Journal of Human Hypertension (1998) 12, 195–202 1998 Stockton Press. All rights reserved 0950-9240/98 $12.00 ORIGINAL ARTICLE Opposite associations of circulating aldosterone and atrial natriuretic peptide with left ventricular diastolic function in essential hypertension RH Fagard, PJ Lijnen and VV Petrov Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, Faculty of Medicine, University of Leuven KU Leuven, Leuven, Belgium It has been shown in animal experiments that angioten- (P Ͻ 0.001) and to plasma aldosterone (P Ͻ 0.01), and sin II and aldosterone have mitogenic effects on the car- positively to plasma atrial natriuretic peptide (P Ͻ 0.05). diovascular system, whereas atrial natriuretic peptide Peak flow velocity during atrial contraction was posi- has antimitogenic properties. The aim of the present tively related to plasma atrial natriuretic peptide both study was to relate plasma renin activity, angiotensin II, before (P Ͻ 0.001) and after (P Ͻ 0.05) controlling for aldosterone and atrial natriuretic peptide to left ventricu- significant covariates (age, sex and blood pressure). We lar structure and function, assessed by use of imaging conclude that circulating renin, angiotensin II, aldos- echocardiography and transmitral Doppler velocimetry terone and atrial natriuretic peptide are not indepen- in 73 patients with essential hypertension, World Health dently related to left ventricular mass in essential hyper- Organization stages I–II, aged 43 ؎ 10 (s.d.) years. Left tension. The inverse association of plasma aldosterone ventricular mass, wall thickness and internal diameter with indices of diastolic function is compatible with a were not independently related to the biochemical vari- stimulating effect of aldosterone on myocardial fibrosis, ables, except for a weak and positive association of wall which is opposed by atrial natriuretic peptide. The -However, apparently conflicting positive association of this pep .(0.06 ؍ thickness with plasma aldosterone (P left ventricular early inflow peak velocity and deceler- tide with atrial peak velocity is most likely due to stimu- ation were independently and inversely related to age lation of its secretion by atrial involvement. Keywords: aldosterone; angiotensin; atrial natriuretic peptide; echocardiography; left ventricular function; left ventricular hypertrophy; renin Introduction because long-term administration of components of the renin-angiotensin-aldosterone-system and of atr- There is evidence from animal experiments that ial natriuretic peptide cannot be performed on ethi- angiotensin II and aldosterone exert mitogenic cal grounds. Therefore researchers have looked for effects on the cardiovascular system, whereas atrial 1–5 associations between cardiac structure and function, natriuretic peptide has antimitogenic properties. and plasma renin activity,13–21 angiotensin The development of cardiac fibrosis on long-term in II,15,17,20,22 aldosterone15,17–20,22,23 and atrial natriur- vivo administration of aldosterone in rats has gener- etic peptide.22,24–27 Another approach has been to ated considerable interest, particularly because of its study the cardiac effects of chronic treatment with seemingly independence of haemodynamic fac- 6–9 drugs which interfere with components of the renin- tors; however, in vitro studies are not in agree- angiotensin-system.28,29 Growth stimulation of myo- ment on the direct effect of aldosterone on collagen 10,11 cytes would lead to an increase in left ventricular synthesis by cultured cardiac fibroblasts. Atrial mass, whereas myocardial fibrosis would mainly natriuretic peptide on the other hand has been result in functional abnormalities, particularly dias- shown to inhibit the proliferation of cultured rat 3 12 tolic dysfunction. Imaging echocardiography is an fibroblasts, but it is not known whether long-term appropriate non-invasive technique to estimate left infusion of atrial natriuretic peptide would counter- ventricular mass, whereas mitral inflow Doppler act or reverse the fibrotic process. Such issues are of velocimetry allows assessment of diastolic func- paramount importance for human hypertensive tion.30 Moreover, echocardiographic indices of dias- heart disease, but are difficult to resolve in man, tolic function correlate with myocardial fibrosis in hypertensive man.31 Few studies have addressed the Correspondence: Dr R Fagard, UZ Pellenberg, Weligerveld 1, B- relationships of plasma atrial natriuretic peptide 3212 Pellenberg, Belgium with left ventricular characteristics,22,24–27 whereas Received 13 June 1997; revised and accepted 26 November 1997 the data on the renin-angiotensin-system, both from Hormones and ventricular diastolic function RH Fagard et al 196 the correlation approach and from intervention sional image, and were recorded on photographic studies are conflicting.13–23,28,29 In addition, most paper at paper speed 100 mm/s for later analysis. reports emphasized cardiac structure, whereas The transducer was angulated to ensure simul- relationships of humoral variables with diastolic taneous visualisation of the left ventricular posterior function have only been studied for atrial natriuretic wall and interventricular septum just below the peptide and not for the components of the renin- mitral valve apparatus, ie, at the level of the pos- angiotensin-system. The purpose of the present terior chordae tendinae. After completion of the study was therefore to assess relationships of echo- study the tracings were digitized and the values of cardiographic left ventricular structural and func- three to five heart beats were averaged. The rec- tional characteristics with plasma renin activity, ommendations of the American Society of Echocar- angiotensin II, aldosterone and atrial natriuretic diography were observed; wall and cavity measure- peptide in patients with essential hypertension, ments were made using the leading edge method.34 studied in well-standardized conditions. The following echocardiographic measurements were obtained: (1) left ventricular end-diastolic internal diameter (LVID; mm), measured at the onset Materials and methods of the QRS complex of the simultaneously recorded Protocol electrocardiogram, and end-systolic internal dia- meter at the nadir of septal motion (LVIDs; mm); and Previously treated or untreated patients, referred for (2) end-diastolic posterior wall and interventricular the evaluation of hypertension, were eligible for the septal thicknesses (PWT; IVST; mm). Several study when no underlying disease could be indexes were derived from these measurements: detected, when organ damage was limited to World (1) mean end-diastolic wall thickness (MWT; mm) Health Organization stages I or II32 and when their as the average of posterior wall and septal thick- echocardiogram was judged to be of good quality by nesses; (2) left ventricular mass (LVM; g) as two investigators. Patients willing to participate described by Devereux et al;35 (3) relative wall thick- were invited for two study visits within the next 6 ness (RWT) as the ratio of MWT to the internal weeks, with 2 to 3 weeks between visits; visits were radius (LVID/2); and (4) the fractional shortening of scheduled in the morning, after the patients had a the LV internal diameter (FS; %) as 100 × (LVID − light breakfast at home. Anti-hypertensive treatment LVIDs)/LVID. was interrupted in patients with mild-to-moderate hypertension. Patients with severe blood pressure elevation were only accepted when they were Pulsed Doppler echocardiography untreated and the two study visits were scheduled With the patient rotated on the left side, the trans- in a shorter period of time. No special diet instruc- ducer was placed at the apex and the apical four- tions were given and sodium intake was assessed chamber image was visualised. The Doppler sample from 24-h urinary sodium excretion. The study was volume was positioned in the orifice of the mitral approved by the Ethics Committee of the Faculty of valve and the ultrasound beam was placed parallel Medicine and participants gave informed consent. to the presumed flow of blood. The transducer was angulated to obtain the best Doppler signal, as judged by the sharpness of the outline of the com- Clinic blood pressure plexes on the visual display and the pitch of the After arrival in the laboratory the patients were left audio sound of the Doppler shift frequencies. Rec- alone in a quiet room, where they rested in the ordings were made at end-expiration. The peak velo- supine position. Twenty minutes later, blood pres- city (m/s) and deceleration (m/s2) of the early filling sure was measured five times by sphygmomanome- curve and the peak velocity of the atrial contraction try and auscultation (Korotkoff phases I and V) by curve (m/s) were measured on three to five heart one of two trained observers; pulse rate was assessed beats, using the middle of the darkest portion of the at the end of the blood pressure measurement by Doppler flow curve. The ratio of the early to atrial palpation of the radial artery during 30 s. The five peak velocity was calculated.36 blood pressures of each visit were averaged and mean blood pressure was calculated as: Biochemical measurements + diastolic pressure After termination of echocardiography, the patients − (systolic pressure diastolic pressure)/3. remained in the supine position for withdrawal of blood from an antecubital vein, for determination of 37 38 Imaging echocardiography plasma renin activity, angiotensin