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(Hypertension. 1996;27:1039-1045.)
© 1996 American Heart Association, Inc.
Articles |
Changes in Left Ventricular Anatomy and Function in Hypertension and Primary Aldosteronism
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, Dipartimento di Medicina Clinica e Sperimentale, Policlinico Universitario, via Giustiniani, 2, 35126 Padova, Italy.
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Abstract |
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Abstract We investigated the effects on the heart of hypertension due to the excess of aldosterone and suppression of the renin-angiotensin system caused by primary aldosteronism with M-mode echocardiography and transmitral Doppler flow velocity measurements. We studied 34 consecutive patients with primary aldosteronism and 34 with essential hypertension individually matched for age, gender, race, body mass index, blood pressure values, and duration of hypertension. The groups were similar in age, body mass index, blood pressure, and duration of hypertension. However, lower serum potassium levels (3.5±0.6 versus 4.1±0.2 mmol/L, P<.0001) and plasma renin activity (0.53±0.45 versus 1.82±1.59 ng Ang I·mL-1·h-1, P<.0001) and higher plasma aldosterone levels (1107±774 versus 206±99 pmol/L, P<.0001), left ventricular wall thickness, and left ventricular mass index (112±4.7 versus 98±3.7 g/m2, P=.029) were found in patients with primary aldosteronism compared with those with essential hypertension. Similarly, the PQ interval was longer (173±20 versus 141±14 milliseconds, P<.001) in primary aldosteronism than in essential hypertension patients. Significantly more primary aldosteronism than essential hypertension patients had left ventricular hypertrophy or left ventricular concentric remodeling (50% versus 15%,
2=11.97, P=.007). Both the E wave flow
velocity integral (1063±65 versus 1323±78, P=.013) and the
E/A integral ratio (0.91±0.05 versus 1.25±0.08, P<.001)
were lower, and atrial contribution to left ventricular
filling was higher (53.3±1.5% versus 45.5±1.3%, P<.001)
in patients with primary aldosteronism compared with essential
hypertension patients. After 1 year of follow-up, highly
significant decreases of left ventricular wall thickness
and mass were observed in patients treated with surgical excision of an
aldosterone-producing tumor, but not in those treated
with medical therapy. Thus, in patients with primary aldosteronism, the
excess aldosterone with suppression of the
renin-angiotensin system is associated with both
increased left ventricular mass and significant changes of
left ventricular diastolic filling. The former
changes appear to be reversible on removal of the cause of excessive
aldosterone production.
Key Words: hypertension, essential • aldosterone • hypertrophy • myocardium • echocardiography • fibrosis
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The most common detrimental consequence of hypertension on the heart is LVH.1 2 Recent evidence has shown that for a similar elevation of BP, the severity and type of LVH vary considerably in relation to genetic, demographic, and biohumoral factors.3 4 Of interest, the renin-angiotensin system is thought to play an important role in the pathogenesis of LVH.4 5 Experimentally, Ang II causes myocardial cell hypertrophy and/or hyperplasia,5 6 whereas excess aldosterone has been related to extracellular matrix and collagen deposition and therefore to myocardial fibrosis.7 8 9 10 11 The latter has been found to be associated with increased diastolic stiffness in vitro in the isolated heart.12 Accordingly, it can be hypothesized that excessive aldosterone might be an etiologic factor of myocardial fibrosis and impaired diastolic function. Primary aldosteronism, being characterized by excessive aldosterone secretion and suppression of the renin-angiotensin system, offers an attractive opportunity for testing this hypothesis. Thus, we have designed this study to investigate prospectively LV anatomy and function in a series of consecutive PA patients compared with a control group of demographically similar EH patients. We also assessed the long-term effects of surgery or medical therapy on LV anatomy in selected PA patients.
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Methods |
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We studied 68 white patients referred for investigation of hypertension to the Clinica Medica I of the University of Padua between 1992 and 1993. In 34 patients (16 women and 18 men), primary aldosteronism (PA group) was diagnosed as reported in detail.13 14 Aldosterone-producing adenoma and idiopathic hyperaldosteronism were the cause of PA in 21 and 13 patients, respectively. Essential hypertension (EH group) was diagnosed after exclusion of all possible causes of hypertension in the remaining 34 patients, who served as controls. All PA patients had previously been on regular antihypertensive therapy, whereas only two of the EH patients were on regular medical therapy and the others had never been treated. In all patients in both groups, treatment was stopped at least 2 weeks before the study. The study design and procedures followed the guidelines of our university for clinical studies, and each patient gave informed consent.
For PRA and aldosterone measurements, 10 mL venous blood was collected into prechilled tubes containing 200 µL Na2EDTA after the patients 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 with 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 Ang I·mL-1·h-1) as generation of Ang I after incubation for 2 hours at 37°C, pH 6.0. Blood samples were taken after patients had been in the supine position 1 hour and again 45 minutes after administration of 50 mg captopril PO, as reported.15
Plasma aldosterone (normal values with a daily sodium intake of 100 to 200 mmol: 33 to 333 pmol/L) was measured by radioimmunoassay with a commercially available kit (Ares Serono).
Each EH patient was individually matched to a PA patient for gender, age, body mass index, casual BP values, and known duration of hypertension. All patients in both groups were in sinus rhythm at the time of the echocardiographic study, as judged from an electrocardiogram on which the PQ interval was measured. None had clinically evident ischemic or valvular heart disease.
Twenty-five PA patients were reassessed echocardiographically 1 year after removal of an aldosterone-producing tumor (n=19) or after the initial evaluation (n=6) while on medical therapy.
Echocardiographic Evaluation
M-mode echocardiograms were recorded under
two-dimensional echocardiographic inspection with a
3.5-MHz probe (model SPR 8000, Esaote Biomedica). LV diameters and
posterior wall and septal thicknesses were measured at the level of the
tip of the mitral valve leaflets, according to the criteria of the
American Society of
Echocardiography,16 17 with a table
digitizer (Summasketch Plus, Summagraphics Co) interfaced to a personal
computer; the average of at least three cardiac cycles was calculated.
LVM was calculated with the method of Devereux corrected with the
appropriate regression equation16 17 and normalized for
body surface area to obtain LVMI. This normalization was appropriate
because only one obese patient was studied in each group.
RWT was calculated at end diastole according to the equation RWT=(Interventricular Septal Thickness+Posterior Wall Thickness)/LV Diameter.
LVH, defined as LVMI greater than 110 g/m2 in women and greater than or equal to 134 g/m2 in men,16 was classified as concentric in the presence of an RWT greater than or equal to 0.45 and eccentric with an RWT less than 0.45. LV concentric remodeling was diagnosed in the presence of an RWT greater than or equal to 0.45 and of a normal LVMI.18 LV meridional end-systolic stress and peak systolic stress were calculated according to Wilson et al.19 BP was measured with a mercury sphygmomanometer and auscultatory method using phase V of Korotkoff for diastolic sounds before and after echocardiography, with the mean of three measurements taken in the supine position at least 3 minutes apart from one another. Mean BP was calculated as diastolic BP plus one third pulse pressure.
Doppler Evaluation
Transmitral flow velocity with Doppler was measured with the
use of the apical four-chamber view, as already
reported.20 To obtain the highest velocities, we
positioned the sample volume below the atrioventricular
plane between the tips of the mitral leaflets,21 paying
utmost attention to maintain the ultrasonic beam as parallel as
possible to the direction of flow.21 22 With minimal
adjustments of the probe, the sampling was optimized so that the
Doppler curve with the maximal flow velocity and minimal spectral
dispersion could be obtained. The following parameters were
measured on the Doppler recording, with the patient in
apnea at the end of a normal expiration and with a paper speed of 50
mm/s: PFVE, PFVA, the PFVE/PFVA ratio, E wave acceleration and
deceleration times, area under the E wave (E wave flow velocity
integral), area under the A wave (A wave flow velocity integral), the
E/A integral ratio, and ACLVF, ie, the percentage of the total area
under the curve of diastolic flow velocity corresponding to
the A wave.21 22 23 24 The E and A flow velocity integrals were
measured according to standard methods.21 22 All
Doppler measurements were performed by the same reader (A.S.), who
was kept unaware of the etiology of hypertension and used the same
table digitizer set to a spatial resolution of 0.1 mm. All indexes were
measured on at least three different cardiac cycles, and the average
value was used for analysis. Mean intraobserver variabilities
(variation coefficients) of selected transmitral flow velocity indexes
were, for E wave flow velocity integral, 3.8%; for peak E wave
velocity, 3.4%; and for E wave duration, 4.5%.
Statistical Analysis
Data are expressed as mean±SD (or ±SE or range, as indicated),
and comparison between groups was performed with Student's
t test for unpaired data and the nonparametric
Wilcoxon test, as appropriate.25 Comparison
between baseline and 1-year follow-up data was carried out with
Student's t test for paired data or the
nonparametric Wilcoxon signed rank test, as
appropriate. The relationship between variables was investigated
with a stepwise multiple regression, using the backward
method26 and a FOUT criterion of 0.100. All
analyses were performed with SPSS-PC+ software (SPSS Inc)
licensed to our department.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical Features of the Patients
After matching, the two groups were comparable in terms of gender; age; body mass index; body surface area; casual systolic, diastolic, and mean BPs; heart rate; and known duration of hypertension (Table 1
). However, they differed
significantly in plasma aldosterone levels, which were
higher in PA patients, and serum potassium levels, as well as supine
baseline and captopril-stimulated PRA values, which were lower in
PA than EH patients. A significantly longer PQ interval was observed in
PA than EH patients (Table 1), which was found to correlate
significantly with LVMI (r=.59, P<.01), duration
of hypertension (r=.53, P<.01), and plasma
aldosterone (r=.52, P<.01).
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Echocardiographic and Doppler
Findings
The PA patients had significantly thicker
interventricular septa and LV posterior walls compared
with EH patients (Table 2). End-systolic and
end-diastolic LV diameters tended to be slightly lower
and higher, respectively, in PA patients. Although these differences
did not reach statistical significance, they translated into a
significant increase of both ejection fraction and cardiac output in PA
compared with EH patients. End-systolic stress was
significantly lower in PA than EH patients because of the increased
ejection fraction and posterior wall thickness (Table 2), whereas peak
systolic stress did not differ significantly (241±11 versus
256±7 dynex103/cm2,
P=NS).
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LVMI was significantly higher in PA compared with EH patients (Table 2
). LVH was present in 9 of the 34 PA patients and in 4 of the 34
EH patients, and LV concentric remodeling was found in 8 PA and 1 EH
patient (Fig 1, 2=11.97,
P=.007). Stepwise multiple regression analysis
showed that both interventricular septal and posterior
wall thicknesses were directly related only to plasma
aldosterone levels (Table 3).
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Doppler flow velocity recordings were judged to be
qualitatively adequate in 30 and 27 patients in the PA and EH groups,
respectively. PFVE (59±3 versus 62±2.3 cm/s, P=NS) and
PFVA (69±3 versus 67±4, P=NS) were below and within the
normal range, respectively, for age22 23 but did not
differ significantly between groups. As a result, the PFVE/PFVA ratio
was decreased in both groups; however, it was below unity only in PA
patients (Table 2 and Fig 2). The E wave flow velocity
integral (Ei) and E/A integral ratio
(Ei/Ai) were
significantly (P=.001) lower, and the ACLVF was
significantly (P<.001) increased in the PA compared with EH
group (Table 2). Stepwise multiple regression analysis showed
that the Ei/Ai
ratio was inversely related to age (ß=-0.41, P=.001)
and plasma aldosterone (ß=-0.33,
P=.0078) and directly related to PRA (ß=0.35,
P=.0049); no correlation with all the other variables,
including BP values, LVMI, serum potassium, and known duration of
hypertension, was found. A regression model including these three
variables explained almost half of the variance of the
Ei/Ai ratio
(adjusted R2=.49, F=13.81,
P=.000). At variance, the ACLVF had a significant direct
relationship only with age (ß=0.50, P=.0057) and plasma
aldosterone (ß=0.36, P=.04). A model with
these two variables accounted for more than one third of the
variance of the ACLVF (adjusted R2=.38,
F=8.21, P=.0022).
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Follow-up Study
Twenty-five PA patients were available at follow-up
1 year after either the initial evaluation or surgery. Of these, 19 had
undergone surgical excision of an aldosterone-producing
adenoma, resulting in cure of hypertension in 8, whereas 11 patients
still required antihypertensive treatment although at a much smaller
dosage and with a fewer number of agents than before surgery. Six
patients were treated with medical therapy either because of idiopathic
hyperaldosteronism (n=4) or because they refused surgery (n=2). In
these latter patients, control of the high BP was achieved with medical
therapy, which included an aldosterone
antagonist in all. The changes of mean BP, LV dimensions,
and LV thickness observed in these patients are shown in Table 4. A highly significant decrease of LV
end-diastolic diameter, wall thickness, and LVM was
evident in the surgically treated patients and not in the patients on
medical therapy. Indeed, in the latter patients, although baseline LVM
was greater than in the surgically treated patients, the decreases in
LVM and LVMI were much smaller and mainly related to the decrease in LV
end-diastolic diameter (Table 4).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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We have compared the echocardiographic features and Doppler flow velocity indexes of LV filling of a group of consecutive PA patients with those of demographically similar EH patients. The latter were individually matched also for casual BP values and known duration of hypertension; therefore, the two groups differed only in the presence or absence of hyperaldosteronism. Despite the fact that at variance with the EH patients, all our PA patients had previously received antihypertensive agents, we found significantly greater interventricular septal and LV posterior wall thicknesses in PA than EH patients (Table 2
), which translated into a
slight but statistically significant increase in LVMI. Thus, these
results confirm and extend those of previous studies. Janota et
al27 found only LV posterior wall thickness to be
increased, whereas Denolle et al28 reported increased LV
posterior wall thickness, interventricular septal
thickness, and LVMI but no excess prevalence of LVH and LV concentric
remodeling in 21 patients with an aldosterone-producing
adenoma compared with other forms of secondary hypertension. In
contrast, in a Japanese study, only an increase in LV
end-diastolic diameter and no difference in wall
thickness and LVM was observed in 19 PA patients compared with
renovascular hypertensive patients.29 Our results clearly
demonstrate an excess of both LVH and concentric LV remodeling compared
with EH patients, not only in patients with an
aldosterone-producing tumor but also in those with
idiopathic hyperaldosteronism (Fig 1). Since both LVH and (more recently) LV concentric remodeling have been shown to be independent predictors of cardiovascular events,1 18 these observations might have important prognostic implications for PA patients. The increase of LVMI occurred despite the fact that none of our PA patients had obvious increases of LV end-diastolic cavity dimension or volume. This was probably because they were studied under a moderate (85±43 mmol/d) sodium intake and diagnosed at an early stage of their disease. However, in keeping with the first report of Tarazi et al,30 later confirmed by Denolle et al,28 the PA patients showed a significant increase of load-dependent indexes of systolic function, such as ejection fraction and cardiac output. The latter has been attributed to a sodium-mediated slight increase of plasma volume, but a possible inotropic effect of aldosterone and/or enhanced sympathetic drive could not be ruled out.30
The increased LV wall thicknesses of PA patients might be
attributed to the excess aldosterone secretion, because
casual BP values and the other demographic variables that can
influence LVM did not differ from those in EH patients. On the basis of
quantitative morphometric analyses of rat models of
hyperaldosteronism, Weber and Brilla8 proposed that
aldosterone can enhance extracellular matrix and collagen
deposition in the myocardium by enhancing the expression of
the collagen type III gene by cardiac fibroblasts and inhibiting
collagenase activity. These effects would lead to fibrosis
and an increased LVM and diastolic
stiffness.7 8 9 10 11 12 Our finding that the increases of LV wall
thicknesses and LVM were only modest may be consistent with
their hypothesis because the weight of myocardial collagen is no more
than 0.02 g/g wet wt heart tissue under normal
conditions,7 and thereby even marked increases in the
collagen volume fraction would correspond to minimal increases of LVM.
However, without histology, which cannot be performed for ethical
reasons, definitive conclusions cannot be reached for the following
reasons. First, the correlation between plasma aldosterone
levels and both interventricular septal and posterior
wall thicknesses does not prove a cause-effect relationship.
Second, the echocardiographic technology available to
us did not provide a myocardial tissue characterization adequate for
detection of the relative contribution of fibrosis to LVM in the two
groups. Third, both casual systolic and diastolic
BP values were almost identical in our groups, but it could be that
profile, variability, and mean values of BP of the 24 hours were
different. This latter possibility, however, is not supported by the
results of a recent study by our group in which no differences in BP
rhythm and variability between PA and EH patients were
found.31 It must be pointed out, however, that removal of
the source of the excess aldosterone with surgery
determined a clear-cut decrease in LV wall thickness and mass after
1 year of follow-up (Table 4). Interestingly, this marked decrease
was not seen in the PA patients in whom a decent BP control was also
achieved with medical therapy based on a multiple drug regimen and
including aldosterone antagonists. The latter
are known to stimulate the renin-angiotensin system and
thereby further enhance overproduction of
aldosterone.
As regards the possible fibrogenetic effect of aldosterone
on the myocardium, while waiting for analyses of
integrated ultrasonic backscatter32 33 34 and magnetic
resonance imaging, one can find useful information from the assessment
of diastolic function. In fact, a predominant increase of
extracellular matrix and collagen should induce an increase in
diastolic stiffness.12 35 36 37 With the
Doppler flow velocity assessment of LV
filling,21 22 35 36 37 38 we have detected a reduction of PFVE,
which translated into a marked reduction of the PFVE/PFVA ratio in PA
patients (Table 2) compared with the normal range in the literature as
well as the values observed in normotensive subjects older than 40
years.20 21 22 However, these changes apparently occurred to
a similar extent in both our groups of hypertensive patients, who had
on average only a modest increase of LVM. These findings are in keeping
with the concept that an impairment of diastolic function
is one of the earliest signs of hypertensive heart disease, often
preceding the onset of overt LVH,35 36 39 and do not seem
to support the hypothesis of an excess impairment of
diastolic function in primary aldosteronism. However, with
more-sensitive Doppler-derived indexes, including
Ei wave flow velocity integral,
Ei/Ai ratio, and
ACLVF, we did find significant differences of LV filling pattern
between PA and EH patients (Fig 2 and Table 2). These differences
consisted of a reduction of early relative to late
diastolic filling, which appears to be disproportionate for
the observed increase of LVM and was not correlated with LVMI.
Furthermore, both
Ei/Ai and ACLVF
had a significant correlation not only with age, a variable that is
well known to deeply affect diastolic
function,40 but also with plasma aldosterone
levels. Thus, these results suggest a greater impairment of
diastolic function in PA patients compared with EH
patients. It is now well appreciated that the
pathophysiological basis for
diastolic dysfunction is multifactorial, including factors
extrinsic to the myocardium, such as the pericardium,
ventricular loading and interdependence, chamber geometry,
and factors intrinsic to the myocardium, such as its rate
of relaxation and elasticity during filling. These properties of the
myocardium are deemed to be critically influenced by its
composition (eg, collagen concentration and relative proportions of
fibrillar type I and type III collagens) as well as its architecture.
Interestingly, in spontaneously hypertensive rats,
interstitial fibrosis and not LVH was found to be
responsible for increased myocardial diastolic stiffness in
vitro in the isolated heart. In this model, blockade of the
renin-angiotensin system and the ensuing
hypoaldosteronism with lisinopril resulted in normalization
of diastolic stiffness, even without a significant decrease
of systolic BP and LVM.12 Thus, it is tempting to
speculate that the changes in LV diastolic filling in our
PA patients are related to the exposure in vivo to increased
aldosterone levels via an increase of the extracellular
fibrotic component of the myocardium.41 This
interpretation is further supported by the significant relationship of
both Ei/Ai ratio
and ACLVF with plasma aldosterone levels. It must be
acknowledged, however, that transmitral Doppler flow velocity
indexes provide only an indirect assessment of diastolic
function.19 20 21 Furthermore, since no concomitant
Doppler evaluation of pulmonary venous flow and
isovolumetric relaxation time, two parameters that can
furnish considerable insight into LV diastolic
function,42 43 was carried out in the present study,
we advise caution in drawing conclusions. It must also be considered
that the Doppler mitral inflow waveform is influenced by a complex
interplay of loading conditions, heart rate, and
atrioventricular conduction time (PQ
interval).42 Differences in afterload and heart rate did
not seem to exist between our PA and EH patients. Since LV filling
pressure was not measured in this study, the possibility that a higher
preload contributes to the change in LV filling cannot be excluded.
However, since the significant difference of E/A integral ratio and
ACLVF between groups seemed to be accounted for by a shortening of the
E wave acceleration and deceleration times as well as total duration
more than by the differences of peak flow velocity, we wonder whether a
difference in PQ interval might contribute to the changes in LV filling
pattern that were found. Interestingly, the PQ interval was longer in
our PA than EH patients, and the difference was highly statistically
significant (P<.001, Table 1). In addition, the PQ interval
was found to be directly related to plasma aldosterone
levels (r=.52, P<.01) and the duration of the A
wave (r=.66, P<.001).
In conclusion, we found a thicker LV posterior wall and interventricular septum and an excess of LVH and LV concentric remodeling in PA patients compared with demographically similar EH patients with lower plasma aldosterone levels. We also detected a positive correlation between plasma aldosterone levels and echocardiographically measured LV wall thickness indexes. In addition, we found significant changes of LV filling velocity profile in PA patients compared with EH patients. These changes, which were also significantly related to plasma aldosterone levels, did not adversely affect systolic function and could be partly accounted for by a prolongation of the PQ interval induced by hypokalemia. The increases of LV wall thickness and LVM were no longer present at 1 year of follow-up after surgical removal of the aldosterone-producing tumor. Thus, taken together, our results show that in humans, aldosterone excess deeply affects the myocardium, both through the effects of hypokalemia on atrioventricular conduction and by increasing LV wall thickness, possibly by promoting the deposition of extracellular matrix and collagen.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported in part by Consiglio Nazionale delle Ricerche (CNR) and Progetto Finalizzato "Prevenzione e Controllo dei Fattori di Malattia (FATMA)": Sottoprogetto "8" Contratto N. 91.00.218 PF41 115.06.654.
Received September 20, 1995; first decision November 29, 1995; accepted January 22, 1996.
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