Repetitive Preload Elevation and Stretch‐Induced Stiffening of Non‐Ischemic Myocardium in a Porcine Model of Multi‐Vessel Coronary Artery Disease

Abstract

Objective We have recently shown that a transient elevation in left ventricular (LV) preload causes stretch-induced myocyte injury, with repetitive episodes resulting in interstitial fibrosis and reduced diastolic compliance. The present study was designed to test the hypothesis that this phenomenon contributes to stiffening of remote, non-ischemic myocardium that is subjected to repetitive preload elevation secondary to demand-induced ischemia in the setting of chronic multi-vessel coronary artery disease (CAD). Methods Swine (n=12) were instrumented with fixed 1.5 mm constrictors on the proximal left anterior descending (LAD) and left circumflex (LCx) coronary arteries. One month later, continuous ECG and LV pressure monitoring was initiated via implantable telemetry (PhysioTel Digital, DSI) to assess the frequency of preload elevation (LV end-diastolic pressure (EDP) > 30 mmHg) and tachycardia (heart rate > 170 beats/min). Serial physiological studies were performed for 3 months to assess stenosis severity (angiography), coronary flow reserve (fluorescent microspheres at rest and during adenosine vasodilation), and LV function (echocardiography). Circumferential diastolic stiffness was derived from stress-strain relationships obtained via speckle tracking echocardiography and invasive measurements of LV minimum pressure and EDP. Myocardial tissue samples were subsequently collected from the LAD (ischemic) and right coronary artery (RCA; non-ischemic) perfusion territories for post-mortem quantification of collagen content (hydroxyproline assay) and comparison to normal controls (n=8). Results By the end of the 3 month study period, animals exhibited severe LAD (93 ± 2 %) and LCx (91 ± 3 %) stenoses and significant reductions in subendocardial flow reserve (LAD: 1.4 ± 0.2; LCx: 1.3 ± 0.2) relative to the RCA territory (3.8 ± 0.6). Although LV EDP was only mildly elevated at rest (18 ± 2 mmHg), transient preload elevation occurred frequently (63 ± 10 episodes/day) and resulted in a total of 199 ± 45 min/day during which LV EDP exceeded 30 mmHg. Spontaneous tachycardia was also common (26 ± 5 episodes/day) and associated with transient elevations in LV EDP (28 ± 2 mmHg; p<0.05 vs. rest). Although LV ejection fraction was preserved (58 ± 3 %), radial and circumferential strain was depressed in ischemic and non-ischemic segments of the LV compared with controls (Table). Non-ischemic segments also exhibited increased diastolic stiffness, which coincided with a significant ~40% elevation in collagen content (0.31 ± 0.03 mg/g) vs. normal controls (0.22 ± 0.03 mg/g) that was comparable to that observed in the ischemic area of the LV (0.29 ± 0.02 mg/g). Conclusions Transient elevations in preload are common in swine with multi-vessel CAD and associated with interstitial fibrosis and myocardial stiffening in normally-perfused segments of the LV. Repetitive stretch-induced stiffening of remote myocardium may contribute to diastolic dysfunction and could explain the high prevalence of angiographically-significant CAD in patients with heart failure with preserved ejection fraction (HFpEF).