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Dr. Alan T. Hirsch, Vascular Medicine Program, Cardiovascular Division, Minnesota Vascular Diseases Center, Mayo Mail Code 508, University of Minnesota Medical School, 420 Delaware Street, SE, Minneapolis, Minnesota 55455, USA.
The Vascular-Hypertension-Prevention (VHP) track bridges the best data from vascular biology, thrombosis, cardiovascular epidemiology, hypertension, and lipid-modifying clinical trials and offers insights into optimal treatment of coronary, cerebrovascular, and peripheral arterial disease (PAD). This is a form of “translational medicine” that extends knowledge “from the vascular endothelium to clinical cardiovascular events.” The VHP track has demonstrated that a better understanding of vascular biology can improve cardiovascular health. New insights from clinical practice can guide a search for biologic mechanisms, just as improved understanding of vascular mechanisms can guide improved practice. Abstracts in this arena now represent an increasingly large component (18%) of the Annual Scientific Sessions.
The first vascular spotlight session
In recognition of rapid scientific expansion, broad scope, and clinical relevance of the VHP initiative, the meeting included a new “Vascular Spotlight” session. This year’s Spotlight Session integrated four components, entitled “From Vascular Biology to Vascular Pathophysiology,” which reviewed endothelial biology and histopathology of atherosclerosis; “From Vascular Pathophysiology to Vascular Disease,” which reviewed cardiovascular risk assessments as well as new insights regarding the treatment of hypertension, hyperlipidemia, and diabetes; “From Vascular Disease to a Vascular Diagnosis,” which reviewed the utility of exercise testing, duplex ultrasound, magnetic resonance angiography, and computed tomographic techniques; and “From Vascular Diagnosis to Vascular Health,” which provided state-of-the-art reviews regarding the therapeutic roles of exercise, pharmacotherapies, percutaneous and surgical PAD interventions.
New insights into cardiovascular risk
These meetings highlighted the expansion of investigations that assess the impact of both classical and non-classical risk factors to predict cardiovascular ischemic events. Two potential predictors of events have served as the focus of increasing investigation: C-reactive protein (CRP), a marker of systemic inflammation, and the metabolic syndrome, defined as abdominal obesity, high triglycerides, and low levels of high-density lipoprotein, hypertension, and insulin resistance or elevated fasting blood sugar values. In 2003, most cardiovascular clinicians are aware of the potential importance of CRP. The work of Mora et al. (1)at this meeting continues to show the predictive value of an elevated CRP value. In this work, the relevance of an elevated CRP level was assessed in high-risk asymptomatic individuals. These data demonstrated that with the addition of each component of the metabolic syndrome, there was a stepwise increase in the CRP value. Thus, the metabolic syndrome appears to be associated with the systemic inflammatory response. This provides insight suggesting one mechanism by which the metabolic syndrome may elicit an inflammatory response and cause unstable atheroma to create clinically recognized ischemic events.
Other new data underpin the value of CRP as a predictor of future cardiovascular ischemic events. Albert et al. (2)have presented an analysis that demonstrates that physical activity is a modulator of inflammation. These data, along with data previously shared in other venues, demonstrate that the level of daily physical activity can predict the CRP level, and might imply that exercise can modulate systemic risk. A dose-response exists between the level of physical activity and CRP level, and even relatively mild physical activity can diminish the systemic inflammatory response and, perhaps, the progression of arterial disease. In previous investigations, therapeutic exercise has been shown to diminish inflammatory markers. Perhaps one of the best “therapeutic anti-inflammatory interventions” is daily physical activity.
The relationship between markers of systemic atherosclerosis and inflammation was also extended by the work of Preis et al. (3). The severity of lower extremity atherosclerosis, as quantified by the ankle-brachial index (ABI) in individuals with PAD, is predictive of the degree of elevation of markers of inflammation and thrombosis. These data demonstrated that elevations in multiple inflammatory markers (CRP, vascular cell adhesion molecule, intercellular adhesion molecule-1, and interleukin-6) correlate with the severity of PAD, but that one marker of a potential prothrombotic state (plasminogen activator inhibitor-1) does not. As well, an elevation in the level of CRP and a diminished ABI value together predict subsequent cardiovascular events. These data suggest that such indices of overt atherosclerotic disease (as objectively indexed by the ABI value) and inflammation might be best used together as we attempt to better refine our risk assessment. Individuals with both overt lower extremity atherosclerosis and elevated inflammatory markers would be expected to suffer more rapid disease progression, as has been demonstrated previously for coronary disease. This supposition will need to be tested in subsequent investigations. We have known for many years that plaque rupture is a central, but unpredictable event in the coronary circulation. Yet, this phenomenon has rarely been investigated in other arterial circulations. Hongo et al. (4)applied the intravascular ultrasound technique in a PAD population being examined for possible limb arterial revascularization. This is a novel report that has demonstrated the characteristics of plaque rupture in a non-coronary atherosclerotic population at risk. In this population, nearly half of these individuals demonstrated plaque morphology that appeared analogous to that which has previously been demonstrated in coronary vessels. Whether such plaque morphology can predict the progression of PAD from asymptomatic to more severe symptom stages (e.g., claudication or critical limb ischemia) will undoubtedly serve as a future research question.
The role of other systemic metabolic abnormalities has continued to expand as we define the cardiovascular risk associated with the metabolic syndrome (the association of dyslipidemia, hypertension, insulin resistance, and obesity). The retrospective analysis from the WOSCOPS trial, by L’Italien et al. (5), demonstrated that the metabolic syndrome provides a powerful contributor to future cardiovascular ischemic risk, even when the impact of other risk factors is accounted for.
The role of the metabolic syndrome as a predictor of risk was also demonstrated in a retrospective analysis of the landmark Multiple Risk Factor Intervention Trial (MRFIT). Such large cardiovascular databases continue to generate powerful observations that were not pre hoc defined as study goals. Cohen et al. (6)performed a retrospective analysis of a subset of the 12,617 men participating in MRFIT at study inception, defined by those factors that are now known to characterize the metabolic syndrome. These components of the metabolic syndrome, as well as classic risk factors, were evaluated for their relative contribution to predict long-term mortality. Overall, these data demonstrated that the metabolic syndrome provides a powerful contribution to risk. The Atherosclerosis Risk In Communities (ARIC) epidemiologic survey has provided abundant data that describe the burden of atherosclerosis in our communities. A new report by Dr. Ballantyne and colleagues, presented at the Late-Breaking Clinical Trials, has described the predictive roles of lipoprotein-associated phospholipase A, CRP, and other factors, and again has demonstrated the contribution of these factors to subsequent ischemic events. These investigators and others have provided data that suggest that the metabolic syndrome may serve as a target of treatment in our effort to improve cardiovascular outcomes in the U.S. and around the world in the years ahead.
In addition to biochemical markers of risk, a large body of evidence has accrued to document that early structural abnormalities of coronary, and peripheral, arteries connote prospective risk of clinical events. The St. Francis Heart Study (presented by Dr. Arad and colleagues at the Late-Breaking Clinical Trials) provided new evidence of the predictive value of coronary calcium scores, above and beyond that provided by serum markers or by Framingham risk scores, to segregate risk in populations of asymptomatic individuals. As the number of markers of risk increases, both clinicians in practice and patients who seek to minimize personal risk will continue to seek simple algorithms regarding which “risk predictors” should be measured. Shall some be applied, all applied, and can society afford this incremental cost? Or can we afford notto utilize our expanding ability to predict cardiovascular risk, when we know that some interventions, such as exercise and pharmacotherapy, can prevent costly, morbid, and mortal events?
The benefit of cardiovascular risk reduction interventions
These meetings continue to demonstrate the power of large-scale clinical trials to elucidate the benefit of pharmacologic interventions. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study has demonstrated that stain therapies (e.g., atorvastatin in ASCOT), applied long-term in a hypertensive population, can offer a stunning reduction in morbid events and reduce mortality (presented by Dr. Sever and colleagues at the Late-Breaking Clinical Trials). As well, evidence from the Coronary Drug Project demonstrated that niacin decreases both rates of myocardial infarction and total mortality in patients with the metabolic syndrome (presented by Dr. Canner and colleagues at the Late-Breaking Clinical Trials). These meetings provided evidence of the cardiovascular benefits of statins, niacin, exercise, and older lipid-modifying medications that provide realistic hope that risk can be diminished. Despite continued concern regarding potential adverse effects of statin medications, these data again show that profoundly beneficial outcomes can be achieved in the relative absence of significant adverse effects. Practicing physicians and the public should feel additional reassurance that the risk-benefit associated with use of statin medications is far weighted toward benefit, and exemplifies how an understanding of a fundamental vascular biologic pathway (lipoprotein metabolism) has improved public health.
Summary and conclusions
The VHP track integrates the full spectrum of knowledge “from endothelium to clinical events” to translate vascular biology into clinical practice. The data presented at ACC’03 demonstrate that there are a series of metabolic and inflammatory markers that predict coronary artery and peripheral arterial risk. This risk describes the future burden of clinical disease and identifies individuals in whom treatment can be effective. This year, this ability to predict risk has been extended to non-coronary circulations such as PAD. These data have further anchored the importance of the metabolic syndrome and, in particular, have outlined the very large contributions to our knowledge base derived from large clinical trials populations, such as the MRFIT, WOSCOPS, ASCOT, and St. Francis Heart Study populations. Vascular biology provides the foundation for understanding the causes of systemic atherosclerosis in all vascular beds as well as its clinical manifestations. Cardiovascular epidemiology and interventional clinical trials can define the populations at risk and methods to effectively lower risk.
- American College of Cardiology Foundation
- Mora S.,
- Blumenthal R.S.,
- Yanek L.R.,
- Moy T.F.,
- Becker L.C.,
- Becker D.M.
- Albert M.A.,
- Glynn R.J.,
- Ridker P.M.
- Preis O.,
- Beckman J.A.,
- Rifai N.,
- Ridker P.M.
- Hongo Y.,
- Hassan A.,
- Sudhir K.,
- et al.
- L’Italien G.J.,
- Ford I.,
- Shepherd J.
- MRFIT group,
- Cohen J.D.,
- Eberly L.B.,
- Prineas R.,
- Vasquez G.