CHAPTER 21 – Mechanisms of Cardiac

Contraction and Relaxation

Vinod Patel, MD
University of South Florida
 Outside Cell
• Action potential
• Na/K/Ca channels
• L type Ca++ channels
• T type Channels
• Adrenergic receptors
• Collagen fibers
 Inside Cell
• Ca release from SR
• Ca acts on actin and myosin
• Ca returns to SR
• Titin
 Length Dependent Activation
• Increase sensitivity to ca++
• Titin
 Froce transmition;
• MLP protein
• Z disk
 Contractile proteins and cardiomyopathy
• Hypertrophic CMP
• Dilated CMP (cytoskeletal proteins)
 Cytoplasmic actin

 Titin

 Nuclear Lamin
 T and L type calcium channels
• The L channels are also part of the cellular cardiac
protective pathway leading from insulin-like growth factor-
1 (IGF-1) via phosphatidylinositol 3-kinase (PI3K) and Akt
to physiological hypertrophy and protection from ischemia-
reperfusion injury
 Turn off calcium release
 Calcium Sparks
 Na/Ca++
 G Proteins
• GS:
alpha subunit of Gs (alphas) combines with GTP and
then separates from the other two subunits to enhance
activity of adenylyl cyclase.
• GI:
 By stimulating the enzyme GTPase, they break down

the active alphas-subunit.

 KACh channel, which, in turn, can inhibit the sinoatrial

node
 G Proteins
• Gq:
 Overexpression of Gq in mice induces a dilated
cardiomyopathy
 angiotensin II and endothelin, which act through Gq
 Beta2 postreceptor signaling involves both the stimulatory and
the inhibitory G proteins
 Beta3-adrenergic receptors, some studies have proposed a
negative inotropic
 INHIBITION OF ADENYLYL CYCLASE.
• Adenosine, by interaction with alpha1 receptors, couples to
Gi to inhibit contraction and heart rate.
 Negative inotropic effect of vagal stimulation:
• (1) heart rate slowing (negative Treppe phenomenon)
• (2) inhibition of the formation of cyclic AMP
• (3) direct negative inotropic effect mediated by cyclic
GMP.
 NO is generated in the vascular endothelium in response to
increased
• blood flow
• Increased cardiac load
• bradykinin.
 REACTIVE OXYGEN SPECIES AS SIGNALING
MOLECULES.
• Protective oxygen-sensing mechanisms, allowing cells to
adapt to hypoxia.
 TNF:
• Formed during challenge by hypoxia, ischemia-
reperfusion, myocardial infarction, or mechanical loading
• One path is adaptive and sends further signals via nuclear
factor kappa B to the nucleus for the manufacture of
protective molecules. The other maladaptive path leads to
apoptosis via the activation of caspases.
 Frank (1895) reported that the greater the initial LV volume,
the more rapid the rate of rise, the greater the peak pressure
reached, and the faster the rate of relaxation.
 Starling (1918) proposed that within physiological limits, the
larger the volume of the heart, the greater the energy of its
contraction and the amount of chemical change at each
contraction.
 Frank-Starling law, which can account for two of the
mechanisms underlying the increased stroke volume of
exercise—namely, increased diastolic filling (Starling's law)
and increased inotropic state (Frank's findings).
 12 to 14% of the oxygen uptake may be converted to external
work
 Internal work: Internal ion fluxes (Na+/K+/Ca2+) account for
about 20 to 30% of the ATP requirement of the heart
 Most ATP is spent on actin-myosin interaction, and much of
that on generation of heat rather than on external work.
 An increased initial muscle length sensitizes the contractile
apparatus to calcium, thereby theoretically increasing the
efficiency of contraction by diminishing the amount of
calcium flux required.
 Diastolic Dysfunction:
 The cytosolic calcium level must fall to cause the
relaxation phase.
 The inherent viscoelastic properties of the
myocardium are of importance. In the hypertrophied
heart with increased fibrosis, relaxation occurs more
slowly.
 Increased phosphorylation of troponin I enhances the
rate of relaxation.
 Relaxation is influenced by the systolic load.
 IMPAIRED RELAXATION AND CYTOSOLIC
CALCIUM.
• The first phase, isovolumic phase
• The second phase of rapid filling provides most of
ventricular filling.
• The third phase, or diastasis, (5%)
• The final atrial booster phase (15%)
 ATRIAL FUNCTIONS:
 Blood-receiving reservoir chamber.
 Contractile chamber.
 As a conduit that empties its contents into the LV down a
pressure gradient after the mitral valve opens.
 Volume sensor of the heart, releasing atrial natriuretic peptide
(ANP) in response to intermittent stretch, so that an ANP-
induced diuresis.
 Contains receptors for the afferent arms of various reflexes,
including mechanoreceptors that causes “Bainbridge reflex”.
 LEFT VENTRICULAR HYPERTROPHY AND
DIASTOLIC DYSFUNCTION: In hearts with concentric
hypertrophy, as in chronic hypertension or severe aortic
stenosis -> A-II and TGF-b being associated not only with
myocyte growth, but also with maladaptive fibrosis, myocyte
degeneration, and eventual myocyte loss
 LEFT VENTRICULAR VOLUME LOADING AND THE
SIGNALS INVOLVED: volume-induced mechanical stress
with progressively greater LV volumes releases increasing
amounts of TNF from the normal myocardium. Passive stretch
of ventricular muscle promotes TNF mRNA synthesis.
 Thank you