Intramyocardial Inflammation after COVID-19 Vaccination: An Endomyocardial Biopsy-Proven Case Series.

Myocarditis in response to COVID-19 vaccination has been reported since early 2021. In particular, young male individuals have been identified to exhibit an increased risk of myocardial inflammation following the administration of mRNA-based vaccines. Even though the first epidemiological analyses and numerous case reports investigated potential relationships, endomyocardial biopsy (EMB)-proven cases are limited. Here, we present a comprehensive histopathological analysis of EMBs from 15 patients with reduced ejection fraction (LVEF = 30 (14-39)%) and the clinical suspicion of myocarditis following vaccination with Comirnaty® (Pfizer-BioNTech) (n = 11), Vaxzevria® (AstraZenica) (n = 2) and Janssen® (Johnson & Johnson) (n = 2). Immunohistochemical EMB analyses reveal myocardial inflammation in 14 of 15 patients, with the histopathological diagnosis of active myocarditis according the Dallas criteria (n = 2), severe giant cell myocarditis (n = 2) and inflammatory cardiomyopathy (n = 10). Importantly, infectious causes have been excluded in all patients. The SARS-CoV-2 spike protein has been detected sparsely on cardiomyocytes of nine patients, and differential analysis of inflammatory markers such as CD4+ and CD8+ T cells suggests that the inflammatory response triggered by the vaccine may be of autoimmunological origin. Although a definitive causal relationship between COVID-19 vaccination and the occurrence of myocardial inflammation cannot be demonstrated in this study, data suggest a temporal connection. The expression of SARS-CoV-2 spike protein within the heart and the dominance of CD4+ lymphocytic infiltrates indicate an autoimmunological response to the vaccination.

Vascular alterations among male elite athletes recovering from SARS-CoV-2 infection.

SARS-CoV-2 may affect the cardiovascular system and vascular impairment has been reported in healthy young adults recovering from COVID-19. However, the impact of SARS-CoV-2 infection on the vascular function of elite athletes is unknown. We examined 30 healthy male elite athletes (age 25.8 ± 4.6 years) pre-season and at a 6-month follow-up (182 ± 10 days). Vascular function and central blood pressure were calculated using transfer function-based analysis of peripheral arterial waveforms obtained by oscillometry. We performed a two-way repeated-measures ANOVA on the biomarker data, with SARS-CoV-2 status as the between-groups factor and time as the within-groups factor. Subjects who tested positive for SARS-CoV-2 were studied 18 ± 4 days after their positive testing date at follow-up. Of 30 athletes, 15 tested positive for SARS-CoV-2 after the first examination and prior to the follow-up. None had severe COVID-19 or reported any persisting symptoms. The results of the two-way repeated measures ANOVA revealed that there was no significant main effect of COVID-19 on any of the investigated biomarkers. However, there was a significant interaction between the effects of SARS-CoV-2 exposure and time on augmentation index (Aix) (p = 0.006) and augmentation index normalized to a heart rate of 75 beats per minute (Aix@75), (p = 0.0018). The observation of an interaction effect on Aix and Aix@75 in the absence of any main effect indicates a cross-over interaction. Significant vascular alterations in male elite athletes recovering from COVID-19 were observed that suggest vascular impairment. Whether these alterations affect athletic performance should be evaluated in future studies.

Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS) - A phase II, randomized, double-blind, multi-center, placebo-controlled trial.

BACKGROUND: Activation of inflammatory pathways during acute myocardial infarction contributes to infarct size and left ventricular (LV) remodeling. The present prospective randomized clinical trial was designed to test the efficacy and safety of broad-spectrum anti-inflammatory therapy with a mammalian target of rapamycin (mTOR) inhibitor to reduce infarct size. DESIGN: Controlled-Level EVERolimus in Acute Coronary Syndrome (CLEVER-ACS, clinicaltrials.gov NCT01529554) is a phase II randomized, double-blind, multi-center, placebo-controlled trial on the effects of a 5-day course of oral everolimus on infarct size, LV remodeling, and inflammation in patients with acute ST-elevation myocardial infarction (STEMI). Within 5 days of successful primary percutaneous coronary intervention (pPCI), patients are randomly assigned to everolimus (first 3 days: 7.5 mg every day; days 4 and 5: 5.0 mg every day) or placebo, respectively. The primary efficacy outcome is the change from baseline (defined as 12 hours to 5 days after pPCI) to 30-day follow-up in myocardial infarct size as measured by cardiac magnetic resonance imaging (CMRI). Secondary endpoints comprise corresponding changes in cardiac and inflammatory biomarkers as well as microvascular obstruction and LV volumes assessed by CMRI. Clinical events, laboratory parameters, and blood cell counts are reported as safety endpoints at 30 days. CONCLUSION: The CLEVER-ACS trial tests the hypothesis whether mTOR inhibition using everolimus at the time of an acute STEMI affects LV infarct size following successful pPCI.

Impact of the COVID-19 pandemic on cardiovascular mortality and catherization activity during the lockdown in central Germany: an observational study.

AIMS: During the COVID-19 pandemic, hospital admissions for cardiac care have declined. However, effects on mortality are unclear. Thus, we sought to evaluate the impact of the lockdown period in central Germany on overall and cardiovascular deaths. Simultaneously we looked at catheterization activities in the same region. METHODS AND RESULTS: Data from 22 of 24 public health-authorities in central Germany were aggregated during the pandemic related lockdown period and compared to the same time period in 2019. Information on the total number of deaths and causes of death, including cardiovascular mortality, were collected. Additionally, we compared rates of hospitalization (n = 5178) for chronic coronary syndrome (CCS), acute coronary syndrome (ACS), and out of hospital cardiac arrest (OHCA) in 26 hospitals in this area. Data on 5,984 deaths occurring between March 23, 2020 and April 26, 2020 were evaluated. In comparison to the reference non-pandemic period in 2019 (deaths: n = 5832), there was a non-significant increase in all-cause mortality of 2.6% [incidence rate ratio (IRR) 1.03, 95% confidence interval (CI) 0.99-1.06; p = 0.16]. Cardiovascular and cardiac mortality increased significantly by 7.6% (IRR 1.08, 95%-CI 1.01-1.14; p = 0.02) and by 11.8% (IRR 1.12, 95%-CI 1.05-1.19; p < 0.001), respectively. During the same period, our data revealed a drop in cardiac catherization procedures. CONCLUSION: During the COVID-19-related lockdown a significant increase in cardiovascular mortality was observed in central Germany, whereas catherization activities were reduced. The mechanisms underlying both of these observations should be investigated further in order to better understand the effects of a pandemic-related lockdown and social-distancing restrictions on cardiovascular care and mortality.

Cardiac arrhythmias in patients with SARS-CoV­2 infection and effects of the lockdown on invasive rhythmological therapy.

BACKGROUND: Since the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, various strategies have been taken worldwide to reduce the risk of infection. As part of the amendment to the Infection Protection Act, elective medical interventions were restricted, leading to a change in patient care. However, the consequences of the lockdown on the treatment of rhythmological patients in Germany remains unclear. OBJECTIVES: The aim of this study was to analyze the reduction in rhythmological interventions and the patient care situation using a nationwide survey during the first lockdown period. METHODS: A survey was sent to all electrophysiological centers certified by the German Society of Cardiology. Here, the treatment volume of tachycardia and bradycardia and their invasive therapy were surveyed before and during the lockdown period. Furthermore, the number of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) treated at these centers and the incidence of cardiac arrhythmias was also recorded. RESULTS: Participating centers performed a total of 24,648 ablation procedures/year and represent approximately 34% (24,648/72,548) of the estimated German ablation treatments. The majority of these centers (33/40; 82.5%) were so-called primary COVID-19 hospitals (level-1). Overall, the number of ablations and pacemaker implantations were reduced by 41% and 18% respectively. Due to postponed ablation procedures and pacemaker implantations, 22/40 (55%) centers reported a worsening of clinical symptoms or early re-hospitalization of their patients. CONCLUSION: These results demonstrate a significant decline in elective rhythmological procedures during the lockdown, as required by the German Federal Government. At the same time, however, more than half of the participating centers reported an increase in patient re-hospitalizations due to postponed procedures.

Case report of severe PCR-confirmed COVID-19 myocarditis in a European patient manifesting in mid January 2020.

BACKGROUND: Viral genesis is the most common cause of myocarditis. COVID-19-associated myocarditis seems to be a notable extrapulmonary manifestation, which may result in the need for a different treatment. There has been no positive polymerase chain reaction (PCR) testing of SARS-CoV-2 in heart specimens, thus far. CASE SUMMARY: A 48-year-old male patient presented with fever, dyspnoea, and haemoptysis. Laboratory findings showed highly elevated inflammatory and cardiac damage markers. Thoracic computed tomography (CT) revealed bilateral, patchy peripheral ground-glass opacities with a crazy-paving pattern, focal consolidations, and mild pleural effusions. Cardiac imaging with echocardiography and magnetic resonance imaging (MRI) detected a reduced biventricular function. MRI additionally showed myocardial oedema and late gadolinium enhancement. Lung and heart biopsies were performed, revealing alveolitis with necrosis and acute lymphocytic myocarditis. Testing for usual cardiotropic viruses was negative, and no aspects of vasculitis or granuloma could be found. Due to fulfilling the criteria, the patient was diagnosed with rheumatic vasculitis. Treatment with cyclophosphamide and steroids was initiated. Later, the patient reported a history of travel to Tyrol in mid January. Consequently, PCR testing for SARS-CoV-2 was performed, which was positive in the heart specimen. Immunosuppressive treatment was discontinued. During a follow-up visit at the end of April, the patient's recovery was stable. DISCUSSION: In COVID-19 infections, myocardial inflammation can be present as an extrapulmonary manifestation. Positive PCR testing confirms myocardial invasion of the virus. Imaging and laboratory studies correlate with the histopathological findings, and thus should be performed in COVID-19 patients who are suspicious for myocarditis. Supportive treatment with steroids may be useful in these patients.

Detection of viral SARS-CoV-2 genomes and histopathological changes in endomyocardial biopsies.

AIMS: Since December 2019, the novel coronavirus SARS-CoV-2 has spread rapidly throughout China and keeps the world in suspense. Cardiovascular complications with myocarditis and embolism due to COVID-19 have been reported. SARS-CoV-2 genome detection in the heart muscle has not been demonstrated so far, and the underlying pathophysiological mechanisms remain to be investigated. METHODS AND RESULTS: Endomyocardial biopsies (EMBs) of 104 patients (mean age: 57.90 ± 16.37 years; left ventricular ejection fraction: 33.7 ± 14.6%, sex: n = 79 male/25 female) with suspected myocarditis or unexplained heart failure were analysed. EMB analysis included histology, immunohistochemistry, and detection of SARS-CoV-2 genomes by real-time reverse transcription polymerase chain reaction in the IKDT Berlin, Germany. Among 104 EMBs investigated, five were confirmed with SARS-CoV-2 infected by reverse real-time transcriptase polymerase chain reaction. We describe patients of different history of symptoms and time duration. Additionally, we investigated histopathological changes in myocardial tissue showing that the inflammatory process in EMBs seemed to permeate vascular wall leading to small arterial obliteration and damage. CONCLUSIONS: This is the first report that established the evidence of SARS-CoV-2 genomes detection in EMBs. In these patients, myocardial injury ischaemia may play a role, which could explain the ubiquitous troponin increases. EMB-based identification of the cause of myocardial injury may contribute to explain the different evolution of complicated SARS-CoV-2-infection and to design future specific and personalized treatment strategies.