Block 4 – 2014 – Week 2

Interactive Session – Wed Feb 19: 8 - 10 am

Medium Group Exercise: “Cardiac Muscle Function at the Cellular and Systems
Levels”
Faculty: George Dubyak, Ph.D.

PRE-CLASS PREPARATION

Two IQ groups (designated Group A or Group B) will be paired together and assigned to
one of 10 medium groups that will be mentored by 1-2 faculty members. The two IQ
groups for each medium group and the room in which the medium group will meet will
be posted on the eCurriculum. The required reading and answers to the eight focus
questions described below must be completed before this in-class activity. As indicated
below, Group A will lead the discussion of four questions while Group B will be
responsible for leading the discussion of the other four questions.

Required Readings:

1) Boron & Boulpaep, Medical Physiology, 2nd Ed. Chapter 9: “Cellular

Physiology of Skeletal, Cardiac, and Smooth Muscle”, pp237-253; and Chapter
22: “The Heart as a Pump”, pp. 529-534; 542-543; 544-547; 550-553.

2) Bers DM and Harris SP. 2011. To the rescue of the failing heart. Nature. 473: 36-
39.

3) Malik FI, et al. 2011. Cardiac myosin activation: A potential therapeutic approach
for systolic heart failure. Science 331: 1439-1443.

4) Betzenhauser MJ and Marks AR. 2010. Ryanodine receptor channelopathies.

Pflugers Arch- Eur J Physiol 460:467–480. (read pp. 460-472)

Focus Question Set 1 (Cellular)

Group A Question 1: The myosin ATPase is the molecular motor of the cardiac
myofibrillar apparatus. Describe the myosin ATPase cycle that occurs when myosin, F-
actin, and ATP interact within the context of the normal cardiac sarcomere. Expain how
this biochemical actomyosin ATPase cycle is related to the mechanical cycle of cross-
bridge attachment/ detachment that underlies sarcomere contraction.

Group A / Question 2: The cardiomyopathies that lead to heart failure involve

progressive decreases in the force-generating capacity (inotropy) of the myofibrils
during each cardiac cycle or heartbeat. “Cardiac myosin activators” (Cf. Bers & Harris
review and Malik et al research paper) are representative of a new class of drugs, so-
called “cardiac myosin activators”, now in clinical trial for the possible treatment of
human heart failure. Explain the mechanism of action of such drugs in terms of the
actomyosin ATPase cycle and its coupling to mechanical cross-bridge cycle. What are
the relative advantages and disadvantages of this therapeutic approach?
1
Focus Question Set 2 (Cellular)
Group B / Question 1: The ability of Ca2+ to regulate both the strength (inotropy) and
rate (chronotropy) of the cardiac myocyte contractile cycle involves the coordinated
actions of multiple types of Ca 2+ transporting proteins. Explain how cytosolic Ca 2+
concentration is dynamically regulated during the contraction and relaxation cycle of a
cardiac myocyte with reference to the specific roles of: 1) dihydropyridine-sensitive L-
type voltage-gated Ca2+ channels; 2) ryanodine-sensitive Ca 2+ release channels; 3)
sarcoplasmic reticulum Ca2+-ATPase (SERCA) pumps; 4) plasma membrane Ca2+-
ATPase pumps; and 5) Na+/Ca2+ exchange transporters.

Group B / Question 2: Skeletal muscle cells express the type 1 ryanodine-sensitive

Ca2+ release channel (RyR1) while cardiac myocytes express the related, but
genetically distinct, type2 ryanodine-sensitive Ca 2+ release channel (RyR2) (Cf
Betzenhauser & Marks review). Mutations in the human genes encoding either the
RyR1 channel or the RyR2 channels can cause life-threatening conditions. Explain
how mutant RyR1 channels are involved in anesthesia-induced “Malignant
Hyperthermia” in skeletal muscle? Similarly, explain how the syndrome of
“Catecholaminergic Polymorphic Ventricular Tachycardia” involves perturbation of RyR2
function in cardiac myocytes.

Question Set 3 (Systems)

Group A Question 3: An examination of a healthy classmate who has been an avid

long distance runner revealed the following: blood pressure 110/70, pulse 64 bpm,
normal 1st and 2nd heart sounds and a physiologic 3rd sound. Construct a Wiggers
diagram to illustrate the events of a normal cardiac cycle and relate the observations of
the examination to these events.

Group A Question 4: Given the same cardiovascular functional parameters, construct

a left ventricular Pressure-Volume Loop for this classmate.

Question Set 4 (Systems)

Group B Question 3: The same classmate described in Question Set 3 was eager to
illustrate some physiologic concepts of cardiac muscle function. The classmate agreed
to the following three (safe) interventions: 1) infusion of dobutamine (beta1-adrenergic
agonis) that acts as a positive inotropic agent; 2) infusion of neosynephrine (alpha1-
adrenergic agonist) that constricts arterioles to elevate the systolic blood pressure to
140 mmHg; and 3) the rapid infusion of 1 liter of normal saline. Illustrate the immediate
changes you would expect to see in the Wiggers diagram and the Pressure-Volume
Loop with each intervention.

Group B Question 4: Explain the effect that each of these three interventions will have
on preload, afterload, and ventricular contractility.