An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog

Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility.Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility.Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling.Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias

Pro-Arrhythmic Ventricular Remodeling Is Associated With Increased Respiratory and Low-Frequency Oscillations of Monophasic Action Potential Duration in the Chronic Atrioventricular Block Dog Model

In addition to beat-to-beat fluctuations, action potential duration (APD) oscillates at (1) a respiratory frequency and (2) a low frequency (LF) (<0.1 Hz), probably caused by bursts of sympathetic nervous system discharge. This study investigates whether ventricular remodeling in the chronic AV block (CAVB) dog alters these oscillations of APD and whether this has consequences for arrhythmogenesis. We performed a retrospective analysis of 39 dog experiments in sinus rhythm (SR), acute AV block (AAVB), and after 2 weeks of chronic AV block. Spectral analysis of left ventricular monophasic action potential duration (LV MAPD) was done to quantify respiratory frequency (RF) power and LF power. Dofetilide (0.025 mg/kg in 5 min) was infused to test for inducibility of Torsade de Pointes (TdP) arrhythmias. RF power was significantly increased at CAVB compared to AAVB and SR (log[RF] of -1.13 ± 1.62 at CAVB vs. log[RF] of -2.82 ± 1.24 and -3.29 ± 1.29 at SR and AAVB, respectively, p < 0.001). LF power was already significantly increased at AAVB and increased even further at CAVB (-3.91 ± 0.70 at SR vs. -2.52 ± 0.85 at AAVB and -1.14 ± 1.62 at CAVB, p < 0.001). In addition, LF power was significantly larger in inducible CAVB dogs (log[LF] -0.6 ± 1.54 in inducible dogs vs. -2.56 ± 0.43 in non-inducible dogs, p < 0.001). In conclusion, ventricular remodeling in the CAVB dog results in augmentation of respiratory and low-frequency (LF) oscillations of LV MAPD. Furthermore, TdP-inducible CAVB dogs show increased LF power

End-diastolic myofiber stress and ejection strain increase with ventricular volume overload

Background Myocardial stress and strain are considered primary mechanical stimuli for hypertrophic remodeling. Their values and significance in the intact beating heart during chronic overload remain poorly characterized. Methods and results Left-ventricular (LV) dimensions (echocardiography) and pressure ( invasive) were simultaneously recorded in anesthetized dogs at sinus rhythm (SR), acute and 1, 2, 6, 12 weeks of atrioventricular block (AVB), leading to structural, electrical and contractile remodeling. Mechanical load of the myocardium was quantified as myofiber stress (sigma(f)), being force along myofiber orientation per cross-sectional area, and natural myofiber strain (e(f)), being change in natural logarithm of myofiber length ( l) divided by its reference length: e(f) = ln( l/l(ref)). Time courses of sigma(f) and e(f) were calculated from LV pressure and dimensions, using a validated mathematical model of cardiac mechanics. End-diastolic sigma(f) increased from 2.0 +/- 0.1 kPa at SR to 3.4 +/- 0.3 kPa at acute AVB, remaining elevated for > 6 weeks. Systolic sigma(f) was not affected by AVB. Ejection strain rose instantly upon AVB, reaching a maximum at 2 weeks: 0.24 +/- 0.02 vs. 0.10 +/- 0.01 at SR. The increase of myofiber stroke work ( sigma(f)-e(f) loop area) from 3.1 +/- 0.3 at SR to 6.0 +/- 0.5 kJ/m(3)/ beat at 1 week AVB was attributed mainly to an increase of strain during ejection. Stroke work and ejection strain remained elevated up to 12 weeks. The rate of LV-mass increase was maximal (2.2 +/- 0.4 g/day) at 1 week AVB. Conclusions Serial mechanical phenotyping is feasible in the intact anesthetized dog with chronic ventricular overload. Our new approach yields values of mechanical load that are comparable to those found in isolated myocardium by others. In chronic AVB, both end-diastolic myofiber stress and ejection strain are increased. Early increases of both parameters coincide with peak hypertrophic growth, suggesting their important role for mechanotransduction. Peak systolic sigma f is likely not important for hypertrophy in this model, since it does not change throughout the experiment

End-diastolic myofiber stress and ejection strain increase with ventricular volume overload

Background Myocardial stress and strain are considered primary mechanical stimuli for hypertrophic remodeling. Their values and significance in the intact beating heart during chronic overload remain poorly characterized. Methods and results Left-ventricular (LV) dimensions (echocardiography) and pressure ( invasive) were simultaneously recorded in anesthetized dogs at sinus rhythm (SR), acute and 1, 2, 6, 12 weeks of atrioventricular block (AVB), leading to structural, electrical and contractile remodeling. Mechanical load of the myocardium was quantified as myofiber stress (sigma(f)), being force along myofiber orientation per cross-sectional area, and natural myofiber strain (e(f)), being change in natural logarithm of myofiber length ( l) divided by its reference length: e(f) = ln( l/l(ref)). Time courses of sigma(f) and e(f) were calculated from LV pressure and dimensions, using a validated mathematical model of cardiac mechanics. End-diastolic sigma(f) increased from 2.0 +/- 0.1 kPa at SR to 3.4 +/- 0.3 kPa at acute AVB, remaining elevated for > 6 weeks. Systolic sigma(f) was not affected by AVB. Ejection strain rose instantly upon AVB, reaching a maximum at 2 weeks: 0.24 +/- 0.02 vs. 0.10 +/- 0.01 at SR. The increase of myofiber stroke work ( sigma(f)-e(f) loop area) from 3.1 +/- 0.3 at SR to 6.0 +/- 0.5 kJ/m(3)/ beat at 1 week AVB was attributed mainly to an increase of strain during ejection. Stroke work and ejection strain remained elevated up to 12 weeks. The rate of LV-mass increase was maximal (2.2 +/- 0.4 g/day) at 1 week AVB. Conclusions Serial mechanical phenotyping is feasible in the intact anesthetized dog with chronic ventricular overload. Our new approach yields values of mechanical load that are comparable to those found in isolated myocardium by others. In chronic AVB, both end-diastolic myofiber stress and ejection strain are increased. Early increases of both parameters coincide with peak hypertrophic growth, suggesting their important role for mechanotransduction. Peak systolic sigma f is likely not important for hypertrophy in this model, since it does not change throughout the experiment