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Objective: Debates about adverse effects of ventricular- vs. atrial-based pacing have never ended, especially regarding cardiovascular outcomes in common pacemaker populations. Methods: To investigate the contribution of right ventricular apical pacing to the left ventricular negative remodeling, we measured the inter- and intraventricular mechanical dyssynchrony by echocardiography as well as plasma N-terminal pro-brain natriuretic peptide (NT-proBNP) level in 116 consecutive patients of symptomatic bradyarrhythmias including sinus node dysfunction (SND) in 80 and atrioventricular block in 36. Dual-chamber rate-modulated pacing (DDDR) pacemakers were implanted in 76 patients (SND, 40), and single-chamber ventricular rate-modulated pacing (AAIR) pacemakers in 40 (all SND). Clinical manifestations were retrospectively correlated. Results: After 3.5 years of pacing, DDDR pacemaker patients demonstrated higher plasma NT-proBNP concentration (503 ± 111 pg/ml) than AAIR patients (194 ± 42 pg/ml, p = 0.002) despite similar cardiovascular function at baseline. Multivariate regression analysis revealed that the only predictor of the highest quartile of plasma NT-proBNP, i.e. ≧386 pg/ml, was the interventricular contraction time difference (p = 0.01). Reprograming to minimize ventricular pacing percentage in 8 patients of SND caused parallel reduction of plasma NT-proBNP. Conclusion: Interventricular mechanical dyssynchrony, imposed mostly by right ventricular apical pacing, could lead to abnormal heightening of plasma NT-proBNP concentration after chronic DDDR pacing in common pacemaker patients with normal baseline left ventricular function.

Objectives: To test the association between renin-angiotensin system gene variants and atrial fibrillation (AF) using a regression approach. Methods: A total of 1,236 consecutive patients (227 with AF and 1,009 with normal sinus rhythm as controls) were recruited. Angiotensin-converting enzyme (ACE) gene I/D polymorphism; T174M, M235T, G–6A, A–20C, G–152A and G–217A polymorphisms of the angiotensinogen (AGT) gene, and A1166C polymorphism of the angiotensin II type I receptor (AT1R) gene were genotyped. We used a regression approach based on a generalized linear model to evaluate haplotype effects and to detect gene-gene interactions by incorporating interaction terms in the model. Results: In single-locus analyses, no locus was associated with AF. After adjustment for AF risk factors, we found significant differences in the global AGT gene haplotype profile (the global score statistic = 30.364, p = 0.001) and individual haplotype frequencies between AF patients and controls. Furthermore, significant 2-way gene-gene interactions between ACE I/D polymorphism and AGT gene haplotypes and between AT1R A1166C polymorphism and AGT gene haplotypes, and 3-way interaction between ACE I/D, AT1R A1166C and AGT gene haplotypes were detected. Conclusions: These results are compatible with the concept of multilocus and multigene effects in determining the risk of complex diseases such as AF, which would be missed with conventional single-locus approaches.

There have been many reports regarding the association between renin-angiotensin system (RAS) gene polymorphisms and coronary artery disease (CAD) or acute myocardial infarction (AMI), but the results are inconsistent. In the present study, we used several new approaches with multilocus data to reappraise this issue in a large and relatively homogeneous Taiwanese population. A total of 1254 consecutive patients who underwent cardiac catheterization (735 with documented coronary artery disease and 519 without) between 1996 and 2003 were recruited. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism; T174M, M235T, G-6A, A-20C, G-152A and G-217A polymorphisms of the angiotensinogen gene; and A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In single-locus analyses, no locus was associated with CAD, history of AMI and three-vessel CAD, either with or without adjustment for conventional CAD risk factors. For multilocus analyses, we recreated a balanced population, with the controls individually matched to the cases regarding the conventional CAD risk factors. We found that the angiotensinogen gene haplotype profile was significantly different between the cases and controls (chi2=31.6, P=0.030) in haplotype analyses. Furthermore, significant three-locus (G-217A, M235T and I/D) gene-gene interactions were detected by multifactor-dimensionality reduction method (highest cross-validation consistency 10.0, lowest prediction error 40.56%, P=0.017) and many even higher order gene-gene interactions by multilocus genotype disequilibrium tests (16 genotype disequilibria exclusively found in the controls, all of which included at least two genes among AGT, ACE and AT1R genes). Our study is the first to demonstrate epistatic, high-order, gene-gene interactions between RAS gene polymorphisms and CAD. These results are compatible with the concept of multilocus and multi-gene effects in complex diseases that would be missed with conventional approaches.

Background: TheI823M polymorphism of the ATP-binding cassette transporter A1 (ABCA1) gene has been reported to affect plasmahigh-density lipoprotein cholesterol (HDL-C) level. Information about its relationship to coronary artery disease (CAD) is limited. Methods and Results: We included 205 patients with angiographically documented CAD and 201 controls from the general population. We found thatI823M polymorphism was a significant source of variation of HDL-C (p = 0.024 after adjustment for age, sex, body mass index, smoking and alcohol drinking). Subjects with M823/M823 homozygotes (n = 103) had a higher HDL-C than those with I823/I823 or I823/M823 genotype (n = 98) (50.5 ± 9.7 vs. 47.6 ± 10.1 mg/dl, p = 0.039). I823M polymorphism was not a predictor of CAD in multivariate analysis (adjusted odds ratio = 1.5 [0.9–2.5], p = 0.145). However, it interacted with low HDL-C level to increase the risk of CAD. The odds ratio of CAD with M823 homozygosity was 5.3 (2.0–20.0) in patients with HDL-C ≤35 mg/dl, but was only 1.0 (0.5–2.0) in those with HDL >40 mg/dl (p = 0.039 for interaction). Conclusions: M823 variant of the ABCA1 gene was associated with a higher HDL-C. Furthermore, I823M polymorphism interacted with low-HDL-C on the risk of CAD. It served as a marker to identify high-risk patients for CAD in subjects with low-HDL-C.

To investigate the prevalence and progression of, and identify risk factors for, pre-hypertension, stage 1 and 2 hypertension in a population-based study.A prospective cohort study.An integrated community-based multiple screening program in Keelung, Taiwan.A total of 67 011 individuals aged 20-79 years between 1999 and 2003 were included. Of these, 22 111 re-attended, yielding 53 689 repeated recordings of blood pressure, including movement between normal and pre-hypertension and progression from pre-hypertension to stage 1 or stage 2 hypertension.Blood pressure was defined and classified according to the JNC 7 Report as normal, pre-hypertension, stage 1, and stage 2 hypertension.Below 50 years of age, males had a higher progression rate, particularly from normal to pre-hypertension, than females. Annual regression rates from pre-hypertension to normal were higher in the young age group than in the old age group, particularly for females. Factors associated with the occurrence of pre-hypertension were old age, male gender, high waist circumference, abnormal blood lipids, smoking, chewing betel nuts, lack of exercise, and having parents with hypertension. Factors associated with regression from pre-hypertension to normal were body mass index, fasting glucose, high-density lipoprotein level, smoking, and parents with hypertension. Progression from pre-hypertension to stage 1 hypertension was positively related to male gender, higher waist circumference, and having parents with hypertension.The rates of progression and regression of hypertension vary with age and gender, anthropometric and biochemical measurements, and family history.

The formation of advanced glycation endproducts (AGEs) on collagen within the arterial wall may be responsible for the development of diabetic vascular injury. This study was to examine the role of aminoguanidine (AG), an inhibitor of AGEs formation, in the prevention of arterial stiffening and cardiac hypertrophy in streptozotocin (STZ) induced diabetes in rats. Diabetes was induced in animals by a single tail vein injection with 65 mg kg(-1) STZ. After confirmation of the development of hyperglycemia (2 days later), rats were treated for 8 weeks with AG (daily peritoneal injections of 50 mg kg(-1)) and compared with the age-matched untreated diabetic controls. After exposure to AG, the STZ-diabetic rats showed no alterations in cardiac output, aortic pressure profiles, total peripheral resistance, and aortic characteristic impedance. By contrast, treatment of this experimental diabetes with AG resulted in a significant increase in wave transit time (tau), from 20.4+/-0.6 to 24.7+/-0.5 ms (P0.05) and a decrease in wave reflection factor (R(f)), from 0.78+/-0.04 to 0.53+/-0.02 (P0.05). The decreased R(f) associated with the increased tau suggest that AG may retard the diabetes-induced augmentation in systolic load of the left ventricle coupled to its arterial system. Meanwhile, the diminished ratio of left ventricular weight to body weight suggests that prevention of the diabetes-related cardiac hypertrophy by AG may correspond to the drug-induced decline in aortic stiffening. Glycation-derived modification on aortic collagen was also found to be enhanced in rats with diabetes (+65.3%, P0.05) and the advanced glycation process was retarded by AG treatment. We conclude that long-term administration of AG to the STZ-treated rats imparts significant protection against the diabetes-derived deterioration in vascular dynamics, at least partly through inhibition of the AGEs accumulation on collagen in the arterial wall.

There is evidence showing that genetic factors contribute to the pathogenesis of atrial fibrillation (Af). We investigated the association between Af and polymorphisms of the connexin 40 (Cx40) gene, which is important in the electrical coupling between atrial myocytes.We performed an association study between two Cx40 single nucleotide polymorphisms (SNPs) (Cx40 -44 and +71 allele) and Af. We enrolled 173 patients with Af, and the control group consisted of 232 patients without Af. The luciferase assay was performed to evaluate the promoter activities of different Cx40 haplotypes in cultured atrial myocytes.We found that the two SNPs were both significantly associated with Af. In pairwise linkage disequilibrium analysis, the two SNPs were completely linked (Cx40 -44G always associated with Cx40 +71A; Cx40 -44A associated with Cx40 +71G, P0.001). In haplotype analysis, we demonstrated that the frequency of Cx40 (-44A,+71G) was significantly higher in the Af group than that in the control group (P0.006, odds ratio=1.514, 95% confidence interval 1.13-2.04). We also performed genotype analysis using several genetic models, finding that the recessive model showed the lowest P value (P0.004) and the largest odds ratio (2.53, 95% confidence interval 1.23-5.19). In promoter activity studies using luciferase as the reporter, Cx40 (-44A,+71G) had significantly lower promoter activity than that of the Cx40 (-44G,+71A) in atrial myocytes.The two SNPs in the promoter region of the Cx40 gene were significantly associated with Af. The Cx40 (-44A +71G) haplotype was associated with a higher risk for Af. This haplotype also had significantly lower promoter activity in atrial myocytes.

Large-scale clinical trials have demonstrated that patients with atrial fibrillation (AF), when treated with a rhythm-control strategy, are still at risk for embolic events. We hypothesized that left atrial (LA) dysfunction persisted even after successful maintenance of sinus rhythm for3 months.A total of 93 patients with AF and satisfactory rhythm control for3 months were included. Satisfactory rhythm control was defined as being free of AF based on patient-reported symptoms, monthly ECG follow-up, and ambulatory Holter ECG if needed. Among the 93 patients, 25 patients had sustained AF that was terminated by electrical or pharmacologic cardioversion, while 68 patients had paroxysmal AF under good medical control. Clinical data were obtained, and transthoracic and transesophageal echocardiography were performed after satisfactory rhythm control for3 months.Among the 93 patients, 34 patients (37%) had LA dysfunction, defined as LA appendage (LAA) peak emptying velocity40 cm/s or spontaneous echo contrast and/or thrombus in the LA or LAA. When compared to the other 59 patients without LA dysfunction, they had larger LA dimension (40 +/- 6 mm vs 36 +/- 8 mm [+/- SD], p = 0.018) but did not differ significantly regarding the left ventricular (LV) chamber size, LV ejection fraction, mitral or tricuspid inflow, and ratio of the amplitude of the waves created by early diastolic filling and atrial contraction. We also analyzed the relationship between LA function and clinical risk factors for stroke, including hypertension, diabetes mellitus, coronary artery disease, age65 years, and prior cerebral vascular accident. LA dysfunction was found in 10 of 17 patients (59%) with three or more risk factors. The odds ratio for having LA dysfunction was 3.1 (p = 0.04; 95% confidence interval, 1.1 to 9.1) when compared with patients with less than three risk factors.LA dysfunction was present in more than one third of AF patients after satisfactory rhythm control for3 months. Patients with higher burden (three or more) of clinical risk factors were more likely to have impaired LA function.

The clinical features and microbiological characteristics of 315 patients with definite or possible infective endocarditis (IE) from January 1995 to December 2003 were evaluated. There were 187 males and 128 females with a mean age of 51 years (range, 1 month to 92 years). Ninety-three patients (30%) had a diagnosis of valvular heart disease and 24 (8%) had received prosthetic valve replacement. Blood culture was negative in 62 patients (20%). Staphylococci (91 patients, 32%), including methicillin-susceptible Staphylococcus aureus (15%), methicillin-resistant S. aureus (11%), and coagulase-negative staphylococci (6%), were the most commonly encountered pathogens followed by viridans group streptococci (77 patients, 24%). Eight patients (25%) had various neurological, renal, embolic, and cardiac complications. Patients with neurological complications [odds ratio (OR) 8·175, PPPP=0·001), or elevated WBC count (>15000/mm3) (OR 2·537, P=0·007) were at significantly increased risk of mortality. This study found mortality from IE was associated with several factors, among which neurological complications were the most hazardous. Patients with more than one risk factor had poorer prognosis. These results suggest the need for more aggressive management in patients with IE when multiple risk factors for mortality are identified.

The clinical importance of white coat hypertension (WCH) remains to be clarified. This study investigated the target organ damage in Taiwanese with WCH.A total of 188 consecutive Taiwanese (88 men and 100 women), aged 26 to 75 years who had an abnormal office casual blood pressure (systolic blood pressure/= 140 mm Hg or diastolic blood pressure/= 90 mm Hg or both) and a normal ambulatory blood pressure (ABP) average (systolic ABP average140 mm Hg and diastolic ABP average90 mm Hg) at the outpatient clinic or from a mass survey were enrolled. Office casual blood pressure measurements were obtained by standard sphygmomanometric methods. Twenty-four-hour blood pressures were recorded by a commercial ambulatory pressure recorder (Del Mar Avionics, Model 1990 Pressurometer IV System). Hypertension-related target organ complications were assessed by electrocardiogram, chest X-ray, urinalysis and eye fundus examinations.Target organ damage was found in 6.4% of subjects with WCH. Roentgenographic left ventricular hypertrophy (LVH) was found in 1.1% of subjects and electrocardiographic LVH in 2.7%. Proteinuria was found in 1.6% of subjects and retinopathy in 1.1%. The frequencies of various target organ damage were not significantly associated with age, gender and the definition of normal ABP average as 135/85 mm Hg or 140/90 mm Hg.WCH represents a low-risk stratum for target organ damage in Taiwanese. These subjects should be identified and followed up regularly. The factors responsible for the low frequency of target organ damage in Taiwanese with WCH need further study.

While balloon valvuloplasty has been widely used for the treatment of congenital valvular pulmonary stenosis (PS) in children and adults, its use in elderly patients is less common. An 80-year-old woman with congenital valvular PS received valvuloplasty with double-balloon technique. Right ventricle systolic pressure and pulmonary valve systolic pressure gradient decreased from 95 to 44 mm Hg and from 75 to 35 mm Hg, respectively. Follow-up Doppler echocardiography 2 months later showed further decrease in the transvalvular systolic pressure gradient to 29 mm Hg. The patient had symptomatic relief, and no major complication was noted. Balloon pulmonary valvuloplasty can be an effective treatment for elderly patients with congenital valvular PS.

Multiple disease screening may have several advantages over single disease screening because of the economics of scale, with the high yield of detecting asymptomatic diseases, the identification of multiple diseases or risk factors simultaneously, the enhancement of the attendance rate, and the efficiency of follow-up.An integrated model of community-based multiple screening was designed and conducted between 1999 and 2001 in Keelung, Taiwan. The authors used a Papanicolaou (Pap) smear screening program as a base to integrate other screening regimens encompassing four other neoplastic diseases and three nonneoplastic chronic diseases. Screening methods, the interscreening interval, and the follow-up for each screening regimen were designed based on evidence-based literature and current national screening policy.A total of 42,387 subjects participated in the screening activities. A 25% increase in the attendance rate for Pap smear screening was demonstrated after the introduction of multiple disease screening programs. At the first screen, this program yielded a total of 677 asymptomatic neoplasms (16.0 per 1000), including a large proportion of precancerous lesions and small presymptomatic tumors without lymph node involvement. The association between the occurrence of neoplasm and the presence of comorbid nonneoplastic chronic disease was found to be statistically significant (odds ratio, 1.64; 95% confidence interval, 1.38-1.94 [P0.05]). The authors also identified 5314 subjects with metabolic syndrome who were at a greater risk for colorectal and oral neoplasias.The results of the current study demonstrate that an outreach and community-based multiple screening program not only enhances attendance rates but also has a high yield of early cases of various diseases simultaneously, and provides a natural opportunity to elucidate the correlation between neoplastic disease and nonneoplastic chronic disease.

There are many reports demonstrating the association of renin-angiotensin system gene polymorphisms with hypertension in different populations. In the present study, we used haplotype analyses of the angiotensinogen gene with a new permutation-based hypothesis testing method to determine the association between multilocus angiotensinogen gene polymorphisms and hypertension in a relatively homogeneous Taiwanese population. We also genotyped angiotensin-converting enzyme gene insertion/deletion polymorphism and angiotensin II type 1–receptor gene A1166C polymorphism to detect epistatic gene-gene interactions. There were 408 patients with hypertension (hypertensives) and 286 controls. The angiotensinogen gene haplotype frequencies were significantly different between hypertensives and controls, and this finding was only present in subjects with angiotensin-converting enzyme gene II genotypes when the analysis was stratified by genotype of this polymorphism. In addition, the angiotensinogen gene haplotype structure of hypertensives was more heterogeneous than that of controls. Our results showed that angiotensinogen gene haplotypes were associated with hypertension and might act synergistically with I allele of the angiotensin-converting enzyme gene.

Background Human minK protein is the β-subunit of I Ks potassium channel and plays an important role in cardiac cellular electrophysiology. We investigated the association between human atrial fibrillation and the polymorphism of minK gene (38G or 38S) with a case-control study. Methods We included 108 patients with atrial fibrillation and 108 control subjects. The case patients and control subjects were matched regarding age, sex, presence of valvular heart disease, and presence of left ventricular dysfunction. The genotype of minK was determined with polymerase chain reaction and restriction fragment analysis. Results The results showed an association between the minK 38G allele and atrial fibrillation. The odds ratios for atrial fibrillation in patients with 1 and 2 minK 38G alleles were 2.16 (95% CI 0.81-5.74) and 3.58 (95% CI 1.38-9.27), respectively, when compared with patients without minK 38G allele. In a logistic regression model, the odds ratio for atrial fibrillation was 1.80 (95% CI 1.20-2.71, P Conclusion We report the association between the minK 38G allele and clinical atrial fibrillation. Our findings suggest possible genetic control on the pathogenesis of atrial fibrillation. (Am Heart J 2002;144:485-90.)

We studied whether the 27 base pair (bp) tandem repeat polymorphism in intron 4 of the endothelial nitric oxide synthase (eNOS) gene was associated with coronary artery disease (CAD) in a hospital-based Taiwanese population. We included 219 consecutive patients who underwent coronary angiography at our institution. Two alleles, containing 4 (eNOS4a) and 5 repeats (eNOS4b), were identified after polymerase chain reaction amplifying intron 4 of the eNOS gene. The genotype frequencies for eNOS4b/b, eNOS4a/b and eNOS4a/a were 77.9, 21.5 and 0.6% in CAD subjects, and 80, 20 and 0% in control subjects (Fisher’s exact test, p = 0.90), respectively. The odds ratio (OR) for CAD in patients with at least one eNOSa allele was 1.2 (0.5–2.9) after adjustment for classical CAD risk factors. The eNOS4a allele was not associated with the severity of CAD (Fisher’s exact test, p = 0.90) and the occurrence of acute myocardial infarction (AMI) or unstable angina (adjusted OR 0.6, 0.3–1.6) in patients with CAD. In conclusion, the 27-bp repeat polymorphism of the eNOS gene was not associated with CAD and the occurrence of AMI or unstable angina in a hospital-based Taiwanese population.

Reports of the association of Chlamydia pneumoniae ( C. pneumoniae ) infection with coronary artery disease (CAD) are scarce in the Oriental population. We therefore conducted a case-control study to explore this issue in Taiwan. There were 242 consecutive subjects (166 men and 76 women) who underwent cardiac catheterization at the National Taiwan University Hospital Cardiac Catheterization Laboratory. Patients with CAD (n = 156) had ≥1 coronary artery lesion of >50% diameter stenosis on angiography. Controls (n = 86) had no demonstrable CAD angiographically. Antibodies to C. pneumoniae were tested by using an enzyme-linked immunosorbent assay. The prevalence of antibodies to C. pneumoniae was as follows: immunoglobulin-G (IgG), 50% (122 of 242 patients); immunoglobulin-A (IgA), 72% (176 of 242 patients); and either IgG or IgA, 79% (192 of 242 patients ). The odds ratio (OR) for CAD with either IgG or IgA was 1.4 (95% confidence interval [CI] 0.7 to 2.7, p = 0.31). After adjusting for the known CAD risk factors, the OR decreased to 0.8 (95% CI 0.3 to 2.1, p = 0.60). The OR for unstable angina or acute myocardial infarction with the presence of either IgG or IgA was 0.5 (95% CI 0.2 to 1.1, p = 0.08) and 0.4 ( 95% CI 0.1 to 1.0, p = 0.049) after adjusting for other risk factors. These results suggest a high prevalence of C. pneumoniae infection in Taiwan. However, C. pneumoniae infection is not associated with angiographically documented CAD, and, in contrast, is a negative predictor for the development of acute coronary syndromes.

Cilostazol, a novel oral phosphodiesterase inhibitor, has shown consistent improvement in exercise tolerance in patients with intermittent claudication (IC). In addition to this effect, cilostazol has previously been shown to have beneficial effects on the dyslipidemia, i.e., combination of high triglycerides with low high-density-lipoprotein cholesterol (HDL-C) levels. Interleukin-6 (IL-6) suppresses the activity of lipoprotein lipase, which modulates the metabolism of triglycerides and HDL-C. To determine whether a reduction of IL-6 contributes to the improvement of lipid profiles, we prospectively investigated the effect of cilostazol (n=16, 100 mg, twice daily) on the changes of lipid profiles and on the association with the changes of IL-6 compared with those of pentoxifylline (n=16, 400 mg, bid) in patients with IC. After eight weeks of administration of cilostazol to patients with IC, walking distances were increased, associated with a 29% decrease in plasma triglycerides and a 13% increase in HDL-C. No significant changes of lipid profiles in the pentoxifylline and placebo groups were observed although a similar improvement in walking distances was achieved in the pentoxifylline group. IL-6 levels were significantly reduced in patients receiving cilostazol as compared with those receiving placebo or pentoxifylline. The cilostazol-induced changes in the IL-6 were positively related to those of triglycerides in the cilostazol group (r=0.63, P

Background: Genes with important functions and rarely expressed would probably more easily be cloned from a modified equalized kidney cDNA library for further investigation. Methods: A kidney cDNA library of a spontaneously hypertensive rat was synthesized by a modified equalization method. Inserts of random clones were amplified by PCR and sequenced. Sequences were compared against a nonredundant database in GenBank. The cDNA profile was compared with an expression profile of a mouse renal proximal tubule cDNA library. Seven clones were analyzed by Northern blot analysis. The cDNA ends of two novel genes were amplified by PCR, sequenced and analyzed. Results: 336 cDNA clones were analyzed and grouped into 323 species of transcript with 77 species similar to previously reported genes. Northern blot analysis identified one kidney-specific, one rarely expressed and lung-specific, and another relatively testis-specific gene. Two novel genes were cloned. One was 4.1 kb in length and encoded a 390-amino acid zinc-finger protein. Another was 2.5 kb and encoded a 474-amino acid protein of unknown function. Compared with the expression profile of a mouse renal proximal tubule cDNA library, this kidney library had a lower proportion of ribosomal genes and had a greater proportion of genes for signal transduction and DNA or RNA binding. Conclusions: Rare or novel genes could be more easily isolated from this library for molecular study of hypertension and renal pathophysiology.

The objective of the present study was to investigate the characteristics of body surface potential map (BSPM) findings during ventricular repolarization in patients with coronary artery disease (CAD). A total of 108 consecutive patients, 99 men and 9 women with angina pectoris and positive treadmill exercise test results as well as angiographically documented CAD underwent BSPM study in a fasting state. Their ages ranged from 30 to 70 years. There were 13 patients with right coronary artery (RCA) lesions, 37 with left anterior descending artery (LAD) lesions, 5 with left circumflex artery (LCX) lesions, 17 with both RCA and LAD lesions, 12 with both LCX and LAD lesions, and 24 with 3-vessel disease, The BSPMs were obtained by using the heart potential map system designed by Toyama et al. There were 59 lead points on the anterior chest wall and 28 on the back. The BSPMs in isopotential distribution were made every one msec throughout the ventricular activation period. The distribution of positive and negative potentials, potential maximum and potential minimum, polarity of potential distribution, and the reversal of potential distribution during ventricular repolarization were analyzed. The following information on BSPMs was obtained: (1) In early ventricular repolarization, the negative potential and the potential minimum appeared abnormally on the anterior thorax. The potential abnormality displayed on the right portion or the inferior portion in patients with RCA lesions, on the middle portion or the left portion in patients with LAD lesions, and on the left-superior portion or the left-middle portion in patients with LCX lesions. In patients with multi-vessel disease, the abnormal potential distribution showed a combined pattern of individual vessel lesions, (2) In some cases, the multipolar potential distribution appeared abnormally during the initial stage and the peak of the T wave. (3) The reversal of potential distribution was observed in about half of the patients. The characteristic findings of the BSPM during ventricular repolarization, including abnormal potential distribution, multipolar potential distribution and reversal of potential distribution, will be of clinical value in patients with CAD.

One of the most important intracellular Ca2+ regulatory mechanisms in nonexcitable cells, "capacitative Ca2+ entry" (CCE), has not been adequately studied in astrocytes. We therefore investigated whether CCE exists in cultured rat cerebellar astrocytes and studied the roles of cyclic AMP (cAMP) and protein kinase C (PKC) in CCE. We found that (1) at least two different intracellular Ca2+ stores, the endoplasmic reticulum and mitochondria, are present in cerebellar astrocytes; (2) CCE does exist in these cells and can be inhibited by Ni2+, miconazole, and SKF 96365; (3) CCE can be directly enhanced by an increase in intracellular cAMP, as 8-bromoadenosine 3',5'-cyclic monophosphate (8-brcAMP), forskolin, and isobutylmethylxanthine have stimulatory effects on CCE; and (4) neither of the two potent protein kinase A (PKA) inhibitors, H8 and H89, nor a specific PKA agonist, Sp-adenosine 3',5'-cyclic monophosphothioate, had a significant effect on cAMP-enhanced Ca2+ entry. The [Ca2+]i increase was not due to a release from calcium stores, hyperpolarization of the membrane potential, inhibition of calcium extrusion, or a change in pHi, suggesting that cAMP itself probably acts as a novel messenger to modulate CCE. We also conclude that activation of PKC results in an increase in CCE. cAMP and PKC seem to modulate CCE by different pathways.

Isthmus-Independent Atrial Flutter. Introduction: We report the electrophysiologic study and radiofrequency catheter ablation of isthmus-independent atrial flutter in 2 patients. The isthmus-independent atrial flutter in these 2 patients had similar ECG and electrophysiologic findings. Both were reproducibly induced by rapid atrial pacing. The atrial activation sequence and entrainment study proved that these atrial flutters were not isthmus-dependent. A high-right atrial site was identified as the critical site of the slow conduction zone of the tachycardia in both. This site showed double potentials and mid-diastolic potentials. Radiofrequency catheter ablation at this site successfully eliminated the isthmus-independent atrial flutter in both patients.

In the presence of a normal atrial systole and optimal AV delay, atrial kick contributes to a significant fraction of the stroke volume. This atrial contribution may be lost during atrial asystole or mismatch in the timing of atrial and ventricular contraction. A patient received atrial compartment operation for his chronic AF. Although the AF was successfully converted to sinus rhythm, the conduction from the right to left atrium was markedly delayed so that the left atrial and ventricular activations occurred almost simultaneously. This delay in left atrial activation resulted in impaired cardiac performance.

The body surface potential map (BSPM) may reflect regional myocardial electrical activity. This technique can thus provide information regarding the excitation of ventricles. This study is an attempt to evaluate the usefulness of BSPM in determining the sites of the atrioventricular (AV) accessory pathway (AP) in patients with Wolff-Parkinson-White (W-P-W) syndrome. The BSPMs were obtained from 40 consecutive patients with W-P-W syndrome in a fasting state, using the heart potential map system designed by Toyama et al. Unipolar electrocardiograms were recorded simultaneously from 87 lead points on the chest surface, including 59 lead points on the anterior chest and 28 on the back. Wilson's central terminal was used as a voltage reference and BSPMs in an isopotential distribution pattern were made every millisecond throughout ventricular activation from these unipolar ECGs with the use of a microcomputer system. All patients underwent an electrophysiologic study (EPS) at cardiac catheterization. We analyzed the potential distribution during ventricular depolarization and compared the results between EPS and BSPM findings. The following results were obtained: (1) seven types of BSPM pattern were identified in accordance with the sites of the AV AP confirmed by EPS; (2) the location of the potential minimum of ventricular depolarization and the direction of the excitation wavefront during early ventricular depolarization, the reversal pattern of ventricular potential distribution, the epicardial right ventricular breakthrough and the dynamic change of ventricular potential distribution were useful for the detection of the ventricular pre-excitation site; (3) epicardial right ventricular breakthrough occurred in nearly all patients with left ventricular free wall accessory AV connections; (4) the abnormal early reversal pattern of ventricular potential distribution did not occur in patients with left ventricular AV connections but did appear in most patients with right ventricular free wall AV connections. Accordingly, BSPM is a reliable non-invasive procedure to determine the ventricular pre-excitation sites of patients with W-P-W syndrome.

Percutaneous balloon pericardiotomy is effective and less invasive for the treatment of recurrent pericardial effusion. This study suggests that the double-balloon method with 1 longer and 1 shorter balloon is the procedure of choice for percutaneous balloon pericardiotomy.

The relation between left ventricular (LV) endsystolic wall stress (sigma es) and rate-corrected velocity of circumferential fiber shortening (Vcfc), which is independent of heart rate (HR) and loading conditions has previously been used to assess cardiac contractility in insulin dependent diabetes mellitus (IDDM). This study is the first report in which this relation has been utilized with data obtained by echocardiography in addition to the traditional indices, to evaluate the cardiac function in asymptomatic, middle-aged patients with noninsulin dependent diabetes mellitus (NIDDM) at baseline and during dobutamine stimulation. There were 16 NIDDM patients in our study and these patients were classified into 2 groups. Group 1 consisted of 11 patients without microvascular complications. Group 2 consisted of the remaining 5 patients with microvascular complications. Ten age- and sex-matched normal subjects were enrolled as a control group. At baseline, diabetic patients tended to have a faster HR and a greater LV enddiastolic dimension, though these values were not significantly different from the normal subjects. Ejection fraction (EF) in group 1 was significantly higher than that of the normal controls (73 +/- 2% vs 65 +/- 2%, p0.005). Mitral inflow pattern was normal (E/A1) in the normal subjects (1.11 +/- 0.06), but reversed in group 1 (0.87 +/- 0.07) and group 2 (0.95 +/- 0.12). Isovolumic relaxation time corrected for HR (IVRTc) and the slope of relation between sigma es and Vcfc were similar among the 3 groups. Comparing Vcfc at 50 g/cm2 of sigma es, it tended to increase from the normal subjects (0.883 +/- 0.057 cir/sec) to 0.969 +/- 0.048 in group 1 and 1.034 +/- 0.101 in group 2, though this result was not statistically significant. During dobutamine stimulation, EF increased and IVRTc shortened significantly only in the normal subjects. E/A became normalized in both diabetic groups. The increment in Vcfc representing cardiac reserve of contractility was significantly lower in the diabetics (0.110 +/- 0.040 in group 1 and 0.057 +/- 0.043 in group 2) than in normal subjects (0.244 +/- 0.044). In conclusion, using the index of relation between sigma es and Vcfc, the cardiac contractility of NIDDM was not impaired at baseline, and even had a tendency to increase. However, during dobutamine stimulation, the inadequate reserve of contractility was exposed, especially in those patients who had microvascular complications. These results indicate the importance of controlling diabetes, not only to prevent the development of microvascular complications but also to preserve cardiac function.

To examine the association of the molecular variants of the angiotensinogen (AGT) gene with essential hypertension in Taiwanese.We conducted a case-control study concerning 151 subjects, 102 hypertensives and 49 normotensives. We created a rapid mini-sequencing method based on dye-terminator cycle sequencing to simultaneously detect the M235T and T174M variants of the AGT gene for each subject.The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (chi 2 = 11.106, P = 0.004 and chi 2 = 6.453, P = 0.011, respectively), whereas those of the T174M variant did not differ (chi 2 = 0.004, P = 0.998 and chi 2 = 0.032, P = 0.858, respectively). The odds ratio for hypertension was 3.64 (95% confidence interval 1.56-8.49) for subjects with the C/C genotype of the M235T variant compared with other genotypes of 2.87 (95% confidence interval 1.76-4.68) for those carrying allele C versus those carrying allele T.The molecular variant M235T, but not T174M, of the AGT gene is associated significantly with essential hypertension in this Taiwanese population. The genotype C/C or allele C is a risk factor for hypertension. The underlying mechanism of this association needs to be elucidated further.

Insertion/deletion (I/D) polymorphism of the angiotensin-converting enzyme (ACE) gene has been postulated as a risk factor for coronary heart disease. We conducted a case-control study of 271 Chinese, including 114 subjects with coronary artery disease (CAD), 42 with non-CAD and 115 apparently normal controls to examine the association of I/D polymorphism and CAD. The genotypes were identified by polymerase chain reaction and the plasma ACE activity was assayed by spectrophotometry. The allele and genotype frequencies were not different among the CAD, non-CAD and apparently normal groups (p = 0.42 and 0.63). Plasma ACE activity was not different among the three groups (p = 0.32). The D-allele and DD genotype were not more prevalent in subjects with low risk CAD (p = 0.07 and 0.16) and subjects with myocardial infarction (p = 0.79 and p = 0.35). No association was found between I/D polymorphism and severity of CAD (p = 0.42 and 0.70). In conclusion, the deletion polymorphism of the ACE gene may not be an independent risk factor in the development of CAD or myocardial infarction in this Chinese population. The unique or synergistic effect of other genes needs further study.

To examine the association between insertion/deletion (I/D) polymorphism of the angiotensin converting enzyme (ACE) gene and essential hypertension in a Chinese population, a case-control study was conducted using 157 hypertensive and 115 normotensive subjects. The I/D polymorphism of the ACE gene was identified by polymerase chain reaction. Plasma ACE activity was determined using spectrophotometry. The difference of allele frequencies between normotensives and hypertensives was statistically significant (X2 = 4.467, P = .035), while the gentotype distribution was not different between normotensive and hypertensive subjects (X2 = 3.954, P = .138). Plasma ACE activity was highest in the DD genotype, followed by the ID genotype, and the lowest in the II genotype (P = .0001 in normotensives and P = .163 in hypertensives, respectively). Thus, we conclude that the ACE gene polymorphism is not associated with essential hypertension in this Chinese population, but plasma ACE activity is genetically determined in the normotensive Chinese.

Wei-Chiao Chiu,1 Jyh-ming Juang,1,2 Shen-nan Chang,2 Cho-kai Wu,2 Chia-ti Tsai,2 Chuen-den Tseng,2 Yung-zu Tseng,1,2 Ming-Jai Su,3 Fu-tien Chiang1,2,41Graduate Institute of Physiology, National Taiwan University College of Medicine, 2Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, 3Graduate Institute of Pharmacology, National Taiwan University College of Medicine, 4Department of Laboratory Medicine, National Taiwan University College of Medicine, Taipei, Taiwan, Republic of ChinaPurpose: Studies to explore angiotensin II (Ang II) and its downstream signaling pathways via Rho guanine nucleotide exchange factors (RhoGEFs) and RhoA signaling are crucial to understanding the mechanisms of smooth muscle contraction leading to hypertension. This study aimed to investigate the Ang II–induced expression of RhoGEFs in vascular smooth muscle cells (VSMCs) of spontaneously hypertensive rats (SHRs) and to identify the possible regulator associated with hypertension.Methods: Cultured VSMCs of the aorta from SHRs and Wistar-Kyoto (WKY) rats were treated with or without Ang II or Ang II plus Ang II type 2 receptor antagonists. The expression levels of RhoGEF messenger RNA (mRNA) and protein were determined. To evaluate the changes of aortic ring contractile force in response to Ang II, a nonviral carrier system was adopted to deliver the leukemia-associated RhoGEF (LARG) small interfering RNA via nanoparticles into aortic rings.Results: The baseline mRNA levels of three RhoGEFs in cultured VSMCs of WKY rats did not increase with age, but they were significantly higher in 12-week-old SHRs than in 5-week-old SHRs. Expression levels of LARG mRNA were higher in SHRs than in age-matched WKY rats. The baseline LAGR protein of 12-week-old SHRs was about four times higher than that of WKY rats of the same age. After Ang II stimulation, LAGR protein expression was significantly increased in 12-week-old WKY rats but remained unchanged in 12-week-old SHRs. LARG small interfering RNA was successfully delivered into aortic rings using nanoparticles. LARG knockdown resulted in 12-week-old SHRs showing the greatest reduction in aortic ring contraction.Conclusion: There were differences in age-related RhoGEF expression at baseline and in response to Ang II stimulation between SHRs and WKY rats in this study. Nanotechnology can assist in studying the silencing of LARG in tissue culture. The findings of this study indicate that LARG gene expression may be associated with the genesis of hypertension in SHRs.Keywords: Rho guanine nucleotide exchange factor, leukemia-associated Rho guanine nucleotide exchange factor, Wistar-Kyoto rats, nanoparticle delivery, hypertension

Forty-two consecutive patients were checked for profiles of platelet aggregability before, during, and 10 and 30 minutes after catheter ablation. They were randomized into Group A (n = 20) who accepted intravenous aspirin (in 0.015 g/kg body weight) and Group P (n = 22) who accepted only placebo treatment. Blood samples were drawn from ascending aorta (Ao) and main pulmonary artery (MPA) simultaneously at each time period. In Group P, the EC50 of substrate induced platelet aggregability decreases significantly during (for ADP, from 1.72 to 0.78 mumol/L for samples from Ao, P < 0.0001; and from 1.68 to 0.69 mumol/L for MPA, P < 0.0001; for collagen, from 2.26 to 1.34 micrograms/mL for Ao, P < 0.005, and from 2.40 to 1.64 micrograms/mL, P < 0.0001) and 10 minutes after successful ablation (for ADP, to 0.70 mumol/L for Ao, P < 0.000, and to 0.61 mumol/L for MPA, P < 0.0001; for collagen, to 1.54 micrograms/mL for Ao, P < 0.01, and to 1.63 micrograms/mL, P < 0.0001), and then returned to baseline levels 30 minutes later (all P = NS) compared with comparative baseline levels. The levels of thromboxane B2 (TXB2) had the similar evolution. The evolution of platelet aggregability profiles was not associated with total energy dose, duration of energy application, duration of procedure, impedance, and ablation site. However, there were moderate positive correlations between the TXB2 levels and tip temperatures (r = 0.56, P < 0.05 for Ao and r = 0.65, P < 0.01 for MPA). These results suggest that increased platelet aggregability can occur during and 10 minutes after radiofrequency current ablation and antiplatelet therapy can maintain "flat" response of platelet aggregability to radiofrequency energy, which may provide possible benefits in preventing the occurrence of the complication.

Background: A recent genome-wide association study in individuals of European ancestry demonstrated a significant association of the single nucleotide polymorphism (SNP) rs13376333 in KCNN3 on chromosome 1q21 with lone AF, indicating a common genetic basis for AF. Objectives: We sought to replicate the association between SNP rs13376333 in KCNN3 and AF in the Taiwanese population. Methods: We conducted a case-control association study and genotyped SNP rs13376333 in 214 lone AF patients (58.3±11.4 years) versus 214 controls (57.7±13.2 years), and 322 structural AF patients (69.6±13.7 years) versus 322 controls (68.4±14.2 years). Results: The associations between SNP rs13376333 and structural or lone AF were significant. In lone AF group, the frequency of the minor allele of SNP rs13376333 was 8.6% compared with 3.0% in controls (allelic p

A residual atrial septal defect with bidirectional shunt was detected by transesophageal echocardiography in a 28-year-old man 3 years after percutaneous transluminal mitral commissurotomy (PTMC) with the antegrade transseptal technique. He had had severe mitral stenosis, pulmonary hypertension, and tricuspid regurgitation before the procedure. The result of PTMC was suboptimal, the pulmonary hypertension regressed only partially, and the tricuspid regurgitation remained severe. These factors contributed to the bidirectional shunt. A bidirectional shunt is known to be associated with systemic desaturation and a higher risk of paradoxical embolization and brain abscess. When PTMC is considered in patients with pulmonary hypertension and tricuspid regurgitation, a retrograde left ventricular approach with or without transseptal puncture can avoid the atrial septotomy, decrease the incidence of significant shunt, and should be a rational alternative.

In a search for features predictive of ventricular arrhythmias in myocardial ischemia, the body surface potential maps of 17 dogs with coronary artery occlusion were studied. Ventricular tachycardia occurred in 9 (53%) of the 17 dogs. Multiple distribution of the abnormal potential minimum was found in 6 (67%) of the 9 dogs with (group A) and none of the 8 dogs without ventricular tachycardia (group B). The difference was statistically significant (p less than 0.01). The abnormal "early reversal" phenomenon of potential distribution was observed in 6 (67%) of group A and 7 (88%) of group B. The difference was not statistically significant (p greater than 0.05). The area of abnormal negative potential was 28.0 +/- 8.5 cm2 for group A and 14.5 +/- 5.5 cm2 for group B (p less than 0.001). The abnormal negative potential lasted for 25.4 +/- 3.5 ms in group A and 10.1 +/- 5.1 ms in group B (p less than 0.001). The abnormally early appearance of potential minimum lasted for 24.2 +/- 5.1 ms in group A and 10.5 +/- 5.4 ms in group B (p less than 0.001). The data suggest that the distribution, area, and duration of the abnormal negative potential of the body surface potential map are useful in the prediction of ventricular tachycardia associated with coronary artery occlusion.

The exact site of reentrant circuit involved in the atrioventricular node reentrant tachycardia was questioned. Seven patients (6 females and 1 male), aged 21 to 64 years (mean = 40 +/- 17 years), with refractory nodal reentry, underwent surgical treatment. The associated cardiac diseases included rheumatic valvar disease in two and an atrial septal defect. Electrophysiologic studies before surgery showed dual nodal pathways in 4 patients. Right atrial endocardial mapping was performed and the earliest retrograde atrial activation during tachycardia was mapped to the apex of the triangle of Koch in 6 patients and near the orifice of coronary sinus in one. Perinodal dissection was performed according to the location of earliest retrograde atrial activity. Care was taken to preserve as much of the atrioventricular node and its arterial supply as was possible. Immediately after surgery, conduction in an antegrade direction recovered and the tachycardia could no longer be reproduced. There was no surgical mortality or morbidity. At 10 to 26 months of follow-up, all patients remain free of tachycardia without antiarrhythmic drugs. Four patients underwent repeated electrophysiologic studies at 2 weeks to 6 months after surgery. Dual nodal pathways were no longer demonstrated. It is concluded that the perinodal atrial tissue plays a part in the atrioventricular nodal reentry, and that surgical dissection is a simple and effective treatment for patients with refractory atrioventricular node reentrant tachycardia.

a b , b b a * Gau-Yang Chen , Chuen-Den Tseng , Kwan-Lih Hsu , Fu-Tien Chiang , Huey-Ming Lo , b c Yung-Zu Tseng , Chang-Her Tsai Department of Internal Medicine, Provincial Tao-Yuan General Hospital, Tao-Yuan, Taiwan, Republic of China Cardiovascular Section, Department of Internal Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan, Republic of China Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, Republic of China