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Mitochondria (MITO) of the failing heart manifest structural and functional abnormalities evidenced by hyperplasia, reduced size and diminished respiration that lead to a defect in ATP synthesis. Bendavia (MTP-131), a novel, first in class, MITO-targeting peptide, enhances ATP synthesis in multiple organs including heart, kidney and skeletal muscle. We examined the effects of Bendavia on LV systolic function and ATP synthesis in dogs with chronic heart failure (HF) (LV ejection fraction, EF∼30%).
12 dogs with microembolization-induced HF were randomized to 3 months therapy with subcutaneous injections of Bendavia (0.5 mg/kg once daily, n=7) or saline (Control, n=7). LV end-diastolic (EDV) and end-systolic (ESV) volumes, EF, heart rate (HR), mean aortic pressure (AP), LV end-diastolic pressure (EDP) and peak LV +dP/dt were measured before (PRE) and after 3 months of therapy (POST). Treatment effect, Δ, was calculated as the difference between PRE and POST. ATP synthesis and ATP/ADP ratio were measured in isolated LV cardiomyocytes using the bioluminescent ApoSENSORTM ATP/ADP assay kit.
Bendavia had no effect on HR or mAP. Compared to Control, Bendavia decreased EDV, ESV and EDP, increased EF and peak LV +dP/dt and increased ATP synthesis and ratio of ATP/ADP (Table).
In HF dogs, long-term therapy with Bendavia improves LV systolic function without increasing HR or decreasing mAP. Bendavia increased ATP synthesis; a likely mediator of improved LV function.
|Δ EDV (ml)||6.0 ± 3.5||2.4 ± 2.5||0.42|
|Δ ESV (ml)||3.9 ± 2.9||−2.9 ± 2.0||0.08|
|Δ EF (%)||−1.7 ± 0.9||6.1 ± 1.2||0.001|
|Δ LVEDP (mmHg)||0.6 ± 0.6||−2.3 ± 0.5||0.003|
|Δ peak LV +dP/dt (mmHg/sec)||−27 ± 39||172 ± 55||0.010|
|ATP Synthesis (RLU/μg protein)||447 ± 85||856 ± 64||<0.05|
|ATP/ADP Ratio||0.38 ± 0.04||1.16 ± 0.15||<0.05|
P-Value = probability value Bendavia vs. Control; RLU = relative light units. ATP = adenosine triphosphate; ADP =adenosine diphosphate
Moderated Poster Contributions
Poster Sessions, Expo North
Saturday, March 09, 2013, 10:00 a.m.-10:45 a.m.
Session Title: Heart Failure: Innovations in Medical Therapy
Abstract Category: 17. Heart Failure: Therapy
Presentation Number: 1133M-268
- 2013 American College of Cardiology Foundation