Danna Spears

The Effect of Air Pollution on Spatial Dispersion of Myocardial Repolarization in Healthy Human Volunteers

OBJECTIVES We tested the hypothesis that exposure to concentrated ambient particles (CAP) and/or ozone (O(3)) would increase dispersion of ventricular repolarization. BACKGROUND Elevated levels of air pollution are associated with cardiac arrhythmias through mechanisms yet to be elucidated. METHODS Each of 25 volunteers (18 to 50 years of age) had four 2-h exposures to 150 μg/m(3) CAP; 120 parts per billion O(3); CAP + O(3); and filtered air (FA). Exposure-induced changes (Δ = 5-min epochs at end-start) in spatial dispersion of repolarization were determined from continuous 12-lead electrocardiographic recording. RESULTS Spatial dispersion of repolarization assessed by corrected ΔT-wave peak to T-wave end interval increased significantly for CAP + O(3) (0.17 ± 0.03, p < 0.0001) exposure only, remaining significant when factoring FA (CAP + O(3) - FA) as control (0.11 ± 0.04, p = 0.013). The influence on repolarization was further verified by a significant increase in ΔQT dispersion (for CAP + O(3) compared with FA (5.7 ± 1.4, p = 0.0002). When the low-frequency to high-frequency ratio of heart rate variability (a conventional representation of sympathetic-parasympathetic balances) was included as a covariate, the effect estimate was positive for both corrected ΔT-wave peak to T-wave end interval (p = 0.002) and ΔQT dispersion (p = 0.038). When the high-frequency component (parasympathetic heart rate modulation) was included as a covariate with corrected ΔT-wave peak to T-wave end interval, the effect estimate for high frequency was inverse (p = 0.02). CONCLUSIONS CAP + O(3) exposure alters dispersion of ventricular repolarization in part by increasing sympathetic and decreasing parasympathetic heart rate modulation. Detection of changes in repolarization parameters, even in this small cohort of healthy individuals, suggests an underappreciated role for air pollutants in urban arrhythmogenesis.

A mutation in the atrial-specific myosin light chain gene (MYL4) causes familial atrial fibrillation

Atrial fibrillation (AF), the most common arrhythmia, is a growing epidemic with substantial morbidity and economic burden. Mechanisms underlying vulnerability to AF remain poorly understood, which contributes to the current lack of highly effective therapies. Recognizing mechanistic subtypes of AF may guide an individualized approach to patient management. Here, we describe a family with a previously unreported syndrome characterized by early-onset AF (age <35 years), conduction disease and signs of a primary atrial myopathy. Phenotypic penetrance was complete in all mutation carriers, although complete disease expressivity appears to be age-dependent. We show that this syndrome is caused by a novel, heterozygous p.Glu11Lys mutation in the atrial-specific myosin light chain gene MYL4. In zebrafish, mutant MYL4 leads to disruption of sarcomeric structure, atrial enlargement and electrical abnormalities associated with human AF. These findings describe the cause of a rare subtype of AF due to a primary, atrial-specific sarcomeric defect.

Bipolar ablation for deep intra-myocardial circuits: human ex vivo development and in vivo experience.

AIMS Current conventional ablation strategies for ventricular tachycardia (VT) aim to interrupt reentrant circuits by creating ablation lesions. However, the critical components of reentrant VT circuits may be located at deep intramural sites. We hypothesized that bipolar ablations would create deeper lesions than unipolar ablation in human hearts. METHODS AND RESULTS Ablation was performed on nine explanted human hearts at the time of transplantation. Following explant, the hearts were perfused by using a Langendorff perfusion setup. For bipolar ablation, the endocardial catheter was connected to the generator as the active electrode and the epicardial catheter as the return electrode. Unipolar ablation was performed at 50 W with irrigation of 25 mL/min, with temperature limit of 50°C. Bipolar ablation was performed with the same settings. Subsequently, in a patient with an incessant septal VT, catheters were positioned on the septum from both the ventricles and radiofrequency was delivered with 40 W. In the explanted hearts, there were a total of nine unipolar ablations and four bipolar ablations. The lesion depth was greater with bipolar ablation, 14.8 vs. 6.1 mm (P < 0.01), but the width was not different (9.8 vs. 7.8 mm). All bipolar lesions achieved transmurality in contrast to the unipolar ablations. In the patient with a septal focus, bipolar ablation resulted in termination of VT with no inducible VTs. CONCLUSION By using a bipolar ablation technique, we have demonstrated the creation of significantly deeper lesions without increasing the lesion width, compared with standard ablation. Further clinical trials are warranted to detail the risks of this technique.

Relationship of bipolar and unipolar electrogram voltage to scar transmurality and composition derived by magnetic resonance imaging in patients with nonischemic cardiomyopathy undergoing VT ablation

BACKGROUND Bipolar voltage mapping has a role in defining endocardial-based scar in postinfarct patients undergoing ventricular tachycardia catheter ablation. The utility of bipolar and unipolar voltages in characterizing scar has not been evaluated in patients with nonischemic cardiomyopathy. OBJECTIVE To relate left ventricular (LV) endocardial bipolar and unipolar voltages in these patients to scar transmurality (endocardial vs nonendocardial) and composition (homogeneous core vs heterogeneous gray). METHODS Ten consecutive cardiomyopathy patients undergoing endocardial LV tachycardia ablation were included (age 48 ± 14 years; left ventricular ejection fraction 43% ± 15%). Preablation late gadolinium-enhanced magnetic resonance imaging was used to quantify core and gray scar by using signal-intensity thresholding. Electroanatomic LV endocardial mapping provided bipolar and unipolar voltages. Electroanatomic maps and late gadolinium-enhanced magnetic resonance imaging were rigidly registered in order to relate voltage to scar (registration error 3.6 ± 2.9 mm). RESULTS Bipolar voltage was lower in endocardial core than in no scar (P <.001). Unipolar voltage was lower in endocardial core and nonendocardial core than in no scar (P <.001). Endocardial and nonendocardial gray scar had an effect similar to that of core in reducing bipolar and unipolar voltages (P <.001). The mass of healthy myocardium and endocardial core scar independently predicted bipolar and unipolar voltages using general estimating equation modeling. With receiver operating characteristic curve analysis, bipolar voltage >1.9 mV and unipolar voltage <6.7 mV had a high negative predictive value (91%) for detecting nonendocardial scar from either endocardial scar or no scar. CONCLUSIONS In patients with nonischemic cardiomyopathy, LV endocardial bipolar voltage is dependent on endocardial core and gray scar, while the unipolar voltage is influenced by core and gray scar across the LV wall as defined by late gadolinium-enhanced magnetic resonance imaging.

Genetics of inherited primary arrhythmia disorders.

A sudden unexplained death is felt to be due to a primary arrhythmic disorder when no structural heart disease is found on autopsy, and there is no preceding documentation of heart disease. In these cases, death is presumed to be secondary to a lethal and potentially heritable abnormality of cardiac ion channel function. These channelopathies include congenital long QT syndrome, catecholaminergic polymorphic ventricular tachycardia, Brugada syndrome, and short QT syndrome. In certain cases, genetic testing may have an important role in supporting a diagnosis of a primary arrhythmia disorder, and can also provide prognostic information, but by far the greatest strength of genetic testing lies in the screening of family members, who may be at risk. The purpose of this review is to describe the basic genetic and molecular pathophysiology of the primary inherited arrhythmia disorders, and to outline a rational approach to genetic testing, management, and family screening.

Patient Outcomes From a Specialized Inherited Arrhythmia Clinic

Background—Patients with inherited arrhythmia syndromes are at an increased risk of sudden cardiac death (SCD). Specialized inherited arrhythmia clinics were founded to optimize management and prevention of SCD in this population. However, the clinical effectiveness of these clinics has never been evaluated. Methods and Results—Clinical outcome data of patients referred to a specialized inherited arrhythmia clinic between 2005 and 2014 for a possible primary electric syndrome or arrhythmogenic right ventricular cardiomyopathy were analyzed. Of 720 patients evaluated, 278 received a definite or probable diagnosis and received long-term management in the inherited arrhythmia clinic. All patients diagnosed with long QT syndrome and catecholaminergic polymorphic ventricular tachycardia received routine &bgr;-blocker therapy and demonstrated >90% long-term compliance. In patients with arrhythmogenic right ventricular cardiomyopathy, those demonstrating an arrhythmia burden on Holter or treadmill testing received &bgr;-blocker therapy (17%). In diagnosed channelopathy or arrhythmogenic right ventricular cardiomyopathy index cases, 44 patients received secondary prevention implantable cardioverter-defibrillators (long QT syndrome, 9; Brugada syndrome, 8; catecholaminergic polymorphic ventricular tachycardia, 3; short QT syndrome, 1; and arrhythmogenic right ventricular cardiomyopathy, 23). Median follow-up was 4.1 years with 43% having a follow-up period of >5 years. SCD occurred in a single patient (annualized risk of SCD, 0.1% per year). In individuals determined to have clinical or genetic disease by cascade screening, no SCD has occurred over a median follow-up of 5.6 years (55%, >5 years). Low event rates occurred despite a low rate (4.0%) of primary prevention implantable cardioverter-defibrillator utilization. Conclusions—Longitudinal care in a specialized inherited arrhythmia clinic is associated with a low incidence of SCD and a low rate of primary implantable cardioverter-defibrillator utilization in patients with inherited arrhythmia syndromes.

Whole exome sequencing identified 1 base pair novel deletion in BCL2-associated athanogene 3 (BAG3) gene associated with severe dilated cardiomyopathy (DCM) requiring heart transplant in multiple family members.

Dilated cardiomyopathy (DCM) is characterized by dilation and impaired contraction of the left ventricle or both ventricles. Among hereditary DCM, the genetic causes are heterogeneous, and include mutations encoding cytoskeletal, nucleoskeletal, mitochondrial, and calcium‐handling proteins. We report three severely affected males, in a four‐generation pedigree, with DCM phenotype who underwent cardiac transplant. Cardiomegaly with marked biventricular dilation and fibrosis were noticeable histopathological findings. The affected males had tested negative on a 46‐gene pancardiomyopathy panel. Whole Exome Sequencing (WES) was performed to reveal mutation in the gene responsible in generation of DCM phenotypes. The 1‐bp (Chr10:121435979delC; c.913delC) novel heterozygous deletion in exon 4 of BAG3, was identified in three affected males, resulted in frame‐shift and a premature termination codon (p.Met306‐Stop) producing a truncated BAG3 protein lacking functionally important PXXP and BAG domains. WES data were further utilized to map 10 SNP markers around the discovered mutation to generate shared disease haplotype in all affected individuals encompassing 11 Mb on 10q25.3–26.2 harboring BAG3. Finally genotypes were inferred for the unavailable/deceased individuals in the pedigrees. Here we propose that Chr10:121435979delC in BAG3 is a causal mutation in these subjects. Our and earlier studies indicate that BAG3 mutations are associated with DCM phenotypes. BAG3 should be added to cardiomyopathy gene panels for screening of DCM patients, and patients previously considered gene elusive should undergo sequencing of the BAG3 gene.

Proving the innocence of a “malignant” coronary artery: Calling dobutamine stress CT for the defence!

a Division of Cardiology, Toronto Congenital Cardiac Center for Adults, Toronto General Hospital, Toronto ON, Canada b Division of Cardiology, Heritable Arrhythmia Program, Toronto General Hospital, Toronto ON, Canada c Division of Cardiac Surgery, Hospital for Sick Children and Toronto General Hospital, Toronto ON, Canada d Joint Division of Medical Imaging, Toronto General Hospital, Toronto ON, Canada

Rapid Device-Detected Nonsustained Ventricular Tachycardia in the Risk Stratification of Hypertrophic Cardiomyopathy.

Nonsustained ventricular tachycardia (NSVT) detected by ambulatory Holter (Holter NSVT) is a major risk factor for sudden cardiac death in hypertrophic cardiomyopathy (HCM). We hypothesized that the prognostic utility of Holter NSVT in HCM would improve with prolonged monitoring and a higher heart rate cut‐off for detection.

Temporal-component analysis of diastolic electrograms in ventricular tachycardia differentiates nonvulnerable regions of the circuit

BACKGROUND Successful activation mapping of ventricular tachycardia (VT) is dependent on the identification of a region of diastolic conduction by use of point-by-point sequential mapping. It is important to identify the site of transition from diastolic conduction to systolic activation of healthy myocardium (exit site) and differentiate this from nonvulnerable regions of the circuit. OBJECTIVE We sought to determine the temporal and component characteristics of exit-site electrograms using simultaneous multielectrode endocardial mapping and to differentiate them from bystander sites during activation mapping. METHODS Sixteen VTs induced in 12 patients with ischemic cardiomyopathy who underwent multielectrode mapping during VT performed with a custom-made 112-bipolar-electrode endocardial array were analyzed retrospectively. The activation sequence in systole and diastole was annotated, and the timing at exit and bystander sites of the near-field component was characterized in relation to surface electrocardiogram activation and to the far-field component. Spectral content of bipolar electrograms recorded at these sites was additionally analyzed to identify the near-field to far-field interval. RESULTS The mean activation time at exit sites was 60.0 ± 31.5 ms (range 21-113 ms) ahead of surface QRS but was not significantly different from bystander sites (72.0 ± 55.0 ms, P = .63). However, the time delay from local to far-field activity was significantly lower at exit sites than at bystander sites (24.9 ± 15.6 vs. 86.6 ± 92.0 ms, P = .003), which was confirmed by spectral analysis (10.0 ± 13.1 vs. 89.0 ± 64.5 ms, P = .003). CONCLUSION Our analysis suggests that temporal-component analysis of diastolic electrograms during activation mapping of VT provides a practical method to differentiate nonvulnerable sites from the exit site without the need for pacing maneuvers.