COVID-19, Myocarditis and Pericarditis.

Viral infections are a leading cause of myocarditis and pericarditis worldwide, conditions that frequently coexist. Myocarditis and pericarditis were some of the early comorbidities associated with SARS-CoV-2 infection and COVID-19. Many epidemiologic studies have been conducted since that time concluding that SARS-CoV-2 increased the incidence of myocarditis/pericarditis at least 15× over pre-COVID levels although the condition remains rare. The incidence of myocarditis pre-COVID was reported at 1 to 10 cases/100 000 individuals and with COVID ranging from 150 to 4000 cases/100 000 individuals. Before COVID-19, some vaccines were reported to cause myocarditis and pericarditis in rare cases, but the use of novel mRNA platforms led to a higher number of reported cases than with previous platforms providing new insight into potential pathogenic mechanisms. The incidence of COVID-19 vaccine-associated myocarditis/pericarditis covers a large range depending on the vaccine platform, age, and sex examined. Importantly, the findings highlight that myocarditis occurs predominantly in male patients aged 12 to 40 years regardless of whether the cause was due to a virus-like SARS-CoV-2 or associated with a vaccine-a demographic that has been reported before COVID-19. This review discusses findings from COVID-19 and COVID-19 vaccine-associated myocarditis and pericarditis considering the known symptoms, diagnosis, management, treatment, and pathogenesis of disease that has been gleaned from clinical research and animal models. Sex differences in the immune response to COVID-19 are discussed, and theories for how mRNA vaccines could lead to myocarditis/pericarditis are proposed. Additionally, gaps in our understanding that need further research are raised.

Management of cardiac sarcoidosis.

Cardiac sarcoidosis (CS) is a form of inflammatory cardiomyopathy associated with significant clinical complications such as high-degree atrioventricular block, ventricular tachycardia, and heart failure as well as sudden cardiac death. It is therefore important to provide an expert consensus statement summarizing the role of different available diagnostic tools and emphasizing the importance of a multidisciplinary approach. By integrating clinical information and the results of diagnostic tests, an accurate, validated, and timely diagnosis can be made, while alternative diagnoses can be reasonably excluded. This clinical expert consensus statement reviews the evidence on the management of different CS manifestations and provides advice to practicing clinicians in the field on the role of immunosuppression and the treatment of cardiac complications based on limited published data and the experience of international CS experts. The monitoring and risk stratification of patients with CS is also covered, while controversies and future research needs are explored.

A Novel Circulating MicroRNA for the Detection of Acute Myocarditis.

BACKGROUND: The diagnosis of acute myocarditis typically requires either endomyocardial biopsy (which is invasive) or cardiovascular magnetic resonance imaging (which is not universally available). Additional approaches to diagnosis are desirable. We sought to identify a novel microRNA for the diagnosis of acute myocarditis. METHODS: To identify a microRNA specific for myocarditis, we performed microRNA microarray analyses and quantitative polymerase-chain-reaction (qPCR) assays in sorted CD4+ T cells and type 17 helper T (Th17) cells after inducing experimental autoimmune myocarditis or myocardial infarction in mice. We also performed qPCR in samples from coxsackievirus-induced myocarditis in mice. We then identified the human homologue for this microRNA and compared its expression in plasma obtained from patients with acute myocarditis with the expression in various controls. RESULTS: We confirmed that Th17 cells, which are characterized by the production of interleukin-17, are a characteristic feature of myocardial injury in the acute phase of myocarditis. The microRNA mmu-miR-721 was synthesized by Th17 cells and was present in the plasma of mice with acute autoimmune or viral myocarditis but not in those with acute myocardial infarction. The human homologue, designated hsa-miR-Chr8:96, was identified in four independent cohorts of patients with myocarditis. The area under the receiver-operating-characteristic curve for this novel microRNA for distinguishing patients with acute myocarditis from those with myocardial infarction was 0.927 (95% confidence interval, 0.879 to 0.975). The microRNA retained its diagnostic value in models after adjustment for age, sex, ejection fraction, and serum troponin level. CONCLUSIONS: After identifying a novel microRNA in mice and humans with myocarditis, we found that the human homologue (hsa-miR-Chr8:96) could be used to distinguish patients with myocarditis from those with myocardial infarction. (Funded by the Spanish Ministry of Science and Innovation and others.).

Long-term impact of myocardial inflammation on quantitative myocardial perfusion-a descriptive PET/MR myocarditis study.

PURPOSE: Whether myocardial inflammation causes long-term sequelae potentially affecting myocardial blood flow (MBF) is unknown. We aimed to assess the effect of myocardial inflammation on quantitative MBF parameters, as assessed by 13N-ammonia positron emission tomography myocardial perfusion imaging (PET-MPI) late after myocarditis. METHODS: Fifty patients with a history of myocarditis underwent cardiac magnetic resonance (CMR) imaging at diagnosis and PET/MR imaging at follow-up at least 6 months later. Segmental MBF, myocardial flow reserve (MFR), and 13N-ammonia washout were obtained from PET, and segments with reduced 13N-ammonia retention, resembling scar, were recorded. Based on CMR, segments were classified as remote (n = 469), healed (inflammation at baseline but no late gadolinium enhancement [LGE] at follow-up, n = 118), and scarred (LGE at follow-up, n = 72). Additionally, apparently healed segments but with scar at PET were classified as PET discordant (n = 18). RESULTS: Compared to remote segments, healed segments showed higher stress MBF (2.71 mL*min-1*g-1 [IQR 2.18-3.08] vs. 2.20 mL*min-1*g-1 [1.75-2.68], p < 0.0001), MFR (3.78 [2.83-4.79] vs. 3.36 [2.60-4.03], p < 0.0001), and washout (rest 0.24/min [0.18-0.31] and stress 0.53/min [0.40-0.67] vs. 0.22/min [0.16-0.27] and 0.46/min [0.32-0.63], p = 0.010 and p = 0.021, respectively). While PET discordant segments did not differ from healed segments regarding MBF and MFR, washout was higher by ~ 30% (p < 0.014). Finally, 10 (20%) patients were diagnosed by PET-MPI as presenting with a myocardial scar but without a corresponding LGE. CONCLUSION: In patients with a history of myocarditis, quantitative measurements of myocardial perfusion as obtained from PET-MPI remain altered in areas initially affected by inflammation. CMR = cardiac magnetic resonance; PET = positron emission tomography; LGE = late gadolinium enhancement.

Autoimmunity in Acute Myocarditis: How Immunopathogenesis Steers New Directions for Diagnosis and Treatment.

PURPOSE OF REVIEW: Over the last decade, myocarditis has been increasingly recognized as common cause of sudden cardiac death in young adults and heart failure overall. The purpose of this review is to discuss hypothesis of development of non-infectious myocarditis, to provide a description of the immunopathogenesis and the most common mechanisms of autoimmunity in myocarditis, and to provide an update on therapeutic options. RECENT FINDINGS: A new entity of myocarditis is immune checkpoint inhibitor (ICI) induced myocarditis. ICIs are used in advanced cancer to "disinhibit" the immune system and make it more aggressive in fighting cancer. This novel drug class has doubled life expectancy in metastatic melanoma and significantly increased progression free survival in advanced non-small-cell lung cancer, but comes with a risk of autoimmune diseases such as myocarditis resulting from an overly aggressive immune system. Myocarditis is an inflammatory disease of the heart with major public health impact. Thorough understanding of its immunopathogenesis is crucial for accurate diagnosis and effective treatment.

Biochemistry and Biology of GDF11 and Myostatin: Similarities, Differences, and Questions for Future Investigation.

Growth differentiation factor 11 (GDF11) and myostatin (or GDF8) are closely related members of the transforming growth factor ß superfamily and are often perceived to serve similar or overlapping roles. Yet, despite commonalities in protein sequence, receptor utilization and signaling, accumulating evidence suggests that these 2 ligands can have distinct functions in many situations. GDF11 is essential for mammalian development and has been suggested to regulate aging of multiple tissues, whereas myostatin is a well-described negative regulator of postnatal skeletal and cardiac muscle mass and modulates metabolic processes. In this review, we discuss the biochemical regulation of GDF11 and myostatin and their functions in the heart, skeletal muscle, and brain. We also highlight recent clinical findings with respect to a potential role for GDF11 and/or myostatin in humans with heart disease. Finally, we address key outstanding questions related to GDF11 and myostatin dynamics and signaling during development, growth, and aging.

Behavioral Cardiovascular Risk Factors　- Effect of Physical Activity and Cardiorespiratory Fitness on Cardiovascular Outcomes.

Primary and primordial prevention of cardiovascular disease (CVD) requires not only identification of risk factors, but also appropriate and timely therapy. In order to prevent the expected increase in prevalence of CVD, it is essential that clinicians are aware of behavioral cardiovascular risk factors. A basic review is critical to clarify the difference between physical activity and fitness, as well as to discuss the role each plays in cardiovascular outcomes. We discuss observational epidemiological studies and randomized control trials that have examined the effect of physical activity and cardiorespiratory fitness on CVD.

Association of growth differentiation factor 11/8, putative anti-ageing factor, with cardiovascular outcomes and overall mortality in humans: analysis of the Heart and Soul and HUNT3 cohorts.

AIMS: Growth differentiation factor 11 and/or its homologue growth differentiation factor 8 (GDF11/8) reverses age-related cardiac hypertrophy and vascular ageing in mice. We investigated whether GDF11/8 associates with cardiovascular outcomes, left ventricular hypertrophy (LVH), or age in humans. METHODS AND RESULTS: We measured plasma GDF11/8 levels in 928 participants with stable ischaemic heart disease in the Heart and Soul study. We adjudicated heart failure hospitalization, stroke, myocardial infarction, death, and their composite endpoint. Left ventricular hypertrophy was evaluated by echocardiography. We used multivariable Cox proportional hazards models to compare rates of cardiovascular events and death across GDF11/8 quartiles and logistic regression models to evaluate the association between GDF11/8 and LVH. Four hundred and fifty participants (48.5%) experienced a cardiovascular event or death during 8.9 years of follow-up. The adjusted risk of the composite endpoint was lower in the highest compared with the lowest GDF11/8 quartile [hazard ratio (HR), 0.45; 95% confidence interval (CI), 0.33-0.60; P < 0.001]. We replicated this relationship of GDF11/8 to adverse events in 971 participants in the HUNT3 cohort (adjusted HR, 0.34; 95% CI, 0.23-0.51; P < 0.001). Left ventricular hypertrophy was present in 368 participants (39.7%) at baseline. Participants in the highest quartile of GDF11/8 were less likely to have LVH than those in the lowest quartile (adjusted OR, 0.55; 95% CI, 0.35-0.86; P = 0.009). GDF11/8 levels were lower in older individuals (P < 0.001). CONCLUSION: In patients with stable ischaemic heart disease, higher GDF11/8 levels are associated with lower risk of cardiovascular events and death. Our findings suggest that GDF11/8 has similar cardioprotective properties in humans to those demonstrated in mice.

Development and Validation of a Protein-Based Risk Score for Cardiovascular Outcomes Among Patients With Stable Coronary Heart Disease.

IMPORTANCE: Precise stratification of cardiovascular risk in patients with coronary heart disease (CHD) is needed to inform treatment decisions. OBJECTIVE: To derive and validate a score to predict risk of cardiovascular outcomes among patients with CHD, using large-scale analysis of circulating proteins. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of participants with stable CHD. For the derivation cohort (Heart and Soul study), outpatients from San Francisco were enrolled from 2000 through 2002 and followed up through November 2011 (≤11.1 years). For the validation cohort (HUNT3, a Norwegian population-based study), participants were enrolled from 2006 through 2008 and followed up through April 2012 (5.6 years). EXPOSURES: Using modified aptamers, 1130 proteins were measured in plasma samples. MAIN OUTCOMES AND MEASURES: A 9-protein risk score was derived and validated for 4-year probability of myocardial infarction, stroke, heart failure, and all-cause death. Tests, including the C statistic, were used to assess performance of the 9-protein risk score, which was compared with the Framingham secondary event model, refit to the cohorts in this study. Within-person change in the 9-protein risk score was evaluated in the Heart and Soul study from paired samples collected 4.8 years apart. RESULTS: From the derivation cohort, 938 samples were analyzed, participants' median age at enrollment was 67.0 years, and 82% were men. From the validation cohort, 971 samples were analyzed, participants' median age at enrollment was 70.2 years, and 72% were men. In the derivation cohort, C statistics were 0.66 for refit Framingham, 0.74 for 9-protein, and 0.75 for refit Framingham plus 9-protein models. In the validation cohort, C statistics were 0.64 for refit Framingham, 0.70 for 9-protein, and 0.71 for refit Framingham plus 9-protein models. Adding the 9-protein risk score to the refit Framingham model increased the C statistic by 0.09 (95% CI, 0.06-0.12) in the derivation cohort, and in the validation cohort, the C statistic was increased by 0.05 (95% CI, 0.02-0.09). Compared with the refit Framingham model, the integrated discrimination index for the 9-protein model was 0.12 (95% CI, 0.08-0.16) in the derivation cohort and 0.08 (95% CI, 0.05-0.10) in the validation cohort. In analysis of paired samples among 139 participants with cardiovascular events after the second sample, absolute within-person annualized risk increased more for the 9-protein model (median, 1.86% [95% CI, 1.15%-2.54%]) than for the refit Framingham model (median, 1.00% [95% CI, 0.87%-1.19%]) (P = .002), while among 375 participants without cardiovascular events, both scores changed less and similarly (P = .30). CONCLUSIONS AND RELEVANCE: Among patients with stable CHD, a risk score based on 9 proteins performed better than the refit Framingham secondary event risk score in predicting cardiovascular events, but still provided only modest discriminative accuracy. Further research is needed to assess whether the score is more accurate in a lower-risk population.

Application of magnetocardiography for myocarditis assessment in a testosterone-substituted female-to-male individual.

Background: The diagnosis of myocarditis remains challenging due to its diverse clinical manifestations. We recently demonstrated the ability of magnetocardiography (MCG) to screen for myocarditis and applied it successfully to detect myocarditis in this case study of a female-to-male (FtM) patient who had undergone sexual reassignment surgery. This case highlights two significant points: first, sex differences in myocarditis may be promoted by higher levels of testosterone, and second, the ability of MCG to diagnose myocarditis. Case presentation: We report on a 38-year-old FtM patient who was hospitalized for chest pain following testosterone therapy. The patient received testosterone every 2 weeks for 6 months following his FtM surgery. Two days after the last administration of testosterone, he developed chest pain. Electrocardiography identified non-significant ST elevations in V3-6, II and aVF and echocardiography revealed reduced left ventricular ejection fraction and apical hypokinesia. High-sensitivity troponin-T (539 ng/L to 676 ng/L) and creatine kinase elevation (592 U/L) were elevated. Coronary CT angiography ruled out coronary artery disease. Cardiac magnetic resonance imaging confirmed suspected myocarditis.Additionally, we used MCG to detect abnormalities in the electromagnetic field. A pathologic vector (0.179) supported the diagnosis of myocarditis in this patient. During therapy with ibuprofen the vector improved to 0.067 after 3 weeks accompanied by symptom improvement. Conclusion: Testosterone treatment may have promoted myocarditis in a FtM individual. Additional MCG assessment was consistent with a diagnosis of myocarditis and highlights the promising potential of this method to facilitate diagnostic screening for cardiomyopathy in the future.

Gut microbiota-related modulation of immune mechanisms in post-infarction remodelling and heart failure.

The immune system has long been recognized as a key driver in the progression of heart failure (HF). However, clinical trials targeting immune effectors have consistently failed to improve patient outcome across different HF aetiologies. The activation of the immune system in HF is complex, involving a broad network of pro-inflammatory and immune-modulating components, which complicates the identification of specific immune pathways suitable for therapeutic targeting. Increasing attention has been devoted to identifying gut microbial pathways that affect cardiac remodelling and metabolism and, thereby impacting the development of HF. In particular, gut microbiota-derived metabolites, absorbed by the host and transported to the peripheral circulation, can act as signalling molecules, influencing metabolism and immune homeostasis. Recent reports suggest that the gut microbiota plays a crucial role in modulating immune processes involved in HF. Here, we summarize recent advances in understanding the contributory role of gut microbiota in (auto-)immune pathways that critically determine the progression or alleviation of HF. We also thoroughly discuss potential gut microbiota-based intervention strategies to treat or decelerate HF progression.

Outcomes in Cardiac Transthyretin Amyloidosis and Association With New York Heart Association Class: Real-World Data.

BACKGROUND: Results from ATTR-ACT (Safety and Efficacy of Tafamidis in Patients With Transthyretin Cardiomyopathy) indicate that tafamidis prolongs survival and reduces cardiovascular hospitalizations in cardiac transthyretin amyloidosis (ATTR-CA). However, real-world data supporting these findings are scarce. Thus, we sought to characterize the clinical outcome of patients with ATTR-CA treated with tafamidis in a real-world setting and assess the prognostic role of the New York Heart Association (NYHA) classification. METHODS AND RESULTS: We conducted a retrospective observational study, enrolling a consecutive sample of patients with ATTR-CA (wild-type or variant) treated with tafamidis. Clinical outcome was tracked through follow-up visits or phone calls. Primary outcomes were death and major adverse cardiac events (MACE), a composite end point of death and hospitalizations for acute cardiac decompensation, myocardial infarction, severe arrythmias, or stroke. Kaplan-Meier analysis estimated overall and MACE-free survival including NYHA subgroups (NYHA I/II versus NYHA III). One hundred sixty-seven patients with ATTR-CA (94.6% wild-type) were enrolled and followed for a median of 539 [323-869] days. Median overall survival was not reached. Estimated 1-year, 2-year, and 5-year overall survival among the whole cohort was 93.5%, 85.9%, and 70.2%, respectively. Overall survival was higher in the NYHA I/II subgroup (P=0.002). Median MACE-free survival time was 1082 (95% CI, 962-1202) days. MACE-free survival was higher in the NYHA I/II subgroup (P<0.001). With respective hazard ratios of 5.85 (95% CI, 1.48-23.18; P=0.012) and 3.95 (95% CI, 1.99-7.84; P<0.001), NYHA III was an independent predictor of death and MACE. CONCLUSIONS: Treatment of ATTR-CA with tafamidis led to substantial improvements of clinical outcome. NYHA classification at treatment initiation is a reliable tool to provide patients with individualized prognostic information.

The inflammatory spectrum of cardiomyopathies.

Infiltration of the myocardium with various cell types, cytokines and chemokines plays a crucial role in the pathogenesis of cardiomyopathies including inflammatory cardiomyopathies and myocarditis. A more comprehensive understanding of the precise immune mechanisms involved in acute and chronic myocarditis is essential to develop novel therapeutic approaches. This review offers a comprehensive overview of the current knowledge of the immune landscape in cardiomyopathies based on etiology. It identifies gaps in our knowledge about cardiac inflammation and emphasizes the need for new translational approaches to improve our understanding thus enabling development of novel early detection methods and more effective treatments.

Diagnostic value of papillary muscle hypertrophy and mitral valve thickness to discriminate cardiac amyloidosis and Fabry disease.

BACKGROUND: Cardiac amyloidosis (CA) and Fabry disease (FD) cause myocardial damage but may also affect the valvular and subvalvular apparatus. We aimed to evaluate the diagnostic accuracy of new echocardiographic indices including mitral valve thickness and papillary muscle (PM) hypertrophy to differentiate CA and FD. METHODS: In patients with confirmed CA and FD, a detailed assessment of valvular function, mitral valve leaflet thickness and PM area as well as PM left ventricular area ratio (PM/LV-ratio) was performed in offline analyses. Receiver operating characteristic curve analyses were conducted to determine the diagnostic accuracy of mitral valve thickness, PM hypertrophy, and PM/LV-ratio to distinguish CA from FD. RESULTS: We retrospectively analyzed a cohort of 129 patients (FD n = 49, CA n = 80). CA patients showed significantly more thickened mitral valve leaflets (4.1 ± 1.3 mm vs. 2.9 ± 1.1 mm, p < 0.001) and a higher PM area [4.0 (3.1-4.6) mm2 vs. 2.8 (2.1-4.6) mm2, p = 0.009] with a comparable PM/LV-ratio in both groups. Mitral valve thickness showed the highest diagnostic accuracy to discriminate CA [AUC 0.77 (95% CI 0.67-0.87)]. The prevalence of aortic, tricuspid, and pulmonary valve regurgitation was significantly higher in CA (aortic regurgitation ≥ II° 13% vs. 4%, tricuspid regurgitation≥ II° 19% vs. 8%, p < 0.001). CONCLUSION: Our results suggest that the assessment of mitral valve thickness may be a new useful echocardiographic parameter to differentiate CA and FD, whereas papillary muscle hypertrophy and PM/LV-ratio showed a limited diagnostic performance to discriminate CA. German clinical trials registry: DRKS00027403.

Sex and Age Characteristics in Acute or Chronic Myocarditis A Descriptive, Multicenter Cohort Study.

BACKGROUND: Understanding the clinical features of myocarditis in various age groups is required to identify age-specific disease patterns. OBJECTIVES: The objective of this study was to examine differences in sex distribution and clinical outcomes in patients with myocarditis of various ages. METHODS: Patients with acute or chronic myocarditis in 3 centers in Berlin, Germany from 2005 to 2021 and in the United States (National Inpatient Sample) from 2010 to 2019 were included. Age groups examined included "prepubescent" (below 11 years for females and below 13 years for males), adolescents (11 [female] or 13 [male] to 18 years), young adults (18-35 years), "middle-aged adults" (35-54 years), and older adults (age >54 years). In patients admitted to the hospital, hospital mortality, length of stay, and medical complication rates were examined. RESULTS: Overall, 6,023 cases in Berlin and 9,079 cases in the U.S. cohort were included. In both cohorts, there were differences in sex distribution among the 5 age categories, and differences in the distribution were most notable in adolescents (69.3% males vs 30.7% females) and in young adults (73.8% males vs 26.3% females). Prepubescent and older adults had the highest rates of in-hospital mortality, hospital length of stay, and medical complications. In the Berlin cohort, prepubescent patients had higher levels of leukocytes (P < 0.001), antistreptolysin antibody (P < 0.001), and NT-proBNP (P < 0.001) when compared to young adults. CONCLUSIONS: In this study, we found that sex differences in myocarditis and clinical features of myocarditis were age-dependent.