Arrhythmogenic right ventricular 2003

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  • 1. Arrhythmogenic right ventricular dysplasia Kumaresan Dr. Kim Vaiphei
  • 2. Introduction
    • ARVD is an unusual, often familial, condition characterized by the replacement of myocardial tissue by fat and fibrous tissue.
    • The name arrhythmogenic right ventricular dysplasia (ARVD) was coined by Frank and Fontaine in 1978.
    • In 1996, WHO and the ISFC: decided that ARVD had to be considered as a manifestation of a cardiomyopathy(ARVD/C).
  • 3. Incidence/prevalence
    • ARVC/D is an important cause of ventricular arrhythmias in children and young adults.
    • 80% of the disease is diagnosed in patients younger than 40 years.
    • It is seen predominantly in males with M:F ratio 2-3:1.
      • It accounts for up to 17% of all sudden cardiac deaths in the young.
      • Prevalence - 0.02% to 0.1% (average 1:5,000) but it is dependent on geographic circumstances.
      • In certain regions of Italy and Greece (Island of Naxos), an increased prevalence of 0.4% to 0.8%.
  • 4. Pathophysiology
    • ARVD is characterized by progressive replacement of the right ventricular myocardium by fibrofatty tissue.
    • The most common location for this tissue transformation is between the anterior infundibulum, right ventricular apex, and inferior or diaphragmatic aspect of the right ventricle, the so-called “ triangle of dysplasia”.
    • Dysplasia in this region usually leads to dilatations or aneurysms having paradoxical systolic motion (expansion with systole instead of contraction).
  • 5. Triangle of dysplasia
  • 6. Genetic factors
    • ARVD is a genetic disease that have a strong familial association, with more than 30-50% of patients.
    • The most common mode of inheritance is autosomal dominant.
    • Several ARVD/C loci have been identified.
    • Mutations in plakoglobin (PKP 2) is the most common cause of ARVD/C, accounting for approximately 20% of the cases.
    • Mutations in desmoglein (DSG 2) and desmoplakin (DSP) each accounts for approximately 10 to 15 of the cases of ARVD/C.
  • 7. Chromosomal loci and causal genes Chromosome Symbol Protein Function ARVD/C 1 14q24.3 TGF  3 TGF  3 Mitotic factor ARVD/C 2 14q42.2 RYR 2 Ryanodine receptor 2 Ca channel ARVD/C 3 1q12 ARVD/C 4 2q32.1 ARVD/C 5 3p23 ARVD/C 6 10p12 ARVD/C 7 10q22 ARVD/C 8 6p24 DSP Desmoplakin Desmosomes ARVD/C 9 12p11 PKP 2 Plakoglobin 2 Desmosomes 18q12.1 DSG 2 Desmoglein 2 Desmosomes Naxos disease 17q21 JUP Plakoglobin Desmosomes
  • 8.
    • “ Disease of desmosomal dysfunction ”
    • Desmosomes bind myocardial cells to one another, providing cellular contact necessary for electrical conduction and mechanical contraction
    • Right ventricular wall and, in particular, “triangle of dysplasia”, is thin, making it prone to disruption
    • Exercise causes increased inotropy. This may worsen disruption and accelerate disease process.
  • 9. Autosomal recessive variant of ARVD/C
    • Naxos disease is an autosomal recessive variant of ARVD, described initially on the Greek island of Naxos .
    • It involves the gene that codes for plakoglobin (a protein that is involved in cellular adhesion), on chromosome 17p.
    • Naxos disease is described as a triad of ARVD, palmoplantar keratosis , and wooly hair.
    • The signs of Naxos disease are more severe than with autosomal dominant ARVD.
  • 10.  
  • 11. Etiopathogenesis
    • The exact pathogenesis of ARVD/C is unknown.
    • Basso et al proposed 4 theories that may potentially explain the development and occurrence of the disease.
    • Dysontogenic
    • Degenerative
    • Inflammatory
    • Apoptotic
    • D’Amati et al proposed a transdifferentiation theory , which is based on the hypothesis that cells can change from muscle to adipose tissue.
  • 12.
    • In the disontogenetic theory, the absence of myocardium is considered to be the consequence of a congenital aplasia or hypoplasia of the right ventricular wall, leading to a parchmentlike appearance.
    • In the degenerative theory, the loss of the myocardium is considered to be a consequence of progressive myocyte death due to some metabolic or ultrastructural defect.
  • 13.
    • In the inflammatory theory, the fibrofatty replacement is viewed as a healing process in the setting of chronic myocarditis.
    • The disappearance of the right ventricular myocardium might be the consequence of an inflammatory necrotic injury followed by fibrofatty repair.
    • Thus, an infectious and/or immune myocardial reaction might intervene in the etiology and pathogenesis of the disease
  • 14.
    • Apoptosis plays a large role and detected in biopsy and autopsy specimens.
    • Abnormal bouts of recurring or continued apoptosis lead to progressive myocardial muscle loss followed by fibrofatty replacement.
    • These apoptotic bouts may enhance the electrical vulnerability of the right ventricle, leading to potentially life-threatening arrhythmias.
  • 15.
    • The " transdifferentiation theory," suggests that cardiomyocytes transdifferentiate into adipocytes in response to stress.
  • 16. Gross
    • Anatomic malformations of RV consist of
    • Mild-to-severe global RV dilation,
    • Thinning of the RV free wall (0.3cm)
    • RV aneurysms
    • Intramural fat infiltration
    • Left ventricle and septum usually spared.
    • In contrast, the trabeculae of the apex and the right side of the ventricular septum are hypertrophied.
  • 17.  
  • 18. Histology
    • The most striking feature of the disease is the diffuse or segmental loss of myocardium with replacement by fat and fibrous tissue.
    • The disease process starts in the subepicardial region and works towards the endocardial surface, leading to transmural involvement (possibly accounting for the aneurysmal dilatation of the RV).
    • Only the subendocardial layers are preserved.
  • 19.
    • There are two pathological patterns seen in ARVD.
    • Fatty infiltration and
    • Fibro-fatty infiltration.
  • 20. Fatty infiltration
    • The first pattern, partial or near-complete replacement of myocardium by fatty tissue without wall thinning.
    • Fatty infiltration is confined to the right ventricle.
    • The left ventricle and ventricular septum are usually spared.
    • No inflammatory infiltrates are seen in this stage.
    • There is evidence of myocyte degeneration ( intracytoplasmic vacuoles and myofibrillar Loss) and apoptosis..
  • 21. Fibro-fatty infiltration
    • Later stage involves the replacement of myocytes with fatty tissue and fibrosis.
    • This leads to thinning of the RV free wall (to < 3 mm thickness).
    • The regions preferentially involved include the RV inflow tract, the RV outflow tract and the RV apex.
    • A patchy myocarditis is seen in 1/3 of cases,with inflammatory infiltrates ( T cells ).
    • Prone to aneurysm formation.
  • 22.
    • LV and IVS are also involved in the late stage of the disease.
    • Fatty infiltration of RV per se probably is a different process that may not be considered synonymous with ARVD/C.
    • Therefore, the diagnosis of ARVD/C should only be made in the presence of fibrosis, which probably is more arrhythmogenic than just fatty infiltration.
  • 23.  
  • 24.  
  • 25. Phases of ARVD
    • The concealed phase . This phase is characterized by RV changes with or without ventricular arrhythmias. It is mostly seen in young people involved in competitive sports. Sudden death is often the first manifestation.
    • The second stage of ARVD is overt electrical disorder. The RV undergoes both functional and structural changes, leading to RV arrhythmias or cardiac arrest.
    • The third phase of ARVD is RV failure. The progression of RV muscle disease leads to RV dysfunction. Left ventricular function is usually spared at this point.
  • 26.
    • The final stage is biventricular pump failure. In this final stage, the LV and IVS is also involved.
    • The progression leads to heart failure, as well as other complications such as atrial fibrillation and thromboembolic events.
  • 27. Clinical presentation
    • In as many as 80% of patients, the first manifestation of the disease is unexplained syncope or sudden cardiac death.
    • The remainder frequently present with palpitations or other symptoms due to right ventricular outflow tract (RVOT) tachycardia .
    • Symptoms are usually exercise-related.
    • The first clinical signs of ARVD are usually during adolescence.
  • 28.  
  • 29. Diagnosis
    • Begins with a thorough personal and family history, ideally of first- and second-degree relatives.
    • A personal history of palpitations, especially in a young person, or a family history of sudden cardiac death or death at an early age should raise the index of suspicion for ARVD.
  • 30. Diagnosis
    • The physical examination is normal in at least 50 percent of patients with ARVD.
    • A definite diagnosis of ARVD/C is based on histologic demonstration of transmural fibrofatty replacement of RV myocardium at autopsy or surgery.
    • Myocardial biopsy lacks sufficient sensitivity because, the biopsy is performed mostly in the IVS, whereas the typical pathologic changes of ARVD/C are more pronounced in the RVFW.
  • 31. Diagnostic Criteria
    • In 1994 , the European Society of Cardiology and International Society and Federation of Cardiology
    • scoring system based on major and minor criteria was introduced
      • Structural changes
      • Histologic tissue changes
      • EKG changes
      • Arrythmias
      • Family History
  • 32.  
  • 33. ECG
      • 10-50% have normal ECG on presentation
    • 50 to 90 % of pts with ARVD will have characteristic findings on ECG.
    • T-wave inversion in the anterior precordial leads (V1 through V6).
      • Prolonged QRS
    • Epsilon waves (30%)- best in leads V1-V3
      • VT with Complete/incomplete RBBB.
  • 34. Epsilon wave
  • 35. RV contrast angiography
    • Angiographic evidence of ARVD/C consists of akinesis/ dyskinetic bulgings localized in the anatomic triangle of dysplasia and the presence of hypertrophic trabeculae .
    • However,
      • the invasive nature of the angiographic technique,
      • x-ray exposure,
      • common occurrence of extrasystoles during contrast injection,
      • and considerable interobserver variability
    •  preclude the use of RV angiography as a primary diagnostic technique.
  • 36. Echocardiography
    • The most widely used noninvasive technique for assessing cardiac performance in ARVD/C.
    • The most conspicuous findings:
    • RV dilation, enlargement of the RA.
    • Isolated dilatation of the RVOT,
    • localized aneurysms and
    • akinesis/ dyskinesis of the inferior wall and the RV apex.
  • 37.
    • Computed Tomography
    • abundant epicardial adipose tissue
    • prominent trabeculations
    • scalloped appearance of the RV free wall
    • intramyocardial fat deposits
    • Magnetic Resonance Imaging
    • It can distinguish fat from muscle
    • It provides information about RV wall motion and function.
  • 38.  
  • 39. Uhl’s anomaly
    • Uhl anomaly was first described in 1952 by Hendry Uhl.
    • Also k/a “parchment right ventricle”
    • It is a very rare congenital heart disease charactrized by absence of the myocardial layer in the right ventricle, with apposition of the endocardium and epicardium.
    • Uhl’s anomaly is rarely familial.
    • CCF is the usual mode of presentation.
    • Arrythmias or heart blocks are rare in this condition.
  • 40.
    • Both sexes are equally affected.
    • Pts age at death ranged from one day to 84 yrs with median of 15 yrs. (In ARVD, males are commonly affected with median age at death of 33yrs).
  • 41. Pathology
    • Complete absence of myocardium in the right ventricle with apposing endocardium and epicardium.
    • No interposed adipose tissue or fibrosis.
    • No evidence of inflammation
  • 42. Exercise and ventricular arrhythmias
    • ARVD/C usually is characterized by the occurrence of symptomatic RV arrhythmias during exercise.
    • These arrhythmias that typically are induced by adrenergic stimulation.
    • During exercise testing, 50% to 60% of patients with ARVD/C show ventricular arrhythmias
    • The occurrence of arrhythmic cardiac arrest due to ARVD/C is significantly increased in athletes.
    • Particularly in certain regions in Italy, ARVD/C has been shown to be the most frequent disease (22%) leading to exercise-induced cardiac death in athletes.
  • 43. Natural history
    • Natural history of ARVD/C: cardiac electrical instability and progressive RV dysfunction .
    • Mortality rates ranged from 4% to 20%.
    • May account for up to 5% of SDs in young adults in the US and 25% of exercise-related deaths.
    • In most patients, the mechanism of SD in ARVD/C is acceleration of VT with ultimate degeneration into VF.
    • Generally, RV failure and LV dysfunction were independently associated with cardiovascular mortality.
  • 44. Treatment
    • There are five therapeutic options in patients with ARVD/C:
      • (1) antiarrhythmic agents
      • (2) radiofrequency ablation
      • (4) Heart failure treatment
      • (5) surgical treatment .