Paul R. Maxwell

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 &mgr;g/L versus 2.9 &mgr;g/L, P <0.001), and PICP (200 &mgr;g/L versus 166 &mgr;g/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.

Plasma tissue inhibitor of metalloproteinase-1 levels are elevated in essential hypertension and related to left ventricular hypertrophy

BACKGROUND Essential hypertensive patients have an increased heart and arterial collagen concentration. Increased collagen synthesis can be assessed using procollagen III N peptide (PIIINP) and reduced collagen degradation measured using tissue inhibitor of metalloproteinase-1 (TIMP-1). METHODS Plasma TIMP-1 and PIIINP levels were measured in 31 patients with essential hypertension and in 17 normotensive control subjects. The hypertensive patients were either treatment naive (n = 18) or had been without treatment for 1 month (n = 13). Both groups of patients were screened to exclude other fibrotic diseases. RESULTS In the hypertensive patients, TIMP-1 levels were significantly (P < .0002) elevated (median 380 ng/ mL, range 160 to 1,560 ng/mL) compared with those of the normotensive control subjects (median 178 ng/mL, range 99 to 330 ng/mL). In hypertensive subjects who had never received antihypertensive therapy there were significant correlations between TIMP-1 and left ventricular posterior wall thickness in diastole (LVPWd) (r = 0.58) (P < .02) and left ventricular mass index (r = 0.58) (P < .02). There was no difference in PIIINP levels (mean +/- 2 SD) between the hypertensive (0.56 U/mL +/- 0.3) and normotensive groups (0.52 U/mL +/- 0.2). CONCLUSIONS The increased tissue collagen III levels found in the heart and vessels of hypertensive patients is due to a reduction in collagen degradation because of high TIMP-1 levels, rather than an increase in synthesis of collagen type III. The tissue source of this TIMP-1 is unclear.

Time course of plasma markers of collagen turnover in patients with acute myocardial infarction

Ventricular remodelling following acute myocardial infarction (AMI) is a powerful adverse prognostic indicator, characterised by alterations to left ventricular (LV) size, shape, and function.1 Until recently, a clear distinction was made between the early changes of infarct expansion and LV dilatation and the later changes of fibrosis, scar formation, and continued alteration to LV geometry and function. However, it is increasingly recognised that remodelling is a continuum,2 starting during the acute event and progressing thereafter. The remodelling continuum is dependent on the balance between extracellular collagen degradation and synthesis,3 the extent of which can be examined biochemically.4 Procollagen type I carboxy-terminal propeptide (PICP) is cleaved from procollagen during the formation of type I collagen and is therefore a marker of collagen synthesis. Similarly, C-telopeptide for type I collagen (CITP) is released by endopeptidase cleavage by matrix metalloproteinases (MMP) during collagen degradation and is a marker of breakdown. Clearly, MMP activity must be tightly regulated and they are specifically inhibited by the tissue inhibitors of metalloproteinases (TIMPs). We examined plasma concentrations of PICP, CITP, and TIMP-1 as serological markers of collagen turnover in patients presenting with AMI. We recruited 64 patients presenting with their first AMI, with electrocardiographic criteria for thrombolysis. Serial blood sampling was performed on admission, at 12 hours, 24 hours, 2 days, 3 days, 4 days, and 30 days for estimation of plasma PICP and CITP concentrations by radioimmunoassay (Orion Diagnostica, …

Effect of alcohol withdrawal on liver transaminase levels and markers of liver fibrosis

Acute alcohol withdrawal causes changes in hepatic blood flow and metabolism that may result in liver damage. This study aims to assess liver function tests and markers of hepatic fibrogenesis following alcohol withdrawal in alcoholics with clinically compensated liver disease.

Tissue Inhibitor of Metalloproteinase‐1 Is Not an Acute‐Phase Protein

The amount of collagen in tissues is tightly controlled by the rate of collagen synthesis and the rate of collagen degradation. Collagen degradation is governed by the hydrolytic actions of matrix metalloproteinases (MMP). The activity of MMP is inhibited by a group of antiproteinases called tissue inhibitor of metalloproteinase (TIMP). 1 TIMP-1, the best characterized of these antiproteinases, has a molecular weight of 28,000 and is glycosylated at two sites. TIMP-1 is an important factor controlling the development of hepatic fibrosis. 2,3 The activity of TIMP-1 is upregulated by IL6, 4 which is also involved in the acutephase response. Since an acute-phase protein response 5 is also found in patients with alcoholic liver disease, we investigated a group of alcoholic patients who were undergoing acute alcohol withdrawal to see if TIMP-1 correlates with a variety of established acute-phase proteins.

Time course of early changes in plasma markers of collagen turnover following percutaneous transluminal coronary angioplasty

INTRODUCTION Marked changes occur in the collagen framework of the heart following acute ischemia, which is associated with adverse ventricular remodelling. Plasma markers of collagen turnover are useful in the assessment of remodelling and have predictive value, but their exact temporal dynamics following ischemia are unclear. OBJECTIVE To characterize the early temporal dynamics of plasma markers of collagen turnover in a human model of coronary artery occlusion. METHODS Fourteen patients undergoing elective percutaneous coronary intervention (PCI) to a single coronary artery were recruited in addition to a control group of eight patients undergoing elective diagnostic coronary arteriography. Sequential assessment of plasma levels of procollagen type I carboxyterminal propeptide and C-telopeptide for type I collagen (CITP) as markers of synthesis and degradation, respectively, was performed over a 16 h period. RESULTS The ischemic burden in the PCI group was high, with 13 of the 14 patients demonstrating transient ST segment shift or positive troponin. Mean plasma levels of CITP on admission were 3.1 ng⁄mL and 3.0 ng⁄mL in the PCI and control groups, respectively (P value nonsignificant). There was a sequential increase in plasma CITP following PCI, peaking at 4.7 ng⁄mL at 16 h (P<0.01), with no change in the control group. There were no significant changes in plasma levels of procollagen type I carboxyterminal propeptide in either group. CONCLUSIONS Plasma levels of CITP demonstrated early temporal dynamics of collagen degradation following transient coronary artery occlusion supporting the use of plasma markers of collagen turnover as an early tool in the assessment of the remodelling process following myocardial ischemia.

Evaluation of α-Glutathione-S-Transferase as a Biomarker of Lamivudine Therapy for Chronic Hepatitis B

Hepatic damage associated with chronic hepatitis B (CHB) relies on measurement of serum transaminases and asssessment of hepatic histology. We determined if serum hepatic function tests, including α-glutathione-S-transferase ((GST), were of value in monitoring or predicting the effect of lamivudine therapy for CHB. Thirty-nine patients received orally 100 mg of lamivudine daily for 48 weeks. Blood samples were obtained at baseline and at 24 and 48 weeks. At the end of the treatment period the patients were then divided into four groups according to the pattern of HBs and HBe antigens. At baseline and at 24 weeks ALT, AST, and (GST had lower values in the complete response compared to the complete failure groups. Using ROC analysis, only ALT at 24 weeks (area under the curve = 0.803) had significant diagnostic ability in detecting responders. These results reaffirm the value of measuring serum ALT as an indicator of treatment response and provide information on the potential use of (GST as an additional prognostic biomarker in this patient group.