Regression of hypertensive myocardial fibrosis by Na(+)/H(+) exchange inhibition

We have recently reported that the inhibition of the Na(+)/H(+) exchanger (NHE) during 1 month in spontaneously hypertensive rats (SHR) is followed by regression of cardiomyocyte hypertrophy but not of myocardial fibrosis. The aim of this study was to evaluate whether a treatment of longer duration could reduce myocardial fibrosis and stiffness. SHR received 3.0 mg/kg per day of the specific NHE-1 inhibitor cariporide; the effect on cardiomyocyte cross-sectional area, myocardial collagen volume fraction, collagen synthesis, and myocardial stiffness (length-tension relation in left papillary muscles) was evaluated at several time points (after 1, 2, or 3 months). A slight decrease of approximately 5 mm Hg in systolic blood pressure was observed after 1 month of treatment with no further changes. After 2 and 3 months of treatment, the size of cardiomyocytes remained within normal values and myocardial fibrosis progressively decreased to normal level. Accordingly, myocardial stiffness and the serum levels of the carboxyterminal propeptide of procollagen type I, a marker of collagen type I synthesis, were normalized after 3 months. Left ventricular weight decreased from 910+/-43 (in untreated SHR) to 781+/-21 mg (treated SHR) after 3 months of treatment. No difference in body weight between treated and untreated SHR was observed after this period of treatment. The present data allow us to conclude that in the SHR the administration of an NHE-1 inhibitor for 2 or 3 months leads to the normalization of collagen type I synthesis, myocardial collagen volume fraction, and stiffness.     

Serum Type I Collagen and N-terminal Peptide of Type III Procollagen in Patients with Alcoholic Liver Disease: Relationship to Liver Histology

This study compared, in patients with alcoholic liver disease, the serum concentration of N-terminal peptide of type III procollagen and of a novel serum marker, type I collagen, with liver histological data and assessed the role of these markers in the diagnosis and follow-up of liver changes. Ninety-six patients (mean age 51 years, 61 men and 35 women) were included. All had alcoholic liver disease diagnosed on usual clinical, biochemical, and histological criteria. Two histological scores, one for alcoholic hepatitis and one for fibrosis, were established. Serum N-terminal peptide of type III procollagen and type I collagen were assayed by liquid phase radioimmunoassay. Significant correlations between serum type I collagen and score of fibrosis (r = 0.34, p less than 0.001) and between serum N-terminal peptide of type III procollagen and score of alcoholic hepatitis (r = 0.60, p less than 0.0001) were noted. There was no significant correlation between serum aminotransferases and the score of alcoholic hepatitis. In 25 patients with alcoholic hepatitis reassessed between 3 and 6 months, serum N-terminal peptide of type III procollagen significantly decreased (p less than 0.05) as did the score of alcoholic hepatitis, but serum type I collagen and the score of fibrosis were not modified. These serum markers of collagen metabolism could be useful for the assessment and follow-up in patients with alcoholic liver disease.     

Serum type I collagen and N-terminal peptide of type III procollagen in chronic hepatitis. Relationship to liver histology and conventional liver tests.

The aim of this study was to compare serum N-terminal peptide of type III procollagen to aminotransferases and gamma-globulins as a marker for histological activity in patients with chronic hepatitis and to assess the role of type I collagen, a new serum marker, as a marker of fibrosis in these patients. Sixty patients with biopsy-proven chronic hepatitis were included in this study. Liver disease was virus B-related in 29, autoimmune in five, drug-induced in five, and of unknown etiology in 21. Each biopsy was independently assessed by two liver pathologists. Two histological scores, a score of activity and a score of fibrosis, were established. Serum N-terminal peptide of type III procollagen and type I collagen were assayed by liquid phase RIA. Significant correlations were noted between serum N-terminal peptide of type III procollagen and scores of activity (r = 0.70, p less than 10(-4)) and fibrosis (r = 0.45, p = 0.0005), and between serum type I collagen and scores of activity (r = 0.46, p = 0.0004) and fibrosis (r = 0.67, p less than 10(-4)). When the correlation between scores of activity and fibrosis (r = 0.52, p = 10(-4)) was considered by partial correlation, serum N-terminal peptide of type III procollagen was correlated with the score of activity (r = 0.63, p less than 10(-3)) but not with the score of fibrosis, and serum type I collagen was correlated with the score of fibrosis (r = 0.58, p less than 10(-3)), but not with the score of activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Myocardial fibrosis and diastolic dysfunction in patients with hypertension: results from the Swedish Irbesartan Left Ventricular Hypertrophy Investigation versus Atenolol (SILVHIA)

OBJECTIVES: Hypertensive left ventricular hypertrophy (LVH) is associated with cardiomyocyte hypertrophy and an excess in myocardial collagen. Myocardial fibrosis may cause diastolic dysfunction and heart failure. Circulating levels of the carboxy-terminal propeptide of procollagen type I (PICP), an index of collagen type I synthesis, correlate with the extent of myocardial fibrosis. This study examines myocardial fibrosis in relation to blood pressure, left ventricular mass (LVM), and diastolic function. METHODS: We examined PICP levels in 115 patients with hypertensive LVH, 38 with hypertension but no hypertrophy, and 38 normotensive subjects. Patients with LVH were subsequently randomly assigned to the angiotensin II type 1 receptor blocker irbesartan or the beta1 receptor blocker atenolol for 48 weeks. Diastolic function was evaluated by tissue velocity echocardiography (n=134). We measured basal septal wall velocities of early (Em) and late (Am) diastolic myocardial wall motion, Em velocity deceleration time (E-decm), and isovolumic relaxation time (IVRTm). RESULTS: Compared with the normotensive group, PICP was elevated and left ventricular diastolic function was impaired in the hypertensive groups, with little difference between patients with and without LVH. PICP related to blood pressure, IVRTm, Em, and E/Em, but not to LVM. Irbesartan and atenolol reduced PICP similarly. Only in the irbesartan group did changes in PICP relate to changes in IVRTm, and LVM. CONCLUSION: Myocardial fibrosis and diastolic dysfunction are present in hypertension before LVH develops. The findings with irbesartan suggest a role for angiotensin II in the control of myocardial fibrosis and diastolic function in patients with hypertension with LVH.     

Identification of a potential cardiac antifibrotic mechanism of torasemide in patients with chronic heart failure.

OBJECTIVES: This study sought to investigate whether torasemide inhibits the enzyme involved in the myocardial extracellular generation of collagen type I molecules (i.e., procollagen type I carboxy-terminal proteinase [PCP]). BACKGROUND: Torasemide has been reported to reduce myocardial fibrosis in patients with chronic heart failure (HF). METHODS: Chronic HF patients received either 10 to 20 mg/day oral torasemide (n = 11) or 20 to 40 mg/day oral furosemide (n = 11) in addition to their standard HF therapy. At baseline and after 8 months from randomization, right septal endomyocardial biopsies were obtained to analyze the expression of PCP by Western blot and the deposition of collagen fibers (collagen volume fraction [CVF]) with an automated image analysis system. The carboxy-terminal propeptide of procollagen type I (PICP) released as a result of the action of PCP on procollagen type I was measured in serum by radioimmunoassay. RESULTS: The ratio of PCP active form to PCP zymogen, an index of PCP activation, decreased (p < 0.05) in torasemide-treated patients and remained unchanged in furosemide-treated patients. A reduction (p < 0.01) in both CVF and PICP was observed in torasemide-treated but not in furosemide-treated patients. Changes in PCP activation were positively correlated (p < 0.001) with changes in CVF and changes in PICP in patients receiving torasemide. CONCLUSIONS: These findings suggest the hypothesis that the ability of torasemide to reduce myocardial fibrosis in chronic HF patients is related to a decreased PCP activation. Further studies are required to ascertain whether PCP may represent a new target for antifibrotic strategies in chronic HF.     

TIMP-1: a marker of left ventricular diastolic dysfunction and fibrosis in hypertension

This study was designed to document noninvasively the pathological mechanisms responsible for myocardial fibrosis and to assess the clinical utility of plasma markers of collagen synthesis and degradation as screening tools for the assessment of fibrosis in hypertension. We studied 100 never-treated hypertensive patients and 50 normal subjects. Echocardiographic assessment was made of left ventricular (LV) mass and diastolic filling using measurement of E:A ratio, E wave deceleration time (E dec), and isovolumic relaxation time (IVRT). The presence of diastolic dysfunction was taken as a surrogate marker for the presence of myocardial fibrosis. Plasma carboxy-terminal propeptide of collagen type I (PICP), carboxy-terminal telopeptide of collagen type I (CITP), and tissue inhibitor of matrix metalloproteinases type I (TIMP-1) were measured as markers of collagen synthesis, degradation, and inhibition of degradation, respectively. Plasma TIMP-1 was significantly elevated in the hypertensive cohort (358 ng/mL versus 253 ng/mL, P<0.001) as were CITP (5.2 microg/L versus 2.9 microg/L, P<0.001), and PICP (200 microg/L versus 166 microg/L, P<0.05). TIMP-1 was significantly elevated in patients with diastolic dysfunction (421 ng/mL versus 283 ng/mL P<0.01) and correlated with markers of diastolic filling, namely E:A ratio (r=0.26, P<0.05) and E Dec (r=0.41, P<0.01). A plasma TIMP-1 level of >500 ng/mL had a specificity of 97% and a positive predictive value of 96% in predicting diastolic dysfunction. In patients with untreated hypertension, there is evidence of increased collagen synthesis, degradation, and inhibition of degradation resulting in fibrosis. Our results demonstrate that plasma TIMP-1 correlates with markers of LV diastolic filling, is predictive of LV dysfunction, and is a potential noninvasive marker of fibrosis.     

Tranilast attenuates myocardial fibrosis in association with suppression of monocyte/macrophage infiltration in DOCA/salt hypertensive rats

OBJECTIVE: In order to study the association between myocardial fibrosis and inflammatory cell infiltration in the hypertensive heart, we investigated whether N(3,4-dimethoxycinnamoyl) anthranilic acid (tranilast), an anti-inflammatory drug, would suppress myocardial fibrosis via inhibition of inflammatory cell infiltration in deoxycorticosterone-acetate (DOCA) hypertensive rats. METHODS: Sprague-Dawley rats treated with DOCA combined with the addition of 1% NaCl and 0.2% KCl in the drinking water after left nephrectomy were given tranilast (100 mg/kg per day, n = 15) or vehicle (n = 15) for up to 4 weeks. Systolic blood pressure (SBP), amount of myocardial interstitial fibrosis, perivascular fibrosis and type I and III collagen, and mRNA expression of procollagen I (PI) and procollagen III (PIII), transforming growth factor (TGF)-beta1, type-1 plasminogen activator inhibitor (PAI-1), monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6 were determined. RESULTS: SBP was increased significantly 2 weeks after treatment with DOCA and salt. Myocardial interstitial fibrosis, perivascular fibrosis and collagen accumulation increased significantly 4 weeks after the treatment. Two weeks after the treatment with DOCA and salt, mRNA expression of PI and PIII, TGF-beta1, PAI-1, MCP-1 and IL-6 increased significantly. Although the SBP was similar in animals treated with tranilast or vehicle, monocyte/macrophage infiltration was suppressed, mRNA expression of TGF-beta1, PAI-1, MCP-1, IL-6, PI and PIII was attenuated, and myocardial fibrosis and collagen accumulation were suppressed in hypertensive animals receiving tranilast. CONCLUSION: Myocardial fibrosis seen in DOCA/salt hypertensive rats might be associated with the inflammation/wound healing response. Tranilast suppresses both infiltration of monocytes/macrophages and myocardial fibrosis.     

慢性乙型肝炎肝纤维化分期与血清肝纤维化标志物的相关性分析

目的 探讨血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原等血清肝纤维化标志物与慢性肝炎肝组织炎症活动度及纤维化程度的相关性。方法 278例慢性肝炎患者经肝脏活栓后常规病理检查,肝活检前同时采血检测血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原,结果应用x^2检验及t检验进行统计学处理。结果 肝组织纤维化程度与炎症活动度呈正相关关系,透明质酸可反映中度以上慢性肝炎炎症活动度及纤维化程度,且呈正相关;肝脏存在纤维化时层粘蛋白水平升高,与纤维化程度正相关;Ⅲ型前胶原、Ⅳ型胶原水平升高与炎症活动度有关。结论 血清透明质酸、Ⅲ型前胶原、层粘蛋白、Ⅳ型胶原可不同程度反映肝纤维纤维化程度,可作为血清肝纤维化检测指标,透明质酸更可反映肝硬化发展趋势。     

Cardiac microinjury measured by troponin T predicts collagen metabolism in adults aged >=65 years with heart failure

BACKGROUND: Repeated myocardial microinjuries lead to collagen deposition and fibrosis, thereby increasing the risk of clinical heart failure. Little is known about the longitudinal association between increases in myocardial injury and the biology of collagen synthesis and deposition. METHODS AND RESULTS: Repeated measures of highly sensitive cardiac troponin T (cTnT) were obtained in participants of the Cardiovascular Health Study (N=353; mean age, 74±6 years; 52% women) at baseline and at 3 years follow-up. Biomarkers of collagen metabolism were obtained at follow-up and included carboxyterminal propeptide of procollagen type I, carboxyterminal telopeptide of type I collagen, and aminoterminal propeptide of procollagen III. Multivariable linear regression analyses were used to examine the association between baseline cTnT and changes in cTnT with collagen metabolism markers at follow-up adjusting for demographics, heart failure status, and cardiovascular risk factors. Results indicated that cTnT increases over 3-years were significantly associated with higher levels of carboxyterminal telopeptide of type I collagen (β=0.22, P<0.001) and aminoterminal propeptide of procollagen III (β=0.12, P=0.035) at follow-up when adjusting for demographic, clinical, and biochemical covariates including baseline cTnT. These associations were stronger in patients with heart failure than in control subjects. Conclusions- Increases in myocardial microinjury measured by changes in cTnT adversely affect markers of collagen metabolism. These findings are important to the biology of myocardial fibrosis and tissue repair. Serial evaluation of cTnT combined with collagen metabolism markers may further elucidate the pathophysiology of heart failure.     

Aldosterone inhibition limits collagen synthesis and progressive left ventricular enlargement after anterior myocardial infarction

BACKGROUND: The reparative process after myocardial infarction is related to active collagen synthesis. Previous experimental studies demonstrated that cardiac fibrosis is mediated by angiotensin II and aldosterone; this mechanism is not clearly confirmed in patients who have had a myocardial infarction. The aim of this study was to evaluate whether the suppression of aldosterone may be helpful in reducing postinfarction collagen synthesis (and progressive left ventricular dilation) in patients treated with an angiotensin-converting enzyme inhibitor for a recent myocardial infarction. METHODS: We enrolled 46 patients (ages 60+/-11 years, 34 males) with a first episode of anterior transmural thrombolized myocardial infarction. At hospital discharge patients were randomized to receive potassium canrenoate, an oral aldosterone inhibitor, 50 mg once daily (group 1, n = 24) or placebo (group 2, n = 22). All enrolled patients were on angiotensin-converting enzyme inhibitor therapy. The serum concentration of the aminoterminal propeptide of type III procollagen was used to measure the collagen synthesis rate; dosage was obtained before enrollment, at hospital discharge, and after 3, 6, and 12 months of follow-up. RESULTS: After 3, 6, and 12 months of treatment, the aminoterminal propeptide of type III procollagen serum levels was significantly higher in the placebo group compared with the aldosterone inhibitor group; after 6 and 12 months we observed significantly smaller left ventricular volumes in the active treatment group. CONCLUSION: Potassium canrenoate, combined with an angiotensin-converting enzyme inhibitor, may reduce postinfarction collagen synthesis and progressive left ventricular dilation.     

Regulation of myocardial fibrillar collagen by angiotensin II. A role in hypertensive heart disease?

Collagen types I and III (Col I and Col III) are the major fibrillar collagens produced by fibroblasts and myofibroblasts in the adult heart. Fibrillar collagen of the heart provides the structural scaffolding for cardiomyocytes and coronary vessels and imparts cardiac tissue with physical properties that include stiffness and resistance to deformation. In addition, fibrillar collagen may also act as a link between contractile element of adjacent cardiomyocytes and as a conduit of information that is necessary for cell function. As in other organs, collagen turnover of normal adult heart results from the equilibrium between the synthesis and degradation of Col I and Col III. A number of factors have been described that may alter the balance in favor of either the synthesis (e.g., angiotensin II-ANG II-) or the degradation. Predominance of synthesis over degradation leads to increased Col I and Col III deposition or fibrosis that accompanies cardiac diseases such as hypertensive heart disease. Fibrosis alters myocardial structure and function and adversely afects the clinical outcome of hypertensive patients. Various lines of evidence suggest that besides hypertension, systemically and/or locally produced ANG II may participate in the development of hypertensive myocardial fibrosis via activation of ANG II type 1 receptors (AT(1)R). The potential clinical relevance of this possibility is linked to the ability of antihypertensive drugs such as angiotensin converting enzyme inhibitors (ACEIs) and AT(1)R antagonists (ARAs) to reverse myocardial fibrosis beyond their antihypertensive efficacy.     

Biochemical diagnosis of hypertensive myocardial fibrosis

A substantial increase in fibrillar collagen has been observed in the left cardiac ventricle of animals and humans with arterial hypertension. Hypertensive myocardial fibrosis is the result of both increased collagen types I and III due to the fact that its synthesis by fibroblasts and myofibroblasts is stimulated and its extracellular collagen degradation unchanged or decreased extracellular collagen degradation. Hemodynamic and non-hemodynamic factors may be involved in the disequilibrium between collagen synthesis and degradation that occurs in hypertension. As shown experimentally and clinically, an exaggerated rise in fibrillar collagen content promotes abnormalities of cardiac function, contributes to the decrease in coronary reserve and facilitates alterations in the electrical activity of the left ventricle. Although microscopic examination of cardiac biopsies is the most reliable method for documenting and measuring myocardial fibrosis, the development of non-invasive methods to indicate the presence of myocardial fibrosis in hypertensive patients would be useful. We have therefore applied a biochemical method based on the measurement of serum peptides derived from the tissue formation when synthesized and degradation of fibrillar collagens to monitor the turnover of these molecules in rats with spontaneous hypertension and patients with essential hypertension.     

Serum procollagen peptides and collagen type VI for the assessment of activity and degree of hepatic fibrosis in schistosomiasis and alcoholic liver disease.

Schistosomiasis, in contrast to alcoholic liver disease, leads to presinusoidal hepatic fibrosis, which determines the prognosis of the disease. Because conventional liver function tests and liver biopsy specimens provide little information about the dynamics of the fibrotic process, we measured the serum concentrations of procollagen type III N-propeptide and procollagen type I C-propeptide, believed to mainly reflect collagen synthesis, and procollagen type IV C-propeptide and collagen type VI, two presumptive markers of collagen degradation. Determinations were performed in 15 healthy control subjects, 69 patients with various stages of infection with Schistosoma mansoni/Schistosoma haematobium (28 with an early active infection and no organ involvement, 27 with hepatosplenic involvement and 14 with complications of portal hypertension) and 16 patients with alcoholic cirrhosis. In addition, liver biopsy specimens were obtained from 30 schistosomal patients (18 with hepatosplenic involvement and 12 with complications of portal hypertension for histopathological grading and collagen histochemistry. Procollagen type III N-propeptide was significantly elevated in the three patient groups with schistosomiasis when compared with controls (p less than 0.01). Also, patients with higher histological grading showed significantly higher procollagen type III N-propeptide values (p less than 0.05). In alcoholic patients, procollagen type III N-propeptide was even higher and increased parallel to the severity of the disease, determined by using a combined clinical and laboratory index. Procollagen type I C-propeptide was only elevated in early infection (p less than 0.05) and steadily decreased with disease progression.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of activated renin-angiotensin system in myocardial fibrosis and left ventricular diastolic dysfunction in diabetic patients--reversal by chronic angiotensin II type 1A receptor blockade.

BACKGROUND: We attempted to test the hypothesis that chronic angiotensin II type 1A receptor blockade (ARB) alters myocardial collagen turnover leading to an improvement of diastolic dysfunction in diabetic patients. METHODS AND RESULTS: Forty-eight type 2 diabetic patients were divided into 2 groups: 38 treated with candesartan for 6 months, and 10 without candesartan, as controls. Doppler mitral flow velocity pattern and biomarkers of collagen type I turnover were assessed before and after ARB during a 6-month period. The mitral E/A ratio increased from 0.65+/-0.11 to 0.75+/-0.19. The carboxy-terminal propeptide of procollagen type I (PIP), an index of collagen type I synthesis, decreased and the carboxy-terminal telopeptide of collagen type I (CITP), an index of collagen type I degradation, increased following ARB. Consequently, the PIP/CITP ratio, an index of coupling between the synthesis and degradation of collagen type I, decreased. None of the indexes changed in the control group. The change in left ventricular chamber stiffness did not correlate with the change in PICP (r=0.08, p=NS), but it did with the changes in CITP or in the PIP/CITP ratio (r=0.35, p<0.05; r=0.39, p<0.05). CONCLUSIONS: Chronic ARB improves diastolic dysfunction in diabetic patients, at least partially through the attenuation of myocardial fibrosis, by regulating collagen turnover, particularly by facilitating collagen degradation.     

Effects of loop diuretics on myocardial fibrosis and collagen type I turnover in chronic heart failure

OBJECTIVES: This individually randomized, open-label, parallel-group pilot study was designed to test the hypothesis that the ability of loop diuretics to interfere with cardiac fibrosis in chronic heart failure (CHF) may be different between compounds. BACKGROUND: The apparent mortality and cardiac benefits seen in studies comparing torasemide with furosemide in CHF suggest that torasemide may have beneficial effects beyond diuresis (e.g., on the process of cardiac fibrosis). METHODS: Patients with New York Heart Association functional class II to IV CHF received diuretic therapy with either 10 to 20 mg/day oral torasemide (n = 19) or 20 to 40 mg/day oral furosemide (n = 17), in addition to their existing standard CHF therapy for eight months. At baseline and after eight months, right septal endomyocardial biopsies were obtained to quantify collagen volume fraction (CVF) with an automated image analysis system. Serum carboxy-terminal peptide of procollagen type I (PIP) and serum carboxy-terminal telopeptide of collagen type I (CITP), indexes of collagen type I synthesis and degradation, respectively, were measured by specific radioimmunoassays. RESULTS: In torasemide-treated patients, CVF decreased from 7.96 +/- 0.54% to 4.48 +/- 0.26% (p < 0.01), and PIP decreased from 143 +/- 7 to 111 +/- 3 microg/l (p < 0.01). Neither CVF nor PIP changed significantly in furosemide-treated patients. In all patients, CVF was directly correlated with PIP (r = 0.88, p < 0.001) before and after treatment. No changes in CITP were observed with treatment in either group. CONCLUSIONS: These findings suggest that loop diuretics possess different abilities to reverse myocardial fibrosis and reduce collagen type I synthesis in patients with CHF.     

Type I and III procollagen propeptides in growth hormone-deficient patients: effects of increasing doses of GH

The effect of increasing doses of growth hormone on collagen synthesis in GH-treated GH-deficient patients was determined in a short-term study. The synthesis of type I and III collagen was estimated by measurements of the carboxyterminal propeptide of type I procollagen and the aminoterminal propeptide of type III procollagen. Type I collagen is mainly found in bone and type III collagen in loose connective tissue. We observed a GH dose dependency of both procollagen propeptides. Serum type I procollagen propeptide was significantly higher following GH doses of 4 and 6 IU/day for 14 days compared with 2 IU/day (normal replacement dose) (p = 0.04). Withdrawal of GH therapy for 14 days resulted in wider variation, but not significantly different from the levels at 2, 4 and 6 IU/day. A dose dependency was found regarding type III procollagen propeptide, showing significantly higher serum concentrations at a GH dose of 4 IU/day compared with 2 IU/day (p = 0.001), and of 6 IU/day compared with 4 IU/day (p = 0.001). Withdrawal of GH therapy resulted in significantly lower type III procollagen propeptide concentrations compared with those at a GH dose of 4 and 6 IU/day (p = 0.03). Serum type III procollagen propeptide increased twice as much as type I procollagen propeptide, by 47 vs 25%, at a GH dose of 6 IU/day compared with 2 IU/day. The differences between the effects on type I and type III collagen may reflect differences in secretion or turn-over rate of collagen in bone and loose connective tissue.(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum laminin and portal pressure in alcoholic cirrhosis. A study of 39 patients

A correlation between serum laminin, a glycoprotein found in basement membranes, and hepatic wedge pressure has previously been reported in a small number of patients with various liver diseases. To study this relationship in patients with alcoholic cirrhosis, we measured the wedge hepatic pressure and venous gradient, in comparison with serum concentrations of laminin and collagen metabolism products: N-terminal peptide of type III procollagen, collagen type I, and collagen type III in 39 patients. A statistically significant correlation was observed between serum laminin and wedged hepatic pressure (r = 0.529; p less than 10(-3] or hepatic venous gradient (r = 0.482; p = 0.002). By contrast, no statistically significant correlation was found between hemodynamic parameters and serum concentrations of N-terminal peptide of type III procollagen, collagen type I or collagen type III. These results suggest that, in patients with alcoholic cirrhosis, portal pressure may be estimated by serum concentration of laminin, and that perisinusoidal fibrosis, especially basement membrane thickening, may play an important role in the pathogenesis of portal hypertension in these patients.     

Mechanisms of cardiac fibrosis in hypertension

Changes in the composition of cardiac tissue develop in hypertensive patients with left ventricular hypertrophy (ie, hypertensive heart disease) and lead to structural remodeling of the myocardium. One of these changes is related to the disruption of the equilibrium between the synthesis and degradation of collagen types I and III molecules, which results in an excessive accumulation of collagen types I and III fibers within the myocardium. Myocardial fibrosis is the consequence of a number of pathologic processes mediated by mechanical, neurohormonal, and cytokine routes. The clinical relevance of fibrosis is that it may contribute to heart failure and other cardiac complications in patients with hypertensive heart disease. This brief review focuses on the mechanisms of hypertensive myocardial fibrosis.     

Early recognition and treatment of hypertensive heart disease

PURPOSE OF REVIEW: Hypertension leads to left ventricular hypertrophy, diastolic dysfunction, and eventually clinical heart failure (hypertensive heart disease). There is an important need for physicians to recognize this entity, understand its pathophysiology, and become fluent in treatment options available. This review of recent basic science and clinical data serves to accomplish this task. RECENT FINDINGS: In the past year, a number of exciting concepts have come to the forefront. First, data on the use of brain natriuretic peptide as a screening biomarker has shown promise in patients with symptoms of heart failure. For the earliest detection of structural changes, serum propeptide of procollagen type I, a marker of the deposition of type I collagen in the cardiac interstitium provides a noninvasive way to quantify myocardial fibrosis. Treatment options in the past few years have focused heavily on the anti-fibrotic effects of inhibitors of the renin-angiotensin-aldosterone system, perhaps supplanting beta blockers as first-line agents to regress left ventricular hypertrophy. The concept of aldosterone escape is discussed, highlighting the importance of aldosterone inhibitors in these patients. Lastly, we provide a comprehensive review of all antihypertensive classes and their effects on hypertensive heart disease. SUMMARY: The incidence of hypertensive heart disease is increasing. Earlier detection may be possible with newly studied serum biomarkers. All anti-hypertensive treatments have shown improvement in regressing left ventricular hypertrophy, but inhibitors of the renin-angiotensin-aldosterone system possess the most potent anti-fibrotic effects. It is increasingly important for clinicians to identify and manage hypertensive heart disease to prevent increased morbidity and mortality.     

Transforming growth factor beta in hypertensives with cardiorenal damage

We investigated whether a relationship exists between circulating transforming growth factor beta -1 (TGF-beta(1)), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-beta(1) and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m(2) for men and >104 g/m(2) for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-beta(1) was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-beta(1), stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-beta(1) and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.