Summary Background Conflicting blood pressure-lowering effects of catheter-based renal artery denervation have been reported in patients with resistant hypertension. We compared the ambulatory blood ...pressure-lowering efficacy and safety of radiofrequency-based renal denervation added to a standardised stepped-care antihypertensive treatment (SSAHT) with the same SSAHT alone in patients with resistant hypertension. Methods The Renal Denervation for Hypertension (DENERHTN) trial was a prospective, open-label randomised controlled trial with blinded endpoint evaluation in patients with resistant hypertension, done in 15 French tertiary care centres specialised in hypertension management. Eligible patients aged 18–75 years received indapamide 1·5 mg, ramipril 10 mg (or irbesartan 300 mg), and amlodipine 10 mg daily for 4 weeks to confirm treatment resistance by ambulatory blood pressure monitoring before randomisation. Patients were then randomly assigned (1:1) to receive either renal denervation plus an SSAHT regimen (renal denervation group) or the same SSAHT alone (control group). The randomisation sequence was generated by computer, and stratified by centres. For SSAHT, after randomisation, spironolactone 25 mg per day, bisoprolol 10 mg per day, prazosin 5 mg per day, and rilmenidine 1 mg per day were sequentially added from months two to five in both groups if home blood pressure was more than or equal to 135/85 mm Hg. The primary endpoint was the mean change in daytime systolic blood pressure from baseline to 6 months as assessed by ambulatory blood pressure monitoring. The primary endpoint was analysed blindly. The safety outcomes were the incidence of acute adverse events of the renal denervation procedure and the change in estimated glomerular filtration rate from baseline to 6 months. This trial is registered with ClinicalTrials.gov , number NCT01570777. Findings Between May 22, 2012, and Oct 14, 2013, 1416 patients were screened for eligibility, 106 of those were randomly assigned to treatment (53 patients in each group, intention-to-treat population) and 101 analysed because of patients with missing endpoints (48 in the renal denervation group, 53 in the control group, modified intention-to-treat population). The mean change in daytime ambulatory systolic blood pressure at 6 months was −15·8 mm Hg (95% CI −19·7 to −11·9) in the renal denervation group and −9·9 mm Hg (−13·6 to −6·2) in the group receiving SSAHT alone, a baseline-adjusted difference of −5·9 mm Hg (−11·3 to −0·5; p=0·0329). The number of antihypertensive drugs and drug-adherence at 6 months were similar between the two groups. Three minor renal denervation-related adverse events were noted (lumbar pain in two patients and mild groin haematoma in one patient). A mild and similar decrease in estimated glomerular filtration rate from baseline to 6 months was observed in both groups. Interpretation In patients with well defined resistant hypertension, renal denervation plus an SSAHT decreases ambulatory blood pressure more than the same SSAHT alone at 6 months. This additional blood pressure lowering effect may contribute to a reduction in cardiovascular morbidity if maintained in the long term after renal denervation. Funding French Ministry of Health.
Immune checkpoint inhibitors (ICI) targeting CTLA4 or PD-1/PD-L1 have transformed cancer therapy but are associated with immune-related adverse events, including myocarditis. Here, we report a robust ...preclinical mouse model of ICI-associated myocarditis in which monoallelic loss of
in the context of complete genetic absence of
leads to premature death in approximately half of mice. Premature death results from myocardial infiltration by T cells and macrophages and severe ECG abnormalities, closely recapitulating the clinical and pathologic hallmarks of ICI-associated myocarditis observed in patients. Using this model, we show that
and
functionally interact in a gene dosage-dependent manner, providing a mechanism by which myocarditis arises with increased frequency in the setting of combination ICI therapy. We demonstrate that intervention with CTLA4-Ig (abatacept) is sufficient to ameliorate disease progression and additionally provide a case series of patients in which abatacept mitigates the fulminant course of ICI myocarditis. SIGNIFICANCE: We provide a preclinical model of ICI-associated myocarditis which recapitulates this clinical syndrome. Using this model, we demonstrate that CTLA4 and PD-1 (ICI targets) functionally interact for myocarditis development and that intervention with CTLA4-Ig (abatacept) attenuates myocarditis, providing mechanistic rationale and preclinical support for therapeutic clinical studies.
.
.
Abstract
Background and Aims
Intra-pocket ultrasound-guided axillary vein puncture (IPUS-AVP) for venous access in implantation of transvenous cardiac implantable electronic devices (CIED) is ...uncommon due to the lack of clinical evidence supporting this technique. This study investigated the efficacy and early complications of IPUS-AVP compared to the standard method using cephalic vein cutdown (CVC) for CIED implantation.
Methods
ACCESS was an investigator-led, interventional, randomized (1:1 ratio), monocentric, controlled superiority trial. A total of 200 patients undergoing CIED implantation were randomized to IPUS-AVP (n = 101) or CVC (n = 99) as a first assigned route. The primary endpoint was the success rate of insertion of all leads using the first assigned venous access technique. The secondary endpoints were time to venous access, total procedure duration, fluoroscopy time, X-ray exposure, and complications. Complications were monitored during a follow-up period of three months after procedure.
Results
IPUS-AVP was significantly superior to CVC for the primary endpoint with 100 (99.0%) vs. 86 (86.9%) procedural successes (P = .001). Cephalic vein cutdown followed by subclavian vein puncture was successful in a total of 95 (96.0%) patients, P = .21 vs. IPUS-AVP. All secondary endpoints were also significantly improved in the IPUS-AVP group with reduction in time to venous access 3.4 vs. 10.6 min, geometric mean ratio (GMR) 0.32 (95% confidence interval, CI, 0.28–0.36), P < .001, total procedure duration 33.8 vs. 46.9 min, GMR 0.72 (95% CI 0.67–0.78), P < .001, fluoroscopy time 2.4 vs. 3.3 min, GMR 0.74 (95% CI 0.63–0.86), P < .001, and X-ray exposure 1083 vs. 1423 mGy.cm², GMR 0.76 (95% CI 0.62–0.93), P = .009. There was no significant difference in complication rates between groups (P = .68).
Conclusions
IPUS-AVP is superior to CVC in terms of success rate, time to venous access, procedure duration, and radiation exposure. Complication rates were similar between the two groups. Intra-pocket ultrasound-guided axillary vein puncture should be a recommended venous access technique for CIED implantation.
Structured Graphical Abstract
Structured Graphical Abstract
Efficacy and safety of intra-pocket ultrasound-guided axillary vein access vs. cephalic vein cutdown for implantation of cardiac electronic devices. CVC, cephalic vein cutdown; IPUS-AVP, intra-pocket ultrasound-guided axillary vein puncture.
Purpose of Review
The identification of BRAF mutation prompted the development of new class of targeted therapy for treating melanoma: BRAF inhibitors and MEK inhibitors. Cardiovascular events have ...been reported with these treatments and could counterbalance their long-term maintenance.
Recent Findings
LVEF decrease due to BRAF and MEK inhibitors appears fairly common (10%) but usually not severe, without impact on patient outcomes. To date, no treatment options have been tested to prevent or to treat a decrease of LVEF associated with BRAF and MEK inhibitors. QTc prolongation was observed in 3% and arterial hypertension in 20% during treatment but only one-third of cases required a therapeutic change.
Summary
BRAF and MEK inhibitors have revolutionized the management and the prognosis of melanoma patients. Cardio-oncology units may be useful for a better care of potential cardiac toxicity and particularly to inappropriately avoid discontinuing BRAF and MEK inhibitors.
Patients with overt and subclinical Cushing's syndrome frequently develop hypertension, metabolism disorders, and atherosclerotic lesions. The aim of the present study was to test the association ...between cortisol and blood pressure (BP), organ damage, and metabolic parameters in hypertensive patients without hypercortisolism.
After exclusion of patients treated with corticosteroids or with Cushing's syndrome, the cohort included 623 hypertensive patients (mean ± SD age 50.3 ± 15.4 years, 50.9% men, median 24-h BP 146/88 mmHg) with an extended work-up (lipid profile, hypertension-mediated organ damage). Cortisol secretion was assessed by plasma cortisol at 0800 and 1600 h, and by 24-h urinary free cortisol (24 h UFC) normalized if required to urine creatinine (UFC/U creat).
Plasma cortisol at 1600 h, 24 h-UFC, and UFC/U creat were significantly and positively correlated with daytime, night-time, and 24-h SBP; plasma cortisol at 0800 h was not associated with BP. The strongest correlations were observed in the subgroup of aged more than 50 years (correlation coefficients between 0.23 and 0.28). These correlations remained after adjustment on plasma aldosterone. Metabolic parameters were weakly associated with cortisol. Arterial stiffness (central pulse pressure and pulse wave velocity), plasma NT-proBNP, and microalbuminuria were significantly correlated with 24 h UFC, UFC/U creat, and plasma cortisol at 1600 h.
Cortisol influences weakly the level of BP independently from plasma aldosterone in hypertensive patients, particularly in older patients, and that there was weak association with HMOD. It may, therefore, be of interest to test specific treatments targeting cortisol excess in selected hypertensive patients.
Tissue renin-angiotensin-aldosterone system (RAAS) has attracted much attention because of its physiological and pharmacological implications; however, a clear definition of tissue RAAS is still ...missing. We aimed to establish a preliminary atlas for the organization of RAAS across 23 different normal human tissues. A set of 37 genes encoding classical and novel RAAS participants including gluco- and mineralo-corticoids were defined as extended RAAS (extRAAS) system. Microarray data sets containing more than 10 normal tissues were downloaded from the GEO database. R software was used to extract expression levels and construct dendrograms of extRAAS genes within each data set. Tissue co-expression modules were then extracted from reproducible gene clusters across data sets. An atlas of the maps of tissue-specific organization of extRAAS was constructed from gene expression and coordination data. Our analysis included 143 data sets containing 4933 samples representing 23 different tissues. Expression data provided an insight on the favored pathways in a given tissue. Gene coordination indicated the existence of tissue-specific modules organized or not around conserved core groups of transcripts. The atlas of tissue-specific organization of extRAAS will help better understand tissue-specific effects of RAAS. This will provide a frame for developing more effective and selective pharmaceuticals targeting extRAAS.
PDF
