CHAPTER 63: MYOCARDITIS

The term myocarditis describes the presence of inflammatory cells in the myocardium and implies that the presenting clinical phenotype is attributable to myocardial inflammation. Therefore, myocarditis is diagnosed when myocardial inflammation is proven and there are clinical manifestations that can be causally linked to the inflammatory substrate. The descriptive diagnosis of myocarditis encompasses a wide spectrum of etiologically different diseases that share, as unique criterion, the presence of myocardial inflammation.

In the 1980s, the World Health Organization and the International Society and Federation of Cardiology defined myocarditis as an inflammatory disease of the myocardium wherein the diagnosis is established by histologic, immunologic, and immunohistochemical criteria. Idiopathic, autoimmune, and infectious forms of inflammatory cardiomyopathy were recognized.² Whereas the Dallas criteria¹ insisted on the demonstration of mononuclear cellular infiltration accompanying a demonstrable and ongoing myocyte damage, the definition of myocarditis recently updated by the European Society of Cardiology (ESC) working group on myocardial and pericardial diseases requires the presence of ≥ 14 lymphocytes/mm² including CD3-positive T lymphocytes ≥ 7 cells/mm² but no more than 4 monocytes/mm².³ These descriptive definitions did not include etiologic basis of myocardial involvement and clinical information.

Myocarditis can be infectious or noninfectious in origin, and the latter includes autoimmune/immune-mediated, hypersensitivity, or toxic causes. Infective myocarditis is induced by myocardiotrophic viruses such as Coxsackie B virus or endotheliotropic parvovirus B19 followed by interstitial inflammatory cell infiltration and myocardial tissue damage manifesting clinically with symptoms, circulating biomarker abnormalities, and imaging-verified myocardial alterations. The clinical presentation is “fulminant,” acute or chronic illness.³ The diagnosis is either pathologically proven or considered suspect; only pathology-based evidence is accepted as a definitive diagnosis of myocarditis,⁴ and surrogate terms such as clinically suspected myocarditis cannot be equated with the diagnostic certainty of histologically verified disease. Development of molecular imaging strategies targeting the presence of myocardial inflammation is not beyond the realm of possibility.⁵

At present, endomyocardial biopsy (EMB) remains the unique tool for the diagnosis in vivo; surgical samples can be equally informative, such as the left ventricular (LV) apex resected during ventricular assist device implantation. Reasons for not performing EMB are numerous. EMB is an invasive procedure and is associated with not negligible complications, such as ventricular wall perforation, pericardial effusion, and tamponade. Although this reason is repeatedly cited as the major limitation, EMBs are routinely and frequently performed to monitor allogeneic reaction and opportunistic infections in transplanted patients and have been reported safe both in adults⁴ and children.⁶ The major reasons why clinical utilization of EMB is discouraged include (1) the lack of evidence-based effective treatment for myocarditis; (2) the nonuniform and non–universally agreed upon diagnostic criteria; and (3) the interobserver variability among pathologists interpreting the same biopsy samples. The reports of limitations of Dallas criteria– based interpretation⁷ and the results of the National Institutes of Health Myocarditis Trial⁸ have effectively changed the diagnostic workup for myocarditis as a disease entity.

Precise epidemiologic estimates are difficult because of the different diagnostic criteria and clinically heterogeneous manifestations of the disease ranging from nonspecific signs and symptoms to life-threatening arrhythmias and cardiogenic shock. Autopsy reports have provided variable data. In a large autopsy report of 377,841 deceased persons, the prevalence of nonspecific myocarditis and giant cell myocarditis was 0.11% and 0.007%, respectively.⁹ In another retrospective review of 17,162 postmortem records, myocarditis was histologically confirmed in 91 cases (0.53%; 95% confidence interval [CI], 0.4%-0.7%). However, in a prospectively planned standardized myocardial sampling in 605 autopsies, the prevalence was 5.1%,¹⁰ which is substantially higher than the 2% rate of incidental myocardial infiltrates associated with myocyte necrosis in consecutive noncardiac deaths.¹¹

Clinical reports have promulgated myocarditis based on varied phenotypes. A search algorithm based on sentinel reports (using International Classification of Diseases, Ninth Revision, codes 420.90, 420.99, 422.90, 422.91, and 429.0) identified 59 cases of suspected myopericarditis among 492,671 US military service personnel who received smallpox vaccine between 2002 and 2003.¹² In a well-characterized series of competitive athletes, myocarditis was reported as the third leading cause of sudden cardiac death.¹³ However, of 672 young Finnish men presenting with myocardial infarction from 1977 to 1996, clinical diagnosis of myocarditis was suggested in 98 (0.17% [95% CI, 0.14%-0.21%]/1000 person-years); Coxsackie virus etiology was confirmed in 4% of the cases.¹⁴ In 3055 patients who underwent EMB, myocardial inflammation was found in 17.2% (n = 525); only 182 of these 525 patients demonstrated decreased ejection fraction (< 45%), and viral genome was identified in 11.8%.¹⁵ In a review of 1,698,397 patients aged ≥ 16 years over 9.5 years from 29 Finnish hospitals, 3198 were discharged as having myocarditis (0.0019%); researchers reported a higher prevalence in affected young men and postmenopausal women.¹⁶ Acute myocarditis has been reported to be more common (in hospitalized patients aged 18 to 29 years) than acute myocardial infarction.¹⁷

A nationwide survey aimed at determining the clinicoepidemiologic features of myocarditis in Japanese children and adolescents demonstrated an incidence of 43.5 cases per year, or 0.24 cases per 100,000 population; pathogens were identified in 37 of 169 subjects, with Coxsackie virus accounting for 60%.¹⁸ Of 62 children with clinical profiles of acute myocarditis and dilated cardiomyopathy (DCM) before diagnosis, 24 (39%) had a final diagnosis of myocarditis.¹⁹ Of the 11 children (median age, 1 year; range 0-9 years) presenting with fulminant myocarditis between 1998 and 2003 in a single center, 5 were confirmed with viral etiology; 10 survivors were asymptomatic with normalized LV ejection fraction (LVEF) at a median follow-up of 58.7 months (range, 33.8-83.1 months).²⁰ Overall, currently available epidemiology data do not allow precise estimates on prevalence, type, and outcomes of myocarditis.

Myocardial inflammatory cells have been observed in autopsy reports of noncardiac death, wherein the inflammation was a presumptive, but not proven, contributor to the final outcome. In 384 consecutive hearts seen in consultation from a single medical examiner’s office, infiltrates were most frequent in natural noncardiac deaths (31%) and least frequent in traumatic deaths (12%); eosinophilic infiltrates were especially common in patients on antibiotics (18%). Incidental inflammation with myocyte necrosis in noncardiac deaths was less common (2%).¹¹ Inflammatory infiltrates have been commonly observed in donor hearts before implantation.²¹ Although normal myocardium is expected to be free from inflammatory infiltrates, incidental detection in noncardiac death suggests that, by itself, inflammatory cells may not have clinical significance (Fig. 63–1).

The list of infectious agents that have been associated with myocarditis include DNA and RNA viruses, bacteria, fungi, protozoa, and helminthes.^22,23,24 Viral infections are the most common causes of myocarditis in both children and adults (Table 63–1).²² Nonviral cardiotropic infections, such as Trypanosoma cruzi in Chagas disease²⁵ and Borrelia burgdorferi in Lyme disease,²⁶ in immunocompetent individuals constitute special subgroups of myocarditis. In immunocompromised patients (eg, immunosuppressed, immunodepressed, malignancy, postsurgical, human immunodeficiency virus [HIV] infected), myocarditis is associated with different infectious agents, such as human cytomegalovirus (HCMV) or Toxoplasma gondii. In pregnancy, HCMV infection could cause fetal malformations wherein the maternal infection remains clinically subtle partly because of delayed lymphoproliferative response in primary infection²⁷ and lower viral load.²⁸ Myocardial infection is diagnosed when the infectious agent is detected in myocardial tissue by pathologic and genomic studies.²⁹

Viral Myocarditis

The diagnostic workup of myocardial infection should begin with timely sampling of informative tissue and paired samples of peripheral blood. The diagnostic processes include cell culture, antibody detection, antigen detection, hemagglutination assay, nucleic acid detection, and gene sequencing. Specific antibodies are always produced when adaptive immune system encounters a virus. As a general rule, immunoglobulin (Ig) Ms are highly effective at neutralizing viruses, are produced only for the initial few weeks, and are indicative of acute infections. IgGs are produced indefinitely and are tested to demonstrate prior infection. Antigens are detected by enzyme-linked immunosorbent assay (ELISA) in biologic fluids with immunofluorescence and immunoperoxidase as the alternative methods. Quantitative assays for measuring the viral genome copy number and nucleic acid sequencing establish the viral presence and the viral load. In the appropriate diagnostic workup, the serology is systematically performed, routine inflammatory markers are tested, and markers of myocardial damage are monitored. Neutralizing antibodies in serum can be tested by the neutralization test based on the enzyme-linked immunospot assay.³⁰

EMB is the gold standard for the confirmation of viral infection.^4,31 Inflammatory cells are detected with routine pathology stains such as hematoxylin and eosin. The immunophenotyping of inflammatory cells for prevalent subtypes of T lymphocytes including CD4⁺ and CD8⁺, B lymphocytes, natural killer cells, or macrophages may add information on the presence of effector and regulatory pathogenetic pathways. Immunohistochemical detection of the infective pathogen and molecular transcription signature from the affected myocardium can contribute to the diagnosis of inflammatory heart diseases.³²

Enteroviruses

Enteroviruses belong to the family of Picornaviridae and are grouped into 12 species: enteroviruses A to H and J and rhinoviruses A to C. The disease in humans is caused by poliovirus, coxsackievirus, rhinovirus, enterovirus, and echovirus serotypes. The clinical presentation may be relatively mild (eg, fever, herpangina, conjunctivitis, hand-foot-mouth disease, tonsillitis, pharyngitis, lower respiratory tract infection, acute gastroenteritis) or, uncommonly, also severe (eg, pneumonia, meningitis, encephalitis, myocarditis, pericarditis, hepatic necrosis, coagulopathy).³³ The cardiotropic coxsackievirus B3 (CV-B3) is one of the most common causes of myocarditis.³³ The myocardial infection is initiated by the transmembrane coxsackievirus-adenovirus receptor (CAR); the ablation of CAR blocks viral affliction of myocardial cells and inflammation in the myocardium in experimental models.³⁴ Similarly, increased cardiac expression of CAR may partially explain increased susceptibility to myocarditis.³⁵ In CV-B3–infected myocytes, the cell damage is induced by direct cytotoxicity and mediated by viral proteinases.³⁶ CV-B3 replicates on the surface of autophagosomes^37,38 and enhances replication by employing microRNA (miRNA)^39,40; CV-B3–induced differential expression of miRNA modulates expression of both host and viral genes.

Patients with defects of dystrophin and dysferlin demonstrate increased susceptibility to myocardial CV-B3 infection by enhancing viral propagation to adjacent cardiomyocytes and disrupting membrane repair function.^41,42,43 The history of a recent flu episode in patients with X-linked DCM caused by defects of dystrophin could mislead the clinical diagnosis, but the possibility that a viral flu triggered the onset of a pre-existing asymptomatic disease cannot be excluded. Although myocarditis and viral genome may not be found in the EMB from patients with X-linked DCM,⁴⁴ the myocardium with dystrophin defects could sustain greater damage from coxsackievirus proteases known to affect host cell proteins such as dystrophin.⁴⁵

In viral infections, the early innate immune response provides the first defense mechanism and is mediated by cytokines. The virus is recognized by specific receptors (toll-like, retinoic acid inducible gene-I–like, nucleotide-binding oligomerization domain-like, and C-type lectin receptors) through pathogen-specific molecules.^46,47 This interaction induces the production of proinflammatory cytokines (eg, tumor necrosis factor-α and interleukin-1) to recruit T cells (including regulatory T cells and interleukin-17–producing cells) and modulate immune response.⁴⁸ The late adaptive immune response contributes to the myocardial lymphocyte infiltration that must clear virus-infected cardiac myocytes in CV-B3 myocarditis and endothelial cells in parvovirus B19 myocarditis. Although this mechanism clears the virus, it also results in myocyte injury. Depletion or ablation of T lymphocytes, both CD4⁺ and CD8⁺, decreases the mortality and reduces cardiac inflammation and injury after CV-B3 infection.⁴⁹ In addition, a molecular mimicry between viral and host antigens has been proposed as a mechanism subsequently responsible for the postinfectious autoimmune-mediated damage of the myocardium.⁵⁰

Acute infections are characterized by febrile illness that commonly evolves without complications; when complicated by myocarditis, the febrile illness is commonly reported as having preceded the cardiac symptoms. The cardiac manifestations range from mild, nonspecific symptoms to life-threatening complications such as cardiogenic chock and sudden cardiac death. The pathologic features of CV-B3 myocarditis are T-lymphocyte inflammatory infiltrate and myocyte damage/necrosis (Fig. 63–2). Markers of myocardial damage and systemic inflammation can be increased. IgMs are usually missed unless the diagnosis of myocarditis is done close to the onset of the systemic illness. In the acute phase, viral particles can be recognized in infected myocytes.^51,52 Polymerase chain reaction (PCR)–based demonstration of the viral genome in the affected myocardium concludes the diagnostic workup; molecular assays are paired in blood and myocardial samples.

Human Parvovirus B19

Human parvovirus B19 (B19V) belongs to the genus Erythroparvovirus of the Parvoviridae family, which is composed of a group of small DNA viruses with a linear single-stranded DNA genome.⁵³ B19V usually infects human erythroid progenitor cells to cause mild-to-severe hematologic disorders,⁵⁴ but may also infect nonerythroid lineage cells such as myocardial endothelial cells.⁵⁵ Therefore, B19V infection typically presents clinically with erythema infectiosum, arthralgia, fetal death, transient aplastic crisis, and persistent infection in immunocompromised hosts; less common clinical manifestations include atypical skin rashes, neurologic syndromes, cardiac manifestations, and cytopenias.^53,55 The cardiac manifestations of B19V infection range from mild and nonspecific symptoms (eg, fatigue, arrhythmias) to cardiogenic shock requiring mechanical support.

Mechanistically, the B19V-antibody complex enters the cells through an endocytosis process mediated by the direct interaction of antibody-bound complement factor C1q with its receptor CD93 on the cell surface.⁵⁶ B19V enters myocardial endothelial cells, but does not replicate intracellularly.⁵⁷ B19V genome has been identified in the myocardial tissue of patients with myocarditis, patients with DCM, and control cases.^58,59 In 72 EMBs from 35 patients with DCM, 17 patients with active myocarditis, and 20 surgical myocardial samples from patients undergoing surgery for valve disease or coronary artery disease, real-time PCR failed to identify enteroviruses, Epstein-Barr virus, or herpes simplex viruses type 1 or 2; only one DCM patient tested positive, but for adenovirus. On the other hand, 20 of 52 patients (38%) with cardiomyopathy and 8 of 20 controls (40%) tested positive for B19V, disproving the hypothesis that persistent myocardial viral infection might be a frequent cause of DCM or myocarditis.⁵⁸ A possible hypothesis that could explain the role of B19V in myocarditis and cardiomyopathy is the potential role of trigger of the viral genome for innate immunity, inducing proinflammatory cytokine secretion⁵⁷ and myocardial inflammation.

EMB typically shows T-lymphocyte inflammatory infiltrates and prominent endothelial cells; myocytes may not show damage or necrosis (Fig. 63–3). B19V infection has also been associated with adult and pediatric autoimmune diseases, including systemic diseases that involve the heart, either directly or indirectly.^60,61,62 Documented mechanisms in B19-associated autoimmunity include molecular mimicry (IgG antibodies to B19 proteins cross-react with human autoantigens), virus-induced apoptosis with presentation of self-antigens to T lymphocytes, and the phospholipase activity of the B19 unique VP1 protein.

Human Herpesviruses

The human herpesviruses (HHV) are currently assigned to three subfamilies: α-, β-, and γ-herpesvirinae. Herpesvirus infections are characterized by their ability to establish lifelong infections with periods of latency followed by reactivation. The diagnosis of HHV myocarditis is based on the demonstration of HHV actively replicating in cardiac cells. In infected cells, HHV typically causes a morphologically manifest cytopathic effect, and commercially available antibodies can detect viral antigens expressed in the immediate/early and late phases of viral replication. PCR can selectively detect genes expressed by replicating viruses, and quantitative PCR measures the number of copies of viral genomes in the affected tissues compared to the peripheral blood. HHV6, adenovirus, and Epstein-Barr virus of the herpesvirinae family are associated with myocarditis, which may occur both in immunocompetent and immunocompromised hosts, as well as in children and adults.^{63,64,65,66,67,68,69} In immunocompromised patients, the HHV6 myocarditis can be fatal.^66,67 The myocarditis is pathologically characterized by T-lymphocyte infiltration and myocyte injury.

Myocardial infection with HCMV is more commonly observed in immunocompromised hosts. The myocardial pathology is characterized by T-cell inflammatory infiltrate and by the presence of typical intranuclear amphophilic inclusion bodies that specifically immune-stain with anti-HCMV antibodies. The virus infects both myocytes and endothelial cells. Seroepidemiologic studies suggest HCMV infection to be widespread and influenced by age, geography, and cultural and socioeconomic status. Children become infected early in life in developing countries. Up to 80% of the adult population is infected in developed nations. The course of primary infection is usually mild or asymptomatic in immunocompetent hosts as HCMV establishes a latent but persistent infection, reflecting the inability of the immune system to clear the infection; immune evasion mechanisms allow infected cells to escape both innate and adaptive effector immunity.⁷⁰ In immunosuppressed patients (eg, solid organ or bone marrow transplantation recipients), the infection can be reactivated to result in systemic and organ infection; the heart is a possible target for tissue infection, especially in heart transplant recipients. The diagnosis and treatment of viral infections in transplanted patients are managed by pre-emptive or prophylactic therapy, and antiviral treatment is based on established protocols.⁷¹ Antiviral treatments can be administered when the viral diagnosis is established. For herpes simplex virus types 1 and 2 and for varicella-zoster virus, acyclovir (or its prodrug valacyclovir) and famciclovir have greatly reduced the burden of disease and have demonstrated a remarkable safety record. Drug resistance, in the otherwise healthy population, has remained below 0.5% after more than 20 years of antiviral use. Resistance is more common in immunocompromised patients, and alternative drugs with good safety profiles are needed. Ganciclovir and valganciclovir remain the drugs of choice for HCMV infection in immunocompromised hosts.^72,73

Postacute Phase of Viral Myocarditis

Evolution of Myocarditis

Myocarditis can have a fulminant course (rare), can heal spontaneously (common) or, in a minority of cases, can evolve into a chronic, low-grade inflammatory myocardial disease (Fig. 63–4). The diagnosis of chronic myocarditis is ideally established by biopsy-proven evidence of the acute phase and demonstration of the persistent myocardial inflammation. Different terms are currently found in the literature describing the latter pathologic substrate, including chronic myocarditis, subacute myocarditis, inflammatory cardiomyopathy, and myocarditis-induced DCM. Each term incorporates the demonstration of myocardial inflammation. The term inflammatory cardiomyopathy was introduced in 1995 by the World Health Organization/International Society and Federation of Cardiology Task Force on the Definition and Classification of Cardiomyopathies, and was defined as myocarditis associated with cardiac dysfunction.² The term and the definition were adopted by the ESC Working Group for Myocardial and Pericardial Diseases.³ The term inflammatory cardiomyopathy does not describe the phenotype (dilated or arrhythmogenic) and does not specify the cause. Most available clinical series have rarely included both baseline and follow-up biopsies^74,75,76 and have only reported the initial EMB performed at onset of the symptoms. The non-EMB series inferred the diagnosis of chronic myocarditis on the basis of clinical presentation suggestive of a recent-onset, flu-like syndrome shortly preceding the onset of cardiac symptoms, elevated inflammatory markers, and imaging characterization in patients with angiographically proven normal coronary arteries.⁷⁷ Past studies estimated that 30% of DCM evolved from myocarditis.^75,76,78,79 In a recent study, 82 patients with biopsy-proven active myocarditis were consecutively enrolled and followed-up for 147 ± 107 months. At 6 months, improvement or normalization of LVEF was observed in 53% of patients.⁷⁸ In another study including 174 patients with either active or borderline myocarditis, 124 patients were alive without being transplanted, 26 were dead or transplanted, and 24 (14%) were lost at a median follow-up of 23.5 months (interquartile range, 10-54 months).⁷⁹ A subsequent study included 181 consecutive patients with clinically suspected viral myocarditis; 69 patients fulfilled Dallas criteria for the diagnosis of myocarditis, 91 showed immunohistologic markers of inflammation, and 79 had a positive PCR-based genome search in the EMB. Twenty-two percent of the patients (n = 40) either died or underwent heart transplantation at a mean of 59 ± 42 months.⁸⁰ In another series of 222 consecutive patients with biopsy-proven viral myocarditis, mortality was 19.2% at a median follow-up of 4.7 years.⁸¹ Overall, about one-fourth of patients with biopsy-proven myocarditis evolve through worsening of cardiac function and either undergo heart transplantation or die.

Predictors of Outcome

Predictors of outcome vary in different myocardial biopsy studies. Persistence of New York Heart Association (NYHA) classes III to IV, left atrium enlargement, and improvement in LVEF at 6 months emerged as independent predictors of long-term outcome in one study.⁷⁸ Biventricular dysfunction at diagnosis was the main predictor of death/transplantation in another study.⁷⁹ Advanced NYHA functional class, immunohistologic signs of inflammation, and lack of β-blocker therapy (but not histologic characteristics [positive Dallas criteria] or detectability of viral genome) were found to relate to poor outcome⁸⁰; high rates of cardiomyocyte apoptosis were associated with functional recovery at 1 year.⁸² The presence of late gadolinium enhancement (LGE) emerged as the best independent predictor of all-cause and cardiac mortality, whereas the initial presentation with heart failure was a predictor of incomplete long-term recovery.⁸¹ Similarly, a high LV end-diastolic dimension Z-score on admission in children also was a predictor of worse outcomes, with higher mortality and incomplete recovery.⁸³ In 203 consecutive patients with an initial cardiac magnetic resonance (CMR)–based diagnosis of acute myocarditis (typical LGE) and a mean follow-up of 18.9 ± 8.2 months, an initial alteration of LVEF was the only independent CMR predictor of adverse clinical outcome.⁸⁴

Therefore, the most consistent predictors of worse outcome included NYHA functional class and presence of heart failure or LV dilation and dysfunction, and suggest little added value to myocarditis or postmyocarditis substrate.

Evolution of Acute Myocarditis to a Dilated Cardiomyopathy–Like Phenotype

Three pathogenetic hypotheses support the evolution from acute to chronic myocarditis or chronic inflammatory heart disease.

Immunopathogenic Hypothesis

It has been proposed that immunopathogenic or inflammatory reactions could lead to tissue damage uncoupled from the original viral injury.³³ The original myocyte damage induced by the acute inflammation might trigger an abnormal immune response that could subsequently smolder into a subacute and chronic phase of myocardial inflammation and myocyte damage. Few studies have reported the presence of anticardiac autoantibodies and immunoglobulins in blood samples.⁸⁵ This hypothesis supports the potential benefit of immunosuppression.

Viral Persistence

However, it has also been suggested that the infectious agent, or virus in particular, could persist and induce chronic inflammation and myocyte damage.³³ Based on this hypothesis, antiviral agents could help cleanse the infected myocardium from the persistent viral infection. However, the pertinent issues include how to detect viral persistence, demonstrate its virulence, and implicate it as the basis of myocardial dysfunction. Several studies have questioned the validity of PCR-based detection of viral genome in myocardial tissue as cause of the underlying myocardial disease, because many nonmyocarditis and noncardiomyopathy controls also test positively for the viral genome load.^86,87,88,89

Combined mechanisms

It is reasonable to propose that both mechanisms—viral persistence and the autoimmune reaction—might contribute to the progression of myocardial damage, chronic myocardial remodeling, and dysfunction. Both mechanisms, although biologically plausible, have been variably demonstrated and lend importance to the antiviral and immunosuppressive interventions. However, the major missing link in patients with poor clinical outcome is the systematic evaluation of the family to exclude underlying genetic causes that can either cause or contribute to the eventual phenotype.⁹⁰

Treatment of Viral Myocarditis

Treatment of myocarditis consists of supportive care with heart failure guideline–directed medical therapy and diuretics to relieve congestion.⁹¹ The use of positive inotropic agents is reserved for patients with reduced cardiac output and impaired organ perfusion. Temporary or implantable mechanical support devices are frequently employed in patients with refractory cardiogenic shock.⁹²

Immunosuppressive Therapy

Current clinical guidelines do not support the use of immunosuppressive therapy in the routine management of acute myocarditis.³ A study of 102 patients with acute-onset DCM classified as either reactive or nonreactive (based on the biopsy or other evidence of inflammation) failed to resolve LVEF after 9 months of prednisone treatment, even after an early transient improvement in reactive patients.⁹³ The multicenter Myocarditis Treatment Trial randomized 111 patients with biopsy-proven myocarditis of unknown etiology and an LVEF less than 45% to conventional therapy versus immunosuppressive therapy consisting of prednisone together with azathioprine or cyclosporine. Both groups experienced an average LVEF increase of 9% over 28 weeks, but immunosuppressive therapy failed to attenuate clinical disease or improve survival.⁸ Reserving immunosuppressive therapy for only those patients with ongoing inflammation has met with mixed success. A randomized study of 84 patients with unexplained DCM and increased human leukocyte antigen expression in biopsy specimens compared guideline-directed medical therapy of heart failure alone or in combination with prednisone and azathioprine.⁹⁴ The addition of immunosuppressive therapy was associated with an increase in LVEF and NYHA functional class at 3 and 24 months, but failed to reduce a primary composite end point of death, transplantation, or hospitalization. The favorable response to immunosuppressive therapy has been reported predominantly in virus-negative, autoimmune forms of myocarditis. In a study of 41 patients with active myocarditis and chronic heart failure treated with prednisone and azathioprine,⁹⁵ 21 patients were considered responders, experiencing an increase in LVEF from an average of 25.7% at baseline to 47.4% following treatment. Cardiac autoantibodies were present in 91% of these patients and in none of the nonresponders. Interestingly, viral genomes were detectable in 85% of the nonresponders and only 14% of responders. The Tailored Immunosuppression in Inflammatory Cardiomyopathy study was a randomized, placebo-controlled trial of prednisone and azathioprine in virus-negative myocarditis⁹⁶; immunosuppressive therapy of 85 patients was associated with an increase in LVEF, reduction in LV volumes, and improved NYHA functional class.

Immunomodulatory Therapies

High-dose intravenous immunoglobulin (IVIG) has both immunomodulatory and antiviral effects. Clinical trial results of its use in myocarditis have been mixed. In an open-label study, 9 of 10 adult patients with new-onset heart failure treated with IVIG had a significant improvement in LV function.⁹⁷ The Intervention in Myocarditis and Acute Cardiomyopathy trial was a randomized, placebo-controlled trial of IVIG that enrolled 62 patients with recent-onset DCM and LVEF < 40%.⁹⁸ Of these, 15% of patients had biopsy-proven myocarditis. No benefit of immunomodulation was demonstrated in terms of ejection fraction or survival at 6 and 12 months. Direct removal of circulating cardiac autoantibodies through the use of immunoadsorption has also been reported in a small, single-center study of patients with recent-onset cardiomyopathy.⁹⁹ In the absence of positive results from randomized controlled trials, it is not possible to make a recommendation for the use of IVIG or immunoadsorption.³

Antiviral Therapies

In patients with enterovirus myocarditis and viral persistence, treatment with interferon-β (IFN-β) has been reported to produce hemodynamic and clinical improvement.^76,100 Twenty-two patients with adenoviral or enteroviral genomes from EMBs and heart failure refractory to guideline-directed medical therapy were treated for 6 months with IFN-β. Treatment produced structural and functional LV improvement, and a majority of patients showed an improvement in NYHA functional class; viral genome was successfully eliminated in all patients, and myocardial inflammation was substantially reduced. Long-term follow-up of this cohort and others who spontaneously cleared enterovirus infection showed improved survival as compared to those with viral persistence.⁷⁶ Elevated levels of IFN-β, either through spontaneous production or exogenous administration over 6 months, were associated with effective enterovirus clearance and improved outcome. Conversely, the lack of spontaneous IFN-β production was associated with enterovirus persistence and reduced long-term survival. In a recent phase II study, 143 patients with symptoms of heart failure and biopsy-based confirmation of the enterovirus, adenovirus, and/or B19V genomes in their myocardial tissue were randomly assigned to double-blind treatment with either placebo (n = 48) or 4 × 10⁶ IU (n = 49) or 8 × 10⁶ IU (n = 46) of IFN-β-1b for 24 weeks, in addition to standard heart failure treatment. Compared to placebo, virus elimination and/or virus load reduction was higher in the IFN-β-1b groups (odds ratio 2.33, P = .048; similarly in both IFN groups). IFN-β-1b treatment was associated with favorable effects on NYHA functional class and improvement in quality of life and patient global assessments. The frequency of adverse cardiac events was similar in the IFN-β-1b groups compared to the placebo group.⁷⁴ Results of major clinical trials are listed in Table 63–2.

Nonviral Infectious Myocarditis

Bacterial Myocarditis

Although the list of the causes of infective myocarditis (see Table 63–1) may include several different bacteria, the proportion of bacterial myocarditis in immunocompetent hosts is low. Recent reports suggest a changing epidemiologic scenario of myocarditis-causing bacterial infections (eg, Corynebacterium diphtheriae infection is increasing worldwide, particularly in the developing countries).^{101,102,103,104} Uncommon pathogens with atypical clinical presentation such as Listeria monocytogenes and Leptospira are rare causes of myocarditis, and Legionella typically associated with pneumonia may occasionally present with fulminant myocarditis.^105,106,107 Warning messages come from single case reports or small clinical series demonstrating myocarditis in both immunocompetent and immunodeficient patients with multidrug-resistant infectious agents.¹⁰⁸ Typhoid infection from H58 lineage is one of the numerous reports on the re-emergence of typhoid in southern and eastern Africa, particularly from in Blantyre since 2011, highlighting the need for identifying the reservoirs and transmission of disease.¹⁰⁸ Recently, nontyphoid Salmonella, most commonly Salmonella enteritidis, was reported to inflict an overall mortality of 24%, wherein 42% of patients required intensive care and myocarditis was associated with poor prognosis and affected young adults.¹⁰⁹ In immunocompromised hosts, myocarditis can complicate meningococcal infection with an extremely poor prognosis and high mortality.^110,111,112

Bacterial coinfections with prevalent Staphylococcus aureus and Streptococcus pneumoniae in patients with influenza can cause myocarditis.¹¹³ Children with pre-existing neurologic conditions and immunocompromise are at increased risk of pH1N1-associated death after intensive care unit admission. Secondary complications of pH1N1, including myocarditis, encephalitis, and clinical diagnosis of early presumed methicillin-resistant S aureus coinfection of the lung, have been reported as fatal risk factors.¹¹⁴ Tubercular myocarditis is still known to occur and cause sudden death.^115,116 Finally, myocarditis can follow medical treatments for rare infections such as ehrlichiosis.^117,118

Fungal Myocarditis

In immunocompetent hosts, fungal myocarditis is rare; Candida and Aspergillus may occasionally cause myocarditis and can represent hospital-acquired infections.^119,120,121 Fungal infections are more commonly associated with endocarditis (see Chap. 67), in particular in postsurgical patients and in patients receiving implantable devices.

Myocarditis Associated With Parasitic Infections

Protozoal Infections

In immunocompetent hosts, Trypanosoma cruzi is the most common parasitic infection known to be associated with myocarditis^22,24,25 (described later). Between 5 and 18 million people are currently infected, and the infection is estimated to cause more than 10,000 deaths annually.^22,24 Toxoplasma gondii causes a disease known as toxoplasmosis.¹²² While the parasite is found throughout the world, the prevalence of human Toxoplasma infection varies in different parts of the world and has been reported with rates up to 75%.^123,124 Few infected individuals have symptoms. However, in pregnant women and individuals who have compromised immune systems, Toxoplasma infection can cause severe consequences. The implementation of prophylaxis with trimethoprim-sulfamethoxazole in transplanted patients has significantly contributed to prevent post-transplantation myocarditis.¹²⁴

A rare infection is sarcocystosis, which typically affects muscle but rarely involves the heart¹²⁵; it can be suspected in travelers returning ill from high-risk areas complaining of myalgia with or without fever. Acute muscular sarcocystosis shows an apparent biphasic course with fever and acute myalgia followed subsequently by elevated creatine phosphokinase, eosinophilia, and possible relapses.¹²⁶

Helminthic Infections

Helminthic infections rarely affect the heart. They can be suspected in endemic areas with trichinosis and echinococcal infections. Cases of cardiac involvement in leishmaniasis¹²⁷ or toxocariasis¹²⁸ are exceptional.

Trichinellosis or Trichinosis

Eosinophilic myocarditis is a possible complication in patients with trichinosis, a zoonosis caused by nematodes of the genus Trichinella. The most common species affecting humans is Trichinella spiralis, which has a global distribution and is most commonly found worldwide in carnivorous and omnivorous animals.^129,130 The burden of annual infection worldwide is estimated around 10,000 cases. Trichinella is endemic in the areas with unregulated slaughter of pigs and particularly in areas where these are in contact with wild animals.^131,132 A systematic analysis of six international databases with 494 studies and 65,818 cases reported 42 deaths in 41 countries from 1986 through 2009. The World Health Organization European Region accounted for 87% of cases; 50% of those occurred in Romania during 1990 to 1999. With a prevalence of 1.1 to 8.5 infected cases per 100,000 population,¹³³ cardiac involvement continues to be a major complication in Romania.¹³⁴ The myocardial involvement occurs in the second phase of the infection cycles, and humans are affected when consuming raw or undercooked meat infected with the Trichinella parasite; high temperatures (> 77°C) and freezing (–25°C) are known to kill the larvae of the parasite. After exposure to gastric acid, the larvae are released from the cysts (after 1 week of the infection) and invade the small bowel mucosa where they develop into adult worms. Then the larvae migrate through peripheral blood and may reach striated muscles where the encystment is completed in 4 to 5 weeks, and the encysted larvae may remain viable for several years. When informative, muscle biopsy shows inflammatory infiltrates, collagen capsule of the “nurse cell,” and intersected muscle larva.^{132,133,134,135}

The clinical presentation depends on the stage of infection, number of invading larvae, infected tissues, and general physical condition of the patient. The course of the infection can remain asymptomatic. Symptoms of trichinosis occur in two stages. Intestinal infection is the first stage and develops 1 to 2 days after consuming contaminated meat. The most common symptoms are nausea, diarrhea, abdominal cramps, and fever. The second stage corresponds to larval invasion of muscles and starts after about 7 to 15 days. The most common symptoms are muscle pain and tenderness, weakness, fever, headache, and swelling of the face, particularly periorbital swelling. The pain is pronounced in the respiratory, masticatory, retropharyngeal, and orbicular muscles and tongue. It may be accompanied by skin rash and ocular involvement.^{132,133,134,135} Eosinophilic myocarditis may occur in the second stage of the disease; it can be life-threatening and may manifest with heart failure and arrhythmias; right ventricular outflow tract obstruction is rarely reported.^132,135 The diagnosis of trichinellosis should be based on clinical findings; pathology findings of muscle and/or EMB detecting larvae; laboratory findings of specific antibody response by indirect immunofluorescence, ELISA, or Western blot; hypereosinophilia (1000 eosinophils/mL) and/or increased total IgE levels; increased levels of muscle enzymes; and investigation of the possible source and origin of infection^{129,130,131,132} (Table 63–3). When the diagnosis is proven, the treatment is based on antihelminthic drugs, such as albendazole or mebendazole, and supportive therapy in patients with heart failure.¹³²

Echinococcosis

Echinococcosis is endemic in several geographic areas such as North Africa, South America (Argentina), New Zealand, Greece, and Iceland. In infected patients, cardiac involvement is uncommon (< 2%), and even in patients with cardiac involvement, signs and symptoms are rare (< 10%). The host of Echinococcus granulosus is the dog; humans could serve as the intermediate host if they accidentally ingest ova from contaminated dog feces. Hydatid cysts more commonly affect liver and lungs and are usually solitary. Combined liver and extraliver cysts are observed in 25% of cases; cardiac cysts comprise 0.5% to 2% of all cases. Within the heart, hydatid cysts are usually located in the left ventricle (up to 60%) or right ventricle (up to 20%) and rarely found in the pericardium (10%-15%).¹³⁶ Pericardial cysts usually do not cause symptoms and remain silent until they grow large and result in cardiac compression, atrial fibrillation, and even sudden death. Myocardial cysts localized in the interventricular septum or LV wall remain segregated and undergo calcification or generate daughter cysts and undergo rupture.^137,138

Depending on the localization, the effects of the ruptured hydatid cysts vary. It could result in pericarditis and may evolve to chronic constrictive pericarditis when ruptured in the pericardium; cardiac tamponade is uncommon.^139,140 When the cyst ruptures in right cardiac chambers, possible complications include pulmonary embolism and pulmonary hypertension.^141,142,143 Syncope can occasionally be the first manifestation of the disease.¹⁴⁴ The rupture of the hydatid cysts with release of the fluid may cause severe anaphylactic reaction. Symptoms may occur in patients with pericardial involvement or with mass-induced right-sided obstruction. Echocardiography and CMR may localize the myocardial cysts.¹⁴⁵ When present, eosinophilia may contribute to the diagnostic suspicion. Serologic tests such as the Casoni test demonstrate false-positive and false-negative results in up to 30% of cases; ELISA test has a sensitivity of 91% and specificity of 82%.¹⁴⁶

Medical treatment is based on albendazole and mebendazole; surgical resection is the treatment of choice for the prevention of rupture of cysts. Novel application of the cardiac stabilizer (Octopus IV) was reported to safely lift the heart up and excise a hydatid cyst that was firmly adherent to the posterior surface of the heart.¹⁴⁷

Toxocariasis

Toxocariasis occurs worldwide. The highest prevalence is reported from tropical and subtropical countries.¹³⁰ Myocarditis is the most frequent clinical presentation (58%), followed by pericarditis (25%) with or without tamponade. Cardiac involvement in Toxocara infection is a potentially life-threatening complication. The cardiac workup is based on electrocardiography (ECG), chest x-ray, echocardiography, and laboratory tests. ECG may show nonspecific abnormalities, including peripheral and thoracic low-voltage and nonspecific ST-T alterations. The chest x-ray shows cardiomegaly and signs of pulmonary congestion. Echocardiography shows wall thickening, hypokinesia, and a reduced LVEF with possible pericardial effusion or endomyocardial fibrosis and restrictive cardiomyopathy. Thrombotic complications may occur. The therapeutic regimens vary widely, especially with regard to the duration of therapy, and the combination of an anthelmintic drug and corticosteroids appears to be a valuable option. Clinical manifestation of the tissue infection by parasites should be considered in cases of nonspecific organ manifestations (ie, heart, lungs, liver) accompanied by fever and eosinophilia, with or without allergic skin rash.^148,149

Myocardial Transmission of Infections in Heart Transplantation

Organ transplant recipients can develop infections as a result of transmission through the graft, reactivation of silent infection, reinfection in a healthy graft, or de novo infection. Infections can manifest in the post-transplant period as a consequence of immunosuppression.

In 2004, the United Network for Organ Sharing introduced the label of “high-risk donor” to identify donors who meet the Centers for Disease Control and Prevention criteria for high-risk behavior for infection.¹⁵⁰ In a recent single-center series including 55 recipients of heart transplants from high-risk donors, survival was excellent (short-term survival [1 year] 94%; long-term survival [3 years] 80%), and there was no increased incidence of perioperative or postoperative complications; the risk of transmission of infection from donors in this subgroup seemed to be minimal; only 1 of 55 patients (1.9%) had hepatitis C seroconversion at 105 days after receiving the transplant. After antiviral treatment, the patient had undetectable viral loads. All other patients (n = 54) had undetectable plasma viral loads of HIV, hepatitis C, and hepatitis B.¹⁵¹ These data encourage revision of criteria for declining grafts from high-risk donors.

Some infectious diseases, such as Chagas disease, endemic fungal infections, tuberculosis (which could be drug resistant), leishmaniasis, and other viral and parasitic diseases, should be considered in the differential diagnosis of post-transplant infections in foreign-born recipients.¹⁵²

Several autoimmune diseases may involve myocardium, endocardium, pericardium, valves, and both small intramural vessels and epicardial coronary arteries. The diagnosis of myocardial involvement in autoimmune disease should be based on the recommendations of scientific societies.³

The diagnosis of isolated autoimmune myocarditis in patients who do not demonstrate systemic or extracardiac autoimmune disease is difficult and requires demonstration of both myocarditis and autoantibodies mediating myocyte damage or inducing inflammatory autoimmune reaction. This complex diagnostic workup is based on the demonstration of circulating autoantibodies. The significance and role of autoantibodies vary in the different diseases wherein they represent markers of disease, disease-inducing autoantibodies, or both. A paradigmatic example of autoimmune myocarditis is neonatal lupus or autoimmune congenital heart block (atrioventricular block) that is caused by the placental transfer of maternal Ro/La autoantibodies (anti-SSA/Ro and anti-SSB/La antibodies) damaging the conduction tissues during fetal development.¹⁵³ Infants may demonstrate transient skin and systemic lesions and permanent atrioventricular block associated with significant morbidity and mortality; pacemakers are implanted in two-thirds of cases. Acute myocarditis may appear in early phases of the disease and is characterized by lymphocytic infiltrates.^154,155

Serum cardiac autoantibodies may be found in autoimmune myocarditis, DCM, and normal controls³ and include anti-sarcolemmal (ASA), anti-fibrillary (AFA), organ-specific and partially organ-specific anti-heart (AHA), anti-intercalated disk (AIDA), anti-adenine nucleotide translocator (anti-ANT), anti-myolemmal (AMLA), anti-adrenergic receptor (anti-AR), anti-interfibrillary (anti-IFA), branched chain α-ketoacid dehydrogenase dihydrolipoyl transacylase (anti-BCKD), anti-heat shock protein (HSP), anti-myosin heavy chain (MHC), anti-myosin light chain 1 ventricular (MLC1v), anti-actin, anti-tropomyosin, and anti-laminin antibodies. The significance of these antibodies is still a matter of research.³ Recommendation 9 of the recent position statement of the ESC Working Group on Myocardial and Pericardial Diseases suggests testing for cardiac autoantibodies based on the availability of tests and center expertise; unfortunately, no commercially available and standardized cardiac autoantibody tests have been validated.³

Autoantibodies in postviral cardiomyopathy can be secondary to the effects of primary myocyte damage induced by the viral infection; picornavirus infections (type 1 diabetes, myocarditis, or paralysis) demonstrate a strong association with autoimmunity, with particular evidence in type 1 diabetes and myocarditis.^156,157 The recent demonstration of T cells expressing dual T-cell receptors on a single cell induced as a natural consequence of Theiler virus infection, which may occasionally cause human myocarditis, could explain the pathogenicity resulting from induction of autoimmunity to organ-specific antigens.¹⁵⁸

Toxic substances can cause myocardial injury and inflammation (see Table 63–1). The myocardial insult can be transient and reversible or chronic and persistent.

Direct Toxic Substances

Well-known examples are myocarditis forms caused by arsenic and lithium. Historically, arsenic was used in agriculture to control parasites and pests, and exposure in industry is possible during processing of minerals and coloring of glass. Elimination from the body is easier for organic than for pentavalent or trivalent inorganic arsenic. Trivalent derivatives are 100 times more toxic than pentavalent forms. Injection of arsenic may cause myocarditis characterized by myocyte necrosis, infiltration of leukocytes and lymphocytes, and neutrophilic perivasculitis.¹⁵⁹ Lithium is used in psychiatry as an antimaniac and mood stabilizer. It can cause various adverse effects including myocarditis and arrhythmias¹⁶⁰; sinus node dysfunction can occur with serum lithium levels in the therapeutic range.¹⁶¹ Zinc phosphide has been used as a rodenticide and is toxic by ingestion; its conversion to phosphine gas that is absorbed into the bloodstream causes metabolic and nonmetabolic toxic effects, including myocarditis, pericarditis, acute pulmonary edema, and congestive heart failure.¹⁶² Several other substances may cause toxic myocarditis (see Table 63–1). Their precise diagnosis is based on the identification of the toxic agent.

Drug-Induced Myocarditis

Different drugs may induce similar cardiac toxicity. The clinical manifestations include the entire spectrum of cardiac phenotypes, including cardiomyopathy, conduction disturbances, arrhythmias, hypertension, and coronary artery disease. Each of them is discussed in their corresponding chapter in this text. Myocarditis is one of the possible complications; it can either regress if the drug is discontinued or persist and evolve through a cardiomyopathy phenotype.

In the acute drug hypersensitivity syndrome, the clinical manifestations occur after a few weeks from initiation of a new drug; less commonly, the syndrome may manifest at any time after drug consumption. Drugs known to potentially cause hypersensitivity syndrome include antibiotics, antiepileptics, allopurinol, and sulfonamide-containing drugs (see Table 63–1). In addition, drugs used for hemodynamic support in patients with cardiogenic shock or acute heart failure, such as dobutamine, may trigger hypereosinophilia and hypersensitivity myocarditis. When present, traits such as cutaneous rash associated with fever, eosinophilia, and multiorgan dysfunction (liver, kidney, and heart) may be indicative of drug toxicity. The cardiac involvement may be extensive and associated with LV dysfunction, hypotension, and thromboembolic risk.

Clozapine is an effective antipsychotic drug¹⁶³ that is selectively and cautiously used in patients with treatment-resistant schizophrenia because of its hematologic and cardiovascular adverse effects.¹⁶⁴ A recent review describes 250 cases of clozapine-induced myocarditis and highlights the possibility that myocarditis is underdiagnosed in patients receiving clozapine.¹⁶⁵ Warning data potentially useful for suspecting myocarditis in patients treated with clozapine include recent onset of treatment (mean 14 days), the occurrence of fever close to the initial administration of the drug, old age, concomitant treatment with sodium valproate, rapid drug titration, respiratory illness, or pneumonia. The incidence of myocarditis was approximately 3%, and the need of implementing monitoring procedures cannot be overemphasized. More precise data on the prevalence of myocarditis would lead to formal indications for cardiac monitoring. The higher prevalence of clozapine myocarditis reported in Australia likely results from awareness of the complications, as well as from the systematic data collection of the treated patients.¹⁶⁵ Clozapine myocarditis can be fatal and only diagnosed at autopsy.¹⁶⁶ Timely early diagnosis is feasible, and drug removal may reverse signs and symptoms.^167,168

Medical History and Physical Examination

Myocarditis is an unexpected, often sudden, and rapidly evolving condition. Patients presenting with acute myocarditis frequently describe episodes of recent febrile illness. The clinical manifestations range from severe and life-threatening, to recent onset of heart failure, to mild signs and symptoms such as fatigue and arrhythmias. Table 63–4 summarizes various scenarios of clinical manifestations. Fulminant myocarditis may present with life-threatening events (in the absence of coronary artery disease and known causes of heart failure), such as cardiogenic shock or aborted sudden death, associated with underlying giant cell myocarditis or acute viral myocarditis. However, patients presenting with aborted sudden death with a history of sudden death in the family should invoke investigation for genetic cardiomyopathy (Fig. 63–5).

Myocarditis may present as a new onset of heart failure with symptoms such as dyspnea and fatigue or arrhythmias and signs of heart failure on physical examination. With ECG nonspecific ST-T wave changes, conduction disturbances, and arrhythmias, these patients may demonstrate echocardiographic evidence of impaired systolic LV and/or right ventricular function, with mildly dilated ventricular chambers. The clinical distinction between such presentation of myocarditis and recent-onset DCM is complex and is dependent on pathologic demonstration of myocarditis as the cause of the phenotype. Family history is usually negative. Chronic forms of myocarditis could also be associated with specific myocardial diseases such as sarcoidosis, autoimmune diseases, Chagas disease, or Lyme disease. The differential diagnosis between chronic myocarditis, inflammatory cardiomyopathy, and DCM is essential to prevent misdiagnosis. In clinical practice, a report concluding with the diagnosis of chronic myocarditis is uncommon, and most patients are diagnosed with DCM. Lack of investigation for genetic cause of the disease in recent-onset DCM may impact not only the management of patients, but also the families.

Uncommonly, acute myocarditis masquerades as an acute coronary event with ST-T wave changes, global or regional LV hypokinesia, and elevated markers of myocyte injury.¹⁶⁹ The ECG alterations and wall motion abnormalities usually extend beyond a single coronary artery territory as expected in a coronary event, and the ECG and biochemical alterations are longer lasting and do not follow the usual pattern of evolution associated with acute coronary events. These abnormalities are likely to be diffuse or unrelated in myocarditis. Infrequently, myocarditis may also present with unexplained ventricular arrhythmias in a setting of DCM. A recent study evaluated fasting positron emission tomography (PET) scan findings in more than 100 consecutive patients referred with unexplained cardiomyopathy and ventricular arrhythmia for possible ablative therapy.¹⁷⁰ Almost 50% of patients exhibited focal fluorodeoxyglucose (FDG) uptake. The EMB revealed granulomatous inflammation representing sarcoidosis in a small subset of patients and also nongranulomatous inflammation suggestive of myocarditis in another. Correlation between low-voltage regions on electroanatomic mapping and FDG uptake was observed in 75%, and magnetic resonance imaging (MRI) findings matched abnormal PET regions in only 40%. These data suggested that significant proportion of patients considered idiopathic could have harbored occult inflammatory myocardial disease. Of the patients with FDG-based evidence of inflammation, 90% received immunosuppressive therapy and 60% underwent ablation; however, because of a lack of a control group, this study cannot be considered prescriptive and remains hypothesis generating.

Variability is immense in different series of reported patients who underwent EMB investigated with the support of molecular and immunohistochemistry; the final interpretation of pathology findings has been fraught with issues involving interobserver variability, tissue quality, stage of presentation, causes, and disease severity. Overall, clinical evaluation of the phenotype, family history, and investigation of autoimmune disease potentially associated with chronic myocardial inflammation are essential to formulate a clinical decision. Imaging strategies and biomarkers are being investigated for the supportive diagnosis, which needs to be validated against EMB.

Imaging

The concept of imaging is progressively evolving from single-modality investigation to multimodality imaging strategies in which each test adds information that increases the specificity of the diagnostic markers for different types of myocarditis.

Echocardiography

Echocardiography is the initial investigation in patients with suspected myocarditis. Echocardiographic findings are nonspecific and include LV global or regional dysfunction with decreased ejection fraction, LV dilation, right ventricular involvement, and pericardial effusion.¹⁷¹ Strain and strain rate imaging using speckle tracking may add information on early regional contractility and dysfunction¹⁷²; in patients with biopsy-proven myocarditis, LV fractional shortening, longitudinal strain, and strain rate are reduced and correlate with the burden of myocardial inflammation.¹⁷³ In patients with suspected, but non-EMB proven, acute myocarditis, longitudinal strain and circumferential strain have specificities of 93% and 94%, respectively; the degree of strain correlates with the risk of future clinical events.¹⁷⁴ Irrespective of the specific contribution to myocarditis, echocardiography remains the first line of investigation.

Cardiac Magnetic Resonance

CMR provides detailed morphofunctional description of ventricular involvement¹⁷⁵ and offers important prognostic information. There is a substantially lower risk of events in patients with suspected myocarditis but normal CMR findings.¹⁷⁶ In addition, CMR also provides information on the presence and extent of pericardial effusion, which is commonly associated with myocarditis.¹⁷⁷ According to the Lake Louise CMR criteria, acute myocarditis is associated with (1) increased regional or global myocardial signal intensity in T2-weighted images (indicating myocardial edema); (2) increased global myocardial early gadolinium enhancement (EGE) ratio between myocardium and skeletal muscle in T1-weighted images (supporting hyperemia/capillary leakage); and (3) at least one focal lesion with nonischemic distribution in LGE T1-weighted images (suggestive of cell injury/necrosis).¹⁷⁵ The diagnostic accuracy does not increase with the addition of pericardial effusion.¹⁷⁸

T2 Mapping for Myocardial Edema

T2-weighted short tau inversion recovery (STIR) imaging can detect and localize epicardial, transmural, or global myocardial edema; T2-STIR high signal intensity identifies areas of tissue edema.¹⁷⁷ When evaluated as an independent measure, T2-STIR has demonstrated variable sensitivity (58%-74%) and specificity (57%-93%).¹⁷⁵ An alternative method for evaluation of myocardial edema is the low b-value diffusion-weighted echo-planar imaging sequence that has offered higher sensitivity (92% vs 54%) and diagnostic accuracy (95% vs 70%) compared with standard STIR-T2 images, but similar specificity, in acute myocarditis.^179,180 T2 mapping is able to quantitatively define the area of edematous myocardium¹⁸¹ through a 16-LV segment T2-mapping protocol, which provides more robust imaging of myocardial edema than standard T2-weighted imaging.¹⁸² Protocols based on gradient spin echo imaging techniques further improve accuracy and reduce acquisition time for T2 mapping.¹⁸¹

Early Gadolinium Enhancement

EGE represents an increased distribution into the interstitial space early in the washout phase⁵ as a result of hyperemia and capillary leakage.¹⁸³ EGE displays a sensitivity of 63% to 85% and specificity of 68% to 100% for the diagnosis of myocarditis in the given clinical context.¹⁷⁵ However, EGE does not describe relative regional distribution of gadolinium uptake and is a time-consuming process. An alternative method, the contrast-enhanced steady-state free precession technique, allows better visualization of hyperintense myocardial regions of gadolinium uptake. In a recent study of 19 patients with myocarditis, hyperemia was observed in 77% of patients and was associated with increased inflammatory markers and greater LGE.¹⁸³ CMR with contrast-enhanced steady-state free precession potentially represents a more efficient method for detecting hyperemia, but it should always be compared directly with traditional EGE.

T1 Mapping

T1 prolongation also indicates myocardial edema and hyperemia.¹⁸⁴ A T1 value more than 990 ms indicates myocardial injury and is used to create topographic maps representative of the degree of myocardial involvement.¹⁸⁵ In patients with clinically suspected myocarditis,¹⁸⁶ T1 mapping seems to be more sensitive and offers similar diagnostic accuracy as that of dark-blood T2 imaging, bright-blood T2 imaging, and LGE. The performance of T1 mapping has been reported to be similar to LGE and better than the T2-weighted imaging methods. Additional modified protocols showed that longer relaxation times were associated with high diagnostic accuracy.¹⁸⁷ Combined native T1 relaxation time combined with T2-weighted imaging criteria increase sensitivity (92%), specificity (97%), and diagnostic accuracy (95%). T1 mapping improves the diagnostic confidence in cases in which traditional methods have failed to recognize any disease; incrementally elevated T1 thresholds were associated with enhancement on LGE images, suggesting a role for the absolute T1 value in determining size of myocardial injury.¹⁸⁸

Late Gadolinium Enhancement

T1-weighted LGE detects irreversible cell injury, myocyte necrosis, and myocardial fibrosis.^175,189 LGE detects the patchy distribution of the disease, but can also demonstrate transmural patterns.¹⁹⁰ In acute myocarditis, automated calculation of LGE^190,191 correlates with LGE quantified by visual assessment.

Limitations and Perspectives

CMR may not be specific for the process of myocardial inflammation and needs to be weaved into the clinical context; it also does not differentiate among the diverse causes of myocarditis.^153,187,188 In biopsy-proven myocarditis, tissue edema, EGE, and LGE were more common in infarct-like patterns; sensitivities in the infarct-like, cardiomyopathy, and arrhythmic patterns of presentations were 80%, 60%, and 40%, respectively. Promising evolution comes from the targeted experimental studies on in vivo uptake of perfluorocarbons in monocytes, macrophages, and granulocytes visualized by CMR imaging.^{192,193 19}F-labeled tracers, which may be incorporated into specific cell types, have been employed for targeted CMR.^{4,5,159,193,194} A recent experimental study demonstrated the clinical feasibility of ¹⁹F-MRI with perfluorooctyl bromide at 3.0 T for targeting myocardial inflammation.¹⁹⁵

¹⁸F-Fluorodeoxyglucose–Positron Emission Tomography

¹⁸F-FDG-PET has played a diagnostic role in myocarditis¹⁹⁶ and in clinically suspected myocarditis, demonstrating a sensitivity of 46% and a specificity of 81%.¹⁹⁷ Although current evidence is not sufficient to support its routine use for the diagnosis of myocarditis, it may add functional information to the currently employed structural imaging. FDG accumulates in inflammatory cells. Sarcoidosis provides an informative example of combined approach of perfusion (eg, ¹³N-NH₃) and inflammation (eg, ¹⁸F-FDG) PET imaging in assessing myocardial inflammation. Normal perfusion and intense ¹⁸F-FDG uptake indicates active cardiac sarcoidosis, hypoperfusion and high glucose metabolism indicate advanced sarcoidosis, and decreased or absent perfusion and negative FDG uptake indicate end-stage cardiac sarcoidosis. Parallel MRI allows localization of myocardial scars by LGE and determination of the extent of disease by T2 edema imaging.¹⁹⁸

Biomarkers

Biomarkers may contribute to the diagnosis of acute myocarditis and its evolution to the chronic state. Beyond serology, antigenemia, viremia, and DNA-emia in infectious myocarditis, biomarkers may inform about inflammatory and myocyte injury processes.

Markers of Myocyte Injury or Damage

Diagnosis

Myocarditis can be associated with increased levels of markers of myocyte injury such as cardiac troponin (cTn; troponins I and T)^{164,165,166,167,198,199,200,201}; elevated cTn has been reported predominantly in myocarditis with either fulminant or acute clinical presentation.²⁰¹ Past studies indicated that sensitivity of cTn for the diagnosis of myocarditis is low. Whereas only 34% of patients enrolled in the Myocarditis Treatment Trial had cardiac troponin I elevation,²⁰² recent studies have demonstrated superior predictive values of high-sensitivity troponin T for acute myocarditis when other causes of increased myocardial necrosis markers, such as myocardial infarction, have been systematically excluded.²⁰³ Cardiac troponin T is routinely used in the clinical workup for both children²⁰⁴ and adult patients.²⁰⁵ In a screening report of 38,197 veterans, 4469 tested positive for influenza virus. Of these, 600 had further cardiac biomarker testing, and 143 (24%) demonstrated an increase in one or more cardiac biomarkers, which was associated with acute congestive heart failure (6%), myocarditis (4%), atrial fibrillation (3%), noncardiac explanations (8%), or no documented explanation (31%).²⁰⁶

Although cTn levels have been reported as a prognostic marker in patients with giant cell myocarditis,²⁰⁷ these data have not been confirmed in other studies, wherein cTn levels predict neither the diagnosis nor severity of disease.²⁰⁸ cTn may be elevated in myocardial toxicity of known and novel drugs: in patients included in phase I trials of novel targeted therapies for a metastatic solid tumor, cTn was one of the most useful markers for measuring cardiac toxicity. In a series of 90 patients, 2 experienced chest pain and troponin I elevation and 8 revealed asymptomatic elevation of troponin I during follow-up.²⁰⁹ Markers of myocyte injury can either contribute to the diagnosis or provide information for correlation with other clinical parameters in all forms of myocarditis with myocyte injury.

Overload

N-terminal pro-B type (brain) natriuretic peptide (NT-proBNP) or brain natriuretic peptide (BNP) levels increase in myocarditis associated with LV dysfunction, but normal values do not exclude myocarditis²¹⁰; levels rapidly decline with recovery of the LV function.²¹¹ In a pediatric series including 58 children with myocarditis and reduced ejection fraction (< 30%), peak BNP > 10,000 ng/L and cardiac MRI late enhancement were identified as predictors of poor outcomes.²¹² In a series of 70 patients with clinically suspected myocarditis and 42 patients with EMB-confirmed myocarditis, NT-proBNP in the highest quartile (> 4225 ng/mL) was predictive for cardiac death or heart transplantation at 7.5 months from the diagnosis.²¹² However, newer biomarkers, such as copeptin or midregional pro-adrenomedullin, have not offered additional diagnostic or prognostic information.^212,213

Serum cardiac autoantibodies (eg, anti-fibrillary, organ-specific and partially organ-specific anti-heart, anti-intercalated disks, anti-interfibrillary) in high levels have been described to be useful in the absence of viral genome in EMB, suggesting an immune-mediated myocarditis or inflammatory cardiomyopathy.^2,3

The role of miRNA profiling is being investigated in acute, chronic, and fulminant myocarditis. miR-208b and miR-499 are upregulated after myocardial damage and can be measured in the plasma of patients with myocarditis.²⁷ Their simultaneous upregulation seems to characterize fulminant viral myocarditis.²¹⁴ Their role as possible positive regulators of toll-like receptor 4 in blood monocyte-derived dendritic cells and macrophages suggests that they can be future diagnostic contributors in patients with suspected myocarditis.²¹⁵ At present, no miRNA is demonstrated to be specific for patients with chronic myocarditis.

Markers of Inflammation

High-sensitivity C-reactive protein and erythrocyte sedimentation rate are routinely measured in patients with suspected myocarditis,²¹⁶ but with limited contribution to the diagnosis. As correlation factors, C-reactive protein at admission does not seem to correlate with LGE on CMR in adult patients with myocarditis.²¹³ Conversely, increased levels of C-reactive protein can be critical early signs of drug toxicity myocarditis (eg, warranting close monitoring and serious consideration for cessation of drugs such as clozapine).^216,217 Experts recommend that C-reactive protein and troponin I levels should be measured at baseline, two times per week for 1 month, then once per week for another 1 month, and then once per month for the remainder of the first year.²¹⁸

Viral serology can provide information in the acute phases of infectious myocarditis. These phases can be missed unless the clinical onset is cardiogenic shock or acute heart failure and patients are tested shortly after onset of the illness. In chronic myocarditis and in inflammatory cardiomyopathy, the clinical contribution of viral serology is limited; IgG antibodies for cardiotropic virus can be found in the bloodstream of the general population without accompanying cardiac involvement.²¹⁹ Serology is routinely performed in parallel with molecular tests seeking genomes of the suspected pathogens. A positive virus PCR in peripheral blood does not prove viral myocarditis. However, when viral genome is present in the EMB, blood viral PCR can exclude or confirm systemic infection.³ It may also differentiate an acute viral infection from endogenous viral reactivation in which there is higher virus replication.

Endomyocardial Biopsy

EMB is the current gold standard for the diagnosis of myocarditis.^3,31 EMB samples are processed with conventional methods. The frozen samples are processed in case of clinical emergency such as nonischemic cardiogenic shock or resuscitated cardiac arrest, when EMB is performed during implantation of the circulatory support devices. EMB offers immediate information about the basis of cardiogenic shock allowing differentiation between fulminant myocarditis and nonmyocarditic causes. Although frozen sections for histomorphologic studies are not optimal, at least the diagnosis of myocarditis is feasible. In patients presenting with clinically stable heart failure, even of recent onset, EMB samples are routinely processed. The interpretation of pathologic features is based on light microscopic examination of routine stains and immunohistochemistry, and electron microscopy is undertaken when possible and indicated. One or more samples are used for viral investigation, both pathogen isolation and search of replicating pathogen.

Inflammation

The extent of myocardial inflammation and the type of inflammatory cells are major pathologic contributors to the diagnosis; acute myocarditis is characterized by conspicuous focal or diffuse inflammatory infiltrates. Inflammatory cells are routinely recognized on cytomorphology, but immunophenotyping of inflammatory infiltrates allows precise characterization of T-cell CD4⁺ and CD8⁺ subsets and identification of the extent of infiltration by the cells of monocyte-macrophage lineage. Neutrophilic and eosinophilic infiltrates, mast cells, and plasma cells are easily detectable using routine stains. Serial sectioning of routine EMB sampling (about 2-3 mm size/sample) usually provides sufficient material for multiple staining and immunohistochemical staining. Immunohistochemical characterization of the inflammatory infiltrate substantially contributes to the diagnosis of rare primary lymphomas of the heart or unusual cardiac involvement in diseases such as Erdheim-Chester disease. The presence of a few scattered inflammatory cells in the myocardium, even when highlighted by immunohistochemical stains, should not be labeled as myocarditis because some inflammatory cells can be present in the normal myocardium⁸ and hearts affected by genetic cardiomyopathy.²²⁰

Eosinophilic inflammatory infiltrates are present in a variety of myocarditides of different origin. Eosinophilic granulocytes may infiltrate in both myocardium and endocardium. EMB can contribute to differentiate neoplastic, reactive, and secondary eosinophilic syndromes and eosinophilic syndromes of unknown significance.

Giant cells are found in giant cell myocarditis (GCM), sarcoid granulomas, tubercular myocarditis, rheumatic heart disease, and brucellosis. In GCM, inflammatory cells heavily infiltrate the myocardial tissue. In small EMB samples, giant cells may be missed.

Small intramural vessels occasionally demonstrate vasculitis, with inflammatory infiltrates involving small arteriolar walls. Small thrombi may occur in intramural vessels (Fig. 63–6). When both interstitial inflammatory infiltrates and vasculitis are present, patterns of myocarditis and ischemic myocyte damage may coexist.

Endocardium may also show inflammatory cell infiltration, which should always be reported. In addition, the endocardium may occasionally show thrombotic stratification with or without inflammation. The finding may provide the rationale for antiaggregation or anticoagulation treatments (Fig. 63–7).

Myocardial Damage

The myocyte injury is typically noncoagulative. It is easy to distinguish it from the coagulative necrosis in small EMB specimens on hematoxylin and eosin stain (Fig. 63–8); acid fuchsin orange G stain may further help differentiation. Myocyte injury in myocarditis reflects the cytotoxic effect exerted by T lymphocytes and related cytokines, and is characterized by discontinuity/rupture of sarcolemma, myocyte edema, and loss of intracellular organelles in the interstitium. Nuclei may be prominent and show evident nucleoli. Unless microthrombi occur in small vessels, coagulative necrosis is absent. The inflammation-induced myocyte injury also differs from contraction band necrosis that may occur in cardiogenic shock in patients with pheochromocytoma.²²¹

Pathologic Evidence of Myocardial Infection

There are pathogens that can be easily seen with routine hematoxylin and eosin stains; parasites, bacteria, and viral infections causing cytopathic effect are unlikely to be missed by routine pathology study. Morphologic evidence of infection is common in transplanted hearts, and HCMV shows a marked endotheliotropic effect usually coincident with increased viremia and DNA-emia. Patients with acute CV-B3 infection with replicating virus in the myocardium may show ultrastructural evidence of viral infection; the confirmation is obtained by molecular analysis with reverse transcriptase PCR, which should be the standard for the etiologic diagnosis. There are viruses or phases of viral infection (and viral replication) that cannot be easily recognized using conventional pathology studies. In these cases, immunohistochemistry for detection of viral antigens is consistent with active viral replication.

Giant cells are the morphologic marker of GCM and sarcoidosis. Touton-like giant cells are also found in diseases such as Erdheim-Chester disease, a rare form of non–Langerhans cell histiocytosis, associated in more than 50% of BRAF^V600E mutations in early multipotent myelomonocytic precursors or in tissue-resident histiocytes. Heart and coronary “pseudo-tumor” infiltration and pleural and pericardial involvement have been reported in 11% and 9% of patients, respectively. The myocardial involvement seems to occur exclusively in old patients.²²² Tuberculosis is a less common cause of myocarditis. Three distinct forms of myocardial involvement are recognized: nodular tuberculosis of the myocardium characterized by granulomatous disease with central caseation; miliary tuberculosis of the myocardium; and an uncommon diffuse giant cell and lymphocyte infiltrative type associated with tuberculous pericarditis.²²³ The myocardium is involved by hematogenous spread, retrograde lymphatic spread from mediastinal lymph nodes, or direct invasion from the pericardium. The confirmatory diagnosis can be made by biopsy of the myocardium or of lymph nodes if clinical suspicion is strong and imaging findings are suggestive.^224,225,226

Giant Cell Myocarditis

GCM is a rare disease characterized by myocardial inflammation with giant cells and myocyte necrosis.^227,228 Although the true statistics are unknown, data from autopsy series indicate relatively low prevalence rates of 0.007% to 0.051%.^229,230,231

Etiology and Pathogenesis

GCM is considered a multifactorial disease. Etiologic hypotheses include infectious causes, autoimmune diseases or autoimmune reactions, and genetic predisposition.^227,228,232 Infections reported in GCM include coxsackie B2 virus,²³³ B19V,²³⁴ and Mycobacterium tuberculosis.²³⁵ In about one-fifth of cases, GCM seems to be associated with autoimmune diseases such as inflammatory bowel disease, cryofibrinogenemia, optic neuritis, fibromyalgia, hyper- or hypothyroidism^227,228 and Hashimoto thyroiditis,²³⁶ rheumatoid arthritis,²²⁷ thymoma,²³⁷ myasthenia gravis,²³⁸ Takayasu arteritis, alopecia totalis, vitiligo, orbital myositis, discoid lupus erythematosus,²³⁶ autoimmune hepatitis,²³⁶ Guillain-Barré syndrome,²³⁹ systemic lupus erythematosus,²³⁶ and Sjögren syndrome.²³⁹ GCM is being reported among novel syndromes such as immune reconstitution inflammatory syndrome that may occur in patients receiving highly active antiretroviral therapy against HIV-1.²⁴⁰

The autoimmune or immune-mediated hypothesis is supported by partial remission of GCM in patients treated with immunosuppression,^227,228 as well as by a nonaggressive occurrence (10%-50%) of the disease during immunosuppression treatment in transplanted patients.²⁴¹ A recent hypothesis highlights the possibility that GCM is characterized by a chemokine profile related to toll-like receptors and dendritic cells.²⁴² Distinct differential gene expression profiles seem to discriminate tissues harboring giant cells (GCM and cardiac sarcoidosis) from those with active myocarditis or inflammation-free controls. The expression levels of genes coding for cytokines or chemokines, cellular receptors, and proteins involved in the mitochondrial energy metabolism are deregulated 2- to 300-fold in GCM.²⁴³ Decreased expression of interleukin (IL)-17– and tumor necrosis factor-α–mediated plakoglobin is observed in GCM, cardiac sarcoidosis, and arrhythmogenic right ventricular cardiomyopathy, but not in lymphocytic myocarditis.²⁴⁴ These data need confirmation.

Clinical Manifestations and Diagnostic Workup

Clinical manifestations of GCM are variable. Most patients commonly present with cardiogenic shock requiring mechanical circulatory support, conduction disease such as atrioventricular nodal or infranodal heart block, and atrial or ventricular arrhythmias, which can be the first manifestation of the disease. Occasionally, GCM may mimic an acute myocardial infarction.^231,235 Less common is presentation as an atrial variant with atrial fibrillation, severe atrial dilation, but preserved ventricular function.^245,246

A precise diagnosis of GCM is established only when typical pathologic features are demonstrated on EMB or surgical samples (Fig. 63–9). The inflammatory infiltrate is comprised of CD8⁺ lymphocytes, eosinophils, and multinucleated giant cells (Fig. 63–10); myocytes show damage and necrosis. Sensitivity of right ventricular EMB is 68% to 80%.^228,247 CMR can guide EMB sampling.²⁴⁸ Differential diagnosis between GCM and cardiac sarcoidosis relies on pathologic features (noncaseating epithelioid granulomas in sarcoidosis) and is supported by the different T-cell subsets (CD4⁺ in sarcoidosis and CD8⁺ in GCM). Gene expression profiles vary between the two disorders and can contribute to differential diagnosis.^242,243,244 EMB is recommended by the Heart Failure Society of America in patients presenting with malignant arrhythmias out of proportion to LV dysfunction or in rapidly progressive clinical heart failure or ventricular dysfunction.²⁴⁹

Evolution

GCM carries a poor prognosis, with a median survival of 5.5 months from the onset of symptoms; in one report, 89% of patients either died or required cardiac transplantation,²²⁷ and another report showed 1-year survival of 30% to 69%.²²⁸ These data may underestimate the risk of death because some patients many die with undiagnosed disease.²⁵⁰

Treatment of Giant Cell Myocarditis

Heart failure treatment includes standard regimen with β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists, as per guidelines.^251,252 The management of GCM has also included the use of muromonab-CD3, pulse steroids, and varying combinations of azathioprine, cyclosporine, and prednisone monitored with surveillance EMB (Table 63–5). Cytolytic therapy with other monoclonal or polyclonal antibodies is debated.^227,253 Mechanical circulatory support for bridge to recovery is rare, whereas it is more commonly used as bridge to transplant^254,255; biventricular support has been frequently required. Patients most commonly end up needing cardiac transplantation despite immunosuppression.^{227,228,255,256} Post-transplant survival is similar to that of patients who underwent heart transplantation for other diseases^227,228; however, GCM may recur in 10% to 50% of transplanted hearts,^227,257 with variable response to immunosuppression,^257,258 and may require novel immune-modifiers such as the CD52-binding monoclonal antibody CAMPATH-1 or alemtuzumab.^241,259

Sarcoidosis

Sarcoidosis is a chronic multisystem inflammatory disease of unknown etiology that carries the pathologic hallmark of noncaseating epithelioid granulomas in the affected tissues.²⁶⁰ The incidence varies between 3 to 4 and 35 to 80 per 100,000, reflecting ethnicity, geographic preponderance, and gender bias.^261,262 The prevalence is 10 to 40 per 100,000 persons in the United States and Europe, and is higher in Scandinavians and lower in Turkish^263,264; the ratio between African Americans and Caucasians is 10:1 to 17:1.²⁶⁵ Women between the age of 20 and 40 years are preferentially affected.²⁶⁶ Cardiac involvement is influenced by ethnicity but not by gender; cardiac involvement is reported in 58% of Japanese patients, which is the cause of death in up to 85%.²⁶⁶ Sarcoidosis typically occurs in adults and is rare in children. It may manifest with the typical involvement of lungs, lymph nodes, and eyes, or with very early onset (“early-onset sarcoidosis”) in skin, joints, and eyes evolving aggressively to cause blindness, joint destruction, and visceral involvement. The latter aggressive form of sarcoidosis is associated with heterozygous mutations in the CARD15 gene that cause constitutive nuclear factor-κB activation.²⁶⁷

The prevalence of cardiac involvement ranges from 2% to 7% in patients diagnosed with systemic sarcoidosis; autopsy studies have demonstrated cardiac involvement in up to 25% of cases.^260,261,264 Greater cardiac involvement is reported in Japanese patients.²⁶⁸ In imaging series, cardiac involvement ranges from 3.7% to 54.9%, depending on the techniques used and the population studied.²⁶⁹ Sarcoid granulomas can be clinically silent.²⁷⁰ Therefore, the real proportion of cardiac sarcoidosis is likely higher than clinically apparent.

Pathogenesis and Etiology

The current pathogenetic paradigm suggests a cell-mediated delayed hypersensitivity reaction in individuals with immune dysfunction. Antigen and effector CD4⁺ helper T-cell interaction leads to secretion of IL-2 and IFN-γ, which stimulate a T-helper-1 (Th1) immune response, dysfunctional regulatory T-cell response, dysregulated toll-like receptor signaling, and oligoclonal expansion of CD4⁺ T cells consistent with chronic antigenic stimulation.²⁷¹ Hyperimmune Th1 response to pathogenic microbial and tissue antigens could be associated with the aberrant aggregation of serum amyloid A within granulomas, which in turn promotes progressive chronic granulomatous inflammation in the absence of ongoing infection.²⁷¹ Mycobacterial ESAT-6 and Propionibacterium acnes proteins have been identified by matrix-assisted laser desorption ionization imaging/mass spectrometry in sarcoidosis granulomas, and immune responses to both microbes have been identified in bronchoalveolar lavage of patients with sarcoidosis,²⁷² which supports the role of infectious agents in the pathogenesis of sarcoidosis. Genetic factors are being investigated in studies of families of probands with sarcoidosis (Table 63–6); the co-twin of an affected twin carries a much greater risk of developing sarcoidosis compared to the general population.²⁷³ In one study (A Case-Control Etiologic Sarcoidosis Study), the relative risk for the first- or second-degree relative of a sarcoidosis patient was 4.7 times that of controls.²⁷⁴ Genetics studies have identified several candidate genes and susceptibility loci²⁷⁵ for both sarcoidosis and autoimmune diseases; these studies are opening novel avenues in the research of the etiology and pathogenesis of the disease.

Clinical Presentation and Diagnostic Workup

The cardiac manifestations are caused by epithelioid granulomas that preferentially affect the myocardial layer, followed by endocardium, pericardium, and valves. They are most commonly located in the septum, free wall, papillary muscles, and right ventricular free wall in the areas that are not commonly involved by ischemic heart disease. The granulomas heal by fibrosis and evolve to form scars that can be transmural in advanced stages mimicking ischemic disease (Fig. 63–11). Clinical manifestations include arrhythmias, conduction disturbances, LV dilation, and systolic or diastolic dysfunction.^260,265 In patients with advanced sarcoidosis, pulmonary hypertension is highly prevalent, may result from both cardiac and pulmonary involvement, and serves as a predictor of poor prognosis.²⁷⁶ Ventricular aneurysms occur in up to 40% of patients and are also associated with poor prognosis.²⁷⁷ Involvement of the pericardium and cardiac valves is uncommon.^260,265

The diagnostic workup of cardiac involvement is relatively straight forward in patients with established systemic sarcoidosis. However, it is more challenging when cardiac disease presents in isolation or represents the phenotype of onset, because of the wide spectrum of clinical manifestations and the possibility that sudden death could be the first clinical manifestation of the disease.^278,279,280 The diagnosis of sarcoidosis is based on EMB or on pathologic evidence of the disease in lung or lymph nodes, and is established on the basis of major and minor criteria recommended by the consensus documents of National Institutes of Health, World Association of Sarcoidosis and Other Granulomatous Disorders, and Heart Rhythm Society (Table 63–7).^{281,282,283,284} The clinical workup should include a thorough discussion of individual and family medical history, physical examination, ECG, 24-hour Holter monitoring, echocardiography, and advanced imaging, as appropriate.

ECG may show conduction disturbances, arrhythmia, or nonspecific ST-segment and T-wave changes. Signal-averaged ECG has a modest diagnostic sensitivity (52%) and reasonable specificity (82%).²⁸⁵ Holter monitoring is often used as a screening tool for cardiac involvement in patients with systemic sarcoidosis; it predicts cardiac involvement with a sensitivity ranging from 50% to 67% and a specificity of 80% to 97% compared to CMR or PET as a reference standard.²⁸⁶ Echocardiography remains the most commonly used imaging investigation in suspected sarcoidosis, but detects late stages of the disease (in up to 80% of advanced cases) with regional wall motion abnormalities, LV dilation, LV aneurysms, thinning of the basal septum, and impaired left or right ventricular systolic function. Diastolic dysfunction may occur early. The right heart pressures are elevated in patients with lung disease. In early cardiac involvement, when LV function and size are normal, strain and strain rate imaging using speckle tracking are potentially useful for identifying subclinical myocardial involvement.^287,288

CMR offers a high sensitivity and specificity for the assessment of cardiac involvement. Whereas T2 hyperenhancement identifies early edema, the LGE in a nonvascular distribution supports myocardial scarring. LGE correlates with cardiac biopsy findings of granulomatous inflammation^289,290; extensive LGE reliably predicts adverse cardiac outcomes²⁹¹ and major cardiac events in survivors of sudden cardiac death.²⁹² The LGE features vary during acute inflammation and with scars. CMR-verified cardiac involvement correlates with decreased LVEF, increased diastolic interventricular septal thickness, and diastolic dysfunction.²⁹³ In patients with preserved LVEF and extracardiac sarcoidosis, major adverse cardiac events including death and ventricular tachycardia are associated with a greater LGE and right ventricular involvement; preserved LVEF does not exclude the risk for adverse events.²⁹³ Right ventricular involvement and dysfunction are common and are associated with LV involvement, lung disease, or pulmonary hypertension or may even be isolated.²⁹⁴ However, cardiac PET using ¹⁸F-FDG identifies regional inflammatory activity, defines the cause of arrhythmia, and guides treatment.²⁹⁵ Quantitative imaging assessment can monitor changes in FDG uptake on serial studies. Reduced inflammatory activity with improvement of LVEF and decrease in size and/or intensity of resting perfusion defects (such as by ¹³N-ammonia imaging) may indicate a favorable response to treatment, but may also indicate progression of scarring processes. Novel indices of FDG uptake allow calculation of the burden of inflammation (cardiac metabolic volume) and the volume-intensity product (cardiac metabolic activity); increased cardiac metabolic activity is associated with adverse clinical events in patients with cardiac sarcoidosis.²⁹⁶ Using ¹⁸F-FDG to assess inflammation after a high-fat/low-carbohydrate diet to suppress normal myocardial glucose uptake, 71 (60%) of 118 consecutive patients with suspected cardiac sarcoidosis demonstrated abnormal cardiac PET findings.²⁹⁷ The presence of focal perfusion defects (rubidium-82 imaging in this report) and FDG uptake identified higher risk of death or ventricular tachycardia.²⁹⁸ Overall, PET studies have proved to be clinically useful for diagnostic and prognostic information, especially for the risk of ventricular arrhythmias in patients with cardiac sarcoidosis. The potential translational impact of the serial PET scans could inform about evolution or regression of cardiac granulomas and about active myocardial inflammation or the process of healing. Although gallium-67 scintigraphy has also been employed for the detection of myocardial inflammation in systemic sarcoidosis and relates to response to treatment,^{299,300 18}F-FDG PET imaging is preferred both for diagnosis and prognostication because of superior sensitivity and reduced radiation exposure. FDG-PET is now included as a diagnostic criterion in the expert consensus statement on the diagnosis of cardiac sarcoidosis²⁸⁴ (see Table 63–7).

Biomarkers are not included in the diagnostic criteria for cardiac sarcoidosis. There are no disease-specific markers for cardiac sarcoidosis.³⁰¹ The circulating level of serum angiotensin-converting enzyme is reported as increased in 60% of patients with systemic sarcoidosis²⁸⁸ and 21.8% of patients with cardiac sarcoidosis.^302,303 Other biomarkers, including serum soluble IL-2 receptor,³⁰⁴ IgG,⁵⁰ high-sensitivity troponin T, ^301,305 and atrial and brain natriuretic peptides,³⁰⁶ are neither sufficiently sensitive nor specific, and there are no data pertaining to their role in management of cardiac sarcoidosis.³⁰⁷

Cardiac sarcoidosis is diagnosed with certainty by EMB demonstrating noncaseating epithelioid granulomas^5,308 (Fig. 63–12). Although EMB has low sensitivity (19%-32%) as a result of the inherent sampling limitation for focal epithelioid granulomas, it offers high specificity for the diagnosis.³⁰⁹ Biopsies are commonly performed in the right ventricle but LV EMB can be performed if necessary.³¹⁰ Besides epithelioid granulomas, EMB commonly reveals nonspecific findings including myocardial interstitial fibrosis, myofibrillar disarrangement and fragmentation, and inflammatory mononuclear cell infiltrates.

Treatment

Treatment options largely depend on the symptoms and the phase of the disease evolution, and are summarized in Table 63–8 based on recommendations of the American College of Cardiology, American Heart Association,³¹⁰ and the Heart Rhythm Society.²⁸³

Chagas Disease

Chagas disease (CD) is caused by the protozoan parasite T cruzi,³¹¹ which is transmitted through the feces of an infected triatomine, direct oral contact, contaminated blood transfusion, or bone marrow transplantation; it can also be congenital and transmitted vertically from mother to infant. Triatomines are found in the southern United States, Mexico, Central America, and South America, where CD is endemic.³¹² Contamination of food and drink has been reported in northern South America, where transmission cycles may involve wild vector populations and mammalian reservoir hosts.³¹³ In the acute phase, the disease can manifest with myocarditis, conduction system abnormalities, and pericarditis. In untreated patients, the disease progresses to the chronic phase.^314,315,316

Etiology and Pathogenesis

The first description dates back to 1909, when Carlos Chagas isolated T cruzi from the blood of a Brazilian patient.³¹⁶ Global population epidemiology considers both the local resident population of Latin America and the population of Latin Americans migrating to other countries, particularly the United States. In endemic regions, infected vectors are prevalent in rural houses where people are exposed to the risk of infection for years. The incidence of new infection and transmission though the feces of an infected vector is relatively low and estimated at 1% per year, with a peak of 4% in Bolivian population.^317,318 The incidence of infected populations and CD cardiomyopathy increases with age. The large-scale migration from rural to urban areas and from Latin America to the United States, Spain, and other countries has been associated with endemic transfer of infected immigrants.^319,320,321 By systematic serologic screening and screening of congenital disease, the National Health Services in Latin America have significantly contained the infection, with the estimated global prevalence of T cruzi infection declining from 18 million in 1991 (when the first regional control initiative began) to 5.7 million in 2010.³¹⁹

Clinical Manifestations and Diagnostic Workup

CD evolves in three phases: acute, intermediate, and chronic (Table 63–9). After the infected vector transmission, the incubation period is 1 to 2 weeks, and the acute disease lasts 2 to 3 months, comprising the period of parasitemia. In the acute phase, patients present with mild and nonspecific symptoms such as fever, malaise, hepatosplenomegaly, and atypical lymphocytosis. Chagoma (an inflammatory nodule at the site of inoculation) or unilateral painless periorbital swelling (Romana sign) is rarely observed. The majority of infections in the acute phase are not detected. Occasionally, acute CD imposes life-threatening consequences, such as meningoencephalitis and myocarditis.³²² About 30% of infected subjects develop cardiac complications³¹⁶ with arrhythmias and transient ECG abnormalities,³²³ and develop systolic and diastolic dysfunction and end-stage DCM.³²⁴ This phase is characterized by positive serologic and parasitologic tests.³²⁵ The cardiac manifestations include ECG abnormalities (prolongation of QRS complex and QT interval, right bundle branch block, and/or left anterior fascicular block) and ventricular segmental wall motion abnormalities; CMR detects cardiac fibrosis and diastolic dysfunction.^325,326 In this phase, illness is severe, with LV dilation and dysfunction, aneurysm, congestive heart failure, thromboembolism, ventricular arrhythmias, and sudden cardiac death, which is the leading cause of death in patients with Chagas heart disease.³²⁷ Chagas cardiomyopathy can be complicated by stroke caused by embolization of intracardiac mural thrombi resulting from depressed LV function and/or aneurysm formation.³²⁷

Although a direct association between parasite burden and CD phase is not clear, parasite persistence remains central to the disease. A serologic test for IgG antibodies to T cruzi is the most effective diagnostic tool.^328,329 The mature form of the parasite (trypomastigote) can be detected by microscopy in blood samples during the acute phase, wherein quantitative PCR is the gold standard for quantitation. After the first 90 days, as the T cruzi burden is decreasing, the antiparasite serum antibodies show rising titers by serologic tests including indirect hemagglutination, indirect immunofluorescence, and enzyme-linked immunosorbent assays.

Management

Management of cardiac CD must importantly consider the high likelihood of ventricular arrhythmias and sudden death in patients with chronic CD.³³⁰ Ambulatory ECG monitoring has been suggested for patients with an abnormal resting ECG or echocardiographic ventricular wall motion abnormalities. Patients with nonsustained ventricular tachycardia are usually candidates for electrophysiologic studies. Echocardiographic monitoring demonstrates both structural and functional changes in the early stages of cardiac involvement, including regional wall motion abnormalities and diastolic dysfunction; the cardiac phenotype shows LV dilation and severe dysfunction in advance phases.³³¹

Two antiparasitic drugs are available for the treatment of CD: benznidazole and nifurtimox.^332,333 These drugs commonly produce dermatologic side effects that are well controlled by antihistaminic drugs. An ongoing prospective international trial testing antitrypanocidal treatment is evaluating the efficacy of benznidazole in patients with chronic Chagas cardiomyopathy.³³⁴ Heart failure is treated according to current guidelines. Because patients with CD may demonstrate lower blood pressure and higher incidence of bradyarrhythmias than non-CD patients, doses of angiotensin-converting enzyme inhibitors and β-blockers are tailored on individual needs. Cardiac resynchronization therapy in patients with severe systolic dysfunction (LVEF < 35%) and prolonged QRS duration³³⁵ has been shown to improve NYHA functional class, increase LVEF, and enhance survival. Patients with end-stage heart failure refractory to medical treatment may receive an LV assist device and undergo cardiac transplantation.^336,337 Implantable cardioverter-defibrillator (ICD) is effective in both primary and secondary prevention of sudden cardiac death. The combination of ICD and amiodarone seems to be superior for secondary prevention, resulting in a 72% reduction in all-cause mortality and a 95% decrease in sudden cardiac death in the ICD group compared to those receiving amiodarone alone.³³⁸ Permanent cardiac pacing is indicated in patients with high-degree atrioventricular block or with symptomatic bradycardia.³³⁹

Lyme Disease

Lyme disease is a tick-borne disease caused by B burgdorferi; 60% to 80% of cases demonstrate a characteristic rash (erythema migrans) typically accompanied by fever, headache, and fatigue. Untreated Lyme disease can evolve to chronic arthritis and neurologic and cardiac manifestations.³⁴⁰ Lyme disease is common in Europe and North America, and may afflict 1 in 1000 persons in some US states and 1 in 300 people in southern Europe. Cardiac involvement occurs in a minority of patients and predominantly manifests with conduction abnormality, followed by arrhythmias, myocarditis, pericarditis, and DCM; the cardiac involvement is known as Lyme carditis. The rates of cardiac involvement in Lyme disease have declined measurably.^341,342 The main vertebrate reservoirs for Lyme Borrelia are small mammals, such as mice and voles, and some species of birds. In most tick habitats, deer are essential for the maintenance of tick populations because they are one of the few wild hosts that can feed sufficient numbers of adult ticks, but they are not competent reservoirs for spirochetes.³⁴³ The reservoir hosts and patients can be coinfected with multiple Borrelia species or other tick-borne pathogens. Most human infections occur during spring, summer, and early fall months.³⁴²

Annual incidence of Lyme disease seems to increase from northern to southern parts of central Europe,³⁴³ and ranges from 69 cases per 100,000 population in Sweden to 111 cases per 100,000 in Germany³⁴⁴ and 155 cases per 100,000 in Slovenia; the lowest incidence in Europe is in the United Kingdom (0.7 per 100,000) and Ireland (0.6 per 100,000).³⁴⁵ The incidence declines from south to north in Scandinavia and north to south in Italy, Spain, and Greece. In France, the yearly Lyme disease incidence rate averages 42 cases per 100,000 inhabitants.³⁴⁶ In the United States and Canada, Lyme disease is the major vector-born zoonosis, with approximately 30,000 reported cases and an estimated 300,000 human cases occurring annually in the United States.^347,348 Men are more commonly infected than women. Although the distribution per age is bimodal (children 5-9 years old and adults 45-59 years old), patients of all ages are exposed to the risk of infection.

Pathogenesis and Etiology

The vector deposits Lyme Borrelia into the skin of a host that disseminates through blood or soft tissue to other locations. Several days or weeks elapse from the infection to the appearance of erythema migrans, which occurs in 60% to 80% of patients.³⁴⁹ In the majority of patients, early infection is asymptomatic or presents with influenza-like symptoms, fever, fatigue, muscle or joint pain, and headache.³⁵⁰ The second phase of involvement of organ systems, such as the cardiac or neurologic systems, may come to attention among untreated patients as part of early disseminated disease (Table 63–10).³⁵¹

Clinical Manifestations and Diagnostic Workup

Lyme carditis is rare and typically manifests 2 to 5 weeks after the erythema migrans. Patients who develop Lyme disease may first manifest atrioventricular block at 14 days (range, 2-24 days) after the onset; only one-third of patients recall the erythema migrans.^352,353 Myopericarditis can present with chest pain, dyspnea, or syncope,³⁵³ and the signs and symptoms of Lyme myopericarditis can mimic acute coronary syndrome, with ECG ST-segment alterations and elevated peripheral blood cardiac biomarkers. In such cases, echocardiography demonstrates diffuse ventricular hypokinesis rather than the focal wall motion abnormalities expected with an acute coronary syndrome.³⁵² The mechanism of the development of cardiomyopathy in Lyme disease is debated, and myocardial persistence of Borrelia may contribute to the pathophysiology in individuals living in endemic areas³⁵⁴; this observation³⁵⁵ seems to be supported by the finding of 20% of unexplained DCM patients who test positive for Borrelia. Diffuse erythema migrans throughout the body indicates dissemination. Subsequently, Lyme disease may present as inflammatory arthritis several months after the initial infection, and has been reported to occur in approximately 11% of patients with untreated erythema migrans.

The history of tick bite combined with erythema migrans (see Table 63–10) should be carefully investigated in patients with suspected Lyme carditis. However, patients may not always recall a tick bite, and 20% to 40% of patients do not develop erythema migrans. The diagnosis is based on Borrelia isolation or on a two-step test including a sensitive ELISA screening test for IgM and IgG antibody and then confirmation through Western blot assay for positive or borderline results.³⁵⁴ In the early stage of the disease, results may be false negative as a result of the delayed immune response. Methods such as immune PCR assay have been validated for detection of antibodies to the Borrelia C6 peptide.³⁵⁶ Immune PCR exploits the amplification property of PCR to increase the sensitivity of standard ELISAs by 100- to 10,000-fold.³⁵⁶ Methods based on metabolomics are being tested³⁵⁷; they are based on the use of liquid chromatography/mass spectrometry and statistical modeling to define a metabolic profile of biosignatures present in patients with early-stage Lyme disease.^355,357

Treatment

Lyme disease is treated with a 10- to 21-day course of doxycycline or amoxicillin orally. Intravenous ceftriaxone (2 g every 24 hours for 2-3 weeks) may be indicated when the infection is not detected in the early stages or is refractory to initial treatments.^347,352 Treated patients who do not recover after Borrelia infection may experience chronic peripheral and central nervous system manifestations, including depression, fatigue, sleep disorders, and memory loss, for months to years after the initial infection. In pregnant women, doxycycline should be avoided because of the potential adverse effects to both fetus and mother.

Eosinophils are the descendants of the granulocytic lineage that differentiate in the bone marrow under the influence of IL-5, IL-3, and granulocyte-macrophage colony-stimulating factor.³⁵⁸ They produce and store enzymes, basic proteins, cytokines, chemokines, membrane-derived factors, and antifibrinolytic mediators.^358,359 Although their function is not fully clarified, they are involved in host immune response to infection, cancer surveillance, and maintenance of other immune cells.^358,359 In peripheral blood, the normal range of eosinophils is 3% to 5%, which corresponds to an absolute count of 350 to 500/μL.^359,360 Eosinophilia refers to an increased absolute eosinophilic count (AEC) in peripheral blood and is graded as mild (AEC from upper normal limit to 1500/μL), moderate (AEC 1500-5000/μL), or severe (AEC > 5000/μL).³⁶⁰ The complex groups of eosinophilias encompasses a broad range of disorders including hematologic eosinophilias (clonal, neoplastic, primary), nonhematologic (secondary or reactive), eosinophilic diseases of unknown significance, and familial diseases with either known or unknown genetic causes; organ damage may occur in several of these forms (Table 63–11).³⁶¹ The heart is either potentially involved in the context of systemic diseases or is the major or unique clinically involved organ. During the course of the past 30 years, the progress of knowledge on both causes and markers of hypereosinophilic syndromes (HES) has led to development of diagnostic criteria³⁶² that were modified in 2006, when the definition of HES was expanded to include other previously distinct disease entities associated with eosinophilia, such as eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome), chronic eosinophilic pneumonia, and eosinophilic gastrointestinal disorders.³⁶³ In 2010, the time limit of a 6-month diagnostic period was substituted with the suggestion of an elevation of the AEC to > 1500/μL on at least two occasions.³⁶⁴ Because tissue eosinophilic infiltration and related end-organ damage may occur in patients with peripheral AEC < 1500/μL, it was recommended that the diagnosis can be formulated in patients with “tissue eosinophilia and marked peripheral eosinophilia”; the AEC value is no longer a requirement for the diagnosis. The definition of HES was also expanded to include molecular evidence of end-organ damage.³⁶⁴

The age-adjusted prevalence is approximately 0.036 per 100,000 wherein the estimates are based on the International Classification of Diseases for Oncology (Version 3), coding 9964/3 (HES including chronic eosinophilic leukemia) and the Surveillance, Epidemiology, and End Results database from 2001 to 2005. In this estimate, eosinophilias with somatic genetic abnormalities (PDGFRA/B, FGFR1) account for a minority of cases (median, 23%; range, 3%-56%).³⁶⁵ In developing countries, the FIP1L1-PDGFRA fusion occurs in approximately 10% to 20% of patients with idiopathic hypereosinophilia.^366,367 Idiopathic hypereosinophilia is usually diagnosed between the ages of 20 and 50 years, but also occurs in children and the elderly.^{368,369,370,371,372} In 131 incident cases observed between 2001 and 2005, the male-to-female ratio was 1.5, and rates increased with age (peak between 65-74 years).³⁶⁵ Most patients with FIP1L1-PDGFRA or myeloproliferative variants are male,^367,373,374 whereas other eosinophilia subtypes do not show differences between the two genders.

Etiology

The causes include malignancies, hypersensitivity myocarditis, autoimmune reactions in the heart (typically related to a drug reaction), parasitic infections, and eosinophilic granulomatosis with polyangiitis (EGPA; also known as Churg-Strauss disease).^{359,360,363,364} Patients who develop eosinophilic myocarditis often demonstrate fever, rash, ECG abnormalities, and peripheral eosinophilia. The pathologic substrate is myocardial eosinophilic inflammation associated with limited myocyte damage and necrosis. Endomyocardial fibrosis that typically affects the right ventricle is a distinct disease of the endocardium and may not be associated with hypereosinophilia. Eosinophilic myocarditis in its end-fibrotic endocardial stage is also distinct from carcinoid heart disease (see Chap. 61).

Clinical Manifestations and Diagnostic Workup

The clinical presentation is heterogeneous and demonstrates nonspecific signs and symptoms, including weakness, fatigue, dyspnea, myalgias, angioedema, rash, fever, rhinitis, and diarrhea.³⁷⁴ Patients demonstrate leukocytosis (eg, 20,000-30,000/μ or higher) with peripheral eosinophilia in the range of 30% to 70%, neutrophilia, basophilia, myeloid immaturity, and both mature and immature eosinophils with varying degrees of dysplasia.^374,375 Anemia occurs in more than 50% of patients; thrombocytopenia, bone marrow eosinophilia with Charcot-Leyden crystals, and possible increased blasts and marrow fibrosis can also recur.^360,361

The most common organ/tissue manifestations occur in skin (about 70% of patients), followed by lung and gastrointestinal manifestations in 40% and 30% of cases, respectively. Cardiac involvement occurs in 20% of patients, in the majority during the course of the disease,^376,377 and affects myocardial layers, endocardium, and valves. Eosinophilic infiltration of the myocardium with release of toxic mediators is associated with heart failure. Endocardial infiltration causes mural thrombi with increased embolic risk. Late phases are characterized by endocardial fibrosis manifesting with restrictive physiology. Valve regurgitation is prominently observed when mural endocardial thrombosis and fibrosis involve leaflets of the mitral or tricuspid valves.^376,377

Eosinophilic Heart Disease

Cardiac involvement is a major cause of morbidity and mortality in HES.³⁷⁸ The cardiac pathology is divided into three stages: (1) an acute necrotic stage, (2) a thrombotic stage, and (3) a fibrotic stage (Table 63–12).

The early, acute necrotic stage is characterized by eosinophilic and lymphocyte infiltration; in the myocardial interstitium, eosinophils undergo degranulation with release of biologically active factors that cause myocyte injury (Fig. 63–13). Clinical presentation may comprise nonspecific manifestations. Patients may infrequently present with acute heart failure or cardiogenic shock at onset.³⁷⁹ ECG may show tachycardia, nonspecific ST-segment changes, or conduction delays. cTn levels may be increased, mimicking acute myocardial infarction.^380,381 Echocardiography may show increased LV wall thickness caused by interstitial edema, LV systolic dysfunction, and wall motion abnormalities. CMR shows endocardial delayed enhancement, and T2 mapping may demonstrate subendocardial edema.³⁸² EMB differentiates eosinophilic infiltration of the endocardium and subendocardial spaces. Corticosteroids inhibit the degranulation of eosinophils and are the first-line treatment for eosinophilic myocarditis.^383,384 In case of fulminant heart failure, mechanical support may become necessary.³⁸⁵

In the thrombotic stage, mural thrombi develop on the endocardium. Mechanisms potentially explaining the endocardial thrombophilia include the release of antifibrinolytic mediators such as plasminogen activator inhibitor-2 and thrombomodulin-eosinophilic proteins that impair the anticoagulant property of the endocardial cells.³⁷⁴ Thrombi most commonly involve the ventricular apex and further extend to subvalvular regions and, occasionally, to atria. Both echocardiography and CMR detect mural thrombi.^374,378 Thromboembolic complications occur in up to 30% of patients; oral anticoagulation is appropriate to prevent major embolic events. Antiplatelet therapy has also been proposed to prevent the formation of thrombi at the stage of eosinophilic myocarditis.

In the scarring, fibrotic stage both ventricles and subvalvular structures of the atrioventricular valves are involved. The functional phenotype is typically restrictive as in endomyocardial fibrosis. Echocardiography demonstrates regurgitation of the atrioventricular valves; spectral Doppler flow shows restrictive pattern. The severity of the endomyocardial fibrosis can be graded according to the combination of major and minor echocardiographic criteria.³⁷⁸ CMR provides better profile of the endocardial diseases and confirms the diastolic dysfunction. The fibrotic state corresponds to an irreversible endomyocardial fibrosis.

Although surgery can be considered for releasing endocardium and subvalvular apparatus from fibrosis (as done in endomyocardial fibrosis), indications should be evaluated on individually tailored programs that consider cause, comorbidity, and complications. Heart transplantation has alternatively been proposed.^386,387

Churg-Strauss Syndrome or Eosinophilic Granulomatosis With Polyangiitis

Churg-Strauss syndrome has recently been renamed EGPA,³⁵⁸ which is a systemic necrotizing vasculitis that affects small to medium-sized vessels. The recommendations for the management of small and medium-sized vessel vasculitides that apply to EGPA have recently been published.³⁸⁸ Much progress has been made over the past 30 years in understanding, redefining, and treating systemic necrotizing vasculitis. EGPA belongs to the group of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) and is characterized by blood and tissue eosinophilia and asthma, thus differing from granulomatosis with polyangiitis (Wegener) and microscopic polyangiitis. ANCA positivity ranges from 30% to 70% of EGPA patients, but is usually less frequently observed than in other AAV. Diagnostic and management algorithms for EGPA are summarized in Table 63–13.³⁸⁸

The term myocarditis remains fundamental to describe myocardial inflammation, but does not specifically describe phenotype and etiologies. The recent advancements in the identification of the different causes of myocarditis; the novel emerging infectious diseases, and drug-resistant infections; the reclassification of syndromes such as eosinophilic diseases; and the recent discovery of “monogenic” myocarditis and autoinflammatory diseases challenge cardiologists in their diagnostic workup, when deciding about performing EMB, progressing from echocardiography to advanced imaging, or establishing appropriate treatments. A systematic approach to precise diagnosis should seek the fundamental diagnostic information about myocardial inflammation. The individual history, family history, imaging, biomarkers, and molecular tests flanking the conventional infectious workup to identify the genome of the pathogens are now necessary for a complete diagnostic workup in infectious myocarditis. Different forms of noninfectious myocarditis and autoimmune or toxic diseases with myocarditis need to be supported by specific diagnostic algorithms. The clear distinction of the different forms of myocarditis would help generate reliable epidemiology data and bases for precise nosology and classification.