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4. Physiology and pathophysiology > CHF > Flashcards

CHF Flashcards

1
Q

Define microcirculation

A

arterioles + capillaries

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2
Q

Anatomy of alveolar capillaries

A
  • Alveolar capillaries: 1 layer ¢ walls
    o Large squamous ¢ (Type I)
    o Granular pneumocytes (Type II): less abundant
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3
Q

Determinants in Starling’s law

A
  • Fluid mvt across membrane = (Pc + pic – Pi - pii) x k
    o Hydrostatic (P) pressure = venous pressure = 0-12mmHg
     Higher vs interstitium (0mmHg) => fluid tend to exit vessels
     Interstitium pressure incr w CHF
    o Osmotic (pi) pressure = plasma [albumin]
     Higher in vessel vs interstitium => fluid tend to enter vessels
    o Membrane characteristics: filtration coefficient (k)
     Vary btwn capillary beds:
  • high in glomerular capillaries vs skeletal muscle
  • low in hepatic sinusoids vs pulmonary capillaries (ascites form at lower pressures)
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4
Q

Role of lymphatics

A

drainage of interstitium back to circulation
o Can accommodate until certain extent of incr pressure
o Pc > 12mmHg = fluid accumulation in interstitium
o Pc > 15-20mmHg = pulmonary edema

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5
Q

Pathophys of pulmonary edema w/ starling forces

A

o Normally arterial end of capillary, Pc = 32mmHg and pic = 25mmHg => net outward = 7mmHg
o Venous end: Pc = 15mmHg and pic = 25mmHg => net inward gradient = 10mmHg
o In HF: failing LV => decr CO from LV => backflow in LA => pressure build up venous side => congestion => incr hydrostatic pressure in pulmonary capillaries > osmotic pressure
 If >18-22mmHg = rate of fluid exit exceed lymphatic drainage => pulmonary edema
 incr load on RV: pump blood to partially constricted pulmonary vessels
o Hu: dilation of PVs => broncho constrictive reflex => cardiac asthma

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6
Q

Myocardial mechanisms that can lead to CHF

A

Pressure overload
Volume overload
Primary myocardial failure

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7
Q

Pathphys pressure overload

A
  • incr afterload => require incr myocardial performance => incr LV wall stress
    o Transmural force tend to dilate the heart => further incr wall stress
    o Sustained incr afterload => concentric hypertrophy
     incr thickness w similar radius => normalized wall stress
     Concentric remodelling: normal LV mass, decr cavity size, incr wall thickness
  • decr SV from: incr afterload and decr preload
  • Worst px (vs other hypertrophy):
    o Risk of potential ischemia
    o ¢ changes: incr ¢ death
  • Growth response: mediated by RAAS and Ang II
    o incr expression RNA for collagen
    o Transforming growth factor beta
    o Fibronectin
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8
Q

Failure and dysfct w/ concentric hypertrophy

A

incr LV wall thickness and mass
 Proportional to degree of incr afterload
 incr O2 distance diffusion => O2 deprivation, myo¢ death, fibrosis
o Greater fibrosis = greater diastolic and systolic dysfct
o Abnormal diastolic properties: loss of distensibility, impaired relaxation, decr early diastolic filling
o Diastolic heart failure: combination of diastolic dysfct + fluid retention
 Can occur w or w/o diastolic failure

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9
Q

Pathphys volume overload

A
  • Hemodynamic disturbance: regurgitation (MV, AoV) => changes in loading conditions + ventricular size
    o incr preload => longitudinal hypertrophy (eccentric)
     incr chamber size w/o incr wall thickness => incr wall tension
     incr early diastolic filling + decr LV stiffness => improve diastolic fct
     Some degree of pressure induced hypertrophy can occur secondary to incr wall stress => allows LV cavity to decr but not fully normalize wall stress
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10
Q

Pathophys of primary myocardial failure

A
  • Inadequate generation of tension because of CM
    o HCM => incr systolic EF%, diastolic dysfct, small LV cavity
     Often dz of sarcomere => muscle ¢ undergo excess growth in response to genetic abnormality of the contractile proteins
    o DCM => enlarge heart, incr EDV + ESV, EF%
     Self-induced volume overload + incr wall stress
     Abnormalities of cytoskeleton
     Tachycardiomyopathy: prolonged pacing tachycardia => upregulation of myo¢ RAAS => promote myo¢ hypertrophy and death
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11
Q

Myocardial injury leads to

A

dilation of ventricle
o Swelling/separation of myocardial fibers
o Depletion stores of Pi and glycogen
o incr lactate production
o incr mitochondrial mass
o incr RNA levels + protein synthesis

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12
Q

How does compensated CHF progresses into overt failure

A
  • Neurohumoral changes in circulation to maintain organ perfusion w decr myocardial fct
    o RAAS activation
    o incr adrenergic state
  • Descending limb of Frank Starling curve
    o incr venous pressure fail to incr CO
    o Ventricular interaction:
     HF incr central blood volume (total blood volume in heart + lungs)
     incr venous return => incr RA filling pressure => incr RV preload => RV dilation => pression on LV => decrLV function
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13
Q

Cellular mechanisms of HF

A

Fibrosis: Ang II and aldosterone

Matrix remodelling

Apoptosis

Ca2+ cycling abn

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14
Q

Role of Ang II and aldosterone in CHF

A

o RAAS: role in irreversible damage + incr afterload
o Ang II (via TGF-B) + aldosterone => major stimulus to fibrosis
o Peripheral arterioles: Ang II promotes
 Formation of reactive O2 species w endothelial dysfct
 incr vasoconstriction

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15
Q

Role of matrix remodelling in CHF

A

o incr collagen tissue:
 May help to limit ventricular dilation if proportional to degree of hypertrophy
 Excessive collagen response to ischemia/metabolic signals => decr compliance and incr stiffness
 Non elastic type I collagen incr more => poor diastolic relaxation

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16
Q

Role of apoptosis in CHF

A

gene directed process => predictable ¢ death
o Expression of Fas gene + inactivation of antiapoptotic bcl-2 gene
o Low incidence of apoptotic ¢ found in HF
o Triggers: mitochondrial damage 2nd to
 ATP depletion
 incr cytosolic Ca2+
 Excess oxidative stress
o Damaged mitochondria liberate cytochrome C => apoptosis

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17
Q

Role of Ca2+ cycling abnormalities in CHF

A

abnormal Ca2+ transients
o decr increase in internal Ca2+ and prolonged decreasing Ca2+ transient
o Tachycardia: not enough time for Ca2+ to be pumped in SR
o Causes: ¢ Ca2+ overload
 SERCA pump: decr expression in failing heart
* incr non Pi form of phospholamban => inhibits Ca2+ uptake by SR
 Ca2+ induced Ca2+ release impaired
* Ryanodine R: hyperphosphorylated by excess B adrenergic stimulation
* Inhibit Ca2+ release
 incr Ca2+ entry via upregulated Na+/Ca2+ exch (via incr B adrenergic stimulation)

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18
Q

Role of FA and glucose pathway in CHF

A

Downreg

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19
Q

Clinical syndrome of CHF

A

Heart that pump inadequate volume of blood or blood is maldistributed => inadequate tissue O2 delivery

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20
Q

Pathophys of diastolic HF

A

decr LA emptying + decr LV filling => pulmonary congestion => incr venous pressures
o Myocardial relaxation is determined by:
 Rate/extent depend on rate of Ca2+ capture by SR => requires ATP + Pi of phospholamban
 Systolic loading conditions: incr afterload improve relaxation up to certain point
 Inherent cardiac viscoelastic properties => myocardial stiffness/compliance
* Stiffness incr w dilation, hypertrophy, firbrosis
 Hypertrophic heart => relax slowly and heterogenously
* Delayed relaxation and decr rate/extent
* Feline HCM => concentric hypertrophy => impaired ventricular relaxation + decr LV compliance

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21
Q

Causes of diastolic HF

A

 Pericardial restraint
 Obstruction to venous flow
 Impaired myocardial relaxation
 decr ventricular compliance
 incr HR
 Weak, absent, poorly timed atrial contractions

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22
Q

Pathophys of systolic HF

A

decr contractility => decr force development (lower Frank Starling curve) => decr CO/SV => decr peripheral perfusion => muscular fatigue

o Reduced myocardial contractility = primary abnormality
 Wall stress: fixed at the end of diastole => will decr throughout systole as blood is ejected (decr chamber diameter + incr wall thickness)
 decr myocardial contractility => decr myocardial shortening => decr SV + incr ESV
* Activation of neurohumoral response to incr HR and fluid retention => normalize SV
 incr wall stress + ESV -> stimulate sarcomere replication in serie = eccentric hypertrophy
* Moderately impaired heart can eject normal SV despite decr contractility

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23
Q

Causes of systolic HF

A

 Primary myocardial failure
* DCM, taurine deficiency
 Chronic volume or pressure overload

24
Q

Neurohumoral changes in HF

A

incr peripheral resistance => incr afterload
o Critical event in progression of systolic HF
o incr symp tone => incr baroreflex activity
o RAAS activation
 Fluid retention => peripheral edema + incr preload
o Aldosterone secretion from adrenal gland
 Na+ retention

25
Q

HF can be defined as

A

o Mechanical: decr maximal shortening velocity
o Chemical: decr rate of E released by ATP
o Functional: decr contractility

26
Q

LV dysfct vs failure

A
  • Dysfct : abnormalities of relaxation/contraction => cannot fill/empty properly
  • Failure: abnormalities result in fluid retention or exercise intolerance
27
Q

Sympathetic system in HF: catecholamines and B-R

A
  • incr plasma [NE]: degree of incr proportional to severity of HF => related to px
  • decr myocardial fct => hypotension => stimulate baroR => symp activation
    o B mediated tachycardia
    o A mediated vasoconstriction
  • Receptors: incr # of B1-R, more prominent B2-R
    o decr inotropic response to catecholamines
    o Inhibit formation of cAMP via Gi signaling

B1-R downregulation
* Chronic/high exposure to catecholamines => decr myocardial responsiveness = desensitization
o B adrenergic R kinase => Pi-B1-R => inactivation
* Role of B2-R: become more prominent as B1-R # decr
o Not full expected inotropic result
o May be linked to Gi protein => negative inotropic antiapoptotic effect

27
Q

HF vs shock

A

Shock has adequate venous return

28
Q

Genesis of pulmonary edema

A
  • icnr LA pressure from failing LV => incr pulmonary venous/capillary pressure => pulmonary congestion
    o icnr lung mass/stiffness => incr difficulty for inspiratory lung expansion
    o PVs dilation => broncho constrictive reflex => cardiac asthma (Hu)
    o Ventilation perfusion inequalities
  • Pulmonary capillary pressure > 18-22mmHg => rate of fluid formation > lymphatic drainage =>pulmonary edema
  • incr load on RV
29
Q

B adrenergic blockers in HF

A
  • Anti-arrhythmic effects
  • Reverse remodelling
  • Improve internal Ca2+ cycling
    o Inhibit hyperphosphorylation of RyR => decr excessive release of Ca2+ and Ca2+ overload
  • decr uptake/use of free fatty acids
30
Q

Neurohumoral changes in CHF

A

RAAS activation
ET-1 activation
ANP

31
Q

RAAS in HF

A
  • Renin release: low renal perfusion + symp stimulation
  • Angiotensin II: incr myocardial + circulating levels
    o Local myocardial growth factor
    o Peripheral vasoconstriction + promotion of vascular SM ¢ growth
    o incr symp activation
    o Aldosterone release => retain Na+ + H20 => incr fluid volume
    o Vasopressin release => vasoconstriction + decr urine production
    o incr thirst
    o Production of free O2 radicals (macrophages/neutrophils) => lipid peroxidation of ¢ membrane, ¢ death, fibrosis replacement
32
Q

Endothelin in CHF

A
  • incr circulating levels in HF
    o Myocardium: incr levels of preproendothelin-1
  • Direct toxic myocardial effect => promote Ca2+ overload
33
Q

ANP/BNP in CHF

A
  • Action is overcome by RAAS activation
    o Diuretic activity
    o Vasodilation
    o Inhibit aldosterone secretion
  • Release by volume/P overload from endocardial layer (incr wall tension)
    o ANP from atrial stretch but can also be released from ventricles
    o BNP from failing ventricles but can also come from atria
34
Q

Physiology of GFR

A

o Glomerular membrane = impermeable to protein => filtrate is low protein
o Non filtered plasma = incr prot => peritubular capillaries
 Fluid in tubules = decr prot
 Oncotic gradient => reabsorption 50 % of filtrate

35
Q

Renal consequences in HF

A
  • decr renal blood flow => RAAS activation
    o incr ADH + aldosterone => Na+ + H2O reabsorption in distal tubules
    o Constriction of efferent arteriole + dilation of afferent arteriole => maintain GFR
     Maintain volume of glomerular filtrate despite decr renal blood flow
     Filtration fraction incr => decr volume of blood to peritubular capillaries
     incr oncotic pressure => incr fluid reabsorption
36
Q

Efficiency of work in CHF

A
  • Unable to generate high pressures enough
  • decr external work, incr potential energy generated
    o incr O2 consumption and decr work efficiency
37
Q

Tx diastolic dysfct: Goals

A
  • Directed to underlying disorder if possible + compensatory responses.
    o Address component that limit diastolic filling
     incr HR, AV dyssynchrony, decr systolic performance
     Constrictive pericarditis => pericardectomy
    o Avoid vasodilators => can precipitate hypotension/worsen dynamic obstruction
  • B blockers:
    o decr HR => improve diastolic filling
    o decr or eliminate LVOT obstruction
  • Ca2+ channel blockers:
    o Improve myocardial relaxation in cats
    o May cause regression of LV hypertorphy
38
Q

Tx diastolic dysfct: drugs

A
  • B blockers:
    o decr HR => improve diastolic filling
    o decr or eliminate LVOT obstruction
  • Ca2+ channel blockers:
    o Improve myocardial relaxation in cats
    o May cause regression of LV hypertorphy
39
Q

Tx systolic dysfct: goals

A
  • Objective: decr afterload, decr preload (venous return), decr compensatory neurohumoral responses

o Chronic volume overload: MR
 decr forward SV: portion of ejected volume = MR
* incr symp activation => incr HR + contractility
 LV eccentric hypertrophy to accommodate volume overload: maintain SV + normal contractility and wall stress
* Progressive enlargement => incr wall stress + O2 consumption
* Activation of neurohumoral responses: incr afterload, preload => incr MR, heart size

o Chronic pressure overload: PS, SAS
 incr ESV + decr SV => LV concentric hypertrophy (sarcomere replication in //) => thickened mucle fibers
* decr capillary density/muscle mass => chronic myocardial hypoxia
o Premature ¢ death => myocardial fibrosis
o Ventricular arrhythmias
* Myocardial fibrosis => decr ventricular compliance => diastolic dysfct

40
Q

Tx systolic dysfct: drugs

A

Positive inotropes: dobutamine, dopamine, digoxin

Arterial vasodilators
o decr MR by decr LA to LV gradient
o incr contraction velocity (thus decr mitral annulus) => decr regurgitant orifice size

41
Q

Vasodilators

A

 Hydralazine
 Nitrates: nitroprusside, nitroglycerin, isosorbide di (or mono)nitrate
 Ca2+ channel blockers : amlodipine
 Adrenergic R blockers : prazosin
* Block A1-R + peripherally inhibits phosphodiesterase
* Arteriolar and venodilator
 ACEi : benazepril, enalapril, lisonipril
* decr ACE activity by binding its zinc ion-containing active site

42
Q

Action of dobutamine/dopamine

A

synthetic catecholamines => bind to cardiac B-R => coupled stimulatory G prot => activate adenylyl cyclase => incr cAMP

43
Q

PharmacoK dobutamine/dopamine

A

 Short ½ life = IV use
 Limited efficacy during chronic use du to B-R downregulation (24-72h)

44
Q

Side effects dobutamine/dopamine

A

tachycardia + arrhythmia => usually dose related

45
Q

Dobutamine specific MOA

A
  • Stim B1-R, weakly peripheral B2-R and A1-R

Incr contractility, little change in HR and afterload

  • Less arrhythmogenic than other sympathomimetic drugs
46
Q

Dopamine specific MOA

A

precursor of NE
* High dose: incr release of NE + can cause systemic vasodilation
* Low dose: selective arteriolar dilation => renal, mesenteric, coronary, cerebral

47
Q

Effect of digoxin/digitalis glycoside

A

Weak positive inotrope = 1/3 effect of sympatomimethics

48
Q

Action of digoxin/digitalis glycoside

A

inhibit Na+/K+ ATPase pump by binding K+ site
* incr intra¢ [Na+] => activate Na+/Ca2+ exchanger => incr [Ca2+] => incr contractility
* Restore baroR reflexes => incr psymp tone to SA, AV nodes + decr [NE] circulating

49
Q

Side effects digoxin/digitalis glycoside

A

 Narrow safety margin: 1.0 to 2.5ng/mL. Intoxication:
* GI dyscfct: chemoR in area postrema in medulla = anorexia, vomiting
* Neuro sigsn: depression, disorientation, delirium
* Myocardial toxicity: disrupt normal electric activity
o Slow conduction/alter RP of myocardial ¢ => re-entrant arrhythmias
o incr symp tone w high doses => enhanced normal automaticity
o Promote abnormal automaticity.
o icnr risk of arrhythmias from after depolarizations (Ca2+ overload)
o HypoK+: predisposing cause for toxicity => compete for binding site

50
Q

Diuretics action

A
  • Most potent agent => act on loop of Henle
  • Interfere with ion transport by altering
    o Intra¢ ionic entry
    o E generation/utilization for ion transport
    o Ion transfer from the ¢ to epritubular capillaries
51
Q

Classes of diuretics

A

Loop diuretics
Thiazide
K+ sparing

52
Q

MOA loop diuretics

A

furosemide, torsemide
 Inibit Na+/K+/Cl- symport in ascending loop of Henle => decr reabsorption
 icnr max fractional Na+ excretion to 23% = most powerful natriuretic agent
 decr renal vascular resistance => incr renal blood flow
 Chronic use => distal tubule hypertrophy => incr Na+ reabsorption

53
Q

MOA thiazide diuretics

A

hydrochlorothiazide
 Inhibit Na+/Cl- cotransporter in distal convoluted tubule
 incr Na+, Cl-, H2O delivery in collecting duct + incr secretion of K+ and H+
* Can induce hypoK+ and metabolic alkalosis

54
Q

MOA K+ sparing diuretics

A

sprionolactone, triamterene
 Inhibit action of aldosterone on distal tubular ¢
* More effective w incr [aldosterone]

4. Physiology and pathophysiology (18 decks)

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