No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
A clinical and histopathologic comparison of cardiac sarcoidosis and idiopathic giant cell myocarditis
Abstract
The goal of this study was to determine the prognostic value of clinical data available at presentation and histology in cardiac sarcoidosis (CS) and idiopathic giant cell myocarditis (IGCM).
The prognosis of patients with nonischemic cardiomyopathy is partly dependent on the histologic diagnosis. Survival in IGCM is poor. The prognosis of a histologically related entity, cardiac sarcoidosis (CS), is less well established, and the prognostic value of the distinction between CS and IGCM on endomyocardial biopsy (EMB) is unknown.
We identified 115 patients from the Multicenter IGCM Registry with CS (n = 42) and IGCM (n = 73). We compared the clinical data for these two groups using Cox proportional-hazards models to assess the association between histologic diagnosis and survival. In order to determine whether histologic features could reliably differentiate these two entities, two cardiac pathologists semiquantitatively graded the inflammatory infiltrate components and compared the results between groups.
Black race was more frequent in the CS group (31% vs. 4%, p < 0.0001). Syncope and atrioventricular block were also more frequently observed in CS than IGCM (31% vs. 5%, p = 0.0002 and 50% vs. 15%, p < 0.0001, respectively). Left-sided heart failure was more common in IGCM (40% vs. 64%, p = 0.013). In CS patients diagnosed by EMB, the five-year transplant-free survival after diagnosis was 69.8% versus 21.9% for IGCM (p < 0.0001, log-rank test). In multivariate models, presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS. Eosinophils, myocyte damage, and foci of lymphocytic myocarditis were more frequent in IGCM, while granulomas and fibrosis were more frequent in CS.
Transplant-free survival is better for patients with CS than for IGCM diagnosed by EMB. Presentation with heart failure predicted IGCM, and presentation with heart block or more than nine weeks of symptoms predicted CS.
... Chest pain occurs in about 19% of GCM patients (68). The pain can be similar to that experienced by patients with acute coronary syndrome, but it can also have a pericardial character. ...
... Palpitations occur due to ventricular and supraventricular arrhythmias, and the substrate for their formation is active inflammation of the heart muscle, infiltration of the myocardium by giant cells, and the development of a residual scar of the myocardium as a consequence of chronic inflammation. About 14% of patients with GCM have ventricular tachycardia on admission, which is accompanied by palpitation, syncope, and if it degenerates into ventricular fibrillation even sudden cardiac death (68,69). The prevalence of ventricular rhythm disorders in GCM is up to 55%, of which episodes of non-sustained VT are most common (69). ...
... The results of the study by Ghaly M. and colleagues suggest that disorders in implementation are registered in as many as 27% of patients with GCM (69). On the other hand, Okura Y. et al. showed that atrioventricular blocks were reported in 15% of patients with GCM, in contrast to approximately 50% in patients diagnosed with cardiac sarcoidosis (68). Studies have also shown that the risk of arrhythmias and sudden cardiac death does not necessarily correlate with severity of myocardial inflammation and that recovery does not necessarily correlate with the disappearance of arrhythmias. ...
Giant cell myocarditis is a rare but extremely severe disease with a frequent need for heart transplantation and a high mortality rate. To this day, the most common reason for the occurrence of this disease has not been precisely determined, but its frequent association with autoimmune diseases speaks in favor of autoimmune etiology. Clinically, it is presented to the greatest extent by symptoms and signs of acute heart failure and ventricular rhythm disturbances, which are registered in as many as half of the patients. Arrhythmias can be accompanied by the occurrence of palpitations, repeated syncope, and even sudden cardiac death. A severe degree of acute heart failure in hemodynamically unstable patents who respond inadequately to the administered therapy for heart failure and refractory heart rhythm disorders and/or conduction disorders that are common in these patients should always raise suspicion of giant cell myocarditis. Given that changes in electrocardiogram, echocardiography and positive biomarker values are not strictly specific for this disease, the diagnosis of giant cell myocarditis is most often established by endomyocardial biopsy, especially in patients with the fulminant form of the disease. Timely endomyocardial biopsy enables not only quick and accurate diagnosis, but also early administration of immunosuppressive therapy, which greatly improves the outcome in these patients. Pathohistological verification of this disease is important so as to rule out cardiac sarcoidosis and other granulomatous infectious and non-infectious diseases. Given that in a large number of patients the disease has a fulminant course, early and rapid diagnosis, application of inotropic stimulation and mechanical circulatory support in hemodynamically unstable patients and adequate modern therapeutic regimen can largely reduce mortality in these patients, which is still high despite modern diagnostics and therapeutic progress of medicine.
... Ekström et al. observed that elevated circulating values of cTnT (identified cut-off: >85 ng/L) at the presentation of GCM were predictive of death or heart transplantation [84]. Furthermore, troponins, as biomarkers of cardiac injury, and NT-proBNP, as a biomarker of cardiac impairment, were independent predictors of poor outcomes in GCM [87]. ...
... It is crucial to note that the clinical and echocardiographic findings of GCM differ depending on whether atrial or ventricular infiltration is prevalent. Atrial fibrillation is widespread among patients with atrial infiltration, while ventricular tachyarrhythmia is the second most common clinical manifestation of GCM [82,87,88]. Data showed high levels of cTnT and NT-proBNP at presentation were associated with ventricular tachyarrhythmias leading to sudden cardiac death during follow-up [89]. ...
... Data regarding the specific role of imaging biomarkers in GCM are limited. GCM does not present pathognomonic echocardiographic patterns, and typical findings include LV dysfunction [87]. The degree of LV systolic function impairment can vary significantly, ranging from acute and severe pump function impairment to mild or preserved EF reduction. ...
Myocarditis is a disease caused by cardiac inflammation that can progress to dilated cardiomyopathy, heart failure, and eventually death. Several etiologies, including autoimmune, drug-induced, and infectious, lead to inflammation, which causes damage to the myocardium, followed by remodeling and fibrosis. Although there has been an increasing understanding of pathophysiology, early and accurate diagnosis, and effective treatment remain challenging due to the high heterogeneity. As a result, many patients have poor prognosis, with those surviving at risk of long-term sequelae. Current diagnostic methods, including imaging and endomyocardial biopsy, are, at times, expensive, invasive, and not always performed early enough to affect disease progression. Therefore, the identification of accurate, cost-effective, and prognostically informative biomarkers is critical for screening and treatment. The review then focuses on the biomarkers currently associated with these conditions, which have been extensively studied via blood tests and imaging techniques. The information within this review was retrieved through extensive literature research conducted on major publicly accessible databases and has been collated and revised by an international panel of experts. The biomarkers discussed in the article have shown great promise in clinical research studies and provide clinicians with essential tools for early diagnosis and improved outcomes.
... It is necessary to distinguish GCM from cardiac sarcoidosis. 85 Whereas infiltration of lymphocytes and eosinophils is predominant with severe myocardial necrosis in GCM (Figure 17A-E), cardiac sarcoidosis shows conspicuous interstitial fibrosis, accompanied by epithelioid cell granuloma formation. The presence of asteroid bodies is a feature characteristic of the latter disease ( Figure 17F). ...
... 12,17, 96 The mean age at diagnosis ranges from 43 to 60 years so that GCM is diagnosed in a wide range of age groups (Table 34). 85 ...
... 387,388 • Approximately 20% of patients concomitantly exhibit various autoimmune disorders and disorders associated with immune abnormalities (Table 1). 85 ...
... 13 However, the characteristics and prognosis of patients with CS have yet to be clarified, as there are few multicentre studies, with a limited number of patients in each study. 11,14,15 Additionally, previous studies have suggested some clinical features, cardiac imaging findings, and laboratory data as associated with the prognosis; however, no study has comprehensively evaluated prognostic factors independently associated with adverse events in patients with CS, mostly due to the small number of events observed in each study. Moreover, most previous studies did not use contemporary CS diagnostic criteria, which were recently proposed, 2,8,14,16,17 and some studies only included patients who were diagnosed at autopsy or cardiac transplantation. ...
... Moreover, most previous studies did not use contemporary CS diagnostic criteria, which were recently proposed, 2,8,14,16,17 and some studies only included patients who were diagnosed at autopsy or cardiac transplantation. 15,18 Therefore, we performed a multicentre retrospective registry study of patients with CS diagnosed according to contemporary diagnostic criteria for the purposes of elucidating their characteristics and prognosis and identifying the factors independently associated with clinical adverse events. ...
... For example, a previous multicentre study of patients with CS diagnosed during autopsy or heart transplantation reported a 5-year survival rate of 70%. 15 Similarly, a Japanese multicentre registry reported 5-year and 10-year survival rates of 75 and 61%, respectively. 14 This difference in survival rates can be attributed to recent advances in diagnostic strategies and therapies for patients with CS, in addition to differences in the patient cohorts. ...
Aims
This study evaluated the prognosis and prognostic factors of patients with cardiac sarcoidosis (CS), an underdiagnosed disease.
Methods and results
Patients from a retrospective multicentre registry, diagnosed with CS between 2001 and 2017 based on the 2016 Japanese Circulation Society or 2014 Heart Rhythm Society criteria, were included. The primary endpoint was a composite of all-cause death, hospitalization for heart failure, and documented fatal ventricular arrhythmia events (FVAE), each constituting exploratory endpoints. Among 512 registered patients, 148 combined events (56 heart failure hospitalizations, 99 documented FVAE, and 49 all-cause deaths) were observed during a median follow-up of 1042 (interquartile range: 518–1917) days. The 10-year estimated event rates for the primary endpoint, all-cause death, heart failure hospitalizations, and FVAE were 48.1, 18.0, 21.1, and 31.9%, respectively. On multivariable Cox regression, a history of ventricular tachycardia (VT) or fibrillation [hazard ratio (HR) 2.53, 95% confidence interval (CI) 1.59–4.00, P < 0.001], log-transformed brain natriuretic peptide (BNP) levels (HR 1.28, 95% CI 1.07–1.53, P = 0.008), left ventricular ejection fraction (LVEF) (HR 0.94 per 5% increase, 95% CI 0.88–1.00, P = 0.046), and post-diagnosis radiofrequency ablation for VT (HR 2.65, 95% CI 1.02–6.86, P = 0.045) independently predicted the primary endpoint.
Conclusion
Although mortality is relatively low in CS, adverse events are common, mainly due to FVAE. Patients with low LVEF, with high BNP levels, with VT/fibrillation history, and requiring ablation to treat VT are at high risk.
... The diagnosis of GCM was confirmed by a histological examination of a myocardial biopsy in all patients and required the presence of a widespread inflammatory infiltrate with multinucleated giant cells in association with myocyte damage [16]. To minimize the risk of misdiagnosis due to an acknowledged histological overlap between CS and GCM [16], all myocardial tissue samples were re-evaluated by a highly-experienced cardiac pathologist (A.O.). ...
... The diagnosis of GCM was confirmed by a histological examination of a myocardial biopsy in all patients and required the presence of a widespread inflammatory infiltrate with multinucleated giant cells in association with myocyte damage [16]. To minimize the risk of misdiagnosis due to an acknowledged histological overlap between CS and GCM [16], all myocardial tissue samples were re-evaluated by a highly-experienced cardiac pathologist (A.O.). The International Classification of Disease, 10th revision codes were used to define prevalent cardiac manifestations: I47.2 (ventricular tachycardia), I49.0 (ventricular fibrillation), I50 (heart failure), R00.1 (bradycardia), I44.1 or I44.2 (second-or third-degree atrioventricular block), I45.3 (trifascicular block), I46 (cardiac arrest), or others [R50.9 (fever); R53 (fatigue); and R42 (dizziness)]. ...
... Conduction abnormalities, ventricular arrhythmias, and HF have been reported as initial clinical manifestations of both entities, albeit the presentation and course seem to be more aggressive in GCM [22,23]. Non-necrotizing myocardial granulomas and fibrosis are considered as the histological hallmarks of CS while prominent necrosis together with multinucleated giant cells and eosinophils are the features of GCM [16,23,24]. ...
Background
Cardiac sarcoidosis (CS) and giant cell myocarditis (GCM) are rare diseases that share some similarities, but also display different clinical and histopathological features. We aimed to compare the demographics, clinical presentation, and outcome of patients diagnosed with CS or GCM.
Method
We compared the clinical data and outcome of all adult patients with CS (n = 71) or GCM (n = 21) diagnosed at our center between 1991 and 2020.
Results
The median (interquartile range) follow-up time for patients with CS and GCM was 33.5 [6.5–60.9] and 2.98 [0.6–40.9] months, respectively. In the entire cohort, heart failure (HF) was the most common presenting manifestation (31%), followed by ventricular arrhythmias (25%). At presentation, a left ventricular ejection fraction of < 50% was found in 54% of the CS compared to 86% of the GCM patients (P = 0.014), while corresponding proportions for right ventricular dysfunction were 24% and 52% (P = 0.026), respectively. Advanced HF (NYHA ≥ IIIB) was less common in CS (31%) than in GCM (76%). CS patients displayed significantly lower circulating levels of natriuretic peptides (P < 0.001) and troponins (P = 0.014). Eighteen percent of patients with CS included in the survival analysis reached the composite endpoint of death or heart transplantation (HTx) compared to 68% of patients with GCM (P < 0.001).
Conclusion
GCM has a more fulminant clinical course than CS with severe biventricular failure, higher levels of circulating biomarkers and an increased need for HTx. The histopathologic diagnosis remained key determinant even after adjustment for markers of cardiac dysfunction.
... Presentation can vary and range from palpitations, fainting episodes, and, in some cases, sudden death, possibly from ventricular arrhythmias or high-grade atrioventricular heart block [8]. Patients with IGCM typically exhibit symptoms of progressive heart failure despite optimal treatment, which inexorably advances to either death or transplantation, with a rate of 70% at 1 year [5,9]. ...
... Nevertheless, current evidence leans toward maintaining immunosuppression using a combination of cyclosporine and azathioprine, with or, if possible, without a minimal dose of prednisone [14]. However, despite GDMT and combined immunosuppression, a significant number of patients with IGCM develop refractory heart failure and/or cardiogenic shock requiring mechanical support and heart transplantation [8]. ...
Patient: Female, 65-year-old
Final Diagnosis: Giant cell myocarditis
Symptoms: Palpitation • shortness of breath
Clinical Procedure: —
Specialty: Cardiology
Objective
Unusual clinical course
Background
Idiopathic giant cell myocarditis (IGCM) is an uncommon and frequently fatal type of myocarditis. It primarily affects young individuals and has the potential to result in heart failure and life-threatening arrhythmias. IGCM seems to be dependent on activation of CD4-positive T lymphocytes and can show improvement with treatment aimed at reducing T-cell function. We present a case of a 65-year-old patient who presented with features of acute heart failure refractory to guideline-directed medical therapy (GDMT), due to IGCM. A review of the natural history and treatment of IGCM is also presented.
Case Report
A 65-year-old woman with multiple comorbidities was admitted to our hospital for ventricular tachycardia in the setting of progressive non-ischemic heart failure, unresponsive to GDMT. This led to further investigation, including an endomyocardial biopsy, which revealed inflammatory infiltration, with multinucleated giant cells and lymphocytes in the absence of granuloma formation, prompting a diagnosis of IGCM. An implantable cardioverter-defibrillator (ICD) was placed for secondary prevention of sudden cardiac death and the patient was initiated on combined immunosuppressive therapy. Owing to numerous comorbidities, she was determined to be unsuitable for a heart transplant. Unfortunately, she eventually died from complications secondary to the disease.
Conclusions
IGCM remains a challenging clinical diagnosis with a poor long-term outcome without heart transplantation. This case highlights the importance of considering atypical causes of heart failure in patients who do not respond to conventional therapies. Early recognition and appropriate management, involving medical and interventional approaches, are crucial in improving outcomes for patients with IGCM.
... Giant cell myocarditis (GCM) is an acute inflammatory cardiomyopathy known for mysterious etiopathogenesis, poor prognosis, and diagnostically challenging overlap with cardiac sarcoidosis (CS). The manifestations common to CS and GCM include high-grade atrioventricular block (AVB), heart failure, and sustained ventricular tachyarrhythmias, of which heart failure predominates in GCM and symptomatic AVB in CS. [1][2][3][4] Their differentiation is complicated further by significant issues of histopathology such as lack of consensus of whether cardiac or even extracardiac granulomas can be present in GCM and what extent of myocardial necrosis, if any, is compatible with the diagnosis of CS. 1,2,[5][6][7][8][9][10][11] The possibility of GCM and CS constituting different severity phenotypes of a single-disease continuum has been debated. 3,5,11 Contrast-enhanced cardiac magnetic resonance (CMR) holds a key position in the diagnostic work-up of myocardial diseases. ...
... Giant cell myocarditis (GCM) is an acute inflammatory cardiomyopathy known for mysterious etiopathogenesis, poor prognosis, and diagnostically challenging overlap with cardiac sarcoidosis (CS). The manifestations common to CS and GCM include high-grade atrioventricular block (AVB), heart failure, and sustained ventricular tachyarrhythmias, of which heart failure predominates in GCM and symptomatic AVB in CS. [1][2][3][4] Their differentiation is complicated further by significant issues of histopathology such as lack of consensus of whether cardiac or even extracardiac granulomas can be present in GCM and what extent of myocardial necrosis, if any, is compatible with the diagnosis of CS. 1,2,[5][6][7][8][9][10][11] The possibility of GCM and CS constituting different severity phenotypes of a single-disease continuum has been debated. 3,5,11 Contrast-enhanced cardiac magnetic resonance (CMR) holds a key position in the diagnostic work-up of myocardial diseases. ...
Aims:
Giant cell myocarditis (GCM) is an inflammatory cardiomyopathy akin to cardiac sarcoidosis (CS). We decided to study the findings of GCM on cardiac magnetic resonance (CMR) imaging and to compare GCM with CS.
Methods and results:
CMR studies of 18 GCM patients were analyzed and compared with 18 CS controls matched for age, sex, left ventricular (LV) ejection fraction and presenting cardiac manifestations. The analysts were blinded to clinical data. On admission, the duration of symptoms (median) was 0.2 months in GCM vs. 2.4 months in CS (P = 0.002), cardiac troponin T was elevated (>50 ng/L) in 16/17 patients with GCM and in 2/16 with CS (P < 0.001), their respective median plasma B-type natriuretic propeptides measuring 4488 ng/L and 1223 ng/L (P = 0.011). On CMR imaging, LV diastolic volume was smaller in GCM (177 ± 32 mL vs. 211 ± 58 mL, P = 0.014) without other volumetric or wall thickness measurements differing between the groups. Every GCM patient had multifocal late gadolinium enhancement (LGE) in a distribution indistinguishable from CS both longitudinally, circumferentially, and radially across the LV segments. LGE mass averaged 17.4 ± 6.3% of LV mass in GCM vs 25.0 ± 13.4% in CS (P = 0.037). Involvement of insertion points extending across the septum into the right ventricular wall, the "hook sign" of CS, was present in 53% of GCM and 50% of CS.
Conclusion:
In GCM, CMR findings are qualitatively indistinguishable from CS despite myocardial inflammation being clinically more acute and injurious. When matched for LV dysfunction and presenting features, LV size and LGE mass are smaller in GCM.
... Granulomatous myocarditis, in comparison, can be seen in patients with cardiac sarcoidosis (CS). This condition is characterized by well-organized noncaseating granulomas, absence of significant myocardial necrosis, and a considerable amount of tissue eosinophilia and fibrosis [27,28]. Compared to patients with GCM, patients with CS have higher survival rates and are more likely to develop atrioventricular block [28]. ...
... This condition is characterized by well-organized noncaseating granulomas, absence of significant myocardial necrosis, and a considerable amount of tissue eosinophilia and fibrosis [27,28]. Compared to patients with GCM, patients with CS have higher survival rates and are more likely to develop atrioventricular block [28]. ...
Purpose of Review
The present review discusses the neurological complications associated with myocarditis of different etiologies.
Recent Findings
Myocarditis can be idiopathic or caused by different conditions, including toxins, infections, or inflammatory diseases. Clinical findings are variable and range from mild self-limited shortness of breath or chest pain to hemodynamic instability which may result in cardiogenic shock and death. Several neurologic manifestations can be seen in association with myocarditis. Tissue remodeling, fibrosis, and myocyte dysfunction can result in heart failure and arrhythmias leading to intracardiac thrombus formation and cardioembolism. In addition, peripheral neuropathies, status epilepticus, or myasthenia gravis have been reported in association with specific types of myocarditis.
Summary
Multiple studies suggest the increasing risk of neurologic complications in patients with myocarditis. Neurologists should maintain a high suspicion of myocarditis in cases presenting with both cardiovascular and neurological dysfunction without a clear etiology.
... 3 Clinical presentations vary from systolic heart failure, ventricular arrhythmias, and de novo heart block. 1,4 Endomyocardial biopsy is the diagnostic gold standard, and histology characteristically shows multinucleated giant cells in the Key Words: giant cells ◼ heart failure ◼ humans ◼ myocarditis ◼ vaccines background of a lymphocytic inflammatory infiltrate in the absence of well-formed granulomas. 1,4,5 Importantly, there are no specific immunosuppression recommendations for lymphocytic myocarditis that is not associated with a systemic illness. ...
... 1,4 Endomyocardial biopsy is the diagnostic gold standard, and histology characteristically shows multinucleated giant cells in the Key Words: giant cells ◼ heart failure ◼ humans ◼ myocarditis ◼ vaccines background of a lymphocytic inflammatory infiltrate in the absence of well-formed granulomas. 1,4,5 Importantly, there are no specific immunosuppression recommendations for lymphocytic myocarditis that is not associated with a systemic illness. Treatment of GCM is multifactorial, but in contrast to other forms of myocarditis, immunosuppression is considered standard of care. ...
... Imaging features including tissue characterization patterns on CMR and regions of inflammation on FGS-PET often overlap [1]. Endomyocardial biopsy is considered the diagnostic gold standard; however, up to 10% of patients may have features typical of both GCM such as eosinophils and poorly formed granuloma more typical of sarcoidosis [2,3]. The diagnosis of CS requires the presence of at least one non-caseating granuloma with or without lymphocytic myocarditis or giant cells, while the diagnosis of GCM requires multinucleated giant cells, active myocyte necrosis and extensive inflammation [4]. ...
... Many cases can only be differentiated by EMB and even then, the histopathological features of GCM and CS can be similar. This similarity has sparked an ongoing discussion regarding whether CS and GCM are entities within a spectrum of the same underlying inflammatory condition [87][88][89][90]. Of note, the presentation of GCM is usually markedly more acute and fulminant. ...
Sarcoidosis is a multisystem disorder of unknown etiology. The leading hypothesis involves an antigen-triggered dysregulated T-cell-driven immunologic response leading to non-necrotic granulomas. In cardiac sarcoidosis (CS), the inflammatory response can lead to fibrosis, culminating in clinical manifestations such as atrioventricular block and ventricular arrhythmias. Cardiac manifestations frequently present as first and isolated signs or may appear in conjunction with extracardiac manifestations. The incidence of sudden cardiac death (SCD) is high. Diagnosis remains a challenge. For a definite diagnosis, endomyocardial biopsy (EMB) is suggested. In clinical practice, compatible findings in advanced imaging using cardiovascular magnetic resonance (CMR) and/or positron emission tomography (PET) in combination with extracardiac histological proof is considered sufficient. Management revolves around the control of myocardial inflammation by employing immunosuppression. However, data regarding efficacy are merely based on observational evidence. Prevention of SCD is of particular importance and several guidelines provide recommendations regarding device therapy. In patients with manifest CS, outcome data indicate a 5-year survival of around 90% and a 10-year survival in the range of 80%. Data for patients with silent CS are conflicting; some studies suggest an overall benign course of disease while others reported contrasting observations. Future research challenges involve better understanding of the immunologic pathogenesis of the disease for a targeted therapy, improving imaging to aid early diagnosis, assessing the need for screening of asymptomatic patients and randomized trials.
... However, several factors can impede the reliability of the procedure. Early samples may turn out negative, as giant cells typically appear after 7-14 days [79]. Furthermore, right ventricular EMB may be prone to the occurrence of sampling errors. ...
Background: Fulminant myocarditis (FM) constitutes a severe and life-threatening form of acute cardiac injury associated with cardiogenic shock. The condition is characterised by rapidly progressing myocardial inflammation, leading to significant impairment of cardiac function. Due to the acute and severe nature of the disease, affected patients require urgent medical attention to mitigate adverse outcomes. Besides symptom-oriented treatment in specialised intensive care units (ICUs), the necessity for temporary mechanical cardiac support (MCS) may arise. Numerous patients depend on these treatment methods as a bridge to recovery or heart transplantation, while, in certain situations, permanent MCS systems can also be utilised as a long-term treatment option. Methods: This review consolidates the existing evidence concerning the currently available MCS options. Notably, data on venoarterial extracorporeal membrane oxygenation (VA-ECMO), microaxial flow pump, and ventricular assist device (VAD) implantation are highlighted within the landscape of FM. Results: Indications for the use of MCS, strategies for ventricular unloading, and suggested weaning approaches are assessed and systematically reviewed. Conclusions: Besides general recommendations, emphasis is put on the differences in underlying pathomechanisms in FM. Focusing on specific aetiologies, such as lymphocytic-, giant cell-, eosinophilic-, and COVID-19-associated myocarditis, this review delineates the indications and efficacy of MCS strategies in this context.
... Cardiac sarcoidosis has an unpredictable course. Early reports indicated a high mortality risk, with 5-year survival of approximately 60% [130,131], whereas more recent series suggest that mortality rates are declining [132], probably because of earlier diagnosis and more efficacious treatments. In a retrospective observational study of 50 patients with CS over a 20-year period, the 1-, 5-, and 10-year event-free survival rates were 96%, 79%, and 58%, respectively [133]. ...
Although sarcoidosis is generally regarded as a benign condition, approximately 20–30% of patients will develop a chronic and progressive disease. Advanced pulmonary fibrotic sarcoidosis and cardiac involvement are the main contributors to sarcoidosis morbidity and mortality, with failure of the liver and/or kidneys representing additional life-threatening situations. In this review, we discuss diagnosis and treatment of each of these complications and highlight how the integration of clinical, pathological and radiological features may help predict the development of such high-risk situations in sarcoid patients.
... GCM frequently presents as CS and with VT or complete AV block. 33 In a single-centre case series of GCM, among patients who underwent CMR, LGE was present in 96% of patients, and it tended to be widespread, involving all layers of the myocardium because of extensive underlying inflammation and/or fibrosis. 13,34 EMB is generally the first diagnostic tool and immunosuppressive therapy should be initiated early, which can achieve remission in up to two-thirds of cases. ...
Acute myocarditis is an inflammatory disease of the heart that may occur in the setting of infection, immune system activation or exposure to certain drugs. Often, it is caused by viruses, whereby the clinical course is usually benign; however, it may also present with rapidly progressive fulminant myocarditis, which is associated with high morbidity and mortality. This review highlights the critical red flags – from the clinical, biochemical, imaging and histopathological perspectives – that should raise the index of suspicion of acute myocarditis. We also present an illustrative case of a young female patient with rapidly progressive cardiogenic shock requiring veno-arterial extracorporeal membrane oxygenation as a bridge to orthotopic heart transplantation. The patient showed no clinical or echocardiographic recovery signs and eventually underwent orthotopic heart transplantation. Furthermore, we elaborate on the classifications of acute myocarditis based on clinical presentation and histopathology classifications, focusing on identifying key red flags that will inform early diagnosis and appropriate management in such challenging cases.
... Moreover, over the past four decades, the rate of cardiac involvement also seems to have been increasing [6]. Indeed, the mean age at the time of initial diagnosis of CS in our recent reports is approximately 50 years, which is higher than the findings of previous reports that included patients diagnosed with CS before the 2000s [7][8][9][10][11]. The clinical phenotype and the risk of cardiac events might vary depending on the age at the diagnosis in patients with CS, as well as other cardiovascular diseases [12,13]. ...
Background
Clinical characteristics and the risk of cardiovascular events in patients with cardiac sarcoidosis (CS) according to the age of initial diagnosis are unclear.
Methods
This study is a sub-analysis of the ILLUMINATE-CS registry, which is a retrospective, multicenter registry that enrolled patients with CS between 2001 and 2017. Patients were divided into three groups according to the tertile of age at the time of initial diagnosis of CS. The study compared the clinical background at the time of CS diagnosis and the incidence rate of cardiac events across age categories.
Results
A total of 511 patients were analyzed in this study. In baseline, older patients were more likely to be female. History of hypertension, heart failure admission, and atrioventricular block were more common in patients with older age. There was no significant difference in the history of ventricular arrhythmias and left ventricular ejection fraction among all age groups. During a median follow-up period of 3.2 [IQR: 1.7–4.2] years, 35 deaths, 56 heart failure hospitalization, and 98 fatal ventricular arrhythmias was observed. The incidence rate of all-cause death and heart failure hospitalization was significantly higher in patients with older age (p < 0.001), while there was no significant difference in the incidence rate of ventricular arrhythmia among age groups (p = 0.74).
Conclusions
In patients with CS, the risk of all-cause death and heart failure hospitalization was higher in older patients compared with other age groups; however, the risk of ventricular arrhythmia was comparable across all age groups.
... Both can present with a short history of arrhythmias, heart block, and heart failure and may rapidly evolve into circulatory collapse needing inotropic or mechanical cardiac support. Lack of peripheral eosinophilia in a significant proportion of EM [1], in 40% of our patients, complicates their differentiation further as does the myocardial histology of GCM often including increased eosinophils along with giant cells, myocyte necrosis and fibrosis [27,28]. The present observations and our recent findings in GCM [29] show that there are no CMR characteristics truly distinctive of either condition, although subendocardial LGE in the apical LV segments may be more common in EM while localized areas of myocardial thinning, septal in particular, favor GCM [29]. ...
Background
Eosinophilic myocarditis (EM) is a life-threatening acute heart disease. Cardiac magnetic resonance (CMR) excels in the assessment of myocardial diseases but CMR studies of EM are limited. We aimed to describe CMR findings in histologically proven EM.
Methods
Patients with histologically proven EM seen at an academic center from 2000 through 2020 were identified. Of the 28 patients ascertained, 15 had undergone CMR for diagnosis and constitute our study cohort.
Results
The patients, aged 51 ± 17 years, presented with fever (53%), dyspnea (47%), chest pain (53%), heart block (20%), and blood eosinophilia (60%). On CMR, all 15 patients had myocardial edema with 10 of them (67%) having abnormally high left ventricular (LV) mass as well. LV ejection fraction measured < 50% in 11 patients (73%) and < 30% in 2 (13%), but only 6 (40%) had dilated LV size. Eight patients (53%) had pericardial effusion. LV late gadolinium enhancement (LGE) was found in all but one patient (13/14; 93%). LGE was always multifocal and subendocardial but could involve any myocardial layer. Patients with necrotizing EM by histopathology (n = 6) had higher LGE mass (32.1 ± 16.6% vs 14.5 ± 7.7%, p = 0.050) and more LV segments with LGE (15 ± 2 vs 9 ± 3 out of 17, p = 0.003) than patients (n = 9) without myocyte necrosis. Two patients had LV thrombosis accompanying widespread subendocardial LGE.
Conclusions
In EM, CMR shows myocardial edema and LGE that is typically subendocardial but can involve any myocardial layer. The left ventricle is often non-dilated with moderate-to-severe systolic dysfunction. Pericardial effusion is common. Necrotizing EM presents with extensive myocardial LGE on CMR.
... In the event of conduction disturbances, patients may complain of unsteadiness while walking, dizziness, lightheadedness or loss of consciousness. Atrioventricular blocks are most often registered in patients with GCM, patients with sarcoidosis or Lyme disease [102][103][104]. In the chronic phase of myocarditis, life-threatening arrhythmias occur due to the development of recurrent myocarditis, residual dysfunction of the left ventricle, and the formation of a post-inflammatory scar of the myocardium. ...
Although the frequency of myocarditis in the general population is very difficult to accurately determine due to the large number of asymptomatic cases, the incidence of this disease is increasing significantly due to better defined criteria for diagnosis and the development of modern diagnostic method. The multitude of different etiological factors, the diversity of the clinical picture and the variability of the diagnostic findings make this disease often demanding both for the selection of the diagnostic modality and for the proper therapeutic approach. The previously known most common viral etiology of this disease is today overshadowed by new findings based on immune-mediated processes, associated diseases that in their natural course can lead to myocardial involvement, but also the iatrogenic cause of myocarditis due to use of immune checkpoint inhibitors in the treatment of cancer patients. Suspecting that a patient with polymorphic and non-specific clinical signs and symptoms, changes in ECG and echocardiography has myocarditis is the starting point in the diagnostic algorithm. Cardio magnetic resonance imaging is non-invasive diagnostic gold standard for diagnosis and clinical follow-up of thses patients. Endomyocardial biopsy as an invasive method is the diagnostic choice in life-threatening patients with suspicion of fulminant myocarditis where the diagnosis has not yet established or there is no adequate response to the applied therapeutic regimen. The treatment of myocarditis is increasingly demanding and includes conservative methods of treating heart failure, immunomodulatory and immunospressive therapy, methods of mechanical circulatory support and heart transplantation. The goal of developing new diagnostic and therapeutic methods is to reduce mortality from this complex disease, which is still high.
... In certain instances, only the heart may be affected (cardiac sarcoidosis). Just a limited fraction of patients can be diagnosed with GCM or CS based only on their initial clinical presentation, necessitating a cardiac tissue diagnosis [58]. Early diagnosis of GCM or CS is essential, as individualized immunosuppressive therapy can drastically modify the clinical outcome of these patients [59]. ...
Giant cell myocarditis (GCM) is a rare, often rapidly progressive, and potentially fatal disease because of myocardium inflammation due to the infiltration of giant cells triggered by infectious as well as non-infectious etiologies. Several studies have reported that GCM can occur in patients of all ages but is more commonly found in adults. It is relatively more common among African American and Hispanic patients than in the White population. Early diagnosis and treatment are critical. Electrocardiogram (EKG), complete blood count, erythrocyte sedimentation rate, C-reactive protein, and cardiac biomarkers such as troponin and brain natriuretic peptide (BNP), echocardiogram, cardiac magnetic resonance imaging (MRI), myocardial biopsy, and myocardial gene profiling are useful diagnostic tools. Current research has identified several potential biomarkers for GCM, including myocarditis-associated immune cells, cytokines, and other chemicals. The standard of care for GCM includes aggressive immunosuppressive therapy with corticosteroids and immunomodulatory agents like rituximab, cyclosporine, and infliximab, which have shown promising results in GCM by balancing the immune system and preventing the attack on healthy tissues, resulting in the reduction of inflammation, promotion of healing, and decreasing the necessity for cardiac transplantation. Without immunosuppression, the chance of mortality or cardiac surgery was 100%. Multiple studies have revealed that a treatment combination of corticosteroids and immunomodulatory agents is superior to corticosteroids alone. Combination therapy significantly increased transplant-free survival (TFS) and decreased the likelihood of heart transplantation, hence improving overall survival. It is important to balance the benefits of immunosuppression with its potentially adverse effects. In conclusion, immunomodulatory therapy adds significant long-term survival benefits to GCM.
... Typically, myocyte necrosis is also present [38]. Well organised follicular granulomas containing central giant cells make the diagnosis of IGCM unlikely [40]. The rationale for establishing a distinction between IGCM and CS is that the natural history of IGCM appears to be favourably influenced by multidrug immunosuppression consisting of high-dose corticosteroids in combination with either cyclosporine or tacrolimus [38]. ...
In this narrative review of cardiac sarcoidosis, based on a literature search using the terms "cardiac sarcoidosis", "tuberculous myocarditis", "Whipple's disease and myocarditis", and"idiopathic giant cell myocarditis", I have defined cardiac sarcoidosis as a disorder which can be diagnosed either by documentation of the presence of sarcoid-related granulomas in myocardial tissue or by documentation of the association of the presence of sarcoid-related granulomas in extracardiac tissue and symptoms such as complete heart block, ventricular tachyarrhythmia, sudden death or dilated cardiomyopathy which are typical of cardiac sarcoidosis. The differential diagnosis of cardiac sarcoidosis includes granulomatous myocarditis attributable to underlying causes such as such as tuberculosis, Whipple's disease, and idiopathic giant cell myocarditis. Diagnostic pathways for cardiac sarcoidosis include biopsy of cardiac and extracardiac tissue, nuclear magnetic resonance imaging, positron emission tomography, and a diagnostic trial of empiric therapy. Problem areas include differentiation between noncaseating granulomatosis attributable to sarcoidosis versus noncaseating granulomatosis attributable to tuberculosis and whether or not the workup of suspected cardiac sarcoidosis should always include evaluation of biopsy tissue by molecular methods for M tuberculosis DNA as well as by mycobacterium tuberculosis culture. The diagnostic significance of necrotising granulomatosis is also unclear. Evaluation of patients on long term immunotherapy should also take due account of the risk of tuberculosis attributable to the use of tumor necrosis factor-alpha antagonists.
... Prior studies have suggested possible overlap between these two diseases including similar pathological characteristics. 37,38 Intriguingly, we found that HLA-DR staining provided a robust approach to distinguish CS from GCM. In CS, GPMNB + multinucleated giant cells were encased by a dense collection of HLA-DR hi macrophages. ...
Background
Cardiac involvement is an important determinant of mortality among sarcoidosis patients. Although granulomatous inflammation is a hallmark finding in cardiac sarcoidosis, the precise immune cell populations that comprise the granuloma remain unresolved. Furthermore, it is unclear how the cellular and transcriptomic landscape of cardiac sarcoidosis differs from other inflammatory heart diseases.
Methods
We leveraged spatial transcriptomics (GeoMx digital spatial profiler) and single-nucleus RNA sequencing to elucidate the cellular and transcriptional landscape of cardiac sarcoidosis. Using GeoMX digital spatial profiler technology, we compared the transcriptomal profile of CD68 ⁺ rich immune cell infiltrates in human cardiac sarcoidosis, giant cell myocarditis, and lymphocytic myocarditis. We performed single-nucleus RNA sequencing of human cardiac sarcoidosis to identify immune cell types and examined their transcriptomic landscape and regulation. Using multichannel immunofluorescence staining, we validated immune cell populations identified by single-nucleus RNA sequencing, determined their spatial relationship, and devised an immunostaining approach to distinguish cardiac sarcoidosis from other inflammatory heart diseases.
Results
Despite overlapping histological features, spatial transcriptomics identified transcriptional signatures and associated pathways that robustly differentiated cardiac sarcoidosis from giant cell myocarditis and lymphocytic myocarditis. Single-nucleus RNA sequencing revealed the presence of diverse populations of myeloid cells in cardiac sarcoidosis with distinct molecular features. We identified GPNMB (transmembrane glycoprotein NMB) as a novel marker of multinucleated giant cells and predicted that the MITF (microphthalmia-associated transcription factor) family of transcription factors regulated this cell type. We also detected additional macrophage populations in cardiac sarcoidosis including human leukocyte antigen–DR isotype ⁺ macrophages, SYTL3 (synaptotagmin-like protein 3) ⁺ macrophages and CD163 ⁺ resident macrophages. Human leukocyte antigen–DR isotype ⁺ macrophages were found immediately adjacent to GPMMB ⁺ giant cells, a distinct feature compared with other inflammatory cardiac diseases. SYTL3 ⁺ macrophages were located scattered throughout the granuloma and CD163 ⁺ macrophages, CD1c ⁺ dendritic cells, nonclassical monocytes, and T cells were located at the periphery and outside of the granuloma. Finally, we demonstrate mTOR (mammalian target of rapamycin) pathway activation is associated with proliferation and is selectively found in human leukocyte antigen–DR isotype ⁺ and SYLT3 ⁺ macrophages.
Conclusions
In this study, we identified diverse populations of immune cells with distinct molecular signatures that comprise the sarcoid granuloma. These findings provide new insights into the pathology of cardiac sarcoidosis and highlight opportunities to improve diagnostic testing.
... This is also an important issue as sarcoidosis patients manifesting with cardiac involvement usually show worse prognosis than those without cardiac involvement [34]. Yazaki et al. [35] reported that the five-year overall survival of 95 Japanese patients with cardiac sarcoidosis was 60%, same as the overall transplantation-free five-year survival rate in another multicenter study [36]. Diagnosis differed considerably between centers in our study. ...
Background and aims:
Liver involvement in sarcoidosis may occur in up to 60% of all patients. As many patients experience only minor symptoms, a high number of undiagnosed cases must be assumed. In order to successfully identify patients with hepatic sarcoidosis, a throughout characterization of these patients and their course of disease is necessary.
Methods:
We collected 40 patients from four German centers to evaluate current treatment standards and course of disease. All of our patients underwent liver biopsy with histologically proven granulomatous hepatitis.
Results:
Detailed characterization of our patients showed an overall benign course of disease. Treatment was very diverse with glucocorticoids for 1 year in 55% (22/40), 5-10 years in 18% (7/40), and permanently in 18% (7/40). Other treatments included disease-modifying anti-rheumatic drugs (DMARDs), the conventional non-biological type in 53% of all patients (of these 81% received azathioprine, 46% metotrexate, 10% hydroxychloroquine, 10% mycophenolate mofetil and 10% cyclophosphamide and biologicals in 8%. Despite these very diverse treatments, patients generally showed slow progression of the disease. Two patients died. None of our patients received a liver transplantation.
Conclusions:
Patients received diverse treatments and generally showed slow progression of the disease. Based on our experience, we proposed a diagnostic work up and surveillance strategy as a basis for future, prospective register studies.
... Although there are a few reports of fulminant cardiac sarcoidosis, the treatment response of our patient could be in favor of GCM than CS. 16,[21][22][23][24] Since the beginning of the COVID-19 disaster, physicians have encountered a variety of clinical manifestations and complications of this disease and it seems that we should expect a stranger behavior of this virus overtime. COVID-19 is associated with a hyperinflammation and activated humoral and cell-mediated immune response in human body, particularly in its severe forms. ...
It has been shown that severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), by coronavirus disease 2019 (COVID‐19), can lead to multi‐organ impairment including cardiac involvement and immunological problems. Acute myocarditis is one of serious and fatal complications of COVID‐19. In this case report, we present a 46‐year‐old lady with a history of lichen planus dermatitis who has developed a rapidly progressive heart failure after an episode of COVID‐19. The pathologic examination of her endomyocardial biopsy specimens was compatible with GCM, and she was successfully treated with a combined immunosuppressive therapy regimen. We reported a case of giant cell myocarditis (GCM) following COVID‐19 infection. The current report supports the role of autoimmunity and immunosuppressive therapy in COVID‐19 myocarditis including the inflammatory ones such as GCM.
... Almost two decades after the first large observational study was published in Japan, the authors show outcomes comparable with other parts of the world. [9][10][11][12] They revealed high event rates during a median follow-up time of 3 years mainly driven by fatal ventricular arrhythmia events (FVAE). Adverse events occurred even though most patients (∼90%) received immunosuppressive therapy during the observation period. ...
Open in new tabDownload slide
Clinical management of cardiac sarcoidosis.
... 17,19,20 Remarkably, severe myocarditis can appear as decompensated heart failure, cardiogenic shock and sudden cardiac death. 17,19,20,22 Differential diagnosis includes: acute coronary syndromes, pneumonitis, other causes of cardiomyopathy (eg, sarcoidosis or arrhythmogenic cardiomyopathy), [21][22][23] heart failure and endocrinopathies. 24 Electrocardiography can show ST changes and T-wave inversions, atrial arrhythmias, transient atrio-ventricular block, QT prolongation, ventricular ectopy and ventricular tachycardia. ...
Immune checkpoint inhibitor (ICI)‐induced cardiotoxicity is a rare immune‐related adverse event (irAE) characterized by a high mortality rate. From a pathological point of view, this condition can result from a series of causes, including binding of ICIs to target molecules on nonlymphocytic cells, cross‐reaction of T lymphocytes against tumor antigens with off‐target tissues, generation of autoantibodies and production of proinflammatory cytokines. The diagnosis of ICI‐induced cardiotoxicity can be challenging, and cardiac magnetic resonance (CMR) represents the diagnostic tool of choice in clinically stable patients with suspected myocarditis. CMR is gaining a central role in diagnosis and monitoring of cardiovascular damage in cancer patients, and it is entering international cardiology and oncology guidelines. In this narrative review, we summarized the clinical aspects of ICI‐associated myocarditis, highlighting its radiological aspects and proposing a novel algorithm for the use of CMR.
... A pathologist, oblivious to the research groups inspected the stained slides under a light microscope. Lung inflammation; goblet cell hyperplasia, lumen occlusion & smooth muscle bundles were graded on a subjective scale of 0 to 4. Fig. 2. B. 19,20 . Cell counts were conducted to figure out the accumulation of inflammatory cells in intraluminal portion along with alveolar and peribronchial parts as well 21 . ...
Optimization of animal model of asthma via toll like receptors-4 (TLR4) activation for bacterial exacerbation of asthma. LPS contributes to asthma exacerbations. Ovalbumin protein sensitization & challenge were examined after LPS exposure. Present research aimed, TLR4 stimulation mediated TLR4/MD2 complex formation is inhibited by TAK-242, a newer compound, for bacterial asthma management in a mouse model. Swiss Albino mice were induced with OVA (10µg, i.p. and 50 µg, i.n.) and LPS (20 µg, i.p. and 4 µg, i.n.), stimulates TLR4 receptor mediated TLR4-MD2 complex formation in toxic groups. Animals were sensitized (i.p.) on 0, 7th and 14th day and challenged (i.n.) followed by TAK-242 treatment (0.1 mg/kg, 1 mg/kg &10 mg/kg i.p.) given on 21st and 22nd days, followed by euthanasia and samples; BALF and lung tissue were collected on 23rd day. Further analysis such as total leukocyte count & differential leukocyte cell count, lung histopathology & immunohistochemistry of NF-κB, proteins like Interleukin-1β in BALF and lungs in toxic, treatment groups in comparison with control group were carried out. TAK-242 reduced TLC/DLC values in BALF, including eosinophil, neutrophil, lymphocyte, macrophage counts, lung histological alterations and immunohistochemical positivity of NF-κB and IL-1β proteins expression.
... Sarcoidosis is a granulomatous disease with multi-system involvement [9]; cardiac involvement can be found in 5% of cases of sarcoidosis [10]. In 27% of autopsy cases, cardiac sarcoidosis can be found [11], and CS is the second most common cause of death in sarcoidosis patients [12,13] prognosis and management of cardiac sarcoidosis have been challenging; the five-year survival of cardiac sarcoidosis was found 60%-70% [14,15]. Though in the absence of left ventricular dysfunction, the prognosis of cardiac sarcoidosis varies in 3% of cases with one-year mortality and 4%-100% of cases with 10-year [4,16]. ...
Sarcoidosis can be presented as cardiac sarcoidosis (CS), which is challenging to diagnose due to its clinical silence. Ventricular arrhythmias and atrioventricular blocks can be fatal and cause sudden death in patients with cardiac sarcoidosis. Five percent of sarcoidosis patients have clinically evident cardiac sarcoidosis. However, autopsy reports and imaging studies have shown a higher prevalence of cardiac involvement. Early recognition is important to prevent such detrimental consequences. Cardiac sarcoidosis is increasingly being diagnosed owing to increased awareness among physicians and new diagnostic tools like MRI and positron emission tomography (PET) scan replacing traditional endomyocardial biopsy. A definitive diagnosis of CS remains challenging due to the non-specific clinical findings that can present similar symptoms of common cardiac disease; therefore, the imaging and biopsies are substantial for diagnosis confirmation. Pharmacological and Implantable devices are two main therapeutic approaches in cardiac sarcoidosis, in which steroids and pacemaker therapy have shown better outcomes. This review summarizes the available data related to the prevalence, prognosis, diagnosis, and management of cardiac sarcoidosis.
Advances in the etiological classification of myocarditis and inflammatory cardiomyopathy (ICM) have reached a consensus. However, the mechanism of myocarditis/ICM remains unclear, which affects the development of treatment and the improvement of outcome. Cellular transcription and metabolic reprogramming, and the interactions between cardiomyocytes and non-cardiomyocytes, such as the immune cells, contribute to the process of myocarditis/ICM. Recent efforts have been made by multi-omics techniques, particularly in single-cell RNA sequencing, to gain a better understanding of the cellular landscape alteration occurring in disease during the progression. This article aims to provide a comprehensive overview of the latest studies in myocarditis/ICM, particularly as revealed by single-cell sequencing.
Graphical Abstract
Background
Despite significant cardiac involvement in sarcoidosis, real‐world data on death due to cardiovascular disease among patients with sarcoidosis is not well established.
Methods and Results
We queried the Centers for Disease Control and Prevention's Wide‐Ranging Online Data for Epidemiologic Research database for data on patients with sarcoidosis aged ≥25 years from 1999 to 2020. Diseases of the circulatory system except ischemic heart disease were listed as the underlying cause of death, and sarcoidosis was stated as a contributing cause of death. We calculated age‐adjusted mortality rate (AAMR) per 1 million individuals and determined the trends over time by estimating the annual percentage change using the Joinpoint Regression Program. Subgroup analyses were performed on the basis of demographic and geographic factors. In the 22‐year study period, 3301 cardiovascular deaths with comorbid sarcoidosis were identified. The AAMR from cardiovascular deaths with comorbid sarcoidosis increased from 0.53 (95% CI, 0.43–0.65) per 1 million individuals in 1999 to 0.87 (95% CI, 0.75–0.98) per 1 million individuals in 2020. Overall, women recorded a higher AAMR compared with men (0.77 [95% CI, 0.74–0.81] versus 0.58 [95% CI, 0.55–0.62]). People with Black ancestry had higher AAMR than people with White ancestry (3.23 [95% CI, 3.07–3.39] versus 0.39 [95% CI, 0.37–0.41]). A higher percentage of death was seen in the age groups of 55 to 64 years in men (23.11%) and women (21.81%), respectively. In terms of US census regions, the South region has the highest AAMR from cardiovascular deaths with comorbid sarcoidosis compared with other regions (0.78 [95% CI, 0.74–0.82]).
Conclusions
The increase of AAMR from cardiovascular deaths with comorbid sarcoidosis and higher cardiovascular mortality rates among adults aged 55 to 64 years highlight the importance of early screening for cardiovascular diseases among patients with sarcoidosis.
Background
Giant cell myocarditis is an inflammatory form of acute heart failure with high rates of cardiac transplantation or death. Standard acute treatment includes multi-drug immunosuppressive regimens. There is a small but growing number of case reports utilizing rabbit anti-thymocyte globulin in severe cases.
Case Summary
Two cases are presented with similar presentations and clinical courses. Both are middle-aged patients with no significant past medical history, who presented with new acute decompensated heart failure that quickly progressed to cardiogenic shock requiring inotropic and mechanical circulatory support. Both underwent endomyocardial biopsies that diagnosed giant cell myocarditis. Both were treated with a multi-agent immunosuppressive regimen, notably including rabbit anti-thymocyte globulin, with subsequent resolution of shock and recovery of left ventricular ejection fraction. Both remain transplant-free and without ventricular arrythmias at 7 months and 26 months, respectively.
Discussion
In aggregate, these cases are typical of giant cell myocarditis. They add to growing observational data that upfront rATG may reduce morbidity and mortality in GCM, including potentially preventing the need for complex interventions like orthotopic heart transplantation.
Aims
Cardiac sarcoidosis (CS) is a potentially fatal condition that varies in its clinical presentation. Here, we describe baseline characteristics at presentation along with prognosis and predictors of outcome in a sizable and deeply phenotyped contemporary cohort of CS patients.
Methods and results
Consecutive CS patients seen at one institution were retrospectively enrolled after undergoing laboratory testing, ECG, echocardiography, cardiac magnetic resonance imaging (CMR) and ¹⁸ ‐Flourodeoxyglucose positron emission tomography (FDG‐ PET) at baseline. The composite endpoint consisted of all‐cause mortality, aborted sudden cardiac death, major ventricular arrhythmic events, heart failure hospitalization and heart transplantation.
A total of 319 CS patients were studied (67% male, 55.4±12 years of age). During median follow‐up of 2.2 years (range:1 month–11 years), 8% of patients died, while 33% reached the composite endpoint. The annualized mortality rate was 2.7% and the 5‐year and 10‐year mortality rates were 6.2% and 7.5%, respectively. Multivariate analysis showed serum brain natriuretic peptide (BNP) levels (HR:2.41, 95%CI 1.34–4.31, p=0.003), CMR‐LVEF (HR:0.96, 95%CI 0.94‐0.98, p<0.0001) and maximum Standardized Uptake Value (SUVmax) of FDG‐PET; HR:1.11; 95%CI 1.04‐1.19, p=0.001) to be independent predictors of outcome. These findings remained robust for different patient subgroups.
Conclusion
CS is associated with significant morbidity and mortality, particularly in those with cardiac involvement as the first manifestation. Higher BNP levels, lower LVEF and more active myocardial inflammation were independent predictors of outcomes.
This article is protected by copyright. All rights reserved.
Although the frequency of myocarditis in the general population is very difficult to accurately determine due to the large number of asymptomatic cases, the incidence of this disease is increasing significantly due to better defined criteria for diagnosis and the development of modern diagnostic methods. The multitude of different etiological factors, the diversity of the clinical picture, and the variability of the diagnostic findings make this disease often demanding both for the selection of the diagnostic modality and for the proper therapeutic approach. The previously known most common viral etiology of this disease is today overshadowed by new findings based on immune-mediated processes, associated with diseases that in their natural course can lead to myocardial involvement, as well as the iatrogenic cause of myocarditis, which is due to use of immune checkpoint inhibitors in the treatment of cancer patients. Suspecting that a patient with polymorphic and non-specific clinical signs and symptoms, such as changes in ECG and echocardiography readings, has myocarditis is the starting point in the diagnostic algorithm. Cardio magnetic resonance imaging is non-invasive and is the gold standard for diagnosis and clinical follow-up of these patients. Endomyocardial biopsy as an invasive method is the diagnostic choice in life-threatening cases with suspicion of fulminant myocarditis where the diagnosis has not yet established or there is no adequate response to the applied therapeutic regimen. The treatment of myocarditis is increasingly demanding and includes conservative methods of treating heart failure, immunomodulatory and immunospressive therapy, methods of mechanical circulatory support, and heart transplantation. The goal of developing new diagnostic and therapeutic methods is to reduce mortality from this complex disease, which is still high.
Background
Isolated cardiac sarcoid (iCS) is reported to have more severe clinical presentation and greater risk of adverse events compared with cardiac sarcoid (CS) with extracardiac involvement (nonisolated CS). Delays in diagnosing specific organ involvement may play a role in these described differences.
Methods and Results
A retrospective observational study of patients with CS over a 20‐year period was conducted. Objective evidence of organ involvement and time of onset based on consensus criteria were identified. CS was confirmed by histology in all patients from myocardium only (iCS) or extracardiac tissue (nonisolated CS). The primary end point was a composite of mortality, orthotopic heart transplant, and durable left ventricular assist device implantation. CS was isolated in 9 of 50 patients (18%). Among baseline characteristics, iCS and nonisolated CS differed significantly only in the frequency of sustained ventricular tachycardia at presentation (78% versus 37%; P =0.03) and delay in CS diagnosis >6 months (67% versus 5%; P <0.01). A nonsignificant trend toward lower left ventricular ejection fraction and more frequent heart failure in iCS was observed. Over a median follow‐up of 9.7 years (95% CI, 6.8–10.8), 18 patients reached the primary end point (13 deaths, 2 orthotopic heart transplants, and 3 durable left ventricular assist device implantations). The 1‐, 5‐, and 10‐year event‐free survival rates were 96% (95% CI, 85%–99%), 79% (95% CI, 64%–88%), and 58% (95% CI, 40%–73%), respectively, without differences between groups. There were no significant predictors of the primary end point, including delayed CS diagnosis.
Conclusions
Long‐term outcomes were similar between iCS and nonisolated CS in patients with histologically documented sarcoid. Diagnostic delays may contribute to differences in the dominant clinical presentation, despite similar outcomes.
This book will provide the proper explanation and the sequences of diagnosis to determine the diseases’ causes in a very sequenced, interesting and scientific manner for the medical field workers and researchers.
It is the first book in this field and the first handbook to talk about the role of the genes therapy and genetic engineering in cancer treatment and other genetic disorders.
At the end of the book, there will be a list of references that can be used for additional information. Also, we talked on many difficult advanced topics with a simpler language than other books to be understandable for everyone in the medical field.
Background:
Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are rare inflammatory diseases of the myocardium with poor prognosis. Little is known about the cardiovascular magnetic resonance (CMR) appearance of GCM and the methods ability to distinguish the two rare entities from one another.
Methods:
We assessed a total of 40 patients with endomyocardial biopsy-proven GCM (n = 14) and CS (n = 26) concerning their clinical and CMR appearance in a blinded manner.
Results:
Patients with GCM and CS were of similar median age (55 vs 56 years), and a male predominance was observed in both groups. In GCM, median levels of troponin T (313 vs 31 ng/L, p < 0.001), and natriuretic peptides (6560 vs 676 pg/mL, p < 0.001) were higher than in CS, and the clinical outcome worse (p = 0.04). On CMR imaging, the observed alterations of left and right ventricular (LV/RV) dimensions and function were similar. GCM showed multifocal LV late gadolinium enhancement (LGE) with a similar longitudinal, circumferential, and radial distribution as in CS, including suggested signature imaging biomarkers of CS like the "hook sign" (71% vs 77%, p = 0.702). The median LV LGE enhanced volume was 17% and 22% in GCM and CS (p = 0.150), respectively. The number of RV segments with pathologically increased T2 signal and/or LGE were most extensive in GCM.
Conclusions:
The CMR appearance of both GCM and CS is highly similar, making the differentiation between the two rare entities solely based on CMR challenging. This stands in contrast to the clinical appearance, which seems to be more severe in GCM.
Background:
Giant cell myocarditis (GCM) and cardiac sarcoidosis (CS) are, in contrast to acute non-fulminant myocarditis (ANFM), rare inflammatory diseases of the myocardium with poor prognosis. Although echocardiography is the first-line diagnostic tool in these patients, their echocardiographic appearance has so far not been systematically studied.
Methods:
We assessed a total of 71 patients with endomyocardial biopsy-proven GCM (n = 21), and CS (n = 25), as well as magnetic resonance-verified ANFM (n = 25). All echocardiographic examinations, performed upon clinical presentation, were reanalysed according to current guidelines including a detailed assessment of right ventricular (RV) dysfunction.
Results:
In comparison with ANFM, patients with either GCM or CS were older (mean age (±SD) 55 ± 12 or 53 ± 8 vs 25 ± 8 years), more often of female gender (52% or 24% vs 8%), had more severe clinical symptoms and higher natriuretic peptide levels. For both GCM and CS, echocardiography revealed more frequently signs of left ventricular (LV) dysfunction in form of a reduced ejection fraction (p < 0.001), decreased cardiac index (p < 0.001) and lower global longitudinal strain (p < 0.001) in contrast to ANFM. The most prominent increase in LV end-diastolic volume index was observed in CS. In addition, RV dysfunction was more frequently found in both GCM and CS than in ANFM (p = 0.042).
Conclusions:
Both GCM and CS have an echocardiographic and clinical appearance that is distinct from ANFM. However, the method cannot further differentiate between the two rare entities. Consequently, echocardiography can strengthen the initial clinical suspicion of a more severe form of myocarditis, thus warranting a more rigorous clinical work-up.
Introduction:
Myocarditis is a severe lymphocyte-mediated inflammatory disorder of the heart, mostly caused by viruses and immune checkpoint inhibitors (ICIs). Recently, myocarditis as a rare adverse event of mRNA vaccines for SARS-CoV-2 has caused global attention. The clinical consequences of myocarditis can be very severe, but specific treatment options are lacking or not yet clinically proven.
Areas covered:
This paper offers a brief overview of the biology of viruses that frequently cause myocarditis, focusing on mechanisms important for viral entry and replication following host infection. Current and new potential therapeutic targets/strategies especially for viral myocarditis are reviewed systematically. In particular, the immune system in myocarditis is dissected with respect to infective viral and non-infective, ICI-induced myocarditis.
Expert opinion:
Vaccination is an excellent emerging preventative strategy for viral myocarditis, but most vaccines still require further development. Anti-viral treatments that inhibit viral replication need to be considered following viral infection in host myocardium, as lower viral load reduces inflammation severity. Understanding how the immune system continues to damage the heart even after viral clearance will define novel therapeutic targets/strategies. We propose that viral myocarditis can be best treated using a combination of antiviral agents and immunotherapies that control cytotoxic T cell activity.
Unlabelled:
A 45-year-old woman with no medical history underwent pacemaker implantation for a symptomatic complete atrioventricular block. On day 6, she noticed diplopia and then fever, general malaise, and elevation of serum creatinine kinase (CK). She was transferred to our hospital on day 21. Serum CK was elevated to 4543 IU/L, and echocardiography revealed a left ventricular ejection fraction of 43 %. We diagnosed her with giant cell myocarditis (GCM) via an emergent myocardial biopsy that revealed a proliferation of lymphocytes, eosinophils, and giant cells without granulomas. Initial treatment with high doses of intravenous methylprednisolone and immunoglobulin improved her symptoms in a few days, and prednisolone was given as follow-up treatment. CK was normalized in a week and a thinning of the interventricular septum mimicking cardiac sarcoidosis (CS) occurred. On day 38, we added a calcineurin inhibitor, tacrolimus, and maintained her with a combination of prednisolone and tacrolimus at a target dose of 10-15 ng/mL. Six months after the onset, there were no signs of relapse despite the persistent mild elevation of troponin I levels. We present a case of GCM mimicking CS successfully maintained by a combination of two immunosuppressive agents.
Learning objective:
Recommended treatment for giant cell myocarditis (GCM), a potentially fatal disease, is a combination of three immunosuppressive agents. However, GCM shares many characteristics with cardiac sarcoidosis (CS), which is treated using prednisolone alone in many cases. Recent studies on GCM and CS suggest they are different spectrums of a common entity. Although they can clinically overlap, they have different progressive speeds and severities. We present a case of GCM mimicking CS successfully treated with a combination of two immunosuppressive agents.
Air pollution and environmental issues significantly impact life, resulting in the emergence and exacerbation of allergic asthma and other chronic respiratory infections. The main objective of this study is to suppress allergic asthma by TAK-242 from lipopolysaccharide-induced airway inflammation primarily stimulating toll-like receptor-4, and also to determine the potential mechanism of asthma eradication. The TAK-242 anti-allergic action was assured through the ovalbumin murine model of asthma via bronchial hyperresponsiveness and inflammation of the respiration tract in a pre-existing allergic inflammation paradigm. Swiss albino mice were sensitized and then challenged by ovalbumin and lipopolysaccharide for 5 days straight. TAK-242 reaction was assessed by inflammatory cytokines, and inflammatory cell count was determined from blood serum and bronchoalveolar lavage fluid, as well as group-wise regular weight assessments. After ovalbumin, lipopolysaccharide infusion, toll-like receptor-4 agonists caused a substantial increase in airway hyperresponsiveness, specific cellular inflammation, histological alterations, and immune mediator synthesis, as well as dose-related body-weight variations. A decrease in lipopolysaccharide-induced leukocyte count and Th1/Th17 related cytokines, TNF-α, and IL-6 expression through the ELISA study was particularly noticeable. Finally in treated groups, TAK-242, a TLR4/MD2 complex inhibitor, reduced airway inflammation and histopathological changes, cytokine expression, and body-weight management. TAK-242 has been found in an ovalbumin allergic asthma model to be a potential inhibitor of lipopolysaccharide-induced respiratory infection.
Objectives:
Diagnosis of cardiac sarcoidosis (CS) without histological evidence remains controversial. This study aimed to compare characteristics and outcomes of histologically proven versus clinically diagnosed cases of CS, which were adjudicated using Heart Rhythm Society or Japanese Circulation Society criteria.
Methods:
A total of 512 patients with CS (age: 62±11 years, female: 64.3%) enrolled in the multicentre registry were studied. Histologically confirmed patients were classified as 'biopsy-proven CS', while those with the presence of strongly suggestive clinical findings of CS without histological evidence were classified as 'clinical CS'. Primary outcome was a composite of all-cause death, heart failure hospitalisation and ventricular arrhythmia event.
Results:
In total, 314 patients (61.3%) were classified as biopsy-proven CS, while 198 (38.7%) were classified as clinical CS. Patients classified under clinical CS were associated with higher prevalence of left ventricular dysfunction, septal thinning, and positive findings in fluorodeoxyglucose-positron emission tomography or Gallium scintigraphy than those under biopsy-proven CS. During median follow-up of 43.7 (23.3-77.3) months, risk of primary outcome was comparable between the groups (adjusted HR: 1.24, 95% CI: 0.88 to 1.75, p=0.22). Similarly, the risks of primary outcome were comparable between patients with clinical isolated CS who did not have other organ/tissue involvement, and biopsy-proven isolated CS (adjusted HR: 1.23, 95% CI: 0.56 to 2.70, p=0.61).
Conclusions:
A substantial number of patients were diagnosed with clinical CS without confirmatory biopsy. Considering the worse clinical outcomes irrespective of the histological evidence, the diagnosis of clinical CS is justifiable if imaging findings suggestive of CS are observed.
Background
Pediatric myocarditis and pericarditis represent an inflammatory process of the myocardium and the pericardium, respectively. Myocarditis is most common in the pediatric population with rising prevalence during the recent coronavirus pandemic. Timely diagnosis and treatment are essential for improving the prognosis and for reducing the occurrence of long-term sequelae.
Aim of review
Discuss the current state of myocarditis and pericarditis with respect to clinical presentation, newest diagnostic modalities, and up-to-date recommendations for treatment and follow-up; and to contrast conventional myocarditis with coronavirus (SARS-CoV-2) associated myocarditis.
Key scientific concepts of review
Myocarditis represents a leading cause of sudden cardiac death, presumably because of fatal dysrhythmia in combination with various degrees of cardiomyopathy. The diagnostic process spans from the clinical presentation to certain EKG findings and serological or tissue markers of inflammation and cardiomyocyte injury, to characteristic findings on echocardiography and magnetic resonance imaging. Various historical, laboratory, hemodynamic, and imaging markers are associated with the prognosis. Treatment of myocarditis is mainly based on the suppression of the inflammation with intravenous immunoglobulin, whereas treatment of pericarditis is most effectively achieved with non-steroidal anti-inflammatory medications. Coronavirus induced cardiomyopathy seems to show a 15-fold increased incidence compared to conventional myocarditis in addition to higher mortality and morbidity. This stands in contrast to the other two milder forms of myocarditis that are related to SARS-CoV-2: Myocarditis as part of the multisystem inflammatory syndrome (MIS-C) and coronavirus mRNA vaccine related myocarditis. Due to the potential for sequelae, late complications, and recurrence, patients with myocarditis require long-term follow-up. Specific guidelines for return to athletic activity have been developed to reduce the sudden death risk.
Although seen in ∼5% of sarcoidosis patients, cardiac sarcoidosis (CS) accounts for nearly 25% of disease-related deaths. This study aimed to describe characteristics and outcomes among CS patients. Patients diagnosed with CS in 2016–2017 in the US National Inpatient Sample Database were evaluated to study patient characteristics, reasons ascribed to admission, in-hospital outcomes, and complications. A total of 2420 patients (median age 56 years) were included in the analysis. Most admissions occurred due to ventricular tachycardia (12.8%), followed by myocarditis (9.9%) with a mean length of stay of 7±7 days. The overall incidence of in-hospital mortality was 2.5%.
Myocardial sarcoidosis is not a rare disease in the UK and it is still probably under-diagnosed. A high index of suspicion in necessary for diagnosis of myocardial sarcoidosis, which should be thought of in any unusual form of heart disease for which there is no adequate explanation, particularly if there are serious rhythm changes or unexplained heart failure. Mitral systolic murmurs occur frequently. Histological proof of the aetiology should be sought. The heart is frequently massively involved when other organs have little involvement. Most of these patients present with cardiac symptoms or signs and the high incidence of sudden death is disturbing. The high rate of occurrence in East Anglia is noted, and merits further study. Treatment should be energetic where indicated--but its effects are difficult to assess. This study, representing the largest single source of information on this topic, continues in the hope of shedding more light on a sinister disease.
Idiopathic giant-cell myocarditis is a rare and frequently fatal disorder. We used a multicenter data base to define the natural history of giant-cell myocarditis and the effect of treatment.
We identified 63 patients with idiopathic giant-cell myocarditis through journal announcements and direct mailings to cardiovascular centers worldwide.
The patients consisted of 33 men and 30 women with an average age of 42.6 years; 88 percent were white, 5 percent were black, 5 percent were Southeast Asian or Indian, and 2 percent were Middle Eastern. Most presented with congestive heart failure (47 patients, or 75 percent), ventricular arrhythmia (9 patients, or 14 percent), or heart block (3 patients, or 5 percent), although in some cases the initial symptoms resembled those of acute myocardial infarction (4 patients). Nineteen percent had associated autoimmune disorders. The rate of survival was worse than among 111 patients with lymphocytic myocarditis in the Myocarditis Treatment Trial (P<0.001); among our patients, the rate of death or cardiac transplantation was 89 percent, and median survival was only 5.5 months from the onset of symptoms. The 22 patients treated with corticosteroids and cyclosporine, azathioprine, or both therapies survived for an average of 12.3 months, as compared with an average of 3.0 months for the 30 patients who received no immunosuppressive therapy (P=0.001). Of the 34 patients who underwent heart transplantation, 9 (26 percent) had a giant-cell infiltrate in the transplanted heart and 1 died of recurrent giant-cell myocarditis.
Giant-cell myocarditis is a disease of relatively young, predominantly healthy adults. Patients usually die of heart failure and ventricular arrhythmia unless cardiac transplantation is performed. Despite the possibility of fatal disease recurrence, transplantation is the treatment of choice for most patients.
Previous studies of the prognosis of patients with heart failure due to cardiomyopathy categorized patients according to whether they had ischemic or nonischemic disease. The prognostic value of identifying more specific underlying causes of cardiomyopathy is unknown.
We evaluated the outcomes of 1230 patients with cardiomyopathy. The patients were grouped into the following categories according to underlying cause: idiopathic cardiomyopathy (616 patients), peripartum cardiomyopathy (51); and cardiomyopathy due to myocarditis (111), ischemic heart disease (91), infiltrative myocardial disease (59), hypertension (49), human immunodeficiency virus (HIV) infection (45), connective-tissue disease (39), substance abuse (37), therapy with doxorubicin (15), and other causes (117). Cox proportional-hazards analysis was used to assess the association between the underlying cause of cardiomyopathy and survival.
During a mean follow-up of 4.4 years, 417 patients died and 57 underwent cardiac transplantation. As compared with the patients with idiopathic cardiomyopathy, the patients with peripartum cardiomyopathy had better survival (adjusted hazard ratio for death, 0.31; 95 percent confidence interval, 0.09 to 0.98), and survival was significantly worse among the patients with cardiomyopathy due to infiltrative myocardial disease (adjusted hazard ratio, 4.40; 95 percent confidence interval, 3.04 to 6.39), HIV infection (adjusted hazard ratio, 5.86; 95 percent confidence interval, 3.92 to 8.77), therapy with doxorubicin (adjusted hazard ratio, 3.46; 95 percent confidence interval, 1.67 to 7.18), and ischemic heart disease (adjusted hazard ratio, 1.52; 95 percent confidence interval, 1.07 to 2.17).
The underlying cause of heart failure has prognostic value in patients with unexplained cardiomyopathy. Patients with peripartum cardiomyopathy appear to have a better prognosis than those with other forms of cardiomyopathy. Patients with cardiomyopathy due to infiltrative myocardial diseases, HIV infection, or doxorubicin therapy have an especially poor prognosis.
Ribonuclease protection assay was used to demonstrate mRNA expression of several cytokines as well as inducible NO synthase (iNOS), constitutive endothelial NO synthase (cNOS) and perforin in the myocardium during the course of experimental autoimmune myocarditis (EAM) in rats. Interleukin 2 (IL-2) appeared in the initial inflammatory phase (day 14), subsided in the maximum inflammatory phase (day 19) and disappeared by the recovery phase (day 25). mRNA of IL-1β, interferon gamma INF-γand tumor necrosis factor alpha (TNF-α) were detected only in the maximum inflammatory phase and iNOS also appeared for several days at this time. In contrast, IL-10 mRNA was detected after the maximum inflammatory stage and persisted into the recovery phase (days 25–36). Although transforming growth factor beta 1 (TGF-β1) could be detected in all phases, the expression was markedly enhanced in the maximum inflammatory phase and gradually diminished (around day 36) to basal levels. Perforin mRNA was not detected at any point in the disease. Besides macrophages and CD4+T cells, a number of neutrophils were found in the myocardium, especially at peak inflammatory stage. We suggest that antigen (Ag) primed Ag presenting cells or macrophages interact with T cells (Th1) to produce IL-2 and subsequent IFN-γ, which further activates macrophages in the myocardium. Consequently, TNF-αand iNOS may inflict tissue damage to myocardium. It is also suggested that TGF-β1 and one representative Th2cytokine, IL-10, help inhibit inflammation. These findings suggest that Th1 and Th2 cytokines are produced at different stages of EAM and modulate the inflammation and the course of EAM.
A diagnostic score with three levels of assessment for cardiac involvement in systemic sarcoidosis is presented. Stage 1 involves symptoms, electrocardiography and echocardiography, stage 2 thallium-201 myocardial imaging at rest and exercise, and stage 3 laevocardiography and myocardial biopsy. The non-invasive score (stage 1) proved to be a sensitive tool for the assessment of heart involvement independent of coronary artery disease in sarcoidosis and was substantiated by 201-thallium myocardial imaging and analysis of segmental wall motion abnormality by laevocardiography.
Eleven cases of idiopathic giant cell myocarditis are described, The pathological features are unmistakable with serpiginous areas of myocardial necrosis, at the margins of which giant cells can be seen on histological examination. The aetiology of the condition remains obscure but associated pathology suggests that altered immunity may be a factor. The rapid clinical course is, however, highly suggestive of an infective cause though none has been found.
Giant cell myocarditis has rarely been diagnosed premortem, and little is known about its natural history. In addition, no comparative studies with lymphocytic myocarditis exist.
The clinical features, serial change in left ventricular fraction (LVEF), and outcomes of all patients with histologically verified myocarditis were retrospectively evaluated. Ten patients (22%) were found to have giant cell myocarditis (group 1), whereas the remaining 36 (78%) had lymphocytic myocarditis (group 2). Age at presentation, gender distribution, duration of symptoms, initial LVEF, and resting hemodynamics did not differ between groups. Ventricular tachycardia was detected in 90% of group 1 patients compared with only 25% of group 2 (p = 0.0007). Atrioventricular block that required pacemaker insertion was also more common in group 1 (60%) than in group 2 (8.3%) (p = 0.001). Left ventricular systolic function declined during follow-up in group 1 patients (LVEF, 0.43 +/- 0.07-0.26 +/- 0.05, p = 0.11) but increased in group 2 patients (LVEF, 0.33 +/- 0.03-0.41 +/- 0.03, p = 0.02). When the net change between initial and final LVEF was assessed, a significant difference was evident (giant cell group, -0.17 +/- 0.06; lymphocytic group, +0.07 +/- 0.03; p = 0.0008). Although a greater proportion of patients in group 1 died or required transplantation (seven of 10 versus 11 of 36, p = 0.03), actuarial survival over 4 years was not different for the giant cell group (50%) than for the lymphocytic group (62%).
Giant cell myocarditis was more prevalent than previously recognized and highly associated with both ventricular tachycardia and pacemaker requirement. The likelihood of an adverse event, either cardiovascular mortality or cardiac transplantation, was significantly greater for patients with giant cell myocarditis than for those with lymphocytic myocarditis, perhaps because of the progressive decline in left ventricular systolic function that was observed in those with giant cell myocarditis.
Giant cell myocarditis is a rare and frequently fatal disorder of unknown origin that is defined histopathologically as diffuse myocardial necrosis with multinucleated giant cells in the absence of sarcoidlike granulomata. The clinical and pathologic features of lymphocytic myocarditis have been described in several recent publications, but the features of idiopathic giant cell myocarditis have not been adequately addressed.
We describe five patients with idiopathic giant cell myocarditis who were seen at Stanford University over the past 10 years. In each case the onset was subacute congestive heart failure. After diagnosis each patient received immunosuppressive therapy and was evaluated for heart transplantation. Progressive heart failure and ventricular arrhythmias developed in all. Three died rapidly, two of progressive heart failure and one of sudden cause. Two patients underwent orthotopic heart transplantation and are currently alive, one with disease recurrence. Pathologic studies, including endomyocardial biopsy and evaluation of postmortem or explanted material at transplantation were reviewed. The pathologic studies provided additional support that the giant cells derive from a monocytic/histiocytic lineage. Segmental wall motion abnormalities suggest giant cell myocarditis can be a focal, as well as diffuse process at certain stages of its course. This experience is compared with published cases and implications for diagnosis and treatment are discussed.
In view of the uniformly fatal nature of the disease, heart transplantation should be a serious consideration, and the patients evaluated once the diagnosis is established. Triple-drug immunosuppressive therapy should be considered at the time of diagnosis.
Sarcoidosis is a multisystem granulomatous disease of unknown etiology characterized by the expansion of activated oligoclonal CD4+ T cells and macrophages at sites of disease. To investigate the immunopathogenesis of sarcoidosis, we analyzed patterns of cytokine expression in bronchoalveolar lavage cells and fluid from patients with pulmonary sarcoidosis and idiopathic pulmonary fibrosis and from normal volunteers. We found dominant type 1 cytokine expression, with elevated mRNA and protein levels of IFN-gamma, but not IL-4, in sarcoid lung cells and fluid compared with those in normal samples. To define immunoregulatory mechanisms important to this type 1 response, we analyzed the expression of IL-12 and IL-10 in lung cells and fluid. Using semiquantitative PCR, we found significantly higher mRNA expression of the regulated IL-12 p40 subunit, but not IL-10, in sarcoid compared with normal lung cells. Consistent with these observations, strikingly elevated levels of p40 protein were found in sarcoid compared with normal bronchoalveolar lavage fluid. Unstimulated and Staphylococcus aureus-stimulated sarcoid alveolar macrophages produced greater amounts of IL-12 than normal alveolar macrophages when cultured in vitro. We hypothesize that sarcoidosis is a Th1-mediated disease driven by chronic, dysregulated production of IL-12 at sites of disease.
Cardiac involvement in patients with sarcoidosis is an important consideration for those who are concerned with this strange disease. Sarcoidosis is not an acute malignant disease but may be noticed at the time of sudden, expected death as fatal myocardial sarcoidosis at autopsy. Even with modern advances in our ability to diagnose heart disease, cardiac sarcoidosis is still often overlooked because of its subclinical disease progression. In view of this, an extensive review of previously published literature and of our own case analyses has been carried out because of the authors' long-term experience with performing Konno's endomyocardial biopsy, which was originally developed in 1962 at the author's institution. However, the sensitivity of endomyocardial biopsy in detecting sarcoid granuloma is low (20-30%), and, instead, various kinds of nongranulomatous pathologies are often seen. During the course of our research it was found that there might exist a racial difference in cardiac sarcoidosis. Cardiac death was much more frequent in Japanese patients. The possibility that heart disease in sarcoidosis is caused by cor pulmonale due to advanced pulmonary fibrosis should be reevaluated because only a limited amount of background data is available. The author's review clarified the fact that cardiac sarcoidosis is caused by myocardial or pericardial involvement, resulting in various kinds of bradyarrhythmias or tachyarrhythmias and/or congestive heart failure. Electrocardiographic (ECG) and Holter monitor readings provide a simple and effective method for early detection of this disease. The incidence of ECG abnormalities in a total of 963 sarcoidosis patients was 22.1%, which was more frequent than that of the sex- and age-matched healthy control subjects (17.9%; p < 0.025). Echocardiography and radionuclide studies also provide useful clinical information. Careful follow-up and early corticosteroid administration followed by small maintenance doses may prevent the progression of the disease and improve prognosis. Owing to the progress in antiarrhythmic drugs and pacemaker implantation, the primary cause of death in cardiac sarcoidosis has changed from sudden death (1976 report) to congestive heart failure (1985 report).
Giant cell myocarditis (GCM) is a rare, rapidly fatal myocarditis with histologic features that have some similarities to cardiac sarcoidosis (CS). The natures of the inflammatory infiltrates of GCM and CS have not been systematically compared. We retrospectively compared the immunohistochemical and light microscopic findings at autopsy in eight hearts with GCM and seven hearts with CS. The patients with GCM were six women and two men (mean age, 50 +/- 13 yr) who presented with congestive heart failure with a mean duration of 46 days until death (range, 1-180 d). We observed three histologic phases, often within a single heart. The acute phase (seven cases of eight) demonstrated an extensive infiltrate of lymphocytes and eosinophils with plentiful macrophages and macrophage-derived KP-1 positive giant cells (GCs) associated with myocytic necrosis. No granulomas were identified. A healing phase (three cases of eight) showed granulation tissue, moderate macrophagic GCs, and scattered KP-1-negative myogenic GCs. A healed phase (three cases of eight) showed dense scar with no GCs. Macrophagic GCs were present preferentially in areas of myocytic damage and were never present in epicardial fat. The majority of lymphocytes were T cells, with a predominance of CD8 cells. The seven patients with CS were men (mean age, 44 +/- 18 yr). Six patients presented with sudden cardiac death and one with congestive heart failure. The histologic patterns were similar in all seven, with scattered interstitial and epicardial (five cases of seven) granulomas composed of KP-1 positive macrophages and macrophagic GCs and T lymphocytes, which were predominantly CD4 cells. Necrosis, myogenic GCs, and significant numbers of eosinophils were absent. Dense scarring was present in five cases of seven. GCM is characterized by myocytic destruction mediated by cytotoxic T cells, macrophagic GCs, and eosinophils. In contrast, CS is an interstitial granulomatous disease without myocytic necrosis.
Teosinophilia occurs in a large number of diseases, and in some of them, eosinophils are the principal effector cells. The production of eosinophils involves the proliferation and differentiation of hematopoietic progenitor cells, and the accumulation of eosinophils involves interactions between eosinophils and endothelial cells, chemotaxis and cellular activation, and a balance between the survival and apoptosis of eosinophils. An understanding of these processes gives the clinician an insight into the pathogenesis of disorders. The identification of molecules specificially involved in eosinophilia (e.g., interleukin-5 and eoxtaxin) offers hope for the development of new drugs that specifically target eosinophil pathways.
Sarcoidosis is an enigmatic disease with extremely variable manifestations in pattern, severity and course. Since Longcope and Freiman's descriptive monograph in 1952 (50) summarizing the clinical findings of the first half of this century, new dimensions of assessing the disease and treatment have been added. The impact of corticosteroids is central. The present review extends the studies to the second half of this century. Earlier diagnosis is facilitated and treatment often reverses many of the disease manifestations and improves the quality and extent of life for the patient. The management issues and guidelines outlined in this paper for both intrathoracic and extrathoracic disease are based on several longitudinal studies of the sarcoidosis patients summarized here, and 50 years of clinical experience by the senior author (CJJ) at Johns Hopkins Hospital, a tertiary referral center with an active Sarcoid Clinic. Case reports are presented in the appendix. It is clear that corticosteroids are the most effective therapeutic agent for sarcoidosis, usually with impressive and prompt response. This represents the dramatic difference in this disease after 1950. No more specific or effective immunosuppressive or antiinflammatory agents have been identified. Undesirable side effects are minimal if excessive doses are avoided. The effectiveness of "steroid-sparing agents" such as methotrexate is uncertain. Although irreversible tissue damage from the disease may limit the effectiveness of treatment, benefits of corticosteroids greatly exceed the negative side effects. Since spontaneous remissions without treatment do occur, a period of observation of 2 years are more is warranted if the patient is relatively asymptomatic. Gradual radiographic progression for 2 or more years, even without major symptoms or reduction in pulmonary function, indicates the need for a trial of corticosteroid treatment, especially in white patients where symptoms may lag behind the radiographic changes. Relapses as treatment is withdrawn are frequent, especially in African-American patients, who tend to have more severe and more prolonged disease than white patients. A minimum of 1 year of treatment is recommended unless no improvement is noted after 3 months. Continued low-dose prednisone at daily doses of 10-15 mg is helpful in preventing relapses and further progression of disease. Periodic attempts at tapering are justified. Repeated relapses may indicate the need for life-long treatment. When irreversible changes are present, especially in the presence of chronic fibrotic disease, changing goals of treatment to provide optimal supportive care may represent better management than having unrealistic expectations from increased corticosteroid dosage or the addition of other potentially toxic immunosuppressive agents. Many agents related to sarcoidosis require further research. The most important question facing sarcoid researchers today is etiology. It is difficult to design specific therapy when the fundamental causes and disease mechanisms are not established. Rather than being a single disease with a single cause, it is possible that a number of genetic factors and environmental or infectious agents may result in an immune response that is manifested as sarcoidosis. Understanding basic causal mechanisms may help explain the varied disease manifestations and aid in designing curative treatments. Such etiologic questions should be explored from both a basic science and an epidemiologic approach. Therapeutic trials of new drugs such as pentoxyfylline and possibly thalidomide are needed to address their potential as well as limitations of steroid therapy. Finally, for patients who have progressed to organ failure, the problems of sarcoid recurrence in transplanted tissue, increased allograft rejection, and long-term prognosis of solid organ transplants have yet to be resolved. (ABSTRACT TRUNCATED)
Cardiac involvement is an important prognostic factor in sarcoidosis, but reliable indicators of mortality risk in cardiac sarcoidosis are unstudied in a large number of patients. To determine the significant predictors of mortality and to assess the efficacy of corticosteroids, we analyzed clinical findings, treatment, and prognosis in 95 Japanese patients with cardiac sarcoidosis. Twenty of these 95 patients had cardiac sarcoidosis proven by autopsy; none of these patients had received corticosteroids. We assessed 12 clinical variables as possible predictors of mortality by Cox proportional hazards model in 75 steroid-treated patients. During the mean follow-up of 68 months, 29 patients (73%) died of congestive heart failure and 11 (27%) experienced sudden death. Kaplan-Meier survival curves showed 5-year survival rates of 75% in the steroid-treated patients and of 89% in patients with a left ventricular ejection fraction > or = 50%, whereas there was only 10% 5-year survival rate in autopsy subjects. There was no significant difference in survival curves of patients treated with a high initial dose (> 30 mg) and a low initial dose (> or = 30 mg) of prednisone. Multivariate analysis identified New York Heart Association functional class (hazard ratio 7.72 per class I increase, p = 0.0008), left ventricular end-diastolic diameter (hazard ratio 2.60/10 mm increase, p = 0.02), and sustained ventricular tachycardia (hazard ratio 7.20, p = 0.03) as independent predictors of mortality. In conclusion, the severity of heart failure was one of the most significant independent predictors of mortality for cardiac sarcoidosis. Starting corticosteroids before the occurrence of systolic dysfunction resulted in an excellent clinical outcome. A high initial dose of prednisone may not be essential for treatment of cardiac sarcoidosis.
Yacoub and A. Pomerance; Hospital Germans Trias I Pujol, Bar-celona, Spain: A. Ariza; Hospital Henri Mondor Tixier; Herzzentrum Bad Krozingen, Bad Kroz-ingen, Germany: N. Bruns and C. Ihling; Instituto de Cardiologica y Cirugia Cardiovascular-Fundacion Favaloro
- Harefield Hospital
- S V London
- R R Perrone
- Favaloro
Harefield Hospital, London, United Kingdom: M. Yacoub and A. Pomerance; Hospital Germans Trias I Pujol, Bar-celona, Spain: A. Ariza; Hospital Henri Mondor, Paris, 328 Okura et al. JACC Vol. 41, No. 2, 2003 Cardiac Sarcoidosis and IGCM January 15, 2003:322–8i France: D. Tixier; Herzzentrum Bad Krozingen, Bad Kroz-ingen, Germany: N. Bruns and C. Ihling; Instituto de Cardiologica y Cirugia Cardiovascular-Fundacion Favaloro, Buenos Aires, Argentina: S. V. Perrone and R. R. Favaloro;
Baptist Medical Center of Oklahoma, Oklahoma City, Oklahoma: D. K. C. Coo-per; Brigham and Women's Hospital
- M M Tolman
- R Grimes
- R Ullrich
- N E Horvat
- G Kantrowitz
- Turi
Tolman, and M. M. Grimes; University of Vienna, Vienna, Austria: R. Ullrich and R. Horvat; Baptist Medical Center of Oklahoma, Oklahoma City, Oklahoma: D. K. C. Coo-per; Brigham and Women's Hospital, Boston, Massachu-setts: S. Davis, M. Givertz, and G. Winters; Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland: J. J. Goy and C. Genton; Elmhurst Hospital Center, Elmhurst, New York: N. E. Kantrowitz and G. Turi;
Vir-ginia: Ohio: P. E. Hill; State University of New York at Buffalo, Buffalo California: S. I. Stark; Honolulu Medical Group
- Holloman
- Charles Prince
- Hospital
- Chermside
- A Australia
- S Galbraith
- J S Graham
- C F Schwartz
- S B Celik
- O Gollub
- K Tawfik
- K Satomi
- Kondou
Holloman; Prince Charles Hospital, Chermside, Australia: A. Galbraith; Royal National Heart and Lung Institute, London, United Kingdom: M. N. Shepherd; Saint Thomas Hospital, Nashville, Tennessee: K. Biersack and C. M. Davis; Sentara Norfolk General Hospital, Norfolk, Vir-ginia: J. M. Herre and L. Ladaga; Split Clinical Hospital, Split, Croatia: S. Polic; St. Elizabeth Hospital Medical Center, Youngstown, Ohio: P. E. Hill; State University of New York at Buffalo, Buffalo, New York: S. Graham, J. S. Schwartz, and C. F. Celik; Sutter Memorial Hospital, Sacramento, California: S. I. Stark; Honolulu Medical Group, Honolulu, Hawaii: T. Hoffmann and K. Tonaki; University of Alabama at Birmingham, Birmingham, Ala-bama: R. B. Bourge; Cleveland Clinic Foundation, Cleve-land, Ohio: N. B. Ratliff; University of Calgary-Foothills Hospital, Calgary, Alberta, Canada: D. Issac, S. Agarwal, and W. Lester; University of California at San Diego, La Jolla, California: L.T. Cooper; University of Kansas Med-ical Center, Kansas City, Missouri: S. B. Gollub and O. Tawfik; University of Pittsburgh Medical Center, Pitts-burgh, Pennslyvania: S. Murali; University of South Florida College of Medicine, Tampa, Florida: G. B. Cintron and S. Brantley; Washington University School of Medicine, St. Louis, Missouri: M. W. Rich; Hospital, Helsinki, Finland: M. Nieminen; Niigata University of Medicine, Niigata, Japan: Y. Aizawa, A. Shibata; Social Health Insurance Medical Center, Tokyo, Japan: K. Satomi, K. Kondou;
South Texas Cardiovascular Consult-ants
- R J Cooper
- Rosser
- Okura
Cooper, R. J. Rosser; South Texas Cardiovascular Consult-ants, San Antonio, Texas: M. J. Wood. 328i JACC Vol. 41, No. 2, 2003 Okura et al. January 15, 2003:322–8i Cardiac Sarcoidosis and IGCM
Giant cell myocarditis: natural history and treatment
- L T Cooper
- G J Berry
- R Shabetai
Cooper LT, Berry GJ, Shabetai R. Giant cell myocarditis: natural
history and treatment. N Engl J Med 1997;336:1860 -6.
Baptist Medical Center of Oklahoma
- M M Tolman
- R Grimes
- R Ullrich
- S Horvat
- M Davis
- G Givertz
- N E Winters
- G Kantrowitz
- Turi
Tolman, and M. M. Grimes; University of Vienna, Vienna,
Austria: R. Ullrich and R. Horvat; Baptist Medical Center
of Oklahoma, Oklahoma City, Oklahoma: D. K. C. Cooper ; Brigham and Women's Hospital, Boston, Massachusetts: S. Davis, M. Givertz, and G. Winters; Centre
Hospitalier Universitaire Vaudois, Lausanne, Switzerland:
J. J. Goy and C. Genton; Elmhurst Hospital Center,
Elmhurst, New York: N. E. Kantrowitz and G. Turi;
- G Hunninghake
- U Costabel
- M Ando
Hunninghake G, Costabel U, Ando M, et al. ATS/ERS/WASOG
statement on sarcoidosis. Sarcoidosis, Vasculitis Diffuse Lung Dis
1999;16:149 –73.
Yacoub and A. Pomerance; Hospital Germans Trias I Pujol
- Harefield Hospital
- United London
- Kingdom
Harefield Hospital, London, United Kingdom: M. Yacoub
and A. Pomerance; Hospital Germans Trias I Pujol, Barcelona, Spain: A. Ariza; Hospital Henri Mondor, Paris,
328
Okura et al.
JACC Vol. 41, No. 2, 2003
Sarcoidosis of the heart
- Johnson
Johnson JB, Jason RS. Sarcoidosis of the heart. Am Heart J 1948;27:
246.
Myocardial sarcoidosis
- Johns
Giant cell versus lymphocytic myocarditis
- Davidoff