Case Discussion <Brief History> A 59-year-old man was admitted due to sudden onset of dyspnea and chest discomfort for two hours. The patient had a medical history of gouty arthritis and hypertension for 20 years that were controlled on a regular basis with regular medical control. He denied other systemic diseases or major operation history. He had suffered from intermittent chest discomfort and palpitation since his mid thirties. The frequency of palpitation was about 3 times per month, and the duration was less than 1 hour and could be shortened by rest. He underwent several times of 24-hour Holter ambulatory electrocadiography (ECG), which reported no significant findings. He had been regularly followed up at the out-patient clinics since 14 years ago. The baseline ECG showed a normal sinus rhythm with T wave inversion in leads V1-4 (Figure1 ). His blood pressure was controlled around 140/90 mmHg with medication. Echocardiography revealed mild septal hypertrophy without systolic and diastolic dysfunction. Treadmill test failed to document any cardiac ischemia. However, intermittent chest discomfort persisted in recent years without symptoms of heart failure and exercise intolerance. The patient worked in a parking lot. He occasionally drank with his friends. He denied a family history of cardiac arrhythmia or sudden death or a personal history of recent traveling or animal contact. He suffered from sudden onset of palpitation and chest discomfort after swimming about 50 meters on the day of admission, which was followed by severe exertional dyspnea. The symptoms lasted for 2 hours and could not be relieved by rest. He drove to our emergency room by himself. Physical examination revealed an acute ill-looking man with an alert consciousness. The body temperature was 35oC, the heart rate was 200bpm, the blood pressure was 79/40 mmHg, and the respiratory rate was 24 per minute. The other physical examinations were all unremarkable. ECG showed a wide QRS complex tachycardia with a ventricular rate of 222 bpm, a QRS interval of 254ms, and a monomorphic left bundle-branch-block configuration (Figure 2).Chest roentgenogram revealed cardiomegaly with enlargement of the right atrium (Figure 3 ). A total of 18mg adenosine and 150mg amiodarone were administered intravenously, but the arrhythmia persisted. Due to the unstable hemodynamic status, electrical cardioversion of 100J was given which restored sinus rhythm to a rate of 66bpm. The blood pressure was stabilized to around 110/70mmHg. Cardiac enzyme was elevated mildly after the cardioversion. He was then admitted to the intensive care unit for further treatment After admission, IV infusion of amiodarone was continued for 48 hours. No more ventricular tachycardia was noted and no chest discomfort was complained after sinus rhythm was restored. Serial ECG follow-up showed no evolutional change. Echocardiography showed a dilated right ventricular (RV) chamber, a normal left ventricle (LV) size with preserved LV systolic function (ejection fraction: 64%) and mild mitral and tricuspid regurgitation. Both the treadmill exercise test and the coronary angiography were normal excepted that the RV angiogram showed an aneurysm near the RV apex (Figure 4). Programmed electrical stimulation failed to induce sustained or nonsustained ventricular tachycardia (VT), but the signal average ECG revealed a positive late potential. Due to the impression of arrhythmogenic right ventricular dysplasia (ARVD), magnetic resonance imaging (MRI) was arranged, which revealed diffuse fatty infiltrations and dyskinesis of the RV wall (Figure 5 ). According to the criteria, ARVD was diagnosed. Internal cardioverter defibrillator (ICD) was implanted smoothly, and he was discharged in stable condition. <Laboratory Examination> 1. Hemogram   WBC RBC Hb Hct MCV MCH MCHC Platelet   K/ul M/uL g/dl % fL Pg g/dl K/ul 940731 9.11 5.38 15.8 46.5 80.4 29.3 36.4 407   Band Seg . Eos Baso Mono Lym Aty.Lym   % % % % % % % 940731 0 58.7 1.1 0.4 4.3 35.5 0 2. Biochemistry   Na K BUN Cr Mg Ca AST   mmol/L mmol/L mg/dl mg/dl mg/dl IU/L U/L 940731 135 5.5 (H8) 14.3 1.4 0.98     940801 131 4.4 12.7 1.1 0.9 2.03 22   T cho. HDL LDL TG UA   mg/dL mg/dL mg/dL mg/dL mg/dL 940801 212 24 150 134 5.9     CK CKMB TnI Date Time (post S/S) U/l U/l Ng/ml 0731 1500 (4hr) 186 21.5 1.69 0731 1900 (8hr) 245 30.8 36.6 0731 2331 (12hr) 321 34.3 4.43 0801 0525 (18hr) 320 29.3   0801 1110 (24hr) 277 29.3   0801 1915 (32hr) 260 24.4 2.36 0802 0100 (38hr) 220 18.2 1.65 0802 1452 (50hr) 165 12.3 0.493 3. PT/PTT   PT INR PTT   sec sec 940731 11.2 0.97 24.1 4. Urinalysis (94/7/31) Appearance Sp. Gr pH Protein Glucose Ketones Urobil Yellowish 1.01 7.0 - - - 0.1 RBC WBC Epithelial Cells O.B. Bil. Bact 0-1 0-1 0-1 - - - <Heart MRI> Diffuse fatty infiltrations in the RV lateral wall, more severe in the basal anteior segment Dyskinesis of the RV wall with multiple small out-pouches during systole is noted. Diffuse delayed myocardial hyperenhancement in the RV lateral wall <Discussion> ARVD is an inherited disorder characterized by the progressive fibrofatty replacement of RV myocardium, initially with typical regional and later global right and some LV involvement, with relative sparing of the septum. The replacement of myocardial tissue with fat or fibrous tissue appears to involve three different mechanisms, including transdifferentiation of myoblasts into adipoblasts, apoptosis, and an inflammatory process. A familial history of ARVD is present in 30% to 50% of cases. The most common pattern of inheritance is autosomal-dominant, although an autosomal-recessive pattern has also been reported. In molecular genetics, several genetic loci and mutations associated with this disease have been discovered. Mutations in genes encoding desmoplakin and plakoglobin suggest that altered integrity at myocyte cell-cell junctions may promote myocyte degeneration and death. It occurred with the repair process consisting of replacement of myocardium by adipose and fibrous tissue. Mutations in the gene encoding the cardiac ryanodine receptor suggest that cytoplasmic calcium overloading may explain the arrhythmic characteristic of ARVD. Clinically, ARVD manifests by means of a wide spectrum of presentations, ranging from isolated premature ventricular beats to sustained VT or ventricular fibrillation (VF) that leads to sudden death. ARVD account for 3% to 10% of unexplained sudden cardiac death at the age of less than 65 years. Diagnosis of ARVD remains a clinical challenge, especially in the early stages. Echocardiographic or angiographic examinations provide the function and morphology of RV. However, it is still difficult to diagnosis in patients with minimal RV abnormalities. Endomyocardial biopsy is the gold standard but the sensitivity is low. Samples are usually taken from septum where ARVD uncommonly involved. MRI is a promising technique for determination of the anatomy, function, and tissue character of RV. However, diagnostic sensitivity and specificity of MRI still need to be defined. Standardized diagnostic criteria have been proposed by the Task Force of the Working Group on Myocardial and Pericardial Disease of the European Society of Cardiology, as well as by the Task Force on the Scientific Council on Cardiomyopathies of the World Heart Federation. The diagnostic criteria involve global and/or regional dysfunction and structural alterations, tissue characterization of walls, repolarization abnormalities, depolarization/conduction abnormalities, arrhythmias, and family history. The diagnosis of ARVD is based upon 2 major criteria, 1 major plus 2 minor or 4 minor criteria A wide range of prognoses from a long-term favorable outcome to adverse events including sudden death and heart failure has been suggested. There are several predictors of worse outcome of patients with ARVD: LV involvement, the presence of RV or LV dysfunction, a history of VT, and a history of syncope. The treatments of ARVD include drugs, catheter ablation, operations and ICD implantation. Management of patients with ARVD is individualized and depends on the risk of patients. Patients with low risk are usually treated empirically with antiarrhythmic drugs, including amiodarone, sotalol, s-blockers, flecainide, and propafenone, alone or in combination. In patients with higher risk, antiarrhythmic drug therapy guided by programmed ventricular stimulation with serial drug testing may be more reliable. Non-pharmacological therapy, including catheter ablation, operation, and ICD use, is reserved for patients with life-threatening VT or VF in whom drug therapy is ineffective, or is associated with serious side effects. ICD is the only effective safeguard against sudden death in the ARVD patients. In patients with very high risk, especially in survivors of cardiac arrest or in patients with a history of ventricular tachycardia with hemo-dynamic compromise, ICD implantation should be encouraged. 繼續教育考題 1. (A) Which part of myocardiaum is involved in early stage of ARVD? A RV B LV C Septum D Atrium 2. (D) In ARVD, which mechanism is not involved in the replacement of myocardial tissue with fat or fibrous tissue disease? A Transdifferentiation of myoblasts into adipoblasts B apoptosis C Inflammatory process D Myocardial ischemia 3. (C) Which way of inheritance can be found in ARVD? A Autosomal-dominant B Autosomal-recessive pattern C Both D Neither 4. (D) Which of the following gene mutation is associated with ARVD? A genes encoding desmoplakin B genes encoding plakoglobin C gene encoding the cardiac ryanodine receptor D All above 5. (D) Which of the following could be the initial symptoms of ARVD? A Palpitation B Syncope C Sudden cardiac death D all above 6. (C) Which of the following is not useful in diagnosing ARVD? A Echocardiogram B Endomyocardial biopsy C Treadmil D Cardiac MRI 7. (D) According to the standardized diagnostic criteria proposed by Task Force of the Working Group on Myocardial and Pericardial Disease of the European Society of Cardiology, which of the following is not taking into consideration in diagnosing ARVD? A Global function of RV B Repolarization abnormalities, C Depolarization or conduction abnormalities D Coronary artery patency. 8. (D) Which of the following is associated with a poor outcome of ARVD? A LV involvement B RV dysfunction C a history of VT D  All above 9. (C) Which of the following condition should the physician consider to use non-pharmacological therapy, such as catheter ablation, operation, or ICD in treating patients with ARVD? A Drug refractory VT B Serious side effects when taking anti-arrhythmic agents C  Both D None 10. (C) In survivors of cardiac arrest with a diagnosis of ARVD, which of the following treatment is most suitable? A Medication only B Catheter ablation only C ICD implantation D Over-drive pacing by pacemaker 答案解析  (A ) ARVD is characterized by the progressive fibrofatty replacement of RV myocardium, initially with typical regional and later global right and some LV involvement, with relative sparing of the septum. (D ) The replacement of myocardial tissue with fat or fibrous tissue appears to involve three different mechanisms, including transdifferentiation of myoblasts into adipoblasts, apoptosis, and an inflammatory process.  (C ) The most common pattern of inheritance is autosomal-dominant, although an autosomal-recessive pattern has also been reported. (D ) In molecular genetics, several genetic loci and mutations associated with this disease have been discovered. Mutations in genes encoding desmoplakin and plakoglobin suggest that altered integrity at myocyte cell-cell junctions may promote myocyte degeneration and death. It occurred with the repair process consisting of replacement of myocardium by adipose and fibrous tissue. Mutations in the gene encoding the cardiac ryanodine receptor suggest that cytoplasmic calcium overloading may explain the arrhythmic characteristic of ARVD. (D) Clinically, ARVD manifests by means of a wide spectrum of presentations, ranging from isolated premature ventricular beats to sustained VT or ventricular fibrillation that leads to sudden death. (C ) Echocardiographic or angiographic examination could provide the function and morphology of RV. Endomyocardial biopsy provides the pathological document of ARVD. MRI is a promising technique for determination of the anatomy, function, and tissue character of RV. Treadmil is not a useful tool in diagnosing ARVD. (D ) Standardized diagnostic criteria have been proposed by the Task Force of the Working Group on Myocardial and Pericardial Disease of the European Society of Cardiology, as well as by the Task Force on the Scientific Council on Cardiomyopathies of the World Heart Federation. The diagnostic criteria involve global and/or regional dysfunction and structural alterations, tissue characterization of walls, repolarization abnormalities, depolarization/conduction abnormalities, arrhythmias, and family history. (D ) There are several predictors of worse outcome of patients with ARVD: LV involvement, the presence of RV or LV dysfunction, a history of VT, and a history of syncope. (C ) Non-pharmacological therapy, including catheter ablation, operation, and ICD use, is reserved for patients with life-threatening ventricular arrhythmias in whom drug therapy is ineffective, is associated with serious side effects, or is not applicable because clinical ventricular arrhythmias cannot be reproducibly induced during electrophysiological study. (C ) ICD is the only effective safeguard against sudden death in the ARVD patients. In patients with very high risk, especially in survivors of cardiac arrest or in patients with a history of ventricular tachycardia with hemo-dynamic compromise, ICD implantation should be encouraged.