What is the pathogenesis of rheumatic heart disease?

Pathogenesis of Rheumatic Heart Disease

Rheumatic heart disease develops through an autoimmune response triggered by group A β-hemolytic streptococcal pharyngitis in genetically susceptible individuals, leading to molecular mimicry between streptococcal antigens and cardiac tissue proteins, resulting in progressive valvular inflammation, fibrosis, and calcification. 1, 2

Initial Trigger: Streptococcal Infection

• The pathogenic cascade begins with group A streptococcal (GAS) pharyngitis, which if left untreated, precipitates acute rheumatic fever in susceptible hosts 3, 1
• A symptom-free interval of 14-21 days follows the initial pharyngeal infection before autoimmune manifestations emerge 2
• During historical epidemics, up to 3% of untreated streptococcal pharyngitis cases progressed to rheumatic fever, though endemic rates are substantially lower 3

Molecular Mimicry and Autoimmune Activation

• The immune system mounts an abnormal response against M-protein serotypes of GAS organisms, which share structural similarities with human cardiac tissues 2, 4
• Cross-reactive antibodies and T cells target cardiac proteins including cardiac myosin epitopes, vimentin, and other intracellular proteins 4
• This molecular mimicry mechanism causes the immune system to attack self-tissues, breaking normal tolerance mechanisms 5

Cellular Immune Response

• Antigen-driven oligoclonal CD4+ T cell expansions infiltrate heart tissue and drive the inflammatory lesions 4
• These T cells produce predominantly Th1-type inflammatory cytokines including TNF-α and IFN-γ, which mediate tissue damage 4, 6
• IL-6 levels are significantly elevated during acute rheumatic fever, promoting antibody production 6
• TNF-α plays a critical role in disease progression and tissue damage during the rheumatic heart disease phase 6

Cytokine Imbalance and Tissue-Specific Damage

• A Th1/Th2 cytokine imbalance contributes to differential healing patterns: myocarditis may heal while valvular lesions progress 4
• IL-4+ regulatory cells (Th2-type) are found in myocardium but are very scarce in valve lesions, explaining why valve damage becomes permanent and progressive 4
• As disease progresses from acute rheumatic fever to chronic rheumatic heart disease, there is a cytokine switch-over from Th1 to Th2 type 6
• The paucity of IL-4-producing regulatory cells in valves prevents resolution of inflammation and allows chronic damage 4

Progression to Chronic Valvular Disease

• After recovery from the initial acute rheumatic fever episode, 60-65% of patients develop valvular heart disease 1, 2
• Long-term inflammation and high-degree fibrosis lead to valve dysfunction through anatomic disruption of the valve apparatus 5
• The disease process involves sequential inflammation, scarring, and eventual calcification of heart valves 1
• Recurrent GAS infections trigger repeated episodes of acute rheumatic fever, which progressively accelerate valvular damage 2, 7

Valvular Pathology

• The mitral valve is preferentially and predominantly affected, followed by the aortic valve 1, 5
• During acute carditis, the mitral valve anterior leaflet tip shows abnormal coaptation with regurgitation typically directed posterolaterally 2
• Chronic rheumatic mitral stenosis results from commissural fusion with scarring and eventual calcification of the cusps 2
• Rheumatic aortic stenosis is less common and invariably accompanied by mitral valve disease 1, 2
• Aortic valve involvement rarely occurs in isolation 2

Genetic Susceptibility

• Multiple HLA antigens have been associated with disease susceptibility, including HLA-B17, B18, B35, and DR2, though findings vary across populations 3
• The disease affects genetically predisposed hosts who mount abnormal immune responses to streptococcal antigens 1, 8

Clinical Implications of Pathogenesis

• The autoimmune nature explains why infection with GAS does not have to be symptomatic to trigger recurrence, and why rheumatic fever can recur even when symptomatic infection is treated 3
• Prevention of recurrent rheumatic fever requires long-term antimicrobial prophylaxis rather than just recognition and treatment of acute GAS pharyngitis episodes 3
• Secondary prophylaxis with continuous antimicrobial therapy is critical to prevent recurrent episodes and further valvular damage 2, 7
• Without intervention, the disease leads to premature cardiovascular death, with mean age of death <25 years in some studies 3