CHAPTER 21 – Mechanisms of Cardiac CHAPTER 21 – Mechanisms of Cardiac

Contraction and RelaxationContraction and Relaxation

Vinod Patel, MDVinod Patel, MDUniversity of South FloridaUniversity of South Florida

Outside CellOutside Cell• Action potentialAction potential• Na/K/Ca channelsNa/K/Ca channels• L type Ca++ channelsL type Ca++ channels• T type ChannelsT type Channels• Adrenergic receptorsAdrenergic receptors• Collagen fibersCollagen fibers

Inside CellInside Cell• Ca release from SRCa release from SR• Ca acts on actin and myosin Ca acts on actin and myosin • Ca returns to SRCa returns to SR• TitinTitin

Length Dependent ActivationLength Dependent Activation• Increase sensitivity to ca++Increase sensitivity to ca++• TitinTitin

Froce transmition;Froce transmition;• MLP proteinMLP protein• Z diskZ disk

Contractile proteins and cardiomyopathyContractile proteins and cardiomyopathy• Hypertrophic CMPHypertrophic CMP• Dilated CMP (cytoskeletal proteins)Dilated CMP (cytoskeletal proteins)

Cytoplasmic actinCytoplasmic actin TitinTitin Nuclear LaminNuclear Lamin

T and L type calcium channelsT and L type calcium channels

• The L channels are also part of the cellular cardiac The L channels are also part of the cellular cardiac protective pathway leading from insulin-like growth factor-protective pathway leading from insulin-like growth factor-1 (IGF-1) via phosphatidylinositol 3-kinase (PI3K) and Akt 1 (IGF-1) via phosphatidylinositol 3-kinase (PI3K) and Akt to physiological hypertrophy and protection from ischemia-to physiological hypertrophy and protection from ischemia-reperfusion injury reperfusion injury

Turn off calcium releaseTurn off calcium release Calcium SparksCalcium Sparks Na/Ca++ Na/Ca++

G ProteinsG Proteins

• GS: GS: alpha subunit of Gs (alphas) combines with GTP and alpha subunit of Gs (alphas) combines with GTP and

then separates from the other two subunits to enhance then separates from the other two subunits to enhance activity of adenylyl cyclase.activity of adenylyl cyclase.

• GI: GI: By stimulating the enzyme GTPase, they break down By stimulating the enzyme GTPase, they break down

the active alphas-subunit.the active alphas-subunit. KACh channel, which, in turn, can inhibit the sinoatrial KACh channel, which, in turn, can inhibit the sinoatrial

node node

G ProteinsG Proteins

• Gq:Gq: Overexpression of Gq in mice induces a dilated Overexpression of Gq in mice induces a dilated

cardiomyopathy cardiomyopathy angiotensin II and endothelin, which act through Gq angiotensin II and endothelin, which act through Gq

Beta2 postreceptor signaling involves both the stimulatory and Beta2 postreceptor signaling involves both the stimulatory and the inhibitory G proteins the inhibitory G proteins

Beta3-adrenergic receptors, some studies have proposed a Beta3-adrenergic receptors, some studies have proposed a negative inotropic negative inotropic

INHIBITION OF ADENYLYL CYCLASE.INHIBITION OF ADENYLYL CYCLASE.

• Adenosine, by interaction with alpha1 receptors, couples to Adenosine, by interaction with alpha1 receptors, couples to Gi to inhibit contraction and heart rate.Gi to inhibit contraction and heart rate.

Negative inotropic effect of vagal stimulation:Negative inotropic effect of vagal stimulation:

• (1) heart rate slowing (negative Treppe phenomenon)(1) heart rate slowing (negative Treppe phenomenon)

• (2) inhibition of the formation of cyclic AMP(2) inhibition of the formation of cyclic AMP

• (3) direct negative inotropic effect mediated by cyclic (3) direct negative inotropic effect mediated by cyclic GMP. GMP.

NO is generated in the vascular endothelium in response to NO is generated in the vascular endothelium in response to increased increased

• blood flowblood flow

• Increased cardiac loadIncreased cardiac load

• bradykinin.bradykinin.

REACTIVE OXYGEN SPECIES AS SIGNALING REACTIVE OXYGEN SPECIES AS SIGNALING MOLECULES. MOLECULES. • Protective oxygen-sensing mechanisms, allowing cells to Protective oxygen-sensing mechanisms, allowing cells to

adapt to hypoxia. adapt to hypoxia. TNF: TNF:

• Formed during challenge by hypoxia, ischemia-Formed during challenge by hypoxia, ischemia-reperfusion, myocardial infarction, or mechanical loading reperfusion, myocardial infarction, or mechanical loading

• One path is adaptive and sends further signals via nuclear One path is adaptive and sends further signals via nuclear factor kappa B to the nucleus for the manufacture of factor kappa B to the nucleus for the manufacture of protective molecules. The other maladaptive path leads to protective molecules. The other maladaptive path leads to apoptosis via the activation of caspases. apoptosis via the activation of caspases.

Frank (1895) reported that the greater the initial LV volume, Frank (1895) reported that the greater the initial LV volume, the more rapid the rate of rise, the greater the peak pressure the more rapid the rate of rise, the greater the peak pressure reached, and the faster the rate of relaxation.reached, and the faster the rate of relaxation.

Starling (1918) proposed that within physiological limits, the Starling (1918) proposed that within physiological limits, the larger the volume of the heart, the greater the energy of its larger the volume of the heart, the greater the energy of its contraction and the amount of chemical change at each contraction and the amount of chemical change at each contraction. contraction.

Frank-Starling law, which can account for two of the Frank-Starling law, which can account for two of the mechanisms underlying the increased stroke volume of mechanisms underlying the increased stroke volume of exercise—namely, increased diastolic filling (Starling's law) exercise—namely, increased diastolic filling (Starling's law) and increased inotropic state (Frank's findings). and increased inotropic state (Frank's findings).

12 to 14% of the oxygen uptake may be converted to external 12 to 14% of the oxygen uptake may be converted to external workwork

Internal work: Internal ion fluxes (Na+/K+/Ca2+) account for Internal work: Internal ion fluxes (Na+/K+/Ca2+) account for about 20 to 30% of the ATP requirement of the heartabout 20 to 30% of the ATP requirement of the heart

Most ATP is spent on actin-myosin interaction, and much of Most ATP is spent on actin-myosin interaction, and much of that on generation of heat rather than on external work. that on generation of heat rather than on external work.

An increased initial muscle length sensitizes the contractile An increased initial muscle length sensitizes the contractile apparatus to calcium, thereby theoretically increasing the apparatus to calcium, thereby theoretically increasing the efficiency of contraction by diminishing the amount of efficiency of contraction by diminishing the amount of calcium flux required. calcium flux required.

Diastolic Dysfunction:Diastolic Dysfunction: The cytosolic calcium level must fall to cause the The cytosolic calcium level must fall to cause the

relaxation phase.relaxation phase. The inherent viscoelastic properties of the The inherent viscoelastic properties of the

myocardium are of importance. In the hypertrophied myocardium are of importance. In the hypertrophied heart with increased fibrosis, relaxation occurs more heart with increased fibrosis, relaxation occurs more slowly. slowly.

Increased phosphorylation of troponin I enhances the Increased phosphorylation of troponin I enhances the rate of relaxation.rate of relaxation.

Relaxation is influenced by the systolic load.Relaxation is influenced by the systolic load.

IMPAIRED RELAXATION AND CYTOSOLIC IMPAIRED RELAXATION AND CYTOSOLIC CALCIUM.CALCIUM.

• The first phase, isovolumic phaseThe first phase, isovolumic phase

• The second phase of rapid filling provides most of The second phase of rapid filling provides most of ventricular filling. ventricular filling.

• The third phase, or diastasis, (5%) The third phase, or diastasis, (5%)

• The final atrial booster phase (15%)The final atrial booster phase (15%)

ATRIAL FUNCTIONS:ATRIAL FUNCTIONS: Blood-receiving reservoir chamber. Blood-receiving reservoir chamber. Contractile chamber.Contractile chamber. As a conduit that empties its contents into the LV down a As a conduit that empties its contents into the LV down a

pressure gradient after the mitral valve opens. pressure gradient after the mitral valve opens. Volume sensor of the heart, releasing atrial natriuretic peptide Volume sensor of the heart, releasing atrial natriuretic peptide

(ANP) in response to intermittent stretch, so that an ANP-(ANP) in response to intermittent stretch, so that an ANP-induced diuresis.induced diuresis.

Contains receptors for the afferent arms of various reflexes, Contains receptors for the afferent arms of various reflexes, including mechanoreceptors that causes “Bainbridge reflex”. including mechanoreceptors that causes “Bainbridge reflex”.

LEFT VENTRICULAR HYPERTROPHY AND LEFT VENTRICULAR HYPERTROPHY AND DIASTOLIC DYSFUNCTION: DIASTOLIC DYSFUNCTION: In hearts with concentric In hearts with concentric hypertrophy, as in chronic hypertension or severe aortic hypertrophy, as in chronic hypertension or severe aortic stenosis -> A-II and TGF-b being associated not only with stenosis -> A-II and TGF-b being associated not only with myocyte growth, but also with maladaptive fibrosis, myocyte myocyte growth, but also with maladaptive fibrosis, myocyte degeneration, and eventual myocyte loss degeneration, and eventual myocyte loss

LEFT VENTRICULAR VOLUME LOADING AND THE LEFT VENTRICULAR VOLUME LOADING AND THE SIGNALS INVOLVED:SIGNALS INVOLVED: volume-induced mechanical stress volume-induced mechanical stress with progressively greater LV volumes releases increasing with progressively greater LV volumes releases increasing amounts of TNF from the normal myocardium. Passive stretch amounts of TNF from the normal myocardium. Passive stretch of ventricular muscle promotes TNF mRNA synthesis. of ventricular muscle promotes TNF mRNA synthesis.

Thank youThank you