A Three-Arm Randomized Trial of Different Renal Denervation Devices and Techniques in Patients With Resistant Hypertension (RADIOSOUND-HTN).

BACKGROUND: Both radiofrequency and ultrasound endovascular renal sympathetic denervation (RDN) have proven clinical efficacy for the treatment of hypertension. We performed a head-to-head comparison of these technologies. METHODS: Patients with resistant hypertension were randomly assigned in a 1:1:1 manner to receive either treatment with (1) radiofrequency RDN of the main renal arteries; (2) radiofrequency RDN of the main renal arteries, side branches, and accessories; or (3) an endovascular ultrasound-based RDN of the main renal artery. The primary end point was change in systolic daytime ambulatory blood pressure at 3 months. RESULTS: Between June 2015 and June 2018, 120 patients were enrolled (mean age, 64±9 years±SD; mean daytime blood pressure, 153/86±12/13 mm Hg). Of these, 39 were randomly assigned to radiofrequency main renal artery ablation, 39 to combined radiofrequency ablation of the main artery and branches, and 42 to ultrasound-based treatment. Baseline daytime blood pressure, clinical characteristics, and treatment were well balanced between the groups. At 3 months, systolic daytime ambulatory blood pressure decreased by 9.5±12.3 mm Hg ( P<0.001) in the whole cohort. Although blood pressure was significantly more reduced in the ultrasound ablation group than in the radiofrequency ablation group of the main renal artery (-13.2±13.7 versus -6.5±10.3 mm Hg; mean difference, -6.7 mm Hg; global P=0.038 by ANOVA, adjusted P=0.043), no significant difference was found between the radiofrequency ablation groups (-8.3±11.7 mm Hg for additional side branch ablation; mean difference, -1.8 mm Hg; adjusted P>0.99). Similarly, the blood pressure reduction was not found to be significantly different between the ultrasound and the side branch ablation groups. Frequencies of blood pressure response ≥5 mm Hg were not significantly different (global P=0.77). CONCLUSIONS: In patients with resistant hypertension, endovascular ultrasound-based RDN was found to be superior to radiofrequency ablation of the main renal arteries only, whereas a combined approach of radiofrequency ablation of the main arteries, accessories, and side branches was not. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02920034.

Outcome of patients with previous coronary artery bypass grafting and severe calcific aortic stenosis receiving transfemoral transcatheter aortic valve replacement.

OBJECTIVES: To evaluate the impact of previous coronary artery bypass grafting (CABG) on early safety at 30 days and 1-year mortality in patients receiving transcatheter aortic valve replacement (TAVR). BACKGROUND: The use of TAVR in patients with previous CABG suffering from severe aortic stenosis has increased in the last years. METHODS: Consecutive TAVR patients were stratified according to previous CABG versus no previous cardiac surgery (control). All-cause 1-year mortality and early safety at 30 days were evaluated. RESULTS: In the unmatched cohort and compared to control (n = 2,364), CABG (n = 260) were younger, more often male and suffered more often from comorbidities leading to an increased STS-score (p < .001). The rate of early safety events at 30 days was comparable between CABG and control (21.2% vs. 24.6%, p = .22) with a higher mortality in CABG (9.6% vs. 5.3%, p = .005). All-cause 1-year mortality was higher in CABG compared to controls (HR 1.51 [95%-CI 1.15-1.97], p = .003). Applying Cox regression analysis, both 30-day (HR 1.57 [95%-CI 0.97-2.53], p = .067) and all-cause 1-year mortality (HR 1.24 [95%-CI 0.91-1.70], p = .174) were not significantly different between groups. After propensity-score matching, the rate of early safety events at 30 days was lower in CABG compared to controls (21.6% vs. 31.7%, p = .02). Thirty-day (9.1% vs. 7.7%, p = .596) and all-cause 1-year mortality (24.0% vs. 23.1%, p = .520, HR 1.14 [95%-CI 0.77-1.69], p = .520) were not different between groups. CONCLUSION: In patients receiving TAVR, previous CABG was not associated with an increase in periprocedural complications and all-cause 1-year mortality when adjusted for other comorbidities.

High-Intensity Interval Training in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Small studies have suggested that high-intensity interval training (HIIT) is superior to moderate continuous training (MCT) in reversing cardiac remodeling and increasing aerobic capacity in patients with heart failure with reduced ejection fraction. The present multicenter trial compared 12 weeks of supervised interventions of HIIT, MCT, or a recommendation of regular exercise (RRE). METHODS: Two hundred sixty-one patients with left ventricular ejection fraction ≤35% and New York Heart Association class II to III were randomly assigned to HIIT at 90% to 95% of maximal heart rate, MCT at 60% to 70% of maximal heart rate, or RRE. Thereafter, patients were encouraged to continue exercising on their own. Clinical assessments were performed at baseline, after the intervention, and at follow-up after 52 weeks. Primary end point was a between-group comparison of change in left ventricular end-diastolic diameter from baseline to 12 weeks. RESULTS: Groups did not differ in age (median, 60 years), sex (19% women), ischemic pathogenesis (59%), or medication. Change in left ventricular end-diastolic diameter from baseline to 12 weeks was not different between HIIT and MCT (P=0.45); left ventricular end-diastolic diameter changes compared with RRE were -2.8 mm (-5.2 to -0.4 mm; P=0.02) in HIIT and -1.2 mm (-3.6 to 1.2 mm; P=0.34) in MCT. There was also no difference between HIIT and MCT in peak oxygen uptake (P=0.70), but both were superior to RRE. However, none of these changes was maintained at follow-up after 52 weeks. Serious adverse events were not statistically different during supervised intervention or at follow-up at 52 weeks (HIIT, 39%; MCT, 25%; RRE, 34%; P=0.16). Training records showed that 51% of patients exercised below prescribed target during supervised HIIT and 80% above target in MCT. CONCLUSIONS: HIIT was not superior to MCT in changing left ventricular remodeling or aerobic capacity, and its feasibility remains unresolved in patients with heart failure. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00917046.

Impact of active cancer disease on the outcome of patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Patients undergoing transcatheter aortic valve replacement (TAVR) are often characterized by risk factors not reflected in conventional risk scores. In this context, little is known about the outcome of patients suffering from an active cancer disease (ACD). The objective was to determine the prevalence, clinical characteristics, perioperative outcomes, and mortality of patients with ACD undergoing TAVR compared to those with a history of cancer (HCD) and controls without known tumor disease. METHODS: TAVR patients between 02/2006 and 09/2014 were stratified according to the presence of ACD, HCD, and control. All-cause-mortality at 1-year was the primary end point. All end point definitions were subject to the Valve Academic Research Consortium II definitions. RESULTS: Overall, 1821 patients were included: 99 patients (5.4%) suffered from ACD and 251 patients (13.8%) had HCD. ACD was related to a solid organ or hematological source in 72.7% and 27.3%, respectively. Patients with ACD were more often male (P = 0.004) and had a lower logisticEuroScore I (P = 0.033). Overall rates of VARC-II defined periprocedural myocardial infarction, stroke, bleeding, access-site complications, and acute kidney injury were not different between groups. Thirty-day mortality did not differ between patients with ACD, HCD, and controls (6.1% vs 4.4% vs 7.6%, P = 0.176). All-cause 1-year mortality was higher in patients with ACD compared HCD and controls (37.4% vs 16.4% vs 20.8%, P < 0.001). ACD was an independent predictor of all-cause 1-year mortality (HR 2.10, 95%-CI 1.41-3.13, P < 0.001). CONCLUSION: The presence of ACD in patients undergoing TAVR is associated with significantly higher 1-year mortality.

Exercise training in patients with chronic heart failure promotes restoration of high-density lipoprotein functional properties.

RATIONALE: High-density lipoprotein (HDL) exerts endothelial-protective effects via stimulation of endothelial cell (EC) nitric oxide (NO) production. This function is impaired in patients with cardiovascular disease. Protective effects of exercise training (ET) on endothelial function have been demonstrated. OBJECTIVE: This study was performed to evaluate the impact of ET on HDL-mediated protective effects and the respective molecular pathways in patients with chronic heart failure (CHF). METHODS AND RESULTS: HDL was isolated from 16 healthy controls (HDL(healthy)) and 16 patients with CHF-NYHA-III (HDL(NYHA-IIIb)) before and after ET, as well as from 8 patients with CHF-NYHA-II (HDL(NYHA-II)). ECs were incubated with HDL, and phosphorylation of eNOS-Ser(1177), eNOS-Thr(495), PKC-ßII-Ser(660), and p70S6K-Ser(411) was evaluated. HDL-bound malondialdehyde and HDL-induced NO production by EC were quantified. Endothelial function was assessed by flow-mediated dilatation. The proteome of HDL particles was profiled by shotgun LC-MS/MS. Incubation of EC with HDL(NYHA-IIIb) triggered a lower stimulation of phosphorylation at eNOS-Ser(1177) and a higher phosphorylation at eNOS-Thr(495) when compared with HDL(healthy). This was associated with lower NO production of EC. In addition, an elevated activation of p70S6K, PKC-ßII by HDL(NYHA-IIIb), and a higher amount of malondialdehyde bound to HDL(NYHA-IIIb) compared with HDL(healthy) was measured. In healthy individuals, ET had no effect on HDL function, whereas ET of CHF-NYHA-IIIb significantly improved HDL function. A correlation between changes in HDL-induced NO production and flow-mediated dilatation improvement by ET was evident. CONCLUSIONS: These results demonstrate that HDL function is impaired in CHF and that ET improved the HDL-mediated vascular effects. This may be one mechanism how ET exerts beneficial effects in CHF.

Age-related effects of exercise training on diastolic function in heart failure with reduced ejection fraction: the Leipzig Exercise Intervention in Chronic Heart Failure and Aging (LEICA) Diastolic Dysfunction Study.

AIMS: Diastolic dysfunction (DD) was identified as a predictor of adverse prognosis in heart failure with reduced ejection fraction (HFREF). It is, however, unknown if DD is improved by exercise training, which is known to induce reverse remodelling, and if the training effect is attenuated in elderly HFREF patients. We therefore assessed DD in a cohort of referent controls (RCs) and HFREF patients and studied the response of DD to endurance exercise in two age groups (≤55 years and ≥65 years). METHODS AND RESULTS: Sixty RC (30 ≤ 55 years, mean age 50 ± 5 years; 30 ≥ 65 years, 72 ± 4 years) and 60 HFREF patients (30 ≤ 55 years, 46 ± 5 years; 30 ≥ 65 years, 72 ± 5 years, EF 28 ± 5%) were randomized to 4 weeks of supervised endurance training or to a control group. Exercise training was effective in reducing LV isovolumetric relaxation time by 29% in young and by 26% in old HFREF patients (P< 0.05 for both). As assessed by tissue Doppler, septal E' increased by 37% in young and by 39% among old HFREF patients (P< 0.005 for both) resulting in a significant decrease in the E/E' ratio from 13 ± 1 to 10 ± 1 in young and 14 ± 1 to 11 ± 1 in old HFREF patients (P< 0.05 for both). Serum levels of N-terminal pro brain natriuretic peptide were significantly reduced after endurance training in HFREF patients of all ages. CONCLUSION: In HFREF, diastolic function is significantly impaired in all age groups. Endurance training is highly effective in improving left ventricular diastolic function in HFREF patients regardless of age. This study is registered at ClinicalTrials.gov (number: NCT00176319).

Maximal exercise, limb ischemia, and endothelial progenitor cells.

OBJECTIVES: The concept of neovascularization in response to tissue ischemia was recently extended by the finding of postnatal vasculogenesis through circulating endothelial progenitor cells (EPCs). The aim of this study was to assess the role of acute ischemia for EPC mobilization in patients with peripheral arterial occlusive disease (PAOD) and in healthy volunteers. METHODS: The number of circulating EPCs was analyzed by flow cytometry in PAOD patients (n = 23) with exercise-induced limb ischemia for up to 72 h after a maximal treadmill test and in healthy volunteers (n = 17) who underwent a 15-min suprasystolic occlusion of one lower extremity to induce limb ischemia. Plasma concentrations of vascular endothelial growth factor, basic fibroblast growth factor, tumor necrosis factor-α, and granulocyte macrophage-colony stimulating factor were determined by ELISA. RESULTS: EPCs (CD 34 pos/KDRpos) increased significantly in both PAOD patients from 82 ± 20 to 256 ± 52 (P < 0.05) and healthy volunteers from 144 ± 39 to 590 ± 61 cells per 1 million events (P < 0.05) in response to induced ischemia, with a maximum after 24 h and returned to baseline within 72 h. The relative increase in EPC numbers was significantly lower in patients with PAOD as compared with healthy volunteers (P < 0.05). Plasma levels of vascular endothelial growth factor increased from 27.4 ± 3.1 to 126.4 ± 12 pg/ml in patients with PAOD (P < 0.05) and from 30.7 ± 6.1 to 134.1 ± 12.4 pg/ml in healthy volunteers (P < 0.05). CONCLUSION: Both patients with symptomatic PAOD and healthy volunteers respond to a single episode of limb ischemia with a time-dependent increase in circulating EPCs. The increase of EPC numbers in response to ischemia is reduced when vascular disease is present, underlining the reduced vasculogenic potential of patients with PAOD.

Left-Atrial Appendage Thrombosis in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND: Data about the impact of left-atrial appendage thrombosis (LAAT) on early safety and mortality in patients undergoing transfemoral transcatheter aortic valve implantation (TF-TAVI) are scarce. We aimed to investigate the prevalence and predictors of LAAT and the outcome associated with this condition in patients treated by TF-TAVI. METHODS: Retrospective data analysis was derived from a prospective single-centre registry comparing patients with and without LAAT regarding early safety at 30 days, according to Valve Academic Research Consortium-2 (VARC-2) and 2-year mortality. RESULTS: LAAT was found in 7.6% of the whole cohort (n = 2527) and in 16.6% in those patients with known pre-existing atrial fibrillation (AF cohort, n = 1099). Compared with controls, patients with LAAT were sicker, indicated by a higher Society of Thoracic Surgeons (STS) score and burden of comorbidities. Neither VARC-2-defined early safety at 30 days nor the rate of stroke was different between LAAT and controls in both the whole (early safety: 29.2% vs 24.2%, P = 0.123; stroke: 5.9% vs 4.7%, P = 0.495) and AF cohort (early safety: 29.1% vs 22.9%, P = 0.072; stroke: 5.6% vs 3.3%, P = 0.142). Evaluating the whole cohort in a univariate analysis, the 2-year mortality was significantly higher in LAAT compared with controls (hazard ratio, 1.41; 95% confidence interval, 1.07-1.86; P = 0.014). However, multivariate analysis of the whole cohort and the AF cohort revealed no association between LAAT and 2-year mortality. CONCLUSIONS: LAAT was frequent in patients undergoing TF-TAVI- in particular, in patients with histories of AF-but it was not associated with an increase in periprocedural complications and did not predict 2-year mortality.

Baseline and Exercise Predictors of V˙O2peak in Systolic Heart Failure Patients: Results from SMARTEX-HF.

PURPOSE: This study aimed to investigate baseline, exercise testing, and exercise training-mediated predictors of change in peak oxygen uptake (V˙O2peak) from baseline to 12-wk follow-up (ΔV˙O2peak) in a post hoc analysis from the SMARTEX Heart Failure trial. METHODS: We studied 215 patients with heart failure with left ventricular ejection fraction (LVEF) ≤35%, and New York Heart Association (NYHA) classes II-III who were randomized to either supervised high-intensity interval training with exercise target intensity of 90%-95% of peak heart rate (HRpeak) or supervised moderate continuous training (MCT) with target intensity of 60%-70% of HRpeak, or who received a recommendation of regular exercise on their own. Predictors of ΔV˙O2peak were assessed in two models: a logistic regression model comparing highest and lowest tertiles (baseline parameters) and a multivariate linear regression model (test/training/clinical parameters). RESULTS: The change in V˙O2peak in response to the interventions (ΔV˙O2peak) varied substantially, from -8.50 to +11.30 mL·kg·min. Baseline NYHA (class II gave higher odds vs III; odds ratio (OR), 7.1 (2.0-24.9); P = 0.002), LVEF (OR per percent, 1.1 (1.0-1.2); P = 0.005), and age (OR per 10 yr, 0.5 (0.3-0.8); P = 0.003) were associated with ΔV˙O2peak.In the multivariate linear regression, 34% of the variability in ΔV˙O2peak was explained by the increase in exercise training workload, ΔHRpeak between baseline and 12-wk posttesting, age, and ever having smoked. CONCLUSION: Exercise training response (ΔV˙O2peak) correlated negatively with age, LVEF, and NYHA class. The ability to increase workload during the training period and increased ΔHRpeak between baseline and the 12-wk test were associated with a positive outcome.

Endothelial progenitor cells: implications for cardiovascular disease.

Endothelial progenitor cells (EPCs) reside in the bone marrow and are mobilized into the circulation by specific stimuli such as certain drugs, ischemia, and exercise training. Once in the circulation EPCs are thought to participate in the maintenance of the endothelial cell layer. Recently it was clearly demonstrated that the amount and function of EPCs is significantly impaired in different cardiovascular diseases. Furthermore, the level of circulating EPCs predicts the occurrence of cardiovascular events and death from cardiovascular causes and may help to identify patients at increased cardiovascular risk. After demonstrating the beneficial effect of applied EPCs in several animal experiments, these cells were also used to treat humans with different cardiovascular diseases. This review will focus on the characterization and liberation of EPCs from the bone marrow, as well as on the most important clinical cardiovascular diseases for which EPCs were used therapeutically.

Gender-dependent association of diabetes mellitus with mortality in patients undergoing transcatheter aortic valve replacement.

BACKGROUND: Diabetes mellitus (DM) is a risk factor for cardiovascular disease. However, its effect on procedural and follow-up performance after transcatheter aortic valve replacement (TAVR) remains controversial. METHODS AND RESULTS: We performed an observational study of all consecutive patients treated with a transfemoral TAVR in a single-center cohort (n = 1818). All patients were stratified by diabetes status and gender. All-cause 3-year mortality was the primary endpoint. Male patients with DM were identified to have substantially increased 3-year mortality [125/314 (39.8%)] compared to males without DM [142/478 (29.7%), p < 0.01]. Male patients with DM had significantly higher 3-year mortality in comparison to female patients with (p < 0.01) or without DM (p < 0.01). There was no difference in 3-year mortality for female patients with [135/465 (29.0%)] and without DM [151/554 (27.3%); p = 0.70]. This increase in mortality in male DM patients was triggered by both cardiovascular and non-cardiovascular mortality. Furthermore, DM served as an independent predictor of 3-year mortality after TAVR selectively only in men. The interaction between male gender and diabetes mellitus was identified as an independent predictor of 3-year mortality [HR 1.88 (1.25; 2.82); p < 0.01]. DM did not affect 30-day mortality for the overall cohort and for males. CONCLUSION: Males with DM are a high-risk subgroup of patients after TAVR and require close medical attention including aggressive therapy of modifiable risk factors. Intensified diabetes management may improve long-term survival after TAVR.

Continued Versus Interrupted Oral Anticoagulation During Transfemoral Transcatheter Aortic Valve Implantation and Impact of Postoperative Anticoagulant Management on Outcome in Patients With Atrial Fibrillation.

The role of continued versus interrupted oral anticoagulation (OAC) in patients with atrial fibrillation (AF) who underwent transfemoral transcatheter aortic valve implantation (TF-TAVI) for severe aortic stenosis is uncertain. The aim of this retrospective investigation was to evaluate the impact (1) of continued versus interrupted OAC on early safety and (2) of postoperative anticoagulant management on the 1-year mortality in patients with AF who underwent TF-TAVI. Consecutive patients with AF and on OAC at admission (n = 598) were stratified according to interrupted (iVKA) versus continued vitamin K antagonist (cVKA) versus continued direct oral anticoagulants (DOAC) at the time of TF-TAVI. Valve Academic Research Consortium-2 early safety was the primary outcome measure. Patients with iVKA (n = 299), cVKA (n = 117), and DOAC (n = 182) had comparable baseline characteristics including age (p = 0.25), gender (p = 0.33), and STS-Score (p = 0.072). The proportion of patients having a CHA2DS2-VASc-Score ≥3 (p = 0.791) and HAS-BLED-Score ≥3 (p = 0.185) was not different between groups. The rate of early safety events (with lower values indicating superior safety) was lowest in DOAC (13.2%) and not increased in cVKA (19.7%) compared to iVKA (23.1%) (p = 0.029). Valve Academic Research Consortium-2 defined stroke (p = 0.527) and bleeding (p = 0.097) did not differ between groups. Renal failure occurred more often in iVKA compared to cVKA and DOAC (p = 0.02). All-cause 1-year mortality was 20.1% in iVKA, 13.7% in cVKA, and 8.8% in DOAC (p = 0.015). Multivariate analysis revealed DOAC to be associated with reduced all-cause 1-year mortality (HR 0.56 (95%-CI 0.32 to 0.99), p = 0.047) whereas cVKA was comparable to iVKA (HR 0.75 (95%-CI 0.43 to 1.31), p = 0.307). In conclusion, cVKA did not increase the rate for the composite end point of early safety at 30 days in this cohort of patients. Treatment with a DOAC was associated with a significantly reduced rate of early safety end points at 30 days and lower 1-year mortality.

Cardiac Surgery Compared With Antibiotics Only in Patients Developing Infective Endocarditis After Transcatheter Aortic Valve Replacement.

Background Infective endocarditis ( IE ) after transcatheter aortic valve replacement is a devastating complication associated with a high mortality. Our objective was to determine the impact of cardiac surgery (CS) and antibiotics ( IE - CS ) compared with medical treatment with antibiotics only ( IE - AB x) on 1-year mortality in patients developing IE after transcatheter aortic valve replacement. Methods and Results Patients developing IE after transcatheter aortic valve replacement were included in this retrospective analysis. All-cause 1-year mortality was the primary end point. A total of 20 patients underwent IE - CS compared with 44 patients treated by IE - AB x. In this unmatched cohort, patients treated by IE - AB x were older ( P=0.006), had a higher Society of Thoracic Surgeons score ( P=0.029), and more often had severe chronic kidney disease ( P=0.037). One-year mortality was not different between groups ( IE -CS versus IE-ABx, 65% versus 68.2%; P=0.802). The rate of any complication during treatment was higher in the IE - CS group ( P=0.024). In a matched cohort, baseline characteristics were not significantly different. All-cause 1-year mortality was not different between groups ( IE -CS versus IE-ABx, 65% versus 75%; P=0.490). A Cox regression analysis revealed any indication for surgery (hazard ratio, 6.20; 95% confidence interval, 1.80-21.41; P=0.004), sepsis on admission (hazard ratio, 4.03; 95% confidence interval, 1.97-8.24; P<0.001), and mitral regurgitation ≥2 (hazard ratio, 2.91; 95% confidence interval, 1.33-6.37) as factors associated with 1-year mortality. Conclusions In patients developing IE after transcatheter aortic valve replacement, mortality was predicted by the severity of IE and concomitant mitral regurgitation. In this small, and therefore statistically limited, but high-risk patient cohort, CS provided no significant mortality benefit compared with medical therapy. Individual decision making by a "heart and endocarditis team" is necessary to offer those patients the most reasonable treatment option.

Predictors of Mortality and Symptomatic Outcome of Patients With Low-Flow Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: Impaired left ventricular (LV) ejection fraction is a common finding in patients with aortic stenosis and serves as a predictor of morbidity and mortality after transcatheter aortic valve replacement. However, conflicting data on the most accurate measure for LV function exist. We wanted to examine the impact of LV ejection fraction, mean pressure gradient, and stroke volume index on the outcome of patients treated by transcatheter aortic valve replacement. METHODS AND RESULTS: Patients treated by transcatheter aortic valve replacement were primarily separated into normal flow (NF; stroke volume index >35 mL/m2) and low flow (LF; stroke volume index ≤35 mL/m2). Afterwards, patients were divided into 5 groups: "NF-high gradient," "NF-low gradient" (NF-LG), "LF-high gradient," "paradoxical LF-LG," and "classic LF-LG." The 3-year mortality was the primary end point. Of 1600 patients, 789 (49.3%) were diagnosed as having LF, which was characterized by a higher 30-day (P=0.041) and 3-year (P<0.001) mortality. LF was an independent predictor of all-cause (hazard ratio, 1.29; 95% confidence interval, 1.03-1.62; P=0.03) and cardiovascular (hazard ratio, 1.37; 95% confidence interval, 1.06-1.77; P=0.016) mortality. Neither mean pressure gradient nor LV ejection fraction was an independent predictor of mortality. Patients with paradoxical LF-LG (35.0%), classic LF-LG (35.1%) and LF-high gradient (38.1%) had higher all-cause mortality at 3 years compared with NF-high gradient (24.8%) and NF-LG (27.9%) (P=0.001). However, surviving patients showed a similar improvement in symptoms regardless of aortic stenosis entity. CONCLUSIONS: LF is a common finding within the aortic stenosis population and, in contrast to LV ejection fraction or mean pressure gradient, an independent predictor of all-cause and cardiovascular mortality. Despite increased long-term mortality, high procedural success and excellent functional improvement support transcatheter aortic valve replacement in patients with LF severe aortic stenosis.

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.

Ultrasound-based renal sympathetic denervation for the treatment of therapy-resistant hypertension: a single-center experience.

INTRODUCTION: The effectiveness of renal sympathetic denervation (RDN) as a treatment for therapy-resistant hypertension has been doubted as the Simplicity-HTN-3 trial was unable to show any treatment benefit over sham procedure. This might partly be explained by a high procedural variability in treatment with radiofrequency-based catheters. Recently, newer systems for RDN, like ultrasound-based devices, have been introduced into practice. To date however, data on their effectiveness for the treatment of resistant hypertension are scarce. We sought to evaluate the safety and effectiveness of an ultrasound-based, balloon-irrigated RDN catheter in a larger single-center cohort. METHODS: Patients with therapy-resistant hypertension [average blood pressure (BP) >135 mmHg SBP or >90 mmHg DBP in ambulatory BP measurement despite at least three antihypertensive drugs, including at least one diuretic] underwent ultrasound-based RDN. Treatment effect was assessed by comparing BP values at baseline and 3 months after the procedure. Patients underwent renal artery duplex sonography or MRI before and after RDN to exclude renal artery stenosis. RESULTS: Fifty consecutive patients underwent ultrasound-based RDN, of which 25 had undergone an unsuccessful radiofrequency RDN before. Mean SBP change at 3 months was -9.7 ±â€Š12.6/-10.6 ±â€Š13.7/-8.2 ±â€Š15.2 mmHg (ambulatory 24-h mean/daytime/night, P < 0.001 for all) and DBP changed by -5.1 ±â€Š7.4/-5.8 ±â€Š7.8/-3.9 ±â€Š10.3 mmHg (P ≤ 0.001/<0.001/0.01). No new renal artery stenosis could be detected after RDN. CONCLUSION: Ultrasound-based RDN seems to be well tolerated and effective for the treatment of patients with therapy-resistant hypertension.

Impact of Rosuvastatin Treatment on HDL-Induced PKC-ßII and eNOS Phosphorylation in Endothelial Cells and Its Relation to Flow-Mediated Dilatation in Patients with Chronic Heart Failure.

Background. Endothelial function is impaired in chronic heart failure (CHF). Statins upregulate endothelial NO synthase (eNOS) and improve endothelial function. Recent studies demonstrated that HDL stimulates NO production due to eNOS phosphorylation at Ser(1177), dephosphorylation at Thr(495), and diminished phosphorylation of PKC-ßII at Ser(660). The aim of this study was to elucidate the impact of rosuvastatin on HDL mediated eNOS and PKC-ßII phosphorylation and its relation to endothelial function. Methods. 18 CHF patients were randomized to 12 weeks of rosuvastatin or placebo. At baseline, 12 weeks, and 4 weeks after treatment cessation we determined lipid levels and isolated HDL. Human aortic endothelial cells (HAEC) were incubated with isolated HDL and phosphorylation of eNOS and PKC-ßII was evaluated. Flow-mediated dilatation (FMD) was measured at the radial artery. Results. Rosuvastatin improved FMD significantly. This effect was blunted after treatment cessation. LDL plasma levels were reduced after rosuvastatin treatment whereas drug withdrawal resulted in significant increase. HDL levels remained unaffected. Incubation of HAEC with HDL had no impact on phosphorylation of eNOS or PKC-ßII. Conclusion. HDL mediated eNOS and PKC-ßII phosphorylation levels in endothelial cells do not change with rosuvastatin in CHF patients and do not mediate the marked improvement in endothelial function.

Long-Term Exercise Training in Patients With Advanced Chronic Heart Failure: SUSTAINED BENEFITS ON LEFT VENTRICULAR PERFORMANCE AND EXERCISE CAPACITY.

PURPOSE: In moderately impaired, stable chronic heart failure (CHF) patients, exercise training (ET) enhances exercise capacity. In contrast, the therapeutic benefits of regular ET in patients with advanced CHF, especially in the long-term, are limited or conflicting. Therefore, the aim of the present investigation was to elucidate whether ET performed over 12 months would improve left ventricular performance and exercise capacity in patients with advanced CHF. METHODS: Thirty-seven patients with CHF and New York Heart Association (NYHA) class IIIb were randomized to a sedentary lifestyle or daily ET on a cycle ergometer (in-hospital and home-based at 50%-60% of maximal exercise capacity). Cardiopulmonary exercise testing and echocardiography were performed at baseline, 3, 6, and 12 months. RESULTS: Exercise training resulted in continuous decreases in left ventricular end-diastolic diameter at 3, 6, and 12 months versus baseline (all P < .05). This was accompanied by a significant increase in resting left ventricular ejection fraction from 24.1% ± 1.2% at baseline to 38.4% ± 2.0% at 12-month followup (P < .05). Moreover, ET patients increased exercise capacity measured by maximal oxygen uptake (Equation is included in full-text article.)O2max at 3, 6, and 12 months compared with baseline: 15.3 ± 0.8 mL/min/kg, 17.8 ± 0.8 mL/min/kg, 19.0 ± 0.7 mL/min/kg, and 19.5 ± 0.9 mL/min/kg, respectively (all P < .05 vs baseline). This was associated with a reduced NYHA classification. CONCLUSIONS: Exercise training over 12 months resulted in an improvement in exercise capacity and reversing of left ventricular remodeling in patients with advanced CHF (NYHA IIIb). These beneficial adaptations continued to improve up to 6 months and remained stable thereafter.

Hemodynamic Assessment of Aortic Regurgitation After Transcatheter Aortic Valve Replacement: The Diastolic Pressure-Time Index.

OBJECTIVES: Assessment of aortic regurgitation (AR) immediately after transcatheter aortic valve replacement (TAVR) is essential to guide further intervention in cases of relevant AR. It was the aim of this study to identify a simple and reproducible hemodynamic parameter for the assessment of AR. BACKGROUND: Relevant AR after TAVR is present in up to 21% of cases and might be associated with adverse long-term outcomes. METHODS: Three hundred sixty-two consecutive patients who were treated with TAVR for symptomatic aortic valve stenosis were analyzed. AR was assessed by aortic root angiography according to the Sellers classification. For hemodynamic evaluation, the diastolic pressure-time (DPT) index was calculated after TAVR: the area between the aortic and left ventricular pressure-time curves was measured during diastole and divided by the duration of diastole to calculate the DPT index. The DPT index was finally adjusted for the respective systolic blood pressure: DPT indexadj = (DPT index/systolic blood pressure) × 100. RESULTS: Patients with angiographically nonrelevant AR (grade <2) had higher DPT indexadj (30.7 ± 6.8) compared with those with relevant AR (grade ≥2) (26.2 ± 5.8) (p < 0.05). Patients with DPT indexadj ≤27.9 had significantly higher 1-year mortality risk in comparison with those with DPT indexadj >27.9: 41.4% versus 13.5% (hazard ratio: 3.8; 95% confidence interval: 2.4 to 5.9; p [log rank-test] < 0.001). In multivariate regression analysis, DPT indexadj ≤27.9 was the strongest independent predictor of 1-year mortality (hazard ratio: 2.5; 95% confidence interval: 1.8 to 3.7; p < 0.001). CONCLUSIONS: DPT indexadj is a simple, investigator-independent parameter that should be considered to differentiate between relevant and nonrelevant AR after TAVR.

Renal denervation improves exercise blood pressure: insights from a randomized, sham-controlled trial.

INTRODUCTION: Despite the ongoing debate on the role of renal sympathetic denervation (RSD) in the management of therapy-resistant hypertension, little is known about its possible effects on exercise blood pressure (BP), a known predictor for future cardiovascular events. We sought to evaluate the effect of RSD on exercise BP in a randomized, sham-controlled trial in patients with mild hypertension. METHODS AND RESULTS: Patients with therapy-resistant mild hypertension (defined by mean daytime systolic BP between 135 and 149 mmHg or mean daytime diastolic BP between 90 and 94 mmHg on 24-h ambulatory BP measurement) were randomized to either radiofrequency-based RSD or a sham procedure. Patients underwent cardiopulmonary exercise testing at baseline and after 6 months. Of the 71 patients randomized, data from cardiopulmonary exercise testing were available for 48 patients (22 in the RSD group, 26 in the sham group). After 6 months, patients undergoing RSD had a significantly lower systolic BP at maximum exercise workload compared to baseline (-14.2 ± 26.1 mmHg, p = 0.009). In contrast, no change was observed in the sham group (0.6 ± 22.9 mmHg, p = 0.45, p = 0.04 for between-group comparison). When analyzing patients with exaggerated baseline exercise BP only, the effect was even more pronounced (RSD vs. sham -29.5 ± 23.4 vs. 0.1 ± 25.3 mmHg, p = 0.008). CONCLUSION: Exercise systolic BP values in patients with mild therapy-resistant hypertension are reduced after RSD as compared to a sham-procedure.