Very early administration of glucose-insulin-potassium by emergency medical service for acute coronary syndromes: Biological mechanisms for benefit in the IMMEDIATE Trial.

AIMS: In the IMMEDIATE Trial, intravenous glucose-insulin-potassium (GIK) was started as early as possible for patients with suspected acute coronary syndrome by ambulance paramedics in communities. In the IMMEDIATE Biological Mechanism Cohort substudy, reported here, we investigated potential modes of GIK action on specific circulating metabolic components. Specific attention was given to suppression of circulating oxygen-wasting free fatty acids (FFAs) that had been posed as part of the early GIK action related to averting cardiac arrest. METHODS: We analyzed the changes in plasma levels of FFA, glucose, C-peptide, and the homeostasis model assessment (HOMA) index. RESULTS: With GIK, there was rapid suppression of FFA levels with estimated levels for GIK and placebo groups after 2 hours of treatment of 480 and 781 µmol/L (P<.0001), even while patterns of FFA saturation remained unchanged. There were no significant changes in the HOMA index in the GIK or placebo groups (HOMA index: placebo 10.93, GIK 12.99; P = .07), suggesting that GIK infusions were not countered by insulin resistance. Also, neither placebo nor GIK altered endogenous insulin secretion as reflected by unchanging C-peptide levels. CONCLUSION: These mechanistic observations support the potential role of FFA suppression in very early cardioprotection by GIK. They also suggest that the IMMEDIATE Trial GIK formula is balanced with respect to its insulin and glucose composition, as it induced no endogenous insulin secretion.

Effect of Implanted Defibrillator on Mortality in Patients With Chronic Kidney Disease.

The beneficial role of implantable cardioverter defibrillators (ICDs) in patients with chronic kidney disease (CKD) is controversial. This meta-analysis aimed to evaluate the effect of ICD on mortality in patients with CKD. A literature search was conducted for studies reporting the effect of ICD on all-cause mortality in patients with CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2). The search was not restricted to time or publication status. The search included the following databases: Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar, and EBSCO CINAHL. The primary end point was all-cause mortality. The minimum duration of follow-up required for inclusion was 1 year. The literature search identified 834 studies, of which 14 studies with 70,661 patients were included. Mean follow-up was 39 months (12 to 81 months). For all patients with CKD, ICD was associated with lower all-cause mortality (log hazard ratio [HR] -0.247, standard error [SE] 0.101, p = 0.015). Heterogeneity: degree of freedom = 13 (p <0.01), I2 = 97.057; test for overall effect: Z = -2.431 (p = 0.015). When further stratified based on dialysis, patients with CKD without the need for dialysis had significantly lower mortality (log HR -0.211, SE 0.095, p = 0.026), with a similar trend in patients who underwent dialysis (log HR -0.262, SE 0.134, p = 0.051). ICD implantation is associated with a significant mortality benefit in patients with CKD.

Effects of GLP-1 Agonists on mortality and arrhythmias in patients with Type II diabetes.

Background: Glucagon-like Peptide-1 Receptor Agonists (GLP-1 RA) are frequently used for the management of diabetes. The impact of GLP-1 RA on cardiovascular outcomes is unclear. We aim to assess the effect of GLP-1 RA on mortality, atrial and ventricular arrhythmias, and sudden cardiac death in patients with type II diabetes. Methods: We searched databases including Ovid MEDLINE, EMBASE, Scopus, Web of Science, Google Scholar and CINAHL, from inception to May 2022, for randomized controlled trials reporting the relationship between GLP-1 RA (including albiglutide, dulaglutide, exenatide, liraglutide, lixisenatide, and semaglutide) and mortality, atrial arrhythmias, and the combined incidence of ventricular arrhythmias and sudden cardiac death. The search was not restricted to time or publication status. Results: A total of 464 studies resulted from literature search, of which 44 studies, including 78,702 patients (41,800 GLP-1 agonists vs 36,902 control), were included. Follow up ranged from 52 to 208 weeks. GLP-1 RA were associated with lower risk of all-cause mortality (odds ratio 0.891, 95% confidence interval 0.837-0.949; P < 0.01) and reduced cardiovascular mortality (odds ratio 0.88, 95% confidence interval 0.881-0.954; P < 0.01). GLP-1 RA were not associated with increased risk of atrial (odds ratio 0.963, 95% confidence interval 0.869-1.066; P 0.46) or ventricular arrhythmias and sudden cardiac death (odds ratio 0.895, 95% confidence interval 0.706-1.135; P 0.36). Conclusion: GLP-1 RA are associated with decreased all-cause and cardiovascular mortality, and no increased risk of atrial and ventricular arrhythmias and sudden cardiac death.

Study design for the Immediate Myocardial Metabolic Enhancement During Initial Assessment and Treatment in Emergency Care (IMMEDIATE) Trial: A double-blind randomized controlled trial of intravenous glucose, insulin, and potassium for acute coronary syndromes in emergency medical services.

BACKGROUND: Experimental studies suggest that metabolic myocardial support by intravenous (IV) glucose, insulin, and potassium (GIK) reduces ischemia-induced arrhythmias, cardiac arrest, mortality, progression from unstable angina pectoris to acute myocardial infarction (AMI), and myocardial infarction size. However, trials of hospital administration of IV GIK to patients with ST-elevation myocardial infarction (STEMI) have generally not shown favorable effects possibly because of the GIK intervention taking place many hours after ischemic symptom onset. A trial of GIK used in the very first hours of ischemia has been needed, consistent with the timing of benefit seen in experimental studies. OBJECTIVE: The IMMEDIATE Trial tested whether, if given very early, GIK could have the impact seen in experimental studies. Accordingly, distinct from prior trials, IMMEDIATE tested the impact of GIK (1) in patients with acute coronary syndromes (ACS), rather than only AMI or STEMI, and (2) administered in prehospital emergency medical service settings, rather than later, in hospitals, after emergency department evaluation. DESIGN: The IMMEDIATE Trial was an emergency medical service-based randomized placebo-controlled clinical effectiveness trial conducted in 13 cities across the United States that enrolled 911 participants. Eligible were patients 30 years or older for whom a paramedic performed a 12-lead electrocardiogram to evaluate chest pain or other symptoms suggestive of ACS for whom electrocardiograph-based acute cardiac ischemia time-insensitive predictive instrument indicated a ≥75% probability of ACS, and/or the thrombolytic predictive instrument indicated the presence of a STEMI, or if local criteria for STEMI notification of receiving hospitals were met. Prehospital IV GIK or placebo was started immediately. Prespecified were the primary end point of progression of ACS to infarction and, as major secondary end points, the composite of cardiac arrest or in-hospital mortality, 30-day mortality, and the composite of cardiac arrest, 30-day mortality, or hospitalization for heart failure. Analyses were planned on an intent-to-treat basis, on a modified intent-to-treat group who were confirmed in emergency departments to have ACS, and for participants presenting with STEMI. CONCLUSION: The IMMEDIATE Trial tested whether GIK, when administered as early as possible in the course of ACS by paramedics using acute cardiac ischemia time-insensitive predictive instrument and thrombolytic predictive instrument decision support, would reduce progression to AMI, mortality, cardiac arrest, and heart failure. It also tested whether it would provide clinical and pathophysiologic information on GIK's biological mechanisms.

Electrical Storm in a Case of Bilateral Pheochromocytomas.

BACKGROUND Pheochromocytomas are catecholamine-secreting tumors that develop within the chromaffin cells of the adrenal glands. They most commonly present with hypertension, and the classic triad of symptoms is headaches, palpitations, and diaphoresis. Electrical storm (ES) is defined as at least 3 sustained episodes of ventricular tachycardia (VT), ventricular fibrillation (VF), or appropriate shocks from an implanted cardioverter-defibrillator (ICD) within 24 h. We discuss the case of a 63-year-old man with known bilateral pheochromocytomas who presented with ES prompting multiple ICD shocks, possibly exacerbated by catecholamine surge from his adrenal tumors. CASE REPORT The patient was a 63-year-old man with an extensive medical history including ischemic cardiomyopathy and congestive heart failure with reduced ejection fraction presented with multiple syncopal episodes secondary to persistent monomorphic ventricular tachycardia (MMVT), polymorphic ventricular tachycardia (PMVT), and VF requiring ICD shocks. He had known bilateral pheochromocytomas. ES was attributed to catecholamine excess in the setting of these tumors, so VT ablation was deferred pending tumor removal. Alpha blockade was initiated preoperatively, and the patient subsequently underwent bilateral adrenalectomy; however, he continued to sustain tachyarrhythmias and eventually died despite resuscitative efforts. CONCLUSIONS Bilateral pheochromocytomas are rare adrenal tumors. In even more infrequent situations, they can cause ES secondary to adrenergic stimulation from catecholamine surges. It is worth considering pheochromocytoma in patients with refractory ES, as treating these tumors could potentially reduce the frequency of this dangerous arrhythmia.

Electrophysiological effects of late percutaneous coronary intervention for infarct-related coronary artery occlusion: the Occluded Artery Trial-Electrophysiological Mechanisms (OAT-EP).

BACKGROUND: The Occluded Artery Trial-Electrophysiological Mechanisms (OAT-EP) tested the hypothesis that opening a persistently occluded infarct-related artery by percutaneous coronary intervention and stenting (PCI) after the acute phase of myocardial infarction compared with optimal medical therapy alone reduces markers of vulnerability to ventricular arrhythmias. METHODS AND RESULTS: Between April 2003 and December 2005, 300 patients with an occluded native infarct-related artery 3 to 28 days (median, 12 days) after myocardial infarction were randomized to PCI or optimal medical therapy. Ten-minute digital Holter recordings were obtained before randomization, at 30 days, and at 1 year. The primary end point was the change in alpha1, a nonlinear heart rate variability parameter, between baseline and 1 year. Major secondary end points were the changes in the filtered QRS duration on the signal-averaged ECG and variability in T-wave morphology (T-wave variability) between baseline and 1 year. There were no significant differences in the changes in alpha1 (-0.04; 95% CI, -0.12 to 0.04), filtered QRS (2.2 ms; 95% CI, -1.4 to 5.9 ms), or T-wave variability (3.0 microV; 95% CI, -4.8 to 10.7 microV) between the PCI and medical therapy groups (medical therapy change minus PCI change). Multivariable analysis revealed that the results were unchanged after adjustment for baseline clinical variables and medication treatments during the Holter recordings. CONCLUSIONS: PCI with stenting of a persistently occluded infarct-related artery during the subacute phase after myocardial infarction compared with medical therapy alone had no significant effect on changes in heart rate variability, the time-domain signal-averaged ECG, or T-wave variability during the first year after myocardial infarction. These findings are consistent with the lack of clinical benefit, including no reduction in sudden death, with PCI for stable patients with persistently occluded infarct-related arteries after myocardial infarction in the main OAT.

Coronary sinus electrode does not reduce atrial defibrillation thresholds.

BACKGROUND: Atrial defibrillation can be achieved with a conventional dual-coil, active pectoral implantable cardioverter-defibrillator (ICD) lead system. Shocking vectors that incorporate an additional electrode in the CS have been used, but it is unclear if they improve atrial DFTs. OBJECTIVE: The objective of this prospective, randomized study was to determine if a coronary sinus (CS) electrode reduces atrial defibrillation thresholds (DFTs). METHODS: This was a prospective study of 36 patients undergoing initial ICD implant for standard indications. A defibrillation lead with superior vena cava (SVC) and right ventricular (RV) shocking coils was implanted in the RV. An active can emulator (Can) was placed in a pre-pectoral pocket. A lead with a 4 cm long shocking coil was placed in the CS. Atrial DFTs were determined in the following 3 shocking configurations in each patient, with the order of testing randomized: RV --> SVC + Can (Ventricular Triad), distal CS --> SVC + Can (Distal Atrial Triad), and proximal CS --> SVC + Can (Proximal Atrial Triad). RESULTS: The Proximal and Distal Atrial Triad configurations were both associated with significant reductions in peak current (p < 0.01), but this effect was offset by significant increases in shock impedance (p < 0.01), resulting in no net change in the peak voltage or DFT energy in comparison to the Ventricular Triad configuration (Ventricular Triad: 4.9 +/- 6.6 J, Proximal Atrial Triad: 3.3 +/- 4.1J, Distal Atrial Triad: 4.4 +/- 6.7 J, p > 0.2). CONCLUSION: Shocking vectors that incorporate a CS coil do not significantly improve atrial defibrillation efficacy. Since the Ventricular Triad shocking pathway provides reliable atrial and ventricular defibrillation, this configuration should be preferred for combined atrial and ventricular ICDs.

Preserved heart rate variability identifies low-risk patients with nonischemic dilated cardiomyopathy: results from the DEFINITE trial.

BACKGROUND: The recent expansion of indications for prophylactic implantable cardioverter-defibrillator (ICD) placement in subjects with nonischemic dilated cardiomyopathy has raised concerns about the cost-effectiveness of this therapy. OBJECTIVES: The purpose of this study was to identify low-risk patients with nonischemic dilated cardiomyopathy who may not require prophylactic ICD placement. METHODS: This was a prospective study of 274 participants in the Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) trial, a randomized controlled trial that evaluated the role of prophylactic ICD placement in patients with nonischemic dilated cardiomyopathy. The patients underwent 24-hour Holter recording for analysis of heart rate variability (HRV). The primary HRV variable was the standard deviation of normal R-R intervals (SDNN). Patients with atrial fibrillation and frequent ventricular ectopy (>25% of beats) were excluded from HRV analysis (23% of patients). SDNN was categorized in tertiles, and Kaplan-Meier analysis was performed to compare survival in the three tertiles and excluded patients. RESULTS: The study population was 73% male, with a mean age of 59 +/- 12 years and mean left ventricular ejection fraction of 21% +/- 6%. After 3-year follow-up, significant differences in mortality rates were observed: SDNN >113 ms: 0 (0%), SDNN 81-113 ms: 5 (7%), SDNN <81 ms: 7 (10%), excluded patients: 11 (17%) (P = .03). There were no deaths in the tertile with SDNN >113 ms regardless of treatment assignment (ICD vs control). CONCLUSION: Patients with nonischemic dilated cardiomyopathy and preserved HRV have an excellent prognosis and may not benefit from prophylactic ICD placement. Patients with severely depressed HRV and patients who are excluded from HRV analysis because of atrial fibrillation and frequent ventricular ectopy have the highest mortality.

Syncope, seizure or both?

Ictal asystole (IA) is a rare phenomenon in patients with seizures with an incidence of 0.27-0.4% and has been proposed as a possible mechanism of sudden unexpected death in epilepsy patients (SUDEP). We present a case of a 53-year-old woman who initially presented with episodes of expressive aphasia and was treated with antiepileptic drugs (AEDs). While on therapy she experienced episodes of syncope. During her hospitalization for tapering of AEDs and 24-hour EEG monitoring, the patient developed a seizure followed by sinus bradycardia and an 18-second sinus pause, resulting in loss of consciousness and slowing of cerebral activity. Ten seconds after the return of cardiac activity, the EEG showed return of cerebral activity. A dual chamber pacemaker was implanted.

Effects of selective autonomic blockade on T-wave alternans in humans.

BACKGROUND: T-wave alternans (TWA) is an important noninvasive measure of ventricular arrhythmia vulnerability. This study tested the hypothesis that the autonomic nervous system influences TWA measurement in high-risk subjects with coronary artery disease. METHODS AND RESULTS: T-wave alternans was measured in 60 patients with coronary artery disease, left ventricular dysfunction, and inducible sustained ventricular tachycardia during electrophysiological studies. All patients had TWA measured at baseline with atrial pacing at 100 bpm (600 ms), 109 bpm (550 ms), and 120 bpm (500 ms). After a 10-minute recovery period, TWA was measured again after sympathetic blockade (esmolol, n=20), parasympathetic blockade (atropine, n=20), or no intervention (control subjects, n=20). The prevalence of significant TWA was unchanged compared with baseline after atropine infusion and in the control group. In contrast, the amplitude of TWA in the vector magnitude lead was significantly reduced after esmolol infusion (P<0.001), and the number of positive TWA tests was reduced by 50% (70% versus 35%, P<0.05). CONCLUSIONS: Our findings have important implications for the use of TWA to risk-stratify patients for life-threatening ventricular arrhythmias and provide a new potential mechanism for the reduction in sudden cardiac death conferred by beta-blockers among patients with coronary artery disease and congestive heart failure.

Clinical predictors of atrial defibrillation thresholds with a dual-coil, active pectoral lead system.

OBJECTIVES: The purpose of this study was to identify clinical predictors of atrial defibrillation thresholds (DFTs) with standard implantable cardioverter-defibrillator (ICD) leads. BACKGROUND: Atrial defibrillation can be achieved with active pectoral, dual-coil transvenous ICD lead systems. If clinical predictors of atrial defibrillation efficacy with these lead systems were identified, they could be used to predict which patients may require more complex lead systems for atrial defibrillation, such as a coronary sinus electrode. METHODS: This was a prospective study of 135 consecutive patients undergoing initial ICD implant for standard indications. The lead system evaluated was a transvenous defibrillation lead with coils in the superior vena cava (SVC) and right ventricular apex (RV), and a left pectoral pulse generator emulator (CAN). The shocking pathway was RV-->SVC+CAN. Atrial DFT was measured using a step-up protocol. Clinical and echocardiographic parameters were evaluated as predictors of atrial DFT and multiple linear regression was performed. RESULTS: Mean atrial DFT was 4.6 +/- 3.8 J. Atrial DFT was < or =3 J in 70 patients (52%) and < or = 10 J in 97% of patients. The highest atrial DFT was 20 J (one patient). Left atrial size (r = 0.21, P = .01) and left ventricular end-diastolic diameter (r = 0.19, P = .02) were independent predictors of atrial DFT. However, these two predictors accounted for only 6% of the variability in atrial DFT. CONCLUSIONS: Clinical parameters are of limited use in predicting atrial DFT with a dual-coil, active pectoral ICD lead system. Because the RV--> SVC + CAN shocking pathway provides reliable atrial and ventricular defibrillation, this configuration should be preferred for combined atrial and ventricular ICDs.

Effect of shock polarity on the efficacy of transthoracic atrial defibrillation.

BACKGROUND: The energy requirement for internal ventricular defibrillation is reduced by reversal of shock polarity. The influence of shock polarity on the efficacy of transthoracic atrial defibrillation is unknown. METHODS: This prospective, randomized study enrolled 110 consecutive patients who were referred for elective cardioversion of persistent atrial fibrillation (AF). The electrodes were placed in the anteroposterior position. The patients were randomized to receive either standard (anterior pad = cathode) or reversed polarity (anterior pad = anode) shocks with a damped sinusoidal monophasic waveform. A step-up protocol was used to estimate the cardioversion threshold. The initial shock energy was 50 J, with subsequent increments to 100, 200, 300, and 360 J in the event of cardioversion failure. RESULTS: Sixty-four percent of the patient population were men, with a mean age of 66 +/- 13 years and a mean duration of AF of 242 +/- 556 days. The overall success rates of cardioversion were 84% for standard polarity and 78% for reversed polarity (P not significant). Among the patients who were successfully cardioverted, the mean atrial defibrillation threshold was 198 +/- 103 J for standard polarity and 212 +/- 107 J for reversed polarity (P not significant). CONCLUSIONS: Reversal of shock polarity does not improve transthoracic cardioversion efficacy with a standard damped sinusoidal monophasic waveform. Alternate strategies should be considered for patients who fail external cardioversion, such as adjunctive pharmacologic treatment, use of a biphasic shock waveform, or internal cardioversion.

Efficacy of transthoracic cardioversion of atrial fibrillation using a biphasic, truncated exponential shock waveform at variable initial shock energies.

Biphasic shocks are more effective than damped sine wave monophasic shocks for transthoracic cardioversion (CV) of atrial fibrillation (AF), but the optimal protocol for CV with biphasic shocks has not been defined. We conducted a prospective, randomized study of 120 consecutive patients with persistent AF to delineate the dose-response curve for CV of AF with a biphasic truncated exponential shock waveform and to identify clinical predictors of shock efficacy. Our data suggest that the initial shock energy for CV with this waveform should be 200 J if the patient weighs <90 kg and 360 J if the patient weighs >/=90 kg.

Effect of shock polarity on defibrillation thresholds with a hybrid patch-coil lead system.

INTRODUCTION: Understanding the factors that affect defibrillation thresholds (DFTs) has important implications both for optimization of defibrillation efficacy and for the design of new lead systems. The objective of this prospective study was to evaluate the effect of shock polarity on defibrillation efficacy at the time of routine pulse generator replacement in patients with a hybrid patch-coil lead system. METHODS: Each patient underwent 4 assessments of DFT: monophasic or biphasic shock with standard or reversed polarity, with the order of testing with respect to polarity randomized. In standard polarity, the right atrial coil is the anode and the left ventricular patch is the cathode. RESULTS: The study population of 30 patients was 80% men with a mean age of 65 +/- 9 years and a mean left ventricular ejection fraction of 33 +/- 12%. There was a significant 21% decrease in the mean monophasic DFT with reversed polarity shocks (13.1 +/- 5.9 J vs. 16.6 +/- 6.5 J, p < 0.01). Reversal of shock polarity did not have a significant effect on the mean biphasic DFT (8.0 +/- 4.8 J vs. 8.5 +/- 4.3 J for reversed and standard polarity respectively, p = NS). However, when an elevated biphasic DFT (>or=15 J) was present in either standard or reversed polarity, a significant decrease in DFT was observed when the opposite polarity was used (16.7 +/- 2.5 J vs. 9.1 +/- 2.7 J, n = 9, p < 0.0001). CONCLUSION: Reversal of shock polarity markedly improves monophasic DFTs with the patch-coil lead configuration. The DFT should be determined with both shock polarities to optimize defibrillation efficacy for patients with high biphasic DFTs (>or=15 J).