European Heart Journal Supplements (2002) 4 (Supplement G), G45–G50 How to best to counteract the enemies? By blocking neurohormonal activation J. Soler-Soler and D. García-Dorado Servicio de Cardiología, Hospital Universitari Vall d’Hebron, Barcelona, Spain regression of myocardial hypertrophy that is associated with certain treatments. The results of clinical studies are not consistent with a prominent role of apoptosis induced by neurohormonal activation in the progression of heart failure. Beta-blockers, inhibitors of the renin–angiotensin–aldosterone system and angiotensin receptor antagonists improve symptoms and prolong life, but are not able to prevent progression of heart failure. The hypothesis that the beneficial effect of blockade of neurohormonal activation in patients with heart failure is, to a significant extent, due to reduced cardiomyocyte apoptosis is still to be proven. (Eur Heart J Supplements 2002; 4 (Suppl G): G45–G50) © 2002 The European Society of Cardiology Introduction adaptive changes in the adrenergic system, the renin– angiotensin–aldosterone system (RAAS) and several other vasoactive hormones (Table 1) that are globally termed ‘neurohormonal activation’. Although it has been well demonstrated that interfering with some of these neurohormones may improve symptoms and prolong survival of patients with heart failure, progression of heart failure continues to be a major challenge because there is no evidence that the present therapeutic approach significantly prevents this relentless progression. Apoptosis probably plays an important role in the progression of heart failure. Therefore, a brief review of the role of neurohormonal activation blockers to prevent cardiomyocyte death may be useful to treating physicians. At the beginning of the 21th century, the principal aetiopathogenic mechanisms of most myocardial diseases are well established. The causative roles of ischaemia/ reperfusion, hypoxia, and injury by pathogenic microorganisms or by the immune system, chemotoxicity and mechanical stress are well defined. Most cardiac diseases are characterized by myocardial dysfunction, and in general involve differing degrees of cardiomyocyte loss (cell death), cardiomyocyte dysfunction (arrhythmias, contractile failure), non-cardiomyocyte cell alterations (microvascular and interstitial cells) and neurohormonal activation. One of the most important clinical manifestation of cardiac diseases is heart failure, a highly prevalent condition that markedly reduces life expectancy and increases morbidity, with an enormous and increasing socioeconomic impact. Heart failure is invariably associated with Correspondence: Jordi Soler-Soler, MD, Servicio de Cardiología, Hospital Universitari Vall d’Hebron, P. vall d’Hebron, 119–129, 08035 Barcelona, Spain. 1520-765X/02/0G0045 + 06 $35.00/0 Key Words: ACE inhibitors, apoptosis, beta-blockers, heart failure, neurohormonal activation. Contribution of cell death to progressive ventricular dysfunction Although not universal, there is wide agreement that cardiomyocyte cell death in failing myocardium occurs mainly through apoptosis[3,4]. Apoptotic cell death is the © 2002 The European Society of Cardiology Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 16, 2014 Progression of heart failure is associated with an increased rate of cardiomyocyte apoptosis, and it has been hypothesized that this may, to an important extent, be due to neurohormonal activation. Experimental studies in cells and intact myocardium show that mild prolonged ischaemia, cytokine activation, and stimulation of G-protein-coupled receptors by adrenergic agonists and angiotensin II may trigger apoptotic cardiomyocyte death. However, the complex intracellular signal cascades that initiate apoptosis are not well understood but are inextricably superimposed on those that trigger hypertrophy. The net effect of neurohormonal activation on cardiomyocyte apoptosis is highly dependent on experimental conditions. In addition, recent studies support the existence of cardiomyocyte regeneration, rendering even more complex the relationship between increased apoptosis and net cell loss. In addition, other studies suggest that apoptotic cell loss may contribute to the G46 J. Soler-Soler and D. García-Dorado Table 1 Chronic heart failure: neurohormones and cytokine activation Norepinephrine Epinephrine Renin Angiotensin II Aldosterone Arginine vasopressin Neuropeptide Y Vasopeptidases Prostaglandins Atrial natriuretic peptide Endothelin Beta-endorphins Calcitonin Growth hormone Cortisol TNF-alpha Neurokinin A Substance P TNF=tumour necrosis factor. Apoptosis in the failing myocardium An increased rate of apoptosis has been convincingly demonstrated in patients with heart failure secondary to cardiomyopathy of various aetiologies. Several mechanisms may account for the increase in rate of apoptotic cell death: focal ischaemia, autoimmune injury and inflammation, and sustained adrenergic or RAAS stimulation associated with neurohormonal activation. Focal ischaemia in the failing heart may occur, among other causes, as a consequence of inadequate microvascular adaptation to hypertrophy, altered perfusion pressure gradient or coronary microvascular disease. During ischaemia, enhanced generation of radical oxygen species (ROS), severe adenosine triphosphate depletion, increased intracellular calcium and other alterations in cell homeostasis are potent stimuli for initiation of apoptosis. Although execution of the apoptotic cell death programme requires energy, in vitro studies have shown that apoptosis can occur under severe hypoxia, and thus during myocardial ischaemia. It has been suggested that apoptosis may be a particularly important form of death in cells exposed to prolonged, mild ischaemia, as can occur in patients with cardiomyopathy and heart failure. However, the importance of apoptosis as a form of cardiomyocyte cell death during ischaemia is unclear because of the increasingly apparent limitations inherent to the methods used for its quantification in reperfused myocardium. Recently, studies conducted in isolated cardiomyocytes and intact hearts found that the susceptibility to develop apoptosis in response to ROS or nitric oxide (NO) is increased in Eur Heart J Supplements, Vol. 4 (Suppl G) November 2002 cardiomyocytes that are re-energized after prolonged ischaemia[10,11]. This protection against apoptosis lasts for the initial few hours of reperfusion, and its mechanism is thus far unknown. Cytokine activation as a consequence of various forms of stress, including ischaemia and inflammation, may lead to cardiomyocyte apoptosis. Myocardial and blood cells (cardiomyocytes, endothelial cells, neutrophils and platelets) may release multiple cytokines (tumour necrosis factor [TNF]-alpha, interleukin-1, interleukin-6, platelet activating factor and growth tissue factor). Cytokines act through an intricate network of signalling systems to induce multiple and important (and often opposed) cellular effects such as hypertrophy, proliferation and apoptosis. Different signalling pathways initiated by a cytokine may have redundant, additive or opposing actions on a downstream step of the signalling cascade, and these actions may be dependent on the concentration of cytokines and time, and may be modulated by signals from other network nodes. The resulting complexity usually makes it impossible to predict the effect of particular cytokines under different conditions. For example, it is well known that TNF-alpha may induce apoptosis, but on the other hand it upregulates nuclear factor-kappaB that has an antiapoptotic effect, and the net effect depends on many conditions. In fact, there is considerable overlap between the signalling systems that are responsible for hypertrophy, proliferation and apoptosis. Accordingly, the observation that in certain conditions up-regulation of a pro-apoptotic cytokine is associated with increased apoptotic rate does not allow one to conclude that a cause–effect relationship exists between them. A similar degree of complexity can be observed in the signalling cascades induced by G-protein-coupled receptor activation or by NO. Role of neurohormonal activation Prolonged exposure to abnormally high levels of adrenergic agonists is a hallmark of neurohormonal stimulation in patients with chronic heart failure. In previous studies conducted in isolated cardiomyocytes, it was shown that sustained beta-1 adrenergic receptor (AR) stimulation may cause apoptotic cell death via cyclic adenosine monophosphate-dependent signalling, involving the voltage-dependent calcium influx channel. In fact, myocardial over-expression of beta-1 AR is Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 16, 2014 result of the execution of a genetic programme that includes activation of specific enzyme systems, among which caspases play a major role, and eventually leads to internucleosomal DNA cleavage and fragmentation of the cell (without sarcolemmal rupture) into vesicles that are phagocytosed by other cells. In contrast to necrotic cell death, apoptosis requires energy, does not result in the release of intracellular contents (enzymes) and results in much less inflammatory reaction. In addition to the its important role in cardiac development during embryogenesis, there is solid evidence that cardiomyocyte apoptosis occurs in many different contexts, including ischaemia/ reperfusion, hypertrophy and regression of hypertrophy, cardiomyopathy, xenograft rejection and heart failure[5–7]. Blocking neurohormonal activation From apoptosis to net cell loss Evidence of cardiomyocyte apoptosis in failing myocardium does not necessarily mean that an abnormal reduction in the number of these cells is taking place. Apoptosis is also consistently found in normal myocardium, which indicates that either a progressive reduction in the number of cardiomyocytes can be normal or that cardiomyocyte regeneration can compensate for apoptotic cell death. Despite occasional reports of cardiomyocyte mitosis in adult myocardium, the impossibility of adult, terminally differentiated cardiomyocytes to undergo mitosis has been and is considered a valid dogma for most scientists. However, recent studies suggest the possibility of cardiomyocyte regeneration from undifferentiated cells (stem cells, cardiomyoblasts or bone marrow cells)[25,26]. Implantation of cytokine mobilized bone marrow cells in infarcted mice hearts, and ultimate differentiation into adult contracting myocytes has recently been demonstrated . The presence of cardiomyocytes with the host genotype in transplanted hearts demonstrates that cardiomyocyte regeneration can occur spontaneously in patients. Recent studies have described the coexistence of increased apoptosis with normal ventricular function in the rat heart. Thus, at present, increased apoptotic rate cannot be assumed to reflect increased cardiomyocyte cell loss because it is not known whether and to what extent increased cell death rate can be compensated for by cardiomyocyte regeneration. Furthermore, a net cell loss does not necessarily imply a relevant deterioration in ventricular function. Finally, to make the issue even more complex, it has been suggested that apoptosis may play an important beneficial role in the regression of hypertrophy secondary to hypertension. Clinical benefit of blockers of neurohormonal activation There is clinical evidence to support the concept that blocking some of the neurohormonal systems has a significant benefit, with prolonged survival and improved morbidity in patients with systolic left ventricular dysfunction, and both patients with ischaemic and those with non-ischaemic heart disease. In fact, at present, the treatment of choice in such patients is blockade of both the RAAS and the sympathetic nervous system. However, all that glitters is not gold, because recent trials have shown that blockade of some neurohormones, on top of standard therapy, did not result in further reduction in mortality. On the other hand, all of these important beneficial effects are not translated into real prevention of progression of heart failure, the prognosis of which continues to be dismal. In the following paragraphs the discussion focuses on clinical experience with several neurohormonal blockers. Eur Heart J Supplements, Vol. 4 (Suppl G) November 2002 Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 16, 2014 associated with myocyte apoptosis and the development of dilated cardiomyopathy. However, the pro-apoptotic effect of beta-1 AR stimulation can be opposed by stimulation of beta-2 AR, whereas stimulation of alpha-1 AR causes myocyte hypertrophy and may exert an antiapoptotic action as well[16,17]. The net balance between proapoptotic and antiapoptotic actions associated with adrenergic up-regulation and desensitization of the betaadrenergic pathway in patients with heart failure is not well established. Angiotensin II was shown in vitro to be able to initiate apoptosis in adult cardiomyocytes, probably via a protein kinase C mediated increase in cytosolic calcium concentration. Autocrine angiotensin II stimulation is an important step in the signalling cascade that leads to stretch-induced cardiomyocyte hypertrophy, and may play a role in the genesis of stretch-induced cardiomyocyte apoptosis. There is evidence that stretch may activate p53, which in turn may enhance expression of pro-apoptotic Bax, reduce expression of antiapoptotic Bcl-2, and up-regulate expression of angiotensin II receptor subtype 1 and angiotensin II genes. On the other hand, it has recently been shown that angiotensin II, endothelin (ET)-1, norepinephrine and other G-proteincoupled agonists may induce cardiomyocyte hypertrophy through generation of ROS, which in turn activates the transcription factor nuclear factor-kappaB via apoptosis signal-regulating kinase-1 . As mentioned above, nuclear factor-kappaB has a clear antiapoptotic effect. The effects of angiortensin II on hypertrophy and apoptosis thus appear closely related. However, the potential importance of angiotensin II stimulation in the genesis of apoptosis is tempered by experimental observations that showed that its continuous intravenous administration for 1 month does not induce apoptosis in mice, even when the angiotensin II receptor subtype 2 is over-expressed. In neurohormonal activation, up-regulation of RAAS is associated with increased plasma levels of ET-1 and other agonists with potential pro-apoptotic actions, including TNF-alpha, as well as with reduced NO availability. Although at high concentrations NO may initiate apoptosis, at low concentrations it has been shown to inhibit apoptosis in various cell types[22,23]. The net effect of this neurohormonal cocktail on the number of cardiomyocytes, myocardial mass, passive properties and function results from extremely complex interactions and cannot be predicted from the effect of individual agonists under experimental conditions. This is best illustrated by the clinical observation that significant RAAS activation may coexist with normal ventricular function for many years in patients with hypertension. Similarly, patients with hepatic cirrhosis and high cardiac output (hyperdynamic syndrome) are exposed to increased sympathetic tone and elevated levels of angiotensin II and ET-1 for years, with essentially normal cardiac function. Moreover, it has recently been observed in cirrhotic rats that the hyperdynamic syndrome is associated with eccentric hypertrophy with strictly normal myocardial function, despite severe neurohormonal activation. G47 G48 J. Soler-Soler and D. García-Dorado Table 2 Angiotensin-converting enzyme inhibition: effect on major cardiovascular events Clinical event Reinfarction Readmission for HF Death or reinfarction Death or readmission for HF Death/MI/readmission for HF Stroke ACE inhibitors (n = 6391) 571 (8·9%) 876 (13·7%) 1725 (27·0%) 1962 (30·7%) 2161 (33·8%) 239 (3·7%) Control (n = 6372) 703 (11·0%) 1202 (18·9%) 2043 (32·1%) 2354 (36·9%) 2610 (41·0%) 249 (3·9%) Odds ratio (95% confidence interval) 0·79 (0·70–0·89) 0·67 (0·61–0·74) 0·77 (0·72–0·84) 0·74 (0·69–0·80) 0·72 (0·67–0·78) 0·96 (0·80–1·15) P 0·0001 <0·0001 <0·0001 <0·0001 <0·0001 0·63 ACE=angiotensin-converting enzyme; HF=heart failure; MI=myocardial infarction. (Data from Flather et al..) Angiotensin-converting enzyme inhibitors Aldosterone receptor inhibition The rationale behind employing inhibition of aldosterone receptors in heart failure is based on the fact that ACE inhibitors do not provide complete, long-term blockade of the RAAS[38,39]. The Randomized Aldactone Evaluation Study (RALES) study demonstrated an impressive Eur Heart J Supplements, Vol. 4 (Suppl G) November 2002 Angiotensin II receptor blockers The incomplete blockade of the RAAS by ACE inhibitors has justified intense research in angiotensin II blockers in heart failure, because they block the system on its distal side, with direct blockade of the type 1 receptor. Although the rationale behind such an approach appears favourable, the recent Evaluation of Losartan in the Elderly (ELITE) II trial and the Valsartan in Heart Failure Trial (Val-HeFT) showed no further benefit on mortality when added to ACE inhibitors. On the other hand, both trials showed an unexpected finding that is of clinical significance, namely the possible harmful effect of too ‘intense’ neurohormonal inhibition. Suspicion of such an effect was raised in a post-hoc analysis that showed that patients who were on three neurohormonal blockers (ACE inhibitor, angiotensin II blocker and beta-adrenergic blocker) did worse than those without beta-blockers. The definite place of angiotensin II blockers in the management of heart failure remains to be elucidated. Three very large trials including more than 30,000 patients, with different angiotensin II blockers (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity [CHARM], Valsartan in Acute Myocardial Infarction Trial [VALIANT] and Optimal Trial in Myocardial Infarction Downloaded from http://eurheartjsupp.oxfordjournals.org/ by guest on September 16, 2014 Angiotensin-converting enzyme (ACE) inhibitors were the first drugs to show increased survival in patients with chronic heart failure. In 253 elderly patients (mean age 74 years) with severe heart failure (New York Heart Association functional class IV) enrolled in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS), enalapril administration resulted in a statistically significant reduction in mortality of 40% (33 deaths in the enalapril arm versus 55 deaths in the placebo arm) at 6 months. Since that report was published (1987), many other studies conducted in various heart failure populations have shown similar results[32,33]. A recent metaanalysis of five major trials of different ACE inhibitors (i.e. Survival and Ventricular Enlargement [SAVE], Acute Infarction Ramipril Efficacy [AIRE], Trandolapril Cardiac Evaluation [TRACE], Studies of Left Ventricular Dysfunction [SOLVD]-Treatment and SOLVD-Prevention), including 12,763 patients followed up for an average of 2·5 years of treatment, demonstrated an absolute death reduction of approximately 6%. Table 2 shows the benefit of ACE inhibition in other major cardiovascular clinical events. In all guidelines on the treatment of heart failure, these data are called upon to support the recommendation of an ACE inhibitor as a first-choice drug in both symptomatic and asymptomatic chronic heart failure associated with systolic left ventricular dysfunction. As mentioned in the introduction to the present review, heart failure is a relentless process. Unfortunately, ACE inhibitors do not stop this progression but just delay the final outcome[35,36]. It is difficult to calculate the net benefit of ACE inhibitors in terms of life prolongation, although some studies suggest a modest additional survival of 0·6–0·9 months[30,35–37]. benefit in terms of global mortality (386 deaths in the placebo arm versus 284 deaths in the treatment arm) of lowdose spironolactone (mean 26 mg . day – 1) when added to conventional therapy (95% on ACE inhibitors), after a mean follow-up period of 24 months. That study included 1663 patients in New York Heart Association functional class III or IV at the time of enrollment. Accordingly, in all guidelines, spironolactone is considered a treatment of choice in severe heart failure. The effect of aldosterone receptor inhibitors on the prevention of heart failure progression is not known, although experimental data indicate an effect on the myocardial interstitial matrix, which might be of important clinical significance. At the present time, a study of mortality in 6000 patients, with a novel selective antagonist of the aldosterone receptor (eplerenone), is underway (the Eplerenone’s Neurohormonal Efficacy and Survival Study [EPHESUS]). Blocking neurohormonal activation with the Angiotensin II Antagonist Losartan [OPTIMAAL]), will clarify this important issue. At present, the use of these drugs is indicated as monotherapy only in patients who are intolerant to ACE inhibitors. Beta-adrenergic blockers Other vasoactive hormone receptors blockers The neurohormonal activation hypothesis, and the beneficial effects of RAAS and sympathetic nervous system blockade stimulated development of blockers of other vasoactive neurohormone receptors related to the cardiovascular system (Table 1). Interestingly enough, preliminary analyses from a number of clinical trials on mortality have been either neutral or negative (endothelin, vasopeptidases, TNF-alpha, etc.), despite the fact that pilot or mechanistic studies had shown clinical and haemodynamic benefit. A typical example of this paradox is the neutral findings of the recent trial of omapratilat (n = 5770), despite the fact that this drug had shown very positive acute and long-term (12 weeks) haemodynamic and neurohormonal effects in 369 patients. These findings raise the very important issue of whether there is a limit of blockade of neurohormonal activation in chronic heart failure, beyond which there is no further benefit of such interventions. It could well be that larger is not better. Conclusion The results of clinical trials show that some neurohormonal blockers may improve survival and symptoms, and delay the progression of heart failure, but they are not able to prevent or reverse it. There is solid evidence of increased apoptosis in many situations associated with heart failure and neurohormonal activation; however, neither the causative role of neurohormonal activation in the genesis of apoptosis nor the role of apoptosis in the progression of heart failure, although likely, have been definitely proven. 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