Michael R. Franz

Mechano-electrical feedback in ventricular myocardium

In the past, cardiac arrhythmias have been most commonly perceived as a result of eEectricaZ disorders of the heart muscle. As this issue of the journal demonstrates, there is mounting evidence that arrhythmias may also be produced by mechanical perturbations or disorders of the myocardium. Clinical data have long suggested that ventricular arrhythmias occur more frequently in patients who suffer from heart failure, dilated cardiomyopathy, ventricular volume or pressure overload, mitral valve prolapse, or dysynergistic ventricular contraction and relaxation [ 1 111. A potential common mechanism underlying all of these observations may be that dilatation or stretch of the myocardial tissue may lead to electrophysiologic changes which produce or facilitate arrhythmias. The phenomenon that electrophysiological changes may result from regional mechanical stretch or global hemodynamic over-load has been termed “contraction-excitation coupling” [12] or “mechano-electrical feedback” 113,141. In the past, however, this phenomenon has not been sufficiently appreciated within the mainstream of cardiovascular research. One reason may be the paucity of direct cellular data on mechano-electrical feedback. It is extremely difficult to maintain a fragile glass-microelectrode stably within a cell of a vigorously beating heart and even harder to ascertain the effects of simultaneously imposed mechanical perturbations. The body surface ECG, on the other hand, is too insensitive and nonspecific to characterize the electrophysiologic changes that result from mechanical strain and promote stretch-activated arrhythmias. Monophasic action potential (MAP) recording, which accurately depicts the time course of transmembrane action potentials while being less sensitive to motion artifacts than intracellular recordings [ 15,161, has been an important tool in evaluating stretch-induced electrophysiological changes in the intact heart. More recently, significant progress has been made toward identifying and characterizing myocardial stretch-activated channels (SACS) by patch clamp technique [17-201. This review summarizes the current state of knowledge on stretch-induced electrophysiological effects and arrhythmias. Some of these concepts have been expressed in a previous publication [21], and newer observations will be presented and discussed in greater detail in the original papers contained in this focus issue of Cardiovascular Research.

Relation Between Repolarization and Refractoriness During Programmed Electrical Stimulation in the Human Right Ventricle Implications for Ventricular Tachycardia Induction

BACKGROUNDnAlthough programmed electrical stimulation is widely used for provoking sustained ventricular tachycardia (VT), the mechanism by which repetitive extrastimulation evokes VT is still little understood. Specifically, it is not clear why several closely coupled extrastimuli are frequently required to induce VT. Although regularly paced human ventricular myocardium exhibits a near constant relation between myocardial repolarization and refractoriness, the effect of repetitive extrastimulation on the relation between repolarization and excitability in the human heart and its relevance for arrhythmia induction by programmed stimulation are unknown. We hypothesized that the induction of VT by repetitive extrastimulation is facilitated by an altered relation between repolarization and refractoriness, and this leads to disturbances in ventricular impulse propagation, which trigger the onset of VT.nnnMETHODS AND RESULTSnTwenty-one patients undergoing routine electrophysiological study were paced from the right ventricular apex and outflow tract endocardium with monophasic action potential-pacing catheters placed at both sites simultaneously Monophasic action potential durations (APDs) and effective refractory periods (ERPs) were measured simultaneously at each site, during regular stimulation (S1-S1) at 400-ms cycle length and during three consecutive extrastimuli (S2 through S4) at the closest coupling intervals at which all three extrastimuli still resulted in capture. Measurements further included the repolarization level at which the earliest capture occurred, the ratio between ERP and APD, and the propagation time between the pacing and distant recording site. APD and ERP both shortened progressively with each extrastimulus. APD at 90% repolarization decreased from a baseline (S1) of 238.1 +/- 19.7 ms by 14.9% at S2, 18.9% at S3, and 22.9% at S4 (P < .0001, S1 versus S4). ERP decreased from 233.1 +/- 19.7 ms (S1) to 180.0 +/- 41.9 ms (S3) (P < .0001, S1 versus S3). While ERP shortening occurred mainly on the basis of APD shortening, there was an additional factor that contributed to ERP shortening independent of APD shortening. Each consecutive extrastimulus was able to elicit a propagated response at earlier repolarization levels than the previous one: the earliest capture for S2 occurred at 85.5 +/- 10.2% of complete repolarization, for S3 at 83.9 +/- 10.5%, and for S4 at 78.4 +/- 11.2% (P < .05 for S2 versus S3; P < .05 for S3 versus S4; P < .01 for S2 versus S4). This progressive encroachment of the earliest capture stimulus onto the preceding repolarization phase (at progressively less repolarized levels) correlated with a progressive delay of impulse propagation between the pacing site and the second recording site: propagation time increased from baseline (S1) by 10.5 +/- 1.3% with S2 to 19.0 +/- 1.6% with S3 and to 22.5 +/- 2.8% with S4 (P < .05, S4 versus S1). VT was induced in 11 of 21 patients. Nine of these had VT induced only when significant encroachment of extrastimuli on the preceding repolarization phase (< 81.3 +/- 7.0%) and associated conduction slowing (> 16.6 +/- 1.8%) were present.nnnCONCLUSIONSnRepetitive extrastimulation not only shortens APD and subsequently ERP but also alters the ERP/APD relation by allowing capture to occur at progressively less complete repolarization levels. This progressive encroachment onto the preceding repolarization phase is associated with impaired impulse propagation and a high incidence of VT induction. This may help explain how repetitive, closely coupled extrastimulation induces ventricular tachycardia in the human heart.

Myocardial vulnerability to T wave shocks: Relation to shock strength, shock coupling interval, and dispersion of ventricular repolarization

Myocardial Vulnerability to T Wave Shocks. Introduction: Induction of ventricular fibrillation (VF) by T wave shocks is of clinical interest due to the correlation between the upper limit of vulnerability (ULV) and the defibrillation threshold (DFT). However, the ULV bas not yet been defined precisely in reference to the entire “area of vulnerability” (AOV), which is defined bifunctionally by both shock strengths and shock coupling intervals, nor has it been related to the dispersion of ventricular repolarization, considered to be an important determinant of vulnerability.

Prolonged action potential durations, increased dispersion of repolarization, and polymorphic ventricular tachycardia in a mouse model of proarrhythmia.

Introduction: In the congenital long QT syndrome, inhomogeneously prolonged action potentials, bradycardia, and hypokalemia can cause afterdepolarizations and torsade de pointes. Other genetic factors may contribute to similar forms of ventricular tachycardias in hypertrophied or failing hearts, especially if the outward current IKr is blocked pharmacologically. We sought to develop a mouse heart model for such arrhythmias in order to identify the proarrhythmic potential in transgenic animals. Methods and results: Hearts of adult wild-type (CD1) mice were isolated and the aorta was retrogradely perfused. Three monophasic action potentials and a volume-conducted ECG were simultaneously recorded. Sotalol (10-5M and 2 × 10-5M) prolonged action potential duration (APD) in a concentration-dependent and reverse frequency-dependent fashion (from 34 ± 1 to 48 ± 2 ms at 100 ms basic cycle length (BCL), from 38 ± 2 to 54 ± 3 ms at 180 ms BCL for APD90, p < 0.05). Sotalol did not alter the relation between refractoriness and APD (ERP/APD ratio = 0.76 - 0.93). AV nodal block caused ventricular bradycardia and doubled dispersion of APD (APD70max-min: 11 ± 1 vs. 4 ± 1 ms, APD90max-min: 12 ± 1 vs. 5 ± 1 ms, p < 0.05). If combined with hypokalemia, afterdepolarizations induced polymorphic ventricular tachycardias in 1 of 8 hearts at K+ =3.0 mM and in 10 of 12 hearts at K+ = 2.0 mM. Prior to polymorphic ventricular tachycardia, dispersion of APD further increased (APD70max-min: 17 ± 3 ms; APD90max-min: 25 ± 3 ms; p < 0.05). Conclusions: This isolated beating mouse heart model can be used to study drug-induced action potential prolongation and repolarization-related ventricular arrhythmias provoked by bradycardia and hypokalemia. It may be suitable to identify a genetic predisposition to ventricular arrhythmias that may only become apparent under such proarrhythmic conditions.

Effect of Sustained Load on Dispersion of Ventricular Repolarization and Conduction Time in the Isolated Intact Rabbit Heart

Effect of Sustained Load on EP Parameters. Introduction: It is well known that myocardial stretch can elicit ventricular arrhythmias in experimental models. However, previous reports have predominantly documented stretch‐induced arrhythmias during short, pulsatile stretch. The arrhythmogenic mechanism of sustained static stretch is incompletely understood.

IS DISPERSION OF VENTRICULAR REPOLARIZATION RATE DEPENDENT

QT dispersion has been adopted as a new index for the noninvasive assessment of the inhomogeneity of repolarization and has been evaluated in several clinical studies as an index of arrhythmia propensity. In most of these studies, indices of dispersion of repolarization were rate corrected by the Bazett formula calculating QT dispersion as QTcmax‐QTcmin or JT dispersion as fTcmax‐fTcmin, implying that dispersion of repolarization also changes with heart rate. This study aimed to determine in the electrically paced isolated heart whether dispersion of ventricular repolarization is rate dependent. Multiple (5–7) monophasic action potentials (MAPs) were recorded simultaneously from the epicardium and endocardium of both ventricles in 18 isolated Langendorff‐perfused rabbit hearts. Hearts were paced from a right ventricular site at basic cycle lengths (CL) between 1,200 and 300 ms in 100‐ms decrements. Action potential duration was measured at 90% repolarization (APD90), and recovery time (RT) was defined as the sum of APD90 and activation time in each of the simultaneous MAP recordings. The dispersion of APD90 ond RT, respectively, were calculated as the maximal difference among all recordings. APD90 and RT shortened continuously throughout the range of paced steady‐state CLs from 1,200 to 300 ms. APD90 was 197.6 ± 6.1 ms at a CL of 1,200 ms and decreased to 148.5 ± 2.5 ms at a CL of 300 ms (P < 0.0001). RT was 228.2 ± 6.2 ms at a CL of 1,000 ms and decreased to 175.9 ± 2.9 at a CL of 300 ms (P < 0.0001). In contrast, dispersion of APD90 and RT did not change significantly. Dispersion of APD90 was 24.8 ± 2.3 ms at a CL of 1,200 ms, 26.1 ± 1.9 msec at a CL of 1,000 ms, and 21.6 ± 2.1 at a CL of 300 ms (NS). Dispersion of RT was 29.7 ± 3.4 ms at a CL of 1,200 ms, 29.0 ± 3.0 ms at a CL of 1,000 ms, and 32.7 ± 3.2 ms at a CL of 300 ms (NS). In contrast to the duration of the QT interval, dispersion of ventricular repolarization does not change significantly with pacing induced changes in CL. Assuming that the rate‐dependent behavior of action potential duration is similar between the rabbit and human heart, a rate correction of parameters of dispersion of repolarization is probably unnecessary.

Differential Effects of D-Sotalol, Quinidine, and Amiodarone on Dispersion of Ventricular Repolarization in the Isolated Rabbit Heart

Drug Effects on Dispersion of Repolarization. Introduction: increased dispersion of ventricular repolarization has been suggested as a cause of proarrhythmic effects of Class IA or III antiarrhythmic drugs, such as d‐sotalol, quinidine, and amiodarone.

Effects of amiodarone on the circadiam pattern of sudden cardiac death (department of veterans affairs Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy)

Some antiarrhythmic drugs have been shown to influence the circadian pattern of sudden cardiac death (SCD). The effect of chronic amiodarone therapy on this pattern is unknown. This study determines the circadian pattern of deaths in the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF-STAT) and compares the distribution of SCD between the amiodarone and the placebo arms of the trial. CHF-STAT was a multicenter trial that determined whether amiodarone reduces mortality in patients with heart failure and asymptomatic ventricular arrhythmias. The time of death was retrospectively analyzed in patients who died from pump failure and SCD. In patients who died suddenly, the circadian pattern of deaths was compared between patients receiving amiodarone and those receiving placebo. In CHF-STAT, 274 patients died during follow-up. The time of death was available in 65 of the 74 patients who died from pump failure, and in 96 of the 139 patients who died suddenly. There was a circadian variation of all SCDs compared with other deaths with a distinct peak during the morning (p = 0.04). A similar morning peak of sudden cardiac death was found in both the amiodarone (n = 42) and the placebo (n = 54) groups, and the overall circadian pattern did not differ between them (p = 0.16). In contrast, death from pump failure occurred equally distributed over time. Thus, SCD occurs predominantly during the morning, whereas death from heart failure does not exhibit a morning peak. Amiodarone does not influence the circadian pattern of SCD.

High dispersion of ventricular repolarization after an implantable defibrillator shock predicts induction of ventricular fibrillation as well as unsuccessful defibrillation.

OBJECTIVESnTo test the hypothesis that post-shock dispersion of repolarization (PSDR) is higher in T wave shocks that induce ventricular fibrillation (VF) than in those that do not, as well as in implantable cardioverter defibrillator (ICD) defibrillation shocks which fail to terminate VF when compared with those that are successful.nnnBACKGROUNDnVentricular fibrillation has been linked to the presence of dispersion of repolarization, which facilitates reentry. Most of the studies have been done in animals, and the mechanism underlying the generation and termination of VF in humans is speculative and remains to be determined.nnnMETHODSnMonophasic action potentials (MAPs) were recorded simultaneously from the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA) in 27 patients who underwent implantation and testing of an ICD. T wave shocks were used to induce VF while the termination was attempted using internal defibrillator shocks. The post-shock repolarization time (PSRT) was measured in both the RVA and RVOT MAPs, and the difference between the two recordings was defined as the PSDR. The averages of PSDR were compared between the successful and unsuccessful inductions and terminations of VF.nnnRESULTSnT wave shocks that induced VF generated a greater PSDR (93.4 +/- 85.1 ms) than the unsuccessful ones (45.1 +/- 55.9 ms, p < 0.001). On the other hand, shocks that failed to terminate VF were associated with a greater PSDR (59.9 +/- 41.2 ms) than shocks that terminated VF (21.1 +/- 20.1 ms), p < 0.001.nnnCONCLUSIONSnA high PSDR following a T wave shock is associated with induction of VF; while following a defibrillating shock, it is associated with its failure and the continuation of VF. Conversely, a low PSDR is associated with failure of a T wave shock to induce VF and successful termination of VF by a defibrillating shock.

Shock-induced dispersion of ventricular repolarization: implications for the induction of ventricular fibrillation and the upper limit of vulnerability.

Shock‐induced Dispersion and VF Induction. Introduction: Shock‐induced dispersion of ventricular repolarization (SIDR) caused by an electrical field stimulus has been suggested as a mechanism of ventricular fibrillation (VF) induction: however, this hypothesis has not been studied systematically in the intact heart. Likewise, the mechanism underlying the upper (ULV) and lower (LLV) limit of vulnerability remains unclear.