Burn-out rheumatic mitral valve disease: Morphology and predictability of repair

1. Burn-out rheumatic mitral valve disease: Morphology and predictability of repair Charité DHZB Charles A. Yankah, MD, PhD. Deutsches Herzzentrum Berlin / Charité Medical University Berlin

2. Rheumatic fever and heart disease in Africa Prevalence: 24/1000, Age: 5-22 years Throat infection by Group A Streptococci

3. Decline in Rheumatic Fever in Developed Countries 1000 USA Denmark 100 Cases per 100,000 population 10 • 1 1930 1940 1950 1960 1970 1980 1990 1920 Time (years) Ayoub EM. Postgrad Med 1992;93:134

4. Prevalence of CVD among children in LiberiaScreened population: 5197 children Prevalence 0.34% Distribution of cardiovascular diseases Congenital 58% Rheumatic 16.7% Others 25.3% Yankah et al. Tropical Cardiology, 1981 Pure MS: 48.7%, Pure MR: 7.7%, Mixed: 42.3% Rettig, Ghana, 2007

5. Prevalence of rheumatic heart diseaseClinical vs echocardiographic diagnosis Cambodia Mozambique n=3677 n=2170 Age 12 years 11 years Boys 52% 48% Clinical 2.2/1000 2.3/1000 Echo 21.5/1000 30.4/1000 Marijon et al. N Engl J Med 2007

6. Patients in the ambulance of CHUB / ButareRuanda Uwe Schultz, Der Kardiologe, 2009, Vol. 3, No. 5

7. Causes of heart insufficiency Butare Heart Failure Study Cor pulmonale 17% Hypertensive heart failure 11% Others ( e.g. EMF,Pericarditis) 6% Dilatative Cardiomyopathy 28% Valvulopathy 38%

8. Death due to rheumatic heart disease in relation to all cardiovascular deaths

9. Burden of rheumatic heart disease in West Africa Rheumatic heart valve disease • 36% of surgical load– Nigeria • 52.8% – Abidjan Pure MR Mixed lesion • Bertrand et al.; Abidjan, Ivory Coast, 1979,

10. Contemporary Use of Mitral Valve Repair 51% Replacement 53.5% Replacement 49% Repair 46.5% Repair Frequency of MV repair? Society of Thoracic Surgeons Database, 2003 n=8086 Euro Heart Survey Iung et al, Eur Heart J 2003;24:1231 n=115

11. Mitral valve rheumatic valvulitis and degeneration Acute valvulitis Subacute valvulitis Post rheumatic valvulitis Pliable valve with mild fibrosis Severe calcification Fibroelastic deficiency Binotto et al. Images Paediatr Cardiol 2002;11:12-25

12. Native and allograft aortic valve degeneration Normal native aortic valve Fibrotic degenerative native AI Severe calcific degenerative native AS Calcific degenerative allograft AS

13. Schematic representation of the pathogenesis of rheumatic heart disease (carditis, valvulitis) A molecular mimicry between streptococcus M protein and human proteins (myosin, tropo-myosin, vimentin) as triggering factor for leading to autoimmunity in RF and RHD Binotto et al. Images Paediatr Cardiol 2002;11:12-25

14. Pathogenesis of rheumatic heart disease: Molecular mimicry between strept. M protein and human proteins (myosin, tropo-myosin, vimentin) as triggering factor for leading to autoimmunity in RF and RHD

15. Histology of a Normal Heart and Rheumatic Carditis Normal heart histology Myocardial Aschoff body – large, elongated, large nuclei/multinucleate cells Binotto et al. Images Paediatr Cardiol 2002;11:12-25

16. Rheumatic Fever and Rheumatic Heart Valve Disease: Autoimune Humoral and Cellular Responses B A Cytokines produced by infiltrating mononuclear cells from heart tissue fragments of RHD patients. IFN- gamma, TNF- alpha, IL-4, and IL-10 (Peroxidase (DAB) and alkaline phosphatase (Fast Red) immunohistochemistry ). Aschoff bodies are indicated by short arrows and mononuclear infiltrating cells by long arrows. neutrophilic infiltrations by long arrows. H&E stain. Original magnifications: x160 (A–D); x20 (E, F). C D F E Guilherme et al. Am J Pathol 2004;165:1583-1591

17. A Histologic and immunohisto-chemical findings of control valves. (A) Valvular leaflets obtained from the control group showed well-preserved leaflet architecture without fibrosis or inflammatory cell infiltration (H&E, ×40). (B) Immunohistochemical staining for TGF- 1 demonstrated positivity in the subendothelial stroma of valvular leaflets (TGF- 1, ×40). B

18. Histology and immunohistochemistry of rheumatic mitral valves. A B • Rheumatic mitral valves showed severe fibrosis and distorted architecture (H&E, ×40). • A high-power view demonstrated small thin-walled vessels and perivascular lymphocytic infiltration (H&E, ×200). • Kim et al. J KoreanMedSci 2008;23:41-8

19. TGF- 1 expression in rheumatic mitral valve C D (C) High TGF- 1 expression was seen in the endothelial cells and smooth muscle cells of the vessels, in the perivascular interstitial cells, and stroma of the valves (×200). (D) Myofibroblasts that were positive for SMA immunostaining were present in the subendothelial densely fibrotic area (×40). Kim et al. J Korean Med Sci 2008;23:41-8

20. Pathways of molecular mechanism of rheumatic heart and valve diseasesEndo-myocarditis, Myocarditis, Valvulitis TGF-Beta1 expression Angiotensin II ▼ Tenascin-C regulation of cell behaviour ▼ EMT stimulation by Endothelin ▼ Myofibroblast proliferation Myocardial fibrosis Endomyocardial fibrosis (EMF) Chondromulin (downregulation) ▼ VEGF-A expression ▼ Vascularisation ▼ VIC ►Myofibroblast proliferation Fibrosis Calcification TGF: Transforming Growth Factor; VEGF: Vascular Endothelial Growth Factor; VIC: Vascular Interstitial cells; EMT: Endothelial-to-Mesenchymal Transition; Ref.: Kim et al. J Korean Med sci 2008, 23: 41-8; Hakuno et al J Mol Med 2006, 12: 115-9

21. Pathways of Molecular Mechanism of Rheumatic Valve Disease Native valves Allografts (Homografts) Inflammatory process by: Streptococcal toxin endocarditis Bacterial endocarditis Immune reaction Remodeling of valve matrix Angiotensin II VEGF –A expression EMT stimulation by endothelin Vascularisation VIC (mesenchymalprofibrotic cells) Myofibroblast proliferation Valvular fibrosis Calcification EMT: Endothelial to mesenchymal transition, TGF: Transforming growth factor , VIC: Vascular interstitial cells