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Arrhythmogenic right ventricular dysplasia Kumaresan Dr. Kim Vaiphei
Introduction <ul><li>ARVD is an unusual, often familial, condition characterized by the replacement of myocardial tissue b...
Incidence/prevalence <ul><li>ARVC/D is an important cause of ventricular arrhythmias in children and young adults. </li></...
Pathophysiology  <ul><li>ARVD is characterized by progressive replacement of the right ventricular myocardium by fibrofatt...
Triangle of dysplasia
Genetic factors <ul><li>ARVD is a genetic disease that have a strong familial association, with more than 30-50% of patien...
Chromosomal loci and causal genes Chromosome   Symbol  Protein  Function  ARVD/C 1 14q24.3 TGF  3 TGF  3 Mitotic facto...
<ul><li>“ Disease of  desmosomal dysfunction ” </li></ul><ul><li>Desmosomes bind myocardial cells to one another, providin...
Autosomal recessive variant of ARVD/C  <ul><li>Naxos disease  is an  autosomal recessive  variant of ARVD, described initi...
 
Etiopathogenesis <ul><li>The exact pathogenesis of ARVD/C is unknown.  </li></ul><ul><li>Basso et al proposed 4 theories t...
<ul><li>In the  disontogenetic  theory, the absence of myocardium is considered   to be the consequence of a congenital ap...
<ul><li>In the  inflammatory  theory, the fibrofatty replacement is viewed   as a healing process in the setting of chroni...
<ul><li>Apoptosis  plays a large role and detected in biopsy and autopsy specimens.  </li></ul><ul><li>Abnormal bouts of r...
<ul><li>The &quot; transdifferentiation  theory,&quot; suggests that cardiomyocytes   transdifferentiate into adipocytes i...
Gross  <ul><li>Anatomic malformations of RV consist of </li></ul><ul><li>  Mild-to-severe global RV dilation, </li></ul><u...
 
Histology <ul><li>The most striking feature of the disease is the diffuse or segmental loss of myocardium with replacement...
<ul><li>There are two pathological patterns seen in ARVD. </li></ul><ul><li>Fatty infiltration and  </li></ul><ul><li>Fibr...
Fatty infiltration <ul><li>The first pattern, partial or near-complete replacement of myocardium by fatty tissue  without ...
Fibro-fatty infiltration <ul><li>Later stage involves the replacement of myocytes with fatty tissue and fibrosis. </li></u...
<ul><li>LV and IVS are also involved in the late stage of the disease. </li></ul><ul><li>Fatty infiltration of RV per se p...
 
 
Phases of ARVD <ul><li>The concealed phase . This phase is characterized by RV changes with or without ventricular arrhyth...
<ul><li>The final stage  is biventricular pump failure. In this final stage, the LV and IVS is also involved. </li></ul><u...
Clinical presentation <ul><li>In as many as 80% of patients, the first manifestation of the disease is unexplained syncope...
 
Diagnosis  <ul><li>Begins with a thorough personal and family history, ideally of first- and second-degree relatives.  </l...
Diagnosis <ul><li>The physical examination is normal in at least 50 percent of patients with ARVD. </li></ul><ul><li>A def...
Diagnostic Criteria <ul><li>In 1994 ,  the European Society of Cardiology and International Society and Federation of Card...
 
ECG <ul><ul><li>10-50% have normal ECG on presentation </li></ul></ul><ul><li>50 to 90 % of pts with ARVD will have charac...
Epsilon wave
RV contrast angiography <ul><li>Angiographic evidence of ARVD/C consists of  akinesis/ dyskinetic bulgings  localized in t...
Echocardiography <ul><li>The most widely used noninvasive technique for assessing cardiac performance in ARVD/C.  </li></u...
<ul><li>Computed Tomography </li></ul><ul><li>abundant epicardial adipose tissue </li></ul><ul><li>prominent trabeculation...
 
Uhl’s anomaly <ul><li>Uhl anomaly  was first described in 1952 by  Hendry Uhl. </li></ul><ul><li>Also k/a “parchment right...
<ul><li>Both sexes are equally affected. </li></ul><ul><li>Pts age at death ranged from one day to 84 yrs with median of 1...
Pathology  <ul><li>Complete absence of myocardium in the right ventricle with apposing endocardium and epicardium. </li></...
Exercise and ventricular arrhythmias <ul><li>ARVD/C usually is characterized by the occurrence of symptomatic RV arrhythmi...
Natural history <ul><li>Natural history of ARVD/C:  cardiac electrical instability  and  progressive RV dysfunction .  </l...
Treatment <ul><li>There are five therapeutic options in patients with ARVD/C:  </li></ul><ul><ul><li>(1)  antiarrhythmic a...
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Arrhythmogenic right ventricular 2003

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