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Circulation. 1997;95:1471-1478

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(Circulation. 1997;95:1471-1478.)
© 1997 American Heart Association, Inc.

Articles

Remodeling of the Left Ventricle in Primary Aldosteronism Due to Conn's Adenoma

Gian Paolo Rossi, MD; Alfredo Sacchetto, MD; Edoardo Pavan, MD; Paolo Palatini, MD; Gian Rocco Graniero, MD; Cristina Canali, MD; Achille C. Pessina, MD, PhD

From the Department of Clinical and Experimental Medicine, University of Padua Medical School and Azienda Ospedaliera di Padova, Italy.

Correspondence to Gian Paolo Rossi, MD, FACC, Department of Clinical and Experimental Medicine, Clinica Medica 1, Policlinico Universitario, via Giustiniani, 2, 35126 Padova, Italy. E-mail gprossi{at}ipdunidx.unipd.it.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
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Background Since hyperaldosteronism has been experimentally related to myocardial interstitial fibrosis, we investigated the effects of hypertension and excess aldosterone due to aldosterone-producing adenomas (APAs) on the heart.

Methods and Results In 52 hypertensive individuals, we performed Doppler echocardiography for estimation of left ventricular (LV) wall thickness and dimensions, transmitral LV filling flow velocity indexes, and 24-hour ambulatory blood pressure monitoring. Consecutive patients with APAs (n=26) and essential hypertension (EH, n=26) were individually matched for age, sex, race, body mass index, casual blood pressure, and known duration of hypertension. The matched groups were similar for demography, casual and 24-hour blood pressure values and variability, and duration of hypertension but differed for serum potassium, plasma renin activity, and aldosterone levels (all P<.001). A thicker interventricular septum (P=.015) and posterior wall (P=.009) and a higher LV mass index (118±5 versus 100±4 g/m2, P=.009) were observed in APA compared with EH patients. Both septum and posterior wall thicknesses had a significant direct relationship with age, plasma aldosterone, and mean blood pressure. The integral of the early diastolic filling wave (Ei) (P=.011) and the ratio Ei/Ai (A wave integral) (P=.038) were lower and the atrial contribution to LV filling was higher (52±2% versus 46±2%, P=.038) in APA than in EH patients. The ratio Ei/Ai was significantly (P=.008) inversely related only to age and plasma aldosterone.

Conclusions In APA patients, the excess aldosterone is associated with both increased LV wall thickness and mass and decreased early diastolic LV filling indexes compared with demographically similar EH with superimposable blood pressure values, profile, and variability.


Key Words: hypertension • hypertrophy • myocardium • hormones • echocardiography


*    Introduction
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 *Introduction
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Left ventricular hypertrophy, the most common cardiac consequence of hypertension, represents a maladaptive response to the increased afterload, since it is an important independent predictor of cardiovascular complications and death.1 2 3 Recent data indicate that the hemodynamic load is not the only determinant of LVH, because for similar elevations of blood pressure, a wide range of severities and types of LVH has been observed in relation to genetic, demographic, and humoral factors.4 5 Among the latter, the RAS has emerged as an important player in the pathogenesis of myocardial hypertrophy.6 7 8 Its active peptide, angiotensin II, may cause myocardial cell hypertrophy and/or hyperplasia through increased expression of the proto-oncogenes c-fos, c-myc, and c-jun and synthesis of the heat shock protein HSP 70 and other proteins.9 However, myocardial hypertrophy also involves extracellular matrix and collagen deposition and variable extents of fibrosis, which were particularly evident in the perivascular areas.10 11 12 The fact that in experimental models of hypertension with excess aldosterone, fibrosis involved not only the left but also the right ventricle, ie, a chamber exposed to the bloodstream but not to the pressure overload, and was prevented by administration of nonantihypertensive dosages of the aldosterone-specific receptor antagonist spironolactone12 13 14 led investigators to hypothesize that aldosterone causes extracellular matrix deposition through type I mineralocorticoid receptor–mediated increased expression of collagen types I and III genes in the myocardium.11 12 13 14 15 Of interest, in a genetic model of hypertension, interstitial fibrosis and not LVH was found to be responsible for abnormal myocardial diastolic stiffness in vitro in the isolated heart.16 It was therefore proposed that excessive aldosterone secretion is a causative factor of both myocardial fibrosis and diastolic dysfunction, although supporting evidence is still limited in humans, most likely because of the lack of models in which the effects of the RAS and aldosterone can be dissociated. PA, being characterized by excess aldosterone secretion and suppression of RAS, offers an appealing opportunity to examine this hypothesis in vivo. We recently reported that in a series of consecutive patients with PA due to different causes, LV wall thickness and mass were slightly increased and Doppler velocity indexes of early diastolic transmitral flow decreased compared with similar patients with similar casual blood pressure values.17 However, only 60% of those PA patients had an APA (Conn's adenoma), and therefore, the fact that their plasma renin and aldosterone levels showed some overlap with those of EH might have hampered detection of more marked differences in the LV between groups. Since suppression of the RAS and aldosterone excess are generally more pronounced in PA patients with an underlying APA than in those with idiopathic hyperaldosteronism, it is conceivable that if the changes of LV anatomy and function are related to the excess aldosterone, they would also be more pronounced in the former patients. In this study, therefore, we investigated the LV changes induced by excess aldosterone and hypertension in patients with confirmed Conn's adenoma.


*    Methods
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 *Methods
down arrowResults
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Patients
We studied 52 Caucasian patients referred to the Centro Regionale Specializzato per l'Ipertensione of the Clinica Medica I of the University of Padua between 1992 and 1996. Twenty-six patients (APA group; 14 women and 12 men) had primary aldosteronism caused by an APA. The diagnosis was based on a demonstration of elevated plasma aldosterone/PRA ratio that was unresponsive to a captopril test18 19 and of unilateral nodular adrenal enlargement shown by CT and MRI in all cases.20 It was confirmed at surgery and histology in 20 patients. In 6 patients, who refused surgery, the diagnosis was based on adrenal vein sampling in 5 and dexamethasone-suppressed adrenocortical scintigraphy in the remaining 1.20 Twenty-six patients with EH (EH group) selected from the Register of Hypertension of the same center in the same period were also studied as control subjects. EH was diagnosed after exclusion of all possible causes of secondary hypertension with measurement of baseline and captopril-stimulated PRA and aldosterone and also of catecholamine excretion, adrenal CT and/or MRI scan, and renal angiography whenever required.

For PRA and aldosterone measurements, 10 mL venous blood was collected into prechilled tubes containing 200 µL Na2EDTA after the subjects had been lying quietly in the supine position for at least 1 hour. Samples were centrifuged immediately at 3000g at 4°C for 15 minutes, and the supernatant was collected and frozen at -20°C until assayed. PRA was measured by a commercially available kit (Ares Serono; supine normal values with a daily sodium intake of 100 to 200 mmol, 0.51 to 2.64 ng angiotensin I·mL-1·h-1) as generation of angiotensin I after incubation for 2 hours at 37°C, pH 6.0. Blood samples were taken after 1 hour in the supine position and again 45 minutes after administration of 50 mg captopril PO.

Plasma aldosterone (normal values with a daily sodium intake of 100 to 200 mmol, 1.2 to 12.0 ng/dL) was measured by radioimmunoassay with a commercially available kit (Ares Serono). All patients were in sinus rhythm at the time of thee-chocardiographic study, and none had any valvular or ischemic heart disease.

Echocardiography
The M-mode echocardiograms were recorded under two-dimensional echocardiographic inspection with a 3.5-MHz probe (model SPR 8000, Esaote Biomedica). The measurement of LV diameters and posterior wall and septal thicknesses was performed at the levels of the tip of the mitral valve leaflets, according to the criteria of the American Society of Echocardiography,21 22 with a table digitizer (Summasketch Plus, Summagraphics Co) interfaced to a personal computer and calculating the average of at least three cardiac cycles. LV mass was calculated with the method of Devereux et al22 23 corrected with the appropriate regression equation and normalized for body surface area to obtain LVMI. This normalization was appropriate because no obese patients were studied.

RWT was calculated at end diastole according to the following equation: RWT=(interventricular septum thickness+posterior wall thickness)/LV diameter.

LVH, defined as an LVMI >110 g/m2 in women and >=134 g/m2 in men,23 was classified as concentric in the presence of an RWT >=0.45 and as eccentric with an RWT <0.45. LV concentric remodeling was diagnosed in the presence of an RWT >=0.45 and of a normal LVMI.24 LV meridional end-systolic and peak-systolic stresses were calculated according to Wilson et al.25

Blood pressure was measured with a mercury sphygmomanometer and the auscultatory method using Korotkoff phase V for diastole before and after echocardiography and the mean of three measurements taken in the supine position at least 3 minutes apart from one another. Nine patients in the APA group and 24 in the EH group also underwent 24-hour ambulatory blood pressure monitoring (A & D TM 2420) while not taking any antihypertensive treatment, as previously reported in detail.26

Doppler Evaluation
Transmitral flow velocity with Doppler was measured in the apical four-chamber view, as reported.27 To obtain the highest velocities, the sample volume was positioned below the AV plane between the tips of the mitral leaflets,28 paying the utmost attention to maintaining the ultrasonic beam as parallel as possible to the direction of flow.28 29 30 With minimal adjustments of the probe, the sampling was optimized to obtain the Doppler curve with the maximal velocity of flow and the minimal spectral dispersion. On the Doppler recording, obtained with the patient in apnea at the end of a normal expiration and with a paper speed of 50 mm/s, the following parameters were measured: PFVE, PFVA, their ratio PFVE/PFVA, E-wave acceleration and deceleration times, Ei, Ai, their ratio Ei/Ai, and ACLVF.31 All Doppler measurements were performed by the same reader (A.S.), who was kept unaware of the cause of hypertension, using the table digitizer set to a spatial resolution of 0.1 mm. The measurements of all indexes were carried out on at least three different cardiac cycles, and the average value was used for the analysis. Mean intraobserver variability (variation coefficients) of selected transmitral flow velocity indexes was, for Ei, 3.8%; PFVE, 3.4%; and E-wave duration, 4.5%.

Follow-up Study
All APA patients (n=20) who underwent surgical removal of the tumor and 2 of the 6 who did not were available for echocardiography and Doppler reassessment 1 year after surgery or the initial evaluation. Four additional PA patients in whom unequivocal evidence of a tumor could not be attained were also reassessed while on medical therapy.

Statistical Analysis
The data are expressed as mean±SD (or SEM or range), and the comparison between groups was performed with Student's t test for unpaired data or the nonparametric Mann-Whitney test for data not normally distributed.32 The relationship between end-diastolic interventricular septum thickness and LV end-diastolic posterior wall thickness, RWT, and the ratio Ei/Ai as dependent variables and the other variables was investigated with a stepwise multiple regression, using the backward method and an F-to-remove criterion of 0.150.33 All analyses were performed with SPSS-PC+ software (SPSS Inc) licensed to our Department.


*    Results
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 *Results
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Clinical Features of the Patients
After the matching, the two groups were demographically similar and had superimposable heart rate, casual systolic, diastolic, and mean blood pressures, and known duration of hypertension (all P=NS, Table 1Down). They differed markedly for serum potassium and supine baseline and captopril-stimulated PRA, which were significantly lower, and for plasma aldosterone, which was more than fivefold higher in APA than in EH patients. A significantly longer PQ ECG interval was also noticed in APA patients (Table 1Down). The two groups did not differ for mean 24-hour blood pressure values and variability, as assessed by SD and peaks of pressure, and for daytime and nighttime blood pressure values (Table 2Down).


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  		Table 1. Clinical Features of Patients With APA and EH


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  		Table 2. Results of 24-Hour Blood Pressure Monitoring

Echocardiographic Thickness and Dimension of the Left Ventricle
The results of the measurements of LV wall thickness and dimensions are shown in Table 3Down. Compared with EH patients, the APA patients had thicker interventricular septum and LV posterior wall. The end-systolic and end-diastolic LV diameters and ejection fractions did not differ between groups. End-systolic stress was significantly (P=.009) lower in APA than in EH patients because of the increased LV posterior wall thickness (Table 3Down).


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  		Table 3. Echocardiographic Features of Patients With APA and EH

RWT, LVM, and LVMI were significantly higher in the APA than in the EH patients. LVH was present in 9 of the 26 APA patients with primary aldosteronism and in 4 of the 26 control subjects with EH; LV concentric remodeling was also more common in APA than in EH patient (8 versus 1, {chi}2=13.64, P=.0034) (Fig 1Down and Table 3Up).



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  		Figure 1. Individual values of LVMI and RWT in Conn's adenoma (solid symbols) and matched EH (open symbols) patients (squares indicate men; circles, women). Vertical lines indicate cutoff value for LVH in each sex. Horizontal line divides those with concentric LVH or LV concentric remodeling from those with eccentric LVH or normal LV, respectively. Patients with Conn's adenoma had a significantly higher proportion of LVH and LV concentric remodeling by {chi}2 test.

Multiple regression analysis showed that thickness of both the interventricular septum and the LV posterior wall was directly related to age, plasma aldosterone, and mean blood pressure (Table 4Down) but not with the other variables tested. A model including age, aldosterone, and mean blood pressure as independent variables accounted for approximately half of the end-diastolic interventricular septum thickness and end-diastolic LV posterior wall thickness variance. LV RWT also had a significant relationship to aldosterone and age but not to casual and 24-hour blood pressure values. A model with these two independent variables explained about one fifth of the variance of RWT.


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  		Table 4. Results of Stepwise Backward Multiple Regression Analyses With LV Wall Thickness, Ei/Ai, and ACLVF as Dependent Variables

Echocardiography Doppler Indexes and Diastolic Function
Qualitatively adequate Doppler flow velocity recordings were obtained in 23 patients of each group (Table 5Down). Both in APA and in EH patients, early PFVE was below and PFVA was within the normal range for age.29 30 34 In the APA group, the average ratio PFVE/PFVA was <1, ie, it showed E/A inversion, whereas it was {approx}1 in the EH group; the difference between groups was not significant (Table 5Down). Both acceleration and deceleration times of the E wave were significantly lower in APA than in EH patients, resulting in a shorter duration of the E wave. Similarly, the Ei wave and the ratio Ei/Ai were significantly lower in APA than in EH patients (Table 5Down). The ACLVF was significantly (P=.038) increased in the APA compared with the EH group. The ratio Ei/Ai and the ACLVF were found to be related inversely and directly, respectively, to both age and plasma aldosterone. A model of regression with these variables explained 44% and 35% of their variance, respectively (Table 4Up).


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  		Table 5. Transmitral Flow Velocity Doppler-Derived Indexes of Diastolic Function in Patients With APA and EH


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
Primary aldosteronism is the most common endocrine cause of secondary hypertension and is increasingly recognized in patients referred to specialized centers for hypertension.35 Although it was long regarded as a benign (ie, devoid of cardiovascular complications) form of hypertension, clinical data are available to challenge this view.36 37 We previously reported that suppression of the RAS and excess aldosterone do not confer upon PA patients any protection from carotid atherosclerosis.38 With regard to the heart, the results of the present study also do not lend any support to this contention. In this study, we have compared the echocardiographic features and Doppler flow velocity indexes of LV filling of a group of consecutive patients with PA caused by an APA with those of a group of demographically similar EH patients. The utmost care was taken to match the patients of the two groups individually for sex, race, age, body mass index, casual systolic and diastolic blood pressure values, and duration of hypertension. As a result, the two groups were similar not only for demography and casual blood pressure values but also for 24-hour blood pressure values and variability. They obviously differed for the cause of hypertension, as confirmed by the marked and highly significant differences of PRA, aldosterone, and serum potassium levels (Table 1Up). Echocardiographic LV measurements showed that APA is associated with an increased thickness of the interventricular septum and posterior wall, as well as increased LV relative wall thickness, LVM, and LVMI (Table 3Up). These changes translated into a significantly higher proportion of patients with LV concentric remodeling and LVH in APA compared with the EH group (Fig 1Up). These results partially agree with a report of increased LV thickness, which was confined to the posterior wall, in patients with PA.39 However, they show that the LV mass changes are more marked in patients with Conn's adenoma than in a series of consecutive patients with PA as a result of different causes,17 thereby suggesting that the cause of PA should be taken into consideration in these studies.

The daily blood pressure load and an increased variability are believed to be important determinants of cardiac changes in hypertensives.40 41 As mentioned, our groups did not differ for 24-hour, daytime, and nighttime blood pressure values and variability, as assessed by SDs and peaks of pressure (Table 2Up), in agreement with a previous study.26 Since a decreased blood pressure variability has also been observed in PA patients,42 the possibility that the more detrimental LV changes of APA patients are due to an enhanced blood pressure variability seems unlikely. At variance with others, who reported a small increase of the LV end-diastolic diameter in 19 PA patients compared with renovascular hypertensives,43 we did not find any difference of left atrium and LV cavity dimension and volume between APA and EH patients (Table 3Up), in agreement with our previous observations.17 Thus, at the time of diagnosis, our APA patients more often had concentric LV remodeling or hypertrophy than eccentric hypertrophy (Table 2Up and Fig 1Up), most likely because they were diagnosed at an early stage of their disease and therefore had no evidence of hypervolemia and/or congestive heart failure.

Several lines of evidence point to an association between the increased LVH and concentric remodeling found in these APA patients and the excess aldosterone secretion. First, a significant relationship of interventricular septum, LV posterior wall thickness, and RWT with plasma aldosterone was observed (Table 4Up). Second, surgical removal of the APA, ie, of the source of the excess aldosterone, was followed by a highly significant decrease of LVMIs at 1-year follow-up. This finding contrasts with the unchanged LV of a smaller group of medically treated PA patients (Table 6Down) in whom blood pressure control was achieved with the use of aldosterone antagonists, which further stimulate aldosterone secretion. Third, as already mentioned, the fact that casual and ambulatory blood pressure values and profiles and LV dimensions did not differ between groups suggests a superimposable hemodynamic load throughout the day, which therefore cannot account for the observed difference of LV wall thickness and LVM. These considerations, however, do not necessarily imply that aldosterone increases LV wall thickness and LVM via enhanced deposition of extracellular matrix in the myocardium,11 12 13 14 15 44 since the tissue characterization provided by the echocardiographic technology used does not provide reliable information from this standpoint. The definitive proof that could be provided by histological analysis of myocardial biopsies was obviously not achievable for ethical reasons. It may be worth noting in this context that excess hormone secretion has been related to LVH in other forms of secondary hypertension as well.6 In Cushing's syndrome, the prevalence and severity of LV concentric remodeling and LVH, particularly of the asymmetrical type, was found to be increased compared with EH.39 45 46 This was attributed to the excess cortisol secretion, which might increase angiotensinogen synthesis and therefore the local production within the septum of angiotensin II through the myocardial RAS.6 7 8 45 46


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  		Table 6. Changes of LV Dimension, Thickness, and Transmitral Flow Indexes, Assessed by Echocardiography and Doppler, in 20 Patients With APA Treated With Surgery and in 6 Medically Treated PA Patients (2 With APA and 4 With Idiopathic Hyperaldosteronism)

Further insight into the myocardial effects of aldosterone could come from additional methodologies, such as MRI, ultrasonic backscatter analysis,47 48 and the assessment of LV diastolic filling with transmitral Doppler flow velocity measurement. It is conceivable that if LV wall thickening is caused by a predominant increase of the extracellular matrix and collagen, an impairment of diastolic function should be apparent.16 49 50 51 52 To investigate this hypothesis, we measured several Doppler-derived indexes of LV filling, which have been widely used for the assessment of diastolic function.28 50 51 52 53 Compared with normal values28 34 and with those found in normotensives >40 years old,27 we have detected a reduction of PFVE in both our groups of hypertensives (Table 5Up), in agreement with the data of the literature that have identified an impairment of early diastolic filling as one of the earliest sign of hypertensive heart disease, often preceding the onset of LVH.49 50 52 54 However, this translated into a more marked reduction of the PFVE/PFVA ratio, with an inversion of PFVE/PFVA only in our APA patients (Table 5Up). Of interest, we also found a significantly greater reduction of Ei and of Ei/Ai ratio in APA compared with EH patients (Table 5Up) and a significant increase of the atrial contribution to LV filling (Table 5Up and Fig 2Down). Taken together, these findings indicate that the LV of APA patients is more dependent on the atrial kick for its filling compared with demographically and hemodynamically similar EH patients. This might suggest the possibility of an additional impairment of diastolic function in hypertensive patients with APA, because this reduction of early diastolic filling appears to be disproportionate for the degree of LVH and showed an inverse relationship with age and plasma aldosterone (Table 4Up). Since PFVE and PFVA did not differ significantly between groups (Table 5Up), these changes of LV filling are likely to be accounted for to a large extent by the significant shortening of acceleration and deceleration times and total duration of the E wave in APA patients (Table 5Up). The pathophysiological basis of changes in LV filling is notoriously pleiotropic, including factors both extrinsic and intrinsic to the myocardium,28 49 50 which are critically influenced by its composition (eg, collagen concentration and relative proportions of fibrillar type I and type III collagens) as well as its architecture. Increased myocardial diastolic stiffness in vitro in the isolated heart of spontaneously hypertensive rats has been attributed to aldosterone-induced interstitial fibrosis and not LVH, because the hypoaldosteronism induced by lisinopril resulted in normalization of diastolic stiffness, despite no significant change of systolic blood pressure and LVM.16 The fact that LV diastolic filling was assessed indirectly by transmitral Doppler flow velocity measurements with no concomitant pressure gradient measurements or analysis of pulmonic venous flow and/or of isovolumetric relaxation time53 55 prevents definitive conclusions to be drawn concerning the causative role of aldosterone in diastolic dysfunction and myocardial fibrosis in this study. Therefore, although the finding of an impairment of LV early diastolic filling in APA patients is consistent with such a role, caution is mandatory in drawing conclusions. Additional factors that may potentially affect LV filling patterns need to be considered. Because the AV conduction time is one of these factors, we measured the PQ interval in our patients. Interestingly, we found a significantly longer PQ interval in APA than in EH patients (Table 1Up). We also found that the PQ duration was directly related to LVMI and inversely related to serum K+. When patients were divided into tertiles of serum K+ levels (Fig 3Down), it was quite obvious that those with the lowest serum K+ levels had not only significantly higher plasma aldosterone but also higher LVMI and longer PQ interval. Since the PQ interval is related directly to the A-wave and inversely to the E-wave duration and since hypokalemia prolongs AV conduction time, one might conclude that the significant changes of LV filling detected in this study could also be a consequence of excess aldosterone and hypokalemia.



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  		Figure 2. Individual and mean values of ACLVF and PQ ECG interval in patients with primary aldosteronism due to Conn's adenoma (APA) and essential hypertensive subjects (EH). Solid symbols identify patients with LVH (squares indicate men; circles, women).



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  		Figure 3. Values (mean±SEM) of plasma aldosterone (A), LVMI (B), and ECG PQ interval duration (C) in patients divided into tertiles of serum K+ levels.

The normalization of all indexes of LV filling observed at 1-year follow-up after surgical removal of APA but not in medically treated PA patients (Table 6Up) despite the achievement of a decent blood pressure control with drugs that increase aldosterone secretion further supports the hypothesis that aldosterone plays a causative role in the changes of LV filling, although through multiple potential mechanisms.

In conclusion, our results show that LV wall thickness and LVM are increased in patients with hypertension due to Conn's adenoma compared with demographically and hemodynamically similar EH with markedly lower plasma aldosterone levels. In the former, we found a significant decrease of LV early filling indexes and an increase of atrial contribution to LV filling, suggesting that in APA patients, filling of the LV occurs predominantly during atrial kick. Both the thickening of the LV walls and the changes of LV filling showed a relationship with plasma aldosterone levels and were corrected by removal of the tumor, ie, the source of excess aldosterone. These results are consistent with the hypothesis that excess aldosterone affects LV anatomy and function both by increasing LV mass, possibly by promoting the deposition of extracellular matrix and/or collagen, and by changing LV filling, in part through a prolongation of the AV conduction time.


*    Selected Abbreviations and Acronyms
 
ACLVF = atrial contribution to LV filling
Ai = A-wave (late diastolic LV filling) integral
APA = aldosterone-producing adenoma
EH = primary (essential) hypertension
Ei = E-wave (early diastolic LV filling) integral
LV = left ventricular
LVH = LV hypertrophy
LVM = LV mass
LVMI = LV mass index
PA = primary aldosteronism
PFVA = late diastolic (A-wave) peak flow velocity
PFVE = early diastolic (E-wave) peak flow velocity
PRA = plasma renin activity
RAS = renin-angiotensin system
RWT = relative wall thickness


*    Acknowledgments
 
This study was supported in part by Consiglio Nazionale delle Ricerche Progetto Finalizzato "Prevenzione e Controllo dei Fattori di Malattia (FATMA)": Sottoprogetto "8" Contratto N. 91.00.218 PF41 115.06.654. Dr Pavan is a recipient of a Bristol-Myers-Squibb fellowship program. We are grateful to Dr G.L. Nicolosi for critically reading the manuscript. We are also grateful to Drs Stefano Bongiovì and Pieralberto Visentin for performing some of the echocardiograms.

Received July 26, 1996; revision received November 7, 1996; accepted November 12, 1996.


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 up arrowResults
 up arrowDiscussion
 *References
 

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