Kathryn A. Glatter

Electrophysiologic Effects of Adenosine in Patients With Supraventricular Tachycardia

BACKGROUND We correlated the electrophysiologic (EP) effects of adenosine with tachycardia mechanisms in patients with supraventricular tachycardias (SVT). METHODS AND RESULTS Adenosine was administered to 229 patients with SVTs during EP study: atrioventricular (AV) reentry (AVRT; n=59), typical atrioventricular node reentry (AVNRT; n=82), atypical AVNRT (n=13), permanent junctional reciprocating tachycardia (PJRT; n=12), atrial tachycardia (AT; n=53), and inappropriate sinus tachycardia (IST; n=10). There was no difference in incidence of tachycardia termination at the AV node in AVRT (85%) versus AVNRT (86%) after adenosine, but patients with AVRT showed increases in the ventriculoatrial (VA) intervals (13%) compared with typical AVNRT (0%), P<0.005. Changes in atrial, AV, or VA intervals after adenosine did not predict the mode of termination of long R-P tachycardias. For patients with AT, there was no correlation with location of the atrial focus and adenosine response. AV block after adenosine was only observed in AT patients (27%) or IST (30%). Patients with IST showed atrial cycle length increases after adenosine (P<0.05) with little change in activation sequence. The incidence of atrial fibrillation after adenosine was higher for those with AVRT (15%) compared with typical AVNRT (0%) P<0.001, or atypical AVNRT (0%) but similar to those with AT (11%) and PJRT (17%). CONCLUSIONS The EP response to adenosine proved of limited value to identify the location of AT or SVT mechanisms. Features favoring AT were the presence of AV block or marked shortening of atrial cycle length before tachycardia suppression. Atrial fibrillation was more common after adenosine in patients with AVRT, PJRT, or AT. Patients with IST showed increases in cycle length with little change in atrial activation sequence after adenosine.

Functional Roles of Cav1.3(α1D) Calcium Channels in Atria Insights Gained From Gene-Targeted Null Mutant Mice

Background— Previous data suggest that L-type Ca 2+ channels containing the Ca v 1.3(α 1D ) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Ca v 1.2(α 1C ) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Ca v 1.3 Ca 2+ channel–deficient mice ( Ca v 1.3 −/− ) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Ca v 1.3(α 1D ) Ca 2+ channel in the atria of Ca v 1.3 −/− mice. Methods and Results— We obtained new evidence to demonstrate that there is significant expression of Ca v 1.3 Ca 2+ channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca 2+ currents ( I Ca,L ) recorded from single, isolated atrial myocytes from Ca v 1.3 −/− mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the I Ca,L recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Ca v 1.3 compared with Ca v 1.2 Ca 2+ channel subunits in a heterologous expression system. The lack of Ca v 1.3 Ca 2+ channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of I Ca,L in atrial myocytes. In addition, the Ca v 1.3 -null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Ca v 1.3 versus Ca v 1.2 by in situ hybridization and immunofluorescence confocal microscopy. Conclusions— Using gene-targeted deletion of the Ca v 1.3 Ca 2+ channel, we established the differential distribution of Ca v 1.3 Ca 2+ channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Ca v 1.3 Ca 2+ channel in atrial tissues.Background—Previous data suggest that L-type Ca2+ channels containing the Cav1.3(α1D) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Cav1.2(α1C) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Cav1.3 Ca2+ channel–deficient mice (Cav1.3−/−) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Cav1.3(α1D) Ca2+ channel in the atria of Cav1.3−/− mice. Methods and Results—We obtained new evidence to demonstrate that there is significant expression of Cav1.3 Ca2+ channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca2+ currents (ICa,L) recorded from single, isolated atrial myocytes from Cav1.3−/− mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the ICa,L recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Cav1.3 compared with Cav1.2 Ca2+ channel subunits in a heterologous expression system. The lack of Cav1.3 Ca2+ channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of ICa,L in atrial myocytes. In addition, the Cav1.3-null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Cav1.3 versus Cav1.2 by in situ hybridization and immunofluorescence confocal microscopy. Conclusions—Using gene-targeted deletion of the Cav1.3 Ca2+ channel, we established the differential distribution of Cav1.3 Ca2+ channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Cav1.3 Ca2+ channel in atrial tissues.

Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice.

Background— Previous data suggest that L-type Ca 2+ channels containing the Ca v 1.3(α 1D ) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Ca v 1.2(α 1C ) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Ca v 1.3 Ca 2+ channel–deficient mice ( Ca v 1.3 −/− ) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Ca v 1.3(α 1D ) Ca 2+ channel in the atria of Ca v 1.3 −/− mice. Methods and Results— We obtained new evidence to demonstrate that there is significant expression of Ca v 1.3 Ca 2+ channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca 2+ currents ( I Ca,L ) recorded from single, isolated atrial myocytes from Ca v 1.3 −/− mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the I Ca,L recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Ca v 1.3 compared with Ca v 1.2 Ca 2+ channel subunits in a heterologous expression system. The lack of Ca v 1.3 Ca 2+ channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of I Ca,L in atrial myocytes. In addition, the Ca v 1.3 -null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Ca v 1.3 versus Ca v 1.2 by in situ hybridization and immunofluorescence confocal microscopy. Conclusions— Using gene-targeted deletion of the Ca v 1.3 Ca 2+ channel, we established the differential distribution of Ca v 1.3 Ca 2+ channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Ca v 1.3 Ca 2+ channel in atrial tissues.Background—Previous data suggest that L-type Ca2+ channels containing the Cav1.3(α1D) subunit are expressed mainly in neurons and neuroendocrine cells, whereas those containing the Cav1.2(α1C) subunit are found in the brain, vascular smooth muscle, and cardiac tissue. However, our previous report as well as others have shown that Cav1.3 Ca2+ channel–deficient mice (Cav1.3−/−) demonstrate sinus bradycardia with a prolonged PR interval. In the present study, we extended our study to examine the role of the Cav1.3(α1D) Ca2+ channel in the atria of Cav1.3−/− mice. Methods and Results—We obtained new evidence to demonstrate that there is significant expression of Cav1.3 Ca2+ channels predominantly in the atria compared with ventricular tissues. Whole-cell L-type Ca2+ currents (ICa,L) recorded from single, isolated atrial myocytes from Cav1.3−/− mice showed a significant depolarizing shift in voltage-dependent activation. In contrast, there were no significant differences in the ICa,L recorded from ventricular myocytes from wild-type and null mutant mice. We previously documented the hyperpolarizing shift in the voltage-dependent activation of Cav1.3 compared with Cav1.2 Ca2+ channel subunits in a heterologous expression system. The lack of Cav1.3 Ca2+ channels in null mutant mice would result in a depolarizing shift in the voltage-dependent activation of ICa,L in atrial myocytes. In addition, the Cav1.3-null mutant mice showed evidence of atrial arrhythmias, with inducible atrial flutter and fibrillation. We further confirmed the isoform-specific differential expression of Cav1.3 versus Cav1.2 by in situ hybridization and immunofluorescence confocal microscopy. Conclusions—Using gene-targeted deletion of the Cav1.3 Ca2+ channel, we established the differential distribution of Cav1.3 Ca2+ channels in atrial myocytes compared with ventricles. Our data represent the first report demonstrating important functional roles for Cav1.3 Ca2+ channel in atrial tissues.

Short-term secondhand smoke exposure decreases heart rate variability and increases arrhythmia susceptibility in mice

Exposure to secondhand smoke (SHS), a major indoor air pollutant, is linked to increased cardiovascular morbidity and mortality, including cardiac arrhythmias. However, the mechanisms underlying the epidemiological findings are not well understood. Impaired cardiac autonomic function, indexed by reduced heart rate variability (HRV), may represent an underlying cause. The present study takes advantage of well-defined short-term SHS exposure (3 days, 6 h/day) on HRV and the susceptibility to arrhythmia in mice. With the use of electrocardiograph telemetry recordings in conscious mice, HRV parameters in the time domain were measured during the night after each day of exposure and 24 h after 3 days of exposure to either SHS or filtered air. The susceptibility to arrhythmia was determined after 3 days of exposure. Exposure to a low concentration of SHS [total suspended particle (TSP), 2.4 +/- 3.2; and nicotine, 0.3 +/- 0.1 mg/m(3)] had no significant effect on HRV parameters. In contrast, the exposure to a higher but still environmentally relevant concentration of SHS (TSP, 30 +/- 1; and nicotine, 5 +/- 1 mg/m(3)) significantly reduced HRV starting after the first day of exposure and continuing 24 h after the last day of exposure. Moreover, the exposed mice showed a significant increase in ventricular arrhythmia susceptibility and atrioventricular block. The data suggest that SHS exposure decreased HRV beyond the exposure period and was associated with an increase in arrhythmia susceptibility. The data provide insights into possible mechanisms underlying documented increases in cardiovascular morbidity and mortality in humans exposed to SHS.

Pregnancy in Postural Orthostatic Tachycardia Syndrome

Introduction: Postural orthostatic tachycardia syndrome (POTS) is a rare disease characterized by syncope, sinus tachycardia, and orthostasis due to autonomic dysfunction.

Prolonged QT Interval Corrected for Heart Rate During Diabetic Ketoacidosis in Children

OBJECTIVE To evaluate the effect of diabetic ketoacidosis (DKA) on the QT interval corrected for heart rate (QTc) in children. Ketosis occurs in several conditions, including DKA and alcoholic ketoacidosis, and during use of very low-carbohydrate diets. Prolongation of the QTc has been described in a few children receiving ketogenic diets, but cardiac effects of ketosis have not otherwise been investigated. DESIGN For this observational study, we performed electrocardiography during DKA and after recovery. We measured QTc as the QT interval divided by the square root of the R-R interval and correlated QTc with clinical variables. SETTING The pediatric emergency department and intensive care unit of an academic medical center. PATIENTS Thirty children with type 1 diabetes mellitus and DKA. MAIN OUTCOME MEASURE The QTc during DKA. RESULTS The mean (SD) QTc during DKA was 450 (38) milliseconds (range, 378-539 milliseconds). After recovery from DKA, the mean (SD) QTc decreased to 407 (36) milliseconds (range, 302-485 milliseconds; difference, 43 milliseconds; 95% confidence interval, 23-63 milliseconds) (P < .001). Fourteen of the 30 children (47%) had prolonged QTc during DKA (range, 450-539 milliseconds). After recovery from DKA, only 4 children (13%) had persistent QTc prolongation (range, 451-485 milliseconds). The anion gap was significantly associated with QTc prolongation (correlation coefficient, 0.49; P = .006). Most patients had no electrolyte abnormalities or hypoglycemia to account for QTc prolongation. CONCLUSIONS Prolonged QTc occurs frequently during DKA and is correlated with ketosis. Current guidelines regarding cardiac monitoring of children during DKA should be strictly followed, and electrocardiographic screening of patients with other ketotic conditions should be considered.

Electrophysiological Response of the Right Atrium to Ibutilide During Typical Atrial Flutter

Background—The efficacy of ibutilide in conversion of atrial fibrillation and flutter (AFL) has been demonstrated. However, its electrophysiological effects on human atria have not been fully studied. Methods and Results—Twelve patients with typical AFL were studied. Electrograms were recorded from the anterolateral right atrium, His bundle position, and coronary sinus. During AFL, we measured the conduction time, CTi, through the isthmus between the tricuspid annulus and eustachian ridge and the conduction time, CTni, through the remainder of the right atrium. Resetting response curves and atrial effective refractory periods were determined with single extrastimuli delivered in the tricuspid annulus–eustachian ridge isthmus. After infusion of ibutilide (2 mg over 15 minutes), AFL cycle length (CL) increased from 260±30 to 295±39 ms (P <0.0003) because of an increase in either CTi, CTni, or both. Effective refractory periods increased from 149±16 to 208±26 ms (P <0.001). AFL CL variability increased, with a rightward shift of the resetting response curves and loss of full excitability. In 8 patients, AFL was terminated by atrial overdrive pacing after ibutilide at CLs equal to or longer than those that were not effective at baseline, which was caused by orthodromic block in the tricuspid annulus–eustachian ridge isthmus or was associated with development of transient rapid rhythms around newly formed sites of intra-atrial conduction block. Conclusions—Ibutilide causes prolongation of AFL CL and increased CL variability by abolishment of a fully excitable gap. Ibutilide may facilitate pace termination of AFL by development of new short-lived reentry around functional blocks.

Malignant Vasovagal Syncope

A 62-year-old man without significant medical history presented to his doctor with repeated episodes of syncope. The episodes were always associated with micturition (often at night) and had caused falls resulting in head injury. His wife was particularly concerned, noting that he became apneic while sleeping. He was diagnosed with sleep apnea. A 24-hour Holter monitor was obtained …

Risk stratification in Brugada syndrome

It is easy to recommend an implantable cardioverter-defibrillator to a patient who has just survived a cardiac arrest, but what do you tell his asymptomatic brother who has the same genetic disease? In this age of gene testing and sophisticated technology, such questions arise frequently, and the answers are complex. Lars Eckardt and colleagues recently addressed this question of risk stratification for asymptomatic patients with Brugada syndrome.1 Brugada syndrome is a genetic disease characterised by mutations in the cardiac sodium-channel (SCN5A), which cause a loss of function of the channel.2–4 Patients with Brugada syndrome have normal heart function but are prone to cardiac arrhythmias and sudden death, especially in middle-aged men. The syndrome is one of the leading causes of death for young men in south-east Asia, where the mutation is particularly common.5 Like most such genetic causes of sudden death, Brugada syndrome is an autosomal dominant disease, meaning that 50% of the progeny will inherit the mutation (and risk of sudden death) from the affected proband. Thus there will probably be more silent carriers of the mutation who may never exhibit disease symptoms (syncope, cardiac arrest, or sudden death) than symptomatic probands. Although drugs such as quinidine and sotalol have been tried in patients with Brugada syndrome, the only real treatment is placement of an implantable cardioverter-defibrillator to prevent sudden death.6,7 Diagnosis of these patients is also problematic because the characteristic ECG findings (figure) may be absent. Genetic testing will only reveal the mutation in 20% of patients with Brugada syndrome. How to treat these asymptomatic patients is controversial.8 Figure 12-lead ECG, 46-year old man with family history of sudden death in men. Asymptomatic patient was originally admitted for stab wound to neck and was found to have this ECG classic for Brugada syndrome. Note pseudoright bundle-branch-block pattern and ... Two major research groups have studied Brugada syndrome and provide much of the available data. The first group is an international registry spearheaded by the Brugada brothers, who initially described the disease in 1992.9 Their cohort of patients is the largest but appears to be one at relatively high-risk for sudden death. Their group reported the clinical prognosis of 547 patients with Brugada syndrome over 24 (SD 33) months of follow-up.2 Despite the short follow-up, 8% of the initially asymptomatic patients died or had ventricular fibrillation. The strongest predictor of adverse outcome was a positive invasive electrophysiology study during which malignant ventricular arrhythmias were induced. Inducible individuals had a six-fold increased risk of sudden death or ventricular fibrillation during the subsequent 2 years compared with non-inducible subjects. The second research group led by Priori et al in Italy reported the natural history of 200 patients with Brugada syndrome.10 Inducibility at electrophysiology study was not predictive of untoward clinical outcomes in their cohort. The highest risk feature was an ECG consistent with the diagnosis at baseline and a history of syncope; 44% of these patients had a cardiac arrest. Their group advocated placement of an implantable cardioverter-defibrillator in such patients and no treatment in asymptomatic patients whose baseline ECG was normal. Eckardt and colleagues describe a large cohort with Brugada syndrome (212 patients) from four European centres with the longest follow-up yet published (40 [SD 50] months). Only 1% of the initially asymptomatic patients had an arrhythmic episode during follow-up. Their cohort seemed to be at lower risk for sudden death than the Brugada registry, perhaps because of a selection bias in the latter group. Importantly, Eckardt did not find that electrophysiology study was useful for risk stratification. Indeed, such testing was negative in four of nine Brugada syndrome patients who eventually had clinical events. Their sentinel work is highly useful because they show that asymptomatic patients with incidentally discovered ECGs consistent with Brugada syndrome are at relatively low-risk for cardiac events. The Second Consensus Conference on Brugada syndrome recently recommended placement of an implantable cardioverter-defibrillator for cardiac-arrest survivors but admitted that it is unclear if asymptomatic patients should receive treatment.11 Eckardt and colleagues’ study suggests that such patients will do well and do not require intervention. Additionally, they did not find that invasive electrophysiology study was a useful tool for risk-stratification and should not be used. All groups sound a word of caution with their findings due to the short follow-up in their studies. Whether initially asymptomatic patients could have a cardiac arrest decades after their diagnosis is unknown. Such findings will only be revealed over time. Affected family members who have not yet had symptoms must wait as we all continue to learn more about the natural history of Brugada syndrome.

Retrograde cycle length alternans during supraventricular tachycardia: an unusual tachycardia mechanism.

Cycle length alternans is occasionally seen during supraventricular tachycardia due to oscillations in the antegrade atrioventricular nodal (AVN) refractoriness. However, alternans due to retrograde variation in AVN conduction has not been reported. This report describes the case of a 36‐year‐old man with atypical AVN reentry tachycardia (AVNRT) whose episodes of tachycardia were characterized by continuous oscillations in retrograde AVN conduction. Ablation at one spot eliminated the tachycardia. Cycle length alternans due to oscillations in retrograde AVN conduction, although rare, can be seen during atypical AVNRT and should be considered. (PACE 2004; 27:1017–1019)