Congenital heart disease combined with Arrhythmogenic Right Ventricular Cardiomyopathy

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Arrhythmogenic right ventricular cardiomyopathy
(ARVC) is a hereditary disease usually causing sudden cardiac death in youth, which indicates the importance of diagnosis in its early stage. 2. According to the pathological and physiological changes caused by ARVC, ARVC tends to be confusing when it combines with some diseases that may also lead to right ventricular enlargement, making the diagnosis more challenging.
Novel Insights: 1. ARVC can accompany with congenital heart disease; in such occasion, careful differential diagnoses are required. 2. Only 5 cases were reported as congenital heart disease combined with ARVC; so the summary of the clinical features of these cases may provide a great reference for further practice.

Introduction
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a family disease related to syncope and sudden cardiac death. It has an estimated prevalence of 1 in 5000 in the general population [1] and characterized by ventricular arrhythmia with left bundle branch block and progressive fibrofatty infiltrations of the right ventricle. The diagnosis of ARVC is rather challenging, especially in the early stage. Here, we present an interesting case of a 58year-old male patient who was referred to us for chest tightness and shortness of breath after physical activities. After careful examination and evaluation, he was diagnosed with the atrial septal defect (ASD) while his clinical features also met the diagnosis criteria of ARVC. According to the literature review, only 5 cases (including the present case) were reported as congenital heart disease (CHD) combined with ARVC. Thus, we summarized these cases here, hoping to provide more data for further clinical practice regarding to these two diseases.

Clinical history
A 58-year-old male was referred to the hospital for chest tightness and shortness of breath after physical activities for over 40 years. His symptoms were exacerbated for 1 month. Since the patient was a 10-year-old boy, he showed decreased exercise capacity compared to his peers. He could only tolerate 200 meters' run before symptoms such as chest tightness, shortness of breath and palpitation appeared. Amaurosis sometimes appeared after physical activities but these symptoms could relieve after rest. Since 8 years ago, the patient could not tolerate 4 to 5 floor climbing. And this year, he had chest tightness and shortness of breath after only 2-floor climbing, accompanied by precardium area pain radiating to the back and shoulders. He could not lie down at night and had edema, abdominal distension, weakness and loss of appetite. The patient had a history of chronic bronchitis which was well controlled. He had been smoking for over 30 years. The family history of the patient deserves to be mentioned. His mother died of a sudden heart attack at about 50 years old. And his daughter was diagnosed with ventricular septal defect (3 mm in diameter) during the antenatal examination. His physical examination results were listed as follow. The left boundary of his heart showed expansion. Cardiac auscultation showed arrhythmia and blowing systolic murmur at 2nd-3rd intercostal space at the left margin of the sternum. Pulse deficit was obvious. No other positive signs were found.

Accessory examination
A series of examinations were carried out after the patient was admitted to the ward. His 24-hour Holter showed that: (1) atrial fibrillation with slightly slow mean heart rate, (2) frequent multi-source premature ventricular contractions, part of which were bigeminal and part paired, (3) occasional ventricular extrasystole, (4) complete right bundle branch block, (5) occasional change of T waves in partial lead connection.
The chest radiography showed an expanded heart boundary, which coincided with the physical examination. He also had an echocardiography examination ( Fig. 1A-C), which shows: (1) ASD (secondary orifice, left to right shunt), about 25.7 mm in diameter, (2) Enlargement of right atrium, right ventricle and left atrium, slightly thin right ventricular wall and irregular shape of the right ventricle, (3) uncoordinated ventricular wall movement, (4) slightly wider ascending aorta, (5) slight reflux in the mitral valve, tricuspid valve and pulmonary valve area, (6) Arrhythmia, (7) normal systolic function of left ventricular and small decrease in the function of right-side heart (EF was only for reference because of atrial fibrillation).
His cardiac MRI ( Fig. 1D-F) showed the possibility of ARVC. The routine 12-leads electrocardiogram of this patient is showed in Fig. 2A. For the purpose of proving the MRI diagnosis, a fontaine lead electrocardiogram was performed in order to show right ventricular myocardial depolarization better. Consequently, a typical epsilon wave was detected (Fig. 2B). In addition, his blood pressure pro-BNP level was elevated evidently. The gene detection related to ARVC was advised to the patient's family. However, his family refused and chose to continue the follow-up.

Therapeutic regimen
After careful consideration, we advised the patients to undergo occlusion of ASD surgery. The patient underwent this surgery and his symptoms were relieved slightly after the surgery. The follow-up was of vital importance for the patient. In addition, gene detection should still be carried out if necessary during further consultation.

Follow-up
The patient went back to the clinic for his reexamination 6 months after the surgery. His symptoms were relieved a lot and his exercise tolerance increased evidently. The patient's blood pressure pro-BNP level decreased to be normal. The 12-lead electrocardiograph showed atrial fibrillation with a low ventricular rate, incomplete right bundle branch block and abnormal T wave (Fig. 3A). The echocardiography showed the decreased cardiac size and effective occlusion ( Fig. 3B-D).

Discussion
ARVC is a type of inherited cardiomyopathy characterized by ventricular arrhythmia with left bundle branch block and progressive fibrofatty infiltrations of right ventricle. [2] Lifethreatening ventricular arrhythmia is very common for ARVC patients and it usually leads to sudden cardiac death. [3] The diagnosis of ARVC is rather complicated. According to the 2010 Revised Task Force Criteria for the diagnosis of ARVC as listed in Table 1, it is based on structural alternations, histologic character, Electrocardiograph, arrhythmic, and familial features. [4] Although the new diagnosis material is more sensitive than the original one in 1994, the diagnosis of ARVC is still challenging, especially for the patients in the early stage of disease [5] and it cannot differentiate cardiac sarcoidosis from ARVC. [6] In the case reported in this article, the patient had a large ASD. However, the patient's clinical presentation and accessory Ren et al. Medicine (2020) Table 2. [7][8][9] Through these cases, we can conclude that for the patients diagnosed with CHD, the clinical presentations of ARVC tend to be covered up. That is because ARVC and left-to-right shunting CHD at times share the common phenotype of right ventricle dysfunction despite different mechanisms of disease. [9] The process of disease can be accelerated by conditions such as physical activities which disproportionately increase right ventricle stress. [10] The study of La Gerche A et al [11] showed that even for a healthy man, chronic right ventricle stress in an otherwise healthy heart could still result in a phenotype similar to ARVC in the absence of impaired desmosome. Thus, we can hypothesize that the chronic right ventricle volume overload secondary to left-to-right shunting CHD may cause structural and electrophysiologic findings to be consistent with those of ARVC. For one thing, the diagnosis of ARVC is challenging for young patients because absent phenotypic features and the overlapping of the findings with CHD are possible. [9] For another, the symptoms of CHD patients sometimes meet the diagnosis criteria of ARVC regarding the secondary pathophysiologic change. Therefore, the early detection of CHD should be emphasized. Moreover, the cardiac MRI [12] and gene detection may assist in the differential diagnosis.
When it comes to the therapy, structural CHD may be managed with percutaneous or surgical interventions, [13] and ARVC can be controlled by activity restriction, medical therapy, and antiarrhythmic therapies. Notably, an implantable cardioverter defibrillator should be placed when necessary. [14,15] With appropriate management, mortality rates of arrhythmogenic right ventricular cardiomyopathy and CHD are both low. Therefore, careful evaluation and differentiation are of vital importance. For this patient, the results of his follow-up proved the effect of therapy. This conclusion illustrates that the treatment for CHD is useful for the relief of symptoms when the CHD is combined with ARVC. Moreover, further reexamination is still of vital importance.
The patient in this case is relatively elder among patients diagnosed with CHD combined with ARVC. And through the literature review, we summarized the similarities and differences between the 2 diseases and emphasize careful evaluation and   Table 1 2010 Revised Task Force Criteria for the diagnosis of arrhythmogenic right ventricular cardiomyopathy.

Major Minor
Global or regional dysfunction and structural alterations By 2D echo: By 2D echo: Regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (end diastole): Regional RV akinesia, dyskinesia, or aneurysm and 1 of the following (end diastole) or fractional area change 33% By MRI: By MRI: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following: Regional RV akinesia or dyskinesia or dyssynchronous RV contraction and 1 of the following: -Ratio of RV end-diastolic volume to BSA ≥110 mL/m 2 (male) or ≥100 mL/m 2 (female) -Ratio of RV end-diastolic volume to BSA ≥110 mL/m 2 (male) or ≥100 mL/m 2 (female) -or RV ejection fraction 40% or RV ejection fraction 40% By RV angiography: By RV angiography: Regional RV akinesia, dyskinesia, or aneurysm Regional RV akinesia, dyskinesia, or aneurysm Tissue characterization of wall Residual myocytes <60% by morphometric analysis (or <50% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy.
Residual myocytes 60%-75% by morphometric analysis (or 50%-65% if estimated), with fibrous replacement of the RV free wall myocardium in ≥1 sample, with or without fatty replacement of tissue on endomyocardial biopsy Repolarization abnormalities Inverted T-waves in right precordial leads (V1, V2, and V3) or beyond in individuals >14 y of age (in the absence of complete RBBB QRS ≥120ms) (1) Inverted T-waves in leads V1 and V2 in individuals A pathogenic mutation is a DNA alteration associated with ARVC/D that alters or is expected to alter the encoded protein, is unobserved or rare in a large non-ARVC/D control population, and either alters or is predicted to alter the structure or function of the protein or has a demonstrated linkage to the disease phenotype in a conclusive pedigree. differentiation. Close follow-up will be necessary for the patients. We hope that more accurate criteria and better therapy for similar cases could be put forward in the near future.