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Biomedical subjects

Andrew D Krahn

Publications and source records attributed to Andrew D Krahn.

At least 19 recordsLinked to original sources
PubMed2026

Catecholaminergic polymorphic ventricular tachycardia mediated by ryanodine receptor 2: a validated risk stratification.

BACKGROUND AND AIMS: Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. METHODS: The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. RESULTS: A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. CONCLUSIONS: These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Humans↗
PubMed2026

RBM20 Truncating Variants and Human Cardiomyopathy.

IMPORTANCE: Genetic diagnosis has become increasingly important to guide clinical decision-making for patients with dilated cardiomyopathy (DCM). Pathogenic or likely pathogenic (P/LP) missense variants in the gene RBM20 cause a highly penetrant arrhythmogenic DCM, but the role of RBM20 truncating variants (RBM20tvs) is unclear. OBJECTIVE: To assess the contribution of RBM20 variants to arrhythmogenic DCM. DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, participants in the genome-first UK Biobank (UKB) and All of Us populations were evaluated to assess the etiologic fraction, natural history and penetrance of RBM20 variants. Retrospective data were collected from an international cohort of patients with DCM and RBM20 variants identified at centers of excellence for genetic heart disease and compared based on time to event. Study dates are not disclosed because the institutional review board did not authorize the sharing of this information. EXPOSURES: RBM20 variants were compared to known P/LP variants and variants of uncertain significance in RBM20 as well as titin truncating variants (TTNtvs). MAIN OUTCOMES AND MEASURES: Major ventricular arrhythmias, end-stage heart failure, and heart failure hospitalization as measured by medical record review (retrospective cohort) and diagnostic codes (UKB). RESULTS: Two main cohorts were studied for this project. In UK Biobank, a cohort of participants with RBM20tvs, RBM20 synonymous variants, and TTNtvs was studied. Of these 4249 participants, 1869 (44%) were male. The mean (SD) age at enrollment was 56 (8.2) years. In the RBM20 registry, of 179 patients, 105 (58.6%) were male, and the mean (SD) age at enrollment was 43.8 (19.1) years. A validation cohort from the All of Us biobank was also used. This consisted of 7002 participants, 4342 of whom (62.0%) were male, and the mean (SD) age was 52.7 (16.7) years. The etiologic fraction of RBM20 variants in arrhythmogenic DCM was 0.53 (95% CI, 0.32-0.67; P&#x2009;<&#x2009;.001). In genome-first biobanks, lifetime incidence of cardiomyopathy, heart failure, or major ventricular arrhythmia diagnosis was lower in participants with RBM20 variants than in those with TTNtvs (hazard ratio, 0.55; 95% CI, 0.36-0.84; P&#x2009;<&#x2009;.001). Patients with RBM20tvs and DCM presented to referral centers later in life than those with P/LP RBM20 and DCM (mean [SD], 53 [10] vs 34 [18] years; P&#x2009;<&#x2009;.001) and were less likely to have a family history of sudden cardiac arrest (2 of 10 [20%] vs 11 of 17 [65%]; P&#x2009;=&#x2009;.046) or cardiomyopathy (2 of 10 [20%] vs 14 of 18 [78%]; P&#x2009;<&#x2009;.001). There was no significant difference in age- and sex-adjusted incident major heart failure or arrhythmia events between patients with RBM20tv and DCM or those with P/LP RBM20 and DCM, though sex-adjusted lifetime hazard was reduced in those with RBM20tv and DCM (hazard ratio, 0.13; 95% CI, 0.03-0.56; P&#x2009;=&#x2009;.01). CONCLUSIONS AND RELEVANCE: This study found that RBM20 variants contributed to arrhythmogenic DCM phenotypes but conferred reduced lifetime disease penetrance compared to TTNtvs and milder disease severity alone than P/LP RBM20 variants. Their potential for additive interactions with other damaging variants should be considered in patients with DCM and their families.

Humans↗
PubMed2006

A novel pacing maneuver to localize focal atrial tachycardia.

BACKGROUND: Although focal atrial tachycardias cannot be entrained, we hypothesized that atrial overdrive pacing (AOP) can be an effective adjunct to localize the focus of these tachycardias at the site where the post-pacing interval (PPI) is closest to the tachycardia cycle length (TCL). METHODS: Overdrive pacing was performed in nine patients during atrial tachycardia, and in a comparison group of 15 patients during sinus rhythm. Pacing at a rate slightly faster than atrial tachycardia in group 1 and sinus rhythm in group 2 was performed from five standardized sites in the right atrium and coronary sinus. The difference between the PPI and tachycardia or sinus cycle length (SCL) was recorded at each site. The tachycardia focus was then located and ablated in group 1, and the atrial site with earliest activation was mapped in group 2. RESULTS: In both groups the PPI-TCL at the five pacing sites reflected the distance from the AT focus or sinus node. In group 1, PPI-TCL at the successful ablation site was 11 +/- 8 msec. In group 2, PPI-SCL at the site of earliest atrial activation was 131 +/- 37 msec (P < 0.001 for comparison). In groups 1 and 2, calculated values at the five pacing sites were proportional to the distance from the AT focus or sinus node, respectively. CONCLUSIONS: The PPI-TCL after-AOP of focal atrial tachycardia has a direct relationship to proximity of the pacing site to the focus, and may be clinically useful in finding a successful ablation site.

Cardiac Pacing, Artificial↗
PubMed2006

Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.

BACKGROUND: Atrial fibrillation is the most common type of cardiac arrhythmia and a leading cause of cardiovascular morbidity, particularly stroke. The cardiac gap-junction protein connexin 40 is expressed selectively in atrial myocytes and mediates the coordinated electrical activation of the atria. We hypothesized that idiopathic atrial fibrillation has a genetic basis and that tissue-specific mutations in GJA5, the gene encoding connexin 40, may predispose the atria to fibrillation. METHODS: We sequenced GJA5 from genomic DNA isolated from resected cardiac tissue and peripheral lymphocytes from 15 patients with idiopathic atrial fibrillation. Identified GJA5 mutations were transfected into a gap-junction-deficient cell line to assess their functional effects on protein transport and intercellular electrical coupling. RESULTS: Four novel heterozygous missense mutations were identified in 4 of the 15 patients. In three patients, the mutations were found in the cardiac-tissue specimens but not in the lymphocytes, indicating a somatic source of the genetic defects. In the fourth patient, the sequence variant was detected in both cardiac tissue and lymphocytes, suggesting a germ-line origin. Analysis of the expression of mutant proteins revealed impaired intracellular transport or reduced intercellular electrical coupling. CONCLUSIONS: Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. Our data suggest that common diseases traditionally considered to be idiopathic may have a genetic basis, with mutations confined to the diseased tissue.

Adult↗
PubMed2006

Using the net benefit regression framework to construct cost-effectiveness acceptability curves: an example using data from a trial of external loop recorders versus Holter monitoring for ambulatory monitoring of "community acquired" syncope.

BACKGROUND: Cost-effectiveness acceptability curves (CEACs) describe the probability that a new treatment or intervention is cost-effective. The net benefit regression framework (NBRF) allows cost-effectiveness analysis to be done in a simple regression framework. The objective of the paper is to illustrate how net benefit regression can be used to construct a CEAC. METHODS: One hundred patients referred for ambulatory monitoring with syncope or presyncope were randomized to a one-month external loop recorder (n = 49) or 48-hour Holter monitor (n = 51). The primary endpoint was symptom-rhythm correlation during monitoring. Direct costs were calculated based on the 2003 Ontario Health Insurance Plan (OHIP) fee schedule combined with hospital case costing of labour, materials, service and overhead costs for diagnostic testing and related equipment. RESULTS: In the loop recorder group, 63.27% of patients (31/49) had symptom recurrence and successful activation, compared to 23.53% in the Holter group (12/51). The cost in US dollars for loop recording was 648.50 dollars and 212.92 dollars for Holter monitoring. The incremental cost-effectiveness ratio (ICER) of the loop recorder was 1,096 dollars per extra successful diagnosis. The probability that the loop recorder was cost-effective compared to the Holter monitor was estimated using net benefit regression and plotted on a CEAC. In a sensitivity analysis, bootstrapping was used to examine the effect of distributional assumptions. CONCLUSION: The NBRF is straightforward to use and interpret. The resulting uncertainty surrounding the regression coefficient relates to the CEAC. When the link from the regression's p-value to the probability of cost-effectiveness is tentative, bootstrapping may be used.

Bayes Theorem↗
PubMed2006

Complications associated with implantable cardioverter-defibrillator replacement in response to device advisories.

CONTEXT: Recent implantable cardioverter-defibrillator (ICD) advisories and recalls have caused management dilemmas for physicians, particularly because there are no specific guidelines or data on outcomes from current management strategies. The risk of ICD generator replacement has not been assessed in this population. OBJECTIVE: To determine the complication rate associated with ICD generator replacement for the current ICD advisories. DESIGN AND SETTING: Seventeen ICD implanting centers in Canada were surveyed to assess complication rates as a result of generator replacements because of ICD advisories from October 2004 to October 2005. MAIN OUTCOME MEASURE: Complications associated with elective ICD generator replacement for current device advisories. RESULTS: At the 17 surveyed centers, 2915 patients had recall devices, including 533 (18.3%) who had advisory ICDs replaced a mean (SD) of 26.5 (11.5) months after their initial implant. Of these patients, 66% had a secondary prevention ICD, and 45% had received a previous appropriate shock. During a mean (SD) of 2.7 (2.8) months' follow-up after ICD generator replacement, complications occurred in 43 patients (8.1%). Major complications attributable to advisory device replacement requiring reoperation occurred in 31 patients (5.8%), with death in 2 patients after extraction for pocket infection. Minor complications occurred in 12 patients (2.3%). There were 3 (0.1%) advisory-related device malfunctions reported, without clinical consequences. CONCLUSIONS: ICD generator replacement in patients with advisory devices is associated with a substantial rate of complications, including death. These complications need to be considered in the development of guidelines determining the appropriate treatment of patients with advisory devices.

Aged↗
PubMed2006

Differentiating arrhythmogenic right ventricular cardiomyopathy from right ventricular outflow tract ventricular tachycardia using multilead QRS duration and axis.

BACKGROUND: Ventricular tachycardia (VT) resulting from arrhythmogenic right ventricular cardiomyopathy (ARVC) may be difficult to differentiate from idiopathic right ventricular outflow tract (RVOT) VT. OBJECTIVES: The purpose of this study was to investigate the hypothesis that QRS characteristics would be different in ARVC because of altered conduction through abnormal myocardium. METHODS: In 24 RVOT VT patients (18 women and 6 men; age 42 +/- 10 years) and 20 ARVC patients (12 women and 8 men; age 38 +/- 14 years), mean QRS duration, frontal plane axis, and precordial R-wave transition were measured in 12-lead ECGs recorded during VT. RESULTS: Mean QRS duration was longer in all 12 leads in ARVC patients. A significant difference was noted in leads I, III, aVL, aVF, V(1), V(2), and V(3) (P <.05). Leads I and aVL had the largest mean difference between ARVC and RVOT VT patients of 17.6 +/- 4.7 ms and 15.8 +/- 7.5 ms, respectively (P <.0001). Lead I QRS duration > or =120 ms had a sensitivity of 100%, specificity 46%, positive predictive value 61%, and negative predictive value 100% for ARVC. The area under the receiver operating characteristic (ROC) curve was 0.89. The addition of mean QRS axis <30 degrees (R<S in lead III) to the above criterion increased specificity for ARVC to 100%. QRS duration remained sensitive and specific in the subgroup of nine ARVC ECGs with an inferior axis (ROC area 0.82). R-wave transition was not different between groups. CONCLUSION: QRS duration is longer in ARVC compared with RVOT VT. An algorithm combining lead I QRS duration for sensitivity and axis for specificity is useful for differentiating the two tachycardia substrates.

Adult↗
PubMed2006

Investigating syncope: a review.

PURPOSE OF REVIEW: This review focuses on recent literature on the cardiovascular investigation of syncope. RECENT FINDINGS: Syncope is a common and complex clinical entity with many varied etiologies, the diagnosis of which can often be elusive. Recent advances in the area of investigation in syncope include improvements in technologies for arrhythmia event monitoring and an increase in applicability and efficacy of traditional investigations. These advances have increased our ability to manage syncope. SUMMARY: A better understanding of the etiology of syncope in certain cohorts has allowed tailoring of investigations and management of syncope. This is evident when syncope occurs in the presence of structural heart disease, which is associated with a higher incidence of arrhythmias and an increased 1-year mortality. Patients with left-ventricular dysfunction should be considered candidates for an implantable cardioverter defibrillator based on heart function and syncopal presentation. In the absence of significant heart disease, investigations need to be tailored to diagnose neurally mediated causes for syncope and detection of intermittent bradycardia. The improved understanding of syncope has arisen from studies using improved investigational tools for syncope, in particular loop recorders, which are able to monitor cardiac rhythm over long periods. In those without structural heart disease and undifferentiated syncope, neurally mediated causes should be pursed initially. Tilt testing and loop recorders are employed most often in this cohort. Electrophysiological studies have largely been supplanted by implantable cardioverter defibrillator use in structural heart disease, with a low yield in patients with preserved heart function.

Cardiac Pacing, Artificial↗
PubMed2006

Age of first faint in patients with vasovagal syncope.

INTRODUCTION: Understanding whether vasovagal syncope is a lifelong disorder might shed insight into its physiology and affect management strategies. Accordingly, we determined the age of the first syncopal spell in adult patients who sought care for syncope. METHODS AND RESULTS: Patients were 42 +/- 18 years old with 64% women. They had had a median 8 syncope spells (interquartile range [IQR]: 4, 20) with a median frequency of 1.0 syncopal spells per year. The range of syncopal spells was 1-3,375, and the range of duration of history of syncope was 0.003-70 years. The first syncopal spell occurred at ages 0-81 in a skewed distribution, with a marked mode age of 13 years, a median age of 18 years (IQR 12, 37), and a mean age of 26 +/- 20 years. The distributions were statistically indistinguishable across countries (P = 0.50), among Canadian regions (P = 0.69), and between the studies (P = 0.49). The same modal values were seen in males and females, and in patients <40 and > or =40 years old. However, patients > or =40 years had median ages of onset older than patients <40 years (36 +/- 23 vs 17 +/- 8 years). Patients had a recalled history of syncopal spells of median duration of 10 years (IQR: 2, 23), with a range of 0.003-70 years. An age of onset <44 years was 86% accurate for vasovagal syncope. CONCLUSION: The most common age at which vasovagal syncope first presents is 13 years, and patients remain at risk of syncope for many years. Lifelong coping strategies may be desirable.

Adolescent↗
PubMed2006

The garden path.

Explore the source record for details and available documents.

Atrial Flutter↗
PubMed2006

Characteristics of slow pathway conduction after successful AVNRT ablation.

BACKGROUND: AV node slow pathway conduction can persist following successful ablation for AV node reentrant tachycardia (AVNRT). We hypothesized that careful examination of AV nodal conduction curves before and after effective AVNRT ablation in patients with persistent slow pathway conduction could shed light on this apparent paradox. METHODS AND RESULTS: Thirty patients (age 40.9 +/- 14.3; 8 male) were included. AV node function curves were created based on pre- and postablation atrial extrastimulus testing. Analysis of slow pathway function curves demonstrated significant decrease in AH for any given coupling interval after ablation (mean difference -68.1 [-94.5, -41.7] P < 0.001), graphically indicated by downward displacement of the curve. In addition, mean slow pathway effective refractory period (ERP) increased from 247.9 +/- 36.1 msec to 288.6 +/- 56.0 msec (P < 0.001); mean maximum AH interval decreased from 361.3 +/- 114.2 msec to 306.9 +/- 65.2 msec (P = 0.013); mean difference in minimum and maximum AH interval during slow pathway conduction decreased (from 94.5 +/- 75.8 msec to 59.6 +/- 46.2 msec (P = 0.016). Finally, mean difference between the fast and slow pathway effective refractory periods, the span of coupling intervals over which slow pathway conduction occurred, decreased (from 113.9 +/- 61.4 msec to 63.2 +/- 41.5 msec, P = 0.001). CONCLUSIONS: Ablation, which successfully eliminates inducible and spontaneous AVNRT in the presence of persistent slow pathway conduction, is associated with significantly altered slow pathway conduction characteristics, indicating the presence of a damaged or different slow pathway after ablation, incapable of sustaining tachycardia.

Adult↗
PubMed2006

Cavotricuspid isthmus conduction is dependent on underlying anatomic bundle architecture: observations using a maximum voltage-guided ablation technique.

OBJECTIVES: We hypothesized an ablation strategy directly targeting muscle bundles might demonstrate functionally distinct "routes" of conduction, potentially shortening ablation times. BACKGROUND: Pathological study demonstrated that the cavotricuspid isthmus is composed of distinct anatomically defined bundles, many with intervening gaps of connective tissue. METHODS: A line was mapped in the "6 o'clock" region and bipolar electrogram amplitude measured during pullback. Zones of peak voltage were ablated first regardless of position. RF was delivered using either a 5-mm externally irrigated catheter, or an 8-mm nonirrigated catheter. The zone of largest remaining voltage was then sequentially targeted until conduction. RESULTS: Eighteen patients were recruited and followed for 7.9 +/- 1.9 months block occurred (mean age 64 +/- 11.6 years, male:female ratio 14:4). Bi-directional block was achieved in all patients with recurrence of atrial flutter in 1 patient. Mean total RF times was 4.7 +/- 2.8 minutes with a mean of 6.1 +/- 3.3 applications, procedure time was 127.3 +/- 37.7 minutes, and fluoroscopy time was 25.5 +/- 12.0 minutes. Two patterns of block were observed in the study group. Pattern A described no change in conduction times until block, observed in 6 (33%); pattern B described a stepwise block with discrete "jumps," observed in 12 (67%). CONCLUSIONS: An ablation strategy targeting high-voltage isthmus electrograms obviates the need for a complete anatomic line. This finding together with discrete "jumps" during ablation is consistent with the concept of conduction over discrete bundles rather than a diffuse sheet of muscle.

Adult↗
PubMed2005

Physiologic pacing in patients with obstructive sleep apnea: a prospective, randomized crossover trial.

OBJECTIVES: This study was designed to assess the impact of prevention of bradycardia with physiologic pacing on the severity of obstructive sleep apnea. BACKGROUND: Apneic episodes during sleep are associated with slowing of the heart rate during apnea and tachycardia with subsequent arousal. Patients with permanent pacemakers may have reduced episodes of sleep apnea when their pacemaker rate is set faster than their spontaneous nocturnal heart rate. METHODS: We conducted a prospective, randomized, single-blind crossover trial of temporary atrial pacing in obstructive sleep apnea to reduce the apnea hypopnea index (AHI). Fifteen patients (age 60 +/- 13 years, 12 men) with moderate to severe obstructive sleep apnea (AHI 34 +/- 14) underwent insertion of an externalized atrial permanent pacing system via the left subclavian vein. Patients underwent overnight respiratory sleep studies in hospital, during atrial pacing at 75 beats/min, and with pacing turned off. The order of pacing mode was randomized, with crossover the subsequent night to the other mode. Patients were blinded to pacing mode, and the analysis of sleep recordings was blind to pacing mode. RESULTS: Pacing was tolerated without complications in all patients. Overnight physiologic pacing did not affect the AHI (pacing 39 +/- 21/h vs. control 42 +/- 21/h, p = 0.23, 95% confidence interval -9.3 to 2.5 for difference), desaturation time (pacing 3.8 +/- 6.0% vs. control 3.5 +/- 4.3%, p = 0.70), or the minimum SaO(2) (pacing 75 +/- 10% vs. control 77 +/- 11%, p = 0.38). There was a borderline significant reduction in circulatory time with pacing (pacing 23.4 +/- 3.2 s vs. control 25.5 +/- 4.4 s, p = 0.09). CONCLUSIONS: Temporary atrial pacing does not appear to improve respiratory manifestations of obstructive sleep apnea. Permanent atrial pacing in this patient population does not appear to be justified.

Aged↗
PubMed2005

Diagnosis of unexplained cardiac arrest: role of adrenaline and procainamide infusion.

BACKGROUND: Cardiac arrest with preserved left ventricular function may be caused by uncommon genetic conditions. Although these may be evident on the ECG, long-term monitoring or provocative testing is often necessary to unmask latent primary electrical disease. METHODS AND RESULTS: Patients with unexplained cardiac arrest and no evident cardiac disease (normal left ventricular function, coronary arteries, and resting corrected QT) underwent pharmacological challenge with adrenaline and procainamide infusions to unmask subclinical primary electrical disease. Family members underwent noninvasive screening and directed provocative testing on the basis of findings in the proband. Eighteen patients (mean+/-SD age, 41+/-17 years; 11 female) with unexplained cardiac arrest were assessed. The final diagnosis was catecholaminergic ventricular tachycardia (CPVT) in 10 patients (56%), Brugada syndrome in 2 patients (11%), and unexplained (idiopathic ventricular fibrillation) in 6 patients (33%). Of 55 family members (mean+/-SD age, 27+/-17 years; 33 female), 9 additional affected family members were detected from 2 families, with a single Brugada syndrome patient and 8 CPVT patients. CONCLUSIONS: Provocative testing with adrenaline and procainamide infusions is useful in unmasking the etiology of apparent unexplained cardiac arrest. This approach helps to diagnose primary electrical disease, such as CPVT and Brugada syndrome, and provides the opportunity for therapeutic intervention in identified, asymptomatic family members who harbor the same disease.

Anti-Arrhythmia Agents↗