Heart failure

Effect on myocardial contractility: Digitalis glycosides are compounds with a steroid nucleus that were originally isolated from a species of foxglove (Digitalis purpura). Digoxin is the drug that is most widely used in clinical practice. Digoxin binds to the energy-dependent Na⁺ pump (Na⁺/K⁺-ATPase) in the myocyte membrane. This pump establishes and maintains the Na⁺ and K⁺ gradients across the cell (Fig. 7.4), producing low intracellular Na⁺ and high intracellular K⁺ concentrations. A separate passive transmembrane exchange of Na⁺ and Ca²⁺ occurs down their concentration gradients, with Na⁺ entering the cell while Ca²⁺ is translocated out. The rate of this exchange is dependent on the intracellular Na⁺ concentration. Digoxin partially inhibits the Na⁺/K⁺-ATPase, which increases the intracellular Na⁺ concentration. This lowers the concentration gradient for Na⁺ across the cell membrane, which in turn reduces the Na⁺/Ca²⁺ exchange so that Ca²⁺ is retained in the cell. The excess intracellular Ca²⁺ is stored in the sarcoplasmic reticulum during diastole and released during cell membrane excitation, leading to enhanced myocardial contraction.

Effects on cardiac action potential and intracardiac conduction: Digoxin can be arrhythmogenic, but also has actions that are useful for treating certain arrhythmias.

Direct actions of digoxin on the heart can provoke arrhythmias by increasing myocardial cell excitability (Ch. 8), as follows.

Digoxin also has useful indirect actions on the heart that arise from stimulation of the central vagal nucleus and enable it to be used for treating arrhythmias (Ch. 8). The vagal effects on the heart are:

 Gastrointestinal disturbances: anorexia, nausea and vomiting (largely a central effect at the chemoreceptor trigger zone; Ch. 32), and diarrhoea.

 Neurological disturbances: fatigue, malaise, confusion, vertigo, coloured vision (especially yellow halos around lights, possibly from inhibition of Na⁺/K⁺-ATPase in the cones of the retina).

 Distinctive changes on the ECG: this includes non-specific T-wave changes and sagging of the S–T segment with an upright T-wave (‘reverse tick’) often referred to as ‘digoxin effect’. These ECG effects do not indicate toxicity, but can be mistaken for myocardial ischaemia.

 Consequences of intracellular Ca²⁺ overload: increased excitability of the atrioventricular node and Purkinje fibres produces atrial or nodal ectopic beats, atrial or nodal tachycardia, ventricular ectopic beats or (less commonly) ventricular tachycardia.

 Consequences of increased vagal activity: excessive atrioventricular nodal block (‘heart block’) can occur. When associated with increased atrial excitability, this produces atrial tachycardia with atrioventricular nodal block, a rhythm characteristic of digitalis toxicity.

 Gynaecomastia: during long-term treatment the steroid structure allows digitalis glycosides to bind to, and stimulate oestrogen receptors in breast tissue.

 Hypokalaemia: reduced extracellular K⁺ concentration increases the effects of digitalis glycosides on the Na⁺/K⁺-ATPase pump. Care must be taken if potassium-losing diuretics, such as furosemide (Ch. 14), are used with digitalis glycosides.

 Renal impairment: reduces the excretion of digoxin.

 Hypoxaemia: this sensitises the heart to digitalis glycoside-induced arrhythmias.

 Hypothyroidism: the renal elimination of digoxin is decreased because of a reduced glomerular filtration rate.

 Drugs that displace digoxin from tissue binding sites and interfere with its renal excretion: these include verapamil (Ch. 5) and quinidine (Ch. 8), which can double the plasma concentration of digoxin. Amiodarone (Ch. 8) produces a less marked effect.

 withholding further doses of digitalis glycoside,

 using K⁺ supplementation (Ch. 14) for hypokalaemia. This is usually given orally, but should be given by slow intravenous infusion if there are dangerous arrhythmias,

 using atropine (Ch. 8) for sinus bradycardia or atrioventricular block. Temporary transvenous pacing is used for marked bradycardia unresponsive to atropine,

 digoxin-specific antibody fragments for serious digoxin toxicity (Ch. 53).

 At low doses, it selectively stimulates peripheral dopamine receptors, which are structurally distinct from those in the central nervous system. This produces renal arterial vasodilation and diuresis (D₁ receptors) and peripheral arterial vasodilation (D₂ presynaptic receptors, which inhibit noradrenaline release from sympathetic nerves).

 At moderate doses, non-selective β-adrenoceptor stimulation produces a positive inotropic response (Fig. 7.5). Tachycardia is more marked than with dobutamine, because of stimulation of both cardiac β₁- and β₂-adrenoceptors and the reflex response to β₂-adrenoceptor-mediated peripheral arterial dilation.

 At high doses, α₁-adrenoceptor stimulation produces peripheral vasoconstriction, which also affects the renal arteries and overcomes D₁-receptor-mediated renal vasodilation.

 Excessive cardiac stimulation, with tachycardia, palpitations and arrhythmias.

 Nausea, vomiting.

 Chest pain, dyspnoea.

 Headache.

 These are mainly a consequence of excessive cardiac stimulation, and include ectopic beats and both ventricular and supraventricular arrhythmias.

 Nausea, vomiting, diarrhoea (milrinone).

 Headache.

 Long-term oral use increases mortality in heart failure. Oral use has therefore been abandoned.

 Weight reduction should be encouraged for an obese person; this improves exercise tolerance.

 Bed rest may be appropriate to rest the heart during acute episodes of fluid retention.

 Modest salt restriction is desirable (severe salt restriction is unpleasant and unnecessary).

 Fluid restriction is rarely required unless profound hyponatraemia accompanies severe oedema. In this situation, diuretics may be ineffective until the plasma Na⁺ concentration is corrected.

 If possible, drugs that exacerbate heart failure by producing myocardial depression (e.g. most calcium channel blockers) or by promoting fluid retention (e.g. non-steroidal anti-inflammatory drugs) should be withdrawn. Beta-adrenoceptor antagonists can cause myocardial depression, but should not be stopped, although a high dose may need to be reduced. Alcohol intake should be moderate at most, since alcohol depresses myocardial contractility and can be arrhythmogenic.

 A graded exercise programme for people with stable heart failure can improve symptoms.

1. When blood pressure falls, sympathetic outflow increases because of an increase in the sensory input from the baroreceptors in the carotid sinus.

2. In the healthy heart, a rise in afterload increases myocardial contractility.

3. Breathlessness and fatigue are common symptoms of heart failure.

4. Pulmonary oedema occurs when the hydrostatic pressure in the pulmonary veins is less than the plasma osmotic pressure.

5. In severe heart failure the attempts of the body to compensate for the cardiac dysfunction are detrimental.

6. Digoxin is the mainstay of the treatment of heart failure.

7. Digoxin inhibits the Na⁺/K⁺-ATPase pump on the cardiac myocyte membrane.

8. Hypokalaemia reduces the action of digoxin on the Na⁺/K⁺-ATPase pump.

9. Digoxin inhibits the vagus, decreasing the refractory period of the atrioventricular node.

10. Dobutamine produces peripheral vasodilation by its effect on β₂-adrenoceptors.

11. Sustained infusion of dobutamine desensitises the receptor response.

12. Milrinone is given intravenously to improve tissue perfusion in cardiogenic shock.

13. Angiotensin-converting enzyme (ACE) inhibitors should not be given together with K⁺-sparing diuretics.

14. ACE inhibitors may cause cough by reducing the synthesis of bradykinin.

15. β-Adrenoceptor antagonists improve survival in chronic heart failure.

16. Hydralazine is a vasodilator with a predominant action on arteries.

A At low doses dopamine produces diuresis.

B Effects of dopamine vary widely among individuals.

C At moderate doses dopamine produces marked tachycardia.

D At moderate doses dopamine is a selective β₁-adrenoceptor agonist.

E At high doses dopamine produces renal arterial vasoconstriction.

A What are the choices of diuretic open to you in treating Mr DY?

B Potassium loss produced by diuretics may lead to hypokalaemia. What is an effective way of reducing urinary K⁺ loss?

C Mr DY was then started on an ACE inhibitor. What precautionary measures should be taken in starting this new medication?

D Could long-term oral digoxin be used as part of the treatment for Mr DY?

E Could the use of a β-adrenoceptor antagonist make Mr DY's condition worse?

1. False. A falling blood pressure reduces the baroreceptor reflex input to the vasomotor centre, resulting in increased sympathetic outflow.

2. True. A rise in afterload decreases stroke volume initially but the consequent sympathetic stimulation increases contractility in the healthy heart and restores the stroke volume. In the failing heart, contractility increases less readily and stroke volume falls.

3. True. The breathlessness is caused by increased pulmonary venous pressure leading to pulmonary oedema; fatigue is caused by reduced cardiac output and impaired perfusion of skeletal muscle.

4. False. Oedema occurs when the net hydrostatic pressure, which moves fluid out of the vessel, is greater than the the plasma osmotic pressure, which moves interstitial fluid into the vessel.

5. True. The fall in cardiac output activates the sympathetic nervous system and the renin–angiotensin-aldosterone system; these changes are appropriate to restore blood pressure in the event of haemorrhage, but are unhelpful in severe heart failure as they increase preload, afterload and heart rate, hence increasing the workload of the failing heart.

6. False. Digoxin may be of benefit but the mainstay of treatment is a diuretic such as furosemide and an ACE inhibitor (or angiotensin II receptor antagonist). If diuretics are given concurrently with digoxin, a K⁺-sparing diuretic such as spironolactone may also be required to prevent hypokalaemia; hypokalaemia increases the risk of digoxin-induced rhythm disturbances.

7. True. By blocking the Na⁺/K⁺-ATPase pump, cellular export of Na⁺ is reduced and intracellular Na⁺ concentrations rise. The reduced Na⁺ concentration gradient across the cell membrane reduces the linked export of Ca²⁺ ions. Increased intracellular Ca²⁺ concentrations enhance contractility.

8. False. Potassium ions and digoxin compete for the pump, so hypokalaemia can increase the activity and pro-arrhythmic risk of digoxin.

9. False. As well as its direct effects on the heart, digoxin increases vagal outflow from the vasomotor centre. This increases the refractory period of the atrioventricular node and is the reason why digoxin is useful in some arrhythmias, such as atrial fibrillation.

10. False. Dobutamine is a selective β₁-adrenoceptor agonist and does not produce peripheral vasodilation.

11. True. Stimulation of β₁-adrenoceptors by dobutamine results in cAMP synthesis and increased cardiac contractility. Prolonged stimulation (48–72 h) desensitises the receptors; this does not occur with phosphodiesterase type 3 inhibitors, such as milrinone, which bypass the receptor and raise levels of cAMP by blocking its breakdown.

12. True. Milrinone inhibits the breakdown of intracellular cAMP by phosphodiesterase type 3 in cardiac and vascular smooth muscle, resulting in an inotropic effect and peripheral vasodilation; it is used in patients with cardiogenic shock not responding to full doses of dobutamine.

13. False. The combination of an ACE inhibitor and spironolactone provides additive clinical benefit but care must be taken to avoid dangerous hyperkalaemia, with regular monitoring of the plasma K⁺ concentration. This is because ACE inhibitors reduce aldosterone-dependent reabsorption of Na⁺ in the collecting duct. As Na⁺ reabsorption at this site occurs in exchange for K⁺ efflux, ACE inhibitors may increase K⁺ retention, particularly in combination with potassium-sparing diuretics.

14. False. ACE inhibitors reduce the breakdown of bradykinin by ACE (also known as kininase II); increased bradykinin levels in the lungs are thought to be responsible for the cough seen in some patients receiving ACE inhibitors. An alternative strategy is to use an angiotensin II receptor antagonist.

15. True. Beta-adrenoceptor antagonists, ACE inhibitors and spironolactone improve survival in chronic heart failure, possibly by reducing the cardiac remodelling effects of catecholamines, angiotensin II and aldosterone respectively.

16. True. Hydralazine is predominantly an arterial vasodilator, while isosorbide mononitrate mainly acts as a venodilator; their combined use may be effective in chronic heart failure in people intolerant to ACE inhibitors or angiotensin II receptor antagonists.

A The treatment of first choice for fluid retention in chronic heart failure is a diuretic. For mild symptoms, a thiazide diuretic may be adequate, but in most people a loop diuretic such as furosemide is used. The loss of renal function in the elderly and renal underperfusion in heart failure means that thiazide diuretics are less effective in older people with this condition, such as Mr DY.

B Hypokalaemia is arrhythmogenic and should be avoided in people with heart failure, particularly those taking digoxin. Urinary K⁺ loss caused by a loop diuretic or thiazide can be reduced by combination with a K⁺-sparing diuretic such as amiloride or spironolactone. Amiloride directly blocks epithelial Na⁺/K⁺ exchange in the collecting duct. In severe heart failure, spironolactone, which competes with aldosterone for the mineralocorticoid receptor, also improves prognosis, possibly by blocking aldosterone-dependent cardiac remodelling.

C ACE inhibitors reduce preload and afterload by reducing the production of angiotensin II, a powerful vasoconstrictor, and by reducing blood volume (via reduced aldosterone production). They also slow the progression of heart failure and improve survival. There is a small risk of severe hypotension following the first dose, and omission of the diuretic immediately prior to this may be helpful.

D The place of digoxin is well established in heart failure associated with atrial fibrillation and a rapid ventricular rate, but the benefit of a low dose of digoxin is now established in heart failure with severe left ventricular systolic dysfunction and sinus rhythm, when combined with a diuretic and an ACE inhibitor.

E β-Adrenoceptor antagonists used injudiciously may worsen heart failure by reducing cardiac output, but low doses are beneficial (see Box 7.2), provided the patient's condition has been stabilised with diuretics and an ACE inhibitor.