Background — This study was designed to investigate whether myocardial collagen content is related to myocardial stiffness in patients with essential hypertension. Methods and Results — The study was performed in 34 patients with hypertensive heart disease. Nineteen of these patients were also evaluated after 12 months of treatment with losartan. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify collagen volume fraction (CVF). Left ventricular (LV) chamber stiffness (K LV ) was determined from the deceleration time of the early mitral filling wave as measured by Doppler echocardiography. Histological analysis at baseline revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 26 with nonsevere fibrosis. Values of CVF and K LV were significantly higher in the 2 subgroups of hypertensives than in normotensives. In addition, compared with patients with nonsevere fibrosis, patients with severe fibrosis exhibited significantly increased values of CVF and K LV . After treatment, CVF and K LV decreased significantly in patients with severe fibrosis (n=7). None of these parameters changed significantly after treatment in patients with nonsevere fibrosis (n=12). CVF was directly correlated with K LV ( r =0.415, P <0.02) in all hypertensives. Conclusions — These findings show a strong association between myocardial collagen content and LV chamber stiffness in patients with essential hypertension. Our results also suggest that the ability of losartan to induce regression of severe myocardial fibrosis is associated with diminution of myocardial stiffness in hypertensive patients.

Background-This study was designed to investigate whether the serum concentration of the carboxy-terminal propeptide of procollagen type I (PIP), a marker of collagen type I synthesis, is related to myocardial fibrosis in hypertensive patients. Methods and Results-The study was performed in 26 patients with essential hypertension in which ischemic cardiomyopathy was excluded after a complete medical workup. Right septal endomyocardial biopsies were performed in hypertensive patients to quantify collagen content. Collagen volume fraction (CVF) was determined on picrosirius red-stained sections with an automated image analysis system. The serum concentration of PIP was measured by specific radioimmunoassay. Compared with normotensives, both serum PIP and CVF were increased (PϽ0.001) in hypertensives. A direct correlation was found between CVF and serum PIP (rϭ0.471, PϽ0.02) in all hypertensives. Histological analysis revealed the presence of 2 subgroups of patients: 8 with severe fibrosis and 18 with nonsevere fibrosis. Serum PIP was higher (PϽ0.05) in patients with severe fibrosis than in patients with nonsevere fibrosis. Using receiver operating characteristic curves, we observed that a cutoff of 127 g/L for PIP provided 78% specificity and 75% sensitivity for predicting severe fibrosis with a relative risk of 4.80 (95% CI, 1.19 to 19.30). Conclusions-These results show a strong correlation between myocardial collagen content and the serum concentration of PIP in essential hypertension. Although preliminary, these findings suggest that the determination of PIP may be an easy and reliable method for the screening and diagnosis of severe myocardial fibrosis associated with arterial hypertension.

Background-We investigated whether increased collagen type I synthesis and deposition contribute to enhancement of myocardial fibrosis and deterioration of cardiac function in patients with hypertensive heart disease (HHD). Methods and Results-We studied 65 hypertensives with left ventricular hypertrophy subdivided into 2 groups: 34 patients without heart failure (HF) and 31 patients with HF. Transvenous endomyocardial biopsies of the interventricular septum were performed to quantify the amount of fibrotic tissue and the extent of collagen type I deposition. The carboxy-terminal propeptide of procollagen type I (PIP), an index of collagen type I synthesis, was measured by radioimmunoassay in serum samples from the coronary sinus and the antecubital vein. Compared with normotensives, the amount of collagen tissue, the extent of collagen type I deposition, and coronary and peripheral PIP were increased (PϽ0.01) in the 2 groups of hypertensives. These parameters were also increased (PϽ0.01) in HF hypertensives compared with non-HF hypertensives. Coronary PIP was higher (PϽ0.01) than peripheral PIP in hypertensives but not in normotensives. The amount of collagen tissue was inversely correlated with the ejection fraction and directly correlated with both coronary and peripheral PIP in all hypertensives. Conclusions-These findings suggest that an excess of cardiac collagen type I synthesis and deposition may be involved in the enhancement of myocardial fibrosis that accompanies the development of HF in HHD. In addition, our data show that the heart secretes PIP via the coronary sinus into the peripheral circulation in patients with HHD. Thus, PIP determined in peripheral blood can be a useful marker of myocardial fibrosis in these patients.

These findings suggest that the ability of antihypertensive treatment to regress fibrosis in hypertensives with biopsy-proven myocardial fibrosis is independent of its antihypertensive efficacy. Our data also suggest that blockade of the angiotensin II type 1 receptor is associated with inhibition of collagen type I synthesis and regression of myocardial fibrosis in hypertensives. Thus, determination of serum PIP may be useful to assess the cardioreparative properties of antihypertensive treatment in hypertensives.

These findings show that the pattern of collagen deposits and the balance of the MMP-1/TIMP-1 system are different in the myocardium of SHF and DHF hypertensive patients. It is proposed that excessive degradation of mysial collagen may be related to the compromise of systolic function in HF hypertensive patients.

These findings suggest that loop diuretics possess different abilities to reverse myocardial fibrosis and reduce collagen type I synthesis in patients with CHF.

Abstract-We investigated whether the quality of myocardial collagen associates with elevated left-sided filling pressures in 38 hypertensive patients with stage C chronic heart failure. Filling pressures were assessed invasively measuring pulmonary capillary wedge pressure. Left ventricular chamber stiffness constant was calculated from the deceleration time of the early mitral filling wave. The fraction of myocardial volume occupied by total collagen tissue and collagen type I fibers was assessed histomorphologically. The degree of collagen cross-linking (CCL), which determines the formation of insoluble stiff collagen, was assessed by colorimetric and enzymatic procedures. Key Words: collagen Ⅲ filling pressures Ⅲ heart failure A rterial hypertension has been long considered as one of the most common etiologic conditions predisposing to heart failure (HF).1 Furthermore, a recent systematic review shows that HF development remains a major problem in treated hypertensive patients.2 It has been shown that myocardial fibrosis, a common finding in postmortem studies and endomyocardial biopsies of patients with hypertensive heart disease (HHD), 3 is associated with the increase of left ventricular (LV) chamber stiffness 4,5 and the development of clinically overt HF in these patients. 6,7 It has been proposed that the increase in LV stiffness can contribute to compromised diastolic function and elevate left-sided filling pressures (FPs) in hypertensive patients. 8 The definition of myocardial fibrosis is based on the quantification of an excess of collagen fiber deposition, as assessed by staining techniques. However, it must be considered that collagen-dependent LV chamber stiffness is influenced not only by the amount of collagen fibers but also by their qualitative properties (ie, the degree of collagen crosslinking [CCL] among collagen fibrils that determines the insolubility, stiffness, and resistance to degradation of the resulting fibers; the relative proportions of collagen types I and III fibers; and the diameter of the collagen fibers and their spatial alignment). 9 In fact, as demonstrated in different experimental models of pressure overload, although LV chamber stiffness is affected by changes in both collagen

Excessive myocardial CCL is associated with HHF in hypertensive patients with HF. In this population, the serum CITP:MMP-1 ratio identifies patients with increased CCL and high risk of HHF.