A new twist on an old idea: a two-dimensional speckle tracking assessment of cyclosporine as a therapeutic alternative for heart failure with preserved ejection fraction

Abstract

We recently reported that mitochondrial dysfunction, characterized by increased mitochondrial permeability transition (MPT), was present in a translational swine model of heart failure with preserved ejection fraction (HFpEF). Cyclophilin D is a key component of the MPT pore, therefore, the purpose of this study was to test the efficacy of a novel cyclosporine (CsA) dosing scheme as a therapeutic alternative for HFpEF. Computed tomography (CT), two‐dimensional speckle tracking two‐dimensional speckle tracking (2DST), and invasive hemodynamics were used to evaluate cardiac function. CT imaging showed 14 weeks of CsA treatment caused eccentric myocardial remodeling (contrasting concentric remodeling in untreated HF animals) and elevated systemic pressures. 2DST detected left ventricular (LV) mechanics associated with systolic and diastolic dysfunction prior to the onset of significantly increased LV end diastolic pressure including: (1) decreased systolic apical rotation rate, longitudinal displacement, and longitudinal/radial/circumferential strain; (2) decreased early diastolic untwisting and longitudinal strain rate; and (3) increased late diastolic radial/circumferential mitral strain rate. LV mechanics associated with systolic and diastolic impairment was enhanced to a greater extent than seen in untreated HF animals following CsA treatment. In conclusion, CsA treatment accelerated the development of heart failure, including dilatory LV remodeling and impaired systolic and diastolic mechanics. Although our findings do not support CsA as a viable therapy for HFpEF, 2DST was effective in differentiating between progressive gradations of developing HF and detecting diastolic impairment prior to the development of overt diastolic dysfunction.

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

“…As shown by our lab17, 23 and others,30, 31, 32 aortic‐banded swine develop significant LV hypertrophy. Regarding our hypothesis, changes in cGMP levels and PDE5 activity following treatment with tadalafil or saxagliptin, respectively, did not limit LV hypertrophic remodeling in response to chronic pressure overload from a gross morphological perspective.…”

“…Animals were initially anesthetized with a telazol (5 mg·kg −1 )/xylazine (2.25 mg·kg −1 ) mix and maintained on propofol (6–10 mg·kg −1 ·min −1 with bolus as needed) as previously described 17. Heparin was given with an initial loading dose of 300 U/kg IV, followed by maintenance of 100 U/kg each hour.…”

“…Transthoracic echocardiography was performed with animals under telazol/xylazine sedation (2.25/1.12 mg·kg −1 ) in the supine/right lateral position 6 months postbanding as previously described 17, 18, 19. Short‐axis 2‐dimensional M‐mode images were recorded at the midpapillary level using a GE Vivid I Ultrasound system with a 2.5‐MHz transducer, and all analyses were performed offline using GE EchoPac Software.…”

“…Relative wall thickness (normalized to LVIDd) was calculated as (LV WTd+IVS WTd)/LVIDd×1000. Six segments of the LV and septum were generated from apical 4‐chamber and short‐axis 2‐dimensional views (acquired at the mitral‐valve and apex levels) and averaged to determine global strain, strain rate, and displacement in the longitudinal, radial, and circumferential directions over 3 cardiac cycles using 2‐dimensional speckle tracking 17, 18, 21. Torsion was calculated as the difference between mitral and apical end‐systolic rotation (degrees) and normalized to both LV hypertrophy (wall thickness) and end‐diastolic chamber length as previously described 17, 22…”

“…Therefore, the purpose of this study was to assess the effects of promoting cGMP signaling on LV remodeling and function via 2 mechanisms: (1) stimulating cGMP synthesis with the DPP‐4 inhibitor saxagliptin; and (2) reducing cGMP catabolism with the PDE5 inhibitor tadalafil. We performed these experiments in aortic‐banded miniature swine exhibiting key clinical characteristics of HFpEF including preserved ejection fraction at rest, diastolic dysfunction, depressed contractile reserve, LV fibrosis, and lung congestion 16, 17, 18, 19. Although we originally hypothesized that preservation of cGMP levels would attenuate pathological remodeling and preserve normal LV function in an experimental setting of HF, our results suggest the myocardial effects of saxagliptin and tadalafil occur independently of increasing downstream protein kinase G (PKG) activity.…”