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(Hypertension. 1995;26:503-508.)
© 1995 American Heart Association, Inc.

Articles

Noninvasive Pulse Wave Analysis for the Early Detection of Vascular Disease

Jay N. Cohn; Stanley Finkelstein; Gary McVeigh; Dennis Morgan; Lisa LeMay; Jennifer Robinson; James Mock

From the Cardiovascular Division (J.N.C., D.M., L.L., J.R., J.M.) and the General and Preventive Medicine Division (G.M.), Department of Medicine, and the Division of Health Computer Sciences, Department of Laboratory Medicine and Pathology (S.F.), University of Minnesota Medical School, Minneapolis.

	Abstract

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Abstract A noninvasive technique has been developed and validated for calculating capacitive and oscillatory systemic arterial compliance with the use of pulse wave analysis and a modified Windkessel model. Application of the technique to subjects with hypertension, postmenopausal women with symptomatic coronary artery disease, and appropriate control subjects has confirmed a reduction of oscillatory compliance in the disease states and an increase in capacitive and oscillatory compliances in response to vasodilator drugs. This method should be useful in screening subjects for early evidence of vascular disease and in monitoring the response to therapy.

Key Words: arterial compliance • cardiac output • vasodilation drugs • atherosclerosis • hypertension

	Introduction

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Functional and structural changes in the arterial wall precede the development of obstructive coronary artery disease and may be early markers for the hypertensive disease process.^{1 2} In previous studies from this laboratory we have used brachial intra-arterial pulse waves to analyze the diastolic pressure decay and have calculated vascular properties based on a modified Windkessel model of the circulation.³ In hypertensive subjects,⁴ in diabetics,⁵ and in the normal aging process⁶ we identified an abnormality in the oscillatory component of the diastolic waveform that could be identified as a reduced compliance in one of the parallel compliances identified in the Windkessel model. On the basis of insights into the structure of the arterial bed, this abnormality in arterial storage capacity likely resides at reflecting sites in the more distal arterial vasculature. Since this abnormality has been detected in asymptomatic individuals and in those without apparent cardiovascular disease, we have previously suggested that alterations in pulse wave contour may prove to be an early marker for the presence of disease and might serve as a guide for pharmacological therapy.⁶

To apply this method more widely in an effort to examine large populations of individuals and monitor responses over time, it was necessary to develop a noninvasive technique that could approximate the data obtained from intra-arterial pressure measurements. Furthermore, since a cardiac output (CO) measurement is required for calculation of arterial compliance using the circulatory model, a reliable noninvasive technique for CO measurement also was required. This report describes these noninvasive techniques and compares noninvasive results with those obtained from simultaneous intra-arterial recordings combined with dye curve CO determinations. We also used the noninvasive technique to examine several groups of subjects to confirm and extend our observations of alterations of compliance in disease and in response to drugs.

	Methods

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Radial arterial pulse waves were recorded with an arterial tonometer sensor array (model N-500, Nellcor Inc). The waveform was calibrated by the oscillometric method with a cuff on the opposite arm and a calibration system internal to the Nellcor device. The tonometer sensor array adjusts itself automatically to obtain the optimal waveform and repeats its calibration until the waveform is stable. At that point, 30-second-long analog tracings of the radial artery waveform were digitized at 200 samples per second and stored in a personal computer system for compliance analysis (Hypertension Diagnostics, Inc). A beat-marking algorithm determined the beginning of systole, peak systole, onset of diastole, and end diastole for all beats in the 30-second measurement period. The marked beats were then cross-correlated, and those with a correlation coefficient greater than .995 were averaged with the use of the upstroke beat mark as the fiduciary time point for the averaging process. In the usual run approximately 70% to 80% of all beats from the 30-second sample satisfied these correlation criteria and were included in the average beat determination. This average beat was representative of the 30-second period of pressure information and was used in all subsequent analyses.

A parameter-estimating algorithm was then applied to this representative beat for determination of the best set of A_i values for matching the diastolic portion of the measured beat to the multiexponential waveform of the following equation:

Once the six A_i values were determined, the modified Windkessel model parameters were calculated from the A_i values and CO by means of the circuit equations that define the operation of the modified Windkessel system (Fig 1). These model parameters represent the capacitive compliance (C₁), oscillatory compliance (C₂), blood volume inertia (L), and systemic vascular resistance (R).

View larger version (8K): [in this window] [in a new window]   Figure 1. Diagram shows modified Windkessel model used for analysis of vascular properties. SV indicates stroke volume; C1, capacitive compliance; C2, oscillatory compliance; R, systemic vascular resistance; L, inertia of the blood; P1, proximal pressure; and P2, distal pressure.

CO was estimated from an algorithm developed in our laboratory to assist in these clinical studies. It is a multivariate function of ejection time, heart rate, body surface area, and age⁷ and can be determined from the arterial pressure waveform, measured with the use of invasive or noninvasive instrumentation, with the following formula developed from an experimental set of "learning" data and validated in an independent set of "test" data: Stroke Volume=-6.6+(0.25 ET)-(0.62 HR)+(40.4 BSA)-(0.51 Age), where ET is ejection time in milliseconds, HR is heart rate in beats per minute, and BSA is body surface area in millimeters squared.

To test CO we performed estimator invasive studies. The brachial artery was cannulated with an indwelling plastic needle and the pulsatile arterial waveform recorded with a Statham transducer (Viggo-Spectramed). A central venous catheter was inserted into an antecubital vein and used for injection of indocyanine green into the superior vena cava. CO was calculated by withdrawal of brachial arterial blood through a densitometer (Waters Instruments, Inc) with the use of a CO computer. Dye curves were performed at least in triplicate with the requirement that three measurements varied by less than 15%. CO estimates from the estimator algorithm were then compared with measurements from the dye curves.

All subjects used in these studies gave informed consent for participating in the protocol, which was approved by the University of Minnesota Institutional Review Board.

Statistical analysis was carried out with correlation coefficient and paired and independent t tests for comparison of subject groups. Differences between methods and repeated studies variability were assessed with the Bland-Altman technique.⁸

	Results

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Invasive Versus Noninvasive Arterial Pressure
In 78 subjects brachial intra-arterial waveforms were compared directly with radial tonometer waveforms. As noted in Fig 2 the tonometer pressures, calibrated with an arm cuff, correlated closely with the directly measured arterial pressures. Examples of waveform differences are displayed in Fig 3. Although the waveforms had similar characteristics, the noninvasive waveform exhibited predictably fewer high-frequency components. The pressure in these 78 subjects averaged 133/71 mm Hg (mean, 95.5 mm Hg). The average pressure difference (invasive minus noninvasive) for mean arterial pressure was 5.0±4.9 (SD) mm Hg; for systolic pressure, 9.2±8.5 mm Hg; and for diastolic pressure, 0.6±6.1 mm Hg. The correlation between noninvasively and invasively measured ejection time (mean, 349 milliseconds), used in the CO estimator, was r=.92, and the difference (invasive minus noninvasive) averaged -15±19 milliseconds.

View larger version (31K): [in this window] [in a new window]   Figure 2. Line graphs show comparison of pressure recordings from brachial arterial cannulation (invasive) and radial artery tonometry (noninvasive) for mean arterial pressure (MAP), heart rate (HR), systolic pressure (SYS), and diastolic pressure (DIA).

View larger version (42K): [in this window] [in a new window]   Figure 3. Tracings show simultaneous recordings of invasive and noninvasive waveforms obtained on two subjects (top and bottom) studied on two occasions at a 6-month interval. Top, Waveforms are quite similar; bottom, noninvasive waveform exhibits damping of some of the high-frequency oscillations.

CO measured by the indocyanine green dye dilution technique was compared directly with CO calculated from the estimator developed in our laboratory in 101 subjects. As shown in Fig 4, agreement was satisfactory between the two methods. The difference (invasive minus noninvasive) between the methods averaged -0.13±0.94 L/min. In 92% of the cases estimated CO was within 25% of measured CO.

View larger version (21K): [in this window] [in a new window]   Figure 4. Line graph shows that cardiac output (CO) calculated from the estimator algorithm exhibits satisfactory agreement with the dye curve–measured CO in 101 subjects. Multiple points overlap in the figure.

Arterial compliance calculated from the noninvasive waveform and noninvasive CO algorithm was compared with the compliance calculated from the brachial arterial invasive pressure measurements and the indocyanine green dye dilution CO measurement. As shown in Fig 5 (top), C₁ measured noninvasively correlated closely with C₁ measured invasively (r=.82, P<.001). The mean difference between the methods (invasive minus noninvasive) was -0.34±0.36 mL/mm Hg (Fig 5, bottom). Noninvasively measured C₂ tended to overestimate invasively measured C₂ (Fig 6, top); nonetheless, the correlation coefficient was significant (r=.62, P<.001). The mean difference was -0.018±0.025 mL/mm Hg (Fig 6, bottom).

View larger version (30K): [in this window] [in a new window]   Figure 5. Top, Line graph shows that capacitive compliance (C1) calculated from the noninvasive waveform exhibits good agreement with that calculated from the invasive waveform (r=.82, P<.001). Bottom, Bar graph shows the frequency distribution of the differences (invasive minus noninvasive) between C1 measurements.

View larger version (39K): [in this window] [in a new window]   Figure 6. Top, Line graph shows that oscillatory compliance (C2) measured noninvasively tends slightly to overestimate invasive C2, but the correlation persists (r=.62, P<.001). Bottom, Bar graph shows the frequency distribution of the differences (invasive minus noninvasive) between C2 measurements.

Reproducibility Studies
In 20 subjects noninvasive studies were repeated at an interval of 1 to 2 weeks with no intervention. Arterial pressure varied considerably between the two studies (first minus second measurement: systolic mean difference, 2.8±11.7 mm Hg; diastolic, 1.0±8.1 mm Hg). C₁ averaged 1.86 mL/mm Hg, and the difference between the two studies averaged 0.015±0.38 mL/mm Hg. C₂ averaged 0.078 mL/mm Hg, and the difference averaged -0.007±0.014 mL/mm Hg.

Arterial Compliance in Hypertension
Noninvasive studies were performed in 32 subjects with essential hypertension on no drug therapy, and data were compared with those from 31 nearly age-matched normotensive control subjects. The hypertensive subjects included 17 men and 15 women with a mean age of 54±7 years and mean blood pressure of 152/86 mm Hg. The normotensive subjects included 20 men and 11 women with a mean age of 47±5 years and mean blood pressure of 115/63 mm Hg. Heart rate in the hypertensive subjects averaged 63 beats per minute and in the normotensive subjects 67 beats per minute. As shown in Fig 7, C₁ was similar in the normotensive and hypertensive subjects (2.24 versus 1.94 mL/mm Hg, P=NS), whereas C₂ was reduced by 31% in the hypertensive subjects (0.075 versus 0.052 mL/mm Hg, P<.05).

View larger version (15K): [in this window] [in a new window]   Figure 7. Bar graphs show comparison of noninvasive measurements of capacitive (C1) and oscillatory (C2) compliance in normotensive (NT) and hypertensive (EH) subjects.

Noninvasive Compliance in Coronary Artery Disease
A group of 29 postmenopausal women with documented symptomatic coronary artery disease (mean age, 55.5 years) was compared with a group of 23 age-matched postmenopausal women with no evidence of vascular disease (mean age, 52.8 years) (Fig 8). Blood pressures were similar (average, 132/70 and 123/68 mm Hg, respectively). C₂ was reduced by 24% in the subjects with coronary disease compared with those without coronary disease (0.067 versus 0.051 mL/mm Hg, P<.05), and C₁ was similar in the two groups (1.78 versus 1.79 mL/mm Hg). Heart rate and CO were not different between the two groups.

View larger version (12K): [in this window] [in a new window]   Figure 8. Bar graphs show comparison of noninvasive measurements of capacitive (C1) and oscillatory (C2) compliance in postmenopausal women without and with symptomatic coronary artery disease (CAD).

Response to Drugs
The sensitivity of the noninvasive technique in identifying vascular effects of vasodilator drugs has been assessed. Fig 9 displays the change in pulse contour elicited by the administration of 25 mg hydralazine and 20 mg isosorbide dinitrate to a hypertensive subject. The altered pulse wave results in prominent increases in C₁ and C₂.

View larger version (23K): [in this window] [in a new window]   Figure 9. Tracings show pulse wave change induced by the vasodilator drugs hydralazine and isosorbide dinitrate (ISDN) in a hypertensive subject. HR indicates heart rate; MAP, mean arterial pressure; C1, capacitive compliance; and C2, oscillatory compliance.

	Discussion

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Earlier invasive studies from this laboratory have identified a reduction of C₂ in hypertensive individuals,⁴ in non–insulin-dependent diabetics without overt vascular disease,⁵ and in the elderly.⁶ These observations made with the use of arterial diastolic pulse wave analysis are consistent with observations in these conditions made with the use of other techniques that have identified an augmentation of reflected waves,^{9 10} a decrease in finger arterial compliance,¹¹ or a decrease in pulsatility of conduit arteries.^{12 13 14} The data from invasive measurements in our laboratory raise the possibility that pulse contour analysis could serve as a valuable technique in assessing the presence of preclinical vascular disease and in identifying individuals whose hypertension or diabetes is characterized by an alteration in small vessel structure or function.¹⁵

Pulse wave analysis carried out at any central or peripheral arterial recording site can result in similar values for total systemic C₁ and C₂. Although the actual contour of the diastolic waveform may differ at different recording sites, these differences relate primarily to varying initial conditions that are not model-dependent parameters.¹⁶ Use of a noninvasive technique for recording of a peripheral waveform requires not only accurate calibration of the pressure measurement but also faithful representation of the slope of the diastolic decay and of the oscillatory component recorded in diastole.

Data from the present study confirm the potential usefulness of such a noninvasive technique. With the use of a radial arterial tonometer, the recorded waveform appears visually to approximate closely the waveforms obtained from direct arterial puncture. Furthermore, the CO algorithm developed in our laboratory appears to be a satisfactory method for estimation of output for use in the modified Windkessel model formula. As noted in Fig 5 (top), the output algorithm tends to overestimate CO when the measured CO is low and to underestimate CO when the measured value is high. When applied to the Windkessel model, the percent error in CO measurement would result in a comparable percent error in compliance estimates. Thus, even a 20% error in CO would result in only a 20% error in C₂, which is less than the average difference detected between normotensive subjects and subjects with vascular disease. The algorithm for CO has been validated only in subjects with well-maintained cardiac function without significant impairment in contractility. Therefore, the subjects used in this noninvasive assessment are those who exhibit no signs or symptoms of heart failure. An algorithm suitable for heart failure is currently under development in our laboratory.

Compliance measurements calculated from noninvasive waveforms tended to overestimate values obtained from invasive studies. C₁ was overestimated by an average of 0.34 mL/mm Hg, and C₂ was overestimated by an average of 0.018 mL/mm Hg. However, the absolute value of the compliance is less important than the sensitivity of the technique to distinguish subjects with and without vascular disease and to detect the effects of vasoactive drugs on the arterial vasculature. We have now explored the usefulness of this noninvasive method in two clinical states that have previously been identified as exhibiting abnormalities of systemic arterial compliance. In subjects with essential hypertension, C₂ was significantly reduced compared with that in normotensive subjects. The magnitude of this reduction was somewhat less than previously reported with the invasive techniques.⁴ This possible reduction of sensitivity of the noninvasive method is not surprising, because the more damped noninvasive waveform might tend to reduce some of the oscillatory components of the waveform used in calculating C₂. Nonetheless, the pulse contour abnormality identified with the noninvasive technique still was effective in characterizing the abnormality in those individuals with essential hypertension. Previous studies have shown conflicting data relating to arterial compliance in hypertension. A reduced arterial compliance has been described in some studies,^{17 18 19 20 21} but in other studies this has been ascribed to the passive decrease in compliance that would be associated with a higher arterial pressure.^{22 23 24 25} Most of these studies have explored single arteries, and a heterogeneity of response in different conduit arteries has been described.²⁶ The abnormality of C₂ detected from pulse contour analysis represents a lumped parameter not generated from the conduit brachial or radial arteries but probably residing in the smaller microcirculatory vessels or branch points that serve as reflecting sites in the circulation.²⁷

Recent studies have suggested that patients with coronary disease may have abnormalities of systemic arterial function. Although atherosclerosis and coronary disease were previously viewed as localized to visible endothelial lesions, abnormalities of structure and function of vessels without plaque formation have been demonstrated.^{12 28} Our studies on arterial compliance in postmenopausal women with and without coronary artery disease are consistent with these observations. A reduction of systemic C₂ in the presence of coronary disease suggests that functional abnormalities possibly related to abnormal endothelial function may exist in areas remote from the clinically apparent atherosclerotic process.

Vasoactive drugs act through effects on vascular smooth muscle on arterial compliance as well as on arteriolar resistance. The example shown in Fig 9 is indicative of the magnitude of the pulse contour and compliance changes that can be detected after short-term drug administration. These observations raise the possibility that this simple noninvasive technique could become a useful means of monitoring the efficacy of antihypertensive drug therapy.

Although noninvasive arterial pulse contour analysis may not yield numbers for arterial compliance identical to those obtained from invasive measurements, the principle of an abnormality in C₂ in the presence of these abnormal states has now been confirmed. These preliminary data suggest that this noninvasive technique may now be applied more widely in an effort to characterize the abnormality of the vasculature in larger populations of subjects and to monitor the response to vasoactive drug therapy. Preliminary studies suggesting that these abnormalities in C₂ can be identified before disease is clinically apparent and before blood pressure elevations are detected in hypertensive individuals raise the possibility of this becoming a sensitive screening technique for identifying individuals who need more aggressive management strategies.

	Footnotes

 
Reprint requests to Jay N. Cohn, MD, Cardiovascular Division, University of Minnesota Medical School, Box 508 UMHC, 420 Delaware St SE, Minneapolis, MN 55455.

	References

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