1. Myocardial Metabolism in Heart Failure Noah Weisleder. PhD Department of Physiology and Cell Biology The Ohio State University College of Medicine noah.weisleder@osumc.edu

2. Learning 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 Ca 2+ cycling and cytokine production Describe the metabolic alterations in diabetic cardiomyopathy and its impact on heart function

3. Introduction: The heart is an energy consuming mechanical pump The 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 because there is small ATP reserve (only 5 µg/g wet weight where the heart uses 30 µg/g /per minute) 80-95% of ATP is derived from fatty acid oxidation. The rest from glucose, lactate and ketone bodies. In a healthy heart at the vast majority of ATP is derived from fatty acids.

4. Major ATP-consuming reactions ( Muscle Contraction and ion transport ) Myosin ATPase (70% of ATP is consumed) Ca uptake by the SR -Ca 2+ ATPase maintains SR Ca 2+ store and causes muscle Relaxation Na/K ATPase (sodium pump) regulates Cytosolic Na and K -ions Minor: Ca 2+ pump in Plasma membrane, DNA/RNA/Protein synthesis

5. The heart can act as an “omnivore” to produce ATP Fatty acids are the preferred substrate in the adult heart but it relies on glucose during 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.

6. Substrate preference for ATP synthesis carb fat Fetal, Newborn Adult Exercise, Hypoxia, Hypertrophy, Failure Fasting, Diabetes

7. Creatine Phosphate Shuttle is central to energy transfer

8. Copyright ©1999 American Heart Association Adenylate kinase (myokinase) is key to convert ADP into ATP

9. 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.

10. 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%.

11. Heart failure involves a number of functional defects of cardiac muscle Systolic and diastolic dysfunction Exercise intolerance and muscle fatigue, due to poor circulation affecting skeletal muscle health Altered calcium homeostasis: increased SR Ca 2+ leak and slowed Ca 2+ uptake contributing to poor systolic and diastolic function Chronic increase in sympathetic tone, cytokines and inflammatory mediators, causing cell death

12. Derangement of Energy Metabolism in Heart failure Impaired oxidative phosphorylation, compromised phospho-creatine shuttle), decreased PCr reserve A switch in substrate utilization with increased glucose use and a net decrease in fatty acid oxidation (reverting to fetal phenotype) Structural abnormalities of the mitochondria 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

13. Lionetti V et al. Cardiovasc Res 2011;90:202-209 Substrate utilization is altered in HF

14. A B PCr ATP PCrATP PPM100-10-20 Healthy dilated cardiomyopathy PCr/ATP is decreased in Failing Human hearts. Ingwall JS, Weiss RG. Circ Res. 2004 Jul 23;95(2):135-45.

15. 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

16. Metabolic remodeling precedes and triggers structural and functional remodeling in the heart High Cardiac Workload due to pressure overload or other stress Metabolic remodeling switches substrate from fatty acid to glucose Structural remodeling of the heart leading to hypertrophy Decreased cardiac function and heart failure Kundu, et al. Cardiology 2015;130:211-220.

17. Ashrafian H et al. Circulation 2007;116:434-448 Copyright © American Heart Association HF by activating SNS/RAS systems Increases Diabetic Risk

18. 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

19. 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)

20. 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.

21. Ventricular hypertrophy / dilation and interstitial fibrosis Systolic and diastolic dysfunction 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

22. Boudina S, and Abel E D Circulation 2007;115:3213-3223 Copyright © American Heart Association Potential contributors to the development of diabetic cardiomyopathy

23. 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.first-linetype 2 diabetesoverweight obese

24. 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 When ATP synthesis is compromised, it can be a contributing factor to heart failure The failing heart increases glycolysis to meet its energy demand but this cannot be done in diabetic cardiomyopathy There are minimal therapies to improve metabolism in failing heart muscle and there is controversy if improving metabolism is sufficient to rescue a failing heart

26. Thank you Thank you for your time and attention. Please contact me with any questions or comments on this module. noah.weisleder@osumc.edu