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Optimal use of amiodarone (AMD) requires information regarding the drug's pharmacokinetics and the influence of various factors on the drug's disposition. This study was conducted to establish the role of patient characteristic in estimating doses of AMD using nonlinear mixed effects modeling in Japanese patients treated with oral therapy.Serum concentrations of AMD were determined by high-performance liquid chromatography. The 151 serum trough concentrations from 23 patients receiving repetitive oral AMD were collected. Analysis of the pharmacokinetics of AMD was accomplished using a 1-compartment open pharmacokinetic model. The effect of a variety of developmental and demographic factors on AMD disposition was investigated.Estimates generated by nonlinear mixed effects modeling indicated that the clearance of AMD was influenced by the demographic variables: total body weight (TBW), daily dosage of AMD (DD), body mass index (BMI), gender (GEN), duration of AMD dosing (DUR), and patient clearance factor (Conc(θ); Conc = serum trough concentration of AMD). The final pharmacokinetic parameters were CL/F (L/h) = 0.072·TBW·Conc(-1.01)·1.95(DD≥200)·0.931(BMI≥25)·1.37(GEN)·DUR(-0.016), and Vd/F (L) = 78.4·TBW, where CL is total body clearance and Vd is volume of distribution. As all doses were given orally, it was impossible to assess the bioavailability (F). DD ≧200 is an indicator variable that has a value of 1 if the patient is receiving more than 200 mg daily dosage of AMD, and 0 otherwise. BMI ≧25 is an indicator variable that has a value of 1 if the BMI is 25 kg/m² and over, and 0 otherwise. GEN is an indicator variable that has a value of 1 if the patient is woman, and 0 otherwise.The authors developed new population pharmacokinetic parameters. Clinical application of the findings in the present study to patient care may permit selection of an appropriate initial maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect.

This study examined the relationship between hypokalemia and ventricular tachyarrhythmia in nonischemic heart, and tried to determine whether hypokalemia enhances the proarrhythmic effect of ventricular repolarization-prolonging drugs. In 12 mongrel dogs (group 1), hypokalemia was produced by infusion of 5.0 g/kg of polystyrene sulfonic acid calcium into the colon while 8 other dogs (group 2) were maintained normokalemic. Programmed ventricular stimulation (PVS) was performed in the two groups before and after injection of disopyramide (i.v., 2.0 mg/kg). In group 1, serum potassium decreased from 4.1±0.3 to 2.7±0.4 mEq/L. QRS duration increased from 49±2 to 60±3 msec (p

近年､わが国では不適切な生活習慣に基づく動脈硬化性心臓血管病が増加している｡不適切な生活習慣が長期間持続すると､肥満､糖尿病､脂質異常症､高血圧などが生じて動脈硬化の進展を促進し､その結果として虚血性心疾患､大動脈瘤､大動脈解離､末梢動脈疾患､脳血管疾患などの動脈硬化性心臓血管病が発症してくる｡その予防には､適切な食習慣や運動習慣､休養､禁煙､節酒 などの生活習慣を維持する必要がある｡本稿では､不適切な生活習慣による動脈硬化性心臓血管病の予防について概説した｡, It is well known that the incidence of atherosclerotic cardiovascular diseases due to bad habits in daily life is recently on the increase in the Japanese people. Bad habits in daily life extending over a long period of time bring about obesity, diabetes mellitus, dyslipidemia and hypertension.These disorders accelerate the development of arterial atherosclerosis causing cardiovascular diseases such as ischemic heart disease, aortic aneurysm, aortic dissection, peripheral vasucular disease, cerebrovascular disease and others. In order to prevent the development of these athero-sclerotic cardiovascular diseases. It is essential to keep a good condition of lifestyle including good eating habit, appropriate physical activity, recess for coping stress, nonsmoking and moderation of drinking.

性ホルモンであるエストロゲンは、摂食調節に関与する内分泌物質でもあり、このエストロゲンの受容体は、脳内では摂食調節に重要な神経核である視床下部弓状核に非常に多く発現している。また、摂食の調節は摂取するエネルギー量のみに規定されているものではなく、摂取する栄養素のそれぞれに対する選択的な調節機構も存在し、これはしばしば嗜好性という形で現れる。本実験では、マクロ栄養素（糖質、脂質及びタンパク質）のそれぞれに特化した３種類の食餌をラットに同時に与え、自由に選択摂食させる手法（self‐selection法）を用いて、ラットの個々の嗜好性を同定するという生理学的な検討に加え、そのラットの視床下部領域における摂食調節に関わるエストロゲン受容体の分布を組織化学的に検討した。これらマクロ栄養素に対する嗜好性とエストロゲン受容体の発現との相関を検証し、嗜好性に対するエストロゲンの作用を明らかにする。, Estrogen, a gonadal hormone, has a function for control of intake. Estrogen receptors (ER) were distributed in hypothalamic arcuate nucleus (ARC), which is important in appetite. The control of food intake is not only based on the number of calories, but also on the each nutrient and its amount, that is indicated as the “preference". In this study, we used three experimental diets, a carbohydrate, a protein and a fat diet and allowed each rat ad libitum access to them. In addition to physiological investigation as an identification of the preferences of the rats with the diets, we examined histochemically about the distribution of ER in ARC. By verifying the correlation of the preferences to macronutrients and the distribution of ER, we tried to elucidate the effect of estrogen to the preferences.

グレリンは２８個のアミノ酸から構成されるペプチドであり、その中枢あるいは末梢投与は、その後の摂食量を増加させることが報告されている。本研究ではグレリンの栄養素の嗜好性への影響を検討するため、３種類のマクロ栄養素食（糖質、タンパク質及び脂質）を同時に与えたラットにグレリン（１００、２００及び ５００ pmol/rat）を脳室内投与し、投与から１、２、４及び２４時間後の摂食量を測定した。２００及び ５００ pmol のグレリン投与は２時間後までの累積総摂食量を、生理的食塩水投与時と比べて有意に増加させた。その内訳を見ると、糖質食及びタンパク質食の累積摂食量が有意に増加していたが、脂質食の摂食量に変化は見られなかった。本研究はグレリンの脳室内投与が糖質及びタンパク質の摂食量を選択的に増加させたことを明らかにした。この結果は、グレリンによる栄養素選択的な摂食調節が行われるメカニズムにおいて迷走神経が関与している可能性を示唆している。, Ghrelin is a ２８-amino acid peptide with an acyl side chain, n-octanoic acid. It was reported that ghrelin infusion centrally and peripherally increases food intake. In this study, to investigate the effect of ghrelin to preference on nutrients, we infused ghrelin centrally（１００, ２００ and ５００ pmol/rat）to three macronutrient diets（carbohydrate, protein and fat）fed rat and measeured food intake at １, ２, ４ and ２４ hours after the infusions. The central infusion of ２００ and ５００ pmol of ghrelin increased cumulative total food intake until ２ h after infusion compared with saline infusion. In regards to the three diets, carbohydrate and protein intakes were increased. But the infusion of ghrelin did not alter fat intake. In this study, we demonstrate the alternation of preference in nutrients, especially carbohydrate and protein, by central ghrelin infusion. It is known that two types of nerve systems involve the orexigenic action of ghrelin；ghrelin neurons in arcuate nucleus and vagal nurves. The differences of preferense of nutrients observed in this study may result from the differences of those nervous systems.

グレリンは２８個のアミノ酸から構成されるペプチドであり、その中枢あるいは末梢投与は、その後の摂食量を増加させることが報告されている。本研究ではグレリンの栄養素の嗜好性への影響を検討するため、３種類のマクロ栄養素食（糖質、タンパク質及び脂質）を同時に与えたラットにグレリン（０.５，１.０及び ５.０nmol/rat）を腹腔内投与し、投与から１、２、４及び２４時間後の摂食量を測定した。総摂食量はグレリンの投与量依存的に、生理的食塩水投与時と比べて増加した。その内訳を見ると、糖質食の摂食量が有意に増加していたが、タンパク質及び脂質食の摂食量に変化は見られなかった。血清グルコース、総タンパク質、中性脂肪、遊離脂肪酸、及びβ-リポタンパク質濃度はグレリン投与による影響は認められなかった。本研究はグレリンが代謝に影響することなく、糖質の摂食量を選択的に増加させたことを明らかにした。この結果は、グレリンが直接的に糖質に選択的な摂食調節に関与していることを示唆している。, Ghrelin is a 28-amino acid peptide with an acyl side chain, n-octanoic acid. It was reported that ghrelin infusion centrally and peripherally increases food intake. In this study, to investigate the effect of ghrelin to preference on nutrients, we infused ghrelin (0.5, 1.0 and 5.0 nmol/rat) intraperitoneally to rats, which were fed simultaneously three macronutrient diets (carbohydrate, protein and fat), and measured food intakes at 1, 2 and 4hr after infusion. Infusions of ghrelin increased dose-dependently total food intake compared with saline infusion. Infusion of ghrelin increased significantly carbohydrate intake, although protein and fat intakes did not altered. Serum glucose, total protein, albumin, triglyceride, free fatty acid and β-lipoprotein levels were did not altered with infusion of ghrelin. This study defined that ghrelin infusion increased selectively carbohydrate intake without metabolic changes. This result suggests that ghrelin may participate directly with the selective control of carbohydrate intake.

Background Population-based cohort studies demonstrate that metabolic syndrome (MeS) is associated with increased risk for cardiovascular diseases and related mortalities. The present study was designed to investigate the prognostic impact of MeS in patients with acute myocardial infarction (AMI). Methods and Results The study group was 461 AMI patients without a history of previous myocardial infarction. On the basis of the National Cholesterol Education Program Adult Treatment Panel III criteria, MeS was defined having at least 3 of the following 5 conditions: dysglycemia (impaired fasting glucose, current use of insulin or oral hypoglycemic drugs), hypertriglyceridemia, low high-density lipoprotein-cholesterol level, hypertension and obesity. The prevalence of MeS was 37% (n=172). C-reactive protein (CRP) levels increased with the increase in the number of conditions of MeS. During follow-up at a median of 17.6 months, the incidence of major adverse cardiovascular events (MACE) was significantly different between patients with and without MeS. Furthermore, after adjustment of predictive factors (age, sex, Killip class, multivessel coronary artery disease, low ejection fraction and high CRP level), MeS was an independent risk factor for MACE. Conclusions In patients with AMI, MeS is associated with systemic inflammation and is an important predictor for MACE, which suggests the need for early identification and medical intervention for secondary prevention of MeS. (Circ J 2008; 72: 415 ‐ 419)

Background:The epidemiology of short QT interval remains unclear. We attempted to determine the incidence and clinical characteristics of short QT interval in a longitudinal cohort study. Methods:A total of 19,153 subjects (7,525 male, 11,628 female) were enrolled in the study and all available electrocardiograms (ECGs) were investigated longitudinally from 1958 through 2003. We defined short QT interval as QTc of less than 350 ms. Results:Of the 19,153 subjects, two met the criteria of short QT interval and allowed for prevalence and incidence estimates for short QT interval as 0.01% and 0.39/100,000 person-years, respectively. Both cases had neither a family history of sudden cardiac death, nor a history of drug use that might have affected for QT interval. Case 1 was a female with history of ischemic heart disease. Case 2 was a 60-year-old male who exhibited a short QT interval for the first time when he was 26 years of age. He had sick sinus syndrome as an underlying heart disease. Conclusions:Of the 19,153 subjects in this study, none were identified as having the short QT syndrome, with associated high risk of ventricular tachyarrhythmia, atrial fibrillation, and sudden death. Two subjects were identified as having QTc of less than 350 ms, and allowed prevalence and incidence estimates to be made of short QT interval. There observations were suggestive of clinical relationships between short QT interval and organic or electrophysiological heart disease.

Background While recent reports suggest that both flow-mediated vasodilation (FMD) in the brachial artery (BA), endothelium-dependent vasodilatation, and intima media thickness (IMT) in the carotid artery correlate with the extent of coronary artery disease (CAD), it is not clear which modality is a better predictor for CAD severity and whether either of these modalities are superior to conventional ST-segment depression in exercise stress electrocardiogram (ECG). Thus, the goal of the present study was to compare the predictive value of FMD and IMT for CAD severity and to evaluate the diagnostic accuracy. Study A total of 103 consecutive patients (62±9 years, 79 men) with clinically suspected CAD underwent FMD and nitroglycerin-induced dilation (NTG-D) in the BA as well as measurement of carotid artery IMT by using high-resolution ultrasound, and exercise treadmill testing. Coronary stenosis index (CSI) was calculated from coronary angiography. Results Seventy-three patients had significant CAD, and 30 patients showed no CAD (NL). FMD was significantly lower and IMT was significantly higher in patients with CAD compared with NL patients (FMD, 3.7±3.0% vs. 7.5±2.9%; IMT, 1.1±0.2 mm vs. 0.7±0.1 mm). FMD and IMT correlated to CSI to a similar degree ( r =−0.67, r =0.69, respectively), and there was a significant correlation between FMD and IMT. In contrast, NTG-D did not correlate with CSI or IMT. Further, the diagnostic accuracy of FMD and IMT was comparable or even better than that obtained with conventional ST-segment depression during exercise in this cohort. Conclusions FMD in BA and IMT could represent a surrogate diagnostic method for assessment of CAD severity.

T-wave changes are thought to be associated with the repolarization phase of myocardial action potential. Although it has been known that persistent T-wave change is associated with the heart disease or the prognosis, the sensitivity and the specificity are not necessarily satisfactory for clinical therapeutic strategy. Recent basic studies have shown that, in some kinds of pathological states, transient repolarization changes of myocardial action potential were associated with life-threatening arrhythmia. Also clinical studies are being conducted to elucidate the clinical implication of transient T-wave changes on electrocardiography (ECG) in such an arrhythmia. Transient repolarization or T-wave change is thought to occur because of environmental or neurohumoral factors, circadian variation, stretching of myocardium or other triggers in daily life, resulting in fatal arrhythmia. Such fatal arrhythmias are thought to occur under restricted conditions even in the patients with serious heart disease. It is important to clarify and utilize the transient T-wave change directly associated with the fatal arrhythmia on a clinical basis. In this article, we first assess the mechanisms of transient repolarization or T-wave changes on ECG concerning fatal arrhythmia, and afterwards refer to possible attempts at clinical evaluation and application.

Background: Our study was planned to investigate the relationship between plasma levels of serum amyloid A protein (SAA) concentrations and the subsequent left ventricular systolic function in patients with acute myocardial infarction (AMI) treated with primary coronary angioplasty. Methods and Results: Reperfusion by primary percutaneous coronary intervention was successful in 486 consecutive AMI patients who were admitted within 12 hours of onset. Plasma SAA concentrations were evaluated 24 hours after onset. Left ventricular (LV) function was serially determined by left ventriculography performed in the acute (soon after recanalization) and chronic phases (6 months after onset). (I) There was no significant correlation between SAA concentration and acute phase left ventricular ejection fraction (LVEF) or regional wall motion (RWM). (II) The SAA concentration was significantly correlated with both highly sensitive C-reactive protein (hs-CRP) and the peak-CK value (hs-CRP: r = 0.69, P < 0.0001, peak-CK: r = 0.21, P = 0.0003). (III) SAA was significantly negatively correlated with both LVEF and RWM in the chronic phase (LVEF: r = -0.42, P = 0.001; RWM: r = -0.41, P = 0.007). (IV) The plasma level of SAA also showed a significant negative correlation with the differences in LVEF between the 2 stages (delta-LVEF) (r = -0.43, P = 0.02). Conclusion: In the setting of AMI, plasma SAA concentrations may be closely related to subsequent left-ventricular systolic dysfunction.

Morning blood pressure (BP) level plays an important role in the incidence of cardiovascular disease. Recently, Kario, et al proposed the usefulness of ME difference (morning minus evening systolic BP) and ME average (average of morning and evening systolic BP) for the evaluation of antihypertensive treatment. Cilnidipine is a novel calcium channel blocker (CCB) that exerts inhibitory actions not only on L-type but also on N-type calcium channels. We investigated the effect of bedtime administration of cilnidipine (10 mg) in addition to the antihypertensive treatment for uncontrolled morning hypertension. Twenty-three hypertensive outpatients (13 males and 10 females; mean age, 66.9 years) with stable antihypertensive medication and uncontrolled morning BP were studied using self-measured BP monitoring in the morning and evening. Morning SBP (P < 0.001) and DBP (P < 0.001) decreased significantly from 150.2 +/- 8.7 and 87.8 +/- 9.3 to 132.7 +/- 7.4 and 77.5 +/- 8.5 mmHg, respectively, after the addition of cilnidipine. Morning heart rate did not change (63.3 +/- 7.0 to 64.1 +/- 9.4). The evening SBP, but not DBP, decreased significantly after treatment. Both the ME average (P < 0.001) and ME difference (P < 0.01) significantly decreased from 143.0 +/- 9.2 and 14.3 +/- 12.4 to 131.3 +/- 7.2 and 2.8 +/- 9.2 mmHg after treatment, respectively. The microalbuminuria decreased from 39.6 +/- 13.2 to 27.3 +/- 8.4 mg/g Cr. In conclusion, L-/N-type CCB cilnidipine may be useful for patients with uncontrollable morning hypertension by reducing both ME average and ME difference.

Relationships between fatty liver and coronary heart disease (CHD) and stroke risk remain ill defined. We investigated whether fatty liver is a predictor of CHD and stroke risk. Until December 2000 we followed 2,024 atomic bomb survivors (775 men: 62.0 +/- 9.9 years old; 1,249 women: 63.2 +/- 8.4 years old) who had basic examinations between November 1990 and October 1992 for clinical and laboratory CHD risk factors and fatty liver and who were initially free of CHD and stroke. Forty-nine cases of CHD and 84 cases of stroke were observed. At the time of the baseline examinations, significant clinical associations were found between fatty liver and obesity (p

This case-control study was designed to assess the incidence and mortality of complete left bundle branch block (LBBB). We investigated 17,361 subjects (6,663 men and 10,698 women) who underwent biennial health examinations, including electrocardiography and cardiothoracic ratio measurements from 1958 to 2002. A total of 110 incident LBBB cases (41 men and 69 women) were observed, and their basic characteristics were compared with those of 456 age- and gender-matched controls (156 men and 300 women). Also, the possible association between LBBB and all-cause and cause-specific mortality was examined using a Cox proportional hazard model adjusted for age, gender, and underlying disease. The average age at LBBB diagnosis was 69.6 +/- 10.0 years in men and 68.3 +/- 10.9 years in women, and the incidence of LBBB increased progressively with age. Also, underlying disease, hypertension, and ischemic heart disease were significantly associated with LBBB. The cardiothoracic ratio was significantly different at the diagnosis of LBBB between those with LBBB and controls. Electrocardiographic manifestations before LBBB diagnosis included a higher rate of left ventricular hypertrophy and ST-T abnormalities in patients with LBBB. On Cox analysis, LBBB did not predict for all-cause mortality, but it did predict for mortality from congestive heart failure. In conclusion, the mean patient age at LBBB diagnosis was relatively elderly, and the LBBB incidence increased progressively with advancing age. Hypertension, ischemic heart disease, left ventricular hypertrophy, ST-T abnormalities, and an increased cardiothoracic ratio were associated with LBBB. LBBB predicted for mortality from heart failure but not for all-cause mortality, independent of age, gender, and underlying disease.

We examined whether central nitric oxide is involved in blood pressure (BP) regulation in deoxycorticosterone acetate (DOCA)-salt hypertension. DOCA-salt rats were intracerebroventricularly infused (ICV) NG-monomethyl L-arginine (L-NMMA) for 4 weeks at either low (0.08 mg/kg/d; n = 8) or high (0.16 mg/kg/d; n = 8) dose. Saline ICV (n = 9) and intraperitoneal infused L-NMMA (low, n = 6; high dose, n = 6) were served as controls. Also, L-NMMA ICV (low, n = 6; high dose, n = 6) was conducted in normal rats. At week 3 and after, DOCA-salt with low L-NMMA ICV showed a higher BP than saline ICV (at week 4: 167.4 +/- 3.6 vs. 150.3 +/- 3.9 mm Hg, P < 0.01); this difference of BP was cancelled after ganglionic block. High L-NMMA ICV did not affect the trend of BP; however, it caused a reduced amount of saline drinking and a less estimated sodium retention than saline or low L-NMMA ICV (for 3 wk; 47.5 +/- 1.1 vs. 66.0 +/- 3.7 and 61.7 +/- 2.5 mmol, P < 0.01). In normal rats, high, but not low, L-NMMA ICV elevated BP with no effect on drinking behavior. Intraperitoneal infused L-NMMA did not affect the development of hypertension and/or sodium balance. These data suggested that, in DOCA-salt, central nitric oxide is involved in BP regulation through the dual action on sympathetic nervous activity and sodium balance.

Elevated coagulative molecular markers could reflect the prothrombotic state in the cardiovascular system of patients with non-valvular atrial fibrillation (NVAF). A prospective, cooperative study was conducted to determine whether levels of coagulative markers alone or in combination with clinical risk factors could predict subsequent thromboembolic events in patients with NVAF.Coagulative markers of prothrombin fragment 1+2, D-dimer, platelet factor 4, and beta-thromboglobulin were determined at the enrollment in the prospective study.Of 509 patients with NVAF (mean age, 66.6 +/- 10.3 years), 263 patients were treated with warfarin (mean international normalized ratio, 1.86), and 163 patients, with antiplatelet drugs. During an average follow-up period of 2.0 years, 31 thromboembolic events occurred. Event-free survival was significantly better in patients with D-dimer level150 ng/ml than in those with D-dimer levelor==150 ng/ml. Other coagulative markers, however, did not predict thromboembolic events. Age (or==75 years), cardiomyopathies, and prior stroke or transient ischemic attack were independent, clinical risk factors for thromboembolism. Thromboembolic risk in patients without the clinical risk factors was quite low (0.7%/year) when D-dimer was150 ng/ml, but not low (3.8%/year) when D-dimer wasor==150 ng/ml. It was5%/year in patients with the risk factors regardless of D-dimer levels. This was also true when analyses were confined to patients treated with warfarin.D-dimer level in combination with clinical risk factors could effectively predict subsequent thromboembolic events in patients with NVAF even when treated with warfarin.

Introduction: Although prolonged and fractionated right atrial electrograms have been reported as predictors of the development of chronic atrial fibrillation in patients with paroxysmal atrial fibrillation (PAF), the effects of angiotensin-converting enzyme inhibitor (ACEI) on these electrophysiologic abnormalities remain unknown. The purpose of this study was to evaluate whether ACEI influences these electrophysiologic abnormalities of atrial muscle in patients with PAF. Methods: While taking oral ACEI for hypertension, 12 patients (ACEI group) with PAF underwent electrophysiologic study (EPS). Catheter mapping of 12 right atrial sites and right atrial extrastimulation were performed during sinus rhythm. Twenty-four age-matched patients with PAF but not taking oral ACEI were included as a control group. Results: The longest duration of the right atrial electrogram was significantly shorter and the maximum number of fragmented deflections per patient was significantly lower in the ACEI group than in the control group (79 ± 15 ms vs 100 ± 15 ms, P < 0.005; 5.5 ± 1.9 vs 7.9 ± 2.4, P < 0.001, respectively). The number of abnormal atrial electrograms per patient was significantly lower in the ACEI group than in the control group (0.5 ± 1.4 vs 2.1 ± 1.8, P < 0.05). The percentage of patients with at least one abnormal atrial electrogram was significantly lower in the ACEI group than in the control group (16.7% vs 79.2%, P < 0.0005). Conclusions: ACEI use is associated with a decrease in the incidence of prolonged and fractionated right atrial electrograms in patients with PAF. In addition, we suggest that ACEI may help prevent PAF from becoming chronic.

A 24-year-old pregnant woman with Marfans syndrome delivered by cesarean section during the 38th week of gestation. Although aortic root dilatation did not increase during pregnancy, three months after delivery, the patient noticed a pulsatile abdominal mass. Aortic aneurysm was diagnosed and surgical replacement of the infrarenal abdominal aorta to the common iliac arteries and reconstruction of the inferior mesenteric artery were performed. Moreover, the patient subsequently developed a Stanford type B thoracic aortic dissection, even after more than four months of β-blockade., Internal Medicine, vol.45(22), pp.1285-1289; 2006

The aim of this study was to conduct a longitudinal follow-up on age-related changes in 24-hour total heart beats (THBs) and total premature beats and their correlations in healthy elderly subjects. In 15 healthy elderly subjects (mean age, 70.0 +/- 4.1, age range at 1st recording, 64 to 80 years, 10 females, 5 males), we conducted Holter monitoring twice at an interval of 15 years and analysed age-related changes in THBs, atrial premature beats (APBs), and ventricular premature beats (VPBs), as well as their correlations. The results indicated that THBs, APBs, and VPBs all significantly increased with age in the healthy elderly subjects at a mean age of 70.0 +/- 4.1 (THB: 91074.1 +/- 11515.3 versus 99457.5 +/- 12131.0; P = 0.0004, APB:119.2 +/- 97.8 versus 884.4 +/- 1193.8; P = 0.0008, VPB: 15.2 +/- 53.6 versus 140.7 +/- 228.9; P = 0.0328). Moreover, we divided the subjects into increase and nonincrease groups based on the age-related changes in APB and VPB for 15 years ([n]; Inc-APB: Noninc-APB = 6 : 9, Inc-VPB: Noninc-VPB = 5 : 10). In the increase groups, premature beats tended to increase in proportion to changes in THBs with age (APB: Y = 207.488 + 0.136 X, r = 0.848, P = 0.0303; VPB: Y = -27.594 + 0.028 X, r = 0.727, P = 0.1921). In conclusion, this 15-year follow-up of Holter recordings in healthy elderly subjects revealed that THBs, APBs, and VPBs increased with age, and that the increases in premature beats, especially APBs, were in proportion to those in THBs.

Few epidemiological studies have been conducted on the prevalence, blood pressure trends by age, and basic characteristics of chronic hypotension. Among 13,370 subjects (5,094 men and 8,276 women) examined from 1958 to 1999 in Japan, 92 were identified as chronic hypotensives (11 men and 81 women) whose systolic blood pressure (SBP, mmHg) was lower than 100 mmHg for 8 or more years. Trends of SBP and body mass index (BMI, kg/m2) were determined over a 16-year period in this group of chronic hypotensives and 276 age- and sex-matched controls (33 men and 243 women); during this 16-year period, the chronic hypotensives and controls ranged in age from 19 to 75 years. BMI, heart rate (HR, bpm), body temperature (degrees C), Hb (g/dl), and creatinine (Cre, mg/dl) were compared between the chronic hypotensives and the controls at the last examination. The chronic hypotensives had a female preponderance (0.2% in men and 1.0% in women, p=0.001), and their SBP and BMI increased little with increasing age. BMI (20.2+/-3.4), BMI-adjusted SBP (101+/-19), HR (63+/-10), body temperature (36.7+/-0.3), Hb (12.5+/-1.1), and Cre (0.81+/-0.13) were lower in the chronic hypotensives than those (22.9+/-3.4, 126+/-20, 68+/-10, 36.8+/-0.3, 12.9+/-1.1, and 0.86+/-0.12, respectively) in controls (p

BACKGROUND The aim of the present study was to identify the relationship between sub-acute stent thrombosis (SAT) and acute-phase inflammatory reactants, such as high-sensitivity C-reactive protein (hs-CRP) and serum amyloid-A protein (SAA), in patients with acute myocardial infarction (AMI) successfully treated with primary coronary stenting. METHODS AND RESULTS The 381 consecutive AMI subjects were reperfused by primary coronary stenting within 24 h of onset. SAT was confirmed angiographically in 10 patients (2.6%). There were no significant differences between the patients with or without SAT in terms of patient characteristics, Killip classification on admission, or stent diameter, nor were there significant differences between the 2 groups in terms of left ventricular function soon after stenting (left ventricular ejection fraction) or end-diastolic volume index. The plasma levels of both hs-CRP and SAA were significantly higher in the SAT patients than in the others (hs-CRP: 6.7+/-6.7 mg/dl vs 3.3+/-3.8 mg/dl, p=0.007; SAA: 699+/-812 mug/dl vs 208+/-273 mug/dl, p

We report a case of a 58-year-old man with Shoshin beriberi who demonstrated ST-segment elevation and myocardial damage without coronary artery stenosis. The patient subsequently recovered with thiamine treatment. We conclude that it is important to consider Shoshin beriberi as part of the differential diagnosis in patients with shock and ST-segment elevation., Internal Medicine, vol.44(6), pp.578-585; 2005

Background The aim of the present study was to investigate the relationship between plasma concentrations of endothelin (ET)-1 and clinical outcome (including mortality) and left ventricular (LV) systolic function in acute myocardial infarction (AMI). Methods and Results The study group comprised 110 consecutive first-AMI patients who were successfully reperfused by primary coronary intervention. Plasma ET-1 concentrations were evaluated 24 h from onset and the patients were divided into 2 groups according to the median value, either a high group (H group: ≥2.90 pg/ml plasma ET-1; n=55) or low group (L group

The purpose of this study was to investigate the relationship between plasma adrenomedullin concentration levels and left-ventricular systolic function in patients with acute myocardial infarction (AMI), and to assess whether these findings can be used to predict clinical outcomes, including mortality. One hundred twenty-four consecutive first AMI attack subjects were successfully reperfused with primary percutaneous coronary intervention therapy. Plasma adrenomedullin concentrations were evaluated at 24 hours from onset. Left ventriculograms of all patients taken in the acute (soon after reperfusion therapy) and subacute (21 ±9 days after onset) phases were used to evaluate left-ventricular ejection fraction (LVEF), and the difference in LVEF (delta-LVEF) between the two stages calculated. There were significantly more patients with cardiogenic shock in the H-Adm group (above the median value of plasma adrenomedullin concentrations ≥3.5 Fmol/mL) than in the L-Adm (

Although no-reflow phenomenon may occur in patients that experience reperfusion after ischemia, there have been no reports describing the postmortem findings in these patients. We describe the findings of an autopsy in a 56-year-old man who experienced acute coronary syndrome with no-reflow phenomenon after coronary intervention. Macroscopic study demonstrated myocardial infarction with diffuse hemorrhage, and microscopic analysis revealed vascular damage and microembolization in the no-reflow area. In conclusion, coronary microembolization and damage to the small coronary artery may contribute to the pathogenesis of no-reflow phenomenon following coronary intervention in humans.

Background Although cardiogenic shock (CS) is the leading cause of death for acute myocardial infarction (AMI) patients, reliable predictive factors in the acute stage, such as cardiovascular peptides, have not yet been identified. Methods and Results In 42 consecutive AMI patients with CS on admission, successfully treated by primary percutaneous coronary intervention (PCI) within 12 h of onset, related factors including brain natriuretic peptide (BNP), atrial natriuretic peptide (ANP), renin, aldosterone, catecholamines, and adrenomedullin, were investigated 24 h from onset, as well as the 1-year mortality rates. During the 12-month follow-up period, 15 patients died from cardiovascular causes (group D). There were no significant differences in patient characteristics, angiographic findings, and left ventricular systolic function between group D subjects and the survivors (group S: n=27). Multivariate analysis identified high levels of adrenomedullin as an independent predictor of 1-year mortality (risk ratio: 6.42, 95% confidence interval, 1.49-43.31, p

Background Fibrosis, as well as myocyte hypertrophy, is the major determinant of prognosis in hypertrophic cardiomyopathy (HCM). Valsartan, an angiotensin II type 1 receptor blocker, may improve myocardial fibrosis in patients with HCM. Methods and Results Twenty-three patients with HCM were randomly divided into 2 groups: 11 patients had valsartan added to conventional treatment (V group) and 12 patients received the conventional therapy (C group). Plasma concentrations of brain natriuretic peptide (BNP), troponin T (TnT), aldosterone (ALDO), procollagen type I (PIP) and procollagen type III aminoterminal peptide (PIIINP) were measured before and 12 months after this study. Left ventricular wall thickness (LVWT) and ejection fraction (LVEF) were measured by echocardiography. PIP was decreased in the V group (123.2±63.1 ng/ml to 102.8±37.6, p

The objective of the present study was to compare left ventricular (LV) function and clinical outcomes in diabetics versus nondiabetics with acute myocardial infarction (AMI) treated by primary coronary angioplasty. A total of 327 consecutive AMI subjects were reperfused by primary coronary angioplasty within 12 hours from onset. Diabetes mellitus (DM) was present in 104 of the 327 patients. LV function was serially determined by left ventriculograms taken in the acute and chronic phases (6 months after onset). (I) The early ST-segment resolution rate was lower in DM patients compared with non-DM patients (59% versus 83%, P < 0.0001). (II) During a 6-month follow-up, the percentages of target vessel revascularization (TVR), coronary aorta bypass grafting (CABG), and cardiac death were higher in the DM patients compared with the non-DM patients (TVR: 29% versus 19%; P < 0.05, CABG: 10% versus 5% ; P < 0.05, cardiac death: 12% versus 4%; P = 0.01). (III) The differences in left ventricular ejection fraction (LVEF) between two stages (delta-LVEF) were significantly lower in the DM patients than the non-DM patients (1 +/- 9% versus 7 +/- 10%, P < 0.0001). (IV) Multivariate analysis identified DM as an independent predictor of cardiac death (Odds ratio 5.5, 95% CI, 1.3-23.7, P < 0.05) and as a sole independent predictor of LVEF deterioration (Odds ratio 5.8, 95% CI, 2.8-11.8, P < 0.001). In patients with AMI treated using primary coronary angioplasty, DM is closely related to left-ventricular systolic dysfunction and a poor patient outcome, including mortality.

Physical or mental exertion is an important antecedent to dissection. A fall is one of the causes of hip fracture in the elderly population. We report the case of a 78-year-old woman who was diagnosed to have a thrombosed aortic dissection after a fall. We wish to emphasize with this case report that aortic dissection should be considered in the differential diagnosis of patients who complain of chest discomfort after a tumbling over., Internal Medicine, vol.44(6), pp.603-606; 2005

Summary Background: Carotid intima-media thickness (IMT), pulse wave velocity (PWV), and the ankle brachial index (ABI) are widely used noninvasive modalities for evaluating atherosclerosis. Hypothesis:The aim of this study was to determine the relationship of carotid IMT, PWV, and ABI with the severity of coronary artery disease (CAD), expressed as the Gensini score, and the presence of coronary risk factors. Methods: We examined 205 consecutive patients (mean age 65 ± 12 years) who were clinically suspected of having CAD and were scheduled to undergo coronary angiography. Carotid intima-media thickness, brachial-ankle PWV (baPWV), and ABI were measured in all subjects before they underwent coronary angiography. Results:Of the 205 patients, 124 patients were diagnosed as having CAD based on the presence of > 50% stenosis in a major coronary artery; the remaining 81 patients did not have CAD. A relatively good correlation was obtained between carotid IMT and the Gensini score (R = 0.411, p < 0.0001), whereas baPWV correlated only weakly with the Gensini score (R = 0.203, p = 0.0035), and ABI did not correlate with it. A multiple regression analysis revealed that the Gensini score correlated significantly and independently with age, male gender, and carotid IMT. Conclusions: Of the three noninvasive methods, carotid IMT may be more useful for determining coronary artery atherosclerosis than baPWV or ABI.

The aim of this study was to investigate whether risk factors for embolism would promote thrombus formation in patients with nonvalvular atrial fibrillation (NVAF).Hemostatic markers for platelet activity (ie, platelet factor-4 and beta-thromboglobulin [TG]), thrombotic status (ie, prothombin fragments 1 and 2), and fibrinolytic status (ie, d-dimer) were determined in 246 patients with NVAF (mean age, 66.1 years) and 111 control subjects without NVAF (68.3 years).The beta-TG level was higher in NVAF patients than in control subjects. D-dimer levels were higher in NVAF patients having risk factors (mean [+/- SE] d-dimer level, 158.6 +/- 9.2 ng/mL) than in those without risk factors (mean d-dimer level, 92.1 +/- 6.7 ng/mL; p0.01) and in control subjects (mean d-dimer level: control subjects with risk factors, 79.1 +/- 10.3 ng/mL; control subjects without risk factors, 31.0 +/- 7.4 ng/mL; p0.01). NVAF (odds ratio [OR], 3.94; 95% confidence interval [CI], 1.87 to 8.30; p = 0.0003) and age of/= 75 years (OR, 5.68; 95% CI, 2.87 to 11.23; p0.0001) emerged as predictors of elevated levels of d-dimer, and only NVAF (OR, 10.30; 95% CI, 5.67 to 18.72; p0.0001) emerged as a predictor of elevated levels of beta-TG.NVAF patients whose conditions were complicated with risk factors for embolism could be in the prothrombotic state. Advanced age is a strong predictor of the prothrombotic state in NVAF patients.

Although electrophysiological abnormalities of atrial muscle have been evaluated in patients with paroxysmal atrial fibrillation (PAF), no prior study has determined the contribution of the patient's history of PAF to electrophysiological abnormalities. The study population consisted of 108 patients (71 men; mean age, 57 +/- 14 years) with symptomatic and idiopathic PAF who underwent electrophysiological study. Before electrophysiological study, histories of frequency, number of PAF episodes per month, and duration, a time interval from the first episode of PAF to electrophysiological study, were examined. At electrophysiological study, endocardial electrograms from 12 right atrial sites were recorded during sinus rhythm, and the right atrial effective refractory period was determined. Longest duration of atrial electrograms, maximal number of fragmented deflections, and number of abnormal atrial electrograms recorded at the right atrial sites were significantly greater in the frequent group (> 1 PAF episode per month, n = 57) than in the infrequent group (< 1 PAF episode per month, n = 51) (98 +/- 18 ms vs 88 +/- 16 ms, P < 0.005; 8.7 +/- 2.6 vs 7.5 +/- 2.6, P < 0.05; and 2.2 +/- 2.2 vs 1.4 +/- 1.6, P < 0.05, respectively). Indices of atrial vulnerability were also greater in the frequent group. Duration of PAF history was significantly correlated with longest duration r = 0.52, P < 0.0001), maximal number of fragmented deflections r = 0.51, P < 0.0001), and number of abnormal atrial electrograms r = 0.58, P < 0.0001). More frequent episodes and longer history of PAF significantly increased the electrophysiological abnormalities of the atrial muscle, suggesting that PAF results in gradual electrical remodeling of the atrial muscle.

Introduction: The Brugada-type ECG, a terminal r′ wave accompanied by ST segment elevation in the right precordial leads, is not a very rare condition. Most of the cases are men in Japan and elsewhere; however, information about the clinical features of these cases is lacking. The aim of this study was to determine the clinical characteristics of subjects with the Brugada-type ECG, specifically Japanese men. Methods and Results: We extracted male Brugada-type ECG cases from 3,374 men followed biennially from 1958 through 2001 in Nagasaki, Japan, and compared the clinical characteristics at diagnosis between these cases and four age-matched male controls for each case. A total of 34 cases with the Brugada-type ECG were observed during follow-up. Body mass index (BMI) at diagnosis was significantly lower in Brugada-type ECG cases than in 136 controls (20.2 ± 2.1 kg/m2 vs 21.8 ± 2.8 kg/m2, P = 0.003). The BMI trend in cases was always lower than that in controls throughout the 8-year observation period (from 4 years before diagnosis to 4 years after diagnosis). Pulse rate at diagnosis was also somewhat lower in Brugada-type ECG cases than in controls (68.9 ± 7.7 beats/min vs 72.7 ± 11.1 beats/min, P = 0.038). The significance disappeared after controlling for BMI (P = 0.131) or body weight (P = 0.153). Conclusion: The cases with the Brugada-type ECG had lower BMI than controls, leading to a clue to possible basic mechanisms of the Brugada-type ECG with a focus on this association. (J Cardiovasc Electrophysiol, Vol. 15, pp. 1-5, June 2004)

The aims of this study were to elucidate the molecular mechanism by which growth hormone (GH) excess is anti-fibrotic in vitro and in vivo model. The in vivo model GH excess showed a significant increase of relative wall thickness with no concomitant disturbance of cardiac diastolic function. Western blot for extracellular matrix (ECM) structural proteins showed minimal change in the GH treatment group, compared to an Angiotensin II (Ang II) subpressor dose group. In cultured cardiac fibroblasts, we investigated the abundance of ECM proteins, phosphorylation of p38 mitogen-activated protein kinase (MAPK), and transforming growth factor-beta (TGF-beta)-specific transcriptional activity. GH down-regulated the expression of PAI-1 and fibronectin proteins activated by TGF-beta. In reporter assays, GH, but not insulin-like growth factor-1 (IGF-1), reduced TGF-beta-specific transcriptional activity. Moreover, GH markedly down-regulated TGF-beta-induced phosphorylation of p38 MAPK. These results demonstrated that a chronic excess of GH have an anti-fibrotic effect on cardiac remodeling, probably through a down-regulation of TGF-beta signaling via de-phosphorylation of p38 MAPK.

Pulse wave velocity (PWV) is an index of arterial stiffness, and a simple device for measuring brachial-ankle PWV (baPWV) has recently been developed. However, the clinical application of baPWV in patients with coronary artery disease (CAD) remains to be fully evaluated. This cross-sectional study was conducted to evaluate whether a higher baPWV predicts the presence of CAD. The baPWV was measured in 123 patients (77 males, 46 females; 63.5+/-11.8 years) who were undergoing coronary angiography. CAD was defined as >50% diameter stenosis. Hemodynamic data and cardiovascular risk factors were examined according to the presence or absence of CAD. Patients with CAD were significantly older across both sexes. The presence of hypertension and chest pain, but not baPWV, was correlated with CAD in females. The baPWV, and the presence of diabetes, hyperlipidemia, and chest pain were related to the presence of CAD in males. Multivariate logistic regression analysis in male patients showed that baPWV, diabetes, hyperlipidemia, and chest pain were independent risk factors for the presence of CAD. Furthermore, high baPWV in males with or without chest pain had a positive predictive value of 81.8% and 71.7% for the presence of CAD, respectively. In conclusion, high baPWV was shown to be a good independent predictor for the presence of CAD in men.

BACKGROUND Elevation of hemostatic markers may account for the increased risk of ischemic stroke in patients with non-valvular atrial fibrillation (NVAF). The aim of this study was to determine the effects of anticoagulation intensity on hemostatic markers in patients with NVAF. METHODS AND RESULTS In 509 patients with NVAF, comprising 263 patients treated with warfarin and 246 patients without warfarin, the hemostatic markers of prothrombin fragment F1.2 (F1.2), fibrin D-dimer, platelet factor 4 (PF4), and beta-thromboglobulin were determined and compared with those in 111 patients with sinus rhythm. F1.2 was inversely related with anticoagulation intensity and D-dimer increased with age. All hemostatic markers, except F1.2, were greater in patients with NVAF than in patients with sinus rhythm. F1.2 and D-dimer were significantly lower in patients with international normalized ratio (INR) > or =1.5 than in NVAF patients without warfarin and were not different between NVAF patients with INR of 1.5-1.9 and with INR > or =2.0. CONCLUSIONS Low intensity of anticoagulation (INR 1.5-1.9) suppresses the elevated concentration of F1.2 and D-dimer in patients with NVAF, and might be favorable in Japanese patients with NVAF in view of the balance between prevention of thromboembolism and the adverse effect by warfarin (ie, bleeding).

A 54-year-old man with severe left ventricular dysfunction due to dilated cardiomyopathy was referred to our hospital for symptomatic incessant sustained ventricular tachycardia (VT). After the administration of nifekalant hydrochloride, sustained VT was terminated. An alternate class III agent, sotalol, was also effective for the prevention of VT. However, one month after switching over nifekalant to sotalol, a short duration of ST elevation was documented in ECG monitoring at almost the same time for three consecutive days. ST elevation with chest discomfort disappeared since he began taking long-acting diltiazem. Coronary vasospasm may be induced by the non-selective β-blocking properties of sotalol., Internal Medicine, vol.43(11), pp.1051-1055; 2004

To investigate the distribution of autonomic nerves in the human heart, six autopsied hearts without cardiovascular disease were studied by a histochemical method for acetylcholinesterase (AChE) and by an immunohistochemical method for tyrosine hydroxylase (TH). The density of nerve distribution was microscopically calculated by the point-counting method to evaluate regional distribution of the autonomic nerves. There were more AChE-positive nerves and TH-positive nerves in the atrium than in the ventricle, and more at the base than at the apex in the ventricle. There were more AChE-positive nerves in the subendocardial area than in the subepicardial area of the myocardium. In the atrium, AChE-positive nerves were more numerous than TH-positive nerves. On the other hand, there were more TH-positive nerves than AChE-positive nerves in the ventricle. Predominancy of the distribution density at the anterior to the posterior wall of the ventricle was observed for TH-positive nerves. The different distribution patterns of sympathetic and parasympathetic nerves could modify cardiac performance under both physiologic and pathologic conditions.

Two brothers had familial hypertrophic cardiomyopathy and vasospastic angina pectoris concurrently. Their family history showed that one of their sisters had hypertrophic cardiomyopathy and another brother died suddenly at age 52. The clinical diagnosis of hypertrophic cardiomyopathy was confirmed by an echocardiogram and left ventriculography. They had typical chest pain at rest, and a significant vasospasm of coronary arteries with chest pain and obvious ST-T changes in the electrocardiograms was provoked by intracoronary injection of acetylcholine in both patients. The administration of a calcium antagonist and nitrate was effective for ameliorating chest pain with no cardiovascular events during the follow up period of more than 3 years. Although underlying pathophysiologic abnormalities of familial hypertrophic cardiomyopathy and vasospastic angina pectoris are considered to be transmitted genetically, the genetic backgrounds of these cases remain to be clarified.

We report a case of hypercalcemia in an elderly patient due to vitamin D intoxication with clinical features and electrocardiogram (ECG) findings mimicking acute myocardial infarction. A 78-year-old man was referred to our department with symptoms of general fatigue, anorexia and chest pain. The ECG demonstrated ST elevation in leads V1 to V3 and diffuse T wave flattening, resulting in myocardial infarction being suspected. However, his symptoms, including chest pain, gradually improved and the ECG returned to normal in accordance with a fall in his serum calcium level. We introduce the use of QaTc interval shortening in differentiating ST-T changes of hypercalcemia from those of true myocardial ischemia.

A 71-year-old Japanese woman presented with a chief complaint of throbbing sensations in the abdomen. When she was 16 years old, she was exposed to atomic radiation since she was 1.2 km away from the drop zone of the Nagasaki atomic bomb. Abdominal CT performed at the age of 61 revealed the presence of localized calcification below the renal artery, together with abdominal aortic aneurysms measuring 4.9 cm in maximum diameter. Since the abdominal aortic aneurysms enlarged in May 2000, the patient was admitted to our department for further examinations and treatment on July 7. Although the patient did not complain of thoracic symptoms, cardiac catheterization revealed the presence of multiple coronary artery aneurysms and severe stenosis in the main trunk of the left coronary artery and proximal regions of the right coronary artery, together with a complicated collateral circulation course. Coronary artery aneurysms were localized similar to the abdominal aortic aneurysms, and were complicated by severe calcification and obstructive lesions. Coronary arterial bypass grafting was performed after the severity of the coronary artery aneurysms was morphologically evaluated. The course of the abdominal aortic aneurysms was followed without surgical treatment. Although the etiology of the aneurysm formation in this patient was investigated, it remained unclear.

In order to clarify the basic mechanism(s) linking radiation exposure and coronary heart disease (CHD), we here collected ultrasonographic data on fatty liver and measured levels of metabolic CHD risk factors from November 1990 through October 1992 in 1,517 Nagasaki atomic bomb survivors (575 men and 942 women). Using a cross-sectional study design, we examined the effects of radiation dose on fatty liver and CHD risk factors by means of a multiple logistic regression model. Fatty liver was related to the metabolic CHD risk factors associated with insulin resistance syndrome: obesity, hypertension, hypercholesterolemia, low high density lipoprotein (HDL)-cholesterol, hypertriglyceridemia, and abnormal glucose metabolism. Radiation dose was positively related to fatty liver, low HDL-cholesterol, and hypertriglyceridemia, whereas it had no effects on obesity, hypertension, hypercholesterolemia, or abnormal glucose metabolism. The present results suggested that radiation dose was related to 1) fatty liver, which clustered the metabolic CHD risk factors associated with insulin resistance syndrome and 2) atherogenic lipid profiles. It is suggested that these associations are involved in the basic mechanism(s) linking radiation exposure and CHD.

A 46-year-old man presented with a huge splenic artery dissecting aneurysm that had been incidentally found and was successfully resected before rupture. The histopathologic findings were compatible with segmental mediolytic arteriopathy (SMA). Simultaneous involvement of the left renal and right common iliac artery was observed. The patient was also found to have an adrenocortical adenoma, gastrointestinal stromal tumor, hepatocellular carcinoma and schizophrenia. The relationship between SMA and other accompanying diseases was discussed.

Mutation of the p53 tumor suppressor gene is recognized to be a key event in the development of the highly aggressive behavior of undifferentiated or anaplastic thyroid carcinomas. Attempts to treat these carcinomas with p53 gene therapy have, however, been largely unsuccessful. Since epigenetic changes such as histone deacetylation are associated with loss of thyroid differentiation, we have evaluated the potential of combining p53 gene therapy with exposure to the histone deacetylase inhibitor (HDAC-1), depsipeptide. We used two carcinoma cell lines: FRO cells that express very low levels of p53 and WRO cells producing a dominant negative p53. A p53 response element luciferase assay showed that stimulation of p53 transcriptional activity by the combined treatment with the HDAC-1 and p53 was 10 to 100 times greater than with p53 alone. Western blot analysis demonstrated that the HDAC-1 increased the expression of acetylated histones, as well as of p21(cip1/waf1), but did not affect levels of total histone and endogenous p53. The combined treatment was much more effective than either treatment alone in inhibiting the growth of both cell lines, and flow cytometric analysis suggested that this was due to an increase in the sub-G1 apoptotic population. Our findings indicate that HDAC-1 enhances apoptotic killing by p53 transfer, and suggest that this combination strategy may be useful in treating undifferentiated thyroid carcinomas.

Cardiac fibrosis results from proliferation of interstitial fibroblasts and concomitant increased biosynthesis of extracellular matrix (ECM) components and is often complicated by cardiac hypertrophy. This study was conducted to investigate whether norepinephrine (NE) potentiates transforming growth factor-beta (TGF-beta)-induced cardiac fibrosis. The expression of the cardiac ECM proteins, plasminogen activator inhibitor-1 (PAI-1), fibronectin, and collagen type I, was examined by Western blotting using extracts from neonatal rat primary cardiac fibroblasts. In cardiac fibroblasts, treatment with a combination of NE and TGF-beta1 increased cell proliferation and ECM expression. Luciferase assays were conducted to clarify the effect of NE on TGF-beta signaling. TGF-beta1 (1 ng/mL) increased the specific signaling activity 2-fold, whereas the combination of NE (10 micro mol/L) and TGF-beta1 (1 ng/mL) resulted in an approximate 10-fold increase in specific signaling activity. We confirmed that treatment with NE markedly enhances TGF-beta-induced phosphorylation of activating transcription factor 2 (ATF-2). These results indicated that NE has a synergistic effect on TGF-beta signaling. To determine whether this activation by NE was mediated by the TGF-beta1 receptor, we used a dominant negative vector of the TGF-beta1 type II receptor, and the synergistic effects were inhibited. Furthermore, this synergistic effect was attenuated by a specific inhibitor of p38, SB203680. These data indicate that NE enhances cardiac fibrosis through TGF-beta1 post-receptor signaling, predominantly via the p38 MAP kinase pathway.