Publications by authors named "Leslie T Cooper"

170 Publications

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Circulation 2021 Nov 15;144(20):1646-1655. Epub 2021 Nov 15.

Department of Cardiology, Barts Heart Centre, Barts Health NHS Trust, London, United Kingdom (M.Y.K., A.A.C.).

Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance. ACM also has wide phenotype variability, ranging from premature ventricular contractions to sudden cardiac death and heart failure. Among other drivers and modulators of phenotype, inflammation in response to viral infection and immune triggers have been postulated to be an aggravator of cardiac myocyte damage and necrosis. This theory is supported by multiple pieces of evidence, including the presence of inflammatory infiltrates in more than two-thirds of ACM hearts, detection of different cardiotropic viruses in sporadic cases of ACM, the fact that patients with ACM often fulfill the histological criteria of active myocarditis, and the abundance of anti-desmoglein-2, antiheart, and anti-intercalated disk autoantibodies in patients with arrhythmogenic right ventricular cardiomyopathy. In keeping with the frequent familial occurrence of ACM, it has been proposed that, in addition to genetic predisposition to progressive myocardial damage, a heritable susceptibility to viral infections and immune reactions may explain familial clustering of ACM. Moreover, considerable in vitro and in vivo evidence implicates activated inflammatory signaling in ACM. Although the role of inflammation/immune response in ACM is not entirely clear, inflammation as a driver of phenotype and a potential target for mechanism-based therapy warrants further research. This review discusses the present evidence supporting the role of inflammatory and immune responses in ACM pathogenesis and proposes opportunities for translational and clinical investigation.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.121.055890DOI Listing
November 2021

Do Genes Influence Susceptibility to Myocarditis?

JACC Basic Transl Sci 2021 Jul 26;6(7):593-594. Epub 2021 Jul 26.

Department of Pathology. Johns Hopkins Medical Center, Baltimore, Maryland, USA.

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http://dx.doi.org/10.1016/j.jacbts.2021.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8326289PMC
July 2021

Sarcoidosis-Related Cardiomyopathy: Current Knowledge, Challenges, and Future Perspectives State-of-the-Art Review.

J Card Fail 2021 Jul 11. Epub 2021 Jul 11.

Infiltrative Cardiomyopathy and Advanced Heart Failure Programs, MedStar Heart and Vascular Institute, Georgetown University, Washington, DC.

The prevalence of sarcoidosis-related cardiomyopathy is increasing. Sarcoidosis impacts cardiac function through granulomatous infiltration of the heart, resulting in conduction disease, arrhythmia, and/or heart failure. The diagnosis of cardiac sarcoidosis (CS) can be challenging and requires clinician awareness as well as differentiation from overlapping diagnostic phenotypes, such as other forms of myocarditis and arrhythmogenic cardiomyopathy. Clinical manifestations, extracardiac involvement, histopathology, and advanced cardiac imaging can all lend support to a diagnosis of CS. The mainstay of therapy for CS is immunosuppression; however, no prospective clinical trials exist to guide management. Patients may progress to developing advanced heart failure or ventricular arrhythmia, for which ventricular assist device therapies or heart transplantation may be considered. The existing knowledge gaps in CS call for an interdisciplinary approach to both patient care and future investigation to improve mechanistic understanding and therapeutic strategies.
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http://dx.doi.org/10.1016/j.cardfail.2021.06.016DOI Listing
July 2021

Diagnosis and Management of Myocarditis in Children: A Scientific Statement From the American Heart Association.

Circulation 2021 Aug 7;144(6):e123-e135. Epub 2021 Jul 7.

Myocarditis remains a clinical challenge in pediatrics. Originally, it was recognized at autopsy before the application of endomyocardial biopsy, which led to a histopathology-based diagnosis such as in the Dallas criteria. Given the invasive and low-sensitivity nature of endomyocardial biopsy, its diagnostic focus shifted to a reliance on clinical suspicion. With the advances of cardiac magnetic resonance, an examination of the whole heart in vivo has gained acceptance in the pursuit of a diagnosis of myocarditis. The presentation may vary from minimal symptoms to heart failure, life-threatening arrhythmias, or cardiogenic shock. Outcomes span full resolution to chronic heart failure and the need for heart transplantation with inadequate clues to predict the disease trajectory. The American Heart Association commissioned this writing group to explore the current knowledge and management within the field of pediatric myocarditis. This statement highlights advances in our understanding of the immunopathogenesis, new and shifting dominant pathogeneses, modern laboratory testing, and use of mechanical circulatory support, with a special emphasis on innovations in cardiac magnetic resonance imaging. Despite these strides forward, we struggle without a universally accepted definition of myocarditis, which impedes progress in disease-targeted therapy.
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http://dx.doi.org/10.1161/CIR.0000000000001001DOI Listing
August 2021

Proinflammatory TH17 cytokine activation, disease severity and outcomes in peripartum cardiomyopathy.

Int J Cardiol 2021 Sep 3;339:93-98. Epub 2021 Jul 3.

University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America. Electronic address:

Background: Immune dysregulation is implicated in the development and clinical outcomes of peripartum cardiomyopathy (PPCM).

Methods And Results: 98 women with PPCM were enrolled and followed for 1 year postpartum (PP). LVEF was assessed at entry, 6-, and 12-months PP by echocardiography. Serum levels of soluble interleukin (IL)-2 receptor (sIL2R), IL-2, IL-4, IL-17, IL-22, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured by ELISA at entry. Cytokine levels were compared between women with PPCM by NYHA class. Outcomes including myocardial recovery and event-free survival were compared by cytokine tertiles. For cytokines found to impact survival outcomes, parameters indicative of disease severity including baseline LVEF, medications, and use of inotropic and mechanical support were analyzed. Levels of proinflammatory cytokines including IL-17, IL-22, and sIL2R, were elevated in higher NYHA classes at baseline. Subjects with higher IL-22 levels were more likely to require inotropic or mechanical support. Higher levels of TNF-α and IL-22 were associated with poorer event-free survival. Higher TNF-α levels were associated with lower mean LVEF at entry and 12 months. In contrast, higher levels of immune-regulatory cytokines such as IL-4 and IL-2 were associated with higher LVEF during follow up.

Conclusion: Proinflammatory cytokines IL-22 and TNF-α were associated with adverse event-free survival. IL-17 and IL-22 were associated with more severe disease. In contrast, higher levels of IL-2 and IL-4 corresponded with higher subsequent LVEF. Increased production of TH17 type cytokines in PPCM correlated with worse disease and outcomes, while an increased immune-regulatory response seems to be protective.
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http://dx.doi.org/10.1016/j.ijcard.2021.06.022DOI Listing
September 2021

Cancer Mortality Rates Increasing vs Cardiovascular Disease Mortality Decreasing in the World: Future Implications.

Mayo Clin Proc Innov Qual Outcomes 2021 Jun 8;5(3):645-653. Epub 2021 Jun 8.

Neurologic Surgery Department, Mayo Clinic, Jacksonville, FL.

Objective: To highlight the current global trends in mortality for cardiovascular disease and cancer.

Methods: The World Health Organization and the World Bank DataBank databases were used to analyze mortality rates for cancer and cardiovascular disease by calculating age-standardized mortality rates (ASRs) from 2000 to 2015 for high-income, upper-middle-income, and lower-middle-income countries. Data for cancer mortality and population for 43 countries representing 5 of the 7 continents (except Australia and Antarctica) were analyzed.

Results: From 2000 to 2015, there was an increase in the ASR for cancer for both men and women irrespective of a country's income status, representing an overall 7% increase in cancer ASR (Pearson , +0.99; <.00001). We report a higher ASR for cancer in high-income countries than in upper-middle-income and lower-middle-income countries specifically; high-income countries saw a 3% increase in cancer ASR vs +31% for upper-middle-income and +19% for lower-middle-income countries (<.01). There has been a decrease in the ASR for cardiovascular disease for the 15 years analyzed (<.00001). In addition, high-income countries had a higher ASR for cardiovascular disease than upper-middle-income countries during the 15-year period (<.05).

Conclusion: We suspect that because of early detection and targeted interventions, cardiovascular disease mortality rates have decreased during the past decade. On the basis of our results, cancer mortality rates continue to rise, with the projection of surpassing cardiovascular disease mortality rates in the near future.
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http://dx.doi.org/10.1016/j.mayocpiqo.2021.05.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240359PMC
June 2021

Myocarditis Following Immunization With mRNA COVID-19 Vaccines in Members of the US Military.

JAMA Cardiol 2021 10;6(10):1202-1206

Mayo Clinic, Jacksonville, Florida.

Importance: Myocarditis has been reported with COVID-19 but is not clearly recognized as a possible adverse event following COVID-19 vaccination.

Objective: To describe myocarditis presenting after COVID-19 vaccination within the Military Health System.

Design, Setting, And Participants: This retrospective case series studied patients within the US Military Health System who experienced myocarditis after COVID-19 vaccination between January and April 2021. Patients who sought care for chest pain following COVID-19 vaccination and were subsequently diagnosed with clinical myocarditis were included.

Exposure: Receipt of a messenger RNA (mRNA) COVID-19 vaccine between January 1 and April 30, 2021.

Main Outcomes And Measures: Clinical diagnosis of myocarditis after COVID-19 vaccination in the absence of other identified causes.

Results: A total of 23 male patients (22 currently serving in the military and 1 retiree; median [range] age, 25 [20-51] years) presented with acute onset of marked chest pain within 4 days after receipt of an mRNA COVID-19 vaccine. All military members were previously healthy with a high level of fitness. Seven received the BNT162b2-mRNA vaccine and 16 received the mRNA-1273 vaccine. A total of 20 patients had symptom onset following the second dose of an appropriately spaced 2-dose series. All patients had significantly elevated cardiac troponin levels. Among 8 patients who underwent cardiac magnetic resonance imaging within the acute phase of illness, all had findings consistent with the clinical diagnosis of myocarditis. Additional testing did not identify other etiologies for myocarditis, including acute COVID-19 and other infections, ischemic injury, or underlying autoimmune conditions. All patients received brief supportive care and were recovered or recovering at the time of this report. The military administered more than 2.8 million doses of mRNA COVID-19 vaccine in this period. While the observed number of myocarditis cases was small, the number was higher than expected among male military members after a second vaccine dose.

Conclusions And Relevance: In this case series, myocarditis occurred in previously healthy military patients with similar clinical presentations following receipt of an mRNA COVID-19 vaccine. Further surveillance and evaluation of this adverse event following immunization is warranted. Potential for rare vaccine-related adverse events must be considered in the context of the well-established risk of morbidity, including cardiac injury, following COVID-19 infection.
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http://dx.doi.org/10.1001/jamacardio.2021.2833DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8243257PMC
October 2021

Sex Differences, Genetic and Environmental Influences on Dilated Cardiomyopathy.

J Clin Med 2021 May 25;10(11). Epub 2021 May 25.

Department of Cardiovascular Medicine, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA.

Dilated cardiomyopathy (DCM) is characterized by dilatation of the left ventricle and impaired systolic function and is the second most common cause of heart failure after coronary heart disease. The etiology of DCM is diverse including genetic pathogenic variants, infection, inflammation, autoimmune diseases, exposure to chemicals/toxins as well as endocrine and neuromuscular causes. DCM is inherited in 20-50% of cases where more than 30 genes have been implicated in the development of DCM with pathogenic variants in (Titin) most frequently associated with disease. Even though male sex is a risk factor for heart failure, few studies have examined sex differences in the pathogenesis of DCM. We searched the literature for studies examining idiopathic or familial/genetic DCM that reported data by sex in order to determine the sex ratio of disease. We found 31 studies that reported data by sex for non-genetic DCM with an average overall sex ratio of 2.5:1 male to female and 7 studies for familial/genetic DCM with an overall average sex ratio of 1.7:1 male to female. No manuscripts that we found had more females than males in their studies. We describe basic and clinical research findings that may explain the increase in DCM in males over females based on sex differences in basic physiology and the immune and fibrotic response to damage caused by mutations, infections, chemotherapy agents and autoimmune responses.
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http://dx.doi.org/10.3390/jcm10112289DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197492PMC
May 2021

Heart Failure Association, Heart Failure Society of America, and Japanese Heart Failure Society Position Statement on Endomyocardial Biopsy.

J Card Fail 2021 07 19;27(7):727-743. Epub 2021 May 19.

Cleveland Clinic, Cleveland Ohio.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumors. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples has significantly improved the diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (1) an overview of the practical approach to EMB, (2) an update on indications for EMB, (3) a revised plan for heart transplant rejection surveillance, (4) the impact of multimodality imaging on EMB, and (5) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1016/j.cardfail.2021.04.010DOI Listing
July 2021

Heart Failure Association of the ESC, Heart Failure Society of America and Japanese Heart Failure Society Position statement on endomyocardial biopsy.

Eur J Heart Fail 2021 06 19;23(6):854-871. Epub 2021 May 19.

Cleveland Clinic, Cleveland, OH, USA.

Endomyocardial biopsy (EMB) is an invasive procedure, globally most often used for the monitoring of heart transplant (HTx) rejection. In addition, EMB can have an important complementary role to the clinical assessment in establishing the diagnosis of diverse cardiac disorders, including myocarditis, cardiomyopathies, drug-related cardiotoxicity, amyloidosis, other infiltrative and storage disorders, and cardiac tumours. Improvements in EMB equipment and the development of new techniques for the analysis of EMB samples have significantly improved diagnostic precision of EMB. The present document is the result of the Trilateral Cooperation Project between the Heart Failure Association of the European Society of Cardiology, the Heart Failure Society of America, and the Japanese Heart Failure Society. It represents an expert consensus aiming to provide a comprehensive, up-to-date perspective on EMB, with a focus on the following main issues: (i) an overview of the practical approach to EMB, (ii) an update on indications for EMB, (iii) a revised plan for HTx rejection surveillance, (iv) the impact of multimodality imaging on EMB, and (v) the current clinical practice in the worldwide use of EMB.
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http://dx.doi.org/10.1002/ejhf.2190DOI Listing
June 2021

Lower Extremity Arterial Disease as a Predictor of Incident Atrial Fibrillation and Cardiovascular Events.

Mayo Clin Proc 2021 05;96(5):1175-1183

Department of Cardiovascular Medicine, Mayo Clinic, Phoenix, AZ. Electronic address:

Objective: To evaluate the relationship between peripheral arterial disease (PAD) and incident atrial fibrillation (AF) and its clinical and pathophysiologic implications on ischemic stroke and all-cause mortality.

Patients And Methods: We identified all adult patients in the Mayo Clinic Health System without a previous diagnosis of AF undergoing ankle-brachial index (ABI) testing for any indication from January 1, 1996, to June 30, 2018. Retrospective extraction of ABI data and baseline echocardiographic data was performed. The primary outcome of interest was incident AF. The secondary outcomes of interest were incident ischemic stroke and all-cause mortality.

Results: A total of 33,734 patients were included in the study. After adjusting for demographic and comorbidity variables, compared with patients who had normal ABI (1.0 to 1.39), there was an increased risk of incident AF in patients with low ABI (<1.0) (adjusted hazard ratio, 1.14; 95% CI, 1.06 to 1.22) and elevated ABI (≥1.4) (adjusted hazard ratio, 1.18; 95% CI, 1.06 to 1.31). The risk was greater in patients with increasing severity of PAD. Patients with abnormal ABIs had an increased risk of ischemic stroke and all-cause mortality. We found that patients with PAD and incident AF have certain baseline echocardiographic abnormalities.

Conclusion: In this large cohort of ambulatory patients undergoing ABI measurement, patients with PAD were at increased risk for incident AF, ischemic stroke, and mortality. In these high-risk patients with abnormal ABI, particularly severe PAD and cardiac structural abnormalities, routine monitoring for AF and management of cardiovascular risk factors may be warranted.
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http://dx.doi.org/10.1016/j.mayocp.2020.07.036DOI Listing
May 2021

Factors associated with change in frailty scores and long-term outcomes in older adults with coronary artery disease.

J Geriatr Cardiol 2021 Mar;18(3):196-203

Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.

Objective: Older adults with coronary artery disease (CAD) are at risk for frailty. However, little is known regarding transition in frailty measures over time or its impact on outcomes. We sought to determine the association of temporal change in frailty with long-term outcome in older adults with CAD.

Methods: We re-assessed for phenotypic frailty using the Fried index (0 = not frail; 1-2 = pre-frail; ≥ 3 frail) in a cohort of CAD patients ≥ 65 years old at 2 time points 5 years apart. Factors associated with frailty worsening were assessed with scatterplots and outcomes estimated using the Kaplan-Meier method. Cox models were used to assess the risk of worsening frailty on outcome.

Results: There were 45 subjects that completed both baseline and 5-year Fried frailty assessment. Mean age was 74.6 ± 5.9 and 30 (67%) were men. Frailty incidence increased over time: baseline (3% frail, 37% pre-frail); 5 years (10% frail, 40% pre-frail). Baseline factors were not predictors of worsening frailty score, while both slower walk time ( = 0.46; = 0.004) and diminishing grip strength ( = -0.39; = 0.01) were associated with worsening frailty transitions. In follow-up (median 5.2 years), long-term major adverse cardiac event (MACE) free survival ( = 0.12) or hospitalization ( = 0.98) was not different for those with worsening frailty score (referent: improved/unchanged frailty). Frailty worsening had a trend towards increased risk of MACE (HR = 1.86; 95% CI: 0.65-5.27, = 0.25).

Conclusions: Frailty transitions, specifically, declines in walk time and grip strength, were strongly associated with worsening frailty score in a cohort of older adults with CAD than were baseline indices, though frailty change status was not independently associated with MACE outcomes.
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http://dx.doi.org/10.11909/j.issn.1671-5411.2021.03.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047182PMC
March 2021

Natural History of Patients Diagnosed with Cardiac Sarcoidosis at Left Ventricular Assist Device Implantation or Cardiac Transplantation.

ASAIO J 2021 05;67(5):583-587

Department of Cardiovascular Medicine.

To our knowledge, natural history has not been reported for cardiac sarcoidosis (CS) diagnosed by pathologic evaluation of the apical core at left ventricular assist device (LVAD) implantation or cardiac transplantation. We retrospectively identified 232 consecutive patients meeting CS criteria. Of these patients, 54 were diagnosed by pathologic confirmation of CS, 10 after evaluation of the apical core (LVAD implant) or explanted heart (transplant). We compared clinical characteristics at initial evaluation and outcomes for these 10 patients with those of 10 patients with known CS before LVAD implant/transplant. In the study group, five patients (50%) had confirmed extracardiac sarcoidosis before LVAD implant/transplant; five had not been diagnosed with sarcoidosis. Mean (standard deviation) left ventricular ejection fraction at initial evaluation was 23% (16%), and left ventricular end-diastolic dimension was 61 (10) mm. Four patients died during follow-up; however, no survival difference was found for the 10 patients diagnosed incidentally and the group with a previous diagnosis or institutional LVAD/transplant cohorts. Patients diagnosed with CS on pathological examination of the apical core/explanted heart may have severe dilated cardiomyopathy as the initial presentation. Outcomes for patients with CS after advanced heart failure therapies may be comparable with those of non-CS patients.
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http://dx.doi.org/10.1097/MAT.0000000000001262DOI Listing
May 2021

Identification of a novel presumed cardiac sarcoidosis category for patients at high risk of disease.

Int J Cardiol 2021 07 18;335:66-72. Epub 2021 Apr 18.

Department of Cardiovascular Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224, United States.

Background: Histologic evidence is required for a definitive diagnosis of cardiac sarcoidosis (CS) by published guidelines; however, the sporadic nature of the disease may produce false negative biopsy results, causing CS to be underdiagnosed. We sought to establish a clinical category of CS absent histologic findings.

Methods: Patients evaluated for CS were stratified into 3 groups: probable CS and definite CS based on Heart Rhythm Society (HRS) criteria and presumed CS, ie, patients without any histologic evidence of sarcoidosis, but with unexplained high-grade atrioventricular block or ventricular arrhythmia and findings suggestive of CS on either cardiac magnetic resonance imaging or positron emission tomography. The primary end point was hospitalization-free and overall survival at 10 years.

Results: A total of 383 patients were included in the study: 59, definite CS; 223, probable CS; and 101, presumed CS (62, isolated CS and 39, systemic CS). Compared with patients meeting HRS criteria for CS, patients with presumed CS had lower odds of New York Heart Association class III or IV symptoms (odds ratio [OR], 0.44 [95% CI, 0.23-0.83]; P = .01) but greater odds of previous ventricular tachycardia (OR, 2.4 [95% CI, 1.4-4.0]; P = .001) or history of resuscitated sudden cardiac arrest (OR, 2.9 [95% CI, 1.0-8.6]; P = .05). Hospitalization-free and overall survival were similar among groups (P = .51 and P = .71, respectively).

Conclusions: Clinical categorization of patients with presumed CS identified a high-risk cohort comparable to patients with histologic evidence of disease, although caution should be exercised in reaching this diagnosis without paying due diligence to the differential diagnosis.
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http://dx.doi.org/10.1016/j.ijcard.2021.04.022DOI Listing
July 2021

What we (don't) know about myocardial injury after COVID-19.

Eur Heart J 2021 05;42(19):1879-1882

Department of Cardiovascular Diseases, Mayo Clinic, Jacksonville, FL, USA.

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http://dx.doi.org/10.1093/eurheartj/ehab145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8108615PMC
May 2021

A Case of Rapidly Progressing Granulomatous Myocarditis: What Is the Diagnosis?

Circ Heart Fail 2021 03 8;14(3):e007800. Epub 2021 Mar 8.

Division of Cardiology (A.N., I.S.O., R.A., R.S.P., E.V.), Northwestern University Feinberg School of Medicine, Chicago, IL.

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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007800DOI Listing
March 2021

Management of Patients With Giant Cell Myocarditis: JACC Review Topic of the Week.

J Am Coll Cardiol 2021 03;77(8):1122-1134

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida, USA.

Giant cell myocarditis is a rare, often rapidly progressive and potentially fatal, disease due to T-cell lymphocyte-mediated inflammation of the myocardium that typically affects young and middle-aged adults. Frequently, the disease course is marked by acute heart failure, cardiogenic shock, intractable ventricular arrhythmias, and/or heart block. Diagnosis is often difficult due to its varied clinical presentation and overlap with other cardiovascular conditions. Although cardiac biomarkers and multimodality imaging are often used as initial diagnostic tests, endomyocardial biopsy is required for definitive diagnosis. Combination immunosuppressive therapy, along with guideline-directed medical therapy, has led to a paradigm shift in the management of giant cell myocarditis resulting in an improvement in overall and transplant-free survival. Early diagnosis and prompt management can decrease the risk of transplantation or death, which remain common in patients who present with cardiogenic shock.
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http://dx.doi.org/10.1016/j.jacc.2020.11.074DOI Listing
March 2021

Rationale and design of the African Cardiomyopathy and Myocarditis Registry Program: The IMHOTEP study.

Int J Cardiol 2021 06 16;333:119-126. Epub 2021 Feb 16.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, USA.

Background: Heart failure (HF), the dominant form of cardiovascular disease in Africans, is mainly due to hypertension, rheumatic heart disease and cardiomyopathy. Cardiomyopathies pose a great challenge because of poor prognosis and high prevalence in low- and middle-income countries (LMICs). Little is known about the etiology and outcome of cardiomyopathy in Africa. Specifically, the role of myocarditis and the genetic causes of cardiomyopathy are largely unidentified in Africans.

Method: The African Cardiomyopathy and Myocarditis Registry Program (the IMHOTEP study) is a pan-African multi-centre, hospital-based cohort study, designed with the primary aim of describing the clinical characteristics, genetic causes, prevalence, management and outcome of cardiomyopathy and myocarditis in children and adults. The secondary aim is to identify barriers to the implementation of evidence-based care and provide a platform for trials and other intervention studies to reduce morbidity and mortality in cardiomyopathy. The registry consists of a prospective cohort of newly diagnosed (i.e., incident) cases and a retrospective (i.e., prevalent) cohort of existing cases from participating centres. Patients with cardiomyopathy and myocarditis will be subjected to a standardized 3-stage diagnostic process. To date, 750 patients have been recruited into the multi-centre pilot phase of the study.

Conclusion: The IMHOTEP study will provide comprehensive and novel data on clinical features, genetic causes, prevalence and outcome of African children and adults with all forms of cardiomyopathy and myocarditis in Africa. Based on these findings, appropriate strategies for management and prevention of the cardiomyopathies in LMICs are likely to emerge.
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http://dx.doi.org/10.1016/j.ijcard.2021.02.026DOI Listing
June 2021

Failure of intravenous immunoglobulin to improve cardiac function in parvovirus B19-associated chronic dilated cardiomyopathy.

Eur J Heart Fail 2021 02 18;23(2):310-311. Epub 2021 Feb 18.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, FL, USA.

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http://dx.doi.org/10.1002/ejhf.2110DOI Listing
February 2021

Bi-directional association between depression and HF: An electronic health records-based cohort study.

J Comorb 2020 Jan-Dec;10:2235042X20984059. Epub 2020 Dec 24.

Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

Objective: To determine whether a bi-directional relationship exists between depression and HF within a single population of individuals receiving primary care services, using longitudinal electronic health records (EHRs).

Methods: This retrospective cohort study utilized EHRs for adults who received primary care services within a large healthcare system in 2006. Validated EHR-based algorithms identified 10,649 people with depression (depression cohort) and 5,911 people with HF (HF cohort) between January 1, 2006 and December 31, 2018. Each person with depression or HF was matched 1:1 with an unaffected referent on age, sex, and outpatient service use. Each cohort (with their matched referents) was followed up electronically to identify newly diagnosed HF (in the depression cohort) and depression (in the HF cohort) that occurred after the index diagnosis of depression or HF, respectively. The risks of these outcomes were compared (vs. referents) using marginal Cox proportional hazard models adjusted for 16 comorbid chronic conditions.

Results: 2,024 occurrences of newly diagnosed HF were observed in the depression cohort and 944 occurrences of newly diagnosed depression were observed in the HF cohort over approximately 4-6 years of follow-up. People with depression had significantly increased risk for developing newly diagnosed HF (HR 2.08, 95% CI 1.89-2.28) and people with HF had a significantly increased risk of newly diagnosed depression (HR 1.34, 95% CI 1.17-1.54) after adjusting for all 16 comorbid chronic conditions.

Conclusion: These results provide evidence of a bi-directional relationship between depression and HF independently of age, sex, and multimorbidity from chronic illnesses.
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http://dx.doi.org/10.1177/2235042X20984059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768856PMC
December 2020

A Case-Control Study of Peripartum Cardiomyopathy Using the Rochester Epidemiology Project.

J Card Fail 2021 Feb 1;27(2):132-142. Epub 2021 Jan 1.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida; Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. Electronic address:

Background: The incidence of peripartum cardiomyopathy (PPCM) is known through referral center databases that may be affected by referral, misclassification, and other biases. We sought to determine the community-based incidence and natural history of PPCM using the Rochester Epidemiology Project.

Methods And Results: Incident cases of PPCM occurring between January 1, 1970, and December 31, 2014, were identified in Olmsted County, Minnesota. A total of 15 PPCM cases were confirmed yielding an incidence of 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Clinical information, disease characteristics, and outcomes were extracted from medical records in a 27-county region of the Rochester Epidemiology Project including Olmsted County and matched in a 1:2 ratio with pregnant women without PPCM. A total of 48 women were identified with PPCM in the expanded 27-county region. There was 1 death and no transplants over a median of 7.3 years of follow-up. Six of the 23 women with subsequent pregnancies developed recurrent PPCM, all of whom recovered. Migraine and anxiety were identified as novel possible risk factors for PPCM.

Conclusions: The population-based incidence of PPCM was 20.3 cases per 100,000 live births in Olmsted County, Minnesota. Cardiovascular outcomes were generally excellent in this community cohort.
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http://dx.doi.org/10.1016/j.cardfail.2020.12.021DOI Listing
February 2021

Global Burden of Cardiovascular Diseases and Risk Factors, 1990-2019: Update From the GBD 2019 Study.

J Am Coll Cardiol 2020 12;76(25):2982-3021

University of Alabama at Birmingham School of Public Health, Birmingham, Alabama, USA.

Cardiovascular diseases (CVDs), principally ischemic heart disease (IHD) and stroke, are the leading cause of global mortality and a major contributor to disability. This paper reviews the magnitude of total CVD burden, including 13 underlying causes of cardiovascular death and 9 related risk factors, using estimates from the Global Burden of Disease (GBD) Study 2019. GBD, an ongoing multinational collaboration to provide comparable and consistent estimates of population health over time, used all available population-level data sources on incidence, prevalence, case fatality, mortality, and health risks to produce estimates for 204 countries and territories from 1990 to 2019. Prevalent cases of total CVD nearly doubled from 271 million (95% uncertainty interval [UI]: 257 to 285 million) in 1990 to 523 million (95% UI: 497 to 550 million) in 2019, and the number of CVD deaths steadily increased from 12.1 million (95% UI:11.4 to 12.6 million) in 1990, reaching 18.6 million (95% UI: 17.1 to 19.7 million) in 2019. The global trends for disability-adjusted life years (DALYs) and years of life lost also increased significantly, and years lived with disability doubled from 17.7 million (95% UI: 12.9 to 22.5 million) to 34.4 million (95% UI:24.9 to 43.6 million) over that period. The total number of DALYs due to IHD has risen steadily since 1990, reaching 182 million (95% UI: 170 to 194 million) DALYs, 9.14 million (95% UI: 8.40 to 9.74 million) deaths in the year 2019, and 197 million (95% UI: 178 to 220 million) prevalent cases of IHD in 2019. The total number of DALYs due to stroke has risen steadily since 1990, reaching 143 million (95% UI: 133 to 153 million) DALYs, 6.55 million (95% UI: 6.00 to 7.02 million) deaths in the year 2019, and 101 million (95% UI: 93.2 to 111 million) prevalent cases of stroke in 2019. Cardiovascular diseases remain the leading cause of disease burden in the world. CVD burden continues its decades-long rise for almost all countries outside high-income countries, and alarmingly, the age-standardized rate of CVD has begun to rise in some locations where it was previously declining in high-income countries. There is an urgent need to focus on implementing existing cost-effective policies and interventions if the world is to meet the targets for Sustainable Development Goal 3 and achieve a 30% reduction in premature mortality due to noncommunicable diseases.
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http://dx.doi.org/10.1016/j.jacc.2020.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755038PMC
December 2020

Outcomes of Mechanical Circulatory Support for Giant Cell Myocarditis: A Systematic Review.

J Clin Med 2020 Dec 1;9(12). Epub 2020 Dec 1.

Division of Cardiac Surgery, Department of Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.

Treatment of giant cell myocarditis (GCM) can require bridging to orthotopic heart transplantation (OHT) or recovery with mechanical circulatory support (MCS). Since the roles of MCS and immunotherapy are not well-defined in GCM, we sought to analyze outcomes of patients with GCM who required MCS. A systematic search was performed in June 2019 to identify all studies of biopsy-proven GCM requiring MCS after 2009. We identified 27 studies with 43 patients. Patient-level data were extracted for analysis. Median patient age was 45 (interquartile range (IQR): 32-57) years. 42.1% (16/38) were female. 34.9% (15/43) presented in acute heart failure. 20.9% (9/43) presented in cardiogenic shock. Biventricular (BiVAD) MCS was required in 76.7% (33/43) of cases. Of the 62.8% (27/43) of patients who received immunotherapy, 81.5% (22/27) used steroids combined with at least one other immunosuppressant. Cyclosporine was the most common non-steroidal agent, used in 40.7% (11/27) of regimens. Immunosuppression was initiated before MCS in 59.3% (16/27) of cases, after MCS in 29.6% (8/27), and not specified in 11.1% (3/27). Immunosuppression started prior to MCS was associated with significantly better survival than MCS alone ( = 0.006); 60.5% (26/43) of patients received bridge-to-transplant MCS; 39.5% (17/43) received bridge-to-recovery MCS; 58.5% (24/41) underwent OHT a median of 104 (58-255) days from diagnosis. GCM recurrence after OHT was reported in 8.3% (2/24) of transplanted cases. BiVAD predominates in mechanically supported patients with GCM. Survival and bridge to recovery appear better in patients on immunosuppression, especially if initiated before MCS.
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http://dx.doi.org/10.3390/jcm9123905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7761005PMC
December 2020

Implications of SARS-CoV-2-Associated Myocarditis in the Medical Evaluation of Athletes.

Sports Health 2021 Mar 17;13(2):145-148. Epub 2020 Nov 17.

Department of Cardiovascular Medicine, Mayo Clinic, Jacksonville, Florida.

Context: Myocarditis is a known cause of death in athletes. As we consider clearance of athletes to participate in sports during the COVID-19 pandemic, we offer a brief review of the myocardial effects of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) through the lens of what is known about myocarditis and exercise. All athletes should be queried about any recent illness suspicious for COVID-19 prior to sports participation.

Evidence Acquisition: The PubMed database was evaluated through 2020, with the following keywords: , and . Selected articles identified through the primary search, along with position statements from around the world, and the relevant references from those articles, were reviewed for pertinent clinical information regarding the identification, evaluation, risk stratification, and management of myocarditis in patients, including athletes, with and without SARS-CoV-2.

Study Design: Systematic review.

Level Of Evidence: Level 3.

Results: Since myocarditis can present with a variety of symptoms, and can be asymptomatic, the sports medicine physician needs to have a heightened awareness of athletes who may have had COVID-19 and be at risk for myocarditis and should have a low threshold to obtain further cardiovascular testing. Symptomatic athletes with SARS-CoV-2 may require cardiac evaluation including an electrocardiogram and possibly an echocardiogram. Athletes with cardiomyopathy may benefit from cardiac magnetic resonance imaging in the recovery phase and, rarely, endocardial biopsy.

Conclusion: Myocarditis is a known cause of sudden cardiac death in athletes. The currently reported rates of cardiac involvement of COVID-19 makes myocarditis a risk, and physicians who clear athletes for participation in sport as well as sideline personnel should be versed with the diagnosis, management, and clearance of athletes with suspected myocarditis. Given the potentially increased risk of arrhythmias, sideline personnel should practice their emergency action plans and be comfortable using an automated external defibrillator.
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http://dx.doi.org/10.1177/1941738120974747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167355PMC
March 2021

Management of Acute Myocarditis and Chronic Inflammatory Cardiomyopathy: An Expert Consensus Document.

Circ Heart Fail 2020 11 12;13(11):e007405. Epub 2020 Nov 12.

Vita Salute University and San Raffaele Hospital, Milano, Italy (P.G.C.).

Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.007405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7673642PMC
November 2020

Management perspectives from the 2019 Wuhan international workshop on fulminant myocarditis.

Int J Cardiol 2021 02 26;324:131-138. Epub 2020 Oct 26.

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. Electronic address:

Fulminant myocarditis (FM) is a form of acute myocardial inflammation leading to rapid-onset hemodynamic instability due to cardiogenic shock or life-threatening arrhythmias. As highlighted by recent registries, FM is associated with high rates of death and heart transplantation, regardless of the underlying histology. Because of a paucity of evidence-based management strategies exists for this disease, an International workshop on FM was held in Wuhan, China, in October 2019, in order to share knowledge on the disease and identify areas of consensus. The present report highlights both agreements and controversies in FM management across the world, focusing the attention on areas of opportunity, FM definition, the use of endomyocardial biopsy and viral identification on heart specimens, treatment algorithms including immunosuppression and the timing of circulatory support escalation. This report incorporates the most recent recommendations from national and international professional societies. Main areas of interest and aims of future prospective observational registries and randomized controlled trials were finally identified and suggested.
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http://dx.doi.org/10.1016/j.ijcard.2020.10.063DOI Listing
February 2021

Myocarditis and inflammatory cardiomyopathy: current evidence and future directions.

Nat Rev Cardiol 2021 03 12;18(3):169-193. Epub 2020 Oct 12.

Berlin Institute of Health Center for Regenerative Therapies (BCRT), Charité - University Medicine Berlin, Campus Virchow Clinic, Berlin, Germany.

Inflammatory cardiomyopathy, characterized by inflammatory cell infiltration into the myocardium and a high risk of deteriorating cardiac function, has a heterogeneous aetiology. Inflammatory cardiomyopathy is predominantly mediated by viral infection, but can also be induced by bacterial, protozoal or fungal infections as well as a wide variety of toxic substances and drugs and systemic immune-mediated diseases. Despite extensive research, inflammatory cardiomyopathy complicated by left ventricular dysfunction, heart failure or arrhythmia is associated with a poor prognosis. At present, the reason why some patients recover without residual myocardial injury whereas others develop dilated cardiomyopathy is unclear. The relative roles of the pathogen, host genomics and environmental factors in disease progression and healing are still under discussion, including which viruses are active inducers and which are only bystanders. As a consequence, treatment strategies are not well established. In this Review, we summarize and evaluate the available evidence on the pathogenesis, diagnosis and treatment of myocarditis and inflammatory cardiomyopathy, with a special focus on virus-induced and virus-associated myocarditis. Furthermore, we identify knowledge gaps, appraise the available experimental models and propose future directions for the field. The current knowledge and open questions regarding the cardiovascular effects associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are also discussed. This Review is the result of scientific cooperation of members of the Heart Failure Association of the ESC, the Heart Failure Society of America and the Japanese Heart Failure Society.
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http://dx.doi.org/10.1038/s41569-020-00435-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7548534PMC
March 2021

Association of Autoimmune Vasculitis and Incident Atrial Fibrillation: A Population-Based Case-Control Study.

J Am Heart Assoc 2020 09 6;9(18):e015977. Epub 2020 Sep 6.

Department of Cardiovascular Medicine Mayo Clinic Rochester Minnesota USA.

Background Recent investigations suggest that inflammation and autoimmunity might have a role in the pathophysiology of atrial fibrillation (AF). Given that abnormal ventriculovascular coupling often coexists with AF, we hypothesize that autoimmune vasculitis plays a significant role in the pathogenetic mechanism of AF. Methods and Results A standardized retrospective population-based case-control study was conducted to evaluate the association between autoimmune vasculitis and AF, and all-cause mortality. The study included 8459 patients with a new diagnosis of AF and 8459 age-, sex-, and registration calendar year-matched controls in Olmsted County, Minnesota, between January 1, 1980 and December 31, 2010. The association of each clinical characteristic, diagnosis, and treatment was assessed using conditional logistic regression to account for the matched case-control study design. Cox proportional hazards regression models and Kaplan-Meier curves were used to detect independent predictors of mortality and examine cumulative survival. Of a total of 16 918 patients (mean age 72.3+14.4 years; 48.7% women), 320 (1.9%) were diagnosed with autoimmune vasculitis before the index date during the 30-year period. Among the cases, the prevalence of any autoimmune vasculitis was 2.3%, whereas the frequency of autoimmune vasculitis in controls was 1.5% (<0.001). After adjusting for potential confounders, the odds of autoimmune vasculitis in AF cases was 1.5 times higher than in controls (odds ratio, 1.47; 95% CI, 1.04-2.01; =0.03). Patients with AF and autoimmune vasculitis had worse 5-year survival than those without autoimmune vasculitis or AF (44.7% versus 77.2%; log-rank <0.001). Conclusions Autoimmune vasculitis is significantly associated with AF and independently confers worse survival. These observations may represent one mechanism linking autoimmunity and inflammation to the pathogenesis and prognosis of AF.
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http://dx.doi.org/10.1161/JAHA.120.015977DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727002PMC
September 2020
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