CHF Flashcards
Define microcirculation
arterioles + capillaries
Anatomy of alveolar capillaries
- Alveolar capillaries: 1 layer ¢ walls
o Large squamous ¢ (Type I)
o Granular pneumocytes (Type II): less abundant
Determinants in Starling’s law
- 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)
Role of lymphatics
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
Pathophys of pulmonary edema w/ starling forces
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
Myocardial mechanisms that can lead to CHF
Pressure overload
Volume overload
Primary myocardial failure
Pathphys pressure overload
- 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
Failure and dysfct w/ concentric hypertrophy
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
Pathphys volume overload
- 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
Pathophys of primary myocardial failure
- 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
Myocardial injury leads to
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
How does compensated CHF progresses into overt failure
- 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
Cellular mechanisms of HF
Fibrosis: Ang II and aldosterone
Matrix remodelling
Apoptosis
Ca2+ cycling abn
Role of Ang II and aldosterone in CHF
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
Role of matrix remodelling in CHF
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
Role of apoptosis in CHF
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
Role of Ca2+ cycling abnormalities in CHF
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)
Role of FA and glucose pathway in CHF
Downreg
Clinical syndrome of CHF
Heart that pump inadequate volume of blood or blood is maldistributed => inadequate tissue O2 delivery
Pathophys of diastolic HF
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
Causes of diastolic HF
Pericardial restraint
Obstruction to venous flow
Impaired myocardial relaxation
decr ventricular compliance
incr HR
Weak, absent, poorly timed atrial contractions
Pathophys of systolic HF
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
Causes of systolic HF
Primary myocardial failure
* DCM, taurine deficiency
Chronic volume or pressure overload
Neurohumoral changes in HF
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
HF can be defined as
o Mechanical: decr maximal shortening velocity
o Chemical: decr rate of E released by ATP
o Functional: decr contractility
LV dysfct vs failure
- Dysfct : abnormalities of relaxation/contraction => cannot fill/empty properly
- Failure: abnormalities result in fluid retention or exercise intolerance
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
HF vs shock
Shock has adequate venous return
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
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
Neurohumoral changes in CHF
RAAS activation
ET-1 activation
ANP
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
Endothelin in CHF
- incr circulating levels in HF
o Myocardium: incr levels of preproendothelin-1 - Direct toxic myocardial effect => promote Ca2+ overload
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
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
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
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
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
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
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
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
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
Action of dobutamine/dopamine
synthetic catecholamines => bind to cardiac B-R => coupled stimulatory G prot => activate adenylyl cyclase => incr cAMP
PharmacoK dobutamine/dopamine
Short ½ life = IV use
Limited efficacy during chronic use du to B-R downregulation (24-72h)
Side effects dobutamine/dopamine
tachycardia + arrhythmia => usually dose related
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
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
Effect of digoxin/digitalis glycoside
Weak positive inotrope = 1/3 effect of sympatomimethics
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
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
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
Classes of diuretics
Loop diuretics
Thiazide
K+ sparing
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
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
MOA K+ sparing diuretics
sprionolactone, triamterene
Inhibit action of aldosterone on distal tubular ¢
* More effective w incr [aldosterone]
