What is the pathophysiology of Rheumatic Heart Disease (RHD)?

Pathophysiology of Rheumatic Heart Disease (RHD)

Rheumatic heart disease (RHD) is an autoimmune disease that develops following group A β-haemolytic streptococcal (GAS) infection of the throat (streptococcal pharyngitis) or skin, leading to progressive valve damage through an abnormal immune response in genetically susceptible individuals. 1

Initiating Event and Autoimmune Response

• Rheumatic fever (RF), the precursor to RHD, begins with a GAS infection, typically of the throat, though streptococcal skin infections have also been implicated in the disease process 1
• The pathogenesis involves molecular mimicry, where antibodies produced against streptococcal M protein cross-react with human cardiac tissues due to structural similarities 2, 3
• This abnormal autoimmune response occurs in genetically susceptible hosts, leading to loss of self-tolerance and subsequent inflammatory damage to cardiac tissues 3, 4
• With repeated GAS infections or exposures to streptococcal antigens, the autoimmune response becomes more pronounced, causing increased cardiac damage 2

Valvular Damage Progression

• After the initial episode of RF, 60-65% of patients develop valvular heart disease 1
• The disease predominantly affects left-sided cardiac valves, with the mitral valve being most commonly involved, followed by the aortic valve 1, 4
• Recurrent episodes of RF lead to progressive valve damage through:
  • Valvular thickening, particularly of the anterior mitral valve leaflet 1
  • Chordal thickening and fusion 1
  • Restricted leaflet motion 1
  • Development of regurgitation and/or stenosis 1
• Long-term inflammation and high degree of fibrosis ultimately leads to anatomic disruption of the valve apparatus 4

Cardiac Complications and Progression

• As RHD progresses, it can cause several serious complications:
  • Atrial fibrillation due to left atrial enlargement 1
  • Heart failure from volume or pressure overload 1
  • Infective endocarditis on damaged valves 1
  • Stroke from thromboembolic events 1
  • Pregnancy-related complications 1
• Electrocardiographic changes, including PR interval prolongation, may occur as the disease progresses 2
• Without intervention, the disease can lead to premature death, with some studies reporting a mean age of death <25 years 1

Immunological Mechanisms

• Both humoral (antibody-mediated) and cellular immune responses contribute to valvular damage 4
• Complement activation and anti-M protein antibodies can contribute to inflammation in heart valves by activating cardiac endothelium 2
• Mononuclear cell infiltration of heart valves increases with repeated exposure to streptococcal antigens 2
• The preferential involvement of the mitral valve is not fully understood but may relate to hemodynamic factors and specific tissue characteristics 4

Epidemiological Factors

• RHD predominantly affects populations in low and middle-income countries and some indigenous populations in high-income countries 1, 3
• The disease is influenced by socioeconomic factors, with poor living conditions and limited access to healthcare contributing to higher prevalence 1
• RHD remains the most common cardiovascular disease in young people aged <25 years worldwide 1, 5
• Women appear to be disproportionately affected, particularly in low and middle-income countries 4

Understanding the complex pathophysiology of RHD is crucial for developing effective prevention strategies, including antibiotic prophylaxis and potential vaccine development, to reduce the global burden of this preventable disease 3, 5.