Yen Bin Liu

Sympathetic Nerve Sprouting, Electrical Remodeling, and Increased Vulnerability to Ventricular Fibrillation in Hypercholesterolemic Rabbits

Abstract— Whether hypercholesterolemia (HC) can induce proarrhythmic neural and electrophysiological remodeling is unclear. We fed rabbits with either high cholesterol (HC, n=10) or standard (S, n=10) chows for 12 weeks (protocol 1), and with HC (n=12) or S (n=10) chows for 8 weeks (protocol 2). In protocol 3, 10 rabbits were fed with various protocols to observe the effects of different serum cholesterol levels. Results showed that the serum cholesterol levels were 2097±288 mg/dL in HC group and 59±9 mg/dL in S group for protocol 1 and were 1889±577 mg/dL in HC group and 50±21 mg/dL in S group for protocol 2. Density of growth-associated protein 43– (GAP43) and tyrosine hydroxylase– (TH) positive nerves in the heart was significantly higher in HC than S in protocol 1. Compared with S, HC rabbits had longer QTc intervals, more QTc dispersion, longer action potential duration, increased heterogeneity of repolarization and higher peak calcium current (ICa) density (14.0±3.1 versus 9.1±3.4 pA/pF;P <0.01) in protocol 1 and 2. Ventricular fibrillation was either induced or occurred spontaneously in 9/12 of hearts of HC group and 2/10 of hearts in S group in protocol 2. Protocol 3 showed a strong correlation between serum cholesterol level and nerve density for GAP43 (R2=0.94;P <0.001) and TH (R2=0.91;P <0.001). We conclude that HC resulted in nerve sprouting, sympathetic hyperinnervation, and increased ICa. The neural and electrophysiological remodeling was associated with prolonged action potential duration, longer QTc intervals, increased repolarization dispersion, and increased ventricular vulnerability to fibrillation.

Coexistence of two types of ventricular fibrillation during acute regional ischemia in rabbit ventricle.

Introduction: We previously reported that a normal ventricle can demonstrate two types of ventricular fibrillation (VF), depending on the underlying electrophysiologic characteristics at the time of VF induction. We hypothesize that the two types of VF can coexist in acutely ischemic ventricles.

2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the management of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained arrhythmia. Both the incidence and prevalence of AF are increasing, and the burden of AF is becoming huge. Many innovative advances have emerged in the past decade for the diagnosis and management of AF, including a new scoring system for the prediction of stroke and bleeding events, the introduction of non-vitamin K antagonist oral anticoagulants and their special benefits in Asians, new rhythm- and rate-control concepts, optimal endpoints of rate control, upstream therapy, life-style modification to prevent AF recurrence, and new ablation techniques. The Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology aimed to update the information and have appointed a jointed writing committee for new AF guidelines. The writing committee members comprehensively reviewed and summarized the literature, and completed the 2016 Guidelines of the Taiwan Heart Rhythm Society and the Taiwan Society of Cardiology for the Management of Atrial Fibrillation. This guideline presents the details of the updated recommendations, along with their background and rationale, focusing on data unique for Asians. The guidelines are not mandatory, and members of the writing committee fully realize that treatment of AF should be individualized. The physicians decision remains most important in AF management.

Downregulated myocardial connexin 43 and suppressed contractility in rabbits subjected to a cholesterol-enriched diet

The effects of hypercholesterolemia on the myocardium per se include electrophysiological and mechanical alterations. Since gap junctions are essential in electromechanical coupling throughout the heart, we examined the correlation between the temporal expression of cardiac connexin 43 (Cx43), contractile function, and conduction velocity in cholesterol-fed rabbits. After a 12-week feeding period, serum cholesterol levels gradually increased (P<0.001). In contrast, expression of cardiomyocyte Cx43 protein progressively decreased (60% reduction at 12 weeks, P<0.001). Such a reduction was also demonstrated by immunoconfocal microscopy, which further showed redistribution of Cx43 gap junctions at the lateral cell membrane. The downregulation of Cx43 protein was associated with increased levels of Cx43 mRNA (3.5 -fold at 12 weeks, P<0.001) and phosphorylated c-Jun N-terminal kinase (three-fold at 12 weeks, P=0.001). Functionally, although fractional shortening of the left ventricle remained unchanged throughout the feeding protocol, the cholesterol-fed rabbits had a reduced cardiac cycle-dependent variation of integrated backscatters, a decreased mitral ring systolic velocity, and an increased modified Tei index (all P<0.001), all of which indicated impaired intrinsic myocardial contractility and attenuated ventricular systolic performance. In Langendorff-perfused hearts of cholesterol-fed rabbits, decreased conduction velocity was observed (P<0.005). Withdrawal of the cholesterol-enriched diet for 18 weeks restored the contractile parameters and Cx43 protein expression. These findings suggest that Cx43 is highly involved in the molecular mechanism of hypercholesterolemia-induced cardiac contractile dysfunction and dysrhythmias.

Optical mapping of myocardial reactive oxygen species production throughout the reperfusion of global ischemia.

Reactive oxygen species (ROS) are short-lived, highly reactive chemical entities that play significant roles in all levels of biology. However, their measurement requires destructive preparation, thereby limiting the continuous measurement of ROS in a living tissue. We develop an optical mapping system to visualize ROS production in an isolated and perfused rat heart. By staining the heart with dihydroethidium (DHE), a 532-nm laser beam is directed to the epicardial surface, where we collect the red fluorescence (>600 nm) for semiquantitative analysis. With this system, ROS production as well as ventricular pressure and ECG in isolated perfused rat hearts are monitored throughout the reperfusion of global ischemia. Ischemia would decrease myocardial ROS production, while reperfusion would immediately result in sustained ROS overproduction. Optical mapping would provide information regarding the spatial distribution and temporal evolution of myocardial ROS production, which would enhance knowledge of the role of free radicals in cardiovascular biology.

Spatial repolarization heterogeneity detected by magnetocardiography correlates with cardiac iron overload and adverse cardiac events in beta-thalassemia major

Background Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. Methods and Results Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD-QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = −0.609, p<0.001), SD-QTc (r = −0.572, p<0.001), and QTc dispersion (r = −0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*. Conclusions Multichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events.

Reducing the cyclic variations of ultrasonic integrated backscatters and myocardial electrical synchronism by reversibly blocking intercellular communications with heptanol.

The purpose of this study is to provide direct evidence for the role of intercellular communications in electrical synchronization and mechanical function of myocardium. We used heptanol, a reversible inhibitor of gap junctions, at low (0.16 mM) and high (0.5 mM) concentration as perfusate for 18 Langendorff-perfused rabbit hearts to study its effects on myocardial electrical and mechanical functions. Optical mapping was performed to measure conduction velocity (CV) and action potential duration (APD). Ultrasonic integrated backscatter and Doppler tissue imaging (DTI) were used to evaluate the intrinsic and global myocardial contractile performance. The CV decreased during low-dose heptanol infusion and became much slower at high dose (high dose vs. baseline, 50.8 +/- 10.2 cm/s vs. 69.3 +/- 8.8 cm/s, p < 0.001). After washout of heptanol, CV completely recovered. The alterations of APD by heptanol infusion were similar to CV. The APD dispersion, standard deviation of APD(80), was increased after heptanol infusion (low dose vs. baseline, 5.9 +/- 1.1 ms vs. 4.3 +/- 1.1 ms, p = 0.004; high dose, 6.0 +/- 1.3 ms, vs. baseline, p = 0.035). However, washout did not restore the APD dispersion which became even larger after washout (13.6 +/- 1.9 ms vs. high dose and baseline, both p < 0.001). Regarding contractile function, heptanol treatment resulted in a progressive decrease of cardiac cycle-dependent variations of integrated backscatter (CVIBS; low dose vs. baseline, 6.1 +/- 1.7 dB vs. 7.2 +/- 1.8 dB, p = 0.007; high dose 1.7 +/- 0.3 dB vs. baseline, p < 0.001) and peak systolic strain rate (low dose vs. baseline, -1.5 +/- 0.6 1/s vs. -1.9 +/- 0.6 1/s, p = 0.014; high dose -0.4 +/- 0.2 1/s; vs. baseline, p < 0.001). That both CVIBS and strain rate incompletely recovered after heptanol washout may be attributed to the increased APD dispersion. In conclusion, uncoupling of gap junctions resulted in slowing CV, increased repolarization heterogeneity, reduced CVIBS and impaired myocardial contractility. There was a reversible dose-response relationship between the myocardial electromechanical functions and gap junction coupling.

Reduced enhancement of high-frequency component in the cross spectrum of ECG and nostril airflow signals in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a chronic airway disease with increased airway resistance. This study investigated the common characteristics of electrocardiographic (ECG) and nostril airflow signals in COPD patients using cross‐spectral analysis. Heart rate variability (HRV) measures and cross‐spectral (cs) measures of ECG and nostril airflow were compared in COPD patients and normal subjects, and correlated with their clinical characteristics. We found that cross‐spectral analysis can lead to a significant increase in normalized high‐frequency power (nHFPcs) and a significant decrease in normalized very low‐frequency power (nVLFPcs), normalized low‐frequency power (nLFPcs), and low‐/high‐frequency power ratio (LHRcs) in both normal subjects and COPD patients, as compared with their corresponding HRV measures. Further analysis showed that the percentage increase in nHFP (%nHFP) and the percentage decrease in LHR (%LHR) due to cross‐spectral analysis in COPD patients were significantly smaller than those of normal subjects. All cross‐spectral measures of ECG and nostril airflow in COPD patients did not significantly correlate with their pulmonary function characteristics. However, the nHFPcs correlated significantly and negatively with body mass index (BMI) in both normal subjects and COPD patients, and the %nHFP correlated significantly and negatively with BMI in COPD patients. We conclude that cross‐spectral analysis of ECG and nostril airflow signals could lead to reduced enhancement in the high‐frequency component in the cross spectrum of COPD patients. The magnitude of reduced enhancement in the high‐frequency component in the cross‐spectrum was related to the BMI of the patients. Cross‐spectral analysis of ECG and nostril airflow might be used to assess the cardiovascular‐related functions of COPD patients.

Visualizing inflammatory activity in isolated perfused rat hearts

Inflammation is a defense mechanism against various noxious stimuli. The recruitment of host leukocytes to sites of injury results in increased regional microvascular leakage and reactive oxygen species (ROS) generation. Excessive inflammatory activity not only eliminates offending stimuli but also result in tissue damage, as evidenced in reperfusion injury of the heart. To investigate spatial-temporal evolution of acute inflammation after myocardial reperfusion injury, we monitored microvascular leakage and reactive oxygen species generation with optical mapping technique. Reperfusion injury was performed on isolated blood-perfused rat heart, and it was labeled with dihydroethidium and large molecular weight tetramethylrhodamine conjugated dextran. Tissue was illuminated with a 532 nm laser, and epifluorescence at 580 and 650 nm was collected through 2 separate band pass filters. Our results indicate that 1. Optical mapping of myocardial inflammation is feasible; and 2. Reperfusion injury elicits substantial microvascular leakage and ROS production.