Cardiac sarcoidosis diagnosed 7 years after detection of ventricular tachycardia during pharmacologic stress testing

Key Teaching Points.

• •This case emphasizes the importance of suspecting cardiac sarcoidosis (CS) in patients with unusual presentations of ventricular arrhythmias.
• •Diagnosing CS remains challenging even with the use of advanced imaging modalities.
• •Atypical responses to standard arrhythmia treatments should raise suspicion for underlying diagnoses.

Introduction

Cardiac sarcoidosis (CS) is a challenging and often elusive diagnosis owing to its variable presentation and dynamic nature. Palpitations and arrhythmias are common manifestations of CS, but findings may be subtle or nonspecific. The prevalence of CS is unknown; although it is recognized in only 5% of patients with systemic sarcoidosis, autopsy studies indicate that it is detectable in 20% of cases.¹ Advanced imaging techniques, including cardiac magnetic resonance imaging (cMRI) and positron emission tomography (PET), enhance the diagnosis of CS, but sensitivity may be limited, particularly in cases where the disease is localized or in its early stages. Therefore, CS is often unrecognized or misdiagnosed, causing a delay in treatment with immunosuppressive medications.

We present a case of a patient who was initially suspected of having idiopathic fascicular ventricular tachycardia (VT) after pharmacologic stress testing. She was evaluated by multiple cardiologists and electrophysiologists at 2 academic institutions and received several ablations before CS was finally diagnosed and effectively treated with immunosuppressants. This case highlights the diagnostic challenges posed by CS and emphasizes the need for maintaining a high index of suspicion while recognizing the limitations of cardiac imaging in establishing a definitive diagnosis.

Case report

A 47-year-old black woman with a medical history of hypertension presented to the family medicine clinic in July 2016 complaining of intermittent left-sided chest pains and palpitations. Family history was positive for coronary artery disease. During regadenoson infusion for stress myocardial perfusion imaging, occasional premature ventricular contractions (PVCs) were noted, and the patient developed T wave inversions, palpitations, and lightheadedness. Beginning approximately 20 seconds into the recovery period, she developed ventricular bigeminy, followed by couplet PVCs continuing for approximately 5 minutes. Subsequently, she had 18 runs of nonsustained monomorphic VT of up to 10 beats in duration, morphology of which suggested left posterior fascicular VT (Figure 1). After the last recorded episode of VT, she was monitored for an additional 17 minutes in the stress laboratory and then overnight on telemetry, with occasional PVCs but no further episodes of VT. Transthoracic echocardiogram demonstrated a structurally normal heart with preserved ejection fraction, whereas left heart catheterization revealed nonobstructive coronary artery disease. She was started on metoprolol and referred to electrophysiology for evaluation of VT.

Figure 1.

Myocardial perfusion imaging electrocardiogram. Twelve-lead electrocardiogram obtained 7’50’’ into the recovery period after intravenous administration of 0.4 mg regadenoson for myocardial perfusion imaging. Note the 9-beat run of nonsustained ventricular tachycardia with morphology consistent with left posterior fascicular ventricular tachycardia.

Because of persistent symptoms, an electrophysiologic study was performed, which demonstrated normal atrioventricular and ventriculoatrial Wenckebach cycle lengths but failed to elicit inducible VT. However, during isoproterenol infusion and burst pacing, PVCs were detected emanating from the left posterior fascicular region that mimicked template PVCs (Supplemental Figure 1). After successful pace mapping, radiofrequency ablation was performed, which eliminated the PVCs. Her palpitations improved after the ablation but did not resolve. Over the ensuing years, she had follow-up visits for palpitations and twice underwent Holter monitoring, which showed PVCs of varying frequency.

During a telehealth visit in January of 2021, the patient reported worsening palpitations, and Holter monitoring demonstrated a 5% PVC burden and 1 4-beat run of VT, along with frequent premature atrial contractions. She was managed with beta blockers and reported some improvement in her symptoms. However, 4 months later, she was found to be in ventricular bigeminy (Supplemental Figure 2). A cMRI with contrast performed to evaluate for underlying cardiac pathology was unremarkable (Supplemental Figure 3). Electrophysiology study again demonstrated normal atrioventricular and ventriculoatrial Wenckebach cycle lengths, and a second ablation targeting PVCs originating from the left ventricular free wall and lateral papillary muscle was performed in July 2021 (intracardiac recordings of template PVCs are shown in Supplemental Figure 4). During follow-up 1 month later, she was found to be in ventricular trigeminy, and a third PVC ablation was performed in October 2021 targeting the anterolateral papillary muscle; an intracardiac recording of the template PVC is shown in Supplemental Figure 5. Her postablation Holter monitoring revealed a 4% PVC burden. She remained stable until December 2022, when she presented with increasing palpitations and was found to be in ventricular bigeminy. Holter monitoring showed a 20% PVC burden; a representative tracing is shown in Supplemental Figure 6.

In January 2023, she was started on flecainide and referred for a second opinion at another academic institution; an electrocardiogram obtained on the day of that visit is shown in Supplemental Figure 7. She was considered to be nonresponsive to flecainide and received an additional ablation at that institution 2 months later. However, she returned to the cardiology clinic with ongoing palpitations and PVCs in May 2023. A fluorodeoxyglucose (FDG)-PET scan performed in June 2023 identified patchy cardiac hypermetabolic activity along with multiple bilateral hilar and mediastinal lymph nodes suggestive of active sarcoidosis, and a repeat cMRI performed the following month demonstrated subendocardial myocardial delayed enhancement in the lateral and posterolateral wall of the left ventricle and a small pericardial effusion (Figure 2). The diagnosis of sarcoidosis was confirmed by a transbronchial lymph node biopsy in September 2023.

Figure 2.

Positron emission tomography (PET) and cardiac magnetic resonance images. Four-chamber view of PET (A) and contrast magnetic resonance (B) images of the heart showing matching fluorodeoxyglucose avidity and late gadolinium enhancement in the basolateral wall (white arrows). Maximum intensity projection symmetric PET image (C) showing fluorodeoxyglucose-avid lymphadenopathy in the mediastinum and hilum (large black arrows) along with multiple foci of inflammation in the left ventricular myocardium (small black arrows).

The patient was initiated on prednisone and mycophenolate to manage CS, with marked improvement in the PVCs. A follow-up PET scan obtained in March 2024 showed resolution of cardiac inflammation, and prednisone was tapered. The patient has remained essentially free of palpitations or other cardiac symptoms since that time.

Discussion

We present a case of a young woman with palpitations and ventricular arrhythmias, initially treated with beta blockers and left posterior hemifascicle PVC ablation, who was ultimately diagnosed as having CS after multiple PVC ablations at 2 different academic medical centers. The initial cMRI study did not demonstrate evidence of CS; only after PET scanning was performed did the diagnosis come into focus. This underscores the importance of considering CS in patients with recurrent and treatment-resistant ventricular arrhythmias, despite the absence of other clinical manifestations of sarcoidosis. It also highlights the challenges in diagnosing CS and the specific utility of FDG-PET scanning in selected cases.

The temporal correlation between regadenoson infusion and VT strongly suggests that regadenoson precipitated the arrhythmia, which is particularly unusual and noteworthy for several reasons. Activation of adenosine receptors may cause transient bradycardia, associated with prolongation of the QT interval, which can induce polymorphic VT during pharmacologic stress testing.² However, this patient developed monomorphic VT more than 6 minutes after regadenoson administration, long after the peak drug effect, in the absence of bradycardia or QT prolongation. Monomorphic VT consequent to adenosine receptor activation has occasionally been reported, attributed to provocation of ischemia in patients with coronary artery disease owing to adenosine-induced coronary steal.³ This explanation also seems unlikely given the lack of demonstrable epicardial coronary artery disease. We cannot exclude the possibility of microvascular coronary artery disease in this patient; however, the long duration of time between regadenoson infusion and the development of monomorphic VT is also inconsistent with this diagnosis. Interestingly, inflammatory cells express adenosine receptors, and regadenoson has been shown to modulate inflammatory responses in vivo and in vitro, but how this might have provoked VT is unclear.⁴ The electrocardiogram captured during the arrhythmia is typical of idiopathic fascicular VT, with a right bundle branch block pattern, left axis deviation, relatively narrow QRS duration, and RS interval of < 80 ms.⁵ However, to the best of our knowledge, monomorphic VT occurring during or after pharmacologic stress testing has not been reported in patients with either idiopathic fascicular VT or CS.

Idiopathic fascicular VT is the most common form of idiopathic VT and is typically diagnosed in young adults, with a male predominance.⁶ It usually occurs in patients with structurally normal hearts, although structural abnormalities may be present, most commonly involving the interventricular septum, a location that is frequently affected by CS. Given the dynamic nature of CS, with spontaneous remission and exacerbations, it is possible that this patient’s unusual arrhythmic event during pharmacologic stress testing was a manifestation of CS.⁷

When the patient was later found to have frequent PVCs with more than 1 morphology, CS was considered given its prevalence in the Southeastern United States and among black women. Other considerations included coronavirus disease myocarditis, which was prevalent at the time, and other etiologies of viral myocarditis. A contrast-enhanced cMRI, which is reported to have high sensitivity and specificity for CS and myocarditis, was unremarkable, and the patient underwent 3 more ablation procedures before an FDG-PET scan was obtained, which ultimately led to the correct diagnosis. Another cMRI was obtained and demonstrated delayed enhancement in the inferior and lateral walls consistent with areas of fibrosis, abnormalities that could be compatible with CS. T2-weighted images showed a suggestion of edema in the anterolateral wall (not shown). It should be noted that T1 and T2 mapping, which can increase sensitivity to detect cardiac inflammation, was not performed on either of the cMRI studies. However, detection of inflammation alone is a nonspecific finding that cannot distinguish sarcoidosis from other diseases, such as viral myocarditis.

Multiple studies have compared the accuracy of cMRI and FDG-PET scans for diagnosing CS. A meta-analysis found that although both have similar specificities (85% for cMRI and 82% for FDG-PET), cMRI tends to have higher sensitivity than FDG-PET (95% vs 84%).⁸ Proper preparation is crucial to obtain high-quality FDG-PET scans, but patients have difficulty complying with the low-carbohydrate, high-protein diet needed to minimize background cardiac FDG activity,⁹ which can affect diagnostic accuracy. This case report indicates that cMRI has limitations, too, given that its ability to detect diseases such as CS depends on the disease stage, extent of inflammation, and timing of the study. At the time of the initial cMRI, the disease was not advanced enough to cause fibrosis. Therefore, no delayed enhancement was seen. In mild cases of CS, FDG-PET may be better at detecting cardiac inflammation, whereas the superior spatial resolution of cMRI may be better suited for identifying fibrosis that occurs in advanced disease.¹⁰ In addition, FDG-PET scanning can be beneficial for establishing a definitive diagnosis owing to its ability to detect lymph nodes suitable for biopsy. Here, the patient’s FDG-PET scan identified bilateral hilar and mediastinal lymph nodes, leading to a confirmed diagnosis of sarcoidosis through transbronchial lymph node biopsy.

Conclusion

We present an unusual case of a patient initially presenting with PVCs and monomorphic VT detected during regadenoson administration for pharmacologic stress testing. The patient underwent multiple PVC ablation procedures before finally being diagnosed as having CS 7 years later. This case illustrates the importance of maintaining a high index of suspicion of CS in patients with unexplained ventricular arrhythmias and understanding the critical role and limitations of advanced cardiac imaging techniques in establishing the diagnosis.

Disclosures

The authors have no conflicts of interest to disclose.