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Diastolic dysfunction is associated with cardiac autonomic neuropathy in type 2 diabetes
S250
Heart, Lung and Circulation 2009;18S:S1–S286
Abstracts
ABSTRACTS
Myocardial 570 CARDIOPROTECTIVE EFFECTS OF NA+/H+ EXCHANGER INHIBITOR ZONIPORIDE IN ISOLATED WORKING RAT HEART IS ASSOCIATED WITH ACTIVATION OF THE RISK PATHWAY J. Tsun, L. Gao, L. Sun, A. Watson, J. Kwan, A. Jabbour, M. Hicks, P. Macdonald St. Vincent’s Hospital and Victor Chang Cardiac Research Institute, Sydney, Australia Aims: To investigate the cardioprotective efficacy of a novel Na+/H+ exchange inhibitor, zoniporide, alone and in combination with drugs (glyceryl trinitrate and PARP inhibitor INO1153) that we have shown to enhance cardiac preservation during hypothermic–ischaemic preservation of the rat heart. Methods: After baseline cardiac function measurement during a period of ex vivo perfusion, isolated rat hearts were arrested and then stored at 4 ◦ C in Celsior solution. Hearts were reperfused after 6 or 10 h of ischaemia and cardiac function re-measured before tissues from left ventricles harvested and stored at −80 ◦ C for Western blot. Drug treatment was added before ischaemia, or to storage solution (celsior) or at reperfusion. Results: Zoniporide pretreatment (30–1000 nM) dosedependently improved all cardiac functional indices after 6 h hypothermic ischemia with 300 and 1000 nM groups demonstrating significantly better cardiac function compared with control and 30 nM groups (p < 0.05). This functional protective effect was also associated with dose-dependent increase of p-ERK expression (p < 0.05). Zonporide at 1000 nM was equally efficacious when added prior to, during or post-storage. Combination of zoniporide and glyceryl trinitrate ± INO-1153 further improved cardiac function at an extended storage time compared to zoniporide only (10 h), and showed significant increases in both p-AKT and ERK1/2 expression compared with control and single therapy (p < 0.05). Conclusion: Zoniporide is an effective cardioprotective agent either alone or in combination with glyceryl trinitrate and INO1153. Its cardio-protective effect is associated with upregulation of p-AKT and p-ERK1/2, which constitute the reperfusion-injury survival kinase (RISK) pathway. doi:10.1016/j.hlc.2009.05.616 571 DIASTOLIC DYSFUNCTION IS ASSOCIATED WITH CARDIAC AUTONOMIC NEUROPATHY IN TYPE 2 DIABETES
the presence and importance of this association in type 2 diabetes (T2DM). Methods: DD and CAN were assessed in 43 apparently healthy pts with T2DM (61 ± 8 years, 53% male). Reduced early diastolic tissue velocity (Em < 7 cm/s, averaged in six basal LV segments), was used to classify diastolic function. CAN was identified from Ewing’s 4 reflex tests (HR responses to deep breathing, Valsalva and standing, and postural change in SBP) and heart rate variability (HRV, spectral power in 3 frequency bands: VLF, LF, HF). CAN score (# abnormal tests) defined borderline (CAN Score = 2) and definite (CAN Score ≥3) autonomic dysfunction. HRV coefficient of variation (CV) of RR intervals was also used as a marker of autonomic function. Results: Borderline or definite CAN was present in 26%, and 77% had DD. Em was lower in pts with definite (4.5 ± 0.2 cm/s) and borderline CAN (5.1 ± 1.9 cm/s) compared with normal autonomic function (6.2 ± 1.3 cm/s, p = 0.02). Em showed a positive correlation with CV (r = 0.56, p < 0.01, Figure), VLF (r = 0.56, p < 0.01), LF (r = 0.55, p < 0.01) and HF (r = 0.51, p < 0.01) and a negative correlation with CAN Score (r = −0.45, p < 0.01). In multiple linear regression (adj. R2 0.34, p-0.001) CV ( = 0.46, p = 0.002) was associated with Em, independent of age, HbA1c and mean BP. Conclusions: CAN is independently associated with DD, and may have a role in the aetiology of subclinical myocardial dysfunction in T2DM.
doi:10.1016/j.hlc.2009.05.617 572 DO ALL PROTEIN BOUND RENAL TOXINS EXERT PHYSIOLOGICAL EFFECTS ON CARDIAC CELLS? P. Iyngkaran 1,2, ,
K.L. Tuck 2 ,
Lekawanvijit 1 ,
Kompa 1 ,
A.
B.
J. Ma 1 , Wang 1 ,
P. Ho 1 ,
S.
H. Krum 1
University of Queensland, Brisbane, Australia
1 Department Epidemiology and Preventive Medicine, Monash University, Victoria, Australia 2 Department of Chemistry, Monash University, Victoria, Australia
Purpose: Diabetic cardiomyopathy, characterised by LV diastolic dysfunction (DD), is linked to cardiac autonomic neuropathy (CAN) in type 1 diabetes. We sought to define
Background: The protein bound renal toxins (PBRT) indoxyl sulphate and homocysteine have known clinical and physiological cardiovascular effects. Several studies
J.W. Sacre, B. Franjic, J.S. Coombes, T.H. Marwick
Heart, Lung and Circulation 2009;18S:S1–S286
Abstracts
ABSTRACTS
Myocardial 570 CARDIOPROTECTIVE EFFECTS OF NA+/H+ EXCHANGER INHIBITOR ZONIPORIDE IN ISOLATED WORKING RAT HEART IS ASSOCIATED WITH ACTIVATION OF THE RISK PATHWAY J. Tsun, L. Gao, L. Sun, A. Watson, J. Kwan, A. Jabbour, M. Hicks, P. Macdonald St. Vincent’s Hospital and Victor Chang Cardiac Research Institute, Sydney, Australia Aims: To investigate the cardioprotective efficacy of a novel Na+/H+ exchange inhibitor, zoniporide, alone and in combination with drugs (glyceryl trinitrate and PARP inhibitor INO1153) that we have shown to enhance cardiac preservation during hypothermic–ischaemic preservation of the rat heart. Methods: After baseline cardiac function measurement during a period of ex vivo perfusion, isolated rat hearts were arrested and then stored at 4 ◦ C in Celsior solution. Hearts were reperfused after 6 or 10 h of ischaemia and cardiac function re-measured before tissues from left ventricles harvested and stored at −80 ◦ C for Western blot. Drug treatment was added before ischaemia, or to storage solution (celsior) or at reperfusion. Results: Zoniporide pretreatment (30–1000 nM) dosedependently improved all cardiac functional indices after 6 h hypothermic ischemia with 300 and 1000 nM groups demonstrating significantly better cardiac function compared with control and 30 nM groups (p < 0.05). This functional protective effect was also associated with dose-dependent increase of p-ERK expression (p < 0.05). Zonporide at 1000 nM was equally efficacious when added prior to, during or post-storage. Combination of zoniporide and glyceryl trinitrate ± INO-1153 further improved cardiac function at an extended storage time compared to zoniporide only (10 h), and showed significant increases in both p-AKT and ERK1/2 expression compared with control and single therapy (p < 0.05). Conclusion: Zoniporide is an effective cardioprotective agent either alone or in combination with glyceryl trinitrate and INO1153. Its cardio-protective effect is associated with upregulation of p-AKT and p-ERK1/2, which constitute the reperfusion-injury survival kinase (RISK) pathway. doi:10.1016/j.hlc.2009.05.616 571 DIASTOLIC DYSFUNCTION IS ASSOCIATED WITH CARDIAC AUTONOMIC NEUROPATHY IN TYPE 2 DIABETES
the presence and importance of this association in type 2 diabetes (T2DM). Methods: DD and CAN were assessed in 43 apparently healthy pts with T2DM (61 ± 8 years, 53% male). Reduced early diastolic tissue velocity (Em < 7 cm/s, averaged in six basal LV segments), was used to classify diastolic function. CAN was identified from Ewing’s 4 reflex tests (HR responses to deep breathing, Valsalva and standing, and postural change in SBP) and heart rate variability (HRV, spectral power in 3 frequency bands: VLF, LF, HF). CAN score (# abnormal tests) defined borderline (CAN Score = 2) and definite (CAN Score ≥3) autonomic dysfunction. HRV coefficient of variation (CV) of RR intervals was also used as a marker of autonomic function. Results: Borderline or definite CAN was present in 26%, and 77% had DD. Em was lower in pts with definite (4.5 ± 0.2 cm/s) and borderline CAN (5.1 ± 1.9 cm/s) compared with normal autonomic function (6.2 ± 1.3 cm/s, p = 0.02). Em showed a positive correlation with CV (r = 0.56, p < 0.01, Figure), VLF (r = 0.56, p < 0.01), LF (r = 0.55, p < 0.01) and HF (r = 0.51, p < 0.01) and a negative correlation with CAN Score (r = −0.45, p < 0.01). In multiple linear regression (adj. R2 0.34, p-0.001) CV ( = 0.46, p = 0.002) was associated with Em, independent of age, HbA1c and mean BP. Conclusions: CAN is independently associated with DD, and may have a role in the aetiology of subclinical myocardial dysfunction in T2DM.
doi:10.1016/j.hlc.2009.05.617 572 DO ALL PROTEIN BOUND RENAL TOXINS EXERT PHYSIOLOGICAL EFFECTS ON CARDIAC CELLS? P. Iyngkaran 1,2, ,
K.L. Tuck 2 ,
Lekawanvijit 1 ,
Kompa 1 ,
A.
B.
J. Ma 1 , Wang 1 ,
P. Ho 1 ,
S.
H. Krum 1
University of Queensland, Brisbane, Australia
1 Department Epidemiology and Preventive Medicine, Monash University, Victoria, Australia 2 Department of Chemistry, Monash University, Victoria, Australia
Purpose: Diabetic cardiomyopathy, characterised by LV diastolic dysfunction (DD), is linked to cardiac autonomic neuropathy (CAN) in type 1 diabetes. We sought to define
Background: The protein bound renal toxins (PBRT) indoxyl sulphate and homocysteine have known clinical and physiological cardiovascular effects. Several studies
J.W. Sacre, B. Franjic, J.S. Coombes, T.H. Marwick