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

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.

Download Full-text

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

10.2337/figshare.13122956.v1 ◽

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.

Download Full-text

Abstract P020: A Bioengineered Neonatal Cardiomyocyte Scaffold Promotes Cell Survival and Improves Left Ventricular Function in Rats with Heart Failure

Circulation Research ◽

10.1161/res.109.suppl_1.ap020 ◽

2011 ◽

Vol 109 (suppl_1) ◽

Author(s):

Jordan Lancaster ◽

Elizabeth Juneman ◽

Nicholle Johnson ◽

Joseph Bahl ◽

Steven Goldman

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cell Survival ◽

Cell Tracking ◽

Left Ventricular ◽

Neonatal Rat ◽

Lv Function ◽

Coronary Artery Ligation ◽

Neonatal Cardiomyocyte

Background: Cell-based regenerative therapies hold promise as a new treatment for heart failure. Tissue engineered scaffolds used for cell delivery enhance potential improvements in cardiac function by providing the structural and nutrient support for transplanted cell survival, integration, and re-population of injured tissues. Previously, our laboratory reported improvements in left ventricular (LV) function in rats with chronic heart failure (CHF) after placement of a neonatal cardiomyocyte (NCM) seeded 3-dimensional fibroblast construct (3DFC). In brief, 3 weeks after implantation of the NCM-3DFC, LV function improves by increasing (p<0.05) ejection fraction 26% and cardiac index 33%, while decreasing (p<0.05) LV end diastolic pressure 38%. The current report focuses on NCM survival and LV improvements out to 7 weeks post NCM-3DFC implantation. Methods and Results: Cardiomyocytes were isolated from neonatal rat hearts and seeded onto a 3DFC. We evaluated NCM-3DFC in vitro for cellular organization and the presence of functional gap junctions, which demonstrated extensive cell-to-cell connectivity. At 5 days in culture, the seeded patch contracted spontaneously in a rhythmic and directional fashion, beating at 43±3 beats/min with a mean displacement of 1.3±0.3 mm and contraction velocity of 0.8±0.2 mm/sec. The seeded patch could be electrically paced at near physiological rates (270±30 beats/min) while maintaining coordinated, directional contractions. For in vivo evaluation, rats underwent coronary artery ligation and allowed to recover for 3 weeks to establish CHF. NCM-3DFC were implanted 3 weeks after ligation and evaluated 3 and 7 weeks later (6 and 10 weeks after ligation respectively). Live cell tracking of implanted NCM using Q-Dots revealed ∼9% survival of transplanted cells 3 weeks after implantation. In addition, improvements in LV function continued at 7 weeks after implantation of the NCM-3DFC by increasing (p<0.05) ejection fraction 37%. Conclusion: A multicellular, electromechanically organized, cardiomyocyte scaffold, engineered in vitro can improve LV function when implanted directly on the hearts of rats with CHF; the transplanted cells survive and improve LV function chronically.

Download Full-text

Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure

European Heart Journal ◽

10.1093/ehjci/ehaa946.1009 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

H Tanaka ◽

F Soga ◽

K Tatsumi ◽

Y Mochizuki ◽

H Sano ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Function ◽

Myocardial Function ◽

Sglt2 Inhibitor ◽

Left Ventricular ◽

Sglt2 Inhibitors ◽

Prospective Multicenter Study ◽

Lv Diastolic Function

Abstract Background Type 2 diabetes mellitus (T2DM) has come to be considered an independent predictor of mortality, and also a contributor to the development of heart failure (HF) with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Left ventricular (LV) longitudinal myocardial dysfunction as assessed in terms of lower global longitudinal strain (GLS), has been identified even in T2DM patients with preserved LV ejection fraction (LVEF), and should be considered the first marker of a preclinical form of DM-related cardiac dysfunction, leading to HFpEF. Sodium glucose cotransporter type 2 (SGLT2) inhibitors represent a new class of anti-hyperglycemic agents for T2DM, but the effect of SGLT2 inhibitors on LV longitudinal myocardial function in T2DM patients with HF remains uncertain. To examine this effect, as well as the association of LV longitudinal myocardial function with LV diastolic function after administration of SGLT2 inhibitor in T2DM patients with stable HF, we analyzed data from our previous prospective multicenter study, in which we investigated the effect of SGLT2 inhibitor on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Methods Our previous trial was a prospective multicenter study of 58 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitors started the administration of 5 mg/day of dapagliflozin. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e' annular velocities (E/e'). LV longitudinal myocardial function was assessed as GLS based on the current guidelines. Results E/e' significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p=0.020) as previously described, while GLS showed significant improvement from 15.5±3.5% to 16.9±4.1% (p<0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HFpEF patients was more significant from 17.0±1.9% to 18.7±2.0% (p<0.001), compared to that in HFrEF patients from 11.3±3.8% to 11.8±4.6% (p=0.13). It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameter for the change in E/e' after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF. Representative case Funding Acknowledgement Type of funding source: None

Download Full-text

Impact of exercise training on ventricular properties in a canine model of congestive heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.3.h1382 ◽

1997 ◽

Vol 272 (3) ◽

pp. H1382-H1390 ◽

Cited By ~ 4

Author(s):

K. Todaka ◽

J. Wang ◽

G. H. Yi ◽

M. Knecht ◽

R. Stennett ◽

...

Keyword(s):

Heart Failure ◽

Exercise Training ◽

Heart Function ◽

Systolic Pressure ◽

Cardiac Pacing ◽

Left Ventricular ◽

Lv Function ◽

Myocardial Stiffness

Exercise training improves functional class in patients with chronic heart failure (CHF) via effects on the periphery with no previously documented effect on intrinsic left ventricular (LV) properties. However, because methods used to evaluate in vivo LV function are limited, it is possible that some effects of exercise training on the failing heart have thus far eluded detection. Twelve dogs were instrumented for cardiac pacing and hemodynamic recordings. Hearts were paced rapidly for 4 wk. Six of the dogs received daily treadmill exercise (CHF(EX), 4.4 km/h, 2 h/day) concurrent with rapid pacing, while the other dogs remained sedentary (CHFs). Hemodynamic measurements taken in vivo at the end of 4 wk revealed relative preservation of maximum rate of pressure rise (2,540 +/- 440 vs. 1,720 +/- 300 mmHg/s, P < 0.05) and LV end-diastolic pressure (9 +/- 5 vs. 19 +/- 4 mmHg, P < 0.05) in CHF(EX) compared with CHFs. The hearts were then isolated and cross perfused for in vitro measurement of isovolumic pressure-volume relations; these results were compared with those of six normal dogs (N). Systolic function was similarly depressed in both groups of pacing animals [end-systolic elastance (Ees) values of 1.66 +/- 0.47 in CHFs, 1.77 +/- 0.38 in CHF(EX), and 3.05 +/- 0.81 mmHg/ml in N, with no changes in volume axis interceptors of the end-systolic pressure-volume relationship]. The diastolic myocardial stiffness constant, k, was elevated in CHFs and was normalized by exercise training (32 +/- 3 in CHFs, 21 +/- 3 in CHF(EX), 20 +/- 4 in N). Thus daily exercise training preserved in vivo hemodynamics during 4 wk of rapid cardiac pacing and was accompanied by a significant change in diastolic myocardial stiffness in vitro. These findings suggest that changes in heart function may contribute to the overall beneficial hemodynamic effects of exercise training in CHF by a significant effect on diastolic properties.

Download Full-text

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

Circulation Research ◽

10.1161/res.115.suppl_1.36 ◽

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.

Download Full-text

Left Ventricular SGLT1 Protein Expression Correlates with the Extent of Myocardial Nitro-Oxidative Stress in Rats with Pressure and Volume Overload-Induced Heart Failure

Antioxidants ◽

10.3390/antiox10081190 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1190

Author(s):

Alex Ali Sayour ◽

Mihály Ruppert ◽

Attila Oláh ◽

Kálmán Benke ◽

Bálint András Barta ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Protein Expression ◽

Volume Overload ◽

Left Ventricular ◽

Diabetic Rat ◽

Strong Positive Correlation ◽

Sodium Glucose Cotransporter ◽

Hemodynamic Overload

Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to be upregulated in humans with heart failure (HF) with or without diabetes. In vitro studies have linked SGLT1 to increased nitro-oxidative stress in cardiomyocytes. We aimed to assess the relation between left ventricular (LV) SGLT1 expression and the extent of nitro-oxidative stress in two non-diabetic rat models of chronic heart failure (HF) evoked by either pressure (TAC, n = 12) or volume overload (ACF, n = 12). Sham-operated animals (Sham-T and Sham-A, both n = 12) served as controls. Both TAC and ACF induced characteristic LV structural and functional remodeling. Western blotting revealed that LV SGLT1 protein expression was significantly upregulated in both HF models (both p < 0.01), whereas the phosphorylation of ERK1/2 was decreased only in ACF; AMPKα activity was significantly reduced in both models. The protein expression of the Nox4 NADPH oxidase isoform was increased in both TAC and ACF compared with respective controls (both p < 0.01), showing a strong positive correlation with SGLT1 expression (r = 0.855, p < 0.001; and r = 0.798, p = 0.001, respectively). Furthermore, SGLT1 protein expression positively correlated with the extent of myocardial nitro-oxidative stress in failing hearts assessed by 3-nitrotyrosin (r = 0.818, p = 0.006) and 4-hydroxy-2-nonenal (r = 0.733, p = 0.020) immunostaining. Therefore, LV SGLT1 protein expression was upregulated irrespective of the nature of chronic hemodynamic overload, and correlated significantly with the expression of Nox4 and with the level of myocardial nitro-oxidative stress, suggesting a pathophysiological role of SGLT1 in HF.

Download Full-text

Nature of heart failure in patients with ventricular septal defect

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.4.h1473 ◽

1995 ◽

Vol 269 (4) ◽

pp. H1473-H1480

Author(s):

J. M. Stewart ◽

T. H. Hintze ◽

P. K. Woolf ◽

M. S. Snyder ◽

K. P. Seligman ◽

...

Keyword(s):

Heart Failure ◽

Ventricular Septal Defect ◽

Septal Defect ◽

Myocardial Function ◽

Left Ventricular ◽

Lv Function ◽

Stress Strain ◽

Maximum Slope ◽

Strain Relation ◽

Stress Strain Relation

To assess the contributions of systolic and diastolic dysfunction to congestive heart failure (CHF) in ventricular septal defect (VSD), we studied 13 children with VSD at catheterization using a Millar catheter. Eight children had CHF, whereas five did not. Phenylephrine was infused at a rate of 5 micrograms.kg-1.min-1, and M-mode echocardiography and pressure were measured simultaneously. Systolic left ventricular (LV) function was assessed by maximum LV pressure (LVP), rate of pressure development (dP/dt), and by the end-systolic pressure-diameter relation (ESPDR). Systolic myocardial function was assessed by the end-systolic stress-strain relation. Diastolic chamber function was assessed by the isovolumic relaxation time constant (tau) and by the end-diastolic pressure-diameter relation (EDPDR). Diastolic myocardial function was measured by the end-diastolic stress-strain relationship. With phenylephrine, maximum LVP increased from 99 +/- 5 to 119 +/- 4 mmHg with CHF and from 106 +/- 6 to 149 +/- 10 mmHg without CHF. +dP/dt was lower with CHF (1,582 +/- 96 mmHg/s) than without CHF (2,300 +/- 200 mmHg/s). The maximum slope of the ESPDR was 39 +/- 8 with CHF and 94 +/- 14 mmHg/cm without CHF. The maximum slope of the midwall stress-strain relation was 223 +/- 37 with CHF and 395 +/- 93 g/cm2 without CHF. tau was 25 +/- 2 without CHF compared with 32 +/- 3 ms with CHF. The EDPDR was shifted leftward with failure, whereas the stress-strain relation was similar for all patients. CHF in patients with VSD results primarily from systolic dysfunction.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure

Cardiovascular Diabetology ◽

10.1186/s12933-019-0985-z ◽

2020 ◽

Vol 19 (1) ◽

Cited By ~ 7

Author(s):

Hidekazu Tanaka ◽

Fumitaka Soga ◽

Kazuhiro Tatsumi ◽

Yasuhide Mochizuki ◽

Hiroyuki Sano ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Diastolic Function ◽

Longitudinal Strain ◽

Myocardial Function ◽

Global Longitudinal Strain ◽

Sglt2 Inhibitor ◽

Left Ventricular ◽

Lv Diastolic Function

Abstract Background The effect of sodium glucose cotransporter type 2 (SGLT2) inhibitor on left ventricular (LV) longitudinal myocardial function in type 2 diabetes mellitus (T2DM) patients with heart failure (HF) has remained unclear. Methods We analyzed data from our previous prospective multicenter study, in which we investigated the effect of the SGLT2 inhibitor dapagliflozin on LV diastolic functional parameters of T2DM patients with stable HF at five institutions in Japan. Echocardiography was performed at baseline and 6 months after administration of dapagliflozin. LV diastolic function was defined as the ratio of mitral inflow E to mitral e′ annular velocities (E/e′). LV longitudinal myocardial function was assessed as global longitudinal strain (GLS), which in turn was determined as the averaged peak longitudinal strain from standard LV apical views. Results E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described, while GLS showed significant improvement from 15.5 ± 3.5% to 16.9 ± 4.1% (p < 0.01) 6 months after administration of dapagliflozin. Furthermore, improvement of GLS in HF with preserved ejection fraction patients was more significant from 17.0 ± 1.9% to 18.7 ± 2.0% (p < 0.001), compared to that in HF with mid-range ejection fraction and HF with reduced ejection fraction patients from 14.4 ± 2.4% to 15.5 ± 1.8% (p = 0.06) and from 8.1 ± 1.5% to 7.8 ± 2.1% (p = 0.44), respectively. It was noteworthy that multiple regression analysis showed that the change in GLS after administration of dapagliflozin was the only independent determinant parameters for the change in E/e′ after administration of dapagliflozin. Conclusion Dapagliflozin was found to be associated with improvement of LV longitudinal myocardial function, which led to further improvement of LV diastolic function of T2DM patients with stable HF. GLS-guided management may thus lead to improved management of T2DM patients with stable HF.

Download Full-text

Abstract 12494: Optimal Timing for Echocardiographic Assessment of Left Ventricular Function During Reduced Left Ventricular Assist Device Support

Circulation ◽

10.1161/circ.132.suppl_3.12494 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Ayesha Salahuddin ◽

Kana Fujikura ◽

Emma J Birks ◽

Chris Cunningham ◽

Faouzi Kallel ◽

...

Keyword(s):

Heart Failure ◽

Speckle Tracking ◽

Circumferential Strain ◽

Myocardial Function ◽

Left Ventricular ◽

Lv Function ◽

Walk Test ◽

Ventricular Assist ◽

Full Support ◽

Left Ventricular Assist

Introduction: In some circumstances left ventricular assist devices (LVAD) can be used to bridge patients with advanced heart failure to myocardial recovery or “remission”. Evaluation of the underlying myocardial function in patients supported with an LVAD is often performed with the pump speed turned down to minimal support for 15 minutes, to simulate unassisted ventricular loading conditions. Longer duration of reduced support and performance of exercise may allow for a more realistic evaluation of myocardial function to assess for recovery. Methods: Nine turn-down exams from 4 patients were analyzed. Subjects were participants in a multi-center prospective non-randomized study of LV recovery with HeartMate II LVAD together with a standardized protocol of pharmacological therapy (REmission from STAGE D Heart Failure (RESTAGE-HF)). LVEF and speckle tracking parameters were measured during full support, at 15 minutes of reduced support (6000 rpm) and again after a 6-min walk test. Averaged radial and circumferential strain, and global circumferential strain were analyzed from papillary muscle level short-axis view using speckle-tracking. Results: LV systolic parameters for each of these patients are shown, (Table). Improvement in LV function was not evident at 15 minutes of reduced support, compared to full support but was evident after the 6-min walk test. Conclusions: After 15 minutes of LVAD turndown, LV systolic parameters did not differ from full support values. Improvement in LV function compared to full support became evident when the protocol was extended to include imaging after a longer period of turndown with the addition of a 6-min walk test.

Download Full-text