Cardiac Death In Young Adults Research Articles

6 Prevalence and CMR characteristics of apical HCM: Abstract 6 Table 1

Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young adults. The 3 main phenotypes are asymmetric (most common), concentric and apical. Literature suggests apical HCM is rare and more benign, but data is scarce. We sought to describe prevalence and characteristics of apical HCM in a large CMR service. Methods We reviewed 3,100 scans (Jan 2014–Mar 2015). Protocol included cines, early and late gadolinium enhancement imaging. 114 consecutive HCM patients were identified. Asymmetric HCM defined as septal/ free wall thickness ratio > 1.3; apical HCM as apical wall thickness > 15mm or apical/basal wall thicknesses ≥ 1.3–1.5. Concentric HCM defined as symmetrical hypertrophy of ventricular wall without regional preferences. Non-apical HCM (asymmetric and concentric phenotypes) were compared with apical HCM. Fisher’s exact t-test and unpaired t-test were performed for statistical significance (P-value Results 10 patients were excluded, leaving 104 patients, median age 60years; 70% male. 70% had non-apical HCM (5 patients concentric HCM, the rest asymmetric HCM) and 30% apical HCM. Mean maximum LV wall thickness, indexed LV mass, stroke volume, prevalence of LVOTO and SAM were greater in non-apical group. Presence of LGE was high in both groups (>85%) and wasn’t statistically different. Univariate predictors of apical HCM included maximum LV wall thickness, indexed stroke volume, LVOT obstruction (Table 1). In the multivariate model, maximum wall thickness remained the only significant predictor. Conclusions Our study suggests that prevalence of apical HCM is almost 1/3rd of all observed cases. It also demonstrates that prevalence of LGE was high in apical HCM, suggesting that better prognosis of apical HCM based on the absence of myocardial fibrosis, should be reconsidered. Further large trials are needed to better understand the pathophysiology.

Novel Approach Targeting the Complex Pathophysiology of Hypertrophic Cardiomyopathy: The Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) Trial.

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disorder, with an overall prevalence of at least 1:500 in the adult population although only a fraction of affected patients come to clinical recognition. It is also the most common cause of sudden cardiac death in young adults and a major cause of morbidity caused by chronic heart failure symptoms. However, more than half a century since the original description of the disease, there is no currently approved therapy for the treatment of patients with HCM, and to date there have been only 5 randomized studies of medical therapies in HCM. As such, unmet medical need in HCM has been highlighted by the National Heart, Lung, and Blood Institute (NHLBI) as a research priority. Encouragingly, the infrastructure needed to conduct rigorous clinical trials in HCM has recently emerged because of the heightened awareness and understanding of the disease, development of clinical centers of excellence, and advances in diagnostic imaging. In this article, we will discuss the complex pathophysiology of HCM, review the current therapeutic landscape, describe new mechanistic insights into the central role of the late sodium current in HCM, and introduce the scientific rationale and execution of the Impact of Late Sodium Current Inhibition on Exercise Capacity in Subjects with Symptomatic Hypertrophic Cardiomyopathy (LIBERTY-HCM) trial, the largest randomized, double-blind, placebo controlled clinical trial, now underway, designed to evaluate the effect of a novel pharmacological approach in patients with symptomatic HCM. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02291237.

Cannabidiol Limits T Cell-Mediated Chronic Autoimmune Myocarditis: Implications to Autoimmune Disorders and Organ Transplantation.

Myocarditis is a major cause of heart failure and sudden cardiac death in young adults and adolescents. Many cases of myocarditis are associated with autoimmune processes in which cardiac myosin is a major autoantigen. Conventional immunosuppressive therapies often provide unsatisfactory results and are associated with adverse toxicities during the treatment of autoimmune myocarditis. Cannabidiol (CBD) is a nonpsychoactive constituent of marijuana that exerts antiinflammatory effects independent of classical cannabinoid receptors. Recently, 80 clinical trials have investigated the effects of CBD in various diseases from inflammatory bowel disease to graft versus host disease. CBD-based formulations are used for the management of multiple sclerosis in numerous countries, and CBD also received U.S. Food and Drug Administration approval for the treatment of refractory childhood epilepsy and glioblastoma multiforme. Herein, using a well-established mouse model of experimental autoimmune myocarditis (EAM) induced by immunization with cardiac myosin emmulsified in adjuvant resulting in T cell-mediated inflammation, cardiomyocyte cell death, fibrosis and myocardial dysfunction, we studied the potential beneficial effects of CBD. EAM was characterized by marked myocardial T-cell infiltration, profound inflammatory response and fibrosis (measured by quantitative real-time polymerase chain reaction, histology and immunohistochemistry analyses) accompanied by marked attenuation of both systolic and diastolic cardiac functions measured with a pressure-volume conductance catheter technique. Chronic treatment with CBD largely attenuated the CD3+ and CD4+ T cell-mediated inflammatory response and injury, myocardial fibrosis and cardiac dysfunction in mice. In conclusion, CBD may represent a promising novel treatment for managing autoimmune myocarditis and possibly other autoimmune disorders and organ transplantation.

Statin Induced Regression of Cardiomyopathy Trial: A Randomized, Placebo-controlled Double-blind Trial.

Background:Hypertrophic cardiomyopathy (HCM), characterized by a thickened, fibrotic myocardium, remains the most common cause of sudden cardiac death in young adults. Based on animal and clinical data, we hypothesized that atorvastatin would induce left ventricular (LV) mass regression.Methods:Statin Induced Regression of Cardiomyopathy Trial (SIRCAT) was a randomized, placebo-controlled study. The primary endpoint was change in LV mass measured by cardiac magnetic resonance imaging 12 months after treatment with once-daily atorvastatin 80 mg or placebo. A key secondary endpoint was diastolic dysfunction measured echocardiographically by transmitral flow velocities. SIRCAT is registered with www.clinicaltrials.gov (NCT00317967).Results:Of 222 screened patients, 22 were randomized evenly to atorvastatin and placebo. The mean age was 47 ± 10 years, and 15 (68%) were male. All subjects completed the protocol. At baseline, LV masses were 197 ± 76 g and 205 ± 82 g in the placebo and atorvastatin groups, respectively. After 12 months treatment, the LV masses in the placebo and atorvastatin groups were 196 ± 80 versus 206 ± 92 g (P = 0.80), respectively. Echocardiographic indices were not different in the two groups at baseline. After 12 months, diastolic dysfunction as assessed using transmitral flow velocities E/E', A/A', and peak systolic mitral velocity showed no benefit from atorvastatin.Conclusions:In patients with HCM, atorvastatin did not cause LV mass regression or improvements in LV diastolic function.

Abstract 12532: Cellular and Cardiac Microtissue Assays of iPSC-derived Myocytes With the Hypertrophic Cardiomyopathy Mutation in MYH7-Val606Met

Introduction: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease affecting 1 in 500 people and is the leading cause of sudden cardiac death in young adults. Mutations in β-myosin heavy chain ( MYH7 ) account for one-third of cases, but the underlying pathogenesis remains unclear. In this study, we investigated myocytes derived from CRISPR-Cas9-engineered isogenic induced pluripotent stem cell cardiomyocytes (iPSC-CMs) with a missense mutation Val606Met by single-cell and microtissue functional assays. Hypothesis: We hypothesize that iPSC-CMs with Val606Met will recapitulate features of HCM in single cell and microtissue assays, such as changes in contractile function and hypertrophic signaling. Methods & Results: Val606Met mutations in MYH7 (VM/+, VM/VM) were introduced by targeting an iPSC line using CRISPR-Cas9. Transfected iPSCs were isolated by FACS to detect green fluorescent protein, clones were expanded, and mutational events were confirmed by Sanger sequencing. Mutant iPSCs, like isogenic wildtype control iPSCs, were differentiated into cardiomyocytes with >90% efficiency. Microtissue studies of mutant iPSC-CMs exhibited increases in contractility (WT=2.96±0.23μN, VM/+ = 3.51±0.34μN, VM/VM = 4.63±0.51; R 2 = 0.963). Mutant iPSC-CMs also showed evidence of altered signaling by increases in spontaneous beating rate (WT < VM/+ < VM/VM; R 2 =0.946), cell size (compared to WT, ~20% increases in both VM/+, p=0.04 and VM/VM, p=0.038), and sarcomere content (compared to WT, ~20% increases in both VM/+, p=4e-06 and VM/VM, p=0.11). These changes are supported by activated expression in myocytes of hypertrophic genes such as NPPA , NPPB , and ACTA2 as well as transcriptional up-regulation of TGF-β. Conclusions: Isogenic iPSC-CMs with MYH7 variant Val606Met created by CRISPR-Cas9 recapitulate features of HCM in vitro . Our data confirms Val606Met as a pathogenic mutation that causes increased contractility in cardiac microtissues and myocyte hypertrophy. We speculate that increased myocyte-derived TGF-β signaling may contribute to the HCM phenotype. This approach could also be used for better understanding of genotype-phenotype correlations in HCM.

Sudden cardiac death in young adults with previous hospital-based psychiatric inpatient and outpatient treatment: a nationwide cohort study from Denmark.

Psychiatric patients have premature mortality compared to the general population. The incidence of sudden cardiac death (SCD) in psychiatric patients is unknown in a nationwide setting. The aim of this study was to compare nationwide SCD incidence rates in young individuals with and without previous psychiatric disease. Nationwide, retrospective cohort study including all deaths in people aged 18-35 years in 2000-2006 in Denmark. The unique Danish death certificates and autopsy reports were used to identify SCD cases. Psychiatric disease was defined as a previous psychiatric hospital contact and was identified using The Danish Psychiatric Central Research Register. All diagnoses in Danish registries are coded according to ICD-8 or ICD-10. All hospital records were retrieved manually. Among 5,178 deaths, 395 were due to SCD and autopsies were performed on 262 (66%). In 77 SCD cases, a previous psychiatric hospital contact was identified. The SCD incidence rate in psychiatric patients was 14.8 (95% CI, 11.7-18.5) per 100,000 person-years versus 3.8 (95% CI, 3.4-4.3) per 100,000 person-years in individuals without psychiatric hospital contact (incidence rate ratio = 3.9; 95% CI, 3.0-5.0; P < .01). Incidence rates per 100,000 persons-years were the highest in patients with schizophrenia-spectrum disorders (38.9; 95% CI, 26.4-55.2) and substance-related disorders (31.6; 95% CI, 19.3-48.8). SCDs in psychiatric patients compared to nonpsychiatric patients were more often unexplained (65% vs 40%, P = .02), and cardiac symptoms were reported prior to death in 46% of psychiatric patients. Patients with prior psychiatric hospital contact have a 4-fold increased risk of SCD. Since almost 50% had possible cardiac symptoms prior to death, cardiovascular risk monitoring and management in the mentally ill are essential.

Sudden Cardiac Death in Three Generations of the Same Family: A case report

Every one of us has heard about tragic and sudden death of a healthy young person and which is often stated as ‘inexplicable’. The current case report focuses on a 20 year old young man with hypertrophic cardiomyopathy facing premature death with history of similar sudden premature death of his grandmother, father and brother. Hypertrophic cardiomyopathy is the commonest cause of sudden cardiac death in young adults and is also an important substrate for heart failure disability at any age.Cardiovasc. j. 2015; 8(1): 73-77

Massive parallel sequencing applied to the molecular autopsy in sudden cardiac death in the young

Sudden cardiac death in the young is a very traumatic event that occurs often in apparently healthy individuals without an explainable cause of death after a comprehensive medico-legal investigation. Knowledge about the pathologies with a risk of sudden death is increasingly showing a greater underlying genetic heterogeneity, which provides one of the main handicaps for molecular autopsy. On the other hand the enormous technological advances in sequencing technologies, allow us to analyse as many genes as we want at a cost increasingly reduced. The sum of these two factors (increased knowledge of genetics and available technologies) allow us to make an individualized study of the causes of sudden cardiac death in young adults, through massive sequencing of all potential genes involved in the process. We define this approach as massive genomic autopsy, and with this review we will try to explain the possible scenarios and methods available for its implementation.

Application of next-generation semiconductor sequencing technologies in genetic diagnosis of inherited cardiomyopathies

Inherited cardiomyopathy is the most common hereditary cardiac disease. It also causes a significant proportion of sudden cardiac deaths in young adults and athletes. So far, approximately one hundred genes have been reported to be involved in cardiomyopathies through different mechanisms. Therefore, the identification of the genetic basis and disease mechanisms of cardiomyopathies are important for establishing a clinical diagnosis and genetic testing. Next-generation semiconductor sequencing (NGSS) technology platform is a high-throughput sequencer capable of analyzing clinically derived genomes with high productivity, sensitivity and specificity. It was launched in 2010 by Life Technologies of USA, and it is based on a high density semiconductor chip, which was covered with tens of thousands of wells. NGSS has been successfully used in candidate gene mutation screening to identify hereditary disease. In this review, we summarize these genetic variations, challenge and application of NGSS in inherited cardiomyopathy, and its value in disease diagnosis, prevention and treatment.

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

Brugada syndrome (BrS) is an inherited cardiac arrhythmia syndrome first described as a new clinical entity in 1992. Electrocardiographically characterized by distinct coved type ST segment elevation in the right-precordial leads, the syndrome is associated with a high risk for sudden cardiac death in young adults, and less frequently in infants and children. The electrocardiographic manifestations of BrS are often concealed and may be unmasked or aggravated by sodium channel blockers, a febrile state, vagotonic agents, as well as by tricyclic and tetracyclic antidepressants. An implantable cardioverter defibrillator is the most widely accepted approach to therapy. Pharmacologic therapy is designed to produce an inward shift in the balance of currents active during the early phases of the right ventricular action potential (AP) and can be used to abort electrical storms or as an adjunct or alternative to device therapy when use of an implantable cardioverter defibrillator is not possible. Isoproterenol, cilostazol, and milrinone boost calcium channel current and drugs like quinidine, bepridil, and the Chinese herb extract Wenxin Keli inhibit the transient outward current, acting to diminish the AP notch and thus to suppress the substrate and trigger for ventricular tachycardia or fibrillation. Radiofrequency ablation of the right ventricular outflow tract epicardium of patients with BrS has recently been shown to reduce arrhythmia vulnerability and the electrocardiographic manifestation of the disease, presumably by destroying the cells with more prominent AP notch. This review provides an overview of the clinical, genetic, molecular, and cellular aspects of BrS as well as the approach to therapy.

The Diagnosis, Risk Stratification, and Treatment of Brugada Syndrome.

Brugada syndrome (BrS) is among the more common familial arrhythmia syndromes, with an estimated prevalence of 1 to 5 per 10 000 persons. It is characterized by a right ventricular conduction delay, dynamic or persistent ST-segment elevations in the precordial leads V1-3 , and an elevated risk of syncope and sudden cardiac death in young adults without structural heart disease. This article is based on original and review articles on BrS that appeared in English from 2010 onward and were retrieved by a selective search in PubMed, with special attention to international consensus publications on inherited arrhythmogenic diseases. According to the new diagnostic criteria, the diagnosis of BrS requires typical ECG changes in only one precordial lead. This will likely increase sensitivity, but may also lead to an increase in asymptomatic patients. Established risk markers include sudden cardiac arrest and a spontaneous type 1 ECG with arrhythmic syncope. Patients with these findings benefit from the implantation of a cardioverter-defibrillator. There is no validated algorithm for risk stratification of asymptomatic patients. Because of the low prevalence of BrS, there have been no randomized controlled trials (RCTs) in this disease, and all recommendations are based on expert opinion. BrS is usually inherited in an autosomal dominant manner. Recently discovered gene polymorphisms modify the risk of BrS, challenging the conception of BrS as a monogenetic disease. Electro-anatomic mapping studies have revealed, for the first time, an arrhythmogenic substrate over the right ventricular outflow tract in BrS patients. BrS is one important differential diagnosis to consider in patients presenting with syncope or sudden cardiac arrest. The goal of current research is to achieve a deeper understanding of the genetic and electrophysiological changes underlying BrS. Further insights in these areas will probably enable better risk stratification of asymptomatic BrS patients in the future.

T2-Mapping CMR increases the diagnostic sensitivity for detection of myocardial inflammation in patients with possible myocarditis - a prospective endomyocardial biopsy-controlled study

Myocarditis has been reported in up to 20% of sudden cardiac death in young adults and is a frequent precursor of dilated cardiomyopathy. Unfortunately, the diagnostic tools for detection of myocarditis are still imperfect: Sensitivity of endomyocardial biopsy (EMB) is reduced largely due to the inherent sampling error. Cardiac magnetic resonance (CMR) offers the advantage of analysing the whole myocardium, but contrast-enhanced as well as T2weighted CMR exhibit inadequate sensitivity, especially during early stages of inflammation. Our hypothesis was that quantitative T2 relaxation mapping increases diagnostic sensitivity in CMR-based diagnosis of myocarditis. Methods We carried out a prospective observational study in patients with probable acute myocarditis characterized by clinical presentation, new global or regional wall abnormalities or arrhythmias or hsTNT-elevation. Of the 55 patients screened, two patients did not undergo CMR (1 pacemaker, 1 ECLS-support) and 16 patients refused EMB. The remaining 37 patients underwent EMB and CMR examination (1.5 T, Archieva, Philips) within 36h. Histological evaluation was performed by two independent pathologists (hematoxylin eosin staining, picrosirius red, IH CD68, CD45R0 and CD3) and by molecular analysis for viral replication/genome. CMR data were analysed blinded with respect to ventricular volumes and ejection fraction as well as T2, LGE and Strain Encoded (SENC)Imaging. A GRASE sequence (15 Echoes separated by 10ms, res: 2x2x10 mm2, 3 short axis slices) was used for localized T2 mapping. Age-matched volunteers (37) served as controls for ROC curve analysis in terms of quantitative T2-mapping. Results were compared by two-sided t-Test; p<0.05 was considered significant. Results

Surgery for hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a genetically determined cardiac disease characterised by otherwise unexplained myocardial hypertrophy of the left ventricle, and may result in left ventricular outflow tract obstruction. It is the most common cause of sudden cardiac death in young adults due to arrhythmias. Septal myectomy is a surgical treatment for HCM with moderate to severe outflow tract obstruction, and is indicated for patients with severe symptoms refractory to medical therapy. The surgical approach involves obtaining access to the interventricular septum via transaortic, transapical or transmitral approaches, and excising a portion of the hypertrophied myocardium to relieve the outflow tract obstruction. Large, contemporary series from centres experienced in septal myectomy patients have demonstrated a low early mortality of <2%, excellent long-term survival that matches the general population, and durable relief of symptoms.

Myocarditis - Diagnosis, treatment, use of cardiac magnetic resonance imaging and case report of a young athlete

Myocarditis is defined as the inflammation of the myocardium. It is an illness with many different faces at the time of clinical presentation or suspicion. The clinical presentation is highly variable ranging from asymptomatic to rapidly progressive and fatal congestive heart failure. Myocarditis accounts for 2-42% of sudden cardiac deaths in young adults based on the autopsy data (1). Use of cardiac magnetic resonance expanded the possibilities of the non-invasive assessment of myocardial inflammation and opened new ways for risk stratification of patients.

Next generation diagnostics on cardiomyopathy

Cardiomyopathies are common, seemingly monogenic autosomal dominant cardiac disorders known as the primary cause of sudden cardiac death in young adults. These diseases are characterized by a remarkable genetic heterogeneity, which makes it difficult to unravel the causative mutation in a diagnostic laboratory that is very laborious and expensive by Sanger sequencing. To circumvent these limitations, we explored solutions of high throughput sequencing of targeted exomes with the aim to implement this approach in routine diagnostics. As a first test we designed a capture microarray with the total genomic length of 1 Mbp that includes all exons/splicing sites of 130 genes involved in cardiovascular mendelian disorders and analyzed simultaneously four samples by multiplexing patients with cardiomyopathies or Long-QT syndrome. Pathogenic mutations and variants of unknown significance were found thus resolving the genetic causes of the cardiopathy in three. In the fourth patient the mutation usually associated with hypertrophic cardiomyopathy was found with Long-QT. Further developments to next generation diagnostics are now in progress, and will be also discussed. In conclusion, high throughput sequencing holds considerable promises for molecular diagnosis of highly heterogeneous disorders in clinical practice and allows a better understanding of the complexity of mendelian disorders.

Congenital and Hereditary Causes of Sudden Cardiac Death in Young Adults: Diagnosis, Differential Diagnosis, and Risk Stratification

Sudden cardiac death is defined as death from unexpected circulatory arrest-usually a result of cardiac arrhythmia-that occurs within 1 hour of the onset of symptoms. Proper and timely identification of individuals at risk for sudden cardiac death and the diagnosis of its predisposing conditions are vital. A careful history and physical examination, in addition to electrocardiography and cardiac imaging, are essential to identify conditions associated with sudden cardiac death. Among young adults (18-35 years), sudden cardiac death most commonly results from a previously undiagnosed congenital or hereditary condition, such as coronary artery anomalies and inherited cardiomyopathies (eg, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy [ARVC], dilated cardiomyopathy, and noncompaction cardiomyopathy). Overall, the most common causes of sudden cardiac death in young adults are, in descending order of frequency, hypertrophic cardiomyopathy, coronary artery anomalies with an interarterial or intramural course, and ARVC. Often, sudden cardiac death is precipitated by ventricular tachycardia or fibrillation and may be prevented with an implantable cardioverter defibrillator (ICD). Risk stratification to determine the need for an ICD is challenging and involves imaging, particularly echocardiography and cardiac magnetic resonance (MR) imaging. Coronary artery anomalies, a diverse group of congenital disorders with a variable manifestation, may be depicted at coronary computed tomographic angiography or MR angiography. A thorough understanding of clinical risk stratification, imaging features, and complementary diagnostic tools for the evaluation of cardiac disorders that may lead to sudden cardiac death is essential to effectively use imaging to guide diagnosis and therapy.

Invited Commentary

HomeRadioGraphicsVol. 33, No. 7 PreviousNext Cardiac ImagingInvited CommentaryDavid A BluemkeDavid A BluemkeAuthor AffiliationsRadiology and Imaging Sciences, National Institutes of Health Clinical Center Bethesda, MD, 20892David A BluemkePublished Online:Nov 1 2013https://doi.org/10.1148/rg.337135169MoreSectionsFull textPDF ToolsImage ViewerAdd to favoritesCiteTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinked In Reference1. Stojanovska J, Garg A, Patel S, Melville DM, Kazerooni EA, Mueller GC. Congenital and hereditary causes of sudden cardiac death in young adults: diagnosis, differential diagnosis, and risk stratification. RadioGraphics 2013;33(7):1977–2001. Link, Google ScholarArticle HistoryPublished online: Nov 2013Published in print: Nov 2013 FiguresReferencesRelatedDetailsRecommended Articles Hypertrophic Cardiomyopathy from A to Z: Genetics, Pathophysiology, Imaging, and ManagementRadioGraphics2016Volume: 36Issue: 2pp. 335-354Cardiovascular CT and MRI in 2020: Review of Key ArticlesRadiology2021Volume: 301Issue: 2pp. 263-277Radiologic-Pathologic Correlation of Primary and Secondary Cardiomyopathies: MR Imaging and Histopathologic Findings in Hearts from Autopsy and TransplantationRadioGraphics2017Volume: 37Issue: 3pp. 719-736Cardiac MRI of Hereditary CardiomyopathyRadioGraphics2022Volume: 42Issue: 3pp. 625-643Fibrofatty Changes: Incidence at Cardiac MR Imaging in Patients with Arrhythmogenic Right Ventricular Dysplasia/CardiomyopathyRadiology2016Volume: 280Issue: 2pp. 405-412See More RSNA Education Exhibits Apical Variant Hypertrophic Cardiomyopathy “Multimodality Imaging Evaluation”Digital Posters2019Challenges and New Perspectives in Pediatric Cardiomyopathies Characterization by Cardiac Magnetic Resonance: What to Know and What to Look ForDigital Posters2019Role of Cardiogenetics Imaging in the Era of Radiogenomics and Precision MedicineDigital Posters2019 RSNA Case Collection Hypertrophic cardiomyopathyRSNA Case Collection2020Chronic myocardial infarctionRSNA Case Collection2020Acute myocardial InfarctionRSNA Case Collection2021 Vol. 33, No. 7 Metrics Altmetric Score PDF download

Earliest electrocardiogram is golden for the diagnosis of Brugada Syndrome

Cardiac syncope can be classified as being either structural or dysrhythmogenic in origin, and it may be the only warning symptom of sudden cardiac death. One of the causes of dysrhythmic sudden cardiac death in young adults with structurally normal hearts is Brugada syndrome. Electrocardiogram (ECG) of Brugada syndrome is characterized by an ST-segment elevation in the right precordial leads. A 23-year-old man was presented to our emergency department (ED) with a history of syncope which has occurred 30 minutes before arrival and lasted for 10 minutes. Both physical and neurological examinations were unremarkable. Family history revealed coronary artery disease of his father and sudden death at 45. Initial ECG performed 3 minutes after his arrival showed a type 2 repolarization variant of Brugada syndrome. This pattern was reverted back to normal 5 minutes later and never showed up again on his future ECGs. In our case, it was only the earliest ECG that made the diagnosis possible since all future ECGs showed a perfectly normal pattern throughout the follow-up period. In all syncope patients, initial ECGs should be kept and filed to be reviewed again in case the primary physician is not competent enough for the evaluation of ECG.

The microRNA 221/222 cluster controls CVB3-induced myocarditis: could tiny microRNAs explain adverse inflammation in the heart?

Background: Viral myocarditis is an important cause of heart failure and sudden cardiac death in young adults. Our previous studies have shown that many microRNAs are differentially expressed in the heart during viral myocarditis, including microRNA-221 and -222. Therefore we aimed at studying the biological role of these miRs during viral myocarditis in mice, induced by human Coxsackie B3 virus. Materials and methods: We measured cardiac microRNA levels during VM with microarrays and qRT-PCR. Wild type C3H mice were intraperitoneally infected with CVB3. Mice were sacrificed at day 4 and day 7 post infection. The hearts, and other organs, were weighted and collected for histological analyses, immunoblotting and qRT-PCR. In vitro experiments were performed in neonatal rat cardiomyocytes (nRCMs). Results: Levels of miR-221 and miR-222 were significantly elevated during acute viral myocarditis in mice, and depressed in biopsies from viral myocarditis patients. In situ hybridization and in vitro experiments showed that both miRs are expressed by cardiomyocytes and cardiac endothelial cells, and are up regulated in neonatal rat cardiomyocytes (nRCMs) in response to enteroviral infection. In vivo inhibition of miR-221 and miRNA-222 by systemically delivered antagomirs (day +1, +3 and +6) aggravated cardiac injury and inflammation at day 7 post-infection, related to a threefold increase of viral loads at day +7 as compared to scrambled antagomiRs. Likewise, inhibition of miR-221 and -222 significantly increased the number of viral particles in nRCMs, whereas overexpression of miR-221 and -222 in nRCMs inhibited enteroviral replication by 30 percent at 48h post-infection. We identified and confirmed a set of conserved miR-221/-222 targets, including ETS1 and ETS2, the chemokine CXCL12, the type I interferon inhibitor IRF2, the T cell development factor TOX and the anti-apoptotic proteins BCL2L11 and BMF. Furthermore, the Coxsackie and adenovirus receptor (CXADR), up regulated in biopsies of patients with dilated cardiomyopathy, is also targeted by miR-221/-222 in mice and rats. De-repression of CXADR upon inhibition of miR-221/-222 may explain the higher viral load observed in vivo and in vitro. Higher CXADR levels contribute to increased viral entry in the cardiomyocyte. Conclusions: Systemic inhibition of miR-221 and miR-222 increases initial cardiac viral loads and resulting inflammation and necrosis during VM in mice. Both targets involved in increased viral replication and enhanced inflammation with inhibition of the miR-221/-222 family are involved. This miR cluster thus represents a master switch in VM.

Cellular mechanisms underlying the effects of milrinone and cilostazol to suppress arrhythmogenesis associated with Brugada syndrome

Brugada syndrome is an inherited disease associated with vulnerability to ventricular tachycardia and sudden cardiac death in young adults. Milrinone and cilostazol, oral phosphodiesterase (PDE) type III inhibitors, have been shown to increase L-type calcium channel current (ICa) and modestly increase heart rate by elevating the level of intracellular cyclic adenosine monophosphate. To examine the effectiveness of these PDE inhibitors to suppress arrhythmogenesis in an experimental model of Brugada syndrome. Action potential (AP) and electrocardiographic recordings were obtained from epicardial and endocardial sites of coronary-perfused canine right ventricular wedge preparations. The Ito agonist NS5806 (5 μM) and Ca(2+) channel blocker verapamil (2μM) were used to pharmacologically mimic Brugada phenotype. The combination induced all-or-none repolarization at some epicardial sites but not others, leading to ST-segment elevation as well as an increase in both epicardial and transmural dispersion of repolarization. Under these conditions, phase 2 reentry developed as the epicardial AP dome propagated from sites where it was maintained to sites at which it was lost, generating closely coupled extrasystoles and ventricular tachycardia. The addition of the PDE inhibitor milrinone (2.5μM) or cilostazol (5-10μM) to the coronary perfusate restored the epicardial AP dome, reduced dispersion, and abolished phase 2 reentry-induced extrasystoles and ventricular tachycardia. Our study identifies milrinone as a more potent alternative to cilostazol for reversing the repolarization defects responsible for the electrocardiographic and arrhythmic manifestations of Brugada syndrome. Both drugs normalize ST-segment elevation and suppress arrhythmogenesis in experimental models of Brugada syndrome.