Arrhythmogenic right ventricular cardiomyopathy is a hereditary disease characterized by progressive replacement of the myocardium by adipose and fibrous tissue, predisposing people to ventricular tachycardia and sudden cardiac death (SCD). Fontaine et al.1 were the first to describe arrhythmogenic right ventricular cardiomyopathy in 1977, and a preliminary description of its clinical profile followed 3 years later.2 These pioneer studies paved the way for others, which helped establish arrhythmogenic right ventricular cardiomyopathy as a cardiomyopathy mainly affecting the right ventricle. The involvement of the left ventricle (LV) was considered only as a late manifestation, and only recently have 3 patterns of the disease been recognized: the classic subtype, with its well-known predilection for the right ventricle; the biventricular variant, defined by parallel involvement of both ventricles; and left dominant arrhythmogenic cardiomyopathy (LDAC), characterized by the early and predominant involvement of the LV. The 3 categories show similar age distributions, lending support to the premise that the patterns are independent and coexist in the arrhythmogenic right ventricular cardiomyopathy population.3 The disease is, therefore, increasingly being referred to as arrhythmogenic cardiomyopathy (AC).2,4

LDAC is characterized pathologically by fibroadipose replacement of the LV, often occurring as a circumferential band in the outer third of the myocardium and on the right side of the interventricular septum.5 This fibrofatty infiltration predisposes patients to LV dysfunction and life-threatening ventricular arrhythmias. There are few data in the literature about this entity, with only isolated reports4,6–12 since Sen-Chowdhry et al.5 first established the clinical diagnostic features of LDAC in 2008. These include unexplained T-wave inversion in V5, V6±V4, I, and aVL on electrocardiogram (ECG); arrhythmias such as sustained or nonsustained ventricular tachycardia of right bundle branch block configuration, documented on ECG or Holter monitoring or during exercise testing; frequent ventricular extrasystoles (right bundle branch block morphology); LV aneurysms on imaging study, mild LV dilation and/or systolic impairment (with arrhythmic presentation); biopsy-proven myocyte loss with fibrofatty replacement; and cardiac magnetic resonance (CMR) imaging that shows LV late gadolinium enhancement (LGE) (with subepicardial/midwall myocardial distribution).

Although to date the reported prevalence of LDAC is low, this may be due to under-recognition. The aim of this study was to describe the most frequent forms of clinical presentation of LDAC, imaging findings and events at follow-up, highlighting the importance of CMR.

We included 74 consecutive patients (mean age, 48.6 years; 50 men [67.6%]). Hypertension was present in 20.3% of the patients, and diabetes in 6.8%. ECG changes (T-wave inversion in I, aVL, II, III, aVF leads) were present in 47.8% of the patients. Baseline characteristics are shown in table 1.

Indications for CMR studies are described in table 2. The most frequent indications in symptomatic patients were chest pain with normal coronary angiography, ventricular arrhythmias, and suspicion of cardiomyopathies in the echocardiographic study. The largest percentage was the group of patients referred for family screening of AC (31.5%).

Cardiac magnetic resonance findings

The most frequent morphological CMR findings were midwall and/or subepicardial pattern of LGE (91.9%), fatty epicardial infiltration (83.8%), and LV segmental contractility abnormalities (47.9%) (table 2). Mean left ventricular ejection fraction was 47.6% (standard deviation 11.8) and 47.3% were dilated (indexed by body surface). In almost half of the cases, the previous echocardiogram was normal. RV systolic dysfunction (right ventricular ejection fraction <50%) was present in 16 patients (21.6%).

The most frequent location of the fibrosis was the inferior and inferolateral walls (n=64), while the involvement of the septum was less frequent. The amount of LV fibrosis was strongly related to the amount of fatty infiltration. In fact, they both had a similar distribution. Fatty infiltration was observed differently depending on the acquisition plane: in short-axis cine views, it was depicted as a circumferential subepicardial band of fatty tissue, usually on the inferior and lateral walls (further demonstrated with T1-weighted images) (figure 1); in 2-, 3- and 4-chamber cine images, it appeared as focal epicardial contour irregularities, which we called “the rat-bite sign” after the resemblance to a piece of cheese bitten by this animal (figure 2).

Figure 1.

Short-axis still cine image and T1-weighted image showing myocardial thinning on the inferior and lateral walls at the expense of a circumferential band of subepicardial fatty infiltration (arrows).

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Figure 2.

2-chamber, 3-chamber and 4-chamber still cine images showing focal epicardial contour irregularities (arrows) in relation to subepicardial foci of fatty infiltration: the “rat-bite” sign.

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Patients with more LV segments affected by fatty infiltration and fibrosis were more likely to have depressed LV function and higher LV volumes.

To date, this is the largest published series of patients with LDAC diagnosed by CMR. In our experience, CMR is an invaluable tool for diagnosing this entity. The main results of our study are as follows. First, subepicardial fatty infiltration (better displayed on 2-, 3- and 4 chamber-view cine images as irregularities on the epicardial contour, in a pattern we call “the rat-bite sign”) was present in 83.8% of cases. Secondly, midwall-subepicardial LGE was observed in 91.9% of patients, usually affecting the inferior and lateral walls and frequently extending to the anterior and septal walls. Third, the prognosis of this population was poor, with a high incidence of SCD and ventricular arrhythmias. Finally, there was a high proportion of genetic tests that were positive for LDAC (72% of the probands).

In 1994, the Task Force criteria were established for arrhythmogenic right ventricular cardiomyopathy.13 These were modified in 2010 and included numerous structural, histopathological, electrocardiographic, familial, arrhythmic, and genetic parameters.14 However, these criteria were derived from cohorts with right ventricular forms of the disease, since biventricular or left dominant patterns had not yet been contemplated. This means that the criteria could potentially be inadequate for a significant proportion of patients whose disease followed these other patterns.

In 2008, Sen-Chowdhry et al.5 established the clinical diagnostic features of LDAC. Since then, only a few reports describing isolated cases4,6–11 or certain genetic mutations associated with the entity12,15–17 have been published.

In the retrospective series of patients with sudden death due to AC by Miles et al.,18 70% of the patients showed biventricular involvement at autopsy, and none of these would have met the Task Force criteria. Therefore, left ventricular variants of arrhythmogenic cardiomyopathy may evade clinical detection using current diagnostic tools. We believe this should be addressed in future revisions of the Task Force criteria. Furthermore, in this same series, over half of the decedents diagnosed with cardiomyopathy in life were labelled as having dilated cardiomyopathy but showed pathological features of AC at autopsy. The overlap between dilated cardiomyopathy and AC may present several diagnostic challenges, especially if the only available imaging technique is echocardiography. Thus, CMR is of the utmost importance in the diagnosis of this entity, enabling the detection of fatty infiltration and fibrosis.

In our series, fatty infiltration was present in 83.8% and late enhancement in 91.9% of our patients. Fibrosis, which has a greater presence on the inferolateral wall, could indicate the onset of disease in these myocardial segments. We identify a new sign, named “the rat-bite,” which has not yet been described in the literature. The characteristic subepicardial fatty infiltration found in macroscopic samples of patients with LDAC (figure 3) is very well depicted on cine-MR images as focal epicardial contour irregularities that resemble bitten cheese. This feature is always associated with LGE (figure 4), representing the fibrofatty infiltration, and it is highly specific to this entity. This sign can be highly useful for diagnosing patients with LDAC. Patients with the biventricular pattern of the disease show similar signs.

Figure 3.

Heart macroscopy (short-axis cut) of a patient with left dominant arrhythmogenic cardiomyopathy. Foci of subepicardial fatty infiltration (arrows) as well as midwall-subepicardial fibrosis (arrowheads) can be observed (courtesy of Dr Beatriz Aguilera).

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Figure 4.

Short-axis still cine image (upper left) showing myocardial thinning on the inferior and lateral walls (arrows) and corresponding LGE image (upper right) in which subepicardial fibrosis can be demonstrated on those locations (arrowheads). Likewise, on the lower images, epicardial contour irregularities on the lateral wall can be demonstrated (arrows) on the 4-chamber still cine image (lower left) and fibrosis in the same location (arrowheads) on the LGE image (lower right). LGE, late gadolinium enhancement.

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The clinical presentation of LDAC is heterogeneous, and its diagnosis can be challenging. In our series, the main indications for a CMR study were sustained ventricular arrhythmias, chest pain with normal coronary angiography or suspected myocarditis, and dilated cardiomyopathy. About 10 years ago, we were satisfied with signs such as chest pain with normal coronary arteries and mild troponin elevation. If there was a minimal history of infection (eg, gastroenteritis, a cold), patients were diagnosed with myocarditis, and no further analysis or follow-up were indicated. Patients with a normal echocardiogram who were otherwise asymptomatic were discharged. Recently, myocardial infarction with no obstructive coronary atherosclerosis (MINOCA) guidelines have shed some light on the approach to patients with chest pain, troponin elevation and a normal coronary angiogram.19 Nowadays, in our area (which includes 1 tertiary hospital and 5 secondary hospitals), patients with chest pain and normal coronary arteries usually undergo a CMR study, either during admission or shortly after discharge. Many patients receive a final diagnosis of infarction with normal coronary arteries, myocarditis or, less frequently (but no less importantly) AC.

We consider showing the prognostic impact of this disease to be of utmost importance. Arrhythmogenic right ventricular cardiomyopathy has a poor prognosis in the mid-term, with a high incidence of major events,20 but the prognosis of LDAC was heretofore unknown. At a mean follow-up of 3.74 years, 24 of our patients (32.4%) had a MACE, including SCD in 8.1%, sustained ventricular arrhythmias in 21.6%, and heart transplant in 4.1%.

Thus, a novel contribution of this report is a list of prognostic predictors that could be very useful in the clinical follow-up of these patients. A CMR study showing severe LGE (> 15 affected segments) (aHR=3.77), independently predicts the appearance of MACE, as well as other clinical factors such male sex (aHR=7.99), and sports practice (aHR=6.60).

Another aspect to highlight is the relevance of the genetic study. In our series, 72% of the genetic studies performed in probands were positive for mutations related to this entity, helping to confirm the suspected diagnosis and to establish the basis for family screening. Relatives with positive mutations may undergo a stricter follow-up and receive behavioral advice, for example to avoid sport, even in the absence of structural findings, with the aim of slowing down disease development.

The natural history of LV involvement in AC is poorly understood. There have been series showing no association between LV involvement and age at death. In addition, the macroscopic appearance of the heart at autopsy corroborates imaging studies that suggest that LV involvement may occur at an early stage.18 Therefore, we should be cautious with the relatives of patients with AC who have negative image tests but positive gene mutations. In our series, there were 2 such relatives of patients with AC, whose young age could explain the absence of structural findings. For these patients, we consider follow-up mandatory to monitor their progress and, if needed, offer them appropriate therapy.

Another issue we find crucial is direct communication between the CMR expert and the clinician, going beyond isolated consultation on image findings. Other diagnostic criteria must be investigated further and genetic tests requested when needed. Synergy between the physician who analyzes the images and the attending clinician who treats the patient is necessary to enable early intervention and correct screening of family members. This symbiosis, grounded in a good understanding of both radiological findings and other clinical parameters (family history, personal history, clinical, follow-up), also favors the avoidance of potentially erroneous oversensing.

CMR is a key tool for diagnosing LDAC: subepicardial fatty infiltration is present in about 83.8% of patients, and midwall-subepicardial LGE in about 91.9%, usually affecting the inferior and lateral walls. The prognosis of this population is poor with a high incidence of SCD and ventricular arrhythmias. The presence of a positive genetic test in patients with LDAC diagnosed by CMR is very high (72%).

One contribution of this study is the identification of a characteristic image finding—irregular epicardial contour seen on CMR cine images, denominated here as “the rat-bite sign”—which we describe for the first time. Revisions of AC diagnostic criteria could consider this as one of the included image features.

None declared.