Prospective Countywide Surveillance and Autopsy Characterization of Sudden Cardiac Death: POST SCD Study.

BACKGROUND: Studies of out-of-hospital cardiac arrest and sudden cardiac death (SCD) use emergency medical services records, death certificates, or definitions that infer cause of death; thus, the true incidence of SCD is unknown. Over 90% of SCDs occur out-of-hospital; nonforensic autopsies are rarely performed, and therefore causes of death are presumed. We conducted a medical examiner-based investigation to determine the precise incidence and autopsy-defined causes of all SCDs in an entire metropolitan area. We hypothesized that postmortem investigation would identify actual sudden arrhythmic deaths among presumed SCDs. METHODS: Between February 1, 2011, and March 1, 2014, we prospectively identified all incident deaths attributed to out-of-hospital cardiac arrest (emergency medical services primary impression, cardiac arrest) between 18 to 90 years of age in San Francisco County for autopsy, toxicology, and histology via medical examiner surveillance of consecutive out-of-hospital deaths, all reported by law. We obtained comprehensive records to determine whether out-of-hospital cardiac arrest deaths met World Health Organization (WHO) criteria for SCD. We reviewed death certificates filed quarterly for missed SCDs. Autopsy-defined sudden arrhythmic deaths had no extracardiac cause of death or acute heart failure. A multidisciplinary committee adjudicated final cause. RESULTS: All 20 440 deaths were reviewed; 12 671 were unattended and reported to the medical examiner. From these, we identified 912 out-of-hospital cardiac arrest deaths; 541 (59%) met WHO SCD criteria (mean 62.8 years, 69% male) and 525 (97%) were autopsied. Eighty-nine additional WHO-defined SCDs occurred within 3 weeks of active medical care with the death certificate signed by the attending physician, ineligible for autopsy but included in the countywide WHO-defined SCD incidence of 29.6/100 000 person-years, highest in black men (P<0.0001). Of 525 WHO-defined SCDs, 301 (57%) had no cardiac history. Leading causes of death were coronary disease (32%), occult overdose (13.5%), cardiomyopathy (10%), cardiac hypertrophy (8%), and neurological (5.5%). Autopsy-defined sudden arrhythmic deaths were 55.8% (293/525) of overall, 65% (78/120) of witnessed, and 53% (215/405) of unwitnessed WHO-defined SCDs (P=0.024); 286 of 293 (98%) had structural cardiac disease. CONCLUSIONS: Forty percent of deaths attributed to stated cardiac arrest were not sudden or unexpected, and nearly half of presumed SCDs were not arrhythmic. These findings have implications for the accuracy of SCDs as defined by WHO criteria or emergency medical services records in aggregate mortality data, clinical trials, and cohort studies.

Novel interstitial 2.6 Mb deletion on 9q21 associated with multiple congenital anomalies.

Array comparative genomic hybridization (aCGH) is now commonly used to identify copy number changes in individuals with developmental delay, intellectual disabilities, autism spectrum disorders, and/or multiple congenital anomalies. We report on an infant with multiple congenital anomalies and a novel 2.6 Mb interstitial deletion within 9q21.32q21.33 detected by aCGH. Her clinical presentation included dysmorphic craniofacial features, cleft palate, atrial septal defect, bicornuate uterus, bilateral hip dislocation, hypotonia, and recurrent pneumonia. Parental aCGH studies were negative for copy loss in this region. To our knowledge, no similar deletions have been reported in available databases or published literature. This deletion encompasses 12 genes, and prediction algorithms as well as experimental data suggest that a subset is likely to be haploinsufficient. Included are a neurotrophin receptor (NKG2D), a gene implicated in cilia function (KIF27), an adaptor protein important for ubiquitin-dependent protein quality control (UBQLN1), a gene important for transcription and signaling (HNRNPK), and a gene involved in maintaining genomic stability (RMI1). Identifying additional patients with similar copy losses and further study of these genes will contribute to a better understanding of the pathophysiology of multiple congenital anomalies.

Plakoglobin immunolocalization as a diagnostic test for arrhythmogenic right ventricular cardiomyopathy.

BACKGROUND: A recent study using an anti-plakoglobin antibody and immunofluorescence methods in endomyocardial tissue specimens found that a marked reduction in plakoglobin staining was highly sensitive and specific for the diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). The purpose of our study was to determine the diagnostic utility of plakoglobin immunolocalization using more standard immunoperoxidase methods suitable for clinical laboratories. METHODS: Between January 2007 and October 2010, all patients at our center with suspected ARVC underwent noninvasive and genetic testing, right ventricular (RV) angiography, electrophysiologic studies, and endomyocardial biopsy from the RV septum. Several studies using anti-plakoglobin antibodies were performed using standard immunoperoxidase methods at concentrations of 1:50,000 and 1:75,000 after serial dilutions. RESULTS: Among 16 patients, nine patients fulfilled the clinical criteria for ARVC, and seven patients were found to have other cardiac diagnoses. In the initial study (1:50,000) only one of nine ARVC patients showed reduced plakoglobin signal while the others had normal staining. On repeat staining (1:75,000), reduced signal was observed in three of five of the ARVC patients compared to none in controls (four patients did not have adequate tissue for the repeat experiment). CONCLUSION: These results confirm that abnormal plakoglobin staining can differentiate biopsies from patients with ARVC from those with other myopathies, but with low sensitivity. Further, each specimen must be studied at a particular concentration due to variable antibody reactivity. The necessity for such fine-tuning of the reaction, as well as the subjectivity involved in interpretation of the results, would make this method difficult to utilize in routine hospital laboratories.

Sudden death due to nonarrhythmic cause in a patient with L-TGA.

We report a case of sudden death in a clinically stable adult with l-transposition of the great arteries (l-TGA). Sudden death has been reported to be the leading cause of death in l-TGA and is often attributed to arrhythmias in the absence of another identifiable cause. However, the contribution of nonarrhythmic causes to the burden of sudden death in this population is unknown. Comprehensive postmortem investigation, including autopsy and pacemaker interrogation, demonstrated that the cause of death was massive pulmonary hemorrhage due to stenosis of the patient's mechanical tricuspid (systemic AV) valve. This report highlights the important contribution of nonarrhythmic causes of sudden death in this population and the value of autopsy and device interrogation in determining true cause of death.

Noncompaction in the fetus and neonate: an autopsy study.

Noncompaction refers to an uncommon structural abnormality of the heart's ventricular myocardium characterized by an abnormally thick layer of left ventricular trabeculations, as well as hypoplastic papillary muscles. The condition is associated with a variable clinical phenotype including heart failure, thromboembolism, and sudden death. In this retrospective study of fetal and neonatal autopsy hearts with noncompaction, clinical profiles were correlated with gross and histologic findings and compared with a set of age-matched controls. Pathologic criteria for noncompaction included hypoplastic left ventricular papillary muscles, abnormal trabecular architecture and greater than 50% penetration of the left ventricular wall thickness by intertrabecular recesses. Among eight fetuses and full-term neonates with pathologic features of noncompaction, all had evidence of severe heart failure, including four with complete heart block and two others with bradycardia. None experienced sudden death. Seven of eight hearts had associated heart malformations-four with left atrial isomerism, two with aortic and/or pulmonary valve dysplasia consistent with stenosis and, one with atrial septal defect. One heart with noncompaction had no associated malformations. With characteristic excessive trabeculation in the left ventricle, noncompaction also included biventricular endocardial fibroelastosis that denoted right ventricular involvement in all hearts. Thus, (1) among autopsied fetuses and neonates with noncompaction, heart failure including heart block is a common cause of death, (2) noncompaction is often associated with various cardiovascular malformations, but even in isolation it can be the basis for severe cardiac failure, and (3) biventricular endocardial fibroelastosis in noncompaction suggests a global pathologic process.

Monoamniotic monochorionic twins discordant for noncompaction cardiomyopathy.

Occasionally "identical twins" are phenotypically different, raising the question of zygosity and the issue of genetic versus environmental influences during development. We recently noted monochorionic-monoamniotic twins, one of which had an isolated cardiac abnormality, noncompaction cardiomyopathy, a condition characterized by cardiac ventricular hypertrabeculation. We examined the prenatal course and subsequent pathologic correlation since ventricular morphogenesis may depend on early muscular contraction and blood flow. The monochorionic-monoamniotic female twin pair was initially identified since one fetus presented with increased nuchal translucency. Complete heart block was later identified in the fetus with nuchal translucency who did not survive after delivery. In contrast, the unaffected twin had normal cardiac studies both prenatally and postnatally. Pathologic analysis of the affected twin demonstrated noncompaction of the left ventricle with dysplasia of the aortic and pulmonary valves. Dissection of the cardiac conduction system disclosed atrioventricular bundle fibrosis. Maternal lupus studies, amniocentesis with karyotype, and studies for 22q11.2 were normal. To test for zygosity, we performed multiple STR marker analysis and found that all markers were shared even using nonblood tissues from the affected twin. These studies demonstrate that monozygotic twins that are monochorionic monoamniotic can be discordant for cardiac noncompaction. The results suggest further investigation into the potential roles of pathologic fibrosis, contractility, and blood flow in cardiac ventricle development.

Evaluation of the acute effects of distal coronary microembolization using multidetector computed tomography and magnetic resonance imaging.

The purpose of this study was to test the potential of clinical imaging modalities, 64-slice multidetector computed tomography (MDCT) and 1.5T magnetic resonance imaging (MRI) for qualitative and quantitative evaluation of acute microinfarcts and to determine the effects of <120 µm microemboli on left ventricular function, perfusion, cardiac injury biomarkers, arrhythmia, and cellular and vascular structures. Under X-ray fluoroscopy, 40-120 µm (16 mm(3) ) microemboli were delivered to embolize the left anterior descending (LAD) coronary artery of nine pigs. MDCT/MRI were performed at 72 h in a single session. Microinfarcts were visible in six of nine animals on delayed contrast-enhanced MDCT/MR images but measurable in all animals using semiautomated threshold methods. Other MDCT and MRI sequences demonstrated decline in left ventricular ejection fraction, regional strain and perfusion in visible and invisible microinfarcted regions. Microemboli caused significant elevation in cardiac injury enzymes and arrhythmias. Various sizes of microinfarcts appeared microscopically as distinct aggregates of macrophages replacing myocardium. Semiautomated threshold methods are necessary to measure and confirm/deny the presence of myocardial microinfarcts. This study offers support for alternative applications of MDCT/MRI in assessing clinical cases in which microemboli <120 µm escape protective devices during percutaneous coronary interventions. Although microembolization resulted in no mortality, it caused left ventricular dysfunction, perfusion deficit, cellular damage increase in cardiac injury enzymes, and arrhythmias.

Anomalous mitral arcade in twin-twin transfusion syndrome.

BACKGROUND: Echocardiography has documented acquired pulmonary stenosis and cardiomyopathy in recipient fetuses in twin-twin transfusion syndrome. At autopsy, we also have identified anomalous mitral arcade, a rare valve deformity associated with mitral regurgitation. METHODS AND RESULTS: To identify a profile for anomalous mitral arcade, we compared clinicopathological data from 11 sets of autopsied twin-twin transfusion syndrome fetuses, including 4 twin pairs in whom the recipient had anomalous mitral arcade (affected) and 7 pairs in whom both had structurally normal mitral valves (unaffected). Anomalous mitral arcade was characterized by a thick fibrous band at the free margin of the leaflets tethering papillary muscles and absent/short tendinous cords. One affected recipient also had pulmonary stenosis and tricuspid valve dysplasia. In all 11 sets, recipient hearts were larger than paired donor hearts. All 11 recipients had moderate to severe cardiac dysfunction by echocardiography. Echocardiography disclosed left atrial enlargement in all affected recipients but none of the unaffected recipients. Mitral regurgitation was present before demise in all affected recipients evaluated with color Doppler. Progressive decrease in mitral leaflet mobility was noted in those affected recipients with serial echocardiography. CONCLUSIONS: Previously unreported in twin-twin transfusion syndrome, anomalous mitral arcade was identified in 4 of 11 recipient fetuses (36%) in this autopsy series. Ultrasound or echocardiographic evidence of left atrial dilation, mitral regurgitation, and decreased leaflet mobility in recipients should raise suspicion for anomalous mitral arcade. Development of anomalous mitral arcade in twin-twin transfusion syndrome recipients suggests that the lesion is an acquired valve deformity in this setting, not a malformation.

Furthering the link between the sarcomere and primary cardiomyopathies: restrictive cardiomyopathy associated with multiple mutations in genes previously associated with hypertrophic or dilated cardiomyopathy.

Mutations in genes that encode components of the sarcomere are well established as the cause of hypertrophic and dilated cardiomyopathies. Sarcomere genes, however, are increasingly being associated with other cardiomyopathies. One phenotype more recently recognized as a disease of the sarcomere is restrictive cardiomyopathy (RCM). We report on two patients with RCM associated with multiple mutations in sarcomere genes not previously associated with RCM. Patient 1 presented with NYHA Class III/IV heart failure at 22 years of age. She was diagnosed with RCM and advanced heart failure requiring heart transplantation. Sequencing of sarcomere genes revealed previously reported homozygous p.Glu143Lys mutations in MYL3, and a novel heterozygous p.Gly57Glu mutation in MYL2. The patient's mother is a double heterozygote for these mutations, with no evidence of cardiomyopathy. Patient 2 presented at 35 years of age with volume overload while hospitalized for oophorectomy. She was diagnosed with RCM and is being evaluated for heart transplantation. Sarcomere gene sequencing identified homozygous p.Asn279His mutations in TPM1. The patient's parents are consanguineous and confirmed heterozygotes. Her father was diagnosed with HCM at 42 years of age. This is the first report of mutations in TPM1, MYL3, and MYL2 associated with primary, non-hypertrophied RCM. The association of more sarcomere genes with RCM provides further evidence that mutations in the various sarcomere genes can cause different cardiomyopathy phenotypes. These cases also contribute to the growing body of evidence that multiple mutations have an additive effect on the severity of cardiomyopathies.

QTc prolongation and family history of sudden death in a patient with desmin cardiomyopathy.

This case report describes a pregnant female patient who presented with new-onset congestive heart failure symptoms and prolonged QTc, with strong family history of sudden death. Endomyocardial biopsy and genetic testing revealed myocardial desmin accumulation and a previously described mutation in the DES (desmin) gene, as well as variants in two LQT genes, SCN5A and KCNH2. The case highlights the phenotypic variability for a particular desmin genotype, and the possible interaction of desminopathy with LQT variants not independently associated with large differences in current properties or QT prolongation from wild type.

Coronary microembolization causes long-term detrimental effects on regional left ventricular function.

OBJECTIVES: To investigate whether coronary microemboli have long-term effects on left ventricular (LV) function in an experimental model. Furthermore, to determine if first-pass perfusion and late gadolinium enhancement (LGE) patterns differs between small- and large-sized microemboli. DESIGN: Six pigs underwent left anterior descending (LAD)-coronary microembolization with small-sized (40-120 µm, n ∼ 250 000) microemboli using a combined x-ray and MRI-system. MR-images before, one hour after and 7-8 weeks after microembolization were obtained. Results were compared to MRI obtained by large-sized (100-300 µm, n ∼ 7200) microemboli. RESULTS: Cine MRI showed an acute drop in ejection fraction (from 49.5 ± 2.6% to 32.5 ± 2.8) that substantially recovered at 7-8 weeks (47.5 ± 3.2%). Regional LV-function assessed as circumferential, longitudinal and radial strain declined in both microinfarcts and remote regions followed by partial recovery at 7-8 weeks. The decline in LV function and the severe perfusion deficit from the small microemboli was similar to the large microemboli at one hour. There was a significant recovery in perfusion at 7-8 weeks in the microinfarcts. LGE demonstrated the microinfarcts at 7-8 weeks but not at one hour and the microinfarcts were confirmed by histopathology. CONCLUSION: Microembolization causes long-term, regional LV dysfunction and this study confirmed the need of a comprehensive MRI-protocol for the detection of microinfarcts. These findings suggest that even small microemboli (40-120 µm in diameter), which may escape the distal protective devices influence cardiac function.

Heterogeneous microinfarcts caused by coronary microemboli: evaluation with multidetector CT and MR imaging in a swine model.

PURPOSE: To directly compare the sensitivity of 64-section multidetector computed tomography (CT) with that of 1.5-T magnetic resonance (MR) imaging in the depiction and measurement of heterogeneous 7-8-week-old microinfarcts and the quantification of regional left ventricular (LV) function and perfusion in the territory of coronary intervention in a swine model. MATERIALS AND METHODS: Approval was obtained from the institutional animal committee. An x-ray/MR system was used to catheterize the left anterior descending (LAD) coronary artery with x-ray guidance and to delineate the perfusion territory. The vessel was selectively microembolized in six pigs with small-diameter embolic material (40-120 microm, 250000 count). At 7-8 weeks after microembolization, multidetector CT and MR imaging were used to assess LV function, first-pass perfusion, and delayed contrast enhancement in remote myocardium and microinfarct scars. Histochemical staining with triphenyltetrazolium chloride (TTC) was used to confirm and quantify heterogeneous microinfarct scars. The two-tailed Wilcoxon signed rank test was used to detect differences between modalities and myocardial regions. RESULTS: The LAD territory was 32.4% +/- 3.8(stadard error of the mean) of the LV mass. Multidetector CT and MR imaging have similar sensitivity in the detection of regional and global LV dysfunction and extent of microinfarct. The mean LV end-diastolic volume, end-systolic volume, and ejection fraction were 93 mL +/- 8, 46 mL +/- 4, and 50% +/- 3, respectively, on multidetector CT images and 92 mL +/- 8, 48 mL +/- 5, and 48% +/- 3, respectively, on MR images (P > or = .05). The extent of heterogeneous microinfarct was not significantly different between multidetector CT (6.3% +/- 0.8 of the LV mass), MR imaging (6.6% +/- 0.5 of the LV mass), and TTC staining (7.0% +/- 0.6 of the LV mass). First-pass multidetector CT and MR imaging demonstrated significant regional differences (P < .05) in time to peak between the heterogeneous microinfarct and remote myocardium (17.0 seconds +/- 0.3 and 12.4 seconds +/- 0.6, respectively, for multidetector CT and 17.2 seconds +/- 0.8 and 12.5 seconds +/- 1.0, respectively, for MR imaging). CONCLUSION: Modern multidetector CT and MR imaging are sensitive modalities with which to depict heterogeneous microinfarcts and determine regional LV dysfunction and decreased perfusion in the territory of intervention. (c) RSNA, 2010.

Left atrial mass: relationship between gross anatomy and quantitative echocardiography.

BACKGROUND: Left atrial (LA) enlargement is associated with increased risk of adverse cardiovascular outcomes. Unlike the left ventricular mass, LA mass has not been described. We sought to define the anatomic mass of the LA using anatomic specimens from autopsy. We hypothesized that LA mass could be estimated by echocardiography. METHODS AND RESULTS: Using anatomic specimens of 22 subjects who died and underwent post mortem examination as well as echocardiogram, we defined normal LA mass by weighing anatomic specimens of those with normal LA volume on echocardiogram. Using 17 subjects with normal LA volume on echocardiogram, we found their LA mass on anatomic specimens to be 25.5 ± 6.3 grams (14.4 ± 3.2 g/m2). We developed an echocardiographic measure of LA mass and validated this measurement with paired LA anatomic specimens. We found the normal LA mass on echocardiogram to be 25.4 ± 6.3 g (14.4 ± 2.8 g/m2) which correlated well with anatomic specimens (ß = 0.99; Confidence interval CI 0.6-1.4, P < .0001; Pearson correlation coefficient r = 0.83). Furthermore, we defined the normal LA volume to mass ratio as 1.38 ± 0.45. CONCLUSIONS: LA mass is an additional parameter with which may contribute to the study of LA morphology.

Magnetic resonance imaging quantification of left ventricular dysfunction following coronary microembolization.

Microembolization is common after coronary interventions, and therefore this MRI study aimed to quantify the effect of coronary microembolization on left ventricular (LV) function. The left anterior descending artery (LAD) was selectively catheterized in an XMR suite (Philips Medical Systems, Best, The Netherlands) in eight pigs to deliver MR contrast media to measure the LAD territory using first-pass perfusion and for intracoronary delivery of the embolic agent. Cine, tagged, and delayed contrast-enhanced MRI (DCE-MRI) was performed to assess LV volumes, ejection fraction, radial and circumferential strain, and viability at baseline, 1 h, and 1 week after microembolization. Histopathology and histochemical staining were used to characterize and measure the extent of microinfarction. The LAD territory was 35% +/- 2% LV mass. Patchy microinfarction on DCE-MRI at 1 week was 22.0% +/- 3.6% LAD territory (7.5% LV mass). Microembolization caused persistent decline in ejection fraction (baseline = 49% +/- 1%, 1 h = 29% +/- 1%, P = 0.02 and 1 week = 36% +/- 1%, P = 0.03) and increased end-diastolic (79.6 +/- 3.9 ml, 85.5 +/- 4.5 ml, P = 0.03 and 92.4 +/- 6.2 ml, P = 0.06, respectively) and end-systolic (40.8 +/- 2.1 ml, 60.2 +/- 3.4 ml, P = 0.02 and 59.3 +/- 4.8 ml, P = 0.03, respectively) volumes. The microembolized territory was manifested as dysfunctional regions for 1 week on cine and tagged MRI. Histopathology revealed occlusive microemboli surrounded by necrotic tissue undergoing repair. Microinfarction was visualized after coronary microembolization and caused LV dysfunction disproportionate to the size of myocardial damage. It also changed LV geometry and decreased radial and circumferential strain over the course of 1 week.

How does Fetal Autopsy after Pregnancy Loss or Termination for Anomalies and other Complications Change Recurrence Risk?

Objective Historically, fetal autopsy was common after terminations for anomalies. Previous studies report that fetal autopsy confirms ultrasound findings in the majority of cases. This study aims to examine correlation between prenatal and autopsy diagnoses at University of California, San Francisco (UCSF) and evaluate whether autopsy adds diagnostic information, specifically information that changes risk of recurrence for future pregnancies. Study Design We conducted a retrospective chart review of all fetal autopsies performed at UCSF between 1994 and 2009. Prenatal diagnosis was compared with autopsy diagnosis; for cases where there was a change in diagnosis, an MFM (maternal-fetal medicine specialist) reviewed the case to assign risk of recurrence before and after autopsy. Results Overall, there was concordance between prenatal diagnosis and autopsy diagnosis in greater than 91.7% of cases. Autopsy added information that resulted in a change in recurrence risk in 2.3% of cases ( n = 9). Conclusion For the vast majority of cases, there is agreement between prenatal and autopsy diagnosis after pregnancy loss or termination for fetal anomalies. Only a small percentage of autopsies change recurrence risk. This may be useful when counseling women about method of termination and when counseling couples about whether to have an autopsy.

Refining the World Health Organization Definition: Predicting Autopsy-Defined Sudden Arrhythmic Deaths Among Presumed Sudden Cardiac Deaths in the POST SCD Study.

BACKGROUND: Conventional definitions of sudden cardiac death (SCD) presume cardiac cause. We studied the World Health Organization-defined SCDs autopsied in the POST SCD study (Postmortem Systematic Investigation of SCD) to determine whether premortem characteristics could identify autopsy-defined sudden arrhythmic death (SAD) among presumed SCDs. METHODS: Between January 2, 2011, and January 4, 2016, we prospectively identified all 615 World Health Organization-defined SCDs (144 witnessed) 18 to 90 years in San Francisco County for medical record review and autopsy via medical examiner surveillance. Autopsy-defined SADs had no extracardiac or acute heart failure cause of death. We used 2 nested sets of premortem predictors-an emergency medical system set and a comprehensive set adding medical record data-to develop Least Absolute Selection and Shrinkage Operator models of SAD among witnessed and unwitnessed cohorts. RESULTS: Of 615 presumed SCDs, 348 (57%) were autopsy-defined SAD. For witnessed cases, the emergency medical system model (area under the receiver operator curve 0.75 [0.67-0.82]) included presenting rhythm of ventricular tachycardia/fibrillation and pulseless electrical activity, while the comprehensive (area under the receiver operator curve 0.78 [0.70-0.84]) added depression. If only ventricular tachycardia/fibrillation witnessed cases (n=48) were classified as SAD, sensitivity was 0.46 (0.36-0.57), and specificity was 0.90 (0.79-0.97). For unwitnessed cases, the emergency medical system model (area under the receiver operator curve 0.68 [0.64-0.73]) included black race, male sex, age, and time since last seen normal, while the comprehensive (area under the receiver operator curve 0.75 [0.71-0.79]) added use of ß-blockers, antidepressants, QT-prolonging drugs, opiates, illicit drugs, and dyslipidemia. If only unwitnessed cases <1 hour (n=59) were classified as SAD, sensitivity was 0.18 (0.13-0.22) and specificity was 0.95 (0.90-0.97). CONCLUSIONS: Our models identify premortem characteristics that can better specify autopsy-defined SAD among presumed SCDs and suggest the World Health Organization definition can be improved by restricting witnessed SCDs to ventricular tachycardia/fibrillation or nonpulseless electrical activity rhythms and unwitnessed cases to <1 hour since last normal, at the cost of sensitivity.

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy.

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal ß-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and ß-catenin. A pharmacological activator of the WNT/ß-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and ß-catenin, and evidence for targeted activation of the WNT/ß-catenin pathway as a potential treatment for this disease.

Sinus of Valsalva Aneurysm and Infective Endocarditis Involving a Bicuspid Aortic Valve in an Infant With Trisomy 21.

A 19-month-old girl with trisomy 21 and a congenitally bicuspid aortic valve died following a short febrile illness. Autopsy disclosed pericarditis, epimyocardial abscess, infective endocarditis, and a sinus of Valsalva aneurysm. Microscopy demonstrated continuity between the aortic wall and valve leaflet, consistent with an acquired aneurysm. Abnormal hemodynamics associated with the valve malformation likely facilitated endocarditis.

A Preliminary Study of Left Ventricular Rotational Mechanics in Children with Noncompaction Cardiomyopathy: Do They Influence Ventricular Function?

BACKGROUND: Current diagnostic criteria for noncompaction cardiomyopathy (NCC) lack specificity, and the disease lacks prognostic indicators. Reverse apical rotation (RAR) with abnormal rotation of the cardiac apex in the same clockwise direction as the base has been described in adults with NCC. The aim of this study was to test the hypothesis that RAR might differentiate between symptomatic NCC and benign hypertrabeculations and might be associated with ventricular dysfunction. METHODS: Echocardiograms from 28 children with NCC without cardiac malformations were prospectively compared with those from 29 age-matched normal control subjects. A chart review was performed to identify the patients' histories and clinical characteristics. Speckle-tracking was used to measure longitudinal strain, circumferential strain, and rotation. RESULTS: RAR occurred in 39% of patients with NCC. History of left ventricular (LV) dysfunction or arrhythmia was universal in, but not exclusive to, patients with RAR. Patients with RAR had lower LV longitudinal strain but similar ejection fractions compared with patients without RAR (median, -15.6% [interquartile range, -12.9% to -19.3%] vs -19% [interquartile range, -14.5% to -21.9%], P < .01; 53% [interquartile range, 43% to 68%] vs 61% [interquartile range, 58% to 67%], P = .08). Only a pattern of contraction with RAR, early arrest of twisting by mid-systole, and premature untwisting was associated with lower ejection fraction (46%; interquartile range, 43% to 52%; P = .006). CONCLUSIONS: RAR is not a sensitive but is a specific indicator of complications in children with NCC. Therefore, RAR may have prognostic rather than diagnostic value. Premature untwisting of the left ventricle during ejection may be an even more worrisome indicator of LV dysfunction.