MEDICAL GRAND ROUNDS W I L L I A M S. WILKE, M D , EDITOR

Heart failure is a fever: The cytokine connection

TAKE-HOME POINTS FROM LECTURES BY CLEVELAND CLINIC AND VISITING FACULTY

JAMES B .YOUNG, M D * Medical Director, Kaufman Center for Heart Failure; Head, Section of Heart Failure and Cardiac Transplant Medicine, Department of Cardiology, Cleveland Clinic; investigator, HOPE trial

ABSTRACT Inflammation probably contributes to the development and progress of heart failure. Proteins called cytokines, which are produced by damaged tissues and leukocytes as part of the inflammatory response, affect the heart both directly and indirectly. They exacerbate hemodynamic imbalances, act as negative inotropes, stimulate left ventricular hypertrophy, and promote the production of still more cytokines, which continue the cycle. Several medications counter these effects in vitro, and some are in clinical testing.

N F L A M M A T I O N is a largely ignored con-tributor to the complex, multifactorial

disease of heart failure. An exploration of the role of inflammation may lead to additional therapies that will reduce the death toll from this disease.

• PREVALENCE OF HEART FAILURE

More than 5 million Americans have conges-tive heart failure; perhaps 3 or 4 times that many have systolic or diastolic left ventricular dysfunction. Despite therapeutic advances, men with a diagnosis of symptomatic heart failure can expect to live only about 2 years; women, 3 years.

'The author has indicated that he is receiving grant or research support f rom Immunex, which is supporting the RENAISSANCE trial of etanercept in congestive heart failure.

• CHANGES IN THE THEORY OF HEART FAILURE

Over the past 40 years, concepts of heart fail-ure have evolved radically. Heart failure was once considered primarily a congestive state to be treated with diuretics. By the 1970s, the condition was considered a hemodynamic abnormality; vasodilators were used to lower preload and afterload, and research focused on developing inotropes. Ten years later, researchers were exploring the effects of the adrenergic and neurohormonal systems: epi-nephr ine and norepinephrine, the renin-angiotensin system, vasopressin, and atrial natriuretic peptide.

More recently, attention has focused at the cellular level. Mature heart myocytes are so-called terminally differentiated cells, not designed to grow or reproduce. W h e n forced to grow by hypertension or the ischemic death of neighboring cells, they do so abnormally; specifically, the membrane receptors involved in receiving adrenergic signals fail to function correctly. These changes contribute to left ventricular hypertrophy and fibrosis, which impair systolic function, diastolic function, or both. Systemic blood flow is reduced and organ perfusion is impaired, which triggers autoregulatory mechanisms that, in turn, act on the heart in an attempt to increase cardiac output.

Each of these new concepts of hear t disease has cont r ibuted to our unders tand-ing. We believe tha t all the mechan i sms— hemodynamic , neurohormona l , and cellu-la r—inte rac t in complex feedback loops to p roduce t h e c l in ica l m a n i f e s t a t i o n s of h e a r t fa i lure : conges t ive hea r t fa i lure , acute pulmonary edema, or sudden cardiac dea th .

Heart failure is an interaction between congestive, hemodynamic, adrenergic, neurohormonal, and inflam-matory factors

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MEDICAL GRAND ROUNDS

Inflammatory cytokines involved include TNF-alpha, IL-1, and IL-6

• INFLAMMATION AS A FACTOR

For at least a century, certain inflammatory conditions have been known to be associated with hypotension and cardiogenic shock, as well as with tumor necrosis. At the beginning of the 20 th century, a physician named William Couley found that a suspension of streptococci and Bacillus prodigiosus could induce tumor necrosis in unresectable metastatic malignancies, but could also pro-duce fatal hypotensive shock and pulmonary edema. Fifty years later, Irvine Page at the Cleveland Clinic found that a similar "pyro-genic" cocktail could temporarily lower arteri-al pressure in patients with malignant hyper-tension, but was fatal to those with cardiac decompensation.

Inflammation is now known to be caused by inflammatory cytokines, small proteins that are involved in the response to bacterial infec-tion, the repair of damaged tissue, and the swelling and elevated temperature typical of inflammation. O n e of these inflammatory cytokines, tumor necrosis factor alpha or TNF-alpha, is also involved in tumor necrosis, as well as in the cachexia and anemia that develop in patients with cancer or chronic dis-ease.

Significantly, chronic advanced heart fail-ure is also associated with cachexia mimicking that of advanced cancer, as well as with ane-mia and fever without infection. T h e link between heart failure and cytokines was first established in a 1990 report showing that T N F was elevated in cachectic patients with heart failure.1 Many other symptoms of advanced congestive heart failure are also typical of cytokine activation: anorexia, malnutrition, hypoalbuminemia, leukopenia, low choles-terol, elevated sedimentation rate, and high levels of fibrinogen and acute-phase reactants.

• TNF-ALPHA ACTS DIRECTLY A N D INDIRECTLY

Further studies suggested that TNF-alpha not only induces cachexia in heart failure patients but also directly and indirectly promotes heart failure itself. In isolated myocyte preparations, muscle preparations, and animal models, TNF-a lpha is a dose-dependent negative

inotrope. A fusion protein made from T N F receptor reverses TNF-induced left ventricular dysfunction. In rats and mice, TNF-alpha infusion or genetic overproduction of TNF-alpha results in progressive left ventricular dysfunction, hypertrophy, and heart failure. Al though TNF-alpha is known to induce both necrosis and apoptosis, the left ventricular hypertrophy appears instead to be a response to TNF-induced collagen breakdown.2

TNF-alpha increases capillary permeabil-ity. T h e mediator of endotoxemic shock, TNF-alpha has long been known to produce so-called "non-card iogenic" pulmonary edema and is probably a mediator of cardio-genic pulmonary edema as well. TNF-alpha is elevated in a variety of cardiac disease states in situations where other causes can be ruled out.3

As heart failure becomes more severe, lev-els of TNF, IL-6, and natriuretic peptides rise. In fact, the TNF-alpha level may be an inde-pendent predictor of adverse outcome.4

• DAMAGED HEART MUSCLE BECOMES INFLAMED

Although TNF-alpha is primarily produced by macrophages and leukocytes, it is also pro-duced by myocytes and fibroblasts. T h e myocyte can be induced to produce TNF-alpha by endotoxin but also by pressure over-load or injury. Thus, in my opinion, we could classify TNF-alpha as a stress protein.

In a vicious circle, TNF-alpha also stimu-lates macrophages and other cell types to pro-duce more TNF-alpha as well as other inflam-matory cytokines such as IL-1 and IL-6, which are responsible for fever and malaise and per-petuate the left ventricular remodeling.

In summary, the cytokine hypothesis holds that cytokines exacerbate hemodynam-ic abnormalities or exert direct toxic effects on the heart to produce and worsen heart failure. Thus, the cytokine mechanism is coupled with all the other mechanisms behind heart failure.

Inf lammation is repair, a response to injury. It makes sense that injured myocardi-um is also inflamed myocardium. Why we ignored the implications for heart disease for so long is a bit of a mystery to me.

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• CYTOKINES A N D THERAPY FOR HEART FAILURE

It certainly seems possible to come up with agents that would reverse or attenuate the effects of inflammatory cytokines on the heart, although it will be important to screen for side effects that might be harmful in patients with heart failure.

A number of current medications are known or suspected to have anti-TNF-alpha effects. T h e phosphodiesterase inhibitors down-regulate product ion of cytokines including TNF, although, unfortunately, these drugs are inotropes and increase mortality in patients with heart failure. Pentoxifylline, a medication approved for treating intermittent claudication, is a potent cytokine inhibitor. In fact, its effectiveness in claudication and peripheral vascular disease may result in part from its anticytokine effects.

T h e antiarrhythmic medication amio-darone, when given in doses so small as to be subtherapeutic against arrhythmia, benefits heart failure patients.5-6 A different mecha-nism of action may be at work, and this mech-anism may be anticytokine. Other potential anticytokine agents include thalidomide and the new angiotensin I I receptor antagonists.

O n the immunologic front, antibodies and antagonists to TNF-a lpha and T N F receptor have been developed. Etanercept (Enbrel), which is very effective for rheuma-toid arthritis, interferes with TNF-alpha sys-temically and in the heart. In a safety study in

pat ients with heart failure, e tanercept decreased levels of biologically active TNF-alpha, made a small but significant improve-ment in ejection fraction, and produced a marked improvement in patients' perceived quality of life.7 This experience set the stage for clinical testing in several ongoing trials: the Randomized Etanercept North American Strategy to Study AntagoNism of CytokinEs (RENAISSANCE) and the RENEWAL and RECOVER trials. i l

• REFERENCES

1. Lev ine B, Ka iman J, M a y e r L, Fi l l i t H M , Packer M . E levated c i r cu la t i ng levels o f t u m o r necrosis f a c t o r in severe ch ron ic hea r t fa i l u re . N Engl J M e d 1990; 323:236-241.

2. B o z k u r t B, Kr ibbs SB, C lubb FJ, e t al. Pa thophys io log ica l l y re levan t concen t ra t i ons o f t u m o r necrosis f a c t o r - a l p h a p r o m o t e progressive le f t ven t r i cu la r d y s f u n c t i o n a n d r e m o d e l i n g in rats. C i rcu la t ion 1998; 97 :1382-1391 .

3. T o r r e - A m i o n e G, Kapad ia S, Bened ic t C. Ora l H, Y o u n g JB. P r o i n f l a m m a t o r y cy tok i ne levels in pa t i en ts w i t h depressed le f t ven t r i cu la r d y s f u n c t i o n (SOLVD). J A m Coll Card 1996; 627 :1201-1206.

4. M a n n DL, Y o u n g JB. Basic mechan isms in conges t i ve hea r t fa i l u re ; r ecogn i z ing t h e r o l e o f p r o - i n f l a m m a t o r y cy tok ines. Chest 1994; 105:897-804.

5. M a h a m a r i a n JJ, Smar t FW, M o y e LA, e t al . Exp lo r i ng t h e m i n i m a l dose o f a m i o d a r o n e w i t h a n t i a r r h y t h m i c a n d h e m o d y n a m i c act iv i ty . A m J Card io l 1994; 74 :681-686 .

6. Si lver MJ, Y o u n g JB, Topo l EJ. A m i o d a r o n e in conges t i ve hea r t f a i l u r e [ le t te r ] , N Engl J M e d 1995; 333 :1639-1641.

7. D e s w a l A , B o z k u r t B, Seta Y, e t al. Safety a n d e f f icacy o f a so lub le P75 t u m o r necrosis f a c t o r r ecep to r (Enbrel , e t ane rcep t ) in pa t ien ts w i t h advanced h e a r t f a i l u re . C i r cu la t i on 1999; 99 :3224-3226.

ADDRESS: James B. Young, MD, Cardiac Catheterization Laboratory, F25, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, e-mail youngj@ccf.org.

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