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