Colchicine restored left ventricular end-diastolic pressure, fractional shortening, and cardiac output to control levels in AngII-induced diastolic dysfunction in mice.
Does colchicine improve cardiac function and reduce inflammation in a mouse model of AngII-induced diastolic dysfunction?
Colchicine effectively reversed AngII-induced diastolic dysfunction and myocardial stiffness in a murine model, highlighting its potential translational relevance for HFpEF.
Absolute Event Rate: 0% vs 0%
Abstract Background Growing evidence suggests that a comorbidity-driven systemic pro-inflammatory state, including activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome, contributes to the pathogenesis of HFpEF. The anti-inflammatory drug colchicine, traditionally used for gout treatment, inhibits NLRP3 activity through its well-known microtubule-disassembling properties. However, its potential to ameliorate diastolic dysfunction remains insufficiently explored. Purpose Building on our previous demonstration of colchicine's cardioprotective effect in a murine model of high-grade inflammation, Coxsackievirus B3-induced myocarditis, we now aimed to examine its impact on inflammation, fibrosis, and cardiac function in a mouse model of low-grade inflammation, Angiotensin II (AngII)-induced diastolic dysfunction with elevated filling pressure. Methods Six-week-old male C57BL/6J mice received daily subcutaneous injections of AngII (1.1 mg/kg BW) for 14 days according to Murdoch et al. (2014). Colchicine (5 µmol/kg BW) was given orally on day 1 (+Col d1) or day 7 (+Col d7). Controls received water. Cardiac function was assessed by invasive pressure–volume analysis and echocardiography. Myocardial stiffness was determined from passive force in isolated cardiomyocytes. Titin phosphorylation and fibrosis were evaluated by Western blot and immunohistochemistry, respectively. Systemic and LV inflammation were assessed using flow cytometry, ELISA, and qPCR of inflammasome markers. Results AngII infusion resulted in increased left ventricular end-diastolic pressure (LVEDP), reduced fractional shortening (FS) and cardiac output (CO), as well as elevated passive tension in isolated cardiomyocytes, with no overt fibrosis observed compared to controls. These functional changes were associated with reduced phosphorylation of the titin N2B segment and were accompanied by systemic inflammasome activation, as indicated by increased proportions of splenic NLRP3+, ASC+, caspase-1+ and IL-1β+ immune cells, along with elevated circulating S100A8/9 levels. In turn, treatment with colchicine after 1 and 7 days restored LVEDP, FS and CO to control levels, reduced passive myocardial stiffness and normalised titin N2B phosphorylation. Furthermore, colchicine attenuated systemic inflammasome activation without inducing adverse structural or functional effects. LV expression of the AngII receptor type 1 and components of the NLRP3 inflammasome was not affected in any group. Conclusion Colchicine effectively reversed AngII-induced diastolic dysfunction, involving amelioration of sarcomere compliance and suppression of systemic NLRP3 inflammasome activation. These findings identify colchicine as a promising therapeutic strategy to mitigate inflammation-driven myocardial stiffness and preserve diastolic function, highlighting its translational relevance for HFpEF.
Perkams et al. (Sun,) reported a other. Colchicine restored left ventricular end-diastolic pressure, fractional shortening, and cardiac output to control levels in AngII-induced diastolic dysfunction in mice.