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The Journal of Clinical Endocrinology & Metabolism Vol. 87, No. 10 4722-4727
Copyright © 2002 by The Endocrine Society

Original Article

Parathyroid Hormone-Related Protein Is Produced in the Myocardium and Increased in Patients with Congestive Heart Failure

Kazuhide Ogino, Kazuyoshi Ogura, Yoshiharu Kinugasa, Yoshiyuki Furuse, Kazuhiko Uchida, Masaki Shimoyama, Toru Kinugawa, Shuichi Osaki, Masahiko Kato, Yoko Tomikura, Osamu Igawa, Ichiro Hisatome, John P. Bilezikian and Chiaki Shigemasa

Division of Cardiology, Department of Medicine, Faculty of Medicine, Tottori University (K.Ogi., K.Ogu., Y.K., Y.F., K.U., M.S., T.K., S.O., M.K., Y.T., O.I., I.H., C.S.), Yonago 683-8504, Japan; and Departments of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons (J.P.B.), New York, New York 10032

Address all correspondence and requests for reprints to: Kazuhide Ogino, M.D., Ph.D., Division of Cardiology, Department of Medicine, Faculty of Medicine, Tottori University, 36-1 Nishimachi, Yonago 683-8504, Japan. E-mail: k-ogino{at}umin.ac.jp.

Abstract

PTHrP is produced in a wide variety of different cells, including cardiomyocytes. Its production is augmented by mechanical and neurohumoral stimulation, and PTHrP has positive chronotropic and vasodilatory effects. Thus, in the heart, PTHrP has the potential to serve as a mechano-sensitive regulatory molecule. We evaluated peripheral and central levels of PTHrP in patients with congestive heart failure (CHF) and tested the hypothesis that PTHrP is released from the heart in patients with CHF. Intact full-length PTHrP (i-PTHrP) and C-terminal PTHrP (c-PTHrP) levels were measured in the plasma of 64 patients with CHF and 12 controls. Plasma PTHrP concentrations in the coronary sinus and aortic root were also measured in 18 CHF patients and 10 controls. Both plasma i-PTHrP and c-PTHrP levels in CHF patients were significantly higher than control levels and increased as a function of New York Heart Association classification. There were significant correlations between c-PTHrP levels and plasma norepinephrine, brain natriuretic peptide, angiotensin II, and endothelin-1 levels. Plasma i-PTHrP was significantly correlated with left ventricular ejection fraction and end-diastolic and end-systolic dimensions. Plasma i-PTHrP levels were significantly higher in the coronary sinus than in the aortic root in CHF patients, but among controls concentrations of i-PTHrP were indistinguishable at these two sites. This is the first report demonstrating that PTHrP is produced in the myocardium and is increased in CHF; these findings suggest that PTHrPs levels might be modulated by cardiac performance in patients with CHF.

LEFT VENTRICULAR DYSFUNCTION stimulates a host of neurohumoral compensatory mechanisms, such as the sympathetic nervous system itself, the renin-angiotensin axis, endothelin, and the natriuretic peptides. These mechanisms appear fundamentally important in determining how and whether congestive heart failure (CHF) progresses (1, 2). It has been demonstrated that angiotensin II and endothelin-1 as well as natriuretic peptides are locally expressed in cardiac tissue and act as autocrine and paracrine regulators (3, 4, 5). In the plasma of patients with CHF, these neurohumoral factors are increased and are independent predictors of a poor prognosis (6, 7, 8, 9). In CHF, atrial (ANP) and brain (BNP) natriuretic peptides are produced in the heart and are significantly higher in the coronary sinus than in the aortic root (10), whereas angiotensin II and endothelin-1 levels are similar at these two sites (11, 12).

PTHrP was discovered in a search for a circulating tumor-derived factor responsible for the hypercalcemia of malignancy (13, 14, 15, 16, 17). In contrast to PTH, PTHrP is not normally found in the circulation in appreciable amounts. However, it is commonly expressed in a wide variety of normal cells, functioning as an autocrine or a paracrine factor. In the cardiovascular system, smooth muscle, a particularly rich source of PTHrP, responds to mechanical stress with a rapid increase in mRNA for the protein (18, 19, 20, 21, 22, 23, 24, 25). In the heart, several groups, including ours, have demonstrated that PTHrP is a vasodilator, directly increasing heart rate independently of autonomic reflexes (26, 27, 28, 29). Interestingly, the myocardium is also a source of PTHrP (23, 30), with some atrial cells producing both PTHrP and ANP (30). Like ANP, therefore, it is possible that PTHrP might serve as a mechano-sensitive peptide for the heart. The purpose of this study was to measure peripheral and central levels of PTHrP in patients with CHF and test the hypothesis that PTHrP is released from the heart in patients with CHF.

Subjects and Methods

Subjects

Protocol 1. We studied 64 consecutive patients with stable CHF. Their New York Heart Association (NYHA) classification was as follows: class I (n = 16), class II (n = 31), or class III (n = 17). CHF was due to dilated cardiomyopathy in 37 patients and to old myocardial infarction in 25 patients. Forty patients were treated with angiotensin-converting enzyme inhibitors, 5 with angiotensin II receptor blockers, 43 with diuretics, 42 with digitalis, and 14 with ß-adrenergic blockers. For comparison, we studied 12 age- and sex-matched normal controls whose coronary angiograms and left ventriculograms were normal. No control subjects or CHF patients had angina pectoris, positive exercise testing, or renal or liver dysfunction. The basal characteristics of CHF patients and normal controls are summarized in Table 1Go.


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  		Table 1. Characteristics of CHF patients and control subjects (protocol 1)

 
Protocol 2. Blood samples were collected simultaneously from the coronary sinus and aortic root in 18 patients of 64 CHF patients and 10 normal controls who had atypical chest pain to measure transcardiac production of PTHrP. CHF was due to dilated cardiomyopathy in 13 patients and to old myocardial infarction in 5 patients. Fourteen patients were treated with angiotensin-converting enzyme inhibitors, 2 with angiotensin II receptor blockers, 12 with diuretics, 11 with digitalis, and 6 with ß-adrenergic blockers.

These protocols were approved by the ethical committee of Tottori University. All subjects in protocols 1 and 2 consented to participate in this study, and written informed consent was obtained from all patients.

Protocol 1

All subjects were rested for more than 15 min in the supine position before blood samples were collected from an antecubital vein. Chest x-ray, electrocardiogram, and echocardiography were then performed. Echocardiography (System Five, GE Medical Systems, Milwaukee, WI) was performed and analyzed by two investigators who were blinded to all clinical data. Left ventricular end-diastolic (LVDd) and end-systolic (LVDs) dimensions were obtained from the left parasternal long-axis view using M-mode echocardiography. Left ventricular end-diastolic (LVEDV) and end-systolic (LVESV) volumes were measured from the apical long-axis view by a modified Simpson’s method (31). The left ventricular ejection fraction (LVEF) was calculated by: (LVEDV - LVESV) ÷ LVEDV.

Protocol 2

Eighteen patients with CHF and 10 normal controls underwent cardiac catheterization for evaluation of cardiac function and atypical chest pain, respectively. First, they were rested in the supine position for more than 15 min. Right-sided cardiac catheterization was performed using a 6F Swan-Ganz catheter (Baxter, Irvine, CA). Cardiac output was determined by the thermodilution method. Six French coronary sinus catheters and pigtail catheters (Goodman Co. Ltd., Tokyo, Japan) were positioned in the coronary sinus and aortic root, respectively. Blood samples were collected simultaneously from the aortic root and coronary sinus. Aortic and left ventricular pressures were measured, and left ventriculography was performed.

Measurement of PTHrP and neurohumoral factors

Blood samples for measurements of plasma intact PTHrP (i-PTHrP), C-terminal PTHrP (c-PTHrP), ANP, BNP, and endothelin-1 were transferred to chilled tubes containing EDTA and aprotinin and centrifuged at 3000 rpm for 15 min at 4 C. The plasma i-PTHrP level was measured with the Allegro immunoradiometric assay (Nichols Institute Diagnostics, San Juan Capistrano, CA) using two polyclonal antibodies against the different epitopes, PTHrP-(1–40) and PTHrP-(60–72), with recombinant human PTHrP-(1–86) as the standard (32). The plasma c-PTHrP level was determined using a C-PTHrP kit (Daiichi Radioisotope Laboratories Ltd., Tokyo, Japan), which is a C-terminal region-specific RIA for human PTHrP-(109–141) using a sheep antiserum immunized with a novel synthetic human PTHrP-(109–141) for immunogen and a novel synthetic [Tyr108]PTHrP-(108–141) for radiolabel (33). Plasma ANP and BNP were determined using the Shionoria RIA kit and the S-1215 RIA kit, respectively, as previously described (34). The plasma endothelin-1 level was determined by RIA using a rabbit antiendothelin-1 serum (Peninsula Laboratories, Inc., Belmont, CA). Blood samples for measurements of plasma angiotensin II and norepinephrine were transferred to chilled tubes containing EDTA and then centrifuged at 3000 rpm for 15 min at 4 C. The plasma angiotensin II level was determined by RIA using the polyethylene glycol method as previously described (35); plasma norepinephrine was determined using the HPLC-diphenylethylene diamine method as previously described (35).

Statistical analysis

All data are expressed as the mean ± SEM. Comparisons between two groups (normal controls vs. CHF patients and aortic root vs. coronary sinus) were determined by paired and unpaired t test, as appropriate, and comparisons among multiple groups were determined by one-way ANOVA with Fisher’s post hoc test. Linear regression analysis was used to determine the correlation between continuous variables. P < 0.05 was considered statistically significant.

Results

Plasma PTHrP levels in patients with CHF (protocol 1)

Both plasma i-PTHrP and c-PTHrP levels were significantly higher in patients with CHF (0.31 ± 0.03 and 37.5 ± 1.3 pmol/liter, respectively) than in normal control subjects (0.24 ± 0.04 and 29.7 ± 1.5 pmol/liter, respectively). Both PTHrP measurements increased according to NYHA class (P < 0.05; Fig. 1Go), with those in NYHA class III having levels of i-PTHrP and c-PTHrP that were 77.5% and 50.5% higher than control values. There was no significant difference in PTHrP levels between normal controls and patients in NYHA class I. There were no significant differences in either i-PTHrP or c-PTHrP levels between patients with and without atrial fibrillation (i-PTHrP, 0.21 ± 0.03 and 0.33 ± 0.03 pmol/liter, respectively; c-PTHrP, 33.7 ± 1.9 and 38.3 ± 1.5 pmol/liter, respectively). Plasma norepinephrine, ANP, BNP, angiotensin II, and endothelin-1 levels also were increased according to NYHA classification (Fig. 2Go).



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  		Figure 1. Peripheral plasma PTHrP levels in normal controls and patients with CHF. *, P < 0.05 vs. normal controls.

 


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  		Figure 2. Peripheral plasma epinephrine, norepinephrine, ANP, BNP, angiotensin II, and endothelin levels in normal controls and patients with CHF. *, P < 0.05 vs. normal controls.

 
Correlations with hemodynamics, echocardiographic parameters, and neurohumoral factors

There were no significant correlations between plasma PTHrP levels and blood pressure or heart rate. There were significant positive correlations between plasma i-PTHrP level and LVDd and LVDs (P < 0.05), and a significant negative correlation between plasma i-PTHrP level and LVEF (P < 0.05; Fig. 3Go). On the other hand, there were no significant correlations between plasma c-PTHrP level and LVDd, LVDs, or LVEF.



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  		Figure 3. Correlations between peripheral plasma PTHrP levels and echocardiographic parameters.

 
There was a weak positive correlation between i-PTHrP and c-PTHrP levels, and this was close to statistical significance (P = 0.053). There were no significant correlations between plasma i-PTHrP and plasma norepinephrine, ANP, BNP, angiotensin II, or endothelin-1 levels. In contrast, there were significant correlations between plasma c-PTHrP and plasma norepinephrine, BNP, angiotensin II, and endothelin-1 levels (r = 0.32, 0.21, 0.21, and 0.33, respectively; P < 0.05).

PTHrP levels in the coronary sinus and aortic root in CHF (protocol 2)

The plasma i-PTHrP level in the coronary sinus was significantly higher than that in the aortic root in CHF patients (P < 0.05); however, it was not different in normal controls (Fig. 4Go). On the other hand, the plasma c-PTHrP level in the coronary sinus was not different from that in the aortic root in either CHF patients or normal controls.



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  		Figure 4. Plasma PTHrP levels in the aortic root (Ao) and coronary sinus (CS). *, P < 0.05 vs. levels in the aortic root.

 
There were no significant relationships between the plasma c-PTHrP level in the coronary sinus and pulmonary capillary wedge pressure, cardiac index, stroke volume index, left ventricular end-diastolic pressure, LVEDV, or LVEF. On the other hand, the plasma i-PTHrP level in the coronary sinus was significantly correlated with LVEDV (r = 0.61; P < 0.05), but it was not correlated with pulmonary capillary wedge pressure, cardiac index, stroke volume index, left ventricular end-diastolic pressure, or LVEF. There were no significant correlations between plasma i-PTHrP or c-PTHrP levels in the coronary sinus and the level of any neurohumoral factors (epinephrine, norepinephrine, angiotensin II, endothelin, ANP, or BNP) in the aortic root and coronary sinus.

Both ANP and BNP levels in the coronary sinus were significantly higher than those in the aortic root (P < 0.01 for both). However, significant transcardiac production of epinephrine, norepinephrine, angiotensin II, or endothelin-1 was not observed in patients with CHF (data not shown).

Discussion

PTHrP responds to mechanical stress with a rapid increase in mRNA for the protein (18, 19, 20, 21, 22, 23, 24, 25). In this study we demonstrate that both plasma i-PTHrP and c-PTHrP levels are increased in patients with CHF, and that the plasma i-PTHrP level is higher in the coronary sinus than in the aortic root in patients with CHF. The results support the concept that PTHrP might serve as a mechano-sensitive peptide in the myocardium, similar to ANP and BNP.

In patients with the most advanced cardiac dysfunction (NYHA class III), PTHrP levels were the highest. In addition, there were significant correlations between i-PTHrP level and LVDd, LVDs, and LVEF. We have demonstrated that i-PTHrP in the coronary sinus is significantly higher than that in the aortic root in patients with CHF, but not in normal controls, and that the plasma i-PTHrP level in the coronary sinus is significantly correlated with LVEDV. Taken together, the production of PTHrP in the heart would appear to be augmented by mechanical stretch of the left ventricle (ventricular dilation and dysfunction). Thus, increased plasma PTHrP levels might be markers of CHF. However, it is not known whether there is a direct causal relationship between ventricular enlargement and PTHrP production despite the correlation between coronary sinus concentrations of PTHrP and left ventricular volume. The direct demonstration that injections of PTHrP into the coronary artery are associated with inotropic, chronotropic, and vasodilatory effects (26, 29) is also compatible with the idea that the failing heart is strengthened by PTHrP. On the other hand, the c-PTHrP level, but not the i-PTHrP level, was significantly correlated with plasma norepinephrine, angiotensin II, and endothelin-1 levels, which are well known to be activated to compensate for declines in cardiac output and blood pressure in patients with CHF and to be useful prognostic markers (6, 7, 8, 9). It is difficult to completely explain the reasons and clinical implications of the differences between correlation of either i-PTHrP or c-PTHrP with cardiac indexes. The more long-lived cleavage fragment, c-PTHrP, might more accurately reflect an integrative function than i-PTHrP. However, c-PTHrP is excreted by the kidney. Thus, c-PTHrP is high in patients with renal failure. Thus, in some patients with latent renal dysfunction, peripheral levels of c-PTHrP might partly reflect reduced renal function in addition to cardiac function. In a similar manner, i-PTHrP might be the initial product of PTHrPs from the heart and might reflect myocardial performance rather than systemic neurohumoral activation. Further studies are needed to clarify the clinical significance of i-PTHrP and c-PTHrP in patients with CHF.

Full length PTHrP (i-PTHrP) is rapidly cleaved to various PTHrP fragments, including c-PTHrP; however, it is not known whether the main source of plasma c-PTHrP is intramyocardial or peripheral metabolism of i-PTHrP. Positive immunostaining was detected in hearts with PTHrP-(1–34) antibodies (36), but immunoreactivity determined by C-terminal fragment PTHrP-(109–141) antisera revealed 2-fold greater amounts of PTHrP peptides in ventricles than immunoreactivity determined by an N-terminal fragment (30). This observation might suggest that C-terminal fragments of PTHrP originate from the myocardium itself, but there are many confounding issues when immunocytochemistry is used to reach conclusions regarding the presence and metabolism of peptides. Differences in species (rat and humans), in the model (normal and failing heart), and in the rates at which fragments are metabolized and released in situ could well account for the differences between our observations and those previously reported.

PTHrP and its mRNA are more abundant in atria than in ventricles (23), which led us do speculate that PTHrP levels in patients with atrial fibrillation and atrial enlargement might be higher than those in patients without them. In this study, however, there were no significant differences in either i-PTHrP or c-PTHrP levels between patients with and without atrial fibrillation. It is possible that in CHF, the contribution of the ventricles to plasma and cardiac levels of PTHrP predominates over atrial sources. Further studies will be required to test this possibility.

Although the groups of patients were matched reasonably well for age and sex, the clinical state of the patients with advanced failure demanded more medications and interventions than the control and less involved groups. Although it is possible that these interventions per se influenced signaling events in the failing hearts and also PTHrP levels, comparisons within the three CHF groups showed no trends that would suggest a correlation between any medication/device and activation of a signaling pathway. We acknowledge that the number of patients, especially patients who had coronary sinus sampling, was relatively small, and some correlations, therefore, are not statistically significant. In other respects, however, we observed statistical significance of data from blood sampling of coronary sinus even in the small number of patients studied.

In conclusion, plasma PTHrP is produced in myocardium and is increased in patients with CHF. Although the plasma i-PTHrP level is correlated with left ventricular dilatation and function, the plasma c-PTHrP level is better correlated with other neurohumoral factors. i-PTHrP and c-PTHrP measurements might each provide different clinical information in patients with CHF, although the utility of plasma PTHrP remains to be established with due regard for the wide variability in plasma levels. Local concentrations of PTHrP, which serves as an autocrine or paracrine factor in the heart, might be more relevant in understanding the pathophysiological implications of heart failure. Taken together, the local myocardial production of PTHrP identifies a new regulatory molecule, adding to the list of molecules, such as ANP and BNP, already recognized to be important in the context of heart failure. Further studies are needed to determine more definitively compensatory and pathophysiological roles as well as clinical implications of PTHrP production in CHF.


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  		Table 2. Characteristics of CHF patients and normal controls (protocol 2)

 
Acknowledgments

Footnotes

Abbreviations: ANP, Atrial natriuretic peptide; BNP, brain natriuretic peptide; CHF, congestive heart failure; c-PTHrP, C-terminal PTHrP; i-PTHrP, intact full-length PTHrP; LVDd, left ventricular end-diastolic dimension; LVDs, left ventricular end-systolic dimension; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; NYHA, New York Heart Association.

Received February 28, 2002.

Accepted June 28, 2002.

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