ORIGINAL ARTICLE Cardiocirculatory manifestations in Parkinson's disease patients without orthostatic hypotension T Pérez 1 , B Tijero 1,2 , I Gabilondo 2 , A Luna 1 , V Llorens 2,3 , K Berganzo 1,2 , M Acera 1 , A Gonzalez 1 , A Sanchez-Ferro 4 , E Lezcano 1,2 , JJ Zarranz 1,2 and JC Gómez-Esteban 1,2 The objective of this study was to characterize cardiac sympathetic denervation in Parkinson's disease (PD) patients without neurogenic orthostatic hypotension (NOH), both in terms of hemodynamics and in its relation with vascular denervation. We studied 20 PD patients without NOH. We analyzed the heart rate and blood pressure variability during various physical maneuvers. The following parameters were calculated: expiratory-inspiratory ratio, stroke volume, cardiac output, cardiac index, left ventricular ejection time, left ventricular work index, thoracic fluid content, total peripheral resistance and baroreflex sensitivity (BRS). We also measured direct and spectral derivatives of cardiac (cardiovagal) parasympathetic function. Myocardial I-123 metaiodobenzylguanidine (MIBG) scintigraphy was performed and early and late heart/mediastinum uptake ratios were analyzed. We observed that the late heart/mediastinum uptake ratio was 1.33 ± 0.21. This parameter was correlated with years since diagnosis (correlation coefficient: - 0.485; P = 0.05), Unified Parkinson’s Disease Rating Scale (UPDRS) III score (cc: - 0.564; P = 0.02) and pressure recovery time in the Valsalva maneuver (cc: 0.61; P o0.001). At rest, it was correlated with BRS (cc:0.75; P = 0.003) and low- frequency diastolic blood pressure (LF DBP ; cc: 0.58;P = 0.017). We found no correlations with any of the cardiography impedance variables. In linear regression models, the variable that best correlated with MIBG results was LF DBP . Our results support that in absence of NOH the degree of denervation of the heart does not produce any effect on its inotropic function. Moreover, BRS and LF DBP can be used as an indirect measure of cardiac sympathetic denervation at rest. Journal of Human Hypertension advance online publication, 29 January 2015; doi:10.1038/jhh.2014.131 INTRODUCTION Neurogenic orthostatic hypotension (NOH) is a common finding in Parkinson's disease (PD) affecting 30–40% of patients. 1,2 It results from the postganglionic sympathetic denervation that affects the heart and blood vessels 3–6 in PD. Interestingly, functional studies using I-123 metaiodobenzylguanidine (MIBG) myocardial scinti- graphy reveal that this denervation is present in up to 80% of PD patients, 7,8 implying that many PD patients with these findings do not have NOH. 8,9 Indeed, cardiac sympathetic involvement seems to occur in the early stages of PD, 10 possibly before the onset of motor clinical symptoms, as described in patients carrying high-penetrance genetic mutations of PD. 11,12 By contrast, NOH is frequently detected later during advanced stages of PD. Furthermore, in early stages of the disease there is no correlation between the symptoms of orthostatic intolerance and myocardial MIBG scintigraphy measures in PD. All these findings rise two main hypotheses regarding the pathophysiology of cardiocirculatory involvement in PD: (1) there is a staged damage and the sympathetic denervation starts in the heart and then spreads to the rest of the vascular system; 8,12,13 (2) there is a simultaneous damage of the innervation for the heart and peripheral vasculature, which is functionally compensated in the initial phases of PD by hemodynamic mechanism counter- acting the vascular denervation. 14 To date, only few studies have analyzed specifically the hemodynamic manifestations of cardiac postganglionic sympathetic denervation in PD patients and its relation with the staging of cardiocirculatory involvement. 15 In this study, we have assessed the hemodynamic behavior of a series of PD patients without NOH using cardiac MIBG scintigraphy and non-invasive autonomic tests. Our objective was twofold: to define the hemodynamic profile of PD patients with cardiac sympathetic denervation, and to assess whether cardiac and vascular sympathetic denervation occurred simultaneously or in an organ-specific manner, with an initial selective affectation of the heart spreading to the rest of the vascular system. MATERIALS AND METHODS We performed a cross-sectional evaluation of 20 patients fulfilling Parkinson’s UK Brain Bank criteria for the diagnosis of PD 16 (mean age 62.9 ± 13.0 years and 7.7 ± 5.9 years since diagnosis; eight women; Table 1). We prospectively selected consecutive eligible patients from the Move- ment Disorders and Autonomic Unit of University Hospital of Cruces who had been evaluated by cardiac MIBG scintigraphy and technetium (99mTc) 6-methoxy isobutyl isonitrile (99mTc-MIBI) single photon emission computed tomography (SPECT) in the last 6 months prior to study inclusion. We excluded patients with diabetes or with myocardial perfusion defects in the 99mTC-MIBI SPECT, and those patients who were not able to complete the test properly due to physical or cognitive disability. In order to discern more clearly the specific hemodynamic effects of cardiac sympathetic denervation, we also excluded subjects who presented NOH 17 in our evaluation, either after 3 min of active standing or in tilt-table test (TTT). Although the primary aim of this study was to analyze the function 1 Unidad de Disautonomía y Trastornos del Movimiento, Servicio de Neurología, Hospital Universitario de Cruces, Departamento de Neurociencias, Universidad del País Vasco, Bilbao, Spain; 2 Grupo de Enfermedades Neurodegenerativas, Biocruces Health Research Institute, Bilbao, Spain; 3 Servicio de Medicina Nuclear, Hospital Universitario de Cruces, Bilbao, Spain and 4 Research Fellow at the Madrid-Madrid-MIT M+Vision Consortium, Massachusetts Institute of Technology, Cambridge, Massachusetts. Correspondence: Dr JC Gómez-Esteban, Unidad de Trastornos del Sistema Nervioso Vegetativo, Servicio de Neurología, Hospital de Cruces, Baracaldo, CP 48903, Spain E-mail: juancarlos.gomezesteban@osakidetza.net Received 30 July 2014; revised 28 November 2014; accepted 5 December 2014 Journal of Human Hypertension (2015), 1 – 6 © 2015 Macmillan Publishers Limited All rights reserved 0950-9240/15 www.nature.com/jhh