Lecture 6 LV Dysfunction and Heart Failure II

Question 1

What is significant about the target for therapeutics in heart failure

Answer 1

Therapeutics don’t target the heart itself but the compensatory response that the body triggers

Question 2

The compensatory mechanism triggered by a drop in cardiac out during heart failure can be divided into the two regions it effects. What are these

Answer 2

Cardiac – effects on the heart itself, system – effects on the vasculature and other organs

Question 3

Why is the compensatory mechanism triggered in heart failure often derogatory

Answer 3

Heart attacks are a relatively recent occurrence, only seen in the last 200 years. As such the body hasn’t evolved to deal with it appropriately. However a number of the changes that occur during heart failure are similar to what is seen during blood loss, something which the body has adapted to. As such the body notices the decrease in cardiac output and other changes occurring during heart failure and wrongly assumes this is due to blood loss. This is why the neurohumoral response is a key target in heart failure treatment

Question 4

There are two compensatory mechanisms triggered in heart failure, the sympathetic nervous system and the RAAS system. Which occurs first

Answer 4

The sympathetic nervous system stimulation is rapid and occurs immediately whereas the RAAS system is much slower and involves protein synthesis and multiple steps

Question 5

Describe how the RAAS acts to compensate for the effects of heart failure

Answer 5

The juxtaglomerular apparatus in the kidney releases renin in response to the decreased cardiac output. Renin acts on angiotensinogen released by the liver, converting it to angiotensin I. Then the ACE enzymes in the lungs convert angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor acting via AT-1 receptors to increase peripheral resistance. Angiotensin II also acts to release aldosterone which promotes Na+ retention and with-it water. This acts to increases blood fluid volume

Question 6

Describe how the SNS acts to compensate for the effects of heart failure

Answer 6

The sympathetic nervous system releases noradrenaline in an attempt to maintain arterial blood pressure and central circulation. This in order to look after the major organs such as the brain, kidney and liver. As blood pressure is controlled by peripheral resistance and cardiac output, noradrenaline acts on both peripheral resistance and cardiac output to increase blood pressure. Firstly is a powerful vasoconstrictor via the α1 adrenergic receptors in vascular smooth muscle, but it also has a positive inotropic effect by stimulation of the β adrenoceptors in the heart.

Question 7

Outline the interplay that exists between the sympathetic nervous system and RAAS systems

Answer 7

Noradrenaline stimulates renin release in the kidney meanwhile, angiotensin II encourages the release of noradrenaline from sympathetic nerve endings. This sort of positive feedback loop acts to amplify the response

Question 8

How are the effects of RAAS and sympathetic nervous system beneficial in blood loss

Answer 8

The sympathetic nervous system stimulation results in a tachycardia which increase cardiac output. It also has a positive inotropic effect increasing the force of contraction which also increases cardiac output. Meanwhile noradrenaline also causes vasoconstriction to increase blood pressure. Finally as a result of RAAS there is a stimulation of Na+ and water retention which acts to increase blood volume and hence blood pressure

Question 9

How are the effects of the RAAS and sympathetic nervous system derogatory in heart failure

Answer 9

The tachycardia caused by the sympathetic nervous system also increases the workload and oxygen demand of the heart, as does the positive inotropic action also. In addition, vasoconstriction increases the afterload which therefore also increases work and oxygen demand of the heart. Meanwhile Na+ and water retention as a result of aldosterone increases preload which due to the shallow Frank-Starling relationship actually does very little to increase cardiac output. Finally, chronic adrenergic stimulation has a toxic effect on the myocytes and causes arrhythmia

Question 10

What are the six different pharmacology’s that can target aspects of the sympathetic nervous system and RAAS system

Answer 10

Diuretics, aldosterone antagonists, ACE inhibitors, angiotensin receptor blockers, β adrenoceptor antagonists or renin inhibitors

Question 11

Below is some data from the RALE trial of aldosterone antagonists in heart failure. Describe what these results show

Answer 11

Placebo – 25% 1-year mortality, Spironolactone – 17.5% 1-year mortality. Hence Aldosterone antagonists correlate with a decreased mortality in patients in heart failure. The curves are continuing to diverge indicating there is an ongoing benefit of aldosterone antagonists

Question 12

Below is some data from the CONSENSUS trial of ACE inhibitors in heart failure. Describe what these results show

Answer 12

Placebo group had a 60% mortality rate over 1 year. This was an extremely severe heart failure patient cohort with NYHA type IV heart failure. However, the patient group treated with the ACE inhibitor enalapril had a 40% mortality rate. Hence the ACE inhibitor reduced the mortality rate in the patients by 1/3.

Question 13

Below is some data from the AIRE trial of ACE inhibitors in heart failure. Describe what these results show

Answer 13

12-month mortality in placebo patients – just under 20%. There as a significant improvement in patients treated with Ramipril with around a 15% mortality

Question 14

Below is some data from the SOLVD trial of ACE inhibitors in heart failure. Describe what these results show

Answer 14

10% rate of death or hospitalisation after 1 year in placebo patients. Improved with enalapril. Greater the annual mortality, the greater the benefit with enalapril

Question 15

What are the clinical indications of ACE inhibitors

Answer 15

Heart failure, hypertension, diabetic nephropathy

Question 16

Give some examples of ACE inhibitors

Answer 16

Captopril, Ramipril, enalapril

Question 17

Which ACE inhibitor is most commonly used

Answer 17

Ramipril

Question 18

ACE inhibitors are used once daily in hypertension, why are they used twice daily in heart failure

Answer 18

Because whereas patients with hypertension really only need the effects on blood pressure during the day, heart failure patients need its effects throughout the night when often it gets worse

Question 19

What are the two broad categories of side effects with ACE inhibitors

Answer 19

Angiotensin II-related and kinin potentiation-related

Question 20

Describe the angiotensin-II related side effects of ACE inhibitors

Answer 20

Hypotension, acute renal failure, hyperkalaemia, teratogenic effects in pregnancy (contraindicated),

Question 21

Describe the kinin potentiation-related side effects of ACE inhibitors

Answer 21

Coughing (dry cough) – will persist until drug not taken, characteristic rash and anaphylactoid reactions, angioedema

Question 22

Why can ACE inhibitors lead to acute renal failure

Answer 22

Angiotensin II in the kidney is responsible for keeping up GFR pressure. Hence ACE inhibitors may lead to a decrease in GFR

Question 23

Why can ACE inhibitors lead to a dry cough

Answer 23

This is due to the potentiation of kinins such as bradykinin. ACE is a non-specific enzyme that also breaks down bradykinins, so inhibiting ACE increases kinin levels. These bradykinins stimulation sensory nerve endings in the airways causing coughing

Question 24

What are the clinical indications of angiotensin II receptor blockers

Answer 24

Heart failure (if ACE inhibitors contraindicated), hypertension and diabetic nephropathy

Question 25

Give some examples of angiotensin II receptor blockers

Answer 25

Losartan, candesartan, valsartan, Irbesartan, telmisartan

Question 26

What are the side effects of angiotensin II receptor blockers

Answer 26

Symptomatic hypotension (especially in volume depleted patients – blood loss and dehydration), hyperkalaemia, potential for renal dysfunction, rashes and angioedema

Question 27

Angiotensin II receptor blockers are generally well tolerated, when are the contraindicated

Answer 27

In pregnancy

Question 28

Which receptors do angiotensin II receptor blockers specifically block

Answer 28

AT-1

Question 29

Give some examples of β blockers licenced for heart failure

Answer 29

Carvedilol, bisoprolol and metoprolol

Question 30

What is different about the doses of β blockers given in heart failure

Answer 30

Unlike hypertension and angina, very small doses of β blockers are given in heart failure. These doses are then gradually increased over time. This is to prevent too much inhibition of the sympathetic nervous system at the early stage which could be supporting the heart failure patients

Question 31

Below is some data from the DIG trial of digoxin in heart failure patients. Describe what this data shows

Answer 31

This data shows that digoxin doesn’t improve mortality compared to placebo patients. Both digoxin and placebo patients had a mortality of 10% after 12months. However, the right-hand graph shows that digoxin does improve hospital re-admission in patients with heart failure, results in a clear decrease in the number of patients hospitalised after treatment

Question 32

Digoxin doesnt improve mortality rates in patients with heart failure, how is it therefore used to treat these patients

Answer 32

Its used as an add-on therapy when other drugs alone aren’t sufficient

Question 33

Ivabradine is a drug that blocks the funny currents (If). What is the mechanism of action and effects of this drug in heart failure

Answer 33

Ivabradine blocks the If (funny current) channels that control the sinus node pacemaker potential. Ivabradine decreases sinus node rate and thus heart rat. It is beneficial in heart failure when β blockers haven’t slowed heart rate adequately and as such is a useful addon therapy

Question 34

When is ivabradine used

Answer 34

If patients in heart failure are on an ACE inhibitor and a β blocker and an aldosterone antagonist and their resting heart rate is still too high then this is when Ivabradine may be useful as it is suggesting that the sympathetic nervous system must still be getting through and overriding treatment. It’s also sometimes used in angina

Question 35

The combination therapy entresto is also used in heart failure. What is this drug

Answer 35

Combination of the neprilysin inhibitor (sacubitril) and the angiotensin II blocker (valsartan)

Question 36

How do patients in acute heart failure often present

Answer 36

Pulmonary oedema to the extent that it is leaving the mouth, sympathetic overdrive meaning that they are pale yet sweating profusely

Question 37

What are the treatments for acute heart failure

Answer 37

Oxygen to maximise O2 gradient across lungs. Then diamorphine, nitrates and loop diuretics

Question 38

How does the treatment for acute heart failure differ to chronic heart failure

Answer 38

Β blockers and ACE inhibitors are never used as this will likely kill the patient. These patients are almost always dependent on sympathetic stimulation to maintain them. Acute heart failure is also the only time that inotropes are used to increase the force of contraction

Question 39

What two classes of inotropes are used in acute heart failure

Answer 39

Adrenergic agonists and PDEIII inhibitors

Question 40

What is the mechanism of action of PDE III inhibitors in acute heart failure

Answer 40

PDE III inhibitors prevent the breakdown of cAMP by PDE. This acts to potentiate cAMP levels which is the main mediator of sympathetic nervous system stimulation

Question 41

Two classes of inotropic adrenergic agonists are used in acute heart failure, inoconstrictors and inodilators. What is the difference between these

Answer 41

Both drugs increase the force of contraction of the heart but whereas inoconstrictors cause vasoconstriction by acting on the α1 receptors, the inodilators causes dilation by acting on the β adrenoceptors

Question 42

Give some examples of inoconstrictors

Answer 42

Noradrenaline, epinephrine, dopamine

Question 43

Give some examples of inocdilators

Answer 43

Dobutamine, dopexamine and isoproterenol

Question 44

Below is some data from the PROMISE trial of PDE III inhibitors in acute heart failure, describe what this data shows

Answer 44

This data shows that patients treated will the PDE III inhibitor milrinone had decreased survival probability than patients who were on placebo. Hence patients on this drug were worse off than placebo

Question 45

What evidence is there that stimulation of a failure heart is the wrong course of action in heart failure

Answer 45

A trial of the PDE III inhibitor milrinone resulted in patients being worse off that on placebo. Milrinone stimulates cAMP and therefore is a sympathetic nervous system agonist. Hence simulating failing hearts with sympathetic nervous system agonists is correlated with a worse outcome for patients in heart failure