Angiotensin converting enzyme as a genetic risk factor for coronary artery spasm. Implication in the pathogenesis of myocardial infarction.

It has been reported that individuals with the D allele of an insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene are at greater risk for myocardial infarction (MI), especially among subjects normally considered to be at low risk. However, little is known about the mechanism by which the ACE polymorphism affects the risk of MI. Coronary artery spasm (CAS) is considered to be one possible mechanism for developing MI. We therefore examined the ACE polymorphism relation to CAS to determine if this was the mechanism by which the DD genotype influences MI. We studied 150 angiographically assessed Japanese males, all more than 60 yr old. CASs were detected using intracoronary injection of ergonovine maleate. Subjects were divided into three groups: those with CAS (group 1), those without CAS, but with fixed organic stenosis (group 2); and those without CAS and no organic stenosis (group 3). DD subjects were significantly represented in group 1 when compared with groups 2 (P = 0.002) and 3 (P = 0.026). These results suggest that the DD genotype relates to the greater risk for MI in the patients with CAS.

Association of a variant of the angiotensinogen gene with pure type of hypertension in pregnancy in the Japanese: implication of a racial difference and significance of an age factor.

The contribution of genetic factors to hypertension in pregnancy, including pre-eclampsia, has been well documented. The association with a common molecular variant of the angiotensinogen (AGT) gene, in which methionine (M235) is substituted for threonine (T235) at residue 235, has been reported in both Caucasians and Japanese. In the present study, we examined 115 cases of pure type of hypertension in pregnancy (PHP) and 381 normal pregnant controls in order to look for subgroups in which the AGT gene is the major factor in the PHP pathogenesis. By classification of PHP cases according to the clinical diagnosis, gravidity, and maternal age, we found significantly higher frequencies of T235 in both all PHP patients and preeclampsia/eclampsia patients than in normal controls. These results are discordant with those reported for Caucasian subjects where only a group of preeclamptic primigravidae was associated with the AGT variant, possibly indicating the existence of a racial difference. We also found that the variant frequency was significantly higher in the PHP subgroup with maternal age of 20-34 years (0.93) than in a subgroup of multigravid PHP patients age 35 years or older (0.77, P < 0.05) or in normal controls of age 20-34 years (0.76, P < 0.001). The result indicates that the AGT variant plays a significant role in hypertension in the age group 20-34 years.

[The association between body mass index and self-assessed symptoms among young women].

Attitudes and behaviours of young women toward dieting and the relationship between body mass index (BMI) and subjective symptoms were studied by a questionnaire survey applied to all the students of a two-year women's college in Sapporo, Hokkaido. The response rate was 96% to yield a total of 608 subjects. 1) Young women showed excessive thinness-oriented attitudes. 2) Over 30 percent of the women reported irregular menstruation, neck pain, fatigue and oversensitiveness to cold. 3) Those who reported oversensitiveness to cold, wearied eyes or stomachache had significantly lower average BMI than those who did not. 4) A U-shaped relationship, with a higher prevalence of complaints of these three symptoms with a low BMI, was shown. Considering these findings, it appears that being excessively thin is related to symptoms and young women's thinness-oriented attitudes are unhealthful.

[Evaluation and improvement of medical and nursing service and caregiving for the elderly using MDS. 3. Revised recording system of diagnoses and symptoms suitable for use in Japan].

Diagnoses and symptoms are recorded by physicians in the chapter E of the Minimum Data Set (MDS), if they are relevant to disabilities of activities of daily living, cognition, behavior, medical treatments or risk of death. We improved the chapter so that it is suited to disease patterns in Japan in a format useful not only for nursing and ADL care but for medical treatment in our practice. In E1, diseases directly underlying the current disability states were recorded in the international classification of Disease, 9th Revision (ICD9). In 24, 670, 195, and 45 patients respectively, there were 0, 1, 2, and 3 separate recorded diseases. A Total of 63 ICD9 codes were observed, but only four codes; 290, 332, 431, and 434, were underlying diseases for 3% or more patients. These codes included mostly ischemic and degenerative disease of the brain.

[Evaluation and improvement of medical and nursing service and caregiving for the elderly using MDS. 2. Diagnosis and symptoms, especially diseases causing care-requiring conditions].

Diagnoses recorded in the chapter E of Minimum Data Set (MDS) were analyzed in patients requiring care admitted in a geriatric hospital in Sapporo, Japan. They were classified as: A-diseases causing care-requiring conditions, B-their symptoms, and C-coexisting diseases requiring no care. Orthopedic diseases were not analyzed because they were not adequately recorded in MDS system. Class A diagnoses varied, but only five diagnoses were responsible for 3% or more of the total patients who required care. They were 1) Alzheimer's disease (AD), 2) Parkinson's disease, 3) dementia other than AD without neurological symptoms, 4) dementia other than AD with sequelae of stroke, and 5) sequelae of stroke without dementia. These diagnoses pooled represented over 90% of all patients. "Diagnoses and symptoms" in MDS were useful to 1) describe medical problems briefly in a predetermined format, 2) evaluate urgent or unstable conditions separately from stable diagnoses and symptoms, and 3) use common information by various professions, but have difficulties because 1) preselected diagnoses were few and unsuited to practices in Japan, 2) it is impossible to record a previous disease in the past that initiated the process leading to the present disabilities, and 3) it is also impossible to record the severities of the diseases and symptoms.

[Evaluation and improvement of medical and nursing service and caregiving for the elderly using MDS. 1. Diagnosis and some problems in dementias].

A Minimum Data Set (MDS) was recorded in two geriatric hospitals every 4 months for about 5 years. The initial records were available in a total of 1,735 disabled elderly. In MDS, about 360 trigger items were recorded. A selection was made to determine whether there were problems of care in 18 areas of Resident Assessment Protocols. We analyzed errors and biases in selection of the diagnosis in the chapter E of MDS disclosing that: 1) they were almost satisfactorily made in diseases except dementias, 2) diagnosis of dementias was biased in several ways, particularly Alzheimer's disease was overselected, and 3) preprinted diagnostic options in MDS were not suited with the Japanese practice and were insufficient for comprehensive medical/nursing service and caregiving.

[A case-control study of life styles associated with myocardial infarction].

Preclinical events, especially life styles associated with myocardial infarction (MI), were evaluated in a case-control study. A total of 56 male cases were studied along with matched (1:2) controls. Cases were diagnosed at the Department of Cardiovascular Medicine, Hokkaido University School of Medicine and its related hospitals. Cases were matched to two controls each according to sex, age (+/- 3 year) and residence in central Hokkaido. Preclinical life events (diet, alcohol and smoking, working environment, health behaviors, social life etc.) were inquired in a one-to-one personal structurized interview. In order to evaluate univariate effects and the combined effects of the major multivariate variables, unconditional logistic model was used. The 14 independent variables revealing significant associations with MI were screened in the four areas of lifestyles, 1) diet: more consumption of rice-based non-fat sweets, less consumption of vegetable salads, irregular meal times, 2) alcohol and smoking: non-drinker as well as excessive drinker of alcohol, more than 30 cigarettes per day, 3) working environment, social association and personality: more than 10 hours work per day, feelings not shared with family about work, difficulty in reorientation during concentration, being easily moved to tears and 4) health-promotion, leisure and life style: not eager to watch TV programs on health, not eager to read health articles in newspaper, irregular sleep times, not watching TV in leisure time. Combined odds ratios were calculated in a multivariate logistic analysis, which disclosed phenomenal elevation of the risks in those having more lifestyle factors associated with MI.

A case-control study of Alzheimer's disease in Japan--significance of life-styles.

A case-control study of Alzheimer's disease was conducted in Japan; it involved 60 cases matched for sex and age with two resident controls each. Life-style was particularly highlighted in this study. Among many factors, 5 were accepted as significant risk factors: psychosocial inactivity, physical inactivity, head injury, loss of teeth and low education. A multiple logistic model was applied in order to evaluate synergism of major factors. Compared with those who have none of the factors, those who have all were 934.5 times more liable to develop Alzheimer's disease. Risk factors are not only useful for etiological studies but they give clues to identify high-risk individuals, and by eliminating these factors, the studies may also be applicable in the primary and the secondary prevention of this tragic disease.

Inhibition of platelet GPIIb/IIIa binding to fibrinogen by serum factors: studies of circulating immune complexes and platelet antibodies in patients with hemophilia, immune thrombocytopenic purpura, human immunodeficiency virus-related immune thrombocytopenic purpura, and systemic lupus erythematosus.

We have studied the conditions of in vitro binding of platelet glycoprotein IIb/IIIa (GPIIb/IIIa) to fibrinogen and applied the results to identify and measure the serum inhibitors to the binding. For the enzyme-linked immunosorbent assay, platelet extract was delivered to a fibrinogen-coated microtiter plate that was incubated for 2 hours, followed by incubation with anti-GPIIb/IIIa monoclonal antibody for another 2 hours. The plate was then incubated with peroxidase-conjugated anti-mouse IgG for color development. The binding was shown to be calcium-dependent. The binding was partially blocked by treating the coated fibrinogen with anti-fibrinogen antibody. Reduction or dissociation of GPIIb/IIIa resulted in the total loss of its ability to bind to fibrinogen. Platelet extracts of patients with hemophilia showed decreased binding (25% and 14%, compared with control platelet extract), and an extract from a patient with Glanzmann's thrombasthenia showed no binding. With the enzyme-linked immunosorbent assay we have measured serum inhibitors to GPIIb/IIIa binding to fibrinogen in 35 hemophilia A, 17 immune thrombocytopenic purpura, 22 human immunodeficiency virus-related immune thrombocytopenic purpura, and 29 systemic lupus erythematosus serum samples. In those patients with inhibition by serum, polyethylene glycol precipitation of circulating immune complexes (CICs) decreased the inhibition by the supernatants, and all the resolubilized CIC precipitates demonstrated inhibition, which indicates that CICs play a major role in the inhibition of GPIIb/IIIa binding to fibrinogen. This, then, provides evidence of CIC-mediated impaired GPIIb/IIIa binding to fibrinogen in hemophilia A, HIV-ITP, and SLE.

Characterization of human platelet IgG Fc receptor associated with membrane glycoprotein.

Human platelets express IgG Fc receptors (Fc gamma R). Previously we reported that circulating immune complexes (CIC) inhibited fibrinogen binding to platelet glycoprotein IIb/IIIa complex (GPIIb/IIIa) and that isolated Fc gamma R were recognized by monoclonal antibodies (mAb's) to GPIIb and GPIIIa (J.Lab. Clin. Med. 117:209-217, 1991). In this study, we further characterized the properties of the Fc gamma R and the activity associated with GPIIb/IIIa. Binding of Fc portion of human IgG (Fc) to the platelet Fc gamma R associated with GPIIb/IIIa complex, unlike fibrinogen receptor, did not require divalent cations. The Fc gamma R bound to immobilized immune complex were recognized by mAb's to GPIIb, GPIIIa, GPIIb/IIIa. Preincubation of platelet extract with fibrinogen inhibited the binding of heat-aggregated IgG (HAG) to the extract. Flow cytometry of whole platelets revealed inhibition of mAb binding to GPIIb/IIIa, when platelets were incubated with Fc fragments or HAG. Using platelet extract coated to microtiter plates, similar findings were noted with Fc and HAG. The dissociation of GPIIb/IIIa complex by incubating platelet extract at 37 degrees C in the presence of EDTA caused a marked decrease in the binding of GPIIb and GPIIIa to the immobilized immune complex. Activation of intact platelets with ADP resulted in an increased binding of HAG to the platelets, indicating that an augmented Fc gamma R activity is associated with the activation of GPIIb/IIIa. These results suggest a close relationship of the Fc gamma R activity to the fibrinogen binding site (GPIIb/IIIa complex).

Human platelet Fc receptors: binding kinetics of Fc derivatives to the receptors.

Human platelets are known to carry Fc receptors (Fc R), but the binding characteristics between ligands and Fc gamma R has not been well elucidated. In this study, we investigated the binding kinetics of IgG Fc fragments (Fc) to Fc R, the association and dissociation characteristics of the ligands to and from Fc gamma R using enzymatically modified Fc fragment derivatives. Approximately 60 minutes and 90 minutes were needed at 37 degrees C and 22 degrees C, respectively, for complete saturation of the Fc binding sites with horseradish peroxidase-conjugated Fc (HPO-Fc). Heat aggregated IgG (HAG) had a greater affinity for the Fc gamma R than Fc monomers. Additional binding of HAG was observed even after the binding sites were saturated with Fc monomers. This could be explained by different binding sites available only for immune complexes or by the partial dissociation of binding sites saturated with Fc by HAG. Further, we noted partial dissociation of HPO-Fc, when HAG was added after saturation of the binding sites with HPO-Fc. In a subsequent experiment, we compared the relative affinities of chemically or enzymatically modified Fc derivatives for Fc gamma R. HAG, which was used as a model for CIC, had a greater affinity for platelet Fc gamma R than IgG monomer and Fc derivatives. Pepsin-digestion of Fc caused a total loss of its affinity for the Fc gamma R, whereas b-mercaptoethanol-treated Fc fragments demonstrated substantial binding to the Fc gamma R. These results indicate that the pepsin digestion affects the Fc portion and causes a disruption in the area of the Fc which is essential for the recognition by the platelet Fc gamma R. On the other hand, cleavage of disulfide bridges by beta-mercaptoethanol resulted in a marked increase in affinity for the Fc gamma R. On the other hand, enzymatic cleavage of the carbohydrate moieties of Fc did not alter the affinity of Fc fragments for the Fc gamma R, indicating that the carbohydrates play an insignificant role or are not involved in their binding to the Fc gamma R.

Multivariate analysis of genetic and acquired factors; T235 variant of the angiotensinogen gene is a potent independent risk factor for preeclampsia.

Preeclampsia is known to be a multifactorial disease. Recently, the angiotensinogen gene has been shown to be a candidate gene that could be related to preeclampsia, and acquired factors such as lifestyle during pregnancy have also been considered to be risk factors. The aim of this study was to investigate the interrelations among the angiotensinogen gene and various acquired risk factors in preeclampsia. Fifty-eight primiparous patients with pre-eclampsia were compared with 164 normal primiparous controls. A variant of the angiotensinogen gene (M235T) was analyzed along with the acquired factors obtained from both medical records and a questionnaire consisting of 98 questions. Univariate analysis disclosed 11 factors that were significantly associated with preeclampsia (P < .05). Multivariate analysis revealed four significant independent factors: "prepregnancy high body mass (body mass index > or = 24)," "T235 homozygotes of the angiotensinogen gene," "mentally stressful condition during pregnancy," and "salty dishes preferred during pregnancy." The odds ratios of the four factors were 6.2, 2.5, 3.0 and 2.6, respectively, in a multiple logistic model. Our results support the concept that T235 of the angiotensinogen gene is a potent, independent risk factor for preeclampsia, as well as other lifestyle-related risk factors.

Angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibrosis in stroke-prone spontaneously hypertensive rats.

Angiotensin-converting enzyme inhibitors (ACEIs) cause regression of hypertensive left ventricular hypertrophy (LVH) by reducing angiotensin II, increasing bradykinin, or both. The mechanisms of these cardioprotective effects remain controversial. The aims of this study were to determine whether the cardioprotective effects of ACEIs are mediated by reducing angiotensin II and whether ACEIs ameliorate the morphologic, physiologic, and biochemical changes in the hearts of stroke-prone spontaneously hypertensive rats (SHRSPs). Male SHRSPs were treated with hydralazine, captopril, or candesartan, an angiotensin II type 1 receptor (AT1R) antagonist, from age 12 to 24 weeks. We measured systolic blood pressure (SBP), left ventricular weight (LVW), left ventricular (LV) myocyte cross-sectional area (myocyte size), LV Interstitial collagen volume fraction (ICVF), perivascular collagen area/luminal area ratio (PVCA/LA), the medial area to luminal area ratio (MA/LA), the relative amount of V3 myosin heavy chain (MHCV3), and coronary reserve maximum (coronary flow max/ventricular weight (CFmax/VW)). These parameters were compared with those of untreated SHRSPs and Wistar-Kyoto rats (WKYs). SHRSPs exhibited decreased coronary reserve and LVH with an increase in myocyte size, PVCA/LA, MA/LA, and MHCV3 at 12 weeks of age. In addition to these changes, 24-week-old SHRSPs showed an increase in ICVF. The LVW, coronary reserve, myocyte size, PVCA/LA, ICVF, and MHCV3 of SHRSPs treated with captopril or candesartan all approached control values. In contrast, hydralazine decreased only ICVF. These results suggest that ACEIs regress LVH and normalize coronary reserve by modulating the effects of angiotensin II via AT1R on the induction of cardiomyocyte hypertrophy, perivascular fibrosis, and medial thickening of intramyocardial coronary arteries in SHRSPs. We concluded that these effects, in addition to the reduction of SBP, are important in causing the regression of LVH.

Long-term blood pressure variability and cerebrovascular changes on CT in a community-based elderly population.

The effects of long-term blood pressure (BP) levels on cerebrovascular changes were analyzed in a community-based healthy elderly population. Cranial computed tomography (CT) was performed for 300 residents aged 69 years and older. Long-term BP during the ten years prior to CT was assessed, and the cerebrovascular changes were compared among different patterns of long-term blood pressure variability. White matter lesions (WML) and/or silent infarctions (SI) were found in 73 subjects (23.6%). Multiple logistic regression analysis showed that subjects with long-term diastolic hypertension (DHT) had the highest risk of cerebrovascular changes (adjusted odds ratio (OR), 95% confidence interval (CI); 7.1, 2.4-21.6, for WML; 7.2, 2.7-19.4, for SI), and that long-term isolated systolic hypertension (ISHT) was significantly associated with SI (adjusted OR, 95%CI, 2.3, 1.1-4.9), but not with WML (adjusted OR, 95%CI, 1.3, 0.5-3.3). Efforts to prevent both DHT and ISHT would be beneficial, though different underlying mechanisms for WML and SI were suggested.