Krekwit Shinlapawittayatorn

Low-amplitude, left vagus nerve stimulation significantly attenuates ventricular dysfunction and infarct size through prevention of mitochondrial dysfunction during acute ischemia-reperfusion injury

BACKGROUND Right cervical vagus nerve stimulation (VNS) provides cardioprotective effects against acute ischemia-reperfusion injury in small animals. However, inconsistent findings have been reported. OBJECTIVE To determine whether low-amplitude, left cervical VNS applied either intermittently or continuously imparts cardioprotection against acute ischemia-reperfusion injury. METHODS Thirty-two isoflurane-anesthetized swine (25-30 kg) were randomized into 4 groups: control (sham operated, no VNS), continuous-VNS (C-VNS; 3.5 mA, 20 Hz), intermittent-VNS (I-VNS; continuously recurring cycles of 21-second ON, 30-second OFF), and I-VNS + atropine (1 mg/kg). Left cervical VNS was applied immediately after left anterior descending artery occlusion (60 minutes) and continued until the end of reperfusion (120 minutes). The ischemic and nonischemic myocardium was harvested for cardiac mitochondrial function assessment. RESULTS VNS significantly reduced infarct size, improved ventricular function, decreased ventricular fibrillation episodes, and attenuated cardiac mitochondrial reactive oxygen species production, depolarization, and swelling, compared with the control group. However, I-VNS produced the most profound cardioprotective effects, particularly infarct size reduction and decreased ventricular fibrillation episodes, compared to both I-VNS + atropine and C-VNS. These beneficial effects of VNS were abolished by atropine. CONCLUSIONS During ischemia-reperfusion injury, both C-VNS and I-VNS provide significant cardioprotective effects compared with I-VNS + atropine. These beneficial effects were abolished by muscarinic blockade, suggesting the importance of muscarinic receptor modulation during VNS. The protective effects of VNS could be due to its protection of mitochondrial function during ischemia-reperfusion.

Vagus nerve stimulation initiated late during ischemia, but not reperfusion, exerts cardioprotection via amelioration of cardiac mitochondrial dysfunction

BACKGROUND We previously reported that vagus nerve stimulation (VNS) applied immediately at the onset of cardiac ischemia provides cardioprotection against cardiac ischemic-reperfusion (I/R) injury. OBJECTIVE This study aimed to determine whether VNS applied during ischemia or at the onset of reperfusion exerts differential cardioprotection against cardiac I/R injury. METHODS Twenty-eight swine (25-30 kg) were randomized into 4 groups: Control (sham-operated, no VNS), VNS-ischemia (VNS applied during ischemia), VNS-reperfusion (VNS applied during reperfusion), and VNS-ischemia+atropine (VNS applied during ischemia with 1 mg/kg atropine administration). Ischemia was induced by left anterior descending (LAD) coronary artery occlusion for 60 minutes, followed by 120 minutes of reperfusion. VNS was applied either 30 minutes after LAD coronary artery occlusion or at the onset of reperfusion and continued until the end of reperfusion. Cardiac function, infarct size, myocardial levels of connexin 43, cytochrome c, tumor necrosis factor α, and interleukin 4, and cardiac mitochondrial function were determined. RESULTS VNS applied 30 minutes after LAD coronary artery occlusion, but not at reperfusion, markedly reduced ventricular fibrillation incidence and infarct size (~59%), improved cardiac function; attenuated cardiac mitochondrial reactive oxygen species production, depolarization, swelling, and cytochrome c release; and increased the amount of phosphorylated connexin 43 and interleukin 4 as compared with the Control group. These beneficial effects of VNS were abolished by atropine. CONCLUSION VNS could provide significant cardioprotective effects even when initiated later during ischemia, but was not effective after reperfusion. These findings indicate the importance of timing of VNS initiation and warrant the potential clinical application of VNS in protecting myocardium at risk of I/R injury.

Continuous positive airway pressure therapy for obstructive sleep apnea reduces interictal epileptiform discharges in adults with epilepsy.

Obstructive sleep apnea (OSA) is highly prevalent, affecting 25% of men and 10% of women. We recently reported a prevalence of OSA of 30% among 130 adults with epilepsy unselected for sleep disorder complaints, including 16% with moderate-to-severe disease, rates that markedly exceed general population estimates. Treatment of OSA with continuous positive airway pressure (CPAP) therapy or upper airway surgery reduces seizures in many cases. A single study reported a reduction in interictal spike rate with CPAP in 6 patients with OSA. We explored the effect of CPAP therapy on spike rate in 9 adults with epilepsy and OSA. Interictal epileptiform discharges were quantified during a diagnostic polysomnogram (PSG) and a second PSG using therapeutic CPAP. Spike rates were calculated for each recording during wake and sleep stages. Continuous positive airway pressure therapy was associated with significant reductions in median (quartiles) spike rate overall (77.9 [59.7-90.7] %), in wakefulness (38.5 [0.3-55] %), and in sleep (77.7 [54.8-94.7] %) but not in REM sleep. Continuous positive airway pressure therapy also produced a significant improvement in oxygen saturation and arousals. Our work extends a single prior observation demonstrating beneficial effects of CPAP therapy on interictal EEG in patients with epilepsy with comorbid OSA and supports the hypothesis that sleep fragmentation due to OSA contributes to epileptogenicity.

Effects of Sildenafil Citrate on Defibrillation Efficacy

Introduction: Although fatal arrhythmia and sudden death have been reported in patients taking sildenafil citrate, its effect on defibrillation efficacy has not been investigated. The aim of this study was to test the hypothesis that sildenafil citrate increases the shock strength required to successfully defibrillate during ventricular fibrillation (VF).

Vagus Nerve Stimulation Exerts the Neuroprotective Effects in Obese-Insulin Resistant Rats, Leading to the Improvement of Cognitive Function

Vagus nerve stimulation (VNS) therapy was shown to improve peripheral insulin sensitivity. However, the effects of chronic VNS therapy on brain insulin sensitivity, dendritic spine density, brain mitochondrial function, apoptosis and cognition in obese-insulin resistant subjects have never been investigated. Male Wistar rats (n = 24) were fed with either a normal diet (n = 8) or a HFD (n = 16) for 12 weeks. At week 13, HFD-fed rats were divided into 2 groups (n = 8/group). Each group was received either sham therapy or VNS therapy for an additional 12 weeks. At the end of treatment, cognitive function, metabolic parameters, brain insulin sensitivity, brain mitochondrial function, brain apoptosis, and dendritic spines were determined in each rat. The HFD-fed with Sham therapy developed brain insulin resistance, brain oxidative stress, brain inflammation, and brain apoptosis, resulting in the cognitive decline. The VNS group showed an improvement in peripheral and brain insulin sensitivity. VNS treatment attenuated brain mitochondrial dysfunction and cell apoptosis. In addition, VNS therapy increased dendritic spine density and improved cognitive function. These findings suggest that VNS attenuates cognitive decline in obese-insulin resistant rats by attenuating brain mitochondrial dysfunction, improving brain insulin sensitivity, decreasing cell apoptosis, and increasing dendritic spine density.

Vagus Nerve Stimulation Improves Cardiac Function by Preventing Mitochondrial Dysfunction in Obese-Insulin Resistant Rats.

Long-term high-fat diet (HFD) consumption leads to not only obese-insulin resistance, but also impaired left ventricular (LV) function. Vagus nerve stimulation (VNS) has been shown to exert cardioprotection. However, its effects on the heart and metabolic parameters under obese-insulin resistant condition is not known. We determined the effects of VNS on metabolic parameters, heart rate variability (HRV) and LV function in obese-insulin resistant rats. Male Wistar rats were fed with HFD for 12 weeks, and were randomly divided into sham and VNS groups. VNS was applied for the next 12 weeks. Echocardiography, blood pressure and HRV were examined. Blood samples were collected for metabolic parameters. At the end, the heart was removed for determination of apoptosis, inflammation, oxidative stress, and cardiac mitochondrial function. VNS for 12 weeks significantly decreased plasma insulin, HOMA index, total cholesterol, triglyceride, LDL and visceral fat. Serum adiponectin was significantly increased in the VNS group. VNS also significantly decreased blood pressure, improved HRV and LV function, decreased cardiac MDA, TNF-α and Bax levels, and improved cardiac mitochondrial function. VNS improves metabolic and hemodynamic parameters, and the LV function via its ability against apoptosis, inflammation and oxidative stress, and preserved cardiac mitochondrial function in obese-insulin resistant rats.

Humanin exerts cardioprotection against cardiac ischemia/reperfusion injury through attenuation of mitochondrial dysfunction

AIM Myocardial reperfusion via the re-canalization of occluded coronary arteries is gold standard for the treatment of acute myocardial infarction. However, reperfusion itself can cause myocardial damage due to increased reactive oxygen species (ROS) production, a process known as ischemia/reperfusion (I/R) injury. Cardiac mitochondria are the major organelle of ROS production in the heart. Cardiac mitochondrial dysfunction caused by an increased ROS production can increase cardiac arrhythmia incidence, myocardial infarct size, and cardiac dysfunction. Thus, preservation of cardiac mitochondrial function is a promising pharmacological approach to reduce cardiac I/R injury. Humanin (HN), a newly discovered 24-amino acid polypeptide, has been shown to exert antioxidative stress and antiapoptotic effects. Although the cardioprotective effects of HN against I/R injury has been reported, the effect of HN on cardiac mitochondrial function has not yet been investigated. Thus, we tested the hypothesis that HN exerts its cardioprotective effects against I/R injury through the attenuation of cardiac mitochondrial dysfunction. METHODS I/R protocol was carried out using a 30-minutes occlusion of a left anterior descending coronary artery followed by a 120-minutes of reperfusion. The plasma HN level, infarct size, arrhythmia incidence, left ventricular function, and cardiac mitochondrial function were determined. RESULTS Endogenous HN level before I/R injury showed no difference between groups, but was markedly decreased after I/R injury. HN analogue pretreatment decreased arrhythmia incidence and infarct size, improved cardiac mitochondrial function, and attenuated cardiac dysfunction. CONCLUSIONS Humanin analogue pretreatment exerted cardioprotective effects against I/R injury through the attenuation of cardiac mitochondrial dysfunction.

Heart Rate Variability as an Alternative Indicator for Identifying Cardiac Iron Status in Non-Transfusion Dependent Thalassemia Patients.

Background Iron-overload cardiomyopathy is a major cause of death in thalassemia patients due to the lack of an early detection strategy. Although cardiac magnetic resonance (CMR) T2* is used for early detection of cardiac iron accumulation, its availability is limited. Heart rate variability (HRV) has been used to evaluate cardiac autonomic function and found to be depressed in thalassemia. However, its direct correlation with cardiac iron accumulation has never been investigated. We investigated whether HRV can be used as an alternative indicator for early identification of cardiac iron deposition in thalassemia patients. Methods Ninety-nine non-transfusion dependent thalassemia patients (23.00 (17.00, 32.75) years, 35 male) were enrolled. The correlation between HRV recorded using 24-hour Holter monitoring and non-transferrin bound iron (NTBI), hemoglobin (Hb), serum ferritin, LV ejection fraction (LVEF), and CMR-T2* were determined. Results The median NTBI value was 3.15 (1.11, 6.59) μM. Both time and frequency domains of HRV showed a significant correlation with the NTBI level, supporting HRV as a marker of iron overload. Moreover, the LF/HF ratio showed a significant correlation with CMR-T2* with the receiver operating characteristic (ROC) curve of 0.684±0.063, suggesting that it could represent the cardiac iron deposit in thalassemia patients. HRV was also significantly correlated with serum ferritin and Hb. Conclusions This novel finding regarding the correlation between HRV and CMR-T2* indicates that HRV could be a potential marker in identifying early cardiac iron deposition prior to the development of LV dysfunction, and may be used as an alternative to CMR-T2* for screening cardiac iron status in thalassemia patients.

Acetylcholine Attenuates Hydrogen Peroxide-Induced Intracellular Calcium Dyshomeostasis Through Both Muscarinic and Nicotinic Receptors in Cardiomyocytes.

Background/Aims: Oxidative stress induced intracellular Ca²⁺ overload plays an important role in the pathophysiology of several heart diseases. Acetylcholine (ACh) has been shown to suppress reactive oxygen species generation during oxidative stress. However, there is little information regarding the effects of ACh on the intracellular Ca²⁺ regulation in the presence of oxidative stress. Therefore, we investigated the effects of ACh applied before or after hydrogen peroxide (H₂O₂) treatment on the intracellular Ca²⁺ regulation in isolated cardiomyocytes. Methods: Single ventricular myocytes were isolated from the male Wistar rats for the intracellular Ca²⁺ transient study by a fluorimetric ratio technique. Results: H₂O₂ significantly decreased both of intracellular Ca²⁺ transient amplitude and decay rate. ACh applied before, but not after, H₂O₂ treatment attenuated the reduction of intracellular Ca²⁺ transient amplitude and decay rate. Both atropine (a muscarinic acetylcholine receptor blocker) and mecamylamine (a nicotinic acetylcholine receptor blocker) significantly decreased the protective effects of acetylcholine on the intracellular Ca²⁺ regulation. Moreover, the combination of atropine and mecamylamine completely abolished the protective effects of acetylcholine on intracellular Ca²⁺ transient amplitude and decay rate. Conclusion: ACh pretreatment attenuates H₂O₂-induced intracellular Ca²⁺ dyshomeostasis through both muscarinic and nicotinic receptors.

Potential Roles of Humanin on Apoptosis in the Heart.

The process of programmed cell death, or apoptosis, is known as a key player in the development and progression of cardiovascular disease. The proposed mechanism for apoptosis is the activation of two main apoptotic signaling pathways (the extrinsic and intrinsic pathways), which lead to cell death. As the rate and amount of cardiomyocyte loss is the most important determinant of patient morbidity and mortality, novel treatment strategies targeting apoptosis are crucial. Recently, Humanin has been shown to exert protective effects against cellular apoptosis in both experimental and clinical studies. The potential cardioprotective mechanisms of Humanin have been shown to involve both the extracellular and intracellular signaling pathways. In this review, the current knowledge and the mechanisms inhibiting cellular apoptosis by Humanin during cardiac injury are comprehensively summarized. In addition, both research and clinical findings regarding the effects of Humanin on the heart and vasculature are also presented and discussed. Currently available information suggests that Humanin may exert cardioprotective benefits and could potentially be used as a novel pharmacological intervention against cellular apoptosis during myocardial injury.