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Updated: Aug 15, 2026
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Published on: November 29, 2024
Myocardial stiffness, cardiac remodeling, and diastolic dysfunction in calcification-prone fetuin-A-deficient mice
Marc W Merx1, Cora Schäfer, Ralf Westenfeld
1Medical Clinic I, RWTH University Hospital, Aachen, Germany. mmerx@ukaachen.de
Insights
Fetuin-A deficiency causes myocardial calcification, leading to impaired cardiac function and fibrosis in mice. This suggests cardiac calcification, independent of arterial stiffness, is a significant cardiovascular risk factor.
Area of Science:
- Cardiovascular Biology
- Mineral Metabolism
- Renal Disease Pathophysiology
Background:
- Dialysis patients exhibit accelerated atherosclerosis and vascular calcification, increasing cardiovascular mortality.
- Arterial stiffness from calcification is a key factor in uremic cardiac failure.
- Fetuin-A, a serum protein, inhibits calcification; its deficiency is linked to mortality in dialysis patients.
Purpose of the Study:
- To investigate the functional impact of isolated myocardial calcification, independent of arterial stiffness.
- To assess the hemodynamics and cardiac function in fetuin-A knockout (fetuin-KO) mice with spontaneous myocardial calcification.
Main Methods:
- Hemodynamic assessment of fetuin-KO mice compared to wild-type (WT) controls.
- Evaluation of cardiac function, including response to dobutamine stimulation and ischemia-reperfusion.
- Analysis of myocardial fibrosis, gene expression (TGF-beta, collagen, fibronectin), and calcium content.
Main Results:
- Fetuin-KO mice showed reduced cardiac output and refractoriness to dobutamine.
- Impaired left ventricular relaxation and reduced pressure development after ischemia were observed in fetuin-KO hearts.
- Dystrophic cardiac calcification in fetuin-KO mice correlated with increased TGF-beta, collagen, and fibronectin mRNA.
Conclusions:
- Calcification-associated "myocardial stiffness" contributes to cardiac dysfunction, including diastolic dysfunction and impaired ischemic tolerance.
- This "myocardial stiffness" is a potential cardiovascular risk factor in conditions prone to calcification.
- Fetuin-A deficiency highlights the detrimental role of myocardial calcification in cardiac failure, separate from arterial stiffness.
Abstract:
Accelerated atherosclerosis in dialysis patients is characterized by severe vascular calcification, and the magnitude of vascular calcification is associated with increased cardiovascular mortality. Calcification-dependent arterial stiffness is considered to be a major determinant of cardiac failure in uremia. Fetuin-A/alpha(2)-Heremans-Schmid glycoprotein is an abundant serum protein with powerful calcification inhibitory properties. Fetuin-A deficiency was recently linked to cardiovascular mortality in dialysis patients. Fetuin-A knockout (fetuin-KO) mice spontaneously develop widespread soft tissue calcification, including significant myocardial calcification, whereas larger arteries are spared. Therefore, this investigation offers the unique opportunity to study the functional role of isolated myocardial calcification independent of arterial stiffness by assessing the hemodynamics of fetuin-KO mice. Cardiac output in fetuin-KO mice was lower than in wild-type mice (fetuin-KO 1.81 +/- 0.18 versus WT 2.45 +/- 0.29 ml/min per g; P < 0.005), and fetuin-KO mice were refractory to dobutamine stimulation. Left ventricular relaxation was significantly impaired in fetuin-KO hearts with the relaxation index reduced by 23% (P < 0.005). After ischemia, fetuin-KO hearts displayed a continuous decline in left ventricular developed pressure after the initial phase of reperfusion, resulting in 77 +/- 15% of preischemic left ventricular developed pressure (P < 0.05 versus wild-type). In fetuin-KO mice, dystrophic cardiac calcification, with myocardial calcium contents increased 60-fold, was associated with profound induction of profibrotic TGF-beta and downstream collagen and fibronectin mRNA synthesis. In conclusion, independent of arterial stiffness, calcification-associated "myocardial stiffness" characterized by cardiac fibrosis, diastolic dysfunction, impaired tolerance to ischemia, and catecholamine resistance thus may constitute an underestimated cardiovascular risk factor that contributes to cardiac failure in calcification-prone states.
