Myocardial Adaptations to Chronic Intermittent Pressure Overload Protect the Heart Against Stretch‐Induced Stunning and Cardiac Troponin I Release

Objective Our laboratory has recently demonstrated that a transient episode of left ventricular (LV) pressure overload produces reversible systolic dysfunction that persists upon normalization of arterial blood pressure in swine. This pattern of stretch‐induced stunning occurs in the absence of ischemia and is accompanied by measurable elevations in serum cardiac troponin I (cTnI) concentrations, indicative of myocardial injury. We hypothesized that two weeks of intermittent pressure overload would elicit myocardial adaptations that protect the heart against stretch‐induced stunning and cTnI release. Methods Propofol‐anesthetized swine (n=9) received intravenous phenylephrine (PE; 300 μg/min) for one hour to transiently raise arterial blood pressure. Hemodynamics and LV function (echocardiography) were monitored every 15‐minutes throughout the PE infusion and for one hour during recovery. Blood samples were collected at baseline, as well as 1‐hour and 24‐hours after PE for assessment of serum cTnI concentrations. Animals were then instrumented with a jugular vein catheter through which PE was infused once daily for two hours to elicit intermittent pressure overload. Two weeks later, PE infusion was repeated in the laboratory and hemodynamics, LV function, and serum cTnI levels were assessed in an identical fashion to the initial study. Results PE induced a significant rise in mean arterial pressure that was similar before (from 86±5 to 176±3 mmHg; p<0.05) and after (84±6 to 179±11 mmHg; p<0.05) two weeks of intermittent pressure overload. During the initial study, PE increased LV end‐diastolic volume (ΔEDV: 34±6 mL, p<0.05) and LV end‐diastolic pressure (ΔEDP: 22±3 mmHg, p<0.05), resulting in systolic dysfunction that persisted 1‐hour after PE along with a significant elevation in serum cTnI (Table). Two weeks later, PE did not significantly affect LV EDV (ΔEDV: 9±3 mL, p=ns) despite a similar increase in LV EDP (ΔEDP: 18±2 mmHg, p<0.05), indicative of elevated LV stiffness during pressure overload (ΔEDP/ΔEDV from 0.7±0.1 to 5.1±2.3 mmHg/mL, p<0.05). This increase in LV stiffness occurred in the absence of LV hypertrophy (LV mass/body mass ratio: 2.3±0.1 vs. 2.4±0.1 g/kg, p=ns) and prevented pressure overload‐induced myocardial stunning and cTnI release (Table). Conclusion These results demonstrate that chronic intermittent pressure overload elicits an adaptive increase in LV stiffness that prevents after load‐induced LV stretch in swine. The attenuation of pressure overload‐mediated LV dilatation protects the heart against stretch‐induced stunning and myocardial injury, as reflected by preserved systolic function and the absence of serum cTnI release 1‐hour after a transient elevation in arterial blood pressure. Support or Funding Information Funding Sources: The National Heart Lung and Blood Institute (HL‐055324, HL‐061610, and F32HL‐114335), the National Center for Advancing Translational Sciences (UL1TR001412), the Department of Veterans Affairs (1IO1BX002659) and the Albert and Elizabeth Rekate Fund in Cardiovascular Medicine.Initial Study (n=9) Final Study (n=8)Baseline 60 minutes Post‐PE Baseline 60 minutes Post‐PEHeart Rate (beats/min) 92 ± 7 90 ± 7 96 ± 4 97 ± 8Mean Arterial Pressure (mmHg) 86 ± 5 80 ± 5 84 ± 6 91 ± 9LV dP/dt max (mmHg/sec) 2243 ± 88 1605 ± 170 * 2465 ± 201 2195 ± 278LV Ejection Fraction (%) 69 ± 3 51 ± 7 * 71 ± 2 70 ± 2 #Serum cTnl (ng/L) 13 ± 9 186 ± 69 * 5 ± 5 15 ± 10 #Values are mean ± SEM; * p<0.05 vs. Baseline; # p<0.05 vs. Initial Study