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High Prevalence of Cardiac Valve Disease in Acromegaly: An Observational, Analytical, Case-Control Study

Departments of Molecular and Clinical Endocrinology and Oncology (A.C., P.M., R.P., C.D.S., G.V., G.L.) and Internal Medicine I (L.S., M.P., D.B.), Federico II University of Naples, 80123 Naples, Italy

Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, via S. Pansini 5, 80123 Naples, Italy. E-mail: colao{at}unina.it.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
To characterize mitral and aortic valve abnormalities we performed M-mode, two-dimensional, and pulsed Doppler echocardiography in 42 patients with active acromegaly, 22 patients cured of acromegaly, and 64 controls pair-matched with the patients for sex and age. The overall prevalence of valve abnormalities was higher in both the active patients (86% vs. 24%; P < 0.0001) and the cured patients (73% vs. 9%; P < 0.0001) than in controls. Left ventricular hypertrophy was higher in active (81% vs. 29%; P < 0.0001), but not in cured (41% vs. 14%; P = 0.09) patients than in controls. Cardiac valve abnormalities were associated with left ventricular hypertrophy in both patients and controls, without any difference between them. Conversely, among subjects without left ventricular hypertrophy, mitral and aortic abnormalities were only present in the patients (75% of active and 54% of cured), but not in controls (3% of active controls and 0% of cured controls).

In conclusion, patients with active acromegaly and those cured of the disease have a high prevalence of mitral and aortic abnormalities. The persistence of valve disease in patients with cured acromegaly is likely to be correlated with the persistence of left ventricular hypertrophy, which should be carefully and continuously monitored as an aspect of the risk of cardiac dysfunction in these patients.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
CHRONIC EXCESS OF GH and IGF-I secretion impairs cardiac morphology and performance; this impairment is the leading cause of increased mortality in patients with acromegaly (1, 2, 3, 4). In acromegalic patients, cardiac involvement in the theoretical absence of other causes of cardiomyopathy defines the acromegalic cardiomyopathy (5). At histology, the most relevant abnormalities are increased extracellular collagen deposition, myofibrillar derangement, interstitial fibrosis, and areas of monocyte necrosis and lympho-mononuclear infiltration, gradually impairing the architecture of the entire organ (6, 7, 8, 9).

Left ventricular hypertrophy has been confirmed by echocardiography in most patients at the time of diagnosis of acromegaly (10, 11, 12, 13, 14, 15); the coexistence of other diseases, such as diabetes mellitus, hypertension, or thyrotoxicosis, further exacerbates left ventricular hypertrophy (16, 17). In addition to morphological alterations, diastolic dysfunction with impaired systolic function on effort has been demonstrated in most patients (18, 19, 20, 21, 22).

Cardiac valve disease is an important component of ventricular dysfunction, but alterations of mitral or aortic valves have seldom been reported in acromegaly. Lie and Grossman (9) found mitral and aortic abnormalities in 19% of their autopsy series. Ohtsuka et al. (23) described ring fragility and leaflet disarray, accompanied functionally by regurgitation and stenosis, and suggested that when the functional complication requires therapeutic intervention, replacement surgery seems to assure a better result than valve plasty. Zlatareva et al. (24) in a controlled study including 32 patients with acromegaly found aortic regurgitation in 31%, mitral regurgitation in 47%, and tricuspid regurgitation in 37% of their cases.

To characterize mitral and aortic valve abnormalities we designed this observational, analytical, case-control study using M-mode, two-dimensional, and pulsed Doppler echocardiography, including patients with acromegaly at the time of diagnosis, patients cured of acromegaly for at least 1 yr, and controls.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

This study included 42 consecutive patients with active acromegaly (19 women and 23 men; age range, 22–70 yr) and 22 patients cured of acromegaly after surgery (9 women and 13 men; age range, 30–75 yr). The group of 42 newly diagnosed patients derives from a larger cohort of 48 patients; 6 were then excluded because of poor quality echocardiographic studies due to lung and/or chest problems. As in our previous study (25), the diagnosis of acromegaly was established by high mean serum GH levels during an 8-h time course, not suppressible below 1 µg/liter after a 75-g oral glucose tolerance test (oGTT), and by high plasma IGF-I levels for age. The presumed duration of acromegaly was estimated by comparing patients’ photographs taken during 1- to 3-decade span and by interviews to date the onset of acral enlargement and facial disfigurement. In this series, disease duration ranged between 3–35 yr. As recommended by Giustina et al. (26), cure criteria were fasting and/or glucose-suppressed GH values below 2.5 and below 1 µg/liter, respectively, together with IGF-I values within the normal range for age. The duration of cure from acromegaly ranged from 1–10 yr (mean, 3.5 ± 0.6 yr; median, 2.5 yr).

Controls

As case-controls, we selected 64 subjects from 100 control subjects recruited from the clinical staff and their relatives. Forty-two subjects (19 women and 23 men; age range, 22–70 yr) were pair-matched for sex and age with the active acromegalic patients, and 22 subjects (9 women and 13 men; age range, 30–75 yr) were pair-matched for sex and age with the cured acromegalic patients. Controls were also selected to provide an identical prevalence of hypertension, diabetes, and impaired glucose tolerance as the two groups of acromegalic patients. All patients and controls gave their informed consent to participate in this study, and the study protocol was approved by the ethics committee of the Medical School of University Federico II (Naples, Italy).

Study design

Within 1 wk after the admission for acromegaly, serum GH profile (at least 3 blood samples at 30-min intervals), plasma IGF-I levels (in 3 determinations), heart rate and blood pressure measurements, electrocardiogram, and echocardiogram were performed at study entry in all patients. Blood pressure was measured using the right arm, with the subjects in relaxed sitting position. The average of 6 measurements (3 taken by each of 2 examiners) with a mercury sphygmomanometer was used for analysis. The fourth Korotkoff phase was considered diastolic blood pressure. Hypertension was diagnosed in the presence of diastolic blood pressure above 90 mm Hg (27). Twelve active patients (29%), 5 cured patients (23%), 12 controls for active patients, and 5 controls for cured patients had hypertension managed with different therapeutic schemes, mainly angiotensin-converting enzyme inhibitors, calcium antagonists, and diuretics. These patients and controls were considered hypertensive even if blood pressure was normalized by drugs at the time of the study. The oGTT was performed by measuring blood glucose every 30 min for 2 h after the oral administration of 75 g glucose diluted in 250 ml saline solution. Diabetes mellitus was diagnosed when fasting glucose was above 126 mg/dl on 2 consecutive measurements or when 2 h after the oGTT the glucose level was 200 mg/dl or more. Impaired glucose tolerance was diagnosed when glucose was between 126 and 200 mg/dl 2 h after the oGTT with an additional value of 200 mg/dl or higher between 0–2 h after glucose load (28). Seven active patients, 7 of their controls (17%), none of cured patients, and none of their controls had diabetes mellitus, treated with insulin in 2 and with oral glucose-lowering drugs in 5 of each group.

Echocardiography study

M-Mode, 2-dimensional, and pulsed Doppler echocardiographic studies were performed with a commercially available ultrasound system (Sonos 2500, Hewlett Packard Co., Andover, MA) using a 2.5-mHz transducer during 3–5 consecutive cardiac cycles. The records were made by 1 investigator (L.S.), who was blind with respect to the patients’ status. All patients were studied in the left lateral recumbent position after a 10-min resting period according to the recommendations of the American Society of Echocardiography (29). M-Mode tracing was used to record the interventricular septum thickness (IVST), the posterior wall thickness (PWT), and the left ventricular (LV) internal diameter (LVID); calculation of the left ventricular mass (LVM) was made using Devereux’s formula according to the Penn convention with the following regression-corrected cube formula: LVM = 1.04[(IVST + LVID + PWT)³) - (LVID)³)] - 14 g. LV hypertrophy was diagnosed when LVM values, corrected for body surface area (LVMi), were 135 g/m² or greater in males and 110 g/m² or greater in females. In the present series 34 patients with active acromegaly (81%), 12 of their controls (29%), 9 patients with cured acromegaly (41%), and 3 of their controls (14%) had LV hypertrophy (² = 24.4; P < 0.0001). Structural alterations in the cusps and annuluses of the heart valves were diagnosed by thickened and bright echoes on both M-mode and cross-sectional echocardiogram using established diagnostic criteria (30). The diagnosis of valve stenosis or valve prolapse was made on the basis of morphological assessment and Doppler echocardiography. Significant regurgitation was defined as a regurgitant jet on the color and pulsed Doppler echocardiogram extending more than 2 cm behind the plane of the aortic or mitral valve and pandiastolic (aortic regurgitation) or pansystolic (mitral regurgitation) regurgitant flow of more than 2 m/sec on continuous wave Doppler. Regurgitation was classified as mild, moderate, or severe on the basis of the extent to which retrograde flow filled the atrium or the ventricle (less than one third, two thirds, more than two thirds).

Assays

Serum GH levels were measured by immunoradiometric assay using commercially available kits (Sorin, Saluggia, Italy). The sensitivity of the assay was 0.2 µg/liter (1 µg/liter corresponds to 2 mU/liter). The intra- and interassay coefficients of variation (CV) were 4.5% and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction using kits from Diagnostic Systems Laboratories, Inc. (Webster, TX). The sensitivity of the assay was 0.8 µg/liter. The normal IGF-I ranges in our laboratory were 110–450 and 100–300 µg/liter for patients aged 20–40 and 41–60 yr, respectively. The intraassay CV were 3.4%, 3.0%, and 1.5% for the low, medium, and high points on the standard curve, respectively. The interassay CV were 8.2%, 1.5%, and 3.7% for the low, medium, and high points on the standard curve.

Statistical analysis

The statistical analysis was performed by means of the SPSS package (SPSS, Inc., Chicago, IL). Data are reported as the mean ± SD. A t test for paired data was performed to compare active patients and cured patients with their controls. Significance was set at 5%. The ² test was used to analyze the prevalence of valve abnormalities in different groups.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Compared with controls, both patients with active disease and those cured of acromegaly had increased prevalence of several mitral or aortic abnormalities (Table 1). In particular, morphological alterations, such as calcifications and thickening of leaflets or annulus, were found in 27 patients with active disease (64%), 6 of their controls (14%; P < 0.0001), 12 patients cured of acromegaly (55%), and two of their controls (9%; P = 0.004) at the mitral valve, and 20 patients with active disease (48%), 5 of their controls (12%; P = 0.012), 13 patients cured from acromegaly (59%), and 1 of their controls (4.5%; P < 0.0001) at the aortic valve. The prevalence of mitral and aortic regurgitation, respectively, was observed in a smaller cohort of patients and controls for both valves (Table 1). In accordance with previous data (15, 16), LVMi was higher in the patients than in controls, and it was higher in active than in cured patients (Table 1); 34 of 42 patients (81%) with newly diagnosed acromegaly had LV hypertrophy compared with 9 of 22 (41%) of those cured of acromegaly (² = 8.8; P = 0.003). Additionally, LVMi was higher in patients with hypertension than in those with normal blood pressure levels in all groups, and patients with active acromegaly and hypertension had the highest LVMi in the current study population (Fig. 1). Cardiac valve abnormalities were associated with LV hypertrophy in both patients and controls, without any difference between them (Table 2). Conversely, among subjects without LV hypertrophy, mitral and aortic abnormalities were only present in the patients (in 75% of active and 54% of cured), but not in controls (3% of active controls and 0% of cured controls). In only 6 patients with active disease (14%) and 6 patients cured from acromegaly (27%) were mitral and aortic valves completely normal compared with 32 (76%) and 20 (91%) controls, respectively. However, all of the patients not showing cardiac valve disease were normotensive, less than 40 yr of age, and had a presumed duration of active disease less than 8 yr (median, 3.5 yr), 5 of the controls were hypertensive and over 40 yr old.

View larger version (28K): [in this window] [in a new window]   FIG. 1. LVMi (mean ± SD) in patients with active acromegaly, patients with cured acromegaly, and controls grouped according to the presence or absence of hypertension.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
The most relevant data of the current study are that patients with active acromegaly as well as those cured of the disease for at least 1 yr have a very high prevalence of morphological and functional alterations of the mitral and aortic valves. The persistence of these abnormalities in patients with cured acromegaly is likely to be correlated with the persistence of LV hypertrophy. In fact, in both patients with acromegaly and controls, the prevalence of cardiac valve abnormalities was higher in subjects with LV hypertrophy.

This hypothesis is based on several pieces of evidence: 1) a direct relationship between the LVM and aortic or mitral regurgitation in a general elderly population (31), 2) a rather high (28–35%) prevalence of valve disease in patients with LV hypertrophy secondary to systemic hypertension (32), and 3) mitral annular calcification as a common echocardiographic finding in nonacromegalic hypertrophic cardiomyopathy with asymmetric septal hypertrophy (33). It is worth noting, however, that in our cohort of active acromegalic patients, the mean age was lower than that of patients studied by both Lindroos et al. (31) and Palmieri et al. (32), whereas the prevalence of valve abnormalities was much higher in both patients with active disease (86%) and those already cured of the disease (73%).

In acromegaly, cardiovascular mortality mainly depends on GH values (2, 4, 34), arterial hypertension, and cardiovascular disease (34). The last known GH and IGF-I values seem to better predict life-threatening complications (2, 4, 35), because mortality is significantly increased in the presence of uncontrolled disease. The suppression of the GH concentration below 5 mU/liter (equal to 2.5 µg/liter) and the inhibition of IGF-I values to the age-adjusted normal range were shown to reduce the mortality to that of the general population (2, 35). Additionally, suppression of GH and IGF-I hypersecretion after surgery or pharmacotherapy was reported to reduce cardiovascular disease in acromegaly (20, 22, 36, 37, 38, 39, 40, 41); this beneficial result regarding cardiac abnormalities suggests that successful treatment of acromegaly can reduce mortality.

Except for many studies on the alterations of cardiac performance in acromegaly (recently reviewed in Ref. 5), cardiac valve abnormalities have rarely been reported; nevertheless, cardiac valve disease is a relevant component of ventricular dysfunction. Autopsy studies documented mitral and aortic abnormalities in 19% of patients (9). Ring fragility and leaflet disarray, accompanied functionally with regurgitation and stenosis were also reported in a cardiac surgery series (23). Operation for valve heart disease was safely performed in 10 of 951 patients, without any difference between patients with active or inactive disease (42). A high prevalence of aortic, mitral and tricuspid regurgitation was also recently suggested (24), although data concerning other cardiac parameters were not available.

In our cohort of patients newly diagnosed with acromegaly and in those who had already undergone successful surgery and thus were cured for at least 1 yr (median, 2.5 yr), we found a very high prevalence of morphological abnormalities at both the mitral and the aortic valve. Fibrosis, fibrosclerosis, thickening and/or calcifications of leaflets, and/or annulus of the mitral and/or the aortic valve were found in as many as 86% of patients with active disease as well as 73% of those achieving successful disease control after surgery. Furthermore, mild mitral regurgitation was found in 26% of active and 27% of cured patients, whereas mild to moderate aortic regurgitation was found in 31% of active and 18% of cured patients. Therefore, the degree of valvular dysfunction observed in our patients was mild to moderate, rarely clinically significant. However, whether this mild valve disease might also play a significant role in the development of acromegalic cardiomyopathy cannot be ruled out at present. As biventricular hypertrophy is a well known feature of acromegalic cardiomyopathy (15), affecting more than 60% of patients, even young patients (40), and approaching 75% of those with diabetes mellitus and hypertension (16), the high prevalence of mitral and aortic valve abnormalities in patients with active disease can be expected as one of the multiple aspects of cardiac derangement after GH and IGF-I hypersecretion. In fact, in the current series 81% of patients with active acromegaly had LV hypertrophy, all presenting with several morphological and/or functional alterations of both mitral and aortic valve. It should be noted that 100% of hypertensive acromegalic patients enrolled in the current study had LV hypertrophy, and the LVMi was in these patients higher than in hypertensive controls. This finding strongly indicates that GH and IGF-I hypersecretion have a direct role in inducing LVM overgrowth independent of hypertension, but potently aggravated by concurrent hypertension. In these patients the high prevalence of other morphological alterations, such as those at the mitral and aortic valves, can be considered one of the aspects of acromegalic cardiomyopathy. It should be pointed out that all six newly diagnosed patients without any detectable alteration at the mitral or aortic valve were young (<40 yr old) and had a rather short duration of disease (1–8 yr); young age and short exposure to GH and IGF-I hypersecretion can be taken as explanations for the lack of valve abnormalities in these patients. A similar situation was observed in the six patients cured of acromegaly who also had normal mitral and aortic echocardiographic results; all but one were young and had had a rather short presumed active disease duration. In addition, all of these patients had normal blood pressure levels, reinforcing the evidence of absence of valve disease in them. The role of hypertension in determining cardiac valve disease is well known, as it induces left atrial enlargement, dilation of the ascending aorta, aortic regurgitation, and valvular abnormalities, such as fibrosis, calcification, and thickening (43).

The high prevalence of valve abnormalities in patients successfully cured of acromegaly was an unexpected result. In fact, cardiac size has been widely reported to decrease after suppressing GH and IGF-I by pharmacotherapy (20, 22, 36, 37, 39, 40) or surgery (44), even after a very short period of treatment (36, 39). The reduction in cardiac size was followed by reversal of LV hypertrophy in several patients, mostly young individuals (40), and by improvement of cardiac performance in most patients after very short (39), short (20, 22, 40), and long periods of treatment (44). However, in no study was cardiac valve dysfunction considered.

The 22 patients cured of acromegaly enrolled in the current study indeed had a LVMi lower than that observed in the active patients, but it was still higher than their controls, with a prevalence of persistent LV hypertrophy of 41%, thus significantly lower than that found in active patients (81%). Five of the 9 patients with LV hypertrophy still had hypertension after cure of acromegaly, explaining the increased LVMi, and the remaining 4 were in or over the middle-age range (59–75 yr). Recently, we reported that the reversibility of acromegalic cardiomyopathy is more likely in young than in middle-aged, well controlled patients (40), hypothesizing that long-standing GH and IGF-I hypersecretion modifies cardiac structure in a way that can no longer be reversed by disease control. Whether the persistence of cardiac hypertrophy and dysfunction also confers to these patients a persistently high mortality risk for cardiovascular disease cannot be definitively determined at the present time. However, the persistence of a high prevalence of mitral and aortic valve dysfunction in patients with long-term cure of acromegaly indicates the need for careful and continuous monitoring of cardiac parameters of morphology and performance by echocardiography. This precaution should be considered particularly in patients with persistent hypertension, because, as in controls, this was associated with LV hypertrophy and a greater prevalence of valve dysfunction.

	Acknowledgments

 
We thank Dr. Edward Laws, Jr., for his kind revision of the manuscript.

	Footnotes

 
Abbreviations: CV, Coefficient of variation; LV, left ventricular; LVM, left ventricular mass; LVMi, left ventricular mass index; oGTT, oral glucose tolerance test.

Received July 15, 2002.

Accepted April 1, 2003.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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