Myocardial Metabolism in Heart Failure

Muthu Periasamy. PhDDepartment of Physiology and Cell BiologyThe Ohio State UniversityCollege of MedicinePeriasamy.1@osu.edu

Objectives

Compare and contrast

how the heart muscle utilizes fatty acids and

glucose to meet its

energy needs both at rest and as well

during exercise (increased

demand)

Describe

how the heart continually

generates ATP and transfers

effectively to the site of utilization -

myofibrils

Describe

the metabolic changes in heart failure and how it

affects cellular function,

especially Ca2+

cycling and cytokine

production

Describe

the metabolic alterations in

diabetic cardiomyopathy and its impact

on heart function

Introduction: The heart is an energy consuming mechanical pumpThe average adult human heart

beats 100,000 times per day. 4,300 gallons of blood pumped against 120 mmHg systolic pressure.

ATP is the currency of energy and 300 gram heart synthesizes and utilizes 5kg ATP/day. ATP is utilized and resynthesized constantly ( Low ATP reserve- 5 µg/g wet weight , uses 30 µg/g /per minute )

70-80% of ATP is derived from fatty acid oxidation. The rest from glucose, lactate and ketone bodies. At rest 100% of the energy is derived from fatty acids.

Major ATP-consuming reactions( Muscle Contraction and ion transport )

Myosin ATPase (70% of ATP is

consumed)

Ca uptake by the SR -Ca2+ ATPase

maintains SR Ca2+

store and causes muscle Relaxation

Na/K ATPase (sodium pump)

regulates Cytosolic Na and K -ions

Minor: Ca2+ pump in Plasma membrane, DNA/RNA/Protein

synthesis

The heart is an omnivore

Fatty acids is the preferred substrate in the adult heart but it relies on glucose during extreme stress such as in exercise

The heart muscle can oxidize lactate, ketone bodies and amino acids.

Less than 10% of ATP is derived from lactate (from skeletal muscle) ketone bodies (liver) , and amino acids.

Substrate preference for ATP synthesis carb

fat

Fetal, Neonatal

Adult

Exercise, Hypoxia, Hypertrophy, Failure

Fasting, Diabetes

Mitochondria produces more than 80% of ATP and occupy 30% of cell volume healthy myocardiumYour Content Here

Metabolism during increased work load and or exercise

During exercise, the healthy heart can increase LV contractile power and myocardial oxygen consumption four- to six fold above resting values .

Creatine Phosphate Shuttle is central to energy transfer

Copyright ©1999 American Heart Association

Adenylate kinase (myokinase ) is key to convert ADP into ATP

Heart failure is a condition that can lead to death Heart failure (HF), often called congestive heart failure

(CHF) or congestive cardiac failure (CCF), occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body.

Common causes of heart failure include ischemic heart disease, hypertension, valvular heart disease and cardiomyopathy.

Heart failure is a common, costly, disabling, and potentially deadly condition. In developed countries, around 2% of adults suffer from heart failure, but in those over the age of 65, this increases to 6–10%.

Heart Failure and muscle dysfunction

• Systolic and diastolic dysfunction• Exercise intolerance and muscle fatigue, due to poor circulation

affecting skeletal muscle health• Altered calcium homeostasis: increased SR Ca2+ leak and slowed

Ca2+ uptake contributing to poor systolic and diastolic function• Chronic increase in sympathetic tone, cytokines and inflammatory

mediators, causing cell death

Derangement of Energy Metabolism in Heart failure • Structural abnormalities of the mitochondria, • Impaired oxidative phosphorylation, a decrease in high

energy phosphate transfer (due to poor phospho-creatine shuttle) decreased PCr reserve

• A switch to increased glucose utilization -reverting to fetal phenotype. Decreased fatty acid oxidation

• Down regulation of peroxisome proliferators activated receptor (PPAR), a transcription factor that regulates genes encoding enzymes of fatty acid uptake and mitochondrial oxidation of lipids

Lionetti V et al. Cardiovasc Res 2011;90:202-209

Substrate utilization is altered in HF

A B

PCr

ATP

PPM 10 0 -10 -20

PCr ATP

PPM 10 0 -10 -20

Healthy dilated cardiomyopathy

PCr/ATP is decreased in Failing Human hearts

Best

Is the failing heart energy starved? On using chemical energy to support cardiac function.Ingwall JS, Weiss RG. Circ Res. 2004 Jul 23;95(2):135-45. Review.

PCr/ATP is a better Predictor of Mortality

Ashrafian H et al. Circulation 2007;116:434-448

Copyright © American Heart Association

HF by activating SNS/RAS systems Increases Diabetic Risk

Inflammatory Cytokines in Heart failure

TNF-α IL-1β IL-6 Chemokines ( MCP1,IL8) during

ischemia

Cardiomyocyte apoptosis

Cardiac hypertrophy Collagen production Reduced contractility Dilated

cardiomyopathy Fibrosis

Diabetes is a Cardiovascular Disease

Diabetes and heart disease share identical risk factors (the “common soil” theory).

Diabetes increases CVD risk by 2-15 fold

Heart disease accounts for 60-70 % of type 2 diabetic deaths (versus 30 % for non-diabetic).

Heart disease is also the leading cause of death for type 1 diabetes. By age 55, 35 % die of heart disease (versus 4 % of non-diabetic subjects)

Metabolic abnormalities in the Diabetic heart

• Decreased glucose uptake and glycolysis, increased reliance on fatty acid utilization

• Hyperglycemia and elevated levels of free fatty acid and ketone bodies,

• Decreased ability to switch substrate utilization during exercise.

• Lipotoxicity due to increased reliance on fatty acid.

• Systolic and diastolic dysfunction

• Ventricular hypertrophy / dilation and interstitial fibrosis

• Endothelial dysfunction and coronary artery disease

• Increased risk for myocardial infarction

• Remodeling and progression to heart failure if untreated

Impact of diabetes on heart function

Boudina S , and Abel E D Circulation 2007;115:3213-3223Copyright © American Heart Association

Potential contributors to the development of diabetic cardiomyopathy

Pharmacological therapy to improve Cardiac Metabolism PPARγ Ligands (Thiazolidinediones - TZDS) : also called glitazones

used in the treatment of Type II diabetes. Example include pioglitazone (Actos) Increases insulin sensitivity by activating genes involved in fat and glucose metabolism.

Metformin : Metformin suppresses hepatic gluconeogenesis and increases oxidation of both glucose (increases insulin sensitivity) and fats (increases CPT1 activity) in muscle. It is the first-line drug for the treatment of type 2 diabetes, particularly in overweight and obese people and those with normal kidney function.

Summary

• The heart muscle relies on continued production of ATP for maintaining its demand

• The heart can use a variety of substrates for energy metabolism including glucose, lactate, ketone, amino acids and fatty acids

• The failing heart increases glycolysis to meet its energy demand but this cannot be done in diabetic cardiomyopathy

• When ATP synthesis is compromised, it can be a contributing factor to heart failure

• There are no effective therapies to improve metabolism in failing heart muscle and there is controversy if improving metabolism is sufficient to rescue a failing heart

Metabolism of Heart Failure Quiz

Thank you!

I hope that I was able to teach the subject clearly.

If you have any questions, comments, suggestions, please write to me: Muthu.Periasamy@osumc.edu

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