All concepts, explanations, trials, and studies have been re-written in plain English and may contain errors. I am not a doctor ----------------------------------------------------------- NOTE: You can make the print bigger with the font button on your browser! (It's usually a big "A") ---------------------------------------------------------- The Neurohormonal and Immune Systems in Heart Failure SUMMARY Chronic heart failure is a complex disorder involving the cardiovascular, immune, and neurohormonal systems. We discuss interactions between the immune and neurohormonal systems in CHF. Cytokines - such as TNF-alpha - interact tremendously in the body's network of energy use, immune system function, and hormonal function. Cytokines are proteins from the immune system. Some are inflammatory and worsen CHF. Advanced CHF can be considered a state of chronic, low-grade inflammation. Even though drugs targeting TNF-alpha have failed in trials, anti-cytokine therapy could help people with advanced CHF. In the future, it may not be enough to monitor heart function alone. CHFers' immune and neurohormonal status may also need to be tracked. LONG VERSION - INTRODUCTION Chronic heart failure (CHF) includes heart dysfunction, as well as non-heart changes resulting the body's responses to damaged heart muscle. We now know that CHF is a multisystem condition. CHFers have neurohormonal and inflammatory cytokine over-activity. CHFers with a wasting, drastic weight-loss condition called "cachexia" have a poor prognosis, with serious endocrine and immune system abnormalities. THE IMMUNE SYSTEM AND CYTOKINES Studies have shown that CHF is linked to increased circulating levels of inflammatory cytokines. Cytokines are low-molecular- weight proteins that are released by most cell types. They have actions on their producing cell and also on other cells. Unlike hormones, cytokines are not stored - they are produced in response to specific situations. The cytokines considered most important in heart failure are TNF-a and IL-6. TUMOR NECROSIS FACTOR-A (TNF-a) TNF is a molecule with a half-life of about 30 minutes. It can be measured in the watery portion of blood by different methods. High TNF levels are seen in both the blood and hearts of CHFers. TNF encourages heart enlargement and harmful shape changing called heart remodeling. TNF levels are particularly high in CHFers with cachexia. Apoptosis (cell death) is frequently seen in CHFers' skeletal muscle, and reduces exercise capacity. Animal trials show that TNF can cause skeletal muscle wasting and apoptosis. The actions of TNF occur when it binds to one of two specific receptors (TNF receptors 1 and 2, or TNFR-1 and TNFR-2). These receptors are found on most cells. Left-over fragments from this binding on cell surfaces can be detected as forms called sTNFR-1 and sTNFR-2. The exact role of sTNFRs is unknown. One idea is that sTNFRs may stabilize the TNF molecule, allowing it to survive longer. However, at higher levels, sTNFRs reduce TNF activity. So another idea is that in CHF - where too much TNF is too active - maybe sTNFRs regulate TNF activity. sTNFR-1 is also increased in stable, non-wasting CHFers. TNF directly influences heat production in the body, and it may encourage high insulin and leptin levels - high leptin is common in CHFers. Artery tightening called vasoconstriction also occurs in CHF. This reduces left heart function by increasing the pressure the heart pumps against. TNF worsens vasoconstriction. IL-1 AND IL-6 IL-1 is produced by several different cell types and is important in immune system response. In CHFers without CAD, IL-1b RNA is seen in coronary arteries and heart tissue but much less is seen in CAD patients. IL-1 reduces the heart's pumping power. IL-1 and TNF both reduce the ability of the heart's beta receptors to function properly. IL-6 is another inflammatory cytokine. CHFers have high IL-6 levels in their blood, and this is linked to poor heart class, longer hospital stays, and poor left heart function. IL-6 may also contribute to osteoporosis. IMMUNE SYSTEM MARKERS IN HEART FAILURE Poor prognosis in CHFers is marked by high blood levels of TNF, sTNFR-1, sTNFR-2, IL-6, and soluble CD14 (the receptor for endotoxin). sTNFR-1 seems to be the most accurate independent predictor of survival in CHF. Unfortunately, measuring for this is very difficult and expensive, so it is not routine. Other measures that indicate sTNFR level may be used though, such as measuring C-reactive protein, uric acid, or erythrocyte sedimentation rate. THEORIES ON IMMUNE SYSTEM ACTIVATION We don't know why the immune system is so overactive in CHF. There are 3 main theories but new ones may pop up any time. One says the heart is the main producer of inflammatory cytokines, since we know the failing heart produces TNF. Studies show that high heart pressures stimulate TNF RNA production. Another idea is that the bowel wall edema and ischemia that occur in CHF due to fluid retention cause unusual bacteria movement, leading to endotoxin release, which triggers the immune system. CHFers have increased endotoxin and cytokine levels when their edema (swelling) flares up. Endotoxin can cause TNF RNA production in the body. If this is true, therapies directed against bacteria in the bowel wall, endotoxin itself, or the binding of endotoxin to cells of the immune system might help CHF. The third idea is that cytokine production outside the heart due to lack of oxygen in tissues may be the primary trigger for increased TNF in CHFers. Tissue oxygen starvation and free radical production are potent triggers for cytokine release. Probably though, more than one mechanism causes the immune activation in heart failure. NEUROHORMONAL ACTIVATION Increased catecholamine level, overactivity of the RAS (renin- angiotensin/aldosterone system) and increased BNP and ANP (natriuretic peptides) all occur in CHF. At first, these changes strengthen the heart but over time they become harmful. Several studies suggest that neurohormonal overactivity is strongly linked to increased risk of death. However, a drug's ability to reduce catecholamine levels is not directly related to its mortality benefit! Both nor- epinephrine and epinephrine increase heart rate and these levels are high in CHFers. Cortisol and aldosterone blood levels are especially high in CHFers with wasting (cachexia). Insulin resistance is often seen in CHFers. High TNF levels are seen in CHFers with insulin resistance and may be one cause of it (as is seen in obesity-related insulin resistance). There are also abnormalities of IGF-1 (insulin-like growth factor-1) in CHFers with wasting. Growth hormone (GH) levels increase, but IGF-1 levels stay the same or may even fall. This suggests resistance to growth hormone occurs. Giving GH to CHFers has shown mixed results. Steroid metabolism is also abnormal in CHFers. Stress hormones like noradrenaline, adrenaline, and cortisol are higher in CHFers with wasting compared to non-wasting patients, but levels of the anabolic hormone DHEA are reduced. The cortisol/ DHEA ratio increases as TNF level increases - as both these measures increase, body mass goes down (wasting). These steroid hormone changes change the balance of T-helper-1 and T-helper-2 cells of the immune system. TREATING NEUROHORMONAL AND IMMUNE SYSTEM OVER-ACTIVITY IN CHF Angiotensin II is a potent stimulator of both the immune system and neurohormones. ACE inhibitors and ARBs block angiotensin II type-1 receptors with excellent results in CHFers. Circulating levels of ANP and BNP, TNF, and IL-6 all go down with ACE inhibitor use. ACE inhibitors can also raise low levels of circulating IGF-1 in CHFers. One trial studied how an ARB called candesartan affected immune system markers in 23 patients with mild to moderate CHF. Candesartan reduced blood levels of TNF, IL-6, and BNP. However, caution is necessary when deciding how significant changes in such levels really are in CHFers! For example, although spironolactone reduces mortality and hospitalizations in CHFers, the drug actually increases neurohormone activity. Inotropes called phosphodiesterase inhibitors, like amrinone, vesnarinone, and pimobendan, all show short-term benefits in CHF. They inhibit production of TNF and other cytokines from lymph cells. However, these drugs increase risk of death long-term in CHFers. NON-DRUG THERAPY Fish oil supplements lowered IL-1b level and improved wasting in CHF. The reduction in IL-1b levels in this study related to survival. Although this may seem a rather basic type of therapy, it suggests that anti-inflammatory cytokine therapy may be useful in treating CHFers. Title: Immune and Neurohormonal Pathways in Chronic Heart Failure. Authors: Rakesh Sharma, BSc, MRCP, Stefan D. Anker, MD, PhD. Source: CHF 8(1):23-28, 48, 2002.