Ultrasound method for assessing ejection fraction using ultrasound contrast agents

The preferred embodiments described herein provide a method for assessing ejection fraction by ultrasonically monitoring a region of a ventricle as contrast agent refills the ventricle following an initial imbalance. In one preferred embodiment, contrast agent is first administered into the body, and then the amount of contrast agent in a ventricle is reduced. In subsequent heart cycles, the ventricle draws contrast-agent-filled blood from the atrium, causing the concentration of contrast agent in the ventricle to increase until it is at equilibrium with the concentration of contrast agent in the atrium. By ultrasonically measuring the increase in contrast agent in the ventricle for one or more heart cycles, ejection faction of the ventricle can be determined without manual or automatic edge detection, assumptions about heart shape, or three-dimensional imaging.

BACKGROUND
 Ejection fraction is a quantitative way of assessing overall cardiac
 function. A low ejection fraction can indicate a number of diseases.
 Quantitative methods of assessing ejection fraction generally require the
 use of multiple ultrasound planes and edge detection. One accepted
 technique is to acquire images in orthogonal planes for each heart chamber
 to be assessed. Tracings of the outline of the chamber in the orthogonal
 images are used to estimate the chamber volume by assuming an elliptical
 shape for each image depth. By estimating the volume of the chamber at end
 of diastole ("ED") and end of systole ("ES"), the ejection fraction can be
 calculated using the following relation: Ejection Fraction=[1-(Volume at
 ES)/Volume at ED)]. With a two-dimensional scanner, this technique can be
 made semi-automatic by automatically detecting the border of the chamber
 from selected sequences from orthogonal planes and performing the
 necessary numerical integrations online. This technique can be improved by
 using additional planes and eliminating the assumption that the heart
 cross section is elliptical. Because of the required orientation and
 calculation, this is generally considered only in three-dimensional
 imaging.
 Because this quantitative method requires that volumes be determined, the
 method functions poorly when the entire heart chamber is poorly
 visualized. Hypoechoic and anisotropic endocardium and myocardium have
 long made it difficult to determine the boundary of the heart, especially
 with hard-to-image patients. In many cases, the boundary of the chamber
 must be estimated because the endocardium is not visible. Ultrasound
 contrast agents improve cardiac chamber edge detection, and left
 ventricular opacification with contrast agents improves ejection fraction
 measurements using manual or automatic techniques. However, the
 three-dimensional shape of the heart must still be acquired either through
 three-dimensional imaging or from assumptions based on orthogonal planes.
 Because of the inaccuracy of the manual technique and the low availability
 of the automated three-dimensional technique, ejection fraction is
 commonly estimated by eye. In practice, an experienced clinician can
 generate a number to describe a qualitative assessment of heart function
 based on viewing several sets of images. This produces an ejection
 fraction percentage that is widely used in describing heart function and
 determining treatment. Although assessment of ejection fraction by eye is
 accepted, scientific physicians prefer to have a truly quantitative method
 of generating this number. This desire drives the application of edge
 detection algorithms in cardiology as well as serving as a clinical
 rational for three-dimensional imaging.
 There is a need, therefore, for an improved method for assessing ejection
 fraction.
 SUMMARY
 The present invention is defined by the following claims, and nothing in
 this section should be taken as a limitation on those claims.
 By way of introduction, the preferred embodiments described below provide a
 method for assessing ejection fraction by ultrasonically monitoring a
 region of a ventricle as contrast agent refills the ventricle following an
 initial imbalance. In one preferred embodiment, contrast agent is first
 administered into the body, and then the amount of contrast agent in a
 ventricle is reduced. In subsequent heart cycles, the ventricle draws
 contrast-agent-filled blood from the atrium, causing the concentration of
 contrast agent in the ventricle to increase until it is at equilibrium
 with the concentration of contrast agent in the atrium. By ultrasonically
 measuring the increase in contrast agent in the ventricle for one or more
 heart cycles, ejection fraction of the ventricle can be determined without
 manual or automatic edge detection, assumptions about heart shape, or
 three-dimensional imaging.
 The preferred embodiments will now be described with reference to the
 attached drawings.

DETAILED DESCRIPTION OF THE PRESENTLY PREFERRED EMBODIMENTS
 Turning now to the drawings, FIG. 1 is a diagram of a heart 100 in a body
 50, which will aid in the illustration of the preferred embodiments. As
 shown in FIG. 1, the heart 100 comprises a pulmonary vein 110, a left
 atrium 120, a left ventricle 130, and an aorta 140. For simplicity , other
 parts of the heart 100 are not shown. The heart 100 is characterized by a
 heart cycle having two phases: a diastole phase and a systole phase.
 During diastole, the left ventricle 130 relaxes and fills with blood from
 the left atrium 120. During systole, the left ventricle 130 contracts,
 pumping blood into the aorta 140.
 By way of overview, ejection fraction of the left ventricle 130 can be
 assessed by ultrasonically monitoring the amount of contrast agent
 refilling the left ventricle 130 after an initial imbalance to determine
 how rapidly the left ventricle 130 refills. In one preferred embodiment,
 contrast agent is first administered into the body 50. The concentration
 of contrast agent in the left ventricle 130 is then reduced so there is
 less contrast agent in the blood in the left ventricle 130 than in the
 blood in the left atrium 120. In each heart cycle after the reduction, the
 left ventricle 130 draws contrast-agent-filled blood from the left atrium
 120. This causes the concentration of contrast agent in the left ventricle
 130 to increase until it is at equilibrium with the concentration of
 contrast agent in the left atrium 120. By ultrasonically measuring the
 increase in contrast agent in the left ventricle 130 for one or more heart
 cycles, ejection fraction of the left ventricle 130 can be determined.
 The reduction of contrast agent and the act of ultrasonically monitoring
 can be performed with one or more transducers (such as transducer 150) of
 a medical diagnostic ultrasound system. It should be noted that any
 appropriate medical diagnostic ultrasound system can be used to implement
 the preferred embodiments described herein. It is preferred, however, that
 the medical diagnostic ultrasound system described in "Contrast Agent
 Imaging with Destruction Pulses in Diagnostic Medical Ultrasound," U.S.
 patent application Ser. No. 09/348,246, filed Jul. 2, 1999, (which is
 assigned to the assignee of the present application and is hereby
 incorporated by reference) be used. As will be appreciated in view of the
 below description, it is preferred that the ultrasound system be operative
 to switch between a destructive (continuous) mode and a non-destructive
 (triggered) mode at the end of systole. In this regard, an ECG system can
 be coupled to the ultrasound system in order to trigger this transition at
 the end of systole or at any selected part of the heart cycle.
 Turning again to the drawings, FIG. 2 is a flow chart of a method of a
 preferred embodiment for assessing ejection fraction, and FIG. 3 is an
 illustration of a series of diagrams showing the size of and the amount of
 contrast agent in the left ventricle at various points in the heart cycle
 and indicating when in the heart cycle that the acts of this method are
 performed. The acts of this preferred method will now be described in
 detail.
 Administer Contrast Agent (Block 200)
 As shown in FIG. 2, the first act of this preferred method is to administer
 contrast agent into the body 50 (block 200). One way in which contrast
 agent can be administered is by venous bolus injection or venous infusion.
 Although more invasive, contrast agent can also be injected into the right
 atrium or ventricle. It is preferred that the contrast agent be
 administered such that the contrast agent is uniformly distributed in most
 or all of the blood pool or such that the blood entering the left
 ventricle 130 contain a constant concentration of contrast agent during
 the ultrasonic monitoring/measuring acts described below.
 Ultrasonically Measure the Amount of Contrast Agent in a Region of the Left
 Ventricle (Block 210)
 Next, the amount of contrast agent in a region of the left ventricle 130 is
 ultrasonically measured (block 210). This provides a measurement of the
 initial or full concentration of contrast agent in the region. The amount
 of contrast agent can be ultrasonically measured/monitored by first
 transmitting and then receiving one or more ultrasonic pulses. By using
 focused beams and time-gating the receive signal from each pulse, the
 signal scattered from a specific volume can be isolated. If this volume
 contains only contrast agents and their concentration is sufficiently low,
 the scattered energy will be proportional to the number of contrast agent
 particles in the volume. Other scatters in the volume can also contribute
 to the received signal, but their contribution can be negated if it is
 constant between measurements. Because of mixing in the ventricle, the
 number of contrast agent particles in the measurement volume is a measure
 of the contrast agent concentration throughout the ventricle. Although a
 single ultrasound line can be used for this measurement, multiple lines
 are preferred in order to reduce measurement uncertainty. Multiple lines
 can be acquired by measuring the backscattered signal from part of an
 ultrasound image contained in the ventricle 130.
 The measuring act can be accomplished with any of a number of techniques
 (harmonic imaging, pulse inversion, alternating line phase, subharmonic,
 etc.) With harmonic imaging, the ultrasound system transmits an ultrasonic
 signal into the region at a first frequency and receives a backscatter
 signal from the contrast agent in the region at a harmonic or sub-harmonic
 of the first frequency. The advantage of using harmonic imaging is that
 background signal from clutter and blood cells is reduced and,
 accordingly, the dynamic range of the measurement is improved. Background
 signal is further reduced in pulse inversion by transmitting two pulses of
 opposite polarity in each measurement direction in quick succession.
 Analytic summation of the received signals from these pulses causes
 cancellation of stationary fundamental signal and addition of stationary
 secondary harmonic signals. A similar result can be attained in the
 alternating line phase technique with less loss in frame rate by
 alternating the phase of adjacent transmit lines and forming analytic
 lines by summation of the received signals. Loss-of-correlation techniques
 that take advantage of contrast agent destruction can also be used to
 assess concentration. In these techniques, the difference between multiple
 pulses fired in quick succession is attributed to the interaction of
 contrast agents with the ultrasound beam.
 In the preferred embodiment shown in diagram 310 of FIG. 3, this
 measurement takes place before the beginning of diastole. It is preferred
 that this measurement take place at the same point in the heart cycle as
 the measurements described below. In one preferred embodiment, the amount
 of contrast agent is measured after a long quiescent period when the
 ultrasound system has not been transmitting (e.g., the first frame after
 long period of Freeze).
 Reduce the Amount of Contrast Agent in the Left Ventricle (Block 220)
 Next, the amount of contrast agent in the left ventricle 130 is reduced
 (block 220). It is preferred that the reduction be significant to ensure
 an accurate assessment of ejection fraction. One way in which contrast
 agent can be reduced is by destroying or disrupting the contrast agent by
 rapidly firing ultrasound pulses into the left ventricle 130 during an
 entire heart cycle (i.e., during both diastole and systole), as shown in
 diagrams 320, 330, and 340 of FIG. 3.
 Because blood containing contrast agent enters the left ventricle 130
 during diastole, it is preferred that destruction continue throughout this
 phase to destroy contrast agent as it enters the ventricle. Destruction
 can continue through systole to destroy additional contrast agent while no
 more agent is entering from the atrium. The end of systole (diagram 350)
 is the preferred time to cease contrast agent destruction and measure the
 contrast agent concentration (as described below) because this should be
 the nadir of the contrast agent's concentration.
 It is preferred that the destruction pulses be aimed so that no destruction
 occurs in the other heart chambers. This can be accomplished by carefully
 selecting the imaging plane. It should be acceptable to destroy contrast
 agent in the right heart if the destruction is carried out over a short
 time (e.g., a few heart cycles) because the concentration of contrast
 agent in the lungs should not be strongly affected. Also, a short axis
 view of the heart 100 should not destroy contrast agent in the left atrium
 120.
 It should be noted that any suitable way of reducing the amount of contrast
 agent can be used. It is preferred, however, that the methods described in
 "Contrast Agent Imaging with Destruction Pulses in Diagnostic Medical
 Ultrasound," U.S. patent application Ser. No. 09/348,246, filed Jul. 2,
 1999, be used. By way of overview, contrast agent can be destroyed by
 using high pulse repetition frequency ("HPRF") destruction pulses, which
 are pulses that are transmitted at a rate faster than required to allow
 the pulses to propagate to the farthest boundary of a region of interest
 and return to the transducer 150. Additionally, closely- or widely-spaced
 multiple transmit beams can be sent out simultaneously. The efficiency of
 destruction can be increased by changing pulse parameters between the
 multiple firings of HPRF destruction pulses. For example, by changing the
 transmit focus, the point of peak intensity changes, thereby varying the
 location of maximum contrast agent destruction. Additionally, by varying
 the transmit frequency, penetration into the body 50 can vary and bubbles
 of various resonating frequencies can be disrupted. Further, increasing
 pulse power can provide better destruction coverage.
 Ultrasonically Measure the Amount of Contrast Agent before Diastole
 Following the Reduction (Block 230)
 Next, before the beginning of diastole following the reduction described
 above, the amount of contrast agent in the region of the left ventricle
 130 is measured (block 230). This provides a measurement of the
 concentration of contrast agent (if any) in the region after reduction. It
 is preferred that this measurement be taken at the end of systole (see
 diagram 350 of FIG. 3) since the measurement described below is also
 preferably taken at the end of systole.
 Ultrasonically Measure the Amount of Contrast Agent after Diastole
 Following the Reduction (Block 240)
 The amount of contrast agent in the region is measured again; this time,
 after diastole following the reduction described above (block 240). Again,
 it is preferred that the measurement be made at the end of systole, as
 shown at 390 in FIG. 3, to provide as much mixing of the contrast agent as
 possible to ensure uniform distribution of contrast agent in the left
 ventricle 130. This measurement represents the concentration of contrast
 agent in the left ventricle 130 after one heart cycle with maximum time
 for mixing in the left ventricle 130.
 Determine the Ejection Fraction of the Left Ventricle (Block 250)
 With the measurements made before the reduction of contrast agent, before
 diastole following reduction, and after diastole following reduction, the
 ejection fraction of the left ventricle 130 can be determined (block 250).
 One way in which ejection fraction can be determined is by using the
 following relationship:
 ##EQU1##
 wherein C.sub..infin. is the steady-state concentration achieved when no
 contrast agent is destroyed for a long period of time (here, the
 concentration of contrast agent before the reduction), C.sub.ES (t-1) is
 the concentration of contrast agent before diastole following the
 reduction, and C.sub.ES (t) is the concentration of contrast agent after
 diastole following the reduction. The derivation of this relationship is
 provided in Appendix I. To provide a more accurate determination of
 ejection fraction, it is preferred that a series of measurement be made so
 that a series of ejection fractions can be calculated and averaged.
 As mentioned above, C.sub..infin. is the steady-state concentration
 achieved when no contrast agent is destroyed for a long period of time. In
 the preferred method described above, C.sub..infin. was the amount of
 contrast agent present in the left ventricle 130 immediately before the
 reduction of contrast agent. Alternatively, the steady-state concentration
 can be measured at an earlier time before the reduction or following the
 reduction after contrast agent concentration has reached equilibrium.
 However, since the steady-state concentration of contrast agent can
 fluctuate with time, it is preferred that the timing of the measurements
 described above be used since concentration levels of contrast agent are
 more stable within a few heartbeats.
 There are several advantages associated with these preferred embodiments.
 First, these preferred embodiments provide a way of assessing ejection
 fraction without manual or automatic edge detection, assumptions about
 heart shape, and three-dimensional imaging. Because computer-intensive
 edge detection algorithms or multiple image planes are not used, these
 preferred embodiments provide a quick method of assessing ejection
 fraction. Also, because edge tracing is unnecessary, these preferred
 embodiments can be used on patients where imaging conditions do not allow
 the boundary of the entire ventricle to be clearly imaged. Additionally,
 these preferred embodiments can be used routinely to quantitatively
 determine ejection fraction in patients that have a venous line for other
 purposes (e.g., pharmacological stress test) without significantly
 increasing the time for the examination. Further, these preferred
 embodiments provide an assessment of ejection fraction that is much more
 accurate than that produced by eye estimation.
 There are several alternative features that can be used with these
 preferred embodiments. First, although the preferred embodiments were
 described above in terms of the left ventricle, it is important to note
 that these preferred embodiments can also be used with the right
 ventricle. Second, it should be noted that the region can comprise all or
 part of the left ventricle 130. Preferably, the region does not contain
 the myocardium, valves, or the right ventricle. The presence of myocardium
 in the region of interest will introduce error since contrast agent will
 eventually enter the myocardium and cause it to brighten. However, since
 the time for this to occur is much longer than that required for the blood
 to return to the left ventricle 130, the presence of myocardium in the
 region of interest should produce little error aside from increasing the
 background (no contrast) signal level.
 In another preferred embodiment, additional measurements are acquired in
 order to reduce the statistical variability of the measurement. This can
 be done by repeating the three-point measurement described above, allowing
 the equilibrium concentration to be reached between measurements.
 Alternatively, if a substantially non-destructive technique is used to
 measure the contrast agent concentration, measurements can be made after
 multiple heart cycles following contrast agent destruction. Subsets of
 these measurements can be used to make separate estimates of the ejection
 fraction, or the entire set can be fit with a curve using a least-square
 or similar technique. The resulting curve is characterized by the
 equilibrium concentration, the initial (post-reduction) concentration, and
 the ejection fraction. One or more measurements of the amount of contrast
 agent present before reduction can also be made to enhance the accuracy of
 this approach. As an example of this alternate embodiment, consider FIG.
 4, which shows an average intensity of pixels in an imaged region of the
 left ventricle 130 over a number of cardiac cycles following the reduction
 of contrast agents. The form of this curve is similar to the solution to a
 dye-dilution-type differential equations: A-B*(exp(-t/.tau.). However,
 because of the stroke nature of flow in the heart, the time constant,
 .tau., is only equal to the reciprocal of the ejection fraction for very
 small ejection fractions.
 In a further alternate embodiment, instead of using destruction to set up
 an imbalance between the left ventricle 130 and the left atrium 120, a
 rapid bolus injection can be used to set up the imbalance. Provided
 regions of interest can be placed in both the left atrium 120 and the left
 ventricle 130 without a significant amount of contrast agent between the
 region of interest and the transducer 150 (to eliminate attenuation
 effects), the concentration in both chambers can be monitored. The delay
 for the contrast agent to fill the left ventricle 130 after it fills the
 left atrium 120 will indicate the ejection fraction of the left ventricle
 130.
 In yet another alternate embodiment, instead of using a medical diagnostic
 imaging system, an imaging system of another modality (e.g., an x-ray
 system) that is sensitive to contrast agents or another appropriate agent
 can be used.
 It is important to note that any of the various aspects of the preferred
 embodiments can be used alone or in combination. Additionally, it is
 preferred that the ultrasound system perform the embodiments described
 above using any appropriate software and/or hardware components. It should
 be understood that any appropriate hardware, analog or digital, and any
 appropriate software language can be used. Additionally, the methods
 described above can be implemented exclusively with hardware.
 It is intended that the foregoing detailed description be understood as an
 illustration of selected forms that the invention can take and not as a
 definition of the invention. It is only the following claims, including
 all equivalents, that are intended to define the scope of this invention.
 APPENDIX I
 The contrast agent mass in the left ventricle can be calculated as:
 P.sub.ES (t)=P.sub.ED (t-1)[1-E], where P.sub.ES (t) is the contrast agent
 mass in the left ventricle at the end of systole, P.sub.ED (t-1) is the
 contrast agent mass in the left ventricle immediately preceding systole at
 time t, and E is the left ventricle's ejection fraction.
 Further, P.sub.ED (t-1)=P.sub.ES (t-1)+P.sub.s, where P.sub.s is the
 contrast agent mass that enters during one stroke of the heart and
 P.sub.ES (t-1) is the mass at the end of systole immediately preceding the
 diastole in question.
 Combining these equations yields:
EQU P.sub.ES (t)=(1-E){P.sub.ES (t-1)+P.sub.S }
 The contrast concentration is given by,
 ##EQU2##
 where
 V.sub.ES is the end systole volume of the left ventricle.
 The stable condition defined for P.sub.s /V.sub.es =constant is
 ##EQU3##
 where V.sub.ed is the end diastolic volume of the left ventricle.
 Identifying C.sub..infin. in the above equation for C.sub.es (t) yields
EQU C.sub.ES (t)=(1-E)C.sub.ES (t-1)+EC.sub..infin..
 This can be solved for E, yielding:
 ##EQU4##