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Cardiovascular Disease - Veterinary Internal Medicine > Pathophysiology of Heart Failure > Flashcards

Pathophysiology of Heart Failure Flashcards

1
Q

Define the two fundamental mechanical functions of the heart

A
  1. Adequate systolic ejection of blood to perfuse the systemic and pulmonary capilliary beds. Must meet the perfusion requirements of the metabolising tissues
  2. To receive blood from the systemic and pulmonary venous system such that there is adequate drainage from the capilliary beds
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2
Q

Define heart disease and cardiac failure

A

Heart disease

  • Defined as any cardiac finding outside the acceptable range of normality.
  • Includes valve disease (murmur), abnormal rhythm, abnormal myocardial function

Heart Failure

  • The heart can no longer meet the requirement to either eject sufficent blood (forward failure - low output failure) to meet tissue perfusion requirements, or receive blood from the venous system (congestive heart failure)
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3
Q

Define the major factors required to maintain normal circulatory function

A
  1. Function heart
  2. Stable vascular bed
  3. Normal blood components including functional red blood cell mass.

As such, circulatory failure can occur with alteration to any of the above components:

eg. severe anaemia - reduced O2 delivery to tissues. Severe vasculitis - ECV reduced due to vascular leak, or increased peripheral resistance reduces the volume of blood reaching the capilliary bed.

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4
Q

What are the major determinants of cardiac output and stroke volume?

A
  1. Preload
  2. Afterload
  3. Heart rate
  4. Myocardial contractility
  5. Ventricular synchrony
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5
Q

Define and categorise the various causes of heart failure

A
  1. Diastolic failure - impaired cardiac filling
    • Pericardial disease
    • hypertrophic and restrictive cardiomyopathy
    • Inflow obstructions - mitral stenosis, cor triatriatum
  2. Systolic failure due to increased resistance to ejection
    • Pulmonic or aortic stenosis
    • HOCM
    • Pulmonary hypertension
    • Major thromboembolic disease
  3. Systolic failure due to impaired ejection or volume overload
    • DCM
    • Secondary myocardial disorders (ischaemia, toxic, myocarditis, thymine deficiency)
    • Mis-directed blood flow - mitral insufficiency, left to right shunt
    • Chronic high-output (thyrotoxicosis, anaemia)
  4. Arrhythmia or conduction disorders
    • Sustained tacharrythmia or sustained bradyarrhythmia
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6
Q

Neurohormonal Alterations with Heart disease

Numerous changes occur that lead heart disease towards failure. List the various systems/hormones that become altered with heart disease

A
  1. Sympathetic nervous system - increased activation
  2. Renin angiotensin aldosterone system (RAAS) - increased
  3. Over-expression of natriuretic peptides (atrial and brain)
  4. Augmented synthesis of
    • adrenomedullin - potent vasodilator
    • endothelin - potent vasoconstrictor
    • vasopressin (ADH) - triggers water retention
  5. Pro-inflammatory cytokines increased
    • TNF-a, IL-6, IL-1
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7
Q

Neurohormonal Alterations with Heart disease

Discuss the major changes caused by increased activation of the sympathetic nervous system (SNS)

A
  • Primary and primitive effect is to increase both contractility and heart rate. These effects combine to increase the cadiac output
  • Increases SNS stimulation is the predominant effect in response to declining cardiac function
  • Increases the rate of SA node depolarisation by activating the beta adrenergic receptors - increased rate of slow calcium influx
  • CO increases linearly to a limit at which rate diastolic filling limits CO
    • stroke volume decreases at a lower rate when there is cardiac disease or heart failure. Hence this adaptive response has limited benefit
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8
Q

Neurohormonal Alterations with Heart disease

Discuss the physiological pathway by which the SNS increases myocardial contractility

A
  1. Contractility can be increased by
    • stimulation of adrenergic receptors in the myocardium
    • Circulating catecholamine binding
    • Increased heart rate
    • Reduced afterload
  2. Gs protein binds to beta 1 adrenergic receptor –> activation of adenylyl cyclase –> formation of cyclic AMP –> activates protein kinase A (PKA)
    • Each Gs bound to receptor can stimulate release of many further G proteins ensuring amplification
    • PKA phosphorylates numerous proteins ultimately increasing calcium transport
    • PKA also increases activity of proteins that augment the rate and force of contraction (troponin 1, myosin binding protein C)
  3. Adrenergic mediated venous constriction leads to an increased preload. This induces a more forceful contraction as increased diastolic stretch increases the sensitivity of contractile elements to cytosolic calcium (length dependent activation)
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9
Q

Neurohormonal Alterations with Heart disease

Describe the evidence for increased SNS activation with heart disease

A

Page 1156!

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10
Q

Neurohormonal Alterations with Heart disease

What are the major physiological triggers of the RAAS

A
  1. Decreased effective renal perfusion
  2. Reduced sodium resorption by the renal tubules
  3. Beta-adrenergic activation

Examples: Acute blood loss, low sodium diet, vigorous exercise

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11
Q

Renin

What is the major action?

A

Renin acts to accelerate the conversion of angiotensinogen to angiotensin I

Produced in the juxtaglomerular cells within the kidney

The overall effect of renin secretion is to increase systemic arterial pressures

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12
Q

Describe the extent of the RAAS in the body

A
  • The various components of the RAAS are found throughout a variety of tissues, with only 10% in the circulation.
  • Tissue components are potentially activated earlier in heart failure that the circulating components.
  • Components are located within the myocardium, brain, vasculature, adrenal gland and kidney
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13
Q

Discuss the actions of angiotensin converting enzyme (ACE)

A
  • ACE is a dipeptidyl carboxypeptidase
  • ACE is primarily located in the capiliaries in the lungs
  • Acts by cleaving terminal dipeptides and is not protein specific
    • Acts to convert angiotensin I to angiotensin II
    • ACE also cleaves bradykinin to an inactive form
    • ACE can also degrade beta-amyloid within the brain
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14
Q

List enzymes that can catalyse the conversion of angiotensin I to angiotensin II

A
  • ACE
  • Cathepsin G
  • Elastase
  • Tissue plasminogen activator
  • Chymase (from mast cell granules)
  • Chymostatin-sensitive AII generating enzyme

Note: Chymase may be more active in the myocardium and ECM in dogs and cats when compared to ACE

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15
Q

Angiotensin II

Role and regulation

A
  1. ATI to converted to ATII by numerous enzymes including ACE, chymase, elastase, tissue plasminogen activator and CAGE.
  2. ATII is rapidly hydrolysed with a half-life of 1-2 minutes.
  3. Hydrolysis is catalysed by angiotensinases
  • Pysiological effect is primarily mediated by AT1 receptors
  • AT1 receptors are located in the blood vessels, heart, kidney, liver, pituitary and adrenal gland
  • Overall effect is to cause vasoconstriction and promote sodium and water retention in the kidneys to cause ECF expansion and increase arterial pressures
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16
Q

Angiotensin II

Describe the effects of ATII at each target organ

A
  1. Blood vessels
    • Vasoconstriction via Gq protein mediated mechanism - increased calcium - increased smooth muscle contraction.
    • Can also lead to smooth muscle hypertrophy
  2. Kidney
    • promotes sodium and water retention via direct effects on the renal tubules
    • Acts via the Na+/H+ exchanger, which is coupled to bicarbonate reabsorption
    • Increase Na+, blood volume and pH,
  3. Myocardium
    • Potent Gq protein stimulator
    • Enhances myocardial hypertrophy
    • Together with aldosterone, promotes reactive oxygen species development - augments hypertrophy and vascular remodelling
  4. Adrenal Gland
    • Stimulates aldosterone production and release - likely in a paracrine manner
  5. Brain
    • Increases production and release of ADH. Ie. Indirectly increases free water resorption
    • Increased thirst
    • Increase drive for salt
    • Potentiates norepinephrine release
17
Q

Aldosterone

List the stimuli for aldosterone production and release

A
  1. Angiotensin II
  2. Increased potassium
  3. Corticotropin
  4. Plasma catecholamines
  5. Endothelin-1
  6. ADH
  7. Plasma acidosis
  8. Stretch receptors in the heart
18
Q

Aldosterone:

Describe the major physiological mechanism of action within the kidney

A
  • Excreted by the zona glomerulosa of the adrenal cortex
  • Primarily acts to cause sodium resoption and potassium excretion.
  • Water is resorbed together with sodium​
  1. Acts on epithelial cells of the distal collecting duct
    • Diffuses into the epithelial cells
    • Binds to cytoplasmic mineralocorticoid receptors - activated MCR’s enter the nucleus
    • Upregulation and expression of basolateral Na+/K+ pump.
      • 3 Na+ ions into the interstitial fluid
        • Sodium (and water) diffuses into the blood via concentration gradient
      • 2 K+ ions into the cell
        • K+ ions then excreted at the luminal surface into the urine
  2. Upregulates expression of the sodium chloride symporter (NCC) in the distal convoluted tubule
    • Transports Na+ and Cl- across the apical membrane
19
Q

Aldosterone:

Describe the effects of aldosterone outside of the kidney

A
  1. Colon:
    • Upregulates epithelial sodium channels
    • Increased apical membrane resorption of sodium
  2. Gut/salivary/sweat glands
    • Na+ absorption in exchange for K+
  3. Nervous System
    • Stimulation of the SNS via inhibition of NE reuptake
  4. Other
    • Mediator of inflammation, fibrosis and oxidative stress
    • Contributes to pathological remodelling in the heart, kidney and vasculature
20
Q

Discuss the clinical relevance of RAAS activation in early heart disease and overt congestive heart failure

A
  • RAAS almost certainly activated during heart disease and prior to heart failure.
  • Early activation within the tissue RAAS, not ciculatory RAAS
  • Clear evidence of substantial increases in renin activity and aldosterone levels with CHF due to MR, DCM, HCM, RCM
  • Physiological negative feedback from RAAS activation leads to downregulation of renin and aldosterone production - thus concealing the activation
  • Uncertainty exists as to the point in heart disease when RAAS activation becomes clinically relevant.
  • Many recent clinical advances in heart failure and hypertension management with ACEI’s, ARB’s and aldosterone antagonists.
21
Q

Angiotensin Converting Enzyme Inhibitors

List actions and clinical implications

A
  • Inhibits the action of ACE via an unknown mechanism. ACE is responsible for converting ATI to ATII
  • Note: There are numerous other pathways for the conversion of ATI to ATII.

The effects of ACEI’s are primarily mediated by decreased angiotensin II production.

  • Reduced arteriolar constriction - effective vasodilatation
  • Reduced bradykinin degradation - increased vasodilation
    • Both above effectively reduce blood pressure
  • Vasodilation reduces afterload, reducing cardiac work
  • Dilatation of the afferent arterioles in the kidney reduces glomerular filtration pressures - reduced protein filtration
  • Enhanced natriuresis - reduced ECV - reduced venous pressures and pre-load
  • Reduced cardiac remodelling and production of ROS
  • Reduced vascular smooth muscle remodelling
22
Q

Angiotensin Receptor Blockers (antagonists)

Discuss their action and clinical indications

A
  1. ARBs (eg telmisartan) selectively block the AT1 rebeceptor
    • Reduce the actions of angiotensin II similarly to ACEI
    • Does not block the AT2 receptor - may be couter-regulatory to the maladaptive actions mediated by AT1
  • Lowers blood pressure in human hypertension - uncertain of this role in dogs/cats
  • Reduces glomerular filtration pressures - useful to reduction of proteinuria due to glomerular disease
23
Q

Aldosterone inhibitors (spironolactone)

Discuss actions and clinical indications/implications

A
  • Competitive inhibiton of aldosterone in the distal renal tubules.
  • No effect on carbonic anhydrase and renal transport mechanisms
  • Kidney
    • Blocks sodium reabsorption and decreased potassium excretion
    • Ammonium, phosphate and acid excretion are also reduced
  • Heart
    • Stabilisation of baroreceptor function in heart failure
    • Reduced sympathetic nervous system activity
    • Increased parasympathetic NS activity
  • Vasculature
    • Aids vascular relaxation by allowing normal NE reuptake
  • May limit the production of pro-inflammatory cytokines and inhibit fibrosis
24
Q

Neurohormonal Alterations of Renal Function in Heart Failure

Discuss the mechanisms by which the kidney responds to congestive heart failure.

A
  • Renal baroreceptors sense a decreased arterial blood volume
    • Primarily activates the SNS and RAAS
      • Vasoconstriction
      • Reduced water excretion
      • Reduced sodium excretion - increased retention
    • Both SNS and ATII stimulate release of ADH in the posterior pituitary
      • Further water retention by action at the late distal tubule and collecting duct
    • Blunted response to atrial natriuretic peptides
25
Q

List the natriuretic peptides and their storage location.

A
  1. Atrial (A-type) natriuretic peptide
    • Myocardial cells in the atria
  2. Brain (B-type) natriuretic peptide
    • Myocardial cells in the ventricles
      • 10 time lower affinity for receptors than ANP
  3. C-type natriuretic peptide
    • Vascular endothelium
26
Q

Describe the triggers for release of the various natriuretic peptides

A

ANP and BNP have similar actions albeit a variable affinity for the ANP receptor (NPRA)

  1. ANP and BNP are primarily released in response to increased atrial stretch (increased pre-load) - via atrial volume receptors
  2. Increased sympathetic stimulation of b-adrenergic receptors
  3. Endothelin-1 triggers release
  4. Indirectly in response to increased sodium concentration (due to volume expansion)

C-type Natriuretic peptide release is stimulated by increased shear stress and in response to pro-inflammatory cytokine release.

C-type NP is a direct agonist for the B type natriuretic receptor (NPRB)

27
Q

Describe the action of the natriuretic peptides

Include receptor types and location together with the mechanism of action

A

ANP and BNP essentially oppose the actions of the RAAS

  1. NPRA / NPR-1
    • Both act via the A-type natriuretic receptor (NPRA / NPR1)
    • Inhibit tubular resporption of sodium and water in the inner medullary collecting duct
    • Induce natriuresis and diuresis
    • Mediate vasodilatation in the systemic and pulmonary arterioles (NPRA)
    • Direct inhibitioin of renin release
    • Direct inhibition of aldosterone release from the adrenal gland
  2. NPRB / NPR-2
    • preferentially mediates vasodilation in response to C-type NP.
    • C type-NP primarily acts in a paracrine fashion and has limited concentration in the circulation
  3. NPRC / NPR-3
    • Acts to clear natriuretic peptides with a greater affinity for ANP than BNP (hence longer half life of BNP)
28
Q

ADH / Vasopressin:

Describe the synthesis and release of ADH including anatomical aspects and stimulators of release.

A
  • Provasopressin is produced from Pre-provasopressin in neurons with cell bodies in the hypothalamus.
  • Provasopressin is processed into ADH in neuronal vesicles
  • ADH is transported in vesicles along the neuronal axon and into the posterior pituitary gland
  • Vesicles containing mature ADH become secretory granules in the nerve endings

ADH is released in response to:

  1. Increased plasma osmolality
  2. Hypovolaemia
  3. Sympathetic NS stimulation
  4. Angiotensin II
29
Q

ADH / Vasopressin:

Discuss the mechanism of action of ADH together with overall effects

A
  • ADH reacts with V1A receptors in the vasculature and hert
    • Vasoconstriction
    • Positive inotropic effects
  • ADH reacts with V2 receptors in the kidney
    • Increased expression of aquaporin-2 channel expression in the luminal membrane of epithelial cells located in the renal collecting ducts
  • Baroreceptor V2 receptors
    • Augments baroreceptor reflexes to lower heart rate in response to vasoconstriction
    • Effectively reduces heart rate to help maintain arterial blood pressures within normal limits
30
Q

Discuss the paradoxical increase of vasopressin release in congestive heart failure.

Briefly detail how this information may be used clinically

A
  • Typically vasopressin is released in response to decreased ECV or hyponatraemia. In CHF, the plasma volume is expanded and sodium concentration may be variable.
  • Baroreceptor signalling due to low arterial pressures may in part trigger ADH release
  • ATII and SNS activation also stimulate ADH release

ADH increase in CHF when compared to healthy dogs has been documented (Scollan et al 2013) and a human enzyme immunoassay has been validated.

  • Selective V2 or V1/V2 blocking agents effect to decrease ADH mediated water resportion.
  • Aquaresis is promoted and congestive signs can improve
31
Q

Endothelin

Discuss physiological control and mode of action of endothelin-1

A
  • Primarily produced in the vascular endothelium
    • Also produced in cardiac myocytes and other cells
  • Secretion is stimulated by
    • hypoxia
    • mechanical factors - stretch and reduced shear stress
    • ATII
    • ADH
    • Noradrenaline - SNS
    • bradykinin
    • growth factors and cytokines (TGFb, TNFa, IL-1)
  1. Potent mediator of vasoconstriction
    • Acts via 2 receptors - ETA, ETB
  2. Increases myocardial contractility
  3. Inhibits the nitric oxide synthase inhibitor, thus increasing NO production. Increased NO, inhibits endothelin production.
  4. Increases aldosterone secretion
  5. Suppresses renin production
32
Q

Nitric Oxide

Describe production and action

A
  • Produced in endothelial cells from L-arginine
    • Catalysed by endothelial nitric oxide synthase
  • Diffuses into smooth muscle cells
  • Very short half-life - acts in an autocrine or paracrine manner
  • Causes vasodilation
    • Activates soluble guanylate cyclase
      • Increases cyclic GMP
    • Activates potassium channels
      • cell hypopolarization
  • Impaired endothelial cell function causes reduced NO synthesis in heart failure
  • Endothelin 1, a potent vasoconstrictor stimulates production and release of NO
33
Q

Adrenomedullin

Overview

A
  • Potent vasodilator
  • Potent natriuretic peptode
  • Positive inotrope
  • Detected in the adrenal gland, heart, lung and kidney
  • Levels have been found increased in human CHF and pacing induced canine CHF
  • ATII stimulates production and release in the cardiac myocytes and fibroblasts
  • May be useful as a marker of ventricular hypertrophy
  • Acts to attenuate myocardial hypertrophy and collagen production
34
Q

Describe the cardiac remodelling that occurs with sustained pressure overload

A
  • Pressure overload causes an increased wall stress during systole
  • Pressure overload triggers primarily concentric hypertrophy
  • Mitochondria size and number increase within myocytes to meet increased energy demands
  • Myocyte sarcomeres replicate in parallel (side to side)
    • Thickening of the muscle fibres - concentric hypertrophy
  • The LV radius is unchanged, but the wall thickness increases to normalize wall stress
  • Fibroblasts increase levels of locally generated TGFb, ATII and aldosterone
    • fibroblast proliferation and increased collagen deposition
  • Reduced collagen breakdown in the interstitium
  • With chronicity, capilliary density and thus mycoardial perfusion do not keep up with hypertrophy
  • Myocardial hypoxia and ischaemia can result together with extensive myocardial fibrosis.
35
Q

Describe the cardiac remodelling that occurs secondary to chronic volume overload

A
  • Pure volume overload results in increased diastolic wall stress
  • Cardiomyocytes replicate new sarcomeres in series (end to end)
  • The chamber becomes more rounded and diameter increases - eccentric hypertrophy
  • There is modest increase in wall thickness to maintain a normal thickness to radius ratio = normalised wall stress
  • There is increased local production of cardiotropin 1, ATII and NE
  • Marked changes in the extracellular matrix occur
    • There is loss of the supportive collagen and collagen synthesis is reduced
    • Increased activity of matrix metalloproteinases - augments collagen breakdown
    • TGFb1 is reduced in early disease (to allow relaxation)
      • Down regulation of the cell-matric scaffolding genes
  • The changes in the ECM tend to normalise over time and then reactivate later in the course of disease.
  • *

Cardiovascular Disease - Veterinary Internal Medicine (10 decks)

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