Fall 2003 Research Q&A Cardiac Output Linked to Severe CFS Cases By Mark Giuliucci Article: “Abnormal Impedance Cardiography Predicts Symptom Severity in Chronic Fatigue Syndrome.” The American Journal of the Medical Sciences. 2003; 326(2):55-60. Synopsis: While the cause of chronic fatigue syndrome (CFS) remains unknown, researchers have noted circulatory irregularities in many patients. These include autonomic nervous system dysfunction, often manifested as orthostatic intolerance; neuroendocrine abnormalities (see story on p. 4); reduced plasma volume; and low red blood cell mass. In combination, some researchers believe, these factors could create deficiencies in blood flow to organs and muscles — with resultant symptoms, such as post-exertional fatigue, that are hallmarks of CFS. New research from the CFS Cooperative Research Center at the University of Medicine and Dentistry of New Jersey has tested the possible link between CFS symptoms and cardiac output (the amount of blood pumped by the heart each minute). Thirty-eight CFS patients participated in the study, along with 27 matched, sedentary controls. All subjects were tested for cardiac output using impedance cardiography, a noninvasive procedure based on the principle that electrical impedance of tissues is proportional to their blood flow. Subjects were tested during a 10-minute resting supine period and a five-minute quiet standing period. Results showed that patients with severe cases of CFS (those who had more symptoms and rated them as substantial or greater in severity) had significantly lower cardiac output than either controls or patients with less-severe CFS — even though mean arterial blood pressure and heart rate did not vary significantly among the groups. Moreover, post-exertional fatigue and flu-like symptoms were predictive of lowered cardiac output (p< 0.0002). The authors say their work suggests that “in some patients with CFS, blood pressure is maintained at the cost of restricted flow, possibly resulting in a low flow circulatory state.” CFS patients with lower cardiac output may not be able to meet the demands of everyday physical activities, leading to fatigue and other symptoms. Lead author Arnold Peckerman, PhD, discusses the study’s findings: Q: What led to the hypothesis that CFS patients may have reduced cardiac output? Dr. Peckerman: Many of the symptoms of CFS, such as post-exertional fatigue, are also symptoms of low cardiac output. A person can have low cardiac output for a number of reasons, but the result is the same — circulation slows down and some organs may not get enough blood flowing through them. If cardiac output falls to the point that it is unable to meet metabolic demands, this is called hypoperfusion. Clinical signs of hypoperfusion include lowering of pulse pressure, cool extremities, altered mentation, rapid resting heart rate, breathing that alternates between deep and shallow, and high blood urea nitrogen relative to creatinine. To be sure, most CFS patients do not show clinical signs of hypoperfusion, and they couldn’t. If you have symptoms like these, you get referred for cardiological evaluation and treated appropriately. You would not be diagnosed with CFS. The point I am making is that the criteria for defining hypoperfusion are conservative. However, if you lower the bar, meaning you entertain a possibility that reduction in blood flow of a lesser degree than that may still be clinically significant, and you pull together the many indications from different research and clinical observations in CFS pointing in this direction, it becomes a reasonable question to ask. Q. The gap in cardiac output between controls and severe CFS cases was wider when subjects were supine than when they were standing. Why might that be? Dr. Peckerman: When you are lying down, blood flow to the heart (venous return or preload) is generally higher compared to what it is when you are standing. Normally, having high blood flow to the heart is good. It helps the heart to work better. But if heart muscle is not working properly, if it is compromised and may become overloaded. Then you have the opposite effect. The more blood goes to the heart, the more the function goes down. This is what happens with heart failure patients. When they’re lying down, their heart’s pumping capacity is reduced. When they stand up, the preload becomes reduced because much of the blood goes to the legs. Normal people have reduced cardiac performance when standing. In these people, it’s the opposite; it improves. In a sense, this is what we found with severe CFS patients. When we looked at the lying position, the difference between controls and the severe patients was greater than when they were standing. If you start with the presumption that these people have orthostatic intolerance due to low blood volume, you’d expect to see larger deviation from the norm when standing. What actually happened was the opposite; it was smaller. Q: Are you saying that some people with severe CFS may have heart failure? Dr. Peckerman: Any such conclusion is really beyond the scope of this study. But what we may be seeing here is a more subtle form. Present medicine is slowly realizing that there are many people with heart failure that is not clinically evident but which may be progressing in that direction. They walk around with an unrecognized disease that is not being treated. Unfortunately, when the symptoms appear, it already may be irreversible. Of course, there could be many other explanations for what we observed in this study. We could not make a statement about heart failure with any certainty based on these preliminary findings. More recently we did a follow-up study that included cardiac stress testing, and the preliminary data we reported at the Experimental Biology conference in April were consistent with this possibility. But much more work still remains to be done. Q. Cognitive dysfunction was not found to be predictive of reduced cardiac output? Dr. Peckerman: That’s true. But this does not mean that cardiac output cannot affect cognitive abilities. It may very well be happening. In fact, patients with severe CFS who had reduced cardiac output rated their problems with memory and concentration quite high. What our analysis did show was that reduced cardiac output was more likely to be found in patients whose main symptoms were some combination of post-exertional fatigue and infectious symptoms such as fever and chills. This was after controlling for headaches, muscle aches, sleep, and other symptoms included in the case definition. The same analysis also found that those patients whose main symptoms related to cognitive functioning had less likelihood of having lowered cardiac output. The most plausible explanation for this is that primary problem in those people is not with low cardiac output, but may lie elsewhere, possibly in the brain. A major stumbling block in studying CFS has been heterogeneity, meaning that different patient groups have different causes for their symptoms — and no reliable means of separating them. This study suggested one way it possibly can be done. Mind you, we wouldn’t find what we found if we didn’t separate our patients into the severe and less severe subsets. However, just looking at symptoms probably would not be sensitive enough. One needs to look for combinations of clinical and physiological markers. The combination we identified was that of low cardiac output, plus high post-exertional fatigue, high fever-chills, and low cognitive problems. This approach seems promising. Q: Can you see any treatments for CFS arising from your findings? Dr. Peckerman: Right now, it’s premature to talk about treatments. We’re looking at a phenomenon that could have a number of different causes. Unless you know the cause, treatment would be a shot in the dark. In fact, it can do harm. For example, if the problem is with the heart it is one thing, but if the problem is with low blood volume it is another. In people with heart failure, blood volume is not low, it is high. So if you assume that low cardiac output is due to low blood volume, and you give someone treatment to increase their blood volume, this isn’t going to make matters better — it may make it worse. Our observations so far have been more consistent with a problem with the heart, but it is too early to tell for sure. The good news is that there are ways to treat the problem of reduced cardiac output if the mechanisms are understood. If you can identify what’s causing it, it’s certainly possible to treat it. Unfortunately, we are nowhere near that point yet in CFS cases.