WEEK 4: Pathophysiology of heart failure

Question 1

Define cardiac output.

State the normal value for cardiac output at rest.

Answer 1

Cardiac output (CO)
is the volume of blood ejected per minute
a combined sum of output from the right and left ventricles
Averages 5L/min at rest

Question 2

State the formula for cardiac output.

Answer 2

CO = Stroke Volume × Heart rate

Question 3

What is stroke volume?

Outline 3 main factors that affect the stroke volume.

Answer 3

Stroke Volume is volume of blood ejected /beat
Affected by

*Pre load
*Afterload
*Contractility

Question 4

Define the following factors.
-Preload
-Afterload
-Contractility

What parameter do they affect?

Answer 4

Preload: The volume of blood in the ventricle before contraction (EDV) affects stroke volume. Increased preload generally leads to higher stroke volume.

Preload refers to the degree of stretch of the cardiac muscle fibers at the end of diastole, just before contraction. Essentially, it’s the amount of blood that fills the heart’s chambers during diastole.

Afterload: The resistance the heart faces while pumping blood (often due to arterial pressure) impacts stroke volume.

Afterload is the pressure against which the heart must work to eject blood during systole.

Contractility: The strength of ventricular contraction affects stroke volume. Enhanced contractility results in increased stroke volume.

2. Stoke volume

Question 5

State the formula for calculating Stroke volume.

Answer 5

t’s obtained by subtracting the end-systolic volume (ESV) (volume of blood in the ventricle at the end of a beat) from the end-diastolic volume (EDV) (volume of blood just before the beat).

SV= EDV-ESV

Question 6

Define the following:
End-Diastolic Volume (EDV):
End-Systolic Volume (ESV):

Answer 6

End-systolic volume (ESV) (volume of blood in the ventricle at the end of a beat)

End-diastolic volume (EDV) (volume of blood just before the beat).

Question 7

State the Average Values (in a healthy 70-kg man).
End-Diastolic Volume (EDV):
End-Systolic Volume (ESV):
Stroke Volume:
Ejection Fraction:

Answer 7

Average Values (in a healthy 70-kg man):
End-Diastolic Volume (EDV): Approximately 120 mL
End-Systolic Volume (ESV): Approximately 50 mL
Stroke Volume: Around 70 mL (EDV - ESV)
Ejection Fraction: Typically 66%

Question 8

Outline factors that affect the heart rate.

Answer 8

Parasympathetic and sympathetic tone

Question 9

Define preload.

Preload is not measured directly. State the indices used.

Answer 9

Is the load or pre-stretch on ventricular muscle at the end of diastole.

Is not measured directly.

Indices used are:
*Left ventricular end- diastolic volume(LVEDV)
*Left ventricular end diastolic pressure (LVEDP)

Question 10

Discuss the effects of preload on force of contraction.

What is the most important determining factor for preload?

Answer 10

Increase in preload increases force of contraction by causing more cross- linking of actin and myosin

The most important determining factor for preload is venous return.

Question 11

Define contractility.

State the formula for Ejection fraction.

Answer 11

Defined as change in performance at a given preload.

A change in the force of contraction at a given sarcomere length.

Estimated by ejection fraction.

𝐸𝐹=(𝑆𝑡𝑟𝑜𝑘𝑒 𝑉𝑜𝑙𝑢𝑚𝑒)/(𝐸𝑛𝑑 𝐷𝑖𝑎𝑠𝑡𝑜𝑙𝑖𝑐 𝑣𝑜𝑙𝑢𝑚𝑒)

Question 12

Define afterload.

What determines afterload?

State the effect of afterload on stroke volume.

Answer 12

Is the force that the muscle must generate to eject blood into the aorta.

LV afterload is determined by aortic pressure which in turn is dependent on peripheral arterial resistance.

Acute increase of afterload reduces SV.

Chronic increase causes hypertrophy (e.g., hypertension)

Question 13

Heart rate.

Heart rate
What is the intrinsic rate about?

Discuss the following control of heart rate.

*Parasympathetic nerves
*Sympathetic nerves
*Atrial stretch

Answer 13

Heart rate
Intrinsic rate is about 110 beats/min
Parasympathetic nerves: reduces the rate
Sympathetic nerves increase the rates
Also increases contractility and CO
Atrial stretch: increases heart rate

Question 14

What is heart failure?

Answer 14

a complex clinical syndrome due to any structural or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.

A clinical syndrome that develops when the heart cannot maintain an adequate cardiac output or can do so only at the expense of an elevated filling pressure.

Question 15

State the different types of heart failure.

Answer 15

1. Left heart failure: Systolic and diastolic heart failure
2. Right heart failure

Question 16

Define congestive heart failure.

Answer 16

A clinical syndrome with features of circulatory congestion (fluid retention) such as jugular venous distension, rales, peripheral edema, and ascites.

In medicine, “rales” refers to abnormal lung sounds heard upon auscultation (listening with a stethoscope). These abnormal sounds are often indicative of underlying respiratory or cardiac conditions. Rales are also known as crackles.

Question 17

Discuss systolic heart failure.

Answer 17

Develop as a result of impaired myocardial contraction.

The dominant cardiac feature is a large, dilated heart and impaired systolic performance.

Question 18

State causes of Systolic HF.

Answer 18

*Reduction in muscle mass (e.g. myocardial infarction)

*Dilated cardiomyopathies

*Pressure overload (e.g. systemic hypertension, aortic valve stenosis)

*Volume overload (e.g. valvular regurgitation, shunts, high out-put states)

Question 19

Discuss Diastolic heart failure.

Answer 19

HF due to impaired filling of the heart

*Due to abnormal ventricular relaxation
caused by a stiff non-compliant ventricle.

*Commonly found in patients with left ventricular hypertrophy

*The ejection fraction at rest is normal.

A cause of HF in up to 50% patients with HF
usually elderly, female, obese, HTN, AF, DM

Question 20

State Causes of Diastolic dysfunction/ Diastolic heart failure.

Answer 20

1. Restricted ventricular filling increased ventricular stiffness.

-Ventricular hypertrophy, hypertrophic cardiomyopathy
-Infiltrative myocardial diseases: Amyloidosis, sarcoidosis, Endomyocardial fibrosis
-Myocardial ischemia & infarction

2. Mitral or tricuspid valve stenosis
3. Pericardial disease: Pericarditis, pericardial tamponade

Question 21

Discuss right heart failure.

Answer 21

impairment of RV systolic function

Question 22

State the causes of right heart failure.

Answer 22

Causes

*Left-sided heart failure (the commonest cause)
severe lung disease with chronic hypoxemia (cor pulmonale)
*Right ventricular myocardial infarction
*Primary pulmonary hypertension
*Congenital abnormalities of the heart.

Left-sided heart failure (the most common cause): Left-sided heart failure, also known as congestive heart failure (CHF), occurs when the left ventricle is unable to pump blood effectively to the body, leading to fluid backup into the lungs (pulmonary congestion). Over time, this can result in increased pressure in the pulmonary circulation, causing strain on the right ventricle and ultimately leading to right-sided heart failure.

Severe lung disease with chronic hypoxemia (cor pulmonale): Chronic lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, and severe asthma can lead to chronic hypoxemia (low oxygen levels in the blood). Chronic hypoxemia can cause vasoconstriction in the pulmonary arteries, leading to pulmonary hypertension and ultimately resulting in right-sided heart failure, a condition known as cor pulmonale.

Right ventricular myocardial infarction: While left ventricular myocardial infarction is more common, a myocardial infarction affecting the right ventricle can also occur. This can lead to right-sided heart failure due to impaired right ventricular function.

Primary pulmonary hypertension: Primary pulmonary hypertension (PPH), also known as idiopathic pulmonary arterial hypertension, is a rare condition characterized by high blood pressure in the pulmonary arteries. Over time, the increased pressure in the pulmonary circulation can lead to right-sided heart failure.

Congenital abnormalities of the heart: Certain congenital heart defects, such as atrial septal defect (ASD), ventricular septal defect (VSD), or Tetralogy of Fallot, can lead to increased strain on the right ventricle, eventually resulting in right-sided heart failure if left untreated.

Question 23

Outline the symptoms of Right heart failure.

Answer 23

*Jugular venous distention
*Peripheral oedema
*Ascites
*Hepatomegaly
*Weight gain
*Nausea
*Lethargic

Question 24

Discuss left heart failure.

Answer 24

Reduction in the left ventricular output and an increase in the left atrial or pulmonary venous pressure.

*An acute increase in left atrial pressure causes pulmonary congestion or pulmonary oedema; a more gradual increase in left atrial pressure

Question 25

State the causes of left heart failure.

Answer 25

*Reduced ventricular contractility due to MI
*Ventricular outflow obstruction: Aortic stenosis
*Ventricular inflow obstruction: Mitral stenosis
*Ventricular volume overload: ASD and VSD
*Arrythmia
*Diastolic disfunction: LVH, Cardiac tamponade

Question 26

State the symptoms of Left heart failure.

Answer 26

Present with pulmonary symptoms due to pulmonary oedema.
*DYSPNEA
*OTHORPNEA
*WEAKNESS
*NOCTURNAL PAROXYSMAL DYSPNEA
*Increased heart rate
*Nagging cough
*Gaining weight

Question 27

Discuss Pathophysiologic Concepts of Heart Failure.

Answer 27

*HF may be viewed as a progressive disorder
*Initiated after an index event either damages the heart muscle or disrupts the ability of the myocardium to contract

-produces an initial decline in the heart’s pumping capacity.

Question 28

Discuss the effect of short-term compensatory mechanisms.

Answer 28

In short term compensatory mechanisms restore cardiovascular function to a normal homeostatic range.

The patient remains asymptomatic.

Question 29

Discuss the effect of long-term compensatory mechanisms.

Answer 29

Sustained activation of these systems cause Secondary end-organ damage.

-Worsening left-ventricular remodeling
-Subsequent cardiac decompensation.
-Fluid overload

Question 30

Outline the Compensatory mechanisms for heart failure.

Answer 30

1. Neuronal: increased sympathetic activity, reduced vagal activity
2. Hormonal: Activation of Angiotensin- aldosterone system, vasopressin, catecholamines and natriuretic peptides
3. Cardiac: Frank- Starling mechanism

Question 31

Discuss Activation of sympathetic nervous system as a compensatory mechanism for Heart failure.

Answer 31

1. One of the first responses to ↓CO
2. Results from reduced baroreceptors firing

-Baroreceptors are mechanosensitive nerve endings in carotid sinuses and aortic arch that function as arterial blood pressure (BP) sensors.

3. This leads to less inhibition to the sympathetic system – hence sympathetic stimulation.
4. Early in HF
   -↑ ventricular contractility and heart rate.

Acutely, and if the heart works properly, this activation of the SNS will promptly restore cardiac function.

5. If the cardiac insult persists over time, SNS will not be able to maintain cardiac function, the heart will progress into a state of chronic decompensated HF, and the hyperactive ANS will continue to push the heart to work at a level much higher than the cardiac muscle can handle.

Question 32

Discuss Antidiuretic hormone (Arginine vasopressin) as a compensatory mechanism for Heart failure.

Discuss the effect of ADH on Sodium levels in the body.

Answer 32

1. Low CO leads to enhanced release of ADH and stimulation of thirst.
2. Elevated levels of ADH cause

-Induces vasoconstriction through a vascular (V1) receptor

-Reduces free water clearance through a renal tubular (V2) receptor

Decreased water excretion + increased water intake via thirst hyponatremia.

This imbalance between water intake and excretion can lead to dilutional hyponatremia, where the concentration of sodium in the blood becomes diluted due to excess water relative to sodium content.

Question 33

Renin–angiotensin system as a compensatory mechanism for Heart failure.

State the stimulus for RAAS system.

Answer 33

Stimulated by
-Decreased stretch of the glomerular afferent arteriole (renal hypoperfusion)
-Increased beta-1 adrenergic activity
-Hyponatremia

Question 34

Describe the Process of RAAS system.

Answer 34

1. Stimulus for Activation:

-Decreased blood flow to the kidneys (renal perfusion) or decreased blood pressure detected by special cells in the kidneys called juxtaglomerular cells.

2.Renin Release by JG cells in the kidney:
*These cells release an enzyme called renin into the bloodstream when they sense reduced renal perfusion or low blood pressure.

3. Conversion of Angiotensinogen to Angiotensin I.
   *Renin acts on a protein in the blood called angiotensinogen, which is produced by the liver. Renin cleaves angiotensinogen to form angiotensin I.
4. Angiotensin I is then converted into angiotensin II by an enzyme called angiotensin-converting enzyme (ACE), which is mainly found in the lungs but also in other tissues.
5. Actions of Angiotensin II:

*Vasoconstriction:

Angiotensin II acts directly on blood vessels, causing them to constrict. This vasoconstriction increases peripheral vascular resistance, which raises blood pressure.

*Stimulation of Aldosterone Release:

Angiotensin II also stimulates the adrenal glands to release aldosterone, a hormone that acts on the kidneys.

Aldosterone Effects: Aldosterone promotes the reabsorption of sodium and water from the kidney tubules into the bloodstream, while simultaneously increasing the excretion of potassium.

This retention of sodium and water expands blood volume and further contributes to increased blood pressure.

*Stimulation of Thirst:

Angiotensin II also acts on the hypothalamus in the brain to stimulate thirst. This leads to increased fluid intake, further contributing to an increase in blood volume and subsequently blood pressure.

*Stimulation of Sympathetic Nervous System:

Angiotensin II stimulates the sympathetic nervous system, leading to increased release of norepinephrine. Norepinephrine acts on alpha-adrenergic receptors in blood vessels, causing vasoconstriction, which further increases peripheral vascular resistance and blood pressure.

Question 35

State the negative effects of Angiotensin II on the heart.

Answer 35

-Salt and water retention
-vasoconstriction of the peripheral vasculature
-Myocyte hypertrophy
-Myocyte cell death
-Myocardial fibrosis
-Heightens SNS activation

Question 36

State the negative effects of Aldosterone on the heart.

Answer 36

-Na+ retention

-Interstitial cardiac fibrosis decreases systolic & diastolic function

-Other target organ fibrosis, vascular remodeling, proinflammatory state, oxidative stress

-Increased risk of arrhythmias

Question 37

Discuss The Frank-Starling law.

Answer 37

1. Increased Preload Leads to Increased Stroke Volume.
   -As the ventricular volume increases and stretches the myocardial muscle fibers, the SV increases, up to its maximum capacity.

After that point, no more increase SV or CO.

2. Optimal length-tension relationship of cardiac muscle fibers:
   -As the myocardial fibers stretch, they reach an optimal length where they generate the greatest force of contraction.

Beyond this point, further stretching may result in reduced contractility and less effective pumping.

3. Automatic regulation;
   -I is an intrinsic property of the heart and operates automatically without neural or hormonal control.

It ensures that cardiac output matches venous return, thereby maintaining adequate circulation and tissue perfusion.

Question 38

Discuss The Frank-Starling law as a compensatory mechanism for heart failure.

Answer 38

-There is a reduction of SV and an increase in the volume of blood remaining after systole (end diastolic volume- EDV).

This increased EDV stretches the myocardial fibers and increases myocardial contraction.

Question 39

What is ventricular performance related to?

Answer 39

Ventricular performance is related to the degree of myocardial stretching.

-An increase in preload enhances function
-Overstretching causes marked deterioration
-In HF the curve moves to the right and becomes flatter.

Question 40

Discuss Natriuretic peptides as a compensatory mechanism for heart failure.

Answer 40

1. Released in response to volume expansion
2. Counterbalance the vasoconstricting and sodium-retaining actions of RAAS & SNS
3. Cause both arterial and venous vasodilation as well as natriuresis and diuresis.

Question 41

Discuss endothelin as a compensatory mechanism for Heart failure.

Answer 41

Produced by the vascular endothelium.

Causes
-Prolonged vasoconstriction
-Reductions in glomerular filtration
-Pulmonary arteriolar constriction
-Over the long term- pathologic remodeling

Question 42

Discuss Autocrine/Paracrine Factors as compensatory mechanisms for heart failure.

Answer 42

Other circulating mediators

*Proinflammatory cytokines TNF-α, IL-6, IL-1β
-Negative inotropic effects
-Reduced β-receptor-mediated responses
-Increased myocardial cell apoptosis
-Stimulate remodeling

Question 43

Neurohormonal changes- summary WITH FAVOURABLE AND UNFAVOURABLE EFFECTS

Check table on slides.

Answer 43

1. Initially
   Initially improve circulation and perfusion of vital organs.
2. Over time
   Prolonged activation of these systems causes maladaptive remodeling of the LV and further dysfunction.

Question 44

Discuss what causes cellular changes as a compensatory mechanism for heart failure.

Answer 44

Caused by

-Mechanical stretch of the myocyte
-Neurohormones- norepinephrine, angiotensin II
-↑inflammatory cytokines (TNF-α, IL-1β, IL-6)
-Peptides and growth factors (e.g., endothelin)

Question 45

Discuss the pharmacological targets for the RAAS system.

Answer 45

1. Ace inhibitors: Prevents conversion of Angiotensin I to angiotensin II.
2. Angiotensin receptor blockers: Prevents the effects of angiotensin II vasoconstriction

3.Beta blockers: Prevents the activation of the SNS by angiotensin II

4. Spironolactone: Prevents the effects of aldosterone AND water retention
5. Diuretics: Prevents water and sodium retention.