Cases Of Sudden Cardiac Death Research Articles

B-AB19-04 DIAGNOSIS OF CORONARY VASOSPASM-INDUCED VENTRICULAR FIBRILLATION DURING PERICARDIAL MAPPING

After excluding cardiac genetic and structural abnormalities, idiopathic VF is estimated to account for ∼5% of cases of sudden cardiac death. In these cases, it may be difficult to identify an etiology for VF. We present a case of idiopathic polymorphic VT/VF (pVT/VF) with the diagnosis made in the EP lab. N/A A 47-year-old man had a witnessed cardiac arrest and was found to be in VF. A work-up including coronary angiography was unrevealing; MRI was largely normal, though suggestive of an inferolateral area of subepicardial scar. A subcutaneous ICD (SICD) was placed. He presented to us with recurrent pVT/VF on sotalol resulting in multiple ICD shocks, some of which failed to immediately defibrillate. At EP study, stimulation did not induce sustained ventricular arrhythmias. Standard pericardial access was obtained to permit epi/endo mapping to identify arrhythmogenic substrate. But immediately upon onset of pericardial mapping, ST segment elevation occurred, and the patient developed non-sustained pVT (Figure). Immediate coronary angiography revealed diffuse coronary spasm, most strikingly in the proximal LAD. With administration of intracoronary nitroglycerin, the LAD spasm and pVT/VF resolved; ST segment abnormalities resolved within minutes. DFT testing revealed a normal functioning SICD. He was discharged on long-acting nifedipine and nitrates for coronary vasospasm. Severe coronary vasospasm may cause idiopathic polymorphic VT/VF. Medical therapy with calcium-channel blockers and oral nitrates are the first-line therapy as ICD therapies alone may be ineffective in the setting of on-going spasm and ischemia.

Histopathological Findings in Sudden Cardiac Death: 5-years Autopsy Experience in a Tertiary Hospital in Bandung, Indonesia

Background: Sudden death (SD) is a sudden and unexpected death with an unknown cause. However, it has been assummed that the most common causes of sudden deaths are cardiovascular or non-cardiovascular causes such as gastrointestinal disease, respiratory disease, genitourinary disease, epilepsy, and trauma. This study aimed to portray histopathological findings and causes of sudden cardiac death (SCD) cases based on 5 year autopsy experience in a tertiary hospital in Bandung, Indonesia. Methods: This study was a descriptive cross-sectional study exploring causes of SCD from 2015 to 2019 at Dr. Hasan Sadikin General Hospital, Bandung, Indonesia. All medical records with SCD and histopathology findings were retrieved from September to December 2020. Only cases with histopathological examination results were included.Results: SCD was found in 7 of 16 patients with sudden death. Coronary atherosclerosis was the most common (n=4), followed by myocardial infarction (n=2) and ruptured aortic aneurysm (n=1). Myocarditis and calcific aortic valve diseases were not found.Conclusions: In this study, the most common cause of SCD is coronary atherosclerosis, which is identified mainly in older and male patients.

Ischemic Heart Disease Related Sudden Cardiac Death in Autopsied Cases: An Egyptian perspective.

Diagnosis of the underlying cause of sudden unexpected death in a previously healthy individual remains one of the important challenges in forensic practice. Ischemic heart disease is the most common cause of sudden death. The current study aims to investigate the incidence and pathology of sudden ischemic cardiac death in Egypt. All cases of sudden cardiac death (SCD) examined by different forensic departments throughout Egypt during the period of January 2010 through December 2014 were included. Cases underwent complete autopsy examination including a thorough gross and microscopic examination of the heart and great blood vessels. Of 535 cases of SCD diagnosed during the period of the study, coronary atherosclerosis was the principle finding in 420 (78.5%) cases. The highest numbers of deaths were reported in fifth and sixth decades with male preference. Other causes of SCD included myocarditis, cardiomyopathies, valvular heart disease, and hypertensive heart disease (7.8%, 4.1%, 4.1%, and 2.8%, respectively). There was severe stenosis (>75%) of at least 1 coronary artery in 74% of cases. Type VI atherosclerosis was found in 40.7% of cases. The left anterior descending branch was the most affected artery by atherosclerosis. Acute coronary pathological events were demonstrated in 27.6% of cases. Recent myocardial infarction was evident in 55.5% of cases, whereas old infarcts were demonstrated in 44.5% of cases. Features of hypertensive heart disease were present in 18.3% of cases. In conclusion, ischemic heart disease is the leading cause of SCD in Egypt.

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals

Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined. To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes. This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021. The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD. The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants. In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

A Functional Indel Polymorphism Within MIR155HG Is Associated With Sudden Cardiac Death Risk in a Chinese Population.

Sudden cardiac death (SCD) is a devastating complication of multiple disease processes and has gradually became a major public health issue. miR-155 is one of the best characterized miRNAs and plays a critical role in several physiological and pathological process, including cardiovascular diseases. In this study, we systematically screened the whole region of miR-155 host gene (MIR155HG) and identified a 4-bp insertion/deletion variant (rs72014506) residing in the intron region of MIR155HG as the candidate polymorphism. The association of rs72014506 with SCD susceptibility was evaluated using 166 SCD cases and 830 healthy controls in a Chinese population. Logistic regression analysis suggested that the homozygote del/del genotype significantly decreased the risk of SCD [odds ratio (OR) = 0.29; 95% confidence interval (CI) = 0.12–0.74; Ptrend = 0.0004]. Further genotype–expression association study using human myocardium tissue samples suggested that the deletion allele was intimately linked to lower the expression of both MIR155HG and mature miR155. Luciferase activity assay also revealed that the deletion allele of rs72014506 inhibited gene transcriptional activity. Finally, we performed electrophoretic mobility shift assay and verified the preferential binding affinity of the deletion allele with POU2F1 (POU domain class 2 transcription factor 1). Collectively, we have successfully identified a SCD risk conferring polymorphism in the MIR155HG gene and a likely biological mechanism for the decreased risk of SCD associated with the deletion allele. This novel variant may thus serve as a potential genetic marker for SCD diagnosis and prevention in natural populations, if validated by further studies with a larger sample size.

Abstract P113: Underestimation Of Sudden Death Due To Restrictive Sudden Cardiac Death Criteria

Background: Efforts to prevent sudden death may be hampered by restrictive case definitions impairing accurate estimates of incidence and risk factors of sudden death. Sudden cardiac death (SCD) definitions include requirements for presence of comorbid coronary artery disease (CAD) and various time criteria since onset of symptoms or when victims were last seen well. We compared prevalence of three SCD definitions within a registry of all-cause natural, sudden deaths. Hypothesis: We assessed the hypothesis that the restrictive criteria of three SCD definitions underestimate sudden death and exclude populations with increased medical comorbidities. Methods: Using a registry of 399 adjudicated sudden death cases among adults aged 18-64 in Wake County, North Carolina in 2013-2015, we included 271 cases after excluding for missing values, chronic kidney disease, or heart failure. Time since last seen alive was classified as less than one hour or 24 hours from scene reports. Presence of CAD and co-morbidities were defined from clinical or autopsy records. Prevalence of SCD using criteria defined by Atherosclerosis Risk in Communities (ARIC), the World Health Organization (WHO), and the Oregon Sudden Unexpected Death (SUD) registry were calculated. Prevalence of SCD risk factors were calculated for the 3 SCD subgroups and compared to the original 271 victims using two-sample t-test and Fisher’s exact test for continuous and categorical variables. Results: Among the 271 cases, criteria were met for the three SCD definitions for n (%): ARIC 28 (10%), WHO 54 (20%), and SUD 90 (33%) (Table 1). ARIC and WHO-defined SCD cases were younger than the original 271 cases. There were no significant differences in sociodemographic and clinical factors by any SCD group compared to the original 271 cases. Conclusion: Restrictive SCD definitions that require the presence of CAD or a specific time frame of identification of death underestimate the incidence of sudden death and hinder effective prevention efforts for sudden death.

Sudden cardiac death due to ARVC in the young: molecular autopsy by whole exome sequencing of DNA from dried blood spots (DBS) collected at birth

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Uppsala University Hospital (ALF) and Marcus Börgström Foundation Background The post-mortem investigation of cases with sudden cardiac death (SCD) is critical for risk stratification and adequate care of surviving relatives. Genetic testing is limited by access to DNA from the proband, as blood samples are not routinely collected at the time of death, or DNA of poor quality obtained from formalin-fixed paraffin-embedded (FFPE) tissues. Whole exome sequencing (WES) on minute amounts of DNA has opened up for the possibility to use DNA from Dried Blood Spots (DBS). Purpose To evaluate the feasibility of WES on DNA from archived DBS collected at the time of newborn screening in cases of SCD. Methods Through National Health Databases and Registries, we identified all cases of SCD in the young (<35 y.o.a.) in Sweden with a post-mortem diagnosis of ARVC between 2000 and 2010 (n = 22). Clinical records, medical and family histories, and autopsy findings were collected. Surviving parents were invited to participate. DNA was extracted from samples in National Biobanks such as DBS collected at birth (n = 19), formalin-fixed paraffin-embedded (FFPE) heart tissues (n = 8) from autopsies, and frozen blood samples (n = 3). Patient and parental DNA samples (when available) underwent WES. DNA- and sequencing-quality check (QC) metrics were compared between two different sequencing platforms and specimen types. We analysed 392 cardiomyopathy and arrhythmia genes and variants were classified as pathogenic or likely pathogenic according to the criteria from the American College of Medical Genetics. Results A higher quality but a lower yield of DNA (7.3 – 140 ng) was obtained from DBS when compared to FFPE samples (515 – 3065 ng). However, 100% of DBS vs. 62,5% of FFPE samples passed QC before sequencing. The average mean target depth for DBS samples (160X) was similar to that in blood samples (155X) and higher than FFPE (82X). Furthermore, >97% of target regions were covered with read depths >30X in DNA from DBS and blood compared to 88% for FFPE samples (Min 63%; Max 97%). Analysis of WES data uncovered clinically relevant variants in 12 out of 19 families (63%), of which four were located in ARVC genes. In six cases, the molecular autopsy identified another arrhythmogenic syndrome. Additionally, we identified one SCD with hemochromatosis and one with myotonic dystrophy as a possible contributing cause. In two additional families, variants of unknown significance fulfilled criteria for further segregation analysis. The concordance of positive results between different tissue samples was 100%. Conclusions DNA obtained from DBS has a quality comparable to that of blood and is a reliable source for WES-based molecular autopsy that may improve the diagnostic yield in cases of SCD. In a proportion of cases diagnosed post-mortem with ARVC, our molecular autopsy analysis pointed to a different diagnosis, highlighting its importance for the correct medical care of surviving relatives.

Outcomes of post mortem genetic diagnosis in SCD victims and primary prevention of cardiac arrest in relatives: a nationwide multidisciplinary and multicentric collaboration in the Czechia

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Supported by Ministry of Health of the Czech Republic Introduction Post mortem genetic analysis in sudden cardiac death (SCD) represents an important diagnostic tool for the primary prevention of cardiac arrest in victim´s relatives. Purpose To assess the underlying molecular pathogenesis of SCD in a representative Czech cohort and to evaluate the effects of primary prevention of SCD in genetic relatives. Patients and Methods Between 2016 and 2020 we have ascertained 100 SCD cases (29 females/71 males; age range 0-52 years). According to autopsy protocols, cases with SCD were divided into categories of sudden arrhythmic death (SADS), sudden unexplained death (in infants; SUD/SUDI), thoracic aortic aneurysm/dissection and cardiomyopathy hypertrophic, arrhythmic, dilated (HCM, ACM, DCM) and sudden infant death syndrome (SIDS). DNA was isolated from post mortem biopsies / relatives blood and subjected to massively parallel sequencing (Illumina, USA) comprising custom-made candidate gene panel (100 genes). Genetic counselling and cardiological examinations were carried out in 245 family members. Results According to post mortem-established diagnosis, we identified 20 victims with SADS and SUD/SUDI, 11 with HCM and DCM, 19 with ACMG, 8 SIDS cases and 9 acute dissection cases. Most of victims died at sleep or at rest, while only 10/100 victims died during strenuous sport activities. About 50% of SCD victims did not report any apparent cardiac complaints. Highly likely or certain molecular etiology (i.e. based on presence of ACMG.net Class 4 to 5 variants) was disclosed in 19/100 (19%) in RYR2, KCNH2, SCN5A, FLNC (stop), TTN, RBM 20, LMNA/C, PRKAG2, MYBPC3, DSC2, FHL1, TGFBR1 and Col3A1 genes (see Tab). Finally, we identified 52/241 phenotype/genotype positive family members who are at risk of cardiac arrest and were offered corresponding cardiological care. Conclusion Multidisciplinary cooperation, together with centralized and standardized molecular genetic testing, enables the primary prevention of cardiac arrest in relatives of SCD victims. Results of post mortem genetic analysis Post mortem diagnosis Nr. Gender Age (years) Nr. of positive cases (DNA variant class IV or V) Gene Nr. examined relatives/phenotype or genotype positive cases SADS 20 8 females12 males 3-52 5/20 (25%) KCNH2 3x RYR2RANGFR 56/11 SUD/SUDI 20 5 females, 15 males 0-50 1/18 (5%, 2 non informative cases) RYR2 45/9 HCM 11 0 females11 males 14-52 3/11 (27%) MYBPC3FHL1PRKAG2 26/9 DCM 11 3 females8 males 8-48 4/11 (36%) TTN (3x)RBM 20FLNC (stop) 24/7 ACM 19 9 females10 males 17 - 49 4/19 (21%) SCN5AFLNC (stop)DSC2LMNA/C 58/9 SIDS 8 3 females5 males < 1 0/8 - 12/0 Acute dissection 9 1 female8 males 16-49 2/9 (22%) TGFBR1Col3A1 24/7

Nationwide burden of sudden cardiac death: A study of 54,028 deaths in Denmark.

A large proportion of all deaths are sudden cardiac deaths (SCDs). Reliable estimates of nationwide incidence of SCD, however, are missing. The goals of this study were to estimate SCD burden across all age groups in Denmark and to compare it with the estimates of other common causes of death. All deaths in Denmark (population of 5.5 million) in 2010 were manually reviewed case by case. Autopsy reports, death certificates, and information from nationwide health registries were systematically examined to identify all SCD cases in 2010. According to the level of detail of the available information, all deaths were categorized as either non-SCD, definite SCD, probable SCD, or possible SCD. There were 54,028 deaths in Denmark in 2010, of which 6867 (13%) were categorized as SCD (591 (9%) definite SCD, 1568 (23%) probable SCD, and 4708 (68%) possible SCD). The incidence rate of definite SCD was 11 (95% confidence interval 10-12) per 100,000 person-years. Including definite, probable, and possible SCD cases, the highest possible overall SCD incidence rate was 124 (95% confidence interval 121-127) per 100,000 person-years. Estimated SCD burden was similar to or greater than the estimates of all other common causes of death. Of all SCD cases, 49% were not diagnosed with cardiovascular disease before death. SCD accounted for up to 13% of all deaths. Almost half of all SCD cases occurred in persons without a history of cardiovascular disease. Consequently, the optimization of risk stratification and prevention of SCD in the general population should be given high priority.

Technical in-depth comparison of two massive parallel DNA-sequencing methods for formalin-fixed paraffin-embedded tissue from victims of sudden cardiac death

Sudden cardiac death (SCD) is a tragic and traumatic event. SCD is often associated with hereditary genetic disease and in such cases, sequencing of stored formalin fixed paraffin embedded (FFPE) tissue is often crucial in trying to find a causal genetic variant. This study was designed to compare two massive parallel sequencing assays for differences in sensitivity and precision regarding variants related to SCD in FFPE material. From eight cases of SCD where DNA from blood had been sequenced using HaloPlex, corresponding FFPE samples were collected six years later. DNA from FFPE samples were amplified using HaloPlex HS, sequenced on MiSeq, representing the first method, as well as amplified using modified Twist and sequenced on NextSeq, representing the second method. Molecular barcodes were included to distinguish artefacts from true variants. In both approaches, read coverage, uniformity and variant detection were compared using genomic DNA isolated from blood and corresponding FFPE tissue, respectively.In terms of coverage uniformity, Twist performed better than HaloPlex HS for FFPE samples. Despite higher overall coverage, amplicon-based HaloPlex technologies, both for blood and FFPE tissue, suffered from design and/or performance issues resulting in genes lacking complete coverage. Although Twist had considerably lower overall mean coverage, high uniformity resulted in equal or higher fraction of genes covered at ≥ 20X. By comparing variants found in the matched samples in a pre-defined cardiodiagnostic gene panel, HaloPlex HS for FFPE material resulted in high sensitivity, 98.0% (range 96.6–100%), and high precision, 99.9% (range 99.5–100%) for moderately fragmented samples, but suffered from reduced sensitivity (range 74.2–91.1%) in more severely fragmented samples due to lack of coverage. Twist had high sensitivity, 97.8% (range 96.8–98.7%) and high precision, 99.9% (range 99.3–100%) in all analyzed samples, including the severely fragmented samples.

Characterisation of hypertensive heart disease: pathological insights from a sudden cardiac death cohort to inform clinical practice.

Hypertensive heart disease refers to changes in the myocardium that result from hypertension. The relationship between hypertensive heart disease and sudden cardiac death is well established, but there are few pathological studies. We examined the clinical and pathological features of hypertensive heart disease in sudden cardiac death victims from a national cardiovascular pathology registry. We investigated 5239 cases of sudden cardiac death between 1994 and 2018. Hearts were examined by two expert cardiac pathologists. Diagnostic criteria included history of hypertension, increased heart weight and left ventricular wall thickness in the absence of other causes. Collagen was quantified using picrosirius red staining and imaging software. Of 75 sudden cardiac death cases due to hypertensive heart disease (age at death: 54 ± 16 years; 56% males), 56 (75%) reported no prior cardiac symptoms. Thirty-four (45%) recorded a BMI ≥ 30. Only two (2.7%) had hypertensive heart disease diagnosed antemortem. Four (5%) were diagnosed clinically with hypertrophic cardiomyopathy, but lacked myocyte disarray at autopsy. All hearts showed concentric left ventricular hypertrophy and myocyte hypertrophy. Fibrosis was identified microscopically in 59 cases (81%). The posterior left ventricular wall showed the greatest increase in the percentage of collagen in hypertensive diseased hearts compared to controls (25.2% vs 17.9%, p = 0.034). Most sudden deaths due to hypertensive heart disease occur without prior cardiac symptoms; thus, clinical risk stratification is challenging. Hypertensive heart disease can be misdiagnosed in life as hypertrophic cardiomyopathy which has major implications for relatives. Pathologists require a history of hypertension and histology for a definitive diagnosis of hypertensive heart disease.

Regulatory variation within 3’UTR of STAT5A correlates with sudden cardiac death in Chinese populations

Definitive diagnosis to sudden cardiac death (SCD) is often challenging since the postmortem examination on SCD victims could hardly demonstrate an adequate cause of death. It is therefore important to uncover the inherited risk component to SCD. Signal transducer and activators of transcription 5 A (STAT5A) is a member of the STAT family and a transcription factor that is activated by many cell ligands and associated with various cardiovascular processes. In this study, we performed a systematic variant screening on the STAT5A to filter potential functional genetic variations. Based on the screening results, an insertion/deletion polymorphism (rs3833144) in 3’UTR of STAT5A was selected as the candidate variant. A total of 159 SCD cases and 668 SCD matched healthy controls was enrolled to perform a case-control study and evaluate the association between rs3833144 and SCD susceptibility in Chinese populations. Logistic regression analysis showed that the deletion allele of rs3833144 had significantly increased the SCD risk (odds ratio (OR) = 1.54; 95% confidence interval (CI) = 1.18–2.01; P = 0.000955). Further genotype-expression eQTL analysis showed that samples with deletion allele appeared to lower expression of STAT5A, and in silico prediction suggested the local 3 D structure changes of STAT5A mRNA caused by the variant. On the other hand, the bioinformatic analysis presented that promoters of RARA and PTGES3L-AARSD1 could interact with rs3833144, and eQTL analysis showed the higher expression of both genes in samples with deletion allele. Dual-luciferase activity assays also suggested the significant regulatory role of rs3833144 in gene transcription. Our current data thus suggested a possible involvement of rs3833144 to SCD predisposition in Chinese populations and rs3833144 with potential function roles may become a candidate marker for SCD diagnosis and prevention.

Circular RNAs in Sudden Cardiac Death Related Diseases: Novel Biomarker for Clinical and Forensic Diagnosis

The prevention and diagnosis of sudden cardiac death (SCD) are among the most important keystones and challenges in clinical and forensic practice. However, the diagnostic value of the current biomarkers remains unresolved issues. Therefore, novel diagnostic biomarkers are urgently required to identify patients with early-stage cardiovascular diseases (CVD), and to assist in the postmortem diagnosis of SCD cases without typical cardiac damage. An increasing number of studies show that circular RNAs (circRNAs) have stable expressions in myocardial tissue, and their time- and tissue-specific expression levels might reflect the pathophysiological status of the heart, which makes them potential CVD biomarkers. In this article, we briefly introduced the biogenesis and functional characteristics of circRNAs. Moreover, we described the roles of circRNAs in multiple SCD-related diseases, including coronary artery disease (CAD), myocardial ischemia or infarction, arrhythmia, cardiomyopathy, and myocarditis, and discussed the application prospects and challenges of circRNAs as a novel biomarker in the clinical and forensic diagnosis of SCD.

Antemortem and Post-Mortem Characteristics of Lethal Mitral Valve Prolapse Among All Countywide SuddenDeaths.

The goal of this study was to investigate the characteristics of mitral valve prolapse (MVP) in a post-mortem study of consecutive sudden cardiac deaths (SCDs) in subjects up to 90 years of age. Up to 2.3% of subjects with MVPs experience SCD, but by convention SCD is rarely confirmed by autopsy. In a post-mortem study of persons<40 years of age, 7% of SCDs were caused by MVP; bileaflet involvement, mitral annular disjunction (MAD), and replacement fibrosis were common. In the San Francisco POST SCD (Postmortem Systematic Investigation of Sudden Cardiac Death) study, autopsies have been performed on >1,000 consecutive World Health Organization-defined (presumed) cases of SCD in subjects aged 18 to 90 years since 2011; a total of 603 were adjudicated. Autopsy-defined sudden arrhythmic death (SAD) required absence of nonarrhythmic cause; MVP diagnosis required leaflet billowing. One hundred antemortem echocardiograms were revised to identify additional MVPs missed on autopsy. Among the 603 presumed SCDs, 339 (56%) were autopsy-defined SADs, with MVP identified in 7 (1%). Six additional MVPs were identified by review of echocardiograms, for a prevalence of at least 2% among 603 presumed SCDs and 4% among 339 SADs (vs. 264 non-SADs; p=0.02). All 6 additional MVPs had monoleaflet rather than bileaflet involvement and mild mitral regurgitation, ruling out hemodynamic cause. Less than one-half had MAD with replacement fibrosis, but all had multisite interstitial fibrosis. In a countywide post-mortem study of all adult cases of SCD, MVP prevalence was at least 4% of SADs,but one-half were missed on autopsy. Monoleaflet MVP was often underdiagnosed post-mortem. Compared withyoung cases of SCD, lethal MVP in older cases of SCD did not consistently have bileaflet anatomy, replacement fibrosis, or MAD.

Witnessed and unwitnessed sudden cardiac death: a nationwide study of persons aged 1-35 years.

The aim of this study is to compare clinical characteristics and causes of death among witnessed and unwitnessed sudden cardiac death (SCD) cases aged 1-35 years. In this retrospective nationwide study, all deaths in persons aged 1-35 years in Denmark during 2000-09 were included (23.7 million person-years). Using the in-depth descriptive Danish death certificates and Danish nationwide registries, 860 cases of sudden, unexpected death were identified. Through review of autopsy reports and register data, we identified 635 cases of SCD of which 266 (42%) were witnessed and 326 (51%) were unwitnessed. In 43 cases (7%), witnessed status was missing. Clinical characteristics were overall similar between the two groups. We found a male predominance among unwitnessed SCD compared to witnessed SCD (71% and 62%, respectively, P-value 0.012), as well as more psychiatric comorbidity (20% and 13%, respectively, P-value 0.029). Unwitnessed SCD more often occurred during sleep whereas witnessed SCD more often occurred while the individual was awake and relaxed (P-value < 0.001). The autopsy rate among all SCD cases was 70% with no significant difference in autopsy rate between the two groups. Sudden unexplained death, which was the leading autopsy conclusion in both groups, was more frequent among unwitnessed SCD (P-value 0.001). Several clinical characteristics and autopsy findings were similar between witnessed and unwitnessed SCD cases. Our data support the inclusion of both witnessed and unwitnessed cases in epidemiological studies of SCD cases aged 1-35 years, although the risk of misclassification is higher among unwitnessed and non-autopsied cases of SCD.

Patients with a DPP6 risk- haplotype for familial idiopathic ventricular fibrillation have normal left systolic function but abnormal deformation

Abstract Funding Acknowledgements Type of funding sources: None. Introduction An aberrant DPP6 mutation haplotype on chromosome 7 is associated with familial idiopathic ventricular fibrillation in severely affected Dutch families with numerous cases of sudden cardiac death (SCD) So far, no clinical parameters could be linked to predict SCD risk other than this genetic predisposition. In various other cardiac disease, global longitudinal strain (GLS) and mechanical dispersion (MD), both markers of left ventricular (LV) dysfunction, are predictive tools for patients at risk for ventricular arrhythmias (VA) and SCD. The goal of the current study was to investigate whether LV dysfunction, detected by GLS and MD, is present in patients with DPP6 haplotype. Method DPP6 risk-haplotype carriers with sufficient echocardiographic images were included as cases (n = 31, 15 males mean age 41 ± 11 years) and individuals evaluated during cascade screening who were tested but appeared not to be affected as controls (n = 14, 7 males, mean age 39 ± 12 years). Echocardiographic bi-plane ejection fraction (LVEF), GLS and MD of the left ventricular were determined. Results LVEF was similar between DPP6 cases (57.3%) and controls (60.5%, p = 0.07). In contrast, the GLS of the LV (-18.0%) of DPP6 cases was significant lower compared to controls (-21.1%, p &amp;lt; 0.0001). MD in DPP6 cases (43.4ms) was significantly higher than in controls (26.7ms, p &amp;lt; 0.0001). Conclusion DPP6 risk- haplotype carriers have similar LVEF, but significant lower LV-GLS and higher mechanical dispersion than controls. These findings can be used for clinical discrimination. Whether these markers can be used for prediction of clinical events has to be determined after a longer follow up. echocardiographic characteristics controls DPP6 p-value LVEF (%) 60.5 57.3 0.07 GLS LV (%) -21.2 -18.0 0.0001 MD ( ms) 26.7 43.4 0.0001

Small Vessel Disease: Another Component of the Hypertrophic Cardiomyopathy Phenotype Not Necessarily Associated with Fibrosis.

Background: Hypertrophic cardiomyopathy (HCM) is characterized by myocardial disarray, small vessel disease (SVD), and fibrosis. The relationship between SVD and replacement-type fibrosis is still unclear. Methods: Histopathologic assessment of replacement-type fibrosis and SVD in HCM patients with either end-stage heart failure (HF) or sudden cardiac death (SCD). Chronic ischemic heart disease (IHD) patients served as controls. Results: Forty HCM hearts, 10 HF and 30 SCD, were studied. Replacement-type fibrosis was detected in all HF and in 57% of SCD cases. In SCD, replacement-type fibrosis was associated with older age, greater septal thickness, SVD prevalence, and score (all p < 0.05). Prevalence of SVD did not show significant differences among SCD, HF, and IHD (73%, 100% and 95%, respectively), while SVD score was higher in HF than IHD and SCD (2.4, 1.95, and 1.18, respectively) and in areas with replacement-type fibrosis vs. those without in HF (3.4 vs. 1.4) and SCD (1.4 vs. 0.8) (all p < 0.05). Conclusions: SVD is a frequent feature in HCM independent of the clinical presentation. A higher SVD score is observed in HCM-HF and in areas with replacement-type fibrosis. Although SVD is part of the HCM phenotype, further remodeling of the microcirculation might occur secondarily to fibrosis.

Sudden cardiac death during nighttime hours

In the absence of apparent triggers, sudden cardiac death (SCD) during nighttime hours is a perplexing and devastating phenomenon. There are few published reports in the general population, with insufficient numbers to perform sex-specific analyses. Smaller studies of rare nocturnal SCD syndromes suggest a male predominance and implicate sleep-disordered breathing. The purpose of this study was to identify mechanisms of nighttime SCD in the general population. From the population-based Oregon Sudden Unexpected Death Study, we evaluated SCD cases that occurred in the community between 10 PM and 6 AM (nighttime) and compared them with daytime cases. Univariate comparisons were evaluated using Pearson χ2 tests and independent samples t tests. Logistic regression was used to further assess independent SCD risk. A total of 4126 SCD cases (66.2% male, 33.8% female) met criteria for analysis and 22.3% (n = 918) occurred during nighttime hours. Women were more likely to present with nighttime SCD than men (25.4% vs 20.6%; P < .001). In a multivariate regression model, female sex (odds ratio [OR] 1.3 [confidence interval (CI) 1.1-1.5]; P=.001), medications associated with somnolence/respiratory depression (OR 1.2 [CI 1.1-1.4]; P = .008) and chronic obstructive pulmonary disease/asthma (OR 1.4 [CI 1.1-1.6]; P < .001) were independently associated with nighttime SCD. Women were taking more central nervous system-affecting medications than men (1.9 ± 1.7 vs 1.4 ± 1.4; P = .001). In the general population, women were more likely than men to suffer SCD during nighttime hours and female sex was an independent predictor of nighttime events. Respiratory suppression is a concern, and caution is advisable when prescribing central nervous system-affecting medications to patients at an increased risk of SCD, especially women.

Autopsy study of sudden cardiac death

BackgroundThe causes of sudden cardiac death are undetected despite detailed postmortem examination, histological examination and toxicological analysis leading to negative autopsy in some cases. The present study is carried out with a view to evaluate the victims of sudden cardiac death (SCD) brought for medicolegal autopsy.The present cross sectional study included 74 cases of sudden cardiac death within 24 hours with history of chest pain or known ischaemic heart disease brought for medicolegal autopsy. During the autopsy, heart and coronaries were dissected to find out any pathology and the subjected for histopathological examination.ResultsThe victims of SCD were mostly males (85.1%) with peak incidence in older ages above 60years (41.9%). Almost 84% of the victims had survival period of less than 6 hours. Left anterior descending artery (64.9%) was the commonest coronary artery involved with atherosclerosis. Most of the victims had double vessel block with 71.6% had coronary narrowing exceeding 75% stenosis. There was statistically significant positive correlation between the coronary block and the age of the victim of sudden cardiac death (p=0.007).Careful and detailed autopsy can be conducted in SCD to find out its cause.

The Contribution of Known Familial Cardiovascular Disease Genes to Sudden Cardiac Death in Patients Undergoing Hemodialysis

Introduction: Patients with chronic kidney disease experience high rates of cardiovascular mortality and morbidity. When kidney disease progresses to the need for dialysis, sudden cardiac death (SCD) accounts for 25–35% of all cardiovascular deaths. The objective was to determine if rare genetic variants known to be associated with cardiovascular death in the general population are associated with SCD in patients undergoing hemodialysis. Methods: We performed a case-control study comparing 126 (37 African American [AfAn] and 89 European ancestry [EA]) SCD subjects and 107 controls (34 AfAn and 73 EA), matched for age, sex, self-reported race, dialysis duration (<2, 2–5 and >5 years), and the presence or absence of diabetes mellitus. To target the coding regions of genes previously reported to be associated with 15 inherited cardiac conditions (ICCs), we used the TruSight Cardio Kit (Illumina, San Diego, CA, USA) to capture the genetic regions of interest. In all, the kit targets 572-kb regions that include the protein-coding regions and 40-bp 5′ and 3′ end-flanking regions of 174 genes associated with the 15 ICCs. Using the sequence data, burden tests were conducted to identify genes with an increased number of variants among SCD cases compared to matched controls. Results: Eleven genes were associated with SCD, but after correction for multiple testing, none of the 174 genes were identified as having more variants in the SCD cases than the matched controls, including previously identified genes. Secondary burden tests grouping variants based on diseases and gene function did not produce statistically significant associations. Discussion/Conclusions: We found no associations between genes known to be associated with ICCs and SCD in our sample of patients undergoing hemodialysis. This suggests that genetic causes are unlikely to be a major pathogenic factor in SCD in hemodialysis patients, although our sample size limits definitive conclusions.