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European Journal of Heart Failure 2000 2(3):229-233; doi:10.1016/S1388-9842(00)00102-1
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© 2000 European Society of Cardiology

Importance of neuroendocrine activation in chronic heart failure. Impact on treatment strategies

Karl Swedberg*

Department of Medicine, Sahlgrenska University Hospital/Östra, Göteborg University SE-41685 Göteborg, Sweden

Received April 24, 2000; Accepted June 12, 2000


   1. Introduction
Top
 Notes
 1. Introduction
2. Neuroendocrine systems
 3. Effects of neuroendocrine...
 4. Treatment of heart...
 References
 
Chronic heart failure is a syndrome where the symptoms and objective evidence of cardiac disease are essential criteria. The pathophysiology behind this syndrome is complex. In a review by Poole-Wilson, several models were discussed [1]. He discussed viscous spirals due to hemodynamic reasons, fluid retention and remodeling, as well as other causes. In most of these spirals, neurohormonal activation is involved in the process. Thus, neuroendocrine activation (NA) has a significant pathophysiologic role in the syndrome of chronic heart failure.


   2. Neuroendocrine systems
Top
 Notes
 1. Introduction
 2. Neuroendocrine systems
3. Effects of neuroendocrine...
 4. Treatment of heart...
 References
 
The classical components of neuroendocrine activation are shown in Table 1. The activation of these systems has developed to protect the circulatory system from failure during volume loss i.e. after hemorrhage. In particular, the perfusion of the heart, brain and kidneys should be maintained. The component discussed first in heart failure was sympathetic activation. As reported by Chidsey in 1965 [2], there is an increased release of norepinephrine in the urine. We demonstrated a marked increase in myocardial norepinephrine release from failing hearts [3]. In an improved model using tritiated norepinephrine, Esler and co-workers described the marked regional differences of sympathetic activation. While plasma norepinephrine levels were doubled, myocardial norepinephrine release was increased 11 times [4]. The interpretation of this increased sympathetic activation seemed simple until Bristow et al. demonstrated that the β-adrenergic receptor function was attenuated in heart failure [5]. Later they showed that both the function and numbers of these receptors were altered. In 1984, Cohn and co-workers reported on the relationship between mortality and plasma norepinephrine [6]. They also found this marker to be the best predictor of prognosis compared to all of the hemodynamic measurements they had assessed.


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  		Table 1 Long-term consequences of chronic NA (after H. Dargie)

 
The activation of the renin–angiotensin system (RAS) in heart failure was reported by Laragh [7]. We reported neuroendocrine activation from the CONSENSUS trial in 1990 [8]. In this trial, only patients with NYHA class IV heart failure were included. Patients on optimal treatment, but with no ACE-inhibitor, were found to have a significant relationship between their plasma hormonal levels and the prognosis for norepinephrine, angiotensin II, aldosterone and atrial natriuretic peptide. The observations from Cohn [6] were then confirmed, and extended to other neuroendocrine systems as well.

The effects of chronic angiotensin II activation are potentially deleterious. This hormone acts locally as well as systemically and causes vasoconstriction, in addition to several other effects. Angiotensin II acts on angiotensin receptors, which are available in several types. The vasoconstrictor type (AT1) is different to the growth promoting receptor AT2. This receptor mediates several other effects considered to be of value in promoting tissue regeneration.

Aldosterone is another important component of the RAS. Stimulated by angiotensin II, it is released to maintain fluid balance. However, in heart failure, aldosterone secretion causes further sodium and fluid retention. Aldosterone can also cause a loss of magnesium. Due to its steroid structure, it can also stimulate fibrosis by collagen production.

The observations from the aldosterone escape led to the RALES program, where the addition of spironolactone in a low dose of 25 mg (–50 mg; average dose 27 mg) had a significant beneficial impact on prognosis in severe heart failure as demonstrated in the RALES study [27] and aldosterone escape during angiotensin-converting enzyme-inhibitor therapy in chronic heart failure [9]. Patients with NYHA class III–IV were randomized to receive a placebo or aldosterone. The mortality was reduced by 30% (RR 0.6–0.82; P<0.0001). Almost all of the patients had a background therapy with ACE-inhibitors, but only 11% were on β-blockers.


   3. Effects of neuroendocrine activation
Top
 Notes
 1. Introduction
 2. Neuroendocrine systems
 3. Effects of neuroendocrine...
4. Treatment of heart...
 References
 
As the circulatory effects of NA are to maintain perfusion of vital organs, the short-term effects are an increased inotropic state, tachycardia, volume expansion and peripheral vasoconstriction. Some of the chronic effects of sustained NA are listed in Table 1.

In a state of hypoperfusion, these effects are appropriate. However, chronic heart failure is a syndrome of hypervolemia and the NA activation becomes inappropriate, particularly if it is sustained. The chronic effects will then become harmful.

The neuroendocrine model may, therefore, be outlined as in Fig. 1. The chronic effects will cause fluid retention, vascular and cellular effects with impact on the symptoms and prognosis of heart failure.


Figure 1
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  		Fig. 1 Neuroendocrine model in heart failure.

 
In addition to the classical components of NA new candidates are emerging, i.e. endothelin, prostaglandins, adrenomedullin and neuropeptide Y. These hormones have all been studied in heart failure and were found to have various degrees of importance.

Recently, Ceconi and co-workers demonstrated that chromogranin A, a small protein produced in chromograffin cells, was increased in heart failure [10]. They studied 160 patients in NYHA class II–IV. A significant relationship was found in the NYHA class. In a multivariate analysis, chromogranin A was found to be more important for prognosis than plasma norepinephrine, ANP or ejection fraction.


   4. Treatment of heart failure and neuroendocrine activation
Top
 Notes
 1. Introduction
 2. Neuroendocrine systems
 3. Effects of neuroendocrine...
 4. Treatment of heart...
References
 
In the 1980s, the standard treatment of heart failure included diuretics, digoxin and vasodilators. The impact of these treatments on morbidity and mortality was unclear.

In 1973, Waagstein and Hjalmarson observed that patients with idiopathic dilated cardiomyopathy (IDC) and heart failure could improve after β-blocker therapy was initiated in a low dose and titrated up [11].

We started to follow patients in a more systematic way. The rationale behind this new approach was the hypothesis that chronic sympathetic stimulation was harmful. Based on observations from patients with myocardial ischemia, sustained tachycardia was one reason why myocardial failure could develop. As an elevated heart rate is common in patients with chronic heart failure, it was postulated that a lower heart rate would be beneficial. One potential side-effect would be reduced contractility. In 1979, we reported on improved survival with β-blockers in patients with IDC [12]. However, this was not a randomized trial but historical controls were used for comparison. These reports were often referred as the ‘Swedish experience’ and were not accepted in general. During the following years, many small under-powered studies were performed with divergent results.

Prior to 1993, only small randomized single center trials were available to assess the effects of β-blocker treatment. The MDC-study was underpowered for mortality, including, in total, 383 patients. A 34% reduction (95% CI, 6–62%; P=0.058) in the combined end-point death or need for cardiac transplantation was reported. The main effect was observed in the number of patients listed for heart transplantation, and there was no effect in the number of deaths [13].

The second, larger randomized trial with a β-blocker, the CIBIS study, was likewise undersized to study mortality (n=641) [14]. In this trial a 20% non-significant reduction in the relative risk for overall mortality was found. In post-hoc analysis, there was a significant effect on mortality in patients who had not experienced a myocardial infarction, whereas no effect was found in patients with a history of infarction.

A breakthrough in the effects of β-blockers on mortality was the publication of the US Carvedilol Heart Failure Program, in which a combined survival benefit was observed in patients on carvedilol. Patients with an ejection fraction ≤0.35% were randomized to carvedilol (n=696) or to placebo (n=398). The overall reduction in mortality risk for patients on carvedilol was 65% (95% CI, 39–80%; P<0.001) [15]. The survival effect was striking, although mortality assessment was not a primary end-point in these studies.

The Australia/New Zealand Heart Failure Research Collaborative Group investigated 415 patients with stable heart failure due to ischemic heart disease and an ejection fraction less than 0.45. These patients had milder heart failure and a lower risk profile; 85% of them were in NYHA class I or II. Death was a secondary end-point and was not significantly reduced by carvedilol treatment, relative risk=0.76 (95% CI, 0.42–1.36) [16].

The first study to primarily investigate β-blocker effects on total mortality was the CIBIS-II study [17]. This study recruited 2647 patients (bisoprolol n=1327, placebo n=1320) to be treated with bisoprolol or the placebo. All-cause mortality was significantly reduced with bisoprolol, hazard ratio=0.66 (95% CI, 0.54–0.81), P<0.0001. Furthermore, all-cause hospital admissions were reduced in the treatment group, hazard ratio=0.80 (0.71–0.91), P=0.0006.

Another important all-cause mortality trial published in 1999 was the MERIT heart failure trial [18]. The study randomized 3991 patients to receive metoprolol CR/XL (controlled release) or a placebo. The relative risk for the metoprolol-treated patients during the study was 0.66 (95% CI, 0.53–0.81), P=0.00009. Similarly, cardiovascular deaths were fewer in the metoprolol group, RR=0.62 (95% CI, 0.45–0.78), P=0.0002, as were heart failure deaths, RR=0.51 (95% CI, 0.33–0.79), P=0.0023.

A meta-analysis of 26 β-blocker trials including 10 502 patients and 1172 deaths demonstrated a highly significant 36% reduction in mortality [19]. This development from contraindicated results to established ones has certainly been remarkable and made possible by the concomitant understanding of the role of NA in heart failure.

In the early 1980s, ACE-inhibitors were introduced for the treatment of hypertension and also evaluated for heart failure. Initially thought to achieve treatment effects through vasodilation, they were found to improve symptoms and exercise [20,21]. The CONSENSUS study was started in 1985, stopped in December 1986, and published in June 1987 [22]. It was conducted in 253 patients with NYHA class IV heart failure. The beneficial effects of enalapril on mortality were marked with a 44% (95%CI, 0.34–0.91) reduction in mortality. The results received wide acceptance, and enalapril was used in advanced heart failure. From this study, we learned that NA was of significant prognostic importance in severe heart failure. The patients that benefited most were those patients with the highest plasma hormone levels [8]. The CONSENSUS study was followed by many studies demonstrating the important effects of ACE-inhibitors.

The most important of these following trials has been the SOLVD (Studies on Left Ventricular Dysfunction) project in 6797 patients. In the treatment arm where 2569 patients were randomized, enalapril reduced mortality by 16% (CI –5 to –26%; P=0.0036), deaths due to progressive heart failure by 22%, and hospitalizations for worsening heart failure by 26%. In several studies of NA in SOLVD, it was clarified that NA was increased in relation to the degree of symptoms of heart failure [23,24]. In the meta-analysis by Garg et al. [25] of 32 trials including 7105 patients, a 23% (CI –12 to –33%) reduction in mortality was demonstrated, and the combination of death and hospitalization was reduced by 35% (CI –43 to –25%). This confirms the important effects of ACE-inhibitors in chronic heart failure. There are also strong reasons to believe that the major treatment effect from these agents is caused by counteraction of the NA associated with chronic heart failure.

For many years it was clear that ACE-inhibitors did not attenuate the RAS activation completely. Neither was the inhibition sustained. Staessen et al. reported increasing plasma aldosterone levels, in spite of increasing doses of captopril [26]. This observation was called aldosterone-escape. The implication of this observation is, of course, that the RAS needs more effective suppression. This extended attenuation could be achieved by the addition of spironolactone. Aldosterone-escape has been studied further by Struthers and co-workers [27]. The possible harmful effects of this residual aldosterone are multiple. Magnesium loss caused by aldosterone and by diuretics could contribute to coronary artery spasm and arrhythmias. Aldosterone blocks norepinephrine uptake by the myocardium; extracellular catecholamines may, therefore, lead to arrhythmias and ischemia. Aldosterone has been shown to have an acute arrhythmogenic effect as well as a detrimental effect on parasympathetic and baroreflex functions. Both angiotensin II and aldosterone stimulate myocardial fibrosis, which may lead to a higher incidence of malignant ventricular arrhythmias. Spironolactone therapy, added to a regimen of an angiotensin-converting enzyme inhibitors and diuretics, has been shown to cause natriuresis, magnesium retention, increased myocardial norepinephrine uptake, and a reduced incidence of ventricular arrhythmias. It may well be that residual aldosterone mediates many harmful effects in chronic heart failure and that to optimize the benefit of blocking the renin–angiotensin–aldosterone system may require the specific blockade of residual aldosterone, as well as traditional angiotensin-converting enzyme inhibition.

The observations from the aldosterone escape led to the RALES program, where the addition of spironolactone in a low dose of 25 mg (–50 mg) had a significant impact on prognosis in severe heart failure as demonstrated in the RALES study [9].

As a consequence of these important studies where neuroendocrine activation was targeted, we now have further therapies to offer our patients. In addition to the previous standard therapies, we have documented that addition of β-blockers, ACE-inhibitors and spironolactone should be considered in all symptomatic patients with left ventricular systolic dysfunction.

However, not every counteraction of NA is beneficial. The rapid initiation of treatments with ACE-inhibitors or β-blockers may provoke hemodynamic side-effects or renal deterioration. Therefore, a careful initiation of NA counteraction must be performed. The difficulty in doing so is illustrated by the recent MOXCON trial where the imidazoline agonist moxonidine, in a sustained release (SR) preparation, was used [28]. Moxonidine has been found to be effective in reducing the plasma levels of norepinephrine [29]. In a pilot trial of moxonidine SR, this preparation was found to be even more effective. However, the extent of the effect was not fully appreciated when the MOXCON trial was started. The dose levels used were very effective and reduced the plasma levels of norepinephrine by 40–50% in 2–3 weeks. When 1973 patients had been randomized, the study was stopped by the DSMB due to significant excess mortality in the moxonidine SR group compared to the placebo-treated group (53 vs. 29 deaths; P=0.002). The deaths occurred, to a large extent, within the first 4 weeks of the trial. The reason for this adverse outcome in MOXCON is unclear, but a too effective and too rapid attenuation of myocardial sympathetic stimulation was suspected.

The future development of NA counteraction includes several possibilities. An AT1 receptor blockade as alternative or additive to ACE-inhibitors is presently under investigation. The combined approach to inhibiting both neutral endopeptidase and ACE in one molecule is another interesting development. Vasopressin antagonists and cytokine inhibitors are also presently under clinical evaluation in chronic heart failure.

However, the many emerging therapeutic options will result in unmanageable treatment packages unless the potential to replace existing therapies is evaluated. We need surrogate markers to help rationalize treatment options. Surrogate markers are difficult to use, particularly for outcome evaluations or for regulatory purposes. Hormonal assessment could describe each patient’s neuroendocrine burden. We should include an assessment of neuroendocrine activation in outcome trials in order to target NA in future clinical management.

In conclusion, NA is of pathophysiological importance in chronic heart failure. Treatment with ACE-inhibitors, β-blockers and spironolactone has demonstrated the importance of counteracting NA. Further developments in the treatment of heart failure should include a better counteraction of NA. However, the value and importance of using markers of NA to individualize clinical management should be assessed in future trials.


   Notes
Top
 Notes
1. Introduction
 2. Neuroendocrine systems
 3. Effects of neuroendocrine...
 4. Treatment of heart...
 References
 
* Tel.: +46-31-343-4000; fax: +46-31-25-89-33. E-mail address: karl.swedberg{at}hjl.gu.se Back


   References
Top
 Notes
 1. Introduction
 2. Neuroendocrine systems
 3. Effects of neuroendocrine...
 4. Treatment of heart...
 References
 

  1. Poole-Wilson P.A. History, definition, and classification of heart failure. In: Heart Failure—Poole-Wilson P., Colucci W.S., Massie B.M., Chatterjee K., Coats A., eds. (1997) New York: Churchill Livingstone. 269–277.
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  22. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian enalapril survival study (CONSENSUS). N Engl J Med 1987;316:1429–1435.
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