‘The imitation game’: a heart failure case report with a great diagnostic twist

Abstract

Background

Arrhythmogenic ventricular cardiomyopathy (AVC) is a hereditary cardiomyopathy that has been associated with mutations in genes encoding for components of the cardiac desmosome including desmoglein-2 (DSG-2).

Case summary

A 49-year-old male presented with decompensated heart failure and ventricular arrythmias. A cardiac magnetic resonance scan demonstrated a dilated left ventricle (LV) with severely impaired systolic function and extensive subepicardial late gadolinium enhancement in the lateral wall. An 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) scan identified myocardial uptake consistent with inflammation. Following treatment with steroids for presumed cardiac sarcoidosis, a repeat FDG-PET confirmed resolution of inflammation. A dilated cardiomyopathy/AVC gene panel, however, subsequently identified a pathogenic variant in the DSG-2 gene.

Discussion

We describe the case of a patient presenting with clinical and imaging features suggestive for cardiac sarcoidosis, however genetic testing established a diagnosis of DSG-2 associated AVC. DSG-2 mutations in AVC are associated with frequent LV involvement and heart failure. Active inflammation has been observed in other cardiomyopathies, specifically in desmoplakin cardiomyopathy which has a similar clinical course to DSG-2. To our knowledge, this is the first case of DSG-2 cardiomyopathy presenting in this manner. We encourage clinicians to have a high index of suspicion of inflammatory cardiomyopathies as a differential to myocarditis and cardiac sarcoidosis, when patients present with evidence of decompensated heart failure, arrhythmias, and active myocardial inflammation.

Learning points.

• The critical role of cardiac magnetic resonance and genetic testing in a challenging diagnosis of heart failure.

• Fluorodeoxyglucose-positron emission tomography is sensitive but not specific for cardiac sarcoidosis, and isolated cardiac sarcoidosis is rare.

• Desmoglein-2 mutations in arrhythmogenic ventricular cardiomyopathy correlate with: high penetrance, left ventricle (LV) involvement, LV dysfunction, and arrhythmias.

Introduction

Arrhythmogenic ventricular cardiomyopathy (AVC) is a hereditary cardiomyopathy that is usually inherited in an autosomal-dominant pattern and is characterized by fibro-fatty myocardial infiltration.¹ Several gene mutations have been associated with the development of AVC.² The importance of mutations in desmoglein-2 gene (DSG-2) associated with this condition was first described in 2006.³ Patients typically present with ventricular arrhythmia or aborted sudden cardiac death (SCD). Diagnosis can be challenging, as the clinical presentation can mimic other conditions such as dilated cardiomyopathy (DCM), myocarditis, and cardiac sarcoidosis. We present the case of a patient that is presented with features suggestive of cardiac sarcoidosis, but genetic testing established the diagnosis of AVC due to a mutation in DSG-2.

Summary figure

Timepoint	Clinical description
−7 months	Presentation at local hospital with decompensated heart failure
−6 months	Cardiovascular magnetic resonance imaging (MRI) showed severe biventricular impairment and extensive late enhancement
−4 months	Cardiac computerized tomography (CT) excluded coronary artery disease
Month 0	Seen in cardiomyopathy clinic at tertiary centre. Genetic testing sent
+1 month	Fluorodeoxyglucose-positron emission tomography (FDG-PET) showed significant myocardial uptake
+2 months	Patient refuses implantable cardioverter defibrillator (ICD) and cardiac biopsy. Following multi-disciplinary team discussion, he is started on steroids
+6 months	Repeat FDG-PET shows reduction in myocardial uptake
+7 months	Genetic testing identifies a pathogenic mutation in DSG-2 rectifying the diagnosis
+12 months	Well, on appropriate heart failure therapies
+24 months	Further admission with decompensated heart failure despite maximal heart failure medical therapy including sacubitril-valsartan and dapagliflozin, currently listed for heart transplantation

Case presentation

A 49-year-old Afro-Caribbean male with no past medical history was presented to his district general hospital with a 4 week history of exertional breathlessness and peripheral oedema. Physical examination revealed an elevated jugular venous pressure, respiratory rales, and pedal oedema. Blood pressure was 110/80 mmHg, heart rate was 112 beats per minute, respiratory rate was 20, and oxygen saturations were 93% on room air. He was apyrexial. His electrocardiogram (ECG) is shown in Figure 1.

Figure 1.

Twelve lead ECG demonstrating widespread T wave inversion.

A transthoracic echocardiogram showed biventricular dilatation with severe impairment of systolic function (see Supplementary material online, Video S1). A cardiac CT scan excluded significant coronary disease and a 24-hour Holter identified non-sustained ventricular tachycardia (NSVT) (Figure 2). A cardiac magnetic resonance (CMR) imaging confirmed a dilated left ventricle (LV) with severely impaired systolic function (see Supplementary material online, Video S2). There was thinning and akinesis of the lateral wall and extensive subepicardial late gadolinium enhancement (Figure 3). There was also late enhancement of both right ventricular insertion points, extending into the right ventricle (RV). Parametric mapping was not performed as this was not available at his local hospital.

Figure 2.

Twenty-four hour holter monitor tracing demonstrating non-sustained ventricular tachycardia (NSVT).

Figure 3.

Four chamber cardiac magnetic resonance (CMR) image post-contrast, demonstrating thinning and akinesis of the lateral wall and extensive subepicardial late gadolinium enhancement.

Upon successful diuresis, he was commenced on heart failure treatment with bisoprolol 3.75 mg once daily (OD), sacubitril-valsartan 49 mg/51 mg twice daily and spironolactone 25 mg OD. He was discharged home and referred to our tertiary centre specialist cardiomyopathy clinic.

At the clinic appointment, comprehensive assessment did not identify any obvious aetiology for his presentation. Detailed family history was limited, as his family lived in Nigeria. Genetic testing for AVC/DCM panel was arranged. There was no history of alcohol intake or illicit drug use. His autoimmune and viral serology screens were negative.

An 18F-FDG-PET scan was organized to investigate the possibility of sarcoidosis. This identified extensive, heterogeneous FDG uptake in the lateral wall of the LV consistent with inflammation, corresponding to the area of late enhancement seen on CMR (Figure 4). There was no extra-cardiac uptake.

Figure 4.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) images demonstrating extensive, heterogeneous FDG uptake in the lateral wall of the left ventricle (LV) consistent with inflammation, corresponding to the area of late enhancement seen on cardiac MRI. There was no extra-cardiac uptake.

The patient was offered a left ventricular myocardial biopsy to confirm the diagnosis particularly as isolated cardiac sarcoidosis is rare, however, he declined this. The patient also declined a primary prevention ICD. Following discussion in our sarcoidosis multi-disciplinary meeting, the decision was made to treat him empirically with steroids for presumed isolated cardiac sarcoidosis: (prednisolone 40 mg once a day for 4 weeks, 30 mg once a day for a further 4 weeks, and 20 mg once a day thereafter).

Three months after steroid treatment, his FDG-PET was repeated and showed no uptake in the myocardium, supporting resolution of the inflammatory process (Figure 5). The excellent response to steroid treatment provided further evidence that the diagnosis of cardiac sarcoidosis was most likely.

Figure 5.

Repeat fluorodeoxyglucose-positron emission tomography (FDG-PET) 3 months after steroid treatment demonstrating the absence of myocardial uptake.

However, a month later, the genetic screening results became available. This identified a pathogenic mutation in DSG-2, thus establishing a diagnosis of AVC, with implications not only for the patient but also for his family. Over a period of months, the steroids were weaned off and the patient remained on heart failure treatment. He continued to decline an ICD and remained stable for 6 months. However, he has recently been admitted with decompensated heart failure and is on the list for an urgent heart transplant.

Discussion

AVC, or arrhythmogenic right ventricular cardiomyopathy (ARVC) as previously known, constitutes a heterogenous disease where there is progressive atrophy of the ventricular musculature due to cumulative myocyte loss and infiltration by fibrous and adipose tissue.¹ In the most common form, the RV is predominantly affected, hence the condition was originally labelled ARVC. However, the term AVC is now preferred because biventricular involvement is frequent and isolated LV involvement can also exist.⁴ LV involvement is associated with poor prognosis.⁵

Patients with AVC typically present with palpitations, arrhythmic pre-syncope, syncope, or aborted SCD. Arrythmia is typically ventricular tachycardia with left bundle brunch block morphology; however, in LV involvement, this would be with right bundle branch block. Although presentation with RV failure symptoms is rare (6% of patients), presentation with congestive cardiac failure is not uncommon if LV involvement exists, such as in the current case.¹

Literature suggests that up to 50% of AVC cases are familial.⁶ AVC is typically inherited in an autosomal-dominant pattern. Mutations in genes encoding components of the cardiac desmosome, including those in plakoglobin, desmoplakin (DSP), and plakophilin-2 (PKP2), were described to be linked with the disease in early studies.^7–9 In 2006, Pilichou et al.³ reported an association of DSG-2 with the condition. Cardiac phenotype in these patients is characterized by typical AVC features, however, frequent LV involvement was also reported. In addition, Syrris et al.¹⁰ reported a high degree of penetrance in patients with DSG-2 mutations and confirmed that LV involvement is a prominent feature. Finally, Hermida et al.¹¹ reported that patients carrying a DSG-2 mutation are more likely to suffer a heart failure related death or require cardiac transplantation in comparison to a PKP2 mutation. The clinical picture of the patient we report is consistent with these literature findings.

In our case, multi-modality imaging allowed better understanding of the patient’s condition. The CMR offered comprehensive assessment of the structure and function of both ventricles and highlighted extensive late enhancement in the lateral wall of the LV. This raised the possibility of several differential diagnoses including DCM (Lamin A/C or Filamin-C), cardiac sarcoidosis, and myocarditis. Active myocardial inflammation on FDG-PET directed the clinicians to a diagnosis of cardiac sarcoidosis. In addition, the findings of the repeat FDG-PET following steroid treatment resulted in further confirmation bias.

To our knowledge, this is the first case described in the literature where a patient with DSG-2 AVC was presented with an inflammatory phase. Acute myocardial injury (‘hot phase’) has been observed in DSP cardiomyopathy,¹² which is a left-dominant form of AVC and displays a similar clinical course to DSG-2 cardiomyopathy. In the ‘hot phase’, patients can present with chest pain, dynamic ECG changes, and arrhythmic episodes, mimicking conditions such as myocarditis or cardiac sarcoidosis. Smith et al.¹³ showed that up to 15% of patients with DSP have episodes of acute myocardial injury, with positive troponin, normal coronaries, and LV late enhancement. In some of these patients, FDG-PET showed active myocardial inflammation which was initially misdiagnosed as myocarditis or cardiac sarcoidosis.

In conclusion, we describe the case of a patient who was presented with clinical features and imaging investigations mimicking cardiac sarcoidosis and who responded well to steroid treatment. Genetic testing in this case was crucial in establishing the correct diagnosis of AVC with an active inflammatory phase. We strongly recommend that clinicians are aware that some cardiomyopathies can present with an active inflammatory phase imitating other conditions. We also encourage the use of genetic testing when there is an index of suspicion for AVC or other inherited cardiomyopathies, as this carries great implications for both the patient and their family.

Lead author biography

I was an ST7 Cardiology SpR at the Queen Elizabeth Hospital in Birmingham at the time of writing this case report. My sub-speciality training is in CMR imaging and heart failure and I have a specialist interest in advanced heart failure.

Supplementary material

Supplementary material is available at European Heart Journal—Case Reports online.

Data availability

The data underlying this article are available in the article and in its online Supplementary material.