Normothermic versus hypothermic hyperkalemic cardioplegia: effects on myocyte contractility.

BACKGROUND: This study was designed to determine the effects of prolonged hyperkalemic cardioplegic arrest under normothermic or hypothermic conditions with respect to left ventricular myocyte contractile performance and beta-adrenergic responsiveness. METHODS: Isolated left ventricular porcine myocytes were randomly assigned to one of three groups: (group 1) normothermic control, (group 2) hypothermic cardioplegic arrest, or (group 3) normothermic cardioplegic arrest. Myocyte contractility was evaluated by high-speed video microscopy at baseline and after beta-adrenergic stimulation with isoproterenol (25 nmol/L). RESULTS: Myocyte velocity of shortening was decreased after both hypothermic and normothermic cardioplegic arrest (68 +/- 2 and 69 +/- 2 microns/s, respectively) compared with normothermic control values (96 +/- 2 microns/s; p < 0.05). This relative reduction in baseline contractile function was equivalent in both cardioplegia groups (p = 0.5356). With beta-adrenergic stimulation, myocyte velocity of shortening was 186 +/- 4 microns/s in the hypothermic and 176 +/- 3 microns/s in the normothermic cardioplegia groups (p = 0.0563). However, myocyte contractility with beta-adrenergic stimulation was reduced in both cardioplegia groups compared with normothermic controls (205 +/- 4 microns/s; p < 0.05, respectively). CONCLUSIONS: Hyperkalemic cardioplegic arrest under either normothermic or hypothermic conditions resulted in an equivalent reduction in baseline myocyte contractile function with reperfusion/rewarming. Hypothermic cardioplegic arrest may have provided mild protective effects on beta-adrenergic responsiveness. Nevertheless, these results suggest that an important contributory factor for diminished myocyte contractility after simulated cardioplegic arrest was prolonged exposure to a hyperkalemic environment.

Downstream defects in beta-adrenergic signaling and relation to myocyte contractility after cardioplegic arrest.

OBJECTIVE: Transient left ventricular dysfunction can occur after hypothermic, hyperkalemic cardioplegic arrest and is associated with decreased beta-adrenergic receptor responsiveness. Occupancy of the beta-adrenergic receptor activates adenylate cyclase, which phosphorylates the L-type Ca2+ channel-enhancing myocyte contractility. The goal of this study was to identify potential mechanisms that contribute to the defects in the beta-adrenergic receptor signaling cascade after cardioplegic arrest. METHODS: Isolated left ventricular porcine myocytes were assigned to one of two treatment groups: (1) cardioplegic arrest (24 mEq/L K+, 4 degrees C x 2 hours, then 5 minutes in 37 degrees C cell media; n = 130) or (2) normothermic control (cell media, 37 degrees C x 2 hours; n = 222). Myocyte contractility was assessed at baseline and after either beta-adrenergic receptor occupancy (25 nmol/L isoproterenol [INN: isoprenaline]), activation of adenylate cyclase (0.5 mumol forskolin), or direct activation of the L-type Ca(2+)-channel (10 nmol/L or 100 nmol/L (-)BayK 8644). RESULTS: Myocyte velocity of shortening (micron/sec) was increased with beta-adrenergic receptor occupancy or direct adenylate cyclase stimulation compared with baseline in the normothermic group (187.3 +/- 6.9, 181.7 +/- 10.2, and 73.9 +/- 2.9, respectively; p < 0.0001) and after cardioplegic arrest (128.6 +/- 8.9, 124.3 +/- 9.4, and 46.1 +/- 2.6, respectively; p < 0.0001). However, the response after cardioplegic arrest was significantly reduced compared with normothermic values under all conditions (p = 0.012). Direct activation of the L-type Ca(2+)-channel, which eliminates beta-adrenergic receptor-dependent events, increased myocyte contractility in the normothermic group (161.90 +/- 12.0, p < 0.0001) and after cardioplegic arrest (92.78 +/- 6.8, p < 0.0001), but the positive inotropic response appeared reduced compared with normothermic control values (p = 0.003). CONCLUSION: These findings suggest that contributory mechanisms for the reduced beta-adrenergic receptor-mediated response after hypothermic, hyperkalemic cardioplegic arrest lie downstream from these specific components of the transduction pathway and likely include defects in Ca2+ homeostasis, myofilament Ca2+ sensitivity, or both.

Left ventricular regional myocyte contractility in normal and heart failure states.

Fundamental determinants of left ventricular (LV) pump performance are preload, afterload and myocyte contractility. Regional variability in LV end systolic wall stress, an important index of LV afterload, has been well defined in both control and congestive heart failure (CHF) states. The goal of this study was to examine end systolic wall stress and myocyte contractile function in three circumferential regions of the LV in both control and CHF states. Accordingly, LV end systolic wall stress and myocyte velocity of shortening were measured from the basal, mid and apical regions in control pigs (n=5) and following the induction of pacing-induced CHF (3 weeks, 240 beats/min, n=5). LV mid wall, circumferential, end systolic wall stress decreased from base to apex in both control (35+/-7 v 16+/-4 g/cm2, P<0.05) and CHF (155+/-23 v 92+/-24 g/cm2, P<0.05) states. In the CHF group, LV end systolic wall stress was elevated by 300% compared to control values in all regions. LV myocyte velocity of shortening was equivalent in the basal and mid regions of control myocytes (52+/-2 v 57+/-2 m/s), and was higher in the apical region (63+/-3 microm/s, P<0.05). In the CHF group, LV myocyte velocity of shortening was reduced by 45% compared to controls with no regional variation. beta-adrenergic stimulation increased myocyte velocity in both the control and CHF groups, however, regional variation was observed only in the CHF group. These unique results demonstrated that minimal regional variations in myocyte contractile function exist in both control and congestive heart failure states, and does not necessarily parallel patterns of regional LV end systolic wall stress.