Effects of standard treatment and renal sympathetic denervation in patients with controlled hypertension and variant angina IJC Metabolic & Endocrine 14 (2017) 81–83 Contents lists available at Scienc[.]
IJC Metabolic & Endocrine 14 (2017) 81–83 Contents lists available at ScienceDirect IJC Metabolic & Endocrine journal homepage: http://www.journals.elsevier.com/ijc-metabolic-and-endocrine Letter to the Editor Effects of standard treatment and renal sympathetic denervation in patients with controlled hypertension and variant angina Variant angina is provoked by reversible coronary artery spasm, which is branded by chest pain with ST-segment elevations on electrocardiogram at rest and is not induced by exercise in the daytime [1] The prognosis of variant angina is fairly benign as long as patients are on vasodilator therapy, and avoid smoking and alcohol drinking [1,2] Variant angina mostly disturbs relatively healthy and young people who are very productive and actively involved in social activities However, variant angina occurrence often requires hospitalization and restricts social activities of such persons In particular, fatal complications, such as acute myocardial infarction, ventricular arrhythmia, and sudden cardiac death, can raise during severe coronary vasospasm [3,4] In accordance to the Guidelines of the Japanese Circulation Society [1], the coronary spasm is well-defined as a fleeting constriction of an epicardial coronary artery higher than 90%, leading to resting angina and dyspnea, beside ischemic ECG changes However, the spasm may also happen in the coronary microcirculation system, with an imitation of symptoms and ischemic ECG changes but without epicardial spasm [5], even though this phenomenon cannot presently be directly observe in humans in vivo In some subjects, spasm may even be present in the coronary epicardial arteries as well as in the microvessels [6] Anatomically, the epicardial coronary spasm is demarcated as focal if it is limited within the limits of a coronary segment agreeing to the 16 segments coronary model of the American Heart Association [7] Diffuse spasm exists if contiguous coronary segments are involved Coronary spasm can arise in only one epicardial artery, but if numerous vessels may be involved, this is termed multivessel spasm Coronary spasm frequently happens spontaneously in an unpredictable way and usually leads to angina at rest but may also be asymptomatic [4,8] However, several other clinical demonstrations of patients with coronary spasm have been described, counting but not limited to angina during exercise [9] or syncope [10] The connection concerning the autonomic nervous system and coronary spasm is multifaceted An upsurge in sympathetic activity may origin coronary spasm through an augment in noradrenaline, the neurotransmitter of efferent sympathetic fibers, triggering vasoconstriction by stimulating vascular smooth muscle cells Based on this, we aim to compare the results between standard treatment and standard treatment + renal sympathetic denervation (RSD) for variant angina therapeutics We selected 29 patients with controlled hypertension, with normal renal function, controlled hypertension and variant angina without previously treatment The study was piloted in agreement with the Helsinki declaration and approved by the ethics committee of our institution All patients signed the informed consent term before inclusion This study was conducted at the Hospital e Clớnica Sóo Gonỗalo in partnership with NitPace, Rio de Janeiro, Brazil Patients were recruited from January 2014 to January 2016 from the Cardiology Division of both Institutions Patients with the combination of the following criteria were consecutively enrolled: (i) mean 24-hour systolic ambulatory blood pressure measurements (ABPM) b130/b80 mm Hg; (ii) essential hypertension for N1 year, (ii) age between 18 and 80 years; (iii) glomerular filtration rate estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI equation), eGFR [11] N 60 mL/min/1.73 m2 (without microalbuminuria); (iv) variant angina: recurrent episodes of rest angina, often occurring in the early morning hours, associated with transient ST segment elevation and prompt alleviated with short-acting nitrates; (v) cardiac magnetic resonance images (MRI) stress testing inducing spasm during the drug infusion hot phase, drug-induced spasm occurring in patients selected; (vi) coronary angiography to exclude the presence of obstructive coronary artery disease; and (vii) the capacity to read, comprehend, and sign the informed consent form and attend the clinical tests The patients that presented any of the subsequent criteria were excluded: (i) pregnancy; (ii) valvular disease with significant adverse sequelae; (iii) unstable angina, myocardial infarction, transient ischemic attack or stroke within the months before the procedure; (iv) renovascular abnormalities; (v) psychiatric disease; (vi) allergy to ionic contrast medium; (vii) the inability to be monitored clinically after the procedure; (viii) or a known addiction to drugs or alcohol that affects the intellect The patients were separated into two groups: standard treatment (n = 16) using Ca++ channel blockers and long-acting nitrates in maximum doses recommended or tolerated by the patients, and standard treatment + renal sympathetic denervation (RSD) (n = 13) All of them were followed during three months to assess the records from a renal function, cardiac MRI parameters, and symptoms RSD, Renal function, 24-hour ABPM and cardiac MRI were previously described [12] Statistical analysis The results are expressed as a mean and standard deviation for normally distributed data and as median with interquartile range otherwise All statistical tests were two-sided Comparisons between two-paired values were performed with the paired t-test in cases of a Gaussian distribution and by the Wilcoxon test otherwise Comparisons between more than two-paired values were made by repeated-measures analysis of variance or by Kruskal–Wallis analysis of variance as appropriate, complemented by a post-hoc test Categorical variables were compared with Fisher's exact test A P-value b0.05 was considered significant Correlations between two variables were performed by Pearson's chi-square test in case of a Gaussian distribution and with the Spearman correlation test otherwise All statistical analyses were performed using the program Graphpad Prism v 7.0 (Graphpad Software, La Jolla, CA, USA) The general features of the 29 patients divided into two groups are listed in Table The renal function and the 24-hour ABPM did not change in both groups (Table 2) However, the left ventricular mass/indexed by the body surface area (LV mass/BSA, g/m2) reduced 10.9 g/m2 in subjects underwent standard therapy + RSD at the 3rd month in comparison to baseline (P = 0.0011), and −7.7 g/m2 at the 3rd month in comparison http://dx.doi.org/10.1016/j.ijcme.2017.01.006 2214-7624/© 2017 The Authors Published by Elsevier Ireland Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) 82 Letter to the Editor Table General features of patients at baseline N Age, years Body mass index, kg/m2 Male gender (%) White ethnicity (%) Type diabetes mellitus (%) Controlled hypertension Creatinine, mg/dL eGFR, mL/min/1.73 m2 (CKD-EPI) ACR, mg/g Mean 24-hour ABPM, mm Hg Std Tx Std Tx + RSD P value 16 58.2 ± 5.9 28.5 ± 5.0 12 (75%) 11 (69%) 10 (63%) 16 (100%) 1.00 ± 0.40 91.0 ± 8.6 19.5 ± 4.0 120.1 ± 5.5/ 75.0 ± 2.4 13 55.0 ± 7.5 30.0 ± 3.3 (62%) 12 (92%) 10 (77%) 13 (100%) 1.08 ± 0.24 82.9 ± 7.0 14.4 ± 7.7 122.0 ± 6.0/ 77.2 ± 2.3 – 0.2090 0.3615 0.6882 0.1834 0.4543 1.0000 N0.9999 0.9786 N0.9999 0.8246/ 0.9080 36.0 ± 6.7 17.8 ± 5.0 33.2 ± 12.4 0.2001 0.2151 0.2038 105.0 ± 8.8 58.5 ± 4.1 85.6 ± 9.0 34.0 ± 6.1 9.0 ± 1.5 13 (100%) 0.9803 0.8299 N0.9999 0.9768 1.0000 0.2104 1.0000 13 (100%) 13 (100%) 13 (100%) 1.0000 1.0000 1.0000 Computed tomography coronary obstruction Anterior descending artery, % 33.1 ± 5.2 Circumflex artery, % 14.5 ± 8.2 Right coronary artery, % 28.0 ± 9.1 Cardiac MRI parameters 104.0 ± 5.5 LV mass/BSA, g/m LVEF, % (Simpson) 60.2 ± 5.0 LVEDVI, mL/m2 83.5 ± 8.8 33.2 ± 5.0 LVESVI, mL/m2 Myocardial scar score, % Ischemic segments, % 7.8 ± 2.2 Long-acting nitrates 16 (100%) Antihypertensive Agents ACE inhibitors/ARB 16 (100%) 16 (100%) Ca++ channel blockers Diuretics 16 (100%) Values are presented as Mean ± SD or %; ABPM, ambulatory blood pressure measurements; ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ARB, angiotensin receptor blocker; BSA, body surface area; EF, ejection fraction; eGFR, estimated glomerular filtration rate; LV, left ventricular; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; MRI, magnetic resonance image; N, number of patients; RSD, renal sympathetic denervation; Std Tx, standard treatment to the group submitted only to standard treatment (P = 0.0225), as weel as, the left ventricular ejection fraction (LVEF, %) measured by Simpson's methodology, that increase 8.0% in subjects underwent standard therapy + RSD at the 3rd month in comparison to baseline (P = 0.0020), and 5.5% at the 3rd month in comparison to the other group Table Changes in variables of patients at 3rd month of follow-up N Creatinine, mg/dL eGFR, mL/min/1.73 m2 (CKD-EPI) ACR, mg/g Mean 24-hour ABPM, mm Hg Cardiac MRI parameters LV mass/BSA, g/m2 LVEF, % (Simpson) LVEDVI, mL/m2 LVESVI, mL/m2 Myocardial scar score, % Ischemic segments, % Long-acting nitrates Antihypertensive Agents ACE inhibitors/ARB Ca++ channel blockers Diuretics Std Tx Std Tx + RSD P value at 3rd month 16 1.05 ± 0.50 82.0 ± 10.5 21.2 ± 5.3 118.5 ± 6.3/ 73.4 ± 3.7 13 1.00 ± 0.30 84.7 ± 8.8 17.0 ± 6.3 118.9 ± 5.8/ 74.0 ± 3.2 – N0.9999 0.9960 N0.9999 0.9979/0.9996 101.8 ± 4.1 61.0 ± 7.0 84.1 ± 10.3 32.7 ± 5.5 3.2 ± 1.5⁎⁎ 94.1 ± 9.0⁎ 66.5 ± 4.0⁎ 79.1 ± 6.8 29.5 ± 4.2 1.1 ± 0.9⁎⁎ 16 (100%) 13 (100%) 0.0225 0.0390 0.9952 0.3690 1.0000 0.0058 1.0000 16 (100%) 16 (100%) 16 (100%) 13 (100%) 13 (100%) 13 (100%) 1.0000 1.0000 1.0000 Fig Patients with episodes of variant angina (%) before the onset of standard treatment or standard treatment + renal sympathetic denervation (baseline) and after the 3rd month of follow-up RSD, renal sympathetic denervation; Std Tx, standard treatment Values are presented as mean ± SD; Std Tx, n = 16; and Stx + RSD, n = 13 (P = 0.0390), as displayed in Table Furthermore, the amount of ischemic segments (%) reduced significantly in subjects underwent only standard treatment and in the individuals submitted to standard treatment + RSD comparing the 3rd month of follow-up vs baseline, −4.6% and − 7.9%, respectively (P b 0.0001 for both comparisons), and the comparison between groups at the 3rd month showed a most significant reduction of −2.1% in the group in which RSD was added (P = 0.0058), as shown in Table The % of patients with variant angina reduced in both groups after the onset of the different treatments, being more pronounced in the group in which RSD was added, at the 3rd month of follow-up (Fig 1) We know that variant angina may be associated with significant morbidity and mortality with infarct-free survival being 60–95% at years Independent elements of infarct-free survival embrace the use of Ca++ channel blockers, extent and severity of coronary artery disease, and multi-vessel spasm [9] Our data show that patients underwent standard treatment + RSD had a reduction in LV mass/BSA, an increase in the LVEF, beyond a most prominent decrease in a number of ischemic segments and in the % of patients with variant angina, in comparison with those that was submitted only to standard treatment Conflict of interest None declared Funding Values are presented as Mean ± SD or %; ABPM, ambulatory blood pressure measurements; ACE, angiotensin-converting enzyme; ACR, albumin:creatinine ratio; ARB, angiotensin receptor blocker; BSA, body surface area; EF, ejection fraction; eGFR, estimated glomerular filtration rate; LV, left ventricular; LVEDVI, left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; MRI, magnetic resonance image; N, number of patients; RSD, renal sympathetic denervation; Std Tx, standard treatment *P b 0.05, and **P b 0.0001 for the same parameter at the 3rd month of follow-up vs respective baseline values This study was funded by Pacemed (US $300,000), Rio de Janeiro, Brazil Acknowledgements The authors are grateful to all participants included in this study The authors also thank Pacemed for stimulating the development of this study and for providing technical support References [1] JCS Joint Working Group, Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary spastic angina) (JCS 2013), Circ J 78 (2014) 2779–2801 [2] M Bory, F Pierron, D Panagides, et al., Coronary artery spasm in patients with normal or near normal coronary arteries Long-term follow-up of 277 patients, Eur Heart J 17 (1996) 1015–1021 Letter to the Editor [3] M Nakamura, A Takeshita, Y Nose, Clinical characteristics associated with myocardial infarction, arrhythmias, and sudden death in patients with vasospastic angina, Circulation 75 (1987) 1110–1116 [4] R.J Myerburg, K.M Kessler, S.M Mallon, et al., Life-threatening ventricular arrhythmias in patients with silent myocardial ischemia due to coronary-artery spasm, N Engl J Med 326 (1992) 1451–1455 [5] P Ong, A Athanasiadis, H Mahrholdt, B.N Shah, U Sechtem, R Senior, Transient myocardial ischemia during acetylcholine-induced coronary microvascular dysfunction documented by myocardial contrast echocardiography, Circ Cardiovasc Imaging (2013) 153–155 [6] F Infusino, G.A Lanza, A Sestito, G.A Sgueglia, F Crea, A Maseri, Combination of variant and microvascular angina, Clin Cardiol 32 (2009) E40–E45 [7] W.G Austen, J.E Edwards, R.L Frye, G.G Gensini, V.L Gott, L.S Griffith, et al., A reporting system on patients evaluated for coronary artery disease: report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association, Circulation 51 (1975) 5–40 (Suppl) [8] M.E Bertrand, J.M LaBlanche, P.Y Tilmant, F.A Thieuleux, M.R Delforge, A.G Carre, et al., Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography, Circulation 65 (1982) 1299–1306 [9] H Yasue, S Omote, A Takizawa, M Nagao, K Miwa, S Tanaka, Circadian variation of exercise capacity in patients with Prinzmetal's variant angina: role of exerciseinduced coronary arterial spasm, Circulation 59 (1979) 938–948 [10] Y Igarashi, M Yamazoe, K Suzuki, Y Tamura, T Matsubara, Y Tanabe, et al., Possible role of coronary artery spasm in unexplained syncope, Am J Cardiol 65 (1990) 713–717 [11] A.S Levey, L.A Stevens, C.H Schmid, Y.L Zhang, A.F Castro 3rd, H.I Feldman, et al., A new equation to estimate glomerular filtration rate, Ann Intern Med 150 (2009) 604–612 83 [12] M.G Kiuchi, E Silva GR, L.M Paz, S Chen, G.L Souto, Proof of concept study: renal sympathetic denervation for treatment of polymorphic premature ventricular complexes, J Interv Card Electrophysiol 47 (2016) 221–229 Márcio Galindo Kiuchi Division of Cardiac Surgery and Artificial Cardiac Stimulation, Department of Medicine, Hospital e Clớnica Sóo Gonỗalo, Sóo Gonỗalo, RJ, Brazil Electrophysiology Division, Department of Cardiology, Hospital e Clínica Sóo Gonỗalo, Sóo Gonỗalo, RJ, Brazil Corresponding author at: Division of Cardiac Surgery and Artificial Cardiac Stimulation, Department of Medicine, Hospital e Clớnica Sóo Gonỗalo, Rua Cel Moreira Cộsar, 138 - Centro, Sóo Gonỗalo, Rio de Janeiro 24440-400, Brazil E-mail address: marciokiuchi@gmail.com Shaojie Chen Department of Cardiology, Shanghai First People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China E-mail address: excellentchenshaojie@126.com 20 December 2016 Available online xxxx ... 1.0000 Fig Patients with episodes of variant angina (%) before the onset of standard treatment or standard treatment + renal sympathetic denervation (baseline) and after the 3rd month of follow-up... an increase in the LVEF, beyond a most prominent decrease in a number of ischemic segments and in the % of patients with variant angina, in comparison with those that was submitted only to standard. .. stimulating the development of this study and for providing technical support References [1] JCS Joint Working Group, Guidelines for diagnosis and treatment of patients with vasospastic angina (coronary