HBOC Attenuates Intense Exercise-Induced Cardiac Dysfunction

Abstract

The purpose of this study was to investigate whether hemoglobin-based oxygen carrier (HBOC) could protect the heart from intense exercise-induced myocardial dysfunction. Adult male Sprague-Dawley rats were subjected to 5-h intense prolonged running on treadmill with or without HBOC pre-treatment. Immediately after exercise, the heart rate (HR) and oxygen delivery capacity of the blood were measured. After 1 h of rest, echocardiography was performed to assess the post-exercise cardiac function. Then all the hearts were isolated and perfused using the Langendorff model for 1 h. Our results proved that pronged exercise caused significant LV dysfunction, while HBOC pre-treatment attenuated such a damage, as evidenced by the increased oxygen delivery, cardiac fractional shortening (FS), rate-pressure product (RPP), ±dp/dt and coronary flow rate (CF) and decreased myocardial necrosis. The releases of cardiac enzymes, including creatine kinase-MB (CK-MB) and cardiac troponin-I (cTnI) were markedly reduced. No significant difference of cardiac infarct size was observed among groups. In addition, HBOC significantly elevated superoxide dismutase (SOD) activity and decreased hydrogen peroxide (H₂O₂) formation, which indicated the exercise-induced cardiac oxidative damage was inhibited. In conclusion, HBOC pre-treatment showed a promising cardioprotective effect on prolonged exercise-induced cardiac dysfunction, which was probably associated with its ability to decrease myocardium oxidative stress.

Key words

hemoglobin-based oxygen carrier - exercise - echocardiography - myocardium - oxidative stress

• References

• 1 D’Agnillo F, Chang TM. Polyhemoglobin-superoxide dismutase-catalase as a blood substitute with antioxidant properties. Nat Biotechnol 1998; 16: 667-671
• 2 Di Meo S, Venditti P. Mitochondria in exercise-induced oxidative stress. Neurosignals 2001; 10: 125-140
• 3 Elosua R, Arquer A, Mont L, Sambola A, Molina L, Garcia-Moran E, Brugada J, Marrugat J. Sport practice and the risk of lone atrial fibrillation: A case-control study. Int J Cardiol 2006; 108: 332-337
• 4 Gannon CJ, Napolitano LM. Severe anemia after gastrointestinal hemorrhage in a Jehovah’s witness: New treatment strategies. Crit Care Med 2002; 30: 1893-1895
• 5 Harriss DJ, Atkinson G. Update – Ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
• 6 Heidbuchel H, Hoogsteen J, Fagard R, Vanhees L, Ector H, Willems R, Van Lierde J. High prevalence of right ventricular involvement in endurance athletes with ventricular arrhythmias. Eur Heart J 2003; 24: 1473-1480
• 7 Hood S, Northcote RJ. Cardiac assessment of veteran endurance athletes: A 12 year follow up study. Br J Sports Med 1999; 33: 239-243
• 8 Jensen-Urstad K, Saltin B, Ericson M, Storck N, Jensen-Urstad M. Pronounced resting bradycardia in male elite runners is associated with high heart rate variability. Scand J Med Sci Sports 1997; 7: 274-278
• 9 Ji LL. Exercise at old age: Does it increase or alleviate oxidative stress?. Ann N Y Acad Sci 2001; 928: 236-247
• 10 Kakarla P, Vadluri G, Sathyavelu Reddy K, Leeuwenburgh C. Vulnerability of the mid aged rat myocardium to the age-induced oxidative stress: Influence of exercise training on antioxidant defense system. Free Radic Res 2005; 39: 1211-1217
• 11 Levy JH, Goodnough LT, Greilich PE, Parr GVS, Stewart RW, Gratz I, Wahr J, Williams J, Comunale ME, Doblar D, Silvay G, Cohen M, Jahr JS, Vlahakes GJ. Polymerized bovine hemoglobin solution as a replacement for allogeneic red blood cell transfusion after cardiac surgery: Results of a randomized, double-blind trial. J Thorac Cardiovasc Surg 2002; 124: 35-42
• 12 Li T, Li J, Liu J, Zhang P, Wu W, Zhou R, Li G, Zhang W, Yi M, Huang H. Polymerized placenta hemoglobin attenuates ischemia/reperfusion injury and restores the nitroso-redox balance in isolated rat heart. Free Radic Biol Med 2009; 46: 397-405
• 13 Li T, Liu J, Yang C. Pretreatment with hemoglobin-based oxygen carriers protect isolated rat heart from myocardial infarction. Artif Cells Blood Substit Immobil Biotechnol 2010; 38: 115-118
• 14 Li T, Liu J, Yang Q, Wu W, Zhang P, Yang J, Li J, Zhang W, Yang C. Polymerized placenta hemoglobin improves cardiac functional recovery and reduces infarction size of isolated rat heart. Artif Cells Blood Substit Immobil Biotechnol 2009; 37: 48-52
• 15 Li T, Yu R, Zhang HH, Wang H, Liang WG, Yang XM, Yang CM. A method for purification and viral inactivation of human placenta hemoglobin. Artif Cells Blood Substit Immobil Biotechnol 2006; 34: 175-188
• 16 Li T, Zhang P, Liu J, Zhou R, Li Q, You Z, Dian K. Protective effects of hemoglobin-based oxygen carrier given to isolated heart during ischemia via attenuation of mitochondrial oxidative damage. Free Radic Biol Med 2010; 48: 1079-1089
• 17 Lieb W, Sullivan LM, Aragam J, Harris TB, Roubenoff R, Benjamin EJ, Vasan RS. Relation of serum leptin with cardiac mass and left atrial dimension in individuals >70 years of age. Am J Cardiol 2009; 104: 602-605
• 18 Middleton N, George K, Whyte G, Gaze D, Collinson P, Shave R. Cardiac troponin t release is stimulated by endurance exercise in healthy humans. J Am Coll Cardiol 2008; 52: 1813-1814
• 19 Moore EE, Johnson JL, Cheng AM, Masuno T, Banerjee A. Insights from studies of blood substitutes in trauma. Shock 2005; 24: 197-205
• 20 Neilan TG, Januzzi JL, Lee-Lewandrowski E, Ton-Nu T-T, Yoerger DM, Jassal DS, Lewandrowski KB, Siegel AJ, Marshall JE, Douglas PS, Lawlor D, Picard MH, Wood MJ. Myocardial injury and ventricular dysfunction related to training levels among nonelite participants in the Boston marathon. Circulation 2006; 114: 2325-2333
• 21 Nie J, Close G, George K, Tong T, Shi Q. Temporal association of elevations in serum cardiac troponin t and myocardial oxidative stress after prolonged exercise in rats. Eur J Appl Physiol 2010; 110: 1299-1303
• 22 Sahlin K, Shabalina I, Mattsson M, Bakkman L, Fernstrm M, Rozhdestvenskaya Z, Enqvist J, Nedergaard J, Ekblom B, Tonkonogi M. Ultra-endurance exercise increases the production of reactive oxygen species in isolated mitochondria from human skeletal muscle. J Appl Physiol 2010; 108: 780-787
• 23 Seddon M, Looi YH, Shah AM. Oxidative stress and redox signalling in cardiac hypertrophy and heart failure. Heart 2007; 93: 903-907
• 24 Shave R, Baggish A, George K, Wood M, Scharhag J, Whyte G, Gaze D, Thompson PD. Exercise-induced cardiac troponin elevation: Evidence, mechanisms, and implications. J Am Coll Cardiol 2010; 56: 169-176
• 25 Shave R, George KP, Atkinson G, Hart E, Middleton N, Whyte G, Gaze D, Collinson PO. Exercise-induced cardiac troponin t release: A meta-analysis. Med Sci Sports Exerc 2007; 39: 2099-2106
• 26 Shave RE, Whyte GP, George K, Gaze DC, Collinson PO. Prolonged exercise should be considered alongside typical symptoms of acute myocardial infarction when evaluating increases in cardiac troponin t. Heart 2005; 91: 1219-1220
• 27 Siscovick DS, Weiss NS, Fletcher RH, Lasky T. The incidence of primary cardiac arrest during vigorous exercise. N Engl J Med 1984; 311: 874-877
• 28 Standl T, Freitag M, Burmeister MA, Horn EP, Wilhelm S, Am Esch JS. Hemoglobin-based oxygen carrier hboc-201 provides higher and faster increase in oxygen tension in skeletal muscle of anemic dogs than do stored red blood cells. J Vasc Surg 2003; 37: 859-865
• 29 Whyte GP. Clinical significance of cardiac damage and changes in function after exercise. Med Sci Sports Exerc 2008; 40: 1416-1423
• 30 Wu W, Li T, Liu J, Yang C. Pretreatment before ischemia induction with polymerized human placenta hemoglobin (polyphb) attenuates ischemia/reperfusion injury-induced myocardial apoptosis. Artif Cells Blood Substit Immobil Biotechnol 2011; 39: 3-6
• 31 You Z, Li T, Yang C, Wu H, Zeng Y. Comparison of the cardioprotective effect of deoxygenated hemoglobin-based oxygen carrier (hboc) pretreatment and ischemia preconditioning. Artif Cells Blood Substit Immobil Biotechnol 2011; 39: 7-11