Costas Tsioufis

ESH position paper: renal denervation - an interventional therapy of resistant hypertension

Experts from the European Society of Hypertension prepared this position paper in order to summarize current evidence, unmet needs and practical recommendations on the application of percutaneous transluminal ablation of renal nerves [renal denervation (RDN)] as a novel therapeutic strategy for the treatment of resistant hypertension. The sympathetic nervous activation to the kidney and the sensory afferent signals to the central nervous system represent the targets of RND. Clinical studies have documented that catheter-based RDN decreases both efferent sympathetic and afferent sensory nerve traffic leading to clinically meaningful systolic and diastolic blood pressure (BP) reductions in patients with resistant hypertension. This position statement intends to facilitate a better understanding of the effectiveness, safety, limitations and issues still to be addressed with RDN.

Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial

Aims Catheter-based renal artery sympathetic denervation has emerged as a novel therapy for treatment of patients with drug-resistant hypertension. Initial studies were performed using a single electrode radiofrequency catheter, but recent advances in catheter design have allowed the development of multi-electrode systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and efficacy of the EnligHTN™ multi-electrode system. Methods and results We conducted the first-in-human, prospective, multi-centre, non-randomized study in 46 patients (67% male, mean age 60 years, and mean baseline office blood pressure 176/96 mmHg) with drug-resistant hypertension. The primary efficacy objective was change in office blood pressure from baseline to 6 months. Safety measures included all adverse events with a focus on the renal artery and other vascular complications and changes in renal function. Renal artery denervation, using the EnligHTN™ system significantly reduced the office blood pressure from baseline to 1, 3, and 6 months by −28/10, −27/10 and −26/10 mmHg, respectively (P < 0.0001). No acute renal artery injury or other serious vascular complications occurred. Small, non-clinically relevant, changes in average estimated glomerular filtration rate were reported from baseline (87 ± 19 mL/min/1.73 m2) to 6 months post-procedure (82 ± 20 mL/min/1.73 m2). Conclusion Renal sympathetic denervation, using the EnligHTN™ multi-electrode catheter results in a rapid and significant office blood pressure reduction that was sustained through 6 months. The EnligHTN™ system delivers a promising therapy for the treatment of drug-resistant hypertension.

Carotid Artery Disease as a Marker for the Presence of Severe Coronary Artery Disease in Patients Evaluated for Chest Pain

BACKGROUND AND PURPOSE We sought in this study to elucidate whether carotid artery disease detected by ultrasonography can be a clinically useful marker for the presence of severe coronary artery disease (CAD) in patients evaluated for chest pain. METHODS Duplex ultrasonography and quantitative coronary angiography were used to assess carotid and coronary artery atherosclerosis in 225 consecutive patients (mean age, 58+/-9 years) with chest pain referred for cardiac catheterization. RESULTS CAD was present in 197 patients (88%). Fifty-seven patients (25%) had 1-vessel disease, 52 (23%) had 2-vessel disease, 53 (24%) had 3-vessel disease, and 35 (16%) had left main stem CAD (LMS-CAD). The incidence of severe CAD (3-vessel disease or LMS-CAD) was 24% and 63% in the normal and impaired ejection fraction (EF) subgroups, respectively (P<0.005). Carotid disease (lumen diameter stenosis of >/=50%) was present in 5.3%, 13.5%, 24.5%, and 40% of patients with 1-, 2-, and 3-vessel disease and LMS-CAD, respectively. Moreover, the incidence of carotid disease in patients with severe CAD was 31% in the entire study population and 46% and 5% in the subgroups with impaired and normal EF, respectively (P<0.005). In the entire study population, the presence of severe CAD was determined by age, male sex, and carotid disease; in the impaired EF group by age and carotid disease; and in the normal EF group only by age. Carotid disease has a high negative (92%) and a high positive (91%) predictive value for the presence of severe CAD in the subgroup with normal and impaired EF, respectively. CONCLUSIONS In patients evaluated for chest pain, carotid disease is significantly correlated with severe CAD. Furthermore, in patients with impaired left ventricular systolic performance the presence of carotid disease reflects the presence of severe CAD, while in patients with normal EF the absence of carotid disease reflects the absence of severe CAD.

Aortic Function in Arterial Hypertension Determined by Pressure-Diameter Relation Effects of Diltiazem

BACKGROUND Aortic elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in hypertension. The aim of this study was to determine aortic function in hypertensive patients and in normal subjects before and after administration of diltiazem, a calcium antagonist widely used in the treatment of essential hypertension. METHODS AND RESULTS The aortic pressure-diameter relation was obtained before and after diltiazem administration in 15 hypertensives and 15 control normotensives. Instantaneous diameter of the thoracic aorta was acquired with a high-fidelity intravascular catheter developed in our institution and previously validated. Instantaneous aortic pressure was measured simultaneously and at the same aortic level with a catheter-tip micromanometer. Energy loss due to the viscosity of aortic wall was measured from the area of the loop. Aortic distensibility was calculated using the formula 2 x (pulsatile change in aortic diameter)/([diastolic aortic diameter] x [aortic pulse pressure]). At baseline, aortic distensibility was lower and energy loss was greater in hypertensives than in normotensives (distensibility: 1.4+/-0.3 versus 3.5+/-0.7 cm2 x dyne(-1) x 10(-6), respectively, P<.001; energy loss: 14.1+/-3.3 versus 8.2+/-2.2 mm x mm Hg, respectively, P<.001). After diltiazem administration, aortic distensibility was increased, whereas energy loss was decreased in both hypertensives (peak response: distensibility, 2.0+/-0.4 cm2 x dyne(-1) x 10(-6), P<.001; energy loss, 9.3+/-1.6 mm x mm Hg, P<.001) and normotensives (peak response: distensibility, 5.2+/-0.5 cm2 x dyne(-1) x 10(-6), P<.001; energy loss, 5.0+/-1.2 mm x mm Hg, P<.001). CONCLUSIONS Aortic elastic properties are compromised and energy loss due to aortic wall viscosity is increased in hypertensives compared with normotensives. Function of the aorta is improved in both hypertensive and normotensive subjects after the administration of diltiazem.

International expert consensus statement: Percutaneous transluminal renal denervation for the treatment of resistant hypertension.

Catheter-based radiofrequency ablation technology to disrupt both efferent and afferent renal nerves has recently been introduced to clinical medicine after the demonstration of significant systolic and diastolic blood pressure reductions. Clinical trial data available thus far have been obtained primarily in patients with resistant hypertension, defined as standardized systolic clinic blood pressure ≥ 160 mm Hg (or ≥ 150 mm Hg in patients with type 2 diabetes) despite appropriate pharmacologic treatment with at least 3 antihypertensive drugs, including a diuretic agent. Accordingly, these criteria and blood pressure thresholds should be borne in mind when selecting patients for renal nerve ablation. Secondary forms of hypertension and pseudoresistance, such as nonadherence to medication, intolerance of medication, and white coat hypertension, should have been ruled out, and 24-h ambulatory blood pressure monitoring is mandatory in this context. Because there are theoretical concerns with regard to renal safety, selected patients should have preserved renal function, with an estimated glomerular filtration rate ≥ 45 ml/min/1.73 m(2). Optimal periprocedural management of volume status and medication regimens at specialized and experienced centers equipped with adequate infrastructure to cope with potential procedural complications will minimize potential patient risks. Long-term safety and efficacy data are limited to 3 years of follow-up in small patient cohorts, so efforts to monitor treated patients are crucial to define the long-term performance of the procedure. Although renal nerve ablation could have beneficial effects in other conditions characterized by elevated renal sympathetic nerve activity, its potential use for such indications should currently be limited to formal research studies of its safety and efficacy.

Hypertension and atrial fibrillation: diagnostic approach, prevention and treatment. Position paper of the Working Group "Hypertension Arrhythmias and Thrombosis" of the European Society of Hypertension

Hypertension is the most common cardiovascular disorder and atrial fibrillation is the most common clinically significant arrhythmia. Both these conditions frequently coexist and their prevalence increases rapidly with aging. There are different risk factors and clinical conditions predisposing to the development of atrial fibrillation, but due its high prevalence, hypertension is still the main risk factor for the development of atrial fibrillation. Several pathophysiologic mechanisms (such as structural changes, neurohormonal activation, fibrosis, atherosclerosis, etc.) have been advocated to explain the onset of atrial fibrillation. The presence of atrial fibrillation per se increases the risk of stroke but its coexistence with high blood pressure leads to an abrupt increase of cardiovascular complications. Different risk models are available for the risk stratification and the prevention of thromboembolism in patients with atrial fibrillation. In all of them hypertension is present and is an important risk factor. Antihypertensive treatment may contribute to reduce this risk, and it seems some classes are superior to others in the prevention of new-onset atrial fibrillation and prevention of stroke. Antithrombotic treatment with warfarin is effective in the prevention of thromboembolic events, although quite recently, new classes of anticoagulants that do not require international normalized ratio monitoring have been introduced with promising results.

Pathophysiology of resistant hypertension: the role of sympathetic nervous system.

Resistant hypertension (RH) is a powerful risk factor for cardiovascular morbidity and mortality. Among the characteristics of patients with RH, obesity, obstructive sleep apnea, and aldosterone excess are covering a great area of the mosaic of RH phenotype. Increased sympathetic nervous system (SNS) activity is present in all these underlying conditions, supporting its crucial role in the pathophysiology of antihypertensive treatment resistance. Current clinical and experimental knowledge points towards an impact of several factors on SNS activation, namely, insulin resistance, adipokines, endothelial dysfunction, cyclic intermittent hypoxaemia, aldosterone effects on central nervous system, chemoreceptors, and baroreceptors dysregulation. The further investigation and understanding of the mechanisms leading to SNS activation could reveal novel therapeutic targets and expand our treatment options in the challenging management of RH.

Catheter-Based Renal Denervation for Resistant Hypertension 12-Month Results of the EnligHTN I First-in-Human Study Using a Multielectrode Ablation System

Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. To date, only limited data have been published using multielectrode radiofrequency ablation systems. In this article, we present the 12-month data of EnligHTN I, a first-in-human study using a multielectrode ablation catheter. EnligHTN I enrolled 46 patients (average age, 60±10 years; on average 4.7±1.0 medications) with drug-resistant hypertension. Eligible patients were on ≥3 antihypertensive medications and had a systolic blood pressure (BP) ≥160 mm Hg (≥150 mm Hg for diabetics). Bilateral renal artery ablation was performed using a percutaneous femoral approach and standardized techniques. The average baseline office BP was 176/96 mm Hg, average 24-hour ambulatory BP was 150/83 mm Hg, and average home BP was 158/90 mm Hg. The average reductions (mm Hg) at 1, 3, 6, and 12 months were as follows: office: −28/−10, −27/−10, −26/−10, and −27/−11 mm Hg ( P <0.001 for all); 24-hour ambulatory: −10/−5, −10/−5, −10/−6 ( P <0.001 for all), and −7/−4 for 12 months ( P <0.0094). Reductions in home measurements (based on 2-week average) were −9/−4, −8/−5,−10/−7, and −11/−6 mm Hg ( P <0.001 at 12 months). At 12 months, there were no signals of worsening renal function and no new serious or life-threatening adverse events. One patient with baseline nonocclusive renal artery stenosis progressed to 75% diameter stenosis, requiring renal artery stenting. The 12-month data continue to demonstrate safety and efficacy of the EnligHTN ablation system in patients with drug-resistant hypertension. Home BP measurements parallel measurements obtained with 24-hour ambulatory monitoring. # Novelty and Significance {#article-title-41}Renal denervation has emerged as a novel approach for the treatment of patients with drug-resistant hypertension. To date, only limited data have been published using multielectrode radiofrequency ablation systems. In this article, we present the 12-month data of EnligHTN I, a first-in-human study using a multielectrode ablation catheter. EnligHTN I enrolled 46 patients (average age, 60±10 years; on average 4.7±1.0 medications) with drug-resistant hypertension. Eligible patients were on ≥3 antihypertensive medications and had a systolic blood pressure (BP) ≥160 mm Hg (≥150 mm Hg for diabetics). Bilateral renal artery ablation was performed using a percutaneous femoral approach and standardized techniques. The average baseline office BP was 176/96 mm Hg, average 24-hour ambulatory BP was 150/83 mm Hg, and average home BP was 158/90 mm Hg. The average reductions (mm Hg) at 1, 3, 6, and 12 months were as follows: office: −28/−10, −27/−10, −26/−10, and −27/−11 mm Hg (P<0.001 for all); 24-hour ambulatory: −10/−5, −10/−5, −10/−6 (P<0.001 for all), and −7/−4 for 12 months (P<0.0094). Reductions in home measurements (based on 2-week average) were −9/−4, −8/−5,−10/−7, and −11/−6 mm Hg (P<0.001 at 12 months). At 12 months, there were no signals of worsening renal function and no new serious or life-threatening adverse events. One patient with baseline nonocclusive renal artery stenosis progressed to 75% diameter stenosis, requiring renal artery stenting. The 12-month data continue to demonstrate safety and efficacy of the EnligHTN ablation system in patients with drug-resistant hypertension. Home BP measurements parallel measurements obtained with 24-hour ambulatory monitoring.

The incremental effect of obstructive sleep apnoea syndrome on arterial stiffness in newly diagnosed essential hypertensive subjects.

Objective Although obstructive sleep apnoea syndrome (OSAS) is accompanied by an increased atherosclerotic cardiovascular disease burden, its relationship with arterial stiffness is not yet well determined. We investigated whether essential hypertensive individuals with OSAS are characterized by increased arterial stiffness. Methods Our study population consisted of 46 consecutive patients with newly diagnosed untreated stage I–II essential hypertension suffering from OSAS (35 men, aged 49 ± 8 years) and 53 hypertensive individuals without OSAS, matched for age, sex, and smoking status. All subjects underwent polysomnography, echocardiography and aortic stiffness evaluation by means of carotid–femoral pulse wave velocity (c–fPWV) measurements. Results Hypertensive subjects with OSAS [apnoea/hypopnoea index (AHI) ≥ 5] compared with hypertensive subjects without OSAS (AHI < 5) demonstrated increased levels of body mass index (31.4 ± 4 versus 29.3 ± 4 kg/m2, P = 0.015), office systolic/diastolic blood pressure (151/99 versus 145/94 mmHg, respectively, P < 0.05, for both cases) and relative wall thickness (RWT; 0.46 ± 0.06 versus 0.42 ± 0.07, P = 0.010). Hypertensive subjects with OSAS compared with those without OSAS had significantly increased c–fPWV by 9% (8.56 ± 0.49 versus 7.85 ± 0.93 m/s, P = 0.001) and this difference remained significant even after adjustment for confounders (P = 0.04). In the total study population, c–fPWV was correlated with age (r = 0.35, P = 0.015), office systolic blood pressure (r = 0.30, P = 0.007), RWT (r = 0.30, P = 0.03), logAHI (r = 0.389, P = 0.0001) and minimum oxygen saturation (r = −0.418, P = 0.0001). Conclusions OSAS has a significant incremental effect on aortic stiffening in the setting of middle-aged essential hypertensive subjects. This finding suggests that the presence of OSAS in a hypertensive patient accelerates vascular damage, increasing cardiovascular risk.

Renal Nerve Ablation for Resistant Hypertension How Did We Get Here, Present Status, and Future Directions

Sympathetic renal denervation, or renal nerve ablation (RNA), has become the new buzz word in hypertension and interventional cardiology. Recent advances in catheter-based approaches have allowed sympathetic fiber interruption through transvascular techniques that are minimally invasive and can be delivered expeditiously and safely. Radiofrequency (RF) energy sources are currently the preferred modalities, but other sources of energy, such as cryoablation, microwave, high-intensity focus ultrasound, and local neurotoxic agent infusion, are under intense investigation. Results thus far have been encouraging and offer promise for the future. The role of the sympathetic nervous system (SNS) in the development of resistant hypertension and cardiovascular disease has long been known, and a great deal of work has been done through the years trying to explore potential interventions to interrupt the sympathetic influence on systemic vasculature and target organs. In this article we attempt an overview of time-dependent interventions on the SNS and examine approaches used in humans and in the many experimental models that offer a better understanding of the role of sympathetic activity in cardiovascular disease. Naturally we focus on methods and techniques addressing sympathetic renal denervation in patients with drug-resistant hypertension, examine the current state of the art, and attempt a look into the future. In 1889, after meticulous experiments on dogs, Bradford1 reported that stimulation of dorsal and splanchnic nerves causes changes in blood pressure (BP) and kidney size measured by plethysmography. Whether BP increased or decreased depended on the anatomic area stimulated, as well as the electric impulse frequency, but outcomes were consistent and reproducible. Neurosurgical treatment of hypertension was independently suggested by researchers in 1923.2 Adson, however, was the first to performed surgical sympathectomy for the treatment of malignant hypertension in 1925.3 During the following years and in the 1930s, Peet in Ann Arbor, Page and …