Yung-Zu Tseng

Renin-Angiotensin System Gene Polymorphisms and Atrial Fibrillation

Background—The activated local atrial renin-angiotensin system (RAS) has been reported to play an important role in the pathogenesis of atrial fibrillation (AF). We hypothesized that RAS genes might be among the susceptibility genes of nonfamilial structural AF and conducted a genetic case-control study to demonstrate this. Methods and Results—A total of 250 patients with documented nonfamilial structural AF and 250 controls were selected. The controls were matched to cases on a 1-to-1 basis with regard to age, gender, presence of left ventricular dysfunction, and presence of significant valvular heart disease. The ACE gene insertion/deletion polymorphism, the T174M, M235T, G-6A, A-20C, G-152A, and G-217A polymorphisms of the angiotensinogen gene, and the A1166C polymorphism of the angiotensin II type I receptor gene were genotyped. In multilocus haplotype analysis, the angiotensinogen gene haplotype profile was significantly different between cases and controls (&khgr;2=62.5, P =0.0002). In single-locus analysis, M235T, G-6A, and G-217A were significantly associated with AF. Frequencies of the M235, G-6, and G-217 alleles were significantly higher in cases than in controls (P =0.000, 0.005, and 0.002, respectively). The odds ratios for AF were 2.5 (95% CI 1.7 to 3.3) with M235/M235 plus M235/T235 genotype, 3.3 (95% CI 1.3 to 10.0) with G-6/G-6 genotype, and 2.0 (95% CI 1.3 to 2.5) with G-217/G-217 genotype. Furthermore, significant gene-gene interactions were detected by the multifactor-dimensionality reduction method and multilocus linkage disequilibrium tests. Conclusions—This study demonstrates the association of RAS gene polymorphisms with nonfamilial structural AF and may provide the rationale for clinical trials to investigate the use of ACE inhibitor or angiotensin II antagonist in the treatment of structural AF.

Down-regulation of L-type calcium channel and sarcoplasmic reticular Ca2+-ATPase mRNA in human atrial fibrillation without significant change in the mRNA of ryanodine receptor, calsequestrin and phospholamban: An insight into the mechanism of atrial electrical remodeling

OBJECTIVES We investigated the gene expression of calcium-handling genes including L-type calcium channel, sarcoplasmic reticular calcium adenosine triphosphatase (Ca(2+)-ATPase), ryanodine receptor, calsequestrin and phospholamban in human atrial fibrillation. BACKGROUND Recent studies have demonstrated that atrial electrical remodeling in atrial fibrillation is associated with intracellular calcium overload. However, the changes of calcium-handling proteins remain unclear. METHODS A total of 34 patients undergoing open heart surgery were included. Atrial tissue was obtained from the right atrial free wall, right atrial appendage, left atrial free wall and left atrial appendage, respectively. The messenger ribonucleic acid (mRNA) amount of the genes was measured by reverse transcription-polymerase chain reaction and normalized to the mRNA levels of glyceraldehyde 3-phosphate dehydrogenase. RESULTS The mRNA of L-type calcium channel and of Ca(2+)-ATPase was significantly decreased in patients with persistent atrial fibrillation for more than 3 months (0.36+/-0.26 vs. 0.90+/-0.88 for L-type calcium channel; 0.69+/-0.42 vs. 1.21+/-0.68 for Ca(2+)-ATPase; both p < 0.05, all data in arbitrary unit). We further demonstrated that there was no spatial dispersion of the gene expression among the four atrial tissue sampling sites. Age, gender and underlying cardiac disease had no significant effects on the gene expression. In contrast, the mRNA levels of ryanodine receptor, calsequestrin and phospholamban showed no significant change in atrial fibrillation. CONCLUSIONS L-type calcium channel and the sarcoplasmic reticular Ca(2+)-ATPase gene were down-regulated in atrial fibrillation. These changes may be a consequence of, as well as a contributory factor for, atrial fibrillation.

Angiotensinogen Gene Haplotype and Hypertension: Interaction With ACE Gene I Allele

Abstract—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.

Angiotensin II Activates Signal Transducer and Activators of Transcription 3 via Rac1 in Atrial Myocytes and Fibroblasts Implication for the Therapeutic Effect of Statin in Atrial Structural Remodeling

Background— Recently, activation of the local renin-angiotensin system and mitogen-activated protein kinase pathways in atrial myocardium has been found to play an important role in atrial structural remodeling related to atrial fibrillation. Another important mediator of the angiotensin II (Ang II) effect is the Janus kinase/signal transducers and activators of transcription (STAT) pathway, which has never been characterized in the atrium. Methods and Results— In cultured atrial myocytes and fibroblasts, Ang II induced tyrosine phosphorylation of STAT3 through a Rac1-dependent mechanism, which was inhibited by dominant-negative Rac1, losartan, and simvastatin. In atrial myocytes, activation of STAT3 by Rac1 was mediated by direct association of Rac1 with STAT3; however, in atrial fibroblasts, it was mediated by an indirect paracrine effect. Constitutively active STAT3 increased protein synthesis, and dominant-negative STAT3 abrogated Ang II-induced protein synthesis in atrial myocytes and fibroblasts. Rats infused long term with Ang II exhibited higher levels of activated Rac1, phospho-STAT3, collagen synthesis, and atrial fibrosis in the atria, all of which were attenuated by oral losartan and simvastatin. In human atrial tissues from patients with atrial fibrillation, Ang II and phospho-STAT3 levels were also elevated. Conclusions— The Ang II/Rac1/STAT3 pathway is an important signaling pathway in the atrial myocardium to mediate atrial structural remodeling, and losartan and statin may be able to reverse Ang II-induced atrial structural remodeling in atrial fibrillation.

Angiotensin II Increases Expression of α1C Subunit of L-Type Calcium Channel Through a Reactive Oxygen Species and cAMP Response Element–Binding Protein–Dependent Pathway in HL-1 Myocytes

Angiotensin II (Ang II) is involved in the pathogenesis of atrial fibrillation (AF). L-type calcium channel (LCC) expression is altered in AF remodeling. We investigated whether Ang II modulates LCC current through transcriptional regulation, by using murine atrial HL-1 cells, which have a spontaneous calcium transient, and an in vivo rat model. Ang II increased LCC α1C subunit mRNA and protein levels and LCC current density, which resulted in an augmented calcium transient in atrial myocytes. An ≈2-kb promoter region of LCC α1C subunit gene was cloned to the pGL3 luciferase vector. Ang II significantly increased promoter activity in a concentration- and time-dependent manner. Truncation and mutational analysis of the LCC α1C subunit gene promoter showed that cAMP response element (CRE) (−1853 to −1845) was an important cis element in Ang II-induced LCC α1C subunit gene expression. Transfection of dominant-negative CRE binding protein (CREB) (pCMV-CREBS133A) abolished the Ang II effect. Ang II (1 μmol/L, 2 hours) induced serine 133 phosphorylation of CREB and binding of CREB to CRE and increased LCC α1C subunit gene promoter activity through a protein kinase C/NADPH oxidase/reactive oxygen species pathway, which was blocked by the Ang II type 1 receptor blocker losartan and the antioxidant simvastatin. In the rat model, Ang II infusion increased LCC α1C subunit expression and serine 133 phosphorylation of CREB, which were attenuated by oral losartan and simvastatin. In summary, Ang II induced LCC α1C subunit expression via a protein kinase C–, reactive oxygen species–, and CREB-dependent pathway and was blocked by losartan and simvastatin.

Recovery of atrial function after atrial compartment operation for chronic atrial fibrillation in mitral valve disease

OBJECTIVES We prospectively studied the recovery of atrial function after atrial compartment operation and mitral valve surgery in patients with chronic atrial fibrillation caused by mitral valve disease. BACKGROUND Chronic atrial fibrillation is the most common arrhythmia in mitral valve disease. This arrhythmia is associated with excessive morbidity and mortality. Mitral valve surgery alone rarely eliminates it. METHODS Twenty-two patients underwent mitral valve surgery and a new surgical method, atrial compartment operation. Doppler echocardiography was performed in all patients before operation and at 1 week and 2 and 6 months after operation in the successful cardioversion group. Peak early diastolic (E) and atrial (A) filling velocities, peak A/E velocity ratio and A/E integral ratio of the mitral and tricuspid valves were measured. RESULTS Sinus rhythm was restored immediately after operation in 91% of patients and was maintained for > 1 week in 15 (68%) of 22 patients and > 6 months in 14 (64%) of 22. Eleven of 15 patients had left atrial paralysis (A/E integral ratio 0) at 1 week and 6 of 14 patients at 2 months. Nine of 15 patients had right atrial paralysis (A/E integral ratio 0) at 1 week and 1 of 14 patients at 2 months. Both left and right atrial contractile function (presence of an A wave on Doppler findings) was detected at 6 months in 14 patients. Mean (+/- SD) peak atrial filling velocity of the mitral valve was 15 +/- 26 cm/s at 1 week, 38 +/- 39 cm/s at 2 months and 93 +/- 32 cm/s at 6 months (p < 0.001). Mean peak atrial filling velocity of the tricuspid valve was 14 +/- 19 cm/s at 1 week, 33 +/- 19 cm/s at 2 months and 50 +/- 19 cm/s at 6 months (p < 0.001). Peak early diastolic and atrial filling velocities, peak A/E velocity ratio and A/E integral ratio of the mitral and tricuspid valves increased significantly from 1 week to 6 months. CONCLUSIONS Chronic atrial fibrillation in mitral valve disease can often be eliminated by atrial compartment operation. No surgical mortality or significant complications were encountered. Both left and right atrial function, as manifested by Doppler findings, recover after compartment operation and improve over time. The mechanical function of the right atrium recovers earlier than that of the left.

Reversal of deteriorated fractal behavior of heart rate variability by beta-blocker therapy in patients with advanced congestive heart failure

Beta‐Blocker Therapy and Heart Rate Variability. Introduction: The slope of the power spectrum in heart rate variability (HRV) reflects the fractal or scaling behavior in HR dynamics and recently was confirmed as an independent predictor of postmyocardial infarction survival. Whether or not the new measurement in HRV foresees the functional evolution in patients with advanced congestive heart failure treated by β blockers is unclear.

Long-term β-blocker therapy improves autonomic nervous regulation in advanced congestive heart failure: A longitudinal heart rate variability study ☆ ☆☆

BACKGROUND beta-Blocker therapy is believed to modulate the detrimental effect of overcompensating neurohormonal activation in chronic heart failure. However, clinical doubts remain, particularly the physiologic sympathovagal balance. METHODS To respond to clinical concern about worsening autonomic nervous perturbation in beta-blocker therapy of advanced congestive heart failure, 15 consecutive patients were longitudinally studied to elucidate the evolution of cardiac function versus 24-hour heart rate variability (HRV) before and after 1, 3, and 6 to 9 months of atenolol-combined therapy. RESULTS Two patients died prematurely within 1 month. All 13 surviving patients showed improvement in New York Heart Association functional class, with decrease in left ventricular end-systolic and end-diastolic dimensions and increase in fraction shortening and ejection fraction by echocardiography after at least 3 months of atenolol use. The retarded therapeutic effect was accompanied by a general rise of total, very low, low-, and high-frequency components (9.0 +/- 0.5, 8.8 +/- 0.5, 6.2 +/- 0.6, and 6.1 +/- 0.5 vs 10.9 +/- 0.3, 10.7 +/- 0.4, 8.6 +/- 0.3, and 7.8 +/- 0.3; all P <.02) of daily HRV. This implied recovery of parasympathetic and baroreceptor function. Return of sympathovagal interaction was further supported by the suppression of Cheyne-Stokes type HRV as detected by Wigner-Ville distribution. CONCLUSIONS Long-term beta-blocker therapy for advanced congestive heart failure upwardly regulates the autonomic nervous interaction in synchrony with the evolution of cardiac function performance.

Molecular variant M235T of the angiotensinogen gene is associated with essential hypertension in Taiwanese

Objective To examine the association of the molecular variants of the angiotensinogen (AGT) gene with essential hypertension in Taiwanese. Methods 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. Results The genotype and allele distribution of the M235T variant differed significantly in hypertensives and normotensives (χ2 = 11.106, P = 0.004 and χ2 = 6.453, P = 0.011, respectively), whereas those of the T174M variant did not differ (χ2 = 0.004, P = 0.998 and χ2 = 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 or 2.87 (95% confidence interval 1.76–4.68) for those carrying allele C versus those carrying allele T. Conclusion 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.

Clinical implications and factors related to left atrial spontaneous echo contrast in chronic nonvalvular atrial fibrillation

The mechanisms leading to formation of spontaneous echo contrast (SEC), a smoke-like echo on echocardiography, are still controversial. To further explore the clinical implications and factors related to SEC formation, the correlation among echocardiographic variables, hematologic parameters or platelet aggregability, and the occurrence of SEC was studied in 119 patients with chronic nonvalvular atrial fibrillation. There were 75 men and 44 women with a mean age of 65 +/- 10 years (range 38-88). Left atrial SEC was detected in 39 patients (33%) by transesophageal echocardiography. Patients with history of systemic embolism were more frequently found to have left atrial SEC and left atrial thrombus by univariate analysis. Multivariate analysis showed that left atrial SEC (p < 0.001) was the only independent predictor of history of systemic embolism. Age, sex, left atrial or left ventricular dimension, left ventricular ejection fraction, antiplatelet or anticoagulant therapy and the percentage of lone atrial fibrillation were not significantly different between patients with and without left atrial SEC. Among the hematologic parameters, higher hematocrit was found in patients with left atrial SEC, while white blood cell and platelet counts were comparable in both groups. Platelet aggregability with different concentrations of inducers, adenosine diphosphate and collagen, was evaluated by the turbidimetric method in 15 patients with left atrial SEC and in 42 patients without left atrial SEC who were not receiving antiplatelet or anticoagulant therapy. No significant difference was found in platelet aggregability using four inducer concentrations between two groups of patients.(ABSTRACT TRUNCATED AT 250 WORDS)