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Matched Legal Cases: ['Application No. 60', 'art 1', 'art 1', 'Application No. 03812666', 'Application No. 03812666', 'Application No. 03812666', 'Application No. 2004', 'Application No. 2004', 'Application No. 2004', 'Application No. 2004']

Patent US8187196 - System for determining endothelial dependent vasoactivity - Google PatentsSearch Images Maps Play YouTube News Gmail Drive More »Sign in<nobr>Advanced Patent Search</nobr>PatentsA method of determining endothelial dependent vasoactivity of a subject, the method is effected by recording pressure-related signals of a plurality of locations adjacent to at least one blood vessel; extracting at least one parameter from the pressure-related signals; and using the at least one parameter...http://www.google.com/patents/US8187196?utm_source=gb-gplus-sharePatent US8187196 - System for determining endothelial dependent vasoactivityAdvanced Patent SearchPublication numberUS8187196 B2Publication typeGrantApplication numberUS 12/149,100Publication dateMay 29, 2012Filing dateApr 25, 2008Priority dateDec 9, 2002Also published asCA2508590A1, DE60333120D1, EP1569550A1, EP1569550B1, US7374541, US20060149152, US20080200820, WO2004052196A1Publication number12149100, 149100, US 8187196 B2, US 8187196B2, US-B2-8187196, US8187196 B2, US8187196B2InventorsGiora Amitzur, Shmuel Einav, Eran Peleg, Elya ZimermanOriginal AssigneeRamot At Tel-Aviv University Ltd.Export CitationBiBTeX, EndNote, RefManPatent Citations (26), Non-Patent Citations (51), Referenced by (2), Classifications (21) External Links: USPTO, USPTO Assignment, EspacenetSystem for determining endothelial dependent vasoactivityUS 8187196 B2Abstract A method of determining endothelial dependent vasoactivity of a subject, the method is effected by recording pressure-related signals of a plurality of locations adjacent to at least one blood vessel; extracting at least one parameter from the pressure-related signals; and using the at least one parameter to determine a change of at least one characteristic of the at least one blood vessel, the change being representative of endothelial functioning; thereby determining the endothelial dependent vasoactivity of the subject.
1. A system for determining endothelial dependent vasoactivity of a subject, the system comprising:
an arrangement of sensors for recording pressure-related signals of a plurality of locations adjacent to at least one blood vessel, said at least one blood vessel being in at least one organ of said subject;
a processing unit configured to extract at least one parameter from said pressure-related signals, and
a spectral analyzer configured for analyzing said at least one parameter and obtaining a frequency decomposition of said at least one parameter, said frequency decomposition being representative of the endothelial dependent vasoactivity of the subject;
wherein said at least one parameter comprises a parameter selected from the group consisting of elapsed time between two successive peaks of one or more of said pressure-related signals, and amplitude of one or more of said pressure-related signals.
2. The system of claim 1, further comprising electronic-calculation functionality for determining an autonomic nervous system activity of the subject.
3. The system of claim 2, wherein said processing unit is configured to calculate heart rate variability from said pressure-related signals thereby to determine said autonomic nervous system activity.
4. The system of claim 2, further comprising at least one electrocardiogram lead.
5. The system of claim 4, wherein said processing unit is operable to calculate heart rate variability from electrocardiogram signals sensed by said at least one electrocardiogram lead, thereby to determine said autonomic nervous system activity.
6. The system of claim 4, wherein said processing unit is configured to extract at least one additional parameter selected from the group consisting of a width of said pressure-related signals, and an elapsed time between peaks of electrocardiogram signals and peaks of said pressure-related signals.
7. The system of claim 1, further comprising a mechanism for stimulating said at least one blood vessel.
8. The system of claim 7, wherein said mechanism for stimulating said at least one blood vessel is selected from the group consisting of a mechanical mechanism, a thermal mechanism, a chemical mechanism an electrical mechanism, a mechanism for generating mental stress and a device for allowing the subject to perform physical exercise.
9. The system of claim 7, wherein said mechanism is configured to apply external pressure on said at least one blood vessel.
10. The system of claim 9, wherein said mechanism comprises a sphingomanometer.
11. The system of claim 7, wherein said mechanism is configured to reduce a temperature of said at least one blood vessel.
12. The system of claim 11, wherein said mechanism selected from the group consisting of a bath of fluid and a cuff of fluid, said fluid being at a predetermined temperature.
13. The system of claim 1, comprising a mechanism configured to reduce a temperature of an organ other than any of said at least one argan.
14. The system of claim 13, wherein said mechanism selected from the group consisting of a bath of fluid and a cuff of fluid, said fluid being at a predetermined temperature.
15. The system of claim 1, wherein said at least one blood vessel is selected from the group consisting of a brachial artery, a radial artery and a carotid artery.
16. The system of claim 1, wherein said at least one characteristic of said at least one blood vessel is selected from the group consisting of a radius of said at least one blood vessel and an elastic modulus of said at least one blood vessel. Description
RELATED APPLICATIONS This application is a Continuation of U.S. patent application Ser. No. 10/537,913 filed on Dec. 6, 2005 which is a National Phase of PCT Patent Application No. PCT/IL03/01025 having International Filing Date of Dec. 3, 2003, which claims the benefit of U.S. Provisional Patent Application No. 60/431,739 filed on Dec. 9, 2002. The contents of the above Applications are all incorporated herein by reference.
FIELD AND BACKGROUND OF THE INVENTION The present invention relates to measuring endothelial dependent vasoactivity and, more particularly, to a non-invasive method and system for determining endothelial dependent vasoactivity.
Several studies have demonstrated that elevated concentration of total cholesterol and low density lipoprotein cholesterol are associated with impaired endothelial function, independent of the presence of coronary heart disease [Robert A. Vogel, �Coronary risk factors, Endothelial function, and atherosclerosis: A review,� Clin. Cardiol 1997, 20:426-432; Robert A. Vogel et al., �Changes in flow-mediated brachial artery vasoactivity with lowering of desirable cholesterol levels in healthy middle aged men,� The American journal of cardiology 1996, 77; Kensuke Egashira et al., �Reduction in serum cholesterol with pravastatin improves endothelium dependent coronary vasomotion in patients with hypercholesterolemia,� Circulation 1994, 89 No 6]. In addition, decreased concentrations of high-density lipoprotein cholesterol and an elevated ratio of total to high-density lipoprotein cholesterol have also been associated with endothelial dysfunction.
Cigarette smoking profoundly impairs endothelial function [Robert W. stadler et al., �Measurement of the time course of peripheral vasoactivity: results in cigarette smokers,� Atherosclerosis 1998 138:197-205; David S. Celermajer et al., �Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults,� Circulation 1993, 88, No 5 part 1]. Endothelial function is reduced in both active and passive smokers in a dose dependent manner. Smoking cessation is associated with improvement in endothelial function.
Other factors which affect endothelial function include hypertension [Perticone F, et al., �Prognostic significance of endothelial dysfunction in hypertensive patients,� Circulation 2001, 104:191-196], diabetes [Cosentino F et al., �Endothelial dysfunction in diabetes mellitus,� J Cardiovasc Pharmacol, 1998, 32:54-61; Cosentino F et al., �High glucose causes upregulation of Cyclooxygenase-2 and alters prostanoid profile in human endothelial cells. Role of protein kinase C and reactive oxygen species,� Circulation 2003, 107:1017-1023], diet and physical exercise [Brendle D et al., �Effects of exercise rehabilitation on endothelial reactivity in older patients with peripheral arterial disease,� Am J Cardiol 2001, 87:324-329].
The full range of different diseases associated with endothelial dysfunction, the nature of endothelial abnormalities and the effects of potential treatments on vasoactivity are yet to be determined. Nevertheless, the measurement of arterial endothelium function is of utmost importance for the purpose of diagnosing endothelial dysfunction related diseases at early stage, for example for diagnostic assessment of atherosclerothic disease in the pre-stenotic stages [Vanhoutte. P. M., �Endothelial dysfunction and atherosclerosis,� Eur Heart J, 1997:18 (sup E) E19-E29; Robert A. Vogel, 1997 ibid; Mary C. Corretti et al., �Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilatation of the brachial Artery,� JACC 2002, 39:257-65; Widlansky M E, Gokee N, Keaney J F Jr, Vita J A, J, �The clinical implications of endothelial dysfunction,� J Am Coll Cardiol 2003, 42:1149-60].
Normal release of NO prevents and/or attenuates arteriosclerosis as well as other major factors such as thrombosis [Robinson Joannides et al., �Nitric oxide is responsible for flow-dependent dilatation of human peripheral conduit arteries in vivo,� Circ. 1995, 91:1311-12; Ian B. Wilkson et al., �Nitric oxide regulates local arterial distensibility in-vivo,� Circ. 2002, 105:213-217].
Many studies have demonstrated that endothelial dysfunction in coronary arteries is concomitant with impaired endothelial brachial, radial and the carotid dysfunction [Corretti et al., 2002 ibid; Tod J. Anderson et al., �Close relation of endothelial function in the human coronary and peripheral circulations,� JACC 1995, 26:1235-41; David S. Celermajer et al., �Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction,� JACC 1994, 24:1468-74; Sorensen K E et al., �Atherosclerosis in the human brachial artery,� JACC 1997, 29:318-22]. In addition, it was found that coronary artery disease is related to atherosclerothic disease in the aorta and the carotid artery [Khoury Z et al., �Relation of coronary artery disease to atherosclerothic disease in the aorta, carotid, and femoral arteries evaluated by ultrasound,� Am J Cardiol 1997, 80:1429-1433].
Over the past two decades, analysis of electrocardiogram (ECG) signals in general and Heart-Rate-Variability (HRV) in particular, have been used to quantify the behavior of the ANS [Malik et al., �Guidelines. Heart rate Variability,� Eur Heart J 1996, 17:354-381]. It was found that about 5 minutes recording of HRV are sufficient for detecting possible existence of coronary artery disease [Parati et al., �Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation. A critical appraisal,� Hypertension 1995, 25(6):1276-86; Hayano J et al., �Decreased magnitude of heart rate spectral components in coronary artery disease and its relation to angiographic severity,� Circulation 1990, 81(4):1217-24].
SUMMARY OF THE INVENTION According to one aspect of the present invention there is provided a method of determining endothelial dependent vasoactivity of a subject, the method comprising: recording pressure-related signals of a plurality of locations adjacent to at least one blood vessel; extracting at least one parameter from the pressure-related signals; and using the at least one parameter to determine a change of at least one characteristic of the at least one blood vessel, the change being representative of endothelial functioning; thereby determining the endothelial dependent vasoactivity of the subject.
DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention is of a non-invasive method and system for determining endothelial dependent vasoactivity which can be used in early stage diagnosis of endothelial dysfunction related diseases. Specifically, the present invention can be used to screen and diagnose large population and to differentiate between subjects being in different stages and combinations of endothelial and coronary artery dysfunction. For example, the present invention can be used to diagnose pathogenesis of cardiovascular disease, atherosclerosis and the like.
c = Eh 2 ⁢ ρ ⁢ ⁢ R , ( EQ . ⁢ 1 ) where ρ is the density of the blood.
For small radii, the elastic modulus of the blood vessel is, to a good approximation, a constant quantity. On the other hand, for large radii the elastic module becomes radius-dependent [Armentano R. L et al., �Arterial wall mechanics in conscious dogs�assessment of viscous, internal, and elastic moduli to characterize aortic wall behavior,� Circulation Research 1995, 76:468-78], and can be determined using the elapsed time parameter.
c 2 c 0 = E 2 ⁢ h 2 ⁢ R 0 E 0 ⁢ h 0 ⁢ R 2 , ( EQ . ⁢ 2 ) where the subscripts �0� and �2� represent values at different states (i.e., relaxation and contraction) of the blood vessel. A consequence of Equation 2 is that as the artery's radius increase the pulse wave velocity decreases. In terms of elapsed time, a decrease in the pulse wave velocity is manifested as an increment of the elapsed time between two peaks of the signals.
NO is known to have a buffering influence on arterial pressure variability. An acute change of arterial pressure alters shear stress, thus modifying NO generation and release. Subsequent vasodilatation or vasoconstriction occurs in response to the varying NO levels, which in turn readjust vascular resistance to reduce arterial pressure variability. NO acts rapidly: it diffuses out of the endothelium to the subjacent vascular smooth muscle cells, where it causes vaso-relaxation within seconds. Thus, NO can affect the regulation of blood pressure more rapidly than the arterial baroreflex. [Persson P B., �Spectral analysis of cardiovascular time series,� Am J Physiol, 273:R1201-R1210, 1997]. For example, it has been found in rats that after NO inhibition, the power in the range of above 0.2 Hz increases significantly, indicating that NO buffers blood pressure variability at these frequencies [Nafz B et al., �Endogenous nitric oxide buffers blood pressure variability between 0.2 and 0.6 Hz in the conscious rat,� Am J Physiol 272:H632-H637, 1997].
In addition, in mice, restoration of NO function improved blood pressure and heart rate variability (Pelat M. et al., �Rosuvastatin decreases caveolin-1 and improves nitric oxide-dependent heart rate and blood pressure variability in apolipoprotein E−/− mice in vivo,� Circulation 107:2480-2486, 2003).
The endothelial function of blood vessels is affected, as stated, by NO release, which is attributed to local platelet aggregation, production of thrombin and release of serotonin and ADP. The response of the blood vessel when exposed to specific conditions and stimuli can serve as an indicator for rate of NO release. To this end see, Vita J A et al., �Patients with evidence of coronary endothelial dysfunction as assessed by acetylcholine infusion demonstrate marked increase in sensitivity to constrictor effects of catecholamines,� Circulation 1992, 85:1390-1397; Deanfield J E et al., �Silent myocardial ischemia due to mental stress,� Lancet 1984, 2:1001-1005; Gage J E et al., �Vasoconstriction of stenotic coronary arteries during dynamic exercise in patients with classic angina pectoris: Reversibility by nitroglycerin,� Circulation 1986, 73:865-876; Gordon J B et al., �Atherosclerosis and endothelial function influence the coronary response to exercise,� J Clin Invest 1989, 83:1946-1952; Nabel E G et al., �Dilation of normal and constriction of atherosclerothic coronary arteries caused by cold pressor test,� Circulation 1988, 77:43-52; Zeiher A M et al., �Coronary vasomotion in response to sympathetic stimulation in humans: Importance of the functional integrity of the endothelium,� JACC 1989, 14:1181-90; Anderson E A et al., �Flow-mediated and reflex changes in large peripheral artery tone in humans,� Circulation 1989, 79:93-100; and Corretti M C et al., �Correlation of cold pressure and flow-mediated brachial artery diameter responses with the presence of coronary artery disease,� Am J Cardiol 1995, 75:783-787.
A representative example of a determination protocol is illustrated in the flowchart diagram of FIG. 3. Hence, the determination protocol preferably include two phases, in which in a first phase, designated by Blocks 22-23, the blood vessel characteristics and the heart rate variability are determined under a first stimulus, thereby obtaining a preliminary diagnosis. The preliminary diagnosis can be characterized, e.g., using a correlation function which correlates between the different measurements. More specifically, the first phase of the determination protocol, allows to preliminary determine of both the level of endothelial dependent vasoactivity, and the level of autonomic nervous system activity. Based on the results of the first phase, a preliminary characterization of the probability that the subject is suffering from endothelial dysfunction can be obtained, using a two-valued index (V, A), where �V� stands for the level of endothelial dependent vasoactivity and �A� stands for the level autonomic nervous system activity. Depending on the two-valued index of the subject, the physician or the nurse can decide whether to finish the protocol (Block 24) or to perform an additional determination phase (Block 26), under other types of stimuli and/or at different locations on the subject's body. The additional determination phase is then preferably used for obtaining a final diagnosis (Block 28).
As a representative example, suppose that the first phase of the determination protocol is performed, under a mechanical stimulus, on the brachial and radial arteries of the subject, and that after the first phase it is possible to differentiate (i) whether the subject has a normal or an abnormal endothelial dependent vasoactivity, and (ii) whether the subject has a normal or an abnormal autonomic nervous system activity. Then, the respective two-valued index can have one of four combinations: (V=�normal�, A=�normal�), (V=�abnormal�, A=�normal�), (V=�normal�, A=�abnormal�) and (V=�abnormal�, A=�abnormal�). One ordinarily skilled in the art will appreciate that the first combination and the fourth combination characterize, respectively subjects having the lowest and highest probabilities of suffering from endothelial dysfunction.
Subjects which are characterized by a combination other than (V=�normal�, A=�normal�) preferably undergo an additional phase of the determination protocol, which may be, for example, a thermal phase (e.g., a cold pressure test) where a thermal stimulus is applied to the brachial, radial and/or carotid arteries of the subjects.
T2 is the sum of two physiological periods: (i) the pre-ejection period, which is the time needed for the electrical activity of the heart to cause the iso-volumic contraction that leads to the opening of the aortic valve; and (ii) the valve-carotid period, which is the time needed for a pulse wave to move from the aortic valve to the measured location on the carotid. These two physiological periods are concomitantly shortened during the exposure to low temperatures. Normally, when the temperature starts to increase (e.g., during the recovery period of the above mention alternating sequence), the shortening of the pre-ejection period continues [Mezzacappa E S, et al., �Vagal Rebound and recovery from psychological stress,� Psychosom Med 2002, 63:650-657] while the aortic-valve-carotid period begins to prolong. Thus, a comparison between the values of T2 at different times can be used to characterize the endothelial activity.
Example 1 First Prototype System A first prototype system has been designed and constructed. The system included (i) transducers and an amplifier, designed and assembled for the research; (ii) a processing unit (desktop computer, Pentium IV); (iii) an A/D sampling card, purchased from National Instruments DAQ NI-488.2; (iv) data acquisition software, purchased from National Instruments� Labview 5.1.1�, custom designed; and (v) data analysis software, purchased from Matlab�, custom designed.
Example 2 In Vivo Measurements Using the First Prototype System In vivo tests were performed on 21 volunteers, using the first prototype system of Example 1. Two transducers were connected to the subject under examination. A first transducer was connected to the radial artery at the wrist, and a second transducer was connected to the brachial artery about 5-10 cm above the elbow on the proximal side of the arm. The transducers were fastened with a cuff inflated to a pressure of 20 mmHg, so as to improve that signal to noise ratio, and to prevent partial occlusion of the vessel. An additional cuff, purchased from Hokanson, US, was positioned above the first cuff, for the purpose of implementing ischemia (mechanical stimulus).
Several factors, such as temperature, food, drugs, physical exercise before examination and sympathetic stimuli, can affect vasomotor activity. In the above tests, it has been observed, that in some cases, examined individuals who were supposed to be with normal endothelium dependent vasoreactivity had different responses to reactive hyperemia at subsequent examinations. It was also found that these changes were in correlation with the elapsed time parameter measured in baseline. When the elapsed time parameter during baseline was relatively high (above 40-42 ms) the subject's response to reactive hyperemia was weak or completely absent. When the elapsed time parameter during baseline was lower (20-40 ms) the subjects' response to reactive hyperemia was normal. This implied that there is a �physiological window� in which the system produces the most reliable results.
Hence, the following standard procedure was developed to increase the probability that examinations were performed within the �physiological window�: (i) subjects were examined after fasting for 6-8 hours; (ii) the examination was performed in a quiet temperature controlled room (18� C.-20� C.); (ii) after three minute recording the subject was disconnected from the transducers, walked moderately for two minutes and returned to a sitting position, so as to enhance sympathetic activity, reduce the elapsed time parameter and induce relaxation; (v) two subsequent examinations under mechanical stimulus as described above, with a 10-minute rest between the examinations to allow full recovery of the artery.
baseline = D 1 + D 2 2 ( EQ . ⁢ 3 ) FMD ⁢ ⁢ % = 100 � D 4 - baseline baseline ( EQ . ⁢ 4 ) where FMD is abbreviation for Flow Mediated Dilatation. Typical FMD measurements are from about −6.2% to about +31.8%. Abnormal FMD was defined when the FMD value was below +6%.
2 < T < 4
Weak (−)
AN = Abnormal;
(−) = Negative
AN = Abnormal
During the first three minutes, the elapsed time was measured and the average was calculated (the dotted line in FIG. 10 a). When the right hand was submerged in cold water for 1 minute the elapsed time (measured on left hand) decreased almost linearly until it reached its lowest value (�70%). Heart rate increased substantially when the right hand was submerged in the cold water (FIG. 10 c). When the right hand was pulled out of the cold water and submerged in room temperature water, the elapsed time increases almost linearly until the initial elapsed time value reached (recovery). When the right hand was submerged again for 2 minutes in the cold water, the elapsed time decreased to a minimum of �60% from the initial baseline and heart rate was increased. Again, when right hand was pulled out of cold water and placed in room temperature water, the elapsed time raised again but did not reach initial baseline level until the examination has terminated.
(1)1-minute
(2)2-minute
(3)recovery
(1)p < 0.001 between control and 1 minute submergence.
(2)p < 2.5E−6 between control and 2 minutes submergence.
(3)p < 0.05 between recovery time of 1 Vs 2 minutes submergence.
(1)after walking
(1)p < 0.05 between values obtained before and after walking
(1)EDV
(1)p < 0.02 US vs. the prototype system
In the thermal stimulus examination the elapsed time parameter, PWT, was recorded from the left hand continuously in all individuals examined (n=6). PWT values decreased substantially relatively to baseline (p<0.001) and heart rate increased when the right hand was submerged in the cold water (30%-40% decrease in PWT) for a period of 1 minute, When the right hand was submerged for a period of 2 minutes the decrease in PWT relative to the 100% baseline was significantly larger (p<2.5 E−6) (60%-80% decrease in PWT). There was also a significant difference (p<0.05) between the recovery times after the hand was pulled out of the cold water.
To this end a �physiological window� has been defined in which the system has an appropriate mode of operation. It was assumed that in cases where the initial PWT value was relatively high (>40 ms), the initial radius before relaxation was also relatively wide. This may explain that the results obtained in a lying position with relatively large initial radius were based on measurements carried out, beyond the �physiological window.� Compared to this, cases in which the initial PWT value was relatively low, as in most examinations performed in a sitting position, it is assumed that the examination was performed within the �physiological window�. Statistical analysis of the data show that the average PWT during baseline is significantly higher in cases where subjects were found to have abnormal endothelium dependent vasoreactivity compared to cases where subjects were found to have normal endothelium dependent vasoreactivity.
The combined stimuli examination showed that a moderate walk for about 2 minutes before the examination, which causes a moderate elevation and alpha sympathetic activity, led to vasoconstriction and PWT reduction, hence allowed the examination to be conduct within the �physiological window�. Intensifying the physical activity (running or jumping) before examination causes an opposite effect in which probably beta receptors are also active causing vasodilatation. In such a case it reduces the probability that the examination will be conducted within the �physiological window.�
A comparison between results obtained by the prototype system and ultrasonography was carried out on a study group of 11 subjects. In 10 out of the 11 subjects the diagnoses determined by both the prototype system and the ultrasonography were compatible (p<0.015). In one case the US examination indicated a slightly higher value than the borderline increase in brachial diameter (7.8% vs. 6%) while the prototype system indicated �no response� in the first examination and a �weak response� in the second examination. In 5 of the cases both devices indicated abnormal endothelium dependent vasoreactivity and in the 5 other cases both devices indicated normal endothelium dependent vasoreactivity.
Example 3 A Second Prototype System A second prototype system has been designed and constructed. The system included: (i) a custom designed data logger; (ii) a brachial, radial and carotid transducers, all being operative at low frequencies and based on piezoelectric ceramic elements; (iii) an electrocardiogram chest electrode; (iv) a standard personal computer; and (v) data analysis software (see Example 1).
The brachial transducer was a coin shaped transducer, about 2 cm in diameter, attached to a dual compartment sphyngmanometric cuff, so as to allow both arterial occlusion (mechanical stimulus) and attachment of the transducer with a constant and controlled force. The dual compartment sphyngmanometric cuff included two separate air compartments: a low pressure compartment (�20 mmHg) for applying force on the brachial transducer thus coupling the transducer to the skin with a controlled force; and a high pressure compartment (up to 300 mmHg) for applying the mechanical stimulus on the artery. The high-pressure compartment facilitates quick release of pressure.
Example 4 In Vivo Measurements Using the Second Prototype System In vivo tests were performed on 22 volunteers, using the second prototype system of Example 2.
FIGS. 14 a-c show the elapsed time (FIG. 15 a), standard deviation (FIG. 15 b) and amplitude (FIG. 15 c) during sitting position of another subject who has been diagnosed by US measurements as having normal endothelial function. The value of PWT was small, about 33 ms, indicating that the measurement was initiated within the �physiological window.� With the increment of the artery's radius, a non-linear region, characterized by a non-linear amplitude increment, was observed.
FIGS. 15 a-c show the elapsed time (FIG. 14 a), standard deviation (FIG. 14 b) and amplitude (FIG. 14 c) during sitting position of a subject who has been diagnosed by US measurements as having abnormal endothelial function. As shown, in this case no change was observed in the elapsed time or in the amplitude, indicating abnormal endothelial function. The value of PWT was short, about 24 ms, indicating that the measurement was carried out within the above mentioned �physiological window.�
In this example, in addition to the elapsed time parameter, the amplitude parameter was included in analysis procedure. As stated in the discussion of Example 2, the measurement of endothelial function was based on the change of elapsed time parameter thereby requiring the measurement to be carried out within the �physiological window,� where the initial radius of the artery diameter is sufficiently small. Under such conditions, the elasticity module of the artery's wall is, to a good approximation, constant causing a linear dependence of the pulse wave velocity on the inverse of the radius (the pulse wave velocity decreased as the arterial radius is increased).
With the addition of pulse wave amplitude to the analysis, sensitivity to changes in artery diameter even beyond the �physiological window� was found. The amplitude parameter was increased for relatively large radius, indicating the participation of collagen in the change. At the same time, no change was observed in elapsed time parameter. On the other hand, no change in the amplitude parameter was observed when the initial radius size was considered to be within the �physiological window.�
Example 5 Measuring Heart Rate Variability Using Electrocardiogram Leads Heart rate variability analysis was carried out in 12 of the subjects who had undergone examination for the endothelial dysfunction measurement of Example 4. In 10 subjects heart rate variability analysis indicated normal autonomic nervous system activity and therefore possible normal coronary function. The analysis is based on 3 min recording using electrocardiogram lead II of the chest of the subjects, during baseline (before application of the mechanical stimulus).
The results are presented in FIGS. 17 a-h. FIGS. 17 a, 17 c, 17 e, and 17 g show heart rate variability analysis of a subject with normal heart rate variability activity and endothelial dysfunction. FIGS. 17 b, 17 d, 17 f, and 17 h show heart rate variability analysis of a subject with abnormal activity but with normal brachial endothelial function. Endothelial function or dysfunction are not shown in FIGS. 17 a-h. FIGS. 17 a-b show beat-to-beat analysis, referred to hereinafter as B2B analysis. For the subjects with the differences between subjects with normal and abnormal heart rate variability activity are manifested by the value of SDNN, which is in the normal range in FIG. 17 a and significantly lower in FIG. 17 b. As stated, a reduced value of SDNN reflects a reduced parasympathetic activity. In addition, high fluctuations between beats are shown in FIG. 17 a, compared to FIG. 17 b. FIGS. 17 c-d show the power spectrum densities. The normal HF peak around 0.3 Hz shown for the normal subject (FIG. 17 c) is absent from FIG. 17 d, hence indicates abnormal heart rate variability. In addition, HF value is relatively high in FIG. 17 c compared to FIG. 17 d, LF/HF is low in FIG. 17 c compared to FIG. 17 d, hence also supporting the abnormal heart rate variability diagnosis of the subject of FIG. 17 d. FIGS. 17 e-f show Fast Fourier Transform analysis of the RRI series. Again, a clear peak shown around 0.3 Hz in FIG. 17 e, is almost completely absent in FIG. 17 f. FIGS. 17 g-h show relative incidence, as a function of B2B (measured in ms). A relatively wide histogram of time intervals between beats is presented in FIG. 17 g, compared to the narrow histogram shown in FIG. 17 h, indicating normal heart rate variability for the subject of FIG. 17 g and abnormal heart rate variability for the subject of FIG. 17 h. Example 6 Cold Pressure Test In this study, a cold pressure test was performed on nine young subjects, 24-35 years of age (30.8+3.8 years) having no known risk factors for coronary heart disease hence assumed to have normal endothelial function.
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"Coronary Vasomotion in Response to Sympathetic Stimulation in Humans: Importance of the Functional Integrity of the Endothelium", JACC (Journal of the American College of Cardiology), 14(5): 1181-1190, 1989.* Cited by examinerReferenced byCiting PatentFiling datePublication dateApplicantTitleUS8439839 *Jun 2, 2008May 14, 2013Panasonic CorporationUltrasonic diagnosis device and ultrasonic probe for use in ultrasonic diagnosis deviceUS20100217125 *Jun 2, 2008Aug 26, 2010Masahiko KadokuraUltrasonic diagnosis device and ultrasonic probe for use in ultrasonic diagnosis device* Cited by examinerClassifications U.S. Classification600/486, 600/485, 600/500International ClassificationA61B5/02, A61B5/021, A61B5/0285Cooperative ClassificationA61B5/0048, A61B5/0285, A61B5/4035, A61B5/726, A61B5/416, A61B5/021, A61B5/02007, A61B5/02405European ClassificationA61B5/021, A61B5/41J4, A61B5/40D4, A61B5/024A, A61B5/00M, A61B5/02D, A61B5/0285RotateOriginal ImageGoogle Home - Sitemap - USPTO Bulk Downloads - Privacy Policy - Terms of Service - About Google Patents - Send FeedbackData provided by IFI CLAIMS Patent Services©2012 Google