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Concept: Ventricular fibrillation

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Transplantation studies in mice and rats have shown that human embryonic-stem-cell-derived cardiomyocytes (hESC-CMs) can improve the function of infarcted hearts, but two critical issues related to their electrophysiological behaviour in vivo remain unresolved. First, the risk of arrhythmias following hESC-CM transplantation in injured hearts has not been determined. Second, the electromechanical integration of hESC-CMs in injured hearts has not been demonstrated, so it is unclear whether these cells improve contractile function directly through addition of new force-generating units. Here we use a guinea-pig model to show that hESC-CM grafts in injured hearts protect against arrhythmias and can contract synchronously with host muscle. Injured hearts with hESC-CM grafts show improved mechanical function and a significantly reduced incidence of both spontaneous and induced ventricular tachycardia. To assess the activity of hESC-CM grafts in vivo, we transplanted hESC-CMs expressing the genetically encoded calcium sensor, GCaMP3 (refs 4, 5). By correlating the GCaMP3 fluorescent signal with the host ECG, we found that grafts in uninjured hearts have consistent 1:1 host–graft coupling. Grafts in injured hearts are more heterogeneous and typically include both coupled and uncoupled regions. Thus, human myocardial grafts meet physiological criteria for true heart regeneration, providing support for the continued development of hESC-based cardiac therapies for both mechanical and electrical repair.

Concepts: Myocardial infarction, Cardiology, Heart, Muscle, Cardiac muscle, Cardiac electrophysiology, Muscular system, Ventricular fibrillation

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BACKGROUND: Heart failure (HF) patients have a high risk of death, and implantable cardioverter defibrillators (ICDs) are effective in preventing sudden cardiac death (SCD). However, a certain percentage of patients may not be immediate candidates for ICDs, particularly those having a short duration of risk or an uncertain amount of risk. This includes the newly diagnosed patients, as well as those on the cardiac transplant list or NYHA class IV heart failure patients who do not already have an ICD. In these patients, a wearable cardioverter defibrillator (WCD) may be used until long term risk of SCD is defined. The purpose of this study was to determine the incidence of SCD in this population, and the efficacy of early defibrillation by a WCD. METHODS: Ten enrolling centers identified 89 eligible HF patients who were either listed for cardiac transplantation, diagnosed with dilated cardiomyopathy, or receiving inotropic medications. Data collected included medical history, device records, and outcomes (including 90 day mortality). RESULTS: Out of 89 patients, final data on 82 patients has been collected. Patients wore the device for 75+/-58 days. Mean age was 56.8+/-13.2, and 72% were male. Most patients (98.8%) were diagnosed with dilated cardiomyopathy with a low ejection fraction (<40%) and twelve were listed for cardiac transplantation. Four patients were on inotropes. There were no sudden cardiac arrests or deaths during the study. Interestingly, 41.5% of patients were much improved after WCD use, while 34.1% went on to receive an ICD. CONCLUSIONS: In conclusion, the WCD monitored HF patients until further assessment of risk. The leading reasons for end of WCD use were improvement in left ventricular ejection fraction (LVEF) or ICD implantation if there was no significant improvement in LVEF.

Concepts: Myocardial infarction, Cardiology, Cardiomyopathy, Heart failure, Ejection fraction, Implantable cardioverter-defibrillator, Cardiac arrest, Ventricular fibrillation

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The Brugada syndrome (BrS) is a malignant, genetically-determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. The diagnosis of the BrS is mainly based on the presence of a spontaneous or Na + channel blocker induced characteristic, electrocardiographic (ECG) pattern (type 1 or coved Brugada ECG pattern) typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal (i.c.) spaces. This pattern needs to be distinguished from similar ECG changes due to other causes (Brugada ECG phenocopies). This review focuses mainly on the ECG-based methods for diagnosis and arrhythmia risk assessment in the BrS. Presently, the main unresolved clinical problem is the identification of those patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD), which is the only therapy with proven efficacy. Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern, and either history of aborted cardiac arrest or documented sustained VT (class I), or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmic events (up to 10% or more annually for those with aborted cardiac arrest). The majority of BrS patients are asymptomatic when diagnosed and considered to have low risk (around 0.5% annually) and therefore not indicated for ICD. The majority of SCD victims in the BrS, however, had no symptoms prior to the fatal event and therefore were not protected with an ICD. While some ECG markers such as QRS fragmentation, infero-lateral early repolarisation, and abnormal late potentials on signal-averaged ECG are known to be linked to increased arrhythmic risk, they are not sufficiently sensitive or specific. Potential novel ECG-based strategies for risk stratification are discussed based on computerised methods for depolarisation and repolarisation analysis, a composite approach targeting several major components of ventricular arrhythmogenesis, and the collection of large digital ECG databases in genotyped BrS patients and their relatives.

Concepts: Cardiology, Implantable cardioverter-defibrillator, Cardiac arrest, Cardiac electrophysiology, Ventricular fibrillation, Sudden cardiac death, Brugada syndrome, Cardiac dysrhythmia

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The aim of this study was to investigate the prognostic impact of acute-phase ventricular tachycardia and fibrillation (VT/VF) on ST-segment elevation myocardial infarction (STEMI) patients in the percutaneous coronary intervention (PCI) era.Methods and Results:Using the database of the Osaka Acute Coronary Insufficiency Study (OACIS), we studied 4,283 consecutive patients with STEMI who were hospitalized within 12 h of STEMI onset and underwent emergency PCI. Acute-phase VT/VF, defined as ≥3 consecutive ventricular premature complexes and/or VF within the 1st week of hospitalization, occurred in 997 (23.3%) patients. In-hospital mortality risk was significantly higher in patients with acute-phase VT/VF than inthose without (14.6% vs. 4.3%, adjusted hazard ratio (HR) 1.83, P=0.0013). Among patients discharged alive, 5-year mortality rates were comparable between patients with and without acute-phase VT/VF. Subgroup analysis showed that acute-phase VT/VF was associated with increased 5-year mortality after discharge in high-risk patients (GRACE Risk Score ≥115; adjusted HR 1.60, P=0.043), but not in intermediate- or low-risk patients.

Concepts: Myocardial infarction, Atherosclerosis, Cardiology, Percutaneous coronary intervention, Ventricular tachycardia, Acute coronary syndrome, Ventricular fibrillation, Premature ventricular contraction

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Background Early defibrillation plays a key role in improving survival in patients with out-of-hospital cardiac arrests due to ventricular fibrillation (ventricular-fibrillation cardiac arrests), and the use of publicly accessible automated external defibrillators (AEDs) can help to reduce the time to defibrillation for such patients. However, the effect of dissemination of public-access AEDs for ventricular-fibrillation cardiac arrest at the population level has not been extensively investigated. Methods From a nationwide, prospective, population-based registry of patients with out-of-hospital cardiac arrest in Japan, we identified patients from 2005 through 2013 with bystander-witnessed ventricular-fibrillation arrests of presumed cardiac origin in whom resuscitation was attempted. The primary outcome measure was survival at 1 month with a favorable neurologic outcome (Cerebral Performance Category of 1 or 2, on a scale from 1 [good cerebral performance] to 5 [death or brain death]). The number of patients in whom survival with a favorable neurologic outcome was attributable to public-access defibrillation was estimated. Results Of 43,762 patients with bystander-witnessed ventricular-fibrillation arrests of cardiac origin, 4499 (10.3%) received public-access defibrillation. The percentage of patients receiving public-access defibrillation increased from 1.1% in 2005 to 16.5% in 2013 (P<0.001 for trend). The percentage of patients who were alive at 1 month with a favorable neurologic outcome was significantly higher with public-access defibrillation than without public-access defibrillation (38.5% vs. 18.2%; adjusted odds ratio after propensity-score matching, 1.99; 95% confidence interval, 1.80 to 2.19). The estimated number of survivors in whom survival with a favorable neurologic outcome was attributed to public-access defibrillation increased from 6 in 2005 to 201 in 2013 (P<0.001 for trend). Conclusions In Japan, increased use of public-access defibrillation by bystanders was associated with an increase in the number of survivors with a favorable neurologic outcome after out-of-hospital ventricular-fibrillation cardiac arrest.

Concepts: Cardiac arrest, Cardiopulmonary resuscitation, Asystole, Ventricular tachycardia, Ventricular fibrillation, Defibrillation, Automated external defibrillator, Fibrillation

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Background Antiarrhythmic drugs are used commonly in out-of-hospital cardiac arrest for shock-refractory ventricular fibrillation or pulseless ventricular tachycardia, but without proven survival benefit. Methods In this randomized, double-blind trial, we compared parenteral amiodarone, lidocaine, and saline placebo, along with standard care, in adults who had nontraumatic out-of-hospital cardiac arrest, shock-refractory ventricular fibrillation or pulseless ventricular tachycardia after at least one shock, and vascular access. Paramedics enrolled patients at 10 North American sites. The primary outcome was survival to hospital discharge; the secondary outcome was favorable neurologic function at discharge. The per-protocol (primary analysis) population included all randomly assigned participants who met eligibility criteria and received any dose of a trial drug and whose initial cardiac-arrest rhythm of ventricular fibrillation or pulseless ventricular tachycardia was refractory to shock. Results In the per-protocol population, 3026 patients were randomly assigned to amiodarone (974), lidocaine (993), or placebo (1059); of those, 24.4%, 23.7%, and 21.0%, respectively, survived to hospital discharge. The difference in survival rate for amiodarone versus placebo was 3.2 percentage points (95% confidence interval [CI], -0.4 to 7.0; P=0.08); for lidocaine versus placebo, 2.6 percentage points (95% CI, -1.0 to 6.3; P=0.16); and for amiodarone versus lidocaine, 0.7 percentage points (95% CI, -3.2 to 4.7; P=0.70). Neurologic outcome at discharge was similar in the three groups. There was heterogeneity of treatment effect with respect to whether the arrest was witnessed (P=0.05); active drugs were associated with a survival rate that was significantly higher than the rate with placebo among patients with bystander-witnessed arrest but not among those with unwitnessed arrest. More amiodarone recipients required temporary cardiac pacing than did recipients of lidocaine or placebo. Conclusions Overall, neither amiodarone nor lidocaine resulted in a significantly higher rate of survival or favorable neurologic outcome than the rate with placebo among patients with out-of-hospital cardiac arrest due to initial shock-refractory ventricular fibrillation or pulseless ventricular tachycardia. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT01401647 .).

Concepts: Myocardial infarction, Cardiology, Cardiac arrest, Ventricular tachycardia, Supraventricular tachycardia, Amiodarone, Ventricular fibrillation, Defibrillation

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The mechanism by which the healthy heart and brain die rapidly in the absence of oxygen is not well understood. We performed continuous electrocardiography and electroencephalography in rats undergoing experimental asphyxia and analyzed cortical release of core neurotransmitters, changes in brain and heart electrical activity, and brain-heart connectivity. Asphyxia stimulates a robust and sustained increase of functional and effective cortical connectivity, an immediate increase in cortical release of a large set of neurotransmitters, and a delayed activation of corticocardiac functional and effective connectivity that persists until the onset of ventricular fibrillation. Blocking the brain’s autonomic outflow significantly delayed terminal ventricular fibrillation and lengthened the duration of detectable cortical activities despite the continued absence of oxygen. These results demonstrate that asphyxia activates a brainstorm, which accelerates premature death of the heart and the brain.

Concepts: Brain, Myocardial infarction, Cardiology, Heart, Cardiac arrest, Asystole, Electroencephalography, Ventricular fibrillation

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Background The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven. Methods We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event. Results The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons). The effect of treatment on PCR conversion varied according to geographic region: in Brazil, the odds ratio for PCR conversion was 3.03 (95% CI, 2.12 to 4.34) at 2 years and 1.87 (95% CI, 1.33 to 2.63) at 5 or more years; in Colombia and El Salvador, the odds ratio was 1.33 (95% CI, 0.90 to 1.98) at 2 years and 0.96 (95% CI, 0.63 to 1.45) at 5 or more years; and in Argentina and Bolivia, the odds ratio was 2.63 (95% CI, 1.89 to 3.66) at 2 years and 2.79 (95% CI, 1.99 to 3.92) at 5 or more years (P<0.001 for interaction). However, the rates of PCR conversion did not correspond to effects on clinical outcome (P=0.16 for interaction). Conclusions Trypanocidal therapy with benznidazole in patients with established Chagas' cardiomyopathy significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up. (Funded by the Population Health Research Institute and others; ClinicalTrials.gov number, NCT00123916 ; Current Controlled Trials number, ISRCTN13967269 .).

Concepts: Clinical trial, Myocardial infarction, Cardiology, Randomized controlled trial, Implantable cardioverter-defibrillator, Chagas disease, Ventricular tachycardia, Ventricular fibrillation

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Background -Current guidelines only recommend the use of an implantable cardioverter defibrillator (ICD) in patients with dilated cardiomyopathy (DCM) for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF)<35%. However, registries of out-of-hospital cardiac arrests demonstrate that 70-80% of such patients have a LVEF>35%. Patients with a LVEF>35% also have low competing risks of death from non-sudden causes. Therefore, those at high-risk of SCD may gain longevity from successful ICD therapy. We investigated whether late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) identified patients with DCM without severe LV systolic dysfunction at high-risk of SCD. Methods -We prospectively investigated the association between mid-wall late gadolinium enhancement (LGE) and the pre-specified primary composite outcome of SCD or aborted SCD amongst consecutive referrals with DCM and a LVEF≥40% to our center between January 2000 and December 2011, who did not have a pre-existing indication for ICD implantation. Results -Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the pre-specified end-point, compared to 7 of 298 (2.3%) without (HR 9.2; 95% CI 3.9-21.8; p<0.0001). Nine patients (8.9%) with LGE compared to 6 (2.0%) without (HR 4.9; 95% CI 1.8-13.5; p=0.002) died suddenly, whilst 10 patients (9.9%) with LGE compared to 1 patient (0.3%) without (HR 34.8; 95% CI 4.6-266.6; p<0.001) had aborted SCD. Following adjustment, LGE predicted the composite end-point (HR 9.3; 95% CI 3.9-22.3; p<0.0001), SCD (HR 4.8; 95% CI 1.7-13.8; p=0.003) and aborted SCD (HR 35.9; 95% CI 4.8-271.4; p<0.001). Estimated hazard ratios for the primary end-point for patients with a LGE extent of 0-2.5%, 2.5-5% and >5% compared to those without LGE were 10.6 (95%CI 3.9-29.4), 4.9 (95% CI 1.3-18.9) and 11.8 (95% CI 4.3-32.3) respectively. Conclusions -Mid-wall LGE identifies a group of patients with DCM and LVEF≥40% at increased risk of SCD and low-risk of non-sudden death who may benefit from ICD implantation. Clinical Trial Registration -https://clinicaltrials.gov/ Identifier: NCT00930735.

Concepts: Myocardial infarction, Cardiology, Heart failure, Ejection fraction, Implantable cardioverter-defibrillator, Cardiac arrest, Ventricular fibrillation, Sudden cardiac death