Cardioprotection Induced by Heat and Stretch but not Ischaemia Preconditioning is Attenuated by Inhibition of Heat Shock Protein 70 (Hsp70)

Abstract

diomyopathy.Angiotensin-converting enzymes inhibitors (ACEIs) are commonly used in the clinical treatment of diabetic heart failure. The aim of the current study was to determine whether the ACEI ramipril protects the diabetic heart against LV dysfunction and remodelling in a mouse model of type 2 diabetes. Non-diabetic db/+ and diabetic db/dbmice received ramipril (3mg/kg/day in drinking water from sixweeks old) for 10weeks. Results werecompared tountreateddb/+anddb/dbmice (n= 11–15 mice/group). Untreated db/db mice exhibited marked increases in heart weight:tibia length ratio (HW:TL), cardiomyocyte hypertrophy (on H&E staining), % collagen deposition (on Sirius red staining), diastolic dysfunction (left ventricular end-diastolic pressure, LVEDP and deceleration time), LV superoxide generation and apoptosis compared to untreated db/+ mice. These changes were all attenuated by treatment with ramipril (table). In conclusion, ramipril effectively limits diastolic dysfunction and adverse cardiac remodelling, as well as preventing cardiomyocyte apoptotic death in type 2 diabetes. Results db/+ untreated db/+ ramipril db/db untreated db/db ramipril HW:TL (mg/mm) 6.4 ± 0.1 6.0 ± 0.1 8.3 ± 0.2* 7.4 ± 0.2**,# Myocyte width ( m) 11.4 ± 0.3 11.4 ± 0.1 16.0 ± 0.5* 12.6 ± 0.2**,# LV collagen deposition (%) 0.41 ± 0.04 0.40 ± 0.02 0.76 ± 0.06* 0.39 ± 0.12# LVEDP (mmHg) 4.3 ± 0.6 5.1 ± 0.3 9.3 ± 0.9* 6.1 ± 0.6# Deceleration time (ms) 29.9 ± 0.3 29.4 ± 0.3 35.7 ± 1.0* 31.3 ± 0.4**,# Superoxide generation (RLU/s/mg) 20.9 ± 1.9 19.7 ± 1.5 32.1 ± 2.1* 23.2 ± 2.7# Apoptotic cells (AU) 1.0 ± 0.7 1.3 ± 0.3 3.9 ± 0.4* 2.3 ± 0.5# hearts (n= 4) underwent the same procedure without PC. Experiments were repeated in the presence or absence of 10 Mof quercetin, a Hsp70 inhibitor. Left ventricular end diastolic pressure (LVEDP) and left ventricular developed pressure (LVDP) were used as indicators of functional recovery and the level of Hsp70 expression was evaluated using Western blot. Results:Hearts treated with IPC, HPC and SPC showed better post-ischaemic LVDP (23.1± 2.6, 45.0± 9.9 and 56.1± 6.9mmHg, respectively, p 120 g/m2) and LAE (left atrial area > 20 cm2) were used as binary “gold standards”. Results:TheECGalgorithmhadonlya19%positivepredictive value (95% CI: 11–31%) for echo-confirmed LVH, but was associated with an 87% (95%CI: 81–91%) negative predictive value. Data on LVH were missing from 20 subjects. In the diagnosis of left atrial enlargement, ECGs had a positive predictive value of 56% (95% CI: 41–70%) and a negative predictive value of 46% (95% CI: 39–52%). ECHO LV ECG LV Total ECHO LA ECG LA Total Hypertrophy Normal Enlarged Normal Hypertrophy 13 23 36 Enlarged 28 115 143 Normal 54 151 205 Normal 22 96 118 Total 67 174 241 Total 50 211 261 Conclusion:ECGsarepoor diagnostic tools for thepresence of LVH and the presence or absence of left atrial enlargement. However, the absence of LVH on ECG may be sufficient for the exclusion of LVH without resort to echocardiography in selected clinical circumstances. doi:10.1016/j.hlc.2011.05.116