Granulomatosis With Polyangiitis Causing Severe Aortic Regurgitation

Abstract

Cardiac granulomatosis with polyangiitis is a rare necrotizing vasculitis impacting small to medium vessels. We present a case of granulomatosis with polyangiitis causing acute aortic valve regurgitation. Imaging reveals valve thickening, inflammation without destruction. Treatment involves glucocorticoids and rituximab for remission, with consideration of surgery for severe valve disease.

Graphical Abstract

History of presentation

A 65-year-old male patient was admitted to the hospital for worsening memory impairment, progressive neurocognitive decline, fatigue, and shortness of breath. He described a history of suspected Lyme meningitis that was treated with ceftriaxone months prior to presentation. His symptoms included progressive fatigue and shortness of breath, occasional paroxysmal nocturnal dyspnea, memory difficulties, gait disturbances, and bilateral hearing loss. Physical exam was notable for euvolemia, a grade 3/4 diastolic murmur best appreciated at the apex with bounding bilateral radial pulses, positive Quincke sign, and a wide-based, unsteady gait.

Take-Home Messages

• •This case highlights the challenges of managing patients with inflammatory vasculitis of the aortic root complicated by severe aortic valve regurgitation.
• •While immunosuppressive medications may treat the active inflammatory vasculitis of the aortic root, the lasting effects of inflammation on the cardiac valves may necessitate definitive surgical repair or replacement.

Past Medical History

Past medical history included third-degree heart block requiring permanent pacemaker placement and progressive neurocognitive decline. He underwent pacemaker placement 1 year before index hospitalization, during a work-up for a fall, which found him in third-degree heart block. The etiology of the complete heart block was not found and was initially presumed to be idiopathic. Transthoracic echocardiogram (TTE) 1 year prior to presentation revealed an ejection fraction (EF) of 65% to 70% with mild aortic regurgitation, mild mitral regurgitation, and mild tricuspid regurgitation.

Differential Diagnosis

Differential diagnosis included meningitis, infective endocarditis, nonbacterial thrombotic endocarditis, heart failure, autoimmune disease, and malignancy.

Investigations

Given his atypical neurologic presentation, he underwent a positron emission tomography–computed tomography scan that showed possible vasculitis involving the aortic root and ascending aorta. There was hypermetabolism at the level of the left ventricular myocardium, interpreted as incomplete myocardial dietary suppression (Figure 1). Brain magnetic resonance imaging revealed extensive pachymeningeal thickening and enhancement with moderate-to-marked occlusion of the intracranial dural venous sinuses.

Figure 1.

PET-CT Scan

Positron emission tomography-computed tomography scan with corresponding coronal computed tomography. Changes consistent with vasculitis involving the aortic root and ascending aorta.

Additional laboratory work-up included negative peripheral blood cultures, elevated myeloperoxidase antibodies at 0.5 U (normal limit [NL] <0.4 U), and elevated erythrocyte sedimentation rate and C-reactive protein at 52 mm/h (NL 2-20 mm/h) and 9.1 mg/L (NL ≤8 mg/L), respectively. Antinuclear antibodies, antineutrophilic cytoplasmic antibodies, and peripheral antineutrophil cytoplasmic antibodies were all normal. β₂-glycoprotein IgG antibodies were positive at 15.8 U/mL (NL <15 U/mL), and anticardiolipin antibodies were negative. The patient underwent Karius testing for his negative blood cultures to rule out culture-negative endocarditis, which was negative for microorganisms.

A TTE was obtained due to the findings of F-fluorodeoxyglucose avidity in the aorta and the new diastolic murmur. This demonstrated a severely enlarged left ventricle with an acute decrease in EF from 65% to 52% with mild generalized hypokinesis, new severe aortic regurgitation, and new enlargement of the sinus of Valsalva measuring 48 mm with effacement of the sinotubular junction compared with an echocardiogram 1 year prior.

He underwent chest computed tomography angiography that showed significant infiltrative tissue surrounding the aortic root, involving the aortic valve commissures, and associated central diastolic noncoaptation of the cusps (Figure 2). The patient underwent a subsequent transesophageal echocardiogram, which confirmed the previous TTE and computed tomography findings (Figures 3 and 4).

Figure 2.

Chest Computed Tomography Angiography

Significant infiltrative tissue surrounding the aortic root involving the aortic valve commissures and associated central diastolic noncoaptation of the cusps. L = left coronary cusp; N = noncoronary cusp; R = right coronary cusp.

Figure 3.

Transthoracic Echocardiogram

Moderately thickened aortic valve leaflets, retracted, with asymmetric leaflet thickening at the commissural insertion points. Abbreviations as in Figure 2.

Figure 4.

Transthoracic Echocardiogram With Color Doppler

Findings with aortic valve leaflet thickening and retraction with a large central coaptation defect resulting in severe aortic valve regurgitation.

Additionally, the patient underwent cardiac magnetic resonance that demonstrated globally depressed left ventricular EF of 45% with generalized hypokinesis. There was nonspecific minimal focal delayed enhancement of the basal inferior right ventricular insertion point on late gadolinium enhancement. Additionally, the basal and mid lateral right ventricular wall was dyskinetic, which was thought to be secondary to right ventricular pacing for history of complete heart block.

Management

The patient underwent an uncomplicated right frontal biopsy of his dura. Neuropathology from his biopsy was significant for extensive necrosis with macrophage infiltration and granulomatosis features with microabscesses consistent with granulomatosis with polyangiitis (GPA).

He was treated with intravenous methylprednisolone 1 g daily for 5 days followed by oral prednisone 60 mg daily with slow taper to oral prednisone 10 mg daily. He also received rituximab induction therapy with 1 g intravenous rituximab while an inpatient and received a subsequent dose 1 month later.

A repeat computed tomography 4 months later showed improving aortic root thickness with immunosuppressive therapy with a maximal root diameter of 45 mm (Figure 5). However, a repeat echocardiogram showed persistent severe aortic regurgitation and severe left ventricular enlargement at follow-up (EF 52%, left ventricular end-diastolic dimension 74 mm, left ventricular end-systolic dimension 54 mm). He underwent aortic valve replacement with a 25 mm St. Jude Medical Epic porcine bioprosthetic valve along with a mitral annuloplasty repair with a 34 mm CarboMedics partial ring. Intraoperatively, there was dilation at the sinuses of Valsalva measuring up to 45 mm and a biopsy was obtained of the noncoronary sinus. The surgical team felt that given improving aortic root thickness and stable size without obvious ongoing inflammation involving the aortic root or ascending aorta, the decision was made to not surgically intervene on the aortic root.

Figure 5.

Follow-Up Chest Computed Tomography Angiography

Overall improvement in the thickness of the aortic root after immunosuppressive therapy (yellow arrows). However, persistent soft tissue thickening is present at the valve commissure insertion points and leaflets (red arrows) resulting in central noncoaptation of the cusps. Abbreviations as in Figure 2.

The aortic valve was sent for pathology review and was notable for gross and microscopic changes consistent with postinflammatory aortic valve disease including fibrotic thickening, neovascularization, and chronic inflammation. The noncoronary cusp annulus showed fibromembranous tissue without active inflammation (Figure 6). There was no evidence of active aortitis or significant adventitial fibrosis.

Figure 6.

Surgically Resected Aortic Valve Cusps

(A) The right (R) and posterior (P) cusps show uniform, marked thickening (compared with the left [L] cusp), with concurrent scar retraction, indicative of postinflammatory changes. Low-power view of (B) a thickened semilunar valve (×50 original magnification) with (C) thick-walled neovascularization (arrows; ×100 original magnification) and (D) chronic inflammation (asterisks; ×100 original magnification). B, C, and D show hematoxylin and eosin staining.

These findings were consistent with granulomatous polyangiitis involvement of the aortic valve, which was responsible for his acutely progressive and severe aortic valve insufficiency. He responded well to immunosuppression eliminating active vasculitis on pathology, but the residual postinflammatory scarring required aortic valve replacement.

Outcome and Follow-Up

After steroids and rituximab, the patient’s neurological symptoms improved dramatically. However, after the aortic valve replacement, his left ventricular EF decreased to 30% from 52% previously. He was not treated with any beta-blockers, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockade prior to surgery but was started on goal directed medical therapy with carvedilol and losartan after surgery due to the reduced EF. A sodium-glucose cotransporter 2 inhibitor was not initiated prior to discharge due to patient cost. He was also started on warfarin for 3 months and lifelong aspirin for his aortic valve replacement. Given review of his new clinical history, it was felt that his prior complete heart block may also have represented an early manifestation of GPA on his conduction system. He was followed locally, and with appropriate goal-directed medical therapy his EF improved to 51% at 1 year after surgery.

Discussion

GPA is characterized by necrotizing granulomatous inflammatory changes affecting both small and medium vessels.¹ Typical organ involvement often manifests in both upper and lower respiratory tract and kidneys but is not confined to any one organ.² Cardiac involvement of GPA is often heterogeneous with a rare occurrence but wide range of 6% to 44%.² Cardiac GPA manifestations may present in a variety of cardiac pathologies including pericarditis, myocarditis, valvular lesions, coronary arteritis, and conduction defects.³

Most frequently, cardiac GPA involves the pericardium, resulting in pericarditis and coronary vasculitis in 50% of cases. More atypical cardiac GPA presentations include myocarditis, endocarditis, and conduction system granulomatas.⁴ In terms of cardiac valve involvement of GPA, there is typically inflammation and valve thickening present that includes surrounding tissue without evidence of mobile vegetations, abscess, or valve destruction. GPA can be a rare cause of acute aortic valve regurgitation and often mimics infective endocarditis, as in this case.²

Cardiac involvement of GPA is an independent risk factor for initial treatment resistance, disease relapse, and overall poor prognosis.² Diagnosis of GPA relies on a combination of serological markers, notably antineutrophil cytoplasmic antibodies (ANCAs) to proteinase 3, myeloperoxidase antibodies, inflammatory markers like C-reactive protein and erythrocyte sedimentation rate; urinalysis; and common radiologic findings of the sinuses, lungs, and orbits; although biopsy remains the gold standard.¹ Proposed diagnostic criteria by the American College of Radiology include urinary sediment indicating red blood cell casts or more than 5 red blood cells per high-power field, abnormal chest radiography findings, oral ulcers or nasal discharge, and granulomatous inflammation on biopsy. The presence of 2 or more of these findings is associated with 92% specificity and 88% sensitivity for GPA.¹

Management is tailored to the extent of disease involvement but consists of decreasing inflammation overall. Typically, treatment consists of an induction phase (first 3-6 months) followed by maintenance therapy, employing a combination of immunosuppressants.¹ Commonly used agents include cyclophosphamide, glucocorticoids, rituximab, azathioprine, methotrexate, and plasmapheresis. In a trial comparing rituximab and cyclophosphamide for induction of remission in ANCA-associated vasculitis, rituximab demonstrating noninferiority to cyclophasphamide and potential superiority in cases of relapsing disease.⁵

Conclusions

This case illustrates the importance of recognizing an atypical presentation of GPA while keeping a broad differential diagnosis for acute causes of aortic regurgitation, including vasculitis. The mainstay of therapy includes immunosuppression ideally with high-dose steroids initially followed by rituximab to achieve remission. While immunosuppression is often effective therapy, it may not necessarily reverse the damage that this vasculitis precipitates, particularly valvular involvement, which may require definitive valve replacement.

In this patient’s case, he presented with progressive neurocognitive decline and was found to have GPA with associated pachymeningitis, bilateral hearing loss, and large-vessel vasculitis. He was treated with both steroids and rituximab for immunosuppression, which he responded well to from a neurological standpoint, as well as showed vasculitis involvement of the aortic valve. He underwent successful aortic valve replacement for GPA involvement of his aortic valve and will continue rituximab 500 mg every 6 months for the next 2 years along with continuing his steroid taper.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

Video 1

TEE X-Plane

Mid-esophageal x-plane color Doppler view of the aortic valve in long and short axis demonstrating severe aortic valve regurgitation.