Physiology

Question 1

Mutations in people causing HCM

Answer 1

Myofibrillar proteins: beta-MHC’ MLC, TnT, TnI, TnC, tropomyosin, actin
Cytoskeleton: Titin, MBPC, LIM, T cap
Glycogen stores: ampk, Danon’s lysosomes protein 2, lysosomes acid glycosidase and alpha galactocidase defects
Other membrane proteins: RyR, Nkx2.5

Question 2

Mutations in people for DCM

Answer 2

Beta MHC, TnT, TnI, TnC, alpha tropomyosin, actin
Titin, z-band, telethoinin, Tcsp, desmin
Dystrophin related proteins, sarcoglacans
Desmosomal related: ARVC, desmoplakin, plakoglobin
Nuclear: emerin, lamin, metavinculin, phospholamban, SUR2A (kATP)

Question 3

Extrinsic factors that affects LV filling

Answer 3

Extrinsic factors:

1. Pericardial elasticity/restraint
2. Right Ventricular loading
3. Coronary vascular turgor
4. External compression – tumor/mass, pleural pressures, etc

Question 4

Intrinsic factors that affect LV filling

Answer 4

1. Passive elasticity of LV wall (stiffness or compliance following complete relaxation)
   - Thickness of LV wall
   - Composition of LV wall (fibrosis, amyloid, infiltrative, etc)
   - Temperature, osmolality
2. Active elasticity of LV wall (residual cross-bridge activation thru part or all diastole)
   - Slow relaxation affecting early diastole only
   - Incomplete relaxation affecting early, mid or late distensibility
   - Diastolic tone, contracture, or rigor
3. Elastic recoil (diastolic suction)
4. Viscoelasticity (stress relaxation, creep)

Diastolic filling is normally largely dependant on EARLY diastolic filling (80%). Late diastolic filling (atrial contraction) contributes ~ 20%.

Question 5

Proportion of early and late diastolic filling depends largely on what factors? (4 major)

Answer 5

1. Elastic recoil (‘suction’)
2. Rate of myocardial relaxation
3. Chamber compliance
4. LA pressure

Question 6

Tau

Answer 6

Time required for pressure to fall from initial baseline to 1/e of that pressure. Aka the negative inverse of the semilogarithmic slope of the LV pressure decline from max -dp/dt to the level of LVEDP.

Question 7

With heart failure, reduced oxygen transport from facilitated transport is limited by production of what enzyme?

Answer 7

Increased levels of 2,3 DPG (diphosphoglycerate)

Question 8

What is ventricular interdependence?

Answer 8

A function of the anatomical arrangement of the ventricles. Overfilling of one chamber displaces the shared interventricular septum and impairs the filling of the contra lateral chamber. Ex pericardial effusion.

Question 9

NE, AVP, and ET-1, effect vaso constriction via what signal transduction process?

Answer 9

Gq activates PLC and IP3. IP3 results in calcium releases from the sarcoplasmic reticulum. Chronic IP3 signaling leads to PKC activation causing vascular remodeling.

Question 10

Function of NO on vasculature.

Answer 10

Increases cGMP which inhibits calcium entry into the cell. And directly activates potassium channels leading to hyperpolarization of the dell and vasodilation.

Question 11

La place.

Answer 11

Wall stress= pressure x radius/ 2x wall thickness.
Sigma= P*r/ 2h.
Examples: HCM: high P, high h(increased thickness) = normal stress.
Athletic: high r, high h= normal stress
DCM: high r, low h= high stress.

Question 12

What is the molecular mechanism of diastole?

Answer 12

Diastole commences with closure of the LTCC and active removal of calcium away from contractile proteins via the SR calcium pump, SERCA. Ca transport via SERCA is a direct inverse function of Ca concentration the SR. SERCA is regulated by phospholamban. Phosphorylation of phospholamban deinhibits SERCA. Phosphorylation of phospholamban is via cAMP activated PKA or via calcium dependent calmodulin kinase.

Question 13

How is calcium handling affected by heart failure and what are the consequences?

Answer 13

Calcium stores decrease in the SR due to 1) decrease SERCA or SERCA ATPase. 2) increased removal of calcium via NCX. 3) altered calcium release from SR via RyR.
Consequences: 1) peak calcium transit is delayed and return to baseline is prolonged. 2) prolonged calcium and NCX activity lead to EAD and DAD.

Question 14

What the fuck is a costamere and what molecules are associated with them?

Answer 14

Aggregates of integrin molecules linked to contractile apparatus via alpha-actinin/talin/vinculin and integrin linked kinase/paxcillin/parvin. Knockouts of these case DCM. Close to costameres are dystrophin, sarcoglycans, caveolin-3.

Question 15

Function of dystrophin

Answer 15

Connects intracellular actin to extra cellular laminin, the major non- collagenous component of the basement membrane. Alterations of any these induce DCM.

Question 16

Three types junctions at intercalated discs

Answer 16

Gap junctions: spread action potential.
Fascia adherens and desmosomes: physically join Z discs and cytoskletons of adjacent myocytes.
Major desmosomes proteins: desmoglein, desmoplakin, plakoglobin, plakophyllin. Defects in these: ARVC

Question 17

Tau vs. -dp/dt

Answer 17

Tau is independent of load

Question 18

What causes decrease in contractility with heart failure?

Answer 18

Decrease in myofibrilliar ATPase activity with altered TnI phosphorylation due to increase PKC activity and decreased PKA activity.

Question 19

Why is end systolic pressure volume loops better for evaluating systolic function vs. dp/dt, EF, ESVI, vmax?

Answer 19

PV loops are measured under increasing loading conditions therefore they remove the confounding effects of after load and preload

Question 20

Mechanism of sympathetic activated increase in contractility

Mech of acetylcholine induced decrease in contractility.

Answer 20

Sympathetic activity increases cAMP which activates PKA leading to activation of

1) LTCC, RyR, phospholamban… All of these in return increase calcium through sarcolemma leading to Ca induced Ca release from SR.
2) PKA also activates cTNI and MYBP-C

Acetylcholine inhibits cAMP via Gi muscarinic receptors.

Question 21

How is beta receptors and NE stores affected by heart failure.

Answer 21

1) Chronic heart failure leads to down regulation and uncoupling of beta-1 receptors» further diminished contractility. (Reduced mRNA transcript.)
2) Myocardial NE stores decrease which renders the heart reliant on circulating catecholamines.
3) increased beta receptor kinase (bARK) facilitates uncoupling of cardiac beta-1 and beta-2 from G proteins via beta-arrestin…. Which all leads to decreased cAMP production….. Which all leads to diminished responses to adrenergic stimulation.

Question 22

Where do the three atrial internodal pathways go?

Answer 22

Paired ventral goto AV, Bachmanns activates LA and then toward AV node.

Question 23

Why is there error in venous sampling in RA for Fick

Answer 23

Due to admixture of bronchial and thebesian venous blood. Also cranial vc, caudal vc, and coronary sinus may not have homogenous oxygen content. With Fick, sodium levels and PCV affect lithium ion CO measurement

Question 24

With thermodilution, does a small area under the curve indicate high or low cardiac output?

Answer 24

Small area means high CO… Faster transit less dilution. Large AUC means low CO

Question 25

Prostacyclin vs. thromboxane

Answer 25

Prostacyclin vaso dilates, thromboxane vasoconstricts

Question 26

Describe the mitochondrial fatty acid transport system

Answer 26

1. FAcoA converted by carnitine acyl transferase to FAacyl carnitine.
2. FA acyl carnitine coA enters mitochondria via carnitine translocase
3. Carnitine is released by carnitine transferase II to FA acyl coA
4. Acyl coA converted to acetyl coA via beta oxidation

Question 27

What is ubiquinone?

Answer 27

Ubiquinone oxidizes NADH dehydrogenase and the electron from this enter electron transport chain
The proton combines with reduced oxygen via cytochrome oxidase to form water

Question 28

What is phosphocreatitine?

Answer 28

ATP is converted to this by creatine kinase and allows transfer of ATP from mitochondria to cytosol.
Creatine phosphate is an energy reserve for the heart.

Question 29

SERCA 2a increases calcium reuptake can be modulated by what two mechanisms?

Answer 29

1. Increases in calcium in cytosol

2. Beta stimulation of phospholamban via PKA which increases rate of relaxation

Question 30

What is the anrep effect?

Answer 30

An abrupt increase in after load results in an increase in inotropy. This also causes a reflex drop in vascular resistance.

Question 31

What enzymes breakdown proBNP?

Answer 31

Corin from myocardium and furin (ubiquitously xpressed)