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The preventive effect of statins on coronary events is not only associated with the cholesterol-lowering effect of these drugs, but also various direct effects on the vascular wall, which include improvement of endothelial function, antioxidant activity, and anti-inflammatory activity. We investigated whether short-term statin therapy could improve arterial stiffness and assessed its mechanism of action in patients with hypercholesterolemia. We assessed arterial stiffness in 10 patients (mean age: 62.9 +/- 9.0 years) with hypercholesterolemia (total cholesterol > or =220 mg/dl). The patients were treated with cerivastatin (0.15 mg/day) for 4 weeks. Before and after 4 weeks of treatment, we determined arterial stiffness from brachial-ankle pulse wave velocity and the ankle-brachial blood pressure index (ABI) using a FORM apparatus (Colin, Komaki, Japan). We also measured the blood levels of high-sensitivity C-reactive protein (hsCRP) and malondialdehyde low-density lipoprotein (MDA-LDL) as markers of inflammation and oxidation, respectively. After statin therapy, both the right and left abPWV were significantly decreased from 1544.6 +/- 157.1 to 1349.0 +/- 223.9 cm/s and from 1592.1 +/- 164.8 to 1424.8 +/- 245.2 cm/s, respectively (P < 0.05). However, the ABI was unchanged after 4 weeks of cerivastatin therapy. MDA-LDL decreased significantly (from 161.2 +/- 42.4 to 119.4 +/- 33.5 U/l, P < 0.05) and hsCRP also decreased. Total cholesterol and LDL-cholesterol decreased, while triglycerides and high-density lipoprotein-cholesterol were unchanged. Blood pressure was not significantly altered from the baseline value by statin therapy. These results suggest that the preventive effect of statins on coronary events is partly associated with the various actions of these drugs on the vascular wall, and that statins are not only cholesterol-lowering agents but also antiatherosclerotic agents.

The microtubule-binding domain of MAP4, a ubiquitous microtubule-associated protein, contains a region rich in proline and basic residues (proline-rich region). We searched the bovine adrenal gland for MAP4 isoforms, and identified a novel variant lacking 72 consecutive amino acid residues within the proline-rich region, as compared with the full-length MAP4. The amino acid sequence of the missing region was highly conserved (about 85% identity/similarity) among the corresponding regions of bovine, human, mouse, and rat MAP4, which suggested the functional significance of this region. A comparison of the genomic sequence with the cDNA sequence revealed that the missing region is encoded by a single exon. A MAP4 variant cDNA homologous to the bovine form was also detected in rat cells, suggesting that the new variant can be generated by alternative splicing, not only in bovine but also in other mammalian species. The mRNA expression of the novel isoform was restricted to the brain and the adrenal medulla, suggesting that this isoform is specific to a certain cell type. Using a bacterially expressed fragment corresponding to the microtubule-binding domain of the novel isoform, we analyzed its in vitro characteristics. The fragment induced microtubule assembly and bound to preformed microtubules, but the activities were slightly lower than those of the conventional MAP4 fragment, which carries the full-length proline-rich region. The microtubules assembled in the presence of the fragment failed to be bundled. Instead, a constant spacing between neighboring microtubules was observed.

Objectives: Nonvalvular atrial fibrillation is a known risk factor for thromboembolism. This study investigated the use of coagulation markers to predict thromboembolism in nonvalvular atrial fibrillation patients., Methods: One hundred thirty nonvalvular atrial fibrillation patients (104 males, 26 females, mean age 63.7 +/- 10.7 years) treated at the Sendai Cardiovascular Center from April 1996 to August 1997 were enrolled in this study. Coagulation markers such as prothrombin fragment 1 + 2, thrombin-antithrombin III complex and D-dimer were measured, and the patients were followed up prospectively to October 2001., Results: One hundred and twenty-six patents (100 males, 26 females, chase rate 96.9%) were included in this investigation based on the medical chart and telephone interview. During five-year follow-up, 16 patients had thromboembolism accidents (3.25%/year) and two were suspected to die of thromboembolism. Three patients died of malignant disease, four of heart disease, and five of other diseases. Eight (25.8%) of the 31 patients with high levels of thrombin-antithrombin III complex and 6 (33.3%) of 18 patients with high levels of D-dimer suffered thromboembolism accidents. High thrombin-antithrombin III complex and D-dimer were statistically positive predictive markers for thromboembolism in patients with nonvalvular atrial fibrillation (p < 0.05)., Conclusions: Coagulation markers such as thrombin-antithrombin III complex and D-dimer can predict thromboembolism accidents in nonvalvular atrial fibrillation patients.

The thrombotest (TT) technique has been widely used in Japan for monitoring oral anticoagulant therapy (OAT). The therapeutic range was originally recommended to be 10%-25%. However, the International Committee for Standardization in Hematology/International Committee on Thrombosis and Hemostasis (ICSH/ICTH) recommended using the international normalized ratio of prothrombin time (PT-INR) for monitoring OAT. It is necessarv to use a universal standard measure for monitoring OAT in accordance with the ICSH/ISTH recommendation. We simultaneously measured TT and PT in blood samples from 1,157 patients on long-term warfarin therapy, and studied the correlation between TT and PT-INR. An excellent linear correlation was obtained between TT-INR and PT-INR with the regression equation PT-INR = 1.0420 TT-INR - 0.0987 (r = 0.905, P < 0.001). We also examined the correlation between the incidence of thromboembolism in 170 patients receiving warfarin therapy after prosthetic valve replacement; 50.5% received concomitant antiplatelet therapy. Thromboembolism occurred in 9 of 170 patients during a mean follow-up period of 2.44 years. The average TT values in patients with and without thromboembolism were 26.4% (PT-INR: 1.53) and 21.1% (1.73), respectively (P < 0.01). The incidence of thromboembolism did not differ significantly between patients on warfarin alone (average TT: 22.2%) and those on warfarin and antiplatelet agent (average TT: 20.9%). Our results suggest that the incidence of thromboembolism is low in Japan despite a less intensive regimen having been adopted.

In 1984, the Scientific and Standardization Committee (formerly ICTH) recommended the use of the International Sensitivity Index and International Normalized Ratio (ISI/INR) System for the monitoring of oral anticoagulant therapy. This system was introduced because the sensitivity of thromboplastin reagents used for the measurement of prothrombin time (PT) was widely different and comparison among hospitals employing different reagents was virtually impossible. In this study, we simultaneously measured the plasma from 7 patients with warfarin therapy at 4 different institutions for PT seconds, PT-INR, thrombotest (TT) seconds and TT-INR. The comparison between these laboratories revealed clinically important variances between the 4 laboratories even when PT was converted to PT-INR. Laboratory 1 and laboratory 3 were using the same thromboplastin reagents for the measurement of PT. The PT (seconds) in both laboratories showed similar numbers, but when they converted into INR, the variances were significant (maximum coefficient of variance 10.44). We investigated the reason why these differences occurred and found that the PT seconds (11.40) for normal control at laboratory 3 were somewhat larger than those of other laboratories. If we assume that PT-INR is identical to TT-INR, the estimated PT (second) for normal control at laboratory 3 can be calculated from TT-INR, and was found to be 10.56 +/- 0.10 seconds. This was nearly the same as the one that was used at laboratory 1. In conclusion, there still exist some difficulties that must be overcome before the ISI/INR system can be used reliably, and we suggest attention be given to the PT seconds used as normal control plasma.

Optimal therapeutic ranges for an oral anticoagulant therapy has been discussed for many years. Prothrombin time, prothrombin time ratios (PTR) and thrombotest have been employed so far, but, recently, International Normalized Ratio of prothrombin time (PT-INR or INR) has been introduced. We investigated paying special interest to INR, the effectiveness of oral anticoagulant therapy in 170 prosthetic valve patients and in 157 patients with various cardiovascular diseases who received warfarin at two different centers. The thrombotest, prothrombin time and INR were measured at follow-up visits every month. Regarding the 170 patients with prosthetic valves with a mean follow-up period of 2.44 years, 9 thromboembolisms (TE) were reported. The average TT and INR values in TE-free patients among 101 in whom coagulability could be measured, were 21.1% and 1.73 respectively. The average TT and INR values in 5 patients with TE were 26.4% and 1.53 respectively and this was significantly (p < 0.01) higher (smaller) than in TE-free patients. 157 patients (mean age 55 +/- 12 y.o.) with various cardiovascular diseases (Table 2) were followed up for a mean of 4.9 +/- 3.2 years. As is seen in figure 4, mean INR values in TE patients were 1.28, in patients with bleeding complications 4.1, and in event free patients 2.07 respectively. In conclusion, with INR greater than 2.75, no thromboembolic complication occurred, but several hemorrhagic complications occurred at INR greater than 3. Therefore INR therapeutic ranges between 2.0-3.0 are recommendable both for the prevention of TE and bleeding complications.

1) Myocardial infarction (MI): Aspirin (160-300 mg/day) therapy started immediately after the onset, with or without simultaneous coronary arterial thrombolytic therapy, reduces the mortality rate in vascular diseases, including MI, and prevents reinfarction. Maintenance therapy with the same dosage is also recommended. 2) Angina pectoris: In unstable angina, aspirin in a dose of 300 mg/day for 2 years reduces the mortality and the incidence of MI. Ticlopidine decreases anginal attacks in a few cases of angina at rest. 3) Coronary artery bypass grafting (CABG): Long-term administration of 325 mg aspirin/day should be started on the day of surgery and combined with 200-400 mg dipyridamole/day administered from 2 days before to 1 week after the surgery. 4) Percutaneous transluminal coronary angioplasty (PTCA): Current antiplatelet drugs prevent post-procedural acute coronary occlusion but not late restenosis.

During the past 15 years, we followed 21 patients with prosthetic heart valves who experienced a total of 24 pregnancies at mean age of 31.3 +/- 3.6 years. The course of these patients and their pregnancies were reviewed to evaluate the problems associated with prosthetic heart valves and anticoagulation. Among the 21 patients, the aortic valve (AV) had been replaced in 10 (12 pregnancies), the mitral valve (MV) in nine (10 pregnancies), AV + MV in one (one pregnancy), and the tricuspid valve (TV) in one (one pregnancy). The implanted prosthetic valves were mechanical type in 16 cases (Björk-Shiley 15, Starr-Edwards 1) and bioprosthetic type in six (Hancock 5, Ionescu-Shiley 1). With the exception of one case of intra-uterine fetal death probably related with warfarin therapy, all the patients with bioprosthetic valves underwent successful deliveries. Anticoagulant therapy was employed for 11 pregnancies; warfarin for 10 and subcutaneous heparin for one. No anticoagulant therapy was performed for 13 pregnancies. Ten of the 21 mothers had atrial fibrillation. Eighteen pregnancies (67%) culminated in uneventful deliveries for both mothers and infants. Three mothers (13%) died of thromboembolic complications; two of cerebrovascular accidents and one of acute heart failure caused by thrombus on the replaced valve. All of them had Björk-Shiley valves. Oral warfarin was administered in one of the three, heparin in one and no anticoagulant in the remaining one. Massive maternal bleeding occurred in two cases (8%). There were three cases (12%) of intra-uterine fetal death which were caused by intracranial hemorrhages.(ABSTRACT TRUNCATED AT 250 WORDS)

The clinical significance of atrial fibrillation was analyzed in cases with chronic or acute heart disease and its significance at the acute and chronic stages of the disease was investigated in various disease groups. The types of disease, number of patients, and incidence of atrial fibrillation were: atrial septal defect (92, 14.1%), mitral valve disease (128, 79.7%), nonrheumatic valvular disease (32, 56.2%), aortic regurgitation (71, 2.8%), aortic stenosis (10, 10.0%), hypertrophic cardiomyopathy (181, 11.6%), dilated cardiomyopathy (111, 37.8%), acute myocardial infarction (823, 9.0%), healthy subjects (31,886, 0.3%). A histopathological and electron-microscopic evaluation of the atrial heart muscle revealed that the advancement of the morphological changes was closely related to the occurrence of atrial fibrillation. Decrease in size of F waves in the electrocardiogram correlated well with the extent of right and left atrial fibrosis. Also, it was noteworthy that the atrial fibrillation in cases with dissecting aneurysm (n = 60) was an expression of the myocardial damage due to the infiltration of the bleeding into the right atrium. Intra-atrial electrogram in 48 patients with various heart diseases revealed that the electric potentials obtained from various parts of the atrium varied to a great extent and finally the patient's condition transformed to that of atrial standstill. We conclude that atrial fibrillation is an expression of some important aspect of the progression of heart disease and is not directly associated with hemodynamic overloading to the atrium. A strategy for quinidine treatment was also introduced.

A total of 1281 patients (594 aortic and 687 mitral) received 734 mechanical valves (320 Björk-Shiley, 283 SJM and 131 Omniscience) and 547 biological (259 ionescu-Shiley, 227 Hancock, and 61 Carpentier-Edwards) were analyzed for postoperative valve dysfunction and thromboembolism. The actuarial survival rates (free from late cardiac deaths and valve-related deaths) were 88.6% (11 years) for mechanical mitral and 86.0% (11 years) for biological mitral valves, and 91.7% (16 years) and 88.5% (12 years), for mechanical and biological aortic valves, respectively. There were no significant differences among these groups. Actuarial rates of freedom from valve-related events were 88.7% (11 years) and 51.7%, for mechanical and biological mitral valves, respectively. There was significant difference between the two types of valves in over 7 years after surgery. In contrast, there were no significant differences between mechanical and biological aortic valves. Actuarial rates of freedom from valve dysfunction were 97.6% (11 years) for mechanical and 56.5% (12 years) for biological mitral valves. The net 12 year results showed no significant differences between the two types of mitral prosthetic valves, but a significantly increased rate of valve dysfunction in the biological mitral valves compared with the mechanical in over 6 years of the study. Concerning AVR, there were no significant differences in the incidence of valve dysfunction between mechanical and biological aortic valves. Actuarial rates of freedom thromboembolism were 92.3% (11 years) and 93.8% (11 years) for mechanical and biological mitral valves, respectively. There were no significant differences between the two types of mitral prosthetic valves.(ABSTRACT TRUNCATED AT 250 WORDS)

To determine whether the distribution of pulmonary perfusion can be applied as a noninvasive means of evaluating patients with mitral valve replacement (MVR), computerized Tc-99m MAA pulmonary perfusion images (digital perfusion images: DPI) were obtained for 32 patients in the preoperative, early postoperative and late postoperative (18 months mean) periods. DPI consisted of isocount areas, and a 100-70% area was defined as a hyperperfusion area. The distribution of pulmonary perfusion was evaluated using patterns of hyperperfusion area in anterior DPI. In 32 patients above-mentioned had the hyperperfusion areas in the upper lung fields preoperatively, the perfusion of the lung base was investigated. In 21 patients hyperperfusion area appeared in the lung base in the late follow-up period (group A), and all patients improved clinically. In 11 patients, the DPI improved to nearly normal patterns. In five patients, the DPI improved after one year postoperatively. In 11 patients, hyperperfusion areas did not appear in the lung base in the late follow-up period (group B). Six of the 11 patients did not improve clinically. There were no significant hemodynamic differences between groups A and B except for slight differences in the postoperative pulmonary vascular resistance. These results suggested significant correlations between the clinical improvement and the normalization of the DPI. The use of DPI patterns may facilitate quantitative and objective estimations of postoperative states. Since DPI are easy to perform noninvasively, DPI may comprise a useful graphic diagnostic method for evaluating patients with MVR.

When the incidence of thromboembolism (TE) as a complication was investigated in 171 patients with prosthetic heart valves using pyrolytic carbon, 10 cases were identified in a mean follow-up period of 2.43 years. Of these 10, two patients had died. The incidence of TE as a percentage per patient--year was 2.41 on the whole, 2.15 in patients with aortic valve replacement (AVR), 2.48 in patients with mitral valve replacement (MVR) and 2.52 in patients with double valve replacement (DVR). It is evident that TE is still an important complication following prosthetic heart valve surgery and the patient's return to society. TE tended to occur somewhat more often in cases of MVR and DVR than in those of AVR. TE was apt to appear early in the postoperative period, often within a year, and was often seen in the brain. To prevent TE, it is necessary to carefully control blood coagulation by the administration of anticoagulants.

From July 1978 to June 1984, 540 St. Jude Medical valve prostheses were implanted in 462 adult patients. Overall operative mortality was 4.8% (22/462): 5.7% after aortic valve replacement (AVR) (8/140); 3.3% after mitral valve replacement (MVR) (8/244); and 7.7% after aortic and mitral valve replacement (DVR) (6/78). There were 16 late deaths among 440 operative survivors; six (38%) were valve related. The actuarial survival rate at six years was 94.5% in AVR and 93.5% in MVR. At five years it was 91.6% in DVR. The freedom from valve-related death at six years after AVR, MVR and at five years after DVR was 97.8%, 98.6% and 95.8%, respectively. The incidence of valve-related complications (expressed as %/patient-year (number of events] was as follows: thrombo-embolism (AVR 0.7 (2), MVR 2.0 (13), DVR 2.8 (5], valve thrombosis (AVR 0.3 (1), MVR 0.2 (1), DVR 0 (0], prosthetic valve endocarditis (AVR 0.3 (1), MVR or DVR 0 (0]. There were no cases of primary structural failure, serious anticoagulant-related hemorrhage or clinical event of hemolysis. The incidence of all valve-related complications in AVR, MVR and DVR was 1.3, 2.2 and 2.8%/pt-yr, respectively. The freedom from thrombo-embolism at six years after AVR and MVR and at five years after DVR were 91.4%, 92.4% and 88.7%, respectively. Re-operation was performed in only one patient with MVR because of valve thrombosis (0.2%/pt-yr after MVR, overall 0.1%/pt-yr). These results indicate that St. Jude Medical prosthesis has provided a satisfactory performance with acceptable risks of late complications in patients who were properly anticoagulated during six-year follow-up period.