HEART FAILURE

Summary Rational treatment of heart failure involves the use of a combination of drugs in an attempt to reverse the detrimental effects of compensatory processes which are set in motion by the body in response to a failing heart. This review covers the aetiology and principles of treatment of patients with mild to severe heart failure. Introduction Heart failure is the commonest reason for admission to a medical ward. It presents with a history of dyspnoea and fatigue, especially on exercise, in combination with fluid retention such as ankle swelling. Confirmation is obtained by examination and special investigations such as chest X ray (increased cardiac size and plethoric lung fields), echocardiography (poor left ventricular function) and ECG (ischaemia and dysrhythmias). There are more than 100,000 new cases per year in the UK (1) and the management of heart failure accounts for more than 1 % of the entire UK health care budget. Despite better treatment of many of the risk factors for coronary disease the prevalence of heart failure continues to rise. The ageing population accounts for about half of the observed increase. Causes and classification of cardiovascular failure

Cardiovascular failure may be defined as a pathological state in which the tissues are insufficiently perfused in relation to their metabolic needs due to inadequate cardiovascular function and may be divided into various types: Depression of myocardial contraction. This may be acute, chronic or acute on chronic and is detected clinically by a reduction in ejection fraction at normal arterial pressures. Left ventricular failure. Interference with left ventricular function leads to a raised left ventricular end-diastolic pressure, raised pulmonary venous pressure and pulmonary oedema. It can be due to depression of myocardial contraction, to excessive afterload (systemic vascular resistance, SVR) or to extremes of heart rate. Right ventricular failure.

Interference with right ventricular function leads to raised right ventricular systolic and enddiastolic pressures and central venous pressure with normal pulmonary capillary wedge and left

atrial pressures.
The congestive syndrome.

This is caused by excessive activation of the plasma renin-angiotensin-aldosterone axis (RAAA) which leads to sodium and water retention by the kidneys. It results in a raised SVR, raised blood volume, oedema and increased extracellular fluid volume and exchangeable sodium. Congestive cardiac failure.

This is the congestive syndrome caused by heart disease. Circulatory failure.

This occurs when the circulation is unable to supply the tissues with a blood flow to match its metabolic demands. It is characterised by an increase in the difference between the oxygen content of arterial and mixed venous blood (A-V02 diff.). It may be caused by primary cardiovascular failure, hypovolaemia or a combination of the two. Pathophysiology Cardiac failure may result either from primary myocardial dysfunction (ischaemic heart disease, valvular disease, dysrhythmias) or secondary to other disease processes or treatment. Secondary myocardial dysfunction is probably more common in a general intensive care unit and may be specific to either the left or right ventricle or affect both. Hypoxia, sepsis, metabolic derangement and electrolyte imbalance cause global myocardial dysfunction as do negative inotropic drugs such as sedatives and beta blockers. Specific ventricular dysfunction is seen with acute changes in the preload or afterload occurring in either ventricle. Preload is the major determinant of left ventricle ejection fraction (LVEF) whereas right ventricular ejection fraction (RVEF) is mainly determined by afterload (i.e. pulmonary vascular resistance, PVR).

Myocardial dysfunction is compensated for by both neurohormonal and haemodynamic changes in order to maintain cardiac output and peripheral perfusion. It is only when these compensatory processes are overwhelmed that heart failure occurs. A decrease in the ability to empty the ventricle during systole increases diastolic tension (preload). The ventricle responds by enhancing its contraction (the Frank-Starling principle). There is also stimulation of beta adrenergic receptors increasing both the force and frequency of contraction. These two mechanisms rely on intracellular calcium dependant pathways (2) which although providing inotropic support for the failing heart also increase the stress on the heart wall during

diastole. Since heart rate, contractile status and left ventricular wall stress are the major determinants of mycocardial oxygen consumption the compensatory processes all conspire to increase the oxygen demand/supply ratio thus producing further myocardial damage. Increased diastolic wall stress triggers the synthesis of myofibrillar proteins. The resulting cardiac hypertrophy reduces stress (stress is proportional to radius divided by wall thickness) and lessens the energy expenditure of the heart. Unfortunately endocardial blood supply is reduced by myocardial hypertrophy leading to endocardial ischaemia and an increased propensity to dysrhythmias. Increased atrial stretch resulting from an increase in diastolic wall tension will inhibit sympathetic outflow from the vasomotor centre and leads to secretion of atrial natriuretic peptide, which inhibits the release of noradrenaline and its actions on peripheral blood vessels (3). The peptide also exerts direct vasodilator and natriuretic effects that reduce the haemodynamic load on the heart.

Long term activation of these mechanisms results in a reduction of their favourable acute physiological effects. There is a reduction in the ability of atrial baroreceptors to inhibit sympathetic outflow and a depletion of natriuretic peptides. Ventricular dilatation progresses, the sympathetic nervous system becomes persistently activated, and heart failure begins.

The myocardium then becomes more dependent on endogenous inotropic processes to maintain cardiac function but as failure progresses the ability of the heart to respond to the positive inotropic effects of catecholamines is diminished. This is the result of the down regulation of beta receptors and the uncoupling of beta receptors from their effector enzyme, adenyl cyclase (4). Function is further compromised because the failing heart loses its capacity to respond to increases in afterload. Sympathetic activity and activation of the RAAA will result in peripheral vasoconstriction, increasing the afterload, with further detrimental effects on the heart. The effects of these vasoconstrictor factors, including vasopressin and endothelin (5), are opposed locally by endogenous vasodilators, including atrial natriuretic peptide and nitric oxide. In heart failure the effects of these vasodilators are diminished and vasoconstriction is unopposed.

Sodium and water reabsorption (6) resulting from RAAA activation are normally offset by atrial

natriuretic peptide, but patients with heart failure have a diminished response to this peptide (7). Treatment This may be subdivided into the management of the underlying condition and the specific treatment of the sodium retention, peripheral vasoconstriction and reduced cardiac contractility. Primary causes of myocardial dysfunction include severe coronary artery stenosis, which may be corrected surgically, and there are a variety of secondary causes, many of which are common in patients treated in an intensive care unit. These include hypoxia, dysrhythmias, sepsis and severe metabolic and electrolyte disturbances, and should be aggressively treated. Treatment of Sodium retention: Diuretics These are the first line treatment of cardiovascular failure and work by inhibiting sodium and chloride reabsorption at specific sites in the renal tubules. There are two classes of agents, those that act on the loop of Henl and those that act on the distal tubule. Drugs acting on the loop of Henl, including frusemide and bumetanide, increase the fractional excretion of sodium and retain their effectiveness when the glomerular filtration rate (GFR) is low. Thiazides and potassium sparing diuretics act on the distal tubule, increasing the fractional excretion of sodium by 5-10%. They are less effective than the loop diuretics when the GFR is low. Diuretics are beneficial in patients with pulmonary or peripheral congestion, rapidly relieving dyspnoea and oedema, and their natriuretic action may enhance the responsiveness of peripheral blood vessels to direct acting vasodilators and angiotensin converting enzyme (ACE) inhibitors (8). However, long-term treatment with diuretics alone in chronic heart failure is ineffective and associated with potassium depletion which may predispose to dysrhythmias. They increase RAAA activity (9) and attenuate the haemodynamic effects and potentiates the potassium losing effects of these drugs. These effects may be countered by ACE inhibitors. These adverse metabolic effects have prompted attempts to develop diuretics that suppress plasma renin excretion. One group of experimental drugs, the atriopeptidase inhibitors (10), inhibit the enzyme that degrades atrial natriuretic peptide. The increased levels of natriuretic peptide promote sodium excretion and suppress renin activity.

Treatment of peripheral vasoconstriction

Angiotensin converting enzyme (ACE) inhibitors ACE inhibitors act on the neurohormonal mechanisms of heart failure by inhibiting angiotensin converting enzyme, which is responsible for converting angiotensin I to angiotensin II. Angiotensin II is a potent vasoconstrictor and, by releasing aldosterone, causes sodium retention (see earlier). It is also directly toxic to myocardial cells (15). This same enzyme is responsible for degradation of bradykinin. Levels thus increase further enhancing vasodilation. ACE inhibitors have been shown to produce symptomatic improvement and extend life in patients with heart failure (16). Guidelines for use include stopping other diuretics for 24 hours prior to the first dose and making sure that the patient sits or lies down for up to four hours after the first dose is administered. Diuretics are then

restarted. Adverse effects include hypotension, renal dysfunction, hypokalaemia and cough, the combination of which may force discontinuation of the drug (17). The combination of diuretics and ACE inhibitors are the mainstay of treatment of cardiovascular failure in the ambulant patient. Angiotensin II antagonists do not produce cough but otherwise are similar in their actions to ACE inhibitors. Unlike ACE inhibitors their beneficial effects on long term survival have not been substantiated to the same degree. Vasodilators Where ACE inhibitors are not tolerated, direct acting vasodilators are employed which relax vascular smooth muscle at specific sites in the peripheral circulation. Nitrates act mainly on peripheral veins. Hydrallazine, minoxidil and calcium-channel blockers act predominantly on peripheral arteries and sodium nitroprusside and flosequinan have actions on both venous and arterial vessels. Some of these vasodilators also have inotropic effects. Hydrallzine and flosequinan (now withdrawn following increased mortality in some studies) increase contractility and calciumchannel blockers (e.g. nifedipine) are negative inotropes. They all produce favourable haemodynamic effects in acute situations. Their long term use in the treatment of chronic heart failure has shown conflicting results (11, 12) and patients treated with calcium-channel blockers had a greater risk of worsening heart failure and cardiovascular death than those not treated with these drugs. These poor clinical results may be due to exacerbation of the neurohormonal activation which occurs in heart failure. Both nitrates and hydrallazine increase activity of the RAAA and the sympathetic nervous system. Treatment of reduced contractility Positive Inotropic Agents

These drugs reduce ventricular wall stress by augmenting the contractility of the failing heart. The enhanced contractility is dependant on an increase in intracellular calcium, which may be achieved by several mechanisms, or increased sensitisation of the contractile proteins to calcium. Intracellular calcium may be increased by: Inhibition of sarcolemmal sodium/potassium ATP ase (Na/K ATP ase): Digoxin Digoxin, a cardiac glycoside, acts by inhibition of Na/K ATP ase at the sarcolemma. This diverts the removal of intracellular sodium to a sodium-calcium exchange pump, leading to an increase in intracellular calcium. This accounts for its positive inotropic action. It also has favourable neurohormonal effects in heart failure reducing activation of both the sympathetic nervous system

and the renin-angiotensin system (18). Long term treatment with digoxin reduces symptoms and decreases the risk of clinical deterioration in heart failure even in the absence of atrial fibrillation (17). Stimulation of beta adrenergic receptors: catecholamines and other inotropes

These drugs act by indirectly activating adenyl cyclase, resulting in increased levels of cyclic adenosine monophosphate (cAMP). Both beta adrenergic stimulation and phosphodiesterase inhibition increase levels of cAMP, an intracellular secondary messenger that promotes protein phosphorylation through activation of intracellular protein kinases. These phosphorylated proteins enhance calcium influx, release and uptake thus promoting both myocardial contraction and relaxation. Many different catecholamines have been used in the treatment of heart failure. Their actions differ depending on the degree of stimulation of alpha and beta adrenergic receptors and dopaminergic receptors. Their use is limited by their side effects, particularly increased myocardial oxygen demand, peripheral vasoconstriction and the development of tachydysrhythmias, and tachyphylaxis. Intravenous dobutamine administration exhibits evidence of tachyphylaxis within 3 days, probably due to down regulation of beta receptors (19). These side effects will depend on the affinity of the drug for a particular type of adrenergic receptor. Dopexamine, by stimulating prejunctional dopaminergic receptors, inhibits the release of noradrenaline, thereby producing vasodilatation, a beneficial effect in treating heart failure. These drugs are increasingly being used in combination to achieve a desirable effect in the treatment of acute failure but there does not appear to be any benefit from their chronic use (20).

Xamoterol is an orally active partial beta receptor agonist of moderate efficacy lying mid way between true beta blockers such as propranolol and full agonists such as isoprenaline. Low efficacy partial beta agonists such as practolol are more aptly classified as beta blockers as it is only in exceptional circumstances of extremely low underlying sympathetic activity (USA) that their partial agonist (intrinsic sympathomimetic) activity is demonstrable. Being of moderate efficacy, xamoterol demonstrates agonist activity even when USA is moderate, as in mild cardiovascular failure, and thus can provide rational treatment. However, when USA is high as in moderately severe to severe

cardiovascular failure it acts as an antagonist (beta blocker) and acutely makes failure worse (17). It is not widely used due to the difficulty in predicting which patients will benefit. Beta blockers are being increasingly used in carefully selected patients with mild to moderate heart failure. Inhibition of phosphodiesterase resulting in accumulation of (cAMP) Five isoenzymes of phosphodiesterase (PDE) have been identified (21). Non-specific PDE inhibitors such as the methylxanthines inhibit all the isoenzymes. They improve myocardial performance at the expense of increased myocardial oxygen consumption and achieve no beneficial effects in patients with cardiac failure (22). Specific PDE inhibitors that act on the isoenzyme present in cardiac and vascular smooth muscle (PDE III) include milrinone and enoximone. The positive inotropic effect of enoximone is dose related and it potentiates the response to adrenaline (23). It is also a directly acting vasodilator, reducing both preload and afterload. Direct i.v. injections of enoximone can significantly increase the cardiac index in critically ill patients treated by adrenergic agents for severe heart failure. The administration of small doses of enoximone is effective and has minimal effect on arterial pressure (24). However, in chronic heart failure there is seemingly no benefit versus placebo (25). Both sulmazol and pimobendan increase the sensitivity of the contractile proteins to calcium and they also act as phosphodiesterase inhibitors. Pimobendan has been shown to have beneficial effects in patients with heart failure, including increased cardiac and stroke volume indices, increased exercise tolerance, and decreased right atrial pressures and catecholamine concentrations. These favourable effects were maintained after one month of treatment (26). Conclusion Following diagnosis, the treatment of heart failure demands a rationale use of a combination of drugs which are used to try and reverse the detrimental effects of compensatory processes which are set in motion by cardiovascular failure. This review has covered the pathophysiology and the drug treatment of patients with mild failure right up to those patients who may require admission to a critical care unit where intensive invasive monitoring becomes necessary. References 1. Cleland JGF, Oldershaw P, Lough M et al. Health gain in heart failure. Submission to the Department of Health. 1993.

2. Kentish JC, ter Kairs KEDJ, Ricciardi L et al. Comparison between the sarcomere length-force relation of intact and skinned trabeculae from rat right ventricle. Circ Res 1986; 58:755-68.

3. Floras JS. Sympathoinhibitory effects of atrial natriuretic factor in normal humans. Circulation 1990;81:1860-73. 4. Bristow MR, Hershberger RE, Port JD et al. b adrenergic pathways in nonfailing and failing human ventricular myocardium. Circulation 1990; 82: (suppl 1) 12-25.

5. Margulies KB, Hildebrand FL, Lerman A et al. Increased endothelin in experienced heart failure. Circulation 1990; 82:2226-30.

6. Eiskjaer H, Bagger JP, Danielsen H et al. Mechanisms of sodium retention in heart failure: relation to the renin-angiotensin-aldosterone system. Am J Physiol 1991; 260:F883-89. 7. Cody RJ, Atlas SA, Laragh JH et al. Atrial natriuretic factor in normal subjects and heart failure patients: plasma levels and renal, hormonal and haemodynamic responses to peptide infusion. J Clin Invest 1986; 78:1362-74.

8. Sinoway L, Minotti J, Musch T et al. Enhanced metabolic vasodilation secondary to diuretic therapy in decompensated congestive heart failure secondary to coronary heart disease. Am J Cardiol 1987;60:107-11.

9. Francis GS, Benedict C, Johnstone DE et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive cardiac failure. Circulation 1990; 82:1724-29. 10. Northridge DB, Jardine AG, Finley IN et al. Inhibition of the metabolism of atrial natriuretic factor causes diuresis and natriuresis in chronic heart failure. Am J Hypertension 1990; 3:682-87.

11. Cohn JN, Johnson G, Zeische S et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325:303-10.

12. Cohn JN, Archibald DG, Zeische S et al. Effect of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans Administration Cooperative Study. N Engl J Med 1986;314:1547-52.

13. Lang D, Lewis MJ. The effects of flosequinan on endothelin induced changes in inositol 1, 4, 5triphosphate levels and protein kinase C activity in rat aorta. Eur J Pharmacol 1992; 226:259-64. 14. Haas GJ, Binkley PE, Leier CV. Chronic vasodilator therapy with flosequinan in congestive cardiac failure. Clin Cardiol 1990; 13:414-20.

15. Tan LB, Jalil JR, Pick R et al. Cardiac myocyte necrosis induced by angiotensin II. Circ Res 1991;69:1185-95.

16. The SOLVD Investigators. Effects of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325:293-302. 17. Dargie HJ, McMurray JJV. Diagnosis and management of heart failure. Br Med J 1994 308 321328

18. Ferguson DW, Berg WJ, Sanders JS et al. Sympathoinhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordings. Circulation 1989; 80:65-77.

19. Unverferth DV, Blanfort M, Kates PE et al. Tolerance to dobutamine after a 72 hour continuous infusion. Am J Med 1980; 69:262-6. 20. Weber KT, Gill SK, Janicki JS et al. Newer positive inotropic agents in the treatment of chronic cardiac failure: current status and future directions. Drugs 1987; 33:503-19.

21. Skoyles JR, Sherry KM. Pharmacology, mechanisms of action and uses of selective phosphodiesterase inhibitors. Br J Anaes 1992; 68:293-302.

22. Chatterjee K. Mechanisms of action of inotropic agents in heart failure. In: Perret C, Vincent JL, eds. Update in Intensive Care and Emergency Medicine 6. Acute Heart Failure. Springer-verlag, Berlin. 1989; 213-33. 23. Latimer MD, Latimer RD, Oduro A. The inotropic effects of enoximone and its potentiation of adrenoreceptor agonists. J Cardiothorac Anaesth 1989; 3(Suppl 1):9.

24. Vincent JL. Leon M. Berre J. Melot C. Kahn RJ. Addition of enoximone to adrenergic agents in the management of severe heart failure. Crit Care Med 1992 20:1102-1106. 25. Uretsky BF, Jessup M, Konstam MA, Dec GW, Leier CV, Benotti J et al. Multicenter trial of oral enoximone in patients with moderate to moderately severe heart failure. Lack of benefit compared to placebo. Circulation 1990; 82: 774-780

26. Renard M, Walter M, Liebens I et al. Pimobendan in chronic congestive heart failure. Chest 1988;93:1159-64.