Heart Failure Definition Systolic factors that contribute to HF Diastolic factors that contribute to HF Extracardiac factors that contribute to HF

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)

Pathophysiology of HF Low cardiac output Reflects... Symptoms Signs Excess volume Reflects... Symptoms Signs

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

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

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)

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

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

Pathophysiology of Congestive Heart Failure Flashcards by Heather Acuff

Heart Failure

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

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)

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Pathophysiology of HF

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

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

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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

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)

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HF vs. Cardiomyopathy

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

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Systolic vs. LV Diastolic Dysfunction

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

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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

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

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Normal Pressure-Volume Relationship

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

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

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Pressure-Volume Relationship Dysfunction

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

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

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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

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

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Determinants of Cardiac Performance

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

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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

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

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Afterload

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

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)

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Contractility

Inotropy
Contractility
Effect on SV & LVEDV
Measures of contractility

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

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Relaxation & Heart Rate

Compliance
Compliance vs. pressure
Heart rate

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

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Wall tension

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

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

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Hemodynamic Pathophysiology Summary

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

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

Compensatory Mechanisms

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

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

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)

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

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)

Cellular Basis of Myocardial Dysfunction in HF

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

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

Myocytes

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

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

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

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

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

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

Neurohormonal Activation in HF

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

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

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

* 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

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

* 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

Renin-Angiotensin-Aldosterone System (RAAS) * Goal * Activated by... * Pathway * Positive feedback loop

* 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

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)

* 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

Endothelium-Derived Vasoactive Substances & Cytokines * Endothelium * Endothelium-derived relaxing factors (EDRF): vasodilators * Endothelium-derived constricting factors (EDCF): vasoconstrictors * Cytokines * Examples of cytokines

* 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

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

* 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

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)

* 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