Medical and socioenvironmental predictors of hospital readmission in patients with congestive heart failure.

BACKGROUND: Patients with chronic congestive heart failure (CHF) require frequent rehospitalization because of the exacerbation of CHF. It is of clinical importance to determine predicting factors for readmission to reduce this likelihood. Previous studies have focused primarily on the demographic and medical characteristics in selected subsets of patients. Therefore, within a broad cohort of consecutively hospitalized patients, we sought to identify not only demographic and medical predictors but also socioenvironmental factors associated with readmission. METHODS: We assessed demographic (age, sex), medical (etiology of CHF, New York Heart Association functional class, left ventricular ejection fraction, previous admission for CHF, length of hospital stay, comorbidity, and medications), and socioenvironmental variables (occupation, financial resources, living alone, and follow-up visits) in 230 patients discharged with a diagnosis of CHF and recorded hospital readmission. RESULTS: Within 1 year after discharge, 81 patients (35%) were readmitted. Five variables, including poor follow-up visits (odds ratio [OR] 4.9, 95% CI 2.0-11.8), previous admission for CHF (OR 3.3, 95% CI 1.8-6.1), no occupation (OR 2.6, 95% CI 1.2-5.5), longer hospital stay (OR 3.2, 95% CI 1.2-8.5), and hypertension (OR 2.0, 95% CI 1.1-3.7), were identified as significant independent predictors for readmission by multivariate logistic regression analysis. CONCLUSIONS: Our independent predictors of readmission support the importance of medical and socioenvironmental factors in the deterioration of CHF. Therefore interventions to decrease readmission should also target social management in all hospitalized patients.

Mortality and readmission of hospitalized patients with congestive heart failure and preserved versus depressed systolic function.

Patients with congestive heart failure (CHF) and preserved systolic function are very common. Despite the high prevalence of this syndrome, very little information is known regarding its mortality and morbidity (e.g., readmission), or the efficacy of drugs. The purpose of this study was to compare the clinical characteristics and prognosis among consecutively hospitalized patients with CHF and preserved versus depressed left ventricular systolic function. Patients with severe aortic or mitral valve disease were excluded from the study. Patients were categorized based on the values of ejection fraction (EF) as having "preserved" (EF>50%), "intermediate" (EF 40% to 50%), or "depressed" (EF<40%) systolic function. Clinical characteristics as well as mortality and hospital readmission rates during 2.4 years of follow-up were recorded for each patient. Sixty-one patients (35%) had preserved systolic function, 73 (43%) had depressed function, and 38 (22%) had intermediate function. Patients with preserved systolic function were more often women and had a higher prevalence of left ventricular hypertrophy (all p <0.05). At follow-up, cumulative survival probabilities were similar between patients with preserved systolic function and those with systolic dysfunction (p = 0.84). Readmission rates were also comparable between preserved and depressed systolic function (36% vs 48%; p = NS). The prognosis of CHF patients with preserved systolic function was similar to those with systolic dysfunction. In light of these findings, effective therapeutic strategy for this subset of patients is needed.

Development of a pharmacokinetic/pharmacodynamic (PK/PD)-simulation system for doxorubicin in long circulating liposomes in mice using peritoneal P388.

The objective of this study was to develop a simulation system that optimizes the pharmacokinetic parameters of drug carriers for anticancer agents in order to maximize their anticancer effects. The pharmacokinetic/pharmacodynamic (PK/PD) model of doxorubicin (DOX) encapsulated into liposomes has been developed for mice and each parameter required for simulations was obtained in the peritoneally inoculated P388 leukemia model in mice. PK parameters, which describe the dispositions of free and liposomally encapsulated DOX, were obtained by kinetic analysis of experimental data in this study, as well as from literature. PD parameters, which describe the growth and death rate of cancer cells in vivo, were also determined. The PK/PD model developed in this study is capable of simulating the time course of the number of cancer cells quantitatively and evaluating the significance of each parameter on the carrier system for DOX. Simulations based on the PK/PD model predict the optimum rate of drug release from long circulating liposomes as 0.06 h(-1) for maximum anticancer effect. Thus, this simulation system provides useful information relative to the optimization of drug carriers for DOX.

Optimization of antitumor effect of liposomally encapsulated doxorubicin based on simulations by pharmacokinetic/pharmacodynamic modeling.

It has been reported that long circulating liposomes enhanced the antitumor effect of doxorubicin (DOX) by increasing delivery of DOX to tumor tissues. However, there is no quantitative information on the relationship between the antitumor effect and liposomal characteristics governing the release rate of entrapped drugs, although the importance of drug release-rate control from liposomes has been pointed out. Here, we developed a physiological model for free and liposomal DOX to calculate the time course of free DOX in the extracellular space and linked this with a cell kill kinetic model to quantify the antitumor effect of DOX. Simulations were performed to clarify the relationship between antitumor effect and pharmacokinetic or physicochemical parameters of liposomes, as well as pharmacological or physiological parameters of tumor tissues. The importance of long circulation time of liposomes was confirmed. The optimum rate of drug release from long circulating liposomes was found at the release rate constant of around 0.06 h(-1). This optimum value was not dependent on the tumor proliferation time, sensitivity of tumor cells to DOX, or the tumor blood flow-rate. This simulation indicated that the optimization of the delivery to tumor tissue by long circulating liposomes could be possible by changing the release rate of DOX for the maximum antitumor effect.

[Determination of the activity of urinary enzymes derived from renal tubulus].

There are several problems in measuring the activities of urinary enzymes, such as alkaline phosphatase (ALP), leucine aminopeptidase (LAP), and gamma-glutamyl transpeptidase (gamma-GTP) which are derived from renal tubulus. The purpose of the present study is to clarify the basic methodological problems in measuring these enzyme activities. Our results indicate that it is not necessary to dialyze urine when determining these three enzymes, except for alkaline phosphatase activity measured by the Kind-King method. Because of contamination of urine by bacteria and cell elements, the enzyme activity is influenced by centrifugal conditions that depend on time and speed. Our results propose that it is necessary, at least, to centrifuge at 3000 rpm for 10 minutes to obtain satisfactory data. Generally, a 24 hour urine sample instead of spot urine sample should be used for measuring the enzyme activity. However if correcting gamma-GTP activity by creatinine, even a spot urine sample may be used for clinical use.

Effect of retinoic acid on contraction of collagen gel induced by fibroblasts.

Retinoic acid inhibited the contraction of collagen gel containing fibroblasts. Moreover, in its presence fibroblasts extensions were shorter, fewer collagen fibers were recognized, cell adhesiveness was inhibited concentration-dependently, and microfilaments appeared to be disrupted, resulting in morphological changes including loss of multipolar cell processes due to changes in cytoskeletal linkages.

Clinical characteristics and prognosis of hospitalized patients with congestive heart failure--a study in Fukuoka, Japan.

The clinical characteristics and prognosis of patients with congestive heart failure (CHF) have been described by a number of previous studies, but very little information is available on this issue in Japan. This study aimed to delineate the clinical characteristics and prognosis of Japanese patients hospitalized with CHF. Medical records were reviewed for 230 consecutive patients at 5 teaching hospitals in Fukuoka, Japan from January to December 1997 and the survival and hospital readmission were followed through December 1999 (mean follow-up, 2.4 years). The study population had a high mean age, contained a larger population of women especially in the older ages, and had a higher incidence of overt HF (48%) despite a relatively normal ejection fraction on echocardiography. Major causes of CHF were ischemic, valvular, and hypertensive heart diseases. The 1-year mortality rate was as low as 8.3% whereas rates of hospital readmission because of an exacerbation of CHF were as high as 40% during the follow-up period. Patients hospitalized with CHF in routine clinical practice in Japan have characteristics that differ from those in the population included in community-based studies or large clinical trials.

Immunohistochemical study of some cytoskeletal proteins in hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle.

We have investigated the expression, using immunohistochemical and Western blot methods, of some cytoskeletal proteins including desmin, vimentin, actin, alpha-actinin, and ubiquitin in hereditary myopathy of the diaphragmatic muscles in Holstein-Friesian cattle (the histochemical and electron microscopical aspects have been previously reported). Immunohistochemically, the expression of desmin was observed strongly in the subsarcolemmal regions, but was lacking or faint in the area corresponding to the core-like structures. Vimentin showed almost the same localization as desmin, but no activity could be observed in the core-like structures. In addition, the core-like structures showed strong immunoreactivity for actin and ubiquitin, but no immunoreactivity for alpha-actinin. F-actin stained with phalloidin-tetramethyl-rhodamine was strongly positive in irregular spots that corresponded to the core-like structures, but was negative for desmin-positive regions. Western blot analysis of the diseased muscles revealed a significant increase in the amount of desmin and vimentin immunoreactivities and similar amounts of actin and alpha-actinin compared with the control muscles. Two-dimensional electrophoresis revealed no isoforms of desmin, suggesting the absence of abnormal phosphorylated forms of desmin. Since the co-localization of desmin and vimentin and the absence of phosphorylated desmin suggest that the overexpression of desmin may be reflected in the reactive change or regenerating process, the present myopathy should be regarded as an entity separate from desmin-storage myopathy or desmin-related myopathies. We also discuss the possibility that the present myopathy could be considered as myofibrillar myopathy, a recently proposed nosological entity.

Coronary revascularization in Japan. Part 1: survey of facilities during 1997.

Coronary artery disease is one of the major causes of morbidity and mortality in industrialized countries, including Japan. Increasing numbers of patients have been treated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), but there is little information in Japan concerning the use of revascularization therapy and the facilities. The Japanese Coronary Intervention Study (JCIS) Group conducted a nationwide survey on coronary revascularization procedures and facilities during 1997. A questionnaire was mailed to the presidents or designated delegates of 8,253 laboratories in 7,986 hospitals that had departments of internal medicine and/or cardiovascular medicine and to 578 facilities in 558 hospitals identified by the PCI survey as performing CABG and/or registered in the annual survey carried out by the Japanese Association for Thoracic Surgery. A total of 109,788 PCIs were performed at 1,023 laboratories, and 17,667 CABGs at 477 facilities. PCI and CABG numbers per 10(6) population were 870 and 140, respectively. The ratio of PCI to CABG was 6.2. The numbers of PCI laboratories and CABG facilities per 10(6) population were 8.1 and 3.8, respectively. The majority of PCI laboratories and CABG facilities had a small annual volume: 44% of PCI laboratories and 77% of CABG facilities had annual volumes of 50 or less. Only half of the PCI laboratories had surgical backup on-site. Despite the small volume for each facility, coronary revascularization, especially PCI, is highly utilized in Japan.

Coronary revascularization in Japan. Part 2: comparison of facilities between 1997 and 1999.

A nation-wide survey on the procedures and facilities of coronary revascularization, percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) conducted by the Japanese Coronary Intervention Study (JCIS) group during 1997 revealed that PCI is more often used than CABG and is mainly carried out in low-volume facilities without surgical backup. The present study aimed to investigate the temporal changes in the usage of revascularization therapies and facilities from 1997 to 1999. A questionnaire was mailed in 1998 to the delegates of 1,086 PCI and 582 CABG facilities identified by the previous survey, and 89% of PCIs surveyed and 94% of CABGs surveyed reported back. The number of PCI procedures had increased by 19% from 97,831 to 116,479 and that of CABG procedures also increased by 21% from 16,374 to 19,846. The ratio of PCI to CABG was 5.9 in 1999, showing no significant change from 6.0 in 1997. In parallel, the number of PCI and CABG facilities increased from 888 to 941 and from 442 to 453, respectively. The use of coronary stents and other interventional devices increased during these 2 years. Coronary stents were used regardless of the annual procedural volume of the facilities, whereas other interventional devices, directional and rotational coronary atherectomy, were used mainly in the high-volume laboratories (p<0.01). Beating-heart, off-pump CABG had increased from 2% to 11% of total cases. Continued monitoring of trends in PCI and CABG facilities and procedures will be needed for nation-wide assessment of the use of new technology.

Mechanism of cardiac involvement in the WBN/Kob rat.

The cardiac characteristics of the WBN/Kob rat resemble those of rats with catecholamine-induced myocarditis. To determine the etiology of these WBN cardiac characteristics, we assessed the number and affinity of beta-adrenergic receptors, and investigated adenylate cyclase activity, the cardiac myocyte cyclic adenosine monophosphate (cAMP) concentration and the activity of guanosine triphosphate (GTP)-binding protein in 3-month-old WBN/Kob rats. Age-matched Wistar rats served as controls. The mean number of beta-adrenergic receptors was similar in WBN/Kob and Wistar rats (28.0+/-9.1 v 28.3+/-8.9 fmol/mg protein), and there was no significant difference in beta-adrenergic receptor affinity between groups (1.09+/-0.54 v 1.26+/-0.60 nM). The mean cAMP concentration in cardiac myocytes was significantly higher in WBN/Kob rats than in Wistar rats 1975.6+/-247.8 v 344.9+/-83.6 pmol/g wet tissue), (P=0.0112) as was adenylate cyclase activity (33.61+/-8.32 v 24.3+/-12.78 pmol/mg/min), (P=0.0174). The activity of GTP-binding protein was significantly higher in WBN/Kob rats than in Wistar rats. After a beta-agonist binds to a beta-adrenergic receptor, activated adenylate cyclase produces cAMP in myocytes, which in turn opens the Ca2+ channel, leading to an influx of Ca2+ into myocytes. Our results suggest that the increase in adenylate cyclase activity in WBN/Kob rats have led to an increase in the cAMP concentration in myocytes. This process may have resulted in excessive beta-adrenergic activity due to high activity of GTP binding protein in WBN/Kob rats, which may explain the hypersensitivity of WBN/Kob rats to isoproterenol and the development of catecholamine-induced myocarditis.

[Immunohistochemical study of the endomyocardial biopsy of systemic lupus erythematosus].

The mechanisms of cardiac involvement in systemic lupus erythematosus (SLE) were studied using immunohistochemical staining of endomyocardial biopsy specimens from 14 patients with SLE and normal coronary arteriograms. All 14 specimens showed mild interstitial edema, 11 showed mild cardiac fibrosis, and another two cases showed moderate cardiac fibrosis with myocardial derangements. Four specimens showed moderate cell infiltration in the interstitium. Area of fibrosis, diameter of myocardium and area of interstitial edema were increased in the SLE patients compared to the control cases. Immunofluorescence showed IgG and fibrinogen deposition in the membrane of cardiac myocytes and in the interstitium. Immunohistochemistry found no B lymphocytes in any of the seven SLE cases. T lymphocytes were observed in all seven SLE cases, and OKT 8 lymphocytes were increased significantly in the interstitial tissue as compared with OKT 4 lymphocytes. At endomyocardial biopsy, all 14 patients were receiving corticosteroid therapy and had low activity disease. The results suggest that cardiac tissue damage was associated with immunological abnormalities and might progress silently under conditions in which the disease activity was suppressed by corticosteroid therapy.

[Two-color flow cytometry analysis of lymphocyte subsets in patients with acute myocardial infarction and post-myocardial infarction syndrome].

Serial changes in lymphocyte subsets were analyzed in 37 patients with acute myocardial infarction (AMI), in 2 patients with postmyocardial infarction syndrome (PMIS), and in healthy subjects (control group) using two-color flow cytometry to investigate cellular immunity after AMI and PMIS. Peripheral blood lymphocyte subsets were measured on admission and at weeks 2, 4, 8, and 16 after the onset of AMI. The white blood cell count was significantly higher on admission and at week 2 in the AMI group compared with the control group. The percentage of CD4-positive helper T cells was significantly higher on admission and at weeks 2 and 4 in the AMI group compared with the control group, and the percentage of CD8-positive suppressor T cells was significantly lower in the AMI group at week 2 than in the control group. The ratio of helper-to-suppressor T cells peaked 2 weeks after the AMI and then decreased gradually. There were no significant changes in the CD4/CD8 ratio, the percentage of cytotoxic T cells, or the percentage of inducer T cells, throughout the observation period. There were no significant differences in the percentage of T cells, B cells, CD4-positive T cells, CD8-positive T cells, and natural killer cells between AMI patients and control subjects. The percentage of activated CD4- and CD8-positive cells was higher in the AMI group at weeks 4 and 8 than in the control group. There was no significant correlation between changes in lymphocyte subsets and infarct size. The percentage of activated CD8-positive cells was consistently higher in the PMIS group compared with the control and AMI groups. The percentage of cytotoxic T cells in one of the PMIS patients was significantly higher than in the AMI group. There were no significant differences in the proportions of other subsets between PMIS and AMI patients. The changes in lymphocyte subsets observed in patients with AMI suggested that immunological competence was enhanced in these patients. Abnormalities in humoral immunity, such as the appearance of anticardiac antibody, have been observed in patients with PMIS. Our results suggest that PMIS is also associated with changes in cellular immunity.

Angiotensin II receptor antagonist, TCV-116, prevents myocardial hypertrophy in spontaneously hypertensive rats.

Recently, it has been suggested that angiotensin II (AII) might be associated with cardiac hypertrophy and fibrosis. We investigated the preventive effect of an AII receptor antagonist, TCV-116, on the development of cardiac hypertrophy and fibrosis in spontaneously hypertensive rats (SHR) at 24 weeks of age through histopathological study and an AII receptor assay. Treatment with TCV-116, enalapril (an angiotensin-converting enzyme inhibitor, ACEI), and hydralazine for 20 weeks lowered systolic blood pressure (SBP) significantly (-39 mmHg, -45 mmHg, and -45 mmHg, respectively). The heart weight/body weight ratio, cardiac myocyte diameter, and percent cardiac fibrosis were significantly reduced by treatment with TCV-116 and enalapril as compared with hydralazine treatment or no treatment. The AII receptor density was significantly increased by treatment with TCV-116 and enalapril as compared with hydralazine treatment or no treatment. The results of this study suggest that AII receptors are involved in the development of cardiac hypertrophy and fibrosis in SHR. It was demonstrated that the AII receptor antagonist, TCV-116, was comparable to the ACEI, enalapril, in inhibiting the progression of cardiac hypertrophy and fibrosis via the AII receptor.

Pharmacokinetic/pharmacodynamic modeling of antitumor agents encapsulated into liposomes.

Pharmacokinetic/pharmacodynamic (PK/PD) modeling of antitumor agents has been developed for doxorubicin (DOX) in order to predict the optimum conditions for a drug carrier to maximize the antitumor effect. A PK model was constructed for free and liposomal doxorubicin using a hybrid model wherein the disposition in the whole body is described by compartment models, which were linked to the tumor compartment via the blood flow rate. The PD model for doxorubicin was described by a cell-kill kinetic model, which represents the number of tumor cells quantitatively, as a function of the free concentration of doxorubicin in the tumor compartment. The influence of each parameter on the antitumor effects was examined by sensitivity analysis based on the PK/PD model, which clearly showed the importance of optimizing the release rate of DOX from liposomes. The validity of the model has been tested using animal experiments. Preliminary simulations were also performed for humans after scaling up the PK/PD model from rodents to humans. The optimum conditions in the rate of drug release from liposomes were different for rodents vis-a-vis humans, which indicates the limitations involved in extrapolating optimum conditions for experimental animals to those for humans.

Standardization of laboratory data and establishment of reference intervals in the Fukuoka Prefecture: a Japanese perspective.

Standardization of 22 clinical chemistry analytes and five serum protein constituents has been performed in the Fukuoka Prefecture, which has a population of approximately five million. The standardization project was established to determine reference intervals for these analytes by educating physicians, medical technologists and staff of medical institutions, and by daily or monthly monitoring the use of common control samples through e-mail. Standardization extended to 97% of the institutions in the prefecture. Results for 14 of the 22 clinical chemistry analytes have become highly reliable and differences between institutions decreased. Standardization of other analytes is now in progress. Regional collaboration based on international guidelines led to a significant improvement in interlaboratory comparability. Areas where further improvements are needed have been identified.