Persistent Left Ventricular Diastolic Stiffening Despite Cessation of Intermittent Myocardial Stretch in Swine
Journal Articles
Overview
Research
Identity
Additional Document Info
View All
Overview
abstract
ObjectiveBuilding on our observation that myocardial stretch induced by an acute elevation in left ventricular (LV) preload produces reversible systolic dysfunction and cardiomyocyte apoptosis, we recently demonstrated that swine subjected to intermittent myocardial stretch (IMS) for 2 weeks exhibit an adaptive increase in LV diastolic stiffness that protects the heart from stretch‐induced injury during subsequent periods of hemodynamic overload. The present study was designed to determine whether this pattern of myocardial remodeling and protection against stretch‐induced stunning is reversed by cessation of IMS.MethodsSwine (n=6) were instrumented with an indwelling jugular vein catheter through which phenylephrine (PE; 300 μg/min; 2 hours/day) was administered via programmable infusion pump to intermittently raise LV end‐diastolic pressure (EDP) for 2 weeks (IMS). Hemodynamic and echocardiographic responses were evaluated under propofol anesthesia at the initial study and after 2‐weeks of IMS. Daily PE infusions were subsequently stopped to provide a 2‐week period in which animals were no longer subjected to IMS. A final physiologic study was then performed (“4‐week study”) to assess the persistence of IMS‐induced alterations in LV function. At each study, serial blood sampling was performed to assess serum cTnI levels via porcine‐specific ELISA. Postmortem analysis of interstitial collagen deposition was completed on picrosirius red‐stained LV tissue sections and compared to animals subjected to 2 weeks of IMS (n=8) and age‐matched controls (n=5).ResultsAt the initial study, PE‐induced preload elevation elicited a significant increase in LV end‐diastolic volume (ΔEDV: 14±3 mL/m2, p<0.05) that caused stretch‐induced stunning and a marked elevation in serum cTnI (Figure). After 2 weeks of IMS, chamber dilatation during PE was attenuated (ΔEDV: 4±1 mL/m2, p=ns) by a significant increase in LV diastolic stiffness (ΔEDP/ΔEDV during PE from 0.8±0.2 to 2.3±0.5 mmHg/mL, p<0.05) that prevented stretch‐induced systolic dysfunction and cTnI release (Figure). Adaptive LV stiffening (ΔEDP/ΔEDV: 3.3±1.4 mmHg/mL) and protection against stretch‐induced injury (ΔEDV: 3±1 mL/m2) were still observed at the 4‐week study despite cessation of IMS during the previous 2 weeks. Persistent LV diastolic stiffening was also demonstrated by admittance catheter‐derived assessment of the EDPVR, which revealed an increase in the LV stiffness constant (β) at the 2‐week (0.055±0.013) and 4‐week (0.043±0.009) studies compared with normal controls (0.025±0.003; both p<0.05). Consistent with the notion that IMS‐induced remodeling is not reversed by cessation of episodic preload elevation, interstitial collagen deposition after the 4‐week study (16.3±1.1%) was comparable to that observed in animals subjected to 2 weeks of IMS (11.2±1.3 %) and significantly higher than normal controls (6.6±0.7 %).ConclusionThese results demonstrate that IMS‐induced LV diastolic stiffening is not reversed by simply discontinuing transient episodes of hemodynamic overload. This likely relates to an inability to replenish myocytes lost to stretch‐induced apoptosis and remove interstitial collagen without additional regenerative and/or anti‐fibrotic therapy. These findings may have implications for the treatment of patients with heart failure with preserved ejection fraction whom exhibit LV stiffening without persistent hypertension or anatomic LV hypertrophy.Support or Funding InformationSupported by the National Heart Lung and Blood Institute (HL‐055324 and HL‐061610), the American Heart Association (17SDG33660200), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659), and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
