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Congestive heart failure in copper-deficient mice
Laila Elsherif1, Raymond V Ortines, Jack T Saari
1Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky 40202, USA.
Insights
Copper deficiency (CuD) causes significant systolic and diastolic heart dysfunction in mice, progressing to heart failure. This study reveals impaired contractility and relaxation, alongside pathological changes, indicating congestive heart failure in CuD models.
Area of Science:
- Cardiovascular Physiology
- Nutritional Biochemistry
- Pathology
Background:
- Copper deficiency (CuD) is known to induce hypertrophic cardiomyopathy in experimental models.
- The progression from compensated hypertrophy to decompensated heart failure in CuD has not been well-studied.
Purpose of the Study:
- To investigate the contractile and hemodynamic parameters in CuD mouse hearts.
- To determine if heart failure develops subsequent to hypertrophy in CuD.
Main Methods:
- FVB mice dams were fed either a CuD or copper-adequate (CuA) diet from day 3 postpartum.
- Weanling pups received the same diet for 5 weeks (pre- and postweaning).
- Cardiac function was assessed at week 4 via left ventricular catheterization.
Main Results:
- CuD mice exhibited significantly decreased left ventricle systolic pressure and depressed contractility (+dP/dt and -dP/dt).
- Elevated left ventricle end-diastolic pressure and prolonged relaxation indicated diastolic dysfunction.
- CuD hearts showed blunted responses to isoproterenol and morphological changes including collagen and lipid deposition.
Conclusions:
- Copper deficiency leads to both systolic and diastolic cardiac dysfunction in mice.
- Histopathological findings in CuD hearts are consistent with diagnoses of congestive heart failure.
- This study establishes a link between CuD and the development of heart failure.
Abstract:
Copper Deficiency (CuD) leads to hypertrophic cardiomyopathy in various experimental models. The morphological, electrophysiological, and molecular aspects of this hypertrophy have been under investigation for a long time. However the transition from compensated hypertrophy to decompensated heart failure has not been investigated in the study of CuD. We set out to investigate the contractile and hemodynamic parameters of the CuD mouse heart and to determine whether heart failure follows hypertrophy in the CuD heart. Dams of FVB mice were fed CuD or copper-adequate (CuA) diet starting from the third day post delivery and the weanling pups were fed the same diet for a total period of 5 weeks (pre- and postweanling). At week 4, the functional parameters of the heart were analyzed using a surgical technique for catheterizing the left ventricle. A significant decrease in left ventricle systolic pressure was observed with no significant change in heart rate, and more importantly contractility as measured by the maximal rate of left ventricular pressure rise (+dP/dt) and decline (-dP/dt) were significantly depressed in the CuD mice. However, left ventricle end diastolic pressure was elevated, and relaxation was impaired in the CuD animals; the duration of relaxation was prolonged. In addition to significant changes in the basal level of cardiac function, CuD hearts had a blunted response to the stimulation of the beta-adrenergic agonist isoproterenol. Furthermore, morphological analysis revealed increased collagen accumulation in the CuD hearts along with lipid deposition. This study shows that CuD leads to systolic and diastolic dysfunction in association with histopathological changes, which are indices commonly used to diagnose congestive heart failure.
