Excess Aldosterone Is Associated With Alterations ofMyocardial 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

Abstract—Hyperaldosteronism has been causally linked to myocardial interstitial fibrosis experimentally, but it remainsunclear if this link also applies to humans. Thus, we investigated the effects of excess aldosterone due to primaryaldosteronism (PA) on collagen deposition in the heart. We used echocardiography to estimate left ventricular (LV) wallthickness and dimensions and for videodensitometric analysis of myocardial texture in 17 consecutive patients with PAand 10 patients with primary (essential) hypertension who were matched for demographics, casual blood pressure, andknown duration of hypertension. The groups differed in serum K�, ECG PQ interval duration, plasma renin activity, andaldosterone levels (all P�0.002) 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/m2.7;P�0.008) and lower values of the cyclic variation index of the myocardial mean gray level of septum (CVIs;�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). Aregression analysis showed that CVIs was predicted by the PQ duration, supine plasma renin activity, plasmaaldosterone, and age, which collectively accounted for �36% of CVIs variance. PA is associated with alterations ofmyocardial textures that suggest increased collagen deposition and that can explain both the dependence of LV diastolicfilling from presystole and the prolongation of the PQ interval. (Hypertension. 2002;40:23-27.)

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

Left ventricular hypertrophy (LVH) is commonly associ-ated with arterial hypertension and represents an impor-

tant independent predictor of cardiovascular events,1 includ-ing congestive heart failure. Extracellular matrix and collagendeposition are invariable findings of LVH and lead to cardiacfibrosis (CF), which occurs particularly in the perivascularareas and correlates directly with the severity of LVH.2 CF isa major cause of cardiac dysfunction because an excessivedeposition of collagen may be responsible for abnormal tissuestiffness and diastolic dysfunction. The latter is an earlymarker of heart involvement in hypertension (for review, seeAgabiti-Rosei and Muiesan3) and is associated with CF moreclosely than with LVH.4,5

Fibroblasts constitute the vast majority (�90%) of non-myocyte cells in the heart; they can increase the production ofextracellular matrix on exposure to a variety of injuries,including pressure overload. The latter seems to be only oneof the determinants of CF, because it was experimentallyshown, both in vitro and in vivo, that CF in both ventricleswas linked to activation of the renin-angiotensin-aldosteronesystem6 and that it could be prevented by non-antihypertensive dosages of spironolactone.7

Thus, angiotensin II and aldosterone play important rolesin the heart (for review, see Swynghedauw8). Angiotensin II

induces cardiomyocyte hypertrophy in both ventricles,9 stim-ulates collagen synthesis by fibroblasts, and regulates colla-gen degradation by blunting the activity of matrixmetalloproteinase-1, the key enzyme of collagen degrada-tion.8 Aldosterone is extracted through the human heartthrough a spironolactone-sensitive pathway10 and promotesCF by acting through different pathogenic mechanisms.8,11 Itincreases types I and III procollagen mRNA in both ventri-cles, although it does not seem to influence matrixmetalloproteinase-1 activity in cultured cardiac fibroblastpreparations.12 Aldosterone may also act on the cardiacangiotensin II receptor, because its administration, along witha high-salt diet, increased angiotensin II type 1 (AT-1)receptor density in the left ventricle of rats; this increase wasprevented by both spironolactone and losartan.13 Thus, aldo-sterone might cause extracellular matrix deposition by en-hancing the transcription of collagen type I and III genes andby augmenting the effects of angiotensin II on AT-1receptors.14

Primary aldosteronism (PA) offers a unique opportunityfor 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

Received March 29, 2002; first decision April 24, 2002; revision accepted May 3, 2002.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@unipd.it© 2002 American Heart Association, Inc.

Hypertension is available at http://www.hypertensionaha.org DOI: 10.1161/01.HYP.0000023182.68420.EB

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excess of LVH15; this finding was thereafter confirmed inJapanese PA patients.16 Doppler flow velocity indexes ofearly diastole transmitral flow are decreased compared withthose from patients with primary (essential) hypertension(EH). These alterations were more marked in patients with aConn’s adenoma, in whom aldosterone excess and reninsuppression were also more prominent, and were corrected byadrenalectomy,17 thus indicating a causative role of excessaldosterone in CF. To prove this link conclusively, histolog-ical analysis of myocardial biopsies would be necessary, butthis is unfeasible for ethical reasons. However, newer nonin-vasive technologies, such as the videodensitometric analysisof myocardial texture that have proven to be accurate forassessing CF,18,19 provide a tool to reexamine this question.Therefore, we sought to compare myocardial texture indexesbetween consecutive PA and EH patients.

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

EchocardiographyAll patients were in sinus rhythm, and none had any valvular orischemic heart disease. Conn’s adenoma patients were studied beforeadrenalectomy. M-mode and 2D echocardiograms and Doppleranalysis 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 thecalculation of LV mass and relative wall thickness were performedas described previously.17 LV mass was normalized for height2.7 toobtain the LV mass index (LVMI). Criteria for concentric andeccentric LVH and LV remodeling have been describedpreviously.17

A single reader (A.S.) blindly performed the following measure-ments on a pulsed Doppler transmitral flow velocity profile: earlydiastolic (E wave) peak flow velocity (PFVE), diastolic peak flowvelocity at atrial contraction (A wave, PFVA), their ratio (PFVE/PFVA), E wave integral (Ei), A wave integral (Ai), their ratio (Ei/Ai),and the atrial contribution to LV filling (ACLVF), as reportedpreviously.17

Blood pressure was measured while the patients were off medi-cations using a mercury sphygmomanometer with phase V ofKorotkoff for diastolic pressure, before and after echocardiography.

VideodensitometryTo achieve a precise and reproducible sampling of textural param-eters, the gain settings and compensation profiles were adjusted forall subjects to obtain uniform myocardial brightness throughout theechocardiogram. The gray scale transfer function was adjusted to belinear for the entire video signal range; no reject, enhancement, ordynamic ranges were used; and a 25 to 30 dB amplification at a depthof 18 cm was set. The optimal echocardiographic images weretransferred to a calibrated video digitization system and convertedinto 256�256 pixels of 256 gray levels, each with a real-timevideodigitizer (Tomtec Imaging Systems).19,22 Each cardiac cyclewas automatically divided into 12 frames independently of heart rate.The images corresponding to the end-diastolic and end-systolicphases, all in long-axis projection, were selected with an optimal

visualization of both the interventricular septum and the LV posteriorwall.

The regions of interest for texture analysis were chosen byconsensus of 2 observers who were blinded to the diagnosis group,as described previously.22 The regions of interest, which were alwaysthe same size (32�42 pixels), were placed in the same location in theseptum (midseptum) and in the posterior wall (midposterior) in bothend-systolic and end-diastolic frames. We also considered the delayor phase-shift of the cyclic variation in all septum and posterior wallsamplings; a time delay of 1.0 corresponded to a peak nearend-diastole, and a nadir near end-systole was found in mean graylevel cyclic variation.19,22 A histogram of the gray level distributionwas 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 eachregions of interest. A quantitative analysis of the shape of eachdistribution was also performed using skewness and kurtosis. Thecyclic variation index (CVI) of the myocardial gray level amplitudewas calculated as described previously.22 Measurements were aver-ages of at least 5 consecutive cardiac cycles. Reproducibility wasestimated by analyzing, in a blinded fashion, all recordings on 2separate occasions by the same (intraobserver variability) or different(interobserver variability) investigators. Intraobserver and interob-server coefficients of variation averaged 7.5% and 10.2%, respec-tively. The intraclass correlation coefficient for septum mean graylevel was 0.92 for diastolic and 0.90 for systolic samples; forposterior wall mean gray level, it was 0.89 for diastolic and 0.91 forsystolic samples.

Statistical AnalysisResults are presented as mean�SD (or SEM or range); comparisonbetween groups was performed with Student’s t test for unpaired dataor the Mann-Whitney test. The relationship between individualvariables was examined by scatter plot analysis and correlationmatrix followed by a stepwise linear regression analysis on the CVIof the septum (CVIs) of the variables that were of interest in thescatter plot analysis.

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

ResultsClinical Features and Echocardiographic andDoppler Indexes of the PatientsAfter matching, the groups were demographically similar andhad superimposable heart rates, blood pressure values, andknown durations of hypertension (Table 1). They differed inserum potassium, supine baseline and captopril-stimulatedplasma renin activity (PRA; which were significantly lower),and plasma aldosterone, which was higher in PA than in EHpatients. A longer PQ ECG interval was also noticed in PApatients. Table 2 shows the results of the measurements of LVwall thickness and dimensions. LVMI was significantlyhigher in PA than in EH patients, whereas relative wallthickness did not differ between groups. LVH was present in30% of the 17 PA and none of the EH patients; LV concentricremodeling was seen in 17% of PA and 10% of EH patients(P�0.05). Doppler flow velocity recordings were qualita-tively adequate in all patients (Table 2). In the PA group,PFVE/PFVA was lower than in EH patients and showed E/Ainversion, whereas E/A was close to unity in the EH group.Similarly, Ai was higher and Ei/Ai was lower in PA than inEH patients; the ACLVF was significantly increased in thePA patients compared with EH patients. A correlation matrixshowed that LVMI correlated with age (r�0.420, P�0.015),PQ duration (r�0.689, P�0.0001), CVIs (r��0.418,

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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).

Videodensitometric Analysis of the Left VentricleMyocardial TextureThe Figure shows the results of the videodensitometricmeasurements of the interventricular septum (CVIs), LVposterior wall (CVIpw), and the mean of the 2 indexes (CVIm).Compared with EH patients, PA patients had lower values ofboth CVIs and CVIm, whereas the difference of CVIpw was ofborderline statistical significance, mainly because of aninferior reproducibility of this measurement compared withthat of measurements of the septum. CVIs correlated withCVIpw (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 correlationwith plasma aldosterone levels was detected. However, aldo-sterone entered in the regression analysis on CVIs (��0.464,P�0.042), as did PQ duration (��0.563, P�0.022), baselinesupine PRA (��0.503, P�0.033), and age (��0.338,P�0.135). This model significantly (P�0.026) predictedCVIs and accounted for �36% (adjusted R2�0.357) of itsvariance.

DiscussionWe compared echocardiographically-derived indexes, whichestimate myocardial texture and were shown to correlate withextracellular matrix and collagen deposition in humans,22

between consecutive hypertensive PA and EH patients. Thesepatients were carefully matched for demographics, casualblood pressure values, and duration of hypertension to min-

imize potential biases due to an unbalanced distribution ofvariables between groups. Accordingly, the groups differedonly 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

TABLE 1. Clinical Features of the Patients With PA and EH

Variable PA (n�17) P EH (n�10)

Gender (female:male), % 35/65 NS 20/80

Age, y 52�13 NS 48�14

Body mass index, kg/m2 27�2 NS 25�3

Body surface area, m2 1.9�0.18 NS 1.9�0.10

Serum K�, mmol/L 3.46�0.10 0.002 4.01�0.07

Known duration ofhypertension, mo

92�74 NS 94�60

ECG PQ interval, ms 175�6 0.002 132�4

Plasma aldosterone, pmol/L 283�34 �0.001 134�6

Supine PRA, ng of angiotensinI � mL�1 � h�1

0.48�0.22 �0.001 0.95�0.35

Captopril-stimulated PRA, ng ofangiotensin I � mL�1 � h�1

0.68�0.77 NS 1.45�1.42

SBP, mm Hg 159�15 NS 165�11

DBP, mm Hg 100�8 NS 101�3.27

MBP, mm Hg 120�10 NS 123�5

Heart rate, bpm 76�10 NS 71�4

Tumor size, mm* 14.1�1.4 � � � � � �

Values are mean�SD. SBP, DBP, and MBP indicate systolic, diastolic, andmean blood pressure, respectively.

*Measured in the 15 PA patients with a Conn’s adenoma.

TABLE 2. Echocardiographic Features and Transmitral FlowVelocity Doppler-Derived Indexes of Diastolic Function of thePatients With PA and EH

Variable PA (n�17) P EH (n�10)

LVEDD, mm 5.32�0.14 NS 5.25�0.09

LVESD, mm 3.51�0.14 NS 3.30�0.07

IVSd, mm 1.07�0.03 NS 0.98�0.03

PWd, mm 1.05�0.03 NS 1.02�0.03

RWT, mm 0.40�0.02 NS 0.38�0.01

LVMI, g/m2.7 53.7�1.8 0.008 45.5�2.0

LAD, mm 38.3�0.3 NS 37.4�0.3

AoD, mm 35.9�0.4 NS 33.8�0.3

LAD/AoD 1.08�0.04 NS 1.11�0.02

FS, % 34.2�1.3 NS 37.2�0.9

LVEDV, mL 138.7�8.8 NS 132.9�4.9

LVESV, mL 53.1�5.8 NS 44.4�2.17

EF, % 62.5�1.8 NS 66.6�1.2

SV, mL 85.6�4.5 NS 88.4�3.6

CO, L/min 6.4�0.3 NS 6.3�0.3

PFVE, mm/s 56.5�2.0 NS 58.5�3.8

PFVA, mm/s 71.9�3.9 0.012 55.4�4.2

PFVE/PFVA 0.83�0.06 0.011 1.09�0.08

Ei, mm 102.8�6.3 NS 102.4�5.3

Ai, mm 84.4�5.3 0.003 52.4�7.4

Ei/Ai 1.26�0.09 �0.001 2.02�0.15

ACLVF, % 45.1�1.6 �0.001 33.6�1.5

Values are mean�SD. ACLVF indicates atrial contribution to LV filling; AoD,aortic root diameter; CO, cardiac output; EF, ejection fraction; Ei, E (earlydiastolic LV filling) wave integral; Ai, A (late diastolic LV filling) wave integral;FS, fraction shortening; LAD, left atrial dimension; LVEDD, LV end-diastolicdimension; LVESD, LV end-systolic dimension; IVSd, end-diastolic interventric-ular septum thickness; LVMI, left ventricular mass index; LVEDV, LV end-dia-stolic volume; LVESV, LV end-systolic volume; PFVE, early diastolic peak flowvelocity; PFVA, late diastolic peak flow velocity; PWd, end-diastolic LV posteriorwall thickness; RWT, relative wall thickness; SV, stroke volume.

The bar graph shows the mean values of CVIs, CVIpw, andCVIm. Patients with PA had significantly lower values for bothindexes compared with EH patients, thus suggesting thepresence of CF.

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translated into a higher prevalence of LVH and of LVremodeling, and significant changes in Doppler-derived in-dexes of LV filling (Table 2) in accord with previousresults.17 Thus, although confirming that excess aldosteroneaffects cardiac mass independent of blood pressure, ourfindings indicate that the left ventricle is more dependent onthe atrial contraction for its filling in PA patients. Noconclusions on the role of CF could be made because LVfilling was assessed indirectly by transmitral Doppler flowvelocity measurements with no concomitant pressure gradientmeasurements, analysis of pulmonic venous flow, and/or ofisovolumetric relaxation time.23

The present results provide an important novel piece ofinformation, which is relevant for the understanding of all theaforementioned changes in LV mass and filling. Despite themodest increase of LV mass and the lack of overt clinicalsigns of diastolic dysfunction, the PA patients exhibitedgreater alterations of videodensitometric indexes of LV myo-cardial texture, compared with demographically and hemo-dynamically similar EH patients. The changes of myocardialtexture involved the interventricular septum and the LVposterior wall and were evident in PA patients with quitesmall Conn’s adenoma, suggesting that these changes occurearly in the course of the disease.

We could identify only a small series of suitable EHpatients to match our PA patients within the time span of thisstudy. However, these EH patients showed values of CVIs

and CVIpw that were almost identical to those found in a largerseries of EH patients with normal LV mass and concentricremodeling,24 thus making a selection bias unlikely. Further-more, in another series of EH patients who had a markedconcentric LVH, CVIs values were quite similar to those seenin the PA patients, who had a much lower LV mass index.24

Thus, excess aldosterone can act synergistically with thepressure overload in altering myocardial texture.

The alterations in the acoustic properties of myocardiummight be explained on several grounds. It is possible that anincreased deposition of extracellular matrix and collagen,occurring as a result of the excess aldosterone in PA, couldcreate increased scattering in systole. One of the mechanismsthat explains the loss of acoustic myocardial reflectivity seenin normal subjects in systole is the shortening of myocardialfibers during contraction. Therefore, an augmented collagencontent, which was found in postmortem specimens of heartsfrom a few patients with autopsy-proven adrenal adenoma,25

could decrease the normal cyclic variation of scattering byimpairing the intrinsic contractile properties of the heart.Another mechanism relates to the pressure-volume overloadwhich, by stretching the myocardium, could change theorientation, structure, or geometry of both the muscle fibersand the collagen network, thereby influencing the acousticproperties of the myocardium. Whatever the mechanisms, ourresults indicate that videodensitometric analysis of myocar-dial texture could be a sensitive test, along with indexes ofLV mass and LV filling changes, for the early identificationof cardiac involvement in patients with PA.

To gain further mechanistic insight, we examined therelationships between individual variables and videodensito-metric indexes of CF. We found a direct relationship of CVIs

with PRA, indicating that lower PRA values are associatedwith higher collagen deposition in the heart. A significantinverse relationship with duration of PQ interval, LVMI, andPFVA was also found, thus showing that increased collagendeposition is associated with prolongation of the PQ interval,which accords well with previous findings,17 and with in-creasing LV mass and peak flow velocity rate during presys-tole. A regression analysis also identified PQ duration,baseline supine PRA, plasma aldosterone, and age as predic-tors of CVIs. Because the ECG PQ interval reflects conduc-tion time from the sinoatrial node through the atria, theatrioventricular node, and the Purkinje fibers to the leftventricle, the highly significant (P�0.009) correlation ofCVIs with PQ duration suggests that CF can also be animportant determinant of the latter.

ConclusionsPA patients exhibit significant changes of myocardial texturecompared with demographically and hemodynamically sim-ilar EH patients, which may be due to CF and occur beforethe development of overt LVH and diastolic dysfunction.These changes correlated with a prolongation of the PQinterval, a decrease of LV early filling, and an increase ofACLVF, thus indicating that LV filling occurs predominantlyduring atrial contraction in PA patients. Collectively, theseresults support the hypothesis that aldosterone excess affectsLV anatomy and function by increasing LV mass throughincreased deposition of extracellular matrix and collagen andby changing LV filling, in part through a prolongation ofatrioventricular conduction time. The greater dependence ofLV diastolic filling from presystole can explain the nefariouseffects of atrial fibrillation in PA patients; the prolongation ofthe PQ interval changes along with hypokalemia mightaccount for their predisposition to atrioventricular block.

PerspectivesThe present results might be relevant for understanding theLV changes of patients with secondary aldosteronism, such asthose with congestive heart failure in whom blockade of themineralocorticoid receptor with spironolactone strikingly im-proved outcome,26 decreased LV mass index and LV end-diastolic diameter and volume, and lowered biochemicalmarkers of myocardial fibrosis and hypertrophy.27 Thenewer technologies, such as backscatter analysis and MRI,that are being developed to assess myocardial texture andextracellular matrix might eventually be useful to confirmthe detrimental role of excess aldosterone on the heartfound in this study in congestive heart failure patients withhyperaldosteronism.

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

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Alessio Bertini, Davide Giorgi, Roldano Scognamiglio, Mario Mariani and Achille C. PessinaGian Paolo Rossi, Vitantonio Di Bello, Chiara Ganzaroli, Alfredo Sacchetto, Maurizio Cesari,

AldosteronismExcess ldosterone Is Associated With Alterations of Myocardial Texture in Primary

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