Search

Background Rapid reduction of heart rate (HR) is the most evident physiological response of vagal nerve stimulation (VNS). Since HR reduction is the most potent factor to decrease myocardial oxygen consumption rate (MVO2), the appropriate VNS can exert cardio-protective effects. It is also known that VNS reduces inflammation, oxidative stress, and sympathetic overload. In addition, the VNS during ischemia-reperfusion is known to attenuate myocardial damage by studies in various animal species. Despite the presence of preclinical evidence of VNS benefits, the lack of the device has limited the translation of this technology to clinical practice. We have recently developed an intravenous VNS catheter (JOHAKU, Neuroceuticals Inc.) that can stimulate the right vagal nerve via superior vena cava (SVC) (Figure 1) on temporary basis. Purpose We aimed to confirm the feasibility of JOHAKU as a device to modulate heart rate and MVO2 rapidly by a canine experiment. Methods In eight beagle dogs, JOHAKU was inserted from the right femoral vein and placed at the SVC level. The stimulation intensity was adjusted to 10–20 V (20 Hz). We simultaneously recorded electrocardiogram and intraarterial blood pressure (BP). In three of eight dogs, we measured the left anterior descending coronary artery flow and oxygen saturations of arterial and coronary sinus blood to calculate MVO2. We compared HR, BP, and MVO2 during JOHAKU stimulation to ones at baseline. Results As shown in Figure 2, JOHAKU attenuated HR immediately after stimulation. Compared with baseline, JOHAKU significantly reduced HR (baseline: 135±13 vs. 5 min on stimulation: 107±13 bpm, p Conclusion JOHAKU rapidly attenuated cardiac metabolism burden via the rapid HR reduction. The controllability of HR by JOHAKU without affecting BP enables us to apply the VNS even for patients with hemodynamic instability, such as heart failure and acute myocardial infarction. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Japan Agency for Medical and Research Development

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Background To clarify the influence of hypertension and blood pressure ( BP ) control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐ RHYTHM Registry was performed. Methods and Results A consecutive series of outpatients with atrial fibrillation was enrolled from 158 institutions. Of 7937 patients, 7406 with nonvalvular atrial fibrillation (70.8% men, 69.8±10.0 years) were followed for 2 years or until an event occurred. Hypertension was defined as a systolic BP ≥140 mm Hg, a diastolic BP ≥90 mm Hg, a history of hypertension, and/or antihypertensive drug use. Hypertension was an independent risk factor for major hemorrhage (hazard ratio 1.52, 95% CI 1.05–2.21, P =0.027) but not for thromboembolism (hazard ratio 1.05, 95% CI 0.73–1.52, P =0.787). When patients were divided into quartiles according to their systolic BP at the time closest to the event or at the end of follow‐up (Q1, CI 1.75–4.74, P CI 1.02–2.53, P =0.041) after adjustment for components of CHA 2 DS 2 ‐ VAS c score, warfarin use, and antiplatelet use. A systolic BP of ≥136 mm Hg was an independent risk factor for thromboembolism and major hemorrhage. Conclusions BP control appears to be more important than a history of hypertension and baseline BP values at preventing thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation. Clinical Trial Registration URL : http://www.umin.ac.jp/ctr . Unique identifier: UMIN 000001569.

45の剖検例において,prospectiveに,Clostridium difficileの細菌的・形態的な検討を行った.17例(37.8%)のS状結腸内容から,C.difficileが検出された.死亡直前に水様便が認められたのは17例中3例.17例中10例の大腸に,抗生物質投与後の偽膜性腸炎といわれてきたものと同じ特徴的な「偽膜性病変」が認められた.C.difficile陰性の症例では「偽膜性病変」は認めなかった.「偽膜性病変」の他に,サイトメガロウィルス感染や真菌感染など,他の病変を伴うこともあった.大腸に全く病変がないものが17例中4例あった.今回のこのようなデータは,本邦では今までなく,C.difficile腸炎について興味ある知見が得られた.

The insertion (I) allele of the human angiotensin-converting enzyme (ACE) gene is associated with lower serum and tissue ACE activity, and with greater endurance performance and enhanced mechanical efficiency of trained muscle. We tested the hypothesis that the ACE-I allele may be associated with increased slow-twitch fiber, which is more efficient than fast-twitch fiber in low-velocity contraction, by examining the association between the ACE genotype and skeletal muscle fiber (SMF) types in 41 untrained healthy young volunteer subjects (31 males, 10 females, age 24 +/- 3 years). Skeletal muscle samples were taken from the left vastus lateralis using the needle-biopsy method. Slow-twitch type I fibers and fast-twitch type IIa and IIb fibers were classified histochemically based on staining for myosin adenosine triphosphatase (ATPase) activity at different pH values. Amylase-periodic acid-Schiff staining was used to visualize capillaries around fibers. ACE-II subjects had significantly (p0.01) higher percentages of type I fibers (50.1 +/- 13.9%vs 30.5 +/- 13.3%) and lower percentages of type IIb fibers (16.2 +/- 6.6%vs 32.9 +/- 7.4%) than ACE-DD subjects. The linear trends for decreases in type I fibers and increases in type IIb fibers from ACE-II --ID --DD genotypes were significant as assessed by an analysis of variance. The ratio of type I:II fibers also differed according to the ACE genotype. A multivariate logistic regression analysis showed that the ACE-I allele had significant additive and recessive (codominant) effects on the increased type I fibers and the ratio of type I:II fibers. No specific pattern of capillarization was observed among the three ACE genotypes. In conclusion, the ACE-I allele was associated with increased type I SMF, which may be a mechanism for the association between the ACE genotype and endurance performance.

We studied the association of angiotensin I-converting enzyme (ACE) gene polymorphism with the depressor response to exercise therapy in 64 Japanese subjects with mild to moderate essential hypertension. Each subject performed 10 weeks of mild (lactate threshold intensity: approximately 50% maximum oxygen consumption) exercise therapy on a bicycle ergometer. Systolic blood pressure (SPB), diastolic blood pressure (DPB), and mean arterial pressure (MAP) were significantly decreased by exercise therapy in subjects with the ACE-II and ID genotypes but not in DD subjects. The time-by-genotype interaction effects were significant for DBP and MAP. According to a multiple logistic regression analysis, the age- and baseline plasma renin activity-adjusted relative risk (odds ratio) for the lack of a depressor response conferred by the D allele (assuming an additive effect) was 2.72 [95% confidence interval (CI), 1.07-6.91; p = 0.034]; for DD genotypes, as compared with the DI and II genotypes (assuming that the D allele is recessive), it was 11.7 (95% CI, 2.25-60.6; p = 0.003). ACE gene I/D polymorphism is associated with the depressor response of essential hypertensives to mild exercise therapy, which suggests that genetic features may underlie, at least in part, the heterogeneity of the depressor response in essential hypertensives to mild exercise therapy.

CS-866 is an angiotensin II type-1 receptor antagonist, the effects of which on systolic blood pressure (BP) and glucose/insulin metabolism are investigated under hyperlipidaemic conditions produced by cholesterol feeding. Thirty-two female Japanese White rabbits (two months old) were assigned randomly into a CS-866-treated group (n = 17) fed a food admixture that contained 0.03% CS-866 and 0.2% cholesterol, or into a control group (n = 15) fed a food admixture containing 0.2% cholesterol only. Systolic BP was measured by an ear-cuff method. Glucose and insulin metabolism was characterised quantitatively from the results of an intravenous glucose tolerance test by a minimal model technique reported previously. After six months treatment, systolic BP in the CS-866-treated group was lower than in the control group (105 +/- 14 mmHg versus 115 +/- 18 mmHg; P0.05), as assessed by analysis of variance and the Wilcoxon rank-sum test. No significant differences were seen in plasma aldosterone concentration, plasma renin activity, or angiotensin-converting enzyme activity between the groups. Administration of CS-866 for six months did not affect either glucose tolerance or insulin sensitivity. Other model parameters such as basal (steady-state) insulin and glucose concentration, first- and second-phase post-hepatic insulin delivery to glucose, and insulin clearance rate constant were unaffected. In conclusion, CS-866 treatment reduced systolic BP without affecting glucose/insulin metabolism under hyperlipidaemic conditions produced by cholesterol feeding.

Combined administration of propranolol and disopyramide treatment often leads to better results in patients with atrial fibrillation refractory to only disopyramide administration. The electrophysiological mechanism of this combination therapy was investigated.Nineteen patients with paroxysmal atrial fibrillation without organic heart disease were studied. The indices for atrial vulnerability were compared in the control state, 10 min after injection of disopyramide (2 mg/kg) and 10 min after additional administration of propranolol (0.2 mg/kg).Administration of both drugs did not significantly change the percentage fragmented atrial activity and the interatrial conduction delay. Disopyramide increased the atrial effective refractory period and the wavelength index, defined as the ratio of the atrial effective refractory period to the interatrial conduction delay and represented the length of the reentry circuit. Additional injection of propranolol caused further increases in both values.Combination therapy with disopyramide and propranolol improves atrial vulnerability by increasing the wavelength.

Genetic variants of human apolipoprotein (apo) A-I, the major protein component of high-density lipoprotein (HDL), with a single amino acid substitution have been reported, and some of these result in very low plasma HDL-cholesterol (C) levels. Examining the kinetics of radiolabelled apolipoprotein is a straightforward technique for determining its metabolism in vivo. In this study, we investigated the in vivo kinetics of several human apo A-I variants, which we had identified previously, in rabbits.Apo A-I variants from heterozygous carriers of Lys-107--0, Lys-107--Met, Pro-3--Arg, Pro-4--Arg, Pro-165--Arg and Glu-198--Lys and the corresponding normal apo A-I were purified and then radioiodinated with 131I and 125I. A kinetic study of apo A-I variants was performed in normolipidaemic rabbits after simultaneous injection of the two isotopes that had been incorporated into HDL. The fractional catabolic rate (FCR) was calculated from the radioactive decay curve.Acidic mature (negatively charged) apo A-I variants caused by a single amino acid substitution (Lys-107--0, and Lys-107--Met) were catabolized faster (FCR, 1.931 +/- 0.539 per day vs. 1.636 +/- 0.460 per day, P/= 0.01 using the Wilcoxon signed-rank test) and basic mature (positively charged) apo A-I variants (Pro-3--Arg, Pro-4--Arg, Pro-165--Arg and Glu-198--Lys) were catabolized more slowly (FCR 1.470 +/- 0.380 per day vs. 1.654 +/- 0.430 per day, P/= 0.01) than the corresponding normal mature apo A-I in vivo in rabbits. In addition, an inverse linear relationship was observed between the deviation in the FCR of variant human apo A-I from that of normal human apo A-I and the number of electric charges that the apo A-I variant carried (r = -0. 90, k = -0.188, P = 0.0003), as assessed by a linear regression analysis, suggesting that the electric charge of apo A-I variants may determine, at least in part, its in vivo kinetics in rabbits.Genetic variants of apo A-I with a single amino acid substitution show abnormal kinetics, and the electric charge of a apo A-I variant could contribute to determining its kinetics in vivo in this xenologous model.

Angiotensin II type 1 (AT(1)) receptor blockers (ARBs) are highly selective for the AT(1) receptor, which is a member of the G protein-coupled receptor superfamily (GPCRs), and block the diverse effects (hypertension, hypertrophy, heart failure, proteinuria etc.) of angiotensin II. Many ARBs are in clinical use and have been shown to be safe and effective. Over the past several years, reports have discussed the different degrees of the beneficial effects of ARBs. As ARBs do not all have the same effects, the benefits conferred by ARBs may not be class effects. These different effects may be due to differences in the molecular characteristics of ARBs. The results reported by Le et al. in this issue highlight the different characteristics of two ARBs, olmesartan and telmisartan, and suggest that the higher degree of insurmountability, slower dissociation, and higher affinity of olmesartan compared to telmisartan for AT(1) receptors may help it to form a tight binding complex with this receptor. A better understanding of the different molecular mechanisms for each ARB could be useful for the treatment of patients.

A 62-year-old man with old myocardial infarction and familial hypercholesterolemia was treated by both probucol and low-density lipoprotein (LDL) apheresis. Coronary angiography was performed before and after 3.5 years of LDL apheresis treatment, and no new lesion or progression of coronary atherosclerosis was observed. LDL apheresis drastically reduced the serum total cholesterol. However, it is still unclear whether LDL apheresis effectively prevented the recurrence of cardiac events and the progression of coronary atherosclerosis in this patient.

We investigated the mechanism of action of gemfibrozil on high-density lipoproteins (HDL) and apolipoprotein (apo) A-I metabolism and atherogenesis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model of familial hypercholesterolemia and HDL deficiency. Two-month-old WHHL rabbits were fed either a normal control diet or a diet containing 0.5% gemfibrozil for 12 months. In vivo apo A-I kinetics, the fractional rate of cholesterol esterification in HDL (FER[HDL]), which reflects the reactivity of HDL to lecithin:cholesterol acyltransferase, and a morphometrical analysis of atherosclerotic lesions in the descending thoracic aorta, were examined. At 12 months, the mean levels of serum total cholesterol, LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) in both groups had decreased to approximately 53%, 57%, and 87% of the initial levels (at 0 month), respectively, which is characteristic of homozygous WHHL rabbits of the physiologic influence of aging, and no differences in the levels of serum LDL-C, HDL-C, and triglycerides were found between the two groups. Rabbits treated with gemfibrozil exhibited a decreased FER(HDL) (38% of the controls, P = 0.039). Gemfibrozil induced a significant increase in the total mass of apo A-I (1.7-fold, P0.05) and in the rate of apo A-I synthesis (1.6-fold, P0.05). The atherosclerotic intimal area was positively correlated with serum LDL-C (P = 0.02) in both groups, but gemfibrozil did not affect the atherosclerotic intimal area. These results indicate that 12 months of treatment with gemfibrozil did not protect against atherosclerosis despite a significant increase in apo A-I synthesis and enhanced HDL function through FER(HDL). It is possible that both the qualitative and quantitative improvement in HDL by gemfibrozil cannot overcome the massive and long-term exposure of the vascular wall to LDL in these animals.

Invasive infection due to Trichosporon is a rare but often fatal disease in immunocompromised patients. In this study, data on patients with hematologic malignancies who had an invasive infection due to Trichosporon diagnosed at the Tokyo Metropolitan Komagome Hospital in Tokyo, Japan, were analyzed.Positive blood cultures obtained between 1986 and 1996 were reviewed. Medical records of all patients who were positive for Trichosporon in their blood culture or autopsy material were then examined.A total of nine patients with hematologic malignancies were reported positive for Trichosporon cutaneum in their blood culture or at the time of autopsy. The average age was 52 years, and all patients except 2 had acute leukemia. All 8 patients with positive blood cultures were neutropenic, and the average duration of neutropenia before the positive blood cultures were obtained was 43 (range, 0-101) days. For prophylaxis of fungal infection, eight patients were kept in a laminar air flow room and also received nebulization with amphotericin B. Five patients received oral amphotericin B. All 9 patients died of the infection an average of 9 days after their blood cultures turned positive. Minimal inhibitory concentrations were evaluated in six available strains obtained from the patients. They were all resistant to amphotericin B and azoles.More effective antifungal agents are required for the treatment of infections with this organism.

A 47-year-old man with heterozygous familial hypercholesterolemia was followed up by coronary angiography for 9 years. During these 9 years, he experienced inferior myocardial infarction twice, at segment 1 of the right coronary artery. A coronary atherosclerotic lesion (50% stenosis) was also present at segment 6 of the left anterior descending coronary artery. This lesion remained unchanged for the first 7 years, but then rapidly progressed to 90% stenosis in the 8th year. While the rate of the progression of coronary atherosclerosis is generally unpredictable, it may progress rapidly in this case of heterozygous familial hypercholesterolemia.

We investigated the association between the serum level of thrombomodulin and known coronary risk factors in 119 men who underwent coronary angiography. Total cholesterol level was significantly higher in patients with coronary atherosclerosis than in those without. Significantly higher frequency of hypertension was noted in patients with coronary atherosclerosis. Uric acid level and frequency of smoking tended to be higher in patients with coronary atherosclerosis but the differences were short short of the significant level. The serum level of thrombomodulin between patients with coronary atherosclerosis and those without was not statistically significant. Age, blood urea nitrogen, and creatinine were positively correlated and creatinine clearance was inversely correlated with the serum level of thrombomodulin. Serum levels of total cholesterol, triglyceride, high-density lipoprotein cholesterol, uric acid, and fasting blood sugar, plasma level of fibrinogen, and body mass index were not related to the serum level of thrombomodulin. There was no significant correlation between the severity of coronary atherosclerosis, hypertension, alcohol use, or smoking and the serum level of thrombomodulin. Restenosis was present in 8 of 16 patients who underwent percutaneous transluminal coronary angioplasty and had a follow-up angiogram at 6.0 +/- 3.0 months. Univariate analysis revealed no significant difference in the thrombomodulin level with and without restenosis. The present findings suggest that elevated thrombomodulin levels in patients with coronary artery disease may reflect retention of thrombomodulin due to decrease in thrombomodulin clearance in the kidney.

Systematic sequencing of the coding and exon flanking regions of the apolipoprotein (apo) A-I gene has identified a new polymorphic Msp I site (C C/T-GG). This polymorphism is situated between the transcriptional starting site and the signal peptide start coding site (intron 1), so may influence the efficiency of surrounding splicing, thereby interfering with the expression of the apo A-I gene product, or serve as a linkage marker with a hitherto unidentified mutation defect responsible for hyperlipidemia and/or premature coronary heart disease. However, there was no significant difference in the allele frequencies between control and coronary heart disease subjects in a Japanese population. The -78 G--A promoter polymorphism of apo A-I, previously reported in Western populations, has also been analyzed. The results show that neither mutation is likely to be the etiology for predisposition to a change of high-density lipoprotein cholesterol and/or variation in lipid and lipoprotein levels, or for the occurrence of coronary heart disease in Japanese populations.

The objective of this study was to assess the medium-term effects of betaxolol, a long-acting, lipid-soluble, cardioselective, beta-adrenergic antagonist, alone and in combination with nitrendipine on blood pressure (BP) and metabolism of lipid, lipoprotein and apolipoprotein in patients with mild to moderate hypertension. Forty-seven patients (21 men, 26 women, average age 54 years) participated in an open controlled clinical trial. After a 4-week washout period, all of the patients received betaxolol monotherapy at a dose of 5-10 mg daily for 6 months (Phase I). From month 7 through month 12 (Phase II), half of the total patients (Group B, n = 23) with diastolic blood pressure (DBP) of 95 mm Hg or more at the end of Phase I were also given nitrendipine (10-20 mg, once daily), while the remaining patients (Group A, n = 24) continued to receive only betaxolol. Systolic blood pressure (SBP), DBP, and heart rate (HR) were monitored once monthly. Serum lipid profiles were measured at study entry and after 6 and 12 months of therapy. Betaxolol significantly reduced SBP, DBP, and HR in both groups during Phase I, and the reductions in SBP and DBP were markedly less in Group B than in Group A. During Phase II, the additional reduction of SBP and DBP to levels similar to those in Group A was achieved by betaxolol in combination with nitrendipine, and HR was slightly but significantly increased. Betaxolol monotherapy reduced serum levels of high density lipoprotein cholesterol (HDL-C) and increased levels of triglyceride, apolipoprotein (apo) C-II and apo C-III. Combination therapy with betaxolol and nitrendipine increased serum apo A-I but did not affect other lipid profiles. Our results indicate that betaxolol is an effective antihypertensive drug which has a preferable effect on HR and HDL profiles when combined with nitrendipine.

Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats.

The effects of the addition of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin, to the medium on sterol synthesis and phosphatidylcholine (PC) synthesis were studied in HepG2 cells. The cells were cultured with simvastatin at concentrations of 10(-7) and 10(-6) mol/L for 6 hours, and radioactive lipid precursors were added 1 hour before harvesting. Simvastatin inhibited cholesterol synthesis from [14C]acetate in a dose-dependent manner. It also decreased the incorporation of [14C]choline into PC by 30%; this decrease was accompanied by a decrease in phosphocholine cytidylyltransferase activity in cell homogenates. Simvastatin had no significant effects on the incorporation of [3H]glycerol into phospholipids. These data indicate that simvastatin has two different functions: inhibition of HMG-CoA reductase and depression of de novo synthesis of PC via the cytidine diphosphate-choline pathway, which, in turn, may result in a decrease in plasma lipid levels.

In oriental medicine there is a hypothesis related to acupuncture that the auricle is a projection of the functional anatomy of the whole human body. In this study reactive electropermeable points (REPP), that is, points on the skin with low electrical resistance, on the auricle were measured on patients with coronary heart disease using a neurometer LC-M. Our findings correlated positively with the particular points--heart I (shin) and heart II (shinzo)*--named by the Chinese group as being related to the functional anatomy of the heart. The incidence of positive REPP test results at the shin and shinzo points for subjects with acute myocardial infarction (AMI) were extremely high, and positive test results for patients with old myocardial infarction (OMI) and angina pectoris (AP) were also significant. There was no significant difference in the incidence rates of REPP at the shin and shinzo points between the OMI and AP groups. High incidence of positive REPP test results at the lung and heart III (shinyu) points occurred only in the AMI group, and this was significantly high when compared with the control group.

Electrocardiographic QTc intervals were measured in twenty-one hypercholesterolemic patients before and after long-term probucol (500-1,000 mg/day for 30 months) treatment. Probucol reduced serum total cholesterol (TC), triglyceride (TG), and high density lipoprotein-cholesterol (HDL-C). Mean QTc interval prolongation after probucol was 17 msec. A positive correlation was found between the change in QTc interval after probucol (delta QTc) and the total amount of probucol administered. delta QTc was negatively correlated to the pre-treatment QTc interval. No correlation was observed between serum probucol concentrations and delta QTc. Neither clinical evidence of cardiotoxicity nor critical arrhythmias were noted during the treatment period.

Forty-five patients with mild to moderate essential hypertension were randomly assigned to receive 10 to 40 mg of manidipine HCl or 15 to 60 mg of delapril daily for 12 months. In the manidipine-treated group were 13 women and 5 men (mean age, 48.2 years) and in the delapril-treated group 11 women and 11 men (mean age, 53.7 years). Blood samples were taken at baseline and after 6 and 12 months of treatment and again at 2 months after treatment discontinuation. Significant reductions in blood pressure were observed in both treatment groups. The reduction in diastolic blood pressure was significantly greater in the manidipine-treated patients than in the delapril-treated patients; no significant between-groups differences in systolic blood pressure were noted. Heart rate increased significantly in the manidipine group. No changes in serum levels of total cholesterol, triglycerides, and high-density and low-density lipoprotein cholesterol were noted during or after treatment. In the manidipine group, a small but significant decrease in apolipoprotein (apo) A-I and an increase in lipoprotein(a) were found at 6 months and a significant increase in apo A-II and apo E at 12 months; in the delapril group a significant decrease in apo A-I was found at 6 months. The results indicate that both manidipine and delapril are lipid-neutral antihypertensive drugs, since neither drug greatly affected serum lipid metabolism.

We investigated the effects of the traditional Chinese herbal drugs, Dai-saiko-to (D) and Saiko-ka-ryukotsuboreito (S) on blood pressure, pulse rates, serum lipids, lipoproteins and apolipoproteins in 30 patients with mild to moderate hypertension in an open, randomised trial. After the drug treatment, BP remained unchanged, but pulse rates declined significantly after 3 months in the S treated group. Serum total cholesterol and triglyceride values did not change, but high density lipoprotein-cholesterol increased significantly (P0.05) in both groups. Apo-AI (P0.1 in S group) and apo-AII (P0.05 in D group, P0.1 in S group) tended to increase 3 months after treatment. These data indicate that both of these traditional Chinese medicines have a preferential effect on lipid metabolism with little antihypertensive action.

Fifty-six hypertensive patients were recruited to participate in a 12 week, randomised, multicentre trial to compare the effects of lisinopril (n = 31) and low-dose trichlormethiazide (n = 25) administration on blood pressure and lipoprotein metabolism. Both systolic and diastolic BPs decreased significantly after administration of lisinopril (5-40mg/day, mean dose 11 mg/day) and trichlormethiazide (2.0-4.0 mg/day, mean dose 2.2 mg/day). There were no significant changes in lipids, lipoproteins or apolipoproteins with either drug for 12 weeks and no significant differences between the two drugs for these parameters. It is concluded that lisinopril and low-dose trichlormethiazide administration are effective antihypertensive measures without any adverse effects after 12 weeks on lipoprotein metabolism in patients with mild to moderate essential hypertension.

The subjects were 61 healthy volunteers who received 15 gm of polydextrose daily for two months. A significant increase in the incidence of soft feces and diarrhea and in the volume of feces was reported during polydextrose treatment. These had returned to normal one month after treatment. Serum levels of total cholesterol, triglycerides, and low-density lipoprotein cholesterol did not change during treatment. Levels of apolipoprotein (apo) A-I and A-II were significantly lowered at one month and high-density lipoprotein cholesterol (HDL-C) and apo A-I were significantly decreased at two months; these returned to normal after treatment. Levels of HDL2-C decreased and HDL3-C levels increased significantly during treatment. The results indicate that polydextrose selectively affected the metabolism of HDL and its major proteins, apo A-I and A-II.

Plasma high density lipoproteins (HDL) and their major proteins--apolipoprotein (apo) AI and apo AII--are subnormal in most patients with familial hypertriglyceridemia. However, the pathophysiology of low plasma apo AI and apo AII is unclear. The kinetic parameters (turnover) of HDL apo AI and apo AII were studied in six lean patients with primary HDL deficiency associated with familial hypertriglyceridemia and normolipidemic healthy controls. The radioactivity decay curve of 125I labelled HDL was used for assessment of kinetics. Mean plasma apo AI and apo AII were significantly lower (p less than 0.001) in patients than normals (70.4 +/- 2.7 v 106.9 +/- 7.0; 24.2 +/- 1.6 v 39.2 +/- 0.9 mg/dl, respectively). The mean fractional catabolic rates (FCR) obtained from plasma 125I-HDL, apo AI, apo AII radioactivity decay curves and by Berson and Yalow's method (urine/plasma radioactivity ratios) were significantly greater (p less than 0.05) in patients than in controls (0.387 v 0.299; 0.391 v 0.309; 0.361 v 0.275; 0.272 v 0.207/d; respectively). The synthetic rates (SR of apo AI and apo AII were significantly lower in patients than in controls (11.12 v 14.17 mg/kg body weight/d. p less than 0.05; 3.53 v 4.68 mg/kg body weight/d, p less than 0.05, respectively). Each patient was also investigated for HDL and triglyceride metabolism immediately before and after 8 wk of gemfibrozil (1200 mg/d) treatment. Gemfibrozil significantly increased plasma HDL cholesterol, apolipoprotein (apo) AI, and apo AII by 36%, 29%, and 38% from baseline, respectively. Plasma TG decreased by 54%. Gemfibrozil increased synthetic rates of apo AI and apo AII by 27% and 34%, respectively, without changing the FCR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of Chinese herbal drug, Dai-saiko-to, on plasma lipids, lipoproteins and liver lipid contents were investigated in guinea pig with/without cholesterol feeding. Guinea pigs were divided into 4 groups (Group 1: normal chow (N) diet, Group 2: N + 1% Dai-saiko-to (D) diet, Group 3: 1% cholesterol (C) diet, Group 4: 1% C+ 1% D diet), and were treated for 5 weeks. Significant body weight reductions were observed in Groups 3 and 4 compared to Groups 1 and 2. Significant reductions of plasma triglyceride (TG) and very low and low density lipoproteins [(V) LDL]-TG were found in Group 3 compared to Groups 1, 2, and 4. (HDL)-TG significantly decreased in Groups 3 and 4 compared to Groups 1 and 2, but no significant difference was noted between Groups 1 and 2, and Groups 3 and 4. Liver lipid contents analysis showed no significant changes between Groups 1 and 2, and Groups 3 and 4, respectively, but the distribution of lipid droplets as pathologically determined using a computer program showed Group 4 had less lipid deposition compared to Group 3. These data suggest that Dai-saiko-to acts on triglyceride metabolism in hypercholesterolemic guinea pigs.

Twenty-two patients with mild to moderate hypertension received 20 mg of pinacidil daily for six weeks, followed by 40 mg daily for another six weeks. Levels of serum triglyceride and apolipoproteins C-II and C-III decreased significantly; high-density lipoprotein cholesterol levels increased significantly during treatment. These changes were more prominent in patients with total triglyceride levels of 150 mg/dl or over. The results suggest that pinacidil has a preferential action on triglyceride-rich lipoprotein metabolism.

To investigate the cardiac function of WHHL rabbit (WHHL), an animal model of familial hypercholesterolemia, electrocardiography (ECG) and echocardiography (UCG) were taken from this species of homozygous type and normolipidemic Japanese White rabbits (controls). In WHHL, two of four had intraventricular conduction disturbances (IVCD) in ECG. UCG study showed that the ejection fraction significantly increased (p less than 0.05) and deceleration time was shortened (p less than 0.01) in WHHL compared to normal controls.

The effects of bezafibrate on serum lipids, lipoproteins, apolipoproteins, and post-heparin lipolytic activities were studied in 17 patients with hypertriglyceridemia. All patients received 400 mg of slow-release (SR) bezafibrate daily for four months. In the nine patients with type IV hypertriglyceridemia, mean serum triglyceride (TG) levels decreased significantly, by 53% (P less than 0.01) at two months and 50% (P less than 0.001) after four months of bezafibrate, while in the eight patients with type V, the levels decreased by 61% (P less than 0.001) and 51% (P less than 0.001), respectively. Total cholesterol levels decreased significantly (P less than 0.05) in type V patients at two and four months, by 19% and 18%, respectively, while low-density lipoprotein cholesterol levels increased significantly (P less than 0.05) in type IV patients at two and four months, by 63% and 62%, respectively. High-density lipoprotein (HDL) levels increased significantly (P less than 0.05) at two months in both patient groups. HDL subfraction analysis showed a significant (P less than 0.05) rise in HDL3-cholesterol levels in type V but not in type IV patients. Apolipoprotein (apo) A-I, A-II, and B levels increased, while apo C-II, C-III, and E levels decreased in both groups. The apo A-I/apo A-II ratio decreased significantly (P less than 0.05) at two and four months in type V patients, which also supports increased HDL3 fractions in that group. Lipoprotein lipase and hepatic TG lipase levels tended to rise, and the particle size of TG-rich lipoprotein (TGRL) and the TGRL-apo C-III/TGRL-apo C-II ratio decreased in both patient groups. These data indicate that bezafibrate-induced changes in lipoprotein profiles differed slightly in type IV and type V patients. The results confirm the usefulness of bezafibrate as a lipid-lowering agent.

The effects of simvastatin (MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum lipids, lipoproteins, and apolipoproteins were investigated in 29 patients (12 men, 17 women, aged 37 to 73) with moderate to severe hypercholesterolemia. It was given in doses of 2.5 mg/day for four months and 5 mg/day for the succeeding four months. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B decreased by 18% (263 +/- 7 mg/dl to 216 +/- 7 mg/dl, P less than 0.01), 24% (180 +/- 7 mg/dl to 136 +/- 7 mg/dl, P less than 0.01), and 21% (133 +/- 4 mg/dl to 104 +/- 3 mg/dl, P less than 0.01), respectively, four months after treatment. Similar reductions (17%, 24%, and 23%, respectively, P less than 0.01) were observed at eight months. A significant reduction in triglyceride (TG) was observed (173 +/- 15 mg/dl to 136 +/- 11 mg/dl at eight months, P less than 0.01), as was a significant increase in serum high-density lipoprotein cholesterol (HDL-C) (48 +/- 2 mg/dl to 52 +/- 2 mg/dl at eight months, P less than 0.01). However, apo AI and apo AII remained unchanged. Atherogenic indices of (TC--HDL-C)/ HDL-C, LDL-C/HDL-C, and apo B/Apo AI ratios were significantly (P less than 0.01) reduced after treatment. No significant changes were observed in lipoprotein lipase, hepatic TG lipase, and lecithin: cholesterol acyltransferase (LCAT) activities. Simvastatin was well tolerated and no critical side effects were noted in the eight-month study period. These data indicate that simvastatin, even at a low dose of 2.5 to 5 mg daily, causes consistent reductions in serum TC, LDL-C, apo B, and TG, and a rise in HDL-C and antiatherogenic lipoproteins.