Burnout rheumatic mitral valve disease Morphology and predictability

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

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

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

Prevalence of CVD among children in Liberia Screened population: 5197 children Prevalence 0. 34% Distribution of cardiovascular diseases Congenital 58% Rheumatic Others Yankah et al. Tropical Cardiology, 1981 16. 7% 25. 3%

Prevalence of rheumatic heart disease Clinical vs echocardiographic diagnosis Age Boys Clinical Echo Cambodia n=3677 12 years 52% 2. 2/1000 21. 5/1000 Mozambique n=2170 11 years 48% 2. 3/1000 30. 4/1000 Marijon et al. N Engl J Med 2007

Patients in the ambulance of CHUB / Butare Ruanda Uwe Schultz, Der Kardiologe, 2009, Vol. 3, No.

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

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

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,

Contemporary Use of Mitral Valve Repair 51% 53. 5% Replacement 49% 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

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

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

Schematic representation of the pathogenesis of rheumatic heart disease (carditis, valvulitis) A molecular mimicry between streptococc us M protein and human proteins (myosin, tropomyosin, vimentin) as triggering factor for leading to autoimmunit y in RF and Binotto et al. Images Paediatr Cardiol

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

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

Rheumatic Fever and Rheumatic Heart Valve Dise Autoimune Humoral and Cellular Responses A B C D 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) F E immunohistochemistry ). Aschoff bodies are indicated by short arrows and mononuclear infiltrating cells by long arrows. neutrophilic infiltrations by Guilherme et al. Am J Pathol 2004; 165: 1583 -1591 long arrows. H&E stain. Original magnifications:

A B Histologic and immunohisto -chemical findings of control valves. (A) Valvular leaflets obtained from the control group showed wellpreserved 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).

Histology and immunohistochemistry of rheumatic mitral valves. A (A) Rheumatic mitral valves showed severe fibrosis and distorted architecture (H&E, × 40). (B) A high-power view demonstrated small thin-walled vessels and perivascular lymphocytic infiltration (H&E, × 200). B

TGF- 1 expression in rheumatic mitral valve C (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 D

Pathways of molecular mechanism of rheumatic heart and valve diseases Endo-myocarditis, Myocarditis, Valvulitis TGF-Beta 1 expression Angiotensin II Chondromulin ▼ (downregulation) Tenascin-C regulation of ▼ cell behaviour VEGF-A expression ▼ ▼ EMT stimulation by Vascularisation Endothelin ▼ ▼ VIC ►Myofibroblast proliferation Fibrosis Myocardial fibrosis Calcification Endomyocardial fibrosis TGF: Transforming Growth Factor; VEGF: Vascular Endothelial Growth Factor; VIC: Vascular Interstitial (EMF) cells; EMT: Endothelial-to-Mesenchymal Transition; Ref. : Kim et al. J Korean Med sci 2008, 23: 41 -8; H a k u n o e t a l J M o l M e d 2 0 0 6 , 1 2 : 1 1 5 - 9

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 (mesenchymal profibrotic cells) Myofibroblast proliferation Valvular fibrosis Calcification EMT: Endothelial to mesenchymal transition, TGF: Transforming growth factor , VIC: Vascular int