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A sixty-two year old female patient with effort dyspnoea and normal coronary arteries

A 62- year old woman with bronchial asthma, Hashimoto’s thyroiditis, positive family history for coronary artery disease (father died at 59 yr old for myocardial infarction and sister, who had underwent coronary artery bypass surgery) and for inflammatory dilated cardiomyopathy (DCM) (paternal cousin, transplanted, and daughter, healed autoimmune DCM in the peri-partum), had been complaining for years of effort dyspnoea and palpitation. She underwent an echocardiogram, showing a dilated and hypertrophic left ventricle with moderate mitral regurgitation and moderately depressed left ventricular ejection fraction (EDV 100 ml/mq, EF 40% with diffuse hypokinesis) and was admitted to a local hospital for further investigations. At admission she had no heart failure signs and symptoms. ECG showed sinus rhythm, frequent ventricular ectopic beats, incomplete right bundle branch block. She underwent selective coronary angiography, which showed normal coronary arteries. She was put on ACE-inhibitor therapy, and discharged. No beta-blockers were given because of asthma. She underwent as ambulatory patient a CMR (Fig 1) which showed: image limitation due to ventricular ectopic beats, left ventricular dilatation and moderately depressed left ventricular ejection fraction (EDV 115 ml/mq, EF 41% with diffuse hypokinesis), normal right ventricular function, inadequate T2 sequences, subepicardial late gadolinium enhancement (LGE) at septal level, and at the posterolateral wall (basal and medium levels), focal pericardial enhancement.

Fig. 1.
CMR images: please note LGE  at septal level (left, arrow), and at the posterolateral wall  (right, arrow).

Because of persistent symptoms of effort dyspnoea and asthenia she was seen by her cardiologist and referred to our centre for further diagnostic work-up.
Upon admission at our cardiology ward, 3 months following her first hospital admission, the patient was haemodynamically stable, in NYHA class II, apyretic, with blood pressure of 150/100 mmHg and a heart rate of 73 beats/min. On physical examination she had no jugular venous distention at 45 degrees, had an audible 2/6 soft systolic murmur at the apex, no pathologic lung findings, no poedal oedema. Her ECG on admission is shown in Figure 1.
High sensitivity cardiac troponin I, blood count, erythrocyte sedimentation rate, reactive C protein (CRP), urea, creatinine, thyroid hormones, liver enzymes, tumour markers, serum protein profile, Quantiferon test, were normal. NTpro BNP was mildly elevated (1277 ng/L, normal range 0-900). Telemetry (Figure 2) showed frequency dependant right bundle branch block, frequent (1605) ventricular ectopic beats, 23 ventricular couplets, a ventricular triplet (FC 123 bpm) and one run of NSVT(9 beats, 134 bpm), one run of PSVT (6 beats, 126 bpm).

Fig. 2.
ECG on admission showed sinus rhythm, 78 bpm, right bundle branch blockPa

Fig. 3. On telemetry documentation of a short run (6 beats, 126 bpm) of asymptomatic supraventricular paroxysmal tachycardia (top strip) and of NSVT (9 beats) 134 bpm (bottom strip):


A repeat echocardiogram showed: a dilated, non hypertrophic left ventricle (EDV 85 ml/mq), severely reduced global left ventricular ejection fraction (LVEF=31%) with diffuse ipokinesis, altered diastolic left ventricular function on mitral Doppler (E/A ratio 0.80, DT 190 ms), normal right ventricular dimension and pump function(FAC=47%, TAPSE=20 mm). There was mild functional mitral regurgitation.


1) Can we make the final diagnosis based on the above cited results and what are the possible etiologies of this non-ischemic biventricular failure?

2) If not, which additional examination would you recommend?

3)  What do you predict will be the clinical outcome in this patient? 

Question 1: Can we make the final diagnosis based on the above cited results and what are the possible etiologies of this severe non-ischemic biventricular failure?

Answer: We can’t make the final diagnosis. The CMR pattern of LGE suggests a previous myocarditis, but is inconclusive in relation to the stage of the disease (T2 sequences were inadequate) (1). The family history of inflammatory autoimmune DCM and the association with Hashimoto’s thyroiditis suggests the possibility of familial autoimmune myocarditis/DCM (2-7). Overall the clinical and imaging results are in keeping with a clinically suspected myocarditis (Myocarditis Position Statement criteria) (3). Anyhow, the final differential diagnosis of infectious (viral or bacterial–positive) or immune-mediated (infection-negative) acute or chronic myocarditis could only be based upon endomyocardial biopsy (EMB) (3,8). An EMB could also rule out myocarditis and establish the diagnosis of idiopathic dilated cardiomyopathy or of other rare causes of myocardial disease (3,8).

Question 2: If not, which additional examination would you recommend?

 Answer: This is a case of new-onset heart failure of 2 weeks to 3 months duration associated with a dilated left ventricle with new-onset ventricular arrhythmia not responsive to usual care within 1 to 2 weeks. Thus there is Class I indication for performing an EMB according to the American Heart Association, the American College of Cardiology and the European Society of Cardiology Scientific Statement on the role of EMB (8). An EMB is also indicated, since the patient has a clinically suspected myocarditis (with exclusion of coronary artery disease and of or other causes likely to explain the clinical presentation), according to the recent Position Statement of the Working Group on Myocardial and Pericardial Disease on Myocarditis (3). The most likely cause of this heart failure presentation is a familial myocarditic process, of autoimmune pathogenesis, given the family history of autoimmune DCM (daughter) and the association with another extra-cardiac autoimmune disease (Hashimoto’s thyroiditis) (2-7, 9-10).
Our patient underwent right ventricular EMB, with classical histology, immunohistochemistry, molecular detection of common cardiotropic viruses by polymerase chain reaction (PCR) in myocardial tissue and on blood, and serum testing for anti-heart autoantibodies (AHA) (2-7, 9-10). EMB showed (Figure 1) by standard histology normally oriented myocytes of variable dimensions (hypo/hypertrophic, mean diameter 21,5 ± 3 μm, range 15-25), only rarely of bizarre shape with rare perinuclear halos, mild interstitial fibrosis, sometimes substitutive, and interstitial monomorphic inflammatory cells in the absence of necrosis. By immunohistochemistry these cells were identified as macrophages (CD68+), negative for lymphocytes (CD3 and CD20 neg). HLA class II expression was enhanced on the endothelium (HLA-DR+). The findings were suggestive of DCM in the setting of chronic inflammation.  The findings were suggestive of chronic inflammatory DCM. PCR was negative for enterovirus, influenza A and B, Cytomegalovirus, Ebstein-Barr virus, Herpes-virus, Human Herpes virus 6, Adenovirus, Parvovirus B19.  AHA test in the patient serum was positive for organ-specific AHA and for anti-intercalated disk autoantibodies (AIDA) (9-10).  The final diagnosis was of an infection-negative chronic autoimmune DCM.

Figure 1. Endomyocardial biopsy diagnostic for chronic inflammatory DCM. A)Hematoxilin eosin stain showed the variable dimension of myocites , rare perinuclear  halos (original magnification 200X). B)Trichrome staining showed the mild interstitial fibrosis (original magnification 200x). C,D) immunohistochemical staining with positivity  for the macrophage marker CD68 and positivity for HLA expression respectively.

Question 3: What do you predict will be the clinical outcome in this patient?

Answer: The patient had DCM with severe left ventricular dysfunction, and an histological diagnosis of an infection-negative chronic autoimmune DCM that has per se a dismal prognosis. She did not respond to standard heart failure therapy with Ace-inhibitors, beta-blockade was contraindicated due to asthma and she was put on ivabradine 10 mg daily. After few months she developed intolerance to ACE-inhibitors (cough) and was put con losartan 100 mg per day. Female gender, left ventricular dysfunction at presentation, and autoimmune pathogenesis are all negative prognostic features in myocarditis (2,3,4,6). Her daughter had been successfully treated years before her mother with immunosuppressive therapy for severe peri-partum autoimmune myocarditis with cardiogenic shock. Based on these considerations, in keeping with a previous study showing beneficial response to azathioprine and steroids in inflammatory DCM with increased HLA expression on EMB (5) and with the expert indications of the Myocarditis Position statement (3), the patient was put on dual immunosuppressive therapy (prednisone 1 mg/kg/day and azathioprine 2 mg/kg/day) as an inpatient, then discharged on such therapy and received cardiological and immunological follow-up as an ambulatory patient. Consideration of ICD implant as primary prevention was delayed by 6 months, pending potential response to immunosuppression and recovery of LV function. Indeed LVEF at 6 months was improved up to 44% and ICD was not placed. Holter monitoring did not reveal significant supraventricular or ventricular repetitive arrhythmia. Immunosuppression was well tolerated. She is alive and well at 34 months follow-up, in NYHA I, has recovered a normal LV function on echocardiography. She is currently on a low dose well-tolerated maintenance immunosuppressive therapy (prednisone 2.5 mg every other day, mainly for asthma control, but azathioprine was stopped at 24 months follow-up).  She is also on regular, life-long, combined immunological and cardiological follow-up. This is a case of infection-negative chronic autoimmune familial DCM in an elderly patient with an optimal response to mild (dual) immunosuppressive therapy, in spite of the dismal prognosis of this disease entity (2,3,6). This case supports the view of an early biopsy-proven diagnosis for safe, patient-tailored, etiology-specific therapy of autoimmune acute and chronic forms of myocarditis/DCM (3).


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Notes to editor

Presented by: ^Alida LP Caforio, MD, PhD, *Annalisa Angelini, MD,PhD, *Marny Fedrigo, MD, PhD, and # Renzo Marcolongo, MD,
^Cardiology, and * Cardiovascular Pathology, Department of Cardiological, Thoracic, and Vascular Sciences,# Haematology and Clinical Immunology, Department of
Medicine, University of Padova, Padova, Italy
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.

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