Yi-Hsin Chan

Incremental Value of Inefficient Deformation Indices for Predicting Response to Cardiac Resynchronization Therapy

BACKGROUND Previous studies have identified four clinical characteristics associated with a favorable response to cardiac resynchronization therapy (CRT): female gender, left bundle branch block (LBBB), QRS duration ≥ 150 msec, and nonischemic etiology of heart failure. The aim of this study was to evaluate the incremental value of baseline inefficient deformation and time delay indices over clinical characteristics for predicting CRT response. METHODS Speckle-tracking longitudinal strain was analyzed in 119 CRT candidates. Patients were divided into subgroups according to sex (male vs. female), QRS morphology (LBBB vs. non-LBBB), QRS duration (≥150 vs. <150 msec), and heart failure etiology (ischemic vs nonischemic). Inefficient deformation was indexed by the septal systolic stretching that occurred after prematurely terminated shortening (systolic rebound stretch in the septal wall) and the absolute differences between peak strain and end-systolic strain across 16 segments (strain delay index). Time to peak strain was measured to derive the septal-to-lateral delay and the 12-segment standard deviation of time to peak strain. CRT response was defined as 6-month end-systolic volume reduction ≥ 15%. RESULTS Patients with one of the four favorable characteristics were more likely to exhibit other favorable characteristics and had greater amounts of inefficient deformation than those without. In contrast, time delay indices were not significantly different in any pairwise comparison except for that between patients with and those without LBBB. Of the 43 patients for whom 6-month follow-up data were available, CRT response was found in 26 (60%). Systolic rebound stretch in the septal wall and strain delay index rather than time delay indices provided significant incremental value over clinical characteristics when predicting CRT response. CONCLUSIONS Combined systolic rebound stretch in the septal wall (or strain delay index) and favorable characteristics may help identify CRT responders.

Prognostic value of global left ventricular strain for conservatively treated patients with symptomatic aortic stenosis

AIMS Impaired left ventricular (LV) strain is associated with an increased risk of cardiac events in asymptomatic severe aortic stenosis (AS). We aimed to evaluate the prognostic value of global LV strain in conservatively treated patients with symptomatic AS. METHODS AND RESULTS This cohort study retrospectively reviewed symptomatic AS patients who were treated conservatively or surgically between July 2007 and April 2010. We measured their global longitudinal strain (GLS) and global circumferential strain (GCS). Clinical events were defined as readmission for heart failure or all-cause death for 2 years. GLS and GCS could predict a worse outcome in the conservatively treated group at cut-offs of =-16.5% (77% sensitivity and 67% specificity) and =-22.2% (92% sensitivity and 83% specificity), respectively. By univariate Cox regression analysis, age, logistic EuroSCORE, aortic valve area, GLS, and GCS were significant predictors. When adjusted for age, logistic EuroSCORE, and aortic valve area, impaired GLS and GCS were independently associated with a higher risk of clinical events. CONCLUSION In conservatively treated patients with symptomatic AS, impaired GLS and GCS were associated with an increased risk of cardiac events during a 2-year follow-up. Global LV strain may help to define a higher risk subset; therefore, a larger and prospective observation study would be necessary.

Incremental value of radial discoordination index for the prediction of response to cardiac resynchronization therapy

AIMS Previous studies have identified four baseline characteristics associated with a favourable response to cardiac resynchronization therapy (CRT): female, non-ischaemic aetiology of heart failure, left bundle-branch block (LBBB), and QRS duration ≥150 ms. This study evaluated the incremental value of discoordination and dyssynchrony indices over these characteristics for the prediction of the response to CRT. METHODS AND RESULTS The speckle-tracking strain analysis was performed in 120 CRT candidates. Patients were divided into subgroups according to the gender (male vs. female), aetiology of heart failure (ischaemic vs. non-ischaemic), QRS morphology (LBBB vs. non-LBBB), and QRS duration (≥150 vs. <150 ms), respectively. Discoordination was measured using the mid-ventricular radial discoordination index (RDI-M), the ratio of the average mid-ventricular thinning to thickening during ejection. Patients with one of the four favourable characteristics were more likely to exhibit other favourable characteristics and had greater amounts of average myocardial thinning during ejection and RDI-M than those without (all P< 0.05). In contrast, dyssynchrony indices failed to demonstrate significant differences between male and female and between ischaemic and non-ischaemic subjects. Of 39 patients who had 6-month follow-up data after CRT, left ventricular reverse remodelling was found in 22 patients (56%). Combining the favourable characteristics and RDI-M provides the best ability to predict reverse remodelling after CRT (area under the curve = 0.85, 95% confidence interval 0.73-0.98, P < 0.001). CONCLUSION Mechanical discoordination rather than mechanical dyssynchrony provides a significant incremental value over the baseline characteristics for the prediction of the response to CRT.

Young Male Patients with Atrial Fibrillation and CHA2DS2-VASc Score of 1 May Not Need Anticoagulants: A Nationwide Population-Based Study

Background It is unclear whether oral anticoagulants are beneficial for atrial fibrillation (AF) patients with low CHA2DS2-VASc score. Age could be important in determining the risk of thromboembolism in low risk AF patients (CHA2DS2-VASc score of 1 for male or 2 for female). Methods The Taiwan National Health Insurance Research Database (NHIRD) was used and 27,521 AF patients with CHA2DS2-VASc score of 1 (male) or 2 (female) not receiving anticoagulants were acquired as the study cohort, which were classified into three age groups: 20–49, 50–64, and 65–74 years. The clinical endpoint was the occurrence of ischemic thromboembolism within one year of follow up. Results During the follow-up of 0.94 ± 0.19 years, 385 (2.19%) male patients experienced ischemic thromboembolism, with annual rate of 2.32%. The annual risk ranged from 1.29%, 2.43% to 2.77% for male patients aged 20–49, 50–64 and 65–74 years respectively. Of the female patients, 218 (2.20%) experienced clinical event with annual rate of 2.32%. The annual risk increased from 1.87%, 2.28% to 2.64% for female patients aged 20–49, 50–64 and 65–74 years respectively. There was no difference in risk between the male patients aged 20–49 years with CHA2DS2-VASc score of 1 and overall male patients with CHA2DS2-VASc score of 0. (P = 0.631) The female patients aged 20–49 years with CHA2DS2-VASc score of 2 was associated with a higher risk of thromboembolic events than overall female patients with CHA2DS2-VASc score of 1 (HR = 1.93; P = 0.008). Conclusions Age is important in determining the risk of thromboembolism in AF patients with single risk factor. In male patients <50 years old with CHA2DS2-VASc score of 1, the risk of ischemic thromboembolism was low. Considering the benefits and the risk of bleeding, oral anticoagulation therapy may not be favorable in these patients.

Combined Global Longitudinal Strain and Intraventricular Mechanical Dyssynchrony Predicts Long-Term Outcome in Patients With Systolic Heart Failure.

BACKGROUND Left ventricular (LV) ejection fraction (EF) and QRS duration enable prediction of outcome in patients with systolic heart failure (SHF). We assessed the predictive value of global longitudinal strain (GLS) and mechanical dyssynchrony for prognosis in SHF patients. METHODS AND RESULTS Two-hundred and forty SHF patients with LVEF ≤40% were studied. Global LV function and intraventricular mechanical dyssynchrony were calculated as GLS and SD of the time to peak longitudinal strain (SDε) over 18 LV segments. The added value of GLS and SDε for outcome prediction was assessed using nested Cox models. Sixty-six patients (28%) reached the study endpoint of all-cause mortality/heart transplantation over a median follow-up period of 45 months. Baseline variables associated with adverse outcome were age, glomerular filtration rate, pulmonary artery systolic pressure, diabetes and LV end-systolic volume (model χ(2)=69.8). The predictive power of the clinical variables was greater with addition of GLS (χ(2)=81.1) or SDε (χ(2)=102.3) than with LVEF (χ(2)=73.9) or QRS duration (χ(2)=75.5; both P<0.005). GLS (HR, 1.88; P=0.03) and SDε (HR, 1.48; P=0.04) were independent predictors after adjustment for the baseline variables. Patients with impaired GLS (≥-7.8%) and mechanical dyssynchrony (SDε ≥72 ms) had poor outcome. CONCLUSIONS Combined assessment of global LV function and mechanical dyssynchrony using speckle-tracking strain enabled the prediction of long-term outcome in SHF patients.

Ratio of transmitral early filling velocity to early diastolic strain rate predicts outcomes in patients with systolic heart failure.

Aims The ratio of transmitral early filling velocity (E) to early diastolic tissue velocity (E′) is a key diastolic function parameter. The early diastolic strain rate (E′sr) has been proposed as a substitute for E′ in the E/E′ ratio for better estimation of left ventricular (LV) filling pressure. This study aims to assess the predictive value of combined E/E′sr ratio and global longitudinal strain (GLS) for prognosis in systolic heart failure (SHF). Methods and results We retrospectively analysed 330 SHF patients with an LV ejection fraction (LVEF) ⩽ 40%. Study end points were defined as all-cause mortality or heart transplantation. The incremental value of GLS and the E/E′sr ratio over LVEF and E/E′ for outcome prediction was assessed using nested Cox models. Ninety-nine (30%) patients reached the end point over a median follow-up of 46 months. Baseline variables associated with outcomes were age, glomerular filtration rate, pulmonary artery systolic pressure, and LV end-systolic volume index. After multivariate adjustment, GLS (hazard ratio: 1.48, P = 0.025) and the E/E′sr ratio (hazard ratio: 1.41, P = 0.002) were both independent predictors. LVEF or E/E′ was not an independent predictor when GLS and E/E′sr were included in the model. Patients with impaired GLS (absolute value <7.5%) and elevated E/E′sr ratios (E/E′sr ≥ 195 cm) showed poor outcomes. Conclusion The E/E′sr ratio is stronger than E/E′ ratio in predicting prognosis of patients with systolic HF. Combined assessments of GLS and E/E′sr by speckle-tracking longitudinal strain facilitate risk stratification of these patients.

MMP9 Rs3918242 Polymorphism Affects Tachycardia-Induced MMP9 Expression in Cultured Atrial-Derived Myocytes but Is Not a Risk Factor for Atrial Fibrillation among the Taiwanese

Matrix metalloproteinase (MMP) plays an important role in the pathogenesis of atrial fibrillation (AF). The MMP9 promoter has a functional polymorphism rs3918242 that can regulate the level of gene transcription. This study recruited 200 AF patients and 240 controls. The MMP9 rs3918242 was examined by polymerase chain reactions. HL-1 atrial myocytes were cultured and electrically stimulated. Right atrial appendages were obtained from six patients with AF and three controls with sinus rhythm undergoing open heart surgery. The MMP9 expression and activity were determined using immunohistochemical analysis and gelatin zymography, respectively. Rapid pacing induces MMP9 secretion from HL-1 myocytes in a time- and dose-dependent manner. The responsiveness of MMP9 transcriptional activity to tachypacing was significantly enhanced by rs3918242. The expression of MMP9 was increased in fibrillating atrial tissue than in sinus rhythm. However, the distribution of rs3918242 genotypes and allele frequencies did not significantly differ between the control and AF groups. HL-1 myocyte may secrete MMP9 in response to rapid pacing, and the secretion could be modulated by rs3918242. Although the MMP9 expression of human atrial myocyte is associated with AF, our study did not support the association of susceptibility to AF among Taiwanese subjects with the MMP9 rs3918242 polymorphism.

The risk of acute kidney injury in Asians treated with apixaban, rivaroxaban, dabigatran, or warfarin for non-valvular atrial fibrillation: A nationwide cohort study in Taiwan

BACKGROUND Whether or not non-vitamin K antagonist oral anticoagulants (NOACs) are associated with a lower risk of acute kidney injury (AKI) in patients with non-valvular atrial fibrillation (NVAF) remains unknown in real world practice. METHODS In this nationwide retrospective cohort study, 1507, 3200, 5765 and 4227 NVAF patients with chronic kidney disease (CKD) and 4368, 16,945, 22,301, and 16,908 NVAF patients without CKD taking apixaban, dabigatran, rivaroxaban, and warfarin, respectively, from June 1, 2012 to December 31, 2016 were enrolled from the Taiwan National Health Insurance Program. Propensity-score weighted method was used to balance covariates across study groups. Patients were followed until occurrence of AKI or end date of study. RESULTS Three NOACs were all associated with a significantly lower risk of AKI compared with warfarin for both CKD-free (hazard ratio, [95% confidential interval]; 0.65, [0.60-0.72] for apixaban; 0.68, [0.64-0.74] for dabigatran; 0.73, [0.68-0.79] for rivaroxaban) and CKD cohorts (0.50, [0.45-0.56] for apixaban; 0.54, [0.49-0.59] for dabigatran; 0.53, [0.49-0.58] for rivaroxaban). The annual incidence of AKI for all NOACs and warfarin increased gradually as the increment of CHA2DS2-VASc for both CKD-free and CKD cohorts after propensity score weighting. The reduced risk of AKI for three NOACs persisted in most subgroups in either CKD-free or CKD cohort. Multivariate analysis indicated that all three NOACs were all associated with lower risk of AKI than warfarin in either CKD-free or CKD cohort. CONCLUSIONS All three NOACs are associated with a lower risk of AKI than warfarin among Asians with NVAF in real-world practice.

The effectiveness and safety of low-dose rivaroxaban in Asians with non-valvular atrial fibrillation

BACKGROUND Rivaroxaban (20 mg/15 mg once daily) is an effective and safe alternative to warfarin for stroke prevention in patients with non-valvular AF (NVAF). Low-dose rivaroxaban (15 mg/10 mg once daily) has been only approved for NVAF patients in Japan and Taiwan, although its effectiveness and safety at low doses remain unclear among Asians with NVAF. The objective of the study is to compare the effectiveness and safety of low-dose rivaroxaban to those of warfarin among Asians with NVAF. METHODS This dynamic cohort study used data from the Taiwan National Health Insurance Database (NHIRD) to enroll 14,971 patients taking 15 mg rivaroxaban, 11,029 patients taking 10 mg rivaroxaban, and 16,000 NVAF patients taking warfarin. Inverse probability of weighting using propensity scores was used to balance covariates across study groups. RESULTS The adjusted hazard ratio [95% confidence interval] comparing rivaroxaban 15 and 10 mg with warfarin (reference) was as follows: ischemic stroke/systemic embolism, 0.84 [0.74-0.96; P = 0.0080], and 0.84 [0.73-0.96; P = 0.0097]; myocardial infarction, 0.53 [0.37-0.74; P = 0.0002], and 0.88 [0.65-1.19; P = 0.3910]; intracranial hemorrhage, 0.44 [0.34-0.55; P < 0.0001], and 0.53 [0.42-0.66; P < 0.0001]; major gastrointestinal bleeding, 0.82 [0.67-0.99; P = 0.0387], and 0.58 [0.47-0.72; P < 0.0001]; all hospitalized major bleeding, 0.63 [0.55-0.73; P < 0.0001], and 0.56 [0.48-0.65; P < 0.0001]; and all-cause mortality, 0.55 [0.51-0.60; P < 0.0001], and 0.58 [0.53-0.63; P < 0.0001]. CONCLUSIONS Both low doses of rivaroxaban were associated with a lower risk of ischemic stroke/systemic embolism, intracranial hemorrhage, gastrointestinal bleeding, all major bleeding, and all-cause mortality compared with warfarin in Asian NVAF patients. The 15 mg rivaroxaban dose was associated with a lower risk of acute myocardial infarction compared to warfarin.

Association evidence of CCTTT repeat polymorphism in the iNOS promoter and the risk of atrial fibrillation in Taiwanese

Inducible nitric oxide synthase (iNOS) plays an important role in the pathogenesis of atrial fibrillation (AF). The iNOS promoter has a CCTTT-repeat length polymorphism that can determine the level of gene transcription. This study enrolled 200 AF patients and 240 controls. The length of CCTTT-repeat polymorphism in the iNOS promoter region was examined by polymerase chain reactions, with the alleles with ≤11 repeats designated as S and alleles with ≥12 repeats designated as L alleles. AF patients carried significantly higher frequencies of the LL genotype than control subjects (40.0% versus 28.3%, P = 0.010). Multivariate analysis showed that the presence of LL genotype was significantly associated with AF (odds ratio: 1.87, 95% CI = 1.10–3.17, P = 0.021). In vitro, transient transfection assay in HL-1 atrial myocytes showed that the responsiveness of iNOS transcriptional activity to tachypacing was correlated with the length of the CCTTT-repeats. Right atrial tissues from patients with chronic AF were investigated with immunoconfocal microscopy. Patients with LL genotype exhibited greater oxidative stress and substrate remodeling in their atria than those with non-LL genotypes. Our results suggest that the iNOS microsatellite polymorphism may contribute to the genetic background of AF in Chinese-Taiwanese patients.