CKM-M swine demonstrated diastolic dysfunction with elevated end-diastolic pressures and increased myocardial stiffness due to mitochondrial dysfunction and oxidative stress.
In a postmenopausal swine model, combined hormonal and metabolic stress induces early mitochondrial dysfunction and oxidative stress, contributing to increased myocardial stiffness and diastolic dysfunction.
Absolute Event Rate: 0% vs 0%
Abstract Background Cardiovascular-kidney-metabolic disease (CKM) reflects the complex interplay among metabolic risk factors, chronic kidney disease, and the cardiovascular system. Within the CKM spectrum, we focus on the postmenopausal phenotype (CKM-M) characterized by combined hormonal and metabolic stress. Our aim is to identify early alterations in the myocardium contributing to the onset and progression of diastolic dysfunction in a post-menopausal swine model of CKM. Elucidating these mechanisms could uncover novel therapeutic targets for this growing patient population. Methods Two-year-old female swine were assigned to either healthy controls (n=7) or CKM-M (n=5). CKM-M swine were exposed for 6 months to combined metabolic stress (hypercholesterolemia by high-fat, high glucose and high salt diet and hyperglycaemia by streptozotocin), chronic kidney disease (renal microembolization), and postmenopausal state (surgical ovariectomy). To comprehensively assess the effects of CKM-M on the myocardium, we combined functional pressure–volume (PV) loop analyses, left ventricular quantitative proteomics, passive force measurement and calcium sensitivity in isolated cardiomyocytes, and respirometry in permeabilized cardiac fibers, using OROBOROS. Results CKM-M swine exhibited elevated end-diastolic pressures and reduced end-diastolic volumes compared to control (Figure 1A, P0.05), suggestive of diastolic dysfunction. End-systolic-pressures remained unchanged indicative of preserved systolic function (not shown). Consistent with increased cardiac stiffness, isolated cardiomyocytes from CKM-M swine displayed greater passive stiffness versus control (Figure 1B, P0.05) and enhanced calcium sensitivity, as reflected by a higher pCa₅₀ (5.78 ± 0.03 in CKM-M vs. 5.69 ± 0.02 in control, P0.01). Myocardial proteome profiling of CKM-M myocardium revealed a reduced mitochondrial metabolism related proteins and antioxidant pathways accompanied by greater oxidative stress from diminished NADH-linked related proteins (not shown). Additionally, high-resolution respirometry in permeabilized cardiac fibers revealed mitochondrial dysfunction (Figure 1C) reflected by impaired complex-I driven respiration in CKM-M swine, characterized by reduced OXPHOS capacity, NADH-linked, and maximal uncoupled respiration, while succinate driven complex-II, and leak respiration remained unaffected. Conclusion In the CKM-M hearts, early mitochondrial dysfunction and oxidative stress emerge as markers of impending cardiac dysfunction, likely increasing myofilament Ca2+ sensitivity and, together contributing to increased myocardial stiffness and diastolic dysfunction.For image description, please refer to the figure legend and surrounding text.
Zandbergen et al. (Sun,) reported a other. CKM-M swine demonstrated diastolic dysfunction with elevated end-diastolic pressures and increased myocardial stiffness due to mitochondrial dysfunction and oxidative stress.