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University Hospital Saint Luc Brussels, Belgium
We read with interest the paper by M. Wolzt et al. (1) related to the hemodynamic effects of parathyroid hormone-related peptide (PTHrP) in man. These authors observed a dose-dependent increase in pulse rate, renal plasma flow, and hand vein diameter without any change in blood pressure in response to the infusion of the PTHrP analog PTHrP (1–34). Although this interesting study is the first to evaluate the effect of PTHrP in man, some conclusions are overdrawn beyond the information provided, mainly because of the lack of hemodynamic and hormonal assessment. As heart rate increased but blood pressure remained unchanged, determination of cardiac output and systemic vascular resistances would have allowed to attribute a peripheral vasodilating effect definitely to PTHrP. Measurement of catecholamines would have helped to differentiate tachycardia due to reflex baroreceptor responses from a direct chronotropic effect of PTHrP, as suggested in experiments using isolated rat hearts (2). The authors also claim that no effect was noted on parameters of cardiac inotropic performance, which were not evaluated as such by the present study even by noninvasive methods (echocardiography). On the contrary, based on a presumable baroreflex-induced tachycardia, there might be an indirect positive inotropic effect. In addition, others have shown that PTHrP might exert inotropic effects mediated via coronary vasodilation (3). Finally, the most important concern is the lack of PTHrP concentration monitoring during the infusion, which would have demonstrated whether the responses were of pharmacological or of pathophysiological relevance. Indeed, in humoral hypercalcemia of malignancy, associated with increased PTHrP concentrations, no cardiovascular changes are systematically present.
As congestive heart failure (CHF) is the most appropriate condition to demonstrate neurohumoral activation, we studied PTHrP plasma concentrations in this condition to establish its clinical relevance as a cardiovascular vasodilator, and we compared PTHrP concentrations with those of cardiac natriuretic peptides activated in CHF. Indeed, a colocalization of PTHrP with natriuretic peptides in myocytes secretory granules was previously suggested (4, 5). Thus, we obtained peripheral venous blood, after 30 min strict recumbency, from 10 healthy volunteers (CTR), 11 patients with angiographically-demonstrated coronary artery disease (CAD) and normal ejection fraction (EF), and 26 patients with congestive heart failure (CHF) in New York Heart Association (NYHA) class II (n = 10; EF: 26 ± 6%) and in NYHA class III-IV (n = 16; EF: 19 ± 5%). PTHrP (1–84) was measured in whole plasma by an immunoradiometric assay (PTHrP IRMA 35400, Incstar, Stillwater, MN; sensitivity: 1.5 pmol/L; intra/interassay CV: 4/8%). Atrial natriuretic factor (C-ANF), the N-terminal part of its precursor (N-ANF), and brain natriuretic peptide (BNP) were measured on the same samples, after acetonitrile extraction on Sep-Pack C18-cartridges (Waters, Milford, MA) and using radioimmunoassays (Peninsula, Belmont, CA; intra/interassay CV: <10% for the three natriuretic peptides).
As expected in CTR, plasma PTHrP levels were less than 1.5 pmol/L; similarly undetectable values were obtained in all CAD and CHF patients. Positive samples (from patients with humoral hypercalcemia of malignancy), similarly handled and included in the same assay, were in the expected range (5–50 pmol/L) and demonstrated dilution curves parallel to standards. In contrast to PTHrP, plasma levels of the atrial (C- and N-ANF) and of the ventricular (BNP) peptides increased with the severity of cardiac disease. Median [range] plasma C-ANF were respectively 32[22–69], 68[22–130], 101[28–495], and 204[54–418] pg/mL in CTR, CAD, CHF I-II, and CHF III-IV patients (P < 0.0001 by Kruskal-Wallis test). N-ANF plasma concentrations were 333[158–762], 596[116–762], 726[434–1926], and 2023[806–4181] pg/mL (P < 0.0001), and BNP levels were 14[9–34], 29[13–77], 66[23–121], and 201[37–336] pg/mL (P < 0.0001).
Thus, in contrast to cardiac natriuretic peptides, the peripheral plasma levels of PTHrP do not increase in the presence of or with the severity of heart failure, at least in the range of sensitivity of presently available assays. Practically, this dismisses the potential interest of PTHrP as a clinically useful marker in CHF as well as its physiological or pathophysiological role in the control of systemic hemodynamics in man. Although a paracrine effect undetected by peripheral plasma levels cannot be ruled out, the actions of PTHrP reported by M. Wolzt et al. (1) might reflect a more pharmacological effect of PTHrP.
Footnotes
Address correspondence to: Professor Michel Rousseau, Division of Cardiology, University Hospital Saint Luc, Avenue Hippocrate 10/2800, B-1200 Brussels, Belgium.
Received October 8, 1997.
References
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