Interdigitating Myocardial Tongues in Pediatric Cardiac Fibromas: Plausible Substrate for Ventricular Tachycardia and Cardiac Arrest.

OBJECTIVES: This study sought to evaluate for the presence of and characterize the interdigitating and entrapped myocardium within cardiac fibromas (CF) and correlate tissue findings with symptoms and surgical outcomes. BACKGROUND: The mechanism of ventricular tachycardia (VT) in CF is unclear. The authors hypothesized that CF harbor tongues of interdigitating myocardium, which could be a substrate for episodes of arrhythmia analogous to peri-infarct zones. METHODS: A total of 29 patients (14 boys) with CF were identified; all subjects had undergone at least partial tumor resection. A semiquantitative grading system was used to assess the degree of myocardial interdigitation and entrapment, myocyte morphology (hematoxylin and eosin stain and immunohistochemical stain for desmin), tumor collagen density, and cellularity (trichrome stain). The subjects' ages at presentation, types of arrhythmia, and responses to surgery were correlated with histology. RESULTS: CF consistently demonstrated interdigitating and entrapped myocardium, and the extent correlated negatively with age at surgery, as did cellularity, whereas collagen increased with age. Median age at arrhythmia recognition was 8 months. Sustained VT was present in 18 of 29 patients (62%), and 5 of 6 patients with prenatally diagnosed conditions developed VT before 8 months. All 8 patients who experienced cardiac arrest had clinically significant arrhythmia events. Sustained arrhythmia episodes correlated with more diffuse myocyte interdigitation. Ten patients had abnormal karyotype: chromosomes 9 (n = 3) and 3 (n = 1) deletions; isolated translocations: t(4;13), t(5;11) and t(1;9); and undefined aberrations (n = 3). All patients who underwent complete resection were cured of arrhythmias, whereas 2 of 14 patients who had subtotal resections had recurrence, with resolution following re-resection in 1 patient. CONCLUSIONS: Interdigitating myocardium represents a potential histopathologic substrate for VT and cardiac arrest in CF, which may also explain the occasional recurrence of arrhythmia following incomplete resection.

Effectiveness of high rate and delayed detection ICD programming by race: A MADIT-RIT substudy.

INTRODUCTION: Data on inappropriate and appropriate ICD therapy, and efficacy of ICD programing strategies by race are limited. METHODS: In MADIT-RIT, we evaluated the risk of ICD therapy by race, and the efficacy of high rate cut-off ventricular tachycardia (VT) zone ≥200 beats per minute (bpm) (Arm B), or 60 seconds delay in VT zone 170-199 bpm (Arm C), compared to 2.5 seconds delay at 170 bpm (Arm A) among black and white patients. RESULTS: MADIT-RIT enrolled 272 (20%) black and 1119 (80%) white patients. The risk of inappropriate therapy was similar among blacks and whites, HR 1.25, 95% CI (0.82-1.93), P  =  0.30. High rate cut-off or delayed VT therapy was associated with significant reductions in inappropriate therapy among whites, Arm B versus Arm A, HR 0.15, 95% CI (0.08-0.29), P < 0.0001, Arm C versus Arm A, HR 0.19, 95% CI (0.11-0.33), P < 0.001, and black individuals Arm B versus Arm A, HR 0.24, 95% CI (0.01-0.56), P  =  0.0001, Arm C versus Arm A, HR 0.30, 95% CI (0.13-0.68), P  =  0.004, P interaction > 0.10). However, delayed VT therapy was associated with a trend toward greater reduction in appropriate therapy in black individuals, HR 0.08, 95% CI (0.03-0.27), P < 0.0001 relative to white individuals, HR 0.27, 95% CI (0.16-0.43), P < 0.0001, P interaction  =  0.077. CONCLUSION: In MADIT-RIT, high rate and delayed detection ICD programming provided similar benefit with reductions in both inappropriate therapy and unnecessary appropriate therapy among black and white individuals. CLINICALTRIALS. GOV IDENTIFIER: NCT00947310.

Incidence and predictors of sudden arrhythmic death or ventricular tachyarrhythmias after acute coronary syndrome: An asian perspective.

BACKGROUND: Current data on the risk of sudden arrhythmic death (SAD) and ventricular tachyarrhythmias (VTs) after acute coronary syndrome (ACS) in the Asian population are limited. OBJECTIVE: The purpose of this study was to investigate the incidence and predictors of SAD or VT after ACS in a contemporary cohort of Chinese patients in the era of early revascularization. METHODS: Consecutive patients admitted to our unit for ACS from 2010 to 2015 were retrospectively reviewed. RESULTS: A total of 918 patients (74.8% male, mean age 65.9 ± 13.4 years) were included in the study. Of these patients, 864 (94.1%) survived to discharge. After a mean of 34.1 ± 21.8 months, 42 (4.9%) had SAD or VT. The event rate was 0.46% in month 1, 0.26% per month in the months 2 to 6, 0.15% per month in months 6 to 12, and 1.23% per year from the second year onward. In multivariate analysis, early VT (hazard ratio [HR] 5.78, 95% confidence interval [CI] 2.63-12.72, P < .01), left ventricular ejection fraction ≤35% (HR 1.96, 95% CI 1.03-3.73, P = .04), prior coronary artery disease (HR 2.50, 95% CI 1.29-4.82, P < .01), triple-vessel disease (HR 3.69, 95% CI 1.81-7.54, P < .01), and chronic kidney disease (HR 2.43, 95% CI 1.21-4.92, P = .01) independently predicted SAD or VT. CONCLUSION: This study reports the rate of SAD or VT among Asian patients after ACS in the era of early revascularization and optimal medical therapy. Aggressive preventive measures should be considered for patients with multiple risk factors for SAD or VT, especially in the initial period after ACS.

R-wave peak time at lead II in Chinese healthy adults.

BACKGROUND: Wide QRS complex tachycardia (WCT) is a common arrhythmia. How to differentiate between WCTs is a challenge in clinical practice. Recently R-wave peak time (RWPT) at lead II was reported to be a helpful and simple tool for differentiating WCTs. However, it has remained unknown about the reference range of RWPT at lead II. In present study, we aimed to investigate the reference range of RWPT at lead II in Chinese healthy adults. METHODS: A retrospective study was conducted in the First Affiliated Hospital of Shantou University Medical College in Southern China. Two thousand four hundred healthy adults aged 21-80 years with no history of structural heart diseases were included. RWPT at lead II was determined. RESULTS: Of 2400 healthy adults, 1200 men and 1200 women were included. The differences of age, mean heart rate and mean QRS duration at lead II between male and female were not significant. RWPT ranged from 16 to 42 ms in male while from 16 to 44 ms in female. The 95 % reference range of RWPT in normal male and female are 19.91 ~ 39.55 ms and 21.75 ~ 37.67 ms, respectively. Compared with the female, the male had a significantly longer RWPT at lead II (29.73 ± 5.01 ms vs 29.71 ± 4.06 ms in female, P = 0.000). CONCLUSION: Our study showed that RWPT at lead II is different between male and female. The male had a significantly longer RWPT at lead II than the female.

Inflammation, Obesity and the Metabolic Syndrome. Implications in Hispanics.

We report clinical and molecular mechanisms relating the process of inflammation involved in the progression of obesity and the metabolic syndrome, emphasizing the cardiovascular problems developed in Hispanic populations. Namely, the incidence, component characteristics and complications of obesity and metabolic syndrome in island Puerto Ricans are described and evidence is presented supporting the fact that the metabolic syndrome may be milder in Puerto Rico than in the mainland United States because it is characterized by less aggressive coronary artery disease and a relatively normal lipid profile. Moreover, data supports the fact that increased serum cholesterol levels produce less myocardial infarctions in Puerto Rico than in mainland Hispanics and Caucasians. In addition, the incidence of ventricular tachycardia, a complication caused by remodeling and ischemia of the heart, may be lower in Puerto Rico than in the United States, although the prevalence of the metabolic syndrome is higher in the island. On the other hand, there is evidence of a rising epidemic of obesity and vascular inflammation in Puerto Rico that suggests that cardiovascular morbidity and mortality in the island will continue to increase in the future decades.

Phenotypic analysis of arrhythmogenic cardiomyopathy in the Hutterite population: role of electrocardiogram in identifying high-risk desmocollin-2 carriers.

BACKGROUND: The p.Gln554X mutation in desmocollin-2 (DSC2) is prevalent in ≈10% of the Hutterite population. While the homozygous mutation causes severe biventricular arrhythmogenic right ventricular cardiomyopathy, the phenotypic features and prognosis of heterozygotes remain incompletely understood. METHODS AND RESULTS: Eleven homozygotes (mean age 32±8 years, 45% female), 28 heterozygotes (mean age 40±15 years, 50% female), and 22 mutation-negatives (mean age 43±17 years, 41% female) were examined. Diagnostic testing was performed as per the arrhythmogenic right ventricular cardiomyopathy modified Task Force Criteria. Inverted T waves in the right precordial leads on ECG were seen in all homozygotes but not in their counterparts (P<0.001). Homozygotes had higher median daily premature ventricular complex burden than did heterozygotes or mutation-negatives (1407 [IQR 1080 to 2936] versus 2 [IQR 0 to 6] versus 6 [IQR 0 to 214], P=0.0002). Ventricular tachycardia was observed in 60% of homozygotes but in none of the remaining individuals (P<0.001). On cardiac magnetic resonance imaging, homozygotes had significantly larger indexed end-diastolic volumes (right ventricular: 122±24 versus 83±17 versus 83±12 mL/m(2), P<0.0001; left ventricular: 93±18 versus 76±13 versus 80±11 mL/m(2), P=0.0124) and lower ejection fraction values compared with heterozygotes and mutation-negatives (right ventricular ejection fraction: 41±9% versus 59±9% versus 61±6%, P<0.0001; left ventricular ejection fraction: 53±8% versus 65±5% versus 64±5%, P<0.0001). Most affected individuals lacked right ventricular wall motion abnormalities. Thus, few met cardiac magnetic resonance imaging task force criteria. CONCLUSIONS: The ECG reliably identifies homozygous p.Gln554X carriers and may be useful as an initial step in the screening of high-risk Hutterites. The cardiac phenotype of heterozygotes appears benign, but further prospective follow-up of their arrhythmic risk is needed.

Probability of a shockable presenting rhythm as a function of EMS response time.

INTRODUCTION: Survival from cardiac arrest is associated with having a shockable presenting rhythm (VF/pulseless VT) upon EMS arrival. A concern is that several studies have reported a decline in the incidence of VF/PVT over the past few decades. One plausible explanation is that contemporary cardiovascular therapies, such as increased use of statin and beta blocker drugs, may shorten the duration of VF/PVT after arrest. As a result, EMS response time would become an increasingly important factor in the likelihood of a shockable presenting rhythm, and consequently, cardiac arrest survival. OBJECTIVE: To develop a model describing the likelihood of shockable presenting rhythm as a function of EMS response time. METHODS: We conducted a retrospective observational study of cardiac arrest using the North Carolina Prehospital Care Reporting System (PreMIS). Inclusionary criteria consisted of adult patients suffering nontraumatic cardiac arrests witnessed by a layperson between January 1 and June 30, 2012. Patients defibrillated prior to EMS arrival were excluded. Chi-square and t-tests were used to analyze the relationship between shockable presenting rhythm and patient age, gender, and race; response time measured as elapsed minutes between 9-1-1 call receipt and scene arrival; and bystander CPR. Logistic regression was used to calculate the adjusted odds ratio (OR) of shockable presenting rhythm as a function of response time while controlling for statistically significant covariates. RESULTS: A total of 599 patients met inclusion criteria. Overall, VF/PVT was observed in 159 patients (26.5%). VF/PVT was less likely with increasing EMS response time (OR 0.92, 95% CI = 0.87-0.97, p < 0.01) and age (OR 0.98, 95% CI = 0.97-0.99, p < 0.01), while males (OR 1.98, 95% CI = 1.29-3.03, p < 0.01) and Caucasians (OR 1.86, 95% CI = 1.17-2.95, p < 0.01) were more likely to have shockable presenting rhythm. Bystander CPR was not associated with shockable presenting rhythm, although EMS response time was longer among patients with bystander CPR compared to those without (9.83 vs. 8.83 minutes, p < 0.01). CONCLUSIONS: We found that for every one minute of added ambulance response time, the odds of shockable presenting rhythm declined by 8%. This information could prove useful for EMS managers tasked with developing EMS system response strategies for cardiac arrest management.

Heart rate is associated with red blood cell fatty acid concentration: the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) study.

BACKGROUND: Consumption of omega-3 fatty acids (FAs) is associated with a reduction in deaths from coronary heart disease, arrhythmia, and sudden death. Although these FAs were originally thought to be antiatherosclerotic, recent evidence suggests that their benefits are related to reducing risk for ventricular arrhythmia and that this may be mediated by a slowed heart rate (HR). METHODS: The study was conducted in Alaskan Eskimos participating in the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study, a population experiencing a dietary shift from unsaturated to saturated fats. We compared HR with red blood cell (RBC) FA content in 316 men and 391 women ages 35 to 74 years. RESULTS: Multivariate linear regression analyses of individual FAs with HR as the dependent variable and specific FAs as covariates revealed negative associations between HR and docosahexaenoic acid (22:6n-3; P = .004) and eicosapentaenoic acid (20:5n-3; P = .009) and positive associations between HR and palmitoleic acid (16:1n-7; P = .021), eicosanoic acid (20:1n9; P = .007), and dihomo-gamma-linolenic acid (DGLA; 20:3n-6; P = .021). Factor analysis revealed that the omega-3 FAs were negatively associated with HR (P = .003), whereas a cluster of other, non-omega-3 unsaturated FAs (16:1, 20:1, and 20:3) was positively associated. CONCLUSIONS: Marine omega-3 FAs are associated with lower HR, whereas palmitoleic and DGLA, previously identified as associated with saturated FA consumption and directly related to cardiovascular mortality, are associated with higher HR. These relations may at least partially explain the relations between omega-3 FAs, ventricular arrhythmia, and sudden death.

Defining the cellular phenotype of "ankyrin-B syndrome" variants: human ANK2 variants associated with clinical phenotypes display a spectrum of activities in cardiomyocytes.

BACKGROUND: Mutations in the ankyrin-B gene (ANK2) cause type 4 long-QT syndrome and have been described in kindreds with other arrhythmias. The frequency of ANK2 variants in large populations and molecular mechanisms underlying the variability in the clinical phenotypes are not established. More importantly, there is no cellular explanation for the range of severity of cardiac phenotypes associated with specific ANK2 variants. METHODS AND RESULTS: We performed a comprehensive screen of ANK2 in populations (control, congenital arrhythmia, drug-induced long-QT syndrome) of different ethnicities to discover unidentified ANK2 variants. We identified 7 novel nonsynonymous ANK2 variants; 4 displayed abnormal activity in cardiomyocytes. Including the 4 new variants, 9 human ANK2 loss-of-function variants have been identified. However, the clinical phenotypes associated with these variants vary strikingly, from no obvious phenotype to manifest long-QT syndrome and sudden death, suggesting that mutants confer a spectrum of cellular phenotypes. We then characterized the relative severity of loss-of-function properties of all 9 nonsynonymous ANK2 variants identified to date in primary cardiomyocytes and identified a range of in vitro phenotypes, including wild-type, simple loss-of-function, and severe loss-of-function activity, seen with the variants causing severe human phenotypes. CONCLUSIONS: We present the first description of differences in cellular phenotypes conferred by specific ANK2 variants. We propose that the various degrees of ankyrin-B loss of function contribute to the range of severity of cardiac dysfunction. These data identify ANK2 variants as modulators of human arrhythmias, provide the first insight into the clinical spectrum of "ankyrin-B syndrome," and reinforce the role of ankyrin-B-dependent protein interactions in regulating cardiac electrogenesis.

Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death.

BACKGROUND: Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. METHODS AND RESULTS: Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca(v beta2b)), CACNA2D1 (Ca(v alpha2delta1)), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca(v)1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals < or = 360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the alpha1- and beta2b-subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca(v)1.2 channels but normal trafficking of channels containing G490R Ca(v)1.2 or S481L Ca(v beta2b)-subunits. CONCLUSIONS: This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

Characteristics of Chinese patients with symptomatic Brugada syndrome in Taiwan.

Since 1992, the Brugada syndrome has been increasingly recognized worldwide, although its incidence and distribution remain unclear. In Asia, several cases have been reported in Japan, Thailand, Singapore, and Vietnam. However, little information is available from the Chinese population. Since June 1997, we have identified 10 patients with the diagnosis of the Brugada syndrome from six hospitals in Taiwan. All patients were male with the mean age of 46 +/- 7 years (range 36-61). They all had a normal chemistry profile, coronary angiography and echocardiography. Clinical presentations varied from seizure and syncope to sudden cardiac death. MRI and ultrafast CT of the heart did not show any abnormalities. Sustained ventricular tachycardia/ventricular fibrillation (VF) was induced in 7 of 8 patients who underwent an electrophysiologic study. The pharmacological provocation test was positive in 4 of 5 patients. One of the 4 patients who had a genetic study showed SCN5A gene mutation. An implantable cardioverter defibrillator (ICD) was implanted in 8 patients. During a mean follow-up of 29 +/- 17 months (range 2-54), 3 of 8 patients who had an ICD received appropriate ICD discharges after implantation. These 3 patients who were subsequently treated with antiarrhythmic agents have had no further recurrent ICD discharges. Two patients who refused ICD implantation are alive and well without taking antiarrhythmic agents. Our study showed that the clinical characteristics of our patients are similar to those described in the literature and that ICD is an effective treatment modality for patients with recurrent VF. However, antiarrhythmic agents may be beneficial for suppressing arrhythmia recurrences in selected patients.

Autosomal recessive catecholamine- or exercise-induced polymorphic ventricular tachycardia: clinical features and assignment of the disease gene to chromosome 1p13-21.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (PVT) is characterized by episodes of syncope, seizures, or sudden death in response to physiological or emotional stress. In 2 families with autosomal dominant inheritance, the disease gene was mapped to chromosome 1q42-43. The objectives of this study were to characterize the clinical features of the disease in a Bedouin tribe from Israel and to map the disease gene. METHODS AND RESULTS: In this Bedouin tribe, 9 children (age, 7+/-4 years) from 7 related families have died suddenly during the past decade, and 12 other children suffered from recurrent syncope and seizures starting at the age of 6+/-3 years. Parents of affected individuals were asymptomatic and were all related (first-, second-, or third-degree cousins). Segregation analysis suggested autosomal recessive inheritance. All 12 symptomatic patients and 1 asymptomatic sibling (mean age, 13+/-7 years) were found to have a relative resting bradycardia (64+/-13 bpm, versus 93+/-12 bpm in the unaffected siblings), as well as PVT induced by treadmill or isoproterenol infusion and appearing at a mean sinus rate of 110+/-10 bpm. Patients responded favorably to treatment with beta-blockers. A genome-wide search using polymorphic DNA markers mapped the disease locus to a 16-megabase interval on chromosome 1p13-21. A maximal lod score of 8.24 was obtained with D1S189 at theta=0.00. Sequencing of KCND3, a gene that encodes an I(tO) potassium channel transporter, did not reveal any significant sequence alterations. CONCLUSIONS: This unique form of autosomal recessive PVT affects young children and may be lethal if left untreated. Linkage analysis maps this disorder to chromosome 1p13-21.

The Brugada syndrome: a recently recognised genetic disease causing sudden cardiac death.

Australian doctors need to be aware of this little-known syndrome, which is a cause of sudden cardiac death. It is more common among Southeast Asian people, who make up a considerable proportion of our population. We report two cases which represent very different clinical presentations of this condition.