Mathias C. Brandt

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.

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.

Cardiorespiratory Response to Exercise After Renal Sympathetic Denervation in Patients With Resistant Hypertension

OBJECTIVES This study sought to investigate the effects of interventional renal sympathetic denervation (RD) on cardiorespiratory response to exercise. BACKGROUND RD reduces blood pressure at rest in patients with resistant hypertension. METHODS We enrolled 46 patients with therapy-resistant hypertension as extended investigation of the Symplicity HTN-2 (Renal Denervation With Uncontrolled Hypertension) trial. Thirty-seven patients underwent bilateral RD and 9 patients were assigned to the control group. Cardiopulmonary exercise tests were performed at baseline and 3-month follow-up. RESULTS In the RD group, compared with baseline examination, blood pressure at rest and at maximum exercise after 3 months was significantly reduced by 31 ± 13/9 ± 13 mm Hg (p < 0.0001) and by 21 ± 20/5 ± 14 mm Hg (p < 0.0001), respectively. Achieved work rate increased by 5 ± 13 W (p = 0.029) whereas peak oxygen uptake remained unchanged. Blood pressure 2 min after exercise was significantly reduced by 29 ± 17/8 ± 15 mm Hg (p < 0.001 for systolic blood pressure; p = 0.002 for diastolic blood pressure). Heart rate at rest decreased after RD (4 ± 11 beats/min; p = 0.028), whereas maximum heart rate and heart rate increase during exercise were not different. Heart rate recovery improved significantly by 4 ± 7 beats/min after renal denervation (p = 0.009). In the control group, there were no significant changes in blood pressure, heart rate, maximum work rate, or ventilatory parameters after 3 months. CONCLUSIONS RD reduces blood pressure during exercise without compromising chronotropic competence in patients with resistant hypertension. Heart rate at rest decreased and heart rate recovery improved after the procedure. (Renal Denervation With Uncontrolled Hypertension; [Symplicity HTN-2]; NCT00888433).

Effects of renal sympathetic denervation on arterial stiffness and central hemodynamics in patients with resistant hypertension.

OBJECTIVES This study investigated the effect of catheter-based renal sympathetic denervation (RD) on central hemodynamics in patients with resistant hypertension. BACKGROUND High central blood pressure (BP) increases cardiovascular events and mortality independently of peripheral BP. The effect of RD on central BP is unclear. METHODS A total of 110 patients underwent bilateral RD. Radial artery applanation tonometry and pulse wave analysis were used to derive central aortic pressure and hemodynamic indices at baseline and 1, 3, and 6 months after ablation. Ten patients with resistant hypertension not undergoing RD served as controls. RESULTS RD significantly reduced mean central aortic BP from 167/92 mm Hg to 149/88 mm Hg, 147/85 mm Hg, and 141/85 mm Hg at 1, 3, and 6 months (p < 0.001), respectively. Aortic pulse pressure decreased from 76.2 ± 23.3 mm Hg to 61.5 ± 17.5 mm Hg, 62.7 ± 18.1 mm Hg, and 54.5 ± 15.7 mm Hg 1, 3, and 6 months after RD (p < 0.001), respectively. Six months after RD aortic augmentation and augmentation index were significantly reduced by -11 mm Hg (p < 0.001) and -5.3% (p < 0.001), respectively. Carotid to femoral pulse wave velocity showed a significant reduction from 11.6 ± 3.2 m/s to 9.6 ± 3.1 m/s at 6 months (p < 0.001). Consistently, ejection duration and aortic systolic pressure load were significantly diminished, indicating improvement of cardiac work load by RD. No significant changes were obtained in control patients. CONCLUSIONS Besides the known effect of RD on brachial blood pressure, the study showed for the first time that this novel approach significantly improves arterial stiffness and central hemodynamics, which might have important prognostic implications in patients with resistant hypertension at high cardiovascular risk.

Direct evidence for calcium conductance of hyperpolarization-activated cyclic nucleotide-gated channels and human native If at physiological calcium concentrations

AIMS The hyperpolarization-activated cyclic nucleotide-gated (HCN) current I(f)/I(HCN) is generally thought to be carried by Na(+) and K(+) under physiological conditions. Recently, Ca(2+) influx through HCN channels has indirectly been postulated. However, direct functional evidence of Ca(2+) permeation through I(f)/I(HCN) is still lacking. METHODS AND RESULTS To possibly provide direct evidence of Ca(2+) influx through I(HCN)/I(f), we performed inside-out and cell-attached single-channel recordings of heterologously expressed HCN channels and native rat and human I(f), since Ca(2+)-mediated I(f)/I(HCN) currents may not readily be recorded using the whole-cell technique. Original current traces demonstrated HCN2 Ca(2+) inward currents upon hyperpolarization with a single-channel amplitude of -0.87+/-0.06 pA, a low open probability of 3.02+/-0.48% (at -110 mV, n=6, Ca(2+) 2 mmol/L), and a Ca(2+) conductance of 8.9+/-1.2 pS. I(HCN2-Ca2+) was significantly activated by the addition of cAMP with an increase in the open probability and suppressed by the specific I(f) inhibitor ivabradine, clearly confirming that Ca(2+) influx indeed was conducted by HCN2 channels. Changing [Na(+)] (10 vs. 100 mmol/L) in the presence or absence of 2 mmol/L Ca(2+) caused a simple shift of the reversal potential along the voltage axis without significantly affecting Na(+)/Ca(2+) conductance, whereas the K(+) conductance of HCN2 increased significantly in the absence of external Ca(2+) with increasing K(+) concentrations. The mixed K(+)-Ca(2+) conductance, however, was unaffected by the external K(+) concentration. Notably, we could also record hyperpolarization-activated Ca(2+) permeation of single native I(f) channels in neonatal rat ventriculocytes and human atrial myocytes in the presence of blockers for all known cardiac calcium conduction pores (Ca(2+) conductance of human I(f), 9.19+/-0.34 pS; amplitude, -0.81+/-0.01 pA; open probability, 1.05+/-0.61% at -90 mV). CONCLUSION We directly show Ca(2+) permeability of native rat and, more importantly, human I(f) at physiological extracellular Ca(2+) concentrations at the physiological resting membrane potential. This might have particular implications in diseased states with increased I(f) density and HCN expression.

K+ channel regulator KCR1 suppresses heart rhythm by modulating the pacemaker current If.

Hyperpolarization-activated, cyclic nucleotide sensitive (HCN) channels underlie the pacemaker current If, which plays an essential role in spontaneous cardiac activity. HCN channel subunits (HCN1-4) are believed to be modulated by additional regulatory proteins, which still have to be identified. Using biochemistry, molecularbiology and electrophysiology methods we demonstrate a protein-protein interaction between HCN2 and the K+ channel regulator protein 1, named KCR1. In coimmunoprecipitation experiments we show that KCR1 and HCN2 proteins are able to associate. Heterologously expressed HCN2 whole-cell current density was significantly decreased by KCR1. KCR1 profoundly suppressed IHCN2 single-channel activity, indicating a functional interaction between KCR1 and the HCN2 channel subunit. Endogenous KCR1 expression could be detected in adult and neonatal rat ventriculocytes. Adenoviral-mediated overexpression of KCR1 in rat cardiomyocytes (i) reduced If whole-cell currents, (ii) suppressed most single-channel gating parameters, (iii) altered the activation kinetics, (iv) suppressed spontaneous action potential activity, and (v) the beating rate. More importantly, siRNA-based knock-down of endogenous KCR1 increased the native If current size and single-channel activity and accelerated spontaneous beating rate, supporting an inhibitory action of endogenous KCR1 on native If. Our observations demonstrate for the first time that KCR1 modulates IHCN2/If channel gating and indicate that KCR1 serves as a regulator of cardiac automaticity.

Baroreflex activation as a novel therapeutic strategy for diastolic heart failure

Diastolic heart failure is a common clinical finding in patients with severe arterial hypertension. While heart failure patients with reduced ejection fraction benefit from improved medical and device therapy, the prognosis of diastolic heart failure has not changed over the last decades and no therapeutic strategy has proven effective to significantly improve the outcome [1–4]. Sympathetic hyperactivity has been implicated in the occurrence of hypertrophy and diastolic heart failure [5, 6]. Moreover, clinically discernible hypertrophy may blunt sympathoinhibitory reflexes in its own right, thus possibly leading to increased sympathetic drive and progressive symptoms in a circulus vitiosus [7]. For patients with therapy-refractory arterial hypertension, a novel treatment option with electrical activation of the carotid sinus nerve baroreflex has been developed (Rheos System, CVRx Inc.). Electrical activation via stimulation of the carotid sinus increases afferent nerve traffic through the carotid sinus nerve to medullary areas controlling sympathetic tone. This results in a reduction of the sympathetic tone, leading to a peripheral vasodilation, lower heart rate, and increased diuresis. The combination of these effects leads to a marked reduction of blood pressure. The Rheos baroreflex activation system consists of an implantable subpectoral pulse generator, subfascial carotid sinus leads, and external programmer system (Fig. 1d). A 47-year-old female with a long history of arterial hypertension presented to our clinic after recurrent pulmonary edema. The patient showed a markedly reduced exercise capacity consistent with NYHA class III. Her 6-min walking distance was 235 m. Despite a combination of nine different antihypertensive drugs (hydrochlorothiazide, torasemide, ramipril, candesartan, nebivolol, lecarnidipin, spironolactone, moxonidin and minoxidil), she still measured systolic home blood pressure values between 170 and 210 mmHg. 24-h ambulatory blood pressure recordings confirmed drug-refractory hypertension (Fig. 1a). A wide range of potential causes of secondary refractory hypertension (including renal artery stenosis and endocrine disorders) had been excluded in the past. The renal function was normal with a GFR of 140 ml/min. Transthoracic echocardiography showed myocardial hypertrophy (interventricular septum diastolic diameter 15 mm) with an ejection fraction of 46% and marked diastolic dysfunction (E/E0 lateral 13.3) with a restrictive ventricular filling pattern (mitral valve E/A 3.9, deceleration time 148 ms, isovolumic relaxation time IVRT 90 ms). Severe pulmonary arterial hypertension was present with a tricuspid dPmax of 65 mmHg. An elevated NT-pro-BNP level of 983 ng/l further supported the diagnosis of DHF. The patient’s exercise capacity was markedly reduced, consistent with NYHA class III. To improve blood pressure control, a device which provided Baroreflex Activation Therapy as detailed above was implanted. The Rheos System effectively decreased blood pressure minutes after activation to the extent that four M. C. Brandt U. C. Hoppe (&) Department of Internal Medicine III, University of Cologne, Kerpener Str. 62, 50937 Cologne, Germany e-mail: uta.hoppe@uni-koeln.de

Percutaneous mitral annuloplasty device leaves free access to cardiac veins for resynchronization therapy

To assess the feasibility to place a left ventricular lead into the coronary sinus following percutaneous mitral annuloplasty.

Effects of KCNE2 on HCN isoforms: distinct modulation of membrane expression and single channel properties.

Hyperpolarization-activated cation (HCN) channels give rise to an inward current with similar but not identical characteristics compared with the pacemaker current (I(f)), suggesting that HCN channel function is modulated by regulatory beta-subunits in native tissue. KCNE2 has been proposed to serve as a beta-subunit of HCN channels; however, available data remain contradictory. To further clarify this situation, we therefore analyzed the effect of KCNE2 on whole cell currents, single channel properties, and membrane protein expression of all cardiac HCN isoforms in the CHO cell system. On the whole cell level, current densities of all HCN isoforms were significantly increased by KCNE2 without altering voltage dependence or current reversal. While these results correlated well with the KCNE2-mediated 2.2-fold and 1.6-fold increases of membrane protein levels of HCN2 and HCN4, respectively, no effect of KCNE2 on HCN1 expression was obtained. All HCN subtypes displayed faster activation kinetics upon coexpression with KCNE2. Most importantly, for the first time, we demonstrated modulation of single channel function by KCNE2, thus supporting direct functional interaction with HCN subunits. In the presence of KCNE2, the single channel amplitudes and conductance of HCN1, HCN2, and HCN4 were significantly increased versus control recordings. Mean open time was significantly increased in cells coexpressing HCN2 + KCNE2, whereas it was unaffected in HCN1 + KCNE2 cotransfected cells and reduced in HCN4 + KCNE2 cotransfected cells compared with the respective HCN subunits alone. Thus, we demonstrate KCNE2-mediated distinct effects on HCN membrane expression and direct functional modulation of HCN isoforms, further supporting that KCNE2 surves as a regulatory beta-subunit of HCN channels.

Impact of dihydrotestosterone on L-type calcium channels in human ventricular cardiomyocytes.

Objectives. Reports of testosterone effects on cardiovascular morbidity remain contradictory. Besides modulating cardiovascular risk factors recent evidence indicates direct actions of testosterone on cardiac tissue. However, the impact on human cardiac L-type calcium channels that play a central role in electro-mechanical coupling is unknown. Methods and Results. Human ventricular myocytes were isolated from patients undergoing heart transplantation. Patch-clamp experiments in whole-cell configuration were performed to evaluate the effect of dihydrotestosterone on cardiac L-type calcium current ICa,L. Treatment of cultured cardiomyocytes with dihydrotestosterone 100 nmol/L for 24–30 h increased the whole-cell ICa,L current density from 2.32 ± 0.17 pA/pF (n = 11) to 3.21 ± 0.17 pA/pF (n = 14) at +10 mV (p = 0.01) without shifting the current–voltage relation. This effect was associated with a 1.35-fold higher expression of the pore-forming CaV1.2 (α1c) subunit of L-type calcium channels in dihydrotestosterone-treated myocytes compared with controls (p = 0.03). Conclusions. Dihydrotestosterone treatment increased L-type calcium current density by the upregulation of CaV1.2 in human ventricular myocytes. These data provide a possible explanation for dihydrotestosterone effects on the cardiovascular system in androgenic steroid abuse.