Increased serum concentrations of procollagen peptides in essential hypertension. Relation to cardiac alterations

BACKGROUND: The serum concentrations of two procollagen-derived peptides, procollagen type III amino terminal peptide (PIIIP) and procollagen type I carboxy terminal peptide (PIP), have been proposed as useful markers of the tissue synthesis of collagen type III and type I, respectively. Therefore, this study was designed to evaluate fibrogenic activity in patients with essential hypertension by measuring serum PIIIP and PIP. Furthermore, since hypertensive heart disease is characterized by myocardial accumulation of collagen type III and type I, a second aim of the study was to assess whether some relation exists between the serum concentrations of PIIIP and PIP and several parameters of left ventricular anatomy and function in hypertensive patients. METHODS AND RESULTS: The study was performed in 50 patients with never-treated essential hypertension and in 30 normotensive control subjects. Measurements were repeated in 43 hypertensive patients after 6 months of treatment with the angiotensin-converting enzyme inhibitor lisinopril. The serum concentrations of PIIIP and PIP were measured by specific radioimmunoassay. Two-dimensional, targeted M-mode and Doppler ultrasound recordings were obtained in every subject to determine several parameters of the left ventricle anatomy and function. Ambulatory ECG monitoring was performed in each patient, and the recorded ventricular arrhythmias were categorized according to Lown-Wolf classification. Baseline serum PIIIP and PIP were increased (P < .001) in hypertensive patients as compared with normotensive subjects. An inverse correlation was found between serum PIIIP and the ratio between maximal early transmitral flow velocity and maximal late transmitral flow velocity measured during diastole (r = .3786, P < .01) in the group of hypertensive patients. Serum PIP was correlated directly with the left ventricular mass index (r = .3277, P < .05) in the group of hypertensive patients. Serum PIP concentrations increased in parallel with the increase in the grade of ventricular arrhythmias in the group of hypertensive patients. Treated patients attained normalization in blood pressure, amelioration of diastolic filling, regression of left ventricular mass index, and a diminution in the number of daily ventricular extrasystoles. In addition, serum PIIIP and PIP concentrations decreased significantly (P < .001) to normal values in patients treated with lisinopril. CONCLUSIONS: These findings suggest that tissue synthesis of collagen type III and type I is abnormally increased in essential hypertension and can be normalized by treatment with lisinopril. On the other hand, our results suggest that serum PIIIP and PIP are related to several anatomic and functional alterations of the hypertensive left ventricle. Serum procollagen peptide measurements may therefore provide indirect diagnostic information on the myocardial fibrosis associated with arterial hypertension

Abnormalities of the extracellular degradation of collagen type I in essential hypertension

BACKGROUND: This study was designed to investigate whether collagen type I degradation is altered in patients with essential hypertension and whether this alteration could be related to disturbances in the serum matrix metalloproteinase pathway of collagen degradation. A second aim of the study was to assess whether some relation exists between serum markers of collagen type I degradation and left ventricular hypertrophy in hypertensive patients. METHODS AND RESULTS: We measured serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation, of total matrix metalloproteinase-1 (MMP-1), or collagenase, of total tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex in 37 patients with never-treated essential hypertension and in 23 normotensive control subjects. Serum concentrations of free MMP-1 and free TIMP-1 were calculated by subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively. Measurements were repeated in 26 hypertensive patients after 1 year of treatment with the ACE inhibitor lisinopril. Baseline free MMP-1 was decreased (P<0.001) and baseline free TIMP-1 was increased (P<0.001) in hypertensives compared with normotensives. No significant differences were observed in the baseline values of CITP between the 2 groups of subjects. Hypertensive patients with baseline left ventricular hypertrophy exhibited lower values of free MMP-1 (P<0.01) and CITP (P<0.05) and higher (P<0.001) values of free TIMP-1 than hypertensive patients without baseline left ventricular hypertrophy. Treated patients attained an increase (P<0.001) in free MMP-1 and a decrease (P<0.05) in free TIMP-1. In addition, serum CITP was increased (P<0.05) in treated hypertensives compared with normotensive subjects. CONCLUSIONS: These findings suggest that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension and can be normalized by treatment with lisinopril. A depressed degradation of collagen type I may facilitate organ fibrosis in hypertensive patients, namely, in those with left ventricular hypertrophy

The A1166C polymorphism of the AT1 receptor gene is associated with collagen type I synthesis and myocardial stiffness in hypertensives

OBJECTIVES: We have investigated whether the A1166C polymorphism of the angiotensin II type 1 (AT1) receptor gene modulates the effects of angiotensin II on collagen type I turnover and myocardial stiffness in hypertension. METHODS: We studied 255 hypertensive patients before and after 1 year of treatment with either losartan (n = 185) or atenolol (n = 70). Serum concentrations of the carboxy-terminal propeptide of procollagen type I (PIP) and the carboxy-terminal telopeptide of collagen type I (CITP), markers of extracellular collagen type I synthesis and degradation, respectively, were measured by specific radioimmunoassays. Left ventricular chamber stiffness (KLV), was determined from the deceleration time of the early mitral filling wave, as measured by Doppler echocardiography. Hypertensives were genotyped by polymerase chain reaction and divided in two subgroups: AA (n = 126) and AC/CC (n = 129). RESULTS: Baseline PIP and KLV were increased (P < 0.01) in AA hypertensives compared with AC/CC hypertensives. No changes in baseline CITP were observed between the two subgroups of hypertensives. Confounding factors were similar between the two subgroups of hypertensives. Administration of losartan was associated with reduction (P < 0.01) in PIP and KLV in AA hypertensives but not in AC/CC hypertensives. Treatment with atenolol did not change PIP and KLV in either subgroup of hypertensives. No changes in CITP were observed with the two treatments. CONCLUSION: These findings suggest that the A1166C polymorphism of the AT1 receptor gene is associated with collagen type I synthesis and myocardial stiffness in patients with hypertensive heart disease