Uta C. Hoppe

Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial.

BACKGROUND Activation of renal sympathetic nerves is key to pathogenesis of essential hypertension. We aimed to assess effectiveness and safety of catheter-based renal denervation for reduction of blood pressure in patients with treatment-resistant hypertension. METHODS In this multicentre, prospective, randomised trial, patients who had a baseline systolic blood pressure of 160 mm Hg or more (≥150 mm Hg for patients with type 2 diabetes), despite taking three or more antihypertensive drugs, were randomly allocated in a one-to-one ratio to undergo renal denervation with previous treatment or to maintain previous treatment alone (control group) at 24 participating centres. Randomisation was done with sealed envelopes. Data analysers were not masked to treatment assignment. The primary effectiveness endpoint was change in seated office-based measurement of systolic blood pressure at 6 months. Primary analysis included all patients remaining in follow-up at 6 months. This trial is registered with ClinicalTrials.gov, number NCT00888433. FINDINGS 106 (56%) of 190 patients screened for eligibility were randomly allocated to renal denervation (n=52) or control (n=54) groups between June 9, 2009, and Jan 15, 2010. 49 (94%) of 52 patients who underwent renal denervation and 51 (94%) of 54 controls were assessed for the primary endpoint at 6 months. Office-based blood pressure measurements in the renal denervation group reduced by 32/12 mm Hg (SD 23/11, baseline of 178/96 mm Hg, p<0·0001), whereas they did not differ from baseline in the control group (change of 1/0 mm Hg [21/10], baseline of 178/97 mm Hg, p=0·77 systolic and p=0·83 diastolic). Between-group differences in blood pressure at 6 months were 33/11 mm Hg (p<0·0001). At 6 months, 41 (84%) of 49 patients who underwent renal denervation had a reduction in systolic blood pressure of 10 mm Hg or more, compared with 18 (35%) of 51 controls (p<0·0001). We noted no serious procedure-related or device-related complications and occurrence of adverse events did not differ between groups; one patient who had renal denervation had possible progression of an underlying atherosclerotic lesion, but required no treatment. INTERPRETATION Catheter-based renal denervation can safely be used to substantially reduce blood pressure in treatment-resistant hypertensive patients. FUNDING Ardian.

Effect of Renal Sympathetic Denervation on Glucose Metabolism in Patients With Resistant Hypertension A Pilot Study

Background— Hypertension is associated with impaired glucose metabolism and insulin resistance. Chronic activation of the sympathetic nervous system may contribute to either condition. We investigated the effect of catheter-based renal sympathetic denervation on glucose metabolism and blood pressure control in patients with resistant hypertension. Methods and Results— We enrolled 50 patients with therapy-resistant hypertension. Thirty-seven patients underwent bilateral catheter-based renal denervation, and 13 patients were assigned to a control group. Systolic and diastolic blood pressures, fasting glucose, insulin, C peptide, hemoglobin A1c, calculated insulin sensitivity (homeostasis model assessment–insulin resistance), and glucose levels during oral glucose tolerance test were measured before and 1 and 3 months after treatment. Mean office blood pressure at baseline was 178/96±3/2 mm Hg. At 1 and 3 months, office blood pressure was reduced by −28/−10 mm Hg (P<0.001) and −32/−12 mm Hg (P<0.001), respectively, in the treatment group, without changes in concurrent antihypertensive treatment. Three months after renal denervation, fasting glucose was reduced from 118±3.4 to 108±3.8 mg/dL (P=0.039). Insulin levels were decreased from 20.8±3.0 to 9.3±2.5 &mgr;IU/mL (P=0.006) and C-peptide levels from 5.3±0.6 to 3.0±0.9 ng/mL (P=0.002). After 3 months, homeostasis model assessment–insulin resistance decreased from 6.0±0.9 to 2.4±0.8 (P=0.001). Additionally, mean 2-hour glucose levels during oral glucose tolerance test were reduced significantly by 27 mg/dL (P=0.012). There were no significant changes in blood pressure or metabolic markers in the control group. Conclusions— Renal denervation improves glucose metabolism and insulin sensitivity in addition to a significantly reducing blood pressure. However, this improvement appeared to be unrelated to changes in drug treatment. This novel procedure may therefore provide protection in patients with resistant hypertension and metabolic disorders at high cardiovascular risk. Clinical Trial Registration— URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT00664638 and NCT00888433.

Ambulatory Blood Pressure Changes after Renal Sympathetic Denervation in Patients with Resistant Hypertension

Background— Catheter-based renal sympathetic denervation (RDN) reduces office blood pressure (BP) in patients with resistant hypertension according to office BP. Less is known about the effect of RDN on 24-hour BP measured by ambulatory BP monitoring and correlates of response in individuals with true or pseudoresistant hypertension. Methods and Results— A total of 346 uncontrolled hypertensive patients, separated according to daytime ambulatory BP monitoring into 303 with true resistant (office systolic BP [SBP] 172.2±22 mm Hg; 24-hour SBP 154±16.2 mm Hg) and 43 with pseudoresistant hypertension (office SBP 161.2±20.3 mm Hg; 24-hour SBP 121.1±19.6 mm Hg), from 10 centers were studied. At 3, 6, and 12 months follow-up, office SBP was reduced by 21.5/23.7/27.3 mm Hg, office diastolic BP by 8.9/9.5/11.7 mm Hg, and pulse pressure by 13.4/14.2/14.9 mm Hg (n=245/236/90; P for all <0.001), respectively. In patients with true treatment resistance there was a significant reduction with RDN in 24-hour SBP (−10.1/−10.2/−11.7 mm Hg, P<0.001), diastolic BP (−4.8/−4.9/−7.4 mm Hg, P<0.001), maximum SBP (−11.7/−10.0/−6.1 mm Hg, P<0.001) and minimum SBP (−6.0/−9.4/−13.1 mm Hg, P<0.001) at 3, 6, and 12 months, respectively. There was no effect on ambulatory BP monitoring in pseudoresistant patients, whereas office BP was reduced to a similar extent. RDN was equally effective in reducing BP in different subgroups of patients. Office SBP at baseline was the only independent correlate of BP response. Conclusions— RDN reduced office BP and improved relevant aspects of ambulatory BP monitoring, commonly linked to high cardiovascular risk, in patients with true-treatment resistant hypertension, whereas it only affected office BP in pseudoresistant hypertension. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00664638 and NCT00888433.

Percutaneous Mitral Annuloplasty for Functional Mitral Regurgitation: Results of the CARILLON Mitral Annuloplasty Device European Union Study

Background— Functional mitral regurgitation (FMR), a well-recognized component of left ventricular remodeling, is associated with increased morbidity and mortality in heart failure patients. Percutaneous mitral annuloplasty has the potential to serve as a therapeutic adjunct to standard medical care. Methods and Results— Patients with dilated cardiomyopathy, moderate to severe FMR, an ejection fraction <40%, and a 6-minute walk distance between 150 and 450 m were enrolled in the CARILLON Mitral Annuloplasty Device European Union Study (AMADEUS). Percutaneous mitral annuloplasty was achieved through the coronary sinus with the CARILLON Mitral Contour System. Echocardiographic FMR grade, exercise tolerance, New York Heart Association class, and quality of life were assessed at baseline and 1 and 6 months. Of the 48 patients enrolled in the trial, 30 received the CARILLON device. Eighteen patients did not receive a device because of access issues, insufficient acute FMR reduction, or coronary artery compromise. The major adverse event rate was 13% at 30 days. At 6 months, the degree of FMR reduction among 5 different quantitative echocardiographic measures ranged from 22% to 32%. Six-minute walk distance improved from 307±87 m at baseline to 403±137 m at 6 months (P<0.001). Quality of life, measured by the Kansas City Cardiomyopathy Questionnaire, improved from 47±16 points at baseline to 69±15 points at 6 months (P<0.001). Conclusions— Percutaneous reduction in FMR with a novel coronary sinus-based mitral annuloplasty device is feasible in patients with heart failure, is associated with a low rate of major adverse events, and is associated with improvement in quality of life and exercise tolerance.

Minimally invasive system for baroreflex activation therapy chronically lowers blood pressure with pacemaker-like safety profile: results from the Barostim neo trial

BACKGROUND Previous trials have demonstrated clinically significant and durable reductions in arterial pressure from baroreflex activation therapy (BAT), resulting from electrical stimulation of the carotid sinus using a novel implantable device. A second-generation system for delivering BAT, the Barostim neo™ system, has been designed to deliver BAT with a simpler device and implant procedure. METHODS BAT, delivered with the advanced system, was evaluated in a single-arm, open-label study of patients with resistant hypertension, defined as resting systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 medications, including ≥1 diuretic. Stable medical therapy was required for ≥4 weeks before establishing pretreatment baseline by averaging two SBP readings taken ≥24 hours apart. RESULTS Thirty patients enrolled from seven centers in Europe and Canada. From a baseline of 171.7 ± 20.2/99.5 ± 13.9 mm Hg, arterial pressure decreased by 26.0 ± 4.4/12.4 ± 2.5 mm Hg at 6 months. In a subset (n = 6) of patients with prior renal nerve ablation, arterial pressure decreased by 22.3 ± 9.8 mm Hg. Background medical therapy for hypertension was unchanged during follow-up. Three minor procedure-related complications occurred within 30 days of implant. All complications resolved without sequelae. CONCLUSION BAT delivered with the second-generation system significantly lowers blood pressure in resistant hypertension with stable, intensive background medical therapy, consistent with studies of the first-generation system for electrical activation of the baroreflex, and provides a safety profile comparable to a pacemaker.

Hyperpolarization-Activated Inward Current in Ventricular Myocytes From Normal and Failing Human Hearts

BACKGROUND The hyperpolarization-activated inward current (I[f]) was found to be overexpressed in hypertrophied rat ventricular myocytes, indicating that I(f) might favor arrhythmias in hypertrophied or failing ventricular myocardium. In the present study, we evaluated whether I(f) is expressed in human ventricular myocardium, if it may be increased in human heart failure, and if its autonomic modulation may be altered. METHODS AND RESULTS The whole-cell patch-clamp technique was used to record I(f) in isolated ventricular myocytes from 34 failing (dilated [DCM] or ischemic [ICM] cardiomyopathy) and 13 donor hearts (NF). I(f) was observed in all myocytes showing typical current properties, ie, time and voltage dependence, block by [Cs+]o, permeability for K+ and Na+, and current increase with raising [K+]o. There was a trend toward larger current densities in myopathic (at -130 mV in [K+]o 25 mmol/L; DCM: -1.37 +/- 0.12 pA/pF, n = 50; ICM: -1.39 +/- 0.24 pA/pF, n = 30) than in nonfailing cells (-1.18 +/- 0.21 pA/pF, n = 24), although this difference did not reach statistical significance (P=.23). Boltzmann distributions yielded an activation threshold of -80 mV and half-maximal activation at -110.96 +/- 0.06 mV in myopathic and normal myocytes. Isoproterenol (10(-5) mol/L) shifted the current activation by 10 mV (31 myopathic, 5 NF). Carbachol and adenosine had no direct effect on I(f) (6 and 12 myopathic, 3 and 3 NF, respectively) but reversibly antagonized beta-adrenergic stimulation (5 and 7 myopathic, 2 and 2 NF, respectively). Autonomic modulation was similar in failing and nonfailing cells. CONCLUSIONS In end-stage heart failure, no significant change of I(f) could be found, although there was a trend toward increased I(f). Together with an elevated plasma norepinephrine concentration and a previously reported reduction in I(K1) in human heart failure, I(f) might favor diastolic depolarization in individual myopathic cells.

Effect of Cardiac Resynchronization on the Incidence of Atrial Fibrillation in Patients With Severe Heart Failure

Background— Atrial fibrillation/flutter (AF) and heart failure often coexist; however, the effect of cardiac resynchronization therapy (CRT) on the incidence of AF and on the outcome of patients with new-onset AF remains undefined. Methods and Results— In the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial, 813 patients with moderate or severe heart failure were randomly assigned to pharmacological therapy alone or with the addition of CRT. The incidence of AF was assessed by adverse event reporting and by ECGs during follow-up, and the impact of new-onset AF on the outcome and efficacy of CRT was evaluated. By the end of the study (mean duration of follow-up 29.4 months), AF had been documented in 66 patients in the CRT group compared with 58 who received medical therapy only (16.1% versus 14.4%; hazard ratio 1.05; 95% confidence interval, 0.73 to 1.50; P=0.79). There was no difference in the time until first onset of AF between groups. Mortality was higher in patients who developed AF, but AF was not a predictor in the multivariable model (hazard ratio 1.17; 95% confidence interval, 0.82 to 1.67; P=0.37). In patients with new-onset AF, CRT significantly reduced the risk for all-cause mortality and all other predefined end points and improved ejection fraction and symptoms (no interaction between AF and CRT; all P>0.2). Conclusions— Although CRT did not reduce the incidence of AF, CRT improved the outcome regardless of whether AF developed.

Leitlinien zur Therapie der chronischen Herzinsuffizienz

)Universitat zu KolnKlinik III fur Innere MedizinKerpener Strase 6250937 Koln, GermanyHerausgegeben vom Vorstand der Deutschen Gesellschaftfur Kardiologie – Herz- und Kreislaufforschung e.V.Bearbeitet im Auftrag der Kommission fur Klinische KardiologieR.H. Strasser, D. Andresen, F. de Haan, G. Ertl, H. Mudra,A. Osterspey, H.J. Trappe, K. Werdan, auserdem G. Arnold,H.M. Hoffmeister, E. FleckDiese Leitlinie ist eine wissenschaftlich und systematisch erarbei-tete Stellungnahme der Deutschen Gesellschaft fur Kardiologie –Herz- und Kreislaufforschung e.V. (DGK), die den gegenwartigenErkenntnisstand zum Thema wiedergibt und allen behandelndenArzten und ihren Patienten die Entscheidungsfindung fur eine an-gemessene Behandlung dieser spezifischen Krankheitssituation er-leichtern soll. Diese Leitlinie ersetzt nicht die arztliche Evaluationdes individuellen Patienten und die Anpassung der Diagnostikund Therapie an die spezifische Situation des einzelnen Patienten.Empfehlungsgrad DefinitionI. Evidenz oder allgemeine Ubereinkunft, dass eine Therapieformoder eine diagnostische Masnahme effektiv, nutzlich oder heil-sam ist.II. Widerspruchliche Evidenz und/oder unterschiedliche Meinun-gen uber den Nutzen/die Effektivitat einer Therapieform odereiner diagnostischen Masnahme.IIa. Evidenzen/Meinungen favorisieren den Nutzen bzw. die Ef-fektivitat einer Masnahme.IIb. Nutzen/Effektivitat einer Masnahme ist weniger gut durchEvidenzen/Meinungen belegt.Evidenzniveau DefinitionA. Die Empfehlung wird mindestens durch zwei randomisierteStudien gestutzt.B. Die Empfehlung wird durch eine randomisierte Studie und/oder eine Metaanalyse nicht-randomisierter Studien gestutzt.C. Konsensus-Meinung von Experten, basierend auf Studien undklinischer Erfahrung.

Treatment of functional mitral regurgitation by percutaneous annuloplasty: results of the TITAN Trial

Functional mitral regurgitation (FMR) contributes to morbidity and mortality in heart failure (HF) patients. The aim of this study was to determine whether percutaneous mitral annuloplasty could safely and effectively reduce FMR and yield durable long‐term clinical benefit.

Rapid actions of androgens

The biological activity of androgens is thought to occur predominantly through binding to intracellular androgen-receptors, a member of the nuclear receptor family, that interact with specific nucleotide sequences to alter gene expression. This genomic-androgen effect typically takes at least more than half an hour. In contrast, the rapid or non-genomic actions of androgens are manifested within in seconds to few minutes. This rapid effect of androgens are manifold, ranging from activation of G-protein coupled membrane androgen-receptors or sex hormone-binding globulin receptors, stimulation of different protein kinases, to direct modulation of voltage- and ligand gated ion-channels and transporters. The physiological relevance of these non-genomic androgen actions has not yet been determined in detail. However, it may contribute to modulate several second messenger systems or transcription factors, which suggests a cross-talk between the fast non-genomic and the slow genomic pathway of androgens. This review will focus on the rapid effects of androgens on cell surface and cytoplasmic level.