Kroekkiat Chinda

Cardioprotective effect of dipeptidyl peptidase-4 inhibitor during ischemia-reperfusion injury.

BACKGROUND Dipeptidyl peptidase-4 (DPP-4) inhibitor is a new anti-diabetic drug for type-2 diabetes mellitus patients. Despite its benefits on glycemic control, the effects of DPP-4 inhibitor on the heart during ischemia-reperfusion (I/R) periods are not known. We investigated the effect of DPP-4 inhibitor on cardiac electrophysiology and infarct size in a clinically relevant I/R model in swine and its underlying cardioprotective mechanism. METHODS Fourteen pigs were randomized to receive either DPP-4 inhibitor (vildagliptin) 50mg or normal saline intravenously prior to a 90-min left anterior descending artery occlusion, followed by a 120-min reperfusion period. The hemodynamic, cardiac electrophysiological and arrhythmic parameters, and the infarct size were determined before and during I/R. Rat cardiac mitochondria were used to study the protective effects of DPP-4 inhibitor on cardiac mitochondrial dysfunction caused by severe oxidative stress induced by H2O2 to mimic the I/R condition. RESULTS Compared to the saline group, DPP-4 inhibitor attenuated the shortening of the effective refractory period (ERP), decreased the number of PVCs, increased the ventricular fibrillation threshold (VFT) during the ischemic period, and also decreased the infarct size. In cardiac mitochondria, DPP-4 inhibitor decreased the reactive oxygen species (ROS) production and prevented cardiac mitochondrial depolarization caused by severe oxidative stress. CONCLUSIONS During I/R, DPP-4 inhibitor stabilized the cardiac electrophysiology by preventing the ERP shortening, decreasing the number of PVCs, increasing the VFT, and decreasing the infarct size. This cardioprotective effect could be due to its prevention of cardiac mitochondrial dysfunction caused by severe oxidative stress during I/R.

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.

T-type calcium channel blockade improves survival and cardiovascular function in thalassemic mice.

Objectives:  Iron‐overload cardiomyopathy is a major cause of morbidity and mortality in patients with thalassemia. However, the precise mechanisms of iron entry and sequestration in the heart are still unclear. Our previous study showed that Fe2+ uptake in thalassemic cardiomyocytes are mainly mediated by T‐type calcium channels (TTCC). Nevertheless, the role of TTCC as well as other transporters such as divalent metal transporter1 (DMT1) and L‐type calcium channels (LTCC) as possible portals for iron entry into the heart in in vivo thalassemic mice under an iron‐overload condition has not been investigated.

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.

Dipeptidyl peptidase-4 inhibitor reduces infarct size and preserves cardiac function via mitochondrial protection in ischaemia-reperfusion rat heart

Aim: We hypothesized that dipeptidyl peptidase (DPP)-4 inhibitor (vildagliptin) reduces fatal arrhythmias, cardiac dysfunction and infarct size caused by ischaemia–reperfusion (I/R) injury via its attenuation of cardiac mitochondrial dysfunction. Methods: In total, 26 rats were randomized to receive either 1 mL normal saline solution or 2.0 mg/kg vildagliptin intravenously (n = 13/group) 30 min prior to a 30-min left anterior descending coronary artery occlusion, followed by a 120-min reperfusion. Arrhythmia scores, cardiac functions, infarct size and mitochondrial function were evaluated. Results: Vildagliptin reduced the infarct size by 44% and mitigated cardiac dysfunction by preserving cardiac function without altering the incidence of cardiac arrhythmias. Vildagliptin increased expression of Bcl-2 and pro-caspase3 in the ischaemic area, whereas Bax and phosphorylated-connexin43/total-connexin43 were not altered. Vildagliptin attenuated cardiac mitochondrial dysfunction by reducing the reactive oxygen species level and mitochondrial swelling. Conclusions: DPP-4 inhibitor provides cardioprotection by reducing the infarct size and ameliorating cardiac dysfunction in I/R hearts by attenuating cardiac mitochondrial dysfunction and cardiomyocyte apoptosis.

Combined Vildagliptin and Metformin Exert Better Cardioprotection than Monotherapy against Ischemia-Reperfusion Injury in Obese-Insulin Resistant Rats

Background Obese-insulin resistance caused by long-term high-fat diet (HFD) consumption is associated with left ventricular (LV) dysfunction and increased risk of myocardial infarction. Metformin and vildagliptin have been shown to exert cardioprotective effects. However, the effect of these drugs on the hearts under obese-insulin resistance with ischemia-reperfusion (I/R) injury is unclear. We hypothesized that combined vildagliptin and metformin provide better protective effects against I/R injury than monotherapy in obese-insulin resistant rats. Methodology Male Wistar rats were fed either HFD or normal diet. Rats in each diet group were divided into 4 subgroups to receive vildagliptin, metformin, combined vildagliptin and metformin, or saline for 21 days. Ischemia due to left anterior descending artery ligation was allowed for 30-min, followed by 120-min reperfusion. Metabolic parameters, heart rate variability (HRV), LV function, infarct size, mitochondrial function, calcium transient, Bax and Bcl-2, and Connexin 43 (Cx43) were determined. Rats developed insulin resistance after 12 weeks of HFD consumption. Vildagliptin, metformin, and combined drugs improved metabolic parameters, HRV, and LV function. During I/R, all treatments improved LV function, reduced infarct size and Bax, increased Bcl-2, and improved mitochondrial function in HFD rats. However, only combined drugs delayed the time to the first VT/VF onset, reduced arrhythmia score and mortality rate, and increased p-Cx43 in HFD rats. Conclusion Although both vildagliptin and metformin improved insulin resistance and attenuate myocardial injury caused by I/R, combined drugs provided better outcomes than single therapy by reducing arrhythmia score and mortality rate.

Mechanisms responsible for beneficial and adverse effects of rosiglitazone in a rat model of acute cardiac ischaemia–reperfusion

•  What is the central question of this study? Controversy exists regarding the beneficial and adverse effects of rosiglitazone. We sought to determine the effects of rosiglitazone in the heart during ischaemia–reperfusion injury. •  What is the main finding and what is its importance? We demonstrated that rosiglitazone simultaneously exerted both beneficial and adverse effects on the heart during ischaemia–reperfusion. These findings provided new mechanistic insights into the effects of this drug, and elucidate the possibility of its undesirable effects in patients taking this drug.

Cardioprotective effects of incretin during ischaemia-reperfusion

Incretin is a gut derived peptide hormone secreted in the intestine after food ingestion, and is degraded rapidly after secretion by dipeptidyl peptidase (DPP)-4. Incretin-based therapy, such as glucagon-like peptide (GLP)-1 and the DPP-4 inhibitor, has been proposed as a new therapeutic approach for the treatment of type 2 diabetic patients. In the past few years, growing evidence also demonstrated the cardioprotective effects of incretin-based therapy, especially during ischaemia-reperfusion (I/R) injury in both the animal models and in clinical studies. However, inconsistent reports exist regarding the use of these pharmacological interventions. In this article, a comprehensive review regarding both basic and clinical studies reporting the effects of GLP-1 and DPP-4 inhibitors on I/R hearts is presented and discussed. The consistent findings as well as controversial results are summarised, focusing on the effects of incretin on the infarct size, left ventricular function and haemodynamic improvement during an I/R injury.

Effects of Kaempferia parviflora Wall. Ex. Baker and sildenafil citrate on cGMP level, cardiac function, and intracellular Ca2+ regulation in rat hearts.

Abstract: Although Kaempferia parviflora extract (KPE) and its flavonoids have positive effects on the nitric oxide (NO) signaling pathway, its mechanisms on the heart are still unclear. Because our previous studies demonstrated that KPE decreased defibrillation efficacy in swine similar to that of sildenafil citrate, the phosphodiesterase-5 inhibitor, it is possible that KPE may affect the cardiac NO signaling pathway. In the present study, the effects of KPE and sildenafil citrate on cyclic guanosine monophosphate (cGMP) level, modulation of cardiac function, and Ca2+ transients in ventricular myocytes were investigated. In a rat model, cardiac cGMP level, cardiac function, and Ca2+ transients were measured before and after treatment with KPE and sildenafil citrate. KPE significantly increased the cGMP level and decreased cardiac function and Ca2+ transient. These effects were similar to those found in the sildenafil citrate–treated group. Furthermore, the nonspecific NOS inhibitor could abolish the effects of KPE and sildenafil citrate on Ca2+ transient. KPE has positive effect on NO signaling in the heart, resulting in an increased cGMP level, similar to that of sildenafil citrate. This effect was found to influence the physiology of normal heart via the attenuation of cardiac function and the reduction of Ca2+ transient in ventricular myocytes.

Ganglionated plexi and ligament of Marshall ablation reduces atrial vulnerability and causes stellate ganglion remodeling in ambulatory dogs

BACKGROUND Simultaneous activation of the stellate ganglion (SG), the ligament of Marshall (LOM), and the ganglionated plexi often precedes the onset of paroxysmal atrial tachyarrhythmia (PAT). OBJECTIVE The purpose of this study was to test the hypothesis that ablation of the LOM and the superior left ganglionated plexi (SLGP) reduces atrial vulnerability and results in remodeling of the SG. METHODS Nerve activity was correlated to PAT and ventricular rate (VR) at baseline, after ablation of the LOM and SLGP, and after atrial fibrillation. Neuronal cell death was assessed with tyrosine hydroxylase and terminal deoxynucleotidyl transferase dUTP nick end label (TUNEL) staining. RESULTS There were 4 ± 2 PAT episodes per day in controls. None were observed in the ablation group, even though SG nerve activity and VR increased from 2.2 µV (95% confidence interval [CI] 1.2-3.3 µV) and 80 bpm (95% CI 68-92 bpm) at baseline, to 3.0 µV (95% CI 2.6-3.4 µV, P = .046) and 90 bpm (95% CI 75-108 bpm, P = .026) after ablation, and to 3.1 µV (95% CI 1.7-4.5 µV, P = .116) and 95 bpm (95% CI 79-110 bpm, P = .075) after atrial fibrillation. There was an increase in tyrosine hydroxylase-negative cells in the ablation group and 19.7% (95% CI 8.6%-30.8%) TUNEL-positive staining in both the left and right SG. None were observed in the control group. CONCLUSION LOM and SLGP ablation caused left SG remodeling and cell death. There was reduced correlation of the VR response and PAT to SG nerve activity. These findings support the importance of SLGP and LOM in atrial arrhythmogenesis.