Juey-Jen Hwang

Cardiopulmonary resuscitation with assisted extracorporeal life-support versus conventional cardiopulmonary resuscitation in adults with in-hospital cardiac arrest: an observational study and propensity analysis

BACKGROUND Extracorporeal life-support as an adjunct to cardiac resuscitation has shown encouraging outcomes in patients with cardiac arrest. However, there is little evidence about the benefit of the procedure compared with conventional cardiopulmonary resuscitation (CPR), especially when continued for more than 10 min. We aimed to assess whether extracorporeal CPR was better than conventional CPR for patients with in-hospital cardiac arrest of cardiac origin. METHODS We did a 3-year prospective observational study on the use of extracorporeal life-support for patients aged 18-75 years with witnessed in-hospital cardiac arrest of cardiac origin undergoing CPR of more than 10 min compared with patients receiving conventional CPR. A matching process based on propensity-score was done to equalise potential prognostic factors in both groups, and to formulate a balanced 1:1 matched cohort study. The primary endpoint was survival to hospital discharge, and analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00173615. FINDINGS Of the 975 patients with in-hospital cardiac arrest events who underwent CPR for longer than 10 min, 113 were enrolled in the conventional CPR group and 59 were enrolled in the extracorporeal CPR group. Unmatched patients who underwent extracorporeal CPR had a higher survival rate to discharge (log-rank p<0.0001) and a better 1-year survival than those who received conventional CPR (log rank p=0.007). Between the propensity-score matched groups, there was still a significant difference in survival to discharge (hazard ratio [HR] 0.51, 95% CI 0.35-0.74, p<0.0001), 30-day survival (HR 0.47, 95% CI 0.28-0.77, p=0.003), and 1-year survival (HR 0.53, 95% CI 0.33-0.83, p=0.006) favouring extracorporeal CPR over conventional CPR. INTERPRETATION Extracorporeal CPR had a short-term and long-term survival benefit over conventional CPR in patients with in-hospital cardiac arrest of cardiac origin.

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.

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.

Multistate Outbreak of Listeriosis Linked to Turkey Deli Meat and Subsequent Changes in US Regulatory Policy

BACKGROUND Data about the efficacy and tolerability of linezolid for the treatment of gram-positive bacterial infections in patients with end-stage renal disease (ESRD) are lacking. METHODS This retrospective case-control study compared the tolerability and efficacy of linezolid therapy for patients with ESRD and patients with non-end-stage renal disease (NESRD), all of whom had gram-positive bacterial infections. RESULTS There were 58 men and 33 women enrolled in the study, with a mean age of 61.5 years (range, 45.4-81.2 years). Among these patients, 28 (30.8%) were receiving hemodialysis at the start of linezolid treatment. The ESRD group had a higher percentage of patients with diabetes mellitus (57.1% vs. 33.3%; P = .029) and an older mean age (+/-SD) (72.1 +/- 10.8 years vs. 56.8 +/- 20.4 years; P < .001), compared with the NESRD group. Severe thrombocytopenia (platelet count, < 100 x 10(9) platelets/L) and anemia were significantly more frequent in the ESRD group, compared with the NESRD group (78.6% vs. 42.9% [P = .003] and 71.4% vs. 36.5% [P = .003], respectively). The independent risk factors for thrombocytopenia identified by logistic regression analysis were pretreatment disease severity score (odds ratio [OR], 1.34; 95%, confidence interval [CI], 1.13-1.60; P = .001), central catheter-related infection (OR, 4.96; 95% CI, 1.08-22.73; P = .046), and ESRD (OR, 6.14; 95% CI, 1.63-23.26; P = .007). ESRD was the only independent risk factor for anemia (OR, 4; 95% CI, 1.50-10.64; P = .006). Survival analysis for the development of thrombocytopenia or death showed significant differences between patients with ESRD and patients with NESRD (P < .001). CONCLUSIONS The lower tolerability of linezolid in patients with ESRD, compared with those with NESRD, is evidenced by the higher rates of thrombocytopenia and anemia in the former group. The severity of these conditions necessitates treatment discontinuation for patients with ESRD more often than for patients with NESRD.

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.

Serum bilirubin is inversely associated with insulin resistance and metabolic syndrome among children and adolescents.

OBJECTIVE Bilirubin is a potent antioxidant and a cyroprotectant. Low serum bilirubin is associated with atherosclerosis. Little is known about its role in metabolic syndrome (MS) among children and adolescents. METHODS We examined 4723 children and adolescents aged 12-17 years with reliable measures of various serum hepatic profiles and metabolic risks from Health and Nutrition Examination Survey 1999-2004. RESULTS The results showed that the prevalence of the MS was from 6.6+/-1.2% in the lowest quartile to 2.1+/-1.9% in the highest quartile of the concentration of total bilirubin. The graded association remained significant after the adjustment of other co-variates. The odds ratios for the MS were around 0.29 (0.08-0.99) and 0.23 (0.08-0.65) for the upper two quartiles when using the lowest quartile as reference for the concentration of total bilirubin. The quartiles of the serum total bilirubin levels were inversely correlated with the homeostasis model assessment (HOMA-IR) and insulin while not associated with the serum C-reactive protein (CRP) levels. CONCLUSIONS The serum total bilirubin levels are inversely correlated with the prevalence of the MS. The mechanism of the association between MS and total bilirubin may be related to the insulin resistance status.

Risk factors and incidence of ischemic stroke in Taiwanese with nonvalvular atrial fibrillation-- a nation wide database analysis.

BACKGROUND Atrial fibrillation (AF) is a risk factor for ischemic stroke. Stroke-prevention strategies based on risk schemes have been developed but most of the data are from western people. Our goal is to investigate the risk factors of ischemic stroke in Taiwanese with AF in a nation-wide database. METHODS A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. By using ambulatory and inpatient claim data, we included subjects with AF and were above 20 years old. We excluded those who had ever taken warfarin or aspirin or had valvular heart diseases. RESULT A total of 7920 patients (3633 women, 4287 men) were included in the final analyses. Cox regression analysis showed that the risk factors for ischemic stroke were age (OR=1.338 for age 65-74 years vs. age 20-64 years, P=0.014; OR=1.652 for age over 75 years vs. age 20-64 years, P<0.001), hypertension (HTN) (OR=2.656, P<0.001), diabetes mellitus (DM) (OR=1.341, P=0.005), heart failure (OR=1.611, P<0.001), previous ischemic stroke or transient ischemic accident (TIA) (OR=2.752, P<0.001) and peripheral arterial disease (PAD) (OR=1.814, P=0.006). The gender, coronary artery disease, history of myocardial infarction and chronic renal insufficiency were not associated with ischemic stroke. The rate of ischemic stroke was much lower in current cohort as compared with that in whites. Frequent used risk schemes including CHADS₂ and CHA₂DS₂-VASC had comparable but only limited ability to predict ischemic stroke in subjects with AF. CONCLUSION Compare with western people, hypertension plays a more important role in ischemic stroke in Taiwanese with AF and the incidence is lower. A substantial number of ischemic strokes cannot be accurately predicted by current risk schemes.

Molecular Genetics of Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. There is genetic predisposition for the development of AF. Recently, by linkage analysis, several loci have been mapped for monogenetic AF, including 11p15.5, 21q22, 17q, 7q35-36, 5p13, 6q14-16, and 10q22. Some of these loci encode for subunits of potassium channels (KCNQ1, KCNE2, KCNJ2, and KCNH2 genes), and the remaining are yet unidentified. All of the known mutations are associated with a gain of function of repolarization potassium currents, resulting in a shortening of action potential duration and atrial refractory period, which facilitate multiple re-entrant circuits in AF. In addition to familial AF, common AF often occurs in association with acquired diseases such as hypertension, valvular heart disease, and heart failure. By genetic association study, some genetic variants or polymorphisms related to the mechanism of AF have been found to be associated with common AF, including genes encoding for subunits of potassium or sodium channels, sarcolipin gene, renin-angiotensin system gene, connexin-40 gene, endothelial nitric oxide synthase gene, and interleukin-10 gene. These observations suggest that genes related to ionic channels, calcium handling protein, fibrosis, conduction and inflammation play important roles in the pathogenesis of common AF. The complete elucidation of genetic loci for common AF is still in its infancy. However, the availability of genomewide scans with hundreds or thousands of polymorphisms has made it possible. However, challenges and pitfalls exist in association studies, and consideration of particular features of study design is necessary before making definite conclusions from these studies.

Increased Expression of Mineralocorticoid Receptor in Human Atrial Fibrillation and a Cellular Model of Atrial Fibrillation

OBJECTIVES This study was designed to evaluate the status of steroidogenesis proteins and de novo synthesis of aldosterone in the atrium, and relationships of these factors to atrial fibrillation (AF). BACKGROUND The role of mineralocorticoid in the pathogenesis of AF is unknown. METHODS We studied atrial expression of steroidogenesis proteins and aldosterone level in patients with and without AF, and in HL-1 atrial myocytes. We also investigated the electrophysiologic effects and signal transduction of aldosterone on atrial myocytes. RESULTS We found basal expressions of mineralocorticoid receptors (MRs), glucocorticoid receptors, and 11-beta-hydroxysteroid dehydrogenase type 2 (11bHSD2) but not 11-beta-hydroxylase (CYP11B1) or aldosterone synthase (CYP11B2) in human atria and HL-1 myocytes. There was no significant difference of mean atrial aldosterone level between patients with AF and those with normal sinus rhythm. However, patients with AF had a significantly higher atrial MR expression compared with those with normal sinus rhythm (1.73 +/- 0.24-fold, p < 0.001). Using mouse HL-1 atrial myocytes as a cellular AF model, we found that rapid depolarization increased MR expression (1.97 +/- 0.72-fold, p = 0.008) through a calcium-dependent mechanism, thus augmenting the genomic effect of aldosterone signaling as evaluated by MR reporter. Aldosterone increased intracellular oxidative stress through a nongenomic pathway, which was attenuated by nicotinamide adenine dinucleotide phosphate oxidase inhibitor diphenyleneiodonium, but not by MR-blockade spironolactone. Aldosterone increased expression of the alpha-1G and -1H subunits of the T-type calcium channel and thus increased the T-type calcium current (-13.6 +/- 2.9 pA/pF vs. -4.5 +/- 1.6 pA/pF, p < 0.01) and the intracellular calcium load through a genomic pathway, which were attenuated by spironolactone, but not by diphenyleneiodonium. CONCLUSIONS Expression of MR increased in AF, thus augmenting the genomic effects of aldosterone. Aldosterone induced atrial ionic remodeling and calcium overload through a genomic pathway, which was attenuated by spironolactone. These results suggest that aldosterone may play a role in AF electrical remodeling and provide insight into the treatment of AF with MR blockade.

Comparing the survival between extracorporeal rescue and conventional resuscitation in adult in-hospital cardiac arrests: Propensity analysis of three-year data

AIM Extracorporeal cardiopulmonary resuscitation (ECPR) has been shown to have survival benefit over conventional CPR (CCPR) in patients with in-hospital cardiac arrest of cardiac origin. We compared the survival of patients who had return of spontaneous beating (ROSB) after ECPR with the survival of those who had return of spontaneous circulation (ROSC) after conventional CPR. METHODS Propensity score-matched cohort of adults with in-hospital prolonged CPR (>10min) of cardiac origin in a university-affiliated tertiary extracorporeal resuscitation center were included in this study. Fifty-nine patients with ROSB after ECPR and 63 patients with sustained ROSC by CCPR were analyzed. Main outcome measures were survival at hospital discharge, 30 days, 6 months, and one year, and neurological outcome. RESULTS There was no statistical difference in survival to discharge (29.1% of ECPR responders vs. 22.2% of CCPR responders, p=0.394) and neurological outcome at discharge and one year later. In the propensity score-matched groups, 9 out of 27 ECPR patients survived to one month (33.3%) and 7 out of 27 CCPR patients survived (25.9%). Survival analysis showed no survival difference (HR: 0.856, p=0.634, 95% CI: 0.453-1.620) between the groups, either at 30 days or at the end of one year (HR: 0.602, p=0.093, 95% CI: 0.333-1.088). CONCLUSIONS This study failed to demonstrate a survival difference between patients who had ROSB after institution of ECMO and those who had ROSC after conventional CPR. Further studies evaluating the role of ECMO in conventional CPR rescued patients are warranted.