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An Investigation of Cardiac Dynamics and Substrate Metabolism in an Animal Heart Failure Model Anna E. Stanhewicz Heart Failure • Heart disease is the primary cause of death in the US • Heart Failure: insufficient blood supply to the body • Progressive disease Early Stage Risk Factors Heart Attack, Hypertension May go unnoticed Compensated Phase Cardiac output is maintained Patient does not experience symptoms Decompensated End Stage Significant decline in cardiac output Patient experiences symptoms Death How the Heart Works Systole – contraction Diastole - relaxation Right Atrium Left Atrium Left Ventricle Right Ventricle Heart Failure is Characterized by a Combination of Dynamic and Metabolic Changes Dynamic Changes Decreased Cardiac Output and Ejection Fraction Key element is cardiac hypertrophy Response to increased vascular resistance Changing size and shape • Diastolic dysfunction • Systolic dysfunction Diastolic Systolic dysfunction dysfunction Cardiac Output Ejection Fraction unchanged Thick Walls Weak Heart Healthy Heart Compensated Heart Failure Metabolic Changes Healthy heart: 60-90% fatty acids 10-40% carbohydrate (glucose) In HF we see a change in substrate preference from fatty acids to carbohydrate % Substrate Utilization Expected Metabolic Profile as HF Progresses 100 Fatty Acid Carbohydrate 0 Time Project Goals: 1. Develop working knowledge of the perfused mouse heart system 2. Use perfused mouse heart to measure cardiac dynamics and substrate metabolism simultaneously Methods Perfused Working Mouse Heart • Allows for measurement of myocardial function and metabolism under defined loading conditions • Ex Vivo - Independent of neurohormonal influence • Desirable – easy genetic modification, rapid reproductive cycle, similarity to human physiology Methods Perfused Working Mouse Heart First perfused through the aorta (retrograde) with KrebsHenseleit solution Then perfused through the left ventricle (anterograde) with physiologic buffers Temperature, filling pressure and resistance to aortic outflow maintained at physiologic levels Methods Dynamic Measurements 1.4F Millar Mikro-Tip® Ultra-miniature P-V Catheter Inserted through the apex of the heart into the left ventricle Measures changing pressures and volumes Data integrated into PVAN software Methods Metabolism- Measurement of 3H2O production from radio labeled substrate • Glycolysis – 5-[3H]glucose → [3H2O] • Fatty Acid Oxidation – 9,10-[3H]palmitate → [3H2O] • 0.2mL of perfusate taken every 10 min • 0.18mL of each sample run through Dowex chromatography column – counted for 3H2O activity Measures of Dynamic Function Left Ventricular Pressure (mmHg) Pressure Waves in Working Mouse Heart Time (sec) HR=300bpm unpaced Dynamic Results Obtained from PVAN Software 340 Stroke Volume (μL) 19.79 Ejection fraction (%) 11.41 Cardiac output (mL/min) 6.68 End-systolic pressure (mmHg) 61.28 End-systolic volume (μL) 160.41 End-diastolic pressure (mmHg) End-diastolic volume (μL) 11.84 171.75 Pressure-Volume Loops in Working Mouse Heart Left Ventricular Pressure (mmHg) Heart Rate (bpm) 70 60 50 40 30 20 10 0 0 10 20 30 40 50 Left Ventricular Volume (μL) 60 Metabolism Results Glycolysis Rate = 4.97 μmoles·g-1dry weight·min-1 Glucose Metabolism in Working Mouse Heart μmole •g dry weight-1 350 y = 4.97x R2 = 0.97 300 250 200 150 100 50 0 0 10 20 30 40 Time (min) 50 60 70 Metabolism Results Fatty Acid Oxidation Rate = 0.80 μmoles· g dry weight-1·min-1 μmole •g dry weight-1 Fatty Acid Metabolism in Working Mouse Heart 30 y = 0.80x + 0.04 R2 = 0.97 25 20 15 10 5 0 0 5 10 15 20 Tim e (m in) 25 30 35 Discussion • With this system dynamic and metabolic measures were obtained simultaneously • This holds great potential for drug development studies • Lays groundwork for more developed understanding of complexities of heart failure Early detection Intervention Acknowledgements Thomas Manfredi, Ph.D. Robert Rodgers, Ph.D. Fredrick Vetter, Ph.D. Arthur Cosmos, Ph.D. Michael Dunn, Ph.D. Candidate