Research matters

News from the Harvard Medical School research community.
Research matters
By Partners Harvard Medical International
Sun 31 Aug 2008 04:00 AM

News from the Harvard Medical School research community.

Radiology

New method shown effective in detecting dangerous coronary plaque

Asignificant number of patients who suffer a heart attack never have any warning signs.

Exercise stress testing and coronary angiography, the standard methods for diagnosing atherosclerosis and heart attack risk, both work by visualizing the lumen, the channel through which blood flows.

For many of these individuals, the source of the problem is noncalcified plaque, a buildup of soft deposits embedded deep within the walls of the heart's arteries, undetectable by angiography or cardiac stress tests - and prone to rupture without warning.

Now a new noninvasive method has shown success in detecting and measuring noncalcified plaque. In a pilot clinical study led by investigators at Beth Israel Deaconess Medical Center (BIDMC), the technique - voxel analysis used in conjunction with MDCTA (multi-detector computed tomography angiography) - was shown to be equally as effective as catheter coronary angiography in identifying patients at risk for heart disease.

Reported in the June 2008 issue of the American Journal of Roentgenology (AJR), the new findings may help doctors monitor the effects of medical treatment to reduce patients' risk of atherosclerosis and heart disease.

"The importance of quantifying plaque is critical because total plaque burden is considered the most important predictor of coronary events," explains the study's senior author Melvin Clouse, MD, PhD, Emeritus Chairman of the Department of Radiology and Director of Radiology Research at BIDMC and Deaconess Professor of Radiology at Harvard Medical School.

"Furthermore, the rupture of soft noncalcified plaque has been implicated as the cause of heart attack."

Exercise stress testing and coronary angiography, the standard methods for diagnosing atherosclerosis and heart attack risk, both work by visualizing the lumen, the channel through which blood flows.

However, because the lumen also increases in size as plaque progresses, coronary artery disease may go undetected until late in the disease process. And, adds Clouse, "Because soft plaque buildup may not significantly narrow the lumen, conventional angiography and stress tests fail to provide a complete picture of plaque accumulation."

The investigators set out to evaluate a new method of plaque assessment using multidetector computed tomography angiography (MDCTA). Unlike coronary angiography, in which a catheter is threaded through the femoral artery and up into the heart, MDCTA is not invasive.The CT scanning method, comprised of 64 separate scans, provides a detailed cross-sectional view of the blood vessel wall based on the amount and volume of blockage present.

Its ability to differentiate plaque density makes it particularly useful in distinguishing between stable plaque and unstable plaque.

"The latest MDCT scanners have made it possible to detect noncalcified plaque," explains Clouse.

Previous research has shown that higher levels of vitamin D reduce the risk of developing colon and rectal cancer by about 50 percent.

"However, due to a number of technical and physiologic factors, accurate and reproducible measurements of this plaque was difficult and time-consuming. We, therefore, developed a new technique that would overcome these obstacles."

Adds Clouse, "Using this new method, we hope to be able to be able to better assess the effects of medication treatment and lifestyle interventions in treating atherosclerosis."

Crohn's disease

International team identifies 21 new genetic risk factors for Crohn's disease

An international consortium of Crohn's disease researchers has combined data from three independent studies to identify 21 new genetic variants associated with the inflammatory bowel disorder, bringing the total number of risk factors to 32.

Several of these are involved with the immune system's inital response to pathogens, supporting earlier evidence that disruptions in a process called autophagy may lead to the disorder's characteristic immune system overactivity.

The report will appear in the journal Nature Genetics and is receiving early online release.

"This greatly increases our knowledge of the genetic architecture of Crohn's and gives us more detailed insight into the biological underpinnings of the disease," says Mark Daly, PhD, of the Massachusetts General Hospital (MGH) Center for Human Genetic Research, the report's senior author.

"Better understanding of the precise functions of these genes and the molecular effects of Crohn's-associated variants should lead us to novel strategies for therapies and, someday, prevention."

In 2007 three separate research teams - a North American-based team, involving Daly and colleagues at six other institutions and clinical sites; a U.K. team supported by the Wellcome Trust; and a group of French and Belgian investigators - each published genome-wide association studies (GWAS) of Crohn's disease that, combined with earlier studies, brought the total number of Crohn's-associated gene sites to 11.

Those explained only a small proportion of the heritability of Crohn's, which affects nearly half a million people in the U.S.

Since the power of any GWAS is limited by the number of samples available for screening, the three teams combined their data through a process called meta-analysis, allowing the comparison of data from more than 3,200 Crohn's patients with more than 4,800 controls.That was supplemented by an analysis of new data from an additional 3,700 patients and matching controls. Both of those analyses strongly confirmed the 11 previously-identified sites and found an additional 21 areas associated with susceptibility to Crohn's.

While the newly identified sites are not as strong as those found in earlier studies, they continue to build a picture of factors leading to the inappropriate immune-system activation that characterizes the disorder.

Colorectal cancer

Study links vitamin D to colon cancer survival

Patients diagnosed with colon cancer who had abundant vitamin D in their blood were less likely to die during a follow-up period than those who were deficient in the vitamin, according to a new study by scientists at Dana-Farber Cancer Institute.

The findings of the study - the first to examine the effect of vitamin D among colorectal cancer patients - merit further research, but it is too early to recommend supplements as a part of treatment, say the investigators from Dana-Farber and the Harvard School of Public Health.

In a report in the June 20 issue of the Journal of Clinical Oncology, the authors note that previous research has shown that higher levels of vitamin D reduce the risk of developing colon and rectal cancer by about 50 percent, but the effect on outcomes wasn't known.

To examine this question, the investigators, led by Kimmie Ng, MD, MPH, and Charles Fuchs, MD, MPH, of Dana-Farber, analyzed data from two long-running epidemiologic studies whose participants gave blood samples and whose health has been monitored for many years.

They identified 304 participants in the Nurses' Health Study and the Health Professionals Followup Study who were diagnosed with colorectal cancer between 1991 and 2002.

All had had vitamin D levels measured in blood samples given at least two year prior to their diagnosis. Each patient's vitamin D measurement was ranked by "quartiles" - the top 25 percent, the next lowest 25 percent, and so on. Those whose levels were in the lowest quartile were considered deficient in vitamin D.

The researchers followed the 304 patients until they died or until 2005, whichever occurred first. During that period, 123 patients died, with 96 of them dying from colon or rectal cancer.

The researchers then looked for associations between the patients' previously measured vitamin D blood levels and whether they had died or survived.

The results showed that individuals with the vitamin D levels in the highest quartile were 48 percent less likely to die (from any cause, including colon cancer) than those with the lowest vitamin D measurements.

The odds of dying from colon cancer specifically were 39 percent lower, the scientists found.

"Our data suggest that higher prediagnosis plasma levels of [vitamin D] after a diagnosis of colorectal cancer may significantly improve overall survival," the authors wrote. "Future trials should examine the role of vitamin D supplementation in patients with colorectal cancer."

Research Matters brings together selected research being conducted at Harvard Medical School and its affiliated teaching hospitals and research institutes. For more information, visit the Harvard Medical School website at www.hms.harvard.edu.

This article is provided courtesy of Partners Harvard Medical International.

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