Restoring mitochondrial function in the treatment of children born with congenital heart - PowerPoint Presentation

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Restoring mitochondrial function in the treatment of children born with congenital heart defects

Steve Black, PhDCo-Director, Cardiovascular Discovery Institute & Mitochondrial Bioenergetics Core Chief, Pulmonary Vascular Disease ProgramVascular Biology CenterGeorgia Regents University

R. Furchgott

L. IgnarroF. MuradThe cells we study

Developed by Reddy et al in Jeffery Fineman

’s lab at UCSFVascular graft (shunt) is placed between aorta and pulmonary artery in fetal lambShunt in place during fetal-newborn transition Model of early alterations that happen in children in with CHD

Ovine Model of a Congenital Heart Defect with Increased Pulmonary Blood Flow

Copyright ©1995 American Heart Association

Circulation 1995;92:606-613

4- Week -Old

Shunt and Twin Control Lamb

There is a Progressive Loss of Endothelial Function in Shunt Lambs

Am J Physiol Lung Cell Mol Physiol. 2008 Nov;295(5):L756-66.NO generation

Mitochondria

The organelle that releases energy in the cell. The powerhouse of the cellMitochondria produce ATP using energy stored in food moleculesAttenuation of mitochondrial function now being investigated in CV disease

Evidence of Mitochondrial Dysfunction in Shunt lambs

Am J Physiol Lung Cell Mol Physiol 294: L46-L56 2008

Lactate

Pyruvate

Lactate:

Pyruvate

(µmols/gww) (µ

mols/gww)

Ratio

Control 1.79+ 0.34 0.144+ 0.03 15.25+ 4.35: 1

Shunt 3.1+ 0.86* 0.057+ 0.008* 51.8+ 10.92: 1*

Data is mean + SE; N=5; *P<0.05

vs

Control.

gww

= gram wet weight.

“

Carnitine Shuttle”

Endothelial cells burn fatty acids rather than glucose for 70% of their energy

ATP

Can Determine Carnitine levels by HPLC

Free Carnitines ( LC + ALC) Total Carnitines

ACYL Carnitines

GOOD

BAD

Our Results:

Total Carnitines Free Carnitine

L-

carnitine

Acylcarnitine

(nmol/gww

) (nmol/gww

) (nmol/gww) (% total)

Control

60.54+ 8.45 67.57+ 13.43 56.42+ 12.27 6.2+ 4.7%

Shunt

72.37+ 10.14 34.86+ 3.35* 20.21+ 4.29* 40.71+ 9%*

Data is mean + SE; N=5; *P<0.05

vs

Control.

gww

= gram wet weight.

Earlier Report

:

A case report with pulmonary hypertension

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review :

Ellen Sigauke, Dinesh Rakheja, Kimberly Kitson and Michael J. Bennett

ACYL-Carnitines

But what

about kids

with CHD?

Am J Physiol Lung Cell Mol Physiol 294: L46-L56 2008

Pre-

operatively, patients with increased PBF have an increased acyl:free Carnitine Ratio*

Surgery increases free carnitine levels in children with VSD

**

Studies from Ames lab have shown that supplementing aged rats with ALCAR improved mitochondrial energy metabolism and improves memory.

Other studies have reported L-carnitine blunts oxidative stress related tissue damage in aging ratsA large clinical trial has shown that L-carnitine reduces ventricular dilation in patients with acute anterior myocardial infarction.Smaller studies have indicated L-carnitine can improve endothelial function in patients with essential hypertension and diabetes.It has been used for >50yrs to treat

various inborn errors of metabolism

with no apparent

side-effects

Why Focus on L-

carnitine

Supplementation?

L-carnitine Supplementation Preserves Endothelial Function in Shunt lambs

Sharma S et al Pediatr Res. 2013 74(1):39-47

Conclusions

Increased PBF induces mitochondrial dysfunction

The

mitochondrial dysfunction is due, at least in part, to a disruption of the

carnitine

shuttle

L-

carnitine

supplementation preserves NO signaling & endothelial function in Shunt lambs

L-

carnitine

may have clinical utility in children with CHD and increased

PBF

Obtained FDA approval & pilot clinical trial will start in Spring 2014

Acknowledgements

All the tremendous efforts of my lab & administrative staff Jeffery Fineman Peter Oishi Angela AmbursoAida Field-Ridley

UCSF

UNC

Cam Patterson

Sohrab Fratz

DHZ-Munich

Acknowledgements

The Money!

Never surrender!!!