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Circulation. 1995;91:1450-1456

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(Circulation. 1995;91:1450-1456.)
© 1995 American Heart Association, Inc.

Articles

Increased Serum Concentrations of Procollagen Peptides in Essential Hypertension

Relation to Cardiac Alterations

Javier Díez, MD, PhD; Concepción Laviades, MD, PhD; Gaspar Mayor, MD; María Jesús Gil, DSc; Ignacio Monreal, MD, DSc

From the Department of Internal Medicine (J.D.), Center for Biomedical Research, School of Medicine, University of Navarra, Pamplona, and the Department of Medicine (J.D.), School of Medicine, University of Zaragoza, Zaragoza; the Division of Medicine (C.L., G.M.), San Jorge General Hospital, Huesca; and the Department of Clinical Biochemistry (M.J.G., I.M.), University Clinic, School of Medicine, University of Navarra, Pamplona, Spain.

Correspondence to Javier Díez, MD, PhD, Unidad de Fisiopatologia Vascular, Dpto de Medicina Interna, Centro de Investigaciones Biomédicas, Facultad de Medicina, C/ Irunlarrea s/n, 31080 Pamplona, Spain.


*    Abstract
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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.


Key Words: hypertension • hypertrophy • peptides


*    Introduction
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 up arrowAbstract
 *Introduction
down arrowMethods
down arrowResults
down arrowDiscussion
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Besides myocyte hypertrophy, a disproportionate accumulation of fibrillar collagen type III and type I occurs within the normal connective tissue structures of the myocardial interstitium in the left ventricle of animals1 2 3 4 5 6 7 and humans8 9 10 11 12 with arterial hypertension. This reactive fibrosis is accomplished by alterations in collagen synthesis and degradation and by fibroblast proliferation.13 14 Hemodynamic loading, ischemia, hormones, and growth factors may participate in the development of myocardial fibrosis that occurs in hypertension.15 16 As shown experimentally3 17 and clinically,18 a rise in collagen content adversely raises myocardial stiffness and promotes abnormalities of cardiac function. In addition, it has been demonstrated that ventricular arrhythmias in hypertensive patients are related to the degree of myocardial fibrosis.19

Although cardiac biopsies are reliable for measuring myocardial fibrosis,10 11 18 20 it seems necessary to develop noninvasive methods that indicate the presence of myocardial fibrosis in hypertensive patients (that is, biochemical markers of collagen synthesis).

Collagen types III and I are synthesized as procollagens with a small amino terminal and a larger carboxy terminal propeptide. Once secreted into the extracellular space, the propeptides are removed by specific endopeptidases, thus allowing integration of the rigid collagen triple helix into the growing fibril.21 The three–amino acid procollagen type III amino terminal peptide (PIIIP) formed during this process is released into the blood. The serum concentration of PIIIP has been proposed as a useful marker of collagen type III synthesis.22 This is supported by a diversity of clinical observations demonstrating that high serum levels of the peptides reflect ongoing tissue fibrosis.23 24 25 26 27 In a preliminary study, we have shown that the serum concentration of PIIIP is abnormally increased in a small group of patients with essential hypertension,28 thus suggesting that collagen type III synthesis and fibril formation is also increased in this condition.

The 10–amino acid procollagen type I carboxy terminal peptide (PIP) is cleaved off procollagen type I during synthesis of the fibril forming collagen type I. In contrast to PIIIP, PIP is completely removed from its procollagen precursor during extracellular processing of collagen type I,21 thus offering the theoretical advantage of directly reflecting fibrogenesis. This has been confirmed in studies conducted in patients with different clinical conditions.29 30 31 Therefore, the serum concentrations of both PIP and PIIIP were measured in the present study to assess more accurately the intensity of the fibrogenic process in patients having essential hypertension. In addition, the relation between serum concentrations of the two peptides and several parameters of left ventricular anatomy and function were analyzed to delineate the value of these peptides as potential markers of ventricular fibrosis in the hypertensive patient.


*    Methods
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 *Methods
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Subjects
The study population consisted of 50 patients with mild to moderate essential hypertension never treated and 30 normotensive control subjects. The hypertensive patients were not the same subjects studied in a previous publication.28 All subjects gave informed consent, and the local committee on human research approved the study protocol.

Arterial blood pressure was measured in the morning, after 10 minutes in the supine position, using a mercury column sphygmomanometer. The I and V phases of the Korotkoff sounds were used; three measurements were obtained on each occasion, at 5-minute intervals, and averaged. Arterial hypertension was said to be present if the systolic blood pressure and diastolic blood pressure were >=140 and 90 mm Hg, respectively. All patients had appropriate clinical and laboratory evaluation to exclude hypertension secondary to the following: renal disorders, renal artery abnormalities, adrenocortical disorders, pheochromocytoma, and iatrogenic causes.32 Conditions associated with elevated serum concentrations of PIIIP (chronic liver disease, pulmonary fibrosis, rheumatoid arthritis, extensive wounds, acute myocardial infarction) or PIP (alcoholic liver disease, metabolic bone disease) were excluded after complete medical examination. We also excluded patients with overt coronary artery disease or other organic heart diseases as evidenced by clinical, ECG, and echocardiographic criteria. None of the women were pregnant or taking oral contraceptives.

Forty-three patients received lisinopril as treatment (range, 10 to 20 mg once daily) for 6 months. The therapeutic goal was to achieve a systolic blood pressure and diastolic blood pressure of <140 and 90 mm Hg, respectively. After the 6-month period of treatment, each patient underwent another complete medical examination.

The control group consisted of 30 subjects with blood pressure <140/90 mm Hg in repeated measurements. They were all healthy blood donors of the Center for Biomedical Research at the University of Navarra. None of the control subjects had echocardiographic evidence of cardiac disturbances.

Cardiac Studies
Echocardiographic Study
Two-dimensional, targeted M-mode and Doppler ultrasound recordings were obtained in each patient. M-mode measurements were taken according to the guidelines laid down by the American Society of Echocardiography.33 Left ventricular mass was calculated using the formula validated by Devereux and Reichek.34 Left ventricular mass index (LVMI) was obtained by dividing left ventricular mass by body surface area. The relative wall thickness (RWT) was measured at end diastole as the ratio of 2x (posterior wall thickness/internal dimensions). The presence of left ventricular hypertrophy was established either when LVMI was >111 g/m2 for men and >106 g/m2 for women or when RWT was >0.44.35 Left ventricular fractional shortening and ejection fraction were calculated according to Quinones et al.36 The following pulsed Doppler measurements were obtained37 : maximal early transmitral velocity in diastole (VE) and maximal late transmitral velocity in diastole (VA). The diagnosis of diastolic dysfunction was established when the ratio of VE/VA was <1.37

Ambulatory ECG Monitoring
All ambulatory ECG tracings were recorded continuously during one 24-hour period of monitoring with the use of portable high-resolution ECG monitoring (Diagnostic Medical Instruments) at baseline and 6 months thereafter. Standard recordings of two leads corresponding to modified leads V1 and V5 were recorded for analysis. The system was fully automated and computerized using an Altair personal computer Holter system with superimposition capability and with a record of <3% misinterpreted ectopic complexes. Ventricular arrhythmias were categorized according to the Lown-Wolf classification38 : grade 0, no premature ventricular complexes; grade 1, <30 premature ventricular complexes per hour; grade 2, >30 premature ventricular complexes per hour; grade 3, multiform; grade 4A, couplets; grade 4B, salvos (>3 consecutive premature ventricular complexes at a rate >110 beats per minute); and grade 5, R-on-T phenomenon.

All cardiac data were evaluated blind by one cardiologist without any knowledge of the biochemical data of the patient or the time sequence of the studies.

Biochemical Determinations
The general biochemical evaluation included plasma glucose concentration and serum lipid profile, measurement of serum potassium, and serum and urine creatinine. Blood samples were drawn in fasting condition. Biochemical parameters were measured by routine laboratory methods. Renal clearance of creatinine was calculated as the product of urine flow rate and the urine creatinine concentration divided by the serum creatinine concentration.

Serum samples to determine PIIIP and PIP were taken at the time of the clinical studies and stored at -40°C for up to 6 months. The 6-month follow-up samples were analyzed together with samples from the initial setup. No changes were observed in the samples analyzed twice.

Serum PIIIP was determined by a coated-tube radioimmunoassay as described previously by Risteli et al,39 using commercial antisera specifically directed against the terminal amino terminal peptide (Behringwerke). The interassay and intra-assay variations for determining PIIIP were both <10%. The sensitivity (lower detection limit) was 1.5 ng of PIIIP/mL.

Serum PIP was determined by a rapid equilibrium radioimmunoassay according to the method by Meikko et al,40 using commercial antisera specifically directed against the terminal carboxy terminal peptide (Farmos Diagnostica). The interassay and intra-assay variations for determining PIP were 7% and 3%, respectively. The sensitivity (lower detection limit) was 1.2 µg of PIP/L.

Hormonal Determinations
Plasma renin activity (PRA) was measured in resting conditions by radioimmunoassay for angiotensin I (Sorin, Sallugia).41 The relation of PRA to the concurrent daily rate of urinary sodium excretion was studied, and three major subgroups of patients were defined according to the appropriateness or normality of the PRA in relation to natriuresis as previously established41 : low renin patients, normal renin patients, and high renin patients. Plasma aldosterone concentration was determined by direct radioimmunoassay (Abbott).41 Blood samples for both measurements were drawn at 9:00 AM.

Statistical Studies
Values are expressed as mean±SEM. A Student's t test for unpaired data was used to assess the statistical significance between control subjects and patients before treatment. A Student's t test for paired data was used to assess the statistical significance between patients before and after treatment. The correlation between continuously distributed variables was tested by univariate regression analysis.


*    Results
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*Results
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Baseline Findings
The baseline demographic, biochemical, hormonal, and echocardiographic parameters are presented in Table 1Down. As expected, the levels of blood pressure were higher in hypertensive patients as compared with normotensive patients. Heart rate and body mass index were increased in hypertensive patients as compared with normotensive patients. The creatinine clearance was higher in the group of patients than in the group of control subjects. Although values of plasma aldosterone were increased in hypertensive patients as compared with normotensive patients, no biochemical abnormalities suggestive of hyperaldosteronism (ie, hypokalemia) were detected in the group of patients. No other differences in clinical, biochemical, and hormonal parameters were found between the two groups of subjects.


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  		Table 1. Baseline Clinical, Biochemical, Hormonal, and Echocardiographic Parameters in Normotensive and Hypertensive Patients

Although posterior wall thickness was increased in hypertensive patients as compared with normotensive patients, the calculated left ventricular mass and the LVMI were similar in the two groups of subjects. This could be due to the fact that the left ventricular internal dimensions and the body surface area were lower and higher, respectively, in hypertensive patients as compared with normotensive patients (data not shown). Left ventricular hypertrophy was present in 15 patients but in none of the normotensive subjects. The ratio between maximal early transmitral flow velocity and maximal late transmitral flow velocity measured during diastole was lesser in the group of hypertensive patients than in the group of normotensive patients. Diastolic dysfunction was diagnosed in 28 patients but in none of the normotensive patients. The parameters of systolic function were within the normal limits in all patients studied.

The Lown-Wolf distribution of patients is presented in Table 2Down. There were no episodes of ventricular fibrillation or R-on-T phenomenon recorded. Mean ventricular ectopic activity was of 148±75 ventricular extrasystoles per day (range, 0 to 3077). No relation was found between the presence or absence of left ventricular hypertrophy and the severity or the number of ventricular arrhythmias in hypertensive patients.


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  		Table 2. Serum Concentrations of Procollagen Type III Amino Terminal Peptide and Procollagen Type I Carboxy Terminal Peptide in Hypertensive Patients Classified According to Lown-Wolf Classification of Ventricular Arrhythmias

As shown in Fig 1Down, serum concentrations of PIIIP and PIP were higher (P<.001) in hypertensive patients than in normotensive patients (PIIIP, 10.08±0.48 versus 8.47±0.77 ng/mL; PIP, 139±6 versus 108±6 µg/L). Eleven hypertensive patients exhibited values of PIIIP above the upper end in normotensive patients (12.32 ng/mL). Eight hypertensive patients exhibited values of PIP above the upper end in normotensive patients (170 µg/L in men and 202 µg/L in women). In three hypertensive patients, the values of the two peptides were above the upper ends measured in normotensive patients. No significant clinical differences were found between patients with abnormally high concentrations of either peptide and patients with concentrations within the normal range.



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  		Figure 1. Bar graphs show serum concentrations of procollagen type III amino terminal peptide (PIIIP) (left) and serum concentrations of procollagen type I carboxy terminal peptide (PIP) (right) in normotensive patients (shaded bars) and essential hypertensive patients before treatment (white bars).

An inverse correlation was found between serum PIIIP and the ratio of VE/VA (y=1.113-0.019x, r=-.3786, P<.01) in the group of hypertensive patients (Fig 2Down). Serum PIP was correlated directly with the left ventricular mass index (y=67.068+0.198x, r=.3277, P<.05) in the group of hypertensive patients (Fig 3Down). No significant correlations were found between PIIIP and LVMI or between PIP and VE/VA in this study.



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  		Figure 2. Scatterplot shows inverse correlation (y=1.113-0.019x) between serum concentrations of procollagen type III amino terminal peptide (PIIIP) and the ratio between maximal early transmitral flow velocity and maximal late transmitral flow velocity measured during diastole (VE/VA) in essential hypertensive patients.



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  		Figure 3. Scatterplot shows direct correlation (y=67.068+0.198x) between serum concentrations of procollagen type I carboxy terminal peptide (PIP) and left ventricular mass index (LVMI) in essential hypertensive patients.

An association was found between serum PIP concentrations and the Lown-Wolf score of ventricular arrhythmias in hypertensive patients. Serum PIP increased in parallel with the increase in the grade of ventricular arrhythmias in hypertensive patients (Table 2Up). No association was found between serum PIIIP and the grade of ventricular arrhythmias.

An association was found between the serum PIIIP concentrations and the appropriateness of PRA to the natriuresis in the group of hypertensive patients (Table 3Down). The higher PIIIP concentrations were found in high renin patients and the lower PIIIP concentrations in the low renin patients, with intermediate PIIIP concentrations in normal renin patients. No association was found between serum PIP and the appropriateness of PRA to the natriuresis.


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  		Table 3. Serum Concentrations of Procollagen Type III Amino Terminal Peptide and Procollagen Type I Carboxy Terminal Peptide in Hypertensive Patients Classified According to Appropriateness of Plasma Renin Activity to Sodium Excretion

Findings After Treatment
As shown in Table 4Down, arterial pressure was normalized in patients receiving lisinopril. A significant decrease in heart rate and body mass index was observed in treated patients. Treatment with lisinopril was associated with the effective blockade of the renin-angiotensin-aldosterone system, as assessed by the significant increase in PRA and the significant decrease in plasma aldosterone observed after treatment.


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  		Table 4. Effects of Treatment With Lisinopril on Clinical, Biochemical, and Hormonal Parameters of Hypertensive Patients

The values of echocardiographic parameters assessing left ventricular mass and dimensions were diminished after the treatment period (Table 5Down). Left ventricular hypertrophy regressed after treatment in 7 of the 14 patients presenting this alteration before treatment. The trend toward normalization of the ratio of VE/VA did not attain statistical significance (Table 5Down). Diastolic function was normalized with treatment in 6 of the 21 patients diagnosed of diastolic dysfunction before treatment. No significant changes were observed in parameters related to systolic function of the left ventricle after treatment with lisinopril (Table 5Down).


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  		Table 5. Effects of Treatment With Lisinopril on Echocardiographic Parameters of Hypertensive Patients

Patients on lisinopril attained ventricular ectopic activity reduction from 154±80 to 118±73 ventricular extrasystoles per day, but the difference did not reach statistical significance. The Lown-Wolf distribution of the patients after treatment was as follows: grade 0, 15; grade 1, 26; and grade 2, 2.

Serum PIIIP and PIP concentrations were diminished (P<.001) after 6 months of treatment with lisinopril (PIIIP, 10.06±0.49 versus 4.82±0.56 ng/mL; PIP, 140±7 versus 111±5 µg/L) (Fig 4Down). This was attributable to the decrease in serum PIIIP and PIP concentrations in 41 and 32 of the patients treated with the drug, respectively. Values of PIIIP or PIP above the upper end in normotensive patients were present in 2 patients after treatment. One of these patients exhibited abnormally high values of the two peptides.



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  		Figure 4. Bar graphs show serum concentrations of procollagen type III amino terminal peptide (PIIIP) (left) and serum concentrations of procollagen type I carboxy terminal peptide (PIP) (right) in essential hypertensive patients before (shaded bars) and after (white bars) treatment with lisinopril.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
In the first part of this study, we confirm our previous finding28 of increased serum concentrations of PIIIP in patients with essential hypertension. In addition, we show that serum concentrations of PIP are also abnormally increased in hypertensive patients. Both alterations are corrected after chronic treatment with the angiotensin-converting enzyme (ACE) inhibitor lisinopril.

As with PIIIP,42 PIP appears to be eliminated from the blood by the liver.40 Taking into account that none of the patients here studied showed altered hepatobiliary function, it can be proposed that elevated serum concentrations of PIIIP and PIP present in hypertensive patients represent an increased production of the two peptides.

Although serum PIIIP has been proposed as a useful marker of fibrogenesis,16 it should be noted that this peptide is not completely removed from its procollagen precursor during the extracellular processing of collagen type III.21 In contrast, the removal of PIP is complete, leading to fibril-forming collagen type I.21 This means that serum PIP reflects fibrogenesis more accurately than does serum PIIIP. Accordingly, the finding of elevated serum concentrations of PIP in essential hypertensive patients reinforces our previous suggestion28 that essential hypertension represents a clinical condition characterized by fibrogenic hyperactivity.

Hypertensive myocyte hypertrophy is believed to be primarily load based, whereas fibroblast activity appears to be primarily regulated by nonhemodynamic mechanisms.15 In this regard, we did observe that patients with high serum concentrations of PIIIP and PIP exhibited similar values of blood pressure and a similar time of exposure to hypertension than patients with normal serum concentrations. Therefore, the role of circulating substances in mediating collagen synthesis and fibrous tissue formation in hypertensive patients must be considered.

In vivo studies have shown that chronic elevations in circulating angiotensin II or aldosterone provoke myocardial accumulation of fibrillar collagen.43 In vitro, effector hormones of the renin-angiotensin-aldosterone system have been shown to directly enhance collagen synthesis of rat fibroblasts.44 45 Therefore, our findings of increased baseline aldosterone levels, the presence of an association between PRA and serum PIIIP and the decrease of serum PIIIP and PIP after blockade of the renin-angiotensin-aldosterone system with lisinopril—a drug that cannot interfere with the hepatobiliary elimination of peptides46 —add support to the involvement of angiotensin II and/or aldosterone in the exaggerated production of collagen in essential hypertensive patients. This possibility can be of particular interest when explaining the exaggerated synthesis of collagen type III, since we have reported previously that a direct correlation exists between serum PIIIP and PRA in hypertensive patients.28

In the second part of the study, we found that serum concentrations of PIIIP and PIP are related to the anatomic, diastolic, and electrical alterations that are characteristic of the hypertensive left ventricle.

A significant increase in fibrillar collagen content has been observed in the cardiac ventricles of both animals1 2 3 4 5 6 7 and humans8 9 10 11 12 with arterial hypertension. Therefore, it is tempting to speculate that increased serum concentrations of PIIIP and PIP present in hypertensive patients studied may reflect an increased ventricular synthesis of collagen types III and I. The observation that serum PIP correlates with left ventricular mass supports this possibility for collagen type I. However, because no cardiac biopsies were performed in this study, the cardiac origin of the two peptides remains speculative, and other extracardiac sources deserve to be considered. This is especially true for PIIIP, since collagen type III is also synthesized by cells of the vascular wall,47 and the collagen content of the arterial wall has been found to be increased in arterial hypertension.48 49 50 51

A diversity of experimental and clinical findings indicate that cardiac collagen accumulation adversely influences diastolic relaxation and stiffness of the left ventricle.3 17 18 On the other hand, in spontaneously hypertensive rats with left ventricular hypertrophy and fibrosis of the cardiac interstitium, lisinopril reversed fibrous tissue accumulation and restored myocardial stiffness.52 We have found that basal serum concentrations of PIIIP are inversely correlated with basal values of the ratio of VE/VA. This is in agreement with the previous observation that PIIIP correlates inversely with VE in hypertensive patients28 and suggests that myocardial accumulation of collagen type III plays a role in the impairment of diastolic function in patients with essential hypertension.

On the other hand, while the serum level of PIIIP was normalized after treatment with lisinopril, the ratio of VE/VA was not. We are aware that by measuring serum PIIIP, we assess the formation of collagen type III but not its degradation. It is likely that preexisting collagen is not removed during the 6-month treatment period, and this continues to influence adversely cardiac function.

Ventricular arrhythmias have been shown to occur more frequently in hypertensive patients with left ventricular hypertrophy than in those without.19 53 54 However, as previously reported by others,55 no differences in ectopic ventricular activity were observed in this study between patients with hypertrophy and patients without.

Alternatively, ventricular arrhythmias in hypertensive patients have been shown to be related to the degree of myocardial fibrosis.19 It has been proposed that myocardial fibrosis might favor ventricular reentry mechanisms by causing local variations in the activation-front conduction velocities.56 We did observe that an association exists between the baseline serum concentration of PIP and the Lown-Wolf grade of ventricular arrhythmias in hypertensive patients. Furthermore, the normalization of the serum concentrations of PIP after treatment was associated with improvement in the Lown-Wolf score of ventricular arrhythmias. Thus, it is tempting to speculate about the possibility that increased myocardial deposition of collagen type I promotes the appearance of alterations in electrical activity of the left ventricle in hypertensive patients.

Summary
The findings presented here show an increase of serum concentrations of PIIIP and PIP in patients with essential hypertension. Elevated serum PIIIP and PIP may be markers of increased collagen type III and type I synthesis in these patients. The effects of lisinopril on serum concentrations of the two peptides suggest that the renin-angiotensin-aldosterone system may participate in the excessive synthesis of collagen types III and I in hypertension. On the other hand, the relations observed between serum PIIIP and PIP and parameters of mass, diastolic function, and electrical activity of the left ventricle permit us to propose that circulating procollagen-derived peptides may reflect ongoing myocardial fibrosis in essential hypertension.

Received July 5, 1994; revision received August 19, 1994; accepted September 23, 1994.


*    References
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 up arrowIntroduction
 up arrowMethods
up arrowResults
up arrowDiscussion
*References
 

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