Original Article
Relationship between right ventricular remodeling and heart rate variability in arterial hypertension Marijana Tadic a,c, Cesare Cuspidi b, Biljana Pencic a, Ljilja Jozika a, and Vera Celic a,c
Objective: We aimed at evaluating right ventricular remodeling (structure, function, and mechanics) and heart rate variability (HRV), as well as their interaction, in untreated hypertensive patients. Method: This cross-sectional study involved 55 untreated hypertensive patients and 40 patients with no risk factors, similar by sex and age. All the patients underwent a 24-h Holter monitoring and comprehensive two-dimensional and three-dimensional echocardiography assessment (2DE and 3DE). Results: All time and frequency domain HRV variables were reduced in the hypertensive patients. Right ventricular systolic and diastolic function, as well as right ventricular longitudinal strain, was significantly impaired in the hypertensive patients. Parameters that indicate comprehensive right ventricular remodeling (right ventricular wall thickness, tricuspid E/e’ ratio, 2DE right ventricular longitudinal strain, and 3D right ventricular ejection fraction) correlated with the parameters of cardiac sympathovagal balance (SD of all normal RR intervals, root mean square of the difference between the coupling intervals of adjacent RR intervals, 24-h low-frequency domain, 24-h high-frequency domain, and 24-h total power). Of note, right ventricular diastolic function, right ventricular longitudinal function, and 3DE right ventricular ejection fraction were associated with cardiac autonomic nervous function, independently of age, BMI, blood pressure, and left ventricular hypertrophy. Conclusions: Right ventricular structure, systolic and diastolic function, as well as right ventricular longitudinal deformation, are significantly impaired in untreated hypertensive patients. HRV variables are also decreased in hypertensive population. 2DE and 3DE parameters resembling right ventricular remodeling are independently associated with cardiac autonomic nervous system markers in the whole study population. Keywords: arterial hypertension, heart rate variability, right ventricle, speckle tracking, three-dimensional echocardiography Abbreviations: 2DE, two-dimensional echocardiography; 3DE, three-dimensional echocardiography; HF, highfrequency domain (0.15–0.40 Hz); HRV, heart rate variability; LF, low-frequency domain (0.04–0.15 Hz); LV, left ventricle; p50NN, percentage of adjacent RR intervals that varied by more than 50 ms; RA, right atrium; rMSSD, root mean square of the difference between the coupling
intervals of adjacent RR intervals; RV, right ventricle; SDANN, SD of the averaged normal RR intervals for all 5-min segments; SDNN, SD of all normal RR intervals; TP, total power (0.01–0.40 Hz)
INTRODUCTION
T
he spectral analysis of heart rate variability (HRV) represents a useful noninvasive tool for assessment of cardiac autonomic control. Studies have shown that HRV has been impaired in hypertensive patients [1,2]. The association between left ventricular hypertrophy and HRV in hypertensive patients was shown more than two decades ago [3–5]. However, there are still many questions about the relation among cardiac structure, and function and HRV. Investigations have revealed that right ventricular structure and function are important predictors of heart failure development and cardiovascular mortality in the general population [6], and significant determinants of survival in different pathological conditions [7–9]. We have previously shown that right ventricular structure, function, and mechanics are significantly impaired in the hypertensive patients compared with the normotensive controls [10]. However, the mechanisms of this relationship between arterial hypertension and right ventricular remodeling are still unclear. In the past few decades, investigations showed that sympathetic activation could significantly contribute to the development and progression of hypertension and its complications [11]. Additionally, studies had revealed the association between increased circulating levels of catecholamines and increased pulmonary resistance that could cause right ventricular structural and functional changes [12].
Journal of Hypertension 2015, 33:1090–1097 a University Clinical Hospital Center ‘Dr Dragisa Misovic – Dedinje’, Department of Cardiology, Heroja Milana Tepica, Belgrade, Serbia, bUniversity of Milan-Bicocca and Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza, Meda, Italy and cFaculty of Medicine, Doktora Subotica, Belgrade, Serbia
Correspondence to Marijana Tadic, MD, PhD, University Clinical Hospital Center ‘Dr Dragisa Misovic – Dedinje’, Cardiology Department, Heroja Milana Tepica 1, 11000 Belgrade, Serbia. Tel: +381 658107085; fax: +381 112411464; e-mail: marijana_ [email protected] Received 15 September 2014 Revised 4 December 2014 Accepted 4 December 2014 J Hypertens 33:1090–1097 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000511
1090
www.jhypertension.com
Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Right ventricular deformation and heart rate variability
Considering the previous findings which demonstrated the predictive value of HRV parameters on cardiovascular morbidity [13], and the great importance of right ventricular structure and function, it would be important to determine their mutual association because it might provide completely new and valuable information about target organ damage in arterial hypertension. To our knowledge, the relation between right ventricular structure, function, and deformation and HRV in hypertensive population has not been studied so far. We sought to investigate the association between right ventricular structure, function, and mechanics using comprehensive two-dimensional and three-dimensional echocardiography (2DE and 3DE) evaluation and HRV in the untreated hypertensive patients.
METHODOLOGY In the present study, we enrolled 55 untreated hypertensive patients and 40 normotensive individuals without cardiovascular risk factors. The control group involved individuals with normal BP values measured on at least two occasions: during examination and before echocardiographic examination. We did not include individuals with family history of cardiovascular events before 55 years for men or 65 years for women (myocardial infarction or stroke). Additionally, in the control group, we also recruited patients who came on echocardiographic examination due to an innocent murmur or a regular check-up. Exclusion criteria were age above 60 years, antihypertensive treatment, white-coat hypertension, sleep apnea syndrome, heart failure, coronary artery disease, previous cerebrovascular events, atrial fibrillation, pace-maker, congenital heart disease, valve heart disease, obesity (BMI 30 kg/m2), neoplastic disease, cirrhosis of the liver, kidney failure, or endocrine diseases including type 2 diabetes mellitus. Clinic BP values were obtained in two separate visits 3 weeks apart. BP was measured by conventional sphygmomanometer in the morning hours by taking the average value of three consecutive measurements in the sitting position 10 min apart. BP was calculated as average values between all the measurements. Arterial hypertension was diagnosed according to the current guidelines [14]. Anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, blood creatinine and urea, total cholesterol, and triglycerides) were obtained from all the patients included in the study. All biochemical analyses were assessed in the serum. BMI and body surface area (BSA) were calculated for each patient. The study was approved by the local Ethics Committee, and informed consent was obtained from all the participants.
Twenty-four-hour Holter monitoring Twenty-four-hour Holter monitoring was performed with a three-channel digital Schiller Microvit MT-101 system (Schiller AG, Baar, Switzerland) and analyzed by a Schiller software (Schiller AG). The minimum duration of recording was 18 h (after exclusion of nonsinusal cardiac cycles). Time–domain HRV parameters were calculated for 24-h, daytime, and night-time recordings after excluding nonsinusal cardiac cycles, according to the guidelines [13]. Journal of Hypertension
SDNN was defined as the SD of all normal RR intervals. SDANN, which reflects long-term HRV and therefore mainly sympathetic activity or sympathovagal balance, was defined as the SD of the averaged normal RR intervals for all 5-min segments. rMSSD was calculated as the root mean square of the difference between the coupling intervals of adjacent RR intervals. p50NN, which reflects shortterm beat-to-beat HRV and consequently primarily vagal activity, was calculated as the proportion of adjacent RR intervals that varied by more than 50 ms. After power spectral density estimation, four standard frequency– domain HRV measures were calculated for 24-h, daytime, and night-time recordings [15]. Low-frequency domain was defined between 0.04 and 0.15 Hz; high-frequency domain was defined between 0.15 and 0.4 Hz; total spectral power for all intervals were up to 0.4 Hz; and the ratio of low-tohigh-frequency power (LF/HF), was determined.
Echocardiography Echocardiographic examinations were performed by using Vivid 7 (GE Vingmed, Horten, Norway) ultrasound machine equipped with both a 2.5-MHz transducer and a 3-V matrix probe for 3DE data set acquisitions. The reported values of all 2DE parameters were obtained as the average value of three consecutive cardiac cycles. Left ventricular diameters and septum thickness were measured according to the current recommendations [16]. Relative wall thickness (RWT) was calculated according to the formula: RWT ¼ (2 posterior wall thickness)/ left ventricular end-diastolic diameter [16]. Left ventricular ejection fraction (LVEF) was calculated by using the biplane method. Left ventricular mass was calculated by using the Devereux formula [17], and indexed for the height powered to 2.7. Pulsed-wave Doppler assessment of transmitral left ventricle (LV) was obtained in the apical four-chamber view according to the guidelines [18]. Tissue Doppler imaging was used to obtain left ventricular myocardial velocities in the apical four-chamber view, with a sample volume placed at the septal and lateral segments of the mitral annulus. The average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus was calculated, and the mitral E/e´ ratio was computed.
Right ventricle and atrium The right ventricular internal diameter was measured in the parasternal long-axis view [19]. Right ventricular thickness was measured in the subcostal view [19]. Right ventricular volume was obtained in the four-chamber view during ventricular end systole [19]. Tricuspid flow velocities were assessed by pulsed wave Doppler in the apical four-chamber view according to the guidelines. Tissue Doppler imaging was used to obtain the right ventricular myocardial velocities in the apical fourchamber view with a sample volume placed at the lateral segment of the tricuspid annulus during early diastole (e´t) and systole (st) [19]. Tricuspid (E/e´)t ratio was determined by using previously estimated Doppler values. Right ventricular global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE) [19]. Right ventricular SBP [systolic pressure in pulmonary artery www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1091
Tadic et al.
(SPAP)] was assessed in patients with minimal/mild tricuspid regurgitation.
TABLE 1. Demographic characteristics and clinical parameters of study population
Two-dimensional strain and strain rate Two-dimensional echocardiography strain imaging was performed by using three consecutive cardiac cycles of 2DE images in the apical four-chamber view [19]. EchoPAC 112 (GE-Healthcare, Horten, Norway), as a commercially available software, was used for the 2DE strain analysis. The variables that were used for the evaluation of right ventricular systolic function and contractility were the longitudinal peak and systolic strain rate, respectively. The parameters of right ventricular early myocardial relaxation and late ventricular filling were estimated by early and late diastolic strain rate.
Three-dimensional echocardiographic acquisition
Age (years) Women (%) BMI (kg/m2) BSA (m2) Clinic heart rate (beat/min) Clinic SBP (mmHg) Clinic DBP (mmHg) Plasma glucose (mmol/l) Creatinine (mmol/l) Urea (mmol/l) Triglycerides (mmol/l) Total cholesterol (mmol/l)
Controls (n ¼ 40)
Hypertension (n ¼ 55)
P
45 7 19 (48) 23.5 2.3 1.89 0.21 74 6 127 9 77 6 5.1 0.5 67 7 5.3 1.1 1.4 0.3 4.9 0.6
46 7 23 (42) 25.2 2.4 2 0.23 75 7 147 7 85 5 5.2 0.5 69 7 5.8 1.3 1.7 0.4 5.3 0.8
NS NS
Relationship between right ventricular remodeling and heart rate variability in arterial hypertension Marijana Tadic a,c, Cesare Cuspidi b, Biljana Pencic a, Ljilja Jozika a, and Vera Celic a,c
Objective: We aimed at evaluating right ventricular remodeling (structure, function, and mechanics) and heart rate variability (HRV), as well as their interaction, in untreated hypertensive patients. Method: This cross-sectional study involved 55 untreated hypertensive patients and 40 patients with no risk factors, similar by sex and age. All the patients underwent a 24-h Holter monitoring and comprehensive two-dimensional and three-dimensional echocardiography assessment (2DE and 3DE). Results: All time and frequency domain HRV variables were reduced in the hypertensive patients. Right ventricular systolic and diastolic function, as well as right ventricular longitudinal strain, was significantly impaired in the hypertensive patients. Parameters that indicate comprehensive right ventricular remodeling (right ventricular wall thickness, tricuspid E/e’ ratio, 2DE right ventricular longitudinal strain, and 3D right ventricular ejection fraction) correlated with the parameters of cardiac sympathovagal balance (SD of all normal RR intervals, root mean square of the difference between the coupling intervals of adjacent RR intervals, 24-h low-frequency domain, 24-h high-frequency domain, and 24-h total power). Of note, right ventricular diastolic function, right ventricular longitudinal function, and 3DE right ventricular ejection fraction were associated with cardiac autonomic nervous function, independently of age, BMI, blood pressure, and left ventricular hypertrophy. Conclusions: Right ventricular structure, systolic and diastolic function, as well as right ventricular longitudinal deformation, are significantly impaired in untreated hypertensive patients. HRV variables are also decreased in hypertensive population. 2DE and 3DE parameters resembling right ventricular remodeling are independently associated with cardiac autonomic nervous system markers in the whole study population. Keywords: arterial hypertension, heart rate variability, right ventricle, speckle tracking, three-dimensional echocardiography Abbreviations: 2DE, two-dimensional echocardiography; 3DE, three-dimensional echocardiography; HF, highfrequency domain (0.15–0.40 Hz); HRV, heart rate variability; LF, low-frequency domain (0.04–0.15 Hz); LV, left ventricle; p50NN, percentage of adjacent RR intervals that varied by more than 50 ms; RA, right atrium; rMSSD, root mean square of the difference between the coupling
intervals of adjacent RR intervals; RV, right ventricle; SDANN, SD of the averaged normal RR intervals for all 5-min segments; SDNN, SD of all normal RR intervals; TP, total power (0.01–0.40 Hz)
INTRODUCTION
T
he spectral analysis of heart rate variability (HRV) represents a useful noninvasive tool for assessment of cardiac autonomic control. Studies have shown that HRV has been impaired in hypertensive patients [1,2]. The association between left ventricular hypertrophy and HRV in hypertensive patients was shown more than two decades ago [3–5]. However, there are still many questions about the relation among cardiac structure, and function and HRV. Investigations have revealed that right ventricular structure and function are important predictors of heart failure development and cardiovascular mortality in the general population [6], and significant determinants of survival in different pathological conditions [7–9]. We have previously shown that right ventricular structure, function, and mechanics are significantly impaired in the hypertensive patients compared with the normotensive controls [10]. However, the mechanisms of this relationship between arterial hypertension and right ventricular remodeling are still unclear. In the past few decades, investigations showed that sympathetic activation could significantly contribute to the development and progression of hypertension and its complications [11]. Additionally, studies had revealed the association between increased circulating levels of catecholamines and increased pulmonary resistance that could cause right ventricular structural and functional changes [12].
Journal of Hypertension 2015, 33:1090–1097 a University Clinical Hospital Center ‘Dr Dragisa Misovic – Dedinje’, Department of Cardiology, Heroja Milana Tepica, Belgrade, Serbia, bUniversity of Milan-Bicocca and Istituto Auxologico Italiano, Clinical Research Unit, Viale della Resistenza, Meda, Italy and cFaculty of Medicine, Doktora Subotica, Belgrade, Serbia
Correspondence to Marijana Tadic, MD, PhD, University Clinical Hospital Center ‘Dr Dragisa Misovic – Dedinje’, Cardiology Department, Heroja Milana Tepica 1, 11000 Belgrade, Serbia. Tel: +381 658107085; fax: +381 112411464; e-mail: marijana_ [email protected] Received 15 September 2014 Revised 4 December 2014 Accepted 4 December 2014 J Hypertens 33:1090–1097 Copyright ß 2015 Wolters Kluwer Health, Inc. All rights reserved. DOI:10.1097/HJH.0000000000000511
1090
www.jhypertension.com
Volume 33 Number 5 May 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Right ventricular deformation and heart rate variability
Considering the previous findings which demonstrated the predictive value of HRV parameters on cardiovascular morbidity [13], and the great importance of right ventricular structure and function, it would be important to determine their mutual association because it might provide completely new and valuable information about target organ damage in arterial hypertension. To our knowledge, the relation between right ventricular structure, function, and deformation and HRV in hypertensive population has not been studied so far. We sought to investigate the association between right ventricular structure, function, and mechanics using comprehensive two-dimensional and three-dimensional echocardiography (2DE and 3DE) evaluation and HRV in the untreated hypertensive patients.
METHODOLOGY In the present study, we enrolled 55 untreated hypertensive patients and 40 normotensive individuals without cardiovascular risk factors. The control group involved individuals with normal BP values measured on at least two occasions: during examination and before echocardiographic examination. We did not include individuals with family history of cardiovascular events before 55 years for men or 65 years for women (myocardial infarction or stroke). Additionally, in the control group, we also recruited patients who came on echocardiographic examination due to an innocent murmur or a regular check-up. Exclusion criteria were age above 60 years, antihypertensive treatment, white-coat hypertension, sleep apnea syndrome, heart failure, coronary artery disease, previous cerebrovascular events, atrial fibrillation, pace-maker, congenital heart disease, valve heart disease, obesity (BMI 30 kg/m2), neoplastic disease, cirrhosis of the liver, kidney failure, or endocrine diseases including type 2 diabetes mellitus. Clinic BP values were obtained in two separate visits 3 weeks apart. BP was measured by conventional sphygmomanometer in the morning hours by taking the average value of three consecutive measurements in the sitting position 10 min apart. BP was calculated as average values between all the measurements. Arterial hypertension was diagnosed according to the current guidelines [14]. Anthropometric measures (height, weight) and laboratory analyses (level of fasting glucose, blood creatinine and urea, total cholesterol, and triglycerides) were obtained from all the patients included in the study. All biochemical analyses were assessed in the serum. BMI and body surface area (BSA) were calculated for each patient. The study was approved by the local Ethics Committee, and informed consent was obtained from all the participants.
Twenty-four-hour Holter monitoring Twenty-four-hour Holter monitoring was performed with a three-channel digital Schiller Microvit MT-101 system (Schiller AG, Baar, Switzerland) and analyzed by a Schiller software (Schiller AG). The minimum duration of recording was 18 h (after exclusion of nonsinusal cardiac cycles). Time–domain HRV parameters were calculated for 24-h, daytime, and night-time recordings after excluding nonsinusal cardiac cycles, according to the guidelines [13]. Journal of Hypertension
SDNN was defined as the SD of all normal RR intervals. SDANN, which reflects long-term HRV and therefore mainly sympathetic activity or sympathovagal balance, was defined as the SD of the averaged normal RR intervals for all 5-min segments. rMSSD was calculated as the root mean square of the difference between the coupling intervals of adjacent RR intervals. p50NN, which reflects shortterm beat-to-beat HRV and consequently primarily vagal activity, was calculated as the proportion of adjacent RR intervals that varied by more than 50 ms. After power spectral density estimation, four standard frequency– domain HRV measures were calculated for 24-h, daytime, and night-time recordings [15]. Low-frequency domain was defined between 0.04 and 0.15 Hz; high-frequency domain was defined between 0.15 and 0.4 Hz; total spectral power for all intervals were up to 0.4 Hz; and the ratio of low-tohigh-frequency power (LF/HF), was determined.
Echocardiography Echocardiographic examinations were performed by using Vivid 7 (GE Vingmed, Horten, Norway) ultrasound machine equipped with both a 2.5-MHz transducer and a 3-V matrix probe for 3DE data set acquisitions. The reported values of all 2DE parameters were obtained as the average value of three consecutive cardiac cycles. Left ventricular diameters and septum thickness were measured according to the current recommendations [16]. Relative wall thickness (RWT) was calculated according to the formula: RWT ¼ (2 posterior wall thickness)/ left ventricular end-diastolic diameter [16]. Left ventricular ejection fraction (LVEF) was calculated by using the biplane method. Left ventricular mass was calculated by using the Devereux formula [17], and indexed for the height powered to 2.7. Pulsed-wave Doppler assessment of transmitral left ventricle (LV) was obtained in the apical four-chamber view according to the guidelines [18]. Tissue Doppler imaging was used to obtain left ventricular myocardial velocities in the apical four-chamber view, with a sample volume placed at the septal and lateral segments of the mitral annulus. The average of the peak early diastolic relaxation velocity (e´) of the septal and lateral mitral annulus was calculated, and the mitral E/e´ ratio was computed.
Right ventricle and atrium The right ventricular internal diameter was measured in the parasternal long-axis view [19]. Right ventricular thickness was measured in the subcostal view [19]. Right ventricular volume was obtained in the four-chamber view during ventricular end systole [19]. Tricuspid flow velocities were assessed by pulsed wave Doppler in the apical four-chamber view according to the guidelines. Tissue Doppler imaging was used to obtain the right ventricular myocardial velocities in the apical fourchamber view with a sample volume placed at the lateral segment of the tricuspid annulus during early diastole (e´t) and systole (st) [19]. Tricuspid (E/e´)t ratio was determined by using previously estimated Doppler values. Right ventricular global systolic function was assessed as the tricuspid annular plane systolic excursion (TAPSE) [19]. Right ventricular SBP [systolic pressure in pulmonary artery www.jhypertension.com
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
1091
Tadic et al.
(SPAP)] was assessed in patients with minimal/mild tricuspid regurgitation.
TABLE 1. Demographic characteristics and clinical parameters of study population
Two-dimensional strain and strain rate Two-dimensional echocardiography strain imaging was performed by using three consecutive cardiac cycles of 2DE images in the apical four-chamber view [19]. EchoPAC 112 (GE-Healthcare, Horten, Norway), as a commercially available software, was used for the 2DE strain analysis. The variables that were used for the evaluation of right ventricular systolic function and contractility were the longitudinal peak and systolic strain rate, respectively. The parameters of right ventricular early myocardial relaxation and late ventricular filling were estimated by early and late diastolic strain rate.
Three-dimensional echocardiographic acquisition
Age (years) Women (%) BMI (kg/m2) BSA (m2) Clinic heart rate (beat/min) Clinic SBP (mmHg) Clinic DBP (mmHg) Plasma glucose (mmol/l) Creatinine (mmol/l) Urea (mmol/l) Triglycerides (mmol/l) Total cholesterol (mmol/l)
Controls (n ¼ 40)
Hypertension (n ¼ 55)
P
45 7 19 (48) 23.5 2.3 1.89 0.21 74 6 127 9 77 6 5.1 0.5 67 7 5.3 1.1 1.4 0.3 4.9 0.6
46 7 23 (42) 25.2 2.4 2 0.23 75 7 147 7 85 5 5.2 0.5 69 7 5.8 1.3 1.7 0.4 5.3 0.8
NS NS
