Cardiac sarcoidosis masquerading as ventricular tachycardia storm: a challenging diagnosis

Abstract

A 67-year-old African-American woman with remote history of complete heart block (s/p pacemaker 3 years ago) and recent onset of ventricular tachycardia (VT) (s/p VT ablation and cardiac resynchronisation therapy defibrillator upgrade 3 months ago) presented to the hospital with VT storm. Workup showed newly reduced left ventricular ejection fraction with global hypokinesis (20%) and restrictive physiology. Positive technetium pyrophosphate scan was suspicious for TTR amyloid while serological workup revealed a monoclonal gammopathy. Cardiac MRI was contraindicated given remote brain aneurysm clip. Given clinical suspicion for cardiac sarcoidosis and divergent non-invasive workup, endomyocardial biopsy was performed which showed non-necrotising granulomas consistent with cardiac sarcoidosis. She was started on steroids with clinical improvement. Cardiac sarcoidosis is a challenging clinical diagnosis, particularly in patients without extracardiac manifestations. This case highlights the importance of a detailed and thorough workup of non-ischaemic cardiomyopathy and being cognizant of infiltrative disease as it can change patient management and outcomes.

Background

The management of non-ischaemic cardiomyopathies vary widely based on the underlying cause of cardiac dysfunction. Delay in diagnosis and ultimately delay in disease modifying treatment is a common barrier to care for patients presenting with non-specific symptoms or for patients receiving fragmented care. Clinicians are tasked with entertaining a broad differential diagnosis and narrowing as new information becomes available. What’s more, positive or negative predictive values of diagnostic testing are dependent on both disease prevalence and pretest probability. As demonstrated in this case, despite a positive 99mTechnetium pyrophosphate (PYP) cardiac scintigraphy’s specificity of 85%–100% for amyloid transthyretin (ATTR) amyloidosis,^{1 2} we decided to proceed with endomyocardial biopsy (EMB) as imaging was suggestive of TTR amyloid, serologies were suspicious for AL amyloid and yet her clinical course seemed consistent with sarcoidosis. Notwithstanding her ultimate infiltrative disease diagnosed, a timely and definitive diagnosis is the crux of forming effective management plans for patients.

Case presentation

A 67-year-old African-American woman with a remote history of complete heart block and non-ischaemic cardiomyopathy presented with a 3-month history of progressive weakness and palpitations. Her clinical course was further complicated by the development of ventricular tachycardia (VT) storm (figure 1), with polymorphic VT, terminating with multiple shocks from her device.

Figure 1.

Telemetry tracings showing episode of ventricular tachycardia with different morphologies.

The patient had a history of complete heart block diagnosed at another hospital 3 years prior to presentation. Diagnostic workup at that time found left ventricular ejection fraction >65% and coronary angiography found no obstructive coronary artery disease. More recently, she had experienced VT requiring VT ablation and cardiac resynchronisation therapy defibrillator upgrade (CRT) 3 months prior to presentation at another hospital. Despite these interventions, she remained unable to perform most independent activities of daily living due to her worsening fatigue.

Investigations

Initial laboratory workup

N-terminal pro-b-type natriuretic peptide was elevated (2150 pg/mL; reference range 0–125) although clinically there were no overt signs of florid heart failure. Sequential cardiac enzymes were negative (troponin I was <0.012 ng/mL; reference range 0–0.034).

Cardiac workup

Initial ECG showed atrioventricular (AV) dual-paced rhythm with biventricular pacing with frequent premature ventricular complexes. Transthoracic echocardiography (TTE) on presentation was suspicious for restrictive physiology, showing grade 3 diastolic dysfunction with decreased mitral inflow deceleration time (figure 2),³ as well as a moderately dilated left ventricle with newly reduced ejection fraction to 20%–25% (online supplemental videos 1–3), moderately reduced right ventricular systolic function. Wall motion abnormalities were noted with anterolateral hypokinesis, inferolateral akinesis, anteroseptal hypokinesis, apicolateral hypokinesis and basal anteroseptal hypokinesis; wall motion abnormalities did not correspond to coronary territories (online supplemental videos 1–3). TTE also showed mild-moderate tricuspid regurgitation with moderate pulmonary hypertension (estimated right ventricular systolic pressure was 50–60 mm Hg). Global strain was −2.3% and not suggestive of amyloidosis (online supplemental video 4).

Figure 2.

Echocardiographic evidence of restrictive physiology. (A) Parasternal long-axis view (B) Mitral inflow E/A ratio >2.5 suggests increased blood flow peak velocity in early diastole (E) compared with peak velocity in late diastole caused by atrial contraction (A) (C) Reduced E' velocities at the lateral annulus with an E/E' ratio >14 (D) Reduced E' velocities at the medial annulus with an E/E' ratio >14.

Prior workup from outside Hospital

Outside hospital records were retrieved and noted extensive endocardial scars during her previous VT ablation in the basal to mid-lateral and inferior aspects.

Serological analysis

Serological workup found no evidence of hemochromatosis with negative infectious serologies (quantiferon tuberculosis testing, HIV, hepatitis C virus) and normal thyroid hormone profile. Further serological testing including serum and urine electrophoresis, immunofixation and free light chain (FLC) testing revealed elevated IgG kappa light chain with K/L ratio 3.9, consistent with monoclonal gammopathy with IgG Kappa.

Advanced cardiac imaging

While cardiac MRI (CMR) is a useful diagnostic tool in infiltrative cardiomyopathies, particularly cardiac amyloidosis, it was contraindicated in our patient given a remote history of brain aneurysm clip. Pyrophosphate cardiac scintigraphy was performed, which was strongly suggestive evidence of cardiac amyloidosis, with semiquantitative visual score of grade 3 and quantitative heart to contralateral lung ratio of 1.61 using American Society of Nuclear Cardiology criteria (figure 3).⁴

Figure 3.

99mTechnetium pyrophosphate (PYP) cardiac scintigraphy with homogeneous radiotracer uptake throughout the myocardium of the left ventricle, grade 3 positive with a ratio >1.5.

Differential diagnosis

The differential diagnosis for the patient’s non-ischaemic cardiomyopathy, complete heart block and VT included: infectious processes such as viral myocarditis, Chagas disease or Lyme disease; infiltrative diseases including amyloidosis, sarcoidosis or malignancy; autoimmune such as systemic lupus erythematosus cardiomyopathy; storage disease mediated including haemochromatosis; toxin mediated; endocrinological; genetic or other idiopathic cause (eg, endomyocardial fibrosis) or giant-cell myocarditis.

Treatment

While the presence of grade 3 positive PYP scintigraphy in the absence of monoclonal protein is highly specific of ATTR amyloidosis and sufficient for diagnosis without a tissue biopsy,⁴ we proceeded with EMB given the high levels of kappa FLCs consistent with light-chain amyloidosis, and also given clinical suspicion for sarcoidosis with complete heart block preceding heart failure and significant arrhythmia burden (polymorphic VT) noted on presentation. Ultimately, EMB showed confluent, non-necrotising granulomatous disease consistent with cardiac sarcoidosis (CS) (figure 4).⁵

Figure 4.

Endomyocardial biopsy showing non-necrotising granulomata with multinucleated giant cells.

Given multiple episodes of VT needing shocks from her device while inpatient, she was loaded with amiodarone, started on propranolol and CRT pacing rate was increased with resolution of electrical instability. Following diagnosis of CS, she was started on immunosuppressive therapy with oral prednisone and referred to the multidisciplinary sarcoidosis care team at our university hospital. In the setting of severely reduced left ventricular systolic function, she was also started on guideline directed medical therapy and was discharged home following clinical and haemodynamic improvement.

Outcome and follow-up

The patient developed moon facies in response to steroid monotherapy. Accordingly, she was transitioned to a tumour necrosis factor antagonist as a second line therapy. It is unclear what recovery of left ventricular function she might experience with appropriate immunosuppression. Though navigating the myriad of diagnostic tests, medication changes and outpatient specialty appointments has proven taxing, fortunately, she has remained electrically stable, has had no recurrence of VT and continues to follow with our university hospital.

Discussion

CS is often an under-recognised inflammatory disorder of unknown aetiology, characterised by non-caseating granulomatous cardiac infiltration. The most frequent clinical manifestations are conduction system disease (44% of patients first present with AV block), ventricular arrhythmias (33% of patients first present with VT or VF) and heart failure (first clinical manifestation in 18% of patients).⁵ Estimates of CS prevalence vary by geography, in the USA, it is thought to affect roughly a quarter of people with systemic sarcoidosis. The natural history of CS is not well characterised and highly variable. As in our patient, CS can occur in isolation without signs or symptoms of extracardiac sarcoidosis in approximately 25% of CS cases.⁶ Moreover, while histological confirmation is the gold standard for definitive diagnosis, EMB has a sensitivity of 20% owing to the patchy nature of disease, which can be increased to 20%–50% with electroanatomic mapping or imaging guidance.⁷ CMR typically demonstrates multifocal subepicardial and/or mid-myocardial late gadolinium enhancement, particularly in the basal and lateral segments with frequent spread to the right ventricle and sparing of the endocardial border, with excellent sensitivity and specificity for CS (100% and 78%, respectively, as reported in this study with biopsy-proved pulmonary sarcoidosis when compared with the Japanese clinical criteria).⁸ 18F-fluorodeoxyglucose positron emission tomography (FDG-PET)—which can detect perfusion deficits and match them with areas of active myocardial inflammation—is another useful imaging modality that can aid in the diagnosis of CS with about 89% sensitivity and 78% specificity (as reported in this meta-analysis when compared with Japanese clinical criteria as the gold standard).⁹ FDG-PET has an additional advantage as it can also be used to help monitor response to treatment. PYP nuclear scintigraphy currently does not have any role in the diagnosis of CS. Diagnosis of cardiac sarcoidosis relies on histological myocardial diagnosis or histological diagnosis of extracardiac tissue combined with non-invasive cardiac features suggestive of cardiac sarcoidosis (such as unexplained non-ischaemic cardiomyopathy, unexplained sustained VT, steroid-responsive cardiomyopathy or heart block, or imaging features on CMR or FDG-PET studies as elucidated above).¹⁰ As such, the true prevalence remains unknown and CS presents a unique diagnostic challenge.

Similarly, cardiac amyloidosis is another heterogeneous disorder with diverse and nonspecific clinical manifestations characterised by extracellular deposition of amyloid fibrils. These misfolded amyloid deposits usually form from transthyretin (ATTR), immunoglobulin light-chain or rarely (in less than 5% of cases) other proteins. Clinically amyloidosis usually presents with systemic symptoms including autonomic dysreflexia (eg, hereditary ATTR) or bilateral carpal tunnel syndrome (eg, wild-type ATTR). Diagnostic testing characteristically demonstrates severe left ventricular hypertrophy on echo with low voltage complexes on ECG, evidence of bi-atrial enlargement, restrictive physiology and typical strain pattern (preserved apical strain and reduced mid and basal strain) on TTE. While elevated IgG Kappa monoclonal gammopathy can be consistent with AL amyloidosis, our patient’s negative EMB (with a sensitivity of nearly 100%) ruled this diagnosis out.¹¹ It is unclear whether our patient’s serologies reflected a concurrent monoclonal gammopathy of undetermined significance or perhaps a byproduct of her systemic sarcoidosis, which has been documented to cause elevated IgG kappa light chains.¹² Our patient’s positive findings on PYP cardiac scintigraphy, while highly suggestive of cardiac amyloidosis in isolation, likely represented a false-positive finding due to confounding blood pool uptake of the radiotracer, given her low cardiac output and absence of myocardial uptake on single-photon emission CT (SPECT) images.¹³ Accordingly, our patient’s progressive disease was more consistent with CS and not attributed to cardiac amyloidosis.

The diagnostic criteria for CS hinges on clinical suspicion among patients with unexplained cardiac symptoms including conduction disease, heart failure and restrictive or dilated cardiomyopathy. If biopsy-proven extracardiac sarcoidosis is present, then advanced imaging with CMR or FDG-PET can establish the diagnosis. Isolated CS should be considered in patients under the age of 60 with unexplained infra-hisian conduction disease. Among this patient population, high-resolution CT chest in addition to CMR or FDG-PET is recommended to both assess for pulmonary and cardiac sarcoidosis. If either pulmonary or cardiac imaging is suggestive of sarcoidosis, biopsy confirmation is recommended.¹⁰

Cardiac sarcoidosis is a challenging clinical diagnosis, particularly in patients without extracardiac manifestations. EMB offers a definitive diagnosis, though generally has low diagnostic yield. This emphasises the importance of performing a full work-up of non-ischaemic cardiomyopathy, given the implications of treatment. It also underlines the importance of interpreting a diagnostic test in light of the patient’s clinical picture and pretest probability. While a positive PYP scan with negative serological workup is highly suggestive of cardiac amyloidosis, it was reflective of a false-positive test in our patient’s case, and her diagnosis would have been missed if testing would have stopped at just PYP nuclear scintigraphy. Clinical manifestations and diagnostic features of cardiac amyloidosis and sarcoidosis are summarised in table 1.

Table 1.

Concise comparison of cardiac amyloidosis and sarcoidosis

	Cardiac amyloidosis13 14	Cardiac sarcoidosis7 14
Aetiology/pathological features	Extracellular amyloid fibril deposition (mutated/native transthyretin (ATTR) or light chain deposition (AL)	Non-caseating granulomata
Clinical manifestations
Systemic	Autonomic dysreflexia, syncope, bilateral carpel tunnel syndrome, nephrotic Syndrome, gastrointestinal symptoms, cardiac thromboembolism, macroglossia.	Syncope, chest pain, fatigue, dyspnoea, fever, arthralgias, cough, lymphadenopathy, uveitis, cranial nerve palsies, pulmonary infiltrates, skin lesions.
Arrhythmias	Conduction system disease, tachyarrhythmias (most commonly atrial fibrillation).	Most common cardiac manifestation of sarcoidosis. Conduction system disease (can commonly present with high-degree AV block), tachyarrhythmias (polymorphic VT is common).
Coronary artery disease	Rare coronary microvascular amyloid deposition.	Premature atherosclerosis, vasculitis.
Cardiomyopathy	Restrictive physiology.	Dilated left ventricle or restrictive physiology.
Heart failure	Predominant biventricular involvement and right ventricular dysfunction is seen frequently.	Isolated right ventricular dysfunction is not common.
Sudden cardiac death	Infrequent (more common in AL).	Attributed to ventricular tachyarrhythmias and conduction block.
Diagnostic findings
Electrocardiography	Low voltage complexes, bi-atrial enlargement.	Conduction disease, frequent ventricular premature beats.
Echocardiography	Preserved ejection fraction (until late stage), severe Left Ventricular Hypertrophy, low-flow aortic stenosis, typical (bulls-eye) strain pattern (preserved apical strain and reduced mid and basal strain).	Variable: dilated left ventricle with reduced ejection fraction, focal oedema leading to increased wall thickness, focal dyskinesis or akinesis in a non-coronary distribution, later findings could include basal septal wall thinning and aneurysms.
Cardiac MR	Early subendocardial LGE, and later transmural LGE with abnormal gadolinium kinetics	Multifocal subepicardial, mid-myocardial LGE, particularly in the basal and lateral segments sparing endocardial border
FDG-positron emission tomography	Investigational, no established role.	Role in diagnosis of equivocal cases or helps in treatment monitoring. Patchy uptake and perfusion defects, or severe perfusion defects with no FDG uptake in advanced, fibrous disease.
PYP nuclear scintigraphy	Avid PYP radiotracer uptake (ATTR)	No role
Endomyocardial biopsy	Amorphous hyaline extracellular deposits (High sensitivity, in ambiguous cases, can help distinguish light chain amyloid from TTR amyloid through mass spectrometry).	Noncaseating granulomata (low sensitivity given patchy endomyocardial involvement).

ATTR, amyloid transthyretin; AV, atrioventricular; FDG, 18F-fluorodeoxyglucose; LGE, late gadolinium enhancement; PYP, positive technetium pyrophosphate; VT, ventricular tachycardia.

Learning points.

• Laboratory and imaging tests should always be combined with patient’s clinical history and pretest probability to help achieve accurate diagnoses. This was especially true in our case, with the divergent non-invasive data suggestive of transthyreti amyloidosis or a monoclonal gammopathy, contrasting with the clinical history suggestive of cardiac sarcoidosis. Hence, diagnostic approach should be individualised to cater to our patient’s clinical scenario and unique needs.

• Our case brings the specificity of cardiac scintigraphy into question, as the positive technetium pyrophosphate (PYP) scan was highly positive in a patient with confirmed cardiac sarcoidosis. All PYP scans should also have single-photon emission CT images available to ensure myocardial uptake, especially in patients with low-output states.

• All non-ischaemic cardiomyopathies should be worked up thoroughly, especially when there is suspicion for infiltrative disease, as management can change significantly depending on the diagnosis.