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Arrhythmogenic Action of CaMKII in Early Post-Ischemic Reperfusion in Isolated Rat Hearts
Abstracts
S39
90
91
Acute Elevation of Serum Triglycerides Increases Left Ventricular Contractility Measured by 2D Strain and Strain Rate
Arrhythmogenic Action of CaMKII in Early Post-Ischemic Reperfusion in Isolated Rat Hearts
D. Holland 1,∗ , D. Erne 1 , R. Leano 1 , B. Haluska 1 , T. Marwick 1 , J. Sharman 2 1 The
University of Queensland, Australia
2 Menzies Research Institute, University of Tasmania, Australia
Purpose: Elevated serum triglycerides are associated with left ventricular (LV) dysfunction and LV hypertrophy (LVH) in addition to increased aortic stiffness, independent of brachial blood pressure (BP). We sought to establish whether an acute rise in serum triglyceride affects cardiac and vascular function. Methods: On two separate days, 12 healthy males (aged 50 ± 8 yrs) underwent blinded, randomised infusion of saline or a high-fat supplement solution (Intralipid) to induce an acute elevation of circulating lipids. Standard 2D echocardiography was used to assess LV function (strain, strain rate) and tonometry was used to record arterial stiffness (aortic pulse wave velocity; PWV) and central BP at baseline and after 1 h infusion of saline or Intralipid. Results: Triglycerides were significantly increased in response to Intralipid, but decreased after saline (Table). Intralipid significantly decreased mean LV end-systolic volume, but did not significantly change aortic stiffness, brachial or central BP. In contrast, both global 2D strain and strain rate decreased significantly (improved) after Intralipid. The lipid-induced change in global 2D strain was significantly correlated with changes in; total cholesterol (r = 0.604), haemoglobin (r = 0.679) and lymphocytes (r = 0.631, P < 0.05 for all). Both age and the change in lymphocytes were independent predictors of the change in 2D strain (adjusted R2 = 0.69; model P = 0.004). Conclusions: Acute elevation of serum triglycerides increases LV contractility and improves myocardial deformation. Chronic exposure to high circulating lipids may mediate the progression of LVH through augmented cardiac workload resulting from increased blood viscosity or substrate delivery. Saline
Triglycerides (mmol/L) LV ejection fraction (%) Mean ESV (mL) Global 2D strain (%) Global 2D strain rate (s−1 )
Intralipid
University of Melbourne, VIC, Australia Ca/calmodulin-dependent protein kinase II (CaMKII) is an integral regulator of the major calcium handling proteins within the heart, and hence a therapeutic target in ischemia/reperfusion. Inhibition of CaMKII has been shown to improve recovery of myocyte calcium cycling following a simulated ischemia/reperfusion intervention (Vila-Petroff M. et al. CV Res: 73: 689–98, 2007). This contrasts with observations in paced, isolated hearts, where CaMKII inhibition reduced post-ischemic mechanical recovery. The effects of CaMKII inhibition on reperfusioninduced arrhythmicity in isolated hearts are unknown. This study investigated the role of CaMKII in the generation of arrhythmias in early post-ischemic reperfusion in isolated hearts. Non-paced male Sprague–Dawley rat hearts (n = 5–7, 16 wks) were treated with a CaMKII inhibitor (KN-93, 2.5 M) 10 min prior to global ischemia (20 min duration) and for the initial 10 min of reperfusion. Pre-ischemia, KN-93 increased coronary flow (49 ± 11% increase, p < 0.05) and was negatively inotropic (34 ± 5% decrease, p < 0.05), but did not affect heart rate. Ischemic contracture was significantly delayed in KN-93 treated hearts (onset, sec: 671 ± 34 vs 1062 ± 71, p < 0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular fibrillation in early reperfusion (7/7 control vs 1/5 KN-93). This was associated with a substantially reduced heart rate throughout reperfusion (101 ± 2 vs 46 ± 8, % basal at 60 min reperfusion, p < 0.05) and a normal recovery of developed pressure (71 ± 5% vs 65 ± 3%, p = ns) compared with control. By preventing potentially fatal arrhythmias and maintaining contraction at a more stable, albeit suppressed level, CaMKII inhibition in early reperfusion may be important in sustaining cardiac function during this crucial period. doi:10.1016/j.hlc.2010.06.758
Between groups P-value
92 Autophagy is Upregulated in Hearts of Insulin Resistant Mice
Pre
Post
Pre
Post
0.97 ± 0.62
0.64 ± 0.41
0.79 ± 0.44
2.84 ± 1.54
<0.001
64 ± 4
62 ± 4
59 ± 3
65 ± 5
0.001
37.9 ± 10.6 40.3 ± 11.3 42.7 ± 10 37.7 ± 12 −19.3 ± 1.8 −19.1 ± 2.1 −18.4 ± 1.6 −20.0 ± 2.3
0.002 0.021
−1.06 ± 0.11 −1.07 ± 0.09 −1.02 ± 0.10 −1.14 ± 0.13
0.014
doi:10.1016/j.hlc.2010.06.757
J. Bell ∗ , M. Reichelt, C. Curl, L. Delbridge
K. Mellor 1,∗ , R. Ritchie 2 , L. Delbridge 1 1 Department
of Physiology, University of Melbourne, VIC, Australia 2 Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, VIC, Australia The recent increase in the prevalence of insulin resistance has coincided with increased fructose consumption. There is emerging evidence that insulin resistance impacts on the heart and the specific cardiac consequences of excess fructose intake require definition. Male C57Bl/6 mice were fed a high fructose diet (60% total weight) for 12 weeks to induce systemic insulin resistance. Myocardial
ABSTRACTS
Heart, Lung and Circulation 2010;19S:S1–S268
S39
90
91
Acute Elevation of Serum Triglycerides Increases Left Ventricular Contractility Measured by 2D Strain and Strain Rate
Arrhythmogenic Action of CaMKII in Early Post-Ischemic Reperfusion in Isolated Rat Hearts
D. Holland 1,∗ , D. Erne 1 , R. Leano 1 , B. Haluska 1 , T. Marwick 1 , J. Sharman 2 1 The
University of Queensland, Australia
2 Menzies Research Institute, University of Tasmania, Australia
Purpose: Elevated serum triglycerides are associated with left ventricular (LV) dysfunction and LV hypertrophy (LVH) in addition to increased aortic stiffness, independent of brachial blood pressure (BP). We sought to establish whether an acute rise in serum triglyceride affects cardiac and vascular function. Methods: On two separate days, 12 healthy males (aged 50 ± 8 yrs) underwent blinded, randomised infusion of saline or a high-fat supplement solution (Intralipid) to induce an acute elevation of circulating lipids. Standard 2D echocardiography was used to assess LV function (strain, strain rate) and tonometry was used to record arterial stiffness (aortic pulse wave velocity; PWV) and central BP at baseline and after 1 h infusion of saline or Intralipid. Results: Triglycerides were significantly increased in response to Intralipid, but decreased after saline (Table). Intralipid significantly decreased mean LV end-systolic volume, but did not significantly change aortic stiffness, brachial or central BP. In contrast, both global 2D strain and strain rate decreased significantly (improved) after Intralipid. The lipid-induced change in global 2D strain was significantly correlated with changes in; total cholesterol (r = 0.604), haemoglobin (r = 0.679) and lymphocytes (r = 0.631, P < 0.05 for all). Both age and the change in lymphocytes were independent predictors of the change in 2D strain (adjusted R2 = 0.69; model P = 0.004). Conclusions: Acute elevation of serum triglycerides increases LV contractility and improves myocardial deformation. Chronic exposure to high circulating lipids may mediate the progression of LVH through augmented cardiac workload resulting from increased blood viscosity or substrate delivery. Saline
Triglycerides (mmol/L) LV ejection fraction (%) Mean ESV (mL) Global 2D strain (%) Global 2D strain rate (s−1 )
Intralipid
University of Melbourne, VIC, Australia Ca/calmodulin-dependent protein kinase II (CaMKII) is an integral regulator of the major calcium handling proteins within the heart, and hence a therapeutic target in ischemia/reperfusion. Inhibition of CaMKII has been shown to improve recovery of myocyte calcium cycling following a simulated ischemia/reperfusion intervention (Vila-Petroff M. et al. CV Res: 73: 689–98, 2007). This contrasts with observations in paced, isolated hearts, where CaMKII inhibition reduced post-ischemic mechanical recovery. The effects of CaMKII inhibition on reperfusioninduced arrhythmicity in isolated hearts are unknown. This study investigated the role of CaMKII in the generation of arrhythmias in early post-ischemic reperfusion in isolated hearts. Non-paced male Sprague–Dawley rat hearts (n = 5–7, 16 wks) were treated with a CaMKII inhibitor (KN-93, 2.5 M) 10 min prior to global ischemia (20 min duration) and for the initial 10 min of reperfusion. Pre-ischemia, KN-93 increased coronary flow (49 ± 11% increase, p < 0.05) and was negatively inotropic (34 ± 5% decrease, p < 0.05), but did not affect heart rate. Ischemic contracture was significantly delayed in KN-93 treated hearts (onset, sec: 671 ± 34 vs 1062 ± 71, p < 0.05). CaMKII inhibition in early reperfusion almost completely abolished the incidence of ventricular fibrillation in early reperfusion (7/7 control vs 1/5 KN-93). This was associated with a substantially reduced heart rate throughout reperfusion (101 ± 2 vs 46 ± 8, % basal at 60 min reperfusion, p < 0.05) and a normal recovery of developed pressure (71 ± 5% vs 65 ± 3%, p = ns) compared with control. By preventing potentially fatal arrhythmias and maintaining contraction at a more stable, albeit suppressed level, CaMKII inhibition in early reperfusion may be important in sustaining cardiac function during this crucial period. doi:10.1016/j.hlc.2010.06.758
Between groups P-value
92 Autophagy is Upregulated in Hearts of Insulin Resistant Mice
Pre
Post
Pre
Post
0.97 ± 0.62
0.64 ± 0.41
0.79 ± 0.44
2.84 ± 1.54
<0.001
64 ± 4
62 ± 4
59 ± 3
65 ± 5
0.001
37.9 ± 10.6 40.3 ± 11.3 42.7 ± 10 37.7 ± 12 −19.3 ± 1.8 −19.1 ± 2.1 −18.4 ± 1.6 −20.0 ± 2.3
0.002 0.021
−1.06 ± 0.11 −1.07 ± 0.09 −1.02 ± 0.10 −1.14 ± 0.13
0.014
doi:10.1016/j.hlc.2010.06.757
J. Bell ∗ , M. Reichelt, C. Curl, L. Delbridge
K. Mellor 1,∗ , R. Ritchie 2 , L. Delbridge 1 1 Department
of Physiology, University of Melbourne, VIC, Australia 2 Heart Failure Pharmacology, Baker IDI Heart & Diabetes Institute, VIC, Australia The recent increase in the prevalence of insulin resistance has coincided with increased fructose consumption. There is emerging evidence that insulin resistance impacts on the heart and the specific cardiac consequences of excess fructose intake require definition. Male C57Bl/6 mice were fed a high fructose diet (60% total weight) for 12 weeks to induce systemic insulin resistance. Myocardial
ABSTRACTS
Heart, Lung and Circulation 2010;19S:S1–S268