A case series on inflammatory cardiomyopathy and suspected cardiac sarcoidosis: role of cardiac PET in management

Abstract

Background

Presentation of life-threatening arrhythmias concomitantly with a new-onset non-ischaemic cardiomyopathy raises concern for an inflammatory cardiomyopathy such as cardiac sarcoidosis or cardiac manifestations of connective tissue disease. Comprehensive workup for specific aetiologies may be unrevealing except for signs of myocardial inflammation identified on cardiac positron emission tomography (PET). Here, we present five cases of such subjects and their clinical course.

Case summary

We collected clinical, imaging, pathological, and follow-up data of five subjects presenting with arrhythmias and unexplained new-onset cardiomyopathy. Mean age was 56.2 ± 5.8 years. Three subjects presented with ventricular tachycardia and two with atrial arrhythmias. Echocardiography showed a mean left ventricular ejection fraction of 37 ± 9%_. Significant coronary artery disease was ruled out in all cases as the cause of the cardiomyopathy. All patients underwent cardiac magnetic resonance imaging (MRI) and PET scan at presentation and follow-up. In all patients, cardiac MRI revealed hyperenhancement in epicardial and mid-myocardial pattern in a non-coronary distribution, while PET scan revealed fluorodeoxyglucose (FDG) mismatch defects in multiple foci in a non-coronary distribution. Right ventricular biopsy was obtained in all patients and revealed interstitial fibrosis and cardiomyocyte hypertrophy. On median follow-up of 210 days, all subjects had improvement in both heart failure symptoms and arrhythmias and repeat PET in four out of five patients showed decreased inflammation.

Discussion

A high level of suspicion for inflammatory cardiomyopathy is needed in patients presenting with new unexplained cardiomyopathy and arrhythmias. A cardiac FDG-PET should be considered for diagnosis if cardiac inflammation is in the differential. This can inform further decisions regarding targeted immunomodulation therapy that may be helpful in this cohort.

Learning points

• Acute inflammatory cardiomyopathy is a diagnosis of exclusion that clinically behaves similar to cardiac sarcoidosis. Establishing a diagnosis is challenging.

• Non-invasive imaging with cardiac magnetic resonance imaging and positron emission tomography (PET) are important diagnostic modalities, as untargeted endomyocardial biopsy has a poor diagnostic yield.

• In the presence of inflammation, identified on PET scan, and a clinical setting of arrhythmias and/or heart failure symptoms, treatment with immunosuppressive therapies and surveillance with cardiac PET can result in favourable outcomes.

Introduction

In patients presenting with new-onset non-ischaemic cardiomyopathies (NICMs), the differential diagnosis is quite broad, including inflammatory, infiltrative, or genetic aetiologies.¹ Inflammatory cardiomyopathy frequently presents with atrial and/or ventricular arrhythmias and can be separated by aetiology into autoimmune, toxic, or infectious inflammatory cardiomyopathy.² Establishing a correct diagnosis can be challenging and remains pivotal for appropriate treatment. Cardiac sarcoidosis (CS) is considered one of the more common causes of inflammatory autoimmune cardiomyopathy and accounts for around 2.5–8% of unexplained cardiomyopathies.^3–5 While echocardiography remains the screening test, the use of cardiac magnetic resonance imaging (MRI) and cardiac positron emission tomography (PET) scan has improved the detection rate for CS.^6–8 However, despite comprehensive workup, a newly diagnosed NICM suspected to be an inflammatory cardiomyopathy often eludes a definitive diagnosis. Herein we report a series of five cases of such patients, presenting with new-onset NICM with a significant burden of arrhythmias, diagnostic, and treatment challenges leading to a diagnosis, and their variable clinical course (Table 1 and Timeline).

Table 1.

Baseline characteristics and imaging findings of five patients

Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Age (years)	56	54	65	49	57
Gender	Female	Male	Male	Male	Male
Ethnicity	Caucasian	African American	Asian	Caucasian	Caucasian
Predominant arrhythmia	VT/VF	VT	AT	A fib	VT/VF
NYHA class (on initial presentation)	III	II	III	II	III
CAD	None	None	LAD stent	None	None
Physical exam
JVP (cm H2O)	8	6	6	6	8
Blood pressure	83/56	120/80	114/72	117/84	123/72
BMI (kg/m2)	20.6	30.8	30.0	31.7	38.7
Labs
BNP (pg/mL)	215	126	402	97	NA
Creatinine (mg/dL)	0.8	1.2	1.3	1.0	1.4
ACE level (unit/L, normal: 8–53 u/L)	36	7	64	24	11
Medications
Steroids	Prednisone	Prednisone	Prednisone	None	None
Steroid-sparing	MMF	No	MMF	No	No
Antiarrhythmics	Amiodarone	Mexiletine	Dofetilitide	Amiodarone	Amiodarone
Beta-blockers	Yes	Yes	Yes	Yes	Yes
ACEi/ARB	No	Yes	Yes	Yes	Yes
Diuretic	No	Yes	Yes	Yes	No
Echocardiogram	kaa332LVEF 40–45%	LVEF 30–35%	LVEF 20–25%	LVEF 20–25%	LVEF 40%
	Normal RV function	Normal RV function	Mild RV dysfunction	Mild RV dysfunction	Moderate RV dysfunction
Cardiac MRI	LVEF 50% Epicardial LGE LV septum, anterior wall, RV free wall	LVEF 50% Epicardial LGE LV septum, anterior/anterolateral walls, RV free wall	LVEF 30-35% Epicardial LGE LV septum, anterior wall, RV free wall	LVEF 49% Epicardial/mid-myocardial LGE septum, anterior, inferior walls	LVEF 45% Mid-myocardial LGE inferolateral, mid-lateral walls, and apex
PET scan Metabolic-perfusion mismatch	Basal-mid inferior wall, basal inferoseptal and anterior walls	Anterior and basal septal walls	Basal-mid anterior, anteroseptal and mid inferior walls	Basal anterolateral and anteroapical walls	Basal septal and basal inferolateral walls

A fib, atrial fibrillation; ACE, angiotensin converting enzyme; ACEi, ACE inhibitors; ARB, angiotensin receptor blocker; AT, atrial tachycardia; BMI, body mass index; BNP, brain natriuretic peptide; CAD, coronary artery disease; JVP, jugular venous pressure; LGE, late gadolinium enhancement; LV, left ventricle; LVEF, left ventricular ejection fraction; MMF, mycophenolate mofetil; MRI, magnetic resonance imaging; NA, not available; NYHA, New York Heart Association; RV, right ventricle; VF, ventricular fibrillation; VT, ventricular tachycardia.

Timeline

Treatment offered, positron emission tomography (PET) scan pre- and post-treatment, and post-treatment outcomes
Characteristics	Patient 1	Patient 2	Patient 3	Patient 4	Patient 5
Initial PET: Metabolic-perfusion mismatch	Basal-mid inferior wall, basal inferoseptal, and anterior walls	Anterior and basal septal walls	Basal-mid anterior, anteroseptal, and mid inferior walls	Basal anterolateral and anteroapical walls	Basal septal and basal inferolateral walls
Treatment plan	Prednisone and mycophenolate mofetil (MMF)	Prednisone	Prednisone and MMF [stopped due to methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia]	Close monitoring (no prednisone due to patient preference)	Close monitoring (no prednisone due to patient preference)
Repeat PET	12 months later: Resolution of previously visualized fluorodeoxyglucose (FDG) avidity and resolution of mid inferior wall perfusion defect	9 months later: Worsening of inflammation in basal septum and basal anterior walls	12 months later: New area of FDG activity in right atrium, ventricular myocardium appeared scarred (after stopping immunosuppressive regimen)	6 months later: Resolution of lateral wall FDG-uptake, persistent anteroapical defect	7 months later: Lesser inflammation in previously described segments
Treatment or follow-up outcome	Improved 1. Clinical resolution of heart failure symptoms (New York Heart Association, NYHA II)	Limited improvement 1. Clinical resolution of exercise intolerance (NYHA I)	Initial improvement (subsequent decline) 1. Initial clinical improvement of heart failure symptoms (NYHA II)	Stable (close monitoring) 1. Clinical resolution of heart failure symptoms (NYHA I)	Stable (close monitoring) 1. Clinical improvement of heart failure symptoms (NYHA II)
	2. No further sustained ventricular tachycardia (VT)/ventricular fibrillation (VF) episodes (on device interrogation)	2. No further sustained VT/VF episodes (on device interrogation)	2. No further atrial tachycardia (AT) episodes (s/p AT ablation)	2. No further atrial fibrillation (AF) episodes (s/p AF ablation) (on device interrogation)	2. No further sustained VT/VF episodes (on device interrogation)
	3. Transthoracic echo (TTE) revealed stable left ventricular ejection fraction (LVEF) 40%	3. TTE revealed slight decline in LVEF to 25%	3. TTE on 3 months: stable LVEF of 30–35%	3. TTE revealed improved LVEF of 40%	3. TTE revealed improved LVEF of 40% (from 20%) on heart failure therapy
	4. Improved inflammation on repeat PET	4. Worsening of inflammation on repeat PET	4. Worsening inflammation on repeat PET (after stopping treatment due to MSSA bacteraemia)	4. Spontaneous improvement of inflammation on repeat PET	4. Lesser degree of inflammation on repeat PET

Case presentation

Patient 1

Patient 1 is a 56-year-old Caucasian woman with a past medical history (PMH) of coeliac disease presented with an out-of-hospital cardiac arrest and was resuscitated after defibrillation for a shockable rhythm. She had more episodic ventricular tachycardia (VT) in the hospital requiring cardioversion and treatment with amiodarone and lidocaine. Initial post-resuscitation electrocardiogram showed a bifascicular block. The family history was unrevealing. The physical exam was unremarkable. Serum markers for rheumatological, infectious, and metabolic diseases were unrevealing. Transthoracic echocardiography revealed a normal sized left ventricle (LV) with reduced ejection fraction (LVEF) of 40–45%, and mild right ventricular (RV) dilation and dysfunction. Cardiac MRI (CMR) showed extensive epicardial hyperenhancement involving the left ventricular septal and anterior walls, and RV free wall (Figure 1). A computed tomography (CT) chest showed innumerable small nodules in the upper lungs and perilymphatic nodules concerning for sarcoidosis but no lymphadenopathy. A cardiac PET demonstrated metabolic-perfusion mismatch [increased FDG (fluorodeoxyglucose) uptake corresponding to myocardial segments with perfusion defects] in the basal-mid inferior wall, basal inferoseptal and anterior walls, suggestive of an acute inflammatory process (Figure 2). However, a myocardial biopsy (typical RV septal site) only showed mild myocyte hypertrophy and patchy interstitial fibrosis without evidence of granulomas or amyloid infiltrates (Figure 3). A coronary angiogram revealed normal coronary arteries. The patient was diagnosed with inflammatory cardiomyopathy. A dual-chamber implantable cardioverter-defibrillator (ICD) was placed. Empiric therapy with prednisone was initiated at 30 mg daily and then slowly tapered off over the course of 4 months. After recurrence of VT off immunosuppression, prednisone was resumed at a dose of 20 mg and mycophenolate mofetil (500 mg twice a day) was added. Further follow-up revealed significant improvement (Timeline).

Figure 1.

ECG on presentation for patient 1.

Figure 2.

ECG on presentation for patient 2.

Figure 3.

ECG on presentation for patient 3.

Figure 4.

ECG on presentation for patient 4.

Figure 5.

ECG on presentation for patient 5.

Patient 2

Patient 2 is a 54-year-old African American man with a PMH of suspected arrhythmogenic right ventricular cardiomyopathy (ARVC) with biventricular involvement (based on report of an outside hospital CMR), referred to the electrophysiology group at our centre for VT. He underwent epicardial VT ablation and subsequent ICD placement. He was referred to our heart failure group due to ongoing dyspnoea symptoms. Further evaluation is summarized in Table 1. On our review of the initial CMR images, concern was raised for an infiltrative cardiomyopathy, as opposed to ARVC. The chest X-ray showed clear lungs. Based on an acute inflammatory process suggested by the cardiac PET, his diagnosis was changed to inflammatory cardiomyopathy. Empiric steroid treatment was initiated (60 mg prednisone with a taper by 20 mg every 2 weeks, then maintenance dose prednisone at 10 mg) and resulted in an overall improved exercise tolerance within 6 weeks, and lack for further arrhythmias. Follow-up revealed limited improvement (Timeline). Additional immunosuppressive therapy was not added due to poor follow-up.

Patient 3

Patient 3 is a 65-year-old Korean man with a PMH of coronary artery disease (CAD) and intermittent atrial tachycardia, developed worsening heart failure symptoms. Detailed initial workup summarized in Table 1. The chest CT showed no pulmonary evidence of sarcoidosis. Based on an acute inflammatory process suggested on cardiac PET and unremarkable RV biopsy (negative for infiltrative disease), the patient was diagnosed with inflammatory cardiomyopathy. The patient was empirically treated with prednisone (20 mg) and mycophenolate mofetil (1000 mg twice a day) with symptomatic improvement after 3 months and a stable LVEF of 30–35%. Follow-up revealed initial improvement with subsequent decline (Timeline). Subsequently, his heart failure worsened and he eventually required implantation of a left ventricular assist device.

Patient 4

Patient 4 is a 49-year-old Caucasian man with no significant PMH presented with new-onset palpitations and an episode of syncope at work. He was found to be in atrial fibrillation (Afib). Detailed initial workup summarized in Table 1. Computed tomography chest showed a calcified granuloma in the right middle lobe but no lymphadenopathy. Based on an acute inflammatory process suggested on cardiac PET and unremarkable RV biopsy (negative for infiltrative disease), the patient was diagnosed with inflammatory cardiomyopathy. He underwent a successful Afib ablation and ICD placement (for persistent LVEF 20%). His LVEF improved to 40–45% after Afib ablation. However, the cardiac PET abnormalities persisted on repeat scan and left ventricular function remained mildly reduced. Hence, despite resolution of presumed tachycardia-induced cardiomyopathy component, we continued close monitoring for inflammatory cardiomyopathy (Timeline).

Patient 5

Patient 5 is a 57-year-old Caucasian man with a PMH of hypertension presented with palpitations; and found to have episodic VT and subsequent complete heart block. A cardiac resynchronization therapy defibrillator device was implanted for secondary prevention (and left bundle branch block). Detailed initial workup summarized in Table 1. A CT chest showed a few small scattered calcified granulomas and intrapulmonary lymph nodes. Based on an acute inflammatory process suggested on cardiac PET and unremarkable RV biopsy (negative for infiltrative disease), the patient was diagnosed with inflammatory cardiomyopathy. Given his family history of sudden cardiac arrest, genetic analyses (GeneDx Combined Cardiac Sequencing panel and ExonArrayDx) was performed that revealed no pathogenic variant. He remained stable with close monitoring (Timeline).

Discussion

In this case series, we report on the diagnostic and therapeutic challenges in five patients presenting with arrhythmias and a newly diagnosed cardiomyopathy, for which an exact diagnosis remained elusive despite comprehensive workup with multiple diagnostic tools available at a tertiary care centre. All of the patients presented with severe arrhythmias and variable degrees of left ventricular dysfunction without evidence of significant CAD (except one patient in whom presentation was not consistent with CAD and revascularization did not yield improvement). Significant heart failure symptoms (New York Heart Association II–III) on initial presentation were likely related to restrictive physiology from cardiac sarcoid (similar to heart failure with preserved ejection fraction). The serum markers for rheumatologic, infectious, and metabolic diseases were mostly negative; right heart biopsies showed signs of fibrosis but no evidence of granulomatous disease, vasculitis or active myocarditis, and cardiac MRI imaging revealed findings consistent with NICM without signs of infiltrative disease (Table 1). The only unifying findings in these patients were signs of focal inflammation on cardiac PET, which suggests an acute inflammatory process (Timeline).

Heterogeneous diseases causing cardiac inflammation through similar immunological pathways are sometimes grouped into ‘inflammatory cardiomyopathies’ that include infectious (Chagas disease, bacterial, and viral causes), autoimmune (eosinophilic, connective tissue disease related, sarcoidosis, or vasculitides) and toxic cardiomyopathies.^2,9 Some of these inflammatory cardiomyopathies are potentially treatable with varying degrees of reversibility. A stepwise diagnostic approach to assess for above-mentioned aetiologies may remain unrevealing, and as a next step, an endomyocardial biopsy is pursued in accordance with the Dallas criteria, which is known to have a poor yield¹⁰ and can often not contribute to establishing a final diagnosis.

Among the causes for inflammatory cardiomyopathies, CS has gained more attention with time, as the incidence of CS appears to be higher than previously reported.¹¹ In all of our patients, sarcoidosis was considered as a cause of new-onset arrhythmias and heart failure. However, biopsy, serology and workup for systemic signs of sarcoidosis, such as pulmonary involvement (based on lack of tissue availability for biopsy on lung imaging), remained negative. The reported sensitivity of endomyocardial and mediastinal lymph node biopsy with single or multiple attempts to diagnose CS remains variable, as low as 20%.^3,12,13

Given the poor sensitivity of the RV septal endomyocardial biopsy and invasiveness of left ventricular septal biopsy, the utility of advanced imaging in establishing a diagnosis has been assessed. In a study testing the utility of cardiac PET to identify patients at risk for cardiac events, Blankstein et al.¹⁴ found that the presence of focal perfusion defects and FDG uptake were able to identify patients at higher risk of death or VT and concluded that this imaging modality offers prognostic value superior to the Japanese Ministry of Health criteria for the diagnosis of presumptive CS and inflammation. Derived from several smaller studies, including between 20 and 70 patients, the reported sensitivity and specificity for cardiac PET to detect inflammation ranges between 85–100% and 39–91%, respectively.¹⁵ Similarly, the late gadolinium enhancement (often in the septal region) on CMR, is considered to be a hallmark sign for CS, with a reported sensitivity of 75–100% and specificity of around 77% to detect CS.^15,16 An emerging technology which may be of great value for diagnosing CS is integrated imaging with cardiac PET-MRI.^17–20

Based on our experience, we suggest routine use of cardiac PET and MRI in suspected cases of inflammatory cardiomyopathy. Our methodical diagnostic approach allowed a narrow differential diagnosis after ruling out other causes of inflammation including infectious, toxic and autoimmune disorders. This prevented a ‘mixed bag’ of disease to be grouped together. However, the suspicion of CS remained a primary concern. Ideally, an endomyocardial biopsy with imaging- or voltage-guidance should be performed to establish CS diagnosis (assuming no other extra-cardiac sources available for biopsy). In our case series, we performed biopsies at the typical RV septal site, which is more consistent with a ‘real-life’ clinical experience (a limitation and a goal of our study).

Hence, we suggest that despite a negative biopsy, treatment with immunosuppressive agents should be considered (similar to treatment of a CS patient) if the non-invasive studies are positive. Due to some inherent variability, if one is considering initiating immunomodulation therapy with biopsy negative (−), cardiac PET positive (+) in the appropriate clinical scenario, a second baseline PET scan may be considered. The response to immunosuppression treatment over and above optimal heart failure and antiarrhythmic therapies is variable. In this small group, the full spectrum is seen: improvement, spontaneous remission of inflammatory markers, lack of response and complications of immunosuppression; however, we cannot draw definitive conclusions based on the limited experience as the treatment was not randomized. There is often a difference between improvement of the arrhythmias and left ventricular function. For surveillance and assessment of treatment response, we recommend a repeat cardiac PET scan at interval of 6 months after initiation of treatment. The patients who are not candidate for, refuse to or do not respond to immunosuppressive therapy should have close clinical follow-up, and a surveillance cardiac PET at an interval of three to 6 months (sooner if the patients have recurrent and/or significant arrhythmias). In cases of clinical decline, such patients may progress to eventual myocardial scarring/burnt out cardiomyopathy and should be considered for advanced heart failure therapies.

Limitations

Given the retrospective nature of this case series, there are some limitations. The endomyocardial biopsies were performed with fluoroscopy guidance. They were not performed with guidance of voltage-mapping. Ventricular arrhythmias were reported in three patients. However, given the unstable nature of arrhythmias, 12-lead electrocardiograms were not obtained to document the arrhythmia. We report the antiarrhythmic medication use in Table 1 per clinical use. However, the eventual goal was to taper these off as possible (which is not reflected in our case series).

Conclusion

Acute inflammatory cardiomyopathy is a diagnosis of exclusion that clinically behaves similar to CS. Establishing a diagnosis is challenging but imperative as untreated inflammatory cardiomyopathy puts patients at risk for progressive heart failure and life-threatening arrhythmias, and on the flip side, empirical treatment without vigilant comprehensive workup can expose patients to potentially prolonged treatment with immunosuppressive therapy and complications thereof. Non-invasive imaging with cardiac MRI and PET are important diagnostic modalities, as untargeted endomyocardial biopsy has a poor diagnostic yield. In the presence of inflammation, identified on PET scan, and a clinical setting of arrhythmias and/or heart failure symptoms, treatment with immunosuppressive therapies and surveillance with cardiac PET can result in favourable outcomes.

Lead author biography

Dr Peter J. Kennel is a cardiology fellow at Columbia University Irving Medical Center. A graduate from University of Munich, he completed his Internal Medicine training at Weill Cornell Medicine. His research interest is in cardiac metabolism and heart failure.