Abstract 90: Bendavia (MTP-131), a Novel Mitochondria-Targeting Peptide, Improves ADP-Stimulated Mitochondrial Respiration in Cardiomyocytes Isolated From Dogs with Chronic Heart failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Hani Sabbah ◽  
Ramesh C Gupta ◽  
Sharad Rastogi ◽  
Paula Mohyi ◽  
Kristina Szekely
Keyword(s):  
Heart Failure ◽  
Mitochondrial Respiration ◽  
Systolic Function ◽  
Atp Synthesis ◽  
Vehicle Control ◽  
Electrode System ◽  
Lv Function ◽  
Targeting Peptide ◽  
Lv Systolic Function ◽  
Mitochondria Targeting

Background: Mitochondria (MITO) of failed human hearts and hearts of dogs with experimental heart failure (HF) manifest structural and functional abnormalities characterized by hyperplasia and reduced organelle size and reduced respiration. These abnormalities lead to reduced ATP synthesis that adversely impacts LV function. We previously showed that chronic therapy (3 months) with Bendavia (MTP-131), a novel mitochondria-targeting peptide, improves LV systolic function in dogs with heart failure (HF), reverses MITO abnormalities and normalizes mitochondria ATP synthesis in myocardium from Bendavia-treated HF dogs. In the present study we examined the direct effects of Bendavia on mitochondria ADP-stimulated state 3 respiration in freshly isolated cardiomyocytes from dogs with advanced chronic HF. Methods: Cardiomyocytes were isolated from LV free wall of 3 untreated dogs with HF produced by intracoronary microembolizations (LV ejection fraction <30%). A standard collagenase-based enzymatic process was used for isolation that yielded ~70% viable rod-shaped cardiomyocytes that excluded trypan blue. Equal aliquotes of cardiomyocytes were incubated in 0, 0.01, 0.10, 1.0 and 10 μM concentration of Bendavia for one hour at 37°C. At the end of incubation, ADP-stimulated state-3 respiration was measured using a Clark electrode system and quatified in nAtom Oxygen/min/mg protein. Results: State-3 respiration in the absence of Bendavia (Vehicle-Control) was 248±9 nAtom Oxygen/min/mg protein. Compared to vehicle-control, incubation of failing cardiomyocytes with Bendavia significantly increased state-3 respiration to 303±33 at 0.01 μM, p<0.05; 405±39 at 0.10 μM, p<0.05; 371±28 at 1.0 μM, p<0.05; and 346±29 at 10.0 μM, p<0.05. Conclusions: Results of this study indicate that the effects of Bendavia on mitochondrial respiration in cardiomyocytes is direct and not a consequence of improved global LV structure or function. Furthermore, the results indicate that the improvement in mitochondrial respiration after treatment with Bendavia can occur early after initiation of therapy (within one hour) and is dose-dependent up to concentrations of 0.10 μM.

Abstract 231: Bendavia, a Novel Mitochondria-Targeting Peptide, Improves Contraction and Relaxation of Failing Cardiomyocytes Isolated From Dogs With Chronic Heart Failure

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Hani N Sabbah ◽  
Ramesh C Gupta
Keyword(s):  
Heart Failure ◽  
Atp Synthesis ◽  
Electrical Field Stimulation ◽  
Lv Function ◽  
Shortening Velocity ◽  
Cell Contractility ◽  
Targeting Peptide ◽  
Reduced Rate ◽  
Systolic And Diastolic Function ◽  
Mitochondria Targeting

Background: Mitochondria (MITO) of humans and dogs with heart failure (HF) manifest functional abnormalities characterized by poor respiration, reduced rate of ATP synthesis and increased production of reactive oxygen species (ROS) that adversely impact LV systolic and diastolic function. We previously showed that chronic therapy with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves global LV function in dogs with HF without affecting heart rate or blood pressure. This improvement was associated with a reversal of MITO abnormalities and normalization of rate of ATP synthesis. This study tested the hypothesis that the improvement in global LV function seen in dogs with HF during treatment with BEN results primarily from enhanced function of constituent LV cardiomyocytes. Methods: Cardiomyocytes were isolated from the LV free wall of 8 untreated dogs with coronary microembolization-induced HF (LV ejection fraction <30%). A collagenase-based enzymatic process was used for the isolation and yielded ~70% viable rod-shaped cardiomyocytes that excluded trypan blue. Extent of cardiomyocytes shortening, shortening velocity and lengthening velocity were assessed during 1.0 Hz electrical field stimulation delivered via a MyoPacer (ION Optix). Measurements were made at baseline and were repeated after one hour of gradual exposure of the same cardiomyocytes to BEN at a concentration of 0.1 μM. Results: At baseline, the extent of cardiomyocyte shortening was 3.7 ± 0.8 μm, shortening velocity was 62.8 ± 16.9 μm /sec and lengthening velocity was -53.8 ± 16.5 μm/sec. Exposure of cardiomyocyte to BEN significantly increased the extent of cardiomyocyte shortening to 5.4 ± 1.1 μm (p<0.012), shortening velocity to 94.5 ± 21.9 μm/sec (p<0.020) and lengthening velocity to -96.8 ± 21.1 μm/sec (p<0.016) compared to baseline. Conclusions: Exposure of failing isolated cardiomyocytes to BEN elicits improvements in the rate of cardiomyocyte shortening and re-lengthening indicative of improved cell contractility and relaxation. This improvement is likely mediated by increased availability of ATP along with reduced ROS production both secondary to improved mitochondrial function elicited by treatment with BEN.

Complete dexrazoxane cardioprotection for cardiac function but incomplete female cardioprotection for cardiac structure in doxorubicin-treated osteosarcoma survivors: Hearts too small for the body.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10519-10519
Author(s):  
Lisa M. Kopp ◽  
Mark L. Bernstein ◽  
Cindy L. Schwartz ◽  
David Ebb ◽  
Vivian L Franco ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Thickness ◽  
Systolic Function ◽  
Posterior Wall ◽  
Left Ventricular ◽  
The Body ◽  
Lv Function ◽  
Lv Systolic Function ◽  
Trastuzumab Cardiotoxicity

10519 Background: Dexrazoxane is protective for lower-dose doxorubicin ( < 300 mg/m2) cardiotoxicity in childhood cancer, but the effect of dexrazoxane (DXRZ) administered with higher-dose (HD) doxorubicin (DOXO) is unknown. Methods: We evaluated patients from Children’s Oncology Group trials for localized (P9754) and metastatic (AOST0121) osteosarcoma (OS) who received HD DOXO (375-600 mg/m2) preceded by DXRZ (10:1 ratio), methotrexate, and cisplatin; some also received ifosfamide alone or ifosfamide/etoposide ± trastuzumab. Cardiotoxicity was identified by echocardiography and by serum N-terminal pro-brain natriuretic peptide (NT-proBNP) concentrations. Results: 81 DXRZ -treated OS patients ( age at enrollment = 13.7 years; range 3.8 - 23.7 years) had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. Female sex and longer follow-up since DOXO were associated with a significantly smaller LV dimension z-score normalized to BSA (μ = -1.20, 95%CI [-1.70, -0.70]). Similarly, in the one-third of patients treated > 81 days after minimal expected treatment (groups equally partitioned by time), significantly thinner LV posterior wall thickness for BSA (μ = -0.57, [-1.05, -0.09]) was found. Interventricular septal wall thickness (μ = -0.84, [-1.2, -0.48]) and LV mass (μ = -0.73, [-1.06, -0.40]) were significantly smaller for BSA than normal for both sexes. For females, these became significantly more abnormal with increasing length of follow-up. Females also showed progressive increases in NT-proBNP. Conclusions: DXRZ is cardioprotective for HD DOXO in terms of LV function and heart failure. Females had progressive abnormalities of LV structure, leading to smaller hearts for body size. This was associated with increasing cardiac stress, as measured by NT-proBNP. DXRZ protection was incomplete for HD DOXO effects on LV structure, resulting in higher LV stress and risk for late LV dysfunction. DXRZ should continue to be used in this population, including for females who exhibit more cardiotoxicity than males at specific cumulative DOXO doses.

Abstract 17367: Infusion of the Ketone Body β-Hydroxybutyrate Improves Left Ventricular Systolic Function in an Animal Model of Heart Failure With Reduced Ejection Fraction

Circulation ◽  
2018 ◽  
Vol 138 (Suppl_1) ◽  
Author(s):  
Carlos G SantosGallego ◽  
Juan Antonio Requena-Ibanez ◽  
Rodolfo San Antonio ◽  
Kiyotake Ishikawa ◽  
Belén Picatoste ◽  
...  
Keyword(s):  
Heart Failure ◽  
Feature Tracking ◽  
Ketone Bodies ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Left Ventricular ◽  
Lv Function ◽  
Contractile Reserve ◽  
Hemodynamic Assessment ◽  
Lv Systolic Function

Introduction: In vitro, ketone bodies (KB) are the most energetically efficient fuel for myocardium. Ex vivo, KB infusion in the perfusion medium of working rat hearts increases the heat of combustion (produced energy) by 31%. However, there is no report about the in vivo effects of KB on LV function. We hypothesized that KB infusion in HFREF would improve energy production and thus LV systolic function. Methods: HFREF was induced in 15 pigs by 2-hour balloon occlusion of LAD: proximal LAD (n=8, severe HREF) and mid LAD (n=7, moderate HFREF). At 2 months, LV systolic function was evaluated during saline infusion and during infusion of the KB β-hydroxybutyrate. Severe HFREF animals underwent cardiac MRI for baseline LVEF, feature tracking strains, and contractile reserve (ΔLVEF under dobutamine 5μg/kg/min). Moderate HFREF pigs underwent invasive hemodynamic assessment (dP/dt) and 3D-echocadiography (3D-LVEF and 3D-strains). Simultaneous sampling from coronary artery and coronary sinus was performed to measure myocardial fuel consumption. Results: Proximal and mid LAD occlusion resulted in severe and moderate LV systolic dysfunction, respectively. In the severe HFREF, ketone infusion improved baseline LVEF, feature-tracking strains (both longitudinal and circumferencial strain), and contractile reserve. In the moderate HFREF, ketone infusion improved 3D-LVEF, 3D-strains and dP/dt (Table). Ketone infusion switched myocardial metabolism from glucose to ketone consumption. Conclusions: Continuous infusion of the KB hydroxybutyrate improves LV systolic function independent of LV systolic dysfunction severity via a shift in myocardial fuel metabolism away from glucose oxidation (energy inefficient) toward a more energy-efficient fuel like KB. This effect can explain the mechanism of action of the benefits of SGLT2 inhibitors in heart failure, as empagliflozin-induced mild kyperketonemia may increase LV systolic function and thus improve patient outcomes.

Abstract 090: Long-term Therapy with a Bendavia (MTP-131), a Novel Mitochondria-Targeting Peptide, Normalizes Cardiolipin Biosynthesis and Remodeling in Left Ventricular Myocardium of Dogs with Advanced Heart Failure

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Hani N Sabbah ◽  
Quan He ◽  
Ramesh C Gupta ◽  
Sharad Rastogi ◽  
Mengjun Wang ◽  
...  
Keyword(s):  
Heart Failure ◽  
Atp Synthesis ◽  
Left Ventricular ◽  
Advanced Heart Failure ◽  
Term Therapy ◽  
Complex Iv ◽  
Targeting Peptide ◽  
Long Term Therapy ◽  
Mitochondria Targeting

Background: Cardiolipin (CL) is a signature phospholipid of the mitochondrial inner membrane and responsible for modulation of activities of various enzymes essential for oxidative phosphorylation. Cardiac CL is biosynthesized in a series of steps from phosphatidic acid and remodeled into a form which contains four 18:2 fatty acid chains, tetralinoleol CL [(18:2) 4 CL]. Long-term therapy with Bendavia (MTP-131), a novel mitochondria-targeting peptide, was previously shown to improve left ventricular (LV) function, increase ATP synthesis, and increase the activity and protein levels of mitochondria cytochrome c oxidase (complex IV) in LV myocardium of dogs with advanced heart failure (HF). This study examined the effects of Bendavia on total CL and (18:2) 4 CL in LV myocardium of dogs with HF. Methods: LV tissue was obtained from 12 dogs with microembolization-induced HF randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV tissue from 7 normal dogs was used for comparison. Total CL and (18:2) 4 CL were measured using electrospray ionization mass spectroscopy and quantified in nmol/mg of non-collagen protein (NCP). Results: Total CL was significantly decreased in LV myocardium of Control dogs compared to normal dogs (19.1±1.1 vs. 26.7±1.4 nmol/mg, p<0.05) as was (18:2) 4 CL (14.2±0.9 vs. 20.5±1.2 nmol/mg, p<0.05). Long-term therapy with Bendavia significantly increased both total CL (23.6±1.1 nmol/mg) and (18:2) 4 CL (17.8±1.0 nmol/mg) to near normal levels in LV myocardium of treated HF dogs compared to untreated HF Controls (p<0.05). Conclusions: Total CL and (18:2) 4 CL are decreased in LV myocardium of dogs with HF. Treatment with Bendavia normalizes total CL and (18:2) 4 CL. These findings are consistent with observed normalization of mitochondrial complex IV activity, normalization of rate of ATP synthesis and improvement of global LV performance in dogs with HF after long-term therapy with Bendavia.

Abstract 85: Long-term Monotherapy with Bendavia (MTP-131), A Novel Mitochondria-Targeting Peptide, Restores H11 Kinase Protein Levels in Mitochondrial Fractions of Left Ventricular Myocardium of Dogs with Advanced Heart Failure

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Ramesh C Gupta ◽  
Kristina Szekely ◽  
Mengjun Wang ◽  
Sharad Rastogi ◽  
Kefei Zhang ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Atp Synthesis ◽  
Term Therapy ◽  
Protein Levels ◽  
Chronic Therapy ◽  
Mitochondrial Fractions ◽  
Targeting Peptide ◽  
Long Term Therapy ◽  
Mitochondria Targeting

Background: The heat shock protein H11 kinase (H11K) is expressed in the heart of dogs, rodents and humans and rapidly increases in response to increased contractile workload. Deletion of H11K in pressure overload transgenic mice accelerates LV dysfunction and remodeling by deactivating STAT3, a stress-inducible transcription factor. Deactivation of STAT3 has been shown to adversely impact mitochondrial respiration and consequently oxidative phosphorylation. We previously showed that chronic therapy (3 months) with Bendavia (BEN, MTP-131), a novel mitochondria-targeting peptide, improves LV systolic function in dogs with heart failure (HF) and normalizes mitochondrial respiration and rate of ATP synthesis in LV myocardium of dogs with HF. This study tested the hypothesis that H11K is reduced in mitochondria of the failing heart and that long-term therapy with BEN normalizes levels of this key heat shock protein. Methods: LV tissue was obtained from 12 dogs with microembolization-induced HF (LV ejection fraction ~30%) randomized to 3 months therapy with subcutaneous injections of BEN (0.5 mg/kg once daily, n=6) or saline (Control, n=6). LV tissue from 6 normal dogs was used for comparison. Tissue samples were used to extract mitochondrial fractions (MF). Protein levels of H11K and Porin, a mitochondrial protein not altered in HF, were determined in MF by Western blotting and protein band were quantified in densitometric units (du). Results: Protein level of Porin in MF was similar among NL, Control and BEN-treated dogs (0.24±0.0 vs. 0.22±0.01 vs. 0.23±0.01 du, respectively). Level of H11K was 0.45±0.03 du in NL, decreased to 0.17±0.02 in Controls (p<0.05vs. NL) and was normalized by BEN (0.37±0.05, p<0.05 vs. Control). H11K normalized to Porin was 1.93±0.23 du in MF of NL dogs, decreased to 0.78±0.0.09 du in Controls (p<0.05 vs. NL) and was restored to near normal levels after treatment with BEN (1.61±0.20 du, p<0.05 vs. Control). Conclusions: H11K protein levels are reduced in MF from LV myocardium of dogs with HF and normalized after chronic therapy with BEN. Restoring H11K with BEN likely contributed to the observed improvement in mitochondrial respiration and rate of ATP synthesis previously reported after long-term therapy with BEN.

Acute coronary syndromes in chronic kidney disease patients: the good, the bad or the ugly?

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Saleiro ◽  
D De Campos ◽  
J Lopes ◽  
R Teixeira ◽  
J.P Sousa ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Systolic Function ◽  
Lv Function ◽  
Angiotensin Ii Antagonist ◽  
All Cause Mortality ◽  
Group A ◽  
Lv Ejection Fraction ◽  
Group B ◽  
Lv Systolic Function

Abstract Background Patients with chronic kidney disease (CKD) are at increased risk of composite cardiovascular (CV) events and all-cause mortality. However, current aggressiveness of therapeutic strategies may minimize the course of the disease. Aim To assess the prognostic impact of optimized medical treatment in a CKD population with acute coronary syndrome (ACS). Methods 355 ACS patients admitted to a single coronary care with CKD who were discharged from hospital were included. Those with end-stage renal disease were excluded. Three groups were created based on the KDIGO classification: Group A (Stage 3A, eGFR [estimated glomerular filtration rate] 45–59mL/min/1.73 m2) N=190; Group B (Stage 3B, eGFR 30–44mL/min/1.73 m2) N=113; and Group C (Stage 3B, eGFR 15–29mL/min/1.73 m2) N=52. The primary endpoint was long-term all-cause mortality. Kaplan-Meyer survival curves and Cox regression were done. The median of follow-up was 32 (IQ 15–70) months. Results Groups were similar regarding demographics, CV risk factors, ACS type, heart failure diagnosis, left ventricular (LV) systolic function, peak troponin, multivessel disease, treatment option (PCI, CABG or OMT) and medical therapy at discharge. More advance renal failure patients had a higher prevalence of diabetes mellitus (DM), a lower haemoglobin, a higher NT-proBNP and were less likely to receive ACE inhibitors/angiotensin II antagonist at discharge. 170 patients met the primary outcome. Kaplan-Meyer curves showed decreased survival with worse renal function (Group A 68% vs Group B 57% vs Group C 37%, Log Rank P=0.006 – Figure 1). After adjustment for age, DM, haemoglobin, NT-proBNP, LV systolic function and ACE inhibitors/angiotensin II antagonist at discharge, eGFR was not associated with increased death (HR 1.00, 95% CI 0.98–1.01). In this model, only age (HR 1.04, 95% CI 1.01–1.07), haemoglobin (HR 0.86, 95% CI 0.979–0.94), Nt-proBNP (HR 1.00, 95% CI 1.00–1.00) and impaired LV function (LV ejection fraction 40–49%: HR 2.95, 95% CI 1.89–4.81; LV ejection fraction &lt;40%: HR 2.15, 95% CI 1.44–3.21) remained associated with the outcome. Conclusion The worse outcome attributed to CKD after an ACS seems to be related not the eGFR itself but to associated comorbidities such as age, anaemia, fluid overload and impaired LV function. The fact that some of these comorbidities may be altered by intensive therapy indicates that CKD patients should also be candidates to optimized medical treatment. Funding Acknowledgement Type of funding source: None

scholarly journals Acute recoordination rather than functional hemodynamic improvement determines reverse remodelling by cardiac resynchronisation therapy

2021 ◽  
Author(s):  
Philippe C. Wouters ◽  
Geert E. Leenders ◽  
Maarten J. Cramer ◽  
Mathias Meine ◽  
Frits W. Prinzen ◽  
...  
Keyword(s):  
Systolic Function ◽  
Cardiac Resynchronisation Therapy ◽  
Left Ventricular ◽  
Lv Function ◽  
Peak Strain ◽  
Cardiac Resynchronisation ◽  
Reverse Remodelling ◽  
Resynchronisation Therapy ◽  
Lv Systolic Function

AbstractPurpose: Cardiac resynchronisation therapy (CRT) improves left ventricular (LV) function acutely, with further improvements and reverse remodelling during chronic CRT. The current study investigated the relation between acute improvement of LV systolic function, acute mechanical recoordination, and long-term reverse remodelling after CRT. Methods: In 35 patients, LV speckle tracking longitudinal strain, LV volumes & ejection fraction (LVEF) were assessed by echocardiography before, acutely within three days, and 6 months after CRT. A subgroup of 25 patients underwent invasive assessment of the maximal rate of LV pressure rise (dP/dtmax,) during CRT-implantation. The acute change in dP/dtmax, LVEF, systolic discoordination (internal stretch fraction [ISF] and LV systolic rebound stretch [SRSlv]) and systolic dyssynchrony (standard deviation of peak strain times [2DS-SD18]) was studied, and their association with long-term reverse remodelling were determined. Results: CRT induced acute and ongoing recoordination (ISF from 45 ± 18 to 27 ± 11 and 23 ± 12%, p < 0.001; SRS from 2.27 ± 1.33 to 0.74 ± 0.50 and 0.71 ± 0.43%, p < 0.001) and improved LV function (dP/dtmax 668 ± 185 vs. 817 ± 198 mmHg/s, p < 0.001; stroke volume 46 ± 15 vs. 54 ± 20 and 52 ± 16 ml; LVEF 19 ± 7 vs. 23 ± 8 and 27 ± 10%, p < 0.001). Acute recoordination related to reverse remodelling (r = 0.601 and r = 0.765 for ISF & SRSlv, respectively, p < 0.001). Acute functional improvements of LV systolic function however, neither related to reverse remodelling nor to the extent of acute recoordination. Conclusion: Long-term reverse remodelling after CRT is likely determined by (acute) recoordination rather than by acute hemodynamic improvements. Discoordination may therefore be a more important CRT-substrate that can be assessed and, acutely restored.

Sign in / Sign up

Export Citation Format

Share Document