Low serum lathosterol levels associate with fatal cardiovascular disease and excess all-cause mortality: a prospective cohort study.

IMPORTANCE: A more precise identification of patients at "high cardiovascular risk" is preeminent in cardiovascular risk stratification. OBJECTIVE: To investigate the relationships between markers of cholesterol homeostasis, cardiovascular events and all-cause mortality. DESIGN, SETTING AND PARTICIPANTS: We quantified markers of cholesterol homeostasis by gas chromatography-mass spectrometry in 377 subjects with suspected coronary artery disease, who were not on lipid-lowering drugs at baseline. All patients were followed for occurrence of cardiovascular events and mortality over a period of 4.9 +/- 1.7 years. The standardized mortality ratio (SMR) was calculated as the ratio of the observed and the expected deaths based on the death rates of the Regional Databases Germany, and Poisson regression (rate ratio, RR) was used to compare subgroups. The SMR and RR were standardized for sex, age category and calendar period. In addition, Cox regression (Hazard ratio, HR) was used to determine the effect of co-variables on (cardiovascular) mortality within the cohort. MAIN OUTCOMES: Cardiovascular events, cardiovascular mortality and all-cause mortality. RESULTS: A total of 42 deaths were observed in 1818 person-years corresponding with an SMR of 0.99 (95% CI 0.71-1.33; p = 0.556). A fatal cardiovascular event occurred in 26 patients. Lower levels of lathosterol were associated with increased cardiovascular mortality (HR 1.59; 95% CI: 1.16-2.17; p = 0.004) and excess all-cause mortality (HR 1.41; 95% CI: 1.09-1.85; p = 0.011). Lower lathosterol tertile compared to the adjacent higher tertile was associated with 1.6 times higher all-cause mortality risk (RR 1.60; 95% CI 1.07-2.40; p for trend = 0.022). This corresponded with a 2.3 times higher mortality risk of a lathosterol-LDL ratio equal to or below the median (RR 2.29; 95% CI 1.19-4.43; p = 0.013). None of the other cholesterol homeostasis markers were associated with cardiovascular and all-cause mortality. CONCLUSIONS: In patients not on lipid-lowering agents, low serum lathosterol correlated with increased risk of cardiovascular events and excess all-cause mortality.

Plasma levels of the oxyphytosterol 7α-hydroxycampesterol are associated with cardiovascular events.

BACKGROUND AND AIMS: There are safety issues regarding plant sterol ester-enriched functional food. Oxidized plant sterols, also called oxyphytosterols, are supposed to contribute to plant sterol atherogenicity. This study aimed to analyze associations of plasma oxyphytosterol levels with cardiovascular events. METHODS: Plasma cholesterol was measured by gas chromatography-flame ionization detection. Plasma campesterol and sitosterol and their 7-oxygenated metabolites were analyzed by gas chromatography-mass selective detection. RESULTS: In 376 patients admitted for elective coronary angiography, who were not on lipid-lowering drugs, 82 cardiovascular events occurred during a follow-up period of 4.2 ±â€¯1.8 years. Patients with cardiovascular events had significantly higher 7α-hydroxycampesterol plasma levels (median, 0.46; [interquartile range (IQR) 0.22-0.81] nmol/L vs. median, 0.25 [IQR, 0.17-0.61] nmol/L; p = 0.003) and 7α-hydroxycampesterol-to-cholesterol ratios (median 0.08 [IQR, 0.04-0.14] nmol/mmol vs. median, 0.05 [IQR 0.03-0.11] nmol/mmol; p = 0.005) than controls without such events. Patients above the median were characterized by higher cumulative event rates in Kaplan-Meier-analysis (Logrank-test p = 0.084 and p = 0.025) for absolute and cholesterol corrected 7α-hydroxycampesterol, respectively. After adjustment for influencing factors and related lipids, the hazard ratios per one standard deviation of the log-transformed variables (HR) were 1.19 [95% confidence interval (CI), 0.95-1.48], p = 0.132 for 7α-hydroxycampesterol and HR, 1.18 [95% CI, 0.94-1.48], p = 0.154 for 7α-hydroxycampesterol-to-cholesterol ratio. None of the other investigated oxyphytosterols showed an association with cardiovascular events. CONCLUSIONS: In patients not on lipid-lowering drugs, absolute plasma levels of 7α-hydroxycampesterol and their ratios to cholesterol are associated with cardiovascular events. Further research is required to elucidate the role of OPS in cardiovascular diseases.

Anatomical and procedural determinants of ambulatory blood pressure lowering following catheter-based renal denervation using radiofrequency.

BACKGROUND/PURPOSE: Catheter-based renal sympathetic denervation (RDN) has been introduced to lower blood pressure (BP) and sympathetic activity in patients with uncontrolled hypertension with at best equivocal results. It has been postulated that anatomic and procedural elements introduce unaccounted variability and yet little is known of the impact of renal anatomy and procedural parameters on BP response to RDN. METHODS/MATERIALS: Anatomical parameters such as length and diameter were analyzed by quantitative vascular analysis and the prevalence of accessory renal arteries and renal artery disease were documented in 150 patients with resistant hypertension undergoing bilateral RDN using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). RESULTS: Accessory renal arteries and renal artery disease were present in 56 (37%) and 14 patients (9%), respectively. At 6-months, 24 h-ambulatory BP was reduced by 11/6 mm Hg (p < 0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of accessory renal arteries (p = 0.543) or renal artery disease (p = 0.598). Patients with at least one main renal artery diameter ≤ 4 mm had a more pronounced reduction of 24 h-ambulatory SBP compared to patients where both arteries were >4 mm (-19 vs. -10 mmHg; p = 0.038). Neither the length of the renal artery nor the number of RF ablations influenced 24 h-ambulatory BP reduction at 6 months. CONCLUSIONS: 24 h-ambulatory BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, accessory arteries or renal artery disease. Further, there was no dose-response relationship observed with increasing number of ablations. CONDENSED ABSTRACT: Because little is known of the impact of renal anatomy and procedural parameters on blood pressure (BP) response to renal denervation (RDN), anatomical and procedural data were analyzed in 150 patients undergoing bilateral RDN. BP lowering was most pronounced in patients with smaller renal artery diameter but not related to renal artery length, the presence of renal artery disease or accessory renal arteries. Further, there was no dose-response relationship observed with increasing number of ablations.

Blood Pressure Response to Main Renal Artery and Combined Main Renal Artery Plus Branch Renal Denervation in Patients With Resistant Hypertension.

BACKGROUND: Single-electrode ablation of the main renal artery for renal sympathetic denervation showed mixed blood pressure (BP)-lowering effects. Further improvement of the technique seems crucial to optimize effectiveness of the procedure. Because sympathetic nerve fibers are closer to the lumen in the distal part of the renal artery, treatment of the distal main artery and its branches has been shown to reduce variability in treatment effects in preclinical studies and a recent randomized trial. Whether this optimized technique improves clinical outcomes remains uncertain. We report a 2-center experience of main renal artery and combined main renal artery plus branches renal denervation in patients with resistant hypertension using a multielectrode catheter. METHODS AND RESULTS: Twenty-five patients with therapy-resistant hypertension underwent renal sympathetic denervation with combined main renal artery and renal branch ablation and were compared to matched controls undergoing an ablation of the main renal artery only. BP change was assessed by ambulatory measurement at baseline and after 3 months. At baseline, BP was balanced between the groups. After 3 months, BP changed significantly in the combined ablation group (systolic/diastolic 24-hour mean and daytime mean BP -8.5±9.8/-7.0±10.7 and -9.4±9.8/-7.1±13.5 mm Hg, P<0.001/0.003 and <0.001/0.016, respectively), but not in patients with main artery treatment (-3.5±11.1/-2.0±7.6 and -2.8±10.9/-1.8±7.7 mm Hg, P=0.19/0.20 and 0.19/0.24, respectively). Systolic daytime BP was significantly more reduced in patients with combined ablation than in patients with main artery ablation (P=0.033). CONCLUSIONS: Combined ablation of the main renal artery and branches appears to improve BP-lowering efficacy and should be further investigated.

A novel constrained, paclitaxel-coated angioplasty balloon catheter.

AIMS: The study aimed to assess drug adherence, transfer to the vessel wall, tolerance and efficacy of a constrained angioplasty balloon coated with an excipient-enhanced paclitaxel coating (Chocolate coated balloon [CCB]) in the porcine model. METHODS AND RESULTS: Drug adherence was investigated in vitro. Drug transfer was evaluated in porcine arteries. A stent overstretch model was chosen to provoke intimal thickening in the efficacy and tolerance study. Conventional uncoated balloons were used as controls. CCB were coated with a nominal (3 µg/mm2) and high dose (two completely overlapping inflations each at 6 µg/mm2) of paclitaxel. Efficacy was assessed by histomorphometry and quantitative coronary angiography (QCA). Tolerance, including potential downstream effects, was assessed by myocardial function and histopathology. The CCB lost 6±12% of dose during in vitro simulated delivery to the lesion; drug transfer to the vessel wall was 14±4%. QCA and histomorphometry revealed no baseline differences between treatment groups. Thirty days after treatment, both doses of the CCB resulted in a 50% reduction in neointimal thickening of arteries relative to the uncoated balloon group. Maximum neointimal thickness was 1.12±0.36 mm for uncoated control specimens and 0.46±0.06 mm and 0.44±0.30 mm for the two CCB doses (3 and 2×6 µg/mm2), respectively. There were no device-related animal deaths or changes in left ventricular ejection fraction or device-specific myocardial histopathologies. There were no statistically significant differences between inflammatory scores among treatment groups. CONCLUSIONS: The results demonstrate efficacy and tolerance of a mechanically unique constrained angioplasty balloon within the tested dose range of the selected paclitaxel coating in the chosen porcine preclinical model.

Anatomical and procedural determinants of catheter-based renal denervation.

BACKGROUND/PURPOSE: Catheter-based renal sympathetic denervation (RDN) can reduce blood pressure (BP) and sympathetic activity in certain patients with uncontrolled hypertension. Less is known about the impact of renal anatomy and procedural parameters on subsequent BP response. METHODS/MATERIALS: A total of 564 patients with resistant hypertension underwent bilateral RDN in 9 centers in Europe and Australia using a mono-electrode radiofrequency catheter (Symplicity Flex, Medtronic). Anatomical criteria such as prevalence of accessory renal arteries (ARA), presence of renal artery disease (RAD), length, and diameter were analyzed blinded to patient's characteristics. RESULTS: ARA was present in 171 patients (30%), and RAD was documented in 71 patients (13%). On average 11±2.7 complete 120-s ablations were performed, equally distributed on both sides. After 6months, BP was reduced by 19/8mmHg (p<0.001 for both). Change of systolic blood pressure (SBP) was not related to the presence of ARA (-18 vs. -20mmHg; p=NS) or RAD (-16 vs. -20mmHg; p=NS). Patients with a bilateral diameter≤4mm had a more pronounced reduction of SBP compared to patients with a unilateral diameter≤4mm or a bilateral diameter>4mm (-29 vs. -26 vs. -17mmHg; p<0.001). Neither the length of the renal artery nor the number of RF ablations influenced BP reduction after 6months. CONCLUSIONS: The diameter of renal arteries correlated with SBP change after RDN at 6-month follow-up. Change of SBP was not related to the lengths of the renal artery, presence of ARA, RAD, or the number of RF ablations delivered by a mono-electrode catheter.

Vena cava compression syndrome in patients with obesity presenting with edema and thrombosis.

OBJECTIVE: Obesity is a risk factor for cardiovascular disease and venous thrombosis. Previous studies have shown that in late pregnancy a compression of the inferior vena cava (VCI) leads to a hypotensive syndrome. The objective of this study was to explore the correlation between obesity and an elevated pressure in the VCI simulating obesity-induced vena cava compression syndrome. METHODS: A left and right heart catheterization was performed in 29 patients. After right atrial pressure measurement, the catheter was pulled back through the VCI, and the pressure gradient between the thoracic and abdominal vena cava was measured. We determined the correlation between the BMI and the pressure gradient. RESULTS: In 29 patients, a high BMI was associated with an increased pressure gradient between the thoracic and abdominal vena cava (r = 0.66). This correlation was particularly close in patients with a BMI >30 kg/m(2) (P = 0.0008). Two patients had complications such as recurrent thrombosis, with one of them having the highest pressure gradient of 16 mm Hg. CONCLUSIONS: Because mechanical obstruction of the VCI leads to an increased risk for venous thrombosis in patients with obesity, this finding needs to be considered in the decision-making for interventional treatments like bariatric surgery.

Novel Sirolimus-Coated Balloon Catheter: In Vivo Evaluation in a Porcine Coronary Model.

BACKGROUND: Limus-eluting stents are dominating coronary interventions, although paclitaxel is the only drug on balloon catheters with proven inhibition of restenosis. Neointimal inhibition by limus-coated balloons has been shown in few animal studies, but data from randomized clinical trials are not available. The aim of the present preclinical studies was to achieve high and persistent sirolimus levels in the vessel wall after administration by a coated balloon. METHODS AND RESULTS: Different coating formulations and doses were studied in the porcine coronary model to investigate sirolimus tissue levels at different time points as well as efficacy at 1 month using quantitative coronary angiography and histomorphometry. Loss of the selected coating in the valve, guiding catheter, and blood was low (2±14% of dose). Acute drug transfer to the vessel wall was 14.4±4.6% with the crystalline coating, whereas the amorphous coatings were less effective in this respect. Persistence of sirolimus in the vessel wall until 1 month was 40% to 50% of the transferred drug. At 1-month follow-up, a modest but significant reduction of neointimal growth was demonstrated in a dose range from 4 µg/mm(2) to 2×7 µg/mm(2), for example, maximum neointimal thickness of 0.38±0.13 versus 0.65±0.21 mm in the uncoated control group. CONCLUSIONS: Various sirolimus-coated balloons effectively reduce neointimal proliferation in the porcine coronary model but differ considerably in retention time in the vessel wall. It has to be determined if such a formulation with persistent high vessel concentration will result in a relevant clinical effect.

Effects of catheter-based renal denervation on cardiac sympathetic activity and innervation in patients with resistant hypertension.

OBJECTIVES: To investigate, whether renal denervation (RDN) has a direct effect on cardiac sympathetic activity and innervation density. BACKGROUND: RDN demonstrated its efficacy not only in reducing blood pressure (BP) in certain patients, but also in decreasing cardiac hypertrophy and arrhythmias. These pleiotropic effects occur partly independent from the observed BP reduction. METHODS: Eleven patients with resistant hypertension (mean office systolic BP 180 ± 18 mmHg, mean antihypertensive medications 6.0 ± 1.5) underwent I-123-mIBG scintigraphy to exclude pheochromocytoma. We measured cardiac sympathetic innervation and activity before and 9 months after RDN. Cardiac sympathetic innervation was assessed by heart to mediastinum ratio (H/M) and sympathetic activity by wash out ratio (WOR). Effects on office BP, 24 h ambulatory BP monitoring, were documented. RESULTS: Office systolic BP and mean ambulatory systolic BP were significantly reduced from 180 to 141 mmHg (p = 0.006) and from 149 to 129 mmHg (p = 0.014), respectively. Cardiac innervation remained unchanged before and after RDN (H/M 2.5 ± 0.5 versus 2.6 ± 0.4, p = 0.285). Cardiac sympathetic activity was significantly reduced by 67 % (WOR decreased from 24.1 ± 12.7 to 7.9 ± 25.3 %, p = 0.047). Both, responders and non-responders experienced a reduction of cardiac sympathetic activity. CONCLUSION: RDN significantly reduced cardiac sympathetic activity thereby demonstrating a direct effect on the heart. These changes occurred independently from BP effects and provide a pathophysiological basis for studies, investigating the potential effect of RDN on arrhythmias and heart failure.

A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis: Results from the multi-center randomized controlled PATENT-C first in human trial.

BACKGROUND: Scoring balloons produce excellent acute results in the treatment of in-stent restenosis (ISR), fibro-calcific and bifurcation lesions but have not been shown to affect the restenosis rate. A novel paclitaxel-coated scoring balloon (SB) was developed and tested to overcome this limitation. METHODS AND RESULTS: SB were coated with paclitaxel admixed with a specific excipient. Patients at four clinical sites in Germany and one in Brazil with ISR of coronary bare metal stent (BMS) were randomized 1:1 to treatment with either a drug-coated or uncoated SB. Baseline and 6-month follow-up quantitative coronary angiography was performed by an independent blinded core lab and all patients will be evaluated clinically for up to one year. The primary endpoint was angiographic in-segment late lumen loss (LLL). Secondary endpoints included the rate of clinically driven target lesion revascularization (TLR), composite of major adverse cardiovascular events (MACE), stent thrombosis and other variables. Sixty-one patients were randomized (28 uncoated and 33 drug-coated SB); mean age 65 years, males 72%, and presence of diabetes 39%. At 6-month angiography, in-segment LLL was 0.48 ± 0.51 mm in the uncoated SB group versus 0.17 ± 0.40 mm in the drug-coated SB group (P = 0.01; ITT analysis). The rate of binary restenosis was 41% in the uncoated SB group versus 7% in the drug-coated SB group (P = 0.004). The MACE rate was 32% with the uncoated SB vs. 6% in the drug-coated SB group (P = 0.016). This difference was primarily due to the reduced need for clinically driven TLR in the coated SB group (3% vs. 32% P = 0.004). CONCLUSIONS: A novel paclitaxel-coated coronary SB has been developed and successfully used in a first-in-human randomized controlled trial [ClinicalTrials.gov Identifier: NCT01495533]. © 2015 Wiley Periodicals, Inc.

A novel drug-coated scoring balloon for the treatment of coronary in-stent restenosis: Results from the multi-center randomized controlled PATENT-C first in human trial

Scoring balloons produce excellent acute results in the treatment of instentrestenosis (ISR), fibro-calcific and bifurcation lesions but have not been shown toaffect the restenosis rate. A novel paclitaxel-coated scoring balloon (SB) was developedand tested to overcome this limitation. Methods and Results: SB were coatedwith paclitaxel admixed with a specific excipient. Patients at four clinical sites inGermany and one in Brazil with ISR of coronary bare metal stent (BMS) were randomized1:1 to treatment with either a drug-coated or uncoated SB. Baseline and 6-monthfollow-up quantitative coronary angiography was performed by an independent blindedcore lab and all patients will be evaluated clinically for up to one year. The primaryendpoint was angiographic in-segment late lumen loss (LLL). Secondary endpoints included the rate of clinically driven target lesion revascularization (TLR), composite ofmajor adverse cardiovascular events (MACE), stent thrombosis and other variables.Sixty-one patients were randomized (28 uncoated and 33 drug-coated SB); mean age65 years, males 72%, and presence of diabetes 39%. At 6-month angiography, insegmentLLL was 0.48 6 0.51 mm in the uncoated SB group versus 0.17 6 0.40 mm inthe drug-coated SB group (P 5 0.01; ITT analysis). The rate of binary restenosis was41% in the uncoated SB group versus 7% in the drug-coated SB group (P 5 0.004). TheMACE rate was 32% with the uncoated SB vs. 6% in the drug-coated SB group(P 5 0.016). This difference was primarily due to the reduced need for clinically drivenTLR in the coated SB group (3% vs. 32% P 5 0.004). Conclusions: A novel paclitaxelcoatedcoronary SB has been developed and successfully used in a first-in-human randomized controlled trial...

Impact of Lesion Placement on Efficacy and Safety of Catheter-Based Radiofrequency Renal Denervation.

BACKGROUND: Insufficient procedural efficacy has been proposed to explain nonresponse to renal denervation (RDN). OBJECTIVES: The aim of this study was to examine the impact of different patterns of lesion placements on the efficacy and consistency of catheter-based radiofrequency RDN in pigs. METHODS: The impact of increasing number of lesions versus location of RDN was investigated in a porcine model (Group 1; n = 51). The effect of treating the main artery, the branches, and the 2 combined was compared in Group 2 (n = 48). The durability of response and safety of combined treatment of the main artery plus branches was examined in Group 3 (n = 16). Renal norepinephrine (NE) tissue content and renal cortical axon density were assessed. RESULTS: Increasing the number of RF lesions (4, 8, and 12) in the main renal artery was not sufficient to yield a clear dose-response relationship on NE content and axon density. In contrast, targeted treatment of the renal artery branches or distal segment of the main renal artery resulted in markedly less variability of response and significantly greater reduction of both NE and axon density than conventional treatment of only the main renal artery. Combination treatment (main artery plus branches) produced the greatest change in renal NE and axon density with the least heterogeneity. The changes were durable through 28 days post-treatment. CONCLUSIONS: These data provide the rationale for investigation of an optimized approach for RDN in future clinical studies. This may have profound implications for the clinical application of RDN, as this approach may not only achieve greater reductions in sympathetic activity but also reduce treatment effect variability.

Blood pressure variability after catheter-based renal sympathetic denervation in patients with resistant hypertension.

BACKGROUND: Renal denervation (RDN) reduces sympathetic activity and blood pressure (BP) in patients with resistant hypertension. Increased 24-h BP variability is associated with adverse cardiovascular outcomes and related to sympathetic activation. METHODS AND RESULTS: This multicenter study investigated the effect of RDN on BP variability in 84 patients with uncontrolled hypertension (office systolic BP ≥140 mmHg) despite treatment with greater than three antihypertensive agents. BP variability was assessed by means of standard deviation, coefficient of variation (standard deviation/mean), and average real variability of 24-h ambulatory SBP at 3-month and 6-month follow-up. RDN significantly reduced office BP by 17/6 mmHg at 3-month and 19/7 mmHg at 6-month follow-up (P < 0.001 for all) and 24-h ambulatory BP by 9/5 mmHg (P < 0.001/P = 0.001) after 3 months and 12/7 mmHg (P < 0.001/P < 0.001) after 6 months. Standard deviation significantly decreased from 17.1 to 14.9 mmHg (P = 0.008) and 15.3 mmHg (P = 0.037), consistent with a reduction of coefficient of variation from 0.116 to 0.103 (P = 0.035) and 0.104 (P = 0.071) and average real variability from 12.3 to 10.9 (P = 0.029) and 11.0 (P = 0.054) after 3-month and 6-month, respectively. Interestingly, also BP nonresponders (change in office systolic BP < 10 mmHg after 6 months) showed a significant reduction of standard deviation after 3 months (P = 0.041, n = 26) and a borderline significant reduction at 6-month (P = 0.057, n = 28). CONCLUSIONS: RDN reduces office and ambulatory BP and BP variability in patients with resistant hypertension. Improvement in BP variability was also documented in patients characterized as office BP nonresponders after 6 months.

Blood pressure changes after catheter-based renal denervation are related to reductions in total peripheral resistance.

BACKGROUND: Renal denervation (RDN) can reduce sympathetic activity and blood pressure (BP) in patients with uncontrolled hypertension. The exact mechanisms by which RDN results in BP reductions are yet not fully established. METHODS AND RESULTS: This study investigated the effects of RDN on office BP, 24-h ambulatory BP, noninvasive 10-min beat-to-beat digital pulse wave analysis, total peripheral resistance (TPR), cardiac output, and plasma renin and aldosterone serum concentrations in 30 patients with resistant hypertension. Adherence to antihypertensive drugs was assessed by liquid chromatography high-resolution tandem mass spectrometry analysis in plasma and urine at baseline and at 6 month. RDN significantly reduced office BP, beat-to-beat BP, and 24-h ambulatory BP by 19/6 (P = 0.021/P = 0.012), 12/7 (P = 0.005/P = 0.005), and 10/5  mmHg (P = 0.001/P = 0.049) at 6 months, respectively. TPR decreased from 1696 to 1377  dyn × s/cm (-19%; P = 0.027). This reduction was not associated with significant changes in cardiac output. The changes in office, ambulatory, and beat-to-beat BP correlated with the reductions of TPR. Adherence to antihypertensive treatment remained unchanged during the study period (84.7% at baseline, 83.6% at 6 months, P = 0.782). CONCLUSION: RDN reduced office BP, beat-to-beat BP, and 24-h ambulatory BP in patients with resistant hypertension after 6 months. The BP changes were associated with reductions in peripheral resistance, whereas cardiac output, plasma renin, and aldosterone levels remained unchanged. The observed effects were not explained by an increased intake of antihypertensive medications.

Blood pressure reductions following catheter-based renal denervation are not related to improvements in adherence to antihypertensive drugs measured by urine/plasma toxicological analysis.

Renal denervation can reduce blood pressure in patients with uncontrolled hypertension. The adherence to prescribed antihypertensive medication following renal denervation is unknown. This study investigated adherence to prescribed antihypertensive treatment by liquid chromatography-high resolution tandem mass spectrometry in plasma and urine at baseline and 6 months after renal denervation in 100 patients with resistant hypertension, defined as baseline office systolic blood pressure ≥140 mmHg despite treatment with ≥3 antihypertensive agents. At baseline, complete adherence to all prescribed antihypertensive agents was observed in 52 patients, 46 patients were partially adherent, and two patients were completely non-adherent. Baseline office blood pressure was 167/88 ± 19/16 mmHg with a corresponding 24-h blood pressure of 154/86 ± 15/13 mmHg. Renal denervation significantly reduced office and ambulatory blood pressure at 6-month follow-up by 15/5 mmHg (p < 0.001/p < 0.001) and 8/4 mmHg (p < 0.001/p = 0.001), respectively. Mean adherence to prescribed treatment was significantly reduced from 85.0 % at baseline to 80.7 %, 6 months after renal denervation (p = 0.005). The blood pressure decrease was not explained by improvements in adherence following the procedure. Patients not responding to treatment significantly reduced their drug intake following the procedure. Adherence was highest for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and beta blockers (>90 %) and lowest for vasodilators (21 %). In conclusion, renal denervation can reduce office and ambulatory blood pressure in patients with resistant hypertension despite a significant reduction in adherence to antihypertensive treatment after 6 months.

Paclitaxel-coated balloon catheter versus paclitaxel-coated stent for the treatment of coronary in-stent restenosis: the three-year results of the PEPCAD II ISR study.

AIMS: Treatment of bare metal in-stent restenosis with the paclitaxel-coated balloon catheter based on the PACCOCATH® technology has yielded superior six-month angiographic and one-year clinical results compared to a paclitaxel-eluting stent. The three-year clinical follow-up is presented. METHODS AND RESULTS: One hundred and thirty-one patients with coronary bare metal in-stent restenosis (>70%, length: <22 mm, vessel diameter: 2.5-3.5 mm) were randomly treated with the paclitaxel-coated balloon (DCB) (3 µg/mm²) or a paclitaxel-eluting stent (DES). Clinical follow-up information was requested from the patients and from their physicians. Quantitative angiographic and demographic baseline data were statistically not different between the groups. Per intention-to-treat analysis at 12 months, the lesion-related rates of major adverse cardiac events were 7.6% and 16.9% (p=0.11) while at 36 months the respective numbers were 9.1% and 18.5% (p=0.14). These differences were primarily due to reduced target lesion revascularisation (TLR) in DCB 4/66 (6.2%) compared to DES patients 10/65 (15.4%) (p=0.10). From 12 to 36 months, 1/65 (1.5%) DCB patients experienced a myocardial infarction while neither TLR nor death occurred in any study patient in either group during that period. CONCLUSIONS: The six-month superiority of the paclitaxel-coated balloon compared to the paclitaxel-eluting stent in the treatment of bare metal coronary in-stent restenosis persisted throughout the three-year clinical follow-up period indicating stability of the lesions treated. (ClinicalTrials.gov Identifier: NCT00393315).

Reduced effect of percutaneous renal denervation on blood pressure in patients with isolated systolic hypertension.

Renal denervation can reduce blood pressure in certain patients with resistant hypertension. The effect in patients with isolated systolic hypertension (ISH, ≥140/<90 mm Hg) is unknown. This study investigated the effects of renal denervation in 126 patients divided into 63 patients with ISH and 63 patients with combined hypertension (CH, ≥140/≥90 mm Hg) defined as baseline office systolic blood pressure (SBP) ≥140 mm Hg despite treatment with ≥3 antihypertensive agents. Renal denervation significantly reduced office SBP and diastolic blood pressure (DBP) at 3, 6, and 12 months by 17/18/17 and 5/4/4 mm Hg in ISH and by 28/27/30 and 13/16/18 mm Hg in CH, respectively. The reduction in SBP and DBP in ISH was lower compared with patients with CH at all observed time points (P<0.05 for SBP/DBP intergroup comparison). The nonresponder rate (change in office SBP <10 mm Hg) after 6 months was 37% in ISH and 21% in CH (P<0.001). Mean 24-hour ambulatory SBP and DBP after 3, 6, and 12 months were significantly reduced by 10/13/15 and 6/6/9 mm Hg in CH, respectively. In patients with ISH the reduction in systolic ambulatory blood pressure was 4/8/7 mm Hg (P=0.032/P<0.001/P=0.009) and 3/4/2 mm Hg (P=0.08/P<0.001/P=0.130) in diastolic ambulatory blood pressure after 3, 6, and 12 months, respectively. The ambulatory blood pressure reduction was significantly lower after 3 and 12 months in SBP and after 12 months in ambulatory DBP, respectively. In conclusion, renal denervation reduces office and ambulatory blood pressure in patients with ISH. However, this reduction is less pronounced compared with patients with CH.

Pulsatile venoarterial perfusion using a novel synchronized cardiac assist device augments coronary artery blood flow during ventricular fibrillation.

Patients with cardiogenic shock have a very high mortality. Here we report the first use of a percutaneous pulsatile cardiac assist device, based on a diagonal pump synchronized with the heart cycle by means of an electrocardiographic signal in adult pigs. Eight domestic pigs underwent mandatory ventilation. During sinus rhythm, there were no differences between pulsatile and nonpulsatile perfusion with regard to pulmonary artery pressure, pulmonary wedge pressure, central venous pressure, mean arterial pressure (MAP), mean pulse pressure, and mean coronary artery flow (CAF). After 2 min of complete cardiac arrest (ventricular fibrillation), circulatory support with the i-cor in venoarterial nonpulsatile extracorporeal membrane oxygenation (ECMO) mode (3 L/min) restored systemic circulation, with an increase of MAP to 78.3 mm Hg and CAF to 5.27 mL/min. After changing from ECMO settings to pulsatile mode (3 L/min, 75 bpm, pulse amplitude range 3500 rpm), MAP did not change significantly (75.6 mm Hg); however, CAF increased to 8.45 mL/min. After changing back to nonpulsatile mode, MAP remained stable (83.6 mm Hg), but CAF decreased to 4.85 mL/min. Thereafter, pulsatile cardiac assist was established with a reduced blood flow of 2.5 L/min, and the pulse amplitude range was extended to 4500 rpm. Under these conditions, MAP remained stable (71.0 mm Hg), but CAF significantly increased to 15.2 mL/min (P < 0.05). Percutaneous cardiac support using a venoarterial cardiac assist device equipped with a novel diagonal pump is able to restore and increase systemic and coronary circulation during ventricular fibrillation. Electrocardiographically triggered synchronized cardiac assist provides an additional increase of coronary artery flow. These promising results are to be confirmed in humans.

Local paclitaxel induces late lumen enlargement in coronary arteries after balloon angioplasty.

BACKGROUND: This study investigated p aclitaxel-induced luminal changes following drug-coated balloon (DCB) angioplasty to treat coronary de novo lesions without additional stenting. DCB-mediated local drug delivery reduces late lumen loss in de novo coronary artery lesions. We performed a retrospective clinical assessment based on a pre-specified quantitative coronary angiography (QCA) protocol. METHODS: QCA was performed for each centre to assess the primary endpoint late lumen changes, i.e. the difference between in-lesion minimal lumen diameter (MLD) at the routine angiographic follow-up as compared to post-procedural in-lesion MLDs. These MLD changes were compared to corresponding reference vessel diameter changes as an intra-patient control. RESULTS: We evaluated 58 consecutive native coronary artery lesions directly after DCB angioplasty and at a routine target follow-up angiography of 4 months by QCA. Target lesion MLD increased significantly within the 4.1 ± 2.1 month observation period (1.75 ± 0.55 vs. 1.91 ± 0.55 mm, p < 0.001, diameter stenosis 33.8 ± 12.3 vs. 26.9 ± 13.8 %, p < 0.001), while there were no changes in non-target reference vessel diameters (2.33 ± 0.60 vs. 2.34 ± 0.61 mm, p = ns). A total of 69 % of patients showed luminal enlargement whereas 29 % had minor luminal loss. CONCLUSION: Local application of paclitaxel by DCB angioplasty to native coronary arteries after pre-dilatation without major dissection and recoil leads to late lumen increase.

Efficacy and safety of catheter-based radiofrequency renal denervation in stented renal arteries.

BACKGROUND: In selected patients with hypertension, renal artery (RA) stenting is used to treat significant atherosclerotic stenoses. However, blood pressure often remains uncontrolled after the procedure. Although catheter-based renal denervation (RDN) can reduce blood pressure in certain patients with resistant hypertension, there are no data on the feasibility and safety of RDN in stented RA. METHODS AND RESULTS: We report marked blood pressure reduction after RDN in a patient with resistant hypertension who underwent previous stenting. Subsequently, radiofrequency ablation was investigated within the stented segment of porcine RA, distal to the stented segment, and in nonstented RA and compared with stent only and untreated controls. There were neither observations of thrombus nor gross or histological changes in the kidneys. After radiofrequency ablation of the nonstented RA, sympathetic nerves innervating the kidney were significantly reduced, as indicated by significant decreases in sympathetic terminal axons and reduction of norepinephrine in renal tissue. Similar denervation efficacy was found when RDN was performed distal to a renal stent. In contrast, when radiofrequency ablation was performed within the stented segment of the RA, significant sympathetic nerve ablation was not seen. Histological observation showed favorable healing in all arteries. CONCLUSIONS: Radiofrequency ablation of previously stented RA demonstrated that RDN provides equally safe experimental procedural outcomes in a porcine model whether the radiofrequency treatment is delivered within, adjacent, or without the stent struts being present in the RA. However, efficacious RDN is only achieved when radiofrequency ablation is delivered to the nonstented RA segment distal to the stent.