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(Hypertension. 2005;46:217.)
© 2005 American Heart Association, Inc.

Fifth International Workshop on Structure and Function of Large Arteries

Arterial Elasticity as Part of a Comprehensive Assessment of Cardiovascular Risk and Drug Treatment

Jay N. Cohn; Daniel A. Duprez; Gregory A. Grandits

From the Cardiovascular Division, Department of Medicine, University of Minnesota, Minneapolis.

Correspondence to Jay N. Cohn, MD, Professor of Medicine, Cardiovascular Division, MMC 508, University of Minnesota, 420 Delaware St SE, Minneapolis, MN 55455. E-mail cohnx001{at}umn.edu

	Abstract

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Early cardiovascular disease can be identified in asymptomatic individuals by noninvasive evaluation of functional and structural abnormalities of the vasculature and heart. These abnomalities are usually a consequence of endothelial dysfunction. A panel of 10 tests, including small and large artery elasticity, has been used as the basis for a screening system that provides a score of 0 to 20 as a guide to the severity of disease. Using that Rasmussen score allows for stratification of patients into low, intermediate, or high risk for progression to cardiovascular morbid events. This comprehensive screening can be performed efficiently in a single room with a single technician. The sensitivity and specificity of this screening system in predicting future cardiovascular events, its superiority to traditional risk factor assessment, and its potential to track the response to therapeutic interventions must be validated in long-term follow-up studies.

Key Words: nitric oxide • arterial compliance • exercise blood pressure • carotid thickness • microalbuminuria • retinal vasculature

	Introduction

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Abnormalities of the arterial vasculature that precede cardiovascular morbid events are likely to occur in a temporal sequence. The initial abnormalities appear to be functional, in large part related to endothelial dysfunction associated with decreased bioavailability of NO (Figure).¹ A decrease in constitutive release of NO, which maintains low small artery tone, may be the initial abnormality, but it is soon accompanied by a decrease in stimulated release of endothelial vasodilators, as manifested by a reduction in flow-mediated dilation of conduit arteries.^2,3

View larger version (22K): [in this window] [in a new window]   Time course of changes in arterial stiffness. The site of sequential vascular changes is shown above, and the method for its detection is shown below. Functional changes on the left merge gradually to structural changes on right. Flow response indicates response to acetylcholine; C2, small artery elasticity; FMD, flow-mediated dilation; reflection, augmentation index; retina, retinal vasculature; IMT, intimal-medial thickness of carotid artery; C1, large artery elasticity; Pres: Vol, pressure/volume relationship of a single artery; Exer BP, blood pressure rise in response to programmed exercise test; PWV, pulse wave velocity; Pulse Pres, auscultatory pulse pressure.

These functional abnormalities of the vasculature should precede and are mechanistic precursors of the structural alterations that are responsible for thickening of the conduit artery wall,⁴ increases in pulse wave velocity,⁵ increases in pulse pressure,⁶ and atherosclerotic plaque development.⁷ These structural changes may also result in additional functional abnormalities. But cross-sectional studies suggest that this sequence of vascular manifestations of vascular disease is not always detectable. Indeed, no single measurement appears adequate to reliably separate healthy individuals with low or absent risk for premature cardiovascular events from those with a higher risk that would benefit from therapy.

The heterogeneity of demonstrable abnormalities may well derive in part from the imprecision of all our methods for quantitating functional and structural abnormalities of the cardiovascular system. Although functional abnormalities may precede structural abnormalities, limitation of methodology may result in an unacceptable rate of false positives and false negatives when a single test is used. Therefore, a series of tests assessing functional and structural abnormalities is more likely to provide sensitivity and specificity for early disease.

The goal of this preventive strategy is to improve the precision for early detection and treatment by identifying a marker or markers for early cardiovascular disease that could serve as a surrogate for disease progression, morbid events, and the response to therapy. Health care expenditures are overwhelming our national and corporate budgets, predominantly because of the escalating costs of care of advanced disease. The only rational way to reduce costs in an aging society is to delay progression of chronic disease so that morbid events do not interrupt normal life expectancy. Efforts to alter lifestyle of the entire population have had mixed success. Pharmacotherapy in appropriate populations has been remarkably effective in delaying events.^8–11 Identifying the proper population for intervention could facilitate more effective and targeted treatment strategies. Therefore, our focus has been on early detection of cardiovascular disease likely to progress.

	Screening Methodology

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In considering the ways to identify functional and structural abnormalities of the vasculature and heart, we considered a variety of techniques we thought would be complimentary. Small artery stiffness influences reflected waves¹² that have been identified in late systole as a pressure augmentation but can also be detected in diastole as an oscillation in the pressure decay that exhibits a frequency and rate of decay.¹³ Small artery compliance or stiffness is a marker for endothelial dysfunction that induces a functional change in the microcirculation^14,15 and is a predictor of adverse cardiovascular events.¹⁶ Resting blood pressure may be elevated when small artery tone is increased, but exercise blood pressure becomes a more sensitive guide to the stiffness of the arterial system.¹⁷ Small artery structural alterations result in vascular abnormalities and can be viewed in the optic fundus¹⁸ or identified by microalbuminuria as a consequence of small artery disease in the kidney.¹⁹ Structural abnormalities in the conduit arteries results in an increase in wall thickness (intimal-medial thickness)²⁰ and a reduction in the capacitive compliance of the arterial vasculature.²¹ These measurements of large artery dysfunction have been shown to be associated with the risk for cardiovascular events.^22–26 Therefore, a series of tests may provide a comprehensive assessment of functional and structural abnormalities of the small and large arteries that should be predictive of cardiovascular morbidity and mortality.

A panel of tests (Table 1) has been established as a standard screening protocol in the Rasmussen Center for Cardiovascular Disease Prevention at the University of Minnesota.²⁷ These measures of early vascular and cardiac disease are augmented by identifying known contributors to disease progression (Table 2). Because all the tests are performed in 1 hour, in 1 room, by 1 technician, the center provides an efficient environment for screening asymptomatic individuals concerned about their cardiovascular health.

View this table: [in this window] [in a new window]   TABLE 1. Tests of Early Cardiovascular Disease

View this table: [in this window] [in a new window]   TABLE 2. Contributors to Disease Progression

The 10 tests of vascular and cardiac health are each evaluated as normal (score 0), borderline abnormal (score 1), and abnormal (score 2). As reported previously,²⁷ the criteria for normal and abnormal has been arbitrarily established on the basis of large published databases. Criteria for some of the tests (small and large artery elasticity, carotid intimal-medial thickness) are age adjusted because such age criteria exist. The other tests are not age related because it has not been traditional to do so. An individual with 10 normal tests would have a Rasmussen score of 0. An individual with 10 abnormal tests would have a score of 20. All tests have been scored equally at the present time, but as outcome data become available, it may be possible to identify a hierarchy that would allow a more graded score for risk.

	Experience to Date

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The Rasmussen Center has now been in operation for 4 years. Recruitment has been stimulated by individual mailings to targeted populations in the Twin Cities community. In nearly all instances, the costs of the billed screening procedures have been covered by health care insurance. The full screen also includes a 1-hour history, physical examination, and lifestyle assessment by a cardiovascular-trained nurse practitioner. This encounter is also covered by insurance. A full report of the findings and recommendations is provided to the patient and to his/her health care provider.

Nearly 1000 patients have now been screened. Of course they do not represent a cross-section of the community because they tend to be more affluent and more concerned about their health. It is possible that this referred or self-referred population harbors a greater burden of cardiovascular disease than in the general population. Rasmussen scores for the first 879 individuals screened are shown in Table 3. These scores are, as expected, age dependent (Table 4). The frequency of individual test abnormalities is shown in Table 5.

View this table: [in this window] [in a new window]   TABLE 3. Frequency Distribution of Rasmussen Score for Rasmussen Center Population

View this table: [in this window] [in a new window]   TABLE 4. Mean Rasmussen Score by Decade of Age for Rasmussen Population

View this table: [in this window] [in a new window]   TABLE 5. Frequency Distribution of Test Scores for Rasmussen Center Population

We have arbitrarily and temporarily (while awaiting long-term outcome data) identified total scores of 0, 1, and 2 as low risk; scores of 3 to 5 as moderate risk; and scores of 6 as high risk. However, if our tests each add incremental evidence for disease, risk should be highly related to score throughout the entire numerical range. In our currently screened population, 36.2% of those presumed healthy individuals have low risk, 34.6% moderate risk, and 29.2% high risk (Table 3). As noted in Table 6, traditional risk factors do not bear a close relationship to Rasmussen scores.

View this table: [in this window] [in a new window]   TABLE 6. Summary Statistics for Risk Factors for Rasmussen Center Population

	Implications for Disease Detection

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Most attempts to identify individuals at risk for cardiovascular morbid events have involved screening for risk factors that are statistically associated with future cardiac or cerebrovascular events. This approach has resulted in several risk factor assessment scales that can identify groups with higher risk.^28,29 However, because the risk factors used are not necessarily disease markers, this approach does not provide any insight as to how the risk factors are impacting the biologic target organs, the vasculature, and the heart. Indeed, these traditional risk factors do not appear to be useful in stratifying the severity of disease in individual patients (Table 6).

The screening tests we use in the Rasmussen Center assess target organ functional and structural abnormalities, not the genetic or environmental factors that may variably impact on the target organs in specific individuals. The sensitivity and specificity of this approach can be established only in long-term follow-up, but it is intuitive that if vascular or cardiac functional and structural abnormalities precede morbid events, then identifying these abnormalities should provide more precision in individual risk assessment. Repeated assessments over time are needed to document reproducibility and the trajectory of prognosis of disease in individual patients.

The medical and financial success of the Rasmussen Center is dependent on an efficient operation, adequate reimbursement for services, and individual care by a knowledgeable nurse practitioner. By confining physician input to a supervisory and report-review role, the costs of the service can be controlled.

If screening of this kind is to be available to large populations, it is clear that it must be provided not by individual physicians but by identified centers with personnel dedicated to the screening process. Such a revision of our current system of health care may be essential to reduce the growing burden of advanced cardiovascular disease.

Perspectives
Noninvasive screening tests to identify vascular and cardiac disease in its early or asymptomatic phase represents a departure from the traditional approach to cardiovascular disease prevention that involves identifying risk factors that are statistically but not necessarily biologically related to disease. Our early experience with a panel of 10 screening tests to detect vascular and cardiac functional and structural abnormalities and a composite scoring system has identified a high prevalence of unsuspected disease. Demonstration that the scoring system provides effective risk stratification and that treatment strategies initiated on the basis of the score can reduce event rates will require large-scale prospective studies. Nonetheless, noninvasive testing may eventually replace or supplement risk factor assessment in improving the sensitivity and specificity of efforts to prevent cardiovascular disease morbid events.

Received February 14, 2005; first decision March 1, 2005; accepted April 1, 2005.

	References

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This Article Abstract Full Text (PDF) All Versions of this Article: 46/1/217    most recent 01.HYP.0000165686.50890.c3v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cohn, J. N. Articles by Grandits, G. A. Search for Related Content PubMed PubMed Citation Articles by Cohn, J. N. Articles by Grandits, G. A. Related Collections Pathophysiology Risk Factors Other arteriosclerosis Imaging Other diagnostic testing