The added value of molecular-based diagnostics in the African forensic medical setting.

Sudden unexpected infant death (SUDI) is reported to be an extraordinarily high burden in sub-Saharan Africa, with the incidence rate in South Africa among the highest in the world. It is common for the cause of many such infant deaths to remain unexplained even after a full medico-legal death investigation, and then to be categorised as a sudden unexplained infant death (SUID). Fortunately, advances in molecular-based diagnostics allow researchers to identify numerous underlying inherited cardiac arrhythmogenic disorders in many SUDI cases, with a predominance of variants identified in the SCN5A gene. Such cardiac arrhythmogenic-related sudden deaths generally present with no structural alterations of the heart that are macroscopically identifiable at autopsy, therefore highlighting the importance of post mortem genetic testing. We report on a significant genetic finding that was made on a SUDI case in which the cause was ascribed to an acute bacterial pneumonia but it was still subjected to post mortem genetic testing of the SCN5A gene. The literature shows that many SUDI cases diagnosed with inherited cardiac arrhythmogenic disorders have demonstrated a viral prodrome within days of their death. It is therefore not uncommon for these cardiac disorders in infants to be mistaken for flu, viral upper respiratory tract infection or pneumonia, and without the incorporation of post mortem genetic testing, any other contributory causes of these deaths are often disregarded. This study highlights the need for research reporting on the genetics of inherited cardiac disorders in Africa.

Has COVID-19 changed the spectrum of arrhythmias and the incidence of sudden cardiac death?

Arrhythmic manifestations of COVID-19 include atrial arrhythmias such as atrial fibrillation or atrial flutter, sinus node dysfunction, atrioventricular conduction abnormalities, ventricular tachyarrhythmias, sudden cardiac arrest, and cardiovascular dysautonomias including the so-called long COVID syndrome. Various pathophysiological mechanisms have been implicated, such as direct viral invasion, hypoxemia, local and systemic inflammation, changes in ion channel physiology, immune activation, and autonomic dysregulation. The development of atrial or ventricular arrhythmias in hospitalized COVID-19 patients has been shown to portend a higher risk of in-hospital death. Management of these arrhythmias should be based on published evidence-based guidelines, with special consideration of the acuity of COVID-19 infection, concomitant use of antimicrobial and anti-inflammatory drugs, and the transient nature of some rhythm disorders. In view of new SARS-CoV­2 variants that may evolve, the development and use of newer antiviral and immunomodulator drugs, and the increasing adoption of vaccination, clinicians must remain vigilant for other arrhythmic manifestations that may occur in association with this novel but potentially deadly disease.

COVID-19 vaccination-related myocarditis: a Korean nationwide study.

AIMS: A comprehensive nationwide study on the incidence and outcomes of COVID-19 vaccination-related myocarditis (VRM) is in need. METHODS AND RESULTS: Among 44 276 704 individuals with at least 1 dose of COVID-19 vaccination, the incidence and clinical courses of VRM cases confirmed by the Expert Adjudication Committee of the Korea Disease Control and Prevention Agency were analyzed. COVID-19 VRM was confirmed in 480 cases (1.08 cases per 100 000 persons). Vaccination-related myocarditis incidence was significantly higher in men than in women (1.35 vs. 0.82 per 100 000 persons, P < 0.001) and in mRNA vaccines than in other vaccines (1.46 vs. 0.14 per 100 000 persons, P < 0.001). Vaccination-related myocarditis incidence was highest in males between the ages of 12 and 17 years (5.29 cases per 100 000 persons) and lowest in females over 70 years (0.16 cases per 100 000 persons). Severe VRM was identified in 95 cases (19.8% of total VRM, 0.22 per 100 000 vaccinated persons), 85 intensive care unit admission (17.7%), 36 fulminant myocarditis (7.5%), 21 extracorporeal membrane oxygenation therapy (4.4%), 21 deaths (4.4%), and 1 heart transplantation (0.2%). Eight out of 21 deaths were sudden cardiac death (SCD) attributable to VRM proved by an autopsy, and all cases of SCD attributable to VRM were aged under 45 years and received mRNA vaccines. CONCLUSION: Although COVID-19 VRM was rare and showed relatively favorable clinical courses, severe VRM was found in 19.8% of all VRM cases. Moreover, SCD should be closely monitored as a potentially fatal complication of COVID-19 vaccination.

Evidence of Autoinflammation as a Principal Mechanism of Myocardial Injury in SARS-CoV-2 PCR-Positive Medical Examiner Cases (preprint)

Background Disease from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains the third leading cause of death in the United States, after cancer and heart disease. Many patients infected with this virus develop later cardiovascular complications including myocardial infarctions, stroke, arrhythmia, heart failure, and sudden cardiac death (20–28%). The purpose of this study is to understand the primary mechanism of myocardial injury in patients infected with SARS-CoV-2.Methods We investigated a consecutive cohort of 48 medical examiner cases who died with PCR-positive SARS-CoV-2 (COVpos) infection in 2020. We compared them to a consecutive cohort of 46 age and sex-matched controls who were PCR-negative for SARS-CoV-2 (COVneg). Clinical information available at postmortem examination was reviewed on each patient. Formalin-fixed sections were examined using antibodies directed against CD42 (platelets), CD15 (myeloid cells), CD68 (monocytes), C4d, Fibrin, CD34 (stem cell antigen), CD56 (natural killer cells), and Myeloperoxidase (MPO) (neutrophils and NETs). We used a Welch 2-sample T-test to determine significance. A cluster analysis of marker distribution was also done.Results We found a significant difference between COVpos and COVneg samples for all markers, all of which were significant at p < 0.001. The most prominent features were neutrophils (CD15, MPO) and MPO positive debris suggestive of NETS. A similar distribution of platelets, monocytes, fibrin and C4d was seen in COVpos cases. Clinical features were similar in COVpos and COVneg cases for age, sex, and body mass index (BMI).Conclusion These findings suggest an autoinflammatory process is likely involved in cardiac damage during these infections.

[Impact of the COVID-19 pandemic on basic resuscitation and success rate after sudden cardiac arrest]. / A COVID­19-pandémia hatása a hirtelen szívmegállást követo alapszintu újraélesztésre és annak sikerességére.

Since the onset of the coronavirus disease, infection-related mortality has been tracked worldwide and the number of deaths caused by the virus is counted daily. The coronavirus pandemic has not only transformed our daily life, but reorganized the whole healthcare system. In response to the increased demand for hospital admissions, leaders in different countries have implemented a number of emergency actions. The restructuring has had both direct and indirect negative effects on the epidemiology of sudden cardiac death, the willingness of lay rescuer to give cardiopulmonary resuscitation and the use of automated external defibrillators, but these negative effects vary widely across continents and countries. In order to protect lay people and health workers as well as to prevent the spread of the pandemic, the previous recommendations of the European Resuscitation Council on basic and advanced life support have undergone a few modifications. Orv Hetil. 2023; 164(13): 483-487.

Cardiovascular Risk Assessment after COVID-19 Infection before Resuming Sports Activities - Practical Flowchart and Meta-Analysis

Abstract Background: The risk of sports-related sudden cardiac arrest after COVID-19 infection can be a serious problem. There is an urgent need for evidence-based criteria to ensure patient safety before resuming exercise. Objective: To estimate the pooled prevalence of acute myocardial injury caused by COVID-19 and to provide an easy-to-use cardiovascular risk assessment toolkit prior to resuming sports activities after COVID-19 infection. Methods: We searched the Medline and Cochrane databases for articles on the prevalence of acute myocardial injury associated with COVID-19 infection. The pooled prevalence of acute myocardial injury was calculated for hospitalized patients treated in different settings (non-intensive care unit [ICU], ICU, overall hospitalization, and non-survivors). Statistical significance was accepted for p values <0.05. We propose a practical flowchart to assess the cardiovascular risk of individuals who recovered from COVID-19 before resuming sports activities. Results: A total of 20 studies (6,573 patients) were included. The overall pooled prevalence of acute myocardial injury in hospitalized patients was 21.7% (95% CI 17.3-26.5%). The non-ICU setting had the lowest prevalence (9.5%, 95% CI 1.5-23.4%), followed by the ICU setting (44.9%, 95% CI 27.7-62.8%), and the cohort of non-survivors (57.7% with 95% CI 38.5-75.7%). We provide an approach to assess cardiovascular risk based on the prevalence of acute myocardial injury in each setting. Conclusions: Acute myocardial injury is frequent and associated with more severe disease and hospital admissions. Cardiac involvement could be a potential trigger for exercise-induced clinical complications after COVID-19 infection. We created a toolkit to assist with clinical decision-making prior to resuming sports activities after COVID-19 infection.

Mechanical Complication of Acute Myocardial Infarction Secondary to COVID-19 Disease.

The aggressive inflammatory response to COVID-19 can result in airway damage, respiratory failure, cardiac injury, and multiorgan failure, which lead to death in susceptible patients. Cardiac injury and acute myocardial infarction (AMI) secondary to COVID-19 disease can lead to hospitalization, heart failure, and sudden cardiac death. When serious collateral damage from tissue necrosis or bleeding occurs, mechanical complications of myocardial infarction and cardiogenic shock can ensue. While prompt reperfusion therapies have decreased the incidence of these serious complications, patients who present late following the initial infarct are at increased for mechanical complications, cardiogenic shock, and death. The health outcomes for patients with mechanical complications are dismal if not recognized and treated promptly. Even if they survive serious pump failure, their CICU stay is often prolonged, and their index hospitalization and follow-up visits may consume significant resources and impact the health care system.

Sudden cardiac arrest during the COVID-19 pandemic: A two-year prospective evaluation in a North American community.

BACKGROUND: Early during the coronavirus disease 2019 (COVID-19) pandemic, higher sudden cardiac arrest (SCA) incidence and lower survival rates were reported. However, ongoing effects on SCA during the evolving pandemic have not been evaluated. OBJECTIVE: The purpose of this study was to assess the impact of COVID-19 on SCA during 2 years of the pandemic. METHODS: In a prospective study of Ventura County, California (2020 population 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first 2 years of the COVID-19 pandemic to the prior 4 years. RESULTS: Of 2222 out-of-hospital SCA cases identified, 907 occurred during the pandemic (March 2020 to February 2022) and 1315 occurred prepandemic (March 2016 to February 2020). Overall age-standardized annual SCA incidence increased from 39 per 100,000 (95% confidence [CI] 37-41) prepandemic to 54 per 100,000 (95% CI 50-57; P <.001) during the pandemic. Among Hispanics, incidence increased by 77%, from 38 per 100,000 (95% CI 34-43) to 68 per 100,000 (95% CI 60-76; P <.001). Among non-Hispanics, incidence increased by 26%, from 39 per 100,000 (95% CI 37-42; P <.001) to 50 per 100,000 (95% CI 46-54). SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15% to 10%; P <.001), and Hispanics were less likely than non-Hispanics to receive bystander cardiopulmonary resuscitation (45% vs 55%; P = .005) and to present with shockable rhythm (15% vs 24%; P = .003). CONCLUSION: Overall SCA rates remained consistently higher and survival outcomes consistently lower, with exaggerated effects during COVID infection peaks. This longer evaluation uncovered higher increases in SCA incidence among Hispanics, with worse resuscitation profiles. Potential ethnicity-specific barriers to acute SCA care warrant urgent evaluation and intervention.

COVID-19 and Heart Failure with Preserved and Reduced Ejection Fraction Clinical Outcomes among Hospitalized Patients in the United States.

Heart failure exacerbations impart significant morbidity and mortality, however, large- scale studies assessing outcomes in the setting of concurrent coronavirus disease-19 (COVID-19) are limited. We utilized National Inpatient Sample (NIS) database to compare clinical outcomes in patients admitted with acute congestive heart failure exacerbation (CHF) with and without COVID-19 infection. A total of 2,101,980 patients (Acute CHF without COVID-19 (n = 2,026,765 (96.4%) and acute CHF with COVID-19 (n = 75,215, 3.6%)) were identified. Multivariate logistic regression analysis was utilized to compared outcomes and were adjusted for age, sex, race, income level, insurance status, discharge quarter, Elixhauser co-morbidities, hospital location, teaching status and bed size. Patients with acute CHF and COVID-19 had higher in-hospital mortality compared to patients with acute CHF alone (25.78% vs. 5.47%, adjust OR (aOR) 6.3 (95% CI 6.05-6.62, p < 0.001)) and higher rates of vasopressor use (4.87% vs. 2.54%, aOR 2.06 (95% CI 1.86-2.27, p < 0.001), mechanical ventilation (31.26% vs. 17.14%, aOR 2.3 (95% CI 2.25-2.44, p < 0.001)), sudden cardiac arrest (5.73% vs. 2.88%, aOR 1.95 (95% CI 1.79-2.12, p < 0.001)), and acute kidney injury requiring hemodialysis (5.56% vs. 2.94%, aOR 1.92 (95% CI 1.77-2.09, p < 0.001)). Moreover, patients with heart failure with reduced ejection fraction had higher rates of in-hospital mortality (26.87% vs. 24.5%, adjusted OR 1.26 (95% CI 1.16-1.36, p < 0.001)) with increased incidence of vasopressor use, sudden cardiac arrest, and cardiogenic shock as compared to patients with heart failure with preserved ejection fraction. Furthermore, elderly patients and patients with African-American and Hispanic descents had higher in-hospital mortality. Acute CHF with COVID-19 is associated with higher in-hospital mortality, vasopressor use, mechanical ventilation, and end organ dysfunction such as kidney failure and cardiac arrest.

Evidence of Autoinflammation as the Principal Mechanism of Myocardial Injury in SARS-CoV-2 PCR-Positive Autopsy Hearts (preprint)

Background Disease from Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) remains the third leading cause of death in the United States, after cancer and heart disease. Many patients infected with this virus develop cardiovascular complications including myocardial infarctions, stroke, arrhythmia, heart failure, and sudden cardiac death. Specifically, patients with SARS-CoV-2 have a high prevalence of severe myocardial injury (20–28%). The purpose of this study is to understand the primary mechanism of myocyte injury in patients infected with SARS-CoV-2.Methods We investigated a consecutive cohort of 84 medical examiner cases who died with PCR-positive SARS-CoV-2 (COVpos) infection prior to availability of therapy or vaccines. We compared them to a consecutive cohort of 42 age- and sex-matched controls who were PCR-negative for SARS-CoV-2 (COVneg). Formalin-fixed paraffin embedded sections of left and right ventricle were examined on each case using antibodies directed against CD42 (platelets), CD15 (myeloid cells), CD68 (monocytes), C4d, Fibrin, CD34 (stem cell antigen), CD56 (natural killer cells), and Myeloperoxidase (MPO) (neutrophils and NETs). Slides were scanned using an Aperio slide scanner and viewer and each digital slide was entirely examined at 5x,10x and 20x. Each slide was graded using a 0–3 scale where 3 indicates the marker was present in every field at 20x. We used a Welch 2-sample T-test to determine significance.Results We found a significant difference between COVpos and COVneg samples for all markers, all of which were significant at p < 0.001. The most prominent features were neutrophils (CD15, MPO) and MPO positive debris suggestive of NETS and were located in or around arterioles, venules, and capillaries. A similar distribution of platelets, monocytes, and C4d was seen in COVpos cases. Fibrin was found scattered in arterioles, venules, interstitial regions, and within ventricular cavities. CD34 highlighted vascular alterations of endothelial cells in some but not all cases.Conclusion Autoinflammation is the primary mechanism of myocyte injury observed in COVpos hearts. The significant increase in platelets, monocytes, and neutrophils and the presence of neutrophil NETs, C4d, and fibrin suggest that myocardial injury involves neutrophils, NETosis, coagulation, complement activation, and monocyte accumulation.

Athlete deaths during the COVID-19 vaccination campaign: contextualisation of online information (preprint)

Background and aim: Lay people and medical professionals have suggested a link between (mRNA) COVID-19 vaccination and a purported increase in sudden cardiac arrest (SCA) and death (SCD) among athletes. We aimed to compare the athlete death rate in 2021-2022 with pre-pandemic estimates and investigate the role of vaccination. Methods: A comprehensive, much referenced, publicly available list of health issues, emergencies, and SCA/SCD in athletes from January 2021 to December 2022 was analysed. Demographic data, country, type of sport, vaccination status, and possible association between reported medical events and vaccination were evaluated for the complete set of athletes. The following data were specifically assessed for cases of SCD in young US athletes and compared to matched data from pre-pandemic studies: average annual SCD number, mean age, male/female ratio, sports with highest death toll, cause and scene of death, and relation to exercise. Descriptive statistics were used. Results: The list contained 1653 entries. (Former) athletes, aged 5-86 years, from 99 countries, participated in 61 different sports. In multiple cases, causes of and circumstances surrounding medical events were irretrievable. Many cases involved non-cardiovascular, exercise-unrelated aetiologies. Vaccination details were scarce. In 63 (3.8%) cases, including 9 fatal events, there was a plausible association with COVID-19 vaccination. In US athletes aged 9-40 (mean 22.7) years, 166 SCD cases were identified (average 83/year), mainly in males (83%) and in football (39.8%) and basketball (16.9%). Main causes of death were non-cardiovascular exercise-unrelated (22.9%) or unknown (50.6%). Deaths primarily occurred at rest (32.5%) or under unknown circumstances (38.6%). SCD characteristics were similar to those of two pre-pandemic studies with comparable datasets. Conclusion: SCD rate among young US athletes in 2021-2022 was comparable to pre-pandemic estimates. There is currently no evidence to substantiate a link between (mRNA) COVID-19 vaccination and SCD in (young) athletes.

Eosinophilic Infiltration of the Sino-Atrial Node in Sudden Cardiac Death Caused by Long QT Syndrome.

Sudden death is defined as the unexpected death of a healthy person that occurs within the first hour of the onset of symptoms or within 24 h of the victim being last seen alive. In some of these cases, rare deleterious variants of genes associated with inherited cardiac disorders can provide a highly probable explanation for the fatal event. We report the case of a 21-year-old obese woman who lost consciousness suddenly in a public place and was pronounced dead after hospital admission. Clinical autopsy showed an inconclusive gross examination, while in the histopathological analysis an eosinophilic inflammatory focus and interstitial fibrosis in the sino-atrial node were found. Molecular autopsy revealed an intronic variant in the KCNQ1 gene (c.683 + 5G > A), classified as likely pathogenic for long QT syndrome according to the guidelines provided by the American College of Medical Genetics and Genomics. Therefore, there were many anomalies that could have played a role in the causation of the sudden death, such as the extreme obesity, the cardiac anomalies and the KNCQ1 variant. This case depicts the difficult interpretation of rare cardiac structural abnormalities in subjects carrying rare variants responsible for inherited arrhythmic disorders and the challenge for the forensic pathologist to make causal inferences in the determinism of the unexpected decease.

Ethnicity-Specific Effects on Cardiac Arrest During the COVID-19 Pandemic: A Two-Year Prospective Evaluation in a North American Community (preprint)

Background: Out-of-hospital sudden cardiac arrest (SCA) is a major public health problem with mortality >90%, and incidence has increased during the COVID-19 pandemic. Information regarding ethnicity-specific effects on SCA incidence and survival is lacking. Methods: In a prospective, population-based study of Ventura County, CA residents (2020 Pop. 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first two years of the COVID-19 pandemic to the prior four years, overall and by ethnicity (Hispanic vs non-Hispanic). Findings: Of 2,222 OHCA cases identified, 907 occurred during the pandemic (March 2020 - Feb 2022) and 1315 occurred pre-pandemic (March 2016 - Feb 2020). Overall age-standardized annual SCA incidence increased from 38.9/100,000 [95% CI 36.8-41.0] pre-pandemic to 53.8/100,00 [95% CI 50.3 - 57.3, p<0.001] during the pandemic. Among Hispanics, incidence increased by 77%, from 38.2/100,00 [95% CI 33.8-42.5] to 67.7/100,00 [95% CI 59.5-75.8, p<0.001]. Among non-Hispanics, incidence increased by 26% from 39.4/100,000 [95% CI 36.9-41.9, p<0.001] to 49.8/100,00 [95% CI 45.8-53.8]. SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15.3% to 10.0%, p<0.001) and Hispanics were less likely than non-Hispanics to have bystander CPR (44.6% vs. 54.7%, p=0.005) and shockable rhythm (15.3% vs. 24.1%, p=0.003). Interpretation: Hispanic residents experienced higher SCA rates during the pandemic with less favorable resuscitation profiles. These findings implicate potential ethnicity-specific barriers to acute care and represent an urgent call to action at the community and health-system levels. Funding: National Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358.

Readiness of Bystander Cardiopulmonary Resuscitation (BCPR) during the COVID-19 Pandemic: A Review.

Early cardiopulmonary resuscitation (CPR) is a strong link in the of survival for sudden cardiac arrest. Hence, bystander CPR (BPCR) plays an important role in curbing mortality and morbidity from out-of-hospital sudden cardiac arrest. However, the recent global Coronavirus disease 2019 (COVID-19) pandemic has impacted both public training and confidence in performing out-of-hospital CPR. This paper reviews detailed information from databases including Google Scholar, Scopus, PubMed and Web of Science on the readiness of BCPR during the pandemic. We also discussed the challenges bystanders encountered during the COVID-19 pandemic and the precautions to follow. Finally, we also highlighted the limitations which would benefit future endeavours in establishing well-planned and sustainable CPR training programs for the public. Therefore, regardless of the existing COVID-19 pandemic, BCPR must be emphasised to curb out-of-hospital cardiac arrest (OHCA) mortality.

Arrhythmogenic Cardiomyopathy: Exercise Pitfalls, Role of Connexin-43, and Moving beyond Antiarrhythmics.

Arrhythmogenic Cardiomyopathy (ACM), a Mendelian disorder that can affect both left and right ventricles, is most often associated with pathogenic desmosomal variants that can lead to fibrofatty replacement of the myocardium, a pathological hallmark of this disease. Current therapies are aimed to prevent the worsening of disease phenotypes and sudden cardiac death (SCD). Despite the use of implantable cardioverter defibrillators (ICDs) there is no present therapy that would mitigate the loss in electrical signal and propagation by these fibrofatty barriers. Recent studies have shown the influence of forced vs. voluntary exercise in a variety of healthy and diseased mice; more specifically, that exercised mice show increased Connexin-43 (Cx43) expression levels. Fascinatingly, increased Cx43 expression ameliorated the abnormal electrical signal conduction in the myocardium of diseased mice. These findings point to a major translational pitfall in current therapeutics for ACM patients, who are advised to completely cease exercising and already demonstrate reduced Cx43 levels at the myocyte intercalated disc. Considering cardiac dysfunction in ACM arises from the loss of cardiomyocytes and electrical signal conduction abnormalities, an increase in Cx43 expression-promoted by low to moderate intensity exercise and/or gene therapy-could very well improve cardiac function in ACM patients.

Heart rate variability and adrenal size provide clues to sudden cardiac death in hospitalized COVID-19 patients.

PURPOSE: To examine the association between a measure of heart rate variability and sudden cardiac death (SCD) in COVID-19 patients. METHODS: Patients with SARS-COV-2 infection admitted to Columbia University Irving Medical Center who died between 4/25/2020 and 7/14/2020 and had an autopsy were examined for root mean square of successive differences (RMSSD), organ weights, and evidence of SCD. RESULTS: Thirty COVID-19 patients were included and 12 had SCD. The RMSSD over 7 days without vs with SCD was median 0.0129 (IQR 0.0074-0.026) versus 0.0098 (IQR 0.0056-0.0197), p < 0.0001. The total adjusted adrenal weight of the non-SCD group was 0.40 g/kg (IQR 0.35-0.55) versus 0.25 g/kg (IQR 0.21-0.31) in the SCD group, p = 0.0007. CONCLUSIONS: Hospitalized patients with COVID-19 who experienced SCD had lower parasympathetic activity (RMSSD) and smaller sized adrenal glands. Further research is required to replicate these findings.