There's what patients have, and then there's what doctors treat.

The way diseases are classified does not necessarily conform to their underlying mechanisms. Medical science always is trying to increase its understanding of the true causes, rather than merely treating the symptoms of disease. Understanding the genetic profile of diseases is one way of doing that, and has led to conceptualizing cancer, for instance, as several separate cellular diseases that are tied together by their symptom of unchecked cell growth, but not necessarily by their causes.

But old-fashioned clinical sleuthing also can lead to a better understanding of the underlying causes of disorders, as two recent papers demonstrate.

A study in the April 2005 issue of the Journal of Cardiac Failure by scientists from Columbia University's College of Physicians and Surgeons showed that a certain type of heart failure apparently is due to a variety of underlying mechanisms.

Big Heart, Small Heart: It's All Relative

The study investigated patients who had heart failure but normal ejection fractions, or diastolic heart failure. The condition describes patients whose hearts pump blood out normally but have trouble filling with blood. It previously was believed that such patients had small hearts that could not hold much. However, the Columbia study showed that many patients with heart failure and normal ejection fractions had hearts that were bigger than average.

In diagnosis, cardiac failure patients' hearts typically are compared to a standardized heart size similar to that of a healthy young person. However, heart failure preferentially affects elderly women, who have smaller hearts. When the researchers compared the hearts of heart failure patients to the hearts of healthy elderly patients, "not only were the heart failure hearts not smaller, but in many cases they were larger," said Mathew Maurer, assistant professor of medicine at the College of Physicians and Surgeons and the study's lead author.

The scientists showed that the patients fell into two groups, and the majority had ventricles with no trouble filling. Maurer and his colleagues concluded that the reason for the heart failure in those patients might not be located in the heart itself, and treating the root causes, such as obesity or hypertension, might be a more promising approach.

The use of the wrong control group to determine normal organ size, by the way, has a long clinical tradition. In the 19th century, most autopsies were performed on cadavers from poorhouses, people who had suffered from chronic stress while alive and, thus, had enlarged adrenal glands. Doctors had a much-inflated idea of the average size of the adrenal glands due to their skewed sample, and the rare middle-class cadaver that made its way to the autopsy table promptly was diagnosed with "idiopathic adrenal atrophy."

Getting At Causes Of Hemolysis Symptoms

While the Journal of Cardiac Failure paper divvies up previously lumped categories of patients, a paper in the April 6, 2005, issue of the Journal of the American Medical Association takes the opposite approach. There, researchers from Alexion Pharmaceuticals Inc., the Leeds Teaching Hospital in Leeds, UK, and the National Institute of Heart, Lung and Blood Disorders in Bethesda, Md., suggested that a variety of disparate symptoms can be explained by an underlying cellular phenomenon.

The JAMA article does not report on new experiments, but instead is a literature review. The study was born out of clinical trial results with Alexion's monoclonal antibody eculizumab, which is in Phase III trials to treat paroxysmal nocturnal hemoglobinuria, or PNH, a disease caused by red blood cells that lack an attachment for complement inhibitors. That defect makes them easy targets for destruction, or hemolysis, by the complement system, a group of proteins that normally defends against harmful substances.

Alexion scientists previously had shown that long-term treatment with eculizumab reduced hemolysis, and also reduced or eliminated a number of the classic symptoms associated with PNH, including abdominal pain, erectile dysfunction and dysphagia, or difficulty swallowing.

"This study provides a mechanism for what we have seen," Russell Rother, vice president of research at Alexion and first author of the JAMA paper, told BioWorld Today. The usual impetus behind literature studies is that "you have some result that needs explaining, so you look in the literature to explain your findings. The advantage is that you can utilize clinical data, in vitro and in vivo data. In this study, we pulled together information from a lot of different disciplines."

The review investigates a variety of consequences of extracellular hemoglobin. Such extracellular hemoglobin arises as a consequence of hemolytic diseases, but also has been administered to volunteers in clinical trials. In those trials, patients had similar symptoms to patients with hemolytic disorders, suggesting those symptoms might be due to excess hemoglobin.

As one of its main hypotheses, the JAMA article tied those disparate symptoms, and the beneficial effects of inhibiting hemolysis, to the effects that hemoglobin has on nitric oxide, a signaling molecule that affects both smooth muscles and platelet cells.

"Nitric oxide plays a key role in maintaining smooth muscle cells in a relaxed state," Rother said. When the body no longer is able to get rid of hemoglobin that has been dumped into the vasculature either by hemolysis or as a blood substitute, that hemoglobin binds nitric oxide. Nitric oxide, in turn, no longer is available to signal to smooth muscle. The smooth muscle, whether it innervates the gut, the vasculature, or the penis, promptly contracts, with consequences from abdominal pain to erectile dysfunction.

The nitric oxide scavenging effects of hemoglobin also could explain why PNH patients suffer from a high rate of thrombosis; platelets are another cell type that are inhibited by nitric oxide, and when nitric oxide is low or absent, activated platelets aggregate and form clots. But Rother noted that an effect of squelching hemolysis on thrombosis has not been demonstrated yet, and necessitates longer-term studies.