Ever since the first identification and coining of the phrase “risk factors for coronary heart disease (CHD)” by the Framingham Investigators in 1959 [1,2], there has been an explosion of literature that has come under the heading of atherosclerotic cardiovascular disease (CVD) risk factor reduction, as if creating a separate subspecialty of cardiology. There was much discussion as to whether CVD risk factor reduction was synonymous with prevention and preventive cardiology and what it means to prevent CVD.[3] Over the past few decades, significant progress has been made in reducing death and disability from CVD. As such, there needs to be a reexamination of CVD risk factor reduction in general and of where we are going with this.

Epidemiologically, CVD, including stroke, has been the leading cause of death of adult Americans since the beginning of the 20th century and has remained so every year except in 1918, when the flu epidemic was the number one cause of mortality. The devastation of CVD was more painful because approximately 50% of the population that died from CHD did so suddenly without warning and thus not allowing for an opportunity to intervene. Hence, the drive to search for any markers to identify the individual at high risk of developing CVD and then plan a strategy to prevent it began and continues to the present. The major longitudinal study with this focus of identifying risk factors and developing prevention strategies is the Framingham Heart Study, sponsored by the National Heart Lung and Blood Institute since 1948, which continues to illuminate our knowledge of CVD risk reduction. The first identified risk factors were cigarette smoking, high blood cholesterol levels, high blood pressure, and electrocardiographic abnormalities, which were reported in 1959 in the American Journal of Public Health with a subsequent report in the Annals of Internal Medicine in 1961.[1-3] Following those reports, physical activity was found to reduce the risk and obesity to increase the risk of heart disease. Hypertension was reported to increase the risk of stroke, and menopause was associated with increased risk of heart disease. Psychosocial factors (Type “A” behavior) were found to affect heart disease events, and high levels of high-density lipoprotein cholesterol (HDL-C) were associated with reduced risk of CHD death. Homocysteine (an amino acid) was found as a possible risk factor for heart disease, and in 1991, the first CHD risk prediction models were produced based on the number of risk factors an individual had. Lipoprotein (a) and apolipoprotein E were later identified as possible risk factors for heart disease, and data began to reveal ethnicity as a risk factor for heart disease. Numerous other studies have associated advancing age, diabetes mellitus, chronic kidney disease, and a whole host of inflammatory markers with increased risk of CHD, with 45 to 55 years as the age of substantial increase in incidence in men and 55 to 65 years as the age of substantial increase in incidence in women.

The risk factors identified were divided into categories of irreversible (gender, family history, and age); reversible (tobacco use, high blood pressure, high cholesterol levels, low HDL-C levels, physical inactivity, obesity, and diabetes); and emerging risk markers (the new inflammatory markers, e.g., high-sensitivity C-reactive protein, interleukin-6, fibrinogen, and lipoprotein-associated phospholipase A2 [LpPLA2]). Randomized controlled trials, the gold standard of research studies to validate a medical intervention, were performed where feasible. They demonstrated that tobacco cessation, regular and adequate physical activity, controlling high blood pressure, modifying one’s diet to be high in fiber and lower in fats and salt, maintaining a normal body mass index (BMI), and lowering one’s low-density lipoprotein cholesterol (LDL-C) to target were all associated with lower risk of CVD events. Risk factors were also evaluated in different clinical situations of known CHD, in which the risk factor reduction was known as secondary prevention measures, or in individuals without known CVD or CHD where risk factor reduction was known as the primary prevention measure. In all of these studies, the goal was to reduce CVD events or mortality (outcomes studies), reduce the risk factor (effectiveness studies), or reduce another marker, e.g., carotid intima media thickness (IMT) and intravascular ultrasound (IVUS) (surrogate marker endpoints).

As of 2008, the initially defined CVD risk factor prevention strategy of tobacco cessation, physical activity, heart-healthy diet, lower cholesterol level, higher HDL-C levels, normal blood pressure, and optimum BMI remains the main strategy of primary and secondary prevention. These risk factors have been the subject of multiple outcome studies and have all been validated, and as such are IA recommendations for prevention of CHD. None of the emerging risk markers have yet achieved this level of research support for their use in reducing CVD events.

The main question of the purpose of risk factor reduction remains unanswered. If the main point of risk factor reduction is to prevent CVD events, then we have seen significant progress made toward this end. But our best efforts have not eliminated CHD, and multiple studies demonstrate that our track record in reducing risk factors is between 30 and 60%, with lower amounts of control as more factors are combined as the goal.[4] In recent studies, there have been significant comments that suggest that the holy grail of prevention is the elimination of atherosclerosis, so that it does not even occur (for primary prevention), or that our management of risk factors will reverse the atherosclerosis that is already present at the point of discovery (secondary prevention). We can look at the comments in the recent PERISCOPE trial in controlling diabetes and evaluating the percent atheroma volume change to determine the effectiveness of an agent to reduce CHD [5] or the ARBITER trials to control and modify lipid levels to reduce carotid IMT.[6,7] Because these studies rely on surrogate markers and imaging to determine the presence or absence of a minimum measurable amount of atherosclerotic disease, we will certainly need further study to determine if we can actually halt and/or reverse the process of atherosclerosis.

So at this time, it would seem that the missing ingredient in prevention of CHD is the knowledge of the process of atherosclerosis: its triggers, provocative and other stimulating factors, other factors that might accelerate the process, and others that might slow the process. Also, the genetic factors that affect the degree and rapidity of the atherosclerotic process are essentially unknown. We do know much about the process of atherosclerosis, beginning with inflammation and cellular activity and LDL-C metabolism, but the whole process from beginning to end remains elusive. Additionally, the individual responses and variability of phenotypic expressions and CVD manifestations are beyond our state of knowledge and are only at the point of being identified in data registries looking at the gross differences of gender and ethnicity; investigations into the genetic differences are just beginning. Without this knowledge base, we cannot begin to know the mechanisms by which risk factor reductions actually reduce CVD events. Also, once the process of atherosclerosis is elucidated, the key risk factor or factors can be identified, and optimum strategies to prevent atherosclerosis can be developed and put into practice. There is evidence that lowering the LDL-C level reduces CVD events with little to no change in atheroma volume or quantitative coronary angiography. There is some suggestion that there is some change in the process that not only slows the atherosclerotic process but also modifies what is going on in the plaque to change the pathologic or ultrasonographic appearance of the plaque from a thin-capped atheroma to a thickened fibrous-capped atheroma that decreases the likelihood of rupture and acute coronary syndromes. But the mechanisms by which these outcomes are achieved are not understood. It seems unlikely that the process of atherosclerosis is completely reversed with the LDL-C lowering by statins, or CHD would have been completely eliminated with the advent of statins; yet CVD still exists and continues to cause disability and death. It is also unlikely that physical activity and diet are the only risk factors that are needed, as we have many well-documented cases of athletes and runners who were extremely fit and eating heart-healthy diets who have died due to CVD.

It is important to address the issue of risk factor reduction as prevention of CVD or just as risk factor reduction. The reason for this discussion is that in the minds of many, there is very strong evidence for the aggressive use of secondary prevention methods to prevent future CVD events.[8] These methods include the use of antiplatelet drugs, the use of angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs), the use of beta-blockers, and the use of statins to achieve even lower LDL-C goals, in addition to risk factor reduction using primary prevention strategies. It is important to recognize that these strategies are primarily for prevention of known symptomatic atherosclerotic CHD events and not specifically for risk factor reduction. There is no disease state that is characterized by the inherent lack of antiplatelet drugs or the lack of beta-blockade in the body where replacing these agents actually reduces the future risk of disease. So as we further refine the field of risk factor reduction, the main goal of risk factor reduction is to prevent symptomatic CHD and reduce the events and mortality of CVD. As such, we do need to include these prevention strategies as part of risk factor reduction.

Our current state of knowledge of cardiac risk factor reduction is that several strategies have been identified and tested that will reduce CVD outcomes. Tobacco cessation and avoidance, regular and adequate exercise, maintaining normal BMI, blood pressure control for the hypertensive patient, and treating LDL-C to target for the clinical situation for primary and secondary prevention, with the addition of antiplatelet drugs, statins, beta-blockade, and ACE-I or ARB use in secondary prevention, have been proven to be effective in randomized controlled trials. The emerging risk markers have not yet been as thoroughly evaluated and will need further research, including the appropriate types of study, to determine if they are to be accepted as risk factors that need to be actively reduced to prevent future CVD events.

Where we are going in this field depends on the ongoing research efforts to elucidate the process of atherosclerosis to identify the true risk factors or steps in the process so that strategies can be developed and implemented to stop and reverse the process of atherosclerosis. Until then, we will probably see more new, emerging risk markers that will reveal other steps along the process of atherosclerosis, and those new factors will need to be validated in randomized controlled trials. Once validated as a real risk factor, then strategies including nonpharmacologic and pharmacologic approaches will need to be developed to achieve reduction in CVD events.

Another discussion point in risk factor reduction is who is responsible for instituting the risk factor reduction strategies in the practice of medicine. For secondary prevention, it certainly makes sense for the cardiologist or specialist in cardiac diseases to be involved and actively participating. But for primary prevention, every provider needs to be involved. Tobacco cessation, physical activity, and heart-healthy diets are issues that need to be taught in schools or to the general public and communities wherever the people learn about health issues. Public health officials need to coordinate their messages with the cardiology community so as to provide a unified voice and message to the community at large. The medical community must also be unified in their message and lessons to patients so that there is no confusion that increases the barrier to successful risk reduction strategies involving the entire population. The field or issue of risk factor reduction is by definition interdisciplinary and requires that every provider and individual take responsibility to implement the proven strategies to reduce CVD.

1. Kannel W, Dawber TR, Kagan A, et al. Factors of risk in the development of coronary heart disease – six-year follow-up experience. The Framingham Study. Ann Intern Med 1961;55:33-50.

2. Dawber T, Kannel WB, Rovotskie N, et al. Some factors associated with the development of coronary heart disease: six years follow-up experience in the Framingham Study. Am J Public Health Nations Health 1959;49:1349-1356.

3. Werko L. Risk factors and coronary heart disease: facts or fancy? Am Heart J 1976;91(1):87-98.

4. Gu Q, Burt VL, Paulose-Ram R, et al. High blood pressure and cardiovascular disease mortality risk among U.S. adults: the third National Health and Nutrition Examination Survey mortality follow-up study. Ann Epidemiol 2008;18(4):302-309.

5. Nissen SE, Nicholls SJ, Wolski K, et al., PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA 2008;299(13):1561-1573.

6. Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months of combination statin and extended release niacin on carotid intima media thickness. ARBITER 3. Curr Med Res Opin 2006;22(11):2243-2250.

7. Taylor AJ, Zhu D, Sullenberger LE, et al. Relationship between glycemic status and progression of carotid intima media thickness during treatment with combined statin and extended release niacin in ARBITER 2. Vasc Health Risk Manag 2007;3(1):159-164.

8. Thomas RJ, King M, Lui K, et al. AACVPR/ACC/AHA 2007 performance measures on cardiac rehabilitation for referral to and delivery of cardiac rehabilitation/secondary prevention services. Circulation 2007;116:1611-1642.

–

The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association