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Departments of Endocrinology and Metabolism (A.M.P., S.W.v.T., F.R., J.W.A.S., J.A.R.), Cardiology (E.E.v.d.W., J.J.B.), and Pathology (H.M.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Cardiovascular Division (J.R.L.), University of Virginia, Charlottesville, Virginia 22908
Address all correspondence and requests for reprints to: Alberto M. Pereira, M.D., Ph.D., Department of Endocrinology and Metabolism, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: a.m.pereira{at}lumc.nl.
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Abstract |
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In a prospective study design, 40 consecutive patients with acromegaly and 120 control subjects (matched for age, sex, hypertension, and left ventricular systolic function) were studied. All patients and controls were evaluated using conventional two-dimensional and Doppler echocardiography.
Significant valve disease was more prevalent in acromegalics compared with controls (22% vs. 6.7%, respectively; P = 0.005). Aortic valve regurgitation (
trace severity) was present in 30% of patients vs. 7% of controls (P < 0.001), and mitral regurgitation (moderate severity) was absent in controls but present in 5% of acromegalics (P = 0.014 vs. controls). Binary logistic regression analysis showed a significant impact only for disease duration on valvular disease, with an odds ratio of 1.19 (95% confidence interval, 1.028–1.376; P = 0.019).
Acromegaly is associated with an increased prevalence of regurgitant valvular heart disease. This is dependent on the duration of exposure to increased GH concentrations, with a 19% increase in odds per year. This increased prevalence of occult valvular disease indicates that these patients require appropriate follow-up care and monitoring, especially patients with inadequate control of GH overproduction.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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(2). These cytokines, in turn, increase gene expression of matrix metalloproteinases (MMPs) that are capable of altering the composition of the extracellular matrix (3). These abnormalities in matrix regulation are associated with cardiac chamber dilation and reduced myocardial tensile strength (4). Abnormalities in matrix regulation have also been implicated in the pathogenesis of aortic and mitral valve disease (5, 6, 7), the latter of which manifests as thickened and redundant valves that are incompetent and have an appearance of myxoid degeneration on pathology.
We hypothesized that patients with acromegaly, in whom GH and IGF-I are pathologically elevated, have an increased incidence of clinically relevant aortic and mitral valve disease. There are anecdotal reports of aortic or mitral valve operations performed in patients with acromegaly that support this concept (8, 9). However, the prevalence of valvular abnormalities in patients with acromegaly has not been documented. Therefore, we prospectively evaluated the prevalence of valvular abnormalities in patients with acromegaly and no prior history of cardiac disease.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In a prospective study design, 40 patients (19 males and 21 females) with acromegaly were studied. The median age of the patients was 57 yr (range, 20–83 yr). Nine patients were untreated (de novo patients), and 31 patients were treated either by transphenoidal surgery (n = 23) or by primary medical treatment (n = 8) (Table 1
). The diagnosis of acromegaly was based on the characteristic clinical features of acromegaly and confirmed by insufficient suppression of GH concentration during a glucose tolerance test and the presence of a pituitary adenoma on radiological imaging. Disease activity was assessed as follows. Patients were classified as having active disease if they had mean fasting GH concentrations (measured every 30 min for 3 h) greater than 5 mU/liter and elevated age- and sex-adjusted IGF-I concentrations. Patients were classified as having inactive disease if the mean GH concentrations during the fasting 3-h profile were less than 5 mU/liter and if IGF-I concentrations were normal. A total of 18 patients were classified as having active disease (nine de novo patients and nine patients treated with depot octreotide acetate), and 22 patients were classified as having inactive disease (eight cured patients and 14 patients treated with depot octreotide acetate). Patients with hemodynamic instability or a prior history of myocardial infarction, thyrotoxicosis, rheumatic fever, endocarditis, anorexigen use, or other connective tissue disease were excluded from the study. Also, in female patients of childbearing age, pregnancy was excluded. None of the patients appeared to be pregnant in the 9 months after echocardiography. The duration of disease was defined by the onset of clinical symptoms related to GH excess (carpal tunnel syndrome, sleep apnea, and arthralgias) and by careful comparison of old photographs. The end of disease duration was defined as the time of successful treatment.
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Echocardiography and data acquisition
Patients were imaged in the left lateral decubitus position using a commercially available system (Vingmed system FiVe, General Electric-Vingmed, Milwaukee, WI). B-mode two-dimensional images were obtained with transmission frequencies of xx-3.5 MHz in the parasternal (standard long and short axis) and apical views (two-, four-, and five-chamber images). Color Doppler echocardiography was performed in all views after optimizing gain and Nyquist limit. Standard continuous-wave and pulse-wave Doppler examinations were performed. M-mode images were obtained from the parasternal long-axis views for quantitative assessment of left ventricular dimensions, fractional shortening, and left ventricular ejection fraction (10). When tricuspid regurgitation was present, pulmonary artery pressure was estimated using the modified Bernoulli equation. The severity of valvular regurgitant was determined by two independent expert readers blinded to the clinical data on a qualitative scale of trace, mild, moderate, or severe, using previously described methods (11, 12). Significant valvular disease was determined using the U.S. Food and Drug Administration (FDA) case definition: mild or greater aortic regurgitation or mitral regurgitation equal to or more than moderate severity (13).
Hormone assays
GH concentrations were quantitated in duplicate using a sensitive time-resolved immunofluorescent assay (Wallac Oy, Turku, Finland) specific for 22-kDa GH protein. The detection limit was 0.03 mU/liter (0.01 µg/liter). Intraassay coefficients of variation were 1.6–8.4% in the GH range of 0.1–18 µg/liter (0.26–47 mU/liter). The total serum IGF-I concentration was determined by RIA after extraction and purification on ODS-silica columns (INCSTAR Corp., Stillwater, MN). The interassay coefficient of variation was less than 11%. The detection limit was 1.5 nmol/liter. Age-related normal data were determined in the same laboratory. IGF-I was also expressed as a SD score from age-related normal levels.
Statistical analysis
The Student’s t test was used for continuous variables. The 
2 test and the Cochrane-Mantell test were used to compare continuous and categorical data to detect trends. Binary logistic regression stepwise analysis was performed to explore possible determinants of valvular disease. SPSS software version 10.0 (SPSS Inc., Chicago, IL) was used. Differences were considered statistically significant at P < 0.05.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). However, 10 patients (25%) had left ventricular hypertrophy, defined by interventricular septum thickness above 12 mm (n = 9) and/or a posterior wall thickness (n = 6) above 12 mm. The corrected left ventricular mass index was above 110 g/m2 (for women) and 125 g/m2 (for men). Five of these 10 patients had significant valve disease. Six patients had slightly increased left ventricular dimensions (left ventricular end-diastolic volume > 59 mm and > 32 mm, corrected for height), five of whom had normal left ventricular mass (four of the six patients had significant valve disease).
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Prevalence of regurgitation (Table 3)
Aortic valve regurgitation was present in 30% (12 of 40) of patients vs. 7% (eight of 120) of controls (P < 0.001). These differences were significant for all grades of severity of regurgitation detected. Significant aortic valve regurgitation (by FDA criteria) was present in 20% (eight of 40) of patients vs. 4% (five of 120) of controls (P = 0.002).
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Tricuspid valve regurgitation was detectable in 28% (11 of 40) of patients vs. 50% (60 of 120) of control subjects. However, pathological tricuspid regurgitation (moderate or severe according to the FDA criteria) was absent in all patients and present in only 3% (three of 120) of control subjects. This difference was not significantly different.
Valvular regurgitation of one valve was present in 10 patients, valvular regurgitation of two valves was present in two patients, and valvular regurgitation of three valves was present in two patients.
Prevalence rates of valvular abnormalities were similar between active and inactive patients.
Determinants of valvular disease
Figure 1 describes the impact of disease duration on valvular disease in the acromegalic patients. Binary logistic regression analysis showed a significant impact of disease duration on valvular disease (odds ratio = 1.19; 95% confidence interval, 1.028–1.376; i.e. every additional year of disease would result in a 19% increase in odds per year).
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In this study, we compared echocardiographic data in patients with acromegaly with active or inactive disease to a control database. Matched database analysis is necessary due to the relatively high prevalence of mild valvular abnormalities in the general population, which tends to increase with age. Studies using two-dimensional color Doppler echocardiography with semiquantitative methods for estimating the severity of regurgitation from trace to severe have demonstrated that the population-based prevalence of minimal or mild mitral and tricuspid valve regurgitation was quite high (58–77%), whereas aortic valve regurgitation was much less prevalent (14, 15). Accordingly, the FDA has defined pathological regurgitation of the mitral and tricuspid valve as more than or equal to moderate severity and pathological regurgitation of the aortic valve as more than or equal to mild severity. However, in the normal offspring in the Framingham Heart Study (14), trace severity for mitral and tricuspid valve was present in 75% of the subjects and independent of age, whereas trace aortic regurgitation was only present in about 5% of the subjects and strongly dependent on age (from about 2% at the age of 26–39 yr to about 10% at the age of 70–83 yr). Therefore, it has been postulated, that the FDA’s criteria for aortic regurgitation may be too narrow, and the case definition for pathologic regurgitation may need to be modified or made age specific (15). Therefore, in our study, we individually matched each acromegalic patient for age, sex, and the presence of hypertension to three nonacromegalic control subjects. We observed prevalence rates of valvular regurgitation in these 120 control subjects that were comparable to those reported in the normal offspring in the Framingham Heart Study. Aortic regurgitation (present in 13% of men and 8% of women in the Framingham Heart Study) was present in 7% of our control subjects vs. 30% of our patients with acromegaly. However, the abnormalities detected were predominantly mitral regurgitation of trace severity. This is due to the temporal/spatial high resolution of the echo equipment available (GE vivid 7, Vingmed system FiVe; General Electric-Vingmed).
The pathogenesis of myxomatous heart valve degeneration remains uncertain. Rabkin et al. (6) proposed a model in which activation of interstitial cardiac valve cells leads to the release of proteolytic enzymes, phenotypic modulation, and proliferation. Subsequently, degradation of collagen, elastin fragmentation, and glycosaminoglycans accumulation produces extracellular matrix remodeling and characteristic leaflet myxomatous thickening and redundancy. However, the primary stimulus for activation of these resting fibroblast-like interstitial cells remains to be elucidated, but mechanical stress and genetic abnormalities are proposed to play a key role. In our three patients who underwent valve replacement surgery, similar pathological changes of myxomatous degeneration were observed (Fig. 2). It is likely that direct or indirect effects of overproduction of GH are the causes for the observed valvular incompetence for the following reasons. First, GH increases gene expression of the MMPs (16), resulting in abnormal matrix regulation. Second, recent data indicate that proinflammatory cytokine levels are increased in acromegalic patients with active disease (17). These cytokines, in turn, can also increase gene expression of MMPs, resulting in abnormal matrix regulation. Finally, the prevalence of valvular regurgitation observed in our acromegalic patients proved to be highly significantly correlated to the duration of the disease. Whereas pathological valvular regurgitation was absent in patients with an estimated disease duration of less than 6 yr, the prevalence of aortic valve regurgitation (mild severity) increased from 12.5% for patients with a disease duration of 6–10 yr to 40% in patients with a disease duration of more than 16 yr. Similarly, prevalence of mitral valve regurgitation (moderate severity) was absent in controls but present in 20% of acromegalic patients with a disease duration of more than 16 yr. Whether the patients had active disease or not at the time of evaluation did not influence these prevalence rates. From a pathophysiological point of view, this is very interesting because the valvular damage is apparently irreversible (in contrast to the already published regression of left ventricular hypertrophy in successfully treated patients). This is also in accordance with the recently published study by Colao et al. (19) who reported an unexpectedly high prevalence of valve abnormalities in patients successfully cured of acromegaly. Hence, chronic exposure to increased GH or IGF-I production predisposes for myxomatous degeneration, with a calculated increase in odds in our study of 19% for the development of valvular disease for every additional year of exposure to tonically elevated GH concentrations. Because the onset of GH overproduction is gradual, there is, in general, a long patient delay before the diagnosis of acromegaly is made. Therefore, it can be argued that an accurate assessment of disease duration is cumbersome. Before the onset of clinical symptoms, careful comparison of old photographs reveal (often subtle but clear) changes of the face. This retrospective evaluation of the combination of the onset of clinical symptoms and comparison of old photographs proved to be reproducible for estimating disease duration and to find significant associations of this estimated disease duration with mortality (20), as well as with left ventricular hypertrophy and cardiac performance (21). However, this way of assessing disease duration will still lead to inaccuracies. Therefore, we also decided to present the impact of disease duration of acromegaly on valvular disease by increasing disease duration stepwise by very large intervals of 5 yr. Highly significant increases in the prevalence of valvular disease were found between every 5-yr interval and the preceding 5 yr (Fig. 1
). Even though there remain uncertainties with respect to the exact start of acromegaly, this analysis strongly supports our notion that the prevalence of valvular heart disease is dependent on disease duration.
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In conclusion, we are the first to report that acromegaly is associated with an increased prevalence of regurgitant valvular heart disease, which is dependent on the duration of exposure to increased GH concentrations and which is not associated with impaired left ventricular function or hypertension. This increased likelihood of valve disease may impact the cardiac surveillance of patients with acromegaly and could provide us more insight on the basic pathophysiological interactions of GH with connective tissues. The increased prevalence of occult valve disease indicates that these patients require appropriate follow-up care and monitoring, especially those with inadequate control of GH overproduction. Moreover, antibiotic prophylaxis for any nonsterile procedures may be required.
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Acknowledgments |
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Footnotes |
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Abbreviation: MMP, Matrix metalloproteinase.
Received May 15, 2003.
Accepted September 15, 2003.
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