The push, the pull and the periphery

Celia M . Oakley Professor of Clinical Cardiology and Direcror of Cardiology, Dcparrnienr of Medicine (Clinical Cardiolog.vJ, Ilammersmirh tiospital and The Royal Postgradriare hfcdical School, Londivi, UK.

Abstract: If the failing left ventricle could be given an effective push, other approaches to the treatment of heart failure would not be needed. W e have inotropes only for short-term parenteral use. W e have no safe inotrope for chronic oral use. The effect of digitalis is only feeble and the phosphodiesterase inhibitors seem to increase mortality from sudden death. Diurerics are dramatic for acute pulmonary oedema and the mainstay for chronic fluid retention bur do not improve thc p u m p and by reducing blood volume stimulate the renin angiotensin system leading to vasoconstriction, further fluid retention and hypokalaemia. Nitrates drop pre-load wirhout reducing blood volume but tolerance is a problem and stroke volume does not increase. Reduction of afterload helps the failing ventricle to empty, the pull and output increases. The angiotensin converting enzyme inhibirors (ACEI) are now the cornerstone of heart failure treatment, reducing mortality in severe heart failure ( C O N S E N S U S ) and superior to standard vasodilator therapy (V-HeFT-2) at improving the survival of patients with mild to moderate heart failure. A C E I can reduce the incidence of ventricular ectopy and probably do this through improving left ventricular junction, from decreasing sympathetic tone, reducing myocardial oxygen demand or increasing serum potassium but A C E I did not diminish the incidence of sudden death in the SOL VD trial despite reducing mortality. Disappointingly little improvement in exercise tolerance and persistence of chronic fatigue in heart failure concentrated attention on the periphery. That the changes found in skeletal muscles are consequent upon the combination of inability to increase perjlision on exercise together with the effects of chronic inactivity are beyond question (though it has been suggested otherwise). Retraining by suitable daily exercise has been shown to improve exercise tolerance in chronic stable heart failure with ~eStOratlOnof lost oxidative fast muscle fibres and capillary network. Rest is no longer the order of the day. (Aust N Z J Med 1992; 22: 587-591.) Key words: Hear! failure, inorropes, diurerics, ACE inhibirors.

INTRODUCTION ardiac failure occurs when the output of the heart is inadequate for the needs of exercise and this is usually associated with abnormally raised filling pressures. Usually one or both ventricles are dilated and poorly contracting, systolic failure, but sometimes the failure results from inability to accept the stroke input except at a great rise in filling pressure, diastolic failure. When the fault is in the myocardium its failure

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usually cannot be corrected but attention is paid to precipitating factors and to correction of heart rate and rhythm. Constrictive pericarditis is a pure example of a non-myocardial diastolic failure which must not be missed as it can be cured by pericardiectomy. Systolic pump failure caused by a toxin such as alcohol may prove reversible with abstinence and cardiomyopathy associated with parturition may also resolve. Congestive heart failure is one of the most

Correspondence ro: Professor M . Oakley, Deparrment of Medicine (Clinical Cardiology), Hammersmith Hospital and The Royal Postgraduate Medical School, I.ondon, W12, ONN, UK. HEART FAILURE TREATMENT

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pressing therapeutic challenges. It has become the most common hospital discharge diagnosis in patients over the age of 65 and still carries a dismal prognosis with a nearly 50% one year mortality in severely symptomatic patients despite striking advances in therapy.' It goes without saying that. if there were an agent which increased contractile force, corrected abnormal left ventricular geometry and myocyte slippage and restored normal diastolic compliance there would be no need for diuretics, vasodilators or Angiotensin converting enzyme (ACE) inhibitors. Because there is no such agent, modern therapy is based on counteraction of enhanced neurohormonal activity and manipulation of the peripheral circulation. The heart and its environs are both abnormal but because there is little to be done for the diseased heart concentration has been on the abnormal environs resulting from it, easing its load with vicarious benefit.

INOTROPES- 'THE PUSH' Digitalis is dramatically successful in improving clinical heart failure when this is associated with the onset of atrial fibrillation and there is still complete agreement that it is the agent of first choice for the control of ventricular rate in patients with chronic atrial fibrillation. Although digitalis folia was introduced 21 5 years ago, controversy has continued over whether it is beneficial to patients who are in heart failure in sinus rhythm. Exercise intolerance in patients with myocardial failure may be related mainly to abnormalities of either systolic or diastolic function and the reason for the continuing discussion has been that the various trials have included all sorts of patients with widely differing conditions. The results of these earlier trials were inconclusive but recent studies have shown unequivocally that digitalis increases the inotropic state and improves contractile force in patients with chronic systolic failure, who have dilated ventricles and who are in sinus rhythm.'-9 Haemodynamic indices and symptoms improved and in placebo controlled studies the benefit was shown to be maintained.5-8 T h e improvement is lost if the drug is withdrawn and re-established if it is Digitalis is not beneficial in patients with hypertrophied hearts and diastolic failure." This group includes patients with hypertension and aortic stenosis but it also includes many old people with heart failure who are the main recipients of prescriptions for the drug. Old hearts become stiff and failure is frequently mainly diastolic. When heart failure in the elderly is associated with atrial fibrillation digitalis is required for control of the ventricular rate even though it may not improve ventricular function but old people who are still in sinus rhythm often have well maintained systolic function and do not need the 588 Aust N Z J Med 1992; 22

drug. Many are not even in heart failure and they are most at risk from toxicity. Neither digitalis nor diuretics have ever been shown to improve prognosis in heart failure. T h e benefits of modern diuretics are so striking that it has never been justified to mount a trial. We have effective inotropes for short-term parenteral use. Both natural and synthetic catecholamines act on the beta-adrenergic receptor,'" but they do not produce sustained haemodynamic benefits, they are arrhythmogenic and may increase mortality in long-term use. The phosphodiesterase inhibitors which mediate positive inotropy and peripheral vasodilatation by increasing intracellular cyclic AMP were introduced as so-called 'inodilators' but have also proved disappointing in chronic oral use." The first of these, amrinone, was highly toxic. The second, milrinone, remained controversial but in a number of trials mortality seemed to be increased in milrinone treated patients even though some patients appeared to benefit. Moreover, in one trial milrinone was shown to produce less increase in ejection fraction than digoxin and no greater improvement in exercise tolerance.' When enoximone was introduced it was hoped that it would prove to be safer and less toxic but sadly, it too has been shown to cause increased mortality in treated patients despite anecdotal evidence of continued individual benefit" and the oral drug has now been withdrawn. Used acutely parenterally, both milrinone and enoximone usually cause an improvement in measured output associated with fall in left ventricular filling pressure. Intravenous enoximone may even prove preferential to the long used combination of dobutamine or adrenaline plus renal doses of dopamine in the treatment of the (now rare) post-operative cardiac patient with a temporary low output state after revascularisation as well as in rescue of Class IV patients awaiting transplantation.

DIURETICS, VASODILATORS AND ACE INHIBITORS 'THE PULL' Thiazides and then loop diuretics were a tremendous advance on mercurials. They are very efficient at reducing ventricular filling pressures and removing the clinical evidence of heart failure. By relieving acute pulmonary oedema they save lives. Intravenous frusemide has a venodilator action which is why relief of pulmonary oedema precedes the onset of a diuresis. T h e development of venodilators logically followed on from observation of the benefits of venesection, leeches and then of venous cuffing in relieving pulmonary oedema and congestive heart failure. The archetypal venodilators are the nitrates which have in many ways similar action to the

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H E A R T FAILURE T R E A T M E N T

diuretics in reducing venous filling pressure without improving cardiac output but with the advantage of not reducing circulating blood volume. Their other disadvantages of headache and the rapid development of tolerance are well known. T h e realisation that systemic vascular resistance is considerably increased in heart failure led to the suggestion of arterial vasodilators to reduce left ventricular work. Their introduction was predicated in the 1950s but had a stuttering start first with a ganglion blocking agent followed by phentolamine and then by nitroprusside." Only in the late 1970s did they come into more regular use with hydralazine (later coupled with nitrates) and prazosin to reduce both pre- and after-load in chronic heart failure but the effects on symptoms and on exercise performance were disappointing.13 T h e V-Heft I study was the first to show improvement in survival of in NYHA Class 11-111 heart failure patients treated with hydralazine plus nitrates but the benefit was very modest and 30% of patients withdrew because of side effect^.'^ Clinically, initial improvement in patients treated with vasodilators tended to be transient and an increase in effort tolerance was not able to be shown compared with patients treated only with digoxin and diuretics. The reason for this ill-sustained benefit was soon shown. Diuretics are unequivocally beneficial but they adversely reduce blood volume and renal blood flow stimulating an already activated renin antiotensin system. This leads to further vasoconstriction and water and salt retention, the components of heart failure which they had been given to counteract. Afterload reducing agents by reducing blood pressure (BP) further intensify angiotensin production and vasoconstriction again opposing the action for which they had originally been prescribed.'s T h e development of the first ACE inhibitor, captopril, ten years ago was a major step forward although when first introduced it was not realised how profound this was. At the beginning captopril was given in excessive dosage and had a high incidence of toxic side effects such as a membranous nephropathy and thrombocytopenia. It could also cause profound hypotension with the first dose given to patients who were taking diuretics. The introductory dosage was lowered, given after reducing or even stopping diuretics and with particular care in patients who were already hypotensive or had renal impairment. Early improvement was gratifying but increase in exercise performance was still disappointing.16 T h e Consensus trial with enalapril was the first to show improvement in survival of patients in Class 111 and IV NYHA failure treated with ACE HEART FAILURE TREATMENT

inhibitors, patients with only a 50% chance of surviving a year." T h e development of the longer acting ACE inhibitors such as enalapril brought about continuous inhibition of angiotensin production and greater benefit. Although some improvement in exercise tolerance was shown, this was still disappointingly small despite ample evidence that ACE inhibitors are superior to direct vasodilators'6 and the reasons for this.I5 In 1991 two important placebo controlled trials (SOLVD and VHEFT 11) each reported improvement in survival in patients with mild heart failure given enalapril, usually in addition to digoxin and d i u r e t i ~ . " , 'It ~ was of interest that (presumably through a quirk of statistics) one trial showed that the reduction in mortality was almost totally attributable to a reduction in sudden death but the other (SOLVD), to a reduction in deaths due to progression of heart failure and hospital admissions for this. Although objective measures of improvement such as left ventricular ejection fraction occurred in both groups, VO, max increased only in the patients treated with hydralazinelisosorbide. It was suggested that both treatments carry independent benefits and that consideration should be given to giving both together. This would be cumbersome and hypotension is likely to be a limiting factor. In the survival and ventricular enlargement trial (SAVE) it was shown that treating patients with ACE inhibitors long-term could save lives and prevent the development of heart failure after myocardial infarction (MI). The SAVE trial used captopril and benefit was not evident until ten months after the start of treatment but with eventual 17% reduction in mortality, 24% reduction in occurrence of infarction, 30% reduction in development of heart failure and 19% reduction in admission to hospital for heart failure. Conversely, the Second Cooperative North Scandinavian Enalapril Survival Study (Consensus 11) which studied the effect of intravenous enalapril in the first 24 hours after infarction was stopped after enrolling 6000 patients because no benefit had been shown. In the SAVE trial a target dose of 150 mg of oral captopril was given three to 16 days post infarction yet the SOLVD trial, which like Consensus 11 used enalapril, showed a 5% reduction in infarction and prevented enlargement of the heart two to three years after infarction with benefits still increasing when the trial was stopped. The difference in timing and route of administration probably explain the difference rather than the choice of ACE inhibitor. By the late 1980s the patient in chronic myocardial failure in sinus rhythm with a dilated Aust NZ

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left ventricle was taking digoxin, a smaller dose of diuretic and a long acting ACE inhibitor. Although he felt better and had no clinical signs of heart failure he still could not exercise much more than he had done b e f ~ r e . ~ ~ - ’ ~ ~ ’ ~

THE PERIPHERY Because of the disappointing improvement in exercise performance, attention turned to the periphery and especially to the resistance vessels and the skeletal muscles which became the subject of intensive A reduced capillary network” and loss of fast oxidative fibres added up to an apparent skeletal myopathy. Heart failure had become a peripheral disease almost as though the heart were no longer the culprit organ. Impaired maximum arterial vasodilatation found in heart failure needed to be explained. Increased sodium content in the arterial wall, altered neurohormonal control mechanisms and disordered endothelial function were possible candidates. Increase in blood flow to exercising skeletal muscles was also likely to be defective because the cardiac output was failing to rise sufficiently on exercise and because of physical deconditioning caused by habitual i n a c t i ~ i t y ’ ~ .often ’~ prescribed by the patients’ physicians. T h e peripheral vascular response to heart failure with increased vasomotor tone and vasoconstriction is an essential adaptation in the short-term as it preserves perfusion pressure to vital organs when the cardiac output is low. However, vasoconstriction becomes detrimental and to some extent increased by therapy with diuretics and non ACE inhibitor vasodilators when sustained over longterm. T h e vasomotor response to a variety of pharmacological agents and metabolic stimuli is impaired in heart failure.” An inadequate vasodilator capacity in the skeletal muscle vessels is an important determinant of continuing exercise intolerance in heart failure. Impaired vasodilator capacity has been attributed to a ‘heart failure stiffness factor’ caused by sodium and water retention in the vascular wall together with the vasoconstriction caused by sympathetic and renin angiotensin axis activation. Maximum pharmacological blockade does not alter maximum vasodilator response but by contrast, chronic treatment with an ACE inhibitor is followed by improved maximum skeletal muscle blood flow during exercise with eventually an improved exercise c a p a ~ i t y . ’T~h e other important factor which has been highlighted recently is physical deconditioning and daily training of patients in chronic treated stable heart failure has been demonstrated to improve exercise capacityz4 although a specific Aust NZ J Med 1992; 22 590

increase in skeletal muscle blood flow has not yet been reported. Much of the benefit of exercise training may well come from increased efficiency of previously inactive limbs. It is possible that the vascular endothelium contributes to the heart failure vascular stiffness factor with abnormal regulation of vasomotor tone of which the endothelium dependent relaxing factor (EDRF) is a major component.26EDRF (nitric oxide) mediates vasodilator tone by activation of soluble guanylate cyclase in vascular smooth muscle and E D R F dependent vasodilatation may also be impaired in heart failure. This may be related to a low flow state since blood flow itself is an important stimulant of EDRF release and controller of vasodilatation in normal health. Certain lymphokines, including tumour necrosis factor have been reported to be elevated in heart failure. Compounds designed to inhibit the endothelial effects of circulating lymphokines or sodium channel blockers may become available in the future to treat the peripheral vascular component of heart f a i l ~ r e . ’ ~ We return to peripheral blood flow and its deficiency, particularly on exercise, as the prime cause of exercise intolerance in chronic treated myocardial failure. This can only be corrected by improving the function of the culprit organ, the heart. H References 1. Smith WF. Epidemiology of congestive heart failure. Am

J Cardiol 1985; 55: 3A-8A. 2. Parmley WW. Should digoxin be the drug of first choice after diuretics in chronic congestive heart failure? Introduction. J Am Call Cardiol 1988; 12: 265-73. 3. Packer M. How should we judge the efficacy of drug therapy in patients with chronic congestive heart failure? T h e insights of six blind men. J Am Call Cardiol 1987; 9: 433-8. 4. Arnold SB, Byrd RC, Meister W er al. Long-term digitalis therapy improves left ventricular function in heart failure. N Engl J Med 1980; 303: 1443-8. 5. Lee DC-S, Johnson RA, Bingham JB er al. Heart failure in outpatients. A randomized trial of digoxin versus placebo. N Engl J Med 1982; 306: 699-705. 6. Guyatt G H , Sullivan MJJ, Fallen E L et al. A controlled trial of digoxin in congestive heart failure. Am J Cardiol 1988; 61: 371-5. 7. T h e Captopril-Digoxin Multicenter Research Group. Comparative effects of captopril and digoxin in patients with mild to moderate heart failure. JAMA 1988; 259: 539-44. 8. DiBianco R, Shabetai R, Kostuk W, Moran J, Schlant R, Wright R and the Milrione Multicenter Trial Group. Oral milrinone and digoxin in heart failure: results of a placebocontrolled, prospective trial of each agent and the combination (Abstr). Circulation 1987; 76: IV:IV-256. 9. T h e German and Austrian Xamoterol Study Group. Doubleblind placebo-controlled comparison of digoxin and xamoterol in chronic heart failure. Lancet 1988; i: 489-93. 10. Maskin CS, Forman R, Sonnenblick EJ, LeJemtel T . Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure. Am J Cardiol 1983; 51: 177-82. H E A R T FAILURE T R E A T M E N T

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The push, the pull and the periphery.

If the failing left ventricle could be given an effective push, other approaches to the treatment of heart failure would not be needed. We have inotro...
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