Lymphocytic myocarditis with suspected granulomatosis with polyangiitis presenting as cardiogenic shock, restrictive cardiomyopathy and complete heart block

Abstract

We report a case of restrictive cardiomyopathy from lymphocytic myocarditis in a patient with suspected granulomatosis with polyangiitis (GPA). The case was complicated by complete heart block and renal failure. The diagnosis was supported by upper airway involvement, elevated serum serine proteinase 3 antibodies, and endomyocardial biopsy with lymphocytic infiltration. The patient responded appropriately to aggressive immunosuppressive therapy.

<Learning objective: Our case reviews an atypical presentation of lymphocytic myocarditis and likely cardiac granulomatosis with polyangiitis (GPA). We also demonstrate an evaluation of restrictive physiology as well as discuss the presentations and management of cardiac GPA with its response to immunotherapy.>

Introduction

Fulminant lymphocytic myocarditis is a rare disease with a high mortality rate. It is important to recognize various manifestations of myocarditis and to identify the underlying etiology. Autoimmune diseases such as vasculitis can have myocardial involvement. Our case outlines biopsy-confirmed lymphocytic myocarditis with elevated serine protease 3 (PR3) antibodies presenting as restrictive cardiomyopathy, complete heart block (CHB), and acute heart failure. We discuss the work-up and treatment of the patient's vasculitis process, restrictive physiology, and heart block. The discussion focuses on a review of the literature explaining the atypical presentation and positive vasculitis biomarkers.

Case report

A 38-year-old male presented to another hospital with worsening dyspnea on exertion and lower extremity swelling. Just a few months prior he had subjective fevers, dyspnea, and edema. An outpatient cardiologist diagnosed him with myocarditis. At that time the patient had a nearly normal echocardiogram and was put on oral diuretics. The symptoms progressed requiring the present hospitalization. On admission, physical examination exhibited bilateral lung crackles, anasarca, and elevated jugular venous pressure. He responded poorly to high-dose intravenous diuretics and renal function began to deteriorate. Further evaluation included a right heart catheterization (RHC) which demonstrated depressed cardiac index (CI) and restrictive physiology. Despite the addition of inotropic support, the patient continued to decline. Ultimately, he required continuous dialysis and transfer to our facility for consideration of advanced heart therapies.

Past medical history

History is pertinent for hypothyroidism. There is no personal or family history of autoimmune disorders or cardiac disease. However, his aunt died of nephritis of unknown etiology. He denied any substance abuse.

Investigations

Laboratory data from the outside facility revealed N-terminal pro-B-type natriuretic peptide 2220 pg/mL and normal serum troponins (0.00 ng/mL). Electrocardiogram (ECG) now showed junctional vs idioventricular escape rhythm with a right bundle branch block (RBBB) (Fig. 1D). This had changed from an essentially normal baseline ECG a month previously. Echocardiogram demonstrated an ejection fraction of 40%, global left ventricular hypokinesis, and restrictive filling as seen in Fig. 2A,B,C. As mentioned, the outside facility RHC showed reduced CI and elevated filling pressures with equalization consistent with restrictive physiology (Table 1). Serum and urine immunofixation, thyroid function, and serum iron studies were within normal limits. Evaluation with cardiac magnetic resonance imaging and coronary angiography was limited by renal failure. The antineutrophil cytoplasmic antibody (ANCA) test resulted positive with elevated PR3 antibodies of 95 AU/ml (<19 AU/mL normal). This was confirmed with repeat testing. Peripheral eosinophils were 0.2 K/uL. High-sensitivity C-reactive protein was elevated at 206 mg/L. Expert rheumatology opinion considered these findings specific for granulomatosis with polyangiitis (GPA), warranting a tissue diagnosis. A repeat RHC with right ventricular endomyocardial biopsy (EMB) was performed. The filling pressure had normalized after successful dialysis, but his CI remained depressed (1.6–1.8 L/min/m²). After a fluid challenge, restrictive physiology was still evident, but there was no evidence of ventricular interdependence to suggest constriction and respiratory fluctuations were a concordant pattern. (Fig. 1E). Also, there was a low suspicion for constriction given the lack of echocardiography findings and normal pericardium on computed tomography scan of the chest. The EMB did not contain a vascular sample but was consistent with lymphocytic myocarditis largely consisting of CD2 and CD5 positive T-lymphocytes with rare scattered CD20 positive B-lymphocytes. There were no granulomas or eosinophils noted in the biopsy (Fig. 1A,B,C). Given the nonspecific findings of lymphocytic myocarditis on EMB, further tissue diagnosis was pursued for GPA. Presenting creatinine at the previous hospital was 0.9 mg/dL and trended up to 3.5 mg/dL prior to starting dialysis. The renal dysfunction was thought to be related to cardio-renal syndrome rather than GPA. Urine studies did not show any hemoglobin or atypical cells. A renal biopsy suggested that the etiology of the renal failure was related to acute tubular necrosis rather than vasculitis. A computed tomography scan of the chest did not show any remarkable findings of pulmonary GPA. The patient had intermittent epistaxis and a head and neck examination demonstrated extensive nasal septal crusting which otolaryngologists felt to be consistent with GPA. However, nasal septal biopsy resulted negative.

Fig. 1.

Right heart tracings, endomyocardial biopsy, and presentation electrocardiogram. (A) Endomyocardial biopsy at 20X magnification with immunohistochemical staining for cluster of differentiation (CD2). (B) Endomyocardial biopsy at 20X magnification with immunohistochemical staining for cluster of differentiation 5 (CD5). (C) Endomyocardial biopsy at 20X magnification with hematoxylin and eosin stain demonstrating lymphocytic infiltration. (D) Presentation electrocardiogram with junctional vs accelerated idioventricular rhythm, right bundle branch block, and right-axis deviation. This electrocardiographic (ECG) tracing is quite different than baseline ECG obtained a few months prior which showed sinus rhythm. (E) Simultaneous right and left ventricular tracings after fluid challenge showing equalization of pressures without ventricular interdependence. The red arrow and blue arrow correspond to inspiration and expiration respectively. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2.

Mitral inflow and tissue Doppler velocities pre- and post-immunosuppression. (A) Mitral inflow velocities on presentation prior to immunosuppression therapy. (B and C) Septal and lateral tissue Doppler velocities respectively on presentation with depressed E’. (D) Improvement in mitral inflow pattern after a month of immunosuppression. (E and F) Septal and lateral tissue Doppler velocities respectively after immunosuppression with improvement in E’ velocities.

Table 1.

Right heart pressures from right heart catheterization during admission.

Hemodynamic pressures (units)	Initial RHC	Second RHC Rest	Second RHC Post Saline	Third RHC Post Immunosuppression
Right Atrium (mmHg)	30	11	20	10
Right Ventricle (mmHg)	48/30	33/11	36/19	33/8
Pulmonary Artery (mmHg)	46/31	31/11	41/23	32/5
Mean Pulmonary Artery (mmHg)	36	16	27	14
Fick CI (L/min/m2)	1.55	2	1.61	2.51
Thermodilution CI (L/min/m2)	1.21	1.67	1.89	2.17
Heart Rate (beat/min)	60	65	65	54
SV Fick (ml/beat)	56.8	65.5	52.8	106.7
SV Thermodilution (ml/beat)	44.4	54.8	62.2	85.7

The initial and second RHCs were performed prior to immunosuppression therapy. The third RHC was after 3 weeks of immunosuppressive therapy showing improvement in CI, SV, and filling pressures. Note that heart rates were similar during each procedure.

RHC, right heart catheterization; CI, cardiac index; SV, stroke volume.

Management

The patient was started on methylprednisolone 500 mg intravascular for three doses, weekly rituximab 375 mg/kg intravascular infusions for four doses, and a slow oral prednisone taper. After four weeks of rituximab and steroids, a repeat RHC showed an improved CI (2.17–2.51 L/min/m²) and repeat echocardiogram showed ejection fraction improved to 55% with resolution of restrictive filling pattern (Fig. 2D,E,F). A positron emission tomography scan at this time showed normal myocardial perfusion without any inflammatory uptake in the myocardium. An electrophysiology study was performed for the arrhythmia establishing the diagnosis of CHB with idioventricular escape requiring permanent pacemaker implantation.

Discussion

This is an atypical case of heart failure with restrictive physiology and biopsy-proven lymphocytic myocarditis complicated by CHB and elevated GPA specific antibodies. GPA is a small-to-medium vessel vasculitis that often affects the lower respiratory tract, paranasal sinuses, and kidneys [1]. The disease is an autoimmune disorder associated with ANCA specific for PR3. The prevalence of cardiac involvement in GPA varies widely in the literature from 5% to 90%, but it is generally considered uncommon and often fatal [2]. This variation is largely dependent on the studies’ qualification of cardiac involvement. Generally, milder forms of GPA have less cardiac involvement when compared to more severe cases [1]. Most reported cases with cardiac GPA have at least one other organ system involved [2]. GPA presenting with cardiac only involvement is atypical and our patient did show other clinical signs of GPA with nose bleeding and a consistent head and neck examination. The European Medicines Agency (EMA) provides a stepwise algorithm that incorporates criteria from other agencies to diagnose GPA and differentiate it from another small vessel vasculitis [3]. According to this algorithm our patients’ evidence of upper airway involvement as well as positive PR3 meets diagnostic criteria for GPA despite the biopsy being negative. The endocardial biopsy showed lymphocytic myocarditis. Histologically, GPA usually consists of ischemic necrosis with geographical organization and a polymorphic granuloma containing polymorphonuclear leukocytes, lymphocytes, plasma cells, dendritic cells, eosinophils, and multinucleated giant cells [4]. The patchy nature of GPA in the heart makes definitive tissue diagnosis difficult.

T-lymphocytes are elevated in ANCA-associated vasculitis and their presence in biopsied tissues is well documented [5]. Polymorphonuclear cells (PMNs) and T-lymphocytes regulate one another. T-lymphocytes help differentiate PMNs into antigen-presenting cells with PR3 on the surface. PR3 recognition by ANCA is the pathogenesis of the GPA [5]. The upregulation of T-lymphocytes and their role in regulating PMNs is an explanation for the lymphocytic infiltration of the myocardium. This type of myocardial infiltration in GPA has also been demonstrated in prior studies [6,7]. Therefore, although the EMB in our patient did not show classic granulomatous inflammation, possibly from the lack of vasculature in the sample, the results are still curious for a vasculitis process. Also, unlike eosinophilic granulomatosis with polyangiitis (EGPA), eosinophilic infiltration and peripheral eosinophilia are minimal in GPA which explains the lack of them in the cardiac biopsy.

The documented cardiac manifestations of GPA include pericarditis, cardiomyopathy, coronary arteritis, valvular heart disease, and conduction disorders [2]. It is uncommon for GPA to present as heart failure with restrictive physiology. In a review of the literature, we found no cases of GPA and only one case of idiopathic (ANCA negative) vasculitis causing restrictive cardiomyopathy [6]. The lymphocytic myocarditis likely explains the patient's restrictive physiology. Left ventricular restrictive filling pattern related to lymphocytic infiltration and cardiac edema is reported in the transplant literature [8].

Vasculitis can have a quick response to immunosuppression. For example, EGPA has been shown to have complete resolution of myocardial inflammation on biopsy as soon as one month after therapy initiation [9]. Our patient got a quick response to aggressive immunosuppression with improvement in CI on repeat RHC several weeks after starting therapy.

Conduction disease is well documented in myocarditis and GPA [2]. It is well established that CI can be depressed by CHB due to atrioventricular dissociation [10]. Our patient did not have CHB at baseline but did at presentation, and this was likely contributing to the low CI. However, CI had improved on the third RHC after immunosuppression as seen in Table 1, but cardiac resynchronization was not pursued until several weeks later. Unfortunately, the conduction disease did not improve with immunosuppression and he was 100% paced at follow-up appointments.

Follow-up

The patient was discharged on oral prednisone to a rehabilitation hospital. At clinic follow-up, the patient had been weaned off dialysis and was euvolemic on oral diuretics. There have been no re-hospitalizations to date. Ultimately, care was transferred to another institution with plans for eventual cardiac magnetic resonance imaging.

Conclusions

Myocarditis can present with a variety of different cardiac manifestations, including heart failure with restriction and heart block from lymphocytic infiltration. The EMA algorithm, positive nasal examination, and elevated serine PR3 antibodies make the case for an atypical presentation of GPA. Immunosuppressive therapy with steroids and rituximab can result in some cardiac recovery as early as 4 weeks.

Declaration of Competing Interest

The authors Wesley Anderson, MD, Mubashir H. Bahrami, MD, Maya Guglin, MD, Roopa Rao, MD, MBBS declare that there is no conflict of interest.