENKLATUR: Die IgG4-assoziierte Erkrankung (IgG4-RD) ist eine erst kürzlich beschriebene heterogene Krankheitsentität, der viele vorher als eigenständige Einzelorganerkrankungen interpretierte Manifestationen zugerechnet werden. Hauptsymptom ist die Schwellung oder Vergrößerung betroffener Organe.Die Diagnose wird in Zusammenschau von Anamnese, klinischem Bild, Bildgebung, Histopathologie und IgG4-spezifischen Tests in Labor und Histologie gestellt.Häufige Laborbefunde sind: erhöhtes Serum-IgG4, IgE und CRP, Hypergammaglobulinämie, Hypokomplementämie und Eosinophilie.Das typische Bild umfasst folgende Hauptcharakteristika: dichte lymphoplasmazelluläre Infiltrate, storiforme Fibrose und obliterative Phlebitis. Ferner treten vermehrte IgG4-positive Plasmazellen auf.Diverse andere Krankheitsbilder können die IgG4-RD imitieren. MEDIKAMENTöSE THERAPIE: Neu sind eine Studie zu Mycophenolat-Mofetil und Daten zu Rituximab bei sonst weitgehend fehlender Evidenz aus Studien zur Behandlung der IgG4-RD.Glukokortikoide (GC) sind die Grundlage der medikamentösen Therapie.Es herrscht weiterhin kein Konsens, ob konventionelle Immunsuppressiva als GC-sparende Therapie immer oder nur in besonderen Fällen Teil der medikamentösen Therapie sein sollten.Rituximab ist eine etablierte Reservetherapie.Mechanische Obstruktionen und Kompressionen können chirurgische und interventionelle Verfahren notwendig machen. more...

Due to a high rate of cardiovascular events and the high-incidence of atrial fibrillation, many patients with chronic kidney disease (CKD) need to be anticoagulated and/or be subjected to anti platelet therapy (APT). As most studies historically excluded patients with CKD and a creatinine-clearance below 30 ml/min, guidelines for this patient group are only slowly being renewed depending on emerging study data.In patients with CKD stage 1-3, any non-vitamin K dependent oral anticoagulant (NOAC) should be preferentially used over vitamin K antagonists (VKA). In CKD stage 4, dabigatran should be avoided.The decision to anticoagulate a maintenance dialysis patient with atrial fibrillation has to be made on an individual basis considering their thrombosis and bleeding risk. Currently, in Europe all oral anticoagulants can be used only on an off-label basis in these patients. Randomized controlled trials investigating the efficacy and safety of apixaban versus VKA are currently underway. Alternative treatment options (e. g. left appendage occlusion) should be considered.Study data on APT in moderate to advanced CKD are similarly scarce. Despite APT not being renally eliminated, bleeding risk is increased due to uremic platelet dysfunction. When combining APT with NOAC, dose reduction of the latter needs to be addressed.ORALE ANTIKOAGULATION BEI NICHT DIALYSEPFLICHTIGER CHRONISCHER NIERENKRANKHEIT: In großen Zulassungsstudien haben sich die Nicht-Vitamin-K-abhängigen oralen Antikoagulanzien (NOAK) bei Patienten mit nicht valvulärem Vorhofflimmern als mindestens so effektiv in der Verhinderung thromboembolischer Ereignisse gezeigt wie Vitamin-K-Antagonisten (VKA). Die NOAK zeigen generell eine geringere Neigung zu schweren, lebensbedrohlichen Blutungen als die VKA. In den Zulassungsstudien wurden Patienten mit einer Kreatinin-Clearance von kleiner 30 ml/min meist nicht inkludiert, sodass für Patienten mit einer Kreatinin-Clearance von 15–30 ml/min zwar für Rivaroxaban, Apixaban und Edoxaban eine Zulassung besteht, die Datenlage zur Effektivität und Sicherheit jedoch nicht so fundiert ist wie bei Patienten mit einer Kreatinin-Clearance von 30 ml/min. ANTIKOAGULATION BEI TERMINALER NIERENINSUFFIZIENZ: Die Indikation zur Antikoagulation muss bei chronischen Dialysepatienten mit Vorhofflimmern derzeit weiterhin individualisiert gestellt werden. Es ist in diesem Kollektiv unklar, ob dialysepflichtige VHF-Patienten überhaupt von einer oralen Antikoagulation profitieren und welches hierfür eine sichere und effektive Substanz ist: Randomisiert-kontrollierte Studien zu Apixaban versus VKA werden klären, ob NOAK eine sichere und effiziente Therapiestrategie bei diesem Patientenkollektiv sind (RENAL-AF, AXADIA). THROMBOZYTENAGGREGATIONSHEMMUNG BEI CHRONISCHER NIERENKRANKHEIT: Generell sollten Patienten auch mit schwerer CKD oder Dialysepflichtigkeit die Thrombozytenaggregationshemmung nach kardiologischer Leitlinienempfehlung erhalten. Auf dem Boden des erhöhten Blutungsrisikos in diesem Kollektiv erscheinen moderne Kombinationen aus NOAK und einer einzelnen TAH-Substanz, die das alte „Triple-Regime“, bestehend aus doppelter TAH plus VKA ersetzen, besonders interessant. more...

Moderate consumption of red wine is associated with fewer cardiovascular events. We investigated whether red wine consumption counteracts the adverse vascular effects of cigarette smoking.Participants smoked 3 cigarettes alone or after drinking a titrated volume of red wine. Clinical chemistry, blood counts, plasma cytokine enzyme-linked immunosorbent assays, immunomagnetic separation of CD14Compared with baseline, leukocytosis (P = .019), neutrophilia (P.001), lymphopenia (P .001), and eosinopenia (P = .008) were observed after only smoking. Endothelial and platelet-, monocyte-, and leukocyte-derived microparticles (P.001 each) were elevated. In monocytes, messenger RNA expression of interleukin (IL)-6 (2.6- ± 0.57-fold), tumor necrosis factor alpha (2.2- ± 0.62-fold), and IL-1b (2.3- ± 0.44-fold) were upregulated, as was IL-6 (1.2 ± 0.12-fold) protein concentration in plasma. Smoking acutely inhibited mononuclear cell telomerase activity. Markers of endothelial damage, inflammation, and cellular aging were completely attenuated by red wine consumption.Cigarette smoke results in acute endothelial damage, vascular and systemic inflammation, and indicators of the cellular aging processes in otherwise healthy nonsmokers. Pretreatment with red wine was preventive. The findings underscore the magnitude of acute damage exerted by cigarette smoking in "occasional lifestyle smokers" and demonstrate the potential of red wine as a protective strategy to avert markers of vascular injury. more...

Mitral regurgitation represents a volume load on the left ventricle leading to congestion and symptoms of heart failure. The aim of this study was to characterize early hemodynamic adaptions after percutaneous mitral valve (MV) repair.Forty-six consecutive patients with symptomatic high-grade MV insufficiency (mean age, 72 years; 54% men) were prospectively included in the study and examined before and after successful catheter-based clip implantation. Seventy percent of patients had secondary mitral regurgitation. Noninvasive pressure-volume loops were reconstructed from echocardiography with simultaneous blood pressure measurements.MV repair reduced left ventricular end-diastolic volume index from 87 ± 41 to 80 ± 40 mL/m(2) (P .0001). End-systolic volume index was 55 ± 37 mL/m(2) before versus 54 ± 37 mL/m(2) after repair (P = .52). Hence, total stroke volume decreased from 60 ± 23 to 49 ± 16 mL (P .0001), as did total ejection fraction (from 41 ± 14% to 37 ± 13%, P = .002) and global longitudinal strain (from -11 ± 4.9% to -9.1 ± 4.4%, P = .0001). Forward stroke volume, forward ejection fraction, and forward cardiac output remained constant (43 ± 12 mL vs 42 ± 11 mL, 33 ± 17% vs 35 ± 18%, and 3.2 ± 0.9 L/min vs 3.4 ± 0.8 L/min, respectively). Parameters of left ventricular contractility (end-systolic elastance and peak power index) and measurements of afterload (arterial elastance, end-systolic wall stress, and total peripheral resistance) were similar before and after MV repair. Forward ejection fraction correlated more strongly with end-systolic elastance (r = 0.61, P .0001) than did total ejection fraction (r = 0.35, P = .0007) or global longitudinal strain (r = -0.38, P = .0002). Total mechanical energy (pressure-volume area) decreased from 10,903 ± 4,410 to 9,124 ± 2,968 mm Hg × mL (P = .0007) because of reduced stroke work (5,546 ± 2,241 mm Hg × mL vs 4,414 ± 1,412 mm Hg × mL, P .0001). At 3 months, symptom status had improved (76% of patients in New York Heart Association classes I and II), and 97% of patients had mitral regurgitation grade ≤2+.Left ventricular contractility and forward cardiac output remained unchanged after percutaneous MV repair despite decreases in total ejection fraction and global longitudinal strain. The left ventricle was unloaded through reduced end-diastolic volume. Thus, MV repair is associated with an improved hemodynamic state in noninvasive pressure-volume analysis. more...

Die Polyarteriitis nodosa (PAN) ist eine nekrotisierende Arteriitis mittelgroser Gefase, die unbehandelt oftmals letal verlauft. Sie manifestiert sich haufig an der Haut (Noduli oder Ulzera), am peripheren Nervensystem (Mononeuritis multiplex) und durch Stenosen und Mikroaneurysmen der viszeralen Gefase. Die Diagnose erfordert eine komplexe diagnostische Aufarbeitung zur Abgrenzung von infektiosen, malignen, medikamenteninduzierten und anderen inflammatorischen Erkrankungen. Die PAN kann in weitere Varianten unterteilt werden (idiopathisch, Hepatitis-B-assoziiert, mit hereditaren inflammatorischen Syndromen assoziiert und eine isoliert kutane Verlaufsform). Wahrend idiopathische und hereditar inflammatorische Formen einer immunsuppressiven Therapie bedurfen, wird die Hepatitis-B-assoziierte Variante mit Virostatika und Plasmapherese behandelt. Die Prognose der isoliert kutanen Form ist gut und bedarf selten hochpotenter Immunsuppression. more...

Objective To evaluate the clinical presentation and long-term outcome of a vasculitis centre cohort of patients with microscopic polyangiitis (MPA) with respect to organ manifestations, treatment, chronic damage and mortality. Methods We performed a retrospective chart review at our vasculitis referral centre. MPA patients admitted between 1991 and 2013 classified by a modified European Medicines Agency algorithm were diagnosed and treated according to a standardized interdisciplinary approach. Results Comprehensive data from standardized interdisciplinary workups was available for 144 patients (median follow-up 72 months). The overall standardized mortality ratio was 1.40 (95% CI 0.91, 2.07; P = 0.13). We observed a higher mortality [hazard ratio (HR) 4.04 (95% CI 1.21, 13.45), P = 0.02] in 17 patients with MPA-associated fibrosing interstitial lung disease (ILD) and 56 patients with peripheral nervous system involvement [HR 5.26 (95% CI 1.10, 25.14), P = 0.04] at disease onset. One hundred and fifteen patients (79.9%) responded to the initial treatment. Sixty-one (42.3%) achieved complete remission and 54 (37.5%) achieved partial remission. Twenty (13.9%) showed a refractory disease course. Conclusion MPA patients at our tertiary rheumatology referral centre seemed to have a less severe phenotype resulting in a less severe disease course and better outcome than reported in other cohorts. Fibrosing ILD was significantly associated with mortality in this cohort. more...

ObjectivesThis study sought to investigate left atrial (LA) remodeling in relation to blood pressure (BP) and heart rate (HR) after renal sympathetic denervation (RDN).BackgroundIn addition to reducing BP and HR in certain patients with hypertension, RDN can decrease left ventricular (LV) mass and ameliorate LV diastolic dysfunction.MethodsBefore and 6 months after RDN, BP, HR, LV mass, left atrial volume index (LAVI), diastolic function (echocardiography), and premature atrial contractions (PAC) (Holter electrocardiogram) were assessed in 66 patients with resistant hypertension.ResultsRDN reduced office BP by 21.6 ± 3.0/10.1 ± 2.0 mm Hg (p < 0.001), and HR by 8.0 ± 1.3 beats/min (p < 0.001). At baseline, LA size correlated with LV mass, diastolic function, and pro-brain natriuretic peptide, but not with BP or HR. Six months after RDN, LAVI was reduced by 4.0 ± 0.7 ml/kg/m2 (p < 0.001). LA size decrease was stronger when LAVI at baseline was higher. In contrast, the decrease in LAVI was not dependent on LV mass or diastolic function (E/E′ or E/A) at baseline. Furthermore, LAVI decreased without relation to decrease in systolic BP or HR. Additionally, occurrence of PAC (median of >153 PAC/24 h) was reduced (to 68 PAC/24 h) by RDN, independently of changes in LA size.ConclusionsIn patients with resistant hypertension, LA volume and occurrence of PAC decreased 6 months after RDN. This decrease was independent of BP and HR at baseline or the reduction in BP and HR reached by renal denervation. These data suggest that there is a direct, partly BP-independent effect of RDN on cardiac remodeling and occurrence of premature atrial contractions. more...

Background Correction of mitral regurgitation (MR) alters the load on the left ventricle. There are few data on the long-term hemodynamic adaptations of the cardiovascular system after transcatheter mitral valve repair (TMVR). The aim of this study was to determine a comprehensive hemodynamic status using noninvasive pressure-volume analysis. Methods Pressure-volume parameters were calculated from echocardiography with simultaneous arm-cuff blood pressure measurements at baseline before TMVR and 12 months after TMVR. Eighty-eight consecutive patients undergoing edge-to-edge mitral clip implantation because of grade 3+ or 4+, symptomatic (79.5% in New York Heart Association functional class ≥III) MR were prospectively enrolled. The mean left ventricular (LV) ejection fraction was 42 ± 14%. Sixty-seven percent of the patients had secondary MR. Results Twelve months after TMVR, 17.7% of patients had died, and 19.0% were rehospitalized because of decompensated heart failure. MR grade was ≤2+ in 90% of surviving patients, and 77% were in New York Heart Association functional class ≤II. LV end-diastolic volume index decreased from 87 ± 38 to 77 ± 40 mL/m2 (P Conclusions One year after TMVR, patients showed reverse remodeling and improved LV performance that was associated with improved symptom status. This hemodynamic improvement supports TMVR as long-term effective therapy for patients with symptomatic MR. more...

Secondary mitral regurgitation (MR) results from left ventricular dilatation and dysfunction. Quantification of secondary MR is challenging because of the underlying myocardial disease. Clinical and echocardiographic evaluation requires a multi‐parametric approach. Severe secondary MR occurs in up to one‐fourth of patients with heart failure with reduced ejection fraction, which is associated with a mortality rate of 40% to 50% in 3 years. Percutaneous edge‐to‐edge mitral valve repair (MitraClip) has emerged as an alternative to surgical valve repair to improve symptoms, functional capacity, heart failure hospitalizations, and cardiac haemodynamics. Further new transcatheter strategies addressing MR are evolving. The Carillion, Cardioband, and Mitralign devices were designed to reduce the annulus dilatation, which is a frequent and important determinant of secondary MR. Several transcatheter mitral valve replacement systems (Tendyne, CardiAQ‐Edwards, Neovasc, Tiara, Intrepid, Caisson, HighLife, MValve System, and NCSI NaviGate Mitral) are emerging because valve replacement might be more durable compared with valve repair. In small studies, these interventional therapies demonstrated feasibility and efficiency to reduce MR and to improve heart failure symptoms. However, neither transcatheter nor surgical mitral valve repair or replacement has been proven to impact on the prognosis of heart failure patients with severe MR, which remains high with a mortality rate of 14–20% at 1 year. To date, the primary indication for treatment of secondary severe MR is the amelioration of symptoms, reinforcing the value of a Heart Team discussion. Randomized studies to investigate the treatment effect and long‐term outcome for any transcatheter or surgical mitral valve intervention compared with optimized medical treatment are urgently needed and underway. more...

Patients with CKD on hemodialysis exhibit increased cardiovascular risk. Fibrin clot structure and clot lysis are crucially involved in development of cardiovascular events, but little is known about the influence of clot density on outcome in patients on hemodialysis. We determined fibrin clot structure parameters and effect on mortality in a prospective cohort of 171 patients on chronic hemodialysis (mean±SD age =59±11 years old; 54% men) using a validated turbidimetric assay. Kaplan–Meier analysis revealed that patients on hemodialysis with a denser clot structure had increased all–cause and cardiovascular mortality risks (log rank P=0.004 and P=0.003, respectively). Multivariate Cox regression models (adjusted for age, diabetes, sex, and duration of dialysis or fibrinogen, C-reactive protein, and complement C3) confirmed that denser clots are independently related to mortality risk. We also purified fibrinogen from healthy controls and patients on hemodialysis using the calcium–dependent IF-1 mAb against fibrinogen for additional investigation using mass spectrometric analysis and electron microscopy. Whereas purified fibrinogen from healthy controls displayed no post-translational modifications, fibrinogen from patients on hemodialysis was glycosylated and guanidinylated. Clots made of purified fibrinogen from patients on hemodialysis exhibited significantly thinner fibers compared with clots from fibrinogen of control individuals (mean±SD =63±2 and 77±2 nm, respectively; P more...

The activation of inflammasome signaling mediates pathology of acute Pseudomonas aeruginosa pneumonia. This suggests that the inflammasome might represent a target to limit the pathological consequences of acute P. aeruginosa lung infection. Pannexin-1 (Px1) channels mediate the activation of caspase-1 and release of IL-1β induced by P2X7 receptor activation. The approved drug probenecid is an inhibitor of Px1 and ATP release. In this study, we demonstrate that probenecid reduces infection and inflammation in acute P. aeruginosa pneumonia. Treatment of mice prior to infection with P. aeruginosa resulted in an enhanced clearance of P. aeruginosa and reduced levels of inflammatory mediators, such as IL-1β. In addition, probenecid inhibited the release of inflammatory mediators in murine alveolar macrophages and human U937 cell-derived macrophages upon bacterial infection but not in human bronchial epithelial cells. Thus, Px1 blockade via probenecid treatment may be a therapeutic option in P. aeruginosa pneumonia by improving bacterial clearance and reducing negative consequences of inflammation. more...

Learning objectives Five years have passed since the first study on percutaneous renal denervation (RDN) to treat resistant hypertension was published.1 During its short life this technique has demonstrated its safety and efficacy in reducing blood pressure (BP), and also its appreciable indirect effects on cardiovascular remodelling and pleiotropic effects on other pathologies characterised by high sympathetic activity. Some questions about renal nerve distribution, predictors of BP response, and indices of effective denervation still remain unanswered. Moreover, the results of the Symplicity HTN-3 study are in contrast with previous findings and have raised many questions. Over time, new devices have been developed that permit a faster and more complete ablation. Sympathetic fibres to the kidneys descend the spinal cord from the brain until they reach the lower thoracic and upper lumbar spinal nerves. Fibres then pass to the adjacent ganglia in the sympathetic trunks, continuing in the postganglionic fibres which form a circumferential ‘basket-weave plexus’w1 in the adventitia of the renal artery (RA). Afferent fibres from the kidneys follow similar routes in the reverse direction. There is still debate regarding the location and distribution of renal nerves … more...

Heart failure is associated with activation of the sympathetic nervous system which presumably results in a progression of the syndrome and thereby in poor outcome. Renal denervation has shown to be effective in conditions with enhanced sympathetic activity like resistant hypertension and metabolic syndrome associated with sleep apnea. The first pilot trials assessing the effect of renal denervation on signs and symptoms of heart failure in patients with both preserved and reduced left ventricular ejection fraction are presently ongoing. The results of these studies will determine whether to proceed with larger prospective outcome trials. Altogether, renal denervation is a promising novel technique that may improve the outcome of patients with sympathetic hyperactivity and cardiovascular diseases. more...

Rheumatologist should be familiar with the concept of IgG4-related disease (IgG4-RD). Due to the clinical spectrum IgG4-RD can fall directly within the scope of rheumatology and are often diagnosed primarily by rheumatologists. Furthermore, IgG4RD are relevant differential diagnoses for many other rheumatic conditions. Finally, there are an increasing amount of data suggesting an important role of immunological processes observed in IgG4-RD for other rheumatic diseases. more...

Atherosclerosis has been characterized as an inflammatory process, in which monocytes and monocyte-derived macrophages are of paramount importance. Contrasting with their established role in atherosclerosis, monocytes have not unanimously been found to predict cardiovascular events in large epidemiological studies. However, in these studies human monocyte heterogeneity has been largely overlooked so far. Three human monocyte subsets can be distinguished: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+) and nonclassical CD14(+)CD16(++) monocytes. Of note, correct enumeration of subset counts requires appropriate staining and gating strategies that encompass a pan-monocytic marker (e.g. HLA-DR or CD86). In experimental studies on murine atherogenesis a monocyte subset-specific contribution to atherosclerosis has been established. However, major interspecies differences in atherogenesis itself, as well as in the immune system (including monocyte subset phenotype and distribution) preclude a direct extrapolation to human pathology. Experimental and pilot clinical studies point to a prominent involvement of intermediate CD14(++)CD16(+) monocytes in human atherosclerosis. Future clinical studies should analyze monocyte heterogeneity in cardiovascular disease. If a specific contribution of intermediate monocytes should be confirmed, immunomodulation of this monocyte subset could represent a future therapeutic target in atherosclerosis. more...

This summary article provides an update on novel clinical trials in the field of cardiovascular medicine which were presented at the annual meeting of the European Cardiac Society, held in Munich, Germany, in August 2012. The data were presented by leading experts in the field with relevant positions in the trials and registries. Unpublished reports should be considered as preliminary data as the analysis may change in the final publications. This article provides the reader with comprehensive summaries of the most recent diagnostic and therapeutic developments in cardiovascular medicine as previously reported (Walenta et al. in Clin Res Cardiol 100:955-971, 2011; Schirmer et al. in Clin Res Cardiol 98:691-699, 2009). more...

ObjectivesThis study investigated the effect of catheter-based renal sympathetic denervation (RD) on left ventricular hypertrophy (LVH) and systolic and diastolic function in patients with resistant hypertension.BackgroundLVH and diastolic dysfunction are associated with elevated sympathetic activity and increased morbidity and mortality. The effect of RD on LVH and LV function is unclear.MethodsForty-six patients underwent bilateral RD, and 18 patients served as controls. Transthoracic echocardiography was performed at baseline, and after 1 month and 6 months.ResultsBesides reduction of systolic and diastolic blood pressure (−22.5/−7.2 mm Hg at 1 month and −27.8/−8.8 mm Hg at 6 months, p < 0.001 at each time point), RD significantly reduced mean interventricular septum thickness from 14.1 ± 1.9 mm to 13.4 ± 2.1 mm and 12.5 ± 1.4 mm (p = 0.007), and LV mass index from 53.9 ± 15.6 g/m2.7 (112.4 ± 33.9 g/m2) to 47.0 ± 14.2 g/m2.7 (103.6 ± 30.5 g/m2) and 44.7 ± 14.9 g/m2.7 (94.9 ± 29.8 g/m2) (p < 0.001) at 1 month and 6 months, respectively. The mitral valve lateral E/E′ decreased after RD from 9.9 ± 4.0 to 7.9 ± 2.2 at 1 month and 7.4 ± 2.7 at 6 months (p < 0.001), indicating reduction of LV filling pressures. Isovolumic relaxation time shortened (baseline 109.1 ± 21.7 ms vs. 85.6 ± 24.4 ms at 6 months, p = 0.006), whereas ejection fraction significantly increased after RD (baseline: 63.1 ± 8.1% vs. 70.1 ± 11.5% at 6 months, p < 0.001). No significant changes were obtained in control patients.ConclusionsBesides the known effect on blood pressure, our study showed for the first time that RD significantly reduces LV mass and improves diastolic function, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk. more...

Aims Peripartum cardiomyopathy (PPCM) is associated with high mortality and morbidity. Endothelial damage involving cathepsin-D to form a 16 kDa prolactin (PRL) peptide is pathogenetically relevant. Inhibiting PRL peptide with bromocriptine has yielded promising results. We investigated whether microparticles (MPs) can be quantified in serum as markers for diagnosis and treatment effects in PPCM. Methods and results Patients with PPCM were compared with age-matched healthy post-partum women (PPCTR), healthy pregnant women (PCTR), healthy non-pregnant women (NPCTR), patients with ischaemic cardiomyopathy (ICM), patients with stable coronary artery disease (CAD) and healthy controls (HCTR). Peripartum cardiomyopathy treated with bromocriptine (PPCM-BR) and with PPCM without bromocriptine-treatment as control (PPCM-BRCTR) were compared. Microparticles were determined by flow cytometry. Endothelial MPs (EMPs) were elevated in PPCM compared with PPCTR, PCTR, and NPCTR, each P < 0.001. They were significantly elevated compared with ICM, CAD, and HCTR ( P < 0.001). Pregnancy (PCTR) exhibited only slight increases vs. ICM, CAD, NPCTR, and HCTR. The increase in PPCM was due to an increase of activated but not apoptotic EMPs. Platelet-derived microparticles were highly increased in PPCM compared with ICM ( P < 0.001) but 9.3 ± 4.4-fold compared with CAD ( P < 0.001). In NPCTR ( P < 0.001) compared with NPCTR, the increase was 5.9 ± 1.7-fold ( P < 0.001). Microparticles generated from monocytes (MMPs) were increased 2.4 ± 1.8-fold in PPCM compared with PCTR ( P < 0.001) and 4.8 ± 3.6-fold compared with CAD ( P < 0.001), whereas leucocyte MPs (LMPs) were not significantly elevated. Endothelial microparticles were significantly reduced in PPCM treated additionally with bromocriptine compared with PPCM treated only with heart failure therapy ( P < 0.001). Conclusion Microparticle profiles may in long-term distinguish PPCM from normal pregnancy, heart failure, and vascular diseases and might be a diagnostic marker related to the pathomechanism of PPCM. more...

Heart failure is a frequent and life-threatening syndrome which is not only the result of myocardial injury or hemodynamic overload as commonly perceived, but appears to be the result of an interplay among genetic, neurohormonal, inflammatory, and biochemical factors, collectively referred to as biomarkers. Biomarkers can become risk factors in case their therapeutic modification results in an improvement of clinical outcomes. Among those markers identified in patients with heart failure, a number appears to have direct clinical relevance in aiding diagnosis, risk stratification, monitoring therapy, and treating to targets in order to improve clinical outcomes. These include brain natriuretic peptides (e.g., BNP, NT-proBNP), inflammatory markers (e.g., hsCRP), neurohormones (e.g., aldosterone), cardiorenal markers (e.g., cycstatin C), and novel markers (e.g., galectin-3). While their utility to indicate risk is mostly well established, there are less data to establish that a treatment using biomarkers as a guidance results in better outcomes than a more generalized intensified treatment of patients with heart failure. Future directions may involve larger platforms that facilitate to simultaneously analyze hundreds of biomarkers and may help to tailor heart failure therapy on a single patient basis, considering the specific pathogenesis and prognosis. Also from a therapeutic perspective there are data that a single intervention such as aldosterone blockade may affect multiple biomarkers at the same time. Taken together the data indicate that biomarkers are evolving into a valuable addendum to the diagnostic and therapeutic armamentarium. more...

Background Whiplash is the most common type of injury reported in traffic accidents, but the effectiveness of conservative treatment for whiplash lacks evidence. Aims To assess the effect of early multidisciplinary evaluation and advice on the frequency of chronic neck pain three years post-injury in persons with minor or moderate traffic injuries. Methods In an insurance setting, we tested the effect by (1) a risk score matched prospective cohort design, (2) a propensity score matched nested case-control design and, (3) a risk and propensity score adjusted multivariate analysis in an unmatched prospective cohort design. We simulated unobserved risk and propensity factors to evaluate the robustness of the results for hidden bias. Results All three designs showed a significantly increased risk for chronic neck pain among those who received the intervention compared to those who did not. The relative risks ranged from 1.7 (95% CI: 1.0–2.6) to 2.6 (95% CI: 1.5–4.0). The results were robust to hidden bias. Conclusion The consistency of the findings across the different designs strongly suggest that early multidisciplinary evaluation and advice increased the risk of having chronic neck pain three years following a minor or moderate traffic injury. Literally, the intervention may therefore have done more harm than good. more...

This review article gives an overview on a number of novel clinical trials and registries in the field of cardiovascular medicine. Key presentations made at the 75th annual meeting of the German Cardiac Society, held in Mannheim, Germany, in April 2009 are reported. The data were presented by leading experts in the field with relevant positions in the trials and registries. These comprehensive summaries should provide the readers with the most recent data on diagnostic and therapeutic developments in cardiovascular medicine similar as previously reported (Rosenkranz et al. in Clin Res Cardiol 96:457–468, 9; Maier et al. in Clin Res Cardiol 97:356–363, 3). peerReviewed more...

During collateral artery growth, monocytes adhere to the endothelium and secrete cytokines from the perivascular space promoting arteriogenesis. Recently, the endothelial glycocalyx has been shown to modulate leucocyte infiltration in atherogenic regions. The role of this endothelial surface coating in arteriogenesis, however, has not been investigated so far. We now report that local plasma levels of hyaluronic acid are specifically increased in collateral arterial blood of coronary artery disease patients and hypothesized that components of the endothelial glycocalyx are shed during arteriogenesis, resulting in decreased glycocalyx dimensions and an increased leucocyte extravasation. In a rabbit model of femoral artery ligation, electron microscopy revealed a decrease in glycocalyx dimensions in collateral arteries compared with quiescent anastomoses (67.5 +/- 47.2 nm versus 101.0 +/- 11.3 nm; P < 0.001). This decrease was correlated with a higher number of perivascular macrophages around collateral arteries. The additional glycocalyx perturbation by local hyaluronidase infusion almost completely removed the endothelial surface layer and temporarily stimulated leucocyte accumulation in the perivascular space. However, complete perturbation of the glycocalyx by hyaluronidase infusion resulted in a significant attenuation of collateral artery growth assessed by microsphere-based perfusion measurements (ml/min/100 mmHg: hyaluronidase: 27.5 +/- 3.5; Controls: 47.1 +/- 3.83; P < 0.001) and a lower percentage of actively proliferating vascular smooth muscle cells. A decreased expression of the shear-stress regulated pro-arteriogenic genes eNOS and TGF-beta1 suggests an impaired mechanotransduction as the underlying mechanisms. For the first time, we describe the role of the endothelial glycocalyx in collateral artery growth. Although complete abrogation led to attenuated arteriogenesis, shedding of glycocalyx components is observed during collateral artery growth more...

Collateral artery growth is a potent natural defence mechanism to prevent death and myocardial infarction in occlusive artery disease. Given the high prevalence of arterial obstructive disease, a therapeutic compound stimulating collateral vessel growth could have a major impact on morbidity and mortality world wide. Although experimental studies on the stimulation of arteriogenesis have been promising, not a single drug has been proved to be applicable in clinical practice, either because of lack of efficacy or because of undesired side effects. This review summarises current knowledge on the mechanisms of collateral artery growth and examines problems that arise from the clinical implementation of pro-arteriogenic treatments to date. Future directions in the translation from bench to bedside and potential new approaches to the stimulation of vascular growth are discussed. more...

Aim: Correlation of outcomes of cyclophosphamide (CP) therapy in antineutrophil cytoplasmic antibody-associated vasculitis with genotype polymorphisms in prodrug activating cytochrome P450 enzyme genes CYP2C9 and CYP2C19. Patients & methods: One hundred and ninety six patients with antineutrophil cytoplasmic antibody-associated vasculitis treated with CP, either as intravenous pulse or as daily oral medication, were included. Genotypes of CYP2C9 and CYP2C19 were correlated with clinical outcomes (leukopenia, infection, urotoxicity and treatment response). Results: Sixty five (33.2%) patients had variant CYP2C9 and 55 (28.1%) had variant CYP2C19 genotype. In patients bearing variant CYP2C9, leukopenia was documented significantly more frequent than in carriers of wild-type CYP2C9 (55.4 vs 37.4%; odds ratio: 2.08; 95% CI: 1.14–3.80; p = 0.017). The impact of the CYP2C9 genotype was stronger in patients treated with oral CP (69.6 vs 45.6%; odds ratio: 2.73; 95% CI: 1.27–5.89; p = 0.009), but was not present in patients treated with intravenous pulsed CP. We observed less refractory disease courses in patients with variant CYP2C9, not reaching statistical significance. Conclusion: Patients with variant CYP2C9 are at increased risk for cyclophosphamide-induced leukopenia but may have a better chance to respond to treatment. more...

Objective To compare the phenotype, clinical course, and outcome of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (Wegener's) (GPA) to proteinase 3 (PR3)-ANCA-positive GPA and to MPO-ANCA-positive microscopic polyangiitis (MPA). Methods We characterized all MPO-ANCA-positive patients classified as having GPA by the European Medicines Agency algorithm who attended our center, in a retrospective chart review. A second cohort of patients with PR3-ANCA-positive GPA matched for age and sex was characterized. Patients with MPO-ANCA-positive MPA from a recently published cohort were also included in the analysis. All patients were diagnosed and treated according to a standardized interdisciplinary approach at a vasculitis referral center. Results Comprehensive data were available for 59 patients with MPO-ANCA-positive GPA, and they were compared to 118 patients with PR3-ANCA-positive GPA and 138 patients with MPO-ANCA-positive MPA. We observed a distinct phenotype in MPO-ANCA-positive GPA as compared to the other 2 cohorts. Patients with MPO-ANCA-positive GPA frequently had limited disease without severe organ involvement, had a high prevalence of subglottic stenosis, and had less need for aggressive immunosuppressive therapy (cyclophosphamide/rituximab). The patients with MPO-ANCA-positive GPA were also younger than the MPA patients and were predominantly female (significantly different than the MPA cohort). While GPA patients had higher survival rates compared to MPA patients (due to a high prevalence of pulmonary fibrosis in MPA), patients with MPO-ANCA had significantly lower relapse rates than those with PR3-ANCA. Conclusion Patients with MPO-ANCA-positive GPA show significantly different clinical courses compared to those with PR3-ANCA-positive GPA or MPO-ANCA-positive MPA, which should be considered in their clinical management. Classification according to ANCA specificity may improve the evaluation of relapse risk. more...

This double-blind, randomized, placebo-controlled, cross-over intervention-study was conducted in healthy volunteers to evaluate the effects of plant sterol ester supplemented margarine on cholesterol, non-cholesterol sterols and oxidative stress in serum and monocytes. Sixteen volunteers, average age 34 years, with no or mild hypercholesterolemia were subjected to a 4 week period of daily intake of 3g plant sterols per day supplied via a supplemented margarine on top of regular eating habits. After a wash-out period of one week, volunteers switched groups. Compared to placebo, a diet supplementation with plant sterols increased serum levels of plant sterols such as campesterol (+0.16±0.19mg/dL, p=0.005) and sitosterol (+0.27±0.18mg/dL, p more...

BACKGROUND: Coronary collateral arteries function as natural bypasses in the event of coronary obstruction. The degree of collateral network development significantly impacts the outcome of patients after an acute myocardial infarction (AMI). MicroRNAs (miRNAs, miRs) have arisen as biomarkers to identify heterogeneous patients, as well as new therapeutic targets in cardiovascular disease. We sought to identify miRNAs that are differentially expressed in chronic total occlusion (CTO) patients with well or poorly developed collateral arteries. METHODS AND RESULTS: Forty-one CTO patients undergoing coronary angiography and invasive assessment of their coronary collateralization were dichotomized based on their collateral flow index (CFI). After miRNA profiling was conducted on aortic plasma, four miRNAs were selected for validation by real-time quantitative reverse transcription polymerase chain reaction in patients with low (CFI0.39) collateral artery capacity. We confirmed significantly elevated levels of miR423-5p (p more...

Background— Granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently shown to increase collateral flow index in patients with coronary artery disease. Experimental models showed beneficial effects of GM-CSF on collateral artery growth in the peripheral circulation. Thus, in the present study, we evaluated the effects of GM-CSF in patients with peripheral artery disease. Methods and Results— A double-blinded, randomized, placebo-controlled study was performed in 40 patients with moderate or severe intermittent claudication. Patients were treated with placebo or subcutaneously applied GM-CSF (10 μg/kg) for a period of 14 days (total of 7 injections). GM-CSF treatment led to a strong increase in total white blood cell count and C-reactive protein. Monocyte fraction initially increased but thereafter decreased significantly as compared with baseline. Both the placebo group and the treatment group showed a significant increase in walking distance at day 14 (placebo: 127±67 versus 184±87 meters, P =0.03, GM-CSF: 126±66 versus 189±141 meters, P =0.04) and at day 90. Change in walking time, the primary end point of the study, was not different between groups. No change in ankle-brachial index was found on GM-CSF treatment at day 14 or at day 90. Laser Doppler flowmetry measurements showed a significant decrease in microcirculatory flow reserve in the control group ( P =0.03) and no change in the GM-CSF group. Conclusions— The present study does not support the use of GM-CSF for treatment of patients with moderate or severe intermittent claudication. Issues that need to be addressed are dosing, the selection of patients, and potential differences between GM-CSF effects in the coronary and the peripheral circulation. more...

e Abstract: Peripheral arterial disease (PAD) affects a large percentage of the elderly population. Standard invasive treatment, apart from risk factor modulation, consists of bypass surgery or percutaneous transluminal angioplasty. However, symptomatic recurrence rates are high for both procedures and a substantial part of the patient population with PAD is not a candidate for invasive revascularization due to complexity of the lesion and/or co-morbidity. Therapeutic arteriogenesis has been proposed as an alternative treatment option. The present paper describes the design of the START-trial. This trial aims to determine the potential of the pro- arteriogenic substance granulocyte/macrophage colony stimulating factor (GM-CSF) to increase maximal walking distance in patients with intermittent claudication. A double-blinded, ran- domized, placebo-controlled study will be performed in 40 patients with peripheral obstructive arterial disease Rutherford grade I, category 2 or 3, that are candidates for bypass surgery or percutaneous transluminal angioplasty. Based on pharmacokinetic and toxicologic studies, a dose of 10 mg/kg will be used. Patients will be treated for a period of 14 days on each consecu- tive day, with the last injection applied on day 12. The primary endpoint will be the change in walking distance from day 0 to day 14 as assessed by an exercise treadmill test. Secondary endpoints will be the ankle- brachial index at rest and after exercise, the pain-free walking dis- tance and cutaneous microcirculatory alterations as assessed by laser Doppler e uxmetry. Iliac e ow reserve and conductance will be measured by magnetic resonance imaging. more...

Objective— Collateral artery growth (arteriogenesis) is an important adaptive response to hampered arterial perfusion. It is unknown whether preventive physical exercise before limb ischemia can improve arteriogenesis and modulate mononuclear cell function. This study aimed at investigating the effects of endurance exercise before arterial occlusion on MNC function and collateral artery growth. Approach and Results— After 3 weeks of voluntary treadmill exercise, ligation of the right femoral artery was performed in mice. Hindlimb perfusion immediately after surgery did not differ from sedentary mice. However, previous exercise improved perfusion restoration ≤7 days after femoral artery ligation, also when exercise was stopped at ligation. This was accompanied by an accumulation of peri-collateral macrophages and increased expression of endothelial nitric oxide synthase and inducible nitric oxide synthase (iNOS) in hindlimb collateral and in MNC of blood and spleen. Systemic monocyte and macrophage depletion by liposomal clodronate but not splenectomy attenuated exercise-induced perfusion restoration, collateral artery growth, peri-collateral macrophage accumulation, and upregulation of iNOS. iNOS-deficient mice did not show exercise-induced perfusion restoration. Transplantation of bone marrow–derived MNC from iNOS-deficient mice into wild-type animals inhibited exercise-induced collateral artery growth. In contrast to sedentary controls, thrice weekly aerobic exercise training for 6 months in humans increased peripheral blood MNC iNOS expression. Conclusions— Circulating mononuclear cell–derived inducible nitric oxide is an important mediator of exercise-induced collateral artery growth. more...

Vitamin K-dependent factors protect against vascular and renovascular calcification, and vitamin K antagonists may be associated with a decreased glomerular filtration rate (GFR).This study analyzed changes in GFR during long-term treatment with warfarin or dabigatran etexilate (DE) in patients enrolled in the RE-LY (Randomized Evaluation of Long Term Anticoagulation Therapy) trial.Of the 18,113 patients in the RE-LY study randomized to receive DE (110 mg or 150 mg twice daily) or warfarin, 16,490 patients with atrial fibrillation had creatinine values measured at baseline and at least 1 follow-up visit. Changes in GFR for up to 30 months were evaluated.GFR declined in all treatment groups. After an average of 30 months, the mean ± SE decline in GFR was significantly greater with warfarin (-3.68 ± 0.24 ml/min) compared with DE 110 mg (-2.57 ± 0.24 ml/min; p = 0.0009 vs. warfarin) and DE 150 mg (-2.46 ± 0.23 ml/min; p = 0.0002 vs. warfarin). A decrease in GFR25% was less likely with DE 110 mg (hazard ratio: 0.81 [95% confidence interval: 0.69 to 0.96]; p = 0.017) or DE 150 mg (hazard ratio: 0.79 [95% confidence interval: 0.68 to 0.93]; p = 0.0056) than with warfarin in the observation period18 months. Patients with poor international normalized ratio control (i.e., time in therapeutic range 65%) exhibited a faster decline in GFR. A more pronounced decline in GFR was associated with previous warfarin use and with the presence of diabetes.Patients with atrial fibrillation receiving oral anticoagulation exhibited a decline in renal function that was greater in those taking warfarin versus DE, and it was amplified by diabetes and previous vitamin K antagonist use. (Randomized Evaluation of Long Term Anticoagulant Therapy [RE-LY] With Dabigatran Etexilate; NCT00262600). more...

Polyarteritis nodosa (PAN) is a necrotizing vasculitis of medium size arteries that may affect various organs. The clinical appearance is very variable. The most common manifestations are of the skin, the peripheral nervous system presenting as mononeuritis multiplex and the mesenteric and renal blood vessels due to the development of stenoses and small aneurysms. Of the cases one third are estimated to be associated with hepatitis B virus (HBV). The therapy depends on the pathogenesis of the disease: primary PAN is treated with immunosuppressants, whereas patients with HBV-related PAN should receive antiviral therapy and plasmapheresis. Differentiating PAN from other forms of vasculitis can be difficult and requires complex differential diagnostics. more...

Atrial fibrillation (AF) is the most common sustained arrhythmia and is associated with significant morbidity and mortality. Currently, atrial endocardial catheter ablation, mainly targeting focal discharges in the pulmonary veins, is the most widely used interventional treatment of drug-refractory AF. Despite technical improvements, results are not yet optimal. There is ongoing search for alternative and/or complementary interventional targets. Conditions associated with increased sympathetic activation such as hypertension, heart failure and sleep apnea lead to structural, neural and electrophysiological changes in the atrium thereby contributing to the progression from paroxysmal to persistent AF and increasing recurrence rate of AF after PVI. Until now, interventional modulation of autonomic nervous system was limited by highly invasive techniques. Catheter-based renal denervation (RDN) was introduced as a minimally invasive approach to reduce renal and whole body sympathetic activation with accompanying blood pressure control and left-ventricular morphological and functional changes in resistant hypertension. This review focuses on the potential atrial antiarrhythmic and antiremodeling effects of RDN in AF patients with hypertension, heart failure, and sleep apnea and discusses the possible role of RDN in the treatment of AF. more...

Heart rate is an easily accessible clinical variable with wide-ranging prognostic impact. Elevated resting heart rate predicts an elevated cardiovascular risk. Epidemiological studies demonstrate a relevant association between heart rate and survival in individuals without diagnosed cardiovascular disease and with cardiovascular disease like hypertension, coronary artery disease (CAD) and heart failure. Whereas a goal directed pharmacological heart rate reduction is not supported by clinical evidence for primary prevention it plays a prognostic role for patients with CAD and chronic heart failure. Moreover heart rate can be characterized as an independent risk factor for patients with heart failure and potentially for those with CAD. As a result the common guidelines recommend heart rate reduction as a target of therapy. more...

(1999). News and views on thioredoxin reductases. Redox Report: Vol. 4, No. 5, pp. 221-228.

Chronic periaortitis is an inflammatory and fibrosing disease presenting as periaortal fibrosis and formation of aortic aneurysms which are mostly localized in the retroperitoneum and occasionally in the mediastinum. Inflammatory vasculitic involvement of large vessels is also possible. In addition to symptoms of systemic inflammation, mechanical complications also occur whereby obstruction of the ureter is the most frequent. The diagnosis is made by contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) and if the findings are atypical the diagnosis should be confirmed by biopsy. After exclusion of a secondary genesis, in which case therapy of the underlying illness would be necessary, idiopathic chronic periaortitis can be treated with steroids. In cases of refractory and relapsing courses the administration of further immunosuppressive medication can be necessary. Duration of therapy, dosage and indications for immunosuppressive medication are currently unclear and have to be defined in further randomized controlled trials with larger cohorts. If complications occur, interventional or operative treatment can be necessary; in cases of hydronephrosis the placement of double-J-stents is usually sufficient. more...

Aleglitazar is a dual PPARα/γ agonist but little is known about its effects on vascular function and atherogenesis. Hence, we characterized its effects on circulating angiogenic cells (CAC), neoangiogenesis, endothelial function, arteriogenesis and atherosclerosis in mice.C57Bl/6 wild-type (WT, normal chow), endothelial NOS (eNOS)(-/-) (normal chow) and ApoE(-/-) (Western-type diet) mice were treated with aleglitazar (10 mg·kg(-1) ·day(-1) , i.p.) or vehicle.Aleglitazar enhanced expression of PPARα and PPARγ target genes, normalized glucose tolerance and potently reduced hepatic fat in ApoE(-/-) mice. In WT mice, but not in eNOS(-/-) , aleglitazar up-regulated Sca-1/VEGFR2-positive CAC in the blood and bone marrow and up-regulated diLDL/lectin-positive CAC. Aleglitazar augmented CAC migration and enhanced neoangiogenesis. In ApoE(-/-) mice, aleglitazar up-regulated CAC number and function, reduced markers of vascular inflammation and potently improved perfusion restoration after hindlimb ischaemia and aortic endothelium-dependent vasodilatation. This was associated with markedly reduced formation of atherosclerotic plaques. In human cultured CAC from healthy donors and patients with coronary artery disease with or without diabetes mellitus, aleglitazar increased migration and colony-forming units in a concentration-dependent manner. Furthermore, oxidative stress-induced CAC apoptosis and expression of p53 were reduced, while telomerase activity and expression of phospho-eNOS and phospho-Akt were elevated. Comparative agonist and inhibitor experiments revealed that aleglitazar's effects on CAC migration and colony-forming units were mediated by both PPARα and PPARγ signalling and required Akt.Aleglitazar augments the number, function and survival of CAC, which correlates with improved vascular function, enhanced arteriogenesis and prevention of atherosclerosis in mice. more...

This study sought to investigate the interaction between blood pressure (BP) and heart rate (HR) reduction and changes in left ventricular (LV) structure and function following renal sympathetic denervation (RDN).Hypertension results in structural and functional cardiac changes. RDN reduces BP, HR, and LV mass and improves diastolic dysfunction.We evaluated LV size, mass, and function before and 6 months after RDN in 66 patients with resistant hypertension and analyzed results in relation to systolic BP (SBP) and HR.SBP decreased by 11 ± 3 mm Hg in the first, 18 ± 5 mm Hg in the second, and 36 ± 7 mm Hg in the third tertile of SBP at baseline (p 0.001). HR decreased by 13 ± 4 beats/min, 8 ± 3 beats/min, and 11 ± 6 beats/min in tertiles of SBP (p for interaction between tertiles = 0.314). In all SBP tertiles, LV mass index (LVMI) decreased similarly (LVMI -6.3 ± 2.2 g/m(2.7), -8.3 ± 2.1 g/m(2.7), and -9.6 ± 1.9 g/m(2.7); p for interaction = 0.639). LVMI decreased unrelated to HR at baseline (p for interaction = 0.471). The diastolic parameters E-wave deceleration time, isovolumetric relaxation time, and E'-wave velocity improved similarly in all tertiles of SBP and HR. Changes in LV mass and function were also unrelated to reduction in SBP or HR. Vascular compliance improved dependently on BP but independently of HR reduction.In patients with resistant hypertension, LV hypertrophy and diastolic function improved 6 months after RDN, without significant relation to SBP and HR. These findings suggest a direct effect of altered sympathetic activity in addition to unloading on cardiac hypertrophy and function. more...

Chronic heart failure is associated with sympathetic activation characterised by elevated circulating norepinephrine levels linked to cardiovascular morbidity and mortality. Norepinephrine induces phenotype changes of the cardiomyocyte, fibrosis and β-adrenergic signal transduction defects implicated in the dysregulation of contractility. Renal denervation reduces left ventricular hypertrophy and improves diastolic dysfunction, partly blood pressure independently. Also, exercise tolerance and cardiac arrhythmias are positively influenced. Furthermore, there is evidence that common comorbidities like sleep apnoea, metabolic disease and microalbuminuria are improved following renal denervation. The available evidence suggests performing randomised controlled trials to scrutinise whether renal sympathetic denervation might be able to improve morbidity and mortality in chronic heart failure with preserved or reduced ejection fraction. more...

Objective Well-developed collaterals provide survival benefit in patients with obstructive coronary artery disease (CAD). Therefore, in this study we sought to determine which clinical variables are associated with arteriogenesis. Design Clinical and laboratory variables were collected before percutaneous coronary intervention. Multivariate analysis was performed to determine which variables are associated with the collateral flow index (CFI). Patients Data from 295 chronic total occlusion (CTO) patients (Bern, Switzerland, Amsterdam, the Netherlands and Jena, Germany) were pooled. In earlier studies, patients had varying degrees of stenosis. Therefore, different stages of development of the collaterals were used. In our study, a unique group of patients with CTO was analysed. Interventions Instead of angiography used earlier, we used a more accurate method to determine CFI using intracoronary pressure measurements. CFI was calculated from the occlusive pressure distal of the coronary lesion, the aortic pressure and central venous pressure. Results The mean CFI was 0.39±0.14. After multivariate analysis, β blockers, hypertension and angina pectoris duration were positively associated with CFI (B: correlation coefficient β=0.07, SE=0.03, p=0.02, B=0.040, SE=0.02, p=0.042 and B=0.001, SE=0.000, p=0.02). Furthermore also after multivariate analysis, high serum leucocytes, prior myocardial infarction and high diastolic blood pressure were negatively associated with CFI (B=−0.01, SE=0.005, p=0.03, B=−0.04, SE=0.02, p=0.03 and B=−0.002, SE=0.001, p=0.011). Conclusions In this unique cohort, high serum leucocytes and high diastolic blood pressure are associated with poorly developed collaterals. Interestingly, the use of β blockers is associated with well-developed collaterals, shedding new light on the potential action mode of this drug in patients with CAD. more...