Review ArticleCytokines and Myocardial Dysfunction: State of the Art
Section snippets
Immune Activation in Heart Failure
CHF may be considered a state of immune activation and persistent inflammation expressed by increased circulating levels of pro- and anti-inflammatory cytokines.7, 8, 9 Immune activation in CHF includes two mechanisms: (1) immune activation by direct antigenic stimulation, as seen with acute myocarditis and heart transplant rejection, and (2) immune activation secondary to cardiac injury that exposes “new antigens” capable of triggering an immune response against the heart, as occurs after
Do Cytokines Antedate or Aggravate Heart Failure?
The increased production of proinflammatory cytokines and other inflammatory markers may identify patients at a greater risk of developing HF in the future.10, 15 The clinical studies evaluating cytokines and HF have been limited to patients with symptomatic disease in the setting of documented systolic dysfunction. However, Vasan et al.16 sought to determine whether elevated levels of inflammatory markers antedate the development of CHF in individuals free of the condition. A subgroup of 732
Cytokines and Neurohormonal Mechanism
The pattern of cytokine expression in HF parallels that seen with classic neurohormones. However, elevated cytokine levels are detectable before neurohormonal activation in early HF,22 making them potentially more sensitive determinants of cardiac function. In neurohormonal substudies of the SOLVD trial,23 TNF-α and IL-6 levels were randomly selected from patients in New York Heart Association (NYHA) functional classes I to III and age-matched healthy subjects. The plasma levels of TNF-α were
Cytokine Hypothesis
Cytokines, when expressed at sufficiently high concentrations, such as those that are observed in HF, are sufficient to mimic some aspects of the so-called HF phenotype, including (but not limited to) progressive LV dysfunction, pulmonary edema, LV remodeling, fetal gene expression, and cardiomyopathy.23, 28, 29, 30 Thus, the “cytokine hypothesis” for HF holds that HF progresses, at least in part, as a result of the toxic effects exerted by endogenous cytokine cascades on the heart and
Amlodipine
In the Prospective Randomized Amlodipine Survival Evaluation trial,73 the plasma levels of TNF-α and IL-6 were measured in patients with NYHA classes III and IV CHF. Patients were randomized to receive amlodipine (10 mg/d) or placebo. The baseline amlodipine and placebo groups did not differ in demographics and cytokine levels; these levels were elevated 6 and 10 times, respectively, compared with those of healthy subjects (P < .001). The levels of TNF-α did not change significantly during the
Anticytokine Therapy in Heart Failure
Many reasons may call for using anti-inflammatory strategies in patients with CHF. For example, the excessive elaboration of proinflammatory cytokines seems to mimic many aspects of the CHF phenotype, many of the deleterious effects of inflammatory mediators are potentially reversible once inflammation subsides, and CHF remains a progressive disease process despite optimal therapy with antifailure therapy.9, 101, 102 The favorable results of anticytokine treatment in other inflammatory diseases
RENAISSANCE, RECOVER and RENEWAL
In the anticytokine clinical trials, the use of either a soluble TNF receptor (RENEWAL) or an anti-TNF antibody (ATTACH) was not beneficial to patients with HF. Etanercept is a recombinant human TNF receptor protein that binds to circulating TNF and functionally inactivates TNF by preventing it from binding to its receptors on cell surface membranes. Thus far, treatment with etanercept has resulted in clinical improvements in patients with rheumatoid arthritis and psoriasis.121, 122 Preclinical
ATTACH Trial
The ATTACH trial (Anti-TNF-α Therapy Against Chronic HF) enrolled 150 patients with CHF to investigate the impact of treatment with infliximab, a chimeric (mouse/human) immunoglobulin-G1 monoclonal antibody that binds both soluble and membrane bound TNF-α.64 Similar to RENAISSANCE and RECOVER, the ATTACH trial was a multicenter, randomized, double-blind, placebo-controlled study. It also was stopped prematurely. However, when analyzing the data from ATTACH, it is noteworthy that the plasma
Food and Drug Administration Report
The Food and Drug Administration reported 47 cases of new and/or worsening CHF in patients receiving anti-TNF therapy for rheumatoid/Crohn's disease: 38 patients (26 receiving etanercept and 12 receiving infliximab) developed new-onset CHF and 9 patients (3 receiving etanercept and 6 receiving infliximab) experienced CHF exacerbation. Nineteen of the 38 patients with new-onset CHF (12 receiving etanercept and 7 receiving infliximab) had no identifiable risk factors. In 10 patients aged less
Failure of Anti-Tumor Necrosis Factor Therapy in Heart Failure
Therapeutic strategies aim at TNF neutralization, with monoclonal antibodies or TNF receptor fusion proteins. By enhancing the production of vascular NO, TNF-α may play an important role in enhancing the production of adrenomedullin and other endogenous vasodilators and maintaining peripheral blood flow in patients with HF.130, 131 Furthermore, TNF-α may prevent apoptosis in myocytes under stress,132 and by enhancing the production of myocardial NO, the cytokine may attenuate responsiveness to
Factors Explain Anticytokine Failure
The low physiologic levels of cytokines probably play an important role in tissue remodeling and repair. It is possible that the current anti-TNF-α therapies decrease TNF-α levels to below the physiologic levels required for myocardium repair, which could worsen CHF and increase mortality.130, 134, 135, 136, 137 The increase in the levels of TNF bound to etanercept and the rapid off-rates can increase the duration of TNF bioactivity as a “stimulating antagonist” and thus worsen CHF. Previous
The Future Immunomodulatory Strategy
The question of whether broader spectrum anti-inflammatory strategies (e.g., statins, immunoadsorption, and immune modulation therapy) will have any added value in HF is in its earlier stages.126 Effective blockade of TNF-α activity has also been accomplished using passive immunization. Monoclonal antibodies against TNF-α have proved successful in ameliorating the effects of sepsis and inflammatory bowel disease.145, 146 Introducing immunosuppressive agents in a patient with a chronic disease
Conclusions
The only published recommendations for the use of TNF blockers152 highlighted many points. First, patients with no history of CHF and a concomitant indication for the use of TNF blockers do not need a baseline Doppler echocardiogram to screen for HF. Second, patients with well-compensated, mild CHF and a concomitant indication for the use of TNF-α blockers should undergo Doppler echocardiography. Patients with a normal EF can receive this therapy after a fully informed discussion with the
References (154)
Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm
Cell
(1994)- et al.
Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension
J Am Coll Cardiol
(1996) - et al.
Role of interleukin 6 in myocardial dysfunction of meningococcal septic shock
Lancet
(2004) - et al.
Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD)
J Am Coll Cardiol
(1996) - et al.
Effect of high- versus low-dose angiotensin converting enzyme inhibition on cytokine levels in chronic heart failure
J Am Coll Cardiol
(1999) - et al.
Relationship between tumor necrosis factor–alpha production and oxidative stress in the failing hearts of patients with dilated cardiomyopathy
J Am Coll Cardiol
(2001) - et al.
Basic mechanisms in heart failure: the cytokine hypothesis
J Card Fail
(1996) - et al.
Tumor necrosis factor-alpha pretreatment is protective in a rat model of myocardial ischemia-reperfusion injury
Biochem Biophys Res Commun
(1992) - et al.
The role of tumor necrosis factor in the pathophysiology of heart failure
J Am Coll Cardiol
(2000) - et al.
Elevated circulating levels of serum tumor necrosis factor-alpha in patients with hemodynamically significant pressure and volume overload
J Am Coll Cardiol
(2000)