Pathophysiology of Congestive Heart Failure

Question 1

Heart Failure

• Definition
• Systolic factors that contribute to HF
• Diastolic factors that contribute to HF
• Extracardiac factors that contribute to HF

Answer 1

• Definition
  
  • Clinical syndrome
  • Heart can’t pump blood at a rate commensurate w/ the metabolic requirements of the body (or does so only w/ elevated ventricular filling pressures)
• Systolic factors that contribute to HF
  
  • Cardiomyopathies (e.g., ischemic, dilated, infeciton, peripartum, drug/toxin, inflammatory, late hypertropihc, cardiomyopathy, endocrinopathy)
  • Valvular (e.g., aortic stenosis)
• Diastolic factors that contribute to HF
  
  • Cardiomyopathies (e.g., infiltrative, hypertensive, early ischemia, hypertrophic)
  • Valvular disease (e.g. mitral stenosis)
  • Pericardial disease (e.g., constriction)
  • Endocardial disease (e.g., endomyocardial fibrosis)
  • Myocardial disease (e.g., amyloidosis)
  • HTN w/o cardiomyopathy
  • Age
  • Gender (esp women)
• Extracardiac factors that contribute to HF
  
  • Renal failure
  • Excess hydration (e.g., IV fluids, blood transfusion)
  • High output failure (e.g., anemia, hyperthyroidism)
  • Liver disease
  • Malnutrition (e.g., hypoalbuminemia)

Question 2

Pathophysiology of HF

• Low cardiac output
  
  • Reflects…
  • Symptoms
  • Signs
• Excess volume
  
  • Reflects…
  • Symptoms
  • Signs

Answer 2

• Low cardiac output
  
  • Reflects…
    
    • Inability to delivery sufficient blood flow (& oxygen) to other organs
  • Symptoms
    
    • Decreased appetite
    • Weakness & fatigue
    • Poor sleep
    • Forgetfulness
  • Signs
    
    • Decreased mentation & confusion
    • Cool extremities
    • Cyanosis / pallor
    • Renal dysfunction
• Excess volume
  
  • Reflects fluid retention within…
    
    • Intravascular spaces (distended jugular veins, elevated JVP, S3)
    • Interstitial spaces (wet crackles or rales, dependent edema)
    • Both intravascular & interstitial spaces (hepatic congestion)
  • Symptoms
    
    • Shortness of breath (orthopena when laying flat)
    • Nocturnal dyspnea
    • Dependent edema
    • Abdominal bloating
    • RUQ tenderness
  • Signs
    
    • Distended jugular veins
    • Elevated JVP
    • Wet crackles or rales
    • S3
    • Liver congestion
    • Ascites
    • Pedal or sacral edema

Question 3

HF Classifying & Staging Symptoms

• NYHA functional class
• ACC/AHA HF stages
• Comparison
  
  • ACC/AHA HF stage A
    
    • NYHA class
  • ACC/AHA HF stage B
    
    • NYHA class I
  • ACC/AHA HF stage C
    
    • NYHA class II
    • NYHA class III
  • ACC/AHA HF stage D
    
    • NYHA class IV

Answer 3

• NYHA functional class
  
  • Based on the ability or inability to perform routine daily activities
  • Dependent on the level of physical incapacitation due to HF related symptoms at the time of evaluation
  • Dynamic
    
    • Respond well to medical therapy –> decrease NYHA class
    • Symptoms worsen –> increase NYHA class
• ACC/AHA HF stages
  
  • Progressive illness
  • Begins w/ the presence of existing risk factors
  • Stages aren’t reversible even if symptoms improve w/ medical therapy
• Comparison
  
  • ACC/AHA HF stage A: predisposing condition (e.g., HTN, CAD) for HF, no structural or funcitonal abnormalities
    
    • NYHA class: no comparable class
  • ACC/AHA HF stage B: structural (e.g., valve disease) & functional abnormalities associated w/ HF, no signs/symptoms
    
    • NYHA class I: no limitation of ordinary physical activity from fatigue, dyspnea, palpitations, etc.
  • ACC/AHA HF stage C: structural/functional abnormalities + prior/current signs/symptoms of HF
    
    • NYHA class II: slight limitation of ordinary physical activity but still able to perform them, comfortable at rest
    • NYHA class III: marked limitation & symptoms at less-than-ordinray physical activities (e.g., dressing, bathing)
  • ACC/AHA HF stage D: advanced structural/functional disease + marked HF symptoms at rest depsite max medical therapy, require specialized interventions
    
    • NYHA class IV: unable to carry out any physical activity, symptoms of cardiac insufficiencty at rest, discomfort increased w/ minimal activity (e.g., talking, eating)

Question 4

HF vs. Cardiomyopathy

Answer 4

• Cardiomyopathies
  
  • Depend on the nature of organ involvement & relative involvement of extra-cardiac disease
  • Cause myocardial dysfunction & arrhythmias
  • May or may not cause systolic myocardial dysfunction
    
    • Ex. WPW syndrome manifests primarily w/ arrhythmias w/ no effect on systolic or diastolic function
• Cardioyopathies in literature
  
  • Common to describe myocardial dysfunction resulting from other CV abnormalities (e.g., ischemic, valvulra, hypertensive, congenital) as specific cardiomyopathies
    
    • Even though they’re not really included in the classificaiton of primary or secondary cardiomyopathies
  • These diseases of myocardial dysfunction result from other primray CV diseases

Question 5

Systolic vs. LV Diastolic Dysfunction

Answer 5

• Systolic dysfunction
  
  • Defect in the ability of heart myofibrils to shorten against increased load
  • Found in both symptomatic & asymptomatic patients
  • Can occur after an MI due to cardiac structural changes (i.e., LV remodeling)
  • Can occur as the end-stage of chronic heart disease (e.g., hypertensive or valvular heart disease)
• LV diastolic dysfunction
  
  • Impaired LV filling at normal LA pressure
  • More common in elderly & women
  • Reponsible for up to 40-50% of HF in adults
  • Many patients have both LV systolic & diastolic dysfunction

Question 6

HF Epidemiology

• Cardinal manifestations of HF
• Age
• Gender
• LV dysfunction causes both…
• Patients w/ preserved EF
• Factors that impact HF mortality
• HF survival
• Medicaire
• Goals of therapy
  
  • Short term
  • Long term

Answer 6

• Cardinal manifestations of HF
  
  • Dyspnea
  • Fatigue
  • Fluid retention
• Age
  
  • Increase age –> increase HF incidence (esp after 45yo)
  • Increase age –> increase other diseases (e.g., HTN, DM, obesity) –> survive early stage cardiac disease (ex. acute MI) –> old enough for HF
• Gender
  
  • Women have better survival than men
  • HF in women is more commonly associated w/ diastolic HF which has a better survival risk than systolic HF
• LV dysfunction causes both…
  
  • Systolic dysfunction: imparied ability to pump blood (worse prognosis)
  • Diastolic dysfunction: impaired ability to fill w/ blood (better prognosis)
• Patients w/ preserved EF
  
  • Often have other co-morbidities that increase risk of death
  • Directly related to HF (e.g., valvular disease, CHD, HTN)
  • Indirectly related (e.g., renal disease, DM, obesity)
• Factors that impact HF mortality
  
  • Etiology of cardiac & myocardial disease
  • Severity of symptoms (not always related to cardiac disease severity)
  • Severity of LV dysfunction
  • Pharmacologica & non-pharmacologic therapies
    
    • ICD: reduce risk of arrhythmic deat, allow HF paitens to survive later disease stages & pump failure
    • Ventricular assist devices: increase survival w/o transplant, avoid pump failure related death, but may still develop arrhythmias or infection- or end-organ-failure-related death
• HF survival
  
  • Improved but still dismal
  • Poor prognosis
  • Sudden death –> most deaths in patients w/ HF, esp in lower NYHA classes
  • Better prognosis: dilated, non ischemic, asymptomatic
• Medicaire
  
  • More $ is spent for diagnosing & treating HF than any other diagnosis
• Goals of therapy
  
  • Short term: relieve symptoms & improve quality of life
  • Long term: prolong life by slowing & reversing the progressive course of the disease

Question 7

Normal Pressure-Volume Relationship

• Point A
• Line AB
• Point B
• Line BC
• Point C
• Line CD
• Point D
• Line DA
• Shaded area

Answer 7

• Point A: end diastole
• Line AB: isovolumic contraction during LV systole
  
  • Myofibrils begin to contract but no ejection occurs
  • Allows LV to generate enough pressure to overcome peripheral arterial resistance & deliver blood forward (cardiac output)
• Point B: aortic valve opening
• Line BC: ejection of blood into aorta
  
  • Difference in LV volume = stroke volume
• Point C: aortic valve closure, end systole
• Line CD: isovolumic relaxation during LV diastole
  
  • Myofibris relax/stretch to allow LV pressure to fall below LA pressure so blood can passively move across the mitral valve
  • Factors that impair this phase (e.g., ishcemia, myocardial infiltration, inflammation) –> diastolic HF
• Point D: mitral valve opening
• Line DA: LV diastolic filling
• Shaded area: external LV stroke work

Question 8

Pressure-Volume Relationship Dysfunction

• Systolic dysfunction
  
  • PV loop changes
  • How HF develops
• Diastolic dysfunction
  
  • PV loop change
  • How HF develops
• Coexisting systolic & diastolic dysfunction

Answer 8

• Systolic dysfunction
  
  • PV loop changes
    
    • PV loop shifts to the right
    • Less steep nd-systolic PV relationship (contractility) –> increased LVEDP
  • How HF develops
    
    • LV requires increased LVEDP & LVEDV to maintain SV & CO
• Diastolic dysfunction
  
  • PV loop changes
    
    • Bottom curve shifts upward
    • Decreased LVEDV –> increased LVEDP to maintain volume
  • How HF develops
    
    • LVEDP is increased during LV filling for any given blood volume
    • LV compliance worsens –> increased LVEDP –> decreased SV (pre-load dependence)
• Coexisting systolic & diastolic dysfunction
  
  • Systolic dysfunction –> hypertrophy & fibrosis –> decrease compliance –> impair LV filling –> disrupt diastolic function
  • Underlying hemodynamic presses differ

Question 9

Frank-Starling Curve

• Normal ventricles
• LV systolic dysfunction
  
  • Effect of decreased contractility
  • Curve changes
  • Mild vs. severe dysfunction
• Factors that may contribute to a plateau in the presence of pressure-volume curve

Answer 9

• Normal ventricles
  
  • Steep & positive relationship b/n LV filling pressures (LVEDP) & SV or CO
• LV systolic dysfunction
  
  • Decrease contractility –> decrease CO & SV
    
    • –> increase sympathetic activity –> increase contractility & HR –> restore cardiac output
    • –> renal salt & water retention –> expand blood volume –> increase end-diastolic pressure –> enhance ventricular performance –> restore SV
  • Curve changes
    
    • Curve shifts to the right: higher filling pressures are needed to achieve the same CO
    • Curve flattens: increasing LV filling pressures has less of an effect on increasing CO
  • Mild vs. severe dysfunction
    
    • Mild: initial reduction in cardiac function can be overcome by raising the LVEDP & via fluid retention
    • Severe: stroke volume isn’t recoverable, & continued incresaed in LVEDP & fluid retention –> pulmonary edema
• Factors that may contribute to a plateau in the presence of pressure-volume curve
  
  • Heart reaches its max capacity to increase contractility in response to increasing stretch
    
    • Sarcomeres lengthen to more-than-optimal degree of overlap of thick & thin myofilaments
    • –> decrease Ca2+ affinity for / binding to troponin C
    • –> decrease Ca2+ available within myocardial cells
    • –> prevents LV from increasing contractile force in response to increased load
  • Reduce in cardiac complicance
    
    • Reduced compliance –> small increase in volume produces a large elevation in LVEDP –> not substantial stretching of the cardiac muscle –> little change in cardiac output

Question 10

Determinants of Cardiac Performance

Answer 10

• Preload
• Afterload
• Contractility
• Relaxation
• Heart rate
• Preload, afterload, contractility & relaxation influence SV
• HR * SV = CO

Question 11

Preload

• Definition
• Determined by…
• Effect on SV & LVEDV
• Factors that influence preload (venous return to the heart)
  
  • Total body volume
  • Body position
  • Venous tone
  • Atrial contraction
  • Skeletal muscle contraction
  • Intrapericardial pressure
  • Intrathoracic pressure
• Measures of preload
• Effect on myocardial fibers

Answer 11

• Definition
  
  • Hemodynamic load on the myocardial wall (or fiber stretch) at the end of diastole just before contraction begins
  • Creates wall tension
• Determined by…
  
  • Venous return to the ventricle
  • Any regurgitant blood across the aortic valve (LV preload) or pulmonic valve (RV preload)
• Effect on SV & LVEDV
  
  • Decrease preload
  • –> decrease SV (normal individuals)
  • –> increase SV (patients w/ HF
  • –> decrease LVEDV
• Factors that influence preload (venous return to the heart)
  
  • Venous return
    
    • Decrease venous return –> decrease preload
    • Increase venous return –> increase preload
  • Total body volume
    
    • Dehydration / blood loss –> decrease preload
    • Hydration / transfusion –> increase preload
  • Body position
    
    • Supine to upright –> decrease preload
    • Upright to sitting/supine –> increase preload
  • Venous tone
    
    • Venodilation –> decrease preload
    • Venoconstriction –> increase preload
  • Atrial contraction
    
    • Atrial fibrillation –> loss of atrial contraciton –> decrease preload
    • Sinus rhythm –> restore atrial contraction –> increase preload
  • Skeletal muscle contraction
    
    • Muscle inactivity –> decrease venous return –> decrease preload
    • Muscle activity –> increase venous return –> increase preload
  • Intrapericardial pressure
    
    • Cardiac tamponade –> decrease preload
    • Pericardiocentesis –> increase preload
  • Intrathoracic pressure
    
    • Expiration / pneumothorax –> decrease preload
    • Inspiration –> increase preload
• Measures of preload
  
  • Key measure: LVEDV
  • Other measures
    
    • LVEDP
    • Pulmonary capillary wedge pressure –> LA pressure
    • Central venous pressure –> RA pressure
    • LVED diameter
    • End-diastolic wall tension
    • Sarcomere length
• Effect on myocardial fibers
  
  • Decrease preload –> insufficient ventricle filling during diastole –> submaximal stretch –> myocardial ocntraction doesn’t occur w/ optimal force
  • Increase preload –> ventricle overfilling –> overstretch mycoardial fibers –> exceed contractile capacity

Question 12

Afterload

• Definition
• Determined by…
• Drugs that improve cardiac output
• Effect on SV & LVEDV
• Measures of afterload

Answer 12

• Definition
  
  • Force that resists myocardial contraction & blood volume ejection out of the ventricle during systole
  • Force that mycoardial fibers must overcome in order to shorten
  • Tension in the myocardium during active contraction
• Determined by…
  
  • Resistance against which the myocardium is contracting
  • Degree of myocardial shortening
    
    • Increase afterload –> decrease myocardial shortening –> decrease SV
    • Systolic HF: ventricle is very sensitive to afterload, so increase afterload –> greater decrease in SV
• Drugs that improve cardiac output
  
  • Arterial vasodilators (ACE-Is, angiotensin receptor blockers) increase SV
• Effect on SV & LVEDV
  
  • Decrease afterload
  • –> increase SV
  • –> decrease ESV –> decrease LVEDV
    
    • LV doesn’t need to generate the same pressure to eject blood forward, so LV can decrease EDV
• Measures of afterload
  
  • Total systemic peripheral resistance (arterial BP)
    
    • ​More convenient & readily obtainable estimate of afterload in absence of aortic stenosis or atherosclerosis
  • LV pressure (aortic valve stenosis)
    
    • More comprehensive measure of LV afterload w/ aortic stenosis or atherosclerosis
  • RV pressure (pulmonic valve stenosis, pulmonary hypertension))
  • Aortic pressure
  • Arterial impedance
  • Myocardial peak wall stress (affected by LV geometry)

Question 13

Contractility

• Inotropy
• Contractility
• Effect on SV & LVEDV
• Measures of contractility

Answer 13

• Inotropy / contractility
  
  • Increase myocardial contractility –> increase SV
  • Describes the forces created by Ca2+ dependent binding b/n myosin & actin
• Contractility vs. afterload & preload
  
  • Increase afterload –> increase contractility to maintain SV
    
    • Also increase LV pressure during isovolumic contraction to maintain systolic ejection
  • Increase preload –> don’t necessarily need to adjust contractility to maintain SV
• Effect on SV & LVEDV
  
  • Increase contractility
  • –> increase SV & CO –> decrease ESV
  • –> decrease LVEDV but not to the same degree as afterload reduction (essentially no effect)
    
    • LV still needs to generate higher pressures to eject blood volume into the aorta than if there were also afterload reduction
    • Need to maintain a greater LV volume in systolic HF
• Measures of contractility
  
  • Fractional shortening
  • Ejection fraction
  • Cardiac output
  • Stroke volume

Question 14

Relaxation & Heart Rate

• Compliance
• Compliance vs. pressure
• Heart rate

Answer 14

• Compliance = ∆V / ∆P
  
  • ∆V = ∆ volume = LVEDV - LVESV
  • ∆P = ∆ pressure = LVEDP - LVESP
• Compliance vs. pressure
  
  • Increase compliance –> decrease pressure for any increase in volume
  • Decrease compliance –> increase pressure for any increase in volume
• Heart rate
  
  • CO = SV * HR

Question 15

Wall tension

• Increased & decreased by…
• Transient vs. chronic changes
• Laplace relationships
• What happens in a chronically volume overloaded state

Answer 15

• Increased & decreased by…
  
  • Increased by…
    
    • Signs of failing LV
    • Intracardiac diameter/radius of the LV from remodeling
    • Intracardiac pressure from volume overload
  • Decreased by…
    
    • Increased wall thickness
• Transient vs. chronic changes
  
  • Transient changes –> little damage or injury
  • Chronic changes –> persistent or permanent changes to the myocardium over time (ex. HTN)
• Laplace relationships
  
  • How risk factors for HF –> copmensatory changes ot the myocardium & LV over time
  • Ex. HTN –> increased afterload –> increased pressure –> chornic exposure to increased wall tension –> LV wall thickening –> hypertrophy
• What happens in a chronically volume overloaded state
  
  • Increase volume –> increase preload –> increase LVEDP –> decrease SW –> dilated LV
  • –> LV can accommodate increased volumes at reduced pressure & still maintain optimal interaction b/n myosin & actin

Question 16

Hemodynamic Pathophysiology Summary

• Pressure-volume loops describe…
• Frank-Starling curves describe…
• Preload affects…
• Afterload affects…
• Stroke volume
• Contractility
• Laplace relationship
• LV compliance

Answer 16

• Pressure-volume loops describe…
  
  • Pressure-volume relationship throughout the cardiac cycle
  • Systolic & diastolic dysfunction separately (may co-exist)
• Frank-Starling curves describe…
  
  • Impact of LVEDV on SV
• Preload affects…
  
  • End-diastolic measurements (volume & pressure)
• Afterload affects…
  
  • End-systolic measurements & LV systolic pressure during isovolumic contraction
• Stroke volume
  
  • Increased by increasing preload & decreasing afterload
  • Doesn’t necessarily mean increased CO unless HR is maintained or increased
• Contractility
  
  • Not affected by preload
    
    • If contractility is kept constant, increasing preload increases SV
    • HF: may not be able to maintain contractility –> decrease SV
  • Increased by increasing afterload to maintain SV
    
    • Inability to increase contractility decreases SV & CO
• Laplace relationship
  
  • Relates wall diameter & intracardiac pressure to wall tension
  • Hypertrophy –> increase wall thickness –> decrease wall tension/stress
• LV compliance
  
  • Increase LV compliance –> LV can fill w/ greater volume in diastole while maintaining constant LVEDP

Question 17

Compensatory Mechanisms

Answer 17

• HF
  
  • –> insults (ischemic injury, HTN, infiltration, valvular heart disease, etc.)
  • –> increase preload &/or afterload
• LV remodeling changes size & shape of heart in response to…
  
  • Excessive neurohormonal activation
  • Altered loading conditions
  • Myocardial injury

Question 18

Ventricular Remodeling

• Benign adaptive response
  
  • Ex. trained athlete
  • Ex. increased metabolic efficiency
• Adverse changes to copmensate for decreased myocardial performance
  
  • Ex. initial MI
  • Ex. LV hypertrophy
  • Ex. LV dilation

Answer 18

• Benign adaptive response
  
  • Ex. trained athlete
    
    • Enlarged, muscular heart –> decreased EF & HR + maintained SV
    • Due to physiologic hypertrophy of muscles & increased compliance of blood vessels
  • Ex. increased metabolic efficiency
    
    • –> decrease oxygen demand in peripheral muscle
    • –> enhance oxygen delivery int he myocardium to improve cardiac performance
• Adverse changes to copmensate for decreased myocardial performance
  
  • Ex. initial MI
    
    • Gradual scarring & thinning in the area of infarction –> global remodeling of the LV (ex. dilation)
  • Ex. LV hypertrophy
    
    • Negatively affects compliance –> systolic dysfunction –> dilation
  • Ex. LV dilation
    
    • Hallmark change in CHF
    • Initial dilation –> accommodate increaed volume w/o increasing LVEDP –> maintain SV
      
      • Doesn’t imply sarcomere lengthening
      • May include myocyte hypertrophy & increased myocyte spacing w/ increased interstitial fibrosis & collagen deposition
    • Long term dilation –> increased wall stress –> histologic changes
      
      • As cellular function –> dysfunctional, disrupted actin/myosin interaction –> decreased power of filament shortening
      • –> clinical decompensation & progression of HF (stage C or D)

Question 19

Compensatory Changes

• Goal of compensatory changes
• Compensatory mechanisms to adapt & maintain LV function
• Ex. of how adverse compensatory mechanisms: neurohormonal activation
• Types of initial insults
• Causes of cardiac injury/dysfunction

Answer 19

• Goal of compensatory changes
  
  • Restore LV function following an initial myocardial insult that adversely affects ventricular function
  • Recover LV performance & delay the onset/progression of HF
  • Long term exposure to these mechanisms may –> adverse remodeling –> secondary myocardial damage –> further LV decline
• Compensatory mechanisms to adapt & maintain LV function
  
  • Salt & water retention –> increase circulating volume & maintain SV
  • SNS activation –> preserve CO
  • Release of circulating vasodilatory molecules (ex. NO, prostaglandins, & natriuretic peptides) –> increase preload & decrease afterload
• Ex. of how adverse compensatory mechanisms: neurohormonal activation
  
  • Underlying cardiac disease –> declining LV contractility –> decreased CO
  • Goal: maintain BP & tissue perfusion by increasing peripheral vascular resistance & LV afterload
  • Long term response –> hasten myocardial deterioration –> worsen ventricular performance
• Types of initial insults
  
  • Acute (ex. MI)
  • Insidious (ex. HTN, valvular heart disease)
• Causes of cardiac injury/dysfunction
  
  • Hereditary (ex. hypertrophic cardiomyopathy)
  • Acquired (ex. peripartum cardiomyopathy)

Question 20

Cellular Basis of Myocardial Dysfunction in HF

• Contractile proteins of the heart
• Normal resting energy supply
• Myocardial contraction
• Metabolic & energetic derangements in HF

Answer 20

• Contractile proteins of the heart
  
  • Lie within myocaridal muscle cells (cardiomyocytes or myocytes)
  • Each myocyte has myofibrils & mitochondria to resist fatigue & maintain aerobic metabolism
• Normal resting energy supply
  
  • 2/3: free fatty acids & triglycerides
  • 1/3: carbohydrates
  • Trace amount: amino acids & ketons
• Myocardial contraction
  
  • Na+ ions initiate APs propogated along the sarcolemma
  • Ca2+ influx –> myocardial contraction –> release of additional Ca2+ from the SR
  • Ca2+ binds to troponin C –> shift in troponin I & T –> tropomyosin release from the actin –> exposed myosin binding sites
  • Binding of myosin to actin: energy dependent
• Metabolic & energetic derangements in HF
  
  • Adversely affect AP propogation, Ca2+ homeostasis, & ATP balance

Question 21

Myocytes

• Held together by…
• Excess collagen
• Myocardial dysfunction results from…
• These changes lead to…

Answer 21

• Held together by…
  
  • Surrounding collagen connective tissue (major component of the ECM) bundled into muscle fibers
  • Damage to these –> remodeling
• Excess collagen
  
  • Causes LV diastolic dysfunction
  • Accumulates as part of hte growth response to LV pressure overload
• Myocardial dysfunction results from…
  
  • Loss of myocytes by necrosis or apoptosis
  • Replacement of myocytes w/ collagen & fibrosis
  • Dysfunction of viable myocardium
• These changes lead to…
  
  • Electrical derangements (ex. atrial or ventricular arrhythmias, conduction defects)
  • Systemic processes affecting other orgnas & tissues (ex. pulmonary contestion, prerenal azotemia)
  • Further myocardial damage
• Imbalance of neurohomonal release is due to…
  
  • Increased circulating catecholamine levels
  • Change in cytokine expression patterns & inflammatory pathways
  • Release of vascular mediators like endothelin-1

Question 22

Myocytes

• Imbalance of neurohomonal release is due to…
• Myocyte necrosis
• Loss of myocytes resulting in cardiac remodeling involves…
• Extracellular changes that contribute to LV dysfunction

Answer 22

• Imbalance of neurohomonal release is due to…
  
  • Increased circulating catecholamine levels
  • Change in cytokine expression patterns & inflammatory pathways
  • Release of vascular mediators like endothelin-1
• Myocyte necrosis
  
  • ​Occurs following myocardial injury (ex. infarction, toxins, inflammation)
  • Triggered by programmed cell death due to…
    
    • ​Genetic mutations
    • Induced cell signaling by cytokines, circulating catecholamines, or angiotensin
  • Results in cytoskeletal changes & fibrosis that may be histologically tracked or have no evidence
• Loss of myocytes resulting in cardiac remodeling involves…
  
  • Early: cardiac myocyte hypertrophy w/ new sarcomeres & elongated/thickened cells
  • Later: myofilament density within myocytes decreases
• Extracellular changes that contribute to LV dysfunction
  
  • Deposition of replacement & reparative collagen –> stiffer walls
  • Myocyte hypertrophy + increased extracellular collagen deposition –> ventricular enlargement –> decreased capillary density –> reduced coronray blood flow reserve –> further damage

Question 23

HF that Doesn’t Present w/ Typical Sequence of Events

• Heart failure w/ preserved EF (diastolic HF)
• Dysfunction of residual viable myocardium in HF
• Stress-related cardiomyopathies

Answer 23

• Heart failure w/ preserved EF (diastolic HF)
  
  • HF patients that experience progressive symptoms in the absence of LV systolic impairment
  • LV structural abnormalities w/o ventricular dilation or systolic dysfunction
  • Progressive hyeprtrophy or increasing chamber wall stiffness –> less compliant LV –> both systolic & diastolic HF
• Dysfunction of residual viable myocardium in HF
  
  • LV enlargement + increased wall tension –> progressive ischemia w/o obstructive epicardial disease
  • Metabolic derangements occur in acute & chronic HF
• Stress-related cardiomyopathies
  
  • Reduced free fatty acid use –> affected myocardium undergoes a “hibernating” process
  • Reduced myocardial contractility despite excess intramyocyte Ca2+
  • No cellular necrosis or ECM changes –> myocardial impairments are metabolic

Question 24

Neurohormonal Activation in HF

• Neurohormonal pathway consists of…
• Neurohormonal pathway cross-talk
• Vasoactive mediators
• Adaptive responses

Answer 24

• Neurohormonal pathway consists of…
  
  • Adrenergic nervous system (mediated by NE & Epi)
  • Renin-angiotensin-aldosterone system (RAAS)
  • Antidiuretic hormone system (vasopressin)
• Neurohormonal pathway cross-talk
  
  • Cross-talk occurs b/n different rogans (brian, heart, peripheral circulation, & kidneys)
  • Vascular, central, & peripheral sensory mechanisms respond to changes in BP to regulate sympathetic & parasympathetic tone
• Vasoactive mediators
  
  • Maintain normal homeostatic conditions
  • Recruited in HF to maintain SV
• Adaptive responses
  
  • Initially helpful
  • Over time contribute to progressive HF & LV remodeling
    
    • Happens when counter-regultaory hormones fail to restore balace against vasoactive hormones

Question 25

Sympathetic (Adrenergic) Nervous System

• General
• Effects to deliver increased blood flow to peripheral muscles
• Predominant mediators
• Heart failure syndrome
• Beta-adrenergic desensitization
• Goal of increasing sympathetic tone
• Mechanism
• Effects of cycle where SNS stimulation necessitates more SNS stimulation

Answer 25

• General
  
  • Initially adaptive compensatory response to myocardial injury & stress
  • Responds to stress w/ physiologic changes evolved to protect & preserve life
  • Activated by central & peripheral stimuli
• Effects to deliver increased blood flow to peripheral muscles
  
  • Increase HR & splanchnic vascular resistance
  • Decrease peripheral vascular resistance
• Predominant mediators
  
  • NE & Epi
• Heart failure syndrome
  
  • Increased catecholamines
  • Increased myocardial tissue levels
• Beta-adrenergic desensitization
  
  • SNS response is reduced despite excess catecholamines
• Goal of increasing sympathetic tone
  
  • Preserve perfusion pressure & BP
• Mechanism
  
  • Decreased mean arterial pressure –> increae contractility & HR to maintain SV –> arteriolar vasoconstriction –> increase afterload –> myocardial stress
• Effects of cycle where SNS stimulation necessitates more SNS stimulation
  
  • Increase catecholamines in blood & tissue
  • Dysregulated adrenergic beta-receptors on myocardial surface
  • Myocardial necrosis & apoptotic signaling

Question 26

Vascular Effects of Adrenergic Stimuli

• alpha1
  
  • Location
  • Effect of SNS
• beta1
  
  • Location
  • Effect of SNS
• beta2
  
  • Location
  • Effect of SNS
• Dopamine 1 & 2
  
  • Location
  • Effect of SNS

Answer 26

• alpha1
  
  • Location
    
    • Vascular wall
  • Effect of SNS
    
    • Arterial vasoconstriction –> increased afterload
    • Venous vasoconstriction –> increased return & increased preload
• beta1
  
  • Location
    
    • Myocardium
  • Effect of SNS
    
    • Increase HR & contractility –> increase CO
    • Increase relaxation & improve LV filling
• beta2
  
  • Location
    
    • Vascular wall
  • Effect of SNS
    
    • Peripheral skeletal muscle vasodilatoin –> decrease afterload
• Dopamine 1 & 2
  
  • Location
    
    • Vascular wall
  • Effect of SNS
    
    • Heart: increase HR & contractility
    • Peripheral circulation: vasoconstriction –> increase afterload
    • Splanchnic circulation: low doses increase splanchnic flow

Question 27

Renin-Angiotensin-Aldosterone System (RAAS)

• Goal
• Activated by…
• Pathway
• Positive feedback loop

Answer 27

• Goal
  
  • Restore adequate circulating volume & BP during dehydration or volume depletion
• Activated by…
  
  • Volume contraction
  • Occurs during true volume depletion or diminished CO
• Pathway
  
  • Kidney releases renin
    
    • Mediates cleavage of angiotensinogen to angiotensin I
  • ACE
    
    • Converts angiotensin I into angiotensin II
    • Found predominantly in lung tissue
    • Also found in the kidney, adrenal gland, brian, & vascular endothelium
  • Angiotensin II
    
    • Increases Na+ reabsorption & water retention in proximal renal tubules
    • Stimulates aldosterone secretion from the adrenal cortex
      
      • Increases Na+ & water retention
    • Stimulates myocardial fibrosis & cellular hypertrophy mediated by endothelin & tumor necrosis factor (TNF)
    • Causes arterial vasoconstriction –> increases afterload
• Positive feedback loop
  
  • RAAS increases sympathetic tone –> activates RAAS
    
    • Short term: RAAS restores homeostasis in response to decreased intravascular tone
    • Long term: RAAS becomes dysregulated in HF & further contributes to volume overload
  • Ex. patient becomes volume overload
    
    • Diminished SV & CO –> renal perfusion drops –> kidney perceives volume depletion –> RAAS activation

Question 28

Antidiuretic Hormone (Vasopressin) Systems

• Vasopressin
• Effects mediated by…
  
  • V1 receptors
  • V2 receptors
• Vasopressin in HF
• Natriuretic peptide hormones relevant to HF
  
  • C-type natriuretic peptide (CNP)
  • Atrial natriuretic peptide (ANP)
  • B-type natriuretic peptide (BNP)
  • Both ANP & BNP
  • ANP & BNP at the kidneys
  • ANP & BNP within the myocardium & other organs
  • Synthetic natriuretic peptide (nesiritide)

Answer 28

• Vasopressin
  
  • Peptide hormone
  • Synthesized in the hypothalamus
  • Stored in the pituitary gland
  • Release stimulated by increased plasma osmolality or decreased effective circulating volume
• Effects mediated by…
  
  • V1 receptors
    
    • Vascular responses to vasopressin –> vasoconstriction
  • V2 receptors
    
    • Increase membrane permeability in renal cortical & medullary collecting tubules in the kidney –> increased water reabsorption
• Vasopressin in HF
  
  • high circulating vasopressin levels –> increased afterload & hyponatremic volume overload
• Natriuretic peptide hormones relevant to HF
  
  • C-type natriuretic peptide (CNP)
    
    • Released in response to vascular shear stress
    • Provides a counterbalance by inhibiting the effects of the vasoconstrictor endothelin
    • Vasodilatory response
  • Atrial natriuretic peptide (ANP)
    
    • Stored in myocardium within granules
    • Secreted by atrial & ventricular myocardium & kidneys
    • Shorter half-life –> levels fluctuate more rapidly
  • B-type natriuretic peptide (BNP)
    
    • Responds to genetic up-regultaion before being released
    • Secreted by ventricular ventricular myocardium
    • Longer half-life –> levels don’t fluctuate as much
  • Both ANP & BNP
    
    • Biomarkers in HF
    • Released in response to myocardial stretch
    • Decrease peripheral vascular tone & increase venous capacitance –> decrease afterload & preload –> decrease intracardiac pressures
  • ANP & BNP at the kidneys
    
    • Sodium excretion (natriuresis) & diuresis
    • Increases glomerular filtration
      
      • Vasodilate afferent arterioles going into the renal tubule
      • Constrict efferent arterioles exiting the renal tubules
  • ANP & BNP within the myocardium & other organs
    
    • Antiproliferative & antifibrotic effects
    • Counter the adverse remodeling changes induced by excess catecholamiens & other molecules like endothelin & TNF
  • Synthetic natriuretic peptide (nesiritide)
    
    • No clinical benefits compared to conventional HF therapy

Question 29

Endothelium-Derived Vasoactive Substances & Cytokines

• Endothelium
• Endothelium-derived relaxing factors (EDRF): vasodilators
• Endothelium-derived constricting factors (EDCF): vasoconstrictors
• Cytokines
• Examples of cytokines

Answer 29

• Endothelium
  
  • Thin lining of cells within arteries & veins
• Endothelium-derived relaxing factors (EDRF): vasodilators
  
  • NO
  • Bradykinin
  • Prostacyclin
• Endothelium-derived constricting factors (EDCF): vasoconstrictors
  
  • Endothelin I
• Cytokines
  
  • Small protein molecules produced by a variety of tissues & cells
  • Negative inotropes
  • Elevated levels associated w/ worse clinical outcomes
• Examples of cytokines
  
  • TNF-alpha
  • IL-1-alpha
  • IL-2
  • IL-6
  • Interferon-alpha

Question 30

Ventricular Remodeling in HF: Summary

• Adverse ventricular remodeling
• Pathologic myocardial hypertrophy
• Interstitial fibrosis & abnormal cardiac myocyte changes
• Compensatory mechanisms
• Cellular function & decreased contractile response
• Neurohormonal model of HF
• Adrenergic nervous system
• RAAS pathway
• Vasopressin
• Natriuretic peptides

Answer 30

• Adverse ventricular remodeling
  
  • Effect of chronic adaptive changes of compensatory mechanisms becoming maladaptive
• Pathologic myocardial hypertrophy
  
  • Structural change that doesn’t provide functional improvement
  • As opposed to benign hypertrophy in an athletic heart
• Interstitial fibrosis & abnormal cardiac myocyte changes
  
  • Underlie remodeling processes that can occur over months to years before progressive HF symptoms develop
• Compensatory mechanisms
  
  • Contribute to adverse remodeling
  • Often result in maladaptive cycles contributing to disease progression
• Cellular function & decreased contractile response
  
  • Results from structurla canges to myofilaments, derangements in AP propagation, Ca2+ homeostasis, & energy metabolism by cardiac myocytes
• Neurohormonal model of HF
  
  • Involves deleterious imbalances of the adrenergic nervous system, RAAS pathway, & circulating vasoactive & inflammatory molecules
  • Results in cell necrosis, apoptosis, tissue fibrosis, & adverse ventricular remodeling
• Adrenergic nervous system
  
  • Stimulated by decreases in MAP
• RAAS pathway
  
  • Initiated by perceived decrease in intravascular volume
• Vasopressin
  
  • Released in response to increased plasma osmolality & decreased effective circulating volume
  • Effects are mediated by V1 (vasoconstriction) & V2 (increased water reabsorption) receptors
• Natriuretic peptides
  
  • Provide counter regulatory responses to the adrenergic & RAAS systems
  • Response may become overwhelmed in HF syndrome

Question 31

Neurohormonal Basis for Pharmacotherapy

• Beta blockers
• ACE inhibitors (ACE-Is)
• Angiotensin receptor blockers (ARBs)
• Aldosterone antagonists
• Inotropes (dobutamine & milrinone) & oral glycosides (digoxin)
• Vasopressin V2 receptor antagonist (tolvptan) & human recombinant B-type natriuretic peptide (nesiritide)

Answer 31

• Beta blockers
  
  • Taget beta-adrenergic receptors on the myocardial surface in competitive inhibition
  • Diminish excess catechol stimulation from the SNS
  • Reduce mortality
• ACE inhibitors (ACE-Is)
  
  • Block the conversion of angiotensin I to angiotensin II
  • Reduce mortality
• Angiotensin receptor blockers (ARBs)
  
  • Inhibit the RAAS pathway by inhibiting the effects of angiotensin II
  • Reduce mortality
• Aldosterone antagonists
  
  • Block the effects of aldosterone in the kidneys
  • Prevent sodium reabsorption
  • Weak diuretic effects
  • Reduce mortality
• Inotropes (dobutamine & milrinone) & oral glycosides (digoxin)
  
  • Provide added contractility to failing myocardium
  • May eventually relieve HF symptoms
  • Don’t directly address the neurohormonal pathway
  • Don’t reduce mortality
• Vasopressin V2 receptor antagonist (tolvptan) & human recombinant B-type natriuretic peptide (nesiritide)
  
  • Improve acute HF symptoms
  • Don’t reduce survival when combined w/ beta blockers, ACE-Is, or ARBs