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Hematology. American Society of... Dec 2022Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life-threatening endomyocardial... (Review)
Review
Hypereosinophilic syndromes (HES) are a heterogenous group of rare disorders with clinical manifestations ranging from fatigue to life-threatening endomyocardial fibrosis and thromboembolic events. Given the broad differential diagnosis of HES, a comprehensive approach is needed to identify potential secondary (treatable) causes and define end-organ manifestations. Classification by clinical HES subtype is also useful in terms of assessing prognosis and guiding therapy. Corticosteroids remain the mainstay of initial therapy in the setting of acute, life-threatening PDGFR mutation-negative HES. Whereas the recent availability of eosinophil-targeted therapies with extraordinary efficacy and little apparent toxicity is changing the treatment paradigm, especially for idiopathic HES and overlap syndromes, questions remain unanswered regarding the choice of agent, impact of combination therapies, and long-term effects of eosinophil depletion. This review provides a case-based discussion of the differential diagnosis of HES, including the classification by clinical HES subtype. Treatment options are reviewed, including novel eosinophil-targeted agents recently approved for the treatment of HES and/or other eosinophil-associated disorders. Primary (myeloid) disorders associated with hypereosinophilia are not be addressed in depth in this review.
Topics: Humans; Hypereosinophilic Syndrome; Antineoplastic Agents; Adrenal Cortex Hormones; Prognosis
PubMed: 36485140
DOI: 10.1182/hematology.2022000367 -
Reviews in Cardiovascular Medicine Sep 2020Sarcoidosis is a chronic inflammatory disease of unknown etiology characterized by multi-organ involvement. End-organ disease consists of granulomatous inflammation,... (Review)
Review
Sarcoidosis is a chronic inflammatory disease of unknown etiology characterized by multi-organ involvement. End-organ disease consists of granulomatous inflammation, which if left untreated or not resolved spontaneously, leads to permanent fibrosis and end-organ dysfunction. Cardiac involvement and fibrosis in sarcoidosis occur in 5-10% of cases and is becoming increasingly diagnosed. This is due to increased clinical awareness among clinicians and new diagnostic modalities, since magnetic resonance imaging and positron-emission tomography are emerging as "gold standard" tools replacing endomyocardial biopsy. Despite this progress, isolated cardiac sarcoidosis is difficult to differentiate from other causes of arrhythmogenic cardiomyopathy. Cardiac fibrosis leads to congestive heart failure, arrhythmias and sudden cardiac death. Immunosuppressives (mostly corticosteroids) are used for the treatment of cardiac sarcoidosis. Implantable devices like a cardioverter-defibrillator may be warranted in order to prevent sudden cardiac death. In this article current trends in the pathophysiology, diagnosis and management of cardiac sarcoidosis will be reviewed focusing on published research and latest guidelines. Lastly, a management algorithm is proposed.
Topics: Adrenal Cortex Hormones; Cardiomyopathies; Death, Sudden, Cardiac; Defibrillators, Implantable; Electric Countershock; Fibrosis; Humans; Immunosuppressive Agents; Myocardium; Risk Factors; Sarcoidosis; Treatment Outcome
PubMed: 33070538
DOI: 10.31083/j.rcm.2020.03.102 -
Nature Sep 2019Fibrosis is observed in nearly every form of myocardial disease. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess...
Fibrosis is observed in nearly every form of myocardial disease. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure. However, clinical interventions and therapies that target fibrosis remain limited. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8 T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.
Topics: Animals; Antigens, Surface; CD8-Positive T-Lymphocytes; Endomyocardial Fibrosis; Fibroblasts; Humans; Immunotherapy, Adoptive; Male; Mice; Ovalbumin; Wound Healing
PubMed: 31511695
DOI: 10.1038/s41586-019-1546-z -
Cells Jul 2021Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are... (Review)
Review
Cardiac fibrosis is the excess deposition of extracellular matrix (ECM), such as collagen. Myofibroblasts are major players in the production of collagen, and are differentiated primarily from resident fibroblasts. Collagen can compensate for the dead cells produced by injury. The appropriate production of collagen is beneficial for preserving the structural integrity of the heart, and protects the heart from cardiac rupture. However, excessive deposition of collagen causes cardiac dysfunction. Recent studies have demonstrated that myofibroblasts can change their phenotypes. In addition, myofibroblasts are found to have functions other than ECM production. Myofibroblasts have macrophage-like functions, in which they engulf dead cells and secrete anti-inflammatory cytokines. Research into fibroblasts has been delayed due to the lack of selective markers for the identification of fibroblasts. In recent years, it has become possible to genetically label fibroblasts and perform sequencing at single-cell levels. Based on new technologies, the origins of fibroblasts and myofibroblasts, time-dependent changes in fibroblast states after injury, and fibroblast heterogeneity have been demonstrated. In this paper, recent advances in fibroblast and myofibroblast research are reviewed.
Topics: Animals; Cardiotonic Agents; Cell Differentiation; Cell Lineage; Collagen; Cytokines; Discoidin Domain Receptor 2; Endomyocardial Fibrosis; Extracellular Matrix; Fibroblasts; Gene Expression Regulation; Humans; Macrophages; Myocardium; Myocytes, Cardiac; Myofibroblasts; Signal Transduction
PubMed: 34359886
DOI: 10.3390/cells10071716 -
Circulation. Heart Failure Nov 2020Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis... (Review)
Review
Myocarditis is an inflammatory disease of the heart that may occur because of infections, immune system activation, or exposure to drugs. The diagnosis of myocarditis has changed due to the introduction of cardiac magnetic resonance imaging. We present an expert consensus document aimed to summarize the common terminology related to myocarditis meanwhile highlighting some areas of controversies and uncertainties and the unmet clinical needs. In fact, controversies persist regarding mechanisms that determine the transition from the initial trigger to myocardial inflammation and from acute myocardial damage to chronic ventricular dysfunction. It is still uncertain which viruses (besides enteroviruses) cause direct tissue damage, act as triggers for immune-mediated damage, or both. Regarding terminology, myocarditis can be characterized according to etiology, phase, and severity of the disease, predominant symptoms, and pathological findings. Clinically, acute myocarditis (AM) implies a short time elapsed from the onset of symptoms and diagnosis (generally <1 month). In contrast, chronic inflammatory cardiomyopathy indicates myocardial inflammation with established dilated cardiomyopathy or hypokinetic nondilated phenotype, which in the advanced stages evolves into fibrosis without detectable inflammation. Suggested diagnostic and treatment recommendations for AM and chronic inflammatory cardiomyopathy are mainly based on expert opinion given the lack of well-designed contemporary clinical studies in the field. We will provide a shared and practical approach to patient diagnosis and management, underlying differences between the European and US scientific statements on this topic. We explain the role of histology that defines subtypes of myocarditis and its prognostic and therapeutic implications.
Topics: Acute Disease; Cardiology; Chronic Disease; Consensus; Humans; Myocarditis; Predictive Value of Tests; Risk Factors; Terminology as Topic; Treatment Outcome
PubMed: 33176455
DOI: 10.1161/CIRCHEARTFAILURE.120.007405 -
European Heart Journal Dec 2022Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular...
Restrictive cardiomyopathy (RCM) is a heterogeneous group of diseases characterized by restrictive left ventricular pathophysiology, i.e. a rapid rise in ventricular pressure with only small increases in filling volume due to increased myocardial stiffness. More precisely, the defining feature of RCM is the coexistence of persistent restrictive pathophysiology, diastolic dysfunction, non-dilated ventricles, and atrial dilatation, regardless of ventricular wall thickness and systolic function. Beyond this shared haemodynamic hallmark, the phenotypic spectrum of RCM is wide. The disorders manifesting as RCM may be classified according to four main disease mechanisms: (i) interstitial fibrosis and intrinsic myocardial dysfunction, (ii) infiltration of extracellular spaces, (iii) accumulation of storage material within cardiomyocytes, or (iv) endomyocardial fibrosis. Many disorders do not show restrictive pathophysiology throughout their natural history, but only at an initial stage (with an evolution towards a hypokinetic and dilated phenotype) or at a terminal stage (often progressing from a hypertrophic phenotype). Furthermore, elements of both hypertrophic and restrictive phenotypes may coexist in some patients, making the classification challenge. Restrictive pathophysiology can be demonstrated by cardiac catheterization or Doppler echocardiography. The specific conditions may usually be diagnosed based on clinical data, 12-lead electrocardiogram, echocardiography, nuclear medicine, or cardiovascular magnetic resonance, but further investigations may be needed, up to endomyocardial biopsy and genetic evaluation. The spectrum of therapies is also wide and heterogeneous, but disease-modifying treatments are available only for cardiac amyloidosis and, partially, for iron overload cardiomyopathy.
Topics: Humans; Cardiomyopathy, Restrictive; Echocardiography, Doppler; Ventricular Dysfunction, Left; Myocardium; Echocardiography
PubMed: 36269634
DOI: 10.1093/eurheartj/ehac543 -
Cardiovascular Diagnosis and Therapy Apr 2020Endomyocardial fibrosis (EMF) is a neglected cardiovascular disease of poverty which carries a poor prognosis with no specific treatment affecting mainly children and...
BACKGROUND
Endomyocardial fibrosis (EMF) is a neglected cardiovascular disease of poverty which carries a poor prognosis with no specific treatment affecting mainly children and young adults. Here, we report our 10-year experience in the therapeutic management and surgical treatment for EMF.
METHODS
From February 2009 to 2019 March, 55 patients diagnosed with EMF from our cardiology unit underwent surgical repair at our department's pediatric surgical division. There were 35 male, and 20 female patients whose ages varied from 1 year 2 months to 12 years mean age 5.7 (±3.2). We designed the study aimed at assessing the cardio-structural abnormalities and coronary vascular changes faced with EMF patients using echocardiography, and coronary angiography with a detailed and thorough surgical examination of each case.
RESULTS
Of the 55 operated patients, 1 had mild lesions, 26 had moderate lesions, and 28 had severe heart disease. All but one patient was in NYHA functional class III or IV at the time of surgery. All but one female patient with mild ventricular lesions and no valvular involvement had severe atrioventricular valve regurgitation with valves considered suitable for both replacements; 45 patients mean age 6.0 (±3.1) and repair nine patients mean age 3.8 (±2.9). The mean endocardial thickness was 3,000 (±1519) µm.
CONCLUSIONS
The echocardiographic changes corresponded well to the findings on surgery and histopathology. The coronary changes seen included a spectrum of fibrin deposition, medial sclerosis and degeneration, and the formation of plexiform lesions. Surgically evaluating the resected cardiac tissue might help improve disease management.
PubMed: 32420101
DOI: 10.21037/cdt.2020.02.10 -
JACC. Heart Failure Sep 2020This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes...
OBJECTIVES
This study prospectively evaluated endomyocardial biopsies in patients with heart failure with preserved ejection fraction (HFpEF) to identify histopathologic phenotypes and their association with clinical characteristics.
BACKGROUND
Myocardial tissue analysis from a prospectively defined HFpEF cohort reflecting contemporary comorbidities is lacking.
METHODS
Patients with HFpEF (EF ≥50%) referred to the Johns Hopkins HFpEF Clinic between August 2014 and September 2018 were enrolled for right heart catheterization and endomyocardial biopsy. Clinical features, echocardiography, hemodynamics, and tissue histology were determined and compared with controls (unused donor hearts) and HF with reduced EF (HFrEF).
RESULTS
Of the 108 patients enrolled, median age was 66 years (25th to 75th percentile: 57 to 74 years), 61% were women, 57% were African American, 62% had a previous HF hospitalization, median systolic blood pressure was 141 mm Hg (25th to 75th percentile: 125 to 162 mm Hg), body mass index (BMI) was 37 kg/m (25th to 75th percentile: 32 to 45 kg/m), and 97% were on a loop diuretic. Myocardial fibrosis and myocyte hypertrophy were often present (93% and 88%, respectively); however, mild in 71% with fibrosis and in 52% with hypertrophy. Monocyte infiltration (CD68+ cells/mm) was greater in patients with HFpEF versus controls (60.4 cells/mm [25th to 75th percentile: 36.8 to 97.8] vs. 32.1 cells/mm [25th to 75th percentile: 22.3 to 59.2]; p = 0.02) and correlated with age and renal disease. Cardiac amyloidosis (CA) was diagnosed in 15 (14%) patients (HFpEF-CA: 7 patients with wild-type transthyretin amyloidosis [ATTR], 4 patients with hereditary ATTR, 3 patients with light-chain amyloidosis, and 1 patient with AA (secondary) amyloidosis), of which 7 cases were unsuspected. Patients with HFpEF-CA were older, with lower BMI, higher left ventricular mass index, and higher N-terminal pro-B-type natriuretic peptide and troponin I levels.
CONCLUSIONS
In this large, prospective myocardial tissue analysis of HFpEF, myocardial fibrosis and hypertrophy were common, CD68+ inflammation was increased, and CA prevalence was 14%. Tissue analysis in HFpEF might improve precision therapies by identifying relevant myocardial mechanisms.
Topics: Aged; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biopsy; Cardiac Catheterization; Female; Heart Failure; Heart Transplantation; Humans; Myocardium; Prevalence; Prospective Studies; Stroke Volume; Tissue Donors
PubMed: 32653448
DOI: 10.1016/j.jchf.2020.04.007