The Challenges of Diagnosis and Treatment of Arrhythmogenic Cardiomyopathy: Are We there yet?

Abstract

Background: we sought to review the evolution in the diagnosis and treatment of Arrhythmogenic Cardiomyopathy (ACM), a clinically multifaceted entity beyond the observation of ventricular arrhythmias, and the outcome of therapies aiming at sudden death prevention in a single center experience.

Methods: retrospective analysis of the data of consecutive patients with an implanted cardioverter-defibrillator (ICD) and a confirmed diagnosis of ACM according to the proposed Padua Criteria, who were referred to our center from January 1992 to October 2021.

Results: we enrolled 72 patients (66% males, mean age at implant 46 $\pm$ 16 years), 63.9% implanted for primary prevention. At the time of ICD implant, 29 (40.3%) patients had a right ventricular involvement, 24 (33.3%) had a dominant LV involvement and 19 (26.4%) had a biventricular involvement. After a median follow-up of 6,1 years [IQR: 2.5-9.9], 34 patients (47.2%) had 919 sustained episodes of ventricular arrhythmias (VA). 27 patients (37.5%) had 314 episodes of life-threatening arrhythmias (LT-VA), defined as sustained ventricular tachycardia $\ge$ 200 beats/min. Considering only the patients with an ICD capable of delivering ATP, 80.4% of VA and 65% of LT-VA were successfully terminated with ATP. 16 (22.2%) patients had an inappropriate ICD activation, mostly caused by atrial fibrillation, while in 9 patients (12.5%) there was a complication needing reintervention (in 3 cases there was a loss of ventricular sensing dictating lead revision). During the follow-up 11 (15.3%) patients died, most of them due to heart failure, and 8 (11.1%) underwent heart transplantation.

Conclusions: ACM is increasingly diagnosed owing to heightened suspicion at ECG examination and to improved imaging technology and availability, though the diagnostic workflow is particularly challenging in the earliest disease stages. ICD therapy is the cornerstone of sudden death prevention, albeit its efficacy is not based on controlled studies, and VT ablation/medical therapy are complementary to this strategy. The high burden of ATP-terminated VA makes shock-only devices debatable. The progressive nature of ACM leads to severe biventricular enlargement and refractory heart failure, which pose significant treatment issues when a predominant RV dysfunction occurs owing to the reduced possibility for mechanical circulatory assistance.

Keywords: ICD therapy; arrhythmogenic cardiomyopathy; diagnosis; treatement.

Fig. 1.

Late-onset biventricular ACM in a 54-years old lady with self-terminating syncopal ventricular tachycardia, screened at 44 as mother of an ALVC proband, both with desmoplakin mutation. While ECHO and ECG were normal at 44, CMR at 54 shows: (A) fibrofatty infiltration located in subepicardic lateral wall of the LV. (B,C) Ring-like LGE located in the inferior wall and in the inferior interventricular septum. (D) Lateral wall focal areas of LGE and mild RV enlargement with anterior hypokinesia. (E) Inferior wall LGE. (F) RVOT bulging. See fragmented QRS mimicking a pseudo-epsilon wave in inferior limbs (negative in aVL) at ECG.

Fig. 2.

Proband, aged 27 years, desmoplakin mutation: poorly tolerated monomorphic VT during training. See a midlayer ring-like fibrotic tissue involvement of the LV, without RV involvement. ECG shows low-amplitude limb leads with multifocal ventricular beats stemming from the anterior LV wall.

Fig. 3.

Progressive fibrofatty replacement of the RV and later of the LV in a patient with PKP2 mutation, detected by serial ECG recordings (A) from age 44 up to 72, implanted in secondary prevention at 66 because of monomorphic VT at 210 bpm. Both ECG and CMR (B) show epicardial, midventricular and also transmural fibrotic involvement of the inferior and the posterior lateral LV wall, mimicking ischemic cardiomyopathy in the absence of coronary artery disease. The RV involvement and the progressive ECG changes along years (transition from a normal pattern to an RV and eventually to extensive LV involvement) hinted at genetic testing for the etiologic diagnosis.

Fig. 4.

48 years old male, endurance sportsman, with active sarcoidosis admitted in class 4 heart failure with recurrent slow monomorphic VTs. The ECG at admission mimics ARVC with a caricatural delayed high-amplitude epsilon wave and precordial T-wave inversion resulting in QT prolongation. Clinical improvement and partial ECG modification occurred after 30 days of steroid treatment. CMR showed biventricular enlargement and systolic dysfunction, with biventricular epicardial and midventricular LGE distribution. This case highlights the diagnostic challenges in ACM.

Fig. 5.

Freedom from ventricular arrhythmias requiring ICD therapy delivery (A,B) and from life-threatening ventricular arrhythmias requiring ICD therapy delivery (C,D).

Fig. 6.

Cycle length and distribution of ATP-terminated vs non-terminated Ventricular Arrhythmias (VA).

Fig. 7.

Freedom from the cumulative end-point of ICD therapy delivery, all-cause death, and heart transplantation (A). Freedom from heart failure-related death + heart transplantation (B).