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Overview Cardiac failure: heart unable to pump blood at a rate required by tissues Caused by: Myocardial death Myocardial death Myocyte dysfunction Myocyte dysfunction Ventricular remodeling Ventricular remodeling Neurohormonal disturbances Neurohormonal disturbances
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Basic Science Series:Basic Science Series:Pathophysiology of Heart Pathophysiology of Heart
FailureFailureOctober 27/2009October 27/2009
The Clinical Syndrome Of Heart The Clinical Syndrome Of Heart Failure Is The Final PathwayFailure Is The Final Pathwayof Diseases That Affect The of Diseases That Affect The
Heart.Heart.
OverviewOverview
Cardiac failure: heart unable to pump blood at a Cardiac failure: heart unable to pump blood at a rate required by tissuesrate required by tissues
Caused by:Caused by: Myocardial deathMyocardial death Myocyte dysfunctionMyocyte dysfunction Ventricular remodelingVentricular remodeling Neurohormonal disturbancesNeurohormonal disturbances
BackgroundBackground
Heart failure pathophysiologyHeart failure pathophysiology Index eventIndex event Compensatory mechanismsCompensatory mechanisms Maladaptive mechanismsMaladaptive mechanisms
Body-Fluid VolumeBody-Fluid Volume
Renal Na and water excretionRenal Na and water excretion Dependent on arterial circulationDependent on arterial circulation Cardiac output and peripheral resistanceCardiac output and peripheral resistance
Decrease in circulation leads to Decrease in circulation leads to arterial arterial underfillingunderfilling Decreased effective circulating volumeDecreased effective circulating volume
NeurohormonalNeurohormonal reflexes are triggered reflexes are triggered
Arterial UnderfillingArterial UnderfillingCauses and consequencesCauses and consequencesCounter-regulationCounter-regulation
Arterial UnderfillingArterial Underfilling
MechanoreceptorsMechanoreceptors Sense arterial fillingSense arterial filling Regulate body-fluid volumeRegulate body-fluid volume LV, carotid sinus, aortic arch, renal afferentsLV, carotid sinus, aortic arch, renal afferents
Decreased activation leads toDecreased activation leads to Increase sympathetic outflowIncrease sympathetic outflow RAAS activationRAAS activation ADH release and thirst activationADH release and thirst activation
Arterial UnderfillingArterial Underfilling
High vs Low Output FailureHigh vs Low Output Failure
Majority of HF is low outputMajority of HF is low output
High output failureHigh output failure Beriberi, thyrotoxicosis, AV fistula, pregnancy Beriberi, thyrotoxicosis, AV fistula, pregnancy
etc.etc. Arterial underfilling results from arterial Arterial underfilling results from arterial
vasodilationvasodilation
Sympathetic Nervous SystemSympathetic Nervous System
Increased sympathetic tone leads toIncreased sympathetic tone leads to Increased myocardial contractilityIncreased myocardial contractility TachycardiaTachycardia Arterial vasoconstriction Arterial vasoconstriction high afterload high afterload Venoconstriction Venoconstriction high preload high preload
Sympathetic NS & Frank-StarlingSympathetic NS & Frank-Starling
In HF, In HF, generalized generalized adrenergic adrenergic activationactivationReduction in Reduction in NE stores and NE stores and beta-R densitybeta-R density
Sympathetic NSSympathetic NS
Sympathetic NSSympathetic NS
Previously, beta-blockade thought to be Previously, beta-blockade thought to be contraindicatedcontraindicated
Now, one of the principal treatmentsNow, one of the principal treatments CIBIS II (bisoprolol, NYHA III-IV)CIBIS II (bisoprolol, NYHA III-IV) MERIT-HF (metoprolol, NYHA II-IV)MERIT-HF (metoprolol, NYHA II-IV) COPERNICUS (carvedilol, NYHA III-IV)COPERNICUS (carvedilol, NYHA III-IV)
Renin Angiotensin AldosteroneRenin Angiotensin Aldosterone
Renin-Angiotensin-AldosteroneRenin-Angiotensin-Aldosterone
RAAS increasedRAAS increased Degree of increase plasma renin prognosticDegree of increase plasma renin prognostic
Mild HFMild HF May have near normal renin/aldosteroneMay have near normal renin/aldosterone Inappropriate given high extracellular volumeInappropriate given high extracellular volume
Severe HFSevere HF High plasma renin and aldosteroneHigh plasma renin and aldosterone
RAASRAAS
Aldosterone activity more persistent in HFAldosterone activity more persistent in HF
In normal person – high mineralocorticoidIn normal person – high mineralocorticoid Initially increases volume 1.5-2LInitially increases volume 1.5-2L Renal Na retention then plateausRenal Na retention then plateaus Usually no detectable edemaUsually no detectable edema
Plateau does not occur in HFPlateau does not occur in HF
RAASRAAS
Angiotensin IIAngiotensin II
Increases aldosterone secretionIncreases aldosterone secretionIncreases proximal Na reabsorptionIncreases proximal Na reabsorptionVasoconstriction of renal arteriolesVasoconstriction of renal arteriolesStimulates central thirstStimulates central thirst
May also have mitogenic effect on myocytesMay also have mitogenic effect on myocytes Decrease in capillary network relative to myocardiumDecrease in capillary network relative to myocardium
Arginine VasopressinArginine Vasopressin
Leads to edema and hyponatremiaLeads to edema and hyponatremiaOminous prognostic indicatorOminous prognostic indicator
Nonosmostic release of ADHNonosmostic release of ADHCarotid baroreceptor activationCarotid baroreceptor activation
Natriuretic PeptidesNatriuretic Peptides
Atrial natriuretic peptideAtrial natriuretic peptide Synthesized in atria > ventriclesSynthesized in atria > ventricles Released into circulation during atrial Released into circulation during atrial
distentiondistention Increased in HF as atrial pressures riseIncreased in HF as atrial pressures rise
Brain natriuretic peptideBrain natriuretic peptide Synthesized primarily in ventriclesSynthesized primarily in ventricles Increased in early LV dysfxnIncreased in early LV dysfxn
Natriuretic PeptidesNatriuretic Peptides
Atrial NP and BNPAtrial NP and BNP Causes renal efferent V/C and afferent V/DCauses renal efferent V/C and afferent V/D GFR risesGFR rises Decreases Na reabsorption inDecreases Na reabsorption in Inhibits secretion of renin and aldosteroneInhibits secretion of renin and aldosterone
In HF, develop resistance to natriuretic effectIn HF, develop resistance to natriuretic effect Down-regulation of receptorsDown-regulation of receptors Increased degradation of peptides by endopeptidaseIncreased degradation of peptides by endopeptidase
RAAS vs Natriuretic PeptidesRAAS vs Natriuretic Peptides
Endothelial HormonesEndothelial HormonesProstacyclin and PG EProstacyclin and PG E Autocrine hormones in glomerular afferents: V/DAutocrine hormones in glomerular afferents: V/D Stimulated by Angiotenin II, NEStimulated by Angiotenin II, NE Counterbalance neurohormone-induced V/CCounterbalance neurohormone-induced V/C
Nitric oxideNitric oxide Potent V/DPotent V/D NO synthase blunted in HFNO synthase blunted in HF
EndothelinEndothelin Potent V/CPotent V/C Increased in HF Increased in HF poor prognostic indicator poor prognostic indicator
Summary of EffectsSummary of Effects
Chronic Myocardial RemodelingChronic Myocardial Remodeling
RemodelingRemodeling
Pressure OverloadPressure OverloadIncrease in Increase in systolicsystolic wall stresswall stressParallelParallel replication of replication of myofibrilsmyofibrilsThickeningThickening of of myocytesmyocytesSmall increase in Small increase in number of myocytesnumber of myocytes
Volume OverloadVolume OverloadIncrease in Increase in diastolicdiastolic wall stresswall stressReplication of Replication of sarcomeres in sarcomeres in seriesseriesElongationElongation of of myoctytesmyoctytesVentricular Ventricular dilatationdilatation
Laplace’s LawLaplace’s Law
Transition to HFTransition to HF
Stress on ventricleStress on ventricle Acute adaptive compensatory mechanismsAcute adaptive compensatory mechanisms
Hemodynamic overload severe / Hemodynamic overload severe / prolongedprolonged Contractility depressedContractility depressed Depressed intramural myocardial shorteningDepressed intramural myocardial shortening
Molecular MechanismsMolecular Mechanisms
Molecular MechanismsMolecular Mechanisms
Myocyte lossMyocyte loss Causes decreased contractile fxnCauses decreased contractile fxn
1.1. NecrosisNecrosis Occurs with O2 / energy deprivationOccurs with O2 / energy deprivation Loss of membrane integrityLoss of membrane integrity Influx of extracellular fluid Influx of extracellular fluid cellular cellular
disruptiondisruption
Molecular MechanismsMolecular Mechanisms
2.2. ApoptosisApoptosisProgrammed cell deathProgrammed cell deathEnergy-dependent processEnergy-dependent processInvolution of myocyte Involution of myocyte phagocytosis by phagocytosis by neighbouring cellneighbouring cell
Increasing evidence of role in HFIncreasing evidence of role in HFCatecholamines, A II, NO, cytokines, Catecholamines, A II, NO, cytokines, mechanical strainmechanical strain
SummarySummary
Pathophysiology based on compensatory Pathophysiology based on compensatory mechanisms becoming maladaptivemechanisms becoming maladaptive
Key players:Key players: Atrial underfillingAtrial underfilling Renin-Angiotensin-Aldosterone SystemRenin-Angiotensin-Aldosterone System Sympathetic systemSympathetic system Natriuretic peptidesNatriuretic peptides
Leads to chronic remodelling via apoptosis and Leads to chronic remodelling via apoptosis and necrosisnecrosis