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Original Studies |
Departments of Internal Medicine (S.F., A.C., E.A.P., G.R., F.B., U.O., L.S.) and Endocrinology (B.B.), "Federico II" University Medical School, 80131 Naples, Italy
Address correspondence and requests for reprints to: Serafino Fazio, M.D., III Division of Internal Medicine, Via S. Pansini, 5, 80131 Naples, Italy.
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Abstract |
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Therefore, we studied by Doppler echocardiography a group of 10 young subjects strictly selected as having short-term (<5 yr) uncomplicated acromegaly. The results of this study have shown that short-term acromegaly is characterized by significantly increased left ventricular mass (P < 0.005), with normal relative wall thickness, associated with Doppler indices of diastolic function in the normal range. Furthermore, stroke index and cardiac index were significantly enhanced in the patient group (P < 0.01 and P < 0.001, respectively), whereas systemic vascular resistance was significantly reduced (P < 0.001).
In conclusion, our study shows that short-term acromegaly significantly affects the heart, but, at variance with long-term disease, it is characterized by increased left ventricular mass, with eccentric remodeling and normal diastolic function. Moreover, short-term acromegaly induces a high cardiac output state with reduction of systemic vascular resistance.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Animal models of GH excess, either induced by GH-secreting tumors or by exogenous administration of large doses of GH or insulin-like growth factor-I (IGF-I), have consistently demonstrated a hypertrophic response of the left ventricle with enhanced cardiac function both in vivo and in vitro (7, 8, 9, 10, 11). These findings are in agreement with the observation that short-term GH administration increases the ejection phase indices in normal subjects (12).
Elucidation of the cardiac consequences of recent onset acromegaly would help to clarify the natural history of the disease and, at the same time, could provide new insight into the mechanisms of GH action on the human heart. Such information seems to be particularly useful in view of recent observation of beneficial effects of GH in experimental and human heart failure.
In an attempt to clarify the cardiovascular effects of short-term GH hypersecretion, we decided to assess cardiac morphology and function in a group of patients with recent onset (<5 yr) acromegaly, by means of complete Doppler echocardiography.
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Patients and Methods |
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The patient selection was made on the basis of a disease duration estimated to be less than 5 yr (3.2 ± 1.2 yr). Duration of acromegaly was assessed by collection of a detailed medical history and comparison of serially taken photographs. We are aware that the precise beginning of GH hypersecretion can only be assessed with biochemical and hormonal parameters and not only on the basis of clinical parameters. However, to achieve a better patient selection, we excluded from the study all subjects who could not provide an accurate anamnesis or serial photographs. All patients were newly diagnosed and, thus, not yet treated.
Latent coronary perfusion defects were excluded in all patients by exercise electrocardiographic test and, if indicated, exercise 201thallium scintigraphy.
Ten normal subjects acted as a control group. They were as comparable as possible with the corresponding patients in terms of age, body weight, and sex distribution. All patients and control subjects had a sedentary lifestyle.
Informed consent was obtained from all participants, and the study protocol was approved by the Ethics Committee of the University Federico II.
Echocardiography
Complete one-dimensional, two-dimensional, and Doppler echocardiography were performed by an ultrasound mechanical system equipped with 2.5–3.5-MHz transducers (Apogee CX; Interspec, Inc., Ambler, PA). One- and two-dimensional recordings were made with the patients in the lateral recumbent position, according to the standardization of the American Society of Echocardiography (13). Electrocardiogram tracing was displayed simultaneously on the echo-tracings. The investigator reading the echoes was blind as to whether the recordings he was interpreting were of an acromegalic or a normal control. The measurements were performed as described previously (4).
The following parameters were assessed: left ventricular (LV) end-diastolic (LVEDD, millimeters) and end-systolic diameters (LVESD, millimeters), LV posterior wall thickness (PWT, millimeters), and interventricular septum thickness (IVST, millimeters), and LV relative wall thickness as the ratio of mean diastolic wall thickness to diastolic radius. LV mass (LVM, grams) was calculated, with the following regression-corrected cube formula: LVM = 1.04 [(IVST + LVEDD + PWT)3 - (LVEDD)3] - 14 (14). LVM index (LVMi, grams/m2) was obtained by dividing LVM by body surface area (BSA, m2). Ejection time (ET, milliseconds) was obtained by the tracing of aortic flow. Mean velocity of circumferential fiber shortening (mVCF, circumference/second) was calculated by dividing fractional shortening by ET. LVED and LVES volumes (V) were obtained by two-dimensional echocardiography with the single plane area-length method (15) and then indexed by BSA (LVEDVi and LVESVi, milliliters/m2, respectively). Stroke index (SI, milliliters/m2) was calculated as LVEDVi - LVESVi. Ejection fraction (EF, %) was calculated as: (LVEDV - LVESV)/LVEDV. Cardiac index (CI, liters/minutes/m2) was determined as (SVi x heart rate)/1000. Systemic vascular resistance (SVR, dynes·sec·cm-5) was calculated as: SVR = (mPA - mPRA)/CO x 80, where mPRA is the mean right atrial pressure, considered equal to zero mm Hg in each subject, mPA is the mean aortic pressure derived by cuff-sphygmomanometer as diastolic blood pressure + 1/3 (systolic-diastolic blood pressure), and CO is the cardiac output (16).
The Doppler tracings were acquired during quiet respiration with the transducer positioned at, or slightly to the left of, the cardiac apical impulse, according to the method previously reported (4). The following parameters were assessed on mitral flow: maximal early diastolic flow-velocity (E, centimeters/second), maximal late diastolic flow velocity (A, centimeters/second), E/A ratio, and mitral deceleration time (MDT, milliseconds). Isovolumic relaxation time (IRT, milliseconds) was obtained as the time interval from aortic valve closure to the onset of early diastolic flow, by simultaneous recording of aortic and mitral flow by continuous-wave Doppler.
Statistical analysis
All data are presented as mean ± SD. The comparison between patients and controls was performed by the Student’s t test for unpaired data, and a P value less than 0.05 was considered significant.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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. The two study
groups were comparable with regard to age, sex distribution, BSA, heart
rate, and arterial pressure, whereas serum GH and IGF-I levels, as
expected, were markedly higher in the patients than in controls.
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and Fig. 1). This was due to a significant
increase of both ventricular dimension and wall thickness, and,
consequently, the relative wall thickness was unchanged.
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and Fig. 1
). This difference was entirely accounted for by the
increased SI in acromegalics, whereas heart rate was comparable in the
two groups. mVCF and EF were comparable in the two groups (data not
shown). SVR was significantly reduced by 18% in the acromegalic
patients as compared with control subjects (Table 3).
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Discussion |
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In an attempt to reconstruct the natural history of acromegalic cardiac disease, we have recently postulated the existence of three main phases: 1) an early stage characterized by a hyperkinetic syndrome, with increased CO and lowered peripheral vascular resistance; 2) an intermediate stage associated with right ventricular and LV hypertrophy, impaired diastolic filling, and abnormal response to physical exercise; and 3) a late stage culminating in cardiac dilatation and congestive heart failure (17). Although a large body of evidence coming from clinical studies strongly supports the existence of an intermediate and a late stage of acromegalic heart disease, the presence of an early stage remains largely speculative (2, 3, 4, 5, 6, 18, 19). This is due to the difficulties in recruiting a sufficient number of patients with a brief duration of disease and no other associated condition, such as hypertension, diabetes, and coronary artery disease, each of which may have a significant impact on the heart.
Using the above strict inclusion criteria, we recruited a group of young acromegalics and were able to characterize an early stage of the acromegalic disease that is associated with a cardiac hyperkinetic syndrome, LV hypertrophy, and no evidence of diastolic dysfunction.
There are several mechanisms that may be potentially responsible for these findings. One possibility is that the predominant effect of short-term GH/IGF-I excess on the human heart is to induce hypertrophy and to enhance cardiac function. This hypothesis is consistent with previous studies performed in animal models and in normal humans exposed to GH excess (7, 8, 9, 10, 11, 12). Furthermore, GH induces sodium retention and volume expansion (20, 21, 22). This effect combined with reduction of peripheral vascular resistance could prevail in the initial stage of the disease. The high preload of acromegalic subjects, who exhibit an increase of approximately 20% of LVEDVi, as compared with controls, supports this view. The pattern of proportional response of LVM and volume may, therefore, be the net result of the combination of the direct "trophic" actions of GH/IGF-I (increasing mostly parietal thickness) and the increased preload (increasing mostly cavity dimension). This, in turn, is the consequence of two factors, i.e. GH-induced volume expansion and increased venous return due to decreased peripheral vascular resistance.
Patients with recent onset acromegaly have a normal diastolic filling pattern. In particular, short-term GH hypersecretion in humans produced an increase in CI and a decrease in SVR, in the absence of diastolic dysfunction. The absence of diastolic dysfunction at this stage might be due to the not yet established interstitial fibrosis, well documented in more advanced stages of the disease. Alternatively, it is possible that the interstitial remodeling has already started but its deleterious effect on diastolic function is offset by the functional advantage that GH per se exerts on LV relaxation (10).
Our results are not entirely consistent with those of Minniti et al. (6), who recently studied a similar patient population. Both in that study and in our patients, LVMi was increased in the acromegalics whereas systolic function was normal. In contrast, in the patients studied by Minniti et al.(6), LV diastolic function was already impaired. There are no obvious explanations for this discrepancy, although it cannot be excluded that the slightly longer duration of active acromegaly (4.4 vs. 3.2 yr) in the previous study may have played a role.
Clinical implications
The clinical relevance of the current study is 2-fold. First, it gives a contribution to better delineate the natural history of active acromegaly in its early, less documented phase. Second, it provides new insight into the mechanisms of GH action on the human heart. In this respect, a growing body of evidence coming from both animal and human studies shows that the activation of the GH/IGF-I axis may be beneficial in the setting of heart failure (23, 24, 25, 26, 27). On the other hand, GH may also have short-term functional effects on the heart as previously postulated both in acromegaly (28) and in patients with heart failure (29). However, it seems difficult to reconcile the beneficial effects observed with the well known deleterious effects of long-standing GH excess on the heart. Based on the results of the current study, we may speculate that a condition of GH excess, well above that recommended for the treatment of heart failure, does not have deleterious cardiac effects, even after approximately 5 yr of activity. Therefore, it is now more readily apparent why the induction of a state of cardiac hyperfunction, such as the one observed in the current study, may be beneficial in the setting of heart failure, which is characterized by inadequate hypertrophy, elevated wall stress and peripheral vascular resistance, and impaired systolic and diastolic function.
Received June 25, 1999.
Revised October 5, 1999.
Accepted October 18, 1999.
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References |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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) and uncomplicated acromegalic patients (
).