Disease Modifying Therapies for Chronic Rheumatic Heart Disease

Corresponding Author

Rheumatic heart disease (RHD) remains one of the major causes of acquired heart valve disease, particularly in developing countries, where health care access is limited and the prevalence of rheumatic fever remains high.¹ Chronic RHD is characterized by progressive valve destruction, yet no well-established medical treatment exists to alter its natural history. Evidence-based interventions for the chronic progressive phase are lacking, and valve surgery is often the last resort once profound structural damage has occurred.²

Pathogenesis of Rheumatic Heart Disease

The hallmark of RHD is chronic valvular inflammation, thought to be triggered initially by Group A Streptococcus (GAS) pharyngitis, followed by acute rheumatic fever. The most widely accepted theory invokes molecular mimicry, in which GAS antigens or self–cross-reactive autoantibodies target valve tissue through humoral and cellular autoimmune responses.³ A major target of these cross-reactive autoantibodies is bacterial M-protein, which shares structural homology with human cardiac proteins, including myosin, tropomyosin, actin, vimentin, and laminin.⁴ The presence of cross-reactive T-cells in resected human rheumatic valves further implicates a sustained immune-mediated process in disease pathogenesis.⁵

Challenges in Identifying Disease-Modifying Therapies

Although the incidence of RHD has declined in developed countries because of the widespread use of antibiotics for streptococcal pharyngitis, the global disease burden remains substantial, affecting more than 50 million people worldwide, predominantly in low-resource settings.⁶ The GOAL trial demonstrated that regular intramuscular benzathine penicillin after acute rheumatic fever reduces the progression of subclinical RHD in children and adolescents.⁷ However, once cardiac and valvular involvement becomes established, no anti-inflammatory or disease-modifying therapy has been proven to alter long-term clinical outcomes.⁸

Conducting randomized controlled trials in RHD presents several hurdles. First, no validated inflammatory marker specifically tracks RHD progression. Although cytokines such as interleukin-6 (IL-6) and tumor necrosis factor–alpha are elevated in RHD patients, none are specific to the disease process.⁹ Second, the disease progresses over decades, meaning that surrogate endpoints such as mitral valve area, mean transmitral gradient, or calcium score on computed tomography would likely require prolonged follow-up to detect meaningful changes. Third, in mild or moderate disease, adverse cardiovascular outcomes including hospitalization or mortality are infrequent; a trial designed around hard clinical endpoints would therefore demand a very large sample size and extended follow-up.

The COL-RHD trial

Colchicine is a widely used oral anti-inflammatory therapy with a well-established safety profile, and its role in cardiovascular disease has expanded considerably in recent years. It has proven efficacy in reducing recurrences of acute pericarditis,¹⁰ and landmark trials including COLCOT¹¹ and LoDoCo2¹² have shown that colchicine reduces major adverse cardiovascular outcomes in patients with coronary artery disease. Whether these anti-inflammatory benefits extend to other cardiac conditions, including RHD, is a question of considerable clinical interest.

The COL-RHD trial,¹³ reported in this issue of JACC: Asia, was designed to address this question. It is a prospective, double-blind, randomized controlled trial evaluating whether colchicine reduces systemic inflammation and improves left atrial (LA) mechanical function in chronic rheumatic mitral valve disease. Patients with chronic moderate to severe rheumatic mitral valve disease were randomized to receive colchicine (0.5 mg twice daily) or placebo for 6 months, in addition to standard therapy. The primary outcome was the change in IL-6 at 6 months. Secondary outcomes included changes in other inflammatory markers, LA strain parameters, NYHA functional class, and correlations between inflammatory markers and LA mechanics.

The trial results are intriguing. The primary endpoint was met, with IL-6 decreasing substantially in the colchicine group, while it progressively increased in the placebo group over the same period. Consistent anti-inflammatory effects were observed across other markers, with significant reductions in both erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein. In terms of functional and mechanical endpoints, at 6 months, LA reservoir strain was significantly higher in the colchicine group compared with placebo, reflecting a marked improvement from baseline in the active treatment arm, whereas it remained persistently impaired in the placebo arm. NYHA functional status also improved. In contrast, no significant changes were observed in structural valvular parameters, including mitral valve area and transmitral gradients, at 6 months.

Mechanistic Link and Safety Considerations

The concomitant improvement in LA strain and NYHA functional class, in the absence of any measurable change in mitral valve area or transmitral gradients, raises an intriguing pathophysiological question. One plausible hypothesis the authors raised is that colchicine exerts its anti-inflammatory effect preferentially on atrial tissue by downregulating IL-6–mediated inflammatory signaling, thereby inhibiting fibroblast activation, reducing myocardial stiffness, and preserving atrial compliance and contractile function. These observed atrial changes warrant further confirmation in larger, adequately powered studies, as well as in experimental models such as the Lewis rat model of autoimmune valvulitis.¹⁴ The trial should therefore be regarded as hypothesis generating rather than definitive. Furthermore, the long-term safety of colchicine also merits careful consideration, given the initial numerical signal toward higher noncardiovascular mortality observed in the colchicine arm of the LoDoCo2 trial (HR: 1.51, 95% CI: 0.99-2.31).¹² Larger trials with extended follow-up will be essential to establish the safety profile of colchicine in this RHD population.

Future Research Directions

Despite no new atrial fibrillation in either arm at 6 months, longer-term trials should monitor incident atrial fibrillation as an exploratory endpoint. The observed improvement in LA strain suggests colchicine may reduce atrial fibrillation burden over time. Beyond NYHA functional class, objective measures such as 6-minute walking distance, cardiopulmonary exercise testing, and N-terminal pro-B-type natriuretic peptide levels could better define functional benefit. Future trials may also incorporate novel biomarkers that reflect the autoimmune inflammatory activity driving RHD progression. Promising candidates identified in preclinical and clinical studies include circulating cytokines,¹⁵ proteomic signatures,¹⁶ microRNAs,¹⁷ and specific leukocyte subsets.¹⁸ They may serve as more disease-relevant endpoints in future anti-inflammatory trials. Larger scale, adequately powered studies with extended follow-up are essential to evaluate these novel endpoints alongside clinical and imaging measures. Until such evidence becomes available, it remains premature to recommend colchicine for routine clinical use in chronic RHD. The road to disease modification in chronic RHD remains long, but the COL-RHD trial¹³ has provided a meaningful step forward.

Funding Support and Author Disclosures

The authors have reported that they have no relationships relevant to the contents of this paper to disclose.