Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chengxue Qin ◽  
Rochelle S S Sleaby ◽  
Lea M Delbridge ◽  
Amy J Davidoff ◽  
John C Chatham ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Male Rats ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Cardiac Phenotype ◽  
Rat Hearts ◽  
The Impact

Metabolism of excess glucose is an important component of the aetiology of type 1 diabetes. The cardiac phenotype includes left ventricular (LV) remodelling and LV dysfunction. Increased hexosamine biosythesis (HBP) and downstream upregulation of protein O-GlcNAcylation has been linked to diabetic complications in many organs. Its impact on LV contractile responsiveness is however not well understood. This study aimed to test the hypothesis that acute inhibition of O-GlcNAc signaling protects inotropic responsiveness in type 1 diabetic heart. Hearts isolated from adult Sprague-Dawley male rats were Langendorff-perfused (constant flow, 10ml/min). Baseline and phenylephrine-stimulated (PE, 10μmol/L) LV function was determined in diabetic (8wks post-streptozotocin diabetes, 55mg/kg i.v.) versus non-diabetic sham rats in the presence of pharmacological inhibitors of HBP/O-GlcNAc including 6-diazo-5-oxo-L-norleucine (DON, 20μM) and alloxan (5mM). Diabetic rats exhibited a marked reduction in inotropic responsiveness to PE (Table, mean±SEM, one-way ANOVA, #P<0.05 vs non-diabetic vehicle rats, *P<0.05 vs diabetic vehicle, at 40 mins). Acute interruption of cardiac HBP/O-GlcNAc by DON and Alloxan significantly rescued LV responsiveness to PE in type 1 diabetic rat hearts. These results support further assessment of the impact of upregulated protein O-GlcNAcylation on LV function, particularly in the diabetic heart. Treatment strategies that target HBP may provide significant benefits alone or in combination with current standard treatments, to reduce progression of heart failure and death in type 1 diabetic patients.

scholarly journals Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench

2020 ◽  
Author(s):  
Ada Admin ◽  
Jhih-Yuan Shih ◽  
Yu-Wen Lin ◽  
Sudeshna Fisch ◽  
Juei-Tang Cheng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Er Stress ◽  
Myocardial Function ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Symptomatic Heart Failure

Dapagliflozin (DAPA) -- a sodium glucose cotransporter 2 (SGLT2) inhibitor, is approved for treatments of diabetic patients. DAPA-HF trial disclosed its benefits in symptomatic heart failure but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular (LV) functions including speckle tracking in diabetic patients free from symptomatic heart failure post DAPA treatment. Using streptozotocin-induce diabetic rat model, we measured the effects of DAPA on myocardial function. In patients with diabetes, following six months of DAPA, despite no significant changes LV ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared to control, the diabetic rat heart developed pronounced fibrosis, a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species and ER stress associated proteins, which were attenuated by the co-incubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis and improved overall function. The results can lead to further improvement in management of LV function in diabetic patients.

scholarly journals Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench

2020 ◽  
Author(s):  
Ada Admin ◽  
Jhih-Yuan Shih ◽  
Yu-Wen Lin ◽  
Sudeshna Fisch ◽  
Juei-Tang Cheng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Er Stress ◽  
Myocardial Function ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Symptomatic Heart Failure

Dapagliflozin (DAPA) -- a sodium glucose cotransporter 2 (SGLT2) inhibitor, is approved for treatments of diabetic patients. DAPA-HF trial disclosed its benefits in symptomatic heart failure but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular (LV) functions including speckle tracking in diabetic patients free from symptomatic heart failure post DAPA treatment. Using streptozotocin-induce diabetic rat model, we measured the effects of DAPA on myocardial function. In patients with diabetes, following six months of DAPA, despite no significant changes LV ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared to control, the diabetic rat heart developed pronounced fibrosis, a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species and ER stress associated proteins, which were attenuated by the co-incubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis and improved overall function. The results can lead to further improvement in management of LV function in diabetic patients.

Aliskiren, exendin-4, and insulin: their impact on endothelin receptor subtype(s) regulation/binding in type 1 diabetic rat hearts

2013 ◽  
Vol 91 (10) ◽  
pp. 830-838 ◽  
Author(s):  
Sawsan M. Al Lafi ◽  
Shushan B. Artinian ◽  
Suzan S. Boutary ◽  
Nadine S. Zwainy ◽  
Khalil M. Bitar ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Diabetic Rat ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Rat Hearts ◽  
Heart Perfusion ◽  
Glucagon Like Peptide 1 ◽  
Coronary Endothelium ◽  
The Impact

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [125I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K–n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.

scholarly journals Dapagliflozin suppresses ER stress and improves subclinical myocardial function in diabetes: from bedside to bench

2020 ◽  
Author(s):  
Ada Admin ◽  
Jhih-Yuan Shih ◽  
Yu-Wen Lin ◽  
Sudeshna Fisch ◽  
Juei-Tang Cheng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Er Stress ◽  
Myocardial Function ◽  
Sglt2 Inhibitor ◽  
Left Ventricular ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Symptomatic Heart Failure

Dapagliflozin (DAPA) -- a sodium glucose cotransporter 2 (SGLT2) inhibitor, is approved for treatments of diabetic patients. DAPA-HF trial disclosed its benefits in symptomatic heart failure but the underlying mechanism remains largely unknown. In this longitudinal and prospective study, we investigated changes of left ventricular (LV) functions including speckle tracking in diabetic patients free from symptomatic heart failure post DAPA treatment. Using streptozotocin-induce diabetic rat model, we measured the effects of DAPA on myocardial function. In patients with diabetes, following six months of DAPA, despite no significant changes LV ejection fraction, the diastolic function and longitudinal strain improved. Likewise, compared to control, the diabetic rat heart developed pronounced fibrosis, a decline in strain and overall hemodynamics, all of which were mitigated by DAPA treatment. In contrast, despite insulin exerting a glucose lowering effect, it failed to improve myocardial function and fibrosis. In our in vitro study, under high glucose cardiomyocytes showed significant activations of apoptosis, reactive oxygen species and ER stress associated proteins, which were attenuated by the co-incubation of DAPA. Mechanistically, DAPA suppressed ER stress, reduced myocardial fibrosis and improved overall function. The results can lead to further improvement in management of LV function in diabetic patients.

Left ventricular dysfunction in normotensive Type 1 diabetic patients: the impact of autonomic neuropathy

2004 ◽  
Vol 21 (6) ◽  
pp. 524-530 ◽  
Author(s):  
M. Taskiran ◽  
V. Rasmussen ◽  
B. Rasmussen ◽  
T. Fritz-Hansen ◽  
H. B. W. Larsson ◽  
...  
Keyword(s):  
Autonomic Neuropathy ◽  
Left Ventricular Dysfunction ◽  
Ventricular Dysfunction ◽  
Left Ventricular ◽  
Diabetic Patients ◽  
Type 1 Diabetic Patients ◽  
The Impact

Subclinical impact of diabetes and hypertention on left ventricular function

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
A Maaroufi ◽  
S Abouradi ◽  
H Zahidi ◽  
H Choukrani ◽  
R Habbal
Keyword(s):  
Sex Ratio ◽  
Systolic Function ◽  
Mitral Annulus ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Lv Function ◽  
Diabetic Patients ◽  
Systolic Performance ◽  
The Mean ◽  
The Impact

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Assessment of longitudinal left ventricular (LV) function has a major clinical significance for the early detection of contractile LV dysfonction. The measurement of the MAPSE (Mitral annular plane systolic excursion) and the systolic peak velocity of the edge of the mitral ring (Sm) allow an accurate assessment of longitudinal systolic performance Objective The aim of this study was to compare the impact of isolated type 2 diabetes and the coexistence of hypertension and diabetes on LV longitudinal systolic performance. Patients and Methods The study included 170 diabetic patients, of whom 85 had both hypertension and diabetes, and 50 controls. The systolic mitral annulus (Sm) velocity by tissue Doppler and the Mitral annular plane systolic excursion (MAPSE) by M mode were measured in all subjects. Results The mean age was 52.8 ± 15 years with a sex ratio M / F 0.23 in diabetic patients, and a mean age 60.8 ± 8 years with a sex ratio M / F 0.45 in control subjects. The mean MAPSE value was reduced in diabetics (11.5 ± 2.6 mm) and even more in hypertensive diabetics (10.5 ± 3.0 mm) compared to controls (16.1 ± 2.4 mm ) (p = 0.02). Similar results were found for Sm (controls, 12.4 ± 2.5 cm / s; diabetics, 9.0 ± "3.3 cm / s; diabetic hypertensive, 7.3 ± 2.0 cm) (p = 0.04). Conclusions diabetics present a depression of the LV longitudinal systolic indices compared to healthy controls; the coexistence of diabetes and hypertension results in further impairment of LV longitudinal systolic function in an additive manner.

scholarly journals Long-Term PDE-5A Inhibition Improves Myofilament Function in Left and Right Ventricular Cardiomyocytes through Partially Different Mechanisms in Diabetic Rat Hearts

Antioxidants ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 1776
Author(s):  
Beáta Bódi ◽  
Árpád Kovács ◽  
Hajnalka Gulyás ◽  
Lilla Mártha ◽  
Attila Tóth ◽  
...  
Keyword(s):  
Right Ventricular ◽  
Troponin I ◽  
Left Ventricular ◽  
Guanosine Monophosphate ◽  
Male Rats ◽  
Diabetic Rat ◽  
Rat Hearts ◽  
Zdf Rats ◽  
Left And Right

Heart failure with preserved ejection fraction (HFpEF) and right ventricular (RV) dysfunction are frequent complications of diabetic cardiomyopathy. Here we aimed to characterize RV and left ventricular (LV) remodeling and its prevention by vardenafil (a long-acting phosphodiesterase-5A (PDE-5A) inhibitor) administration in a diabetic HFpEF model. Zucker Diabetic Fatty (ZDF) and control, ZDF Lean (Lean) male rats received 10 mg/kg vardenafil (ZDF + Vard; Lean + Vard) per os, on a daily basis for a period of 25 weeks. In vitro force measurements, biochemical and histochemical assays were employed to assess cardiomyocyte function and signaling. Vardenafil treatment increased cyclic guanosine monophosphate (cGMP) levels and decreased 3-nitrotyrosine (3-NT) levels in the left and right ventricles of ZDF animals, but not in Lean animals. Cardiomyocyte passive tension (Fpassive) was higher in LV and RV cardiomyocytes of ZDF rats than in those receiving preventive vardenafil treatment. Levels of overall titin phosphorylation did not differ in the four experimental groups. Maximal Ca2+-activated force (Fmax) of LV and RV cardiomyocytes were preserved in ZDF animals. Ca2+-sensitivity of isometric force production (pCa50) was significantly higher in LV (but not in RV) cardiomyocytes of ZDF rats than in their counterparts in the Lean or Lean + Vard groups. In accordance, the phosphorylation levels of cardiac troponin I (cTnI) and myosin binding protein-C (cMyBP-C) were lower in LV (but not in RV) cardiomyocytes of ZDF animals than in their counterparts of the Lean or Lean + Vard groups. Vardenafil treatment normalized pCa50 values in LV cardiomyocytes, and it decreased pCa50 below control levels in RV cardiomyocytes in the ZDF + Vard group. Our data illustrate partially overlapping myofilament protein alterations for LV and RV cardiomyocytes in diabetic rat hearts upon long-term PDE-5A inhibition. While uniform patterns in cGMP, 3-NT and Fpassive levels predict identical effects of vardenafil therapy for the diastolic function in both ventricles, the uneven cTnI, cMyBP-C phosphorylation levels and pCa50 values implicate different responses for the systolic function.

Cardiac responses to insulin-induced hypoglycemia in nondiabetic and intensively treated type 1 diabetic patients

2001 ◽  
Vol 281 (5) ◽  
pp. E1029-E1036 ◽  
Author(s):  
Raymond R. Russell ◽  
Deborah Chyun ◽  
Steven Song ◽  
Robert S. Sherwin ◽  
William V. Tamborlane ◽  
...  
Keyword(s):  
Type 1 Diabetes ◽  
Radionuclide Angiography ◽  
Left Ventricular ◽  
Cardiac Response ◽  
Left Ventricular Ejection ◽  
Diabetic Patients ◽  
Plasma Catecholamine ◽  
Ventricular Ejection Fraction ◽  
Type 1 Diabetic Patients

Insulin-induced hypoglycemia occurs commonly in intensively treated patients with type 1 diabetes, but the cardiovascular consequences of hypoglycemia in these patients are not known. We studied left ventricular systolic [left ventricular ejection fraction (LVEF)] and diastolic [peak filling rate (PFR)] function by equilibrium radionuclide angiography during insulin infusion (12 pmol · kg−1 · min−1) under either hypoglycemic (∼2.8 mmol/l) or euglycemic (∼5 mmol/l) conditions in intensively treated patients with type 1 diabetes and healthy nondiabetic subjects ( n = 9 for each). During hypoglycemic hyperinsulinemia, there were significant increases in LVEF (ΔLVEF = 11 ± 2%) and PFR [ΔPFR = 0.88 ± 0.18 end diastolic volume (EDV)/s] in diabetic subjects as well as in the nondiabetic group (ΔLVEF = 13 ± 2%; ΔPFR = 0.79 ± 0.17 EDV/s). The increases in LVEF and PFR were comparable overall but occurred earlier in the nondiabetic group. A blunted increase in plasma catecholamine, cortisol, and glucagon concentrations occurred in response to hypoglycemia in the diabetic subjects. During euglycemic hyperinsulinemia, LVEF also increased in both the diabetic (ΔLVEF = 7 ± 1%) and nondiabetic (ΔLVEF = 4 ± 2%) groups, but PFR increased only in the diabetic group. In the comparison of the responses to hypoglycemic and euglycemic hyperinsulinemia, only the nondiabetic group had greater augmentation of LVEF, PFR, and cardiac output in the hypoglycemic study ( P < 0.05 for each). Thus intensively treated type 1 diabetic patients demonstrate delayed augmentation of ventricular function during moderate insulin-induced hypoglycemia. Although diabetic subjects have a more pronounced cardiac response to hyperinsulinemia per se than nondiabetic subjects, their response to hypoglycemia is blunted.

scholarly journals The impact of Wilson disease on myocardial tissue and function: a cardiovascular magnetic resonance study

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Janek Salatzki ◽  
Isabelle Mohr ◽  
Jannick Heins ◽  
Mert H. Cerci ◽  
Andreas Ochs ◽  
...  
Keyword(s):  
Cardiovascular Magnetic Resonance ◽  
Magnetic Resonance ◽  
Myocardial Fibrosis ◽  
Wilson Disease ◽  
Left Ventricular ◽  
Myocardial Tissue ◽  
Cardiovascular Magnetic Resonance Study ◽  
Structural Remodeling ◽  
Cardiac Phenotype ◽  
The Impact

Abstract Background Systemic effects of altered serum copper processing in Wilson Disease (WD) might induce myocardial copper deposition and consequently myocardial dysfunction and structural remodeling. This study sought to investigate the prevalence, manifestation and predictors of myocardial tissue abnormalities in WD patients. Methods We prospectively enrolled WD patients and an age-matched group of healthy individuals. We applied cardiovascular magnetic resonance (CMR) to analyze myocardial function, strain, and tissue characteristics. A subgroup analysis of WD patients with predominant neurological (WD-neuro+) or hepatic manifestation only (WD-neuro−) was performed. Results Seventy-six patients (37 years (27–49), 47% women) with known WD and 76 age-matched healthy control subjects were studied. The prevalence of atrial fibrillation in WD patients was 5% and the prevalence of symptomatic heart failure was 2.6%. Compared to healthy controls, patients with WD had a reduced left ventricular global circumferential strain (LV-GCS), and also showed abnormalities consistent with global and regional myocardial fibrosis. WD-neuro+ patients presented with more severe structural remodeling and functional impairment when compared to WD-neuro− patients. Conclusions In a large cohort, WD was not linked to a distinct cardiac phenotype except CMR indexes of myocardial fibrosis. More research is warranted to assess the prognostic implications of these findings. Trial registration: This trial is registered at the local institutional ethics committee (S-188/2018).

ID: 137: GRK2 INHIBITION REDUCES POST-MYOCARDIAL INFARCTION CARDIAC FIBROBLAST MEDIATED ADVERSE REMODELING

2016 ◽  
Vol 64 (4) ◽  
pp. 912.1-912
Author(s):  
M Razzaque ◽  
JL Philip ◽  
X Xu ◽  
M Han ◽  
J Li ◽  
...  
Keyword(s):  
Collagen Synthesis ◽  
Left Ventricular ◽  
Male Rats ◽  
Lv Function ◽  
Intracellular Camp ◽  
Adrenergic Signaling ◽  
Adenoviral Delivery ◽  
Collagen Iii ◽  
Adverse Remodeling ◽  
Fractional Shortening

ObjectivesRemote (non-infarct) territory fibrosis is a significant cause of post-infarction heart failure (HF). We have previously shown that increased G protein-coupled receptor kinase-2 (GRK2) activity in adult human cardiac fibroblasts (CF) isolated from failing hearts is an important mechanism of cardiac fibrosis through uncoupling β-adrenergic receptor (β-AR) signaling. This study investigates the potential therapeutic role of GRK2 inhibition on CF biology in vivo.MethodsAdult male rats underwent LAD ligation to induce post-MI HF. Left ventricular (LV) function was assessed by echocardiography. Myocardial fibrosis was quantitated by histologic staining. LV CF were isolated and cultured. GRK2 was inhibited by intra-coronary adenoviral-mediated delivery of a GRK2 inhibitor (Ad-GRK2ct) immediately following LAD ligation (n=11). Control rats received a null adenovirus (n=10). Animals were studied prior to and 12 weeks post-MI and adenoviral delivery.ResultsThere was a significant decline in LV function at 12 weeks post-MI which [Fractional shortening: 0.35±0.01 vs. 0.52±0.01, p<0.01]. There was significant increase in remote territory (non-infarct area) fibrosis at 12 weeks post-MI compared to control [12±1% vs. 2±1% fibrosis, p<0.05], consistent with adverse remodeling. Additionally, collagen synthesis was significantly upregulated in isolated CF 12 weeks post-MI compared to control CF [3559±760 vs. 1029±45 cmp/mg protein, p<0.02]. At 12 weeks post-MI, GRK2 activity was increased 1.4-fold [p<0.01]. There was a 42% decrease in intracellular cAMP [p<0.05] and loss of b-agonist (isoproterenol)-stimulated inhibition of collagen synthesis characteristic of normal CF, indicating uncoupling of β-AR signaling post-MI. Adenoviral mediated overexpression of GRK2ct, GRK2 inhibitor, in vitro in the cultured CF post-MI led to a 50% decrease in aSMA expression (p<0.01) as well as a significant decreased collagen expression and synthesis compared to null adenovirus (Ad-Null) control [1928±126 vs. 2611±213 cmp/mg protein, p<0.05], restoring the control CF phenotype. Intra-coronary delivery of Ad-GRK2ct following MI significantly reduced post-MI LV dysfunction vs. Ad-Null as measured by improved fractional shortening [0.42±0.01 vs. 0.30±0.02, p<0.01] and ejection fraction [72±1% vs. 57±2%, p<0.03]. Ad-GRK2ct also decreased peri-infarct and remote territory fibrosis by 60% [p<0.03]. Consistent with these findings, Ad-GRK2ct resulted in an over 25% decreased in α-SMA, collagen I, and collagen III expression in CF isolated 12 weeks post-MI vs. Ad-Null [p<0.04] providing evidence of decreased post-MI CF activation and myofibroblast transformation with Ad-GRK2ct.ConclusionsUncoupling of β-adrenergic signaling in CF via increased GRK2 appears to be a key mechanism of post-MI fibrosis. Targeted inhibition of GRK2 and restoration of b-adrenergic signaling/cAMP production in CF may represent a novel therapeutic approach to prevent pathological fibrosis and maladaptive remodeling.

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