What is the pathophysiological progression of rheumatic heart disease from acute rheumatic fever to chronic valvular damage?

Pathophysiological Progression of Rheumatic Heart Disease

Rheumatic heart disease (RHD) is an autoimmune sequela of group A β-hemolytic streptococcal (GAS) pharyngeal infection that progresses from acute rheumatic fever to chronic valvular damage through a complex inflammatory cascade involving molecular mimicry and persistent inflammation. 1

Initial Infection and Immune Response

• Rheumatic fever begins with a GAS throat infection (streptococcal pharyngitis) that triggers an abnormal autoimmune response in genetically susceptible individuals 1
• The immune response is directed against the M-protein serotypes of the GAS organism, which share structural similarities with human cardiac tissues 1
• After recovery from the initial episode of rheumatic fever, 60-65% of patients develop valvular heart disease 1

Acute Phase: Rheumatic Fever

• The autoimmune reaction begins in the periphery following a symptom-free interval of 14-21 days after the GAS pharyngitis 1
• The inflammatory process involves activation of adhesion molecules (VCAM and ICAM) that facilitate leukocyte migration to cardiac tissues, particularly the valves 2
• Specific chemokines (CXCL3/MIP1α, CCL1/I-309, and CXCL9/Mig) attract T cells to the myocardium and valves 2
• T helper 1 (Th1) and Th17 cytokines mediate the inflammatory damage to heart tissues 2
• Molecular mimicry between streptococcal M protein and human cardiac proteins triggers cross-reactive antibody and T-cell responses 2

Cardiac Manifestations of Acute Rheumatic Fever

• Carditis is a major manifestation of acute rheumatic fever according to the revised Jones criteria 1
• Carditis can be clinical (with audible murmurs) or subclinical (detected only by echocardiography) 1
• Valvulitis primarily affects the mitral valve, with the anterior leaflet tip showing abnormal coaptation and regurgitation typically directed posterolaterally 1
• Aortic valve involvement is less common and rarely occurs in isolation 1

Transition to Chronic Rheumatic Heart Disease

• Recurrent GAS infections lead to repeated episodes of acute rheumatic fever, which progressively damage the heart valves 1
• The activin/Smad2 and Smad3 signaling pathway is activated during valvular damage, contributing to endothelial-mesenchymal transition (EndMT) 3
• EndMT plays a key role in cardiac fibrosis and valvular remodeling 3
• Inflammatory markers remain elevated even in the chronic phase, indicating ongoing inflammation 4
• High-sensitivity C-reactive protein (hs-CRP) levels are significantly higher in patients with chronic rheumatic valve disease compared to healthy controls, suggesting persistent inflammatory activity 4

Chronic Valvular Damage

• Rheumatic mitral stenosis results from fusion of the commissures with scarring and eventual calcification of the cusps 1
• Rheumatic aortic stenosis is less common and is invariably accompanied by mitral valve disease 1
• As the disease progresses, valvular fibrosis and calcification lead to permanent structural changes 1
• The chronic phase is characterized by progressive valvular stenosis and/or regurgitation 1
• Long-term complications include atrial fibrillation, heart failure, stroke, infective endocarditis, and pregnancy-related complications 1

Factors Affecting Disease Progression

• Genetic susceptibility plays a significant role in determining which individuals develop rheumatic fever after GAS infection 2
• Recurrent GAS infections accelerate the progression of valvular damage 1
• Secondary prophylaxis with continuous antimicrobial therapy is critical to prevent recurrent episodes of rheumatic fever and further valvular damage 1
• The duration of prophylaxis depends on whether carditis was present and if residual heart disease persists 1

Molecular and Cellular Mechanisms

• Inflammation and oxidative stress are key components in the pathogenesis of RHD 5
• The inflammatory process involves both B and T cell responses that begin in the periphery and migrate to the heart 2
• Low numbers of IL-4 producing cells in valvular tissue contribute to the maintenance and progression of valve lesions 2
• Increased expression of apoptosis-related markers (BAX and cleaved caspase-3) and valvular inflammation markers (p-NF-κB) are observed in RHD 3

Clinical Implications

• Early recognition and treatment of GAS pharyngitis is essential for primary prevention of rheumatic fever 1
• Secondary prophylaxis with penicillin is crucial to prevent recurrent episodes of rheumatic fever and further valvular damage 1
• Patients with rheumatic heart disease require regular clinical follow-up to monitor disease progression 1
• The rate of progression of valvular stenosis appears to be more rapid in patients with degenerative calcific disease than in those with congenital or rheumatic disease 1