Csaba Lengyel

Restricting excessive cardiac action potential and QT prolongation: a vital role for IKs in human ventricular muscle.

Background—Although pharmacological block of the slow, delayed rectifier potassium current (IKs) by chromanol 293B, L-735,821, or HMR-1556 produces little effect on action potential duration (APD) in isolated rabbit and dog ventricular myocytes, the effect of IKs block on normal human ventricular muscle APD is not known. Therefore, studies were conducted to elucidate the role of IKs in normal human ventricular muscle and in preparations in which both repolarization reserve was attenuated and sympathetic activation was increased by exogenous dofetilide and adrenaline. Methods and Results—Preparations were obtained from undiseased organ donors. Action potentials were measured in ventricular trabeculae and papillary muscles using conventional microelectrode techniques; membrane currents were measured in ventricular myocytes using voltage-clamp techniques. Chromanol 293B (10 &mgr;mol/L), L-735,821 (100 nmol/L), and HMR-1556 (100 nmol/L and 1 &mgr;mol/L) produced a <12-ms change in APD while pacing at cycle lengths ranging from 300 to 5000 ms, whereas the IKr blockers sotalol and E-4031 markedly lengthened APD. In voltage-clamp experiments, L-735,821 and chromanol 293B each blocked IKs in the presence of E-4031 to block IKr. The E-4031–sensitive current (IKr) at the end of a 150-ms-long test pulse to 30 mV was 32.9±6.7 pA (n=8); the L-735,821–sensitive current (IKs) magnitude was 17.8±2.94 pA (n=10). During a longer 500-ms test pulse, IKr was not substantially changed (33.6±6.1 pA; n=8), and IKs was significantly increased (49.6±7.24 pA; n=10). On application of an “action potential–like” test pulse, IKr increased as voltage became more negative, whereas IKs remained small throughout all phases of the action potential–like test pulse. In experiments in which APD was first lengthened by 50 nmol/L dofetilide and sympathetic activation was increased by 1 &mgr;mol/L adrenaline, 1 &mgr;mol/L HMR-1556 significantly increased APD by 14.7±3.2% (P<0.05; n=3). Conclusions—Pharmacological IKs block in the absence of sympathetic stimulation plays little role in increasing normal human ventricular muscle APD. However, when human ventricular muscle repolarization reserve is attenuated, IKs plays an increasingly important role in limiting action potential prolongation.

Pharmacological block of the slow component of the outward delayed rectifier current (IKs) fails to lengthen rabbit ventricular muscle QTc and action potential duration

The effects of IKs block by chromanol 293B and L‐735,821 on rabbit QT‐interval, action potential duration (APD), and membrane current were compared to those of E‐4031, a recognized IKr blocker. Measurements were made in rabbit Langendorff‐perfused whole hearts, isolated papillary muscle, and single isolated ventricular myocytes. Neither chromanol 293B (10 μM) nor L‐735,821 (100 nM) had a significant effect on QTc interval in Langendorff‐perfused hearts. E‐4031 (100 nM), on the other hand, significantly increased QTc interval (35.6±3.9%, n=8, P<0.05). Similarly both chromanol 293B (10 μM) and L‐735,821 (100 nM) produced little increase in papillary muscle APD (less than 7%) while pacing at cycle lengths between 300 and 5000 ms. In contrast, E‐4031 (100 nM) markedly increased (30 – 60%) APD in a reverse frequency‐dependent manner. In ventricular myocytes, the same concentrations of chromanol 293B (10 μM), L‐735,821 (100 nM) and E‐4031 (1 μM) markedly or totally blocked IKs and IKr, respectively. IKs tail currents activated slowly (at +30 mV, τ=888.1±48.2 ms, n=21) and deactivated rapidly (at −40 mV, τ=157.1±4.7 ms, n=22), while IKr tail currents activated rapidly (at +30 mV, τ=35.5±3.1 ms, n=26) and deactivated slowly (at −40 mV, τ1=641.5±29.0 ms, τ2=6531±343, n=35). IKr was estimated to contribute substantially more to total current density during normal ventricular muscle action potentials (i.e., after a 150 ms square pulse to +30 mV) than does IKs. These findings indicate that block of IKs is not likely to provide antiarrhythmic benefit by lengthening normal ventricular muscle QTc, APD, and refractoriness over a wide range of frequencies.

Combined pharmacological block of IKr and IKs increases short-term QT interval variability and provokes torsades de pointes

Assessing the proarrhythmic potential of compounds during drug development is essential. However, reliable prediction of drug‐induced torsades de pointes arrhythmia (TdP) remains elusive. Along with QT interval prolongation, assessment of the short‐term variability of the QT interval (STV(QT)) may be a good predictor of TdP. We investigated the relative importance of IKs and IKr block in development of TdP together with correlations between QTc interval, QT interval variability and incidence of TdP.

Usefulness of Short-Term Variability of QT Intervals as a Predictor for Electrical Remodeling and Proarrhythmia in Patients With Nonischemic Heart Failure

The high incidence of sudden cardiac death in heart failure (HF) reflects electrophysiologic changes in response to myocardial failure. We previously showed that short-term variability of QT intervals (STV(QT)) identifies latent repolarization disorders in patients with drug-induced or congenital long QT syndrome. This study sought to determine (1) if STV(QT) is increased in patients with dilated cardiomyopathy (DC) and moderate congestive HF and (2) if increased STV(QT) is associated with ventricular arrhythmia in patients with HF. Sixty patients (53 +/- 12 years of age, 14 women) with DC and moderate HF (New York Heart Association classes II to III) were compared to matched controls. Twenty patients had implantable cardiac defibrillators secondary to a history of ventricular tachycardia (VT). Two cardiologists blinded to diagnosis manually measured QT intervals. Beat-to-beat variability of repolarization was determined from Poincaré plots of 30 consecutive QT intervals as was STV(QT). QTc intervals were comparable in patients and controls (419 +/- 36 vs 415 +/- 32 ms, respectively, p >0.05), whereas STV(QT) was significantly higher in patients with HF (7.8 +/- 3 vs 4.1 +/- 2 ms, respectively, p <0.05). STV(QT) was more increased in patients with a history of VT compared to those without VT (10.1 +/- 2 vs 6.6 +/- 2 ms, respectively, p <0.05). Increased STV(QT) and decreased ejection fraction were associated with a history of VT; however, STV(QT) was the strongest indicator. In conclusion, the present study demonstrates for the first time that STV(QT) is increased in patients with DC with HF. Patients with DC and HF and implantable cardiac defibrillators for secondary prevention had the highest STV(QT). Thus, increased STV(QT) in the context of moderate HF may reflect a latent repolarization disorder and increased susceptibility to sudden death in patients with DC, which is not identified by a prolonged QT interval.

Ionic mechanisms limiting cardiac repolarization reserve in humans compared to dogs.

•  Cardiac repolarization, through which heart‐cells return to their resting state after having fired, is a delicate process, susceptible to disruption by common drugs and clinical conditions. •  Animal models, particularly the dog, are often used to study repolarization properties and responses to drugs, with the assumption that such findings are relevant to humans. However, little is known about the applicability of findings in animals to man. •  Here, we studied the contribution of various ion‐currents to cardiac repolarization in canine and human ventricle. •  Humans showed much greater repolarization‐impairing effects of drugs blocking the rapid delayed‐rectifier current IKr than dogs, because of lower repolarization‐reserve contributions from two other important repolarizing currents (the inward‐rectifier IK1 and slow delayed‐rectifier IKs). •  Our findings clarify differences in cardiac repolarization‐processes among species, highlighting the importance of caution when extrapolating results from animal models to man.

Reduced aortic distensibility and coronary flow velocity reserve in diabetes mellitus patients with a negative coronary angiogram

BACKGROUND Structural and functional abnormalities of the aortic wall and disturbances of the coronary circulation with presumed microvascular complications have been reported in patients with diabetes mellitus. OBJECTIVES To simultaneously establish the coronary flow velocity reserve (CFVR) and aortic distensibility indexes in type 2 diabetes mellitus patients who have normal epicardial coronary arteries by stress transesophageal echocardiography (STEE). METHODS The elastic properties of the descending aorta and the CFVR were evaluated simultaneously in 18 type 2 diabetes mellitus patients who had negative coronary angiograms. These results were compared with those of 21 nondiabetic subjects with normal epicardial coronary arteries and 24 patients with left anterior descending coronary artery (LAD) stenosis. STEE was used for the evaluation of elastic moduli of the descending aorta. The CFVR was calculated as the ratio of the average peak diastolic flow velocity during hyperemia to that at rest. RESULTS The CFVR of diabetic patients with normal epicardial coronary arteries and those with LAD stenosis was similarly decreased compared with the controls (2.10+/-0.63 and 1.78+/-0.47 versus 2.76+/-1.25, P<0.05 and P<0.001, respectively). The elastic modulus (in 103 mmHg) was similarly increased in patients with diabetes mellitus and normal epicardial coronary arteries, and in those with LAD stenosis, compared with the control subjects (0.94+/-0.82 and 0.91+/-0.59 versus 0.49+/-0.19, P<0.05 and P<0.05, respectively). CONCLUSIONS It may be stated that reduced aortic distensibility (increased elastic modulus) and the CFVR were demonstrated simultaneously during STEE in diabetic patients compared with nondiabetic subjects with negative coronary angiograms.

Suppression of Erythromycin‐induced Early Afterdepolarizations and Torsade de Pointes Ventricular Tachycardia by Mexiletine

Erythromycin is a selective IKr‐blocking, action potential duration (APD)‐prolonging drug, which may induce early afterdepolarizations (EADs) and torsade de pointes ventricular tachycardia. The successful termination of an erythromycin‐induced clinical torsades de pointes by the authors with mexiletine prompted them to investigate in vitro whether erythromycin is able to induce EADs in Purkinje fibers and, if so, whether EADs are suppressible or not by mexiletine. Electrically stimulated canine Purkinje fibers (n=9) were superfused with erythromycin (200 mg/l) and action potentials were recorded by an intracellular microelectrode technique. Erythromycin induced a pronounced prolongation of APD and the appearance of EADs in all Purkinje preparations (9/9). After the addition of mexiletine (10 mM), a marked shortening of APD and the disappearance of EADs (7/9) were observed. Mexiletine, an inhibitor of the tetrodotoxin‐sensitive window Na+‐current, may prevent IKr‐blocking drug‐induced torsade de pointes ventricular tachycardia by abolishing APD prolongation and EADs.

Diabetic Gastroparesis: Functional/Morphologic Background, Diagnosis, and Treatment Options

The regulation of gastrointestinal motility mainly involves the smooth muscle, neural (extrinsic and intrinsic), and hormonal elements, the glial cells, and the interstitial cells of Cajal. An orchestrated function of all these components is required for the appropriate propulsive movement of the food in the gastrointestinal tract. Gastroparesis, a pathological slowing-down of gastric emptying, is a result of the damage to the tissue elements involved in the regulation of motility. Gastroparesis is one of the well-known complications of long-standing diabetes mellitus. Although it is rarely a life-threatening complication, it has a deteriorating effect on the quality of life, leads to unpredictable oscillation of the blood glucose level, and increases the time required for the absorption of food and medicines. This review describes the clinical characteristics of diabetic gastroparesis and summarizes the organic and functional motility abnormalities caused by this complication. Finally, the currently available and potential future therapeutic approaches are summarized.

Comparison of three-dimensional speckle tracking echocardiography and two-dimensional echocardiography for evaluation of left atrial size and function in healthy volunteers (results from the MAGYAR-Healthy study).

Noninvasive accurate assessment of left atrial (LA) size and function is an essential requirement in daily clinical practice. Real time three‐dimensional (3D) echocardiography (RT3DE) with direct volumetric method has been found to be a highly accurate and reproducible noninvasive tool for the evaluation of LA dimensions and functional properties. Three‐dimensional speckle tracking echocardiography (3DSTE) has just been introduced for volumetric assessments, which uses different, as called “block‐matching” algorithm by strain analysis. This study was designed to compare two‐dimensional (2D) echocardiography with 3DSTE for calculation of LA volumes and assessment of LA functional properties in healthy subjects.

Effect of a neuroprotective drug, eliprodil on cardiac repolarisation: importance of the decreased repolarisation reserve in the development of proarrhythmic risk

The aim of this study was to analyse the effects of eliprodil, a noncardiac drug with neuroprotective properties, on the cardiac repolarisation under in vitro circumstances, under normal conditions and after the attenuation of the ‘repolarisation reserve’ by blocking the inward rectifier potassium current (IK1) current with BaCl2. In canine right ventricular papillary muscle by applying the conventional microelectrode technique, under normal conditions, eliprodil (1 μM) produced a moderate reverse rate‐dependent prolongation of the action potential duration (7.4±1.5, 8.9±2.1 and 9.9±1.8% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=9). This effect was augmented in preparations where IK1 was previously blocked by BaCl2 (10 μM). BaCl2 alone lengthened APD in a reverse frequency‐dependent manner (7.0±1.3, 14.2±1.6 and 28.1±2.1% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). When eliprodil (1 μM) was administered to these preparations, the drug induced a marked further lengthening relative to the APD values measured after the administration of BaCl2 (12.5±1.0, 17.6±1.5 and 20.5±0.9% at cycle lengths of 300, 1000 and 5000 ms, respectively; n=8). In the normal Langendorff‐perfused rabbit heart, eliprodil (1 μM) produced a significant QTc prolongation at 1 Hz stimulation frequency (12.7±1.8%, n=9). After the attenuation of the ‘repolarisation reserve’ by the IK1 blocker BaCl2 (10 μM), the eliprodil‐evoked QTc prolongation was greatly enhanced (28.5±7.9%, n=6). In two out of six Langendorff preparations, this QTc lengthening degenerated into torsade de pointes ventricular tachycardia. Eliprodil significantly decreased the amplitude of rapid component of the delayed rectifier potassium current (IKr), but slow component (IKs), transient outward current (Ito) and IK1 were not considerably affected by the drug when measured in dog ventricular myocytes by applying the whole‐cell configuration of the patch‐clamp technique. The results indicate that eliprodil, under normal conditions, moderately lengthens cardiac repolarisation by inhibition of IKr. However, after the attenuation of the normal ‘repolarisation reserve’, this drug can induce marked QT interval prolongation, which may result in proarrhythmic action.