Jan Nemec

Abnormal Heart Rate Regulation in GIRK4 Knockout Mice

Acetylcholine (ACh) released from the stimulated vagus nerve decreases heart rate via modulation of several types of ion channels expressed in cardiac pacemaker cells. Although the muscarinic-gated potassium channel I(KACh) has been implicated in vagally mediated heart rate regulation, questions concerning the extent of its contribution have remained unanswered. To assess the role of I(KACh) in heart rate regulation in vivo, we generated a mouse line deficient in I(KACh) by targeted disruption of the gene coding for GIRK4, one of the channel subunits. We analyzed heart rate and heart rate variability at rest and after pharmacological manipulation in unrestrained conscious mice using electrocardiogram (ECG) telemetry. We found that I(KACh) mediated approximately half of the negative chronotropic effects of vagal stimulation and adenosine on heart rate. In addition, this study indicates that I(KACh) is necessary for the fast fluctuations in heart rate responsible for beat-to-beat control of heart activity, both at rest and after vagal stimulation. Interestingly, noncholinergic systems also appear to modulate heart activity through I(KACh). Thus, I(KACh) is critical for effective heart rate regulation in mice.

Catecholamine-induced T-wave lability in congenital long QT syndrome: A novel phenomenon associated with syncope and cardiac arrest

OBJECTIVE To determine the effects of phenylephrine and dobutamine on repolarization lability in patients with genotyped long QT syndrome (LQTS). PATIENTS AND METHODS Between December 1998 and August 2000, 23 patients with genotyped LQTS (13 LQT1, 7 LQT2, and 3 LQT3) and 16 controls underwent electrocardiographic stress testing at the Mayo Clinic in Rochester, Minn. Aperiodic repolarization lability was quantified from digitized electrocardiograms recorded during catecholamine stress testing with phenylephrine and dobutamine. T-wave lability was quantified as a root-mean-square of the differences between corresponding signal values of subsequent beats. The magnitude of aperiodic T-wave lability was quantified by using a newly derived T-wave lability index (TWLI). RESULTS The TWLI was significantly greater in patients with LQTS than in controls (0.0945 +/- 0.0517 vs 0.0445 +/- 0.0123; P < .003). Marked T-wave lability (TWLI > or = 0.095) was detected in all 3 LQTS genotypes (10/23) but in no controls (P < .003). There was no correlation between the TWLI and the baseline corrected QT interval. All high-risk patients having either a history of out-of-hospital cardiac arrest or syncope had a TWLI of 0.095 or greater. CONCLUSIONS Beat-to-beat nonalternating T-wave lability occurs in LQT1, LQT2, and LQT3 patients during catecholamine provocation and is associated with a history of prior cardiac events. The quantification of this novel phenomenon may assist in identifying LQTS patients with increased risk of sudden cardiac death.

Increase in Heart Rate Precedes Episodes of Ventricular Tachycardia and Ventricular Fibrillation in Patients with Implantable Cardioverter Defibrillators: Analysis of Spontaneous Ventricular Tachycardia Database

Patients with heart disease and decreased heart rate variability (HRV) have an increased risk of all‐cause mortality as well as arrhythmic death. The question of acute changes in HRV immediately preceding arrhythmic events remains unanswered. We analyzed data from patients with implantable cardioverter defibrillators who had ventricular tachycardia (VT) or ventricular fibrillation (VF) detected by the device. The device stores 1,000 consecutive RR intervals preceding the arrhythmic event detection and before device interrogation. Compared to this control segment, the mean heart rate (HR) increased prior to the arrhythmic event for both VT (88.5 vs 72.7 beats/min, P < 0.0005) and VF (85.4 vs 73.3 beats/min, P < 0.05) patients. No difference in HRV (as analyzed by a time‐domain, frequency‐domain [fast Fourier transform], and a nonlinear technique) has been detected. We estimated the amount of ectopic beats from the number of RR intervals that differed from the preceding RR interval by > 10%. The frequency of such beats was significantly higher in the prearrhythmic data segments than in the control segments for VT(10.7 vs 6.6/50 beats, P < 0.05) although not for VF(9.8 vs 6.1/50 beats, NS). We conclude that the HR and frequency of ectopic beats are higher prior to onset of the arrhythmic events, although HRV does not change markedly. These results are consistent with sympathetic activation being the predominant autonomic change prior to VT/VF onset in this patient population.

Arrhythmogenic right ventricular dysplasia masquerading as dilated cardiomyopathy

This is a case report of 2 patients with severe left ventricular dysfunction and ventricular arrhythmias. At the time of cardiac transplantation they were found to have right ventricular dysplasia with left ventricular involvement.

Gβγ Binding Increases the Open Time of IKACh: Kinetic Evidence for Multiple Gβγ Binding Sites

Abstract I KACh is an inwardly rectifying potassium channel that plays an important role in the regulation of mammalian heart rate. I KACh is activated by direct interaction with G βγ subunits of pertussis toxin-sensitive heterotrimeric G-proteins. The stoichiometry of the G βγ /channel complex is currently unknown, and kinetic analysis of the channel behavior has led to conflicting conclusions. Here, we analyze the kinetics of the native I KACh channel in inside-out cardiomyocyte patches activated directly by G βγ . We conclude that the channel has at least two open states and that binding of G βγ prolongs its mean open time duration. These findings imply the existence of at least two binding sites on the channel complex for G βγ . We also show that the duration of the channel opening is negatively correlated with the duration of subsequent channel closing, which further constrains the possible kinetic models. A simple qualitative model describing the kinetic behavior of I KACh is presented.

Catecholamine-provoked microvoltage T wave alternans in genotyped long QT syndrome.

Macrovoltage T wave alternans (TWA) has been described in congenital long QT syndrome (LQTS). Microvoltage T wave alternans (μV‐TWA) at low heart rate (HR) is a marker of arrhythmogenic risk in many conditions, but its significance in LQTS has not been established. Twenty‐three genotypically heterogeneous patients with LQTS and 16 control subjects were studied at rest and during phenylephrine and dobutamine provocation. Genotyping was established by PCR amplification and DNA sequencing of the three most common LQTS genes; KCNQ1/KVLQT1 (LQT1), KCNH2/HERG (LQT2), and SCN5A (LQT3). μV‐TWA was determined using Fast Fourier transform. Precluded by ectopy, μV‐TWA could not be assessed in 8 of 23 patients with LQTS. In the remaining 15 patients with LQTS, μV‐TWA occurred at lower HR in LQTS than in controls ( 117 ± 49 vs 153 ± 37  beats/min; P < 0.05 ). Patients with LQTS developed μV‐TWA at HR < 150 beats/min more often than controls (10/15 vs 2/16; P = 0.003). However, μV‐TWA was not detected in the 3 individuals with a history of out‐of‐hospital cardiac arrest including a 14‐year‐old male with an F339del‐KVLQT1 mutation (LQT1) who had dobutamine‐provoked polymorphic ventricular tachycardia requiring external defibrillation. Catecholamine‐provoked μV‐TWA occurs at lower HR in patients with LQTS than in healthy people but does not identify high risk subjects. (PACE 2003; 26:1660–1667)

Structure, G Protein Activation, and Functional Relevance of the Cardiac G Protein‐Gated K+ Channel, IKACh

ABSTRACT: The muscarinic‐gated atrial potassium channel IKACh has been well characterized functionally, and has been an excellent model system for studying G protein/effector interactions. Complementary DNAs encoding the composite subunits of IKACh have been identified, allowing direct probing of structural and functional features of the channel. Here, we highlight recent approaches taken in our laboratory to determine the oligomeric structure of native cardiac IKACh, the mechanism of activation of IKACh by G proteins, and the relevance of IKACh to cardiac physiology.

Pharmacotherapy of atrial fibrillation

Atrial fibrillation (AF) remains a widespread health problem and the drugs available for its treatment suffer from several drawbacks, including potentially lethal proarrhythmia, serious non-cardiac toxicity and limited efficacy. The evidence for efficacy of currently available anti-arrhythmic agents for sinus rhythm restoration and maintenance is reviewed, with emphasis on randomised trials when available. The current approach to thromboembolism prophylaxis in AF is summarised.

Asymptomatic Occlusion of the Left Main Coronary Artery by an Aortic Pseudoaneurysm

Extrinsic compression of the left main coronary artery is a rare cause of coronary ischemia. We describe a 35-year-old Asian woman with complete asymptomatic occlusion of the left main coronary artery by a large aortic pseudoaneurysm. She underwent repair of the pseudoaneurysm and coronary artery bypass grafting at the Mayo Clinic in Rochester, Minn. The differential diagnosis is discussed. Based on this patients age and associated vascular lesions, we conclude that Takayasu arteritis was the most likely cause of her condition.

Recent heart rate history affects QT interval duration in atrial fibrillation

QT interval prolongation is associated with a risk of polymorphic ventricular tachycardia. QT interval shortens with increasing heart rate and correction for this effect is necessary for meaningful QT interval assessment. We aim to improve current methods of correcting the QT interval during atrial fibrillation (AF). Digitized Holter recordings were analyzed from patients with AF. Models of QT interval dependence on RR intervals were tested by sorting the beats into 20 bins based on corrected RR interval and assessing ST-T variability within the bins. Signal-averaging within bins was performed to determine QT/RR dependence. Data from 30 patients (29 men, 69.3±7.3 years) were evaluated. QT behavior in AF is well described by a linear function (slope ~0.19) of steady-state corrected RR interval. Corrected RR is calculated as a combination of an exponential weight function with time-constant of 2 minutes and a smaller “immediate response” component (weight ~ 0.18). This model performs significantly (p<0.0001) better than models based on instantaneous RR interval only including Bazett and Fridericia. It also outperforms models based on shorter time-constants and other previously proposed models. This model may improve detection of repolarization delay in AF. QT response to heart rate changes in AF is similar to previously published QT dynamics during atrial pacing and in sinus rhythm.