Fast delivery of flecainide via the pulmonary (bolus) or intravenous (rapid infusion) routes reduces atrial fibrillation conversion dose and minimizes negative inotropic burden

Abstract Background/Introduction The negative inotropic effect of certain antiarrhythmic drugs limits their use for acute cardioversion of new-onset paroxysmal atrial fibrillation (AF). Purpose In an intact porcine model of AF, we examined the effects of pulmonary and intravenous (IV) administration of flecainide on left ventricular (LV) contractility, i.e., LV dP/dt max, at doses that are effective in converting AF to sinus rhythm. The magnitude of the decrease in LV dP/dt max and time that it remained below baseline, measured by the area under the curve (AUC), is referred to as negative inotropic burden. Methods Flecainide was delivered via intratracheal administration at 1.5 mg/kg bolus and compared to IV infusion at 1.0 mg/kg over 2 min (lower-dose, rapid) and 2.0 mg/kg over 10 min (ESC guideline) in 11 closed-chest, anesthetized Yorkshire pigs. These doses of flecainide have been shown effective in converting AF to sinus rhythm. Catheters were fluoroscopically positioned in the right atrium for pacing at 140 beats/min and in the LV to measure QRS complex duration and contractility (LV dP/dt). Intratracheal flecainide was delivered via a catheter positioned at the bifurcation of the main bronchi. Results The peak plasma levels (Cmax values) were similar but the AUC of plasma concentrations over time was greater for the higher-dose, slow IV infusion of flecainide than for either intratracheal instillation (by 32%) or lower-dose, rapid IV infusion (by 88%). Based on AUCs of LV dP/dt max (figure, left panel), the negative inotropic burden is 3.1- to 3.8-fold greater for the higher IV (1006% • min) than for the lower IV (323%·min) or the intratracheal doses (263% • min). There was a corresponding inverse increase in the AUC of QRS complex prolongation. The decrease in LV dP/dt max (Δ%) was correlated with the prolongation of the QRS complex (Δms) (y = −1.4337x + 3.6613, r2=0.69, p&amp;lt;0.0001) (figure, right panel). Conclusion Rapid delivery of pulmonary or IV flecainide reduces the dose of drug required to achieve Cmax levels associated with conversion of AF. The attendant decrease across time in exposure of the ventricles to flecainide reduces QRS complex prolongation and the accompanying negative inotropic burden. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): InCarda Therapeutics, Inc. </jats:sec

Multi-year improvement in autonomic tone, baroreceptor sensitivity, and cardiac electrical stability using vagus nerve stimulation in patients with HFrEF in the ANTHEM-HF study

Abstract Background HFrEF patients experience long-term deterioration of autonomic function and cardiac electrical stability linked to increased sudden cardiac death risk. ANTHEM-HF (NCT01823887) reported improved baroreceptor sensitivity (heart rate turbulence, HRT), heart rate variability (rMSSD), and reduced cardiac electrical instability (T-wave alternans, TWA) after 12 months of chronic vagus nerve stimulation (VNS). It is unknown whether these benefits persist long-term. Methods HRT, rMSSD, TWA, and VT occurrence were evaluated during chronic VNS in all patients with symptomatic HFrEF with available 36-month follow-up data (n=25). ECGs were analyzed before Autonomic Regulation Therapy system implantation (LivaNova USA) and after chronic cervical VNS. Results Improvement in HRT slope persisted at 24 months (8.1±1.2 ms/RR interval, p=0.02) and 36 months (7.9±0.9 ms/RR interval, p=0.03) of VNS compared to baseline. RMSSD increase continued at 24 months (34.6±2.7 ms2, p&amp;lt;0.02) and 36 months (36.4±2.0 ms2, p=0.002). Peak TWA levels remained reduced at 24 months (47.8±1.3 μV, p&amp;lt;0.0001) and 36 months (46.1±1.6 μV, p&amp;lt;0.0001). No sudden death, VF, or sustained VT occurred, and patients with nonsustained VT decreased from 11 (44%) at baseline to 1 (5%) at 24 months (p&amp;lt;0.003) and 2 (11%) at 36 months (p&amp;lt;0.02). Conclusion In patients with HFrEF, chronic VNS appears to confer persistent 3-year improvements in autonomic tone, baroreceptor sensitivity, and cardiac electrical stability. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): LivaNova PLC </jats:sec

Pre-implantation interlead EKG heterogeneity is superior to QRS complex duration in predicting mechanical super-response and survival in patients receiving cardiac resynchronization therapy

Abstract Background Reliable quantitative predictors of response to cardiac resynchronization therapy (CRT) are needed. We compared the utility of pre-implantation R-wave and T-wave heterogeneity (RWH, TWH) to standard QRS complex duration for determination of mechanical super-response and mortality risk. Methods Of patients who received CRT devices between 2006 and 2018 at our institution, we retrospectively analyzed resting 12-lead ECG recordings from all 155 who met class I and IIA ACC/AHA/HRS guideline-based indications and had echocardiograms before and after implantation. Super-responders (n=35) (patients with ≥20% increase in LVEF and/or ≥20% decrease in LVESD) were compared to non super-responders (n=120), who did not. RWH and TWH, i.e., interlead splay, were measured by second central moment analysis. QRS complex duration was computed from the longest interval in a representative non-premature beat. Results Pre-implantation RWHV1–3 (p=0.01) and TWH in all lead sets tested (p=0.004 to 0.04) were significantly lower in super-responders than in non super-responders with corresponding significance for area under the curve (AUC) (p=0.002 to 0.03). Preimplantation QRS complex duration did not differ between super-responders and non super-responders (166±3 vs. 167±2 ms, p=0.8); the AUC for QRS complex duration (0.48, p=0.74) was not significant. RWHV1–3LILII at &amp;gt;420 μV predicted 3-year all-cause mortality (p=0.037) with a hazard ratio of 7.440 (95% CI: 1.015–54.527, p=0.048) but QRS complex duration &amp;gt;150 ms did not predict mortality (p=0.27). Conclusion Pre-implantation interlead EKG heterogeneity is superior to QRS complex duration in predicting mechanical super-response to CRT and survival. Bortolotto ESC graph Funding Acknowledgement Type of funding source: None </jats:sec

Repolarization heterogeneity measured with T-wave area dispersion in standard 12-lead ECG predicts sudden cardiac death in general population.

Background: We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population. Methods and Results: TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9&plusmn;12.5 years) participating in the Health 2000 Study - an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7&plusmn;13.7 years; mean follow-up, 8.8&plusmn;1.1 years). During follow-up (7.7&plusmn;1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32&plusmn;0.36 versus 0.60&plusmn;0.19; P&lt;0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (&le;0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4; P&lt;0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4; P&lt;0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5; P&lt;0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; P&lt;0.05). Conclusion: Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population