Vol. 5 • Issue 1
• Page 33
Cardiovascular disease (CVD) is the leading cause of death in the United States,1with more than 600,000 coronary heart disease (CHD) deaths occurring annually. Every 26 seconds, an American will suffer a coronary event, and about every minute, someone will die from one. It's sobering to realize that 67 percent of patients who survive a heart attack never make a complete recovery. Tragically, 20 percent will develop heart failure within six years.
Stroke, a major form of CVD, is the third leading cause of death in the United States. Every 40 seconds, someone in America has a stroke. On average, about every three minutes, someone dies from a stroke. Approximately 83 percent of all strokes, classified as ischemic, are caused by inadequate supply of blood to the brain.2Strokes are the biggest cause of disability in the United States and exact a financial toll from our health care system. Combined, heart disease and stroke cost the United States more than $220 billion annually.1
Several factors increase a person's risk of a heart attack and stroke, including high cholesterol, high blood pressure, obesity, diabetes, smoking and physical inactivity.3The more risk factors a person has, the greater the risk of having a heart attack or stroke. Some risk factors are inherent and cannot be changed, such as increasing age, family history and gender. Several risk factors, however, can be addressed with lifestyle changes, such as exercise and diet, as well as medication.
While risk factor identification remains one of the most important approaches to preventing CVD, traditional risk factors lack the precision to identify many people with hidden CVD risk.4Approximately 50 percent of all coronary events strike people with low to moderate cholesterol levels, and about 20 percent occur in people with none of the four major risk factors (high cholesterol, high blood pressure, smoking or diabetes). Therefore, hidden CVD is prevalent, and a critical need exists to identify all at-risk patients.
Most heart attacks and strokes occur when a blood clot forms in an artery, cutting off the blood supply to the affected tissue. Blood clots frequently occur when soft plaque in an artery ruptures. Part of the CVD disease process involves inflammation of the artery. Inflammation may be involved with all stages of this disease from its inception to the culmination in a vascular event, such as a heart attack or stroke.5Reliable tests for vascular inflammation are available and beneficial for predicting risk of CVD.
Because traditional methods for predicting heart attacks and strokes, such as cholesterol levels and stress tests, often miss many people who go on to have cardiovascular (CV) events, these inflammatory markers may aid in identifying a substantial number of people with hidden cardiovascular risk. Those people may be able to avoid a CVD event if medical management is initiated and sustained over a lifetime.
Several markers of arterial inflammation exist.
Microalbumin-creatinine ratio (ACR) is a simple and inexpensive urine test. ACR should be measured routinely to assess CV risk.6In the Framingham Study, which is one of the best studies looking at CV risk, numerous biomarkers were measured. When an analysis was done to see which biomarkers independently predicted CV risk, only two measurements qualified. One of those was the ACR.7Fibrinogen is an indicator of inflammation as well. However, many factors other than arterial inflammation can affect the levels, rendering it unreliable as a sole test of vascular inflammation.
Highly sensitive C-reactive protein (hs-CRP) is elevated with inflammation. While hs-CRP is a good test to identify inflammation in the body, the measure frequently cannot identify inflammation that's specific to just the arteries. Factors, such as periodontal (gum) disease, infection and arthritis, will elevate the hs-CRP level. Therefore, hs-CRP cannot be relied upon as a definite indicator of increased CV risk. Both fibrinogen and hs-CRP were measured in the Framingham Study, and neither independently predicted CV risk.7
Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a cardiovascular-specific inflammatory enzyme implicated in the formation of vulnerable, rupture-prone plaque. In the blood, Lp-PLA2 associates primarily with low-density lipoprotein (LDL, the "bad" cholesterol). Lp-PLA2 is carried to the walls of coronary arteries by LDL, where the enzyme can activate an inflammatory response, making plaque more prone to rupture. In more than 65 studies, Lp-PLA2 was linked to CV risk. It was FDA-approved for coronary heart disease risk assessment in 2003 and for ischemic stroke risk assessment in 2005. It is now the only blood test approved to assess stroke risk.8Myeloperoxidase (MPO) is an evolving inflammatory marker, which has recently gained FDA approval for clinical use in people experiencing acute chest pain. Substantial evidence shows that an elevated level of MPO in patients with chest pain is a strong indication of unstable coronary artery disease. When it's high, a much greater risk for heart attack exists immediately and throughout the next six months. It's an enzyme that can stimulate vascular inflammation and death of endothelial cells. Mounting evidence suggests that MPO may be involved in all stages of atherosclerosis. It may prove to be a valuable marker of CV risk beyond the acute circumstance, but further research is necessary.
Can an argument be made that some of the above tests are better than others?
From the standpoint of reliable risk assessment, it appears that ACR and Lp-PLA2 are superior. The ACR has years of data demonstrating its association with CV risk; it is an independent predictor. Lp-PLA2 has similar data and is known to be specific for arterial inflammation.9Another important consideration in differentiating the tests is the evidence for involvement in the atherosclerotic disease process. Evidence suggests that hs-CRP is not involved in atherosclerosis.
A recent study evaluated subjects who have hs-CRP levels 64 percent higher than normal due to their genetic make-up. If hs-CRP were a player in the disease process, one would expect these people to have higher CV risk. They were found not to have any higher risk.10 Additional evidence revolves around the KIF6 test, a genetic test related to a person's response to statin drugs to reduce CV event risk. If someone is a noncarrier, he would not get a good response to mono-statin therapy for preventing CV events. One study demonstrated that regardless of KIF6 status, the statin loweredhs-CRP identically.
However, if someone were a noncarrier, despite the same reduction in hs-CRP, he would derive no benefit in terms of preventing a heart attack.11One would postulate that, if hs-CRP were involved in the disease process, the noncarrier would have a lower risk for an event. There is no evidence to support fibrinogen or albuminuria as players in the evolution of the disease.
This stands in stark contrast to Lp-PLA2. An eloquent study was reported in 2008 that indicates Lp-PLA2 is a player in the disease process. This was shown by administering a drug that blocks the activity of Lp-PLA2 in the wall of the artery to patients with known coronary artery disease. Through sophisticated measurements, researchers demonstrated that blocking the activity prevented the enlargement of the necrotic core of atherosclerotic lesions.12Advancement of the necrotic core is linked to an increased risk of an event.13Therefore, this is evidence that Lp-PLA2 is involved in the atherosclerotic process, making it a potential target for therapy, as well as a valuable marker of risk.12With this knowledge, several aspects of the recently reported JUPITER trial become apparent. In that study, hs-CRP was used as the sole indicator of inflammation and risk.14Therefore, some of these patients did not actually have arterial inflammation or increased CV risk. ACR and Lp-PLA2 would be superior markers. Patients with elevated levels of either one would most likely have arterial inflammation and increased CV risk.
Unfortunately, these biomarkers were not measured or reported in this trial. I hope this additional information will be gathered and reported since it would aid significantly in analyzing which people derived the greatest benefit from statin therapy. It also would be interesting to overlay the KIF6 gene on all the patients in this study.
With the current evidence, we can hypothesize that the KIF6 carriers derived the greatest benefit from the statin therapy. Statins appear to be wonderful agents for decreasing arterial inflammation and reducing CV risk.15Huge financial and physical side effect considerations are associated with treating millions of people with statins, as implied by the JUPITER trial. Adding ACR, Lp-PLA2 and KIF6 to the JUPITER trial could help considerably in narrowing down the best candidates for statin therapy.
Let's look at the following case studies to determine who would be best suited for statins.
Case study A. A 63-year-old woman was taking estrogen since 1988 for surgically induced menopause. She presented to our center for heart attack and stroke prevention with concern over her "borderline high cholesterol." She was found to be in excellent health: height, 5 feet 4 inches; weight 121 pounds; waist 26 inches; and BP 120/80. Her lifestyle habits were excellent with diet and daily exercise. She had no known CV disease or symptoms. Her hs-CRP was elevated at 2.9 mg/L and her LDL was 110 mg/L.
She would have qualified in the JUPITER study for statin therapy. Further testing revealed normal Lp-PLA2 and ACR. In addition, no evidence was found of subclinical atherosclerosis. She had a normal ankle-brachial index, normal ultrasound of the abdominal aorta, normal carotid B-mode ultrasound and a zero score on coronary artery calcification testing. She also was negative for the myocardial infarction gene test. The only abnormality was her hs-CRP, which is known to increase simply with estrogen therapy.16As such, she does not need statin therapy, as the other two more precise inflammatory markers would indicate.
Case study B. A 60-year-old white woman participated in a CV risk assessment offered as part of a wellness screening program. At the time of her initial assessment, she was apparently healthy and asymptomatic. She was a thin nonsmoker with a blood pressure reading of 120/80 and excellent cholesterol values without any treatment (total cholesterol, 161 mg/dL; LDL, 38 mg/dL; HDL, 108 mg/dL; triglyceride, 75 mg/dL). Her Framingham 10-year risk of developing heart disease was low at 1 percent.
Fortunately, Lp-PLA2 was one of the few screening tests provided. To everyone's surprise, it was very elevated. At the time of her initial screening, this vascular specific biomarker was the only abnormal measurement found. This result brought her for further evaluation to an advanced center for CV prevention.
A carotid B-mode ultrasound evaluation revealed atherosclerosis, with plaque at the bifurcation of the right carotid artery. This documented a definite risk for stroke. She had a family history for strokes and heart attacks, but had always been reassured by her physician that she need not worry since her cholesterol levels were fantastic. It's interesting to note that further evaluation revealed a slightly elevated hs-CRP and fibrinogen. More remarkable was her highly elevated ACR. Her MPO was assessed as a research measurement and was found to be extremely high. The MPO may explain why, despite a life-long remarkably high HDL, she still had atherosclerosis with risk for a stroke.
Traditional methods for detecting CV risk fail to identify many people who have a heart attack or stroke. The tests I've discussed can help detect these people. This is particularly true with ACR and Lp-PLA2. Once we've identified these people, we can deliver more aggressive management to avoid the fatal or disabling consequences of a heart attack or stroke.
What does the future hold? Be on the lookout for MPO. It appears to be not only a marker, but also a player in atherosclerosis. It can render HDL dysfunctional and inflammatory.17Dysfunctional HDL is on the horizon as a clinical measurement. When it arrives, it will be most welcome.
For a list of references, go to www.advanceweb.com/healthyaging and click on the references toolbar.
Bradley Field Bale, MD, is the founder of the Center for Heart Attack and Stroke Prevention in Spokane, Wash. He is a clinical assistant professor at Texas Tech School of Medicine in Lubbock, Texas, and adjunct professor at Texas Tech School of Nursing. He is medical director of the Heart Health Program for the Grace Clinic in Lubbock, Texas. Case study A was provided by Amy Doneen, ARNP, who is the director of the Center for Heart Attack and Stroke Prevention in Spokane. Disclosure: Dr. Field Bale indicates that he's on the speakers' bureau of Abbott, Takeda, Berkeley Heart Lab and Solvay. He's also a consultant for deCode Genetics and receives honoraria from Abbott and diaDexus.
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