4. Physiology and pathophysiology > CHF > Flashcards

CHF Flashcards

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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

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A

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

24
Q

Neurohumoral changes in HF

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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
HF can be defined as
o Mechanical: decr maximal shortening velocity o Chemical: decr rate of E released by ATP o Functional: decr contractility
26
LV dysfct vs failure
* Dysfct : abnormalities of relaxation/contraction => cannot fill/empty properly * Failure: abnormalities result in fluid retention or exercise intolerance
27
Sympathetic system in HF: catecholamines and B-R
* 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
HF vs shock
Shock has adequate venous return
28
Genesis of pulmonary edema
* 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
B adrenergic blockers in HF
* 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
Neurohumoral changes in CHF
RAAS activation ET-1 activation ANP
31
RAAS in HF
* 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
Endothelin in CHF
* incr circulating levels in HF o Myocardium: incr levels of preproendothelin-1 * Direct toxic myocardial effect => promote Ca2+ overload
33
ANP/BNP in CHF
* 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
Physiology of GFR
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
Renal consequences in HF
* 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
Efficiency of work in CHF
* Unable to generate high pressures enough * decr external work, incr potential energy generated o incr O2 consumption and decr work efficiency
37
Tx diastolic dysfct: Goals
* 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
Tx diastolic dysfct: drugs
* 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
Tx systolic dysfct: goals
* 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
Tx systolic dysfct: drugs
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
Vasodilators
 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
Action of dobutamine/dopamine
synthetic catecholamines => bind to cardiac B-R => coupled stimulatory G prot => activate adenylyl cyclase => incr cAMP
43
PharmacoK dobutamine/dopamine
 Short ½ life = IV use  Limited efficacy during chronic use du to B-R downregulation (24-72h)
44
Side effects dobutamine/dopamine
tachycardia + arrhythmia => usually dose related
45
Dobutamine specific MOA
* 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
Dopamine specific MOA
precursor of NE * High dose: incr release of NE + can cause systemic vasodilation * Low dose: selective arteriolar dilation => renal, mesenteric, coronary, cerebral
47
Effect of digoxin/digitalis glycoside
Weak positive inotrope = 1/3 effect of sympatomimethics
48
Action of digoxin/digitalis glycoside
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
Side effects digoxin/digitalis glycoside
 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
Diuretics action
* 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
Classes of diuretics
Loop diuretics Thiazide K+ sparing
52
MOA loop diuretics
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
MOA thiazide diuretics
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
MOA K+ sparing diuretics
sprionolactone, triamterene  Inhibit action of aldosterone on distal tubular ¢ * More effective w incr [aldosterone]
4. Physiology and pathophysiology
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