Prolonged PR Research Articles

Bioelectrical Impedance Phase Angle Value and Prolongations of PR and Corrected QT Intervals in Patients Undergoing Dialysis

Introduction: Phase angle value, derived from bioelectrical impedance analysis, represents the body cell mass and nutritional status of patients undergoing hemodialysis. Although the phase angle value has clinical significance in these patients, its relationship with electrocardiogram (ECG), another clinically relevant bioelectrical examination, has not yet been well clarified. Methods: Two hundred and twenty-four patients undergoing dialysis (80 females and 144 males; mean ± SD, 72.2 ± 12.0 years old; 117 diabetic and 107 nondiabetic patients) were studied retrospectively. Multifrequency bioelectrical impedance analysis was performed immediately after the end of dialysis therapy. The phase shift was geometrically converted into a phase angle value. The ECG was recorded simultaneously, and the upper limits of the PR interval, QRS width, and corrected QT interval (QTc) were set at 0.20, 0.12, and 0.44 s, respectively. The geriatric nutritional risk index (GNRI), a representative nutritional index, was also determined. In addition, we examined the incidence of cardiac events, including heart failure, myocardial infarction, cardiac revascularization procedure, cardiac arrhythmia, and cardiac death, or all-cause death. Results: Of 224 patients undergoing dialysis, the prolongation of the PR interval, QRS width, and QTc was found in 30.7, 17.4, and 62.1%, respectively. The prevalence of QTc prolongation was higher in females and diabetic patients than in males and nondiabetic patients. An inverse relationship between phase angle value and QTc was observed only in males and nondiabetic patients. The relationships of GNRI both with phase angle value and QTc were stronger in males and nondiabetic patients. In addition, PR interval was inversely correlated with a phase angle value only in nondiabetic patients. No significant correlation was found between phase angle value and QRS width. Five-year survival probability for the composite endpoints was significantly worse in patients with lower phase angle values. QTc prolongation was associated with survival in males and nondiabetic patients. Prolonged PR was associated with survival in nondiabetic patients. Discussion: Relationships between phase angle value and ECG findings were demonstrated in patients undergoing dialysis, especially in males and nondiabetic patients. Although the phase angle value has been considered as an index for evaluating nutritional status, another clinical application of phase angle value in predicting cardiac complications seems to be useful.

Predictors of pacemaker requirement in patients receiving implantable loop recorders for unexplained syncope: A systematic review and meta-analysis

BackgroundImplantable loop recorders (ILRs) are increasingly used to evaluate patients with unexplained syncope. Identification of all predictors of bradycardic syncope and consequent permanent pacemaker (PPM) insertion is of substantial clinical interest as patients in the highest risk category may benefit from upfront pacemaker insertion. ObjectiveWe performed a systematic review and meta-analysis to identify risk predictors for PPM insertion in ILR recipients with unexplained syncope. MethodsAn electronic database search (MEDLINE, Embase, Scopus, Cochrane) was performed in June 2023. Studies evaluating ILR recipients with unexplained syncope and recording risk factors for eventual PPM insertion were included. A random effects model was used to calculate the pooled odds ratio (OR) for clinical and electrocardiographic characteristics with respect to future PPM requirement. ResultsEight studies evaluating 1007 ILR recipients were included; 268 patients (26.6%) underwent PPM insertion during study follow-up. PPM recipients were older (mean age, 70.2 ± 15.4 years vs 61.6 ± 19.7 years; P < .001). PR prolongation on baseline electrocardiography was a significant predictor of PPM requirement (pooled OR, 2.91; 95% confidence interval, 1.63–5.20). The presence of distal conduction system disease, encompassing any bundle branch or fascicular block, yielded a pooled OR of 2.88 for PPM insertion (95% confidence interval, 1.53–5.41). Injurious syncope and lack of syncopal prodrome were not significant predictors of PPM insertion. Sinus node dysfunction accounted for 62% of PPM insertions, whereas atrioventricular block accounted for 26%. ConclusionApproximately one-quarter of ILR recipients for unexplained syncope require eventual PPM insertion. Advancing age, PR prolongation, and distal conduction disease are the strongest predictors for PPM requirement.

Outcomes of rheumatic fever in Uganda: a prospective cohort study

Rheumatic heart disease is the largest contributor to cardiac-related mortality in children worldwide. Outcomes in endemic settings after its antecedent illness, acute rheumatic fever, are not well understood. We aimed to describe 3-5 year mortality, acute rheumatic fever recurrence, changes in carditis, and correlates of mortality after acute rheumatic fever. We conducted a prospective cohort study of Ugandan patients aged 4-23 years who were diagnosed with definite acute rheumatic fever using the modified 2015 Jones criteria from July 1, 2017, to March 31, 2020, enrolled at three rheumatic heart disease registry sites in Uganda (in Mbarara, Mulago, or Lira), and followed up for at least 1 year after diagnosis. Patients with congenital heart disease were excluded. Patients underwent annual review, most recently in August, 2022. We calculated rates of mortality and acute rheumatic fever recurrence, tabulated changes in carditis, performed Kaplan-Meier survival analyses, and used Cox regression models to identify correlates of mortality. Data were collected between Sept 1 and Sept 30, 2022. Of 182 patients diagnosed with definite acute rheumatic fever, 156 patients were included in the analysis. Of these 156 patients (77 [49%] male and 79 (51%) female; data on ethnicity not collected), 25 (16%) died, 21 (13%) had a cardiac-related death, and 17 (11%) had recurrent acute rheumatic fever over a median of 4·3 (IQR 3·0-4·8) years. 16 (24%) of the 25 deaths occurred within 1 year. Among 131 (84%) of 156 survivors, one had carditis progression by echo. Moderate-to-severe carditis (hazard ratio 12·7 [95% CI 3·9-40·9]) and prolonged PR interval (hazard ratio 4·4 [95% CI 1·7-11·2]) at acute rheumatic fever diagnosis were associated with increased cardiac-related mortality. These are the first contemporary data from sub-Saharan Africa on medium-term acute rheumatic fever outcomes. Mortality rates exceeded those reported elsewhere. Most decedents already had chronic carditis at initial acute rheumatic fever diagnosis, suggesting previous undiagnosed episodes that had already compounded into rheumatic heart disease. Our data highlight the large burden of undetected acute rheumatic fever in these settings and the need for improved awareness of and diagnostics for acute rheumatic fever to allow earlier detection. Strauss Award at Cincinnati Children's Hospital, American Heart Association, and Wellcome Trust.

PR Interval as a Novel Therapeutic Target of Ivabradine Therapy-Prognostic Impact of Ivabradine-Induced PR Prolongation in Heart Failure Patients.

Ivabradine reduces heart rate by inhibiting the "funny current" expressed on the sinoatrial node and improves mortality and morbidity in patients with systolic heart failure and sinus tachycardia. The funny current is known to be expressed also on the atrioventricular node according to experimental studies. However, the impact of ivabradine on PR interval remained unknown. Patients with a left ventricular ejection fraction of less than 50% who received 1 month of ivabradine were screened. Electrocardiographic and echocardiographic data, particularly concerning heart rate, the PR interval, and trans-mitral flow pattern, were collected at baseline and 1-month follow-up. The primary endpoint was defined as the composite of cardiovascular death and hospital readmission for worsening heart failure following ivabradine administration. In the cohort of 29 enrolled patients (median age: 66 years, 62% male), the median baseline heart rate was 86 beats per minute and the median PR interval was 168 milliseconds. Following ivabradine administration, a significant decrease of 20 beats per minute in the heart rate and a significant increase of 24 milliseconds in the PR interval were observed. The truncated interval of the A-wave, detected in the trans-mitral flow, consistently demonstrated a negative correlation with the PR interval both before and after the administration of ivabradine. During a median of 1.8 years of follow-up, six patients reached the primary endpoint. A combination of heart rate reduction and PR prolongation following ivabradine administration, both of which were independent factors associated with the primary endpoint (p < 0.05 for both), was associated with greater freedom from the primary endpoint compared with either/neither of them (p = 0.002). Ivabradine seems to prolong PR interval, which is a novel surrogate marker of favorable clinical outcomes in patients with systolic heart failure. This effect may be associated with the dynamics of the trans-mitral flow pattern, in conjunction with heart rate and the PR interval. Clinical implications of PR interval-guided ivabradine therapy remains the future concern.

Post-transcatheter aortic valve implantation isolated PR prolongation: incidence and clinical significance.

Conduction abnormalities post-transcatheter aortic valve implantation (TAVI) are common. Post-TAVI PR prolongation was mainly studied as an adjunct to new-onset bundle branch block. The net effect of isolated PR prolongation (IPRP) without post-TAVI QRS changes is not well known. The aim of this study was to define the incidence and clinical significance of post-TAVI IPRP. A total of 1108 consecutive TAVI patients were reviewed. Patients with IPRP were compared with patients without post-TAVI electrocardiogram (ECG) changes. Clinical outcomes included permanent pacemaker implantation (PPI) and overall mortality. A total of 146 patients with IPRP were compared with 290 patients without post-TAVI ECG changes. At 1 year follow-up, 4 (2.7%) and 7 (2.4%) patients underwent PPI (P = 0.838) and 10 (6.8%) and 25 (8.6%) died (P = 0.521), from the study and control groups, respectively. No patient with IPRP and narrow QRS underwent PPI during 1 year post-TAVI, and all death events were non-cardiac except one unknown cause. Permanent pacemaker implantation rates among patients with IPRP and wide QRS were higher (n = 4, 12.1%), compared with patients with wide QRS without post-TAVI ECG change (n = 3, 4%) however not reaching statistical significance (P = 0.126). Multivariate Cox proportional hazards model demonstrated that in patients with narrow QRS, neither PR prolongation nor baseline or maximal PR intervals was associated with the combined endpoint of PPI and mortality. However, in patients with wide QRS, baseline PR intervals and QRS width, but not PR prolongation were associated with the combined outcome. Post-TAVI IPRP in patients with narrow QRS is not associated with adverse outcome. This finding may translate clinically into a more permissive approach to these patients.

Incidence, clinical characteristics, electrophysiological characteristics and outcomes of patients with baseline PR prolongation undergoing radiofrequency ablation for Atrioventricular nodal reentrant tachycardia

Aims and objectivesAtrioventricular nodal reentrant tachycardia (AVNRT) is the most common supraventricular tachycardia (SVT). Prolonged PR interval(>200 ms) on baseline electrocardiogram (ECG) is uncommon in such patients. The aim of the current study was to evaluate the incidence, clinical, electrophysiological characteristics, and outcomes of patients with baseline prolongation of PR interval undergoing radio-frequency ablation (RFA) for AVNRT. MethodsOver 10 years, out of the total number of 1435 patients with diagnosed AVNRT, 16 patients had prolonged PR intervals at baseline. All underwent elective RFA. A retrospective analysis of clinical, and electrophysiological characteristics and outcomes was done. The PR interval and atria-ventricular block cycle length values were compared with those patients with a normal interval at baseline and had undergone a successful slow pathway modification for AVNRT. ResultsOut of 1435 patients with AVNRT, 16 (0.9 %) patients had baseline PR prolongation on ECG. The mean(+SD) age of the study population was 62.9 + 15.9 years. 10 (62.5 %) were males. The average PR interval was 264.2 + 24.1 ms. Slow fast AVNRT was seen in all. The anatomical site of success for ablation was the lower part of Koch's triangle in all patients. During ablation, a good sustained junctional rhythm was noted in all, with no AV (Atrioventricular) block or PR prolongation noted during ablation in any of the patients. PR interval decreased by more than 20 ms in 10 (62.5 %) patients. AVBCL (AV node block cycle length) increased on an average of 58.7 ms post-ablation. Only one patient developed AV block on follow-up. ConclusionA prolonged PR interval on baseline ECG is uncommon in patients with AVNRT. In these patients, slow pathway modification can be done safely and effectively. AVBCL (AV node block cycle length) increases immediately post-ablation. The risk of AV block though low persists on follow-up.

Paradoxical interatrial conduction recovery after cavotricuspid isthmus ablation: A case report

We present a case of a patient with advanced interatrial block who was admitted for cavotricuspid isthmus ablation as treatment of typical atrial flutter. A baseline advanced interatrial block pattern turned into partial interatrial block pattern and prolonged PR interval after the procedure. We discuss the mechanism underlying that change.

Prevalence and Prognostic Value of Atrial Cardiopathy in Embolic Stroke of Undetermined Source

Introduction: We utilized data from the Third China National Stroke Registry to investigate the prevalence of atrial cardiopathy markers in patients with embolic stroke of undetermined source (ESUS) and to assess their association with death and stroke recurrence. Methods: In China, patients experiencing transient ischemic attack or ischemic stroke were recruited consecutively by the Third China National Stroke Registry. We compared atrial cardiopathy markers, such as left atrial (LA) enlargement, increased P-wave terminal force in lead V1 (PTFV1), premature atrial contractions, paroxysmal supraventricular tachycardia, advanced interatrial block, prolonged PR interval, prolonged P-wave dispersion, and prolonged P-wave duration between ESUS patients and those with small vessel disease and large artery atherosclerosis strokes. The association between these markers and the recurrence of stroke as well as mortality risk in ESUS patients was evaluated using Cox regression analysis. Results: Of 8,528 ischemic stroke patients who underwent a standard diagnostic workup, 2,415 were identified as having ESUS. Multivariable analysis revealed a significant association between elevated PTFV1 and an increased risk of stroke recurrence (HR: 2.50; 95% CI: 1.53–4.09; p < 0.01) as well as mortality (HR: 3.76; 95% CI: 1.58–8.91; p < 0.01) at 1 year in patients with ESUS. Furthermore, we observed that moderate-severe LA enlargement slightly increased the risk of stroke recurrence in patients with ESUS (HR: 1.95; 95% CI: 0.90–4.26; p = 0.09). Both LA diameter (HR: 1.03; 95% CI: 1.00–1.06; p = 0.03) and the top quartile of the LA diameter index (HR: 1.56; 95% CI: 1.03–2.40; p = 0.04) were associated with stroke recurrence in patients with ESUS. Conclusions: PTFV1 was independently associated with an elevated risk of stroke recurrence and mortality in ESUS patients. Additionally, a trend toward a correlation between LA enlargement and high stroke recurrence risk after ESUS was observed.

Cardiac Abnormalities in a Predictive Mouse Model of Chagas Disease.

Chronic Chagas cardiomyopathy (CCC) results from infection with the protozoan parasite Trypanosoma cruzi and is a prevalent cause of heart disease in endemic countries. We previously found that cardiac fibrosis can vary widely in C3H/HeN mice chronically infected with T. cruzi JR strain, mirroring the spectrum of heart disease in humans. In this study, we examined functional cardiac abnormalities in this host:parasite combination to determine its potential as an experimental model for CCC. We utilised electrocardiography (ECG) to monitor T. cruzi-infected mice and determine whether ECG markers could be correlated with cardiac function abnormalities. We found that the C3H/HeN:JR combination frequently displayed early onset CCC indicators, such as sinus bradycardia and right bundle branch block, as well as prolonged PQ, PR, RR, ST, and QT intervals in the acute stage. Our model exhibited high levels of cardiac inflammation and enhanced iNOS expression in the acute stage, but denervation did not appear to have a role in pathology. These results demonstrate the potential of the C3H/HeN:JR host:parasite combination as a model for CCC that could be used for screening new compounds targeted at cardiac remodelling and for examining the potential of antiparasitic drugs to prevent or alleviate CCC development and progression.

Frontiers in conduction system pacing: treatment of long PR in patients with heart failure.

Patients with heart failure who have a prolonged PR interval are at a greater risk of adverse clinical outcomes than those with a normal PR interval. Potential mechanisms of harm relating to prolonged PR intervals include reduced ventricular filling and also the potential progression to a higher degree heart block. There has, however, been relatively little work specifically focusing on isolated PR prolongation as a therapeutic target. Secondary analyses of trials of biventricular pacing in heart failure have suggested that PR prolongation is both a prognostic marker and a promising treatment target. However, while biventricular pacing offers an improved activation pattern, it is nonetheless less physiological than native conduction in patients with a narrow QRS duration, and thus, may not be the ideal option for achieving therapeutic shortening of atrioventricular delay. Conduction system pacing aims to preserve physiological ventricular activation and may therefore be the ideal method for ventricular pacing in patients with isolated PR prolongation. Acute haemodynamic experiments and the recently reported His-optimized pacing evaluated for heart failure (HOPE HF) Randomised Controlled Trial demonstrates the potential benefits of physiological ventricular pacing on patient symptoms and left ventricular function in patients with heart failure.

Abstract 12362: High Rates of Mortality in Uganda Following Acute Rheumatic Fever: Findings From a Community-Based Prospective Cohort Study

Introduction: Rheumatic heart disease (RHD) is the largest contributor to cardiac mortality in children worldwide. Little contemporary data exist on its antecedent illness, acute rheumatic fever (ARF). There is an urgent need to understand outcomes following ARF in RHD-endemic settings. We aimed to describe medium-term mortality, disease recurrence, and change in carditis among Ugandan children following ARF diagnosis, and to identify correlates of mortality. Methods: We conducted a prospective cohort study of children diagnosed with definite ARF in 2017-2020 during a community-based incidence study. Patients were enrolled in a national registry and followed with annual review, most recently in August 2022. Kaplan-Meier (KM) survival analysis was used to describe all-cause mortality and individual Cox proportional hazards regression models were used to identify correlates of death. Descriptive statistics were used to characterize changes in carditis. Results: Among 135 children with definite ARF, 22/135 (16.3%) experienced death, 19/135 (14.1%) cardiac death, 5/135 (3.7%) ARF recurrence, and 5/135 (3.7%) surgery over a median (interquartile range) of 4.25 (3.4, 5.1) years. KM analysis saw 14/22 (63.6%) of deaths occur by one year, 16/22 (72.7%) by two years, and 20/22 (90.9%) by three years. The presence of moderate/severe carditis (HR 14.1, 95% CI 4.2, 47.7) and PR prolongation (HR 3.9, 95% CI 1.5, 9.9) at diagnosis was associated with increased cardiac mortality. Among 107 survivors included in echocardiographic sub-analysis, 27/107 (25.2%) had improvement in carditis, 70/107 (65.4%) no change, and 10/107 (9.4%) progression. Conclusions: These are the first contemporary data from sub-Saharan Africa reviewing medium-term outcomes following ARF. Adverse outcome rates exceeded those reported elsewhere. Most decedents already had advanced cardiac involvement upon first ARF diagnosis, as evidenced by PR prolongation and high-grade carditis, suggesting a history of prior undiagnosed ARF recurrences that had already compounded into RHD. These data indicate that a high burden of ARF exists in the community that is undetected by current methods, emphasizing the need for better point-of-care diagnostics to improve early ARF detection.

Abstract 13443: Dead Antegrade Fast Pathway: A Dilemma for Atrioventricular Nodal Re-Entry Tachycardia Ablation

Background: Catheter ablation is the first-line treatment option for symptomatic atrioventricular nodal re-entry tachycardia (AVNRT). Ablation of the slow pathway is preferred over the fast pathway in Typical AVNRT, given that it has a lower risk of heart block. Still, baseline conduction abnormalities and findings on the Electrophysiology (EP) study can alter the ablation strategy. Case: We report a case of a 61-year-old male who was referred to EP clinic for symptomatic suspected AVNRT. His baseline electrocardiogram (EKG) showed normal sinus rhythm with PR prolongation, right bundle branch block, and left anterior fascicular block. EP study was performed, which showed prolonged AH interval with normal HV interval (Figure 1). Typical AVNRT was induced with a premature atrial complex; there was no AV nodal jump before the tachycardia, but it had a long AH interval (Figure 2). There was no evidence of pre-excitation. Discussion: Since there was no antegrade conduction through the fast pathway, conventional slow pathway ablation was not viable as it would make the patient pacemaker (PM)-dependent. Even ablating the fast pathway, though not PM-dependent, would still put him at risk for complete heart block, especially when his antegrade conduction via the slow pathway was unreliable. Hence PM was discussed with the patient before ablation. The fast pathway was mapped and ablated (Figures 3, 4, and 5) without complication, and PM was implanted. Conclusion: This case emphasizes the role of fast pathway ablation in symptomatic AVNRT in patients with conduction abnormalities and the importance of EP study to see the need for PM post-ablation.

Abstract 15936: Prospective Evaluation of Anti-Ro Pregnancies Supports the Utility of Ambulatory Fetal Heart Rate Monitoring in Detecting Fetal Atrioventricular Block

Introduction:: The management of anti-Ro/SSA positive pregnancies is challenging because fetal atrioventricular (AV) block is rare and fetal echo seldom detects reversible injury. Hypothesis: We hypothesized that ambulatory fetal heart rate/rhythm monitoring improves detection of fetal AV block when compared with echo. Methods: Anti-Ro antibody subjects from 21 US centers at less than 20 weeks of gestation were risk stratified into high and low anti-Ro60 and 52 titers at the New York University (NYU) core laboratory. Low titer was defined by previous NYU data demonstrating no fetal AV block in subjects with anti-Ro60 and 52 less than 1000 arbitrary units per mL. High titer subjects performed 3x/day fetal heart rate/rhythm monitoring and underwent weekly or bi-weekly surveillance fetal echos at 18-26 weeks of gestation. Low titer subjects underwent site-specific surveillance. Abnormal fetal heart rate/rhythm monitoring prompted urgent diagnostic fetal echo. All infants received electrocardiograms. Results: We enrolled 405 subjects (fig). None of the 150 (37%) low titer subjects developed fetal AV block. Of 255 high titer subjects, 241 completed surveillance. High titer subjects monitored 44,187 times; 37 (0.08% ) monitoring episodes were deemed abnormal. Urgent fetal echos of the 37 diagnosed 9 with fetal AV block (7 with 2° AV block), 14 with atrial ectopy and 14 with normal rhythms. No fetal AV block, endocardial fibroelastosis or cardiac dysfunction was detected in the 871 surveillance fetal echoes of high titer subjects following normal FHRM. No fetus developed AV block after the surveillance period; one baby had transient prolonged PR interval, which resolved spontaneously. Conclusions: This prospective study suggests that ambulatory fetal heart rate/rhythm FHRM is superior to echo surveillance for fetal AV block, and antibody titers are useful in risk stratification of anti-Ro positive pregnancies.

Abstract 14488: Male Predominant Cardiac Phenotype in Cardiac-Specific Gpd1-l Knockout Mice

Introduction: We reported that a mutation in Glycerol-3-Phosphdate Dehydrogenase-1 Like (GPD1L-A280V) is linked to Brugada Syndrome (BrS). This mutation increases acetylation and reduces surface expression of Nav1.5, and reduces inward Na+ current (INa) in HEK293 cells and rat neonatal cardiac myocytes. Global homozygous knockout of Gpd1-l in mice (Gpd1l-/-) was usually lethal, though we noted increased Nav1.5 acetylation, decreased INa, and pharmacologically inducible arrhythmias in Gpd1l+/- heterozygotes. Cardiac-specific deletion of Gpd1l (cGpd1l-/-) led to ventricular arrhythmias, contractile dysfunction, and a BrS-like ECG phenotype in males. Here, we extend our study to female cGpd1l-/- mice. Methods: cGpd1l -/- mice were generated by crossing floxed (Gpd1l fl/fl ) mice with αMHC-Cre expressing mice. ECGs and echocardiograms (echos) were recorded at 6 and 9 months of age in cGpd1l -/- mice and Gpd1l fl/fl littermate controls. Results: At 9 months of age, male cGpd1l-/- mice compared to Gpd1lfl/fl controls had increased end diastolic and end systolic volumes (EDV, 108±67 vs 27±3 μL, p=0.02; ESV; 80±66 vs 6±2 μL; p=0.03), and markedly reduced ejection fractions (EF, 33±18% vs. 77±7%, p=0.001). Female cGpd1l-/- mice, on the other hand, had no changes to EDV, ESV, or EF (Figure A). The echo changes in male mice were minimal at 6 months. ECG recordings of ~9-month-old cGpd1l-/- male mice compared to Gpd1lfl/fl controls showed prolonged PR interval (52±1.1 vs. 40±2.7 ms; p=0.05) and QRS duration (17.8±1.5 vs. 15.2±1.1 ms; p=0.01) with no change in heart rate (Figure B). ECG parameters were also unchanged in cGpd1l-/- female mice. Conclusions: Cardiac-specific disruption of Gpd1l causes ventricular dysfunction, conduction abnormalities and arrhythmias in male but not female mice. Further investigation into the mechanisms underlying the sex-dependent phenotype of Gpd1l-/-mice and whether this impacts the male predominance of BrS in humans is warranted.

Lamotrigine use and potential for adverse cardiac effects: A retrospective evaluation in a Veteran population

ObjectiveTo identify the impact of lamotrigine (LTG) on cardiac rhythm and conduction abnormalities for Veterans, an especially vulnerable population. BackgroundIn October 2020 the US Food and Drug Administration (FDA) added a new warning to the label of lamotrigine (Lamictal™) regarding its potential to cause cardiac rhythm and conduction abnormalities [1]. This warning came following in vitro data which suggested Class IB antiarrhythmic effects occurring at clinically achievable concentrations of lamotrigine [2]. However, it is unclear whether the in vitro findings will result in adverse clinical outcomes. Our objective was to assess for evidence for adverse clinical outcomes in a vulnerable population and examine for subtler signs of an association between lamotrigine and cardiac rhythm disturbances. MethodsA retrospective chart review was conducted using records between 10-01-2017 and 07-06-2021, identifying patients at the William S. Middleton Memorial Veterans Hospital who were prescribed lamotrigine. Data collected included: dates of lamotrigine initiation or discontinuation, lamotrigine dosing over the time of the prescription and maximum lamotrigine dose, any cardiac-related ICD-10-CM codes or a history of a cardiology appointment, EKGs with any abnormalities or changes, any concomitantly prescribed medications with known potential to cause cardiac abnormalities, any cardiac deaths. This retrospective chart review was approved by the University of Wisconsin-Madison Institutional Review Board. ResultsTwo hundred and thirty-three (189 male) patients with a lamotrigine prescription and 41.2 % (n = 96) of these patients had an EKG performed while prescribed lamotrigine. The average age of patients was 64.3 ± 13.0 (range 29 to 90) years and mean maximum lamotrigine daily dose was 250.8 ± 148.2 mg (range 25 to 800 mg). Nearly half (47.9 %, 46/96) of the patients were prescribed a concomitant sodium channel blocking medication in addition to lamotrigine. Eighty-four of the patients (87.5 %, 84/96) had a cardiac diagnosis, while 12 (12.5 %, 12/96) did not. A total of 12 deaths occurred within the review period, with two cardiac deaths from congestive heart failure. Four cases did not have information on cause of death. No LTG-associated cardiac adverse effects were noted as part of clinical care, though rash was noted in 5 cases. A total of 7 (7.3 %, 7/96) patients were found to have EKG abnormalities potentially related to lamotrigine, including 7.1 % (6/84) of those with a cardiac diagnosis and 8.3 % (1/12) of those without a cardiac diagnosis. ConclusionsWhile recent FDA warnings have suggested caution regarding cardiac complications associated with lamotrigine based on in vitro studies, the clinical implications are uncertain. Despite selecting a particularly vulnerable population, this retrospective chart review did not identify any deaths due to cardiac rhythm or conduction causes, nor demonstrate unambiguous cardiac complications related to lamotrigine. Even using permissive criteria (including any prolonged PR or QTc) to examine for subtle effects, only a low incidence (<10 %) of potential complications was found. Broader implications of this study are limited by the number of patients included and the retrospective nature of the study. Therefore, further studies are warranted to evaluate a link between cardiac complications and the use of lamotrigine, including the role of concomitant medications such as other sodium channel blocking agents and psychotropic medications.

Prolonged PR intervals are associated with epicardial adipose tissue and recurrence after catheter ablation in persistent atrial fibrillation.

Epicardial adipose tissue (EAT) has been reported to promote myocardial fibrosis and to affect intracardiac conduction. The PR interval reflects the conduction from the atria to the Purkinje fibers and may be associated with the EAT volume, especially in persistent atrial fibrillation (AF) patients. We aimed to investigate the relationship between the EAT and PR interval in patients with persistent AF. We enrolled 268 persistent AF patients who underwent catheter ablation (CA) and divided the patients into two groups: the normal PR interval group (PR interval less than 200ms: Group N) and long PR interval group (PR interval 200ms or more: Group L). We then analyzed the association between the total EAT volume around the heart and PR interval and calculated the ratio of the duration of the P wave (PWD) to the PR interval (PWD/PR interval). Moreover, we investigated whether a long PR interval was associated with the outcomes after ablation. The total EAT volume was significantly larger in Group L than Group N (Group N: 131.4 ± 51.8ml vs. Group L: 151.3 ± 63.3ml, p = 0.039). A positive correlation was also observed between the PWD/PR interval and EAT volume in Group L (r = 0.345, p = 0.039). A multivariate analysis also revealed that a long PR interval was independently associated with AF recurrence after CA (hazard ratio [HR] 2.071, p = 0.032). The total EAT volume was associated with a long PR interval, and a long PR interval was a significant risk factor for recurrence after ablation in persistent AF patients.

Electrophysiological basis of cardiac arrhythmia in a mouse model of myotonic dystrophy type 1.

Introduction: Myotonic dystrophy type 1 (DM1) is a multisystemic genetic disorder caused by the increased number of CTG repeats in 3' UTR of Dystrophia Myotonia Protein Kinase (DMPK) gene. DM1 patients experience conduction abnormalities as well as atrial and ventricular arrhythmias with increased susceptibility to sudden cardiac death. The ionic basis of these electrical abnormalities is poorly understood. Methods: We evaluated the surface electrocardiogram (ECG) and key ion currents underlying the action potential (AP) in a mouse model of DM1, DMSXL, which express over 1000 CTG repeats. Sodium current (INa), L-type calcium current (ICaL), transient outward potassium current (Ito), and APs were recorded using the patch-clamp technique. Results: Arrhythmic events on the ECG including sinus bradycardia, conduction defects, and premature ventricular and atrial arrhythmias were observed in DMSXL homozygous mice but not in WT mice. PR interval shortening was observed in homozygous mice while ECG parameters such as QRS duration, and QTc did not change. Further, flecainide prolonged PR, QRS, and QTc visually in DMSXL homozygous mice. At the single ventricular myocyte level, we observed a reduced current density for Ito and ICaL with a positive shift in steady state activation of L-type calcium channels carrying ICaL in DMSXL homozygous mice compared with WT mice. INa densities and action potential duration did not change between DMSXL and WT mice. Conclusion: The reduced current densities of Ito, and ICaL and alterations in gating properties in L-type calcium channels may contribute to the ECG abnormalities in the DMSXL mouse model of DM1. These findings open new avenues for novel targeted therapeutics.

Complete heart block is a significant predictor of mortality in immune checkpoint inhibitor myocarditis

BackgroundImmune checkpoint inhibitor (ICI) myocarditis is associated with significant mortality risk. Electrocardiogram (ECG) changes in ICI myocarditis have strong prognostic value. However the impact of complete heart block (CHB) is not well defined. This study sought to evaluate the impact of CHB on mortality in ICI myocarditis, and to identify clinical predictors of mortality and CHB incidence.MethodsWe conducted a retrospective cohort study of patients with ICI myocarditis at three Mayo Clinic sites from 1st January 2010 to 31st September 2022 to evaluate mortality rates at 180 days. Clinical, laboratory, ECG, echocardiographic, and cardiac magnetic resonance imaging (CMR) characteristics were assessed. Cox and logistic regression were performed for associations with mortality and CHB respectively.ResultsOf 34 identified cases of ICI myocarditis, 7 (20.6%) had CHB. CHB was associated with higher mortality (HR 7.41, p = 0.03, attributable fraction 86.5%). Among those with CHB, troponin T (TnT) < 1000 ng/dL, low white blood cell count and high ventricular rate at admission were protective. There was trend towards increased survival among patients who underwent permanent pacemaker insertion (p = 0.051), although most experienced device lead complications. Factors associated with development of CHB included prolonged PR and QRS intervals and low Sokolow Lyon Index. Where these were normal and TnT was < 1000 ng/dL, no deaths occurred. Impaired myocardial longitudinal strain was sensitive for ICI myocarditis but was not prognostically significant.ConclusionThere is a strong temporal association between CHB and early mortality in people with ICI myocarditis. Focusing on arrhythmogenic complications can be helpful in predicting outcomes for this group of critically ill individuals.

Reversible Pulsed Electrical Fields as an In Vivo Tool to Study Cardiac Electrophysiology: The Advent of Pulsed Field Mapping.

During electrophysiological mapping of tachycardias, putative target sites are often only truly confirmed to be vital after observing the effect of ablation. This lack of mapping specificity potentiates inadvertent ablation of innocent cardiac tissue not relevant to the arrhythmia. But if myocardial excitability could be transiently suppressed at critical regions, their suitability as targets could be conclusively determined before delivering tissue-destructive ablation lesions. We studied whether reversible pulsed electric fields (PFREV) could transiently suppress electrical conduction, thereby providing a means to dissect tachycardia circuits in vivo. PFREV energy was delivered from a 9-mm lattice-tip catheter to the atria of 12 swine and 9 patients, followed by serial electrogram assessments. The effects on electrical conduction were explored in 5 additional animals by applying PFREV to the atrioventricular node: 17 low-dose (PFREV-LOW) and 10 high-dose (PFREV-HIGH) applications. Finally, in 3 patients manifesting spontaneous tachycardias, PFREV was applied at putative critical sites. In animals, the immediate post-PFREV electrogram amplitudes diminished by 74%, followed by 78% recovery by 5 minutes. Similarly, in patients, a 69.9% amplitude reduction was followed by 84% recovery by 3 minutes. Histology revealed only minimal to no focal, superficial fibrosis. PFREV-LOW at the atrioventricular node resulted in transient PR prolongation and transient AV block in 59% and 6%, while PFREV-HIGH caused transient PR prolongation and transient AV block in 30% and 50%, respectively. The 3 tachycardia patients had atypical atrial flutters (n=2) and atrioventricular nodal reentrant tachycardia. PFREV at putative critical sites reproducibly terminated the tachycardias; ablation rendered the tachycardias noninducible and without recurrence during 1-year follow-up. Reversible electroporation pulses can be applied to myocardial tissue to transiently block electrical conduction. This technique of pulsed field mapping may represent a novel electrophysiological tool to help identify the critical isthmus of tachycardia circuits.

Neonatal Cardiac Arrest Following Lacosamide Treatment: A Case Report

BackgroundLacosamide is an antiepileptic drug with US Food and Drug Administration approval for the treatment of partial-onset seizures in patients older than one month. Lacosamide works by selective enhancement of proteins that induce preferential slow promotion of sodium channels to the hyperpolarized inactive state. Lacosamide is generally well-tolerated; however, clinical and nonclinical studies have linked its use with cardiac side effects including PR prolongation and atrioventricular (AV) block. ResultsWe present the case of a three-week-old female neonatal patient born at 25 weeks’ gestation who developed second-degree AV heart block and cardiac arrest after initiating lacosamide therapy. The patient was being treated for neonatal seizure complicated by intraventricular hemorrhage (grade II) and electrolyte disturbances with phenobarbital, levetiracetam, and phenytoin. Before addition of lacosamide therapy, the patient had an unremarkable electrocardiogram and no known cardiac risk factors for lacosamide. After medication discontinuation, the patient experienced no reoccurring episodes or other cardiac events. ConclusionUse of lacosamide for neonatal populations is currently under evaluation. This is the first report of adverse cardiac event (AV block) in the setting of neonatal lacosamide use. Risk of future adverse cardiac events should be evaluated when determining the safety and efficacy of lacosamide in the neonatal population.