Recent studies have reported that carotid plaque area is more closely associated with cardiovascular events than average IMT 18,19, possibly because carotid plaque may reflect cumulative damage from exposure to different atherosclerotic risk factors and is therefore more specific than IMT in reflecting the burden of atherosclerosis. In this study, we found that the maximum patch area measured from both long-axis and short-axis views increased significantly in the placebo group over 24 months, but remained unchanged in the Tongxinluo group, resulting in a significant difference in the maximum patch area between the two groups. These results were consistent with average carotid IMT measurements and validated the therapeutic role of Tongxinluo in delaying the progression of atherosclerotic lesions.

Vascular remodeling refers to compensatory vasodilation (positive remodeling) or contraction (negative remodeling) in response to plaque growth. Our previous research has shown that in patients with angina, coronary artery RI is an independent predictor of coronary plaque rupture. A recent meta-analysis confirmed that RI measured by CT angiography was an independent predictor of future acute coronary syndrome28. In this study, RI increased significantly in patients with RI < 0.95 at baseline, but decreased significantly after Tongxinluo treatment > 1.05 at baseline in patients with RI. These results are consistent with carotid plaque measurements and suggest that Tongxinluo therapy may have the potential to stabilize atherosclerotic plaque in high-risk patients. In our study, the incidence of major cardiovascular events, especially unstable angina, was significantly reduced in patients treated with Tongxinluo, further confirming the anti-atherosclerosis effect of Tongxinluo therapy.

The mechanism of Tongxinluo's anti-atherosclerotic effect is not fully understood. At the end of the study, the absolute difference in lipid levels between the two groups was too small to explain the morphological changes in carotid plaque, possibly because the average lipid levels in both groups were within the normal range according to the latest Chinese guides29. These results contrast with previously reported studies of anti-atherosclerosis therapy, which showed significantly elevated blood lipid levels in patients and animals at baseline 4, 5, 15, 16. Another possible mechanism is the Tongxinluo-mediated anti-inflammatory effect. Tongxinluo therapy can reduce the incidence of recurrent plaque rupture and healing, thereby delaying the progression of carotid plaque, which is supported by the reduction of the incidence of unstable angina in patients with Tongxinluo therapy. A recent study in our lab showed that Tongxinluo treatment reduced angiogenesis in atherosclerotic plaques dose-dependent by inhibiting local expression of inflammatory cytokines and angiogenic factors in ApoE−/- mice, 5 which may prevent angiogenesis and bleeding within the plaques, thereby inhibiting plaque growth.