Balanced multi‐ion channel‐blocking drugs have low torsade risk because they block inward currents. The Comprehensive In Vitro Proarrhythmia Assay (Ci PA ) initiative proposes to use an in silico cardiomyocyte model to determine the presence of balanced block, and absence of heart rate corrected J‐T peak (J‐T peak c) prolongation would be expected for balanced blockers. This study included three balanced blockers in a 10‐subject‐per‐drug parallel design; lopinavir/ritonavir and verapamil met the primary end point of ΔΔJ‐T peak c upper bound < 10 ms, whereas ranolazine did not (upper bounds of 8.8, 6.1, and 12.0 ms, respectively). Chloroquine, a predominant blocker of the potassium channel encoded by the ether‐à‐go‐go related gene (hERG), prolonged ΔΔ QT c and ΔΔJ‐T peak c by ≥ 10 ms. In a separate crossover design, diltiazem (calcium block) did not shorten dofetilide‐induced Δ QT c prolongation, but shortened ΔJ‐T peak c and prolonged ΔT peak ‐T end . Absence of J‐T peak c prolongation seems consistent with balanced block; however, small sample size (10 subjects) may be insufficient to characterize concentration‐response in some cases.

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Aims The aim of this study is to explore the relationships of tricuspid annulus area (TAA) with right atrial maximal volume (RAVmax) and right ventricular end-diastolic volume (RVEDV) in healthy subjects and patients with functional tricuspid regurgitation (FTR) of different aetiologies and severities. Methods and results We enrolled 280 patients (median age 66 years, 59% women) with FTR due to left heart disease (LHD), pulmonary hypertension (PH), corrected tetralogy of Fallot (TOF), chronic atrial fibrillation (AF), and 210 healthy volunteers (45 years, 53% women). We measured TAA at mid-systole and end-diastole, tenting volume of tricuspid leaflets, RAVmax, and RVEDV by 3D echocardiography. Irrespective of TA measurement timing, TAA correlated more closely with RAVmax than with RVEDV in both controls and FTR patients. On multivariable analysis, RAVmax was the most important determinant of TAA, accounting for 41% (normals) and 56% (FTR) of TAA variance. In FTR patients, age, RVEDV, and left ventricular ejection fraction were also independently correlated with TAA. RAVmax (AUC = 0.81) and TAA (AUC = 0.78) had a greater ability than RVEDV (AUC = 0.72) to predict severe FTR (P &lt; 0.05). Among FTR patients, those with AF had the largest RAVmax and smallest RVEDV. RAVmax and TA were significantly dilated in all FTR groups, except in TOF. PH and TOF had largest RVEDV, yet tenting volume was increased only in PH and LHD. Conclusion RA volume is a major determinant of TAA, and RA enlargement is an important mechanism of TA dilation in FTR irrespective of cardiac rhythm and RV loading conditions.

Aims Quantitative echocardiography parameters are seldom used to grade tricuspid regurgitation (TR) severity due to relative paucity of validation studies and lack of prognostic data. To assess the relationship between TR severity and the composite endpoint of death and hospitalization for congestive heart failure (CHF); and to identify the threshold values of vena contracta width (VCavg), effective regurgitant orifice area (EROA), regurgitant volume (RegVol), and regurgitant fraction (RegFr) to define low, intermediate, and high-risk TR based on patients’ outcome data. Methods and results A cohort of 296 patients with at least mild TR underwent 2D, 3D, and Doppler echocardiography. We built statistical models (adjusted for age, NYHA class, left ventricular ejection fraction, and pulmonary artery systolic pressure) for VCavg, EROA, RegVol, and RegFr to study their relationships with the hazard of outcome. The tertiles of the derived hazard values defined the threshold values of the quantitative parameters for TR severity grading. During 47-month follow-up, 32 deaths and 72 CHF occurred. Event-free rate was 14%, 48%, and 93% in patients with severe, moderate, and mild TR, respectively. Severe TR was graded as VCavg &gt; 6 mm, EROA &gt; 0.30 cm2, RegVol &gt; 30 mL, and RegF &gt; 45%. Conclusion This outcome study demonstrates the prognostic value of quantitative parameters of TR severity and provides prognostically meaningful threshold values to grade TR severity in low, intermediate, and high risk.

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