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Departments of Internal Medicine (L.S., M.P., A.P., D.B.), Biomorphological and Functional Sciences (G.C., A.A.V., A.Cu.), Molecular and Clinical Endocrinology and Oncology (A.Co.), and Institute of Biostructures and Bioimages of the National Council of Research (W.A., A.Cu.), Federico II University, 80131 Naples, Italy; and Scientific Institute for Research and Care Neuromed (G.V., A.Cu.), 86077 Pozzilli, Italy
Address all correspondence and requests for reprints to: Alberto Cuocolo, Department of Biomorphological and Functional Sciences, University Federico II, via Pansini, 5, 80131 Napoli, Italy. E-mail: cuocolo{at}unina.it.
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Abstract |
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duration) (r = -0.54; P < 0.01). At stepwise regression analysis, rest ejection fraction and duration were the only variables that independently influenced (P < 0.001) ejection fraction at peak exercise. Diastolic dysfunction is important in determining cardiac performance during exercise in patients with acromegaly and normal resting systolic function. Combined analysis of pulmonary vein and mitral flow velocity curves allows the identification of impaired LV diastolic function in such patients.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Cardiac performance during exercise depends on an adequate LV diastolic filling and compliance (10, 11). Therefore, it can be hypothesized that LV diastolic dysfunction might be responsible for reduced systolic performance observed in many patients with acromegaly during physical activity. Mitral flow velocity curves by Doppler echocardiography are useful in estimating LV filling pressures in patients with LV dysfunction. However, because of the complexity of the multiple interrelated factors that determine diastolic filling of the left ventricle, these flow velocity curves are less useful in patients with other diseases (12). On the other hand, combined analysis of mitral and pulmonary flow velocity curves at atrial contraction allows reliable prediction of increased LV stiffness and end-diastolic pressure, irrespective of systolic function (13, 14, 15, 16). Radionuclide angiography also provides accurate noninvasive assessment of rapid diastolic filling (10, 17, 18, 19). The aim of this study was to clarify the role of diastolic dysfunction in the abnormal adaptation to physical exercise in patients with acromegaly. To address this issue, we assessed the relationship between cardiac performance during exercise, the severity of LV hypertrophy, and indexes of LV diastolic function at rest in patients with active acromegaly.
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Patients and Methods |
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Forty-eight consecutive patients with active acromegaly (30 men and 18 women; mean age, 43 ± 11 yr) were studied. Patients with concomitant diseases, such as diabetes mellitus, coronary artery disease, long-standing hypertension, and hyperthyroidism, were excluded. Silent coronary artery disease was ruled out using stress myocardial perfusion tomography. The diagnosis of acromegaly was performed in keeping with high serum GH levels during an 8-h time course, not suppressible less than 1 µg/liter after 75-g oral glucose load, and high plasma IGF-I levels for sex and age (20, 21). Presumed duration of disease was assessed by comparison of patient’s photographs taken during a one- to three-decade span and by patient interviews to date the onset of acral enlargement, and it was assumed as the interval between the clinical onset and the time of treatment. In this series, disease duration was 13 ± 7 yr. There were 30 newly diagnosed patients who had not yet been prescribed any pharmacological treatment, and 18 patients who had previously been unsuccessfully treated with surgery, radiotherapy, and bromocriptine. All patients had interpretable Doppler recordings of transmitral flow and pulmonary flow velocity curves. The study was conducted in accordance with the guidelines in the Declaration of Helsinki. All patients gave their informed consent to participate in the study, and the ethical committee of our university approved the study protocol.
Assays
Serum GH levels were measured by immunoradiometric assay using commercially available kits (HGH-CTK-IRMA Sorin, Saluggia, Italy). Sensitivity of the assay was 0.2 µg/liter. Intra- and interassay coefficients of variation were 4.5 and 7.9%, respectively. Plasma IGF-I was measured by immunoradiometric assay after ethanol extraction using commercially available kits (Diagnostic Systems Laboratories, Webster, TX). The intraassay coefficients of variation were 3.4, 3.0, and 1.5% for the low, medium, and high points of the standard curve, respectively. Interassay coefficients of variation were 8.2, 1.5, and 3.7% for the low, medium, and high points of the standard curve, respectively.
Echocardiography
Complete M-mode, two-dimensional, and Doppler echocardiographic studies were performed using an ultrasound system (Sonos 2000, Hewlett-Packard, Andover, MA) equipped with a 2.5-MHz transducer. LV chamber dimensions, septum and posterior wall thickness were measured according to recommendations of the American Society of Echocardiography (22). Penn Convention was used to calculate LV muscle mass (23). LV mass index was obtained by dividing LV mass by body surface area. Doppler velocity curves were recorded at a horizontal sweep speed of 100 mm/sec on videotape, with the patient held in expiration and measured by two observers using electronic pointer devices. Average of three consecutive beats was used for the analysis. Transmitral flow velocity was obtained by pulsed Doppler interrogation from a four-chamber apical view, with sample volume placed at the level of the mitral valve leaflet tips. Pulmonary vein flow velocities were recorded with sample volume 0–1 cm into the right superior pulmonary vein. Continuous wave Doppler echocardiography was used to simultaneously obtain transmitral flow velocity curve and aortic valve closure click. Transmitral flow velocity curve was analyzed for measurement of early diastolic and late diastolic peak velocities, deceleration time of the mitral early velocity wave, and mitral duration. Isovolumic relaxation time was measured as the interval from the aortic component of the second sound to the beginning of early mitral wave. Pulmonary vein flow velocity curve was analyzed for measurement of peak velocity of systolic and diastolic forward waves. Peak velocity and duration of pulmonary venous flow wave at atrial contraction were also determined. Finally, the difference between duration of pulmonary vein reverse flow and duration of mitral flow at atrial contraction ( duration) was calculated. Reproducibility of Doppler measurements from our laboratory has been previously reported (24).
Radionuclide angiography
In vivo labeling of red blood cells was performed with 555 MBq technetium-99m. Equilibrium radionuclide angiography was performed at rest and during dynamic physical exercise as previously described (2, 3). A small field of view 
-camera (Elscint Apex SP-4HR, Haifa, Israel) equipped with a low-energy all-purpose collimator was used. Exercise studies were performed using a bicycle ergometer. Exercise loads were increased by 25 W every 2 min until angina, limiting dyspnea, or fatigue developed. Heart rate and blood pressure were monitored during exercise at each stage. No patient experienced high-grade ventricular arrhythmia necessitating interruption of exercise. Radionuclide angiography studies were performed using a standard commercially available software system. Indices of LV function were derived by computer analysis of the background corrected time-activity curve, as reported previously (4). Ejection fraction was computed on the basis of relative end-diastolic and end-systolic counts, and it was considered impaired if less than 50% at rest and/or if it increased less than 5% at peak exercise compared with resting conditions (10, 25). Peak ejection rate (PER) and peak filling rate (PFR) were computed in LV counts/sec normalized for the number of counts at the end-diastole and expressed as end-diastolic volume per second. When normalized for end-diastolic volume, both PER and PFR are influenced directly by the magnitude of ejection fraction (17). To minimize this effect, we also analyzed PFR by using two additional normalization methods: PFR was expressed relative to LV stroke volume per second and as the ratio PFR/PER (4, 19). These two latter methods have the additional advantage of being background independent.
Statistical analysis
Continuous variables were expressed as mean ± SD, and categorical data as percentage. Paired t test was used to compare the values of LV ejection fraction at rest and at peak exercise. Pearson correlation coefficients were calculated to assess the relationships between exercise LV ejection fraction and clinical, echocardiographic, and radionuclide angiographic data. Finally, stepwise linear regression analysis was performed to assess which variables independently influence LV ejection fraction at peak exercise. For this purpose, only variables showing significant univariate association (P < 0.05) were considered for the multivariate analysis. The R2 coefficient of the final model, indicating the fraction of the total variance in the dependent variable explained by the regression equation, was calculated. The statistical software used was SPSS statistical package (release 11.0 for Microsoft Windows, SPSS Inc., Chicago, IL).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. At radionuclide angiography, LV ejection fraction at rest was at least 50% in 37 (77%) patients. With exercise, LV ejection fraction increased from 58 ± 10% to 62 ± 11% (P < 0.005). A normal response to exercise (
5% increase) was observed in 18 patients (38%), whereas in the remaining 30 patients LV ejection fraction did not change or decreased with exercise.
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. As expected, cardiac performance during exercise was directly related to LV ejection fraction and PER under resting conditions and inversely to LV mass index. Moreover, LV ejection fraction at peak exercise was significantly related to radionuclide angiographic and Doppler echocardiographic indexes of diastolic function at rest. In particular, an inverse correlation between LV ejection fraction at peak exercise and duration of pulmonary venous flow wave at atrial contraction and duration was found. Mitral flow velocity and pulmonary vein flow velocity tracings in two representative patients, one with normal and another with abnormal LV ejection fraction response to exercise, are reported in Fig. 1. In the patient with normal cardiac performance during exercise, the duration of late mitral flow wave exceeded that of pulmonary venous flow wave at atrial contraction. Differently, in the patient with abnormal ejection fraction response to exercise, pulmonary venous flow wave was longer than mitral flow velocity wave at atrial contraction (Fig. 1).
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duration were independently associated with cardiac performance during exercise (Table 3). The R2 coefficient of the model was 0.80.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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In our study population, the majority of patients with acromegaly had normal (50%) LV ejection fraction at rest, impaired diastolic filling, and abnormal cardiac adaptation to physical exercise without symptoms of heart failure. Thus, considering the impact of cardiac involvement in the clinical course of patients with acromegaly (9), it seems important to detect preclinical cardiac dysfunction in this setting. These findings are in agreement with those of previous studies (2, 3, 4, 5, 6, 7, 9). Radionuclide angiography is capable of revealing impaired systolic function under stress conditions in patients with acromegaly and preserved function at rest (3, 4). Recently, in a few patients with uncomplicated acromegaly, an impairment of LV regional systolic function in the presence of a normal ejection fraction has been reported, as detected by pulsed wave tissue Doppler imaging (26). However, clinical significance of the results of this new echocardiographic technique has to be proven. The majority (62%) of patients included in this study had an impaired cardiac systolic performance during exercise. LV ejection fraction at peak exercise was inversely related to LV mass index. Cardiac hypertrophy in uncomplicated acromegaly represents a unique model of hypertrophy associated with normal or decreased wall stress, as a result of myocardial thickening and normal ventricular tension (9). Our findings indicate that the severity of LV hypertrophy contributes to the impaired systolic functional response to exercise in these patients. According to the results of previous studies, LV systolic function during exercise was significantly related to diastolic filling at rest (2, 3). However, at multivariate regression analysis, the difference between the duration of pulmonary vein flow velocity wave and that of mitral flow velocity wave at atrial systole was the only parameter able to provide additional information to rest LV ejection fraction in predicting systolic function at peak exercise. Combined analysis of mitral flow and pulmonary vein flow velocity curves contributes to understanding the hemodynamic interplay between left atrium and left ventricle (13, 14, 15, 16). Early diastolic Doppler indexes are affected by LV relaxation, compliance, and systolic function as well as by left atrial compliance and are useful to predict LV filling pressures in patients with systolic dysfunction, but are inaccurate when systolic function is preserved (12). Conversely, the analysis of both flow velocity curves at atrial contraction may allow the reliable prediction of increased LV filling pressures irrespective of systolic function (13, 14, 15, 16). High LV resistance to filling in late diastole, due to reduced ventricular compliance, results in increased pressure into the left atrium, yielding a prolongation of the duration of reverse pulmonary vein flow at atrial systole. Pulmonary vein reverse flow and mitral flow at atrial contraction are related to ventricular compliance but change in an opposite manner. The difference between duration of pulmonary vein reverse flow and duration of mitral flow at atrial contraction is useful for detecting elevated end-diastolic pressure associated with reduction in ventricular compliance (16).
In patients with acromegaly and impaired exercise performance, an increased LV stiffness, yielding elevation of filling pressure at the end of diastole, can be supposed. It has been demonstrated, using invasive (27) or noninvasive (10) techniques, that exercise limitation in patients with preserved LV systolic function at rest is due to the limited ability to increase cardiac output by means of the Frank- Starling mechanism. Increased diastolic stiffness prevents the increase in LV end-diastolic volume that normally accompanies exercise. In well-controlled type 2 diabetes, without overt symptoms of heart failure, LV diastolic dysfunction, detected by a reverse pulmonary vein flow velocity wave longer than mitral flow velocity wave at atrial systole, was associated with a limited cardiac performance during treadmill exercise (28). This mechanical impairment, which did not limit daily life activities, became important when a greater exercise performance was required. Interestingly, LV diastolic dysfunction may also induce heart failure symptoms in the presence of normal systolic function (29). In patients with acromegaly, LV diastolic dysfunction can be caused by mechanisms that are intrinsic to the cardiac muscle cells themselves or by changes in the structures within the extracellular matrix. Chronic GH excess produces a direct anabolic effect on cardiac muscle (30) and promotes cellular proliferation by means of an IGF-I mediated effect (31). Furthermore, growth factors mainly affect extracellular matrix collagen biosynthesis and degradation (32). Focal areas of replacement fibrosis and diffuse interstitial fibrosis, in combination with muscle fiber disarray, lymphocyte infiltrates, and small vessel disease have been described (33, 34). Cardiac apoptosis has been demonstrated in acromegalic cardiomyopathy (35). These cardiovascular alterations are likely to play a key role in deterioration of cardiac function over time in patients with acromegaly. Finally, it is not clear whether the effects on cardiac function are directly dependent on high GH levels or on LV hypertrophy induced by chronic GH excess. It has been recently demonstrated that disease control after 12 months of treatment with long-acting release octreotide normalized LV mass in 100% of young and in 50% of middle-aged patients, and LV ejection fraction response at peak exercise in 80% of young and in 50% of middle-aged patients (36). Therefore, it may be speculated that LV hypertrophy induced by chronic GH excess is the major determinant of cardiac dysfunction in acromegaly.
In conclusion, the findings of the present study provide insights into the mechanisms that cause cardiac impairment during physical exercise in patients with acromegaly and preserved LV systolic function at rest. Doppler echocardiographic assessment of LV filling is able to detect diastolic dysfunction representing a limiting factor for cardiac exercise performance in these patients.
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Footnotes |
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Received March 17, 2003.
Accepted May 19, 2003.
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