Integrative cardiovascular physiology: a primer to hypothesis driven - - PowerPoint PPT Presentation

Integrative cardiovascular physiology: a primer to hypothesis driven research

Peter B. Raven, Ph.D.

• Univ. of N. TX. HSC

@ Fort Worth & Craig G. Crandall, Ph.D.

• Inst. of Ex. and Environ. Med.

@ Dallas

Harvard Fatigue Laboratory 1927– 1946 August Krogh Inst. 1970- CMRC 1994-2003 CIM 2005- Founded 1474 Founded 1264 Founded 1636 University Laboratory of Physiology-1882-

History of Exercise Physiology

1820-1885 Peter Ludvig Panum U of Copenhagen 1864 Physiology Laboratory 1855-1911 Christian Bohr Bohr Effect Father of Niels Bohr Atomic Theory & Quantum Mech. Karl A. Hasselbach 1874-1962 Lawrence J Henderson 1878-1942 Founder Harvard Fatigue Lab 1927

• Dir. David B. Dill

August Krogh 1874-1949

Start of Exercise Physiology

1874-1949 August Krogh Student of C. Bohr Zoophysiologist, D.Sc. Equipment Inventor 1920 Nobel Prize for Capillary Recruitment Johannes Lindhard, MD 1870-1947 Student of Hasselbach Interest in Exercise Theory of Gymnastics 1909 U of Copenhagen Laboratory of Gymnastics Erik Howhu-Christensen Erling Assmussen Marius Neilsen 1904-1996 1907-1991 1903-2000

The Three Musketeers

Translation and Integration

Identify a Question

• Background Literature

1.

• 1.
• 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)

Old thinking vs Current thinking

Develop a Hypothesis

• A Hypothesis is a proposed explanation for an
• bservable 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

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

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

Duration of ischemia related to IR injury

Myocardial injury

• Arrhythmias—Ventricular tachycardia/ fibrillation
• Stunning – impaired contractility in the absence of

cell death

• Myocyte death – apoptosis and necrosis

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

Cellular events leading to ischemia-reperfusion injury in the heart

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

Endurance exercise protects against IR injury

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

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

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

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)

Summary of several exercise-induced cardioprotective mechanisms