WO2010052303A1 - Analyse de données d'activation électromécanique ventriculaire - Google Patents

Analyse de données d'activation électromécanique ventriculaire Download PDF

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WO2010052303A1
WO2010052303A1 PCT/EP2009/064748 EP2009064748W WO2010052303A1 WO 2010052303 A1 WO2010052303 A1 WO 2010052303A1 EP 2009064748 W EP2009064748 W EP 2009064748W WO 2010052303 A1 WO2010052303 A1 WO 2010052303A1
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onset
segment
left ventricular
active force
time
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PCT/EP2009/064748
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English (en)
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Kristoffer Russell
Otto A. Smiseth
Anders Opdahl
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Oslo Universitetssykehus Hf
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/02028—Determining haemodynamic parameters not otherwise provided for, e.g. cardiac contractility or left ventricular ejection fraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/08—Detecting organic movements or changes, e.g. tumours, cysts, swellings
    • A61B8/0883—Detecting organic movements or changes, e.g. tumours, cysts, swellings for diagnosis of the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
    • A61B8/48—Diagnostic techniques
    • A61B8/485—Diagnostic techniques involving measuring strain or elastic properties
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/02—Detecting, measuring or recording pulse, heart rate, blood pressure or blood flow; Combined pulse/heart-rate/blood pressure determination; Evaluating a cardiovascular condition not otherwise provided for, e.g. using combinations of techniques provided for in this group with electrocardiography or electroauscultation; Heart catheters for measuring blood pressure
    • A61B5/021—Measuring pressure in heart or blood vessels
    • A61B5/0215—Measuring pressure in heart or blood vessels by means inserted into the body
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/24—Detecting, measuring or recording bioelectric or biomagnetic signals of the body or parts thereof
    • A61B5/316—Modalities, i.e. specific diagnostic methods
    • A61B5/318—Heart-related electrical modalities, e.g. electrocardiography [ECG]
    • A61B5/346—Analysis of electrocardiograms
    • A61B5/349—Detecting specific parameters of the electrocardiograph cycle
    • A61B5/352—Detecting R peaks, e.g. for synchronising diagnostic apparatus; Estimating R-R interval
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/50—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications
    • A61B6/503—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment specially adapted for specific body parts; specially adapted for specific clinical applications for diagnosis of the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
    • A61B6/52—Devices using data or image processing specially adapted for radiation diagnosis
    • A61B6/5211—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data
    • A61B6/5229—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image
    • A61B6/5247—Devices using data or image processing specially adapted for radiation diagnosis involving processing of medical diagnostic data combining image data of a patient, e.g. combining a functional image with an anatomical image combining images from an ionising-radiation diagnostic technique and a non-ionising radiation diagnostic technique, e.g. X-ray and ultrasound
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
    • A61N1/362—Heart stimulators
    • A61N1/3627—Heart stimulators for treating a mechanical deficiency of the heart, e.g. congestive heart failure or cardiomyopathy

Definitions

  • the present invention relates to assessment of ventricular dyssynchrony that has gained great attention after the introduction of cardiac resynchronisation therapy (CRT) which has shown to be a promising treatment option for patients with heart failure and ventricular electrical conduction delay.
  • CRT cardiac resynchronisation therapy
  • the present invention relates to a combination of imaging modalities that display changes in left ventricular dimension and pressure to construct pressure-dimension loops for assessment of the left ventricle.
  • CRT cardiac resynchronisation therapy
  • ECG echocardiographic
  • TDI tissue Doppler Imaging
  • 2D imaging 2D imaging
  • LV ejection fraction EF
  • EF LV ejection fraction
  • an improved assessment of global left ventricular function, markers for regional electro-mechanical activation and function, assessment of ventricular synchronicity including distinguishing between mechanical and electrical dyssynchrony and assessment of viability in infarcted myocardium would be advantageous in the clinical setting. Furthermore this could directly aid patient selection for the about 30 % of non-responders that are selected for CRT on basis of QRS criteria.
  • an object of the present invention relates to assessment of ventricular dyssynchrony in patients that are potential candidates for cardiac resynchronisation therapy (CRT).
  • CRT cardiac resynchronisation therapy
  • OAF active force
  • Another embodiment of the present invention relates to a method for evaluating OAF in right ventricular muscle segments.
  • OAF onset of mechanical activation
  • AVG onset of active force generation
  • OAF is preferably determined using a parametric curve showing ventricular pressure (or analogues) versus ventricular muscle segment dimension or length (or analogues).
  • Such curves may be constructed using a combination of left ventricular pressure (or pressure analogues) and segment length (or analogues such as strain, strain rate or displacement) in left ventricular muscle segments.
  • These curves typically form loops referred to as P-L loop or just "the curve".
  • OAF is preferably defined as the point where the P-L loop curve deviates from passive behaviour during diastolic expansion/elongation.
  • ventricular pressure - ventricular volume (P-V) curves are known from the prior art such as from e.g. WO 06/104869, WO 07/022505, WO 03/037428, or US 2008/0195167. These are considerably different from the P-L curves applied in the invention.
  • the dimension or length applied in the curves of the invention is a regional parameter for individual ventricular muscle segments.
  • the ventricular volume applied in the P-V curves of the prior art is a global parameter for the ventricle, and does not correlate with each individual segment dimension/length.
  • Onset of active force defined as the deviation from passive behaviour, may result from either:
  • (b) is an entirely new way of looking at activation of ventricular muscle segments.
  • the "inertia" in the filling of blood means that the onset of active force in the muscle (b) does not momentarily result in a shortening of the muscle segment, but initially manifests itself as a deceleration in the diastolic elongation, i.e. a shift away from a passive elongation.
  • a deceleration brings the elongation to a halt, will the shortening against increasing pressure (a) set in.
  • (b) is where the muscle segment reacts to its activation
  • (a) is where this reaction results in a shortening of the muscle segment.
  • muscle segment activation almost immediately results in shortening of the muscle and (a) and (b) occurs practically simultaneously.
  • (b) typically occurs before (a).
  • the terms "passive behaviour” and "passive elongation” designates the behaviour of a segment as it elongates during the late diastolic filling. This is considered normal terminology in the field, but for the sake of clarity, an illustrative explanation is given here with reference to Figure 1.
  • ventricular filling segments are stretched as volume increases. While filling during the late diastole, a segment is in an inactivated state and is therefore stretched passively (intervals indicated by thick lines).
  • In early diastole a segment has started to relax, but may not be fully relaxed and we therefore concentrate on the late diastolic phase where the segment is known to be completely passive and inactivated.
  • P(t) may be a directly measured pressure, or may be estimated from secondary data, or may be any analogue thereto which are proportional to the left ventricular pressure (LVP).
  • LVP left ventricular pressure
  • Different ways of determining P(t) will be described later in relation to Table 1.
  • P(t) is measured non-invasively, several examples for such noninvasive determination of P(t) will be given.
  • the length L,(t) may be a measured length, strain, strain rate or displacement of one or more sections in the LV muscle segment, i.
  • the chosen value depends on the imaging modality, e.g. echocardiography, MRI, CTI, ventriculography, sonomicrometry/implantable radio-opaque markers, changes regional left ventricular volume by conductance catheters as a length surrogate, etc. Different ways of determining L(t) will be described later in relation to Table 1. In a preferred embodiment, L(t) is measured non-invasively, several examples for such non-invasive determination of L(t) will be given.
  • the L and P values are preferably measured in an interval comprising the onset of electrical and active force of the left ventricle.
  • a preferred interval is from at least the onset of the QRS complex in a simultaneously recorded ECG and at least the following 150 ms.
  • L and P values are measured continuously over several heartbeats.
  • P and L are measured and values are stored in appropriate electronic memory or storage.
  • P and L data can be retrieved from this storage by the computer.
  • the method is carried out during measurement of P and/or L.
  • these are preferably measured non-invasively so as not to involve surgical steps.
  • QRS refers to the QRS complex, which is a structure on the electrocardiogram (ECG) that corresponds to the depolarization of the ventricles.
  • ECG electrocardiogram
  • a typical ECG tracing of a normal heartbeat (or cardiac cycle) comprises a P wave, a QRS complex and a T wave.
  • a QRS complex refers to a Q wave, an R wave, and an S wave or any combinations thereof.
  • onset of active force is determined as the first point where the parametric curve C,(t) deviates from a passive-elastic curve PE(L) for the muscle segment.
  • the passive-elastic curve PE(L) is a trend curve describing the segment's passive properties, or equivalent late diastolic trend or behaviour of C(t).
  • a passive-elastic curve will follow the bottom section of C(t) during which the left ventricle is relaxed and multiple P/L coordinates can be extracted during late diastole (only interrupted by atrial filling) from which the passive elastic curve may be determined by mathematical regression or as a fit to part of this bottom section. Different ways of determining PE(L) will be described later in relation to Table 1.
  • That the parametric curve C(t) deviates consistently means that it does not return towards PE(L) after the first point, e.g. by approaching PE(L) to take a value closer to PE(L) that it had at the first point or by becoming parallel to PE(L) after having broken off at the first point in the preferred interval or in the diastole of the same heartbeat.
  • Time marker t C c is a fixed time in the cardiac cycle, meaning that its position is constant and reproducible from beat to beat and from individual to individual.
  • Such marker may be determined from several modalities, such as: ECG, a reference image-frame in a simultaneously obtained MRI, CT or ultrasound sequence, or the start of increasing pressure, i.e. first time where dP(t)/dt>0 after atrial filling (a wave in LVP) in each cycle.
  • Other applicable markers may exist or be developed.
  • t cc may preferably be a time marker, t 0 EA, fixed to the onset of electrical activation. This is advantageous for use in distinguishing between primary electrical and primary mechanical dyssynchrony.
  • Such maker, t 0 EA may be the onset of, or one or more peaks within (e.g. peak R, peak S), the QRS complex in a simultaneously recorded ECG.
  • comparing of t cc and t 0A F, ⁇ may be as simple as presenting values side by side, or may be implemented as a parameter based on the difference between t C c and toAF, ⁇ , such as the value t C c - toAF, ⁇ or any function thereof.
  • t 0 AF, ⁇ Can be compared to toAF j of other segments, j, thereby evaluating the activation sequence of the different ventricular muscle segments.
  • step B in the above aspect may be replaced by: Selecting a point in parametric curve C,(t) representative of an onset of active force in left ventricular muscle segment i, C,(t 0 AF, ⁇ ), the selection being performed in accordance with the definition that OAF is where C(t) deviates from passive-elastic behaviour, and determining the corresponding time, t 0 AF, ⁇ -
  • step B may, in a second alternative, be replaced by: presenting corresponding curves of P(t), L,(t) and C,(t) to a user; and receiving user selection of a point in parametric curve C,(t) for an onset of active force in left ventricular muscle segment i, C,(t 0 AF, ⁇ ), and determining the corresponding time, t 0 AF, ⁇ -
  • toAF is determined by a computer program using an appropriate algorithm, it may be preferred to have a human checking, approving, and possibly correcting or adjusting the OAF determined by the computer program.
  • the determined onset of active force is a suggested C,(t 0 AF, ⁇ ), and wherein determining onset of active force comprises; presenting the parametric curve C,(t) with a marked up suggested C(t 0 AF, ⁇ ) to a user; and receiving user input related to an optional adjustment of the suggested C,(t 0 AF, ⁇ ) and an approval of the suggested or adjusted C,(t 0 AF, ⁇ )-
  • presenting the parametric curve C,(t) to a user preferably comprises also presenting P(t) and L,(t) with a marked up t 0A F, ⁇ corresponding to the suggested C,(t 0 AF, ⁇ )-
  • aspects of the present invention relates to a computer program product, or a computer program product for updating a medical monitoring apparatus, for preparing data related to onset of active force in left ventricular muscle segments, the product comprising software applications which provides the following when executed by a processor or a computer:
  • A. generating a parametric curve C,(t) (L,(t), P(t)) of concurrent values of a left ventricular pressure, P(t) and a length, L,(t), in a left ventricular muscle segment, i, as a function of time;
  • the invention provides a medical monitoring apparatus comprising a unit for analysing and presenting data, the apparatus further comprising software means for performing the functions of steps A-D in the previous section.
  • Medical monitoring apparatus may be apparatus capable of measuring and analysing dimension/pressure changes from a patient, or apparatus capable of receiving and analysing dimension/pressure changes of a patient measured by other apparatus.
  • Typical apparatus may be MRI apparatus, CT scanners, echocardiography machines, as well as image view workstations that may or may not be coupled to any such apparatus.
  • the invention may be applied to determine whether an electro-mechanical dyssynchrony can be characterised as a primary electrical dyssynchrony or a primary mechanical dyssynchrony. This may be of utmost important, since present CRT results in little or no improvement in patients with primary mechanical dyssynchrony, and the invention may thereby be applied to selecting patients with dyssynchrony symptoms for CRT.
  • the invention provides a method for determining whether a patient has a primary electrical dyssynchrony or a primary mechanical dyssynchrony, comprising:
  • - generating, by means of a computer, a parametric curve C,(t) (L,(t), P(t)) of concurrent values of a left ventricular pressure, P(t) and a length, L,(t), in two or more left ventricular muscle segments, i, as a function of time;
  • the invention provides a method for selecting patients for cardiac resynchronisation therapy (CRT), comprising
  • This method may be applied to patients with a potential dyssynchrony disorder, and such have typically previously been selected based on analysis of a QRS complex from an electrocardiogram.
  • the precise determination of active force generation in the left ventricle may be applied to improve or optimize settings and electrode placements for Cardiac Resynchronisation Therapy (CRT) device.
  • CRT Cardiac Resynchronisation Therapy
  • the invention provides a method for using onset of active force in left ventricular muscle segment i, t 0A F,i, according to the previous aspects, as a marker for mechanical activation in left ventricular muscle segment i.
  • This marker may be applied to patients to better adjust and optimise settings of or trig medical equipment such as CRT.
  • one aspect of the invention provides a method for adjusting settings of a cardiac Resynchronisation therapy (CRT) device after implementation, the method comprising - obtaining onset of active force (t 0A F) in ventricular muscle segments, using any method described in previous aspects, and determine relative mechanical activation times of these segments;
  • CTR cardiac Resynchronisation therapy
  • Another aspect of the invention provides a method for determining electrode placement of a CRT device - obtaining onset of active force in left ventricular muscle segments using the method according to any previous described methods;
  • the electrodes have to be placed at the right locations on a segment. Now only one lead is used but this method could be extended and used if multiple leads were to be placed on the same segment.
  • Ci(t 0 AF,i) as the first point on a diastolic part of the curve where the parametric curve C ⁇ (t) deviates, such as consistently deviates, such as over a period of at least 30 ms, from passive behaviour for the muscle segment, i.e. from the segment's passive elongation during the late diastolic filling phase, and determining the corresponding time, toAF,.; C. identifying t 0 AF,i in the parametric curve as the onset of regional LV mechanical activation;
  • a further aspect of the present invention provides a cardiac Resynchronisation therapy (CRT) device wherein the interventricular (v-v) and atria-ventricular (a-v) delays have been adjusted using the method described above.
  • CRT cardiac Resynchronisation therapy
  • the basic idea of the invention is to utilise a new way of defining the onset of active force of left ventricular segments to prepare data related to onset of active force in left ventricular muscle segments.
  • the new way of defining OAF is based on a pressure-length loop, C(t), as described, and OAF is defined as where this loop deviates from passive behaviour.
  • the prepared data may later be used to assess types of ventricular dyssynchrony (primary electrical or primary mechanical) in patients that are potential candidates for cardiac resynchronisation therapy (CRT).
  • Figure 1 is an illustration of the passive behavious of muscle segments during the late diastole.
  • Figure 2 shows a flow diagram illustrating a method and a computer program product according to embodiments of the present invention.
  • Figure 3 illustrates a medical monitoring apparatus according to an embodiment of the present invention.
  • Figures 4A, A', B and B' illustrates the differences between OAF as used in the the present invention and onset of shortening.
  • Figure 5 illustrates ways of determining C,(t 0 AF) in an exemplary pressure-length loop.
  • Figure 6 illustrates the determination of OAF according to an embodiment of the invention.
  • LVP left ventricular pressure
  • A The passive-elastic curve is derived from repeated end diastolic segment lengths. LVP measurements describe these passive characteristics for a given myocardial segment, i) Pressure segment length loops during caval constriction, ii) High gain LV pressure (LVP) showing end-diastolic points, iii) Exponential fit to end-diastolic points.
  • onset of myocardial activation is deducted from the construction of the passive elastic curve - for a segment to leave the passive elastic curve it must generate active force.
  • onset of AFG is defined as the first coordinate of the pressure segment length loop that leads to a deviation from the passive curve.
  • C Timing of onset AFG was extracted from either LVP or segment length traces.
  • FIG. 7 Schematic illustration of placement of myocardial crystals.
  • IM-EMG intramyocardial electromyogram
  • LBBB left bundle branch block.
  • Figure 8 Representative traces showing (A) segment length, shortening velocity (dL/dt) and intramyocardial electromyogram (IM-EMG) for an anterior and posterior segment during baseline and ischemia and baseline and caval constriction, and (B) corresponding pressure-length loops.
  • Figure 9 are representative traces showing (A) segment length, shortening velocity (dL/dt) and intramyocardial electromyogram (IM-EMG) for a septal and lateral segment during baseline and left bundle brach block (LBBB), and (B) corresponding pressure-length loops.
  • Figure 1OA shows pooled data from all experiments illustrating the variability in time from onset R in ECG to timing of different dyssynchrony indices by sonomicrometry during baseline, load alteration and ischemia.
  • 1OB shows peak intersegment time difference for baseline, load alteration and ischemia. Mean ⁇ lSD is indicated for each index.
  • Figure HA shows peak intersegment time difference during baseline and left bundle branch block (LBBB).
  • HB shows ime delay in activation of the lateral vs. septal wall for different dyssynchrony indices during LBBB. Mean ⁇ lSD is indicated for each index.
  • FIG. 12 Relationships between time for onset R in intramyocardial electromyogram (IM-EMG) to onset active force generation (AFG) and peak myocardial ejection velocity (S) by sonomicrometry (12A) and echocardiography (12B), measured from onset R in ECG. Data from all interventions are included. Time to onset AFG showed strong correlation with time to onset R in IM-EMG by sonomicrometry as well as echocardiography.
  • FIG. 13A shows representative traces for anterior (thick line) and posterior (thin line) segments during ischemia.
  • 13B shows representative traces from septal (thick line) and lateral (thin line) segments during left bundle branch block (LBBB).
  • Strain measurements are performed by STE in parasternal short axis view.
  • electrical activation for the two walls is measured by intramyocardial electromyograms (IM-EMG).
  • Pressure-strain loops are constructed by combining strain by STE and LVP.
  • Aortic valve opening (AVO) and closing (AVC) indicated by arrow.
  • Figure 14 is a chart showing segment length, shortening velocity (dL/dt) and intramyocardial electromyogram (IM-EMG) for an anterior segment during ischemia, illustrating that a myocardial segment may stretch even after it has been activated.
  • Figure 15 is a flow-chart over the architecture of a software application for preparing data related to determination of onset of active force in left ventricular muscle segments.
  • the invention can be implemented as a method, as a computer program product (software), as software in a data analysis unit of a medical monitoring apparatus, or as software for updating a medical monitoring apparatus.
  • a computer program product software
  • software software
  • a data analysis unit of a medical monitoring apparatus or as software for updating a medical monitoring apparatus.
  • Figure 2 represents a flow chart 19 for illustrating the architecture of an embodiment of a software product in accordance with an aspect of the invention, such as a computer program product for preparing data related to onset of active force in left ventricular muscle segments.
  • the flow chart 19 illustrates an embodiment of the method for preparing data related to onset of active force in left ventricular muscle segments in accordance with another aspect of the invention. Some of the steps are optional or serve to illustrate the flow of data, and are thus not part of the broadest aspects of the invention as defined by the claims.
  • data 2 representing concurrent L(t) and P(t) are accessed or received.
  • This data may e.g. be received directly from dedicated apparatus for measuring segment length/strain/strain rate/displacement and LV pressure, respectively, from a local memory such as RAM or a hard disk, or from a remote location accessible via a network connection.
  • a local memory such as RAM or a hard disk
  • LV pressure a pressure
  • Different ways of determining L(t) and P(t) will be described later in relation to Table 1.
  • L,(t) from more segments, the above and following processes are carried out for each segment, i, either in parallel or successively. Box 1 and data 2 serves to illustrate the flow of data.
  • C,(t) is generated, with concurrent values of L,(t) and P(t) as first and second coordinates in an L-P coordinate system.
  • C,(t) is generated at least within the interval [t QRS ; t QR s+150 ms], where t QRS is the time for onset of QRS complex determined from a simultaneously recorded ECG or equivalent.
  • t QRS is the time for onset of QRS complex determined from a simultaneously recorded ECG or equivalent.
  • C,(t) is generated for an entire cardiac cycle.
  • a passive-elastic curve, PE,(t) for the ventricular segment is either accessed, received or generated.
  • PE(L) may be generated specifically for the ventricular segment in question, or may be a generalised expression or standard curves for different types of ventricular segments (axial, lateral, posterior, anterior), which may be fitted to the actual P and or L values in C,(t). Different ways of determining PE(L) will be described later in relation to Table 1, and Box 4 serves to illustrate the flow of data.
  • a point representative of OAF is selected in C,(t) in box 8 using an appropriate algorithm or assessment method.
  • the selection may be carried out by a user or a software application, or a combination of these.
  • a multitude of different algorithms and assessment methods are described later in relation to Table 1.
  • a first suggested OAF is determined in box 9 using an appropriate algorithm or assessment method.
  • the parametric Pressure-Length curve, C,(t) is then presented to a user, box 10, with the suggested OAF, C,(t 0 AF), marked up as shown in the inserted curves 12.
  • the pressure and length traces are also presented with marked up t 0A F- The purpose of this is to allow the user to assess the validity of the suggested OAF in C,(t), e.g. by support in P(t) and L,(t), and to correct C,(t 0 AF) if not in agreement, box 11.
  • Such correction if performed via a software application can e.g.
  • the software application comprises or can make use of a user interface (UI) such as a mouse and a graphical user interface (GUI) such as cursors and drag/drop functionality provided by most computer operating systems.
  • UI user interface
  • GUI graphical user interface
  • the parametric Pressure-Length curve, C,(t) is presented to a user, box 13.
  • the pressure and length traces are also presented.
  • This presentation is equivalent to the curves 12 without indication of a suggested OAF.
  • the user can select an OAF in C,(t), possibly with support in P(t) and L,(t), by selection, dragging and dropping a circle indicating OAF to the a position on C,(t).
  • the time for onset of active force for segment i, t 0 AF, ⁇ can be determined, see box 15. This may be by reading the t-values for the L(t) or P(t) sampling points corresponding to the determined OAF, or by using the interpolation algorithm used to connect data points for C,(t).
  • a fixed time marker in the cardiac cycle, t C c is obtained.
  • Such time marker may be received from another apparatus, and different ways of determining a t C c will be elaborated later in relation to Table 1.
  • the function of the time marker is to provide a consistent reference point within the cardiac cycle for timing of t 0 AF, ⁇ , as t 0 AF, ⁇ may otherwise be a floating value.
  • a comparison between the obtained t C c and t 0 AF, ⁇ are made in box 17 as the result of the preparation of data according to embodiments of the invention.
  • Box 18 illustrates an optional display of such comparison as a table listing parameters ⁇ t for different left ventricular segments.
  • FIG. 3 illustrates another implementation of the invention, here an embodiment of a medical monitoring apparatus 20, with a unit 21 for preparing and presenting data.
  • the apparatus will have a display 22 for presenting data to a user in a GUI, and a UI 23 such as a mouse and keyboard for receiving user input.
  • Exemplary apparatuses could be echocardiography machines, MRI apparatuses, CT scanners etc., their data processing units and their analysis software (work station).
  • the apparatus may comprise or be connected to units, apparatus or systems, 24 and 25, for measuring P(t) and L(t) respectively, as described previously in relation to Table 1.
  • the apparatus 20 may access P(t) and L(t) data over a network connection 26.
  • Computer program products for performing data preparation as described in relation to Figure 2 can be stored in memory 27 and executed by processor 28 of the unit 21.
  • the invention can also be embodied by a computer program product for updating a medical monitoring apparatus to prepare data related to onset of active force in left ventricular muscle segments.
  • a computer program product for updating a medical monitoring apparatus to prepare data related to onset of active force in left ventricular muscle segments.
  • Such product can be embodied as a packet managing system or an installation program for downloading and installing the software described in relation to Figure 2 on the apparatus 20 described in relation to Figure 3 over the network connection 26.
  • Such program can be stored and executed by memory 27 and processor 28, or stored and executed by a server (not shown) over network connection 26. Description of measurements, parameters, values etc from Table 1
  • PE(L) Passive-elastic curve, PE(L) Selecting or suggesting an OAF may in some cases require that a passive-elastic curve is determined.
  • the determined PE(L) can be shown as a curve plotted into the P-L loop to facilitate visual selection of OAF or to be used in algorithms for determining OAF.
  • PE(L) can be an algebraic function, e.g. resulting from a regression, fitting or extrapolation of one or more p-L loops Table 1.
  • An estimate of PE(L) can also be determined from measurements from different passive lengths or preload levels (caval constriction, etc.)-
  • An estimate of the passive elastic curve can be made from non linear regression of measured data points (L,P) after onset of QRS in ECG.
  • Similar regression equations can be set up using strain, strain rate, or displacement of ventricular muscle segments instead of length.
  • An estimate of the PE-curve can also be made with the measured length-pressure points during the transition from diastole to systole.
  • a non-linear fit representing the PE-curve including a variance measure can be drawn.
  • the following will be evaluated; 1) a) is the new datapoint statistically shifted relative to the estimated PE-curve? b) if yes; is the shift permanent within this early systole? If yes: datapoint n-1 is OAF (end loop). 2) If no in 1); calculate new PE-curve incl. variance measure including datapoint n and loop again with next datapoint.
  • the left ventricular pressure as a function of time, P(t) can be measured invasively or estimated by a non-invasive measurement technique. As it is the dynamics, i.e. variation as a function of time, and not the absolute numerical value that determines the shape of the pressure/length loop, any time resolved absolute or relative pressure signal may be used for preparing data related to onset of active force.
  • LVP can be estimated non-invasively utilizing microbubble-based ultrasound contrast agents. Pressure dependant changes in the first, second, and subharmonic amplitudes of the ultrasound contrast agents may yield a dynamic pressure estimate facilitating assessment of OAF.
  • an estimated P can be determined in patients with mitral regurgitation by estimating the velocity profile on the mitral regurgitation jet and a simplified Bernoulli equation. This may be performed on any image modality that allows estimation of the regurgitation jet velocity or similar.
  • P can be estimated via linear or non-linear (power, exponential) functions.
  • LVEDP can be estimated depending of clinical condition (non-heart failure 10, heart failure 20 mmHg), by echo measurements (E/e') or neglected (0 mmHg).
  • the time for EIVC can be measured by measuring aortic flow by Doppler.
  • the estimated start- and stop coordinates, t OnS etQRs, LVEDP and t E ivc, LVEIVC can be utilized to determine the time course for LVP, and used in combination with length or a length analogue to determine OAF.
  • Measurements of aortic pressure can be done by a blood pressure device and aortic valve opening pressure can be estimated. This is then time shifted so that systolic rise coincides with aortic opening by Doppler. (O'Rourke et al.)
  • Another technique to determinate the pressure could be to use an apex cardiogram. This is a technique of recording pulsations of the chest wall produced by the beating heart. Comparison with measurements of left ventricular pressure made using micromanometer pressure catheters has shown that the upstroke and down stroke of the apex cardiogram is virtually synchronous with the rise and fall of ventricular pressure (Willems et al). When we are assessing onset AFG we are only dependant on early filling and the initial upstroke of ventricular pressure, therefore measurements from an apex cardiogram could be used as a non invasive pressure analogue for assessing onset AFG. Left ventricular segment lengths and analogues, L,(t)
  • the length of a section in a left ventricular muscle segment can be measured by several image modalities. Also, as described previously, there exist a number of length analogues (e.g. strain, S, strain rate SR, and displacement, D) that display an equivalent variation as a function of time, and which may be used instead.
  • length analogues e.g. strain, S, strain rate SR, and displacement, D
  • the length, L(t), strain, S(t), strain rate SR(t), or displacement, D(t) of sections in different left ventricular muscle segments may be determined by sonomicrimetry, conductance measurements (regional volumes), ventriculography (radioopaque markers), tagged- and non-tagged MRI, echocardiography (TDI and STE) and by CT (multi modality tracking).
  • the modalities provide the parameters automatically, or semi automatically with varying degree of user interaction, see Anderson et al. for description of different techniques.
  • the parametric curve C,(t), or P_L loop, for LV segment i is generated using corresponding P (measured or estimated) and L (or S or D) values for LV segment i.
  • the P_L loop need not be determined for the full cardiac cycle, can e.g. be determined only from onset of QRS complex in ECG and next 150 ms.
  • OAF takes this into consideration by including both length (or strain analogues) and LVP in the determination. These combined data are used to form a pressure-length loop, and OAF is defined as the point where this loop deviates from passive behaviour.
  • the deviation from passive behaviour may be either (a) ventricular muscle segment shortening against increased pressure, or (b) a shift in ventricular muscle segment elongation against increased pressure.
  • (a) is comparable to interpretations of OMA in the prior art
  • (b) is an entirely new way of looking at activation of ventricular muscle segments.
  • an "inertia" in the increasing pressure means that the activation does not momentarily result in a shortening, but initially manifests itself as a deceleration in the continued elongation. First when this deceleration brings the elongation to a halt, the shortening against increasing pressure will set in.
  • Figures 4A and A' shows representative pressure-segments length loops.
  • the loops in Panel A shows representative pressure-segments length loops and passive trend curves (dotted lines) with identification of onset active force generation (circle AFG).
  • Figures 4B and B' shows LV pressure with high gain and illustrates how onset AFG was defined in segments with early-systolic lengthening. In these cases onset AFG corresponded to onset of an upward-shift of the pressure-segment length loop relative to the passive curve. Also seen in the loops of 4B and B' are where the onset of shortening (onset of mechanical activation) happens (marked with an X). As can be seen in these examples, the onset for these two activations does not have to take place at the same time.
  • the task at hand is therefore to develop algorithms for selecting a point in parametric curve C,(t) representative of an OAF in left ventricular muscle segment i, Ci(t 0 AF,i), the selection being performed in accordance with the definition that OAF is where C(t) deviates from passive-elastic behaviour.
  • OAF OAF selection
  • the selection of OAF can also be based on one of the algorithms for suggesting an OAF described in the following. Whether an OAF selected by use of such algorithm need to be approved by a user depends on the detailed implementation and factors such as the performance of the algorithm, the complexity of the P-L loops in the relevant class of patients, the requirements to the stability or precision in the selected OAF, and others.
  • a software application or an apparatus utilising the invention may give a first suggestion of OAF to the user. If in agreement, the user can then approve the suggestion and the suggested OAF will be used in the further analysis. If not in agreement, the user can adjust the suggested OAF, and then approve the adjusted OAF which will then be used in the further analysis.
  • C ⁇ (t 0 AF, ⁇ ) can be determined as the first deflection point that results in C,(t) leaving a region defined by the passive elastic curve PE(L) ⁇ K.
  • leaving is meant that C,(t) takes values outside this region in the direction of increasing time.
  • a deflection point is a point where the parametric curve has having a clearly identifiable change of gradient or inclination, or where its gradient 10 deviates from the gradient of PE(L), see also next algorithm.
  • Figure 5 illustrates the region 30 defined by the passive elastic curve PE(L) ⁇ K.
  • the first 15 point of deflection 31 that results in C,(t) leaving the region 30 is also shown, as is a earlier point of deflection 32 that does not result in C,(t) leaving the region 30.
  • C ⁇ (t 0 AF, ⁇ ) can be determined as the first point where the gradient of C,(t) deviates from the gradient of PE(L) over a period of at least 30 20 ms. This can be expressed as a criteria: dP ⁇ t) dPE(L)
  • the time period of 30 ms can be a longer or shorter period.
  • the time period serves to ensure that the gradient deviation is not simply a small loop as for point 25 32 in Figure 5, but that it results in that C,(t) breaks off for good, ⁇ can be adjusted so that small fluctuations in the bottom part of C,(t) are disregarded.
  • dt ⁇ t 1 is tne vector product between the asymptote to
  • the residual/error of each new point (m) in relation to either P M or P m- i is evaluated; if above a certain threshold value, the m th point is not included in the fitting (to not include get rid of small loops and not include a slow bending in the regression).
  • the gradient is the same as the derivative of the function.
  • the change of gradient can therefore be interpreted as the second derivative of a function.
  • the maximum change of gradient is the point where the function has the largest curvature, or where it bends the most. It is envisioned that OAF will most often be the point in the lower right corner with the largest change in gradient.
  • the derivative of a function is a mathematical term related to continuous functions. In practice, this is never the case.
  • a loop consists of discrete depth measurements.
  • algorithms can be used, which approximates the second derivative.
  • the algorithm is similar to the definition of the derivative except that because the function is not continuous, the limit value which tends towards zero is exchanged with a finite difference.
  • the forward difference method This is called the forward difference method.
  • a similar method which involves X 1 and Xi-i is called the backward difference method.
  • the second derivative may be calculated by using the result of one method as input to the other. It can be proved by using Taylor's Theorem that this approximation gives good results if the input points are regularly sampled ( ⁇ X
  • -i ⁇ x,). It is important to note that the derivative at the point x, only involves the value at x, and its two neighbouring points. The algorithm is therefore very sensitive local variations. Two solutions to this problem may be 1) use more data points than the nearest neighbours on each side, and 2) use methods for generating more points between the original data points.
  • the first derivative giving the gradient of the loop at point m can be defined as:
  • the second derivative giving the change of gradient at point m (time t m ) can be defined as: dG,. G - G
  • CiL 1 (O LXtJ- LXt n J
  • the gradient of the loop at time t m can be defined as:
  • This ⁇ G m may be used to select OAF as the first point with a considerable difference to the average of the preceding points.
  • one method uses the average gradient in a given interval before and after the point, and compare the two to find the change of gradient in that point.
  • the algorithm can use two different methods for computing the average derivative at an interval. These two methods are explained in the article ""The effects of using different algorithms for calculating the foot of slope based on the maximum change of gradient" by Jon Mugaas found on www ; ggocap.,. ⁇ .o.
  • All the above algorithms can be applied in a process where the criteria of the algorithm are tried successively for each data point on C,(t) in the direction of increasing time, e.g. starting at onset of QRS complex.
  • the time for onset of active force, t 0 AF is the look up time, e.g. in P(t) or L(t) measurements, for a selected, determined or suggested C(t 0 AF)- If a selected, determined or suggested C(t 0A F) lies between (L(t) , P(t)) data points, a value for toAF can be interpolated or extrapolated using neighbouring data points.
  • t C c is a time marker with a constant and reproducible position from beat to beat and from individual to individual.
  • a t C c can be obtained through a reference image-frame in a simultaneously obtained MRI, CT or ultrasound sequence, e.g. image-frame, external making, extra spike on ECG.
  • a tcc can also be obtained from start of increasing pressure e.g. the first time in cycle where dP(t)/dt>0 after atrial filling (a wave).
  • a t cc can be the onset of electrical activation, t 0E A, determined from peaks in QRS complex in ECG e.g. onset of QRS/first deflection of the QRS complex, onset of Q, R or s wave, peak Q, R or S wave or a time that refers to any of these points (eg +- 50ms) or a measurement of onset of systole defined by the first "kick" of the heart measured by micromanonetry over the apex of the heart, see e.g. Malonas et al.
  • peaks from global strain, S G (t) may be used to define onset of shortening as a reference marker, i.e. onset deformation in global strain can be used as a marker for t cc - S G (t) is calculated as an average function of typical 6-12 strain values from different segments and can often be automatically generated by imaging devices, such as echocardiography machines, when the individual strain measurements are performed.
  • the times t C c and t 0 AF, ⁇ can be compared to determine the time for active force of LV muscle segment i, as there may otherwise be a risk that t 0 AF, ⁇ is floating.
  • the comparison can be parameterized by a function of t cc and t 0A F, ⁇ , such as the difference t cc - t 0 AF, ⁇ -
  • the time for onset of active force for segment i, toAF, ⁇ is compared to time for onset of active force for other ventricular segments instead of to a fixed marker.
  • time for onset of active force is determined for two or more muscle segments in the ventricle, and these are compared to each other in order to determine abnormal delays between these.
  • segment i denotes the segment that physiologically should be activated first, and j counts over all the other segments.
  • ⁇ t, 7j can be a matrix with all permutations of i and j.
  • time for OAF a) Look up time for selected measurements b) Interpolate or extrapolate from (L(t) , P(t)) data points
  • t cc fixed time in Time marker with a constant the cardiac cycle and reproducible position from beat to beat and from individual to individual a) reference image-frame in a
  • Sonomicrometry crystals with intramyocardial electromyocardiograms were placed in the apex and circumferentially around LV equator and in RV free wall. We also implanted an additional crystal anterio-apical and posterio-apical in LV. Four circumferential and two longitudinal segments were analyzed for group with LAD occlusion, during LBBB two additional longitudinal segments were analyzed. The crystals were connected to a sonomicrometer (Sonometrics Corp), and data were digitized at 200 Hz.
  • OAF was defined as the time when the myocardial pressure-segment length coordinate deviated from its passive-elastic curve (Fig. 6B). Calculation of time to OAF was done by taking the pressure-segment length coordinate for OAF finding the corresponding time on the ECG trace (Fig. 6C). If a segment is completely passive it will not deviate from the passive elastic curve. We define these segments as inactivated and OAF can not be measured in these circumstances. To quantify a segments deviation from its passive curve we used two confidence intervals as cut off.
  • TPS Time to peak systolic strain
  • ToS time to onset peak myocardial ejection velocity
  • TOAF time to OAF
  • End diastole was defined as onset R in ECG. End systole was defined as dP/dt min.
  • Preload was reduced by transient caval constrictions. Hemodynamic variables were allowed to return to baseline values before the start of each intervention.
  • Ischemia was induced by placing a suture around the left anterior descending artery and occluding it using a patch. Recordings were performed during baseline and during 15 min of ischemia. Ischemia was assessed by looking at myocardial dysfunction as measured by sonomicrometry. The heart was dissected into 1- 1,5cm slices and was stained with 1% solution of TTC for 15-30min in 37C. Two dogs showed minimal subepicardial infarct in ant-apical and apico-septal region of the LV.
  • Dyssynchrony is defined as uncoordinated regional myocardial contractions and may in principle have the following etiologies; 1) Electrical conduction delay which causes non-uniform timing of myocyte depolarization, 2) abnormalities in excitation-contraction coupling, and 3) abnormal myocardial contractility or load which cause regional delay in fiber shortening.
  • the different etiologies we will refer to the different etiologies as primary electrical dyssynchrony, excitation-contraction related dyssynchrony and primary mechanical dyssynchrony, respectively. The latter two we also refer to as non-electrical etiologies of dyssynchrony. We believe that clear differentiation between etiologies is essential for the understanding and appropriate clinical interpretation of dyssynchrony indices.
  • the general objective of this study was to establish a method which can differentiate between electrical and non-electrical etiologies of left ventricular (LV) dyssynchrony.
  • onset R in intramyocardial electromyograms (IM-EMG).
  • mechanical activation we introduce onset of active myocardial force generation (AFG) calculated from regional myocardial pressure-segment length and pressure- strain loops.
  • Electromechanical activation time was used as an index of excitation- contraction coupling, and was measured as time from onset R in IM-EMG to onset AFG.
  • Mechanical dyssynchrony was measured as regional differences in timing of myocardial shortening velocity and strain. By exclusion, dyssynchrony was categorized as primary mechanical when it could not be attributed to delay in electrical activation or prolongation of electromechanical activation time.
  • onset AFG had a constant time delay relative to local electrical activation, and we therefore propose onset AFG as a surrogate for timing of electrical activation.
  • the specific objectives of the study were to test the hypotheses that onset AFG represents a means to quantify LV primary electrical dyssynchrony and to differentiate between electrical and nonelectrical etiologies of LV intraventricular dyssynchrony.
  • onset AFG represents a means to quantify LV primary electrical dyssynchrony and to differentiate between electrical and nonelectrical etiologies of LV intraventricular dyssynchrony.
  • myocardial shortening velocity and strain were evaluated the ability of myocardial shortening velocity and strain to serve as markers of primary electrical dyssynchrony. The study was carried out in a dog model during different loading conditions, during myocardial ischemia and after the induction of left bundle branch block (LBBB).
  • a 7F ablation catheter (Celsius, Biosense Webster, Inc., CA) was introduced via a carotid artery, advanced to the LV apex and then pulled back to the basal septum where the left bundle potential was identified. Radiofrequency energy was delivered at a location with a large left bundle potential. This position was at a relative distance 2/3 from the atrial and 1/3 from the ventricular signal and was delivered in the temperature mode with a set temperature of 50 degrees Celsius and 30 watts. Energy was delivered 30 seconds after LBBB had been induced.
  • Aortic, left atrial and LV pressures were measured by micromanometers (MPC-500, Millar Instruments Inc, Houston, Tex).
  • MPC-500 Millar Instruments Inc, Houston, Tex.
  • a fluid-filled catheter placed in the left atrium served as an absolute pressure reference for the LV micromanometer.
  • a Vivid 7 ultrasound scanner (GE Vingmed Ultrasound AS, Horten, Norway) was used to record color-coded TDI images in apical 4 and 2 chamber views.
  • conventional 2-D grayscale images (frame rate 63 ⁇ 13 s "1 ) of the LV equatorial short-axis were acquired for speckle tracking echocardiography (STE).
  • Timing of regional electrical activation was measured as onset R in IM-EMG, defined as the first deflection of more than 20% of total QRS amplitude.
  • the time of onset AFG was determined by analyzing myocardial pressure-segment length loops, and was defined as the time when the pressure-segment length coordinate was shifted upwards relative to the passive curve for the same segment.
  • the calculation of onset AFG is illustrated in Figure 6.
  • the passive curve was constructed by an exponential fit to a series of end-diastolic pressure- segments length coordinates obtained during caval constriction. Since the pressure-segment length relationship provides no timing information, onset AFG was extracted from a corresponding time point in either the pressure or the segment length curve (Figure 6c). In segments with no sharp deflection from the passive curve after onset of R in ECG (12 of 266 segments) we used 2 confidence intervals of the fitted passive curve as cut off to define a shift from a passive to active state.
  • Timing of onset AFG by speckle tracking echocardiography and LVP Onset AFG was also assessed by combining LVP with strain by STE. Strain traces extracted from equatorial short-axis and 2 chamber views were used as substitutes for the segment length traces in the AFG analysis. Because strain represents a relative value, this analysis does not provide a range of end-diastolic pressure-dimension relations, and the diastolic portion of each loop was used to define the passive state. Identification of onset AFG was based on subjective, visual assessment, defined as the first marked upward deviation of the pressure- strain loop that resulted in a continued upward shift after onset of R in ECG.
  • Electromechanical activation time was calculated as time from onset R in IM-EMG to onset AFG.
  • Left ventricular dyssynchrony was quantified by two different approaches; 1) as peak intersegment time difference, measured as time difference between the earliest and the latest activated segments, and 2) as standard deviation for 6-8 segments of time from onset R in ECG to timing of each of the indices, and will be referred to as SD of timing.
  • Baseline recordings were performed after a 30-minute stabilization period following completion of instrumentation. To avoid interference between sonomicrometry and echocardiography, recordings were performed. Data were recorded with the ventilator off. In all animals caval constriction was performed to enable construction of passive curves.
  • BVP biventricular pacing
  • FIGS. 8 and 9 are representative traces showing (A) segment length, shortening velocity (dL/dt) and intramyocardial electromyogram (IM-EMG) for a septal and lateral segment during baseline and left bundle brach block (LBBB), and (B) corresponding pressure-segments loops with passive curves.
  • dotted lines define timing of first onset R in IM-EMG (R), onset active force generation (AFG) (O), onset of ejection velocity ( ⁇ ) and peak systolic shortening (D) .
  • the actual onset for these parameters for each trace is also shown by the same symbols in each trace.
  • Aortic valve opening (AVO) and closing (AVC) indicated by arrow.
  • onset AFG is identified with a circle.
  • FIGS. 8 and 9 show IM-EMG traces with representative, distinct R waves which were used as markers of regional electrical activation.
  • the recordings demonstrate that onset R was essentially simultaneous in all segments except during LBBB.
  • the SD of timing of onset R in IM-EMG was 4 ⁇ lms during baseline, reduced preload and ischemia, and peak intersegment time differences were 10 ⁇ 3, 10 ⁇ 4 and 9 ⁇ 2ms, respectively, indicating synchronous electrical activation of all segments (Table 2, Figure 10, lower panel).
  • Figure 10, upper panel displays pooled data from all animals and shows very limited variability in timing of onset R in IM-EMG during baseline, reduced preload and ischemia.
  • onset R in subepicardium and subendocardium from all interventions we found no significant changes during any of the interventions
  • SD of timing decreased to 7 ⁇ 2 ms
  • Figures 8A and B and 9A and B illustrate how onset AFG was identified by combining LV pressure-segment length loops and passive curves.
  • onset AFG was represented by a sharp deflection in the lower right corner of the LV pressure-segment length loop, and in most cases coincided with onset of shortening.
  • ischemic segments however, there was early-systolic lengthening, and onset of shortening was markedly delayed and did not coincide with onset AFG.
  • the electromechanical activation time measured as time from onset R in IM-EMG to onset AFG, was essentially similar during baseline, reduced preload, ischemia and LBBB, with mean values ranging from 12 to 16 ms for the different interventions (Table 2).
  • FIGS 8 and 9 show representative examples of shortening indices measured by sonomicrometry, and their relationship to regional electrical activation by onset R in IM-EMG, and to mechanical activation by onset AFG.
  • the variability in peak intersegment time difference for the shortening indices was substantial, and far exceeded the variability in onset R in IM-EMG and in onset AFG (Tables 2, 3 and 4, Figure 10).
  • the SD of timing for shortening indices exceeded the values for onset R in IM-EMG and onset AFG.
  • the present study introduces assessment of onset AFG as a method to quantify LV electrical dyssynchrony and to differentiate between dyssynchrony with primary electrical and primary mechanical etiologies. In a clinical setting this differentiation is essential since only dyssynchrony with primary electrical etiology can be treated by CRT.
  • the principle behind this novel method is that onset of active force generation is the first mechanical sign of actine-myosin interaction, and in contrast to indices based on myocardial velocity and strain, it is independent of loading conditions and contractility.
  • Onset AFG was defined as the time when the LV pressure-segment length coordinate leaves the passive diastolic curve, and was compared to onset of electrical activation defined as onset R in IM-EMG from the same myocardial segment.
  • onset R onset of electrical activation
  • myocardial ischemia and LBBB the electromechanical activation time was essentially constant. Accordingly, onset AFG, which directly measures mechanical activation, was an accurate measure of electrical activation as well. This method was feasible not only with sonomicrometry, but also when strain by STE was used as an analog for segment length, suggesting a potential for measuring onset AFG clinically during left heart catheterization.
  • onset R in IM-EMG as reference method for electrical activation we demonstrated that onset AFG was superior to conventional timing indices based on myocardial velocity and deformation. There was a trend that onset of ejection velocity performed better than peak values of ejection velocity and systolic strain.
  • each of the three components that may contribute to LV dyssynchrony i.e. delay in electrical conduction, delay in electromechanical activation and delay due to mechanical factors such as reduction or delay in regional force development.
  • Electrical conduction time was measured from onset R in ECG to onset R in regional IM-EMG, and electromechanical activation time from onset R in IM-EMG to onset AFG. By exclusion, delay was attributed to mechanical factors when onset AFG was synchronous throughout the ventricle.
  • LV mechanical dyssynchrony there was significant LV mechanical dyssynchrony, but there were no regional differences in intraventricular conduction time measured in the subendocardium or in endo-to-epicardial conduction time.
  • ischemia induces primary mechanical dyssynchrony and is not likely to respond to CRT. Relationship between regional electrical activation and shortening indices During load alterations and ischemia there were marked regional differences in timing of myocardial velocity and strain indices, whereas onset R in IM-EMG and onset AFG indicated synchronous electrical and mechanical activation in the different LV myocardial regions. Therefore, the segmental differences in time to onset S, peak S and peak strain could not be accounted for by differences in onset of electrical activation or onset AFG and were attributed to primary mechanical dyssynchrony.
  • the temporal resolution of measurements of timing of onset R in IM-EMG and onset AFG were 5 ms, and smaller regional differences in timing may not have been detected.
  • the magnitude of electrical and mechanical dyssynchrony was in the order of 40-100 ms and therefore the temporal resolution was sufficient for the purpose of exploring mechanisms of dyssynchrony.
  • onset R in ECG as time reference for calculation of LV intraventricular conduction would tend to underestimate the time intervals.
  • IM-EMG in the earliest activated segment or a His bundle signal.
  • this does not make a difference, and therefore should not change our conclusions regarding the role of intraventricular conduction.
  • Echocardiographic indices provide quantitative information about the magnitude of dyssynchrony, but do not provide conclusive information regarding etiology. Because regional differences in timing of myocardial ejection velocities and strain represent the sum of all mechanisms that may contribute to dyssynchrony, these echocardiographic indices have limited ability to identify electrical conduction delay. This may help to explain why some patients with dyssynchrony are non-responders to CRT and why echocardiography in patients with narrow QRS may fail to identify patients who may benefit from CRT.
  • onset AFG represents a means to identify patients with primary electrical dyssynchrony. Since most patients who are evaluated for CRT undergo left heart catheterization, invasive pressure is available and pressure- strain loops can be constructed. We therefore propose that onset AFG may be used to identify LV dyssynchrony caused by electrical conduction delay and may be used as a reference method for future search for markers of primary electrical dyssynchrony.
  • onset AFG is an accurate marker of timing of regional electrical activation, allowing for differentiation between primary electrical and primary mechanical dyssynchrony, independent of regional differences in load and contractility. Furthermore, it shows that current indices based on myocardial shortening velocity and strain have significant limitations, and although they measure dyssynchrony, they are unable to establish underlying etiology. Further studies should be performed to investigate if onset AFG can be used clinically for identifying patients who may benefit from CRT. Table 2. Hemodynamic and timing variables
  • LV dP/dt max maximal time derivative of LV pressure
  • LV EDP LV end-diastolic pressure
  • IM-EMG intramyocardial electromyography
  • AFG active force generation
  • S myocardial shortening velocity during ejection.
  • LBBB left bundle branch block
  • AFG active force generation
  • STE Speckle Tracking Echocardiography
  • S myocardial shortening velocity during ejection
  • TDI Tissue Doppler Imaging. * P ⁇ 0.05 vs. baseline.
  • the invention provides combination of imaging modalities that display changes in dimension with left ventricular (LV) pressure or estimates of LV pressure to construct pressure-dimension or pressure segment loops for optimizing CRT device settings and lead placement site by a) identification of onset of regional and global LV mechanical activation and b) assessment of LV regional and global function.
  • LV left ventricular
  • the invention provides methods according to claims 14, 15 or 16, a computer program product according to claim 17 and a CRT device according to claim 18.
  • CRT Cardiac resynchronisation therapy
  • LVOT flow by echocardiography is used to optimize interventricular delay (v-v delay) and assessment of E and A wave patterns are used for intraventricular delay (a-v delay) settings.
  • v-v delay interventricular delay
  • a-v delay intraventricular delay
  • Optimal lead placement may also be of critical importance to improve outcome of CRT.
  • the aim when assessing lead placement site is to establish the LV region that is activated last.
  • echocardiography indices exist to aid in this assessment, however, they have proved to give little added value.
  • pressure-dimension loops can be used for optimizing CRT device settings and lead placement site by a) identification of onset of regional and global LV mechanical activation using onset of active force, and b) assessment of LV regional and global function.
  • onset of active force generation defined as the coordinate were a segment leaves its passive curve, reflects electro-mechanical coupling and thus mechanical activation. This is previously described in relation to Figure 5. Assessment of ventricular regional activation to guide device settings and lead placement.
  • onset OAF By using onset OAF on several walls of the left ventricle one can define onset of mechanical activation in the different ventricular walls, this is previously described and shown in Figure 9. Echocardiographic parameters alone have not been able to differentiate between mechanical and electrical dyssynchrony within the ventricle. However, by combining strain/dimension measurements by novel imaging techniques with left ventricular pressure or pressure analogues we are able to differentiate between the two.
  • dotted lines define timing of the first onset of R in EMG (R), onset AFG (O), onset of ejection velocity ( ⁇ ) and peak systolic shortening (D) in the segment length and velocity (dL/dt) traces. The actual onset for these parameters for each trace is also shown by the same symbols in each trace. It can be seen that during LBBB, OAF (O) in the lateral segment is delayed in relation to the first OAF in the septal segment (dotted line marked O). As OAF accurately reflects regional electrical activation, this allows for identification of latest activated region or segment.
  • Disparity in onset of activation will allow us to assess synchronicity of activation within the ventricle and will be of great value when optimizing the CRT device. This will allow the device operator to program the device in a fashion that most accurately reflects normal physiology by adjusting v-v and a-v delays on the CRT device. This will also allow us to select the latest activated region of the LV for placement of the LV CRT lead.
  • OAF is a potentially powerful tool for selecting patients for CRT, optimizing device settings and guiding lead placement.
  • Using pressure- volume-loops or pressure- global/regional strain/dimension-loops we are able to assess left ventricular function in a more precise manner that also is virtually operator independent.
  • a software application for preparing data related to determination of onset of active force in left ventricular muscle segments has been written in MatLab®.
  • the software application is adapted to use the different algorithms for the determination of t 0 AF presented previously.
  • Figure 15 is a flow-chart over the software architecture.
  • the first part (1) is to start the software and load the necessary data;
  • a file comprising the pressure curve and also high sample rate ECG data.
  • a picture file comprising e.g. ultrasound images of the heart.
  • the next step (2) is to, if needed, adjust the two ECG plots so that they are synchronized on the same time axis.
  • a time interval for the heart beat is defined since the strain and the pressure files could comprise data from more than one heart beat.
  • the last part at this stage is to define to (or onset of QRS) from which the AFG point can be defined. The used could then choose to either set the AFG point manually or automatically (3).
  • the last part (5) is to either print a report or save that could later be re-opened.
  • Figures 16A and B show an example from a patient with synchronous onset AFG.
  • Figure 16A shows strain traces and P-L loops for late diastole for various myocardial segments.
  • 16B shows a report displaying the time of OAF for each segment and the difference between early and later activated segments. Max delay between earliest and latest activated wall is 17ms (circle) indicating synchronous activation.
  • Figures 17A and B show the same patient and recordings as in Figure 16A, however now onset of shorting is used as activation point. Note that the lateral segment now is delayed by 35ms (circle) compared to early activated anterior- septal wall indicating dyssynchrony of mechanical shorting also seen on standard echocardiography. This is a patient that therefore has synchronous OAF but dyssychronous onset of shorting and will therefore not respond to pacing treatment, because the underlying mechanism of dyssynchrony is mechanical not electrical. References
  • PRINZEN FW AUGUSTIJN CH, ALLESSIE MA, ARTS T, DELHASS T, RENEMAN RS.

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Abstract

La présente invention porte sur l'évaluation d'une dyssynchronie ventriculaire en relation avec une thérapie de resynchronisation cardiaque (TRC) à l'aide d'une combinaison de modalités d'imagerie qui affichent des modifications de dimension et de pression ventriculaire gauche pour construire des boucles dimension-pression destinées à une évaluation du ventricule gauche. Une nouvelle façon de définir le début d'une force active (OAF) est basée sur une boucle pression-longueur, C(t). Une évaluation améliorée de la fonction ventriculaire gauche globale, des marqueurs pour une force et une fonction actives régionales, l'évaluation d'une synchronicité ventriculaire comprenant la distinction entre une dyssynchronie mécanique et électrique et une évaluation de la viabilité lors d'un infarctus du myocarde devraient être avantageux pour environ 30 % des non-répondeurs qui sont sélectionnés pour une TRC sur la base de critères de QRS.
PCT/EP2009/064748 2008-11-06 2009-11-06 Analyse de données d'activation électromécanique ventriculaire WO2010052303A1 (fr)

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Cited By (10)

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US9272148B2 (en) 2013-07-23 2016-03-01 Medtronic, Inc. Combination of feedback on mechanical and electrical resynchronization to select therapy parameters
EP3068484A4 (fr) * 2013-11-15 2017-08-23 The Regents of the University of California Compositions, dispositifs et méthodes permettant le diagnostic d'une insuffisance cardiaque et une modélisation propre au patient visant à prédire les résultats d'un traitement de resynchronisation cardiaque
GB2583501A (en) * 2019-04-30 2020-11-04 Pacertool As Characterisation of cardiac dyssynchrony and dyssynergy
WO2021090659A1 (fr) * 2019-11-07 2021-05-14 テルモ株式会社 Dispositif, procédé et programme permettant de prédire l'effet thérapeutique d'une thérapie de resynchronisation cardiaque
US11189092B2 (en) 2015-12-22 2021-11-30 The Regents Of The University Of California Computational localization of fibrillation sources
US11475570B2 (en) 2018-07-05 2022-10-18 The Regents Of The University Of California Computational simulations of anatomical structures and body surface electrode positioning
RU2806486C1 (ru) * 2022-11-23 2023-11-01 Федеральное государственное бюджетное учреждение науки институт иммунологии и физиологии Уральского отделения Российской академии наук Способ прогнозирования эффективности сердечной ресинхронизирующей терапии с использованием оптимизации расположения стимулирующих электродов
US11925808B2 (en) 2019-04-30 2024-03-12 Pacertool As Characterisation of cardiac dyssynchrony and dyssynergy
EP4338680A1 (fr) * 2022-09-16 2024-03-20 Koninklijke Philips N.V. Procédés et systèmes d'analyse de la fonction diastolique à l'aide d'images échocardiographiques 2d
WO2024056472A1 (fr) * 2022-09-16 2024-03-21 Koninklijke Philips N.V. Procédés et systèmes d'analyse de la fonction diastolique utilisant uniquement des images échocardiographiques 2d

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Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9700728B2 (en) 2013-07-23 2017-07-11 Medtronic, Inc. Combination of feedback on mechanical and electrical resynchronization to select therapy parameters
US9272148B2 (en) 2013-07-23 2016-03-01 Medtronic, Inc. Combination of feedback on mechanical and electrical resynchronization to select therapy parameters
EP3068484A4 (fr) * 2013-11-15 2017-08-23 The Regents of the University of California Compositions, dispositifs et méthodes permettant le diagnostic d'une insuffisance cardiaque et une modélisation propre au patient visant à prédire les résultats d'un traitement de resynchronisation cardiaque
US11380055B2 (en) 2015-12-22 2022-07-05 The Regents Of The University Of California Computational localization of fibrillation sources
US11676340B2 (en) 2015-12-22 2023-06-13 The Regents Of The University Of California Computational localization of fibrillation sources
US11189092B2 (en) 2015-12-22 2021-11-30 The Regents Of The University Of California Computational localization of fibrillation sources
US11475570B2 (en) 2018-07-05 2022-10-18 The Regents Of The University Of California Computational simulations of anatomical structures and body surface electrode positioning
GB2583501A (en) * 2019-04-30 2020-11-04 Pacertool As Characterisation of cardiac dyssynchrony and dyssynergy
GB2583501B (en) * 2019-04-30 2022-02-02 Pacertool As Characterisation of cardiac dyssynchrony and dyssynergy
US11925808B2 (en) 2019-04-30 2024-03-12 Pacertool As Characterisation of cardiac dyssynchrony and dyssynergy
WO2021090659A1 (fr) * 2019-11-07 2021-05-14 テルモ株式会社 Dispositif, procédé et programme permettant de prédire l'effet thérapeutique d'une thérapie de resynchronisation cardiaque
EP4338680A1 (fr) * 2022-09-16 2024-03-20 Koninklijke Philips N.V. Procédés et systèmes d'analyse de la fonction diastolique à l'aide d'images échocardiographiques 2d
WO2024056472A1 (fr) * 2022-09-16 2024-03-21 Koninklijke Philips N.V. Procédés et systèmes d'analyse de la fonction diastolique utilisant uniquement des images échocardiographiques 2d
RU2806486C1 (ru) * 2022-11-23 2023-11-01 Федеральное государственное бюджетное учреждение науки институт иммунологии и физиологии Уральского отделения Российской академии наук Способ прогнозирования эффективности сердечной ресинхронизирующей терапии с использованием оптимизации расположения стимулирующих электродов

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