Mechanism of heart failure

Question 1

What is heart failure?

Answer 1

Heart’s inability to meet metabolic needs of peripheral tissues or heart can only do so with increased venous filling pressures

Heart failure can manifest as either forward or backward heart failure.

Question 2

What are the mechanisms of cardiac injury?

Answer 2

• Alterations of intracellular calcium cycling
• Myocardial + vascular remodeling
• Deficiencies in myocardial ATP production

These mechanisms contribute to the development and progression of heart failure.

Question 3

What characterizes forward heart failure?

Answer 3

insufficient cardiac performance to provide adequate CO

Symptoms include weakness, syncope, activity intolerance, hypothermia, hypotension, depressed mentation, and inadequate tissue perfusion.

Question 4

List symptoms associated with forward heart failure.

Answer 4

• Weakness
• Syncope
• Activity intolerance
• Hypothermia
• Hypotension
• Depressed mentation
• Inadequate tissue perfusion –> lactic acidosis, azotemia, oliguria

These symptoms arise due to inadequate blood flow and oxygen delivery to tissues.

Question 5

What characterizes backward heart failure?

Answer 5

Elevated venous filling pressure causing exudation of fluid from pulmonary or systemic capillary beds.

This form of heart failure leads to fluid accumulation in various body compartments.

Question 6

What pulmonary venous pressure produces congestion in backward heart failure?

Answer 6

> 25 mmHg

This pressure can lead to pulmonary edema and pleural effusion, particularly in cats.

Question 7

What systemic venous pressure produces ascites in backward heart failure?

Answer 7

> 20 mmHg.

This pressure can lead to fluid accumulation in the abdominal cavity.

Question 8

Describe the vicious cycle of heart failure

Answer 8

Question 9

What is the overall effect of RAAS activation in heart failure?

Answer 9

Fluid retention + maladaptive myocardial and vascular remodeling

This leads to further cardiac injury and depression of cardiac function.

Question 10

What is the primary trigger for RAAS activation?

Answer 10

Decreased renal blood flow –> decreased sodium delivery to macula densa –> renin release

This leads to decreased sodium delivery to the macula densa.

Question 11

What happens after decreased renal blood flow triggers renin release?

Answer 11

angiotensinogen to angiotensin I –> angiotensin I to angiotensin II by ACE in pulmonary vasculature

This process is followed by conversion of angiotensin I to angiotensin II by ACE.

Question 12

What roles does angiotensin II play in heart failure?

Answer 12

• Increases production of aldosterone
• vasoconstriction
• promotes cardiac myocyte hypertrophy + fibrosis
• induces myocardial apoptosis
• stimulation of thirst

Angiotensin II can also be generated from pathways independent of ACE.

Question 13

How does aldosterone contribute to heart failure?

Answer 13

• Sodium + water retention
• cardiac and vascular remodeling + fibrosis
• myocardial apoptosis

It accelerates the mitochondrial apoptotic pathway.

Question 14

Explain RAAS

Answer 14

Question 15

What are the main effector molecules of the SNS in heart failure?

Answer 15

Epinephrine
norepinephrine

These molecules play a key role in cardiovascular responses.

Question 16

What is the effect of epinephrine and norepinephrine on heart rate?

Answer 16

• Positive chronotropic effect
• increase CO
• increase blood flow to important stress organs (e.g. skeletal muslce)

This means they increase the heart rate.

Question 17

What are the chronic effects of SNS activation in heart failure?

Answer 17

• Adrenergic receptor downregulation
• Persistent tachycardia
• Increased myocardial oxygen demand
• Myocyte necrosis

These effects contribute to further cardiac damage.

Question 18

What is one of the earliest systemic responses to cardiac injury?

Answer 18

Increased SNS activity

This response occurs soon after cardiac injury.

Question 19

What is a significant risk factor for mortality in people with heart disease?

Answer 19

Increased norepinephrine concentrations

High levels of norepinephrine are associated with worse outcomes.

Question 20

What are the consequences of natriuretic peptides?

Answer 20

Natriuresis
Diuresis
Vasodilation

These effects help regulate blood pressure and fluid balance.

Question 21

What triggers the production of natriuretic peptides?

Answer 21

Stretch or stress of myocardial tissue

This is a response to increased blood volume or pressure.

Question 22

What system does the natriuretic peptide system counterregulate?

Answer 22

RAAS + SNS

RAAS: Renin-Angiotensin-Aldosterone System; SNS: Sympathetic Nervous System.

Question 23

What happens to the natriuretic peptide system in the later stages of heart failure?

Answer 23

Beneficial activity is overwhelmed –> CHF

CHF: Congestive Heart Failure.

Question 24

What causes the loss of natriuretic peptide efficacy?

Answer 24

• Downregulation
• Inappropriate or inadequate production/processing
• Increased peptide clearance/degradation

These factors reduce the effectiveness of the peptides.

Question 25

Name 5 components involved in neurohormonal changes in heart failure

Answer 25

1. RAAS 2. SNS 3. Natriuretic peptides 4. Endothelin 5. Vasopressin

Question 26

What is the vascular effect of Endothelin 1?

Answer 26

* potent vasoconstrictor --> increased afterload * produced by vascular endothelial cells in response to sheer stress, angiotensin II (AT II), and various cytokines ## Footnote Endothelin 1 causes vasoconstriction and increases afterload in the heart.

Question 27

What effect does Endothelin 1 have on muscle cells?

Answer 27

Alters normal calcium cycling within muscle cells and is directly toxic to myocardiocytes ## Footnote This toxicity contributes to cardiac dysfunction in heart failure.

Question 28

What triggers the release of ADH in heart failure?

Answer 28

Stimulation of baroreceptors in the carotid and aortic arch due to decreased intravascular pressure ## Footnote This response leads to increased water reabsorption in the kidneys.

Question 29

What is the effect of ADH on renal function?

Answer 29

Increases reabsorption of free water within the renal collecting duct (aquaporin II) ## Footnote This results in water retention and can lead to congestive heart failure (CHF).

Question 30

What does dilutional hyponatremia indicate?

Answer 30

* Heightened free water retention with decreased serum sodium despite an overall excess of body sodium * marker of severe neurohormonal activation * poor prognostic indicator ## Footnote It is a marker of severe neurohormonal activation and poor prognosis.

Question 31

What are the consequences of water retention due to ADH?

Answer 31

VO CHF ## Footnote This condition exacerbates heart failure symptoms.

Question 32

What triggers the production of endothelin 1?

Answer 32

* produced by vascular endothelial cells in response to 1. sheer stress 2. AT II 3. various cytokines

Question 33

What is myocardial remodeling?

Answer 33

Cardiac hypertrophy + alteration of cardiac architecture due to increased: * AT II * Norepinephrine * Aldosterone * Other signaling molecules ## Footnote Myocardial remodeling refers to structural changes in the heart muscle often due to pathological conditions.

Question 34

What are the two patterns of hypertrophy in myocardial remodeling?

Answer 34

1. Concentric = pressure overload 2. Eccentric = volume overload ## Footnote These patterns are responses to different types of cardiac stress.

Question 35

What triggers concentric hypertrophy?

Answer 35

Pressure overload ## Footnote Concentric hypertrophy is characterized by an increase in ventricular wall thickness.

Question 36

Name 2 causes of increased afterload in concentric hypertrophy?

Answer 36

Systemic hypertension subaortic stenosis ## Footnote These conditions lead to increased pressure that the heart must work against.

Question 37

What are the effects of concentric hypertrophy?

Answer 37

* Increased myocardial oxygen demand * endocardial ischemia * fibrosis * collagen disruption * injury to small coronary vessels ## Footnote These effects can lead to further heart complications.

Question 38

What triggers eccentric hypertrophy?

Answer 38

VO conditinos (e.g. MVR, DCM) ## Footnote Eccentric hypertrophy is characterized by dilation of ventricular chambers.

Question 39

Name 2 causes of eccentric hypertrophy?

Answer 39

VO conditions (e.g. MV, DCM) ## Footnote These conditions lead to an increase in chamber size rather than wall thickness.

Question 40

What are the effects of eccentric hypertrophy?

Answer 40

* Increased myocardial wall stress * myocyte injury or necrosis * myocyte slippage ## Footnote These effects can compromise heart function significantly.

Question 41

True or False: Interventions that reduce or reverse remodeling are associated with improved survival.

Answer 41

True ## Footnote Effective interventions can enhance cardiac function and patient outcomes.

Question 42

How does the replication of sarcomeres differ between concentric and eccentric hypertrophy?

Answer 42

concentric --> sarcomeres replicate in paralell eccentric --> sarcomeres replicate in series

Question 43

What relies on the influx and efflux of Ca++ within myocardial cells?

Answer 43

Proper cardiac contraction ## Footnote Inadequate calcium handling can lead to heart dysfunction.

Question 44

What can inappropriate intracellular calcium distribution lead to?

Answer 44

* Electrical abnormalities * apoptosis * necrosis ## Footnote Abnormal calcium handling is detrimental to heart cell health.

Question 45

What occurs during systole regarding calcium handling?

Answer 45

Ca++ enters myocardial cell, triggers release of additional Ca++ from sarcoplasmic reticulum through ryanodine channel --> binds to troponin C --> sarcomere contractions ## Footnote This process is crucial for heart muscle contraction.

Question 46

What initiates the relaxation cycle during diastole?

Answer 46

Release of Ca++ from troponin C ## Footnote This release is essential for the heart to relax after contraction.

Question 47

What is the role of SERCA channel in diastole?

Answer 47

Sequestering of Ca++ back into sarcoplasmic reticulum ## Footnote SERCA is responsible for calcium reuptake, crucial for muscle relaxation.

Question 48

What is the main storage area of Ca++ in myocardial cells?

Answer 48

Sarcoplasmic reticulum ## Footnote The sarcoplasmic reticulum is essential for calcium storage and release.

Question 49

Which molecule helps regulate the reuptake of Ca++?

Answer 49

Phospholamban ## Footnote It plays a critical role in cardiac muscle relaxation by influencing SERCA.

Question 50

What is the SERCA channel?

Answer 50

sarcoplasmic/endoplasmic reticulum Ca++-ATPase that transports Ca++ back into sarcoplasmatic reticulum inside the cardiomyocyte

Question 51

Explain the myocyte Ca++ cycling in heart failure

Answer 51

Question 52

What do myocyte mitochondria provide for the heart?

Answer 52

High-energy phosphate molecules ## Footnote These molecules fuel calcium and other ion pumps, sarcomere contraction and relaxation, maintenance of resting membrane potential, and propagation of cardiac action potential.

Question 53

What occurs in severe heart disease related to myocardial oxygen and ATP production?

Answer 53

1. Decreased myocardial oxygen and substrate delivery --> ischemia --> inefficient ATP production via anaerobic metabolism 2. Oxidative phosphorylation chain located within mitochondria lack critical cytochromes + enzymes needed for ATP production ## Footnote This results from a lack of critical cytochromes and enzymes in the oxidative phosphorylation chain located within mitochondria.

Question 54

Which substrates can the heart utilize for ATP production?

Answer 54

* Glucose * free fatty acids ## Footnote The heart preferentially uses glucose in heart disease because it requires less oxygen to metabolize than fatty acids.

Question 55

Fill in the blank: In heart disease, the heart preferentially uses _______ for ATP production. Why is that?

Answer 55

glucose --> requires less oxygen to metabolize

Question 56

What is the role of ATP in myocardial function?

Answer 56

* fuel Ca++ and other ion pumps * sarcomere contraction and relaxation * maintenance of resting membrane potential * propagation of cardiac action potential

Question 57

True or False: The heart primarily uses fatty acids for energy production in heart disease.

Answer 57

False

Question 58

What does the Frank-Starling mechanism describe?

Answer 58

The relationship between preload and CO ## Footnote The Frank-Starling mechanism explains how changes in ventricular volume affect heart contractions.

Question 59

How does an increase in volume or pressure within the ventricle affect subsequent ventricular contraction?

Answer 59

It increases subsequent ventricular contraction up to a physiologic limit (positively associated) ## Footnote This relationship indicates that preload and contractility are positively associated.

Question 60

In health, how does the heart operate regarding preload conditions?

Answer 60

heart self-regulates its performance based on ventricular volume and pressure ## Footnote The heart self-regulates its performance based on ventricular volume and pressure.

Question 61

What happens to the Frank-Starling relationship during times of increased adrenergic drive, such as exercise?

Answer 61

It is shifted up and leftward, improving cardiac performance ## Footnote This shift is necessary to support increased metabolic demands of skeletal muscle and other organs.

Question 62

What occurs to the Frank-Starling relationship in disease?

Answer 62

It is depressed downward and rightward --> less contraction ## Footnote This results in less vigorous contractions despite fluid retention and increased preload.

Question 63

What is a consequence of low-output failure in relation to preload?

Answer 63

Changes in preload produce inadequate contractile response ## Footnote This results in clinical signs of low-output failure.

Question 64

Describe the Frank Starling curve in a diseased heart

Answer 64

Question 65

Explain the Frank Starling curve in health and heart failure

Answer 65

Question 66

What effect do diuretics have on the Frank-Starling curve?

Answer 66

Reduce preload + IV pressures through fluid loss --> shifting heart to the left along its curve ## Footnote Excessive diuresis could move heart farther to the left + reduce CO, though this is unlikely to occur in congested patients.

Question 67

What are positive inotropes and their effect on the Frank-Starling curve?

Answer 67

improve contractility and shift the curve upward --> improved CO even with reduced preload ## Footnote Positive inotropes enhance the heart's ability to pump blood.

Question 68

Name 4 examples of arterial vasodilators and their effect on the heart and the Frank Starling curve

Answer 68

* Nitroprusside * Nicardipine * Clevidipine * Hydralazine --> afterload reduction --> shift heart upward along the curve ## Footnote Arterial vasodilators reduce afterload and improve cardiac performance.

Question 69

What is the effect of arterial vasodilators on the Frank-Starling curve?

Answer 69

Reduce afterload and improve cardiac performance by shifting the curve upward ## Footnote This effect is similar to that of positive inotropes.

Question 70

What do venous vasodilators do to the Frank-Starling curve? Name one example.

Answer 70

Reduce preload and increase capacitance of the venous system, shifting the curve leftward (similar to diuretics) Low dose nitrates ## Footnote Low dose nitrates are examples of venous vasodilators.

Question 71

Name an example of a mixed vasodilator and its effect on the Frank Starling curve

Answer 71

ACE inhibitors --> shift heart left + upward --> improved CO ## Footnote Mixed vasodilators have both arterial and venous effects.

Question 72

What is the overall effect of medications that shift the heart left and upward on the Frank-Starling curve?

Answer 72

Improve cardiac output (CO) ## Footnote This occurs through various mechanisms, including reducing preload or afterload.

Question 73

Reduce afterload and improve cardiac performance by shifting the curve upward ## Footnote This effect is similar to that of positive inotropes.

Answer 73

What is the effect of arterial vasodilators on the Frank-Starling curve?

Question 74

What is the consequence of poor diastolic function?

Answer 74

* reduction in CO * neurohormonal activation (same as in systolic dysfunction) ## Footnote This drives the same neurohormonal responses and clinical consequences as in systolic dysfunction.

Question 75

Name 3 things that are primarily impaired in diastolic heart dysfunction?

Answer 75

* Ventricular relaxation * filling * compliance ## Footnote An example is hypertrophy cardiomyopathy in cats.

Question 76

What allows the ventricular chamber to expand readily in diastole?

Answer 76

High compliance at low hydrostatic filling pressure ## Footnote Compliance is the ability of the ventricle to accommodate blood volume at a low hydrostatic filling pressure.

Question 77

What factors affect ventricular compliance?

Answer 77

* Thickness of ventricular wall * Changes in cytoskeleton and extracellular matrix * Function of pericardium

Question 78

What is required for relaxation in the early phase of diastole? Why is that?

Answer 78

ATP --> movement of Ca++ back into SR uses ATP-driven pumps ## Footnote The movement of Ca++ back into the sarcoplasmic reticulum operates using ATP-driven pumps.

Question 79

What can cause delayed active relaxation and diminish early ventricular filling?

Answer 79

Myocardial ischemia and ATP deficit

Question 80

What are the treatment goals for diastolic heart dysfunction?

Answer 80

* Improving ventricular relaxation * Increasing ventricular compliance * Alleviating existing pericardial disease * Increasing time available for diastolic filling by decreasing heart rate * Suppression of arrhythmias * Alleviation of congestion (diuretics, vasodilators)