Abstract Body: Hypertension affects nearly half of American adults, inevitably leading to cardiac dysfunction and heart failure. Cardiac fibrosis is a major factor contributing to cardiac dysfunction during hypertension progression. However, the mechanisms involved in cardio-fibrogenesis remain to be elucidated. In the past decade, studies revealed that macrophages could differentiate into professional fibrotic cells, myofibroblasts, through a process termed macrophage to myofibroblast transition (MMT), helping maintain the integrity of major organs, such as the kidney. However, it is unknown whether MMT contributes to fibrotic remodeling in hypertensive hearts. Here, we aim to identify this phenomenon in the hearts of hypertensive animals and determine the role it plays in the pathological progression from hypertension to cardiac diastolic dysfunction.
In this study we adopt the classic DOCA + Salt model of hypertension and utilized cardiac ultrasound and direct left ventricular (LV) pressure catheterization to gauge diastolic function. Heart sections from hypertensive and sham mice were stained with Masson’s trichrome to assess the extent of cardiac fibrosis. Furthermore, flow cytometry was utilized to identify MMT cells, which express both CD68 (monocytes) and α-SMA (myofibroblast) markers. These methods gave insight into the role that MMT plays in the degradation of heart function during hypertension.
Direct left ventricle pressure catheter revealed that DOCA + salt mice exhibited impaired diastolic function. This result is supported by cardiac ultrasound showing that the compliance of the heart had significantly decreased, as evidenced by the lowering of the efferent/atrial (E/A) ratio and deceleration time (DcT). In addition to this evidence of mechanical cardiac degradation, leukocytes isolated from the heart and stained with macrophage and myofibroblast markers revealed a significant increase in CD68+ & αSMA+ cells—a result reflected by increased fibrotic remodeling via Masson’s trichrome stain, in the hypertensive animals.
This study demonstrated an onset of diastolic dysfunction in the heart of DOCA + salt hypertensive mice. Moreover, we found a positive association between MMT cells and fibrosis in the hearts of hypertensive animals. Future studies will aim to parse out both the gravity of MMT in hypertensive heart dysfunction and the mechanism by which macrophages undergo this transition to find new targets against this debilitating disease.