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

Charles A. Yankah, MD, PhD. Deutsches Herzzentrum Berlin / Charité Medical University Berlin

DHZBDHZB

CharitéCharité

Throat infection by Group A Streptococci

Rheumatic fever and heart disease in Africa

Prevalence: 24/1000, Age: 5-22 years

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Ayoub EM. Ayoub EM. Postgrad MedPostgrad Med 1992;93:134 1992;93:134

19301930 19401940 19501950 19601960 19701970 19801980 19901990

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Decline in Rheumatic Fever in Developed Decline in Rheumatic Fever in Developed CountriesCountries

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

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

Patients in the ambulance of CHUB / ButareRuanda

Uwe Schultz, Der Kardiologe, 2009, Vol. 3, No. 5

Causes of heart insufficiency Butare Heart Failure Study

Valvulopathy 38%

Others ( e.g. EMF,Pericarditis) 6%

Cor pulmonale 17%

Hypertensive heart failure 11%

Dilatative Cardiomyopathy

28%

Rheumatic Heart Disease

0%

4%

8%

12%

Mozambique Nigeria Kenya Uganda Cambodia Pakistan USA Worldw ide

% o

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VD

death

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Overall

0-14 years

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

Rheumatic heart valve disease ►36% of surgical load– Nigeria►52.8% – Abidjan

Pure MR Mixed lesion

Burden of rheumatic heart disease in West Africa

•Bertrand et al.; Abidjan, Ivory Coast, 1979,

Contemporary Use of Mitral Valve RepairContemporary Use of Mitral Valve Repair

49%49%

RepairRepair

51%51%

ReplacementReplacement

Society of Thoracic SurgeonsSociety of Thoracic SurgeonsDatabase, 2003Database, 2003

n=8086n=8086

53.5%53.5%

ReplacementReplacement46.5%46.5%

RepairRepair

Euro Heart SurveyEuro Heart SurveyIung et al, Iung et al, Eur Heart JEur Heart J 2003;24:1231 2003;24:1231

n=115n=115

Frequency of MV repair?Frequency of MV repair?Frequency of MV repair?Frequency of MV repair?

Mitral valve rheumatic valvulitis and degeneration

Acute valvulitis Subacute valvulitis

Binotto et al. Images Paediatr Cardiol 2002;11:12-25

Fibroelastic deficiency Pliable valve with mild fibrosis

Severe calcification

Post rheumatic valvulitis

Native and allograft aortic valve degeneration

Normal native aortic valve Fibrotic degenerative

native AI

Severe calcific degenerative

native AS

Calcific degenerativeallograft AS

Schematic representation of the pathogenesis of rheumatic heart disease (carditis, valvulitis)

Binotto et al. Images Paediatr Cardiol 2002;11:12-25

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

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

Myocardial Aschoff body – large, elongated, large nuclei/multinucleate cells

Binotto et al. Images Paediatr Cardiol 2002;11:12-25

Histology of a Normal Heart and Rheumatic Carditis

Normal heart histology

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).Guilherme et al. Am J Pathol 2004;165:1583-1591

Rheumatic Fever and Rheumatic Heart Valve Disease: Autoimune Humoral and Cellular Responses

A B

C D

E F

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

B

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).

Kim et al. J Korean Med Sci 2008;23:41-8

Histology and immunohistochemistry of rheumatic mitral valves.

A B

(C) High TGF- 1 expression was seen in the endothelial cells and smooth muscle cells of the vessels, in the perivascularinterstitial 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

TGF- 1 expression in rheumatic mitral valve

C D

Pathways of molecular mechanism of rheumatic heart and valve diseases

Endo-myocarditis, Myocarditis, Valvulitis

Angiotensin II ▼Tenascin-C regulation of cell behaviour ▼EMT stimulation by Endothelin ▼Myofibroblast proliferationMyocardial fibrosisEndomyocardial fibrosis (EMF)

Chondromulin(downregulation) ▼VEGF-A expression ▼Vascularisation ▼VIC ►Myofibroblast proliferationFibrosisCalcification

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

TGF-Beta1 expression

Pathways of Molecular Mechanism of Pathways of Molecular Mechanism of Rheumatic Valve Disease Rheumatic Valve Disease

Native valves Native valves

Immune reactionImmune reactionInflammatory process by: Inflammatory process by:

Streptococcal toxin endocarditis Streptococcal toxin endocarditis Bacterial endocarditis Bacterial endocarditis

AllograAllografts (Homografts) fts (Homografts)

EMT stimulation by endothelin EMT stimulation by endothelin VascularisationVascularisation

VIC (mesenchymal profibrotic cells)VIC (mesenchymal profibrotic cells) Myofibroblast proliferationMyofibroblast proliferation

Valvular fibrosisValvular fibrosisCalcification Calcification

EMT: Endothelial to mesenchymal transition, TGF: Transforming growth factor , VIC: Vascular interstitial cellsEMT: Endothelial to mesenchymal transition, TGF: Transforming growth factor , VIC: Vascular interstitial cells

VEGF –A expression VEGF –A expression

Remodeling of valve matrixRemodeling of valve matrixAngiotensin IIAngiotensin II