Angiotensin-Converting Enzyme Inhibition, the Sympathetic Nervous System, and Congestive Heart Failure Graeme Sloman, ED, FRCP (LOND), FRCP (EDIN), FRACP, for the Australian Zestril (Lisinopril) Study Group
Catecholamines have been found to be powerful indiaors of prognosis in patients with congestive heart failure. However, lt is uncertain whether catecholamines are a marker for decreased cardiac performance or part of the pathologk process. Catecholamines, exogenously derived p-adrenergic stimulants, and drugs that amplify sympathetic responsiveness produce early hemodynamic benefii, but do not appear to provide long-term improvement in terms of symptoms or exercise tolerance, whereas blockade of the padrenoceptor appears to have little early benefit but may improve longterm prognosis. This suggests that in the long term, increased catecholamine levels may be deleterious. Angiotensin-converthtg enzyme (ACE) inhibitors can modulate circulating catecholamines, and the persistence and degree of ACE inhibition may be important not only in reducing catecholamines, but possibly also in reducing mortality in heart failure. It appears that ACE inhibitors definitely reduce mortality in congestiie heart failure. It remains to be documented whether the persistence and degree of ACE inhibition is a factor in this effect, and, thus, comparison of short- with long-acting ACE Inhibitors and study of the dosage of ACE inhibitors are of importance. The extent to which modulatiin of the sympathetic nervous system by ACE inhibitors is an important mechanism in their effect in reducing mortality remains to be establiihed.
From the Cardiovascular Unit, Clinical Sciences Building, Epworth Hospital, Richmond, Victoria, Australia. Address for reprints: Graeme Sloman, Cardiovascular Unit, Clinical Sciences Building, Epworth Hospital, 62 Erin Street, Richmond, 3121 Victoria, Australia.
T
he sympathetic nervous system and its modulation represents one of the major noncardisc compensatory mechanisms that the body mobilizes in the presence of reduced cardiac output in congestive heart failure (CHF).i Several questions arise when presented with the rational treatment of heart failure: 1. Are the changes in the sympathetic nervous system necessary to the maintenance of cardiovascular homeostasis in the patient? 2. Are they beneficial or detrimental in the short term? 3. Are they beneficial or detrimental in the long term? 4. Is therapeutic intervention aimed at reducing sympathetic nervous system activation a worthwhile or practicable target? THE SYMPATHETIC NERVOUS SYSTEM AND HEART FAILURE Any decline in cardiac function that results in a decrease in central blood pressure is rapidly detected by the baroreceptors, which in turn reactively increase sympathetic tone via the central nervous system.2 If subsequent sympathetic nervous system-mediated vasoconstriction and increased cardiac output fail to achieve the desired blood pressure, activation of the baroreceptor function may continue unchecked, encouraging in turn, further neurohormonal activation3 baroreceptor dysfunction4 and a hyperadrenergic state. In many ways, this upwardly spiralling cycle of increasing adrenergic tone reflects the downwardly spiralling myocardial function of CHF. The inverse relation between the cardiac function and sympathetic tone is well documented, and in patients with CHF, plasma norepinephrine levels are increased in proportion to the clinical severity of the disease.5 It remains to be established whether this increased sympathetic activity merely reflects the deterioration of cardiac function, or whether it is A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
li.3c
contributory to the decline in cardiac performance. Early in CHF, when cardiac output is limited only by exercise, plasma epinephrine and norepinephrine concentrations reflect this, being normal at rest and increasing abnormally on exertion.6>7 Cardiac output becomes progressively reduced at rest as the heart failure syndrome increases in severity. As a result, catecholamines become elevated at rest and their elevation on exercise closely reflects the severity of functional and hemodynamic impairment.5T8 Increased sympathetic tone may be evident before activation of the renin-angiotensinaldosterone system (RAAS). Increased sympathetic tone may also be reflected in down-regulation of adrenergic receptors in heart failure.9,10 SYMPATHEW NERVOUS SYSTEM ACTlVATlON IN HEART FAILURE-G0~D OR BAD? Perhaps clues to’the answer to this question can be gleaned from reflecting on the effects of various drugs on heart failure and sympathetic activity. Treatment with pi-selective or Bz-selective adrenoceptor agonists has failed to improve exercise capacity or symptoms in double-blind, placebocontrolled trials.ll-l3 Nevertheless, these agents undoubtedly have early and apparently beneficial hemodynamic effects when used in the short term, but prolonged use results in a further reduction of B-receptor sensitivity and a reduction in hemodynamic effectiveness.14 Additional risks of adrenergic stimulation are increased myocardial ischemia and arrhythmogenesis. 15,16 If l3 receptor downregulation is a self-protecting mechanism used to limit “overenthusiasm” by the sympathetic nervous system, then blockade of the adrenergic/sympathetic nervous systems should produce beneficial effects. Long-term treatment with low doses (6.25100 mg daily, average) of the l.3blocker metoprolol in carefully selected patients (with CHF resulting from cardiomyopathy with normal coronary angiograms and stable compensated heart failure)17-l9 produced evidence of improved left ventricular function and symptoms in congestive cardiomyopathy. Greatest improvement was seen in those with the poorest ejection fractions and highest heart rates prior to treatment, and presumably those patients also had the highest catecholamine levels (vide supra) .20 The use of B stimulants has been associated with high rates of mortality in heart failure patients,21,22 as have phosphodiesterase inhibitors, (drugs that enhance levels of cyclic adenosine monophosphate, the intracellular messenger of 114c
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adrenergic stimulation in cardiac tissue).23 These findings come from relatively long-term use; these contrast with the observation of much improved hemodynamics when these drugs are used for short periods (4-8 weeks). 24 It has been established for some years that long-term (> 6 months) B blockade increases B-receptor density and responsiveness to adrenergic stimulation.25,26 Just as the early hemodynamic benefits seen with P-adrenergic stimulants do not seem to be translated into long-term beneficial effects, so acute treatment (
Catecholamines have been found to be powerful indiaors of prognosis in patients with congestive heart failure. However, lt is uncertain whether catecholamines are a marker for decreased cardiac performance or part of the pathologk process. Catecholamines, exogenously derived p-adrenergic stimulants, and drugs that amplify sympathetic responsiveness produce early hemodynamic benefii, but do not appear to provide long-term improvement in terms of symptoms or exercise tolerance, whereas blockade of the padrenoceptor appears to have little early benefit but may improve longterm prognosis. This suggests that in the long term, increased catecholamine levels may be deleterious. Angiotensin-converthtg enzyme (ACE) inhibitors can modulate circulating catecholamines, and the persistence and degree of ACE inhibition may be important not only in reducing catecholamines, but possibly also in reducing mortality in heart failure. It appears that ACE inhibitors definitely reduce mortality in congestiie heart failure. It remains to be documented whether the persistence and degree of ACE inhibition is a factor in this effect, and, thus, comparison of short- with long-acting ACE Inhibitors and study of the dosage of ACE inhibitors are of importance. The extent to which modulatiin of the sympathetic nervous system by ACE inhibitors is an important mechanism in their effect in reducing mortality remains to be establiihed.
From the Cardiovascular Unit, Clinical Sciences Building, Epworth Hospital, Richmond, Victoria, Australia. Address for reprints: Graeme Sloman, Cardiovascular Unit, Clinical Sciences Building, Epworth Hospital, 62 Erin Street, Richmond, 3121 Victoria, Australia.
T
he sympathetic nervous system and its modulation represents one of the major noncardisc compensatory mechanisms that the body mobilizes in the presence of reduced cardiac output in congestive heart failure (CHF).i Several questions arise when presented with the rational treatment of heart failure: 1. Are the changes in the sympathetic nervous system necessary to the maintenance of cardiovascular homeostasis in the patient? 2. Are they beneficial or detrimental in the short term? 3. Are they beneficial or detrimental in the long term? 4. Is therapeutic intervention aimed at reducing sympathetic nervous system activation a worthwhile or practicable target? THE SYMPATHETIC NERVOUS SYSTEM AND HEART FAILURE Any decline in cardiac function that results in a decrease in central blood pressure is rapidly detected by the baroreceptors, which in turn reactively increase sympathetic tone via the central nervous system.2 If subsequent sympathetic nervous system-mediated vasoconstriction and increased cardiac output fail to achieve the desired blood pressure, activation of the baroreceptor function may continue unchecked, encouraging in turn, further neurohormonal activation3 baroreceptor dysfunction4 and a hyperadrenergic state. In many ways, this upwardly spiralling cycle of increasing adrenergic tone reflects the downwardly spiralling myocardial function of CHF. The inverse relation between the cardiac function and sympathetic tone is well documented, and in patients with CHF, plasma norepinephrine levels are increased in proportion to the clinical severity of the disease.5 It remains to be established whether this increased sympathetic activity merely reflects the deterioration of cardiac function, or whether it is A SYMPOSIUM:
HEART FAILURE
MANAGEMENT
li.3c
contributory to the decline in cardiac performance. Early in CHF, when cardiac output is limited only by exercise, plasma epinephrine and norepinephrine concentrations reflect this, being normal at rest and increasing abnormally on exertion.6>7 Cardiac output becomes progressively reduced at rest as the heart failure syndrome increases in severity. As a result, catecholamines become elevated at rest and their elevation on exercise closely reflects the severity of functional and hemodynamic impairment.5T8 Increased sympathetic tone may be evident before activation of the renin-angiotensinaldosterone system (RAAS). Increased sympathetic tone may also be reflected in down-regulation of adrenergic receptors in heart failure.9,10 SYMPATHEW NERVOUS SYSTEM ACTlVATlON IN HEART FAILURE-G0~D OR BAD? Perhaps clues to’the answer to this question can be gleaned from reflecting on the effects of various drugs on heart failure and sympathetic activity. Treatment with pi-selective or Bz-selective adrenoceptor agonists has failed to improve exercise capacity or symptoms in double-blind, placebocontrolled trials.ll-l3 Nevertheless, these agents undoubtedly have early and apparently beneficial hemodynamic effects when used in the short term, but prolonged use results in a further reduction of B-receptor sensitivity and a reduction in hemodynamic effectiveness.14 Additional risks of adrenergic stimulation are increased myocardial ischemia and arrhythmogenesis. 15,16 If l3 receptor downregulation is a self-protecting mechanism used to limit “overenthusiasm” by the sympathetic nervous system, then blockade of the adrenergic/sympathetic nervous systems should produce beneficial effects. Long-term treatment with low doses (6.25100 mg daily, average) of the l.3blocker metoprolol in carefully selected patients (with CHF resulting from cardiomyopathy with normal coronary angiograms and stable compensated heart failure)17-l9 produced evidence of improved left ventricular function and symptoms in congestive cardiomyopathy. Greatest improvement was seen in those with the poorest ejection fractions and highest heart rates prior to treatment, and presumably those patients also had the highest catecholamine levels (vide supra) .20 The use of B stimulants has been associated with high rates of mortality in heart failure patients,21,22 as have phosphodiesterase inhibitors, (drugs that enhance levels of cyclic adenosine monophosphate, the intracellular messenger of 114c
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
70
adrenergic stimulation in cardiac tissue).23 These findings come from relatively long-term use; these contrast with the observation of much improved hemodynamics when these drugs are used for short periods (4-8 weeks). 24 It has been established for some years that long-term (> 6 months) B blockade increases B-receptor density and responsiveness to adrenergic stimulation.25,26 Just as the early hemodynamic benefits seen with P-adrenergic stimulants do not seem to be translated into long-term beneficial effects, so acute treatment (
