Concept: Sudden cardiac death
Sudden cardiac death exhibits diurnal variation in both acquired and hereditary forms of heart disease, but the molecular basis of this variation is unknown. A common mechanism that underlies susceptibility to ventricular arrhythmias is abnormalities in the duration (for example, short or long QT syndromes and heart failure) or pattern (for example, Brugada’s syndrome) of myocardial repolarization. Here we provide molecular evidence that links circadian rhythms to vulnerability in ventricular arrhythmias in mice. Specifically, we show that cardiac ion-channel expression and QT-interval duration (an index of myocardial repolarization) exhibit endogenous circadian rhythmicity under the control of a clock-dependent oscillator, krüppel-like factor 15 (Klf15). Klf15 transcriptionally controls rhythmic expression of Kv channel-interacting protein 2 (KChIP2), a critical subunit required for generating the transient outward potassium current. Deficiency or excess of Klf15 causes loss of rhythmic QT variation, abnormal repolarization and enhanced susceptibility to ventricular arrhythmias. These findings identify circadian transcription of ion channels as a mechanism for cardiac arrhythmogenesis.
Anomalies of coronary number and course represent an opinion-dividing topic in cardiopathology, particularly for their relationship with sudden cardiac death. To the best of our knowledge, we herein report the first fatal case of a young female whose coronary anatomy was characterised by the absence of any septal perforator branch in the proximal segment of the LAD. This case could be useful for pathologists, coronary angiographers, and interventional cardiologists in detecting this infrequent anomaly, thus providing a more accurate estimation of its incidence. Virtual Slides The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/3570015858473043.
The Brugada syndrome (BrS) is a malignant, genetically-determined, arrhythmic syndrome manifesting as syncope or sudden cardiac death (SCD) in individuals with structurally normal hearts. The diagnosis of the BrS is mainly based on the presence of a spontaneous or Na + channel blocker induced characteristic, electrocardiographic (ECG) pattern (type 1 or coved Brugada ECG pattern) typically seen in leads V1 and V2 recorded from the 4th to 2nd intercostal (i.c.) spaces. This pattern needs to be distinguished from similar ECG changes due to other causes (Brugada ECG phenocopies). This review focuses mainly on the ECG-based methods for diagnosis and arrhythmia risk assessment in the BrS. Presently, the main unresolved clinical problem is the identification of those patients at high risk of SCD who need implantable cardioverter-defibrillator (ICD), which is the only therapy with proven efficacy. Current guidelines recommend ICD implantation only in patients with spontaneous type 1 ECG pattern, and either history of aborted cardiac arrest or documented sustained VT (class I), or syncope of arrhythmic origin (class IIa) because they are at high risk of recurrent arrhythmic events (up to 10% or more annually for those with aborted cardiac arrest). The majority of BrS patients are asymptomatic when diagnosed and considered to have low risk (around 0.5% annually) and therefore not indicated for ICD. The majority of SCD victims in the BrS, however, had no symptoms prior to the fatal event and therefore were not protected with an ICD. While some ECG markers such as QRS fragmentation, infero-lateral early repolarisation, and abnormal late potentials on signal-averaged ECG are known to be linked to increased arrhythmic risk, they are not sufficiently sensitive or specific. Potential novel ECG-based strategies for risk stratification are discussed based on computerised methods for depolarisation and repolarisation analysis, a composite approach targeting several major components of ventricular arrhythmogenesis, and the collection of large digital ECG databases in genotyped BrS patients and their relatives.
- Proceedings of the National Academy of Sciences of the United States of America
- Published about 1 year ago
Cardiopulmonary complications are the leading cause of mortality in sickle cell anemia (SCA). Elevated tricuspid regurgitant jet velocity, pulmonary hypertension, diastolic, and autonomic dysfunction have all been described, but a unifying pathophysiology and mechanism explaining the poor prognosis and propensity to sudden death has been elusive. Herein, SCA mice underwent a longitudinal comprehensive cardiac analysis, combining state-of-the-art cardiac imaging with electrocardiography, histopathology, and molecular analysis to determine the basis of cardiac dysfunction. We show that in SCA mice, anemia-induced hyperdynamic physiology was gradually superimposed with restrictive physiology, characterized by progressive left atrial enlargement and diastolic dysfunction with preserved systolic function. This phenomenon was absent in WT mice with experimentally induced chronic anemia of similar degree and duration. Restrictive physiology was associated with microscopic cardiomyocyte loss and secondary fibrosis detectable as increased extracellular volume by cardiac-MRI. Ultrastructural mitochondrial changes were consistent with severe chronic hypoxia/ischemia and sarcomere diastolic-length was shortened. Transcriptome analysis revealed up-regulation of genes involving angiogenesis, extracellular-matrix, circadian-rhythm, oxidative stress, and hypoxia, whereas ion-channel transport and cardiac conduction were down-regulated. Indeed, progressive corrected QT prolongation, arrhythmias, and ischemic changes were noted in SCA mice before sudden death. Sudden cardiac death is common in humans with restrictive cardiomyopathies and long QT syndromes. Our findings may thus provide a unifying cardiac pathophysiology that explains the reported cardiac abnormalities and sudden death seen in humans with SCA.
On autopsy, a patient is found to have hypertrophic cardiomyopathy. The patient’s family pursues genetic testing that shows a “likely pathogenic” variant for the condition on the basis of a study in an original research publication. Given the dominant inheritance of the condition and the risk of sudden cardiac death, other family members are tested for the genetic variant to determine their risk. Several family members test negative and are told that they are not at risk for hypertrophic cardiomyopathy and sudden cardiac death, and those who test positive are told that they need to be regularly monitored for cardiomyopathy . . .
Survival after sudden cardiac arrest (SCA) remains low, and tools for improved prediction of patients at long-term risk for SCA are lacking. Alternative short-term approaches aimed at preemptive risk stratification and prevention are needed.
Sudden cardiac death (SCD) is a leading cause of death in the United States and often occurs without previous cardiac symptoms. Lifetime risk for SCD and the influence of established risk factors on lifetime risks for SCD have not been estimated previously.
To determine the incidence of sudden cardiac arrest (SCA) and sudden cardiac death (SCD) in men and women.
- The American journal of forensic medicine and pathology
- Published over 4 years ago
The rise in popularity of “bath salts” as safe alternatives to MDMA (3,4-methylenedioxymethamphetamine), methamphetamine, and other illicit substances has resulted in increased scrutiny of the contents and toxicology associated with these products. We report a case of sudden death related to the synthetic cathinone methylone (3,4-methylenedioxy-N-methylcathinonmethylone) in a previously healthy 19-year-old man. Although several fatal case reports have been published involving methylone and other synthetic cathinones, this is the first reported case of sudden cardiac death associated with methylone use. Although lack of published data prevented a comparison of blood methylone concentrations between our case and existing reports, the amount of methylone we detected postmortem (0.07 mg/dL) is below those reported in MDMA-related fatalities. Our report suggests that methylone toxicity has been greatly underestimated by users of this synthetic cathinone.
SCN5A encodes the α subunit of the major cardiac sodium channel NaV1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5AE558X/+ pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5AE558X/+ hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5AE558X/+ pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.