July 12, 2007

Linking Phosphorus with CVD Risk
Framingham Data Show Increased Risk with Elevated Levels
By Julie McDowell

Over the past 50 years, findings from the Framingham Heart Study have revolutionized the prevention, diagnosis, and treatment of cardiovascular disease (CVD). Framingham researchers continue to analyze data from the study’s Offspring Cohort, as evident in a recent study that found levels of serum phosphorus currently considered within the normal range were associated with an increased risk of CVD. This issue of Strategies examines these findings and what it means for the early detection of CVD.

CVD continues to be the leading cause of death and serious illness in the U.S. However, by studying a large group of participants without initial overt CVD over a long period of time, the National Heart, Lung, and Blood Institute’s (NHLBI) Framingham Heart Study has been able to identify common factors or characteristics that contribute to risk of CVD.

    The initial Framingham study was launched in 1948 with a cohort of 5,209 men and women between the ages of 30 and 62. In 1971, the study enrolled the Offspring Cohort—over 5,000 of the original participants’ adult children and their spouses. Researchers are continuing to mine the data to uncover CVD risks, such as the association between higher levels of serum phosphorus and an increased CVD risk, as examined in a May 14th study in the Archives of Internal Medicine (2007;167:879-885).

    Previous evidence indicated an association between CVD risk, morbidity, and mortality among patients with chronic kidney disease, explained Ramachandran S. Vasan, MD, a Senior Investigator with the Framingham Heart Study and Professor of Medicine at the Boston University School of Medicine. “We found evidence that high levels of serum phosphate are associated with CVD in patients with chronic kidney disease, and in high-risk individuals who have had a myocardial infarction, but we wanted to study this association in individuals in the general community,” he explained.

    With a sample size of 3,368 from the Offspring Cohort and a mean follow-up time of 16 years, Vasan and his fellow researchers used statistical methods to relate serum phosphate levels to the occurrence of a first CVD event. Then they adjusted for traditional risk factors, including age, sex, smoking, diabetes, high blood pressure, and other standard risk factors that appear to influence phosphate levels, including estimated glomerular filtration rate (eGFR), hemoglobin, serum albumin, proteinuria, and C-reactive protein.

    The patients were divided into quartiles according to their phosphate levels. There were four quartiles: quartile 1 (1.6-2.8 mg/dL); quartile 2 (2.9-3.1 mg/dL); quartile 3 (3.2-3.4 mg/dL); and quartile 4 (3.5 mg/dL or more). Currently, the normal range is 2.8-4.5 mg/dL, so patients falling in the top quartile are within the normal range, said Vasan.

    Analysis of this data showed that as phosphate levels increased, there was a continuous gradient of CVD risk—about a 30% increase in risk between each quartile of phosphorus levels. “When we compared the top quartile—the upper quartile—with the lowest quartile, the people who were in the upper end of the distribution seemed to have a 55% higher CVD risk compared to the lower quartile, after accounting for all of the traditional risk factors,” said Vasan. “That’s the importance of this study. Within this so-called normal range of serum phosphate levels, there seems to be a continuous increase of risk for cardiovascular disease. The higher the serum phosphate, the greater the CVD risk.”

A New CVD Risk Marker?

While this study indicates an association between phosphorus levels and CVD risk, considerable research will be required to understand whether elevated phosphorus levels truly cause CVD, according to Robert N. Foley, MD, who wrote an accompany editorial in the Archives of Internal Medicine (2007;167:873-874).

    Nevertheless, this data could lead to additional CVD risk prevention measures. “If confirmed, these findings immediately suggest new avenues for reducing cardiovascular disease in the general population,” said Foley, who is with the U.S. Renal Data System Coordinating Center at the Minneapolis Medical Research Foundation in Minnesota. “Experience over many years in patients with chronic kidney disease has shown that many interventions can be used to reduce phosphorus levels. For example, dietary phosphorus intake can be reduced, orally-active phosphorus binding agents can prevent absorption from the gastrointestinal tract, and urinary phosphorus excretion can be manipulated in the renal tubules.”

    Compared to other modifiable risk factors, high phosphorus levels also tend to be found more often in patients with otherwise favorable levels of classic metabolic cardiovascular risk factors, noted Foley. For example, in Vasan’s study, higher phosphorus levels were associated with younger age, absence of diabetes, lower body mass index and lower blood pressure—factors not typically associated with CVD risk.

Getting to the Root of the Association

Beyond these recent findings, future research must determine the exact relationship between phosphorus and CVD risk, said Vasan. The authors have proposed three explanations. “It could be that high serum phosphate is a marker of a high level of circulating parathyroid hormones or PTH, which we know can influence inflammation and can promote tissue damage,” he said. “Or it could be serum phosphate itself, since experimental studies have shown that high levels can cause direct injury to the blood vessels and cause calcification of the vessels.” The third possibility is that patients in the quartile associated with high CVD risk might have subclinical chronic kidney disease. But Vasan doubts this is the case, because researchers adjusted for eGFR.

    As researchers look more closely at the relationship between serum phosphorus and cardiovascular disease in the general population, the clinical laboratory community needs to examine the normal phosphate range used today. “Currently, we call 2.8-4.5 mg/dL normal,” said Vasan. “But at the upper distribution, we have shown there is increased risk. If this is confirmed by other studies, and if there is research done to demonstrate the mechanism by which higher serum phosphate within the normal range predisposes you to CVD risk, then we need to reevaluate the normal range of serum phosphate.”

Dr. Foley is a paid consultant with Genzyme Corp. (Cambridge, Mass.).

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