Heart Failure

Question 1

Define heart failure. What does it result in?

Answer 1

• Definition:
  
  • “State in which the heart is unable to pump blood at a rate sufficient to meet the requirements of metabolizing tissues, or is only able to do so only if the cardiac filling pressures are abnormally high (or both)”
• Produces a complex of symptoms related to inadequate perfusion of tissues and retention of fluid
• Final and the most severe form of nearly every form of cardiac disease

Question 2

Define cardiac output. What determines cardiac output?

Answer 2

• Normally, cardiac output is matched to metabolic needs
  
  • CO = HR x SV
• Three major determinants of stroke volume:
  
  1. Contractility
  2. Preload
  3. Afterload

Question 3

Define preload. What increases as a function of preload?

Answer 3

• Measured as LV end-diastolic volume or pressure
• Cardiac performance increases as a function of preload

Question 4

Define afterload.

• What is afterload related to?
• What does afterload respond to?

Answer 4

• Resistance the ventricle must overcome to empty its contents
  
  • Largely a consequence of aortic pressure
• Related to Laplace’s Law:
  
  • ​Wall stress (σ) = (P x r)/2h
• Rises in response to higher pressure load (hypertension) or increased chamber size (dilated LV)
  
  • Increases in wall thickness serves a compensatory role to reduce wall stress

Question 5

Define contractility.

• What influences it?
• How does appear on the Frank-Starling curve?

Answer 5

• Accounts for the changes in myocardial force for a given set of preload and afterload conditions
  
  • Influenced by the availability of intracellular Ca²⁺
• On a Frank–Starling curve, a change in contractility shifts the curve in an upward or downward direction

Question 6

Pressure volume loop (a-d):

Answer 6

Relates changes in ventricular volume to corresponding changes in pressure through a cardiac cycle

• a, mitral valve opening and beginning of diastole
• a-b, diastolic filling; compliance
• b, mitral valve closure; end diastolic volume (EDV)
• b-c, isovolumic contraction
• c, aortic valve opening
• c-d, ejection (reflects afterload)
• d, aortic valve closure; end systolic volume (ESV)
• d-a, isovolumic relaxation

Question 7

How does a change in preload affect the PV loop?

Answer 7

• Increase in preload augments stroke volume via the Frank-Starling mechanism
• If compliance is reduced, curve will be steeper, and SV will be reduced
  
  • less stretching of the ventricles and less EDV

Question 8

How does a change in afterload affect the PV loop?

Answer 8

• If afterload is increased, then pressure generated during ejection increases
  
  • More work is expended to overcome resistance to eject, and less fiber shortening occurs
• Relationship between end-systolic volume and afterload is approximately linear
  
  • End-systolic volume pressure-volume relationship (ESPVR)
  • Greater the afterload the higher the end systolic volume

Question 9

How does a change in contractility affect the PV loop?

Answer 9

• Slope of the ESPVR line is a function of contractility
  
  • With increased contractility, the line becomes steeper
  • Hence, the ventricle empties more completely resulting in a smaller end-systolic volume
    
    • thus increased stroke volume

Question 10

Describe the general pathophysiology of heart failure:

Answer 10

1. Result of a wide variety of CV diseases, those that:
   
   • Impair ventricular contractility
   • Increase afterload
   • Impair relaxation and filling
2. Heart failure due to abnormal:
   
   • Emptying, i.e., systolic dysfunction
   • Filling, i.e., diastolic dysfunction
3. Patients categorized according to ejection fraction (EF):
   
   • Heart failure with reduced EF
   • Heart failure with preserved EF

Question 11

What does heart failure with reduced ejection fracture affect?

Answer 11

• Ventricle has diminished capacity to eject blood because of impaired contractility or pressure overload
• May result from:
  
  • destruction of myocytes
  • abnormal myocyte function
  • fibrosis
• With pressure overload, ejection is impaired by increased resistance to flow

Question 12

What does heart failure with preserved ejection fraction affect?

Answer 12

• Usually demonstrate abnormalities in diastolic function
  
  • Impaired early relaxation and/or increased stiffness
• For instance:
  
  1. Acute ischemia
  2. Hypertrophy
  3. Fibrosis
  4. Restrictive cardiomyopathy
  5. Pericardial diseases

Question 13

What is the pathophysiology of right-sided heart failure?

Answer 13

• RV has high compliance
• Susceptible to failure with a sudden increase in afterload
• Right-sided heart failure that results from a primary pulmonary process
  
  • Cor pulmonale

Question 14

How does the body compensate to a change in SV?

Answer 14

• Frank-Starling mechanism and hypertrophy serve to maintain:
  
  • forward stroke volume
  • perfusion of vital organs
• However, chronic increase in EDV and left ventricular stiffness increase atrial pressure

Question 15

What will decreased CO activate?

Answer 15

Decreased CO will cause neurohormonal activation

• Expanded activation of the sympathetic system
• Activation of the renin-angiotensin-aldosterone axis
• Release of anti-diuretic hormone
• Help to maintain perfusion of vital organs by increasing cardiac output and maintaining blood pressure
• However, adverse consequences with chronic activation include an increase in afterload and fluid retention

Question 16

What are the precipitating factors to heart failure?

Answer 16

1. Increased metabolic demands
2. Increased circulating volume (increased preload)
3. Conditions that increase afterload
4. Conditions that impair contractility
5. Failure to take prescribed heart failure medications
6. Excessively slow heart rate

Question 17

How does heart failure clinically manifest?

• **Left-sided: **
• **Right-sided: **

Answer 17

Left-sided

1. Dyspnea Symptoms:
   
   • Diaphoresis (sweating)
2. Orthopnea Symptoms:
   
   • Tachycardia, tachypnea
3. Paroxysmal nocturnal dyspnea Symptoms:
   
   • Pulmonary rales
4. Fatigue Symptoms:
   
   • Loud P2
   • S3 gallop (in systolic dysfunction)
   • S4 gallop (in diastolic dysfunction)

Right-sided

1. Peripheral edema
   
   • Jugular venous distention
2. Right upper quadrant discomfort (because of hepatic enlargement)
   
   • Hepatomegaly
   • Peripheral edema

Question 18

New York Heart Association (NYHA) Classification of Heart Failure:

Answer 18

1. Class I (mild)
   
   • Cardiac disease, but no limitation in physical activity
2. Class II (mild)
   
   • Slight limitation of physical activity
   • Dyspnea and fatigue with moderate exertion (i.e., walking up stairs quickly)
3. Class III (moderate)
   
   • Marked limitation of physical activity
   • Dyspnea with minimal exertion (i.e., slowly walking up stairs)
   • Comfortable only at rest
4. Class IV (severe)
   
   • Severe limitation of activity
   • Symptoms are present at rest

Question 19

Heart Failure:

Prognosis

Answer 19

• 5-year mortality rate: 45 – 60%
• With severe symptoms (NYHA class III-IV): 40% 1-year survival rate
• Mortality due to refractory heart failure, but also sudden cardiac death
• Similar between heart failure with preserved EF as those with reduced EF

Question 20

What is another name for heart failure with reduced ejection fraction?

Answer 20

Systolic Heart Failure

Question 21

Heart Failure with Reduced Ejection Fraction:

Goals for Therapy

Answer 21

• Correct underlying condition causing heart failure
• Eliminate acute precipitating cause of symptoms
• Management of heart failure symptoms
  
  • Pulmonary and systemic vascular congestion
  • Provide measures to increase forward cardiac output
• Modulation of neurohormonal response
• Prolong survival

Question 22

Drugs used for Heart Failure with Reduced Ejection Fraction:

Answer 22

1. Diuretics
2. Inhibitors of RAA system
   
   • ACE inhibitors
   • ARBs
   • Aldosterone antagonists
3. β adrenergic blockers
4. Vasodilators
5. Positive inotropic agents
   
   • digoxin

Question 23

List the positive inotropes:

Answer 23

1. Digoxin
2. β adrenergic agonists (dobutamine, dopamine)
   
   • Used i.v. for temporary hemodynamic support for acutely ill patients (acute decompensated heart failure)
3. Phopsphodiesterase inhibitors (milrinone)
   
   • Use limited to i.v. administration for acutely ill patients
   • Positive inotrope and also produce vasodilation

Question 24

What are the direct and secondary effects of digoxin?

Answer 24

• Direct Effects:
  
  • Positive inotropic effect
    
    • Due to a direct effect to increase the contractile state of the myocardium
    • Increases stroke volume
  • Increases vagal tone
    
    • Slows heart rate (negative chronotropic)
• Secondary Effects:
  
  • Decreased heart rate
  • Arterial and venous dilation
  • Decreased venous pressure
  • Normalized arterial baroreceptors
• With positive inotropic effect and secondary effects, shifts the F-S curve to point labeled I+V

Question 25

**Digoxin:** * **Site of action** * **Electrophysiological actions**

Answer 25

**Molecular site of action:** * **Positive inotropic effect** due to _inhibition of the Na_⁺_,K_⁺_-ATPase_ * results in increased intracellular [Na⁺] thereby decreasing driving force for Ca²⁺ extrusion by Na⁺/Ca²⁺ exchanger * indirectly results in increased intracellular concentration of Ca²⁺ * K⁺ competes for binding of digoxin to the Na⁺,K⁺-ATPase **Electrophysiological actions:** * At therapeutic concentrations, _mainly related to increased vagal nerve activity_ * Reduced firing rate of SA node * Decreased conduction velocity in AV node * Heart block can develop * Main observation on the ECG – **increased PR interval**

Question 26

**Digoxin:** **Pharmacokinetics**

Answer 26

* **t ½ = 36 h** (permits daily dosing) * **Orally** absorbed (60 – 75% absorbed) * Excreted unchanged by the kidneys (renal elimination) * Max. increase in contractility observed at serum concentration of 1.4 ng/ml * Neurohormonal benefits occur at lower concentrations (0.5 – 0.8 ng/ml)

Question 27

**Digoxin:** **Adverse Effects**

Answer 27

* **Low therapeutic index (~2)** * **Affects all excitable tissues** * **GI tract (most common)** * anorexia, nausea, vomiting, diarrhea * Visual disturbances * Blurred vision, photophobia, color disturbances * Neurologic * disorientation, hallucinations * Muscular * muscle weakness, fatigue * Cardiac – arrhythmias (any type) * _Toxicity enhanced with hypokalemia_ (can be related to diuretic use) * Drug interactions - (quinidine, verapamil, amiodarone)

Question 28

Why is digoxin not a first line treatment?

Answer 28

* **Low therapeutic index** * _Use limited to heart failure patients with LV systolic dysfunction in atrial fibrillation_ or in some cases to patients in sinus rhythm who remain symptomatic despite maximal therapy with other therapies * If used, _administer a low dose_

Question 29

What is the **mainstay for heart failure treatment?** Why?

Answer 29

**Diuretics** * Reduce fluid volume and preload * Reduction in heart size improves efficiency and reduces wall stress * Reduce edema (and its symptoms)

Question 30

What are **loop diuretics** used for? What do they promote?

Answer 30

**Loop diuretics – furosemide** * **Widely used** – most heart failure patients require chronic therapy with a loop diuretic to maintain euvolemia * Promote K⁺ loss - **hypokalemia**

Question 31

What are **thiazide diuretics** used for? What do they promote?

Answer 31

**Thiazide diuretics – chlorothiazide** * _Rarely used alone_ * **Combination therapy with loop diuretics** in patients refractory to loop diuretics alone * Promote K⁺ loss - **hypokalemia**

Question 32

What are the **K⁺- sparing diuretics** and what do they promote?

Answer 32

**K+-sparing diuretics – amiloride, triamterene** * _Weak_ diuretic activity but _limited K_⁺ _and Mg_²⁺ _wasting_

Question 33

List the vasodilators: * Venodilators: * Arterial dilators: * Balanced/Mixed:

Answer 33

* Venodilators: * Nitroglycerin * Isosorbide dinitrate * Arterial dilators: * Hydralazine * Minoxidil * Balanced/Mixed: * Nitroprusside * Captopril * Enalapril * Hydralazine + Nitroglycerine

Question 34

What is the difference between the vasodilators?

Answer 34

* **Venodilators** * Increase venous capacitance and thereby decrease preload * **Arterial vasodilator** * Reduce systemic vascular resistance * Results in increased stroke volume * hydralazine * **Balanced or mixed vasodilators** * ACE inhibitors, ARBs, isorbide dinitrate/hydralazine combination

Question 35

**The failing heart is very sensitive to changes in …**

Answer 35

**The failing heart is very sensitive to changes in _afterload_**

Question 36

What effects does **angiotensin** have on the CV system?

Answer 36

* **Potent arterial constrictor (afterload)** * _Na+ and water retention_ through its effects on glomerular filtration and aldosterone secretion * _Promotes sympathetic activation_ by increasing neuronal and adrenal medullary catecholamine release * _Arrhythmogenic_ * _Promotes myocardial hypertrophy and apoptosis_

Question 37

What effects does **aldosterone** have on the CV system?

Answer 37

* **Promotes Na+ and water retention and potassium secretion** * _Stimulates fibrosis_ in the heart and vasculature * _Cardiac hypertrophy_

Question 38

List the ACE inhibitors:

Answer 38

1. captopil 2. lisinopril 3. enalapril 4. others

Question 39

**What actions do ACE inhibitors have on the heart?** What can they cause?

Answer 39

* **Actions in heart failure** * Decrease systemic vascular resistance **(afterload)** * Reduce left ventricular filling pressure **(preload)** * **Reduces Na+ retention, cardiac fibrosis, hypertrophy** * Found to increase survival rate * Can decrease renal function particularly in heart failure patients * **Hyperkalemia may develop particularly if used with aldosterone antagonist**

Question 40

What is an **Angiotensin Receptor1 Blocker**?

Answer 40

**Losartan**

Question 41

What is the **action of Angiotensin Receptor1 Blockers?** What are they used for?

Answer 41

* **Actions in heart failure** * similar to ACE inhibitors * Like ACE inhibitors, beneficial effect on survival * **Alternative for patients that cannot tolerate ACE inhibitor therapy**

Question 42

What is the **action of Isosorbide Dinitrate/Hydralazine Combination?** What is its clinical use?

Answer 42

* **Provides mixed arterial and venous dilation** * _Decreases preload and afterload_ * As a result, _increases stroke volume_ * Like ACE inhibitors, found to improve survival rate in clinical trials * Particularly effective in the African American population * Used when ACE inhibitors or ARBs not tolerated * Less development of tolerance with combination

Question 43

List the **Aldosterone Antagonists:**

Answer 43

1. **spironolactone** 2. **eplerenone**

Question 44

What is the **action of Aldosterone Antagonist?** What can they cause?

Answer 44

* **Actions in heart failure** * Reduce edema * Decrease fibrosis in myocardium and vessels * _Improve mortality rate and reduce symptoms_ * _even in the presence of an ACE inhibitor_ * **Hyperkalemia** – necessary to monitor potassium levels * _Added with moderately severe to severe symptoms (NYHA III or IV) of heart failure_

Question 45

* What is the action of **β-Adrenergic Receptor Antagonists?** * What will be seen at the start of treatment with these drugs? * What can limit their effectiveness?

Answer 45

* **Actions** * **Decrease:** arrhythmias, oxygen demand, blood pressure * _Prevent disease progression_ (remodeling) * _Inhibit cardiotoxic actions of catecholamines_ * _Reduce b1 receptor down-regulation_ * **Can initially worsen cardiac function** * must start at a low dose and gradually increased to a maximum tolerated dose * _Genetic variabilty can limit effectiveness_

Question 46

What are the benefits of neurolysin inhibitors?

Answer 46

* Neprolysin is a peptidase that degrades endogenous vasoactive peptides including bradykinin, ANPs, and others * Combination found to be superior to enalapril in reducing risks of death and of hospitalizations for heart failure

Question 47

What are some non-drug therapies used to treat heart failure?

Answer 47

* Salt restriction * Bi-ventricular pacing * Implantable Cardiodefibrillator Devices (ICD) * Left ventricular assist device (LVAD) * Heart transplant * Cell therapy??

Question 48

What is another name for heart failure with preserved ejection fraction?

Answer 48

**Diastolic heart failure**

Question 49

**Treatment of Heart Failure with Preserved Ejection Fraction:** **Goals of therapy**

Answer 49

* **Relief of pulmonary and systemic congestion** * _Address correctable causes of impaired diastolic function_ * **Diuretics to reduce pulmonary congestion and peripheral edema** * Use cautiously to avoid under filling of LV * Could reduce stroke volume * _ACE inhibitors, b blockers, ARBs have no demonstrated mortality benefit_ * Because contractile function is preserved, inotropic drugs have no role in this condition