Simplified and refined murine model of reversible aortic constriction for characterizing cardiac functional recovery

Abstract

BackgroundHeart failure with reduced ejection fraction (HFrEF) is a major clinical issue with a poor prognosis. Structural and functional recovery, known as "reverse remodeling (RR)," has been observed in subsets of patients who respond favorably to treatment. However, progress in understanding the mechanisms behind RR has been hindered by a lack of animal models that accurately replicate this complex process. ObjectivesWe introduced a convenient and reproducible modification to the widely used transaortic constriction (TAC) procedure that allows for refined, timed, and noninvasive aortic de-banding (de-TAC), and functional recovery. MethodsA modified and releasable knot was used for an initial aortic constriction. Suture ends were left accessible from underneath the skin layer following the TAC surgery. After three weeks, deTAC was performed by re-opening in the skin layer and pulling on the suture to release the constriction. We assessed cardiac function, strain, and geometry with 2D and 4D ultrasound at baseline, 3 weeks after TAC, 1 week- and 4 weeks after deTAC. Tissue remodeling and cellular infiltration was characterized by quantifying fibrosis and fibroblast numbers via immunofluorescence. ResultsUltrasound revealed that aortic de-banding was associated with both functional and mechanical recovery. Cardiac function and strain decreased due to pressure overload, exhibiting characteristics of systolic dysfunction, but recovered to near baseline values by 1 week after deTAC. However, left ventricular mass, fibrosis and fibroblast numbers remained elevated, despite functional recovery. ConclusionThis simplified and refined TAC-based model of RR significantly facilitates and enhances research on cardiac remodeling and recovery. CONDENSED ABSTRACTA subset of heart failure patients (HF) respond favorably to treatment, displaying functional recovery via a process known as reverse remodeling (RR). Developing RR models will be key to characterizing currently elusive mechanisms driving this process and ultimately identifying potential therapeutic targets. Transverse aortic constriction (TAC) in rodents increases the afterload on the LV and is a common model of heart failure due to pressure overload. Here, we report a convenient and reproducible method that allows for precisely timed and surgery-free removal of aortic constriction (de-TAC). When performed 3-weeks after TAC, de-TAC produced significant cardiac functional recovery, with normalization of ejection fraction and strain assessed by 2D and 4D echocardiography, respectively. However, signs of adverse myocardial remodeling persisted, including hypertrophy, fibrosis, and elevated fibroblast numbers. In the relatively young field of cardiac RR, our method could facilitate investigations of functional, structural, cellular, and molecular changes underlying recovery from HF. VISUAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=194 HEIGHT=200 SRC="FIGDIR/small/646758v2_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@7b0d62org.highwire.dtl.DTLVardef@abc428org.highwire.dtl.DTLVardef@db2fe0org.highwire.dtl.DTLVardef@243950_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LIAdaptation to the widely used transverse aortic constriction (TAC) procedure allows for minimally invasive de-TAC for studying reverse remodeling. C_LIO_LIThis model increases feasibility and reproducibility, with no requirement for additional instruments or materials. C_LIO_LIState-of the art 4DUS assessment of cardiac function, mechanics, and geometry shows extensive left-ventricular remodeling and significant recovery of function following de-TAC. C_LIO_LICardiac fibrosis is persistent following functional recovery from heart failure with reduced ejection fraction (HFrEF). C_LI