A possible contribution of lipocalin-2 to the development of dermal fibrosis, pulmonary vascular involvement and renal dysfunction in systemic sclerosis.

BACKGROUND: Lipocalin-2 is an adipocytokine implicated in apoptosis, innate immunity, angiogenesis, and the development of chronic kidney disease. OBJECTIVES: To investigate the role of lipocalin-2 in systemic sclerosis (SSc). MATERIALS AND METHODS: Serum lipocalin-2 levels were determined by enzyme-linked immunosorbent assay in 50 patients with SSc and 19 healthy subjects. Lipocalin-2 expression was evaluated in the skin of patients with SSc and bleomycin (BLM)-treated mice and in Fli1-deficient endothelial cells by reverse transcriptase-real time polymerase chain reaction, immunoblotting and/or immunohistochemistry. RESULTS: Although serum lipocalin-2 levels were comparable between patients with SSc and healthy controls, the prevalence of scleroderma renal crisis was significantly higher in patients with SSc with elevated serum lipocalin-2 levels than in those with normal levels. Furthermore, serum lipocalin-2 levels inversely correlated with estimated glomerular filtration rate in patients with SSc with renal dysfunction. Among patients with SSc with normal renal function, serum lipocalin-2 levels positively correlated with skin score in patients with diffuse cutaneous SSc with disease duration of < 3 years and inversely correlated with estimated right ventricular systolic pressure in total patients with SSc. Importantly, in SSc lesional skin, lipocalin-2 expression was increased in dermal fibroblasts and endothelial cells. In BLM-treated mice, lipocalin-2 was highly expressed in dermal fibroblasts, but not in endothelial cells. On the other hand, the deficiency of transcription factor Fli1, which is implicated in SSc vasculopathy, induced lipocalin-2 expression in cultivated endothelial cells. CONCLUSIONS: Lipocalin-2 may be involved in renal dysfunction and dermal fibrosis of SSc. Dysregulated matrix metalloproteinase-9/lipocalin-2-dependent angiogenesis due to Fli1 deficiency may contribute to the development of pulmonary arterial hypertension associated with SSc.

Histological features of localized scleroderma 'en coup de sabre': a study of 16 cases.

BACKGROUND: Early lesions of localized scleroderma are histologically characterized by perivascular lymphocytic infiltrate in the reticular dermis and swollen endothelial cells. However, there have been few information regarding histological features other than these findings in localized scleroderma. OBJECTIVE: Since en coup de sabre (ECDS) is a certain subset of localized scleroderma with a relatively uniform clinical manifestation, we focused on this disease subset and evaluated its histopathological features. METHODS: A total of 16 patients with ECDS were retrospectively evaluated on the basis of clinical and histological findings. RESULTS: Regardless of clinical manifestations, vacuolar degeneration was found in all of the ECDS patients. Importantly, keratinocyte necroses were restricted to early and active ECDS lesions. In early ECDS patients (disease duration of <3 years), moderate to severe perivascular and/or periappendageal lymphocytic infiltrate and vacuolar changes in follicular epithelium were more prominent, whereas epidermal atrophy was less frequently observed, than in late ECDS patients (disease duration of ≥6 years). CONCLUSION: Vacuolar degeneration at the dermoepidermal junction is a common histological feature in ECDS and perivascular and/or periappendageal lymphocytic infiltrate and vacuolar degeneration of follicular epithelium are characteristic especially in early ECDS, further supporting a canonical idea that the elimination of mutated epidermal cells by immune surveillance contributes to tissue damage and resultant fibrosis in localized scleroderma.

Serum levels of ADAM12-S: possible association with the initiation and progression of dermal fibrosis and interstitial lung disease in patients with systemic sclerosis.

BACKGROUND: A disintegrin and metalloprotease (ADAM) 12 is one of the metalloproteinase-type ADAMs and possesses extracellular metalloprotease and cell-binding functions. ADAM12 is expressed in two alternative forms, such as a membrane-anchored form (ADAM12-L) and a short secreted form (ADAM12-S). OBJECTIVE: To investigate the clinical significance of serum ADAM12-S levels in systemic sclerosis (SSc). METHODS: Serum ADAM12-S levels were determined by a specific enzyme-linked immunosorbent assay in 61 SSc patients and 18 healthy controls. RESULTS: Serum ADAM12-S levels were significantly increased in diffuse cutaneous SSc (dcSSc) patients than in healthy controls (0.417 ± 0.389 vs. 0.226 ± 0.065 ng/mL; P < 0.05), while being comparable between limited cutaneous SSc (0.282 ± 0.258 ng/mL) and healthy controls. Serum ADAM12-S levels significantly elevated in dcSSc patients with disease duration of ≤ 6 years (0.537 ± 0.449 ng/mL, P < 0.05), but not in dcSSc with disease duration of >6 years (0.225 ± 0.049 ng/mL), compared to healthy controls. Furthermore, in dcSSc patients with disease duration of ≤ 6 years, serum ADAM12-S levels correlated positively with modified Rodnan total skin thickness score, ground glass score, and serum C-reactive protein values, while showed inverse correlation with fibrosis score. CONCLUSION: Elevated serum ADAM12-S levels are associated with elevated serum inflammatory marker, severity of skin fibrosis, and activity of interstitial lung disease in dcSSc, suggesting the possible contribution of ADAM12-S to the pathological events in this disorder.

Clinical significance of serum retinol binding protein-4 levels in patients with systemic sclerosis.

BACKGROUND: Retinol binding protein-4 (RBP-4) is a member of adipocytokines, which is potentially associated with fibrosis, vasodilation, and angiogenesis in addition to insulin resistance. OBJECTIVE: To investigate the clinical significance of serum RBP4 levels in patients with systemic sclerosis (SSc), which is a systemic autoimmune disease characterized by fibrosis and vasculopathy. METHODS: Serum RBP4 levels were determined by enzyme-linked immunosorbent assay in 62 SSc patients and 19 healthy controls. RESULTS: Similar to patients with chronic kidney disease, serum RBP4 levels inversely correlated with estimated glomerular filtration rate in SSc patients with renal dysfunction. Therefore, analyses were carried out by excluding SSc patients with estimated glomerular filtration rate <60 mL/min/1.73 m(2) . Serum RBP4 levels were significantly lower in diffuse cutaneous SSc (dcSSc) than in control subjects [median (25-75 percentile); 25.8 µg/mL (19.6-47.0) vs. 43.1 µg/mL (31.7-53.4), P < 0.05], while there was no significant difference between limited cutaneous SSc (lcSSc) [28.0 µg/mL (25.4-43.3)] and control subjects. In both of dcSSc and lcSSc, patients with Raynaud's phenomenon had RBP4 levels significantly lower than those without. Furthermore, serum RBP4 levels inversely correlated with pulmonary function test results in dcSSc and with right ventricular systolic pressure in lcSSc. CONCLUSION Decreased RBP4 levels are associated with the prevalence of Raynaud's phenomenon in dcSSc and lcSSc, with the severity of interstitial lung disease in dcSSc, and with the degree of pulmonary vascular involvement in lcSSc, suggesting the possible contribution of RBP4 to the pathological events in this disorder.

Constitutive activation of c-Abl/protein kinase C-δ/Fli1 pathway in dermal fibroblasts derived from patients with localized scleroderma.

BACKGROUND: A noncanonical pathway of transforming growth factor-ß signalling, the c-Abl/protein kinase C-δ (PKC-δ)/Friend leukemia virus integration 1 (Fli1) axis, is a powerful regulator of collagen synthesis in dermal fibroblasts. OBJECTIVES: To investigate the significance of the c-Abl/PKC-δ/Fli1 pathway for the establishment of the profibrotic phenotype in lesional dermal fibroblasts from patients with localized scleroderma (LSc). METHODS: The activation status of the c-Abl/PKC-δ/Fli1 pathway was evaluated by immunoblotting and chromatin immunoprecipitation using cultured dermal fibroblasts from patients with LSc and closely matched healthy controls and by immunostaining on skin sections. The effects of a platelet-derived growth factor receptor inhibitor AG1296 and gene silencing of c-Abl on the expression levels of type I collagen were evaluated by immunoblotting. RESULTS: The phosphorylation levels of Fli1 at threonine 312 were increased, while the total Fli1 levels and the binding of Fli1 to the COL1A2 promoter were decreased, in cultured LSc fibroblasts compared with cultured normal fibroblasts. Furthermore, in cultured LSc fibroblasts, the expression levels of c-Abl were elevated compared with cultured normal fibroblasts and PKC-δ was preferentially localized in the nucleus. These findings were also confirmed in vivo by immunohistochemistry using skin sections. Moreover, gene silencing of c-Abl, but not AG1296, significantly suppressed the expression of type I collagen in cultured LSc fibroblasts. CONCLUSIONS: Constitutive activation of the c-Abl/PKC-δ/Fli1 pathway at least partially contributes to the establishment of the profibrotic phenotype in LSc dermal fibroblasts, which provides a novel molecular basis to explain the efficacy of imatinib against skin sclerosis in a certain subset of LSc.

Augmented production of soluble CD93 in patients with systemic sclerosis and clinical association with severity of skin sclerosis.

BACKGROUND: The cell surface protein CD93, expressed on endothelial and myeloid cells, mediates phagocytosis, inflammation and cell adhesion. A soluble form of CD93 (sCD93) is released during inflammation. OBJECTIVES: To determine the serum sCD93 level and its association with clinical parameters in patients with systemic sclerosis (SSc). METHODS: Serum sCD93 levels were examined by enzyme-linked immunosorbent assay in 59 patients with SSc, 24 patients with systemic lupus erythematosus and 47 healthy individuals. The expression of CD93 in skin tissues was examined immunohistochemically. In a retrospective longitudinal study, sera from 11 patients with SSc were analysed. RESULTS: Serum sCD93 levels were increased in patients with SSc compared with healthy individuals (P<0·001). Patients with diffuse cutaneous SSc showed greater levels of sCD93 than those with limited cutaneous SSc (P<0·01) or systemic lupus erythematosus (P<0·01). Serum sCD93 levels correlated positively with the severity of skin sclerosis. Strong CD93 immunostaining was observed on endothelial cells in lesional skin tissues. In the longitudinal study, sCD93 levels decreased in parallel with improvement in skin sclerosis. CONCLUSIONS: Serum sCD93 levels are increased in patients with SSc and correlate with the severity and activity of skin sclerosis. CD93 may contribute to the development of skin fibrosis in SSc.

Effects of bosentan on nondigital ulcers in patients with systemic sclerosis.

BACKGROUND: Bosentan is an oral dual endothelin receptor antagonist, which has been shown to be efficacious for preventing new digital ulcers in patients with systemic sclerosis (SSc) in two high-quality randomized controlled trials. However, its efficacy for nondigital ulcers in SSc remains unknown. OBJECTIVES: To evaluate the efficacy of bosentan on nondigital ulcers in patients with SSc. METHODS: Bosentan was administered to five patients with SSc with pulmonary arterial hypertension, who also had nondigital ulcers refractory to conventional treatments. The efficacy of bosentan on nondigital ulcers and its association with clinical features of ulcers were analysed. RESULTS: The nondigital ulcers refractory to conventional treatments were significantly improved by the administration of bosentan in cases surrounded with severe cyanosis. In contrast, nondigital ulcers without cyanosis were still refractory to bosentan therapy. CONCLUSIONS: Bosentan may be efficacious for accelerating the healing of nondigital ulcers with severe cyanosis, suggesting that nondigital ulcers caused by severely impaired peripheral circulation are highly responsive to this treatment.

PACAP receptor (PAC1-R) expression in rat and rhesus monkey thymus.

The expression of PACAP receptor (PAC1-R) was investigated in the thymus of rats and rhesus monkeys. In the rat thymus, PAC1-R positive cells were found in the intermediate type of thymic epithelial cells of the medulla. PAC1-R-positive cells were also seen in the thymic medulla of the rhesus monkey. The thymus showed unusual structures in some rhesus monkey dams (F0) and offspring (F1) exposed to 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). Additionally, in these rhesus monkeys, PAC1-R expression was different from that in the control thymus.

Does passive smoking impair endothelium-dependent coronary artery dilation in women?

OBJECTIVES: This study sought to examine whether passive smoking is associated with endothelial dysfunction in the coronary arteries. BACKGROUND: Long-term exposure to cigarette smoking has been reported to suppress endothelium-dependent arterial dilation in humans. Endothelial dysfunction is an early feature of atherogenesis, and the impairment of acetylcholine (ACh)-induced coronary artery dilation indicates coronary endothelial dysfunction. METHODS: We studied 38 women (40 to 60 years old) who had no known risk factors for coronary artery disease other than tobacco smoking: 11 nonsmokers who had never smoked and had never been regularly exposed to environmental tobacco smoke; 19 passive smokers with self-reported histories of exposure to environmental tobacco smoke of > or = 1 h/day for > or = 10 years; and 8 active smokers. We examined the response of the epicardial coronary artery diameters (proximal and distal segments of the left anterior descending [LAD] and left circumflex [LCx] coronary arteries) to the intracoronary injection of ACh into the left coronary artery by means of quantitative coronary angiography. RESULTS: ACh significantly dilated the distal segment in nonsmokers (percent change from baseline diameter: LAD 13.7+/-3.4%, p < 0.05; LCx 18.8+/-2.9%, p < 0.01) but not the proximal segment (LAD 7.4+/-3.5%; LCx 3.1+/-5.0%). ACh significantly constricted all segments of the left coronary artery in passive smokers (LAD: proximal -20.3+/-3.7%, p < 0.05; distal -22.3+/-4.1%, p < 0.01; LCx: proximal -20.8+/-3.1%, p < 0.05; distal -17.3+/-2.9%, p < 0.01) and active smokers (LAD: proximal -14.8+/-3.4%, p < 0.05; distal -27.2+/-6.0%, p < 0.01; LCx: proximal -14.5+/-6.6%, p < 0.05; distal -22.4+/-4.0%, p < 0.01). Thus, ACh constricted most coronary arteries in both passive and active smokers and dilated the coronary arteries in nonsmokers. CONCLUSIONS: Impairment of ACh-induced coronary artery dilation, indicating coronary endothelial dysfunction, may occur diffusely in passive smokers as well as in active smokers.

Enhanced secretion of cardiac hepatocyte growth factor from an infarct region is associated with less severe ventricular enlargement and improved cardiac function.

OBJECTIVES: We hypothesized that the hepatocyte growth factor (HGF) may play a cardioprotective role in human myocardial infarction (MI). BACKGROUND: The HGF is a novel, multifunctional growth factor implicated in wound healing, angiogenesis and promotion of cell survival. Recent animal studies have demonstrated the existence of an HGF system in the heart, where it is activated in response to myocardial ischemia and reperfusion. METHODS: We studied 40 patients with acute myocardial infarction (AMI), who underwent coronary reperfusion therapy upon admission. Approximately four weeks later, left ventricular (LV) catheterization was repeated to determine the LV ejection fraction (EF), end-diastolic volume index (EDVI) and pressure (EDP). The levels of HGF and brain natriuretic peptide (BNP) were measured by collecting blood samples from cardiac veins draining the infarcted region (MI region) and those draining the noninfarcted region (non-MI region). The ratio of the HGF level in the MI region to that in the non-MI region (= MI/non-MI ratio) was calculated in each patient as an index of the MI-related HGF secretion. The MI/non-MI ratio for BNP was also calculated. RESULTS: The MI/non-MI ratio for HGF correlated inversely with LVEDP (r = -0.644, p < 0.0001) and LVEDVI (r = -0.843, p < 0.0001) and positively with LVEF (r = 0.763, p < 0.0001). These correlations were completely opposite in direction from those for BNP and LVEDP (r = 0.678, p < 0.0001), LVEDVI (r = 0.783, p < 0.0001) and LVEF (r = -0.805, p < 0.0001). These findings indicate that cardiac HGF acts in contrast to BNP, a biochemical marker for the development of LV remodeling. CONCLUSIONS: Enhanced secretion of cardiac HGF from the MI region is associated with an attenuation of ventricular enlargement and an improvement in cardiac function. The HGF system may modulate the process of ventricular remodeling and thus have important clinical implications.

Comparison of secretion pattern between A-type and B-type natriuretic peptides in patients with old myocardial infarction.

OBJECTIVES: The present study was designed to compare the secretion patterns of two cardiac hormones--A-type (atrial) and B-type (brain) natriuretic peptides--from the ventricles in patients with old myocardial infarction. BACKGROUND: Plasma levels of these two natriuretic peptides are increased, and their secretion from the ventricles is augmented, in patients with congestive heart failure. METHODS: We measured the plasma levels of these two types of natriuretic peptides at the aortic root and the anterior interventricular vein in 42 patients with old myocardial infarction (anterior in 22 and inferior in 20) and 18 control subjects. RESULTS: The difference between the plasma levels of both A- and B-type natriuretic peptide in the anterior interventricular vein and aortic root was significantly greater in the groups with anterior and inferior infarction than in the control group (A-type [mean +/- SD] 380 +/- 290 and 247 +/- 205 pg/ml in the infarction groups vs. 11 +/- 14 pg/ml; B-type 497 +/- 445 and 75 +/- 73 pg/ml vs. 23 +/- 16 pg/ml, respectively). The difference between the plasma levels of each peptide at the anterior interventricular vein and aortic root had a significant negative linear correlation with left ventricular ejection fraction in both groups with infarction. The slope of the regression line of the arteriovenous difference of B-type natriuretic peptide at the anterior interventricular vein was significantly steeper in the anterior than in the inferior infarction group (left ventricular ejection fraction -12.801 vs. -1.891, p < 0.01). CONCLUSIONS: These results indicate that 1) the secretion of A- and B-type natriuretic peptide from the left ventricular increases in proportion to the severity of left ventricular dysfunction, and 2) secretion of B-type natriuretic peptide is much greater from the infarct than from the noninfarct region, suggesting that the regional ventricular wall stretch caused by infarction strongly stimulates secretion of B-type natriuretic peptide.

Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin.

OBJECTIVES: We examined the vasomotility of the entire epicardial coronary artery system in patients with and without coronary spastic angina. BACKGROUND: The coronary arteries of patients with variant angina are hyperreactive to diverse constrictor stimuli. It is unclear whether the abnormal responses to constrictive or dilative stimuli, or both, result from a localized or diffuse disorder in the coronary artery tree. METHODS: Coronary artery diameter responses to intracoronary acetylcholine and nitroglycerin were examined at the proximal, middle and distal segments of three principal coronary arteries in 36 patients with coronary spastic angina without significant stenosis and in 12 young (< or = 30 years old) and 20 older control subjects (> 30 years old) with normal coronary arteriographic findings. In 10 patients with significant coronary stenosis, the responses of the prestenotic segments were also examined. RESULTS: In patients with coronary spastic angina, coronary spasm was induced in 23 left anterior descending, 13 left circumflex and 17 right coronary arteries by acetylcholine. Multivessel spasm was observed in 15 patients. Acetylcholine had a dilator effect on most segments in young control subjects and a mild constrictor effect in older control subjects and in patients with significant stenosis. Comparison of the responses to acetylcholine among groups demonstrated that the constrictor response of the artery with spasm was enhanced significantly and diffusely. That of the artery without spasm also tended to be enhanced. Coronary artery diameters after nitroglycerin did not differ in any segment among patients with coronary spastic angina and both control groups. In patients with coronary spastic angina, nitroglycerin significantly enhanced dilation in all segments of the artery with spasm compared with that observed in both control groups and in most segments of the artery without spasm. Patients with significant coronary stenosis had a reduced response compared with that in control subjects. CONCLUSIONS: Hyperreactive responses not only to the constrictor effects of acetylcholine, but also the dilator effects of nitroglycerin were detected diffusely in the epicardial coronary arteries of patients with coronary spastic angina. This finding indicates that a diffuse, not localized, disorder in vasomotility is involved in the pathogenesis of coronary spastic angina.

Angiotensin-converting enzyme inhibition restores hepatocyte growth factor production in patients with congestive heart failure.

Endothelium-dependent vasodilation is impaired in patients with congestive heart failure. For vascular endothelium, hepatocyte growth factor (HGF) is one of the most potent and specific growth factors, which acts protectively against endothelial dysfunction. HGF production is downregulated by angiotensin II (Ang II) in vitro. We hypothesized that HGF production is impaired as the result of increased Ang II in patients with congestive heart failure, and that if so, the impaired production should be restored with angiotensin-converting enzyme inhibitors (ACE-I). We studied 16 patients with congestive heart failure caused by previous anterior myocardial infarction in whom left ventricular ejection fraction was 35+/-8% (mean+/-SD). Before and approximately 4 weeks after the treatment with ACE-I, blood samples were collected to measure the levels of HGF, Ang II, and brain natriuretic peptide as a biochemical marker for severity of heart failure. We also studied 5 control subjects, in whom heparin increased HGF production to 48+/-5-fold. However, in patients with heart failure, HGF response to heparin was significantly attenuated (24+/-5-fold, P<0.05 vs control). Therapy with ACE-I decreased the levels of Ang II and brain natriuretic peptide and restored HGF production in response to heparin by 43+/-7-fold, comparable to the control response. In conclusion, impaired HGF production was restored after the treatment with ACE-I probably by the mechanism of Ang II suppression. This novel effect of ACE-I may contribute to the clinical improvement in patients with heart failure and thereby may have an important therapeutic implication.

Enhanced expression of mitochondrial genes in senescent endothelial cells and fibroblasts.

It has been suggested that some mitochondrial genes are important in cellular senescence. In order to identify the mitochondrial genes that are involved in cellular senescence, we have constructed a cDNA library from senescent human vascular endothelial cells and isolated 86 senescence-specific cDNA clones by differential screening. Among the clones, we identified four distinct mitochondrial genes including NADH dehydrogenase subunit 2 (ND2), ND3, ATPase 6 and 16S ribosomal RNA. We then compared the levels of expression of these genes in young and senescent cells by using two endothelial and two fibroblast cell strains. Northern blot and slot blot hybridization confirmed that the expression levels of ND3, ATPase 6 and 16S rRNA were elevated in senescent cells of all four strains. The expression level of ND2 was also elevated during cellular senescence in three of the four strains. Because mitochondria are actively involved in oxidative phosphorylation and respiratory functions, the altered expression levels of these genes may participate in aging processes.

Diuretic effect of phosphodiesterase inhibitors depends on baseline renal function in patients with congestive heart failure.

We examined the diuretic effects of phosphodiesterase inhibitors in heart failure patients with and without renal failure. We found that, despite the improvement in central hemodynamics, phosphodiesterase inhibitors do not necessarily facilitate diuresis in heart failure in patients with concomitant renal failure.

Effects of angiotensin-converting enzyme inhibitor alacepril in patients with stable effort angina during chronic isosorbide dinitrate treatment.

Nitrate tolerance has been reported to be reversed by certain types of angiotensin-converting enzyme (ACE) inhibitors. We examined whether alacepril, a new long-acting oral ACE inhibitor, has beneficial effects against exercise-induced angina in patients with stable effort angina after substantial isosorbide dinitrate (ISDN) treatment. Thirteen men with stable effort angina were treated with oral ISDN (80 mg/d) for >3 weeks. After this period, efficacy of single oral administration of either alacepril (50 mg) or its placebo on exercise-induced angina and electrocardiographic changes was examined by treadmill exercise test in a double-blind crossover design. Alacepril significantly improved the exercise duration by 9.1% (p=0.03), the time to 1 mm ST-segment depression by 19% (p<0.01), and the maximal ST-segment depression by 33% (p=0.015) compared with placebo. Alacepril did not significantly alter the rate-pressure product, a marker of myocardial oxygen demand, during exercise test compared with placebo. Plasma renin activity was significantly increased (p<0.05) after administration of alacepril, indicating that alacepril significantly blocked ACE activity in our patients. In conclusion, a single oral administration of the ACE inhibitor alacepril (50mg) elicited beneficial effects against exercise-induced myocardial ischemia in patients with stable effort angina during chronic nitrate treatment. These effects may be mediated by increased coronary blood flow.

Cardiac angiotensin-converting enzyme activity in myocardial infarction.

The cardiac renin-angiotensin system is regarded as an important modulator in the infarct heart. Little is known about their presence and regulation in human hearts. We measured angiotensin-converting enzyme (ACE) and renin activities at the aortic root and anterior interventricular vein (AIV) in 51 patients with previous myocardial infarction (MI): anterior wall MI in 31 and inferior wall MI in 20 and 33 control subjects. In the anterior wall MI group, the serum ACE activity was increased significantly in the AIV than in the aortic root (16.2 +/- 5.3 vs 15.3 +/- 5.0 nmol/min/ml, p <0.001), whereas the activity was not different between the aortic root and AIV in the control (14.4 +/- 3.7 vs 14.4 +/- 3.7 nmol/min/ ml) and in the inferior wall MI (16.5 +/- 4.8 vs. 17.0 +/-5.2 nmol/min/ml) groups. On the other hand, there was no significant difference in plasma renin activity between the AIV and aortic root in the 3 groups (control group, 1.0 +/- 0.5 vs 1.0 +/- 0.5 pg/ml/hour; anterior wall MI group, 1.3 +/- 0.8 vs 1.3 +/- 0.8 pg/ml/hour; inferior wall MI group, 1.2 +/- 0.7 vs 1.3 +/- 0.8 pg/ml/ hour). The difference in serum ACE activity between the AIV and aortic root had a significant positive linear correlation with pulmonary capillary wedge pressure (r = 0.606, p <0.001), and had a significant negative linear correlation with left ventricular ejection fraction (r = -0.620, p <0.001) in the anterior wall MI group. Serum ACE activity from the infarct region of the left ventricle was augmented in patients with MI, and the activity was increased in proportion to the severity of left ventricular dysfunction.

Usefulness of serum troponin T levels on day three or four in predicting survival after acute myocardial infarction.

The appearance of serum troponin T (tn-T) on day 1 after acute myocardial infarction (AMI) strongly depends on coronary reperfusion. In contrast, the kinetics of tn-T release after day 1 after AMI are unaffected by the reperfusion status, and reflect the degradation of myofilaments in irreversibly damaged cells. However, it is not known whether serum tn-T levels after day 1 after AMI can be used to predict the long-term outcome. The purpose of this study was to elucidate the prognostic value of determining the tn-T level on day 3 or 4 after AMI. Serum tn-T levels on day 3 or 4 after AMI were measured in 121 patients (92 men and 29 women, mean age 65 years). Mean follow-up period was 526 days. There were 12 deaths (9 cardiac and 3 noncardiac) during the follow-up period. By Kaplan-Meier analysis, patients with tn-T levels higher than the median level (6.9 ng/ml) had a significantly higher mortality rate than those with submedian levels (p <0.01). By multivariate Cox proportional-hazards regression analysis, the serum tn-T level was an independent predictor of the long-term outcome after AMI (p <0.01). Futhermore, in patients with a first AMI, the serum tn-T level exhibited a significant negative linear correlation with left ventricular ejection fraction assessed 4 weeks after AMI (r = -0.48, p <0.001). Increased serum tn-T levels on day 3 or 4 after AMI are a powerful noninvasive predictor of poor long-term prognosis, reflecting residual left ventricular function after AMI.