Biomarkers May Help Predict Ischemic Stroke Risk

Anything in here that tests for stiff arteries?  What about for hemorrhagic strokes? 

Biomarkers May Help Predict Ischemic Stroke Risk

Patients with high levels of four blood biomarkers may be more likely to have an ischemic stroke than those with low rates of the markers, researchers reported.
In an observational study, natural logarithmic statistical transformation of markers of inflammatory, endothelial, and oxidative stress – C-reactive protein (CRP), tumor necrosis factor 2 (TNF2), total homocysteine (tHcy), and vascular endothelial growth factor (VEGF) – were each tied to a greater risk of incident ischemic stroke, Ashkan Shoamanesh, MD, of McMaster University, and colleagues reported online in Neurology.
"Identification of persons at high risk of stroke allows for development of targeted interventions to reduce the burden of stroke at the individual and population levels," study co-author Jose Romero, MD, of Boston University, told MedPage Today.
Using the biomarkers also helped better predict the risk of a stroke over the more traditionally used Framingham Stroke Risk Study, Romero said.
However, given that the study was observational, the results don't mean that elevation of these markers causes strokes, "nor do we provide thresholds for clinicians to consider increased risk," Romero noted.
Additionally, while the study doesn't suggest that these markers should be measured routinely in clinical practice, it does shed light on additional markers to identify those at a greater risk of a stroke, he said.
For their study, the researchers measured the levels of 15 biomarkers associated with inflammation in the blood of those from the Framingham Heart Study Offspring Cohort who'd never had a stroke. The 3,224 participants averaged 61 years of age at the study's onset and were observed for an average of nine years. During that period, 98 had a stroke.
In a model adjusted for age and sex, four of the 15 biomarkers were linked to an increased stroke risk, they found:

• CRP: HR 1.28, 95% CI 1.04 to 1.56
• TNFR2: HR 1.33, 95% CI 1.09 to 1.63
• tHcy: HR 1.32, 95% CI 1.11 to 1.58
• VEGF: HR 1.25, 95% CI 1.07 to 1.46

Three of the biomarkers remained significantly associated with stroke risk in a model adjusted for systolic blood pressure, hypertension treatment, current smoking, diabetes, cardiovascular disease, and atrial fibrillation. Only CRP was no longer significant, the researchers said.
Adding the four biomarkers to the Framingham Stroke Risk Profile improved the ability to predict which patients would be at greatest risk for ischemic stroke, they reported.
They also found in exploratory analyses a significant relationship between CRP and a subtype of ischemic stroke: atherosclerotic brain infarction (HR 1.31, 95% CI 1.06 to 1.33). They also saw a relationship between cerebral embolism and both interleukin 6 (HR 1.11, 95% CI 1.06 to 1.33) and fibrinogen (HR 1.40, 95% CI 1.06 to 1.86).
The study was limited by the fact that conditions that may affect vascular and systemic inflammation, such as chronic inflammatory diseases and infections, and long-term use of medications that have anti-inflammatory properties, were unaccounted for. Also, the biomarkers were measured at single time points and not repeated over time, the researchers said.
Deepak Gulati, MD, of the Ohio State University who wasn't involved in the study, called it "preliminary" in terms of establishing any solid evidence of an association between the biomarkers and ischemic stroke, but said it "brings about this important concept that needs to be explored further."
Gulati said that biomarkers must be accurately and reproducibly measurable, clinically feasible, cost effective, and prospectively validated in randomized clinical trials.
"Biomarkers are interesting, but nothing has yet been validated in terms of an ischemic stroke," he said.
Romero said future research could abet the development of "clinically meaningful thresholds" that may be used in practice and the testing of treatments and drugs in clinical trials that incorporate these markers to assess their benefit in treatment decisions for stroke risk reduction.
In an accompanying editorial, Stephen Williams, PhD, of the University of Virginia, and Svetlana Lorenzano, MD, PhD, of Sapienza University in Rome, agreed that the study "helped refine a well-established stroke risk clinical model ... and helped enhance individual stroke risk prediction," but similarly cautioned that it "should be further assessed in prospective investigations."
As of now, added Romero, stroke prevention should continue to focus on the assessment and treatment of modifiable risk factors as suggested by current stroke prevention guidelines.

Neither the researchers nor the editorialists reported any financial relationships with industry.

• Reviewed by Henry A. Solomon, MD, FACP, FACC Clinical Associate Professor, Weill Cornell Medical College

• Primary Source

  Neurology

  Source Reference: Shoamanesh A, et al "Circulating biomarkers and incident ischemic stroke in the Framingham Offspring Study" Neurology 2016; 87: 1-6.

• Secondary Source

  Neurology

  Source Reference: Williams SR, Lorenzano S "Seeking the 'holy grail' of biomarkers to improve stroke risk prediction of clinical scores" Neurology 2016; 87: 1-2.

Vitamin D: Too Much May Erase Heart Benefit

Two earlier posts on Vitamin D are here; read them all and talk to your doctor.
http://oc1dean.blogspot.com/2011/12/vitamin-d-fails-again-to-affect-cv.html
http://oc1dean.blogspot.com/2011/11/excessive-amounts-of-vitamin-d-linked.html
The latest one here:
http://www.medpagetoday.com/Cardiology/Prevention/30514?utm_source=cardiodaily&utm_medium=email&utm_content=aha&utm_campaign=01-05-12&eun=gd3r&userid=424561&email=oc1dean@yahoo.com&mu_id=

Action Points

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• Note that prior studies assessing the relationship between vitamin D status and markers of inflammation have yielded inconsistent results.
  



• Point out that this study found a significant inverse relationship between CRP and 25-hydroxyvitamin D levels less than 21 ng/mL.
  

Low levels of vitamin D may confer a cardiovascular benefit, but too much vitamin D may have the opposite effect, according to a large cross-sectional study.

The critical threshold appears to be a serum 25-hydroxyvitamin D concentration of 21 ng/mL -- more than that level increases C-reactive protein (CRP), a biomarker for cardiovascular disease, but lower serum concentrations of 25-hydroxyvitamin D lower CRP levels, reported Muhammad Amer, MD, and Rehan Qayyum, MD, MHS, from Johns Hopkins University School of Medicine. Their findings were published online in the American Journal of Cardiology.

A multivariate analysis that tracked 25-hydroxyvitamin D concentrations as well as CRP in more than 15,000 healthy adults revealed that above the threshold for benefit, CRP increased with each 10-ng/mL increase in 25-hydroxyvitamin D.

In a univariate analysis, CRP levels decreased as levels of 25-hydroxyvitamin D increased up to the median of 21 ng/mL.

The authors analyzed data from participants in the National Health and Nutrition Examination Survey (NHANES). Researchers combined three two-year cycles of continuous NHANES surveys from 2001 to 2006.

The mean age of participants was 46, and the median serum 25-hydroxyvitamin D and CRP levels were 21 ng/mL and 0.21 mg/dL, respectively. The proportion of men to women was close, 48% versus 52%, with no significant difference in levels of 25-hydroxyvitamin D between the two groups.

Whites had significantly higher baseline levels of 25-hydroxyvitamin D than nonwhites.

Significantly more people with a body mass index greater than 30 kg/m² had lower 25-hydroxyvitamin D levels at baseline (41% versus 25%, P<0.0001); the same was true for smokers (22% versus 18%, P=0.004).

However, the mean total cholesterol was significantly higher for those with higher levels of vitamin D at baseline (201.6 versus 198.6 mg/dL, P=0.001).

"From our results, it appears that vitamin D supplementation among asymptomatic subjects with baseline vitamin D values of greater than 21 ng/mL might have no additional effects on systemic inflammation, as measured by changes in the serum CRP levels," Amer and Qayyum concluded.

Researchers admitted they could not determine a temporal relation between 25-hydroxyvitamin D and CRP. Another limitation was the inability to adjust for geographic location or time of year.

CRP Not Cause of Heart Disease

C-reactive protein, read the article and ask your doctor.
http://www.webmd.com/heart-disease/news/20081029/crp-not-cause-of-heart-disease
C-reactive protein is linked to heart disease, but it's an innocent bystander and not a cause of disease, a new study shows.

People with high levels of C-reactive protein (CRP) in their blood are at high risk of heart disease. The protein is part of the body's inflammatory immune response.

Inflammation swells cholesterol-crammed artery walls, making the lining of those arteries vulnerable to breaking down or bursting. When the lining of an artery wall is disrupted, a cascade of events is set off culminating in the formation of a blood clot, which can go on to cause a potentially deadly heart attack or stroke. Earlier studies have suggested that CRP plays a key role in this process.

Drug companies already are racing to make drugs that target CRP. But taking aim at CRP will miss the real causes of heart disease, suggests new evidence from Borge Nordestgaard, MD, DMSc, professor and chief physician at Copenhagen University Hospital, Denmark, and colleagues.

"There is nothing wrong with using CRP as a marker of higher risk for heart disease and stroke," Nordestgaard tells WebMD. "We just say it is not causing the disease."

CRP and Heart Disease

Scientists know cholesterol directly causes heart disease because in clinical trials, people taking cholesterol-lowering drugs have less heart disease. Yet there's no drug that directly targets CRP.

Fortunately, nature has provided its own version of a clinical trial. Some people carry variant CRP genes that make more or less CRP than the normal CRP gene. Do people with naturally high CRP levels have more heart disease and stroke?

First, Nordestgaard's team measured CRP levels in more than 10,000 people. They found that high levels of CRP increased risk of heart disease by 60% and risk of stroke by 30%. That's the same degree of risk seen in previous studies.

Then the researchers analyzed CRP genes and measured CRP levels in more than 31,000 people. They found that people with certain CRP genes made 64% more CRP than people with the least active CRP genes. This allowed them to calculate that if CRP caused disease, people with the most active CRP genes should get up to 32% more heart disease and up to 25% more strokes.

Finally, the researchers looked at people who actually had heart disease or stroke and compared them to people who remained disease free. The big surprise: People with the most active CRP genes were at no higher risk for heart disease and stroke than were people with the least active CRP genes.

To make sure their calculations were correct, the researchers also studied people with variant cholesterol genes. Those with genes that made the most cholesterol were indeed at highest risk of heart disease and stroke -- almost exactly as their calculations predicted.

This means CRP does not cause heart disease, says cardiologist Heribert Schunkert, MD, director of Germany's Luebeck University Hospital and professor of cardiology at the University of Leicester, England.

"It is pretty definitive. Genetic markers that increase CRP don't increase disease," Schunkert tells WebMD.

Also convinced is Thomas A. Pearson, MD, PhD, MPH, senior associate dean for clinical research at the University of Rochester Medical Center. Pearson led a recent study group that evaluated CRP research for the CDC and the American Heart Association.

"This is a nail in the coffin for the idea that CRP is a causal factor in heart disease," Pearson tells WebMD. "This is a very useful study, and cleverly done, and their conclusion is right on the money."

That conclusion: CRP is an indicator of heart disease and stroke risk, but not a cause.

The Nordestgaard study and an editorial by Schunkert and colleague Nilesh J. Samani, MD, FmedSci, appear in the Oct. 30 issue of TheNew England Journal of Medicine.