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(Hypertension. 2002;40:23.)
© 2002 American Heart Association, Inc.

Scientific Contributions

Excess ldosterone Is Associated With Alterations of Myocardial Texture in Primary Aldosteronism

Gian Paolo Rossi; Vitantonio Di Bello; Chiara Ganzaroli; Alfredo Sacchetto; Maurizio Cesari; Alessio Bertini; Davide Giorgi; Roldano Scognamiglio; Mario Mariani; Achille C. Pessina

From the Cardiac and Thoracic Department, University of Pisa (V.D.B., A.B., D.G., M.M.); and the Department of Clinical and Experimental Medicine, University of Padua Medical School (G.P.R., C.G., A.S., M.C., R.S., A.C.P.), Italy.

Correspondence to Prof Gian Paolo Rossi, MD., F.A.C.C, F.A.H.A., Department of Clinical and Experimental Medicine, Clinica Medica 4, Policlinico Universitario, via Giustiniani, 2, 35126 Padova, Italy. E-mail gianpaolo.rossi{at}unipd.it

	Abstract

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Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remains unclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primary aldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wall thickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PA and 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, and known duration of hypertension. The groups differed in serum K⁺, ECG PQ interval duration, plasma renin activity, and aldosterone levels (all P0.002) but not for casual blood pressure values, demographics, and duration of hypertension. Compared with hypertensive patients, PA patients showed a higher LV mass index (53.7±1.8 versus 45.5±2.0 g/m^2.7; P=0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVI_s; -12.02±5.84% versus 6.06±3.08%; P=0.012) and posterior wall (-11.13±6.42% versus 8.63±9.62%; P=0.012). A regression analysis showed that CVI_s was predicted by the PQ duration, supine plasma renin activity, plasma aldosterone, and age, which collectively accounted for 36% of CVI_s variance. PA is associated with alterations of myocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolic filling from presystole and the prolongation of the PQ interval.

Key Words: hypertension, endocrine • aldosterone • myocardial • hypertrophy • fibrosis • echocardiography

	Introduction

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Left ventricular hypertrophy (LVH) is commonly associated with arterial hypertension and represents an important independent predictor of cardiovascular events,¹ including congestive heart failure. Extracellular matrix and collagen deposition are invariable findings of LVH and lead to cardiac fibrosis (CF), which occurs particularly in the perivascular areas and correlates directly with the severity of LVH.² CF is a major cause of cardiac dysfunction because an excessive deposition of collagen may be responsible for abnormal tissue stiffness and diastolic dysfunction. The latter is an early marker of heart involvement in hypertension (for review, see Agabiti-Rosei and Muiesan³) and is associated with CF more closely than with LVH.^4,5

Fibroblasts constitute the vast majority (>90%) of nonmyocyte cells in the heart; they can increase the production of extracellular matrix on exposure to a variety of injuries, including pressure overload. The latter seems to be only one of the determinants of CF, because it was experimentally shown, both in vitro and in vivo, that CF in both ventricles was linked to activation of the renin-angiotensin-aldosterone system⁶ and that it could be prevented by non-antihypertensive dosages of spironolactone.⁷

Thus, angiotensin II and aldosterone play important roles in the heart (for review, see Swynghedauw⁸). Angiotensin II induces cardiomyocyte hypertrophy in both ventricles,⁹ stimulates collagen synthesis by fibroblasts, and regulates collagen degradation by blunting the activity of matrix metalloproteinase-1, the key enzyme of collagen degradation.⁸ Aldosterone is extracted through the human heart through a spironolactone-sensitive pathway¹⁰ and promotes CF by acting through different pathogenic mechanisms.^8,11 It increases types I and III procollagen mRNA in both ventricles, although it does not seem to influence matrix metalloproteinase-1 activity in cultured cardiac fibroblast preparations.¹² Aldosterone may also act on the cardiac angiotensin II receptor, because its administration, along with a high-salt diet, increased angiotensin II type 1 (AT-1) receptor density in the left ventricle of rats; this increase was prevented by both spironolactone and losartan.¹³ Thus, aldosterone might cause extracellular matrix deposition by enhancing the transcription of collagen type I and III genes and by augmenting the effects of angiotensin II on AT-1 receptors.¹⁴

Primary aldosteronism (PA) offers a unique opportunity for investigating the role of excess aldosterone in humans, independent of that of angiotensin II, which is suppressed. We previously reported that in white PA patients there is an excess of LVH¹⁵; this finding was thereafter confirmed in Japanese PA patients.¹⁶ Doppler flow velocity indexes of early diastole transmitral flow are decreased compared with those from patients with primary (essential) hypertension (EH). These alterations were more marked in patients with a Conn’s adenoma, in whom aldosterone excess and renin suppression were also more prominent, and were corrected by adrenalectomy, ¹⁷ thus indicating a causative role of excess aldosterone in CF. To prove this link conclusively, histological analysis of myocardial biopsies would be necessary, but this is unfeasible for ethical reasons. However, newer noninvasive technologies, such as the videodensitometric analysis of myocardial texture that have proven to be accurate for assessing CF,^18,19 provide a tool to reexamine this question. Therefore, we sought to compare myocardial texture indexes between consecutive PA and EH patients.

	Methods

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Patients
We studied 27 white hypertensive patients; 17 were consecutive cases of PA, which was caused by a Conn’s adenoma in 15 patients and by idiopathic hyperaldosteronism in 2 patients.²⁰ In all cases, Conn’s adenoma was identified with adrenal vein sampling²¹ and confirmed at surgery, by histological analysis, and by correction of PA at follow-up. Ten patients (2 female and 8 male) in whom EH was diagnosed after the exclusion of all possible causes of secondary hypertension were studied as controls.

Echocardiography
All patients were in sinus rhythm, and none had any valvular or ischemic heart disease. Conn’s adenoma patients were studied before adrenalectomy. M-mode and 2D echocardiograms and Doppler analysis were performed with a commercially available apparatus (Hewlett-Packard Sonos 2500). The measurement of left ventricular (LV) diameters and posterior wall and septum thickness and the calculation of LV mass and relative wall thickness were performed as described previously.¹⁷ LV mass was normalized for height^2.7 to obtain the LV mass index (LVMI). Criteria for concentric and eccentric LVH and LV remodeling have been described previously.¹⁷

A single reader (A.S.) blindly performed the following measurements on a pulsed Doppler transmitral flow velocity profile: early diastolic (E wave) peak flow velocity (PFVE), diastolic peak flow velocity at atrial contraction (A wave, PFVA), their ratio (PFVE/PFVA), E wave integral (E_i), A wave integral (A_i), their ratio (E_i/A_i), and the atrial contribution to LV filling (ACLVF), as reported previously.¹⁷

Blood pressure was measured while the patients were off medications using a mercury sphygmomanometer with phase V of Korotkoff for diastolic pressure, before and after echocardiography.

Videodensitometry
To achieve a precise and reproducible sampling of textural parameters, the gain settings and compensation profiles were adjusted for all subjects to obtain uniform myocardial brightness throughout the echocardiogram. The gray scale transfer function was adjusted to be linear for the entire video signal range; no reject, enhancement, or dynamic ranges were used; and a 25 to 30 dB amplification at a depth of 18 cm was set. The optimal echocardiographic images were transferred to a calibrated video digitization system and converted into 256x256 pixels of 256 gray levels, each with a real-time videodigitizer (Tomtec Imaging Systems).^19,22 Each cardiac cycle was automatically divided into 12 frames independently of heart rate. The images corresponding to the end-diastolic and end-systolic phases, all in long-axis projection, were selected with an optimal visualization of both the interventricular septum and the LV posterior wall.

The regions of interest for texture analysis were chosen by consensus of 2 observers who were blinded to the diagnosis group, as described previously.²² The regions of interest, which were always the same size (32x42 pixels), were placed in the same location in the septum (midseptum) and in the posterior wall (midposterior) in both end-systolic and end-diastolic frames. We also considered the delay or phase-shift of the cyclic variation in all septum and posterior wall samplings; a time delay of 1.0 corresponded to a peak near end-diastole, and a nadir near end-systole was found in mean gray level cyclic variation.^19,22 A histogram of the gray level distribution was generated for each region of interest.

The mean gray level of each cavity region (background signal) was subtracted from the absolute mean gray level obtained for each regions of interest. A quantitative analysis of the shape of each distribution was also performed using skewness and kurtosis. The cyclic variation index (CVI) of the myocardial gray level amplitude was calculated as described previously.²² Measurements were averages of at least 5 consecutive cardiac cycles. Reproducibility was estimated by analyzing, in a blinded fashion, all recordings on 2 separate occasions by the same (intraobserver variability) or different (interobserver variability) investigators. Intraobserver and interobserver coefficients of variation averaged 7.5% and 10.2%, respectively. The intraclass correlation coefficient for septum mean gray level was 0.92 for diastolic and 0.90 for systolic samples; for posterior wall mean gray level, it was 0.89 for diastolic and 0.91 for systolic samples.

Statistical Analysis
Results are presented as mean±SD (or SEM or range); comparison between groups was performed with Student’s t test for unpaired data or the Mann-Whitney test. The relationship between individual variables was examined by scatter plot analysis and correlation matrix followed by a stepwise linear regression analysis on the CVI of the septum (CVI_s) of the variables that were of interest in the scatter plot analysis.

An expanded Methods section can be found in an online data supplement available at http://www.hypertensionaha.org.

	Results

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Clinical Features and Echocardiographic and Doppler Indexes of the Patients
After matching, the groups were demographically similar and had superimposable heart rates, blood pressure values, and known durations of hypertension (Table 1). They differed in serum potassium, supine baseline and captopril-stimulated plasma renin activity (PRA; which were significantly lower), and plasma aldosterone, which was higher in PA than in EH patients. A longer PQ ECG interval was also noticed in PA patients. Table 2 shows the results of the measurements of LV wall thickness and dimensions. LVMI was significantly higher in PA than in EH patients, whereas relative wall thickness did not differ between groups. LVH was present in 30% of the 17 PA and none of the EH patients; LV concentric remodeling was seen in 17% of PA and 10% of EH patients (P<0.05). Doppler flow velocity recordings were qualitatively adequate in all patients (Table 2). In the PA group, PFVE/PFVA was lower than in EH patients and showed E/A inversion, whereas E/A was close to unity in the EH group. Similarly, A_i was higher and E_i/A_i was lower in PA than in EH patients; the ACLVF was significantly increased in the PA patients compared with EH patients. A correlation matrix showed that LVMI correlated with age (r=0.420, P=0.015), PQ duration (r=0.689, P<0.0001), CVI_s (r=-0.418, P=0.015), baseline supine PRA (r=-0.376, P=0.029), PFVA (r=0.411, P=0.017), and ACLVF (r=0.376, P=0.046).

View this table: [in this window] [in a new window]   Table 1. TABLE 1. Clinical Features of the Patients With PA and EH

View this table: [in this window] [in a new window]   Table 2. TABLE 2. Echocardiographic Features and Transmitral Flow Velocity Doppler-Derived Indexes of Diastolic Function of the Patients With PA and EH

Videodensitometric Analysis of the Left Ventricle Myocardial Texture
The Figure shows the results of the videodensitometric measurements of the interventricular septum (CVI_s), LV posterior wall (CVI_pw), and the mean of the 2 indexes (CVI_m). Compared with EH patients, PA patients had lower values of both CVI_s and CVI_m, whereas the difference of CVI_pw was of borderline statistical significance, mainly because of an inferior reproducibility of this measurement compared with that of measurements of the septum. CVI_s correlated with CVI_pw (r=0.528, P=0.02), PQ duration (r=-0.0451, P=0.009), baseline supine PRA (r=0.435, P=0.013), LVMI, and the Doppler-derived index of LV filling PFVA (r=-0.340, P=0.041), whereas no significant correlation with plasma aldosterone levels was detected. However, aldosterone entered in the regression analysis on CVI_s (ß=0.464, P=0.042), as did PQ duration (ß=0.563, P=0.022), baseline supine PRA (ß=0.503, P=0.033), and age (ß=0.338, P=0.135). This model significantly (P=0.026) predicted CVI_s and accounted for 36% (adjusted R²=0.357) of its variance.

View larger version (11K): [in this window] [in a new window]   The bar graph shows the mean values of CVIs, CVIpw, and CVIm. Patients with PA had significantly lower values for both indexes compared with EH patients, thus suggesting the presence of CF.

	Discussion

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We compared echocardiographically-derived indexes, which estimate myocardial texture and were shown to correlate with extracellular matrix and collagen deposition in humans,²² between consecutive hypertensive PA and EH patients. These patients were carefully matched for demographics, casual blood pressure values, and duration of hypertension to minimize potential biases due to an unbalanced distribution of variables between groups. Accordingly, the groups differed only for PRA, aldosterone, and serum potassium levels, because of the different causes of hypertension. Nonetheless, PA patients exhibited notable differences in LV mass, filling, and myocardial textures, including a higher LVMI, which translated into a higher prevalence of LVH and of LV remodeling, and significant changes in Doppler-derived indexes of LV filling (Table 2) in accord with previous results.¹⁷ Thus, although confirming that excess aldosterone affects cardiac mass independent of blood pressure, our findings indicate that the left ventricle is more dependent on the atrial contraction for its filling in PA patients. No conclusions on the role of CF could be made because LV filling was assessed indirectly by transmitral Doppler flow velocity measurements with no concomitant pressure gradient measurements, analysis of pulmonic venous flow, and/or of isovolumetric relaxation time.²³

The present results provide an important novel piece of information, which is relevant for the understanding of all the aforementioned changes in LV mass and filling. Despite the modest increase of LV mass and the lack of overt clinical signs of diastolic dysfunction, the PA patients exhibited greater alterations of videodensitometric indexes of LV myocardial texture, compared with demographically and hemodynamically similar EH patients. The changes of myocardial texture involved the interventricular septum and the LV posterior wall and were evident in PA patients with quite small Conn’s adenoma, suggesting that these changes occur early in the course of the disease.

We could identify only a small series of suitable EH patients to match our PA patients within the time span of this study. However, these EH patients showed values of CVI_s and CVI_pw that were almost identical to those found in a larger series of EH patients with normal LV mass and concentric remodeling, ²⁴ thus making a selection bias unlikely. Furthermore, in another series of EH patients who had a marked concentric LVH, CVI_s values were quite similar to those seen in the PA patients, who had a much lower LV mass index.²⁴ Thus, excess aldosterone can act synergistically with the pressure overload in altering myocardial texture.

The alterations in the acoustic properties of myocardium might be explained on several grounds. It is possible that an increased deposition of extracellular matrix and collagen, occurring as a result of the excess aldosterone in PA, could create increased scattering in systole. One of the mechanisms that explains the loss of acoustic myocardial reflectivity seen in normal subjects in systole is the shortening of myocardial fibers during contraction. Therefore, an augmented collagen content, which was found in postmortem specimens of hearts from a few patients with autopsy-proven adrenal adenoma,²⁵ could decrease the normal cyclic variation of scattering by impairing the intrinsic contractile properties of the heart. Another mechanism relates to the pressure-volume overload which, by stretching the myocardium, could change the orientation, structure, or geometry of both the muscle fibers and the collagen network, thereby influencing the acoustic properties of the myocardium. Whatever the mechanisms, our results indicate that videodensitometric analysis of myocardial texture could be a sensitive test, along with indexes of LV mass and LV filling changes, for the early identification of cardiac involvement in patients with PA.

To gain further mechanistic insight, we examined the relationships between individual variables and videodensitometric indexes of CF. We found a direct relationship of CVI_s with PRA, indicating that lower PRA values are associated with higher collagen deposition in the heart. A significant inverse relationship with duration of PQ interval, LVMI, and PFVA was also found, thus showing that increased collagen deposition is associated with prolongation of the PQ interval, which accords well with previous findings,¹⁷ and with increasing LV mass and peak flow velocity rate during presystole. A regression analysis also identified PQ duration, baseline supine PRA, plasma aldosterone, and age as predictors of CVI_s. Because the ECG PQ interval reflects conduction time from the sinoatrial node through the atria, the atrioventricular node, and the Purkinje fibers to the left ventricle, the highly significant (P=0.009) correlation of CVI_s with PQ duration suggests that CF can also be an important determinant of the latter.

	Conclusions

Top Abstract Introduction Methods Results Discussion Conclusions References

 
PA patients exhibit significant changes of myocardial texture compared with demographically and hemodynamically similar EH patients, which may be due to CF and occur before the development of overt LVH and diastolic dysfunction. These changes correlated with a prolongation of the PQ interval, a decrease of LV early filling, and an increase of ACLVF, thus indicating that LV filling occurs predominantly during atrial contraction in PA patients. Collectively, these results support the hypothesis that aldosterone excess affects LV anatomy and function by increasing LV mass through increased deposition of extracellular matrix and collagen and by changing LV filling, in part through a prolongation of atrioventricular conduction time. The greater dependence of LV diastolic filling from presystole can explain the nefarious effects of atrial fibrillation in PA patients; the prolongation of the PQ interval changes along with hypokalemia might account for their predisposition to atrioventricular block.

Perspectives
The present results might be relevant for understanding the LV changes of patients with secondary aldosteronism, such as those with congestive heart failure in whom blockade of the mineralocorticoid receptor with spironolactone strikingly improved outcome,²⁶ decreased LV mass index and LV end- diastolic diameter and volume, and lowered biochemical markers of myocardial fibrosis and hypertrophy.²⁷ The newer technologies, such as backscatter analysis and MRI, that are being developed to assess myocardial texture and extracellular matrix might eventually be useful to confirm the detrimental role of excess aldosterone on the heart found in this study in congestive heart failure patients with hyperaldosteronism.

	Acknowledgments

 
This study was supported by grants from the Italian Cabinet of University and Scientific Research (MURST) to A.C.P. (9906193152_001/06) and from Regione Veneto to G.P.R. (863/01/98).

Received March 29, 2002; accepted May 3, 2002.

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