Cardiovascular Disease & Risk Factors (3) Heart Failure

Question 1

The hypertension continuum

Answer 1

Hypertention
>>CAD
>>Stroke (MI)
>>Remodelling
>>End stage heart disease

> Not surprising that similar drugs are effective in these conditions

Question 2

Neural and hormonal influences on blood pressure

Answer 2

BP = TPR x CO
CO = HR x SV

Brain
>Sympatetic nerves 
>Noradrenaline
>A1-AR (blood vessel constriction)
>B1-AR (HR, Contractile force, kidney production of renin)

> Rein > Ang II
>AT1 Receptors
BV, Heart, Kidney
»Barorecptors and Osmosreceptors

Question 3

Cardiac Output

Answer 3

Input
>Can only pump out what comes in
>Venous return
>PRELOAD

Rate
>How fast the pump runs
>HEART RATE

Strength
>how strong is the pump
>CONTRACTILITY

Resistance
>more is pumped if less resistance
>AFTERLOAD

Question 4

Neural control of heart rate and contractility

Answer 4

Autonomic nerves regulate intrinsic pacemaker activity of the heart
>Denervated heart continues to beat

Parasympathetic division
>Sino-atrial (SA) node, and atrio-ventricular (AV) node
>Acertylcholine, Muscarininc (M2) Receptors
>Gi reduction cAMP, opening K+ channels (cell hyperpolarises, less excitable)
>Decreases rate

Sympathetic division
>SA node, conducting tissue and myocardial cells
>Noradrenaline, B1-Adrenoceptors
(also circulating hormone - adrenaline)
>Gs increase cAMP, increase Ca2+
>Increases rate and contractility
(potential for dysrythmia)

Question 5

Electrical activity in the heart

Answer 5

SA node
>Pacemaker cells that have intrinsically unstable membrane potential
>Will beat even if denervated
>QRS complex is ventricles
>Resting heart rate 60-70BPM
>Cells have to be ready to receive the next electrical impulse - leads to contraction of cardiac muscle

Question 6

Four major classes of drugs used to control rate

Answer 6

Class 1
>Na+ channel block

Class 2
>Beta-Adrenoceptor antagonism

Class 3
>K+ channel blockade

Class 4
>Ca2+ channel blockade

Unclassified:
>Atropine, adenosine, cardiac glycosides, electrolyte supplements

**Always consider the no treatment option
>Many antiarrythmics have proarrythmic activity and may worsen arrythmias and cause sudden death

Question 7

Class 1 - NA+ Channel Blockers

Answer 7

Lignocaine (Lidocane)
>rapid blockade of activated Na+ channels
(slow phase 0 of ventricular action potential)

> depresses conduction and excitability in heart
Local anaesthetic actions on all excitable cells
(because they can also block Na channels that are located on may other cells, anaesthetic use restricted to site of action where sensory/motor fibres are causing pain)

Use:
Post MI, i.v., in ventricular dysrythmias and fribrillations
*only use as anti-arrythmic following a cardiac event
e.g. used to get ventricular rhythm back to baseline then think of another beta blocker to maintain baseline till next episode

Question 8

Class 3 - K+ Channel inhibitors

Answer 8

Prolongs ventricular action potential
>slowing of phase 3 repolarisation
>decreases incidence of re-entry
>increases risk of triggered events

Amiodarone
>also blocks Na+, Ca+ and B-ARs
(probably this combination of effects that leads it to be a good antiarrythmic drug)
>reversible photosensitisation, skin discolouration and hypothyroidism
>pulmonary fibrosis with long term use
>distinctive side effect profile
*we get these side effects due to lack of selectivity of K+ channels

Question 9

Digoxin - Cardiac Glycoside

Answer 9

Slows AV conduction, increasing vagal input to heart (via CNS effect)
>anti-arrythmic mechanism of this drug is CNS, switches on reflex
>Useful in atrial fibrillation, slows down ventricular rate, improves filling
>may cause ventricular fibriliaton

> Symptomatic relief if Dropsy
fatigue, oedema, SOB, palpitations

Question 10

Cardiac glycoside effect on ventricular myocytes

Answer 10

With moderate dose digoxin
>More calcium influx into cardiac myocyte
>Benefit = increased contractility

With high dose digoxin
>Still relatively improved contraction, but not as good as earlier (time is a factor)
>Relatively unstable (bit of calcium leaking in and setting off another AP)
>if cells not reset to resting state, can trigger arrythmias
>Risk = dysrythmia

LAD = Late afterdepolarisation

Question 11

Cardiac contraction and relaxation

Answer 11

1) Action potential enters from adjacent cell
2) Voltage-gated Ca2+ channel open, Ca2+ enters cell
3) Entry of Ca2+ triggers release of Ca2_ from sarcoplasmic reticulum
4) Most Ca2+ comes from SR
5) Ca2+ ions bind to troponin to initiate contraction

6) Relaxation occurs when Ca2+ unbinds from troponin
7) Ca2+ is pumped back into SR for storage
8) Ca2+ is also exchanged with Na+, out of cell
9) Na+ gradient is maintained by Na+/K+ ATPase

Digoxin
>inhibits Na+/K+ ATPase
>increased [Na+]i decreases Ca2+ extrusion
>increase Ca2+ in SR
>Increase Ca2+ release with each action potential
>Increase contractility

Question 12

Glycosides in heart failure

Answer 12

Narrow margin of safety, low therapeutic index

Affect all excitable tissues 
(NA+/K+ ATPase fundamental for maintaining NA/K Balance)
>gut = anorexia, nausea, diarrhoea
>CNS = drowsiness, confusion, psychosis
>Cardiac = ventricular dysrythmias

Increased toxicity with
>low K+ (decreased competition for binding)
>high Ca2+ (decreased gradient for Ca2+ efflux)
>Renal impairment

Oral absorption, T1/2 ~40hr
Vd ~ 400L, due to high affinity binding to muscle

Question 13

Sympathetic stimulation increases contractility

Answer 13

Noradrenaline, Dobutamine (partial B1-agonist)
>act on B1-AR
>Gs-GPCR
>adenylate cyclase
> ATP into cAMP
>activates PKA
>Phosphorylates L-type Ca2+ channels, increase open probability
>Influx of Ca2+ into cell

Milrinone
>Phosphodiesterase inhibitor
>inhibits enzyme that deactivates cAMP

Question 14

B-Adrenoceptor agonists and PDE inhibitors in HF

Answer 14

Intravenous, short term support for acute heart failure, caridogenic shock (heart just stops and needs to get stimulated)

B-adrenoceptor agonists
>NA, Adr (activate both alpha and beta ARs)
>Dobutamine (selective B1-AR agonist - cardiac selective)

> > > Adverse effects
Increase cardiac work, O2 demand
Risk of dysrythmias (wrong dose, heart beat too fast)

Phosphodiesterase inhibitors
>Milrinone (same issues as B-agonists)
>used when beta receptors downregulated, if in some heart conditions, overactive sympathetic NS causes downregulation of B-ARs

Question 15

Heart Failure

Answer 15

Inotropes
>increase contractile force of cardiomyocytes
>symptomatic relief
»increase work on the heart
»short term benefit (no increase in lifespan with these drugs, just provide symptomatic relief)

Symptoms progress
>chest pain
>fainting
>death

Cardiac remodelling

More than loss of cardiac pump function
>Other strategies needed to increase long term survival

Question 16

Heart failure

Answer 16

Insufficient CO to meet tissue perfusion needs

Multiple causes for acute and chronic heart failure

CONTRACTILITY
>Loss of myocardial muscle
»ischaemic heart disease
»cardiomyopathy

AFTERLOAD
>Pressure overload
»Aortic stenosis
»Hypertension

PRELOAD
>Volume overload
»Valve regurgitation
»Shunts (e.g. septal defects)

Question 17

Preload reduction

Answer 17

Venodilators
- Nitrates
>Angina (where o2 supply to heart is compromised), venous dilation > arterial dilation
>1st pass metabolism (given as patches or sublingual), tolerance (effect wears off, 2nd messenger desensitises)

Diuretics (affecting blood volume)
- Furosemide/Frusemide (loop diuretics)
>act at Loop of Henle

Aldosterone receptor antagonists

Aquaretics (drugs that influence movement of water in and out of the body effective in affecting preload
>Vasopressin receptor antagonists

Question 18

Aldosterone receptor antagonists

Answer 18

E.g. spironolactone
>inhibit aldosterone action on cortical (adrenal) and distal tubules
(K+ sparing diuretics)

> improves survival with combination therapy in severe heart failure

> require close monitoring of hyperkalaemia and renal function

Question 19

Afterload reduction (antihypertensive drugs)

Answer 19

Arterial vasodilators
>reflex tachycardia

ACE inhibitors
>First line therapy
>decrease constriction
>also decrease fluid retention, slow progression of hypertrophy
(Angiotensin directly stimulates hypertrophy, ACEIs will slow the progression)

AT1 antagonist
>alternative to ACEI

B-AR antagonists
-stimulating B-ARs is good for acute heart failure, but for chronic heart failure, where there has been excessive sympathetic drive, we should block sympathetic systems in PTs

Question 20

Targeting Angiotensin II to treat Heart Failure

Answer 20

Effects of Angiotensin II
>vasoconstriction (more potent than noradrenaline)
= afterload

> fluid retention due to increased aldosterone release from adrenal cortex
= preload, oedema

> Ventricular hypertrophy
= remodelling

Inhibiting ALL synthesis/actions is beneficial in reducing cardiac work and symptoms of heart failure
>ACEIs, ARBs = decrease preload and afterload

Question 21

ACEIs, (ARBs) - decrease morbidity and mortality

Answer 21

ACEI first line therapy for both early and moderate CHF
- ARBs effective alternative in ACEI intolerant patients
>effective at all grades of heart failure, including astymptomatic
>improve symptoms, delay progression
>titrate dosage to achieve target maintenance dose with proven survival benefits
»SE’s as covered in hypertension lectures (dry cough, angioedema for ACEIs)

Maintain at tolerated dose and combine with other therapies (B-blockers, diuretics, glycosides)

Question 22

Use of B-AR antagonists for heart failure

Answer 22

What about negative Inotropic/chronotropic effects?
- despite B1 blockade, stroke volume increases

Counter intuitive therapy
>attempt to inhibit the disease progress in early stages
>care needed at start of treatment (titrate to maintenance dose)

B1 blockade (cardiac) - Metoprolol
>reduces tachycardia, cardiac work
>inhibits renin release and subsequent AngII effects
>Protects against receptor downregulation

B1 and A1 blockade (vascular, carvedilol only)
>vasodilation reduces afterload, cardiac work

Question 23

Clinical trial data for Beta-AR Antagonists in Heart Failure

Answer 23

US Carvedilol study
>improved ejection fraction
>trial stopped after 65% reduction in mortality in treated group

Further support in COMET study
>decreased fatal stroke or MI by 54%

Used in early and mild to moderate CHF - start treatment early

Question 24

Congestive heart failure - The “donkey” analogy

Chronic Heart Failure

Answer 24

1)

Decompensated CHF
>cardiac output not able to keep up with demand (heart overworked, and results in failure)
>preload increased due to fluid and sodium retention
>afterload increased due to sympathetic nervous system activation and vasoconstriction

Question 25

Congestive heart failure - The “donkey” analogy

Treatment: Reducing cardiac load

Answer 25

2)

ACE inhibitors/ARBs
>reduce afterload/preload by blocking angiotensin/aldosterone

Loop Diuretics
>Reduces preload by decreasing fluid and sodium retention

Hydralazine/Nitrates
>reduces afterload/preload by blocking vasoconstriction/vasodilation

Question 26

Congestive heart failure - The “donkey” analogy

Treatment: Slowing down heartrate without reducing load

Answer 26

3)

Beta-blockers
>inhibit negative remodeling from activated sympathetic nervous system
(inhibiting AngII mitogen remodelling, reduced TPR, reduced BP)

Question 27

Congestive heart failure - The “donkey” analogy

Treatment: Supercharging the heart

Answer 27

4)

Inotropes (digoxin, dobutamine, milrinone)
>increase contractility and cardiac output