Blood cardioplegia reduces intraoperative ventricular fibrillation and transfusion requirements compared to crystalloid cardioplegia in canine mitral valve repair.

OBJECTIVE: Cardioplegic solutions are indispensable for open-heart surgeries, including mitral valve repair (MVR), a potentially curative treatment for myxomatous mitral valve disease in dogs. However, procedural methodologies are not fully established, and complications are yet to be comprehensively understood. Cardioplegic solutions contain various substances to protect the myocardium under temporal cardiac arrest. Nevertheless, ventricular fibrillation (VF) occurs as a common complication after releasing the crossclamp. Based on these backgrounds, the search for optimal cardioplegic solutions in dogs undergoing MVR is an urgent issue. This study aims to evaluate the occurrence of VF in dogs treated with blood cardioplegia (BCP) versus crystalloid cardioplegia (CCP) during MVR. ANIMALS: A total of 251 client-owned dogs who underwent MVR from November 2015 to November 2017 were included. METHODS: We retrospectively assessed the relationship between VF and type of cardioplegia (CCP or BCP) based on surgical records, including VF incidence, transfusion use, crossclamp time, and echocardiographic measurements. RESULTS: Logistic regression analysis showed that the CCP group was associated with the occurrence of VF (OR, 2.378; CI, 1.133-4.992; P = .022). In addition, the CCP group was associated with transfusion use (OR, 2.586; CI, 1.232-5.428, P = .022). There was no difference between the groups for the pre- and postoperative echocardiographic measurements. CLINICAL RELEVANCE: The BCP group had a lower incidence of VF and less transfusion use than the CCP group. This finding indicates that BCP may be a superior cardioplegic technique for MVR in dogs.

Comparison of amiodarone and esmolol for prevention of reperfusion ventricular fibrillation in individuals undergoing heart valve or aortic surgery: a study protocol for a randomized controlled clinical trial.

BACKGROUND: Amiodarone and esmolol can help to prevent and treat post-cardiac surgery reperfusion ventricular fibrillation. However, the relative efficacies of these two drugs remain unknown. The aim of the current trial is to compare the performances of amiodarone and esmolol for preventing reperfusion ventricular fibrillation following open heart surgery. METHODS/DESIGN: This is a single-center, prospective, double-blind, controlled clinical trial. A total of 260 patients undergoing heart valve or aortic surgery will be assigned randomly to treatment with prophylactic esmolol (intervention group) or amiodarone (control group). The main outcome is the incidence of reperfusion ventricular fibrillation following aortic opening during extracorporeal circulation. The secondary outcomes are the rate of automatic cardiac resuscitation, energy and frequency of electrical defibrillation, number of electrical defibrillations, and pacemaker use in the two groups of patients. Information on the patients' general condition and the durations of anesthesia, extracorporeal circulation, aortic occlusion, and operation time will be recorded. We will also compare the heart rate, mean arterial pressure, and central venous pressure between the two groups of patients at induction of anesthesia (T1), start of surgery (T2), start of extracorporeal circulation (T3), aortic block (T4), aortic opening (T5), after opening for 10 (T6), 20 (T7), and 30 min (T8), at cessation of extracorporeal circulation (T9), and at the end of surgery (T10) and compare blood gas analysis results at T1, T5, T9, and T10. DISCUSSION: This study will determine if prophylactic esmolol is more effective than amiodarone for reducing the incidence of reperfusion ventricular fibrillation in patients undergoing heart valve or aortic surgery. TRIAL REGISTRATION: China Clinical Trials Registry ChiCTR1900026429. Registered on 2019.10.9.

Right ventricular function is a predictor for sustained ventricular tachycardia requiring anti-tachycardic pacing in arrhythmogenic ventricular cardiomyopathy: insight into transvenous vs. subcutaneous implantable cardioverter defibrillator insertion.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) patients develop ventricular arrhythmias (VAs) responsive to anti-tachycardia pacing (ATP). However, VA episodes have not been characterized in accordance with the device therapy, and with the emergence of the subcutaneous implantable cardioverter defibrillator (S-ICD), the appropriate device prescription in ARVC remains unclear. Study aim was to characterize VA events in ARVC patients during follow-up in accordance with device therapy and elicit if certain parameters are predictive of specific VA events. METHODS AND RESULTS: This was a retrospective single-centre study utilizing prospectively collated registry data of ARVC patients with ICDs. Forty-six patients were included [54.0 ± 12.1 years old and 20 (43.5%) secondary prevention devices]. During a follow-up of 12.1 ± 6.9 years, 31 (67.4%) patients had VA events [n = 2, 6.5% ventricular fibrillation (VF), n = 14], 45.2% VT falling in VF zone resulting in ICD shock(s), n = 10, 32.3% VT resulting in ATP, and n = 5, 16.1% patients had both VT resulting in ATP and ICD shock(s). Lead failure rates were high (11/46, 23.9%). ATP was successful in 34.5% of patients. Severely impaired right ventricular (RV) function was an independent predictor of VT resulting in ATP (hazard ratio 16.80, 95% confidence interval 3.74-75.2; P < 0.001) with a high predictive accuracy (area under the curve 0.88, 95%CI 0.76-1.00; P < 0.001). CONCLUSION: VA event rates are high in ARVC patients with a majority having VT falling in the VF zone resulting in ICD shock(s). S-ICDs could be of benefit in most patients with ARVC with the absence of severely impaired RV function which has the potential to avoid consequences of the high burden of lead failure.

Levosimendan attenuates electrical alternans and prevents ventricular arrhythmia during therapeutic hypothermia in isolated rabbit hearts.

BACKGROUND: Therapeutic hypothermia (TH) increases the susceptibility to ventricular arrhythmias (VAs) by prolonging action potential duration (APD) and facilitating arrhythmogenic spatially discordant alternans (SDA). Levosimendan, a calcium sensitizer, has been reported to shorten APD by enhancing the adenosine triphosphate (ATP)-sensitive K current. OBJECTIVE: The purpose of this study was to test the hypothesis that, during TH, levosimendan shortens the already prolonged APD, attenuates SDA, and prevents VA. METHODS: Langendorff-perfused isolated rabbit hearts were subjected to TH (30°C) for 15 minutes, followed by treatment with either levosimendan 0.5 µM (n = 9) or vehicle (n = 8) for an additional 30 minutes under TH. Using an optical mapping system, epicardial APD was evaluated by S1 pacing. SDA threshold was defined as the longest pacing cycle length (PCL) that induces the phenomenon of SDA. Ventricular fibrillation (VF) inducibility was evaluated by burst pacing for 30 seconds at the shortest PCL that achieved 1:1 ventricular capture. RESULTS: During TH, levosimendan shortened ventricular APD (PCL 400 ms; from 259 ± 8 ms to 241 ± 18 ms; P = .036) and decreased SDA threshold (from 327 ± 88 ms to 311 ± 68 ms; P = .011). VF inducibility was lowered from 39% ± 30% to 14% ± 12% with levosimendan (P = .018), whereas APD at PCL 400 ms (P = .161), SDA threshold (P = 1), and VF inducibility (P = .173) were not changed by vehicle. CONCLUSION: During TH, levosimendan could protect hearts against VA by shortening APD and decreasing SDA threshold. Enhancing ATP-sensitive K current with levosimendan might be a novel approach to preventing VA during TH.

Trimetazidine Alleviates Postresuscitation Myocardial Dysfunction and Improves 96-Hour Survival in a Ventricular Fibrillation Rat Model.

Background Myocardial dysfunction is a critical cause of post-cardiac arrest hemodynamic instability and circulatory failure that may lead to early mortality after resuscitation. Trimetazidine is a metabolic agent that has been demonstrated to provide protective effects in myocardial ischemia. However, whether trimetazidine protects against postresuscitation myocardial dysfunction is unknown. Methods and Results Cardiopulmonary resuscitation was initiated after 8 minutes of untreated ventricular fibrillation in Sprague-Dawley rats. Animals were randomized to 4 groups immediately after resuscitation (n=15/group): (1) normothermia control (NTC); (2) targeted temperature management; (3) trimetazidine-normothermia; (4) trimetazidine-targeted temperature management. TMZ was administered at a single dose of 10 mg/kg in rats with trimetazidine. The body temperature was maintained at 34.0°C for 2 hours and then rewarmed to 37.5°C in rats with targeted temperature management. Postresuscitation hemodynamics, 96-hours survival, and pathological analysis were assessed. Heart tissues and blood samples of additional rats (n=6/group) undergoing the same experimental procedure were collected to measure myocardial injury, inflammation and oxidative stress-related biomarkers with ELISA-based quantification assays. Compared with normothermia control, tumor necrosis factor-α, and cardiac troponin-I were significantly reduced, whereas the left ventricular ejection fraction and 96-hours survival rates were significantly improved in the 3 experimental groups. Furthermore, inflammation and oxidative stress-related biomarkers together with collagen volume fraction were significantly decreased in rats undergoing postresuscitation interventions. Conclusions Trimetazidine significantly alleviates postresuscitation myocardial dysfunction and improves survival by decreasing oxidative stress and inflammation in a ventricular fibrillation rat model. A single dose of trimetazidine administrated immediately after resuscitation can effectively improve cardiac function, whether used alone or combined with targeted temperature management.

Effect of Dexmedetomidine on Tachyarrhythmias After Cardiac Surgery: A Systematic Review and Meta-Analysis.

ABSTRACT: Tachyarrhythmias after cardiac surgery is a common occurrence in clinical practice, which can be life threatening. We searched 6 databases, including Embase, PubMed, Cochrane, CNKI, Wanfang, and Sinomed, to evaluate the effect of dexmedetomidine on tachyarrhythmias after adult cardiac surgery. The primary end point was the number of patients with atrial fibrillation (AF) after cardiac surgery. The secondary end points included the number of patients with supraventricular tachycardia or with ventricular tachycardia or with ventricular fibrillation or with myocardial infarction or deceased patients, the duration of mechanical ventilation, the intensive care unit stay, hospital stay, and the number of patients with bradycardia and those with hypotension. Among the 1388 retrieved studies, 18 studies (n = 3171 participants) met our inclusion criteria. Dexmedetomidine reduced the incidence of AF by 17% [relative risk (RR) = 0.83; 95% confidence interval (CI), 0.73-0.93; P = 0.002]. Through subgroup analysis, we found that when the maintenance dose of dexmedetomidine was >0.7 µg·kg-1·h-1, the effect of preventing AF was obvious (RR = 0.58; 95%CI 0.43-0.78; P = 0.0003). Dexmedetomidine also reduced the incidence of supraventricular tachycardia by approximately 70% (RR = 0.29; 95% CI, 0.11-0.77; P = 0.01) and the incidence of ventricular tachycardia by approximately 80% (RR = 0.23; 95% CI, 0.08-0.63; P = 0.004) but had no effect on ventricular fibrillation (RR = 1.02; 95% CI, 0.14-7.31; P = 0.99). The major side effect of dexmedetomidine was bradycardia. Dexmedetomidine can reduce the incidence of AF (especially high dosages), supraventricular tachycardia, and ventricular tachycardia after cardiac surgery in adults, but it does not affect the occurrence of ventricular fibrillation.

Limited Left Thoracoscopic Sympathectomy Effectively Silences Refractory Electrical Storm.

BACKGROUND: An electrical storm (ES) is a life-threatening condition that affects up to 20% of patients with implantable cardioverter defibrillators. In this small retrospective study, we report our results with left video-assisted thoracoscopic sympathectomy/ganglionectomy (VATSG) to treat refractory ES in low-ejection fraction patients who were not candidates for catheter ablation. METHODS: We identified 12 patients who presented with ES and underwent a total of 14 video-assisted thoracoscopic sympathectomy/ganglionectomy, including 3 patients on venoarterial extracorporeal membrane oxygenation. We reviewed demographic data, survival to discharge, number of cardioversions (before and after VATSG), need for readmissions, and need for right-sided procedures. RESULTS: In the 30 days before a left VATSG, mean number of shocks was 22.67 for all patients. For the patients who survived to discharge, the mean was 3.55 since surgery and the median was zero shocks after a median follow-up of 358 days. Six patients did not experience further cardioversions since the last VATSG and 5 were not readmitted for ventricular tachycardia. Two patients had staged bilateral procedures owing to recurrences; of those, 1 did not require further cardioversions. CONCLUSIONS: Limited left VATSG is an appropriate and effective initial treatment for ES patients who are not candidates for catheter ablation, including those on venoarterial extracorporeal membrane oxygenation for hemodynamic support.

Electrical storm after correction of an uncomplicated congenital atrial septal defect in an adult: a case report.

BACKGROUND: There is a paucity of published literature describing electrical storm after the correction of uncomplicated atrial septal defect (ASD) in an adult. CASE PRESENTATION: We present a 49-year-old woman with a congenital ASD combined with mild tricuspid regurgitation who denied any history of arrhythmia or other medical history. She suffered from electrical storm (≥ 3 episodes of ventricular tachycardias or ventricular fibrillations) in the early stage after ASD repair with combined tricuspid valvuloplasty. During electrical storm, her electrolytes were within normal ranges and no ischemic electrocardiographic changes were detected, which suggested that retained air embolism or acute coronary thrombosis were unlikely. Additionally, echocardiographic findings and her central venous pressure (5-8 mmHg during the interval between attacks) failed to support the diagnosis of pericardial tamponade. After a thorough discussion, the surgeons conducted an emergent re-exploration and repeated closure of the ASD with combined DeVega's annuloplasty. Eventually, the patient recovered uneventfully, without reoccurring arrhythmias during follow-up. Although we fail to determine the definite cause, we speculate that the causes probably are iatrogenic injury of the conduction system due to a rare anatomic variation, poor intraoperative protection, latent coronary distortion during tricuspid valvuloplasty, or idiopathic or secondary abnormalities of the conduction system. CONCLUSIONS: For most surgeons, performing re-exploration without a known etiology is a difficult decision to make. This case illustrates that re-exploration could be an option when electrical storm occurs in the early stage postoperatively. Nevertheless, surgeons should assess the benefit-risk ratio when taking this unconventional measure.

Resveratrol Confers Protection Against Ischemia/Reperfusion Injury by Increase of Angiotensin (1-7) Expression in a Rat Model of Myocardial Hypertrophy.

ABSTRACT: Left ventricular hypertrophy (LVH) makes the heart vulnerable to ischemia/reperfusion (IR) injury. Angiotensin (Ang) (1-7) is recognized as a cardioprotective peptide. We investigated the effect of polyphenol resveratrol on myocardial IR injury after hypertrophy and examined cardiac content of Ang (1-7) and transcription of its receptor (MasR). Rats were divided into sham-operated, LVH, IR, LVH + IR, and resveratrol + LVH + IR groups. Myocardial hypertrophy and IR models were created by abdominal aortic banding and left coronary artery occlusion, respectively. To evaluate the electrocardiogram parameters and incidence of arrhythmias, electrocardiogram was recorded by subcutaneous leads (lead II). Blood pressure was measured through the left carotid artery. Infarct size was determined by the triphenyl tetrazolium chloride staining. The Ang (1-7) level was evaluated by immunohistochemistry. The Mas receptor mRNA level was assessed by the real-time real time reverse transcription polymerase chain reaction technique. QT-interval duration, infarct size, and incidence of ischemia-induced arrhythmia were significantly higher in the LVH + IR group. However, in the resveratrol-treated group, these parameters were decreased significantly. The cardiac level of Ang (1-7) was decreased in untreated hypertrophied hearts (LVH and LVH + IR groups). Pretreatment with resveratrol normalized the cardiac level of Ang (1-7). The mRNA level of Mas receptor was increased in all of hypertrophied hearts in the presence or absence of resveratrol. Resveratrol can decrease IR injury in rats with LVH. The anti-ischemic effect of resveratrol may be related to the enhancement of Ang (1-7)/MasR axis.

Macrophage depletion in stellate ganglia alleviates cardiac sympathetic overactivation and ventricular arrhythmogenesis by attenuating neuroinflammation in heart failure.

Cardiac sympathetic overactivation is involved in arrhythmogenesis in patients with chronic heart failure (CHF). Inflammatory infiltration in the stellate ganglion (SG) is a critical factor for cardiac sympathoexcitation in patients with ventricular arrhythmias. This study aims to investigate if macrophage depletion in SGs decreases cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Surgical ligation of the coronary artery was used for induction of CHF. Clodronate liposomes were microinjected into bilateral SGs of CHF rats for macrophage depletion. Using cytokine array, immunofluorescence staining, and Western blot analysis, we found that macrophage expansion and expression of TNFα and IL-1ß in SGs were markedly increased in CHF rats. Flow cytometry data confirmed that the percentage of macrophages in SGs was higher in CHF rats than that in sham rats. Clodronate liposomes significantly reduced CHF-elevated proinflammatory cytokine levels and macrophage expansion in SGs. Clodronate liposomes also reduced CHF-increased N-type Ca2+ currents and excitability of cardiac sympathetic postganglionic neurons and inhibited CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-h, continuous telemetry recording in conscious rats demonstrated that clodronate liposomes not only restored CHF-induced heterogeneity of ventricular electrical activities, but also decreased the incidence and duration of ventricular tachycardia/fibrillation in CHF. Macrophage depletion with clodronate liposomes attenuated CHF-induced cardiac sympathetic overactivation and ventricular arrhythmias through reduction of macrophage expansion and neuroinflammation in SGs.

Effects of Preoperative Statin on the Frequency of Ventricular Fibrillation and C-Reactive Protein Level in Patients Undergoing Isolated Coronary Artery Bypass Grafting.

OBJECTIVE: To investigate the effects of statin use in preoperative period on the development of ventricular fibrillation (VF) following the removal of aortic cross-clamp (ACC) and on the levels of inflammation biomarker C-reactive protein (CRP) in patients who undergo elective isolated coronary artery bypass grafting (CABG). STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Department of Cardiovascular Surgery, Yuksek Ihtisas Training and Research Hospital, Bursa, Turkey, between May 2019 and January 2020. METHODOLOGY: A total of 104 patients, who underwent elective isolated CABG with cardiopulmonary bypass, were included in this prospective study. Fifty patients, who received statin treatment for at least 16 weeks in preoperative period, were identified as Group S; and 54 patients, who did not receive statin treatment, were identified as Group N. The frequency of VF and defibrillation counter shock (DCS) requirement and postoperative CRP levels were compared in groups after ACC removal. RESULTS: VF development and related DCS counts were lower at significant levels in Group S compared to Group N (p <0.001 for both). Although no statistically significant differences were detected between the median preoperative CRP levels of the groups; median CRP levels, which were measured in postoperative 2nd and 7th days, were found to be significantly lower in Group S (p <0.001 for both). CONCLUSION: Preoperative statin use significantly reduced VF development after the removal of ACC, and decreased postoperative CRP levels. Key Words: Coronary artery bypass grafting, Statins, Pleiotropic effect, Ventricular fibrillation, C-reactive protein.

Integrin-Linked Kinase Activation Prevents Ventricular Arrhythmias Induced by Ischemia/Reperfusion Via Inhibition of Connexin 43 Remodeling.

Ischemia reperfusion (I/R)-induced arrhythmia is a serious complication in patients with cardiac infarction. Remodeling of connexin (Cx) 43, manifested as phosphorylation, contributes significantly to arrhythmogenesis. Integrin-linked kinase (ILK) attenuated ventricular remodeling and improved cardiac function in rats after myocardial infarction. We hypothesized that ILK, through Cx43 phosphorylation, would be protective against I/R-induced ventricular arrhythmias. Our study showed that I/R-induced ventricular arrhythmias were attenuated by an ILK agonist LPTP and worsened by the ILK inhibitor Cpd22. I/R disrupted Cx43 distribution, but it was partially normalized in the presence of LPTP. Compared with I/R, the phosphorylation of Akt was increased significantly after pretreatment with LPTP. The increase in phosphorylated Akt was physiologically significant because, in the presence of the Akt inhibitor MK2206, the protective effects of LPTP were blocked. This indicated that ILK activation prevented I/R-induced-ventricular arrhythmia, an effect potentially related to inhibition of Cx43 remodeling via Akt activation.

Chronic sigma-1 receptor activation ameliorates ventricular remodeling and decreases susceptibility to ventricular arrhythmias after myocardial infarction in rats.

The present study aimed to assess the effect of sigma-1 receptor (S1R) stimulation on ventricular remodeling and susceptibility to ventricular arrhythmias (VAs) after myocardial infarction (MI) in rats. Wild-type male rats were placed into one of the following four treatment groups. For four weeks, animals in the Sham group and MI group received intraperitoneal (i.p.) injections of 0.9% saline (1 ml/kg/day); those in the MI + F group received fluvoxamine (FLV) (0.3 mg/kg/day); and those in the MI + F + BD group received FLV plus BD1047 (0.3 mg/kg/day). After that, the ventricular electrophysiological parameters were measured via the langendorff system. Ventricular fibrosis quantification was determined with Masson staining. Cardiac function was evaluated by echocardiography. The protein levels of S1R, connexin (Cx)43, Cav1.2, Kv4.2, Kv4.3, tyrosine hydroxylase (TH), nerve growth factor (NGF), growth-associated protein 43 (GAP43) were detected by Western blot assays. Our results indicated that fluvoxamine significantly prolonged the ventricular effective refractory period (ERP), shortened action potential duration (APD), reduced susceptibility to VAs after MI. Masson staining showed a decrease in ventricular fibrosis in the MI + F group. Furthermore, the contents of Cx43, S1R, Cav1.2, Kv4.2, Kv4.3 were increased in the MI + F group compared with the MI group (all P < 0.05). The contents of TH, NGF, GAP43 were reduced in the MI + F group compared with the MI group. (all P < 0.05). However, BD1047 reduces all of these effects of FLV. The results suggest that S1R stimulation reduces susceptibility to VAs and improves cardiac function by improving myocardial fibrosis, lightning sympathetic remodeling, electrical remodeling, gap junction remodeling and upregulating S1R content.

Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators.

Implantable cardioverter defibrillators (ICD) are the most effective therapy to terminate malignant ventricular arrhythmias (VA) and therefore to prevent sudden cardiac death. Until today, there is no way to predict the onset of such VA. Our aim was to develop a mathematical model that could predict VA in a timely fashion. We analyzed the time series of R-R intervals from 3 groups. Two groups from the Spontaneous Ventricular Tachyarrhythmia Database (v 1.0) were analyzed from a set of 81 pairs of R-R interval time series records from patients, each pair containing one record before the VT episode (Dataset 1A) and one control record which was obtained during the follow up visit (Dataset 1B). A third data set was composed of the R-R interval time series of 54 subjects without a significant arrhythmia heart disease (Dataset 2). We developed a new method to transform a time series into a network for its analysis, the ε-regular graphs. This novel approach transforms a time series into a network which is sensitive to the quantitative properties of the time series, it has a single parameter (ε) to be adjusted, and it can trace long-range correlations. This procedure allows to use graph theory to extract the dynamics of any time series. The average of the difference between the VT and the control record graph degree of each patient, at each time window, reached a global minimum value of -2.12 followed by a drastic increase of the average graph until reaching a local maximum of 5.59. The global minimum and the following local maxima occur at the windows 276 and 393, respectively. This change in the connectivity of the graphs distinguishes two distinct dynamics occurring during the VA, while the states in between the 276 and 393, determine a transitional state. We propose this change in the dynamic of the R-R intervals as a measurable and detectable "early warning" of the VT event, occurring an average of 514.625 seconds (8:30 minutes) before the onset of the VT episode. It is feasible to detect retrospectively early warnings of the VA episode using their corresponding ε-regular graphs, with an average of 8:30 minutes before the ICD terminates the VA event.

Activating the interleukin-6-Gp130-STAT3 pathway ameliorates ventricular electrical stability in myocardial infarction rats by modulating neurotransmitters in the paraventricular nucleus.

BACKGROUND: Malignant ventricular arrhythmia (VA) is the most common cause of death associated with acute myocardial infarction (MI). Recent studies have revealed direct involvement of the paraventricular nucleus (PVN) in the occurrence of VA. However, the underlying mechanisms remain incompletely understood. In this study, we investigated changes in the interleukin-6 (IL-6)-glycoprotein 130-signal transducer and activator of transcription 3 (STAT3) pathway in the PVN during acute MI and the effects of this pathway on ventricular stability. METHODS: Rats were divided into a control group, a MI group, a PVN-injected anti-IL-6 antibody group and a PVN-injected SC144 group to observe how IL-6 and its downstream glycoprotein 130-STAT3 pathway in the PVN affect ventricular stability. The left anterior descending coronary artery was ligated to induce MI. After that, an anti-IL-6 antibody and SC144 were injected into the PVNs of rats. All data are expressed as the mean ± SE and were analysed by ANOVA with a post hoc LSD test. p < 0.05 was considered to indicate statistical significance. RESULTS: After MI, the concentration of the inflammatory factor IL-6 increased, and its downstream glycoprotein 130-STAT3 pathway was activated in the PVN. After injection of MI rat PVNs with the anti-IL-6 antibody or glycoprotein 130 inhibitor (SC144), glutamate levels increased and γ-aminobutyric acid (GABA) levels decreased in the PVN. Plasma norepinephrine concentrations also increased after treatment, which increased the vulnerability to VA. CONCLUSIONS: In summary, IL-6 in the PVN exerts a protective effect in MI rats, and the glycoprotein 130-STAT3 pathway plays a key role in this process. We anticipate that our findings will provide new ideas for the prevention and treatment of arrhythmia after MI.

Low-Intensity Ultrasound Modulation May Prevent Myocardial Infarction-induced Sympathetic Neural Activation and Ventricular Arrhythmia.

BACKGROUND: Low-intensity focused ultrasound (LIFU) has been shown to be a beneficial tool for autonomic nervous system modulation, but its effect on the left stellate ganglion (LSG) remains unknown. OBJECTIVE: To seek the effect of LIFU on myocardial infarction (MI)-induced LSG activation and ventricular arrhythmias (VAs). METHODS: In this study, 20 dogs were included and randomly divided into the LIFU (LIFU & MI, n = 8), Sham (sham LIFU & MI, n = 8), and Control group (sham LIFU & sham MI, n = 4). For each LIFU intervention (1.0-2.0 W, 10 minutes) of the LSG, the LSG function, ventricular effective refractory period (ERP), and temperature were tested pre-intervention and postintervention. Thereafter, MI was induced by left anterior artery ligation and VAs were recorded for 1 hour. At the end, both the LSG and the heart were extracted for biomedical and histological analysis. RESULTS: In the Sham group, no significant change was shown in ventricular ERP or LSG function for any intensity settings of sham LIFU intervention when compared with the group baseline. In the LIFU group, however, both 1.5 and 2.0 W LIFU modulation of LSG resulted in significant prolongation of ERP and attenuation of LSG function. Furthermore, the incidence of VAs was significantly attenuated in the LIFU group compared with the Sham group. Moreover, histological analysis showed that no damage or apoptosis was observed in LSG although a statistically significant increase was shown in temperature (maximal increase <1°C) with 1.5 and 2.0 W LIFU intervention. CONCLUSION: LIFU stimulation may be a safe and beneficial tool for LSG attenuation and VA prevention in the MI canine model.

Single Bolus Rosuvastatin Accelerates Calcium Uptake and Attenuates Conduction Inhomogeneity in Failing Rabbit Hearts With Regional Ischemia-Reperfusion Injury.

Acute statin therapy reduces myocardial ischemia/reperfusion (IR) injury-induced ventricular fibrillation (VF), but the underlying electrophysiological mechanisms remain unclear. This study sought to investigate the antiarrhythmic effects of a single bolus rosuvastatin injection in failing rabbit hearts with IR injury and to unveil the underlying molecular mechanisms. Rabbits were divided into rosuvastatin, rosuvastatin + L-NAME, control, and L-NAME groups. Intravenous bolus rosuvastatin (0.5 mg/kg) and/or L-NAME (10 mg/kg) injections were administered 1 hour and 15 minutes before surgery, respectively. Heart failure was induced using rapid ventricular pacing. Under general anesthesia with isoflurane, an IR model was created by coronary artery ligation for 30 minutes, followed by reperfusion for 15 minutes. Plasma NO end product levels were measured during IR. Then, hearts were excised and Langendorff-perfused for optical mapping studies. Cardiac tissues were sampled for Western blot analysis. Rosuvastatin increased plasma NO levels during IR, which was abrogated by L-NAME. Spontaneous VF during IR was suppressed by rosuvastatin (P < 0.001). Intracellular calcium (Cai) decay and conduction velocity were significantly slower in the IR zone. Rosuvastatin accelerated Cai decay, ameliorated conduction inhomogeneity, and reduced the inducibility of spatially discordant alternans and VF significantly. Western blots revealed significantly higher expression of enhancing endothelial NO-synthase and phosphorylated enhancing endothelial NO-synthase proteins in the Rosuvastatin group. Furthermore, SERCA2a, phosphorylated connexin43, and phosphorylated phospholamban were downregulated in the IR zone, which was attenuated or reversed by rosuvastatin. Acute rosuvastatin therapy before ischemia reduced IR-induced VF by improving SERCA2a function and ameliorating conduction disturbance in the IR zone.

Myocardial Fibrosis as a Pathway of Prediction of Ventricular Arrhythmias and Sudden Cardiac Death in Patients With Nonischemic Dilated Cardiomyopathy.

The mechanism of sudden cardiac death (SCD) in patients with nonischemic dilated cardiomyopathy (NIDCM) is mostly due to sustained ventricular tachycardia and ventricular fibrillation. The clinical guidelines for the therapeutic management of this set of patients are mostly based on left ventricular ejection fraction value which has a low specificity to differentiate the risk of SCD from the risk of mortality associated with heart failure or other comorbidities. Moreover, since SCD can occur in patients with normal or mildly depressed ejection fraction, it is necessary to identify new markers to improve the prognostic stratification of SCD. Several studies that analyzed the ventricular arrhythmia substrate found that myocardial fibrosis plays an important role in the genesis of ventricular arrhythmias in patients with NIDCM. The surrounding zone of the area of fibrosis is a heterogeneous medium, where tissue with different levels of fibrosis coexists, resulting in both viable and nonviable myocardium. This myocardial fibrosis may constitute a substrate for ventricular arrhythmias, where slow and heterogeneous conduction may favor the genesis of reentry mechanism increasing the chance to develop sustained ventricular tachycardia or ventricular fibrillation. Therefore, the evaluation of ventricular fibrosis by late gadolinium enhancement (LGE) cardiac magnetic resonance imaging has been suggested as an indicator for SCD risk stratification. Indeed, LGE in patients with NIDCM is associated with increased risk of all-cause mortality, heart failure hospitalization, and SCD. Detection of myocardial fibrosis as LGE by cardiac magnetic resonance imaging can be considered as a useful pathway of prediction of malignant ventricular arrhythmias since it has excellent prognostic characteristics and may help guide risk stratification and management in patients with NIDCM.

Whole-Body Vibration Training Increases Myocardial Salvage Against Acute Ischemia in Adult Male Rats / Treinamento de Vibração de Corpo Inteiro Aumenta o Resgate Miocárdico contra Isquemia Aguda em Ratos Machos Adultos

Abstract Background: Whole body vibration training (WBV) is a new training program, which is safe and effective. It can be followed by the public. However, data on the safety and efficacy of vibration on myocardial ischemia reperfusion (IR) injury are lacking. Objective: To examine the effect of WBV on the tolerance of the myocardium to acute IR injury in an experimental rat model. Methods: Twenty-four male Wistar rats were divided into control and vibration groups. Vibration training consisted of vertical sinusoidal whole body vibration for 30 min per day, 6 days per week, for 1 or 3 weeks (WBV1 and WBV3 groups, respectively). All the rats were submitted to myocardial IR injury. Myocardial infarct size and ischemia-induced arrhythmias were assessed. Differences between variables were considered significant when p < 0.05. Results: No differences were observed between the groups regarding the baseline hemodynamic parameters. Infarct size was smaller in the experimental group (control, 47 ± 2%; WBV1, 39 ± 2%; WBV3, 37 ± 2%; p < 0.05, vs. control). Vibration produced a significant decrease in the number and duration of ventricular tachycardia (VT) episodes compared to the control value. All ventricular fibrillation (VF) episodes in the vibration groups were self-limited, while 33% of the rats in the control group died due to irreversible VF (p = 0.02). Conclusion: The data showed that vibration training significantly increased cardiac tolerance to IR injury in rats, as evidenced by reduction in the infarct size and cardiac arrhythmias, and by facilitating spontaneous defibrillation.

Resumo Fundamento: O treinamento com vibração de corpo inteiro (WBV) é um novo programa de treinamento seguro e eficaz, e pode ser seguido pelo público. No entanto, dados sobre a segurança e eficácia da vibração na lesão de isquemia e reperfusão (IR) do miocárdio estão em falta. Objetivo: Examinar o efeito da WBV na tolerância do miocárdio à lesão aguda por IR em um modelo experimental em ratos. Métodos: Vinte e quatro ratos Wistar machos foram divididos em 2 grupos: controle e vibração. O treino de vibração consistiu em vibração sinusoidal vertical de corpo inteiro durante 30 min por dia, 6 dias por semana, durante 1 ou 3 semanas (grupos WBV1 e WBV3, respectivamente). Todos os ratos foram submetidos a lesão por IR do miocárdio. O tamanho do infarto do miocárdio e as arritmias induzidas por isquemia foram avaliados. As diferenças entre as variáveis foram consideradas significativas quando p < 0,05. Resultados: Não foram observadas diferenças entre os grupos em relação aos parâmetros hemodinâmicos basais. O tamanho do infarto foi menor no grupo experimental (controle, 47 ± 2%; WBV1, 39 ± 2%; WBV3, 37 ± 2%; p < 0,05, vs. controle). A vibração produziu uma diminuição significativa no número e duração das taquicardia ventriculares (TV) em comparação com o valor de controle. Todos os episódios de fibrilação ventricular (FV) nos grupos de vibração foram autolimitados, enquanto 33% dos ratos do grupo controle morreram devido a FV irreversível (p = 0,02). Conclusão: Os dados mostraram que o treinamento com vibração de corpo inteiro aumentou significativamente a tolerância cardíaca à lesão de IR em ratos, como evidenciado pela redução do tamanho do infarto e arritmias cardíacas, e pela facilitação da desfibrilação espontânea.

Usefulness of Exchanged Protein Directly Activated by cAMP (Epac)1-Inhibiting Therapy for Prevention of Atrial and Ventricular Arrhythmias in Mice.

BACKGROUND: It has been suggested that protein directly activated by cAMP (Epac), one of the downstream signaling molecules of ß-adrenergic receptor (ß-AR), may be an effective target for the treatment of arrhythmia. However, there have been no reports on the anti-arrhythmic effects or cardiac side-effects of Epac1 inhibitors in vivo. Methods and Results: In this study, the roles of Epac1 in the development of atrial and ventricular arrhythmias are examined. In addition, we examined the usefulness of CE3F4, an Epac1-selective inhibitor, in the treatment of the arrhythmias in mice. In Epac1 knockout (Epac1-KO) mice, the duration of atrial fibrillation (AF) was shorter than in wild-type mice. In calsequestrin2 knockout mice, Epac1 deficiency resulted in a reduction of ventricular arrhythmia. In both atrial and ventricular myocytes, sarcoplasmic reticulum (SR) Ca2+ leak, a major trigger of arrhythmias, and spontaneous SR Ca2+ release (SCR) were attenuated in Epac1-KO mice. Consistently, CE3F4 treatment significantly prevented AF and ventricular arrhythmia in mice. In addition, the SR Ca2+ leak and SCR were significantly inhibited by CE3F4 treatment in both atrial and ventricular myocytes. Importantly, cardiac function was not significantly affected by a dosage of CE3F4 sufficient to exert anti-arrhythmic effects. CONCLUSIONS: These findings indicated that Epac1 is involved in the development of atrial and ventricular arrhythmias. CE3F4, an Epac1-selective inhibitor, prevented atrial and ventricular arrhythmias in mice.