Drugs for Heart Failure

Question 1

Heart Failure:

Answer 1

is an abnormality of CARDIAC STRUCTURE OR FUNCTION leading to the failure of the heart to deliver oxygen at a rate that fulfills the requirements of the tissues in the body

Question 2

What do most patients have when they have Heart Failure?

Answer 2

• high BP
• enlarged heart muscle & chamber
• low “ejection fraction” - % of blood pumped from the heart - the heart doesn’t provide adequate perfusion to the body
• may occur due to history of heart attacks, diabetes or other diseases
• about 1/2 patients die within 5 years of diagnosis

Question 3

What is the Ejection fraction (%)?

Answer 3

Amount of blood pumped out of the ventricle/Total amount of blood in ventricle

(denominator is greater)

Question 4

Echocardiography:

Answer 4

– Send soundwaves into the body which are reflected at the interfaces between tissue

– Return time tells us the depth of the reflecting surface

Question 5

What is the Ejection fraction for Heart failure?

Answer 5

</ 50%

Question 6

What do Cardiomyocytes do?

Answer 6

• Cardiomyocytes respond to action potential by depolarization of the membrane
• Starts by shortening of contractile proteins and ends with relaxation and return to resting state
• Cardiomyocytes are interconnected in intercalated discs that respond to stimuli as a unit
• Force of muscle contraction is related to the amount of cytosolic Ca2+
• Ca2+ comes from outside the cell first which triggers release from SR and mitochondria stores
• Muscle relaxation is achieved through removal of free Ca2+ by the Na+/Ca2+ exchangers and reuptake into SR and mitochondria

Question 7

What is Heart Failure?

Answer 7

• the heart is failing (obvious)
• basically heart is failing to pump sufficient blood to meet needs of the body
• most failure - low output failure – the pump is failing (slowly)

– the body compensates (how?)
– initially failure is not perceived by the patient due to compensation

– as failure increases, compensatory mechanisms keep increasing
– but at some point
– no longer able to improve condition – decompensated HF
– “compensatory” mechanisms become part of the problem

Question 8

What is the progression of Chronic Heart Failure?

Answer 8

• Age
• Smoking
• Obesity
• Hypertension
• Coronary artery disease
• Diabetes
• Dyslipidemia

1. Damage to cardiac myocytes & EC matrix leads to changes in the size, shape & function of the heart (remodeling) & cardiac wall stress
2. These changes lead to systemic neurohormonal imbalance
3. This may lead to fibrosis, apoptosis, hypertension, hypertrophy, cellular & molecular alterations, myotoxicity
   4a. Remodeling & progressive worsening of LV function
   4b. Hemodynamic alteractions, salt & water retention
   5a. Morbidity & mortality arrhythmias, pump failure
   5b. HF symptoms dyspnea, edema, fatigue

Question 9

What Is the Physiological Response to Heart Failure?

How does the body try to correct this failure?

Answer 9

Slight decreases in blood pressure corrected by:

1. increased SODIUM RETENSION (slow benefit)
   - with water retention this increases blood volume
2. activation of RENIN ANGIOTENSION ALDOSTERONE system
   - angiotensin - constricts arteries/veins (fast benefit)
   - aldosterone -sodium retention (slow benefit)
3. SYMPATHETIC NERVE ACTIVATION
   - increase heart rate (fast benefit)
   - increase contractility (fast benefit)

Question 10

EARLY in heart failure (COMPENSATED) these things are good:

Answer 10

Increased plasma volume and constriction of veins
- increased venous return stretches the ventricles - increases contraction

Increased constriction of arteries
- increased peripheral resistance but heart still strong enough to pump against increased resistance

Cardiac stimulation
- heart is able to respond to increased sympathetic nerve activity
- increased heart rate and contraction

All of these work to correct the drop in blood pressure
- initially patient may be unaware of early heart failure

Question 11

LATE in heart failure (DECOMPENSATED) these things worsen the condition (remember that the heart tissue itself is failing):

Answer 11

Overly increased plasma volume and constriction of veins
- increased venous return stretches already overstretched ventricles
- heart no longer able to increase force of contraction
- heart size enlarges (dilates) and muscle thickens (hypertrophy)
- venous pressure increases
- edema
- peripheral and pulmonary

Overly increased constriction of arteries
- greatly increased peripheral resistance hard for heart to empty against
- increased resistance to outflow more than heart can now overcome

Cardiac overstimulation – but now little response – heart has failed
- overstimulation of -adrenergic receptors
- -down regulation of these receptors
– increased fibrosis
– increased apoptosis (cell death)

Patient no longer able to compensate and overt signs of heart failure appear

But now heart must deal with LARGE INCREASES IN RAAS, SNS AND BLOOD VOLUME

Question 12

What happens in LEFT SIDE failure?

Answer 12

may prevent right side pumping and blood backs up into veins

blood backs-up into lungs and periphery
- pulmonary (edema)
- life threatening
- sitting-up helps
– more blood in lower veins

Question 13

What happens in RIGHT SIDE failure?

Answer 13

blood backs-up into periphery
- peripheral edema

Question 14

What are the main symptoms of Heart Failure?

Answer 14

• Shortness of Breath
• Shortness of Breath at Night
• Need to sit or stand to breath easily
• Reduced exercise tolerance
• Fatigue
• Ankle swelling
• Peripheral Edema
• Pulmonary Edema

Question 15

What are the main signs of Heart Failure?

Answer 15

• Sweating
• Increased heart rate
• Elevated jugular venous pressure
• Hepato-jugular reflux
• Rapid Breathing
• Cardiac murmur

Question 16

What is the symptomatic severity of heart failure?

Answer 16

• Clearr elationship between severity of symptoms and survival
• Poor relationship between severity of symptoms and ventricular function
• Patients with mild symptoms may still have a relatively high absolute risk of hospitalization and death

Question 17

Heart Failure is a Progressive Condition with High Mortality:

Answer 17

• Increasing frequency of acute events with disease progression leads to high rates of hospitalization and increased risk of mortality
• With each acute event, myocardial injury may contribute to progressive LV dysfunction

Question 18

Heart Failure is an…

Answer 18

abnormality of cardiac structure or function leading to failure of the heart to deliver sufficient oxygen to metabolizing tissues

Question 19

What is the most common cause of HF?

Answer 19

coronary artery disease

Question 20

What are the most frequently reported signs & symptoms of HF?

Answer 20

fatigue, edema and cough

Question 21

HF has a complex pathophysiology involving activation of two key neurohormonal systems:

Answer 21

–Renin–angiotensin–aldosterone system
–Sympathetic nervous system

Question 22

What drugs are inhibitors of renin angiotensin system?

Answer 22

• ACEI, enalapril
• ARB, losartan, valsartan

Question 23

What drugs are ARNIs?

Answer 23

• Entresto (sacubitril/valsartan)

Question 24

What drugs are B-adrenergic receptor blockers?

Answer 24

• metoprolol, carvedilol

Question 25

What drugs are inotropes?

Answer 25

• digoxin, dobutamine

Question 26

What drugs are diuretics?

Answer 26

• furosemide, metolazone
• aldosterone antagonist
  – spironolactone

Question 27

Why decrease formation of angiotensin II?

Answer 27

• compensation to heart failure involves the renin angiotensin aldosterone system
• in the long term, vasoconstriction and blood volume retention become a problem
• ACE inhibitors (eg. enalapril)

Question 28

ACE Inhibitors are…

Answer 28

• started soon after diagnosis
• excellent single therapy
• improve clinical signs and symptoms
• significantly decrease morbidity and mortality
• reduces death caused by:
• progressive heart failure - cardiac arrhythmia
• myocardial infarction
• stroke

Question 29

What are the uses of Diuretics in the Treatment of Heart Failure?

Answer 29

• Fluid retention in heart failure may result in edema
  – pulmonary edema is life threatening
  – loop diuretic (furosemide) useful here
• Chronic Heart Failure
  – Salt restriction in the diet
  – Use diuretics to maintain euvolemia with the lowest possible dose
  while avoiding dehydration, hypotension, kidney dysfunction
  – Loop diuretics (furosemide) most commonly used
  – Always combined with neurohormonal blocking
  – Sometimes diuretics are withdrawn or the dose is reduced in well
  managed patients to prevent adverse effects
  – Sometimes combined with spironolactone to gain added benefit of antagonising the harmful effects of aldosterone on the heart
  – Careful monitoring of electrolytes performed
• Diuretic Resistance
  – Common problem in Heart Failure
  – Defined as persistence of edema despite salt restriction and adequate diuretic therapy (usually loop diuretic)
  – Consequence of RAAS-induced adaptive responses by the kidney
  – Increasing the dose or more frequent dosing of loop diuretics is used
  – Combination therapy of loop and thiazide diuretics also used
  – Both approaches have associated risks of excessive depletion of water or electrolytes

Question 30

What is the treatment of HF?

Answer 30

• Manage conditions that contribute to heart failure
  – identify and treat risk factors (hypertension, diabetes, lipids, etc) – diet, physical activity and lifestyle changes
• start with ACEi or B-adrenergic receptor blockade
  – Lower BP and reduce stress on heart
• diuretic – in patients with edema
  – Remove excess fluid and sodium from body
• extreme failure - add inotrope
  – Increase contractility to alleviate heart failure symptoms

Question 31

Sequence for a “typical” patient:

Answer 31

Loop diuretic
- act to rapidly control symptoms of volume overload (edema)
- more important in overt heart failure - may not need early

ACEis
- once diuretic therapy optimized – if needed
- start at low dose

Beta blockers
- once patient stable on ACEi.
- start at low dose

Inotropes
- in those that have symptoms of heart failure in spite of the above regimen