Renal sympathetic ablation - new approach of hypertension therapy

2013/2014 Joana Filipa Lopes Figueiredo de Carvalho Paulo Renal Sympathetic Ablation New approach of hypertension therapy março, 2014 Mestrado Integrado em Medicina Área: Cardiologia Trabalho efetuado sob a Orientação de: Prof. Doutor Manuel Joaquim Lopes Vaz da Silva Revista Portuguesa de Cardiologia Joana Filipa Lopes Figueiredo de Carvalho Paulo Renal Sympathetic Ablation New approach of hypertension therapy março, 2014 Renal Sympathetic Ablation New approach of hypertension therapy Joana Paulo Faculty of Medicine of the University of Porto (FMUP) Al. Prof. Hernâni Monteiro 4200-319 Porto, Portugal e-mail: [email protected] / [email protected] Telephone: 00351 963216814 Total de palavras: 5171 i INDEX List of Abbreviations -------------------------------------------------------------------------------------------------------- ii List of Figures ---------------------------------------------------------------------------------------------------------------- iii List of Tables ----------------------------------------------------------------------------------------------------------------- iii Abstract ----------------------------------------------------------------------------------------------------------------------- iv Resumo ------------------------------------------------------------------------------------------------------------------------ v Introduction ------------------------------------------------------------------------------------------------------------------ 1 Material and Methods ----------------------------------------------------------------------------------------------------- 3 Hypertension Treatment -------------------------------------------------------------------------------------------------- 3 Role of SNS in Hypertensive states -------------------------------------------------------------------------------------- 4 Renal Sympathetic Denervation (RSD) – New treatment for old disease Historical basis for RSD ------------------------------------------------------------------------------------------ 6 Renal radiofrequency ablation procedure – Pioneering work ---------------------------------------- 7 Recent clinical Evidence Symplicity system and trials ------------------------------------------------------------------------- 8 Others renal sympathetic denervation trials --------------------------------------------------- 12 Ablation criteria ------------------------------------------------------------------------------------------------------------ 14 Prospective developments ---------------------------------------------------------------------------------------------- 15 Additional effects ---------------------------------------------------------------------------------------------------------- 16 Conclusion ------------------------------------------------------------------------------------------------------------------- 18 Acknowledgments --------------------------------------------------------------------------------------------------------- 19 References------------------------------------------------------------------------------------------------------------------- 20 Annex ------------------------------------------------------------------------------------------------------------------------- 43 ii LIST OF ABBREVIATIONS ABPM Ambulatory blood pressure monitoring BP Blood pressure CKD Chronic kidney disease DBP Diastolic blood pressure ESH/ESC European Society of Hypertension/European Society of Cardiology GFR Glomerular filtration rate HF Heart failure HT Hypertension HR Heart rate LV Left ventricular NA Noradrenaline RFA Radiofrequency ablation RH Resistant hypertension RSD Renal sympathetic denervation SBP Systolic blood pressure SNS Sympathetic nervous system iii LIST OF FIGURES Figure 1 ----------------------------------------------------------------------------------------------------------------------- 26 Figure 2 ----------------------------------------------------------------------------------------------------------------------- 27 Figure 3 ----------------------------------------------------------------------------------------------------------------------- 28 Figure 4 ----------------------------------------------------------------------------------------------------------------------- 29 Figure legends -------------------------------------------------------------------------------------------------------------- 30 . LIST OF TABLES Table 1 ------------------------------------------------------------------------------------------------------------------------ 31 Table 2 ------------------------------------------------------------------------------------------------------------------------ 32 Table 3 ------------------------------------------------------------------------------------------------------------------------ 34 Table 4 ------------------------------------------------------------------------------------------------------------------------ 35 Table 5 ------------------------------------------------------------------------------------------------------------------------ 37 Table 6 ------------------------------------------------------------------------------------------------------------------------ 38 Table 7 ------------------------------------------------------------------------------------------------------------------------ 41 iv ABSTRACT Hypertension is the most common attributable risk factor for stroke and myocardial infarction, leading to death when inappropriately treated. Despite the wide pharmacological available selection, blood pressure remains uncontrolled in a significant proportion of patients. Resistant hypertension is an increasingly common clinical condition, defined by blood pressure ≥140/90 mmHg (or ≥130/80 mmHg in diabetes or renal Insufficiency) regardless concurrent use of 3 or more antihypertensive drugs from different classes, including one diuretic, all at the optimal doses. As patients with hypertension are at elevated risk for cardiovascular morbidity and mortality, this review summarizes the available data, based on bibliographic research using PubMed’s data base, of new interventional approaches taking into account renal sympathetic activation’s role in hypertension pathogenesis. Renal Sympathetic Denervation is a novel catheter percutaneous procedure based on a therapeutic old concept which intends to ablate the nerves in order to interrupt the central nervous system and kidneys’ bidirectional connection. So far, trials have demonstrated convincing and safe blood pressure-lowering effects in majority of treated patients. Moreover, potential additional benefits on hypertension’s comorbidities, such as left ventricular hypertrophy and renal impairment, have been identified. Although this current evidence is mainly based on ablation through radiofrequency energy, several second-generation catheters have been developed aiming at safety and efficacy improvement. Therefore, renal sympathetic denervation appears as a future potential hypertension treatment option, despite being already conducted, under severe controlled conditions, in some countries. KEYWORDS Blood pressure; Radiofrequency ablation; Resistant Hypertension; Renal Sympathetic Denervation; Sympathetic nervous system activity 5 sympathetic outflow with a mean elevation of 2 or 3 times the normal value.13,16 Therefore, the hyperkinetic circulation profile is early established in HT development with raised resting heart rate (HR) and cardiac output, increased peripheral and renovascular resistance and elevated plasmatic levels of NA, independent of disease severity stage.19 The involvement of the renal SNS in the BP control is complex since it is simultaneously the receiver and originator of sympathetic signals by the efferent and afferent fibers, respectively, both located within the renal artery.20 The efferent renal sympathetic nerves are regulated by central sympathetic outflow, vagal tone and renorenal reflexes. These fibers affect renal function not only by inducing antinatriuresis through elevation of renin secretion via the juxtaglomerular apparatus (β1-adrenoceptors) but also by enhancing sodium and water reabsorption through activation of the Na+/K+ adenosine triphosphatase in the renal tubular cells (α1B-adrenoceptors). On the other hand, they also decrease GFR by inducing direct renal vasoconstriction (α1A-adrenoceptors) which decreases renal blood flow. However, there seems to be a graded response depending on the effect of the sympathetic signal on adrenoceptors’ differential activation: low frequency stimulation only affects renin secretion whilst higher frequencies also influence sodium reabsorption and renal vascular tone.23 The afferent renal sympathetic nerves are stimulated by chemoreceptors in renal interstitium and mechanoreceptors in the renal wall. The former are sensitive to variations in electrolyte concentration and plasma osmolality and renal ischemia. The mechanoreceptors are stimulated by signaling changes in hydrostatic renal pelvic pressure.20 The stimulation of these fibers modulates autonomic centers in the hypothalamus, the paraventricular nucleus, which increases (directly or through rostral ventrolateral medulla neurons’ activation) the sympathetic outflow to the kidney and other organs involved in the cardiovascular control, contributing to the neurogenic elevation of BP.13,15 Despite central sympathetic system’s predominant role, raised BP is also influenced by peripheral adrenergic abnormalities as inappropriate neuronal reuptake of NA or peripheral α- 6 adrenoceptors’ downregulation.19 Consequently, through the influence on the regulation of overall sympathetic tone, afferent fibers have a predominant role in the genesis and maintenance of HT. Furthermore, these fibers are essential to preserve hydrolytic balance in case of unilateral excretion disorder since there is a direct communication with the contralateral kidney (renorenal reflex).7 Subsequently, neurogenic primary HT is considered to be responsible for more than 50% of all cases of high BP.16 Although mechanisms of SNS overdrive are not completely understood, some hypotheses have been considered such as the impairment of volume-sensitive receptors or arterial chemoreceptors. Also, the contribution of humoral elements (insulin, angiotensin II) and the involvement of nutritional or behavioral features are suggested.19 RENAL SYMPATHETIC DENERVATION (RSD) NEW TREATMENT FOR OLD DISEASE HISTORICAL BASIS FOR RSD SNS has been considered a possible therapeutic target in cases of RH since the early 20th century as its effect on vasoconstriction was already acknowledged. There were many surgical sympathectomy approaches with different removal extension.24 According to Gulati and White25, the radical lumbodorsal splanchnicectomy was firstly developed in 1938 by Smithwick. Despite being extremely effective in BP control with reported cardiac size reduction, renal function improvement, decreased incidence of precordial pain and cerebrovascular events and mortality rate7, these procedures were associated with intolerable side effects like severe orthostatic hypotension, syncope, paradoxical excessive sweating, sphincter incontinence and erectile dysfunction. Moreover, the technique’s significant invasiveness associated with the development of effective and better tolerable oral sympathetic-blocking drugs led to its abandonment.26 7 Nonetheless, it was an undisputable proof-of-concept of SNS overdrive in RH, confirming BP control’s achievement through reduction in sympathetic tone. Besides, it revealed that adequate renal function is independent of intact renal SNS, confirmed by transplantation, since kidneys are still capable of maintaining electrolyte and volume homeostasis and adrenaline-mediated stress responses over time despite reduction in the sympathetic input.27 RENAL RADIOFREQUENCY ABLATION (RFA) PROCEDURE – PIONEERING WORK Recently, RSD has been receiving additional interest as an HT therapeutic option not only because of sympathetic fibers’ activation role (in particular renal network) in disease’s progression and complications but also due to significant degree of SNS overdrive demonstrated in RH.19,28 The development of a new endovascular approach was based on cardiac arrhythmias efficient treatment with percutaneous radiofrequency ablation (RFA)24, aiming to avoid surgical denervation side effects and still achieve its success. Therefore, percutaneous renal RFA appears as a selective and minimally invasive procedure, with limited periprocedural risk and shorter recovery time. The catheter-based RSD therapy using radiofrequency was firstly outlined by Krum et al in an international Proof-of-principle study29 which included 50 patients with RH (table 3); 5 were excluded based on anatomical criteria. This group was followed-up during the trial and had comparable baseline patient characteristics (table 4). After renal artery angiography and heparin administration to achieve 250s activated clotting time, the “Symplicity” catheter was placed onto the distal renal artery wall via femoral artery. The catheter was connected to a radiofrequency generator which enabled energy delivery to endoluminal surface according to a predetermined algorithm and data on temperature, length of treatment and impedance, constantly monitored in order to prevent arterial injury. Radiofrequency energy, lower than that used for cardiac electrophysiological procedures, was delivered 4 to 6 times in each artery in a helical pattern lasting up to 2 minutes (figure 3). 8 The procedure was initially conducted in a 2-stage way (10 patients had contralateral artery ablation 1 month later). As safety was established, it became a simultaneous bilateral procedure. Both treatment compliance and maintenance were emphasized to patients and physicians, respectively. In every visit after the procedure both office SBP and DBP revealed a significant decrease when compared to baseline (p<0.05). Although the extent of BP reduction is significantly different taking into account BP measurement method (table 4), office and ABPM decrease are strictly related. RFA efficiency was sustained even when medical treatment alterations were considered. Regardless the 12-month promising outcomes, 6 patients’ BP decreased less than 10 mmHg (non-responders) which may point out to either ablation failure or SNS overdrive’s secondary role in some cases of RH. However, the mean decrease in renal NA spillover rate of 47% in 10 patients 15-30 days after the procedure associated with the significant reduction of total body NA spillover in 1 patient30 attested RSD effectiveness in kidney’s both efferent and afferent sympathetic drive reduction. No significant side effects were detected, both procedure-related renovascular damages (confirmed by 18 patients’ 14-30 days angiogram and 14 patients’ 6-month magnetic resonance angiogram) and renal function deterioration (GFR estimated in 25 patients). Only 2 surgical complications were identified which were immediately resolved: renal artery dissection through stenting and femoral artery aneurysm with antibiotics and analgesics. Also, the considerable amount of pain during the procedure (common pathway of sympathetic nerves and C pain fibers) led to a more aggressive control in the subsequent trials.31 RECENT CLINICAL EVIDENCE  Symplicity system and trials Despite being the first evidence of RSD’s safety and efficiency, the small number of patients treated limited Proof-of-principle’s relevance. Therefore, investigators decided to spread the therapeutic approach to 153 patients, including the patients already treated and increase the follow-up period to 9 36-month (Symplicity HTN-1 Trial).32 After the first 12 months, patients were given the choice of a 24 or 36 months follow-up period, 111 of whom agreed on the second period. The respective baseline data, BP variations and complications are reported on table 4. BP control (<140 mmHg) was significantly augmented through the follow-up period, contrarily to the decrease of patients with SBP >180 mmHg (from 30% at baseline to 5% at 36-month). Although re-innervation was hypothesized, BP-lowering persisted and even augmented at 36-month when compared with 12-month decrease, without HR’s significant alteration. One eventual explanation is the afferent renal fibers’ probable role on central sympathetic overdrive, changing the baroreflex to lower homeostatic regulation point.30,33 However, antihypertensive drug therapy’s influence remains undetermined since it could be changed after the 12th month. No significant differences were detected in BP-lowering considering age, renal function or diabetes status. Despite being overall well preserved, the 10 patients’ 24month GFR revealed a decrease of 16 mL/min/1.73m2.34 Nevertheless, according to Sadowski et al (2011) quoting Bakris and Williams, RSD has a renoprotective effect since GFR decline is lower than it would be expected considering baseline SBP. The 3 deaths that occurred (1 myocardial infarction, 1 sudden death syndrome and 1 cardiac and respiratory arrest) were considered to be independent from the ablation procedure. No vascular alteration was detected at 6-month follow-up imaging (available in 81 patients)34 and stenosis rate was really low. Consequently, the results of the expanded-cohort were the first to demonstrate not only a sustained BP reduction but also a preserved safety and maintained renal function 3 years after the procedure. Nevertheless, Symplicity HTN-1 upholds Proof-of-study’s weaknesses since they lack a control group (risk of placebo and Hawthorne effect) and both the RH definition (without screening of HT etiology and no BP measurement method established) and exclusion criteria are inadequate. Moreover, follow-up numbers remain reduced and the antihypertensive regime adjustments and adherence were not taken into account. The unblinded analysis might also lead to observer bias. Besides, selection bias cannot be excluded.7,29,32,33,35 10 Meanwhile, in order to validate the outcomes obtained, the Symplicity HTN-236, an international randomized clinical trial, recruited 190 patients according to inclusion criteria (table 3). After recording medication intake and BP values for 2 weeks, 106 of these were randomly distributed in 1:1 ratio to RSD or control groups, both continuing the previous antihypertensive treatment without adjustments except if medically required. At baseline, patients’ characteristics, mean BP and antihypertensive therapeutics between the two groups were identical. The primary endpoint was achieved in 49 of the treated patients (94.2%) and in 51 of the controls (94.4%), with a significantly different BP reduction between-group (p<0.05). However, once again these results differ from the 6-month 24h-ABPM (table 4). Six-month BP control (SBP <140 mmHg) was reached in 39% of RSD group compared to 6% of controls. Six-month SBP reduction ≥10 mmHg was also significantly different between-group. It is noteworthy to report the procedure’s complete inefficiency (no BP reduction) in 5 of the treated patients (10%). The antihypertensive treatment’s decrease was significantly different between groups: 20.4% in RSD and 5.9% in control group. Contrarily, pharmacological intensification was not. Besides, there was no significant alteration in renal function in both groups during the follow-up period. Through 6-month imaging tests undertaken in 43 of the 49 patients no difference was detected in renal vascular anatomy. Although progression of a pre-existent atherosclerotic lesion was observed, it was placed away from the RSD ablation site. Bradycardia cases were successfully managed as well as the 5 minor periprocedure complications reported. Major complications during follow-up period were similar in both groups (table 4). Also, the occurrence of adverse effects was comparable between groups, without severe procedure or device-related complications in RSD group. After the 6-month follow-up period, control patients were offered the RSD procedure as long as they maintained SBP ≥160 mmHg.37 The crossover group (35 patients) had baseline demographic features and antihypertensive treatments comparable to the initial RSD group. This 12-month follow-up data exhibited not only persistence of significant BP reduction in the initial RSD group compared to 11 baseline (28/10 mmHg) but also an equivalent significant decrease in the crossover group: a variation of -24/-8 mmHg, comparable to the 6-month change in the initial interventional group (-32/-8 mmHg, p=0.15). Besides, therapy regimens’ modifications were not significantly different between the initial RSD and the crossover groups. GFR remained stable in both groups. Also, safety was confirmed through only 1 case of artery dissection, 3 hypertensive and 1 hypotensive episodes and no deaths. Symplicity HTN-2’s results, notwithstanding being on behalf of previous findings, are still questionable due to similar previous limitations: non-double blinded analysis, incomplete exclusion criteria (no secondary HT screening) and small sample size and follow-up period, which may mask the development of complications. Despite being a randomized trial, group baseline characteristics like sex, diabetes and coronary artery disease rates are different leading to a severity discrepancy into RSD group. Besides, since baseline 24h-ABPM was not measured, white-coat HT was not excluded. Although the included patients had to carry out a 2-week antihypertensive therapy, there was no systematic adherence assessment during follow-up.38-40 RSD future trials need to respond to some of the questions brought up by past trials’ limitations. It is Symplicity HTN-3’s purpose41, a multicenter randomized single-blinded trial conducted in America, with wider inclusion and exclusion criteria in order to assess RSD’s both effectiveness and safety in true RH patients (table 5). Six-month both office-BP and 24h-ABPM are, respectively, primary and secondary efficiency outcomes, in order to clarify the differences observed in the previous trials. The 6-month incidence of major adverse effects is the primary safety outcome. Following recruitment phase, in which were enrolled patients with SBP ≥160 mmHg while on stable treatment with 3 or more different drugs (including one diuretic) for no less than 2 weeks, there was the screening period with ABPM and therapy adherence registries for at least 2 weeks. Patients with sustained high SBP and mean 24h-ABPM ≥135 mmHg undertook selective renal angiography to verify 12 the accomplishment of anatomic criteria. 530 patients were posteriorly randomized in a 2:1 ratio to RSD or sham procedure, both continuing the previous medical treatment. As a blinded study, patients were unaware of randomization attribution with similar follow-up in both groups. Moreover, staff measuring BP was also blinded throughout all trial. Before 6-month evaluation, which includes renal artery duplex imaging, patients recorded ABPM and therapy intake for 2 weeks. Follow-up period is 3 years for both groups. The announcement made by Medtronic (symplicity system’s producer) on January the 9th 2014 about Symplicity HTN-3’s results tempered RSD enthusiasm on RH treatment. Despite guaranteeing primary safety endpoint, the primary efficacy endpoint (a sustained SBP reduction at 6-month) was not accomplished. (http://newsroom.medtronic.com/phoenix.zhtml?c=251324&p=irolnewsArticle&id=1889335) According to Bakris, co-principal investigator, even though BP reduction was not statistically significant, the methodology used is far more rigorous than in previous trials. Therefore, despite believing European guidelines will be reformulated, he considers procedure’s dismissal ethically unacceptable. (http://www.medscape.com/viewarticle/819018) Besides, Dr. Marco Valgimigli, on behalf of the ESC, argues the importance of having the complete data since treatment’s efficacy is not determined by studies’ primary endpoint success. These concepts are also supported by Dr. Sanjay Kaul. Other investigators consider Symplicity HTN-3’s results as a possible failure's consequence of either procedure or Medtronic’s device. (http://www.medpagetoday.com/Cardiology/Hypertension/43726) However, only through the final data will definite conclusions be defined.  Others Renal Sympathetic Denervation trials 24h-BP profile has been recognized as organ damage independent prognostic factor. Despite not established, autonomic dysfunction seems to be the probable underlying mechanism. Taking into 13 account RSD’s effect both on renal and total body sympathetic activity30, Zuern et al hypothesized a similar outcome regarding 24h-BP variability.42 Inclusion and exclusion criteria and methodology were comparable to Symplicity’s. Six months after the procedure, the selected patients (n=11) revealed both an office-SBP decrease equivalent to previous trials (-30.4 mmHg, p=0.007) and a significant 24h-BP variability reduction (systolic coefficient of variation: from 0.11 to 0.09, p=0.041; diastolic coefficient of variation: from 0.14 to 0.11, p=0.024), more pronounced than 24h-ABPM decline (SBP from 149 to 142 mmHg, p=0.086; DBP from 82 to 79 mmHg, p=0.167). SNS dysfunction is also a predictor of Chronic Kidney Disease’s (CKD) development and progression as afferent and efferent renal fibers contribute to the sympathetic overactivity vicious cycle. Hence, 15 patients with concomitant RH and moderate to severe CKD underwent renal ablation.43 12-month results suggest not only RSD’s efficacy and safety since BP was significantly reduced (∆ office-BP=- 33/-19 mmHg) without procedure-related complications, but also maintenance of renal function (electrolyte and water homeostasis preserved; ∆GFR with p>0.05). Moreover, as all patients had baseline and follow-up 24h-ABPM, a significant effect on nocturnal BP was detected after only 3 months (∆ABPM night-time=-14/-8 mmHg, p=0.03/0.02), through physiologic dipping pattern reestablishment (p=0.01). As BP reduction has enormous cardiovascular benefits (stroke, myocardial infarction, heart failure and death) RSD was recently performed in 20 cases of long-standing mild RH (even with 3 or more antihypertensive drugs, SBP=[140-160] mmHg) in order to determine procedure’s efficacy and safety.44 Six-month outcomes demonstrated office-SBP as well as mean systolic-ABPM significant decrease despite more modest than in Symplicity’s patients, respectively, -13.1 mmHg (p<0.01) and - 11.3 mmHg (p<0.01), associated with the absence of renal stenosis and preserved renal function (p=0.5). Therefore, further evidence is required to establish RSD as second-line therapy in mild RH. 14 In a multicenter national Portuguese registry, 78 patients were submitted to RSD, between July-2011 and November-2012, using both Symplicity (n=75) and EnligHTN (n=3) catheters. Among the included patients mean office-BP was 176.5/94.7 mmHg, most having HT for more than 10 years. Despite the fact that 2 cases of significant stenosis at the final angiogram and 2 pseudoaneurysms were detected, RSD’s efficacy was proven by the 74% response rate in 23 patients with more than 6-month followup.45 Already in September 2011 the procedure’s feasibility was confirmed by a Portuguese two-case report.46 ABLATION CRITERIA Nowadays, based on clinical trial’s evidence, RSD via Symplicity catheter has been already approved in Australia47, Europe48 and Canada49 exclusively for RH treatment in patients with preserved renal function (GFR ≥45 mL/min/1.73m2). Therefore, only patients with raised office-SBP (≥160 mmHg or ≥150 mmHg in type 2 diabetes patients) despite the combination of at least 3 antihypertensive drugs (including one diuretic) and without contributing factors, like increasing BP substances or inappropriate lifestyles, are recommended to this procedure. Secondary HT causes must be excluded as well as non-compliance to antihypertensive treatment. Moreover, confirmation of high BP through 24h-ABPM is required in order to exclude white-coat HT. Although medical therapy may be optimized with association of mineralocorticoid receptor antagonist, prolonged treatment with this drug is restricted due to its adverse effects. An imaging test of the renal system should be realized before the procedure since it is recommended in renal arteries ≥ 4mm in diameter and ≥ 20 mm in length before any major branch bifurcation (figure 4). As there is unsatisfactory clinical evidence, RSD is not recommended in cases of significant renal artery abnormalities (hemodynamically or anatomically), past renal interventions (angioplasty or stents), unstable clinical conditions (e.g. acute coronary event), pulmonary arterial HT, chronic 21 9. Kaplan NM, Calhoun DA. Treatment of resistant hypertension. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on 27/12/2013.). 10. Kaplan NM, Calhoun DA. Definition, risk factors, and evaluation of resistant hypertension. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on November 25, 2013.). 11. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. J Am College Cardiol. 2008;52(22):1749-57. 12. Pathak A, Girerd X, Azizi M, et al. Expert consensus: Renal denervation for the treatment of hypertension. Diagn Interv Imaging. 2012;93(5):386-94. 13. Esler M. 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J Am Coll Cardiol. 2012;59(10):901-9. 57. Ukena C, Mahfoud F, Kindermann I, et al. Cardiorespiratory response to exercise after renal sympathetic denervation in patients with resistant hypertension. J Am Coll Cardiol. 2011;58(11):1176-82. 58. Ukena C, Mahfoud F, Spies A, et al. Effects of renal sympathetic denervation on heart rate and atrioventricular conduction in patients with resistant hypertension. Int J Cardiol. 2013;167(6):2846-51. 59. Mahfoud F, Schlaich M, Kindermann I, et al. Effect of renal sympathetic denervation on glucose metabolism in patients with resistant hypertension: a pilot study. Circulation. 2011;123(18):1940-6. 60. Witkowski A, Prejbisz A, Florczak E, et al. Effects of renal sympathetic denervation on blood pressure, sleep apnea course, and glycemic control in patients with resistant hypertension and sleep apnea. Hypertension. 2011;58(4):559-65. 26 Fig. 1 - Algorithm for hypertension management. Adapted from James, Oparil and Carter (2013).14 β-blockers are not recommended for HT’s initial treatment since not only compared with the 4 recommended classes the results were similar in some studies but also stroke’s incidence was higher compared with ARB. *No diabetes or CKD. ǂ with or without diabetes. ACEI – angiotensin converting enzyme inhibitors; ARB – angiotensin receptor blockers; BP – blood pressure; CCB – calcium channel blockers; CKD – chronic kidney disease; DBP – diastolic blood pressure; SBP – systolic blood pressure. Adult aged ≥18 years with hypertension LIFESTYLE INTERVENTIONS (continue throughout management) Set BP goal and initiate medication based on age, diabetes and CKD General population * Diabetes or CKD present ≥60 years <60 years All ages CKD ǂ SBP <150 mmHg DBP <90 mmHg SBP <140 mmHg DBP <90 mmHg SBP <140 mmHg DBP <90 mmHg SBP <140 mmHg DBP <90 mmHg All races ACEI or ARB, alone or in combination with other drug class THIAZIDE-DIURETIC, ACEI, ARB or CCB, alone or in combination THIAZIDE-DIURETIC or CCB, alone or in combination Black Nonblack Select a drug treatment titration strategy 1. First drug maximization before second addition 2. Second drug addiction before first drug’s dose maximization 3. Initiation with 2 drugs, separately or as fixed-dose combination BP goal achieved? No Continue current treatment and monitoring All ages diabetes, no CKD GOAL  Medication and lifestyle adherence reinforcement  Addition and titration of drug class not previously selected, avoiding ACEI and ARB’s combination. Yes 27 Fig.2 – Sympathetic nervous system role in Hypertension. Adapted from Bunte, Infante-Oliveira and Shishehbor (2013)21; Kanai and Krum (2013)22. GFR – glomerular filtration rate. 28 Fig.3 – The radiofrequency ablation procedure and simplicity cathether. Adapted from Kanai and Krum(2013)22. 29 Fig.4 – Recommended pathway to determine patients’ eligibility for Renal Sympathetic Denervation procedure. Adapted from Schlaich, Schmieder, Bakris et al(2013)50; Mahfoud, Luscher, Andersson et al(2013)48. ABPM – ambulatory blood pressure monitoring; BP – blood pressure; CKD – chronic kidney disease; DM – diabetes mellitus; GFR – glomerular filtration rate; HThypertension; NSAID’s – non-steroidal anti-inflammatory drugs; OSA – obstructive sleep apnea; RSD – renal sympathetic denervation; SBP – systolic blood pressure. 30 FIGURE LEGENDS Fig. 1 - Algorithm for hypertension management. Adapted from James, Oparil and Carter (2013).14 βblockers are not recommended for HT’s initial treatment since not only compared with the 4 recommended classes the results were similar in some studies but also stroke’s incidence was higher compared with ARB. *No diabetes or CKD. ǂ with or without diabetes. ACEI – angiotensin converting enzyme inhibitors; ARB – angiotensin receptor blockers; BP – blood pressure; CCB – calcium channel blockers; CKD – chronic kidney disease; DBP – diastolic blood pressure; SBP – systolic blood pressure. Fig.2 – Sympathetic nervous system role in Hypertension. Adapted from Bunte, Infante-Oliveira and Shishehbor (2013)21; Kanai and Krum (2013)22. GFR – glomerular filtration rate. Fig.3 – The radiofrequency ablation procedure and simplicity cathether. Adapted from Kanai and Krum(2013)22. Fig.4 – Recommended pathway to determine patients’ eligibility for Renal Sympathetic Denervation procedure. Adapted from Schlaich, Schmieder, Bakris et al(2013)50; Mahfoud, Luscher, Andersson et al(2013)48. ABPM – ambulatory blood pressure monitoring; BP – blood pressure; CKD – chronic kidney disease; DM – diabetes mellitus; GFR – glomerular filtration rate; HThypertension; NSAID’s – non-steroidal anti-inflammatory drugs; OSA – obstructive sleep apnea; RSD – renal sympathetic denervation; SBP – systolic blood pressure. 37 Table 5 – Symplicity HTN-3 INCLUSION CRITERIA EXCLUSION CRITERIA EFFECTIVENESS ENDPOINTS SAFETY ENDPOINTS ▪18-80 years ▪office-SBP ≥160 mmHg (initial and confirmatory screening) ▪stable medication regimen for at least 2 weeks before initial screening and no changes planned for 6 months ▪written informed consent ▪renovascular ineligibilities (diameter <4mm or length <20mm; multiple renal arteries; stenosis>50% or aneurysm; previous interventions) ▪GFR <45 mL/min/1.73m2 ▪average ABPM <135 mmHg ▪pregnancy, nursing ▪chronic oxygen support or mechanical ventilation beyond night ▪primary pulmonary HT, type 1 DM, pheochromocytoma, cushing’s disease, hyperthyroidism, hyperparathyroidism, coarctation of aorta, severe cardiac valve stenosis ▪MI, unstable angina, syncope or cerebrovascular accident (prior 6 months) ▪planned surgery or CV intervention in the next 6 months ▪history of dependency, inability to comprehend instructions, unable to comply with trial’s requirements Primary ▪office-SBP change Secondary ▪average 24h-ABPM change ▪incidence of: SBP reduction ≥10, 15, 20 mmHg; SBP control (<140 or 130 mmHg in DM and RD); medication changes; home-BP change ▪12, 18, 24 and 36-month BP change Primary ▪major adverse events (MAE) incidence (composite of many events) ▪new renal artery stenosis >70% (6-month angiography) Secondary: ▪each component of MAE ▪chronic safety ▪change in renal function ABPM – ambulatory blood pressure monitoring; CV – cardiovascular; DM – Diabetes Mellitus; GFR – glomerular filtration rate; HT – Hypertension; MI – myocardial infarction; RD – renal disease; SBP – systolic blood pressure. 38 Table 6 – Overview of Renal Denervation systems PRODUCT NAME AND SPONSOR DESIGN OPERATING MODE ? CLINICAL TRIAL RADIOFREQUENCY ABLATION Symplicity catheter Medtronic Inc. Single-electrode catheter Multiple rotations through spiral pattern Symplicity HTN 1-3; Renal Nerve Ablation in CKD patients; RDN in patients with RH and OSA EnligHTN catheter St. Jude Inc. Multi-electrode catheter Simultaneous energy delivery to 4 sites along arterial surface ARSENAL Vessix V2 catheter Vessix Vascular Inc. Balloon-mounted catheter Low-pressure balloon with superficial bipolar electrodes REDUCE-HTN OneShot catheter Maya Medical Inc. Irrigated balloon-mounted catheter Energy delivery by spiral electrode with cooling irrigation holes RAPID 39 Table 6 – Overview of Renal Denervation systems (continuation) PRODUCT NAME AND SPONSOR DESIGN OPERATING MODE ? CLINICAL TRIAL RADIOFREQUENCY ABLATION ThermoCool cryoablative catheter † Biosense Webster Inc. Irrigated catheter Constant preset energy delivery with maintenance of lower temperatures SWAN HT; SAVE; RELIEF Chilli II cryoablative catheter † Boston Scientific Inc. Irrigated catheter SAVE ULTRASONIC ABLATION PARADISE catheter ReCor Medical Inc. US balloon catheter Circumferential energy by inflatable balloon with cooled fluid flow REALISE TIVUS catheter Cardiosonic Ltd. US autoregulating balloon catheter High-intensity, non-focused, selfregulating ablation ǂ 40 Table 6 – Overview of Renal Denervation systems (continuation) PRODUCT NAME AND SPONSOR DESIGN OPERATING MODE ? CLINICAL TRIAL ULTRASONIC ABLATION Kona medical US system Kona Medical Inc. Low intensity external US ablation catheter Non-invasive low-intensity focused energy with imaging modality ǂ TISSUE-DIRECTED PHARMACOLOGICAL ABLATION Bullfrog micro-infusion catheter Mercator MedSystems Inc. Microneedle-equipped balloon catheter Perivascular direct delivery of neurotoxins ǂ Adapted from Bunte, Oliveira-Infante and Shishehbor (2013).21 ARSENAL – Safety and Efficacy Study of Renal Artery Ablation in Resistant Hypertension Patient trial; CKD – chronic kidney disease; HTN – Hypertension; OSA – obstructive sleep apnea; PARADISE – ReCor Percutaneous Renal Denervation System catheter; RAPID – Rapid Renal Sympathetic Denervation for Resistant Hypertension trial; RDN – Renal Denervation; REALISE – Renal Denervation by Ultrasound Transcatheter Emission trial; REDUCE-HTN – Treatment of Resistant Hypertension Using a Radiofrequency Percutaneous Transluminal Angioplasty Catheter; RELIEF – Renal Sympathetic Denervation for the Management of Chronic Hypertension trial; RH – resistant hypertension; SAVE – Impact of Renal Sympathetic Denervation on Chronic Hypertension study; SWAN HT – Renal Sympathetic Modification in Patients With Essential Hypertension study; SYMPLICITY HTN-1 – SYMPLICITY I: One-Year Results Following Sympathetic Renal Denervation in Refractory Hypertension trial; SYMPLICITY HTN-2 – Renal Sympathetic Denervation in Patients With Treatment-Resistant Hypertension trial; SYMPLICITY HTN-3 – Renal Denervation in Patients With Uncontrolled Hypertension trial; TIVUS – therapeutic intravascular ultrasound; † - unknown mechanism; ǂ - under development 41 Table 7 – RSD’s effect on left ventricular hypertrophy and cardiac function HEMODYNAMIC LV HYPERTROPHY SYSTOLIC FUNCTION DIASTOLIC FUNCTION SBP/DBP (mmHg) HRR (bpm) LV mass/BSA (g/m2) IV septum thickness (mm) LV endsystolic volume (mL) LV ejection fraction (%) Mitral E-wave deceleration (ms) Isovolumic relaxation time (ms) Diastolic relaxation velocity * (cm/s) LV filling pressure ǂ LA size (mm) RSD group (n=48) Baseline 180.7/95.8 66.5 112.4 14.1 32.8 63.1 227.2 109.1 8.1 9.9 45.2 6 month 152.9/87.0 (p<0.001) 60.9 94.9 (p<0.001) 12.5 (p=0.009) 25.6 (p=0.001) 70.1 (p=0.001) 185.2 (p=0.013) 85.6 (p=0.006) 9.9 (p=0.001) 7.4 (p=0.001) 42.5 (p<0.001) Controls (n=18) Baseline 184.5/98.2 66.3 114.8 14.2 31.1 64.3 236.0 119.4 6.6 10.9 43.7 6 month 182.8/99.8 64.3 118.7 14.2 31.8 62.9 233.4 11.6 6.3 12.1 46.0 p for trend † 0.0396/0.041 0.047 0.004 0.032 0.015 0.048 0.008 <0.001 0.023 0.001 0.021 Adapted from Brandt et al(2012)56. BSA – body surface area; DBP – diastolic blood pressure; HRR – heart rate at rest; IV – interventricular; LA – left atrium; LV – left ventricular; RSD – renal sympathetic denervation; SBP – systolic blood pressure.* of the lateral mitral annulus; ǂ ratio of mitral inflow velocity to annular relaxation velocity); † differential efficacy between RSD and control group. 42 ANEXOS Normas de publicação da Revista Portuguesa de Cardiologia A Revista Portuguesa de Cardiologia, órgão oficial da Sociedade Portuguesa de Cardiologia, é uma publicação científica internacional destinada ao estudo das doenças cardiovasculares. Publica artigos em português na sua edição em papel e em português e inglês na sua edição online, sobre todas as áreas da Medicina Cardiovascular. Se os artigos são publicados apenas em inglês, esta versão surgirá simultaneamente em papel e online. Inclui regularmente artigos originais sobre investigação clínica ou básica, revisões temáticas, casos clínicos, imagens em cardiologia, comentários editoriais e cartas ao editor. Para consultar as edições online deverá aceder através do link www.revportcardiol.org. Todos os artigos são avaliados antes de serem aceites para publicação por peritos designados pelos Editores (peer review). A submissão de um artigo à Revista Portuguesa de Cardiologia implica que este nunca tenha sido publicado e que não esteja a ser avaliado para publicação noutra revista. Os trabalhos submetidos para publicação são propriedade da Revista Portuguesa de Cardiologia e a sua reprodução total ou parcial deverá ser convenientemente autorizada. Todos os autores deverão enviar a Declaração de Originalidade, conferindo esses direitos à RPC, na altura em que os artigos são aceites para publicação. Envio de manuscritos Os manuscritos para a Revista Portuguesa de Cardiologia são enviados através do link http://www.ees.elsevier.com/repc. Para enviar um manuscrito, é apenas necessário aceder ao referido link e seguir todas as instruções que surgem. 43 Responsabilidades Éticas Os autores dos artigos aceitam a responsabilidade definida pelo Comité Internacional dos Editores das Revistas Médicas (consultar www.icmje.org). Os trabalhos submetidos para publicação na Revista Portuguesa de Cardiologia devem respeitar as recomendações internacionais sobre investigação clínica (Declaração de Helsínquia da Associação Médica Mundial, revista recentemente) e com animais de laboratório (Sociedade Americana de Fisiologia). Os estudos aleatorizados deverão seguir as normas CONSORT. Informação sobre autorizações A publicação de fotografias ou de dados dos doentes não devem identificar os mesmos. Em todos os casos, os autores devem apresentar o consentimento escrito por parte do doente que autorize a sua publicação, reprodução e divulgação em papel e na Revista Portuguesa de Cardiologia. Do mesmo modo os autores são responsáveis por obter as respetivas autorizações para reproduzir na Revista Portuguesa de Cardiologia todo o material (texto, tabelas ou figuras) previamente publicado. Estas autorizações devem ser solicitadas ao autor e à editora que publicou o referido material. Conflito de interesses Cada um dos autores deverá indicar no seu artigo se existe ou não qualquer tipo de Conflito de Interesses. Declaração de originalidade O autor deverá enviar uma declaração de originalidade. Ver anexo I 44 Proteção de dados Os dados de carácter pessoal que se solicitam vão ser tratados num ficheiro automatizado da Sociedade Portuguesa de Cardiologia (SPC) com a finalidade de gerir a publicação do seu artigo na Revista Portuguesa de Cardiologia (RPC). Salvo indique o contrário ao enviar o artigo, fica expressamente autorizado que os dados referentes ao seu nome, apelidos, local de trabalho e correio eletrónico sejam publicados na RPC, bem como no portal da SPC (www.spc.pt) e no portal online www.revportcardiol.org, com o intuito de dar a conhecer a autoria do artigo e de possibilitar que os leitores possam comunicar com os autores. INSTRUÇÕES AOS AUTORES Todos os manuscritos deverão ser apresentados de acordo com as normas de publicação. Pressupõese que o primeiro autor é o responsável pelo cumprimento das normas e que os restantes autores conhecem, participam e estão de acordo com o conteúdo do manuscrito. NOTA IMPORTANTE! Para que se possa iniciar o processo de avaliação, o documento com o corpo do artigo deverá incluir todos os elementos que fazem parte do artigo: Títulos em português e em inglês; autores; proveniência; palavras-chave e keywords; Resumos em português e em inglês; Corpo do artigo, incluindo as tabelas; bibliografia; legendas das figuras e das tabelas. 1. Artigos Originais Apresentação do documento: • Com espaço duplo, margens de 2,5 cm e páginas numeradas. • Não deverão exceder 5.000 palavras, contadas desde a primeira à última página, excluindo as tabelas. 45 • Consta de dois documentos: primeira página e manuscrito • O manuscrito deve seguir sempre a mesma ordem: a) resumo estruturado em português e palavras-chave; b) resumo estruturado em inglês e palavras-chave; c) quadro de abreviaturas em português e em inglês; d) texto; e) bibliografia; f) legendas das figuras; g) tabelas (opcional) e h) figuras (opcional)- Primeira página Título completo (menos de 150 caracteres) em português e em inglês. Nome e apelido dos autores pela ordem seguinte: nome próprio, seguido do apelido (pode conter dois nomes) Proveniência (Serviço, Instituição, cidade, país) e financiamento caso haja. Endereço completo do autor a quem deve ser dirigida a correspondência, fax e endereço eletrónico. Faz-se referência ao número total de palavras do manuscrito (excluindo as tabelas). Resumo estruturado O resumo, com um máximo de 250 palavras, está dividido em quatro partes: a) Introdução e objetivos; b) Métodos; c) Resultados e d) Conclusões. Deverá ser elucidativo e não inclui referências bibliográficas nem abreviaturas (exceto as referentes a unidades de medida). Inclui no final três a dez palavras-chave em português e em inglês. Deverão ser preferencialmente selecionadas a partir da lista publicada na Revista Portuguesa de Cardiologia, oriundas do Medical Subject Headings (MeSH) da National Libray of Medicine, disponível em: www.nlm.nihgov/mesh/meshhome.html. O resumo e as palavras-chave em inglês devem ser apresentados da mesma forma. 46 Texto Deverá conter as seguintes partes devidamente assinaladas: a) Introdução; b) Métodos; c) Resultados; d) Discussão e e) Conclusões. Poderá utilizar subdivisões adequadamente para organizar cada uma das secções. As abreviaturas das unidades de medida são as recomendadas pela RPC (ver Anexo II). Os agradecimentos situam-se no final do texto. Bibliografia As referências bibliográficas deverão ser citadas por ordem numérica no formato ‘superscript’, de acordo com a ordem de entrada no texto. As referências bibliográficas não incluem comunicações pessoais, manuscritos ou qualquer dado não publicado. Todavia podem estar incluídos, entre parêntesis, ao longo do texto. São citados abstracts com menos de dois anos de publicação, identificando-os com [abstract] colocado depois do título. As revistas médicas são referenciadas com as abreviaturas utilizadas pelo Index Medicus: List of Journals Indexed, tal como se publicam no número de Janeiro de cada ano. Disponível em: http://www.ncbi.nlm.nih.gov/entrez/citmatch_help.html#JournalLists. O estilo e a pontuação das referências deverão seguir o modelo Vancouver 3. Revista médica: Lista de todos os autores. Se o número de autores for superior a três, incluem-se os três primeiros, seguidos da abreviatura latina et al. Exemplo: 17. Sousa PJ, Gonçalves PA, Marques H et al. Radiação na AngioTC cardíaca; preditores de maior dose utilizada e sua redução ao longo do tempo. Rev Port cardiol, 2010; 29:1655-65 Capítulo em livro: Autores, título do capítulo, editores, título do livro, cidade, editora e páginas. Exemplo: 23. Nabel EG, Nabel GJ. Gene therapy for cardiovascular disease. En: Haber E, editor. Molecular cardiovascular medicine. New York: Scientific American 1995. P79-96.