Metabolic syndrome (MetS) is associated with Heart Failure with Preserved Ejection Fraction (HFpEF), characterized by diastolic dysfunction, notably affecting elderly menopausal women. To improve treatment strategies, deepened pathophysiological understanding of potential gender-specific mechanisms contributing to ventricular stiffening is needed.

We hypothesized that lymphatic alterations in the heart may contribute to cardiac inflammation and edema promoting cardiac fibrosis and dysfunction in a gender-specific manner.

We investigated cardiovascular function by echocardiography, hemodynamic analyses, MRI, ex vivo coronary arteriography, and cardiac remodeling and inflammation by immunohistochemistry and flow cytometry in male and ovariectomized (ovx.) female obese Zucker (fa/fa) rats and their lean controls up to 24-weeks of age.

Whereas body weight gain, insulin resistance, and diastolic dysfunction were similar in 24-weeks-old obese animals of both genders, only male obese rats displayed coronary endothelial dysfunction and reduced cardiac perfusion as compared to lean animals. In contrast, only female ovx. obese rats displayed significant cardiac hypertrophy as well as remodeling and rarefaction of cardiac lymphatics accompanied by persistent low-grade cardiac inflammation at both 14- and 24-weeks of age. The cardiac infiltration was characterized by increased levels of B lymphocytes, and both pro-inflammatory (M1) and non-classical (M2-like) monocytes, as well as increased frequency of M1 type macrophages. The monocytosis was linked to increased cardiac expression of CCL2. Studies are ongoing to determine chemokine expression changes in coronary endothelial cells.

In conclusion, our data show that gender-specific mechanisms involving cardiac lymphatics may underlie development of MetS-related diastolic dysfunction, suggesting novel therapeutic targets to prevent HFpEF in patients with MetS.