Bodo Cremers

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.

Paclitaxel-Coated Balloon Catheter Versus Paclitaxel-Coated Stent for the Treatment of Coronary In-Stent Restenosis

Background— Treatment of in-stent restenosis with paclitaxel-coated balloon catheter as compared with plain balloon angioplasty has shown surprisingly low late lumen loss at 6 months and fewer major adverse cardiac events up to 2 years. We compared the efficacy and safety of a paclitaxel-coated balloon with a paclitaxel-eluting stent as the current standard of care. Methods and Results— One hundred thirty-one patients with coronary in-stent restenosis were randomly assigned to treatment by a paclitaxel-coated balloon (3 &mgr;g/mm2) or a paclitaxel-eluting stent. The main inclusion criteria encompassed diameter stenosis of ≥70% and ≤22 mm in length, with a vessel diameter of 2.5 to 3.5 mm. The primary end point was angiographic in-segment late lumen loss. Quantitative coronary angiography revealed no differences in baseline parameters. At 6 months follow-up, in-segment late lumen loss was 0.38±0.61 mm in the drug-eluting stent group versus 0.17±0.42 mm (P=0.03) in the drug-coated balloon group, resulting in a binary restenosis rate of 12 of 59 (20%) versus 4 of 57 (7%; P=0.06). At 12 months, the rate of major adverse cardiac events were 22% and 9%, respectively (P=0.08). This difference was primarily due to the need for target lesion revascularization in 4 patients (6%) in the coated-balloon group, compared with 10 patients (15%) in the stent group (P=0.15). Conclusions— Treatment of coronary in-stent restenosis with the paclitaxel-coated balloon was at least as efficacious and as well tolerated as the paclitaxel-eluting stent. For the treatment of in-stent restenosis, inhibition of re-restenosis does not require a second stent implantation.

Renal Hemodynamics and Renal Function After Catheter-Based Renal Sympathetic Denervation in Patients With Resistant Hypertension

Increased renal resistive index and urinary albumin excretion are markers of hypertensive end-organ damage and renal vasoconstriction involving increased sympathetic activity. Catheter-based sympathetic renal denervation (RD) offers a new approach to reduce renal sympathetic activity and blood pressure in resistant hypertension. The influence of RD on renal hemodynamics, renal function, and urinary albumin excretion has not been studied. One hundred consecutive patients with resistant hypertension were included in the study; 88 underwent interventional RD and 12 served as controls. Systolic, diastolic, and pulse pressure, as well renal resistive index in interlobar arteries, renal function, and urinary albumin excretion, were measured before and at 3 and 6 months of follow-up. RD reduced systolic, diastolic, and pulse pressure at 3 and 6 months by 22.7/26.6 mm Hg, 7.7/9.7 mm Hg, and 15.1/17.5 mm Hg (P for all <0.001), respectively, without significant changes in the control group. SBP reduction after 6 months correlated with SBP baseline values (r=−0.46; P<0.001). There were no renal artery stenoses, dissections, or aneurysms during 6 months of follow-up. Renal resistive index decreased from 0.691±0.01 at baseline to 0.674±0.01 and 0.670±0.01 (P=0.037/0.017) at 3- and 6-month follow-up. Mean cystatin C glomerular filtration rate and urinary albumin excretion remained unchanged after RD; however, the number of patients with microalbuminuria or macroalbuminuria decreased. RD reduced blood pressure, renal resistive index, and incidence of albuminuria without adversely affecting glomerular filtration rate or renal artery structure within 6 months and appears to be a safe and effective therapeutic approach to lower blood pressure in patients with resistant hypertension.

Renal Denervation in Moderate to Severe CKD

Sympathetic activation contributes to the progression of CKD and is associated with adverse cardiovascular outcomes. Ablation of renal sympathetic nerves reduces sympathetic nerve activity and BP in patients with resistant hypertension and preserved renal function, but whether this approach is safe and effective in patients with an estimated GFR (eGFR) < 45 ml/min per 1.73 m(2) is unknown. We performed bilateral renal denervation in 15 patients with resistant hypertension and stage 3-4 CKD (mean eGFR, 31 ml/min per 1.73 m(2)). We used CO(2) angiography in six patients to minimize exposure to contrast agents. Estimated GFR remained unchanged after the procedure, irrespective of the use of CO(2) angiography. Mean baseline BP ± SD was 174 ± 22/91 ± 16 mmHg despite the use of 5.6 ± 1.3 antihypertensive drugs. Mean changes in office systolic and diastolic BP at 1, 3, 6, and 12 months were -34/-14, -25/-11, -32/-15, and -33/-19 mmHg, respectively. Night-time ambulatory BP significantly decreased (P<0.05), restoring a more physiologic dipping pattern. In conclusion, this study suggests a favorable short-term safety profile and beneficial BP effects of catheter-based renal nerve ablation in patients with stage 3-4 CKD and resistant hypertension.

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.

Long-Term Follow-Up After Treatment of Coronary In-Stent Restenosis With a Paclitaxel-Coated Balloon Catheter

OBJECTIVES This study presents long-term clinical follow-up, including binary restenosis rate and major adverse cardiovascular events, of the PACCOCATH-ISR (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons) I and II trial. BACKGROUND The PACCOCATH-ISR trial was a first-in-human study with a drug-coated balloon catheter and the first study for the treatment of coronary ISR with a drug-coated balloon. So, far no long-term follow-up data have been presented. METHODS This study enrolled 108 patients in a randomized, double-blinded multicenter trial on the efficacy and safety of a paclitaxel-coated balloon (3 μg/mm(2) balloon surface; PACCOCATH [Bayer AG, Germany]) compared with an uncoated balloon. The main inclusion criteria were a diameter stenosis of ≥ 70% and <30-mm length with a vessel diameter of 2.5 to 3.5 mm. The primary endpoint was angiographic late lumen loss in-segment after 6 months. Combined antiplatelet therapy was continued only for 1 month followed by treatment with aspirin alone. RESULTS During a follow-up of 5.4 ± 1.2 years, the clinical event rate was significantly reduced in patients treated with the drug-coated balloon (major adverse cardiovascular events: 59.3% vs. 27.8%, p = 0.009), which was mainly driven by the reduction of target lesion revascularization from 38.9% to 9.3% (p = 0.004). CONCLUSIONS Treatment of coronary ISR with paclitaxel-coated balloon catheters is safe and persistently reduces repeat revascularization during long-term follow-up. The initial results were sustained over the 5-year period. (Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR I]; NCT00106587. Treatment of In-Stent Restenosis by Paclitaxel Coated PTCA Balloons [PACCOCATH ISR II]; NCT00409981).

Monocyte heterogeneity in obesity and subclinical atherosclerosis.

AIMS Monocytes and monocyte-derived macrophages have been recognised as the cellular hallmark of atherosclerosis decades ago. Recently, they have also been shown to play a pivotal role in obesity. Monocytes display immunophenotypic heterogeneity with functionally distinct subpopulations. We initiated the I LIKE HOMe study to examine monocyte heterogeneity in obesity and subclinical atherosclerosis. METHODS AND RESULTS We assessed carotid intima media thickness (IMT), body mass index (BMI), and other cardiovascular risk factors in 622 healthy volunteers. Using flow-cytometry, we differentiated monocytes into CD14(++)CD16(-) and CD16(+) cells, which we further subdivided into CD14(++)CD16(+) and CD14((+))CD16(+) cells. Body mass index was significantly correlated with carotid IMT. High CD16(+) monocyte counts were significantly associated with both higher BMI and increased carotid IMT. Adjustment for CD16(+) monocyte counts weakened the correlation between BMI and carotid IMT, suggesting that the increase in CD16(+) monocyte numbers in obesity may partly explain the association between obesity and IMT. CONCLUSION Our results reveal a significant univariate association between CD16(+) monocytes and both obesity and subclinical atherosclerosis in low-risk individuals. They are in line with recent observations that CD16(+) monocytes show high endothelial affinity and a potent capacity to invade vascular lesions and to transform into pro-inflammatory cytokine producing macrophages.

Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension.

BACKGROUND Renal sympathetic denervation (RDN) reduces sympathetic activity and blood pressure (BP) in patients with resistant hypertension. The present study aimed to investigate the effects of RDN on HR and other electrocardiographic parameters. METHODS 136 patients aged 62.2 ± 0.8 years (58% male, BP 177 ± 2/93 ± 1 mmHg) with resistant hypertension underwent RDN. BP and a 12-lead electrocardiogram (ECG) were recorded before, 3 months (n=127), and 6 months (n=88) after RDN. RESULTS After 3 months (3M) and 6 months (6M), systolic BP was reduced by 25.5 ± 2.4 mmHg (p<0.0001) and 28.1 ± 3 mmHg (p<0.0001). HR at baseline was 66.1 ± 1 beats per minute (bpm) and was reduced by 2.6 ± 0.8 bpm after 3 months (p=0.001) and 2.1 ± 1.1 bpm after 6 months (p=0.046). Patients with HR at baseline between 60-71 bpm and ≥ 71 bpm had a reduction of 2.9 ± 7.6 bpm (p=0.008) and 9.0 ± 8.6 bpm (p<0.0001), respectively, whereas in patients with baseline HR<60 bpm HR slightly increased after 3 months (2.7 ± 8.4 bpm; p=0.035). Neither baseline HR nor change of HR correlated with the reduction of systolic BP. The PR interval was prolonged by 11.3 ± 2.5 ms (p<0.0001) and 10.3 ± 2.5 ms (p<0.0001) at 3 and 6 months after RDN, respectively. CONCLUSIONS Renal sympathetic denervation reduced heart rate and the PR interval as indicators of cardiac autonomic activity.

Drug-eluting balloon: Very short-term exposure and overlapping

Paclitaxel balloon coating has shown promising effects in inhibiting restenosis in initial clinical trials. The aim of the present study was to evaluate the influence of two critical features of drug-eluting balloon (DEB) application - inflation time and increased dose due to overlapping balloons. Fifty-six stainless steel stents were implanted in the left anterior descending and circumflex coronary arteries of 28 domestic pigs using a 1.2:1.0 overstretch ratio. Stents were mounted on conventional uncoated and paclitaxel-coated angioplasty balloon catheters. The animals were randomized to five different treatments with a range of short (10 seconds [s] inflation using 1 DEB) to extended (2x60 s inflation using 2 DEB) intima contact time. After 28 days, quantitative angiography and histomorphometry of the stented arteries was performed on a total of 23 pigs. Paclitaxel balloon coating led to a marked reduction of parameters characterizing in-stent stenosis: Late lumen loss was 1.37 +/- 0.49 mm for uncoated balloons, 0.23 +/- 0.42 mm for one coated balloon 60 s inflation time, 0.37 +/- 0.28 mm for 10 s inflation time and 0.30 +/- 0.19 mm for the vessel segment treated by two coated balloons with 60 s inflation each. Neointimal areas were 4.26 +/- 1.18, 1.68 +/- 0.23, 1.83 +/- 0.40 and 1.67 +/- 0.46 mm(2), respectively (p = 0.001 versus control, p > 0.05 between paclitaxel-treated groups). Despite the marked reduction of neointimal proliferation, endothelialization of stent struts was present in all samples. DEB were found to effectively reduce neointimal proliferation regardless of inflation time and dose within the tested range. No adverse reactions were seen as dose was increased to more than three times the clinically tested dose.

Dose response to Paclitaxel-coated balloon catheters in the porcine coronary overstretch and stent implantation model.

Objective:There is little published information regarding the efficacy of paclitaxel-coated balloon catheters except for the iopromide-containing formulation, and less is known about the kind of toxicity at overdose. The aim of our study was to assess 2 different paclitaxel matrix formulations on angioplasty balloon catheters in vitro, with respect to pharmacokinetics, and efficacy and tolerance to determine the minimum effective dose and local toxicity at extremely high dose which is only achieved in experimental studies. Methods and Materials:Adherence of coatings was tested in vitro in dry state and during passage through hemostatic valves, guiding catheters, and blood. Drug release, transfer to the vessel wall during coronary angioplasty, inhibition of neointimal proliferation, and tolerance were investigated in swine. Efficacy and tolerance of balloons were examined for doses ranging from 1 to 9 &mgr;g/mm2 and 3 overlapping applications of balloons coated with 3 times the regular dose of 3 &mgr;g/mm2. Paclitaxel concentrations were determined by high performance liquid chromatography, efficacy and tolerance by vital signs, clinical observation, quantitative coronary angiography, and histomorphometry 4 weeks after implanting premounted bare stents in coronary arteries applying 1:1.2 overstretch. Results:Under worst-case conditions, drug loss on the way through the guiding catheter and blood was in the range of 30%. After inflation of balloons coated with the clinically tested dose of 3 &mgr;g/mm2 in a coronary artery about 10% of drug remained on balloons, 20% to 30% was taken up into the vessel wall (∼200 &mgr;g). Neointimal area on cross sections was 6.8 ± 2.2 mm2 (uncoated control); 3.1 ± 1.1 mm2 (iopromide-matrix) and 3.0 ± 0.5 mm2 (urea-matrix) at 1 &mgr;g/mm2; 2.0 ± 0.4 mm2 versus 1.7 ± 1.1 mm2 at 3 &mgr;g/mm2 with no further decrease at higher doses. Thrombotic occlusions were observed in 3 of 15 vessel segments treated with overlapping inflations of 3 high-dose balloons but without any signs of aneurysms. Conclusion:In the animal model, 2 paclitaxel matrix formulations were similar in respect of uptake in the vessel wall, and effective already at a dose of 1 &mgr;g/mm2. Except thrombotic events for the intentionally excessive dose, paclitaxel-coated balloons were well tolerated in the animal model.