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CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure

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Abstract

Background

Inhibition of myocardial fatty acid oxidation has been suggested as a therapeutic approach for improving cardiac function in chronic heart failure (HF). The novel piperazine derivative CVT-4325 was shown to inhibit fatty acid oxidation in cardiac mitochondria and in isolated perfused rat hearts. In the present study, we tested the hemodynamic and metabolic effects of acute intravenous CVT-4325 in dogs with HF.

Methods and results

HF (LV ejection fraction ≤35%) was created in eight dogs by multiple sequential intracoronary microembolizations. Treatment with CVT-4325 administered intravenously as 0.5 mg/kg bolus followed by a continuous infusion of 0.8 mg/kg/h for 40 min reduced free fatty acid (FFA) uptake (4.51 ± 0.96 to 1.65 ± 0.32 μmols/min, p < 0.04), coronary blood flow (56 ± 3 to 46 ± 4 ml/min, p < 0.01), and myocardial oxygen consumption (MVO2) (240 ± 23 to 172 ± 7 μmols/min, p < 0.03), and increased LV ejection fraction (30 ± 2 to 37 ± 1%, p < 0.0001). In the same study, but on a different day, the same dogs were treated with an inactive analogue of CVT-4325 (CVT-2540), and no hemodynamic or metabolic effects were observed.

Conclusions

In dogs with HF, acute intravenous infusion of CVT-4325 reduces FFA uptake and improves LV systolic function without increasing MVO2. The improvement in LV systolic function in the absence of an increase in MVO2 and a lower FFA uptake is consistent with the concept that inhibition of myocardial fatty acid oxidation may be an effective treatment for HF.

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Abbreviations

LV:

left ventricular

HF:

heart failure

FFA:

free fatty acid

MVO2 :

myocardial oxygen consumption

EF:

LV ejection fraction

EDV:

LV end-diastolic volume

ESV:

LV end-systolic volume

SV:

stroke volume

CBF:

total LV coronary blood flow

LCX:

left circumflex coronary artery

ATP:

adenosine triphosphate

ADP:

adenosine diphosphate

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Author information

Authors and Affiliations

  1. Departments of Medicine, Division of Cardiovascular Medicine, Henry Ford Heart and Vascular Institute, Detroit, MI, USA

    Makoto Imai, Sharad Rastogi, Victor G. Sharov & Hani N. Sabbah

  2. Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, USA

    Naveen Sharma, Margaret P. Chandler & William C. Stanley

  3. CV Therapeutics, Inc., Palo Alto, CA, USA

    Brent Blackburn & Luiz Belardinelli

  4. Cardiovascular Research, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI, 48202, USA

    Hani N. Sabbah

Authors
  1. Makoto Imai
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  2. Sharad Rastogi
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  3. Naveen Sharma
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  4. Margaret P. Chandler
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  5. Victor G. Sharov
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  6. Brent Blackburn
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  7. Luiz Belardinelli
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  8. William C. Stanley
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  9. Hani N. Sabbah
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Corresponding author

Correspondence to Hani N. Sabbah.

Additional information

Supported, in part, by a research grant from CV Therapeutics, Inc., and by a Program Project Grant from the National heart, Lung, and Blood Institute PO1 HL074237-03.

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Imai, M., Rastogi, S., Sharma, N. et al. CVT-4325 Inhibits Myocardial Fatty Acid Uptake and Improves Left Ventricular Systolic Function without Increasing Myocardial Oxygen Consumption in Dogs with Chronic Heart Failure. Cardiovasc Drugs Ther 21, 9–15 (2007). https://doi.org/10.1007/s10557-006-0496-5

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  • DOI: https://doi.org/10.1007/s10557-006-0496-5

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