Pituitary 4: 251–257, 2001

C© 2002 Kluwer Academic Publishers. Manufactured in The Netherlands.

Cardiovascular Complications in Acromegaly:Methods of Assessment

Giovanni Vitale1, Rosario Pivonello1, MaurizioGalderisi 2, Arcangelo D’Errico 2, Letizia Spinelli 3,Giovanni Lupoli1, Gaetano Lombardi1,and Annamaria Colao1

Departments of 1Molecular and Clinical Endocrinologyand Oncology, 2Clinical and Experimental Medicine, Chairof Emergency Medicine, 3Medicine I, “Federico II” Universityof Naples, Via Pansini 5, 80131 Naples, Italy

Abstract. Cardiac involvement is common in acromegaly.

Evidence for cardiac hypertrophy, dilation and diastolic fill-

ing abnormalities has been widely reported in literature.

Generally, ventricular hypertrophy is revealed by echocar-

diography but early data referred increased cardiac size by

standard X-ray. Besides, echocardiography investigates car-

diac function and value disease. There are new technologic

advances in ultrasonic imaging. Pulsed Tissue Doppler is a

new non-invasive ultrasound tool which extends Doppler

applications beyond the analysis of intra-cardiac flow ve-

locities until the quantitative assessment of the regional

myocardial left ventricular wall motion, measuring directly

velocities and time intervals of myocardium. The radionu-

clide techniques permit to study better the cardiac perfor-

mance. In fact, diastolic as well as systolic function can be

assessed at rest and at peak exercise by equilibrium ra-

dionuclide angiography. This method has a main advantage

of providing direct evaluation of ventricular function, be-

ing operator independent. Coronary artery disease has been

poorly studied mainly because of the necessity to perform

invasive procedures. Only a few cases have been reported

with heart failure study by coronarography and having al-

terations of perfusion which ameliorated after somatostatin

analog treatment. More recently, a few data have been pre-

sented using perfusional scintigraphy in acromegaly, even

if coronary artery disease does not seem very frequent in

acromegaly. Doppler analysis of carotid arteries can be also

performed to investigate atherosclerosis: however, patients

with active acromegaly have endothelial dysfunction more

than clear-cut atherosclerotic plaques. In conclusion, care-

ful assessments of cardiac function, morphology and activity

need in patients with acromegaly.

Key Words. GH, IGF-I, acromegaly, echocardiography,

doppler ultrasonography, radionuclide angiography, left

ventricular hypertrophy, endothelial dysfunction

Introduction

The cardiovascular involvement of GH and IGF-I excessis known since the first description of acromegaly. Inphysiological condition these hormones modulate thedevelopmental growth of the heart and the maintenanceof its structure [1–3], while chronic excess of GH and

IGF-I secretion affects cardiac morphology and perfor-mance inducing a specific acromegalic cardiomyopathy(Fig. 1) [4–6]. GH and IGF-I excess exposes these pa-tients to a doubled mortality rate, mostly for cardiovas-cular diseases.

Biventricular concentric hypertrophy is a commonfeature in acromegaly [5,7]. Cardiac walls are thickened,but cardiac chambers are rarely enlarged, an event re-sulting from the relative increase of cardiac myocyteswidth, due to the parallel assembling of new contractile-protein units [8]. Mitral and aortic valve disease, as wellas cavity dilation, may be observed in the late stage[9]. Besides, the coexistence of other cardiovascularand metabolic diseases (hypertension, abnormal glu-cose tollerance or diabetes mellitus, arrhythmias, coro-nary artery disease, thyroid disorders) induces a moresevere cardiac impairment and a premature atheroscle-rosis [10,11]. At histology, the most relevant abnormali-ties are interstitial fibrosis, increased extra-cellular col-lagen deposition, myofibrillar derangement, and areasof monocyte necrosis and lympho-mononuclear infiltra-tion, gradually impairing the whole organ architecture[12–15].

The natural hystory of acromegalic cardiomyopathyincludes a first stage, characterized by a hyperkinetic leftventricle with an increase in contractility and cardiacoutput; a second stage, at the time of the diagnosis, withleft ventricular (LV) hypertrophy, diastolic filling abnor-malities at rest, and impaired cardiac performance dur-ing physical exercise; a third phase, when acromegaly isleft untreated or in case of late diagnosis, characterizedby valve disease and impaired systolic and diastolic per-formance with low cardiac output even at rest, leadingto congestive heart failure [9].

Therefore, the evaluation of cardiac performanceand morphology represents a crucial step in themanagement of acromegaly.

Address correspondence to: Annamaria Colao, Department ofMolecular and Clinical Endocrinology and Oncology, “Federico II”University of Naples, via S. Pansini 5, 80131 Napoli, Italy. Tel: +39-081-7462132; Fax: +39-081-5465443; E-mail: colao@unina.it.

252 Vitale et al.

Fig. 1. Cardiac complications in acromegaly.

Methods of Assessments

Standard X-ray

LV hypertrophy is one of the most common manifesta-tions of acromegaly found in over 90% of patients withlong-standing disease. Hypertrophy does not only affectthe left ventricle but also the right ventricle and haspeculiar characteristic to occur in absence of hyperten-sion. Standard X-ray and the 12-lead electrocardiogramhave been first methods able to detect the increase incardiac size [16,17]. However, after the introduction ofechocardiography both methods had a less impact in theclinical management.

Echocardiograpic techniques

Echocardiography is used for the evaluation of cardiacperformance and morphology because of high resolu-tion in assessing ventricular anatomy and function, non-invasive nature, moderate cost and good reproducibil-ity (Fig. 2) [18]. LV mass is an important parameter todetect LV hypertrophy [19]. It is frequently performedusing the Penn convention or by the more widely usedconvention of the american Society of Echocardiogra-phy [19,20]. However, the relation between heart andbody size should be taken into account for the detec-tion of LV hypertrophy. Therefore, LV mass is indexedto body surface area, height or height powered to 2.7in order to remove the effect of normal variation inbody size from the clinical evaluation of LV hypertro-phy [20–22]. All previous trials concerning acromegaly

have detected LV hypertrophy on the basis of LV massindexed for body surface area (≥135 g/m2 in men and ≥110 g/m2 in women) [22]. This method is very com-mon, but has been criticized for disregarding the effectsof overweight [21]. Echocardiography can also revealabnormalities of the interventricular septum that diag-noses the so-called asymmetric hypertrophy. In otheracromegalic patients echocardiography presents an in-crease of LV mass mainly due to the increase of LVchamber size. This is the eccentric hypertrophy whichcorresponds to a high LV mass index but also to a relativediastolic wall thickness (septal wall thickness + poste-rior wall thickness/LV internal end-diastolic diameter)normal, i.e. <0.44 [19].

Moreover, by Doppler standard echocardiography, itis possible to investigate cardiac function. At diagnosis,patients with acromegaly generally present alteration ofthe diastolic filling and more rarely inadequacy of sys-tolic function [7,23,24]. Doppler ultrasonography docu-ments that both the early diastolic filling velocity andthe early to late mitral and tricuspid velocity ratio aregenerally decreased [25], whereas a limited elasticity ofmyocardial fibers can also prolong the isovolumic relax-ation time [7,10]. This disorder can be asymptomatic foryears before clinical and instrumental signs of cardiacinvolvement are experienced.

However, this cardiac impairment is negatively af-fected by hypertension and/or diabetes mellitus. Wereported [10] an higher prevalence of LV hypertrophy,impaired diastolic and systolic function in acromegalicpatients with hypertension (75%, 50% and 18.7%, re-spectively) than uncomplicated acromegaly (37.2%, 7.8%and 3.9%, respectively), whereas patients with glucosetolerance abnormalities but without hypertension hadonly an increase in the prevalence of impaired diastolic(39.7%) and systolic function (31.7%). Besides, patientswith hypertension and diabetes mellitus had the high-est prevalence of LV hypertrophy (84.6%), diastolic fill-ing impairment (69.2%) and impaired systolic functionat rest (53.9%) [10]. Cardiac valve disease is anotherrelevant component of ventricular dysfunction. This iswell detected by echocardiographic techniques. Lie andGrossman [14] found mitral and aortic abnormalities in19% of their autoptic series. Zlatareva et al. [26] in a con-trolled study including 32 patients with acromegaly de-tected aortic regurgitation in 31%, mitral regurgitation in46.8% and tricuspid regurgitation in 37.5% of their cases.We have found a very high prevalence of morphologicalabnormalities both at the mitral and at the aortic valve inpatients with active acromegaly and in those already un-dergone successful surgery, and thus cured for at leastone year. Fibrosis, fibrosclerosis, thickening and/or cal-cifications at leaflets and/or annulus of the mitral and/orthe aortic valve were found in as high as 87% of pa-tients with active disease as well as 73% of those curedfrom acromegaly (unpublished data). Furthermore, mildmitral regurgitation was found in 26% of active and27% of cured patients while mild to moderate aortic

Assessment of Acromegalic Cardiomyopathy 253

Fig. 2. Detection of biventricular hypertrophy by echocardiography in acromegaly.

regurgitation was found in 31% of active and 18% ofcured patients. Therefore, both patients with activeacromegaly and those successfully cured by surgeryhave unexpectedly a very high prevalence of mitral andaortic valve abnormalities: the persistence of these ab-normalities in patients with cured acromegaly is likelyto be correlated with the persistence of LV hypertrophy(81% in active and 41% in cured patients), that shouldbe carefully and continuously monitored for the risk ofcardiac dysfunction (unpublished data). It is worth not-ing that surgical treatment of valvular heart disease wassafely performed in 10 of 951 patients, without any differ-ence in patients with active or inactive disease [27]. Oht-suka et al. [28] described ring fragility and leaflets dis-array, accompanied functionally with regurgitation andstenosis, suggesting that when the functional compli-cation requires a therapeutic intervention, replacementsurgery seems to assure a better result than valve plasty.

Radionuclide techniques

Radionuclide techniques allow a better investigationof cardiac performance: in fact, diastolic as well assystolic function can be assessed at rest and at peakexercise by equilibrium radionuclide angiography thathas a main advantage of providing direct evaluation ofventricular function, being operator independent. It al-lows the measurement of the ejection fraction relativelyto end-diastolic and end-systolic counts; furthermore,

filling and ejection rate can be normalised to the end-diastolic heart rate [29–32].

Impairments of diastolic filling capacities and ejec-tion fraction after exercise have been detected in 73%of patients by radionuclide angiography [33]. Accordingto age stratification, in a group of acromegalic patientswithout evidence of other complications we have ob-served an impairment of the ejection fraction at peak ex-ercise in 40% of those aged under 40 years and in 95% ofolder patients. The estimated disease duration was sig-nificantly and directly correlated with age, but inverselywith LV ejection fraction response at peak exercise andwith peak rate of LV filling. Therefore, patients’ age anddisease duration appeared to influence cardiac perfor-mance in acromegaly [34]. On these basis, equilibriumradionuclide angiography represents a valid method toinvestigate diastolic and systolic function. It should beincluded in the workup of acromegalic patients.

Coronary angiography

In acromegaly coronary artery disease has been poorlystudied because of the necessity to perform inva-sive procedure, but a prevalence of coronaropathyoscillating between 3 and 37% of cases has beenreported in different studies [35]. Post-mortem andheart-catheterization studies showed a prominent in-volvement of small vessels, and the thickening of theintramural vessels has been described in up to 22% of

254 Vitale et al.

cases [12–14]. Proximal arteries are generally normal,but they can either be enlarged and tortuous or, rarely,stenotic [14]. In addition, episodes of angina pectoris arerarely reported, but the presence of chronic myocardialischemia cannot be excluded. Coronary angiography isthe gold standard for the detection of obstructive coro-nary disease, but because of the risks related to thistechnique and the low prevalence of coronary diseases,it should be suggested only in acromegalic patients withangina or when the diagnosis of coronary artery diseaseis uncertain and cannot be reasonably excluded by non-invasive testing.

Twenty-four hours Holter electrocardiogram

Abnormalities of cardiac rhythm have been well doc-umented, both with electrocardiography studies andHolter recordings in acromegalic patients [36,37].

Several pathogenetic mechanisms contribute to thedevelopment of arrhythmias: anatomical uncoupling ofcardiomyocytes, re-entry events with zig-zag propaga-tion of transverse waveform, adaptational phenotypicchanges in membrane proteins [38]. The frequency ofsupraventricular premature complexes in acromegalyis not significantly higher as compared to the normalpopulation [36], while ectopic beats, paroxysmal atrialfibrillation, paroxysmal supraventricular tachycardia,sick sinus syndrome, ventricular tachycardia and bun-dle branch blocks are more frequently recorded than incontrol subjects, particularly during physical exercise[38,39]. Rodrigues et al. reported conduction disordersup to 41% of patients, but recovery from acromegalydoes not significantly improve this rate [39].

The results of an Italian multicenter study showeda significant decrease in mean 24 hours rate (from71.5 ± 20 to 66.5 ± 11 beats/minute) and in ventricularpremature beats after 6 months of lanreotide treatment[40]. Ventricular premature beats (>50/24 hours) werefound in 33% of the patients before treatment and in16.5% after therapy with lanreotide, while supraventric-ular premature beats showed scarce variation after thetherapy [40].

Doppler ultrasound of carotid arteries

and endothelial function study

Ultrasound of both carotid arteries permits to detect al-terations of vessels’ morphology and blood flow, in orderto evaluate vascular damages induced by the excess ofGH.

We have found a significant increase of the carotidintima-media thickness (IMT) without an increasedprevalence of atherosclerotic plaques both in acrome-galic patients with active disease and in patients curedfrom this disease compared to controls [41]. Further-more, patients with acromegaly have increased insulinlevels, which are known to be directly correlated withIMT [42–44]. In addition, the prevalence of hyperten-sion, glucose tolerance alterations, impaired lipid pro-file and increased fibrinogen levels, was found slightlyhigher in the group of cured acromegalic patients than

in controls [41]. However, lanreotide treatment signifi-cantly inhibited GH and IGF-I secretion, decreased in-sulin, triglyceride and fibrinogen levels and reduced IMTin both carotid arteries in most normotensive patientswith acromegaly [45].

An early step in atherogenesis is the alteration of thenormal properties of the endothelium, among which theability to release nitric oxide and induce vasodilation inresponse to physiological stimuli, such as increase inblood flow [46]. Endothelial function, as expressed byflow-mediated dilation (FMD), can be measured by avalidated, reproducible technique [47]. The reduction inFMD is a marker of endothelial dysfunction, a general-ized process, not necessarily confined to vascular bedwith overt atherosclerosis. It may represent a measureof susceptibility to atheroma. In fact, it is possible to ob-serve an impairment in FMD of the brachial artery of pa-tients with coronary [48] and peripheral arterial disease[49], without angiographically apparent disease [50].

A recent report provides direct evidence for earlyfunctional and morphological alterations in the vascu-lature of patients with acromegaly. In active acrome-galic patients, FMD of the brachial artery was lowerthan in both healthy subjects and matched controlsfor age, sex, classical risk factors and treatments.No difference between groups was observed forendothelium-independent vasodilation [51]. Acrome-galic patients had also higher IMT of the carotid ar-teries than healthy controls, while no difference wasobserved with matched controls. In cured acromegalicpatients FMD was significantly lower than in healthycontrols, but higher than in active patients. No differ-ence in IMT was observed between active and curedpatients. Therefore, endothelial dysfunction, but notintima-media thickening, is attenuated in patients curedfrom acromegaly. This indicates that the vascular defectis reversible, at least in its earlier manifestation [51].

Future Perspectives in the Assessmentof Cardiovascular Complications

There are new technologic advances in ultrasonicimaging.

Pulsed Tissue Doppler (TD) is a new non-invasiveultrasound tool which extends Doppler applications be-yond the analysis of intra-cardiac flow velocities untilthe quantitative assessment of the regional myocardialLV wall motion. While standard echocardiography col-lects data about the cardiac function either from param-eters measured from the blood-myocardial boundariesor from Doppler flow, Pulsed Tissue Doppler has the pe-culiarity of measuring directly velocities and time inter-vals of myocardium by placing a sample volume withinthe chosen myocardial walls [52–54]. Mercuro et al. [55]confirmed the known abnormal LV filling and relaxationpattern diastolic dysfunction, that frequently occurs inacromegaly, by pulsed TD. In addition, this method wasable to reveal an impaired systolic cardiac performance

Assessment of Acromegalic Cardiomyopathy 255

Fig. 3. Evaluation of coronary flow reserve at baseline (panel A and B) and after dipyridamole administration (panel C and D) in

acromegalic patient.

in acromegalic patients at rest. At present, radionuclideangiography still remains the only technique able of de-tecting a worsening of the systolic performance, at leaston effort [33]. Therefore, pulsed TD appears to give newphysiopathological details of the impaired cardiac per-formance in acromegaly.

In the last years, a great technologic development hasbeen also observed in vascular ultrasound. Presently,we can assess coronary blood flow by noninvasivetechniques.

The visualization of the distal left anterior descen-dent artery is possible using a modified foreshortened2-chamber view obtained by sliding the transducer onthe upper part and medially from an apical 2-chamberview [56,57]. Subsequently, coronary flow in the distalleft anterior descendent artery is searched under theguidance of Color Doppler flow mapping. The admin-istration of contrast flow enhancement could improvesignals of pulsed Doppler [56]. Under normal condition,flow in the coronary exibits a characteristic biphasicpattern with larger diastolic and smaller systolic compo-nent. Systolic and diastolic peak velocities are measuredat baseline and after dipyridamole infusion. Doppler as-sessment of coronary flow reserve (CFR) represents avalid parameter in evaluating alterations of coronaryflow. CFR is defined as the ratio between hyperemicand basal diastolic peak velocities (Fig. 3). In clinical

practice CFR <2 is an indicator of hemodynamically sig-nificant coronary lesions. This technique is easy to use.Although it is still in development, it appears likely to bea useful tool to assess coronary damages [56,57]. There-fore, in future CFR should be used to evaluate coronaryartery disease in acromegalic patients.

Conclusions

In the management of patients with acromegaly a care-ful evaluation of cardiac function, morphology and ac-tivity at the diagnosis and during the follow-up seems,thus, to be mandatory. Echocardiography remains themost useful method to detect cardiac disease, espe-cially LV hypertrophy. This technique should be asso-ciated with equilibrium radionuclide angiography, in or-der to evaluate cardiac performance on effort, and withtwenty-four hours Holter electrocardiogram to investi-gate arrhythmias.

New echocardiographic methods are available, butthey should be furtherly tested in acromegalic patients.

Acknowledgments

This study has been partially supported by a grant from RegioneCampania L.R. 41/94 1999, N.7492.

256 Vitale et al.

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