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Inflammatory Cardiomyopathy After Delivery

2019; Lippincott Williams & Wilkins; Volume: 140; Issue: 16 Linguagem: Inglês

10.1161/circulationaha.119.041693

1524-4539

Berlinde von Kemp, Vincent Michiels, Bernard Cosyns,

Cardiomyopathy and Myosin Studies

HomeCirculationVol. 140, No. 16Inflammatory Cardiomyopathy After Delivery Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBInflammatory Cardiomyopathy After Delivery Berlinde von Kemp, MD, Vincent Michiels, MD and Bernard Cosyns, MD, PhD Berlinde von KempBerlinde von Kemp Berlinde von Kemp, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, B-1090 Brussel, Belgium. Email E-mail Address: [email protected] Cardiology Department, Centrum Hart- en Vaatziekten, Universitair Ziekenhuis Brussel, Brussels, Belgium. , Vincent MichielsVincent Michiels Cardiology Department, Centrum Hart- en Vaatziekten, Universitair Ziekenhuis Brussel, Brussels, Belgium. and Bernard CosynsBernard Cosyns Cardiology Department, Centrum Hart- en Vaatziekten, Universitair Ziekenhuis Brussel, Brussels, Belgium. Originally published14 Oct 2019https://doi.org/10.1161/CIRCULATIONAHA.119.041693Circulation. 2019;140:1354–1358Information about a real patient is presented in stages (boldface type) to an expert clinician (Professor Cosyns), who responds to the information and shares his reasoning with the reader (regular type). A discussion by the authors follows.Patient presentation: A 31-year-old Moroccan woman was admitted at the infectious diseases department because of a clinically unexplained inflammatory syndrome after recent delivery. Three weeks earlier, she had given birth to a healthy girl, during uncomplicated delivery and after unremarkable pregnancy. Obstetric history included 2 other uncomplicated pregnancies and deliveries. Medical history consisted of asthma, hypothyroidism, and frequent sinusitis episodes. Long-term treatment included levothyroxine 125 µg QD, as well as combination inhalation therapy (fluticasone furoate 92 µg and vilanterol 22 µg QD). She initially presented at the emergency department with general malaise, diffuse myalgias, arthralgias, and fever peaks. Clinical examination revealed an ill patient with symptomatic hypotension (96/48 mm Hg) and tachycardia (117 bpm) but no fever (37.8°C). Peripheral oxygen saturation at breathing room air was normal (97%) despite mild orthopnea. Cardiopulmonary auscultation revealed regular heart sounds without a murmur and bibasilar pulmonary rales. There was mild ankle pitting edema and a subtle purpura on the dorsal side of both feet. C-reactive protein level was 107.5 mg/L (normal range, 0–5 mg/L), and leukocyte count was 39.8×103/mm3 (normal range, 3.6–9.6×103/mm3) with a strong eosinophilic pattern (63.5% eosinophils; absolute value, 25.3×103/mm3). Renal, thyroid, and hepatic function were normal, as was hemoglobin concentration; troponin T levels were elevated at 1.4 µg/L (normal range, 0.000–0.005 µg/L), with creatinine kinase levels of 424 IU/L (normal range, 30–135 IU/L). Urinary sample was negative for pyuria, and serial blood cultures were taken. Contrast-enhanced thoracoabdominal computed tomography scan demonstrated a tree-in-bud pattern at the left upper lobe, suggesting bronchiolitis in the absence of clear consolidations with associated signs of pulmonary congestion. A minimal autoimmune workup consisting of antinuclear antibodies and anti-neutrophil cytoplasmic antibodies was negative. Skin biopsy of the foot lesions was performed. An urgent cardiac consultation was requested.Prof Cosyns: As consulting cardiologist for this case, we are confronted with a young, severely ill patient, after recent (though uncomplicated) delivery. Clinically and radiographically, there are signs of heart failure and inflammation, but without a straightforward source of infection. Cardiac biomarkers are clearly elevated. At this moment, the differential diagnosis is broad and should include acute peripartum cardiomyopathy with sepsis, preexisting cardiomyopathy with sepsis, a new-onset inflammatory cardiomyopathy, and infectious endocarditis. Acute coronary syndrome, in particular spontaneous coronary artery dissection, in this young woman should also be taken into account and be excluded promptly. Acute pulmonary embolism with pulmonary infarction, cholesterol embolism, hyperthyroidism, or community-acquired pneumonia are unlikely based on the diagnostic tests already performed. A 12-lead ECG and transthoracic echocardiography (TTE) need to be performed urgently.Patient presentation (continued): ECG demonstrated sinus tachycardia (114 bpm) with nonspecific repolarization abnormalities, without signs of ongoing ischemia. TTE revealed severely reduced systolic function of a nondilated left ventricle (LV): LV ejection fraction calculated by the modified biplane Simpson method was measured at 30% because of diffuse hypokinesia, with elevated LV end-diastolic pressures and pseudonormal relaxation pattern on pulsed-wave Doppler and tissue Doppler. Right ventricular function was reduced, and continuous-wave Doppler of the tricuspid valve regurgitation jet suggested increased pulmonary pressures up to 37 mm Hg. A small pericardial effusion without hemodynamic impact was observed. Valvular function was normal, and no vegetation was seen. Inferior vena cava was not dilated but showed <50% respiratory variation.Prof Cosyns: Electrocardiographic and echocardiographic findings confirm the diagnosis of heart failure with reduced ejection fraction; the absence of regional changes corresponding to a coronary artery territory makes an acute coronary syndrome unlikely. The absence of a murmur and of valvular vegetations on TTE makes infectious endocarditis improbable (although it does not exclude the diagnosis and should be repeated); moreover, multiple blood cultures taken on admission were negative during observation. This leaves us with the diagnosis of an inflammatory cardiomyopathy that could be infectious, toxic, or autoimmune. An important clue to the correct diagnosis is the striking eosinophilia. Further testing is required to accurately specify this probable autoimmune eosinophilic myocarditis and most importantly to continue to exclude other more prevalent causes of myocarditis.Patient presentation (continued): Complementary autoimmune testing was performed, and other causes of hypereosinophilia were excluded: broad viral (HIV, hepatitis B and C, cytomegalovirus, Epstein-Barr virus, parvovirus B19), bacterial, and parasitological cultures remained negative. Hematologic workup, including cellular and humoral immunologic testing as well as bone marrow biopsy, demonstrated only reactive changes without signs of underlying hematologic malignancy. Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) with hypersensitivity myocarditis was considered unlikely because the patient was not taking any medication at admission. Tests for both antinuclear antibodiesand anti-neutrophil cytoplasmic antibodieswere repeated but remained negative. However, we observed markedly increased levels of immunoglobulin E (2.545 kIU/L; reference range, 10% on differential white blood cell count), transient pulmonary opacities detected radiographically, paranasal sinus abnormalities, and biopsy confirming extravascular eosinophil accumulation.1 There was no notion of polyneuropathy or mononeuropathy.Download figureDownload PowerPointFigure 3. Differential diagnosis of eosinophilic cardiomyopathies. Eosinophilic cardiomyopathies are cardiomyopathies in which eosinophils are presumed to play an essential role in their etiopathogenesis. Differential diagnosis is broad and is summarized in the diagnostic scheme. Hypersensitivity myocarditis is drug or vaccine related, usually resolving after cessation of the inciting agent. Endomyocardial fibrosis is the most common form of restrictive cardiomyopathy in the world, endemic in tropical and subtropical parts of the world. Hypereosinophilic syndromes (HES) are conditions defined as the combination of an important peripheral hypereosinophilia (>1.5×109/L) along with organ damage not attributable to another cause. It can be idiopathic, neoplastic, or reactive as in eosinophilic granulomatosis with polyangiitis (EGPA). The clinical spectrum is wide, ranging from a mild pericardial effusion to a fulminant endomyocarditis, often referred to as Löffler endocarditis (after Wilhelm Löffler, who first described it in 1936). In EGPA, situated at the crossroads between asthma, vasculitis, and HES, both vessel inflammation and eosinophilic proliferation are responsible for the cardiac damage. The clinical history of asthma and the striking hypereosinophilia in a patient with an inflammatory cardiomyopathy are the most important initial clues for diagnosing EGPA-associated myocarditis.Patient presentation (continued): After multidisciplinary consultation with internal medicine and nephrology consultants, an immunosuppressive treatment was initiated that consisted of high-dose corticosteroids (intravenous methylprednisolone 500 mg QD for 3 days, followed by oral methylprednisolone 1 mg/kg QD, slow tapering) and intravenous cyclophosphamide (15 mg/kg, biweekly administration), as per standard protocol for EGPA with myocardial involvement. In parallel, standard heart failure treatment was initiated (carvedilol 6.25 mg BID, lisinopril 2.5 mg QD); uptitration of therapy was limited by symptomatic hypotension. Oral bumetanide was initiated for treatment of congestive signs. Breastfeeding was discouraged. A rapid decline of peripheral blood eosinophilia was observed after 48 hours of immunosuppressive therapy; reduction of C-reactive protein and troponin T levels occurred later. After 5 days on treatment, repeat TTE was performed, showing persistently reduced LV function. The pericardial effusion had diminished, but an apical 4-chamber view confirmed the presence of 3 large intraventricular thrombi, of which the largest measured 30×19 mm, with a heterogeneous echodensity, appositioned to the apicoseptal endocardial wall (Figure 4).Download figureDownload PowerPointFigure 4. One of 3 intraventricular thrombi (star) on apical 4-chamber TTE view. TTE indicates transthoracic echocardiography.Prof Cosyns: In EGPA-associated myocarditis, the presence of intraventricular thrombi is described in ≈19% of cases, necessitating adjuvant anticoagulant treatment.2 In our case, subcutaneous treatment with low-molecular-weight heparin was prescribed, while vitamin K antagonists were started for long-term anticoagulation (international normalized ratio target range 2.0–3.0). Because of the high risk of emboligenic complications, endomyocardial biopsy (EMB) was not performed, nor was coronary angiography. The diagnostic yield of EMB is known to be low in EGPA-associated myocarditis because of the patchy disease dispersion in the myocardium.2 Nevertheless, EMB remains the "gold standard" for diagnosis of myocarditis, typically showing eosinophilic myocardial infiltration and signs of endomyocarditis (inflammatory infiltrates in association with myocyte necrosis) but no typical vasculitis.3 Recent literature suggests that an image-guided or electrogram-guided EMB could increase the diagnostic accuracy.2Patient presentation (continued): Gradual clinical recovery occurred, despite a persistently reduced LV function. The patient was discharged, and outpatient follow-up was performed at the heart failure clinic and at the internal medicine short-stay clinic. After 2 months of anticoagulant treatment, all intraventricular thrombi resolved completely. A slow but incomplete recovery of LV function followed: after 3 months of treatment, LV ejection fraction was measured at 35% on TTE and at 28% on CMR (Figure 2B). The latter also confirmed the presence of patchy subendocardial fibrosis at the midseptal and apical level, with involvement of both papillary muscles. After 4 months of cyclophosphamide–corticosteroid combination treatment, immunosuppressive therapy was switched to azathioprine–corticosteroid treatment (azathioprine 50 mg BID) as maintenance therapy, according to current EGPA guidelines. After 6 months of immunosuppressive therapy, LV ejection fraction recovered to 40%, and the patient was in New York Heart Association functional class II, which allowed her to resume physical exercise in a cardiac rehabilitation program, as well as to resume her professional activities. Three-monthly cardiological follow-up was scheduled. Future pregnancies were discouraged.DiscussionThe final diagnosis consisted of EGPA-associated myocarditis, with potential triggering of the acute phase because of the hemodynamic, hormonal, and immunologic changes associated with pregnancy and delivery. The differential diagnosis with classic peripartum cardiomyopathy was made on the basis of the nearly pathognomonic clinical disease spectrum for EGPA.EGPA (formerly Churg-Strauss syndrome) is classified as vasculitis of small to medium blood vessels, with multiorgan involvement (pulmonary, renal, cutaneous, vascular, neurological, and myocardial), but it overlaps significantly with hypereosinophilic syndromes.4 EGPA-associated myocarditis is probably underreported (and not unfrequently a postmortem diagnosis), likely because of the often oligosymptomatic disease course, negative peripheral blood eosinophilia at diagnosis (25% of cases), and a lack of data in the literature: the largest case series include 179 cases of histologically proven eosinophilic myocarditis, of which only 23 cases of EGPA-associated myocarditis were described.2,3 Nevertheless, an incidence of cardiovascular involvement of 27% to 47% is suspected in new EGPA cases, which makes noninvasive cardiac imaging a valuable screening tool in newly diagnosed EGPA.5Clinical manifestations can be nonspecific and often consist of chest pain or dyspnea; severe cases may present as cardiogenic shock.2 Despite EMB being the gold standard in the diagnosis of acute myocarditis, diagnosis often relies mainly on the typical disease spectrum combined with autoimmune testing, troponin levels, and noninvasive cardiac imaging (usually TTE and CMR).3 Biopsy of another affected organ that is often more accessible (as in our case, skin) can be of great value in making a diagnosis. In 30% to 40% of cases, both antinuclear antibodiesand anti-neutrophil cytoplasmic antibodiesremain negative, and the diagnosis of "autoimmunity" is based on levels of complement factors, immunoglobulin G4, and immunoglobulin E.2 Patients with cardiac involvement are less likely to have a positive anti-neutrophil cytoplasmic antibody testand more likely to have higher eosinophilia than other patients with EGPA.2 Peripheral blood eosinophilia is present in 90% of cases but may be negative at initial presentation, which underlines the importance of repeated measurements in suspected eosinophilic myocarditis.2 The underlying pathophysiological mechanism is incompletely understood.3 Treatment is usually based on steroids, but there are no strict evidence-based guidelines or consensus statements to guide therapy.3 First-line treatment includes corticosteroid therapy, eventually combined with cyclosporine A or azathioprine.3 The role of intravenous immunoglobulins or monoclonal anti-interleukin 5 antibodies (mepolizumab) remains unclear.2 Short-term in-hospital mortality is high (21.7%), and mechanical circulatory support (by whatever means) or heart transplantation may be needed, but long-term survival data, albeit sparse, suggest that recovery of LV function is common.2ConclusionsEGPA is a rare but severe multisystem disease, mostly known for its pulmonary, renal, and vascular complications.2,5 Myocardial disease manifestations probably remain underdiagnosed.2 Nevertheless, in-hospital mortality during the acute phase is particularly high.2 TTE should be considered at baseline in all new EGPA diagnoses. CMR may be useful when myocardial disease is suspected.2 EMB remains the gold standard for diagnosis,2,3 although the combination of clinical signs, cardiac imaging, and biomarkers with extracardiac biopsy can provide a reliable diagnosis. Treatment is complex and requires both heart failure treatment and immunosuppressive therapy, consisting of corticosteroids and a second immunosuppressor.3DisclosuresNone.Footnoteshttps://www.ahajournals.org/journal/circBerlinde von Kemp, Universitair Ziekenhuis Brussel, Laarbeeklaan 101, B-1090 Brussel, Belgium. Email berlinde.[email protected]beReferences1. Masi AT, Hunder GG, Lie JT, Michel BA, Bloch DA, Arend WP, Calabrese LH, Edworthy SM, Fauci AS, Leavitt RY. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis).Arthritis Rheum. 1990; 33:1094–1100. doi: 10.1002/art.1780330806CrossrefMedlineGoogle Scholar2. Brambatti M, Matassini MV, Adler ED, Klingel K, Camici PG, Ammirati E. Eosinophilic myocarditis: characteristics, treatment, and outcomes.J Am Coll Cardiol. 2017; 70:2363–2375. doi: 10.1016/j.jacc.2017.09.023CrossrefMedlineGoogle Scholar3. Caforio AL, Pankuweit S, Arbustini E, et al; European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases.Eur Heart J. 2013; 34:2636–2648a. doi: 10.1093/eurheartj/eht210CrossrefMedlineGoogle Scholar4. Mahr A, Moosig F, Neumann T, Szczeklik W, Taillé C, Vaglio A, Zwerina J. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): evolutions in classification, etiopathogenesis, assessment and management.Curr Opin Rheumatol. 2014; 26:16–23. doi: 10.1097/BOR.0000000000000015CrossrefMedlineGoogle Scholar5. Comarmond C, Cacoub P. Myocarditis in auto-immune or auto-inflammatory diseases.Autoimmun Rev. 2017; 16:811–816. doi: 10.1016/j.autrev.2017.05.021CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails October 15, 2019Vol 140, Issue 16 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.041693PMID: 31609654 Originally publishedOctober 14, 2019 Keywordsheart failureeosinophilic granulomatous vasculitisPDF download Advertisement SubjectsEchocardiographyHeart FailureInflammatory Heart DiseaseMagnetic Resonance Imaging (MRI)