Enhanced diastolic dysfunction but preserved systolic function after acute pressure overload in the absence of smoothelin-like 1 protein

Abstract Aims Smoothelin-like 1 (SMTNL1), a protein kinase A/G target protein, modulates the activity and expression of myosin light chain phosphatase and thus plays an important role in regulating vasoconstriction. Increased myogenic reactivity of resistance arterioles is associated with SMTNL1 silencing, and elevated baseline vascular tone is increasingly recognized as a risk factor for development of hypertension and chronic congestive heart failure. Hence, in this study we assessed cardiac function in SMTNL1 knockout mice with and without accompanying acute cardiac stress (i.e., pressure overload by transverse aortic constriction). Methods and Results Male and female, global Smtnl1 knockout (KO) & wild-type (WT) mice were assessed at 10 weeks of age by echocardiography and electrocardiography to define baseline cardiac function. Gross dissection revealed distinct cardiac morphology only in male mice; hearts from KO animals were significantly smaller than WT littermates but the proportion of heart mass taken up by LV was greater. Non-invasive analyses of KO mice showed reduced resting heart rate with improved ejection fraction and fractional shortening as well as elevated aortic and pulmonary flow velocities relative to their WT counterparts, but only in the male cohort. We further investigated the impact of acute pressure overload on cardiac morphometry and hemodynamics in the absence of SMTNL1 in male cohort using echocardiography and pressure-volume (PV) loop measurements. Interestingly, PV loop analysis revealed diastolic dysfunction with significantly increased end diastolic pressure and LV relaxation time along with a steeper end diastolic pressure-volume relationship an indicator of stiffer heart, in the KO group when compared to WT Sham-operated group. Sham KO mice also showed elevated arterial elastance and total peripheral resistance. With acute pressure overload, systolic function was preserved, but diastolic dysfunction was exacerbated in KO mice with higher E/E’ ratio and myocardial performance index along with a prolonged isovolumetric relaxation time relative to the aortic-banded WT group. Conclusion Taken together, the findings support a novel, sex-dimorphic role for SMTNL1 in modulating cardiac structure and diastolic function. Significantly, impairment of diastolic function following pressure overload in young animals lacking SMTNL1 is mainly driven by increased systemic vascular resistance, which mimics the clinical pathophysiology of heart failure with preserved ejection fraction (HFpEF). Translational Perspective Heart failure with preserved ejection fraction (HFpEF) is characterized by the impairment of diastolic function and accounts for half of all heart failure cases. Unfortunately, there is as yet no proven therapy available for these patients as the pathophysiology is complicated with the presence of multiple comorbidities, microvascular dysfunction and a lack of an ideal animal model. The phenotype of Smtnl1 global deletion male mice exhibits intriguing similarities to HFpEF, with elevated microvascular resistance driving diastolic dysfunction and LV remodeling. As such the SMTNL1 KO mouse represents a novel pre-clinical model to study the molecular etiology of HFpEF.

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