Background: Catheter ablation as first-line therapy for ventricular tachycardia (VT) at the time of implantable cardioverter defibrillator (ICD) implantation has not been adopted into clinical guidelines. Also, there is an unmet clinical need to prospectively examine the role of VT ablation in patients with nonischemic cardiomyopathy, an increasingly prevalent population that is referred for advanced therapies globally. Methods: We conducted an international, multicenter, randomized controlled trial enrolling 180 patients with cardiomyopathy and monomorphic VT with an indication for ICD implantation to assess the role of early, first-line ablation therapy. A total of 121 patients were randomly assigned (1:1) to ablation plus an ICD versus conventional medical therapy plus an ICD. Patients who refused ICD (n=47) were followed in a prospective registry after stand-alone ablation treatment. The primary outcome was a composite end point of VT recurrence, cardiovascular hospitalization, or death. Results: Randomly assigned patients had a mean age of 55 years (interquartile range, 46–64) and left ventricular ejection fraction of 40% (interquartile range, 30%–49%); 81% were male. The underlying heart disease was ischemic cardiomyopathy in 35%, nonischemic cardiomyopathy in 30%, and arrhythmogenic cardiomyopathy in 35%. Ablation was performed a median of 2 days before ICD implantation (interquartile range, 5 days before to 14 days after). At 31 months, the primary outcome occurred in 49.3% of the ablation group and 65.5% in the control group (hazard ratio, 0.58 [95% CI, 0.35–0.96]; P =0.04). The observed difference was driven by a reduction in VT recurrence in the ablation arm (hazard ratio, 0.51 [95%CI, 0.29–0.90]; P =0.02). A statistically significant reduction in both ICD shocks (10.0% versus 24.6%; P =0.03) and antitachycardia pacing (16.2% versus 32.8%; P =0.04) was observed in patients who underwent ablation compared with control. No differences in cardiovascular hospitalization (32.0% versus. 33.7%; hazard ratio, 0.82 [95% CI, 0.43–1.56]; P =0.55) or mortality (8.9% versus 8.8%; hazard ratio, 1.40 [95% CI, 0.38–5.22]; P =0.62]) were observed. Ablation-related complications occurred in 8.3% of patients. Conclusions: Among patients with cardiomyopathy of varied causes, early catheter ablation performed at the time of ICD implantation significantly reduced the composite primary outcome of VT recurrence, cardiovascular hospitalization, or death. These findings were driven by a reduction in ICD therapies. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02848781.

The mechanism responsible for premature ventricular complex (PVC)-mediated left ventricular (LV) dysfunction remains unclear. We sought to determine the electrocardiographic and electrophysiological characteristics of PVC-mediated LV dysfunction. One hundred and twenty-seven patients who underwent radiofrequency catheter ablation (RFCA) for frequent PVCs (PVCs burden ≥10%/24 h) and had no significant structural heart disease were investigated. Left ventricular dysfunction (ejection fraction < 50%) was present in 28 of 127 patients (22.0%). The mean PVC burden (31 ± 11 vs. 22 ± 10%, P < 0.001), the presence of non-sustained ventricular tachycardia (53.6 vs. 33.3%, P = 0.05), and the presence of a retrograde P-wave following a PVC (64.3 vs. 30.3%, P = 0.001) were significantly greater in those with LV dysfunction than in those with normal LV function. The cut-off PVC burden related to LV dysfunction was 26%/day, with a sensitivity of 70% and a specificity of 78%. The PVC morphology, QRS axis, QRS width, coupling interval, the presence of interpolation, and PVC emergence pattern during exercise electrocardiogram were not significantly different between the two groups. The origin sites of PVCs, the acute success rate, and the recurrence rate during follow-up after RFCA were similar. In a multivariate analysis, the PVC burden (odds ratio 2.94, 95% confidence interval 0.90–3.19, P = 0.006) and the presence of retrograde P-waves (odds ratio 2.79, 95% confidence interval 1.08–7.19, P = 0.034) were independently associated with PVC-mediated LV dysfunction. A higher PVC burden (>26%/day) and the presence of retrograde P-waves were independently associated with PVC-mediated LV dysfunction.

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BACKGROUND: Current clinical biomarkers for the programmed cell death 1 (PD-1) blockade therapy are insufficient because they rely only on the tumor properties, such as programmed cell death ligand 1 expression frequency and tumor mutation burden. Identifying reliable, responsive biomarkers based on the host immunity is necessary to improve the predictive values. METHODS: We investigated levels of plasma metabolites and T cell properties, including energy metabolism markers, in the blood of patients with non-small cell lung cancer before and after treatment with nivolumab ( n = 55). Predictive values of combination markers statistically selected were evaluated by cross-validation and linear discriminant analysis on discovery and validation cohorts, respectively. Correlation between plasma metabolites and T cell markers was investigated. RESULTS: The 4 metabolites derived from the microbiome (hippuric acid), fatty acid oxidation (butyrylcarnitine), and redox (cystine and glutathione disulfide) provided high response probability (AUC = 0.91). Similarly, a combination of 4 T cell markers, those related to mitochondrial activation (PPARγ coactivator 1 expression and ROS), and the frequencies of CD8 ⁺ PD-1 ^hi and CD4 ⁺ T cells demonstrated even higher prediction value (AUC = 0.96). Among the pool of selected markers, the 4 T cell markers were exclusively selected as the highest predictive combination, probably because of their linkage to the abovementioned metabolite markers. In a prospective validation set ( n = 24), these 4 cellular markers showed a high accuracy rate for clinical responses of patients (AUC = 0.92). CONCLUSION: Combination of biomarkers reflecting host immune activity is quite valuable for responder prediction. FUNDING: AMED under grant numbers 18cm0106302h0003, 18gm0710012h0105, and 18lk1403006h0002; the Tang Prize Foundation; and JSPS KAKENHI grant numbers JP16H06149, 17K19593, and 19K17673.