Which factors predict the recovery of natural heart function after insertion of a left ventricular assist system?

BACKGROUND: Recent reports have demonstrated that use of a left ventricular assist system (LVAS) can initiate recovery of cardiac function, and subsequent weaning from the LVAS has attracted considerable interest. In this study we investigated reliable predictors of LVAS weaning. METHODS: Eighty-two patients underwent LVAS implantation between April 1994 and July 2006 at our institution. Cardiac function was restored in 8 patients, who were weaned from LVAS after a mean of 5 months (Group R). Thirty-three patients remained on LVAS support for >1 year (Group N) because natural heart function did not show adequate improvement. We retrospectively evaluated the differences between these two groups. Group R was younger, and had a shorter duration of heart failure than Group N (23.4 vs 36.7 years and 13.3 vs 56.1 months, p < 0.01, respectively). Pathologic findings showed that the interstitial fibrosis score was lower in Group R (p < 0.01). Three months after LVAS insertion, B-type natriuretic peptide (BNP) and fractional shortening (FS) were more favorable (66.6 +/- 46 vs 264.5 +/- 170 pg/ml, p < 0.01, and 23 +/- 17.1 vs 12 +/- 9.1%, p < 0.05, respectively) in Group R. Furthermore, Group R received a higher dose of beta-blocker (15.4 +/- 8.4 vs 5.8 +/- 3.9 mg, p < 0.05). CONCLUSIONS: Younger age, shorter history of heart failure, and less interstitial fibrosis were effective predictors of weaning from LVAS. Restoration of natural heart function was more rapid and more persistent in candidates for LVAS explantation, and presence of beta-blocker played a prominent role in improving cardiac function after LVAS implantation.

Drug interactions between tacrolimus and phenytoin in Japanese heart transplant recipients: 2 case reports.

OBJECTIVE: The purpose of the study was to demonstrate how the interaction between phenytoin and tacrolimus (FK 506) can be managed clinically and to characterize the change in FK 506 levels after discontinuation of phenytoin in two Japanese heart transplant recipients with different dosing periods ofphenytoin. METHODS: A drug interaction between phenytoin and FK 506 was investigated in 2 patients. The concentration-dose ratios (CDR: trough blood FK 506 level (ng/ml)/FK 506 dose (mg/day) on the previous day) were calculated as an index of the induction of the CYP3A4 enzyme during and after phenytoin therapy. RESULTS: About 2- to 3-fold dosages of FK 506 were required to maintain the required blood level when phenytoin was used concomitantly in the two cases examined. The FK 506 dose was constant within 21 days after discontinuing phenytoin in Patient 1 who had 36 days of phenytoin therapy. In Patient 2 with 21-day phenytoin therapy, the FK 506 doses and CDR varied for 10 days after discontinuing phenytoin, and expected FK 506 C0 levels were achieved within 11 days. CONCLUSIONS: The persistence of CYP induction after discontinuing phenytoin is dependent on the history of administration and, perhaps, on the dosing period in particular.

Two young adults who had acute coronary syndrome after regression of coronary aneurysms caused by Kawasaki disease in infancy.

We report two young adult patients who had acute coronary syndrome after regression of coronary aneurysms caused by Kawasaki disease (KD). A 26 year-old man had acute anterior myocardial infarction at midnight after drinking alcohol. He had had bilateral coronary aneurysms caused by KD at the age of 8 months. Selective coronary angiograms (CAGs) at the age of 7 years revealed regression of both coronary aneurysms. He had no symptoms until the onset of acute myocardial infarction. The other patient was a 24 year-old man diagnosed as having a subendocardial infarction. He had had bilateral coronary aneurysms caused by KD at the age of 1 year. CAGs at the age of 9 years showed that both had regressed. It should be recognized that young adults with apparently normal coronary arteries angiographically after regression of large coronary aneurysms caused by KD may occasionally have acute coronary syndromes. We suspect intimal involvement of the coronary arterial wall after regression of the large aneurysms underlies the acute coronary syndrome in adults. Risk factors for atherosclerosis must be avoided in this population.

Heart-type fatty acid binding protein is a novel prognostic marker in patients with non-ischaemic dilated cardiomyopathy.

OBJECTIVE: To determine whether concentrations of heart-type fatty acid binding protein (H-FABP) measured before hospital discharge predict critical cardiac events in patients with idiopathic dilated cardiomyopathy (DCM). PATIENTS: 92 consecutive patients with DCM were enrolled and followed up for four years. MAIN OUTCOME MEASURES: Serum concentrations of H-FABP, brain natriuretic peptide (BNP), cardiac troponin T before hospital discharge and survival rate. RESULTS: 23 patients died of cardiac causes, received a left ventricular assist device or underwent heart transplantation during the four-year follow up. Univariate analyses showed that New York Heart Association functional class, heart rate, ejection fraction, serum H-FABP and plasma BNP were significant variables. According to multivariate analysis, serum H-FABP and plasma BNP concentrations were independent predictors of critical cardiac events. Cardiac troponin T before hospital discharge was not a predictor. The area under the receiver operating characteristic curve for death from critical cardiac events was similar between H-FABP and BNP. Patients with an H-FABP concentration at or above the median (> or = 5.4 ng/ml) had a significantly lower survival rate than those below the median, according to analysis by log rank test (p < 0.0001). When combined with BNP concentration at or above the median (> or = 138 pg/ml), H-FABP below the median predicted the worst prognosis among the combinations. CONCLUSIONS: The concentration of serum H-FABP before discharge from hospital may be an independent predictor for critical cardiac events in DCM.

Comparative left ventricular functional and neurohumoral effects of chronic treatment with carvedilol versus metoprolol in patients with dilated cardiomyopathy.

The efficacy of treating dilated cardiomyopathy with metoprolol was compared with that of carvedilol. Metoprolol was administered to 29 patients, and carvedilol to 62. Patients who could not be dosed with up to 40 mg daily of metoprolol or 20 mg daily of carvedilol were defined as intolerant. As well as the tolerability of these beta-blockers, the effects on left ventricular end-diastolic dimension (LVDd), fractional shortening (FS), plasma atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations, the delayed heart and mediastinum (H/M) ratio determined from metaiodobenzylguanidine imaging were compared. Drug intolerance occurred in 24% of patients in the metoprolol group and 19% in the carvedilol group. Among the drug-tolerant patients, LVDd, FS and plasma BNP concentration improved in both groups and to the same degree. Only 25% of drug-tolerant patients in the metoprolol group had a delayed H/M ratio below 1.9 compared with 57% in the carvedilol group. Both metoprolol and carvedilol, when tolerated, improve cardiac function and neurohumoral factors to the same degree. However, carvedilol is preferable to metoprolol for patients with a low delayed H/M ratio.

An enhanced method for left ventricular volume and ejection fraction by triggered harmonic contrast echocardiography.

To elucidate the validity and reproducibility of the use of intravenous echo-contrast agent in the evaluation of left ventricular (LV) performance, we measured LV volume and ejection fraction (EF) in 42 patients with triggered harmonic contrast imaging (THCI), compared with continuous harmonic imaging without contrast agent (CHI) and with cineventriculography (CVG). In 10 of 42 patients, THCI improved LV border delineation which could not be obtained even with CHI. LV end-diastolic, end-systolic volumes and EF by both CHI and THCI correlated well with those by CVG. Although LV volumes are underestimated, THCI lessened the mean differences to about in half, compared with CHI. The observer variabilities obtained using THCI were smaller than those by CHI. These results indicate the validity of LV enhancement and the measurement of EF using THCI. We suggest that this method noninvasively provides more accurate LV systolic function with the acceptable reproducibility.

Expression of p22-phox and gp91-phox, essential components of NADPH oxidase, increases after myocardial infarction.

Recent studies have shown that oxidative stress plays an important role in cardiovascular diseases. NADPH oxidase is one of the major sources of superoxide anions and a candidate for the initiation and development of atherosclerosis, which involves the remodeling of vasculature. However, the relevance of NADPH oxidase in ventricular remodeling has not been well-characterized. This is the first report showing that the expression of p22-phox and gp91-phox, essential components of NADPH oxidase, are increased in the infarcted sites after myocardial infarction. The levels of thiobarbituric acid reactive substance, which indicates the lipid peroxidation level, and nuclear factor-kappaB (NF-kappaB) DNA binding activity are also increased in infarcted sites. Our results suggest that the increased expression of NADPH oxidase may have an effect on left ventricular remodeling by increasing the redox-sensitive NF-kappaB DNA binding activity as well as the lipid peroxidation level.

[Clinical validation of accuracy of anatomical M-mode measurements: effect of harmonic imaging].

OBJECTIVES: Recent advances in ultrasound technology allow reconstruction of images from stored radiofrequency information and creating of M-mode echocardiograms along an M-mode cursor of any direction (anatomical M-mode echocardiography). METHODS: The accuracy of the measurements obtained by anatomical M-mode echocardiography was evaluated by comparing the measurements with those by B-mode echocardiography with or without harmonic imaging in 8 normal subjects and 14 patients with cardiac disorders. Measurements used the left ventricular short-axis image in 4 different directions (0 to 6, 3 to 9, 1 to 7 and 5 to 11 o'clock). RESULTS: Anatomical M-mode and B-mode measurements showed good linear relationships with correlation coefficients of 0.90 to 0.99 in any of the 4 directions. However, measurements in the lateral direction (3 to 9 o'clock) showed larger errors than those in the other directions (p < 0.05). With the use of harmonic imaging, the errors tended to become smaller, although it did not reach statistical significance. CONCLUSIONS: Anatomical M-mode echocardiography accurately measures the left ventricular internal diameter in any direction except the lateral direction. Harmonic imaging is useful to decrease the errors.

Differences in time course of myocardial mRNA expression in non-infarcted myocardium after myocardial infarction.

In non-infarcted myocardium after myocardial infarction, the change of cardiac phenotypic modulation of contractile protein, extracellular matrix and intracellular Ca2+ transport protein, such as sarcoplasmic reticulum Ca2+(SR-Ca2+)-ATPase, Na+-Ca2+ exchanger, have a important role during cardiac remodeling. However, the time course in this gene expression in the adjacent and remote left ventricular, or right ventricular myocardium after myocardial infarction has not been well examined. The purpose of this study was to examine the left ventricular function and regional cardiac gene expression after myocardial infarction. Myocardial infarction was produced in Wistar rats by the ligation of the left anterior descending coronary artery. After 3 weeks, 2 months and 4 months from myocardial infarction, we performed Doppler echocardiography and measured the systolic and diastolic function. Then, we analyzed the contractile protein, extracellular matrix and intracellular Ca2+ transport protein mRNAs of cardiac tissues in the adjacent and the remote noninfarcted myocardium, and right ventricular myocardium by Northern blot hybridization. Fractional shortening of infarcted heart progressively decreased. Peak early diastolic filling wave (E wave) velocity increased, and the deceleration rate of the E wave velocity was more rapid in myocardial infarction areas. Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity. Expression of myocardial alpha-skeletal actin, beta-MHC and ANP mRNA, or collagen I and III mRNA were higher at 3 weeks after myocardial infarction. SR Ca2+-ATPase mRNA in the adjacent non-infarcted myocardium was decreased at 2 months, and that in remote myocardium was decreased at 4 months after infarction. Na+-Ca2+ exchanger mRNA levels were increased at 3 weeks, but was decreased at 2 months in the adjacent non-infarcted myocardium and at 4 months in the remote myocardium. These findings suggest that the compensation for myocardial infarction by myocardial gene expression in non-infarcted myocardium may occur at an early phase after myocardial infarction, and myocardial dysfunction may begin from adjacent to remote non-infarcted myocardium during progressive cardiac remodeling.

Improvement in cardiac function and free fatty acid metabolism in a case of dilated cardiomyopathy with CD36 deficiency.

A 27-year-old man diagnosed as having dilated cardiomyopathy (DCM) without myocardial accumulation of 123I-beta-methyl-iodophenylpentadecanoic acid, and he was found to have type I CD36 deficiency. This abnormality of cardiac free fatty acid metabolism was also confirmed by other methods: 18F-fluoro-2-deoxyglucose positron emission tomography, measurements of myocardial respiratory quotient and cardiac fatty acid uptake. Although the type I CD36 deficiency was reconfirmed after 3 months, the abnormal free fatty acid metabolism improved after carvedilol therapy and was accompanied by improved cardiac function. Apart from a cause-and-effect relationship, carvedilol can improve cardiac function and increase free fatty acid metabolism in patients with both DCM and CD36 deficiency.

Cardiac transplantation under new legislation for organ transplantation in Japan: report of two cases.

During the past 2 years since new legislation for organ transplantation from brain-dead donors came into effect in Japan, 3 cardiac transplants have been carried out, 2 of which were performed at the National Cardiovascular Center (NCVC). The recipient cases were 46- and 25-year-old male patients who suffered from end-stage dilated cardiomyopathy and had been listed for cardiac transplantation in the Japan Organ Transplantation Network as status I candidates. The first patient was supported by the use of a paracorporeal air-driven left ventricular assist device of the NCVC type, and had a moderate degree of renal and hepatic dysfunction at the time of transplantation. Donor hearts were transported from distant hospitals (Tokyo and Miyagi prefecture) and the transportation time was 1 h 33 min and 2h 4 min, respectively. The operation was performed by the standard technique (Lower-Shumway) in the first patient and by the bicaval anastomosis technique in the second patient. Reperfusion of the transplanted heart was performed retrogradely through the coronary sinus utilizing leukocyte-depleted blood with a gradual increase in temperature. Total ischemic time was 3 h 34 min and 3 h 35 min, respectively. Weaning from the cardiopulmonary bypass was easy and uneventful in each patient. Immunosuppressive therapy was conducted with OKT-3 induction in the first patient because of the coexisting renal dysfunction and with a triple immunosuppressive regimen for both patients. Routine endomyocardial biopsy showed acute rejection of less than grade Ib, and the patients were discharged on the 65th and 46th postoperative day, respectively. At present, both patients are in the NYHA class I state and are ready to return to work. The uneventful recovery seen in these patients shows the advances made in transplant medicine, including the progress and improvement of immunosuppressive therapy, surgical techniques, myocardial protection, and detection and treatment of infection. Further efforts are required to fully establish the cardiac transplantation program in Japan.

Validity and reproducibility of echocardiographic measurement of left ventricular ejection fraction by acoustic quantification with tissue harmonic imaging technique.

The tissue harmonic imaging technique can enhance detection of the cardiac endocardial border. When combined with an acoustic quantification (AQ) method, an improvement of accuracy and reproducibility of real-time measurement of left ventricular (LV) function might be expected. However, few data exist regarding the measurement of LV function by AQ with the harmonic imaging technique. Therefore, we evaluated the validity and reproducibility of AQ measurement of LV ejection fraction with or without harmonic imaging technique. A total of 50 patients (mean age 58 +/- 10 years) who underwent left ventriculography were included in our study. The LV end-diastolic and end-systolic volumes by ventriculography were 131 +/- 52 mL and 72 +/- 43 mL, respectively, and were underestimated by both conventional (70 +/- 32 mL and 36 +/- 25 mL) and harmonic (67 +/- 30 mL and 34 +/- 22 mL) AQ obtained in the apical 4-chamber view. The calculated ejection fraction by ventriculography was 0.49 +/- 0. 11 and correlated with that by conventional AQ (0.51 +/- 0.11; y = 0. 72x + 0.152; r = 0.73). This was a marked improvement when compared with the ejection fraction by harmonic AQ (0.50 +/- 0.11; y = 0.89x + 0.065; r = 0.91). Interestingly, interobserver and intraobserver variabilities of conventional AQ, which were 15.6% and 8.6%, respectively, were much improved by harmonic AQ (8.9% and 4.5%, respectively). These results indicate the feasibility of real-time measurement of LV ejection fraction by harmonic imaging, although absolute LV volume can be underestimated even by this technique.

Enhanced methods for visualizing myocardial perfusion with peripheral venous injection of levovist: application of triggered harmonic imaging and triggered harmonic power Doppler imaging techniques.

OBJECTIVES: The purpose of this study was to determine whether triggered harmonic imaging (THI) or triggered harmonic power Doppler imaging (THPDI) could obtain the myocardial contrast enhancement using peripheral venous injection of a first generation echocardiographic contrast agent, Levovist. METHODS: In a phantom model, we examined the influence of an acoustic power, harmonic filters, transmitted frequencies and focus positions of transducer on Levovist. Then fundamental, harmonic or harmonic power Doppler imaging were performed with ECG-triggered imaging in eight closed-chest dogs using bolus injection of Levovist. RESULTS: In a phantom model, the highest transmission power (Mechanical index 1.6), a medium harmonic filter and a focus position (6 cm) resulted in the best enhanced contrast in both THI and THPDI. Furthermore, higher pulse repetition frequency (5500 Hz) of harmonic power Doppler made clearer enhancement. In animal models, we could not observe the apparent myocardial contrast using triggered fundamental imaging, and the intensity of each region of interest (ROI) of myocardium had not changed significantly. However, homogeneous myocardial contrast could be obtained using THI, which was conditioned on the highest transmission power, a medium harmonic filter same as the phantom model, at a lower transmitted frequency (1.8 MHz) and a focus position, which were located in the middle portion of the left ventricle. The peak intensity of each ROI increased significantly in a gray level. Furthermore, THPDI caused emphasized myocardial contrast visually. CONCLUSIONS: These results indicate that THI and THPDI produce obvious MCE using peripheral venous injection of Levovist.

Angiotensin II type 1-receptor antagonist candesartan cilexitil prevents left ventricular dysfunction in myocardial infarcted rats.

The purpose of this study was to analyze the effect of the angiotensin II type 1-receptor antagonist candesartan cilexitil on left ventricular systolic and diastolic function and mRNA expression of contractile proteins, collagen, and Ca2+ handling protein in myocardial-infarcted rats. After myocardial infarction, the animals were randomly assigned to candesartan cilexitil-treated or untreated groups (MI). We performed Doppler-echocardiographic examination and measured the hemodynamics at four and twelve weeks after myocardial infarction. Following these measurements, their cardiac mRNA was analyzed. At four weeks in MI, left ventricular end-diastolic dimension increased (Control, 6.2+/-0.6 mm; MI, 8.7+/-0.6 mm; P < 0.01), fractional shortening decreased (Control, 41+/-5%; MI, 16+/-3%; P < 0.01) and E wave deceleration rate increased (Control, 14.3+/-2.0 m/sec2; MI, 23.3+/-2.3 m/sec2; P < 0.01). Candesartan cilexitil significantly prevented these changes. The mRNA expressions of beta-myosin heavy chain, alpha-skeletal actin, atrial natriuretic peptide, and collagens I and III in the non-infarcted left ventricle and right ventricle were increased at four weeks and were significantly suppressed by treatment with candesartan cilexitil. At four weeks, Na+-Ca2+ exchanger mRNA expression was increased, and candesartan cilexitil suppressed this increase. At twelve weeks, sarcoplasmic reticulum Ca2+-ATPase mRNA expression in the infarcted region including the adjacent non-infarcted left ventricle and right ventricle were decreased and candesartan cilexitil restored it to the control level. Candesartan cilexitil prevented the systolic and diastolic dysfunction and abnormal cardiac mRNA expression in myocardial-infarcted rats.

[Evaluation of patients with cerebral infarction using transesophageal echocardiography: atherosclerotic changes in the thoracic aorta and the branches of the aortic arch].

Atherosclerotic disease of the aortic arch is thought to be a potential source of cerebral emboli, but this disease in the branch of the aortic arch has not been extensively explored. This study assessed atherosclerotic lesions in the thoracic aorta and the branches of the aortic arch using transesophageal echocardiography in patients with cerebral infarction, and simultaneously searched for potential cardiac sources for emboli. Thrombi were detected in the left atrial appendage in nine of 54 patients with cerebral infarction and these patients were excluded. The remaining 45 patients with cerebral infarction (31 males and 14 females aged 68.5 +/- 7.4 years) and 35 normal subjects (21 males and 14 females aged 69.2 +/- 9.5 years) were evaluated. The thickness of the wall was measured in the branches of the aortic arch (brachiocephalic trunk, left common carotid artery and left subclavian artery) as well as the thoracic aorta (ascending aorta, aortic arch and descending aorta). Atherosclerotic lesions were defined as increased echogenicity of the intima (intimal thickening), calcification, protruded plaque, ulceration or plaque with cystic lesion. The thicknesses of the wall in the aortic arch (3.84 +/- 1.25 vs 2.71 +/- 1.33 mm, p < 0.01), left common carotid artery (2.67 +/- 1.10 vs 2.16 +/- 0.91 mm, p < 0.05) and the left subclavian artery (2.52 +/- 0.67 vs 2.15 +/- 0.88 mm, p < 0.05) were significantly greater in patients than in the normal subjects. The incidence of plaque or ulceration was significantly increased in patients with cerebral infarction compared with the normal subjects in the aortic arch (76% vs 43%, p < 0.05) and left common carotid artery (44% vs 17%, p < 0.05). Transesophageal echocardiography can detect possible sources of emboli in the branches of the aortic arch as well as the thoracic arch in patients with cerebral infarction.

Assessment of cardiac function and gene expression at an early phase after myocardial infarction.

The purpose of this study was to examine left ventricular function and cardiac gene expressions at an acute phase after myocardial infarction (MI). MI was induced in rats by ligation of the left coronary artery. Two days after MI, we performed Doppler-echocardiography and measured the systolic and diastolic function. We then analyzed the contractile protein and extracellular matrix mRNAs of cardiac tissues in the infarcted region, including the adjacent noninfarcted myocardium (the adjacent noninfarcted myocardium) and the remote noninfarcted myocardium, by Northern blot hybridization. Fractional shortening decreased significantly to 28%. Peak early diastolic filling wave (E wave) velocity increased in MI rats (MI; 90 +/- 3 cm/s versus the control; 71 +/- 2 cm/s, p < 0.05), and the deceleration rate of the E wave velocity was more rapid in MI rats (MI; 22.0 +/- 2.6 m/s2 versus the control; 16.5 +/- 2.0 m/s2, p < 0.01). Atrial filling wave (A wave) velocity decreased, resulting in a marked increase in the ratio of E wave to A wave velocity (MI; 3.1 +/- 0.3 versus the control; 2.1 +/- 0.2, p < 0.01). In the adjacent noninfarcted myocardium, mRNA levels for alpha-skeletal actin, atrial natriuretic polypeptide (ANP), transforming growth factor-beta 1(TGF-beta 1), fibronectin, and collagen types I and III increased significantly. In the remote noninfarcted myocardium, mRNA levels for alpha-skeletal actin, ANP, and collagen types I and III increased, while mRNA levels for beta-myosin heavy chain, TGF-beta 1 and fibronectin did not change. We observed left ventricular dysfunction and different gene expression between adjacent noninfarcted myocardium and in the remote noninfarcted myocardium two days after MI. These findings suggest that cardiac gene expression after MI may be a compensation reaction for cardiac dysfunction induced by myocardial damage.

Doppler echocardiographic assessment and cardiac gene expression analysis of the left ventricle in myocardial infarcted rats.

The purpose of this study was to examine cardiac geometry and function by Doppler echocardiography and to analyze mRNA expression of cardiac phenotype and extracellular matrix in myocardial infarcted rats. Doppler echocardiograms and hemodynamics were measured 2 weeks after myocardial infarction (MI). mRNA levels in the non-infarcted left ventricle (LV) and infarct site were measured by Northern blot analysis. LV internal diastolic dimension was greater in infarcted (MI) than in sham-operated rats (control) (MI 7.2+/-0.3 mm vs control 4.6+0.3 mm, p<0.01). The fractional shortening decreased in MI rats (MI 32+4% vs control 61+/-3%, p<0.01). Peak early filling velocity increased in MI rats (MI 91+/-5 cm/sec vs control 72+/-4 cm/sec, p<0.05), and deceleration rate of the early filling wave was more rapid in rats with MI (MI 25.1+/-2.8 m/sec2 vs control 12.4+/-1.7 m/sec2, p < 0.01). Late filling velocity decreased (MI 16+/-3 cm/sec vs control 35+/-6 cm/sec, p <0.05), resulting in a marked increase in the ratio of early filling to late filling (MI 7.1+/-1.2 vs control 2.5+/-0.4, p<0.01). mRNA levels for beta-myosin heavy chain (beta-MHC), a-skeletal actin, atrial natriuretic polypeptide (ANP), collagen types I and III, and matrix metalloproteinase 2 (MMP-2) in the non-infarcted LV increased significantly by 1.8-, 2.4-, 4.7-, 2.6-, 2.1- (all p<0.01) and 1.4-fold (p<0.05), respectively, compared with sham-operated myocardium. In the infarct site, mRNA levels for transforming growth factor (TGF)-beta1, collagen types I and III, and MMP-2 significantly increased by 3.2-, 11.0-, 9.7-, and 6.3-fold (all p<0.01), respectively, compared with sham-operated myocardium. Myocardial infarcted rat was characterized by cavity dilation and marked abnormalities of systolic and diastolic function, accompanied by a shift of myocytes to fetal phenotype and activation of collagen genes in the non-infarcted myocardium.

Activation of mitogen-activated protein kinases and activator protein-1 in myocardial infarction in rats.

OBJECTIVE: The purpose of this study was to examine the activation of mitogen-activated protein kinases (MAPK) plus activator protein-1 (AP-1) and nuclear factor-kB (NF-kB) DNA binding activities, all of which seem to be important in a signal transduction cascade upstream of the increased level of mRNA expression observed after myocardial infarction. METHODS: Myocardial infarction was produced in Wistar rats. The activities of MAPKs in the ischemic region were measured using an in-gel kinase method or an in vitro kinase method. AP-1 and NF-kB binding was determined using an electrophoretic mobility shift assay. Levels of transforming growth factor beta-1(TGF-beta-1) and collagen I and III mRNAs were analyzed by Northern blot hybridization. RESULTS: p42 Extracellular signal-regulated kinase (ERK), p44ERK and p38MAPK activities increased 5.2-fold, 4.3-fold and 1.9-fold (P < 0.01), respectively, at 5 min after coronary artery ligation but returned to normal levels by 30 min. p55c-Jun NH2-terminal kinase (JNK) and p46JNK activities increased 4.0-fold and 3.2-fold (P < 0.01), respectively, at 15 min and returned to normal levels by 24 h after ligation. AP-1 DNA and NF-kB binding activities increased 8.7-fold and 7.1-fold (P < 0.01), respectively, at 3 days but returned to normal levels by 7 days after ligation. Interestingly, analyses of the levels of TGF-beta-1, collagen I and III mRNAs revealed increases of 6.3-fold, 15.2-fold and 12.0-fold (P < 0.01), respectively, at 1 week after myocardial infarction. CONCLUSIONS: Myocardial ischemia increased MAPK activities, which were followed by enhancement of AP-1 and NF-kB DNA binding activity in areas of myocardial infarction in rats. These signal transduction mechanisms may contribute to the myocardial ischemia and injury associated with myocardial infarction by causing an increased expression of TGF-beta-1 mRNA, collagen I and III in the area.

Spectroscopic investigation on the interaction of NCA0424, a potent antitumor indoloquinoxaline derivative, with DNA.

NCA0424 (1), an indoloquinoxaline derivative, has a potent antitumor activity against in vitro and in vivo tumor models. To elucidate its structure-activity relationship, the interactions with various B-form DNAs were investigated by thermal denaturation, viscosity and circular dichroism (CD) measurements. The thermal stability of the DNA duplex was increased by the interaction with 1, and preferable binding for alternative purine-pyrimidine base sequence was suggested. Comparative viscometric measurements with ethidium bromide (an intercalator) and distamycin (a minor groove binder) suggested that 1 is an intercalator. The interaction of DNA with 1 revealed a new CD band at 340-390 nm. Taking advantage of this induced CD band, the equilibrium binding constants were determined for various DNAs, and the binding preference of 1 for the alternative purine-pyrimidine base sequence, especially for the case of guanine as purine base, was indicated. The appearance of the induced CD band implies the importance of 1 side chain for the effective and/or stable intercalation of the aromatic ring into the DNA base pair.