Comportamiento Antiarritmico de la Hipoxia, Conclusiones

En este trabajo se ha presentado un modelo de pared transmural heterogénea cardiaca en presencia de una lesión isquémica subepicárdica. Los diferentes gradientes bioquímicos de la isquemia fueron modelados, presentándose un comportamiento antiarrítmico de la activación de los canales de potasio dependientes de ATP si su valor ha de exceder la cantidad normal.

La activación de los canales KATP mostró una alteración marcada del proceso de repolarización del tejido virtual en la zona lesionada, y un aumento de la velocidad de conducción del frente después de presentarse el bloqueo unidireccional en la zona de borde.

La heterogeneidad del tejido acrecienta los gradientes de repolarización y velocidad de conducción en el tejido, conllevando un aumento de la vulnerabilidad a presentar reentradas de potencial en la pared transmural.

Las alteraciones en la posrepolarización en la refractariedad en la zona de borde isquémica conforman el lecho funcional para la desestabilización del frente de onda del potencial. Estas alteraciones también detienen el frente reentrante de manera espontánea en la zona distal de la lesión modelada.

Los electrogramas de los diferentes componentes de la isquemia presentan alteraciones en el segmento ST y depresiones en el segmento TQ debido al gradiente de potasio extracelular entre la zona de borde y la lesionada.

Alteraciones de la onda T concuerdan con el gran desbalance del proceso de repolarización del tejido. Cuando se aplica el estímulo prematuro, existen deformaciones en amplitud y tiempo de duración en los segmentos RS y ST presentando evidencia conformacional del comienzo de una taquicardia polimórfica transmural debido a las diversas alteraciones producidas por la isquemia sub-epicárdica. (Lea también: Reentrada Espiral en Pared Transmural Heterogénea Sometida a Isquemia Regional)

Agradecimientos

Este trabajo fue parcialmente financiado por el Plan Nacional de Investigación Científica, Desarrollo
e Innovación Tecnológica del Ministerio de Educación y Ciencia de España (proyectos TIN2004-03602 y TEC 2005-04199/TCM).

Conflicto de Intereses

Los autores declaran que no existe conflicto de intereses en el desarrollo de este trabajo de investigación en ciencia básica cardiaca.

Referencia

1. Noma,A. ATP-regulated K+ channels in cardiac muscle. Nature. 1983; 305, 5930; 147-148.
2. Nichols,CG, Ripoll,C, and Lederer,WJ. ATP-sensitive potassium channel modulation of the guinea pig ventricular action potential and contraction. Circ. Res. 1991; 68, 1; 280-287.
3. J. M. jr. Ferrero , A. Ferrero, B. Trenor, F. Montilla, J. Saiz, and B. Rodriguez, “Ischemia,” in Wiley Encyclopedia of Biomedical Engineering. M. Akay, Ed. John Wiley & Sons,Inc, 2006, pp. 2086-2103.
4. Carmeliet,E. Cardiac ionic currents and acute ischemia: from channels to arrhythmias. Physiol Rev. 1999; 79, 3; 917-1017.
5. Cascio,WE, Johnson,TA, and Gettes,LS. Electrophysiologic changes in ischemic ventricular myocardium: I. Influence of ionic, metabolic, and energetic changes. J Cardiovasc. Electrophysiol. 1995; 6, 11; 1039-1062.
6. Gilmour,RF, Jr. and Zipes,DP. Different electrophysiological responses of canine endocardium and epicardium to combined hyperkalemia, hypoxia, and acidosis. Circ. Res. 1980; 46, 6; 814-825.
7. Furukawa,T, Kimura,S, Furukawa,N, Bassett,AL, and Myerburg,RJ. Role of cardiac ATP-regulated potassium channels in differential responses of endocardial and epicardial cells to ischemia. Circ. Res. 1991; 68, 6; 1693-1702.
8. Miyoshi,S, Miyazaki,T, Moritani,K, and Ogawa,S. Different responses of epicardium and endocardium to KATP channel modulators during regional ischemia. Am. J Physiol. 1996; 271, 1 Pt 2; p. H140-H147.
9. Di Diego,JM and Antzelevitch,C. Pinacidil-induced electrical heterogeneity and extrasystolic activity in canine ventricular tissues. Does activation of ATP-regulated potassium current promote phase 2 reentry? Circulation. 1993; 88, 3; 1177-1189.
10. Lowe,JE, Cummings,RG, Adams,DH, and Hull-Ryde,EA. Evidence that ischemic cell death begins in the subendocardium independent of variations in collateral flow or wall tension. Circulation. 1983; 68, 1; 190-202.
11. Alekseev,A, Hodgson,D, Karger,A et al. ATP-sensitive K+ channel channel/enzyme multimer: Metabolic gating in the heart. Journal of Molecular and Cellular Cardiology. 2005; 38, 6; 895-905.
12. Zingman,LV, Alekseev,AE, Hodgson-Zingman,DM, and Terzic,A. ATP-sensitive potassium channels: metabolic sensing and cardioprotection. J Appl Physiol. 2007; 103, 5; 1888-1893.
13. Ferrari,R. Pathophysiological vs biochemical ischaemia: a key to transition from reversible to irreversible damage. European Heart Journal Supplements. 2001; 3, C; p. C2-C10.
14. Jennings,RB and Reimer,KA. Lethal myocardial ischemic injury. Am. J Pathol. 1981; 102, 2; 241-255.
15. Eltzschig,HK and Collard,CD. Vascular ischaemia and reperfusion injury. Br. Med. Bull. 2004; 70; 71-86.
16. Gallagher,KP, Gerren,RA, Stirling,MC et al. The distribution of functional impairment across the lateral border of acutely ischemic myocardium. Circ. Res. 1986; 58, 4; 570-583.
17. Heusch,G, Schulz,R, and Rahimtoola,SH. Myocardial hibernation: a delicate balance. Am. J Physiol Heart Circ. Physiol. 2005; 288, 3; p. H984-H999.
18. Heusch,G and Sipido,KR. Myocardial hibernation: a double-edged sword. Circ. Res. 2004; 94, 8; 1005-1007.
19. Luo,CH and Rudy,Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ. Res. 1994; 74,6; 1071-1096.
20. Viswanathan,PC, Shaw,RM, and Rudy,Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation. 1999; 99, 18; 2466-2474.
21. Zeng,J, Laurita,KR, Rosenbaum,DS, and Rudy,Y. Two components of the delayed rectifier K+ current in ventricular myocytes of the guinea pig type. Theoretical https://encolombia.com/medicina/academedicina/Academ330111/Formulation and their role in repolarization. Circ. Res. 1995; 77, 1; 140-152.
22. Henao,O, Ferrero,JMj, Ramírez,E, and Sáiz,J. Arritmias cardiacas generadas por heterogeneidad electrofisiológica: estudio mediante simulación. Rev. Colomb. Cardiol. 2007; 14, 4; 185-197.
23. Weidmann,S. Electrical constants of trabecular muscle from mammalian heart. J. Physiol. 1970; 210, 4; 1041-1054.
24. Jongsma,HJ and Wilders,R. Gap junctions in cardiovascular disease. Circ. Res. 2000; 86, 12; 1193-1197.
25. Kleber,AG and Rudy,Y. Basic mechanisms of cardiac impulse propagation and associated arrhythmias. Physiol Rev. 2004; 84, 2; 431-488.
26. Beaumont,J, Davidenko,N, Davidenko,JM, and Jalife,J. Spiral waves in two-dimensional models of ventricular muscle: formation of a stationary core. Biophys. J. 1998; 75, 1; 1-14.
27. Winfree,AT. Sudden cardiac death: a problem in topology. Sci. Am. 1983; 248, 5; 144-7, 160.
28. Coronel,R, Fiolet,JW, Wilms-Schopman,JG et al. Distribution of extracellular potassium and electrophysiologic changes during two-stage coronary ligation in the isolated, perfused canine heart. Circulation. 1989; 80, 1; 165-177.
29. Kim,RJ, Fieno,DS, Parrish,TB et al. Relationship of MRI delayed contrast enhancement to irreversible injury, infarct age, and contractile function. Circulation. 1999; 100, 19; 1992-2002.

30. Coronel,R. Heterogeneity in extracellular potassium concentration during early myocardial ischaemia and reperfusion: implications for arrhythmogenesis. Cardiovasc. Res. 1994; 28, 6; 770-777.
31. Ferrero,JM, Jr., Trenor,B, Rodriguez,B, and Saiz,J. Electrical activity and reentry during acute regional myocardial ischemia:insights from simulations. International Journal of Bifurcation and Chaos. 2003; 13, 12; 3703-3715.
32. Rubart,M and Zipes,DP. Mechanisms of sudden cardiac death. J. Clin. Invest. 2005; 115, 9; 2305-2315.
33. Ferrero,JM, Jr., Saiz,J, Ferrero,JM, and Thakor,NV. Simulation of action potentials from metabolically impaired cardiac myocytes. Role of ATP-sensitive K+ current. Circ. Res. 1996; 79, 2; 208-221.
34. Wu,J and Zipes,DP. Transmural reentry during acute global ischemia and reperfusion in canine ventricular muscle. Am. J. Physiol Heart Circ. Physiol. 2001; 280, 6; p. H2717-H2725.
35. Yan,GX, Shimizu,W, and Antzelevitch,C. Characteristics and distribution of M cells in arterially perfused canine left ventricular wedge preparations. Circulation. 1998; 98, 18; 1921-1927.
36. Poelzing,S and Rosenbaum,DS. Nature, significance, and mechanisms of electrical heterogeneities in ventricle. Anat. Rec. A Discov. Mol. Cell Evol. Biol. 2004; 280, 2; 1010-1017.
37. Akar,FG, Yan,GX, Antzelevitch,C, and Rosenbaum,DS. Unique topographical distribution of M cells underlies reentrant mechanism of torsade de pointes in the long- QT syndrome. Circulation. 2002; 105, 10; 1247-1253.
38. Dumaine,R, Towbin,JA, Brugada,P et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ. Res. 1999; 85, 9; 803-809.
39. Liu,DW and Antzelevitch,C. Characteristics of the delayed rectifier current (IKr and IKs) in canine ventricular epicardial, midmyocardial, and endocardial myocytes. A weaker IKs contributes to the longer action potential of the M cell. Circ. Res. 1995; 76, 3; 351-365.
40. Clayton,RH and Holden,AV. Propagation of normal beats and re-entry in a computational model of ventricular cardiac tissue with regional differences in action potential shape and duration. Prog. Biophys. Mol. Biol. 2004; 85, 2-3; 473-499.
41. Geselowitz,DB. On the theory of the electrocardiogram. Proceedings of the IEEE. 1989; 77, 6; 857-876.
42. Janse,MJ, van Capelle,FJ, Morsink,H et al. Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ. Res. 1980; 47, 2; 151-165.
43. Olshansky,B, Moreira,D, and Waldo,AL. Characterization of double potentials during ventricular tachycardia. Studies during transient entrainment. Circulation. 1993; 87, 2; 373-381.
44. Antzelevitch,C. Cellular Basis for the Repolarization Waves of the ECG. Ann. N. Y. Acad. Sci. 2006; 1080; 268-281.
45. vanOosterom,A. The dominant T wave and its significance. J Cardiovasc. Electrophysiol. 2003; 14, 10 Suppl; p. S180-S187.
46. Ferrero,J, Jr., Torres,V, Montilla,F, and Colomar,E. Simulation of reentry during acute myocardial ischemia: role of ATP-sensitive potassium current and acidosis. Computers in Cardiology. 2000; 27; 239-242.
47. Remme,CA and Wilde,AA. KATP channel openers, myocardial ischemia, and arrhythmias–should the electrophysiologist worry? Cardiovasc. Drugs Ther. 2000; 14, 1; 17-22.
48. Saito,T, Sato,T, Miki,T, Seino,S, and Nakaya,H. Role of ATP-sensitive K+ channels in electrophysiological alterations during myocardial ischemia: a study using Kir6.2-null mice. Am. J Physiol Heart Circ Physiol. 2005; 288, 1; p. H352-H357.
49. Jahangir,A and Terzic,A. K(ATP) channel therapeutics at the bedside. J Mol. Cell Cardiol. 2005; 39, 1; 99-112.
50. Seino,S and Miki,T. Physiological and pathophysiological roles of ATP-sensitive K+ channels. Prog. Biophys. Mol. Biol. 2003; 81, 2; 133-176.
51. Craig,TJ, Ashcroft,FM, and Proks,P. How ATP inhibits the open K(ATP) channel. J Gen. Physiol. 2008; 132, 1; 131-144.
52. Flagg,TP and Nichols,CG. Sarcolemmal K(ATP) channels: what do we really know? J Mol. Cell Cardiol. 2005; 39, 1; 61-70.
53. Taggart,P and Yellon,DM. Preconditioning and arrhythmias. Circulation. 2002; 106, 24; 2999-3001.
54. Yan,GX, Yamada,KA, Kleber,AG, McHowat,J, and Corr,PB. Dissociation between cellular K+ loss, reduction in repolarization time, and tissue ATP levels during myocardial hypoxia and ischemia. Circ Res. 1993; 72, 3; 560-570.
55. Janse,MJ and Wit,AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev. 1989; 69, 4; 1049-1169.
56. Taggart,P, Sutton,PM, Opthof,T et al. Transmural repolarisation in the left ventricle in humans during normoxia and ischaemia. Cardiovasc. Res. 2001; 50, 3; 454-462.
57. Sutton,PMI, Taggart,P, Opthof,T et al. Repolarisation and refractoriness during early ischaemia in humans. Heart. 2000; 84, 4; 365-369.
58. Kimura,S, Bassett,AL, Kohya,T, Kozlovskis,PL, and Myerburg,RJ. Simultaneous recording of action potentials from endocardium and epicardium during ischemia in the isolated cat ventricle: relation of temporal electrophysiologic heterogeneities to arrhythmias. Circulation. 1986; 74, 2; 401-409.
59. Donaldson,RM, Nashat,FS, Noble,D, and Taggart,P. Differential effects of ischaemia and hyperkalaemia on myocardial repolarization and conduction times in the dog. J Physiol. 1984; 353; 393-403.
60. Wilde,AA and Kleber,AG. The combined effects of hypoxia, high K+, and acidosis on the intracellular sodium activity and resting potential in guinea pig papillary muscle. Circ. Res. 1986; 58, 2; 249-256.
61. Morena,H, Janse,MJ, Fiolet,JW et al. Comparison of the effects of regional ischemia, hypoxia, hyperkalemia, and acidosis on intracellular and extracellular potentials and metabolism in the isolated porcine heart. Circ. Res. 1980; 46, 5; 634-646.
62. Weiss,JN, Venkatesh,N, and Lamp,ST. ATP-sensitive K+ channels and cellular K+ loss in hypoxic and ischaemic mammalian ventricle. J. Physiol. 1992; 447; 649-673.
63. Janse,MJ, van Capelle,FJ, Morsink,H et al. Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ. Res. 1980; 47, 2; 151-165.
64. Henao,O, Ferrero,JM, Saiz,J et al. Effect of Regional Ischemia in Arrhythmia Vulnerability for Heterogeneous Transmural Cardiac Wall: A Simulation Study. Annals of 33 Computers in Cardiology. 2006; 33, 1; 777-780.
65. Henao,O, Ferrero,JMj, Ramírez,E, and Sáiz,J. Arritmias cardiacas generadas por heterogeneidad electrofisiológica: estudio mediante simulación. Rev. Colomb. Cardiol. 2007; 14, 4; 185-197.
66. Weiss,JN and Lamp,ST. Cardiac ATP-sensitive K+ channels. Evidence for preferential regulation by glycolysis. J. Gen. Physiol. 1989; 94, 5; 911-935.
67. Cole,WC, McPherson,CD, and Sontag,D. ATP-regulated K+ channels protect the myocardium against ischemia/ reperfusion damage. Circ. Res. 1991; 69, 3; 571-581.
68. Cole,WC. ATP-sensitive K+ channels in cardiac ischemia: an endogenous mechanism for protection of the heart. Cardiovasc. Drugs Ther. 1993; 7 Suppl 3; 527-537.
69. Grover,GJ and Garlid,KD. ATP-Sensitive potassium channels: a review of their cardioprotective pharmacology. J. Mol. Cell Cardiol. 2000; 32, 4; 677-695.
70. Hiraoka,M and Furukawa,T. Functional Modulation of Cardiac ATP-Sensitive K(+) Channels. News Physiol Sci. 1998; 13; 131-137.
71. Rodriguez,B, Ferrero,JM, Jr., and Trenor,B. Mechanistic investigation of extracellular K+ accumulation during acute myocardial ischemia: a simulation study. Am. J. Physiol Heart Circ. Physiol. 2002; 283, 2; p. H490-H500.
72. Terzic,A, Jahangir,A, and Kurachi,Y. Cardiac ATP-sensitive K+ channels: regulation by intracellular nucleotides and K+ channel-opening drugs. Am. J Physiol. 1995; 269, 3 Pt 1; p. C525-C545.
73. Hearse,DJ, Maxwell,L, Saldanha,C, and Gavin,JB. The myocardial vasculature during ischemia and reperfusion: a target for injury and protection. J. Mol. Cell Cardiol. 1993; 25, 7; 759-800.
74. Hearse,DJ. Activation of ATP-sensitive potassium channels: a novel pharmacological approach to myocardial protection? Cardiovasc. Res. 1995; 30, 1; 1-17.
75. Punske,BB, Cascio,WE, Engle,C et al. Quantitative characterization of epicardial wave fronts during regional ischemia and elevated extracellular potassium ion concentration. Ann. Biomed. Eng. 1998; 26, 6; 1010-1021.
76. Cascio,WE. Myocardial ischemia: what factors determine arrhythmogenesis? J. Cardiovasc. Electrophysiol. 2001; 12, 6; 726-729.
77. L. S. Gettes and W. E. Cascio, “Effect of acute ischemia on cardiac electrophysiology,” in The Heart and Cardiovascular System. H. A. Fozzard, E. Haber, R. Jennings, A. Katz, and H. Morgan, Eds. New York: Raven Press ltd, 1992, pp. 2021-2053.
78. Wang,Y, Cheng,J, Tandan,S et al. Transient-outward K+ channel inhibition facilitates L-type Ca2+ current in heart. J Cardiovasc. Electrophysiol. 2006; 17, 3; 298-304.
79. Burton,FL and Cobbe,SM. Dispersion of ventricular repolarization and refractory period. Cardiovasc. Res. 2001; 50, 1; 10-23.
80. Caldwell,J, Burton,FL, Smith,GL, and Cobbe,SM. Heterogeneity of Ventricular Fibrillation Dominant Frequency During Global Ischemia in Isolated Rabbit Hearts. J Cardiovasc. Electrophysiol. 2007.
81. Franz,MR and Zabel,M. Electrophysiological basis of QT dispersion measurements. Prog. Cardiovasc. Dis. 2000; 42, 5; 311-324.
82. Osaka,T, Kodama,I, Tsuboi,N, Toyama,J, and Yamada,K. Effects of activation sequence and anisotropic cellular geometry on the repolarization phase of action potential of dog ventricular muscles. Circulation. 1987; 76, 1; 226-236.
83. Yuuki,K, Hosoya,Y, Kubota,I, and Yamaki,M. Dynamic and not static change in ventricular repolarization is a substrate of ventricular arrhythmia on chronic ischemic myocardium. Cardiovasc. Res. 2004; 63, 4; 645-652.
84. Restivo,M, Caref,EB, Kozhevnikov,DO, and El-Sherif,N. Spatial dispersion of repolarization is a key factor in the arrhythmogenicity of long QT syndrome. J Cardiovasc. Electrophysiol. 2004; 15, 3; 323-331.
85. Keener,J. A mathematical model for the vulnerable phase in myocardium. Mathematical Biosciences. 1988; 90, 1; 3-18.
86. Winfree,AT. Electrical instability in cardiac muscle: phase singularities and rotors. J. Theor. Biol. 1989; 138, 3; 353-405.
87. Enkvetchakul,D, Loussouarn,G, Makhina,E, Shyng,SL, and Nichols,CG. The kinetic and physical basis of K(ATP) channel gating: toward a unified molecular understan ding. Biophys. J. 2000; 78, 5; 2334-2348.
88. Enkvetchakul,D and Nichols,CG. Gating mechanism of KATP channels: function fits form. J. Gen. Physiol. 2003; 122, 5; 471-480.

Recibido para evaluación: 16 de septiembre de 2010
Aceptado para publicación: 2 de Diciembre de 2010

Correspondencia:

Oscar Henao Gallo
oscarhe@utp.edu.co