Short- and Long-Time Improvement of Graft Function Using Iron-Chelator Supplemented Bretschneider Solution in a Canine Model of Orthotopic Heart Transplantation

Abstract An increasing organ demand is facing a constant number of donors. Nevertheless, not all organs are utilized due to a limited time window for heart transplantation (HTX). Therefore, we aimed to evaluate, if iron chelator supplemented Bretschneider solution can protect the graft in a clinically relevant canine model of HTX with prolonged ischemic storage.HTX was performed in foxhounds. The ischemic time was standardized to 4h, 8h, 12h or 16h depending on the experimental group. Left ventricular (LV) and vascular function were measured. Additionally, myocardial high energy phosphate and iron content and in-vitro myocyte force were evaluated.Iron chelator supplementation proved superior at a routine preservation time of 4h as well as for prolonged times of 8h and longer. The supplementation groups recovered quickly compared to their controls. The LV function was preserved and coronary blood flow increased. This was also confirmed by in vitro myocyte force and vasorelaxation experiments. Additionally, the biochemical results showed significantly higher adenosine-triphosphate content in supplementation groups. The iron chelator LK614 played an important role in this mechanism by reducing the chelatable iron content.This study shows that iron chelator supplemented Bretschneider solution effectively prevents myocardial/endothelial damage during short as well as long term conservation.

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Abstract 427: Tissue Inhibitor of Matrix Metalloproteinase-3 (TIMP3) Provides Beneficial Effects Post-MI by Promoting Angiogenesis

Circulation Research ◽

10.1161/res.119.suppl_1.427 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Abhijit R Takawale ◽

Pu Zhang ◽

Ratnadeep Basu ◽

Abul Azad ◽

Maikel Farhan ◽

...

Keyword(s):

Endothelial Cells ◽

Left Ventricular ◽

Tissue Inhibitor Of Metalloproteinase ◽

Lv Function ◽

Vascular Density ◽

Tissue Inhibitor ◽

Infarct Zone ◽

Fibrin Gel ◽

Beneficial Effects

Introduction: Myocardial infarction (MI) results in loss of cardiomyocytes, adverse extracellular matrix (ECM) remodelling, leading to left ventricular (LV) dilation and dysfunction. Tissue inhibitor of metalloproteinase (TIMPs) are MMP inhibitors, main regulators of ECM integrity. TIMPs can also regulate other aspects of myocardial remodeling such as hypertrophy, fibrosis and inflammation. TIMP3 levels are reduced in the peri-infarct zone within 24 hours post-MI in mice. Hypothesis: Replenishment of TIMP3 post-MI limit infarct expansion, and attenuate LV dilation and dysfunction. Methods: MI was induced in adult male wildtype (C57BL/6) mice by ligation of the left anterior descending artery. Adenoviral constructs expressing human TIMP3 (Ad- hTIMP3) or no-TIMP (Ad-Null, control) were injected in the peri-infarct zone (5.4x10 7 pfu, 5 injections/heart). Cardiac function was assessed by echocardiography. Cardiomyocyte density (WGA/DAPI staining), vascular density (Fluo-lectin injection, CD31 IHC), ECM composition (PSR staining) were assessed at 3 and 7 days post-MI. In vitro, angiogenic potency of TIMP3 (rTIMP3) was assessed using the 3D fibrin gel-based angiogenesis assay using primary human vascular (HUVECs) and coronary artery endothelial cells (HCAECs), and co-IP between TIMP3 and VEGFR2. Results: Ad-TIMP3 injections significantly improved LV function and reduced LV dilation as compared to Ad-Null group post-MI. Infarct size was markedly reduced with TIMP3 injections and more viable myocytes were preserved in the infarct zone at 1wk post-MI. Ad-TIMP3-MI group showed a higher density of endothelial cells and increased coronary density in the infarct and peri-infarct regions compared to the Ad-null group. This suggested that Ad-TIMP3 promotes angiogenesis in the infarcted myocardium. In vitro studies confirmed that rTIMP3 promoted angiogenesis/sprouting in human endothelial cells up to100ng/ml. However at higher concentrations (>1ug/ml), rTIMP3 exerted anti-angiogenic effects by binding to VEGFR2. This function of rTIMP3 appears to be through an MMP-inhibitory mechanism. Conclusion: The novel pro-angiogenic function of TIMP3 post-MI could provide additional beneficial effects in post-MI treatment.

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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.

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Antibody-mediated rejection with detection of de novo donor-specific anti-human leucocyte antigen Class II antibodies 3 years after heart transplantation: a case report

European Heart Journal - Case Reports ◽

10.1093/ehjcr/ytz246 ◽

2020 ◽

Vol 4 (1) ◽

pp. 1-4

Author(s):

Bernd Ludwig ◽

Johanna Schneider ◽

Daniela Föll ◽

Qian Zhou

Keyword(s):

Heart Transplantation ◽

De Novo ◽

Survival Rates ◽

Graft Function ◽

Left Ventricular ◽

Cardiac Allograft ◽

Left Ventricular Ejection ◽

High Dose ◽

Ventricular Ejection Fraction ◽

Antibody Mediated Rejection

Abstract Background Antibody-mediated rejection (AMR) in cardiac transplantation may manifest early within the first weeks after transplantation but also late after months to years following transplantation resulting in mild heart failure to cardiogenic shock. While patients with early cardiac AMR are less affected and seem to have survival rates comparable to transplant recipients without AMR, late cardiac AMR is frequently associated with graft dysfunction, fulminant forms of cardiac allograft vasculopathy, and a high mortality rate. Nevertheless, AMR of cardiac allografts remains difficult to diagnose and to treat. Case summary We report the case of a 47-year-old male patient with late AMR of the cardiac allograft 3 years after heart transplantation. Antibody-mediated rejection was confirmed by endomyocardial biopsy and the presence of donor-specific antibodies (DSA). The patient was treated with high dose of prednisolone, plasmapheresis, intravenous Gamma Globulin, rituximab, immunoadsorption, and bortezomib. Under this treatment regimen left ventricular ejection fraction and pro B-type natriuretic peptide recovered, and the patient improved to New York Heart Association Class I. Currently, 3 years after the diagnosis of cardiac AMR, graft function continues to be nearly normal, and there is no evidence for transplant vasculopathy. Discussion This case illustrates that AMR can occur at any time after transplantation. Although graft function fully recovered after treatment in our patient, the level of DSA remained high, suggesting that DSA may not be a reliable parameter to determine the intensity and duration of the therapy.

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Function and bioenergetics in isolated perfused trained rat hearts

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.272.1.h409 ◽

1997 ◽

Vol 272 (1) ◽

pp. H409-H417 ◽

Cited By ~ 5

Author(s):

R. G. Spencer ◽

P. M. Buttrick ◽

J. S. Ingwall

Keyword(s):

Diastolic Function ◽

Citrate Synthase ◽

Recovery Of Function ◽

Complete Recovery ◽

High Energy ◽

Left Ventricular ◽

Female Rats ◽

Saturation Transfer

To evaluate the resistance of physiologically hypertrophied hearts to hypoxic insult, we quantified the development of functional deficits during hypoxia and reoxygenation in hypertrophied hearts from swim-trained female rats and we correlated this with assessment of high-energy phosphate (HEP) metabolites from simultaneous 31P nuclear magnetic resonance (NMR) measurements. Furthermore, in vivo enzymatic studies were carried out with saturation transfer NMR under well-oxygenated perfusion conditions for both beating and KCl-arrested hearts. Finally, in vitro enzymatic assays were performed. During hypoxia, the trained hearts exhibited improved systolic and diastolic function compared with hearts from sedentary animals. After 16 min of hypoxia, left ventricular (LV) developed pressure fell to 9% of baseline in control hearts but to only 21% of baseline in trained hearts (P < 0.01). LV diastolic function was also improved by training, increasing during hypoxia from a baseline of 10 to 71.0 +/- 3.3 mmHg in control hearts and to 55.3 +/- 4.8 mmHg in trained hearts (P < 0.05). Trained hearts also showed more rapid and complete recovery of function during reoxygenation and greater coronary flow per gram of heart throughout the entire protocol. Functional differences were not accompanied by differences in HEP at baseline; moreover, ATP and phosphocreatine (PCr) loss during hypoxia was similar between control and trained hearts, as was the recovery of PCr during reoxygenation. Saturation transfer experiments showed an increase in the forward creatine kinase (CrK) rate constant in trained hearts of 18% while beating, whereas in vitro enzymatic analysis revealed a 16% increase in the ratio of mitochondrial CrK to citrate synthase activity in LV tissue. Thus the relative preservation of function in hearts from trained rats could not be accounted for by overall HEP levels but may reflect adaptations in the CrK system.

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Effects of metoprolol on left ventricular function in rats with myocardial infarction

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.2.h787 ◽

1994 ◽

Vol 266 (2) ◽

pp. H787-H794 ◽

Cited By ~ 4

Author(s):

W. J. Cherng ◽

C. S. Liang ◽

W. B. Hood

Keyword(s):

Diastolic Pressure ◽

Pressor Response ◽

Left Ventricular ◽

Lv Function ◽

Sham Operation ◽

Pressure Function ◽

Tension Development ◽

Beta Receptor ◽

Significant Difference

To study the effect of beta-receptor-blocking agents in an animal model of left ventricular (LV) dysfunction, we measured LV performance in vivo and in vitro in 69 rats with or without metoprolol (M) treatment 3 wk after left coronary arterial ligation or sham operation. Rats were divided into six groups including control (C) and M noninfarct (C-N and M-N), C and M small infarct (C-S and M-S), and C and M large infarct (C-L and M-L). LV function was measured as slope of change in systolic vs. diastolic pressure (pressure-function curve) during pressor response after administration of a bolus of phenylephrine (5 micrograms/kg i.v.). Reduction of LV function was noted in C-L compared with C-N and C-S (slope of pressure-function curve 3.3 +/- 0.3 vs. 11.0 +/- 1.9 and 11.9 +/- 2.3, respectively) and in M-L compared with M-N and M-S rats (slope of 5.5 +/- 1.4 vs. 11.3 +/- 2.0 and 12.1 +/- 1.4, respectively). There was no significant difference between C and M rats, although there was a trend toward partial correction of the pressure-function curves in M-L compared with C-L rats. In muscle bath preparations the uninfarcted LV posterior papillary muscle from shams and rats with small infarcts showed a dose-related increase in peak rate of tension development with isoproterenol stimulation, but this response was lacking in both C-L and M-L. Tissue assays showed no change in beta-receptor number.(ABSTRACT TRUNCATED AT 250 WORDS)

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

10.2337/figshare.13122956 ◽

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.

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

10.2337/figshare.13122956.v2 ◽

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

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Effect of endogenous natriuretic peptide system on ventricular and coronary function in failing heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1997.273.5.h2406 ◽

1997 ◽

Vol 273 (5) ◽

pp. H2406-H2414 ◽

Cited By ~ 12

Author(s):

Kazuhiro Yamamoto ◽

John C. Burnett ◽

Margaret M. Redfield

Keyword(s):

Blood Flow ◽

Natriuretic Peptide ◽

Coronary Blood Flow ◽

Vascular Function ◽

Ventricular Myocytes ◽

Left Ventricular ◽

Anesthetized Dogs ◽

Peptide System ◽

Natriuretic Peptide System

Ventricular concentrations of atrial, brain (BNP) and C-type natriuretic peptide are enhanced in congestive heart failure (CHF). Natriuretic peptide receptors are present on ventricular myocytes and stimulate guanosine 3′,5′-cyclic monophosphate (cGMP) production. cGMP has been demonstrated to affect myocyte function in vitro. Thus we hypothesized that the intracardiac natriuretic peptide system may modulate myocardial and coronary function in CHF. To test this hypothesis, the effects of an intracoronary infusion of the natriuretic peptide receptor antagonist HS-142–1 on ventricular and coronary function were examined in anesthetized dogs with chronic CHF. To determine whether receptor stimulation had contrasting effects to those of receptor blockade, intracoronary BNP was infused in anesthetized normal and CHF dogs. Low-dose HS-142–1 delayed and slowed left ventricular (LV) relaxation and decreased coronary blood flow without changes in LV pressures. Higher doses further impaired LV relaxation without further decreases in coronary blood flow. In normal and CHF dogs, exogenous BNP produced the opposite effect with a quicker onset and faster rate of LV relaxation without effects on LV pressures or coronary blood flow. The endogenous natriuretic peptide system has an autocrine-paracrine role to modulate LV and coronary vascular function in CHF.

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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.

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Abstract 16434: IL-6 Signaling is Crucial for Cardiomyocyte Hypertrophy and Left Ventricular Dysfunction Induced by Pressure Overload

Circulation ◽

10.1161/circ.132.suppl_3.16434 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

Lin Zhao ◽

Guangming Cheng ◽

Yanjuan Yang ◽

Anweshan Samanta ◽

Rizwan R Afzal ◽

...

Keyword(s):

Therapeutic Potential ◽

Pressure Overload ◽

Left Ventricular ◽

Cardiomyocyte Hypertrophy ◽

Lv Function ◽

Ang Ii ◽

Adult Cardiomyocytes

Introduction: Interleukin-6 (IL-6), a proinflammatory cytokine, has been implicated in ischemic cardiac pathologies. Very little is currently known regarding the role of IL-6 signaling in pathological cardiomyocyte hypertrophy and LV dysfunction. Hypothesis: We hypothesized that IL-6 signaling plays a central role in cardiomyocyte hypertrophy and exerts a deleterious impact on LV remodeling induced by pressure overload. Methods: In vitro, adult cardiomyocytes from C57BL/6 (WT, control) and IL-6 knockout (KO) mice were stimulated by IL-6 and pro-hypertrophic agent angiotensin II (Ang II). The expression of hypertrophy markers and related signaling molecules were examined by real-time quantitative RT-PCR. In vivo, weight-matched male WT and IL-6 KO mice underwent transverse aortic constriction (TAC) or a sham procedure. Serial echocardiograms and a terminal hemodynamic study were performed. Results: After exposure to IL-6 and hypertrophic agonists, the expression of hypertrophy related genes, BNP, GATA-4, αSK actin, and β-MHC increased significantly in WT cardiomyocytes (Fig). These effects were significantly attenuated in IL-6 knockout cardiomyocytes (Fig), indicating an essential role of IL-6 in cardiomyocyte hypertrophy. In vivo, the worsening in LV contraction as well as relaxation after TAC was significantly attenuated in IL-6 KO mice, indicating superior preservation of LV function in the setting of pressure overload in the absence of IL-6 signaling. Conclusions: The protection against Ang II-induced hypertrophy observed in IL-6 KO adult cardiomyocytes in vitro, and in hearts of IL-6 KO mice after TAC in vivo illustrates a crucial role played by IL-6 in pathogenesis of pressure overload-induced LV hypertrophy. Modulation of IL-6 signaling may have preventive therapeutic potential for countless hypertensive patients at risk for LV hypertrophy and failure.

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