Pierre Lantelme

Optimum and stepped care standardised antihypertensive treatment with or without renal denervation for resistant hypertension (DENERHTN): a multicentre, open-label, randomised controlled trial

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.

Expert consensus: Renal denervation for the treatment of hypertension

Catheter-based renal denervation is a new method able to disrupt renal sympathetic nerves located in the adventitia of renal arteries. A randomized clinical trial showed a decrease in blood pressure in resistant hypertensive patients. In order to guide clinicians and interventional practitioner for the use of this new approach, different French scientific societies (Hypertension, Cardiology and Radiology) decided to combine their expertise and propose an expert consensus to assess benefit/risk ratio of this technique in the field of arterial hypertension. In 2012, this expert consensus propose to limit renal denervation technique to patients with essential hypertension uncontrolled by four or more antihypertensive therapies with at least one treatment being a diuretic and spironolactone at a dose of 25mg shown to be unable to control blood pressure. Measurement of office BP should be at least with SBP more than 160mmHg and/or DBP more than 100mmHg confirmed by ambulatory BP measurement (home or ABP measurement with SBP more than 135mmHg and DBP more than 85mm during daytime period). Finally, renal artery anatomy and function should allow proper intervention (i.e., two functional kidneys, absence of previous renal angioplasty). Renal enervation is a complex interventional procedure with potentially arterial complications, training is required for practitioners. Antihypertensive treatment should not be interrupted immediately after renal denervation since blood pressure lowering effect are delayed and reached maximum effect after 3 months. Monitoring of blood pressure, renal function and anatomy of renal arteries is required 12 months and 36 months after procedure. The expert consensus requires the inclusion of patients experiencing this procedure in a observational study with record form and follow-up.

Significance, prognostic value and management of heart rate in hypertension

Many epidemiological studies have demonstrated that resting heart rate is a risk marker but also a risk factor in patients with coronary artery disease and heart failure. In hypertensive subjects free from overt cardiac disease, the question has been less frequently addressed. A few cohort studies have shown that hypertensive patients with a high resting heart rate have an increased risk of all-cause and cardiovascular death. However, intervention trials have not demonstrated that lowering the heart rate is beneficial in hypertensive subjects. Studies with an assessment of ambulatory heart rate tend to demonstrate a better association between cardiovascular outcomes and variables, including nighttime heart rate. Clinical trials comparing beta-blockers with non-slowing antihypertensive drugs have not demonstrated the superiority of the former. Finally, an elevated resting heart rate in hypertensive subjects free from overt cardiac disease seems to be more a risk marker than a risk factor. Although these patients are at high risk, no scientific data exist to support targeting heart rate. In this review, we describe the pathophysiological effects of heart rate, including vascular cell signalling, link with sympathetic activity and influence on central blood pressure, and the prognostic value and management of HR in hypertensive patients free from overt cardiac diseases.

Diastolic blood pressure, aortic atheroma, and prognosis in hypertension: New insights into a complex association

OBJECTIVES Our study aimed at determining the interaction between the prognostic value of diastolic blood pressure (DBP) and aortic atherosclerosis (ATS). BACKGROUND With aging, equal systolic blood pressures (SBPs) become associated with low DBPs; i.e., high pulse pressures (PPs) become associated with a high risk of cardiovascular death. This association is usually ascribed to aortic stiffening with age but the precise impact of low DBP per se is yet uncertain. METHODS 938 hypertensive patients recruited in the seventies had an aortic ATS score at pretreatment aortography. All-cause and cardiovascular deaths were assessed 20 years later. The prognostic values of DBP and SBP were assessed by a multivariate Cox regression model and their interactions with ATS examined. RESULTS In the presence of ATS, an increase of 10 mmHg in DBP was associated with a protective effect: hazard ratios 0.84 [0.72-0.99] for cardiovascular death and 0.88 [0.78-1.00] for all-cause death. However, in the absence of ATS, DBP had no prognostic value: hazard ratios 1.05 [0.89-1.23] for cardiovascular death and 0.99 [0.88-1.11] for all-cause death (p for interaction: 0.061 and 0.087, respectively). No interaction was found between SBP and ATS (p for interaction > 0.40). CONCLUSIONS The prognostic values of DBP and aortic atheroma are not superimposable; yet, they are tightly connected: a low DBP is disadvantageous only in the presence of a pathologic aorta. Aortic atherosclerosis may explain, at least partly, in some high risk populations, the J-shape of the already reported DBP-outcome relationship.

Baroreceptor stimulation for resistant hypertension: First implantation in France and literature review

Despite a wide choice of effective antihypertensive treatments, blood pressure (BP) in roughly half of hypertensive subjects is not controlled. Resistant hypertension is defined as an uncontrolled BP despite optimal doses of three antihypertensive treatments, including a diuretic. After confirmation of resistant BP using home BP measurement or 24-hour ambulatory BP monitoring (ABPM), patients usually go through a work-up to rule out secondary hypertension. If secondary hypertension is ruled out, the recent European guidelines on hypertension consider baroreceptor stimulation or renal denervation to be possible options. The prevalence of resistant primary hypertension may reach up to 10% in specialized centres. The two proposed non-pharmacological therapeutic strategies have been developed recently to inhibit sympathetic overactivity in resistant hypertension. Among them, baroreceptor activation therapy (BAT) is an innovative approach that interferes with baroreflex function. The first-generation BAT device (Rheos(®); CVRx, Inc., Minneapolis, MN, USA) demonstrated good efficacy in lowering office BP and ABPM, but had an insufficient safety profile due to complex surgery. The second-generation BAT device (Barostim neo™ system; CVRx, Inc.) seems to share the same BP-lowering efficacy but has a better safety profile. We report the first French case of baroreceptor stimulation for hypertension using the Barostim neo™ system. We also discuss the pathophysiological features of and current levels of evidence for this technique.

Auto-amplification of cortisol actions in human carotid atheroma is linked to arterial remodeling and stroke

High cortisol and aldosterone levels increase cardiovascular risk, but the respective roles of each hormone within the arterial wall remain controversial. We tested the hypothesis that cortisol production within the arterial wall may contribute to atherosclerotic remodeling and act through illicit activation of the mineralocorticoid receptor (MR). Gene expression studies of the corticoid system components and marker genes of the atherosclerotic process in human carotid atheroma plaque and nearby macroscopically intact tissue (MIT) were considered together with clinical data and compared with pharmacological stimulations of human vascular smooth muscle cells (VSMCs) in contractile or lipid‐storing phenotypes. The components of corticoid production and action were present and active within the human carotid wall and VSMCs. Atheroma plaque and lipid‐storing VSMCs expressed 11β‐hydroxysteroid deshydrogenase‐1 (11β‐HSD1) at two‐ to tenfold higher levels than MIT or contractile VSMCs. The 11β‐HSD1 expression was stimulated by cortisol and cortisone, especially in lipid‐storing VSMCs. MR mRNA level was lower in atheroma and lipid‐storing VSMCs and downregulated via MR by fludrocortisone and cortisol. Cortisol upregulated collagen1 and MCP‐1 mRNAs via the glucocorticoid receptor (GRα), in both VSMC phenotypes, whereas fludrocortisone stimulated the collagen1 expression only in lipid‐storing VSMCs. The GRα mRNA level in MIT was higher in patients with previous stroke and correlated positively with the collagen1 mRNA but negatively with diastolic blood pressure. Local cortisol production by 11β‐HSD1, and its action via high parietal GRα could be relevant from the first step of atherosclerotic remodeling and auto‐amplify with transdifferentiation of VSMCs during atheroma progression.

Aorta calcification burden: Towards an integrative predictor of cardiac outcome after transcatheter aortic valve implantation

OBJECTIVE The principal objective was to determine the effect of total aortic calcification (TAC) burden on outcomes (cardiac mortality, all-cause mortality, and heart failure (HF)) after transcatheter aortic valve implantation (TAVI). The secondary aim was to assess the contribution of each segment of the aorta to these outcomes. BACKGROUND Indications for TAVI are increasing in number. Even after procedural success, however, some patients die soon afterwards, indicating the futility of TAVI in certain cases. METHODS Aortic calcifications were measured on computed tomography in 164 patients treated by TAVI. TAC, ascending aortic calcification (AsAC), descending aorta calcifications, and abdominal aorta calcifications were expressed as tertiles and their prognostic values were assessed in a multivariable cox analysis adjusted for major confounders including EuroSCORE. RESULTS Median duration of follow-up was 565 (interquartile range: 246 to 1000) days. TAC (tertile3 vs. tertile1) was significantly and strongly associated with cardiac mortality (hazard ratio [HR]: 16.74; 95% confidence interval [CI]: 2.21 to 127.05; p = 0.006) and all-cause mortality (HR: 2.39; 95% CI: 1.18 to 4.84; p = 0.015) but not with HF (HR: 1.84; 95% CI: 0.87 to 3.90; p = 0.110). Each segment was associated with cardiac mortality, while only AsAC (tertile 3 vs. tertile 1) appeared predictive of HF (hazard ratio: 2.29; 95% CI: 1.12 to 4.66; p = 0.023). CONCLUSIONS TAC is an integrative predictor of cardiac and all-cause mortality after TAVI. It should be included in the assessment of patients before TAVI in order to predict cardiac outcome after valve replacement and avoid futile interventions.

Dénervation rénale dans le traitement de l’hypertension artérielle résistante : expérience du CHU de Lyon

AIM We report the first experience of Lyons university hospital regarding renal denervation to treat patients with resistant essential hypertension. PATIENTS AND METHODS Over a one-year period, 17 patients were treated (12 men, 5 women) with renal denervation. Baseline characteristics were as follows: age 56.5±11.5 years, BMI 33±5kg/m(2) and ambulatory blood pressure 157±16/87±13mmHg with 4.2±1.5 anti-hypertensive treatment. RESULTS We did not observe intra-operative or early complications. After a median follow-up of 3 months and with the same anti-hypertensive treatment, office systolic blood pressure (SBP) and diastolic blood pressure (DBP) decrease respectively of 20±15 (P<0.001) and 10±13mmHg (P=0.014) (n=17). After six months of follow-up, ambulatory blood pressure (ABPM) decrease of 17.5±14.9mmHg (P=0.027) for SBP and of 10.5±9.6mmHg (P=0.029) for DBP (n=6). Among these patients, five of them were controlled (ABPM inferior to 130/80mmHg) and electrical left ventricular hypertrophy indexes decreased: R wave in aVL lead of 4±3mm (P=0.031), Sokolow index of 3±3mm (P=0.205), Cornell voltage criterion of 9±7mm (P=0.027) and Cornell product of 1310±1104 (P=0.027). CONCLUSION Our results are in accordance with data from other centers. On average blood pressure decreases significantly but important inter individual variations are observed. The procedure seems safe.

MRI-based detection of renal artery abnormalities related to renal denervation by catheter-based radiofrequency ablation in drug resistant hypertensive patients

ObjectivesEndovascular renal denervation (RDN) using catheter-based radiofrequency (RF) ablation has emerged as a potential treatment option for drug-resistant hypertension. Its efficacy is currently under debate. We aimed to evaluate the capability of contrast-enhanced magnetic resonance imaging (MRI) to assess the effects of RDN on the renal arterial wall in patients presenting with drug-resistant hypertension.MethodsPatients were included prospectively following institutional review board approval and written informed consent. Renal arteries were imaged using a two-dimensional T1-weighted TSE sequence pre- and post-administration of a gadolinium-based contrast agent, before (D0), 2 days (D2) and 6 months (M6) after RDN. Mean enhancement of the wall (mENH) and mean wall thickness (mWT) were compared across time using an ANOVA with repeated measures and post-hoc paired t-test.ResultsFollow-up was completed for 23 patients (median age, 57 years; 16 men). The mENH at D2 (96.3 ± 36.0 %) was significantly higher than at D0 (61.1 ± 26.3%, p < 0.001) and M6 (66.1±22.7%, p < 0.001). Similarly, mWT was significantly higher at D2 (3.1 ± 0.4 m) than at D0 (2.7 ± 0.4mm, p < 0.001) and M6 (2.9 ± 0. 5 mm, p = 0.002).ConclusionsMRI demonstrated abnormalities of the arterial wall 2 days after RDN that had resolved at 6 months.Key Points• Contrast-enhanced MRI provides anatomic evidence of renal artery RF ablation• Temperature increase related to RF ablation induces transient arterial wall inflammation• Morphological effects observed 2 days post RF ablation are not visible after 6 months

Stretching the carotid sinus to treat resistant hypertension

www.thelancet.com Published online September 1, 2017 http://dx.doi.org/10.1016/S0140-6736(17)32298-5 1 Around a quarter of adults have hypertension, and by 2025, the number affected might be more than 1·5 billion people worldwide. Despite important advances in pharmacotherapy in the past 40 years, resistant hypertension—that is, persistently raised ambulatory blood pressure despite treatment with at least three antihypertensive drugs, including a diuretic—occurs in about 13% of treated adults. Optimisation of treatment is crucial in people with resistant hypertension because of the increased risk of cardiovascular disease. Two main pathophysiological mechanisms can be targeted: volume excess related to dietary sodium, reduced renal function, or aldosterone excess; and vascular resistance increased by overactivity of the renin–angiotensin–aldosterone system (RAAS) or sympathetic nervous system. Excess volume may be counterbalanced by use of high-dose diuretics or by adding a mineralocorticoid-receptor antagonist. Vascular resistance may be reduced with RAAS blockers, β blockers, or interventional strategies. The baroreflex, which is controlled by the sympathetic nervous system, is mainly directed at short-term control of blood pressure. Several concepts have emerged suggesting that strong interactions between the sympathetic nervous system, the kidneys, and the RAAS contribute to long-term regulation of blood pressure. Device therapies have been developed to target the sympathetic nervous system by baroreceptor stimulation or renal denervation. In The Lancet, Wilko Spiering and colleagues present the CALM-FIM_EUR study, which is a first-in-human, proof-of-principle, open-label trial testing the safety and blood-pressure efficacy of a new interventional strategy to stimulate the endovascular baroreflex. The MobiusHD device (Vascular Dynamics, Mountain View, CA, USA) used in this study is a passive stentlike device that is implanted in the carotid artery to reshape the carotid sinus and reduce sympathetic outflow. 30 patients with baseline office blood pressure of 184/109 mm Hg and 24 h ambulatory blood pressure of 166/100 mm Hg underwent successful implantation. After 6 months, the values were significantly reduced by 24/12 mm Hg and 21/12 mm Hg, respectively. Five serious adverse events occurred in four patients (13%): hypotension, worsening hypertension, and intermittent claudication, each in one patient, and transient ischaemic attack in two patients. This technique, based on a new concept, brings hope through a simple and efficient interventional strategy. However, similar blood-pressure drops were previously achieved with renal denervation or secondgeneration baroreceptor activation therapy in openlabel studies, but the effects were overestimated due to several confounders, such as the placebo effect, the Hawthorne effect, or treatment adherence. Assessments in randomised studies, therefore, were disappointing, with either no or limited blood-pressure benefits being seen. Although the authors included measurements of ambulatory blood pressure, which theoretically limits the placebo effect, the true blood-pressure benefit with the MobiusHD device, if any, might be lower than in the initial findings. The main objective of the study was safety, and the profile is presented as acceptable compared with that for more invasive techniques. This statement, however, should be interpreted with caution owing to the two transient ischaemic attacks encountered. The risk-tobenefit balance needs to be more precisely assessed. The long-term efficacy of passive reshaping of the carotid is unclear because of the known dynamic physiology of the baroceptor reflex and the classic resetting phenomenon and possible late neoatherosclerosis around the MobiusHD device. Finally, Spiering and colleagues did Stretching the carotid sinus to treat resistant hypertension