Physiology Flashcards
(31 cards)
Mutations in people causing HCM
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
Mutations in people for DCM
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)
Extrinsic factors that affects LV filling
Extrinsic factors:
- Pericardial elasticity/restraint
- Right Ventricular loading
- Coronary vascular turgor
- External compression – tumor/mass, pleural pressures, etc
Intrinsic factors that affect LV filling
- 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 - 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 - Elastic recoil (diastolic suction)
- Viscoelasticity (stress relaxation, creep)
Diastolic filling is normally largely dependant on EARLY diastolic filling (80%). Late diastolic filling (atrial contraction) contributes ~ 20%.
Proportion of early and late diastolic filling depends largely on what factors? (4 major)
- Elastic recoil (‘suction’)
- Rate of myocardial relaxation
- Chamber compliance
- LA pressure
Tau
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.
With heart failure, reduced oxygen transport from facilitated transport is limited by production of what enzyme?
Increased levels of 2,3 DPG (diphosphoglycerate)
What is ventricular interdependence?
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.
NE, AVP, and ET-1, effect vaso constriction via what signal transduction process?
Gq activates PLC and IP3. IP3 results in calcium releases from the sarcoplasmic reticulum. Chronic IP3 signaling leads to PKC activation causing vascular remodeling.
Function of NO on vasculature.
Increases cGMP which inhibits calcium entry into the cell. And directly activates potassium channels leading to hyperpolarization of the dell and vasodilation.
La place.
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.
What is the molecular mechanism of diastole?
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.
How is calcium handling affected by heart failure and what are the consequences?
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.
What the fuck is a costamere and what molecules are associated with them?
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.
Function of dystrophin
Connects intracellular actin to extra cellular laminin, the major non- collagenous component of the basement membrane. Alterations of any these induce DCM.
Three types junctions at intercalated discs
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
Tau vs. -dp/dt
Tau is independent of load
What causes decrease in contractility with heart failure?
Decrease in myofibrilliar ATPase activity with altered TnI phosphorylation due to increase PKC activity and decreased PKA activity.
Why is end systolic pressure volume loops better for evaluating systolic function vs. dp/dt, EF, ESVI, vmax?
PV loops are measured under increasing loading conditions therefore they remove the confounding effects of after load and preload
Mechanism of sympathetic activated increase in contractility
Mech of acetylcholine induced decrease in contractility.
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.
How is beta receptors and NE stores affected by heart failure.
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.
Where do the three atrial internodal pathways go?
Paired ventral goto AV, Bachmanns activates LA and then toward AV node.
Why is there error in venous sampling in RA for Fick
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
With thermodilution, does a small area under the curve indicate high or low cardiac output?
Small area means high CO… Faster transit less dilution. Large AUC means low CO
