Integrative cardiovascular physiology: a primer to hypothesis driven research

Transcription

1 Integrative cardiovascular physiology: a primer to hypothesis driven research Peter B. Raven, Ph.D. Univ. of N. TX. Fort Worth & Craig G. Crandall, Ph.D. Inst. of Ex. and Environ. Dallas

2 Founded 1264 Founded 1636 Founded 1474 University Laboratory of Physiology Harvard Fatigue Laboratory August Krogh Inst CMRC CIM 2005-

3 History of Exercise Physiology U of Copenhagen 1864 Physiology Laboratory Bohr Effect Peter Ludvig Panum Christian Bohr Father of Niels Bohr Atomic Theory & Quantum Mech. Karl A. Hasselbach Lawrence J Henderson Founder Harvard Fatigue Lab 1927 Dir. David B. Dill August Krogh

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5 Translation and Integration

6 Identify a Question Background Literature Self or Mentor directed 2. -Epidemiology 3. -Previous Investigations often raise questions How?, Why? 4. -has it been addressed before? 5. -If it has been addressed, do you agree? e.g.? Blood vessel recruitment in contracting muscle-1920 Nobel Prize-August Krogh? Heart Rate increasing from rest during dynamic exercise (Rowell)

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8 Old thinking vs Current thinking

9 Develop a Hypothesis A Hypothesis is a proposed explanation for an observable phenomenon (finding); Statisticians prefer Null Hypotheses I prefer directed hypotheses i.e. will cause, results in, is mediated by, plays a pivotal role in, etc The hypothesis must be testable by the research team

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13 Background literature Previous data from lab. New published findings Multiple inputs used to Construct testable statement Hypothesis tested by experiments Results analyzed and Hypothesis either Supported or rejected

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16 Mechanisms of Exercise-Induced Cardioprotection Scott K. Powers et al. Physiology 19: 27 38, 2014 Coronary Artery Disease (CAD) major cause of death worldwide Directly associated with Ischemia-reperfusion (IR) injury Human and Animals studies indicate that endurance exercise training provides robust cardioprotection from IR injury Three stages of IR injury, Arrythmia, Stunning and Cell Death

17 Duration of ischemia related to IR injury

18 Myocardial injury Arrhythmias Ventricular tachycardia/ fibrillation Stunning impaired contractility in the absence of cell death Myocyte death apoptosis and necrosis

19 Question What are the cellular events leading to IR-Induced cardiac injury?

20 Cellular events leading to ischemia-reperfusion injury in the heart

21 Exercise Promotes Cardioprotection Phase 1 acquired rapidly (30 min), lost rapidly within 3 hours activation of SOD2 located within the mitochondria Phase 2 24hrs after exercise persists for 9 days after a 5-day training period in rats

22 Endurance exercise protects against IR injury

23 What Mediator(s) are responsible for exercise-induced cardioprotection

24 How and what cellular mechanisms are involved? 1. Exercise-Induced Changes in Coronary Circulation -- not required 2. Energy production during ischemia switches from CHO to FFA no direct evidence links exercise training to glycolytic flux changes cardioprotection 3. NO signaling is involved in exercise induced cardioprotection

25 How and what cellular mechanisms are involved? (cont.) 4. Elevated Myocardial Heat Shock Proteins Are Not Essential for Exercise-Induced Cardioprotection 5. Increased Myocardial Cyclooxygenase-2 is not Responsible for Exercise-Induced Cardioprotection 6. Elevated Endoplasmic Reticulum Stress Proteins do not Contribute to Exercise-Mediated Cardioprotection

26 Probable cellular mechanisms involved in cardioprotection Sarcolemmal and/or Mitochondrial ATP- Sensitive Potassium Channels Increased Cytosolic Antioxidant Capacity Exercise-Induced Alterations in Mitochondrial Proteins and Phenotype Are Central to Exercise-Induced Cardioprotection (drug development)

27 Summary of several exercise-induced cardioprotective mechanisms