1. Section III: Neurohormonal strategies in heart failure
B. Mechanisms of heart failure: Cardiovascular dysfunction
Progression from hypertension to HF
Content points:
HF may be viewed as a progressive disorder initiated after an index event either damages heart muscle or disrupts the ability of the myocardium to contract normally, impairing the ability of the ventricle to fill with or eject blood.6 Hypertension and myocardial infarction (MI) are the most important risk factors for HF.
Onset of the index event may be abrupt (eg, myocardial infarction), or gradual (eg, hemodynamic pressure or volume overload related to hypertension).
In most instances, compensatory mechanisms are activated and patients remain asymptomatic following the initial decline in pumping capacity. Symptoms develop after the dysfunction has been present for some time.
The principal manifestation of HF progression is remodeling, which occurs in conjunction with homeostatic attempts to decrease wall stress through increases in thickness. To compensate for increased peripheral resistance in hypertension, the heart may hypertrophy with left ventricular (LV) enlargement accompanied by fibrosis and reduced contractility. Ultimately, the hypertrophied or fibrotic myocardium can no longer maintain normal cardiac output and LV failure occurs.

2. Interplay between cardiac function and neurohormonal system in HF
Content points:
Myocardial injury of many origins can depress cardiac function, resulting in activation of compensatory mechanisms, notably the adrenergic nervous system (ANS) and the renin-angiotensin aldosterone system (RAAS). Elaboration of endothelin (a potent vasoconstrictor polypeptide), arginine vasopressin (antidiuretic hormone), and cytokines (polypeptides that act as mediators) form part of the complex and multifaceted response to injury.7
In acute HF, these mechanisms are adaptive and tend to maintain arterial pressure and cardiac function.
In chronic HF, activation of these mechanisms in the failing heart promotes maladaptive growth, remodeling, and progressive myocardial dysfunction. Inhibition of these systems with neurohormonal blockade prevents or reverses these adverse biological processes, leading to improvement in the natural history of HF. Drugs that antagonize the RAAS and ANS, including ACE inhibitors, angiotensin type 1 (AT1) receptor blockers, and β-blockers, reduce HF progression.
Drugs under development that have potential for preventing HF progression include blockers of endothelin-A receptors (ETA), which mediate the proliferative and vasoconstrictive effects of endothelin, and agents that block receptors for tumor necrosis factor-α (TNF-α).

3. Pathophysiology of myocardial remodeling: Transition from compensated hypertrophy to HF
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Myocardial remodeling and the transition from compensated hypertrophy to failure of the myocardium involves multifaceted events at the molecular and cellular level.8
Remodeling stimuli, such as increased mechanical wall stress and neuroendocrine activation, lead to manifold molecular and cellular events.
– Hypertrophy of cardiac myocytes
– Changes in the quantity and nature of the interstitial matrix
– Changes in gene expression with re-expression of fetal programs and decreased expression of adult programs
– Cell death
These events precipitate changes in the structure and function of the ventricle, which may result in added pump dysfunction and increased wall stress, promoting further pathologic remodeling.

4. Biologic effects of neurohormones coactivated in HF
Content points:
Regardless of etiology, cardiac remodeling and disease progression are driven by expression of groups of biologically active molecules that are stimulated in patients with compensated cardiac hypertrophy before the onset of HF.9
Coactivation of norepinephrine, angiotensin II (Ang II), endothelin, and TNF, as well as aldosterone in compensated hypertrophy contributes to cardiac remodeling and disease progression through toxic effects on the heart and circulation. Neurohormonal activation worsens myocardial dysfunction and remodeling, through effects on myocyte apoptosis, necrosis, and hypertrophy, by activation of the fetal gene pattern, and by contributing to extracellular matrix alterations. Norephineprine and TNF promote uncoupling of β-adrenoreceptors

5. Induction of fetal gene pattern in hypertrophy and HF
Content points:
The process of hypertrophy is accompanied by qualitative changes in the expression of genes that depress contractile function.10 The changes in myocardial gene expression in hypertrophy and HF are termed fetal gene reinduction because they resemble the prenatal pattern.
Human myocardium undergoes changes in expression of myosin heavy chain isoforms and sarcoplasmic reticulum Ca++-handling proteins that interfere with contractile function and decrease systolic and diastolic function. This mechanism of fetal gene reinduction probably contributes to failure of the myocardium in the context of pathological hypertrophy.

6. Diagnostic and prognostic significance of neuroendocrine factors in HF
Content points:
Neuroendocrine factors are elevated in compensated cardiac hypertrophy and HF. These markers might be useful in HF diagnosis and prognosis.11,12
Elevated plasma norepinephrine levels are directly related to prognosis. Endothelin-1 (ET-1) plasma levels are elevated in HF and correlate with both hemodynamic severity and symptoms. Plasma levels of ET-1 are strong independent predictors of mortality in HF.
Elevated levels of the proinflammatory cytokines have prognostic significance. TNF-α is increased in HF and seems to reflect the severity of the disease. The strongest prognosticator in the TNF- α system seems to be the soluble TNF receptor-1. It has also been shown that TNF- α is increased especially in cachectic HF patients. B-type or brain natriuretic peptide (BNP) is a balanced vasodilator with no inotropic nor chronotropic properties. Plasma levels can be used in diagnosis and prognosis of patients with HF.
A neuroendocrine profile can also shed light on different aspects of HF. For example, BNP and ANP increase early in HF progression in asymptomatic patients. They are sensitive markers of HF severity and closely related to LV function.
At present, no hormone measurement alone is sufficient for making a diagnosis of HF, but a combination of echocardiography and one neurohormonal value—for example, BNP—would give a firmer diagnosis than echocardiography alone. Kell and coworkers showed that plasma interleukin-6 (IL-6) concentrations might be a clinically useful marker for long-term survival (>1 year) in NYHA class III patients.12 Combining IL-6 concentrations with LV ejection fraction increases the predictive power.

7. ß-Blockade decreases TNF-α and natriuretic peptides in HF patients treated with ACEI
Content points:
Ohtsuka et al evaluated the effect of β-blockade on circulating cytokine levels in patients with dilated cardiomyopathy.13 The study included 32 patients who had been treated with ACE inhibitors for 6 months. Baseline levels of TNF-α were significantly higher in patients than in control subjects and decreased significantly after 12 weeks of β-blockade.
In another study, the same Japanese research team showed that plasma levels of the natriuretic peptides ANP and BNP decreased significantly after 6 months of β-blockade in HF patients treated with ACE inhibitors for 6 months.14
ACE inhibition has been shown to reduce IL-6, but demonstrated no effect on other inflammatory cytokines.15 It therefore appears that ACE inhibition and β-blockade have different mechanisms and that combination therapy may be better able to modify the dysregulated cytokine network in HF patients.13

8. Biological responses mediated by adrenergic receptors in the human heart
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The failing human heart is adrenergically activated, which initially helps to maintain cardiac performance by increasing contractility and heart rate. Chronic adrenergic signaling, however, is a harmful compensatory mechanism.16
Human cardiac myocytes have three adrenergic receptors (β1, β2, and α1) coupled to a positive inotropic response and cell growth. Increased sustained sympathetic drive downregulates β1-receptors and desensitizes the β-adrenergic system. The adrenergic receptor profile in the cardiac myocyte changes from >70% β1-adrenergic receptors to more of a mixed, 2:1:1 (β1: β2: α1) ratio in end-stage HF.
Continuously increased adrenergic drive in chronic HF delivers adverse biological signals in cardiac myocytes via β1- and β2-adrenergic receptors, and possibly via α1-adrenergic receptors. The data are extremely convincing for chronic β1-receptor signaling and less convincing, but likely, for chronic β2- and α1-receptor pathway activation. Elimination of these adverse signals is the fundamental basis for the use of antiadrenergic agents in the treatment of chronic HF.

9. Metoprolol upregulates cardiac β1-receptor density in the failing heart
Content points:
Gilbert and coworkers showed that metoprolol (a β1-selective agent), increased total β-receptor density in the heart, presumably because of upregulation of the β1-receptor subtype, which is downregulated in the failing human heart.17 The observations were made in endomyocardial membrane biopsy specimens obtained at baseline and after 6 months of treatment from patients with mild or chronic HF. By comparison, there was no change in cardiac β-receptor density in the group receiving carvedilol (a nonselective β-blocker). Markers of myocardial function, such as LV ejection fraction, improved in both the metoprolol and carvedilol groups, regardless of the effect on β-receptor activation.
Downregulation of β-adrenergic receptors in the failing heart appears to contribute to a loss of maximal exercise responses, which would be expected as a result of diminished adrenergic signal transduction. The effect of metoprolol (a β1-selective agent) on total β-receptor density in the heart, as well as changes in receptor affinity, may explain why exercise capacity improves in some patients with long-term treatment with β1-selective agents, and not with nonselective agents such as carvedilol.18

10. ß-Blockade reduces cardiomyocyte apoptosis in dogs with HF
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Chronic therapy with metoprolol for 3 months decreased cardiomyocyte apoptosis (programmed cell death) in LV myocardium in dogs with moderate HF.19 In metoprolol-treated dogs, the incidence of cardiomyocyte apoptosis was lower in LV regions bordering old infarcts and in regions remote from any infarcts. As shown in this slide, cardiomyocyte apoptosis was also lower in LV tissue homogenates.
Observations in this study are in agreement with recent reports that norepinephrine-mediated apoptosis occurs via a β1-adrenergic receptor pathway. Preventing or attenuating loss of cardiomyocytes in HF by apoptosis may be one mechanism by which β-blockade achieves beneficial effects in patients with HF.

11. Strategies to prevent/reverse HF progression
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Neurohormonal activation in HF leads to progression of the disease as a result of overexpression of biologically active molecules that exert toxic effects on the heart independent of the patient’s hemodynamic status. Current neurohormonal treatment strategies employ neurohormonal antagonists that are known to blunt HF progression.20 Patients with asymptomatic and symptomatic LV dysfunction should receive both ACE inhibitors and β-blockers to antagonize the RAS and adrenergic systems. However, HF may progress in patients receiving optimal ACE inhibition and β-blockade because these agents do not directly and/or sufficiently antagonize all biologically active systems in HF.
One logical future therapeutic direction will be to develop strategies that more effectively antagonize neurohormonal systems believed to be deleterious. The use of ARBs and new antagonists of vasopeptidase, aldosterone, endothelin, and TNF, for example, will probably be adjuncts to existing clinical strategies in the future.
Novel approaches extend beyond neurohormonal antagonism to reversal of HF phenotype. Preliminary work suggests that gene therapy may one day be used to attenuate HF progression. Surgical, mechanical, and pacing devices, as well as stem cell research, may eventually offer new approaches to prevent or reverse HF progression.