Metabolic Modulation and Cellular Therapy of Cardiac Dysfunction and Failure

Abstract

At present the prevalence of heart failure rises along with aging of the population. Current heart failure therapeutic options are directed towards disease prevention via neurohormonal antagonism (beta blockers angiotensin converting enzyme inhibitors and/or angiotensin receptor blockers and aldosterone antagonists), symptomatic treatment with diuretics and digitalis and use of biventricular pacing and defibrillators in a special subset of patients. Despite these therapies and device interventions heart failure remains a progressive disease with high mortality and morbidity rates. The number of patients who survive to develop advanced heart failure is increasing. These patients require new therapeutic strategies. In this review two of emerging therapies in the treatment of heart failure are discussed: metabolic modulation and cellular therapy.

Metabolic modulation aims to optimize the myocardial energy utilization via shifting the substrate utilization from free fatty acids to glucose. Cellular therapy on the other hand has the goal to achieve true cardiac regeneration. We review the experimental data that support these strategies as well as the available pharmacological agents for metabolic modulation and clinical application of cellular therapy.

List of abbreviations

ACE

angiotensin converting enzyme

ACEi

angiotensin converting enzyme inhibitor

Acetyl – CoA

acetyl-coenzyme A

ADP

adenosine diphosphate

AMP

adenosine monophosphate

ATP

adenosine triphosphate

BMC

bone marrow derived cells

CK

creatine kinase

CO2

carbon dioxide

CPT-I

carnitine palmitoyltransferase I

CSC

cardiac stem cell

DNA

Deoxyribonucleic acid

EPC

endothelial stem cell

EPO

epogen

ESC

embryonic stem cell

ETC

electron transport chain

FADH2

reduced form of flavin adenine dinucleotide

FAT

fatty acids translocase

FFA

free fatty acid

G-CSF

granulocyte –colony stimulating factor

GLUT

glucose transporter

GM-CSF

granulocyte macrophage colony stimulating factor

HGF

hepatocyte growth factor

HSC

hematopoietic stem cell

LVAD

left ventricular assist device

LVEF

left ventricular ejection fraction

MSC

mesenchymal stem cell

mRNA

messenger ribonucleic acid

NAD

nicotine amide dinucleotide

NADH

reduced form of nicotine amide dinucleotide

NYHA

New York Heart Association

PDH

pyruvate dehydrogenase

PDHK

pyruvate dehydrogenase kinase

PET

positron emission tomography

PPAR

peroxisome proliferator-activated receptors

PPRE

peroxisome proliferator response element

SCF

stem cell factor

SDF

stromal cell derived factor

STEMI

ST-elevation myocardial infarction

TNFα

tumor necrosis factor α

UCP-3

uncoupling protein -3

VEGF

vascular endothelial growth factor

VEGFR

vascular endothelial growth factor receptor

VLDL

very low density lipoprotein

3-KAT

3-ketocyl CoA thiolase