The burden of proof: the current state of atrial fibrillation prevention and treatment trials

Atrial fibrillation (AF) is an age-related arrhythmia of enormous socioeconomic significance. In recent years, our understanding of the basic mechanisms that initiate and perpetuate AF has evolved rapidly, catheter ablation of AF has progressed from concept to reality, and recent studies suggest lifestyle modification may help prevent AF recurrence. Emerging developments in genetics, imaging, and informatics also present new opportunities for personalized care. However, considerable challenges remain. These include a paucity of studies examining AF prevention, modest efficacy of existing antiarrhythmic therapies, diverse ablation technologies and practice, and limited evidence to guide management of high-risk patients with multiple comorbidities. Studies examining the long-term effects of AF catheter ablation on morbidity and mortality outcomes are not yet completed. In many ways, further progress in the field is heavily contingent on the feasibility, capacity, and efficiency of clinical trials to incorporate the rapidly evolving knowledge base and to provide substantive evidence for novel AF therapeutic strategies. This review outlines the current state of AF prevention and treatment trials, including the foreseeable challenges, as discussed by a unique forum of clinical trialists, scientists, and regulatory representatives in a session endorsed by the Heart Rhythm Society at the 12th Global CardioVascular Clinical Trialists Forum in Washington, DC, December 3–5, 2015

A Novel Method to Capture the Onset of Dynamic Electrocardiographic Ischemic Changes and its Implications to Arrhythmia Susceptibility

Background: This study investigates the hypothesis that morphologic analysis of intracardiac electrograms provides a sensitive approach to detect acute myocardial infarction or myocardial infarction‐induced arrhythmia susceptibility. Large proportions of irreversible myocardial injury and fatal ventricular tachyarrhythmias occur in the first hour after coronary occlusion; therefore, early detection of acute myocardial infarction may improve clinical outcomes. Methods and Results: We developed a method that uses the wavelet transform to delineate electrocardiographic signals, and we have devised an index to quantify the ischemia‐induced changes in these signals. We recorded body‐surface and intracardiac electrograms at baseline and following myocardial infarction in 24 swine. Statistically significant ischemia‐induced changes after the initiation of occlusion compared with baseline were detectable within 30 seconds in intracardiac left ventricle (P<0.0016) and right ventricle–coronary sinus (P<0.0011) leads, 60 seconds in coronary sinus leads (P<0.0002), 90 seconds in right ventricle leads (P<0.0020), and 360 seconds in body‐surface electrocardiographic signals (P<0.0022). Intracardiac leads exhibited a higher probability of detecting ischemia‐induced changes than body‐surface leads (P<0.0381), and the right ventricle–coronary sinus configuration provided the highest sensitivity (96%). The 24‐hour ECG recordings showed that the ischemic index is statistically significantly increased compared with baseline in lead I, aVR, and all precordial leads (P<0.0388). Finally, we showed that the ischemic index in intracardiac electrograms is significantly increased preceding ventricular tachyarrhythmic events (P<0.0360). Conclusions: We present a novel method that is capable of detecting ischemia‐induced changes in intracardiac electrograms as early as 30 seconds following myocardial infarction or as early as 12 minutes preceding tachyarrhythmic events

Acquired Resistance to KRAS (G12C) Inhibition in Cancer

BACKGROUND: Clinical trials of the KRAS inhibitors adagrasib and sotorasib have shown promising activity in cancers harboring KRAS glycine-to-cysteine amino acid substitutions at codon 12 (KRAS(G12C)). The mechanisms of acquired resistance to these therapies are currently unknown. METHODS: Among patients with KRAS(G12C) -mutant cancers treated with adagrasib monotherapy, we performed genomic and histologic analyses that compared pretreatment samples with those obtained after the development of resistance. Cell-based experiments were conducted to study mutations that confer resistance to KRAS(G12C) inhibitors. RESULTS: A total of 38 patients were included in this study: 27 with non-small-cell lung cancer, 10 with colorectal cancer, and 1 with appendiceal cancer. Putative mechanisms of resistance to adagrasib were detected in 17 patients (45% of the cohort), of whom 7 (18% of the cohort) had multiple coincident mechanisms. Acquired KRAS alterations included G12D/R/V/W, G13D, Q61H, R68S, H95D/Q/R, Y96C, and high-level amplification of the KRAS(G12C) allele. Acquired bypass mechanisms of resistance included MET amplification; activating mutations in NRAS, BRAF, MAP2K1, and RET; oncogenic fusions involving ALK, RET, BRAF, RAF1, and FGFR3; and loss-of-function mutations in NF1 and PTEN. In two of nine patients with lung adenocarcinoma for whom paired tissue-biopsy samples were available, histologic transformation to squamous-cell carcinoma was observed without identification of any other resistance mechanisms. Using an in vitro deep mutational scanning screen, we systematically defined the landscape of KRAS mutations that confer resistance to KRAS(G12C) inhibitors. CONCLUSIONS: Diverse genomic and histologic mechanisms impart resistance to covalent KRAS(G12C) inhibitors, and new therapeutic strategies are required to delay and overcome this drug resistance in patients with cancer. (Funded by Mirati Therapeutics and others; ClinicalTrials.gov number, NCT03785249.)

DW-MRI as a Biomarker to Compare Therapeutic Outcomes in Radiotherapy Regimens Incorporating Temozolomide or Gemcitabine in Glioblastoma

The effectiveness of the radiosensitizer gemcitabine (GEM) was evaluated in a mouse glioma along with the imaging biomarker diffusion-weighted magnetic resonance imaging (DW-MRI) for early detection of treatment effects. A genetically engineered murine GBM model [Ink4a-Arf−/− PtenloxP/loxP/Ntv-a RCAS/PDGF(+)/Cre(+)] was treated with gemcitabine (GEM), temozolomide (TMZ) +/− ionizing radiation (IR). Therapeutic efficacy was quantified by contrast-enhanced MRI and DW-MRI for growth rate and tumor cellularity, respectively. Mice treated with GEM, TMZ and radiation showed a significant reduction in growth rates as early as three days post-treatment initiation. Both combination treatments (GEM/IR and TMZ/IR) resulted in improved survival over single therapies. Tumor diffusion values increased prior to detectable changes in tumor volume growth rates following administration of therapies. Concomitant GEM/IR and TMZ/IR was active and well tolerated in this GBM model and similarly prolonged median survival of tumor bearing mice. DW-MRI provided early changes to radiosensitization treatment warranting evaluation of this imaging biomarker in clinical trials

Stress-Induced Cardiomyopathy Secondary to COVID-19

A 67-year-old female with prior medical history of HTN and asthma presented with acute-onset dyspnea and nausea for 4 days prior to admission. Upon initial encounter in the emergency room, she was found to have findings of abnormal pulmonary infiltrates and consequent workup revealed COVID-19. During further hospital course, the patient developed abnormal EKG and echocardiographic findings consistent with stress-induced cardiomyopathy

Can cardiac resynchronization therapy be used as a tool to reduce sudden cardiac arrest risk?

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Retrospective review of 65 atrioesophageal fistulas post atrial fibrillation ablation

Background: Although a rare complication of catheter based ablation for atrial fibrillation (AF), atrioesophageal fistula (AEF) is a serious and fatal event [1–5]. Most reports of AEF are single cases or small case series. Objective: The purpose of this study was to perform a comprehensive literature search of all published atrioesophageal fistula following catheter ablation for AF in order to identify the mortality rates associated with therapeutic modalities and suggest the most definitive management in reducing mortality. Methods: A comprehensive literature review of reported observational cases of atrioesophageal fistula post catheter based ablation for atrial fibrillation was performed. Results: Sixty-five cases of AEF post atrial fibrillation ablation were reviewed. The mean age was 55 years old. 73.8% (48/65) of the identified cases occurred in males (p < 0.001). Of the 65 cases, 13 underwent surgical radiofrequency ablation (RFA) and 52 underwent percutaneous RFA. Mortality resulted in 53.8% of those who underwent surgical RFA and in 55.8% of those who underwent percutaneous RFA (p = .888). The time range interval from procedure to onset of symptoms was 1–60 days. The most prevalent symptom, fever, occurred in 52 of the 65 cases, followed by neurological symptoms (n = 44). CT of the chest (n = 37), transthoracic echocardiogram (n = 21), and CT of the head (n = 18) were the preferred diagnostic modalities. Patients who underwent surgical correction with esophageal repair for treatment were more likely to survive, in comparison to patients who were treated with non-surgical interventions, such as antibiotic therapy, anticoagulation therapy or esophageal stenting. Of the total 34 patients who were treated surgically, 27 survived (79.4%). Of the total 31 patients who were treated non-surgically, only 2 survived (6.5%), reflecting significantly lower mortality with surgical versus non-surgical therapy (p < 0.001). Conclusion: Atrioesophageal fistula is an uncommon but potentially fatal complication of atrial fibrillation ablation. Patients who underwent surgical repair were twelve times more likely to survive than those treated with stenting, antibiotic therapy or no intervention. Based on the observation that patients are 12 times more likely to survive an AEF with surgery than without, the authors believe that prompt surgical correction of AEF should be considered as standard of care when dealing with this dreaded complication

Management strategies in atrial fibrillation in patients with heart failure

Atrial fibrillation (AF) and heart failure (HF) frequently occur together, and their coexistence is associated with a poor prognosis. AF and HF share risk factors, but their relationship involves complex hemodynamic, neurohormonal, inflammatory, ultrastructural, and electrophysiologic processes that extend beyond epidemiological associations. The shared mechanisms underlying AF and HF have important implications for the treatment of AF in patients with HF. This article focuses on reviewing contemporary data as it pertains to AF management in patients with HF and provides insight into investigational therapies currently under development