Jih-Kai Yeh

Circadian CLOCK Mediates Activation of Transforming Growth Factor-β Signaling and Renal Fibrosis through Cyclooxygenase 2

The circadian rhythm regulates blood pressure and maintains fluid and electrolyte homeostasis with central and peripheral clock. However, the role of circadian rhythm in the pathogenesis of tubulointerstitial fibrosis remains unclear. Here, we found that the amplitudes of circadian rhythm oscillation in kidneys significantly increased after unilateral ureteral obstruction. In mice that are deficient in the circadian gene Clock, renal fibrosis and renal parenchymal damage were significantly worse after ureteral obstruction. CLOCK-deficient mice showed increased synthesis of collagen, increased oxidative stress, and greater transforming growth factor-β (TGF-β) expression. TGF-β mRNA expression oscillated with the circadian rhythms under the control of CLOCK-BMAL1 heterodimers. The expression of cyclooxygenase 2 was significantly higher in kidneys from CLOCK-deficient mice with ureteral obstruction. Treatment with a cyclooxygenase 2 inhibitor celecoxib significantly improved renal fibrosis in CLOCK-deficient mice. Taken together, these data establish the importance of the circadian rhythm in tubulointerstitial fibrosis and suggest CLOCK/TGF-β signaling as a novel therapeutic target of cyclooxygenase inhibition.

CLOCK modulates survival and acute lung injury in mice with polymicrobial sepsis.

Polymicrobial sepsis is a potentially fatal condition and a significant burden on health care systems. Acute lung injury is the most common complication of sepsis and results in high mortality. However, there has been no recent significant progress in the treatment of sepsis or acute lung injury induced by sepsis. Here we show that mice deficient in the circadian protein CLOCK had better survival than wild-type mice after induction of polymicrobial sepsis by cecal ligation and puncture. Inflammatory cytokine production was attenuated and bacterial clearance was improved in CLOCK-deficient mice. Moreover, acute lung injury after induction of sepsis was significantly decreased in CLOCK-deficient mice. Genome-wide profiling analysis showed that inhibin signaling was reduced in CLOCK-deficient mice. These data establish the importance of circadian CLOCK-inhibin signaling in sepsis, which may have potential therapeutic implications.

Circadian rhythm of RNA N6-methyladenosine and the role of cryptochrome

Methylation of RNA N(6)-methyladenosine has fundamental cellular functions, including translation regulation, RNA export, and stem cells renewal. However, the regulation of RNA N(6)-methyladenosine methylation is poorly understood. Here, we observed a robust circadian rhythm in N(6)-methyladenosine modifications of RNA. Deficiency of core mammalian clock genes, cryptochromes, decreased the levels of N(6)-methyladenosine in RNA. Cryptochrome1/2 knockout mice had significantly lower N(6)-methyladenosine methylation of RNA and lost the circadian rhythm of N(6)-methyladenosine levels in RNA. Global analysis of the circadian methylomes of N(6)-methyladenosine in RNA revealed that gene transcription, translation regulation, and RNA metabolism were highly correlated with N(6)-methyladenosine oscillation. Our findings extended a fundamental link between the circadian rhythm and N(6)-methyladenosine modification of RNA and suggested that this link is critical in controlling post-transcriptional gene expression and RNA metabolism.

Serum irisin levels are associated with adverse cardiovascular outcomes in patients with acute myocardial infarction

Irisin, a recently identified myokine, regulates mitochondrial function and energy expenditure. The concentration of irisin is significantly altered after ST-elevation myocardial infarction (STEMI). We hypothesized that serum irisin concentration is associated with adverse cardiovascular outcomes after myocardial infarction. Serum irisin concentrations were measured using enzyme-linked immunosorbent assay (ELISA) in 399 patients 28d after the onset of STEMI in a prospective single-center cohort study. We assessed the association between irisin concentrations and adverse cardiovascular events during a 3-year follow-up. The excess risks of cardiovascular mortality, stroke, heart failure, and revascularization were predominantly seen among those with the highest concentrations of irisin, with concentrations higher than 75th percentile of the overall distribution had a ~4-fold increase in risk (hazard ratio=3.96, 95% confidence interval 1.55 to 10.11, P<0.01). Our findings showed that serum concentrations of irisin are elevated in post-STEMI patients with increased risk for adverse cardiovascular events. Novel therapies targeting irisin may represent a new direction in the treatment of STEMI.

Clinical outcomes of peripartum cardiomyopathy: a 15-year nationwide population-based study in Asia

Abstract Peripartum cardiomyopathy (PPCM) is the development of heart failure during late pregnancy to months postpartum with potential fatal outcome. However, the disease is not well-studied in Asia. We aimed to investigate the epidemiology and clinical outcomes of PPCM in Taiwan. Electronic medical records were retrieved from Taiwan National Health Insurance Research Database from 1997 to 2011. Patients with PPCM were separated into 3 groups based on the timing of diagnosis. Early: PPCM diagnosed first to ninth month of pregnancy. Traditional: PPCM diagnosed last month of pregnancy till fifth month post-delivery. Late: PPCM diagnosed sixth to twelfth month post-delivery. Primary outcomes defined as cardiac death, all-cause mortality, and major adverse cardiovascular events (MACE) within 1 year. A total of 3,506,081 deliveries during 1997 to 2011 were retrieved and 925 patients with PPCM were identified. Overall incidence of PPCM was 1:3,790 during the 15 years. Early, Traditional, and Late group each had 88, 742, and 95 patients. Cardiac death occurred in 31 patients, all-cause mortality in 72 patients, and MACE in 65 patients. Late group had 2- to 3-fold event rates in cardiac death, all-cause mortality, and MACE compared with Early and Traditional groups. Cumulative incidence showed significant differences for cardiac death (P = .0011), all-cause mortality (P = .0031), and MACE (P = .0014) among 3 groups. Multivariate Cox model showed Late group had significantly worse outcomes after adjusted for clinical variables compared with 2 other groups. Our study is the largest national cohort among Asian countries that showed timing of diagnosis of PPCM had different outcomes. Late diagnosis portended significantly increased morbidity and mortality, even after adjusted for clinical variables.

Predictors of subsequent myocardial infarction, stroke, and death in stable post-myocardial infarction patients: A nationwide cohort study

Background: This study investigated the predictors of subsequent cardiovascular events in stable post-myocardial infarction patients in Taiwan. Methods: A total of 11,183 patients were recruited who had survived one year post-myocardial infarction without subsequent events of recurrent myocardial infarction or stroke from the Taiwan National Health Insurance Research Database. Their composite cardiovascular event rates were identified. Results: The composite cardiovascular events rate in three year follow-up in the post-myocardial infarction population was 13.8%. Corresponding event rates were 5.8% recurrent myocardial infarction, 5.0% stroke, and 5.2% death. Independent factors associated with a higher risk of ischemic events or death included heart failure (hazard ratio (HR)=1.19), hypertension (HR=1.16), age (65–75 vs <65 years: HR=1.29; 75–85 vs <65 years: HR=1.50; >85 vs <65 years: HR=1.70), diabetes (HR=1.33), prior stroke (HR=1.24), chronic kidney disease (HR=1.4), atrial fibrillation (HR=1.27), and underutilization of guideline-based medication (HR=1.73). Composite risk for myocardial infarction, stroke and death increased progressively from 4.9% in patients with zero risk factor to 100.0% in patients with eight risk factors. Conclusions: For acute myocardial infarction patients surviving one year without subsequent events of recurrent myocardial infarction or stroke, the risk of cardiovascular events remained high. Eight predictors identified patients at increased risk for subsequent cardiovascular events within the next three years. These results suggest an unmet need, particularly in patients with additional risk factors.

Conjunction of Endocardial and Coronary Venous System Mapping to Ablate Ventricular Arrhythmias

BACKGROUND Ablation of idiopathic ventricular arrhythmias (VAs) with epicardial or intramural origins is technically challenging. Herein, we have described the successful ablation of left VAs via the coronary venous system (CVS) in conjunction with endocardial map guided by three-dimensional electroanatomical map in six patients. METHODS Out of a total consecutive 84 patients with symptomatic idiopathic VAs, radiofrequency ablation via the CVS was performed on six patients (7%). Furthermore, we reviewed patient records and electrophysiologic studies with respect to clinical characteristics. RESULTS Activation map was conducted in 5 patients, and the earliest activation sites were identified within the CVS. The preceding times to the onset of QRS complex were longer than those at the earliest endocardial sites (36.2 ± 5.6 ms vs. 14.2 ± 6.4 ms, p = 0.02, n = 5). Spiky fractionated long-duration potentials were recorded at the successful ablation sites in all 5 patients. The other patient received pacemapping only because of few spontaneous VAs during the procedure, and the best pacemap spot was found within the CVS. Irrigated catheters were required in 4 out of 6 patients because VAs were temporarily suppressed with regular ones. CONCLUSIONS Idiopathic VAs can be ablated via the CVS in conjunction with endocardial mapping. Additionally, spiky fractionated long-duration potential can function as a clue to identify the good ablation site.

Complete and incomplete revascularization in non-ST segment myocardial infarction with multivessel disease: long-term outcomes of first- and second-generation drug-eluting stents

The therapeutic effects of reperfusion strategies with complete revascularization (CR) or incomplete revascularization (IR) in non-ST segment myocardial infarction (NSTEMI) patients with multivessel disease (MVD) are controversial. In such patients, whether utilization of different generations of drug-eluting stents (DES) for IR or CR affect long-term major adverse cardiovascular events (MACE) is unknown. This study included 702 NSTEMI patients with MVD who received first-generation (1G) or second-generation (2G) DES. In multivariable analysis, chronic kidney disease, chronic total, 1G DES and IR were independent predictors of long-term MACE. In patients receiving 1G DES, no significant differences of MACE were observed between the IR and CR groups (39.1% vs. 36.2%, p = 0.854). However, in patients receiving 2G DES, significantly fewer MACE were observed in the CR group than in the IR group (3.7% vs. 10.2%, p = 0.002). Compared with patients receiving 1G DES for IR, those receiving 2G DES for IR and CR exhibited significantly lower risk of MACE (59% and 83% lower, respectively). CR could not provide clinical benefits over IR in NSTEMI patients with MVD receiving 1G DES. However, in patients receiving 2G DES, compared with IR, CR was associated with a lower risk of long-term MACE, which was mainly caused by low rates of non-TLR and any revascularization.

Predictors of Long-Term Outcomes After Drug-Eluting Balloon Angioplasty for Bare-Metal Stent Restenosis

BACKGROUND Clinical trials have investigated efficacy of drug-eluting balloon (DEB) angioplasty for bare-metal stent (BMS) in-stent restenosis (ISR). Few studies have investigated predictors of long-term outcomes following BMS-ISR treatment with DEB. METHODS From June 2011 to April 2015, 105 patients with 125 BMS-ISR lesions were enrolled from the Cardiovascular Atherosclerosis and Percutaneous TrAnsluminal INterventions (CAPTAIN) registry. All these lesions were treated with DEB angioplasty as final therapy. The major adverse cardiac events (MACEs) were recurrent clinically driven target lesion revascularisation (TLR), myocardial infarction, and cardiac death after DEB angioplasty. RESULTS After DEB angioplasty, the angiographic stenosis decreased from 84.8%±12.4% to 22.6%±10.4%. Over a mean follow-up duration of 21.7±13.4months, the rates of TLR at 1-12 months and 12-48 months were 4.8% and 4.2%, respectively. The rates of MACEs at 1-12 months and 12-48 months were 6.7% and 6.1%, respectively. Chronic haemodialysis, calcified lesion, chronic total occlusion lesion before stenting, stent with metal-to-artery ratio >16.5%, and residual stenosis >25% after DEB angioplasty were potential risk factors for MACEs in univariate analysis. After adjustment in multivariate analysis, independent predictors of long-term MACEs were identified as chronic haemodialysis, chronic total occlusion lesion before stenting, and residual stenosis >25% after DEB angioplasty. CONCLUSIONS The long-term results of DEB angioplasty for BMS-ISR are acceptable in this real-world registry. Patient (chronic haemodialysis), lesion (chronic total occlusion) and angioplasty (residual stenosis percentage) related factors predicted long-term outcomes following BMS-ISR treatment with DEB angioplasty.