| Abstrakt: |
Background:Cardiopulmonary complications are the leading cause of death in people with sickle cell disease (SCD). Cardiac complications, including left ventricular (LV) dysfunction, are prevalent in both young and adult SCD patients. Our prior studies in the Townes transgenic murine model indicate mice with homozygous SCD (SS) recapitulate the age-related clinical deterioration seen in humans, as evidenced by the sudden decline in survival of SS mice during the transition from adolescence to adulthood. We previously determined that concurrently, the severity of intravascular hemolysis increases during this transition period. The cardiac phenotype of this murine model of SCD has not been defined.Hypothesis:Townes sickle cell mice display age related structural and functional cardiac changes, comparable to people with sickle cell diseaseMethods:We performed high resolution 2D echocardiographic imaging in 1-, 3- 6- and 10- month-old Townes SS mice and littermates with the normal adult human hemoglobin A (AA mice). Standard indices of LV systolic function, size, and mass were derived from short axis B-mode images.Results:There were significant differences in the cardiac phenotype in SS vs AA littermates at 6 and 10 months of age. At 10 months, SS mice had larger hearts (p< 0.0001) vs AA littermates. Compared to AA littermates, SS mice developed LV hypertrophy: LV systolic and diastolic internal dimensions and LV Mass Index were higher in SS mice (p=0.03). Similarly, systolic (p< 0.0001) and diastolic volumes (p=0.0002) were higher in SS mice vs AA littermates, with a trend towards an increase in stroke index (p=0.06) and cardiac index (p=0.06) in SS mice. LV systolic dysfunction was evidenced at 10 months by a lower ejection fraction (p=0.003) and fractional shortening (p=0.02) in SS vs. AA mice, with some SS mice exhibiting myocardial fibrosis on post mortem histology. Compared to baseline, LV mass, LVID, LV volumes and LV systolic dysfunction significantly increased with age in SS, but not AA mice.Conclusion:Townes SS mice develop LV systolic dysfunction, LV enlargement and dilation as they age. Future studies are aimed at delineating the specific molecules and cognate pathways downstream of intravascular hemolysis that promote cardiomyopathy in SCD. |
