Canadian Journal of Cardiology 30 (2014) 188e194
Clinical Research
Abnormal Regulation of Renin Angiotensin Aldosterone System Is Associated With Right Ventricular Dysfunction in Hypertension Mario Gregori, MD,a Giuliano Tocci, MD, PhD,a,b Benedetta Giammarioli, MD,a Alberto Befani, MD,a Giuseppino Massimo Ciavarella, MD,a Andrea Ferrucci, MD,a and Francesco Paneni, MDa,b a
Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Rome, Italy b
Istituto di Ricerca a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy
See editorial by Harrison et al., pages 155-158 of this issue. ABSTRACT
RESUM E
Background: Right ventricular dysfunction (RVD) is a major predictor of cardiovascular mortality. Inadequate suppression of the reninangiotensin-aldosterone system (RAAS) after postural manoeuvres favours alterations of left ventricular (LV) function. The effects of RAAS dysregulation on RV performance remain elusive. The present study investigated RV function in hypertensive patients with or without altered RAAS activation. Methods: Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 104 newly diagnosed hypertensive patients after both supine and upright positioning to assess dynamic changes of RAAS induced by antigravitational stress. Twenty-fourehour ambulatory blood pressure monitoring and echocardiographic evaluation of the right ventricle including tissue Doppler imaging (TDI) were performed. Patients were divided as follows: (1) normal PRA and PAC (N group [n ¼ 58]), (2) suppressible RAAS after supine positioning (SR group [n ¼ 24]), and (3), nonsuppressible RAAS (NSR group [n ¼ 22]). RVD was identified by the TDI-derived myocardial performance index (MPI) calculated with a multisegmental approach. Results: Patients in the NSR group had reduced indices of RV function
Introduction : La dysfonction ventriculaire droite (DVD) est un dicteur important de la mortalite cardiovasculaire. La suppression pre quate du système re nine-angiotensine-aldoste rone (SRAA) après inade rations de la fonction venles manœuvres posturales favorise les alte gulation du SRAA sur la triculaire gauche (VG). Les effets de la dysre cis. La pre sente e tude a examine performance du VD demeurent impre la fonction VD chez les patients hypertendus ayant ou non une alte ration de l’activation du SRAA. thodes : L’activite re nine plasmatique (ARP) et la concentration Me rone (CPA) ont e te mesure es chez 104 patients plasmatique d’aldoste cemment un diagnostic d’hypertension après la mise en ayant reçu re cubitus dorsal et en position debout pour e valuer les place en de changements dynamiques du SRAA induits par l’effort antigravitationnel. rielle pendant 24 heures et La mesure ambulatoire de la pression arte valuation e chocardiographique du ventricule droit incluant l’imagerie l’e te re alise es. Les patients ont e te re partis Doppler tissulaire (IDT) ont e comme suit : 1) les ARP et CPA normales (groupe N [n ¼ 58]); 2) le après la mise en place en de cubitus dorsal (groupe RS SRAA supprime (groupe RNS [n ¼ 22]). Le DVD a e te [n ¼ 24]); 3) le SRAA non supprime
Left ventricular dysfunction (LVD) is a frequent clinical condition associated with increased cardiovascular morbidity and mortality.1 Among the complex pathophysiologic factors contributing to the development of LVD, the reninangiotensin-aldosterone system (RAAS) is considered a
major player.2 Notably, altered RAAS activation induces pathologic changes of cardiac structure and function, regardless of blood pressure values.3 Previous reports showed that a lack of RAAS suppression after postural manoeuvres is associated with increased left ventricular (LV) mass and impaired systolic properties.4 However, although the relationship between RAAS activity and LV function has been explored previously, the impact of RAAS dysregulation on the right ventricle remains to be elucidated. A growing body of evidence suggests that RV function is a key determinant of survival in different clinical conditions.5 Early detection of altered RV performance and function may help to prevent or delay heart failure and cardiovascular death.6
Received for publication August 25, 2013. Accepted November 4, 2013. Corresponding author: Dr Mario Gregori, Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome “Sapienza,” Sant’Andrea Hospital, Via di Grottarossa 1035-1039, Rome, Italy. Tel.: þ39-06-3377-5563; fax: þ39-06-3377-5061. E-mail: [email protected] See page 193 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.11.009
Gregori et al. RAAS Dysregulation and RVD
189
compared with patients in the N and SR groups. MPI of the right ventricle as well as prevalence of RVD were also significantly higher in the NSR group. Regression models showed that inadequate RAAS suppression was independently associated with RVD, regardless of blood pressure values and LV dysfunction (LVD). Conclusions: Patients without supine normalization of RAAS display a significant impairment of RV function. Our findings suggest that a dynamic RAAS evaluation may help to identify hypertensive patients at higher risk of RVD.
termine par l’indice de performance myocardique (IPM) à l’IDT de par une approche multisegmentaire. calcule sultats : Les patients du groupe RNS par rapport à ceux des Re groupes N et RS ont eu une diminution des indices de la fonction VD. valence de DVD ont aussi e te L’IPM du ventricule droit ainsi que la pre leve s dans le groupe RNS. Les modèles de significativement plus e gression ont montre que la suppression inade quate du SRAA e tait re pendamment associe e au DVD quelles que soient les valeurs de la inde rielle et de la dysfonction ventriculaire gauche (DVG). pression arte cubitus dorsal ne s’est Conclusions : Les patients dont le SRAA en de montrent une de te rioration significative de la fonction pas normalise sultats montrent qu’une e valuation dynamique du SRAA VD. Nos re terminer les patients hypertendus expose s à un risque peut aider à de leve de DVD. plus e
We and others have recently demonstrated that tissue Doppler imaging (TDI) of the right ventricle is a reliable tool for a preclinical evaluation of chamber dysfunction.7-10 Notably, the TDI-derived myocardial performance index (MPI) provides a reliable estimate of systodiastolic function and correlates with magnetic resonance measurements.7 The present study was designed to investigate the impact of inadequate RAAS suppression on RV function, as assessed by TDI.
interstitial pneumopathy, connective tissue disorders, chronic thromboembolic disease, congenital left-to-right shunts, or primary pulmonary hypertensiondwere also ruled out. Patients with primary aldosteronism (aldosterone-to-renin ratio > 20 ng/dL per ng/[ml/h] or suspicious adrenal masses [or both] on standard and Doppler ultrasonography of the kidneys) were excluded. All patients signed an informed consent form before entering the study. PRA and aldosterone levels
Methods A detailed description of the methods used in this study is provided in the Supplemental Methods section. Study population A total of 104 hypertensive patients (of 270 ambulatory patients) were recruited consecutively at the Hypertension Unit of Sant’Andrea Hospital. According to PRA and PAC, hypertensive patients were stratified as follows: (1) normal PRA and PAC (N group [n ¼ 58], (2) suppressible RAAS after supine positioning (SR group [n ¼ 24], or (3) nonsuppressible RAAS (NSR group [n ¼ 22]). Study patients were newly diagnosed with hypertension and were referred to our hypertension unit; they underwent a full screening for causes of secondary hypertension because of a highly suspicious clinical history or physical examination, or both.11 All patients with a history of previous cardiovascular disease were excluded. Hence, PRA and PAC were assessed in patients who had never been treated with RAAS blockers or other antihypertensive drugs. To avoid an uncontrollable influence of different levels of daily salt intake, patients enrolled in the study had been advised to ingest a fixed sodium diet (8 g per day) for the 7 days preceding the hormonal assessment. All patients were screened for secondary hypertension because of young age, family history of kidney disease, variable blood pressure values, electrolyte abnormalities, and the presence of signs or symptoms such as sweating, headache, anxiety, palpitations, weakness, abdominal murmurs, muscle tremors, or a combination of these factors.11 Family dyslipidemia, dysthyroidism, liver disease, renal failure, malignancies, peripheral artery disease, myocardial infarction or stroke (or both), arrhythmias, valvular disease, and heart failure (ejection fraction [EF] < 55%) were exclusion criteria. Indeed, clinical conditions that might predispose to pulmonary hypertensiondsuch as chronic obstructive pulmonary disease,
Plasma aldosterone and renin measurements were first assessed after overnight rest and after participants had been standing for at least 30 minutes. A second blood sample was collected after 2 hours of the patient lying in the supine position. Blood for PRA and PAC assessment was drawn from participants at midmorning between 8:30 and 10:30 AM to standardize the measurements for all patients and to avoid a possible bias related to circadian rhythm of hormone release. Elevated standing PAC (>300 pg/mL) and PRA (>5.7 ng/ mL/h) with complete normalization in the supine position (PAC < 160 pg/mL and PRA < 2.8 ng/mL/h) was defined as suppressible RAAS hyperactivation (SR group). By contrast, evidence of elevated PAC and PRA even after supine positioning was considered nonsuppressible RAAS hyperactivation (NSR group). Echocardiography All patients underwent transthoracic echocardiography, including conventional and TDI of both the left and right ventricles. Echocardiography was performed using an Acuson Sequoia C256 ultrasound system (Siemens Medical Solutions, Malvern, PA) equipped with phased-array electronic transducer with variable frequency from 2.5 to 4 MHz. All the examinations were supervised on-line by 2 expert ultrasonographers (GMC and GT), and measurements were taken using electronic proprietary markers. LV diameters, as well as septal and posterior wall thickness, were measured according to American Society of Echocardiography guidelines.12 Regional pulsed TDI data were obtained both from the septal and lateral mitral annuli in the apical 4-chamber view. The average regional MPI for the left ventricle was assessed (MPImitral þ MPIseptal)/2.4 LVD was identified by an average regional MPI value greater than the 75th percentile (TDI average MPI > 0.57).
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Canadian Journal of Cardiology Volume 30 2014
Table 1. Anthropometric, clinical, and biochemical characteristics of the study population*
Age (y) Sex (M/F) BMI (kg/m2) Office SBP (mm Hg) Office DBP (mm Hg) 24-h mean SBP (mm Hg) 24-h mean DBP (mm Hg) Daytime mean SBP (mm Hg) Daytime mean DBP (mm Hg) Nighttime mean SBP (mm Hg) Nighttime mean DBP (mm Hg) Nondipping pattern (%) Sokolow-Lion index Cornell index Creatinine (mg/dL) Sodium (mg/dL) Potassium (mg/dL) Urine sodium excretion (mEq/24h) Supine PRA (ng/mL/h) Standing PRA (ng/mL/h) Supine aldosterone (pg/mL) Standing aldosterone (pg/mL)
N n ¼ 58
SR n ¼ 24
NSR n ¼ 22
P value
43.8 9.8 32:26 25.4 4.4 140.6 18.1 89.5 11.2 135.1 4.6 84.3 3.3 139.8 4.1 86.9 3.6 119.1 10.8 73.5 10.1 16 (27.6) 30.2 2.9 16.4 7.5 0.89 0.21 140.1 1.6 4.1 0.38 176.6 13.5 1.49 0.7 3.1 1.7 93.5 40.3 176.6 56.1
42.1 8.1 14:10 25.1 3.1 144.9 11.1 91.9 6.5 139.2 3.5y 87.1 3.7y 143.3 5.2y 88.8 3.3 120.6 7.1 74.4 5.5 6 (25) 32.4 3.1y 17.6 4.3y 0.92 0.26 141.7 2.7y 3.7 0.21y 151.6 6.3y 1.49 0.5 6.6 0.7y 138.1 21.6y 457.8 143.2y
42.2 10.3 11 11 24.6 3.9 147.8 9.5 93.6 7.5 147.4 9.8z 89.5 3.6z 147.8 6.8z 93.1 6.5z 129.2 4.9z 80.3 3.9z 14 (63.6) z 36.4 3.1z 21.1 7.4z 0.84 0.25 142.1 2.8y 3.7 0.30y 130.5 8.3z 6.4 5.1z 10.6 5.8z 195.2 36.6z 464.7 123.8z
NS NS NS NS NS
Clinical Research
Abnormal Regulation of Renin Angiotensin Aldosterone System Is Associated With Right Ventricular Dysfunction in Hypertension Mario Gregori, MD,a Giuliano Tocci, MD, PhD,a,b Benedetta Giammarioli, MD,a Alberto Befani, MD,a Giuseppino Massimo Ciavarella, MD,a Andrea Ferrucci, MD,a and Francesco Paneni, MDa,b a
Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome “Sapienza”, Rome, Italy b
Istituto di Ricerca a Carattere Scientifico (IRCCS) Neuromed, Pozzilli, Italy
See editorial by Harrison et al., pages 155-158 of this issue. ABSTRACT
RESUM E
Background: Right ventricular dysfunction (RVD) is a major predictor of cardiovascular mortality. Inadequate suppression of the reninangiotensin-aldosterone system (RAAS) after postural manoeuvres favours alterations of left ventricular (LV) function. The effects of RAAS dysregulation on RV performance remain elusive. The present study investigated RV function in hypertensive patients with or without altered RAAS activation. Methods: Plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were measured in 104 newly diagnosed hypertensive patients after both supine and upright positioning to assess dynamic changes of RAAS induced by antigravitational stress. Twenty-fourehour ambulatory blood pressure monitoring and echocardiographic evaluation of the right ventricle including tissue Doppler imaging (TDI) were performed. Patients were divided as follows: (1) normal PRA and PAC (N group [n ¼ 58]), (2) suppressible RAAS after supine positioning (SR group [n ¼ 24]), and (3), nonsuppressible RAAS (NSR group [n ¼ 22]). RVD was identified by the TDI-derived myocardial performance index (MPI) calculated with a multisegmental approach. Results: Patients in the NSR group had reduced indices of RV function
Introduction : La dysfonction ventriculaire droite (DVD) est un dicteur important de la mortalite cardiovasculaire. La suppression pre quate du système re nine-angiotensine-aldoste rone (SRAA) après inade rations de la fonction venles manœuvres posturales favorise les alte gulation du SRAA sur la triculaire gauche (VG). Les effets de la dysre cis. La pre sente e tude a examine performance du VD demeurent impre la fonction VD chez les patients hypertendus ayant ou non une alte ration de l’activation du SRAA. thodes : L’activite re nine plasmatique (ARP) et la concentration Me rone (CPA) ont e te mesure es chez 104 patients plasmatique d’aldoste cemment un diagnostic d’hypertension après la mise en ayant reçu re cubitus dorsal et en position debout pour e valuer les place en de changements dynamiques du SRAA induits par l’effort antigravitationnel. rielle pendant 24 heures et La mesure ambulatoire de la pression arte valuation e chocardiographique du ventricule droit incluant l’imagerie l’e te re alise es. Les patients ont e te re partis Doppler tissulaire (IDT) ont e comme suit : 1) les ARP et CPA normales (groupe N [n ¼ 58]); 2) le après la mise en place en de cubitus dorsal (groupe RS SRAA supprime (groupe RNS [n ¼ 22]). Le DVD a e te [n ¼ 24]); 3) le SRAA non supprime
Left ventricular dysfunction (LVD) is a frequent clinical condition associated with increased cardiovascular morbidity and mortality.1 Among the complex pathophysiologic factors contributing to the development of LVD, the reninangiotensin-aldosterone system (RAAS) is considered a
major player.2 Notably, altered RAAS activation induces pathologic changes of cardiac structure and function, regardless of blood pressure values.3 Previous reports showed that a lack of RAAS suppression after postural manoeuvres is associated with increased left ventricular (LV) mass and impaired systolic properties.4 However, although the relationship between RAAS activity and LV function has been explored previously, the impact of RAAS dysregulation on the right ventricle remains to be elucidated. A growing body of evidence suggests that RV function is a key determinant of survival in different clinical conditions.5 Early detection of altered RV performance and function may help to prevent or delay heart failure and cardiovascular death.6
Received for publication August 25, 2013. Accepted November 4, 2013. Corresponding author: Dr Mario Gregori, Division of Cardiology, Department of Clinical and Molecular Medicine, University of Rome “Sapienza,” Sant’Andrea Hospital, Via di Grottarossa 1035-1039, Rome, Italy. Tel.: þ39-06-3377-5563; fax: þ39-06-3377-5061. E-mail: [email protected] See page 193 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.11.009
Gregori et al. RAAS Dysregulation and RVD
189
compared with patients in the N and SR groups. MPI of the right ventricle as well as prevalence of RVD were also significantly higher in the NSR group. Regression models showed that inadequate RAAS suppression was independently associated with RVD, regardless of blood pressure values and LV dysfunction (LVD). Conclusions: Patients without supine normalization of RAAS display a significant impairment of RV function. Our findings suggest that a dynamic RAAS evaluation may help to identify hypertensive patients at higher risk of RVD.
termine par l’indice de performance myocardique (IPM) à l’IDT de par une approche multisegmentaire. calcule sultats : Les patients du groupe RNS par rapport à ceux des Re groupes N et RS ont eu une diminution des indices de la fonction VD. valence de DVD ont aussi e te L’IPM du ventricule droit ainsi que la pre leve s dans le groupe RNS. Les modèles de significativement plus e gression ont montre que la suppression inade quate du SRAA e tait re pendamment associe e au DVD quelles que soient les valeurs de la inde rielle et de la dysfonction ventriculaire gauche (DVG). pression arte cubitus dorsal ne s’est Conclusions : Les patients dont le SRAA en de montrent une de te rioration significative de la fonction pas normalise sultats montrent qu’une e valuation dynamique du SRAA VD. Nos re terminer les patients hypertendus expose s à un risque peut aider à de leve de DVD. plus e
We and others have recently demonstrated that tissue Doppler imaging (TDI) of the right ventricle is a reliable tool for a preclinical evaluation of chamber dysfunction.7-10 Notably, the TDI-derived myocardial performance index (MPI) provides a reliable estimate of systodiastolic function and correlates with magnetic resonance measurements.7 The present study was designed to investigate the impact of inadequate RAAS suppression on RV function, as assessed by TDI.
interstitial pneumopathy, connective tissue disorders, chronic thromboembolic disease, congenital left-to-right shunts, or primary pulmonary hypertensiondwere also ruled out. Patients with primary aldosteronism (aldosterone-to-renin ratio > 20 ng/dL per ng/[ml/h] or suspicious adrenal masses [or both] on standard and Doppler ultrasonography of the kidneys) were excluded. All patients signed an informed consent form before entering the study. PRA and aldosterone levels
Methods A detailed description of the methods used in this study is provided in the Supplemental Methods section. Study population A total of 104 hypertensive patients (of 270 ambulatory patients) were recruited consecutively at the Hypertension Unit of Sant’Andrea Hospital. According to PRA and PAC, hypertensive patients were stratified as follows: (1) normal PRA and PAC (N group [n ¼ 58], (2) suppressible RAAS after supine positioning (SR group [n ¼ 24], or (3) nonsuppressible RAAS (NSR group [n ¼ 22]). Study patients were newly diagnosed with hypertension and were referred to our hypertension unit; they underwent a full screening for causes of secondary hypertension because of a highly suspicious clinical history or physical examination, or both.11 All patients with a history of previous cardiovascular disease were excluded. Hence, PRA and PAC were assessed in patients who had never been treated with RAAS blockers or other antihypertensive drugs. To avoid an uncontrollable influence of different levels of daily salt intake, patients enrolled in the study had been advised to ingest a fixed sodium diet (8 g per day) for the 7 days preceding the hormonal assessment. All patients were screened for secondary hypertension because of young age, family history of kidney disease, variable blood pressure values, electrolyte abnormalities, and the presence of signs or symptoms such as sweating, headache, anxiety, palpitations, weakness, abdominal murmurs, muscle tremors, or a combination of these factors.11 Family dyslipidemia, dysthyroidism, liver disease, renal failure, malignancies, peripheral artery disease, myocardial infarction or stroke (or both), arrhythmias, valvular disease, and heart failure (ejection fraction [EF] < 55%) were exclusion criteria. Indeed, clinical conditions that might predispose to pulmonary hypertensiondsuch as chronic obstructive pulmonary disease,
Plasma aldosterone and renin measurements were first assessed after overnight rest and after participants had been standing for at least 30 minutes. A second blood sample was collected after 2 hours of the patient lying in the supine position. Blood for PRA and PAC assessment was drawn from participants at midmorning between 8:30 and 10:30 AM to standardize the measurements for all patients and to avoid a possible bias related to circadian rhythm of hormone release. Elevated standing PAC (>300 pg/mL) and PRA (>5.7 ng/ mL/h) with complete normalization in the supine position (PAC < 160 pg/mL and PRA < 2.8 ng/mL/h) was defined as suppressible RAAS hyperactivation (SR group). By contrast, evidence of elevated PAC and PRA even after supine positioning was considered nonsuppressible RAAS hyperactivation (NSR group). Echocardiography All patients underwent transthoracic echocardiography, including conventional and TDI of both the left and right ventricles. Echocardiography was performed using an Acuson Sequoia C256 ultrasound system (Siemens Medical Solutions, Malvern, PA) equipped with phased-array electronic transducer with variable frequency from 2.5 to 4 MHz. All the examinations were supervised on-line by 2 expert ultrasonographers (GMC and GT), and measurements were taken using electronic proprietary markers. LV diameters, as well as septal and posterior wall thickness, were measured according to American Society of Echocardiography guidelines.12 Regional pulsed TDI data were obtained both from the septal and lateral mitral annuli in the apical 4-chamber view. The average regional MPI for the left ventricle was assessed (MPImitral þ MPIseptal)/2.4 LVD was identified by an average regional MPI value greater than the 75th percentile (TDI average MPI > 0.57).
190
Canadian Journal of Cardiology Volume 30 2014
Table 1. Anthropometric, clinical, and biochemical characteristics of the study population*
Age (y) Sex (M/F) BMI (kg/m2) Office SBP (mm Hg) Office DBP (mm Hg) 24-h mean SBP (mm Hg) 24-h mean DBP (mm Hg) Daytime mean SBP (mm Hg) Daytime mean DBP (mm Hg) Nighttime mean SBP (mm Hg) Nighttime mean DBP (mm Hg) Nondipping pattern (%) Sokolow-Lion index Cornell index Creatinine (mg/dL) Sodium (mg/dL) Potassium (mg/dL) Urine sodium excretion (mEq/24h) Supine PRA (ng/mL/h) Standing PRA (ng/mL/h) Supine aldosterone (pg/mL) Standing aldosterone (pg/mL)
N n ¼ 58
SR n ¼ 24
NSR n ¼ 22
P value
43.8 9.8 32:26 25.4 4.4 140.6 18.1 89.5 11.2 135.1 4.6 84.3 3.3 139.8 4.1 86.9 3.6 119.1 10.8 73.5 10.1 16 (27.6) 30.2 2.9 16.4 7.5 0.89 0.21 140.1 1.6 4.1 0.38 176.6 13.5 1.49 0.7 3.1 1.7 93.5 40.3 176.6 56.1
42.1 8.1 14:10 25.1 3.1 144.9 11.1 91.9 6.5 139.2 3.5y 87.1 3.7y 143.3 5.2y 88.8 3.3 120.6 7.1 74.4 5.5 6 (25) 32.4 3.1y 17.6 4.3y 0.92 0.26 141.7 2.7y 3.7 0.21y 151.6 6.3y 1.49 0.5 6.6 0.7y 138.1 21.6y 457.8 143.2y
42.2 10.3 11 11 24.6 3.9 147.8 9.5 93.6 7.5 147.4 9.8z 89.5 3.6z 147.8 6.8z 93.1 6.5z 129.2 4.9z 80.3 3.9z 14 (63.6) z 36.4 3.1z 21.1 7.4z 0.84 0.25 142.1 2.8y 3.7 0.30y 130.5 8.3z 6.4 5.1z 10.6 5.8z 195.2 36.6z 464.7 123.8z
NS NS NS NS NS
