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Clinical Studies |
Department of Cardiology (T.S., H.F., J.K-S., S.G., J.B-K.) and the Department of Surgery, Division of General Surgery (C.A., B.N.), University of Vienna Medical School, Austria
Address correspondence and requests for reprints to: Thomas Stefenelli, MD, FACC, Associate Professor for Internal Medicine, Department of Cardiology, University of Vienna, Währinger Cpürtel 18-20, A-1090-Vienna, Austria.
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Abstract |
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In a blinded fashion, aortic and mitral valve calcifications were determined in 46% and 39% of patients with PHPT. Calcific deposits in the myocardium were found in 74% of patients. Follow-up studies after parathyroidectomy disclosed no evidence of progression of these calcifications. Before operation left ventricular hypertrophy was detected in 82%. After parathyroidectomy and 41 months of normocalcemia and normal PTH concentrations, a regression of hypertrophy of the interventricular septum and the posterior wall by -6% and -19% (P < 0.05) was observed. Subgroup analysis disclosed the most impressive long-term reduction of left ventricular hypertrophy in patients without a history of hypertension (-11% and -21%; P < 0.05 and P < 0.005); no changes were determined in 9 patients who developed secondary hyperparathyroidism after operation.
The present data show a high incidence of left ventricular hypertrophy and aortic and/or mitral valve calcifications in patients with PHPT. Follow-up at 1 year and at 41 months after successful parathyroidectomy disclose regression of hypertrophy. Our results give evidence that parathyroid hormone per se plays an important role in the maintainance of myocardial hypertrophy. Post-surgical restoration of normocalcemia and normalization of parathyroid hormone valvular sclerosis persists without evidence of progression. We further conclude that patients with PHPT and parathyroidectomy are at low risk for the development of severe aortic and mitral valve stenosis within this period of time.
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Introduction |
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In the current uncontrolled and unblinded study, we report the follow-up data of patients with PHPT who underwent parathyroidectomy between 1988 and 1990. The aim of this study was three-fold: 1) to determine the long-term natural course of cardiac abnormalities detected by echocardiography; 2) to clarify the etiology and clinical significance of previously described bright echoes in the myocardium of PHPT patients by using the noninvasive method of magnetic resonance imaging (MRI) (16, 21). Do these echoes represent metastatic calcifications in the myocardium or structural changes in patients with left ventricular hypertrophy? 3) We tried to attribute pathological findings in the heart to hypercalcemia, phosphate levels, and/or elevated concentrations of PTH. The latter differentiation became possible, as a subgroup of patients developed secondary hyperparathyroidism with still elevated PTH but normal or reduced serum calcium levels after the surgical removal of parathyroid glands.
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Methods |
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We prospectively studied 123 consecutive patients who were referred for initial exploration for PHPT and parathyroidectomy between 1988 and 1990 to the Division of General Surgery, University of Vienna. After baseline screening, 119 out of 123 patients with PHPT underwent bilateral cervical exploration with removal of pathologically altered parathyroid glands. Four patients refused operation. Histological examination revealed single chief-cell adenoma in 90 patients, 2 and 3 adenomas in 1 patient, oxiphil ademona in 11 subjects, hyperplasia in 11 patients, a parathyroid carcinoma in 2 patients, and water clear-cell hyperplasia in 2 patients. In 1 subject cervical exploration was negative; further examinations disclosed a mediastinal chief-cell adenoma.
Baseline screening
The standardized baseline screening included complete history, physical examination, skeletal radiographs, roentogenography and sonography of the abdomen, a 12-lead electrocardiogram, and echocardiography. Blood pressure was measured by auscultation after 20 min resting in supine position. Blood chemistries, including levels of serum calcium, phosphate, creatinine, and alkaline phosphatase, were analyzed on a standard autoanalyzer (SMAC 20 Technican Autoanalyser). Immunoreactive intact parathyroid hormone (iPTH; Nichols Institute Diagnostics, San Juan Capistrano, CA) was measured by radioimmunoassay. At least 2 measurements were averaged. Baseline echocardiograms were recorded in all patients during hypercalcemia 1–5 days before operation.
Follow-up
Follow-up examinations included questionaire, physical examination, and the measurements of iPTH and electrolytes at least every 6 months.
Among 119 consecutive patients who underwent parathyroidectomy after baseline screening 50 subjects were excluded because of either limited quality of echocardiograms, technical problems, or incomplete recordings or noncompliance of 21 patients to appear for further echocardiographic studies. Finally, 69 PHPT patients with complete baseline examinations gave their informed consent to enter the long-term follow-up study. Echocardiographic examinations were repeated 12.7 ± 6.2 months (n = 59) and 41.2 ± 13.4 months (n = 53) after parathyroidectomy. The reasons for the loss of patients during follow-up were death (n = 6) and emigration to another country (n = 3); 8 patients with normal iPTH and calcium levels after parathyroidectomy refused further echocardiographic studies after clinical examinations. Patients who had been included in the echocardiographic follow-up program and those subjects who refused further examinations or moved or patients without technically readable echoes were not significantly different regarding age, serum calcium, iPTH concentrations, history of hypertension or severity of myocardial hypertrophy or valvular sclerosis in baseline echocardiography. Thus, the group that had echocardiographic follow-up studies is representative of the group as a whole.
Echocardiography
Echocardiograms were performed with a SSH 160A Toshiba (Toshiba Medical Systems, Japan), a SONOS 1000 (Hewlett-Packard Co., MA) or a Vingmed (VINGMED CFM 750) ultrasonoscope and a 2.5 or 3.75 MHz transducer in the semilateral recumbent position. Studies included 2D and M-mode recordings of the parasternal long- and short-axis views and the apical four-chamber view as well as pulsed-wave Doppler. M-mode recordings for measurement of left ventricular end-systolic and end-diastolic diameters and shortening fraction were done with the parasternal short-axis view, as described previously (29, 30, 31). Just below the tips of the opened mitral valve leaflets the M-mode cursor was directed across the left ventricular cavity at its widest point. The M-mode tracings were recorded at a paper speed of 50 mm/sec. If possible, the end-diastolic diameters of the left ventricle, as well as septal and posterior wall thickness, were measured at the beginning of the R-wave of the QRS-complex. The end-systolic diameters were determined at the maximal systolic thickness of the interventricular septum. Aortic valve calcification was recognized as thickening and as bright echoes in both M-mode and 2D echocardiographic recordings (15). Aortic stenosis was defined as aortic cusp separation of less than 1.5 cm calculated from the M-mode echocardiogram and a maximum aortic flow velocity of over 1.3 m/sec measured by Doppler ultrasound. Mitral and aortic calcification was graded as 0 (none), 1 (mild), 2 (moderate) or 3 (severe) (32). Calcium in the mitral or submitral anulus was recognized as a uniform dense band of bright echoes posterior to the mitral leaflets and anterior to the left ventricular wall (14, 15). The detection of bright echoes by 2D and M-mode echocardiography, possibly compatible with calcific deposits in the myocardium, has been described in detail previously (16, 21): after overall gain reduction, the remaining signal intensity of intramyocardial structures was compared with pericardial echoes and, if possible, with further calcified structures in at least 2 different views (21). Pulsed-wave Doppler measurements were performed by placing the sample volume just below the tips of the mitral valve leaflets; the diastolic flow through the mitral valve was recorded at a speed of 50 mm/sec. Peak early filling (E - wave) and peak late filling (A - wave) was measured for calculating the E/A ratio. A ratio less than 1 indicated an abnormal left ventricular filling. All echocardiograms were analyzed blind to clinical details by 2 observers who had no information whether the patients had baseline screening, intermediate-, or long-term follow-up examination.
Magnetic resonance imaging (MRI)
To get further insights into the etiology of echocardiographic findings in the myocardium, MRI-studies were performed in 11 PHPT patients before parathyroidectomy. MRI studies were done on a 0.5 T Philips Gyroscan using ECG gatted double angulated gradient-echo sequences (FFE) in 3 slices. We have chosen gradient echo sequences because of its better delineation of myocardial calcifications compared with spin-echo techniques (33). The sequence was oriented along the long axis of the heart in a sagittal-coronal double-angulated fashion. The echo delay time (TE) was 19 m/sec, repetition time was (TR) 50 m/sec, and a flip angle of 30° was used. FFE sequences were obtained using a slice thickness of 8 mm, a field of view of 40 cm, a matrix of 256 x 128 and 2 numbers of acquisition.
Statistical analysis
Data are expressed as mean values ± SD and
SEM (see below, Fig. 2
). Statistical comparisons were
performed using analysis of variance (ANOVA) and t-test for
continuous variables. A P value of less than 0.05 was
considered to indicate statistical significance.
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Results |
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The clinical and biochemical characteristics of the patients
before parathyroidectomy are summarized in Table 1. At
time of operation, 53 subjects had a history of hypertension lasting
10.8 ± 3.7 yr and were receiving antihypertensive therapy.
Antihypertensive drugs and doses were not changed throughout the study,
except in 1 patient (ACE-inhibitor instead of calcium channel blocker).
Seventeen patients with a history of effort angina were asymtomatic
when treated with nitroglycerin and/or betablockers. None of the PHPT
patients complained from recent dyspnea, dizziness, or syncope.
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The laboratory follow-up examinations after operation showed serum calcium levels and iPTH concentrations rapidly declining to the normal range in 115 patients. According to previous findings, we observed no changes in phosphate levels (16, 21). However, 9 patients developed secondary hyperparathyroidism, defined as elevated iPTH concentrations (mean iPTH: 121.6 ± 40.9 U/L) and low serum calcium levels (mean serum calcium: 2.21 ± 0.16 mmol/L), detected 2–6 months after the removal of parathyroid glands. In this group of patients oral calcium substitution therapy and vitamin D led to a normalization of serum calcium; iPTH remained elevated in 5 subjects (iPTH: 66–145 U/L).
Left ventricular function
The mean circumferential fiber shortening was 38.99 ± 9.8% and within the normal range. Quantitative measurements of fiber shortening or qualitative judgement of left ventricular function disclosed reduced systolic function in 9 patients only. No changes were observed in the follow-up echocardiograms.
Pulsed-wave Doppler recordings for the determination of the diastolic
function have not been documented accurately in the first studies of
most patients. However, the long-term follow-up examinations after
parathyroidectomy included the measurement of the E/A ratio and showed
impairment of the left ventricular filling in 63% of patients.
Subgroup analysis revealed a compliance problem in 58% of patients
without hypertension as compared with 69% in patients who were
receiving antihypertensive treatment (Table 2).
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Three patients with myocardial infarction and one with
aortocoronary bypass grafts showed asymmetric hypertrophy of the
myocardium and were excluded from further analysis. The results of the
mean thickness of the interventricular septum and the posterior wall of
the remaining subjects are shown in Table 2
. Before operation, 81.6%
of patients with PHPT had hypertrophy of the interventricular septum,
78.2% showed hypertrophy of the posterior wall. Left ventricular
hypertrophy was more distinctive in patients with a history of
hypertension. We observed a correlation between the duration of
hypertension and the thickness of the interventricular septum
(P = 0.03; R = 0.49).
Forty-one months after parathyroidectomy, the mean thickness of the interventricular septum decreased by 0.62 mm (-6%; P = NS), the thickness of the posterior wall was reduced by 2.21 mm (-19%; P = 0.005). During this period of time the blood pressure did not change significantly in either group. However, the reduction in the thickness of the left ventricular wall was different in patients without history of hypertension and those subjects who were receiving antihypertensive therapy. Patients without hypertension revealed a significant reduction of wall thickness by 1.29 mm in the interventricular septum (-11.3%; P < 0.05) and 2.32 mm in the posterior wall (-20.7%; P = 0.004). Subjects with PHPT who were receiving antihypertensive treatment showed no significant changes of the wall thickness of the septum (+ 0.26 mm; P = NS) and posterior wall (-1.59 mm; P = NS). After follow-up, the overall thickness of the interventricular septum as well as the presence of bright echoes correlated with reduced left ventricular filling (P = 0.01, R = 0.36 and R = 0.37).
Nine patients who developed secondary hyperparathyroidism disclosed no
significant change in wall thickness during follow-up (interventricular
septum: 14.6 ± 4.3 mm before operation versus
14.8 ± 4.9 mm after 1 yr, and 15.5 ± 4.8 mm after 40
months; P = NS). Three of these patients had no history
of hypertension. Figure 1 shows the different behavior
of left ventricular hypertrophy during long-term follow-up of patients
with secondary hyperparathyroidism after operation and those patients
with successful parathyroidectomy with and without a history of
hypertension.
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Echocardiographic studies before parathyroidectomy disclosed
bright echoes in 74% of patients. After overall gain reduction we
detected up to 5 isolated bright echoes in 36 patients and 5–10 bright
echoes in 10 subjects. Five patients showed more than 10 bright echoes
in the myocardium. A typical example is shown in Fig. 2.
Follow-up examinations showed only minor changes in 5 patients,
detected by one of the two independent observers.
MRI studies were performed in 11 patients with echocardiographically detected bright echoes; 10 with up to 10 isolated bright echoes after gain reduction showed no evidence of calcification in MRI. However, 1 patient with bright confluing structures after gain reduction in the echocardiographic study has shown an isolated hypointense signal by MRI. This hypointense signal, which is evidence of calcification, had a diameter of 7 mm and was located at the same position in the interventricular septum as confirmed by echocardiography.
Valvular calcifications
The incidence and severity of calcification of the aortic or
mitral valves detected by echocardiography are given in Table 3. Fifty-four percent of patients with PHPT disclosed
evidence of valvular calcification, 46% in the aortic valve and 39%
in the mitral valve. Calcification in both the aortic and mitral valves
was observed in 25% of patients. Subjects with moderate or severe
aortic calcification at baseline showed aortic stenosis with an aortic
valve velocity ranging from 1.5 m/sec to 3.1 m/sec and a calculated
aortic valve area between 1.5 cm2 and 2.5 cm2.
The valvular area of moderately to severely calcified mitral valves
ranged from 1.5 cm2 to 2.5 cm2. Our follow-up
echocardiograms 41 months after parathyroidectomy revealed no
significant progression of valvular calcifications as well as no
significant changes of Doppler measurements and calculated valvular
area.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The high incidence of hypertension in our patients with PHPT is in accordance with previous observations (7, 9, 40). Elevated blood pressure is a major cause of left ventricular hypertrophy. In the present study however, only 55% of patients with left ventricular hypertrophy had a history of hypertension. Moreover, the extent of regression of left ventricular thickness after operation and normalization of PTH and serum calcium levels was different in patients with and without history of hypertension. Although the subgroup of patients who were receiving antihypertensive treatment had no significant changes in resting blood pressure throughout the study and denied changes in life style or salt intake, parathyroidectomy was not followed by a reduction of left ventricular hypertrophy. Indeed, we did not test blood pressure behavior during exercise, and thus we cannot exclude an abnormal elevation of pressure during such activity. It was, however, not the goal of the present study to examine a relationship between resting cuff pressures and myocardial mass. On the other hand, our patients without evidence of hypertension (or any other disease that potentially might influence left ventricular mass) disclosed a significant reduction of left ventricular wall thickness by -11% (septum) and -20% (posterior wall). This subgroup analysis gives evidence that hyperparathyroidism and/or elevated serum calcium caused reversible left ventricular hypertrophy. The regression of left ventricular thickness continued for longer than a year and was totally reversed in the last control of most patients without hypertension.
It is still unclear whether the elevation of serum calcium, PTH, or the calcium-phosphate-product is mainly responsible for cardiac abnormalities. Basic studies showed that both elevated calcium and PTH exert a hypertrophic effect on cardiomyocytes (41, 42). On the other hand, PTH augments the entry of calcium into tissues independent of the levels of calcium in serum (43, 44). In all of our subgroups the phosphate levels and the calcium-phosphate-product were within the normal range and unchanged. In normotensive patients with successful parathyroidectomy, rapid normalization of serum calcium and PTH where followed by a reduction of left ventricular thickness. By contrast, a small group of our patients with seconary hyperparathyroidism after operation showed no significant change of myocardial hypertrophy. The latter observation may give evidence that PTH per se plays an important role in the mantainance or progression of hypertrophy and is in accordance with data from Symons et al. (17), who showed that changes in cardiac hypertrophy are related to PTH and not to hypercalcemia.
A possible drawback may be the fact that other techniques like magnetic resonance imaging or computed tomography are more accurate and reproducible than echocardiography to measure left ventricular diameters (45). Since these methods are more precise, fewer subjects are needed to detect changes in serial measurements (45). In the present study, we indeed had to exclude some patients because of bad quality of echocardiographic recordings. However, echocardiography is an established method for the estimation of myocardial hypertrophy (30, 35, 38), and all of our echocardiograms have been evaluated by two independent observers. Furthermore, we wanted to choose a method that is readily available as well as cost-effective for routine examinations in the follow-up of most patients.
Left ventricular hypertrophy is often accompanied by an impaired filling of the heart during diastole. We observed abnormal left ventricular filling in 69% and 58% of our patients with treated hypertension and patients without history of hypertension after follow-up that was not severe enough to produce diastolic heart failure in our patients. Impaired relaxation may be caused by myocardial textural changes and intracardiac calcifications and/or fibrosis (46, 47). In our patients, impaired diastolic filling showed a relation to the left ventricular thickness as well as bright echo dense bands, detected mainly in the interventricular septum. These bright echoes persisted independently from the reduction of myocardial hypertrophy. At least the larger areas of persisting echoes after gain reduction in echocardiography represent calcifications in MRI. Indeed, we have no histological proof of calcifications. However, it is obvious, that echocardiography has a better spatial resolution than MRI in detection of interventricular calcifications. Therefore, small isolated bright echoes by echocardiography could not be confirmed as calcifications by MRI, and MRI did not provide further information of these observations.
In a previous study, we observed calcifications in the aortic and/or mitral valve significantly more often in patients with PHPT than in control subjects (16, 21). The high incidence of premature valvular calcification has been further reported in patients with primary as well as secondary hyperparathyroidism (14, 15, 16, 21, 48). In a small number of these patients aortic sclerosis was severe enough to produce aortic stenosis (14, 15). The presence and potential progression of aortic stenosis may have prognostic clinical implications (39). In our patients, aortic sclerosis was classified as mild and moderate in most patients with a calculated aortic valve area greater that 1.5 cm2. More important, long-term follow-up examinations showed no evidence of progression after successful parathyroidectomy. Accordingly, none of our patients complained of syncope, severe dyspnea, or new onset of angina pectoris in this period of time. Thus, we conclude from our uncontrolled and unblinded long-term follow-up observations that patients with PHPT surgical restoration of normocalcemia and/or normalization of PTH concentrations are at low risk for the development of severe aortic and mitral valve stenosis within 41 months after parathyroidectomy. Our data support the recommendation that parathyroidectomy should be performed in all patients with PHPT because the procedere stops the progression of valvular sclerosis and reverses myocardial hypertrophy (49).
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Acknowledgments |
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Received June 13, 1995.
Revised July 15, 1996.
Revised August 22, 1996.
Accepted September 11, 1996.
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