FIELD OF THE INVENTION

The present invention generally pertains to systems and methods for non-invasively monitoring hemodynamic status of a patient's heart.

BACKGROUND OF THE INVENTION

Heart failure (HF) is a growing epidemic and a leading cause of morbidity and mortality across the globe. Despite a number of important therapeutic advances for the treatment of symptomatic HF, the prevalence, mortality, hospitalizations and cost associated with this condition continue to grow in Europe, the United States, and in developed countries (McMurray JJ et al. Eur. Heart J. 1998 (19) (suppl. P), 9-16).

Due to aging of the population and improvement in treatment heart failure reached an endemic proportion. Heart failure's incidence has increased by more than 100% over the last 20 years, affecting 5.8 million Americans, 15 million Europeans and 23 million people worldwide. Each year 670,000 Americans and 3.6 million Europeans are diagnosed. 280,000 deaths are attributed to the disease in the US only - nearly half of all heart disease related deaths.

Heart failure (HF) is also an extremely high-cost illness. In US alone, it accounts for over $39.2 billion per year. Of which, there is approximately 1 million hospital stays costing $20.9 billion. Particularly, high cost and mortality are associated with recurrent hospitalizations: 8-15% die and 30-38% are readmitted to the hospital within 90 days of hospitalization.

Most of the recurrent episodes are preventable. Early detection in the outpatient setting, and early intervention, has the potential of significantly reducing many of these hospitalizations and readmissions.

Congestion is a main feature in patients with heart failure leading to hospitalization and re-admissions (Hunt SA et al, Heart Rhythm Society Circulation 2005; 112:e 154-235). Small increases in cardiac filling pressures (including LVEDP,PA, and PCWP) caused by increased intravascular volume occur very early in the decompensation process. The elevation of the left ventricular end diastolic pressure (LVEDP) in HF patients without overt clinical congestion (asymptomatic phase) has been termed "hemodynamic congestion" (Fonarwo, Rev Cardiovasc Med 2003). This early phase of "hemodynamic congestion" can antedate by days or weeks of the symptomatic phase of "clinical congestion".

Filling pressures rise early (days to weeks prior to start symptoms) in the pathophysiology of worsening heart failure and ultimately, if not treated, will lead to clinically symptomatic congestion (Adamson P et al. European Heart Journal 2012 (33): pp.650-651). High filling pressure is associated with increased risk for HF events (Stevenson LW. Circ Heart Fail 2010; 3(5): 580-7). Early interventions for managing increased filling pressures with proactive titration of medications improve outcomes (Abraham WT et al. Lancet. 2011 ; 377(9766): 658-66; Ritzema J et al. Circulation 2010; 121 : 1086-1095). Therefore, accurate identification of start of lung fluid accumulation prior to occurrence of symptoms may prevent hospitalizations and perhaps improve prognosis.

Current pressure LVEDP measurement devices are usually invasive, risky and frequently requires hospitalization. US patent application 2002/0035331 disclosed a device that measures pressures in animals and humans and includes a pressure transmission catheter (PTC) filled with a pressure transmitting medium and implantable in an area in having a physiological pressure.

US patent No. 7,054,679 disclosed a method of and a device for non-invasively measuring the hemodynamic state of a subject or a human patient involve steps and units of non-invasively measuring cardiac cycle period, electrical-mechanical interval, mean arterial pressure, and ejection interval and converting the measured electrical-mechanical interval, mean arterial pressure and ejection interval into the cardiac parameters such as Preload, Afterload and Contractility, which are the common cardiac parameters used by an anesthesiologist.

Therefore, there is still unmet need to develop systems and methods for non-invasively monitoring pre-symptomatic hemodynamic changes in cardiac pressure (such as LVEDP) in patients with chronic congestive heart failure, at home, in order to allow therapeutic interventions to reduce hospitalizations.

SUMMARY OF THE INVENTION

It is another object of the present invention to provide a method of non-invasively monitoring change in hemodynamic status of a subject's heart, comprising steps of:

a. acquiring at least one bio-impedance waveform of said subject, said bio-impedance waveform is the change of bio-impedance during at least one cardiac cycle of said subject; b. analyzing said at least one bio-impedance waveform and extracting at least one waveform parameter P;

wherein said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter P.

It is another object of the present invention to provide the method as defined above, wherein change in said at least one impedance waveform parameter P is correlated with change in left ventricular end-diastolic pressure (LVEDP) such that an estimated value of change in LVEDP is determined.

It is another object of the present invention to provide the method as defined above, additionally comprising step of alerting if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 2 mmHg.

It is another object of the present invention to provide the method as defined above, additionally comprising step of alerting if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 10%.

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P is defined as:

p area of average waveform

absolute area of average waveform'

where average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P =0 and fully positive area is 1.

It is another object of the present invention to provide the method as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through quadratic polynomial fit of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the method as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through at least one fitting function selected from a group consisting of Log, Ln, Linear, Parabolic, Exponent, Polynomial and any combination thereof; of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the method as defined above, wherein said estimated value of change in LVEDP is determined from said change in said at least one impedance waveform parameter P via acquired predictive algorithm. It is another object of the present invention to provide the method as defined above, wherein said estimated value of said LVEDP is determined from said at least one impedance waveform parameter P via acquired predictive algorithm

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P is morphology of said bio-impedance waveform selected from the group consisting of timing of critical point, shape of said waveforms, slope, relative area and any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said acquiring bio-impedance waveform is via a plurality of electrodes placed on said subject's chest.

It is another object of the present invention to provide the method as defined above, further comprising the step of measuring ECG of said subject.

It is another object of the present invention to provide the method as defined above, wherein said cardiac cycle is determined by ECG signal of said subject via synchronizing measurement of said bio-impedance waveform to R wave of ECG such that the accurate start point of each of said waveform in said cardiac cycle is determined.

It is another object of the present invention to provide the method as defined above, further comprising the step of transmitting acquired at least one bio-impedance waveform in wired or wireless manner to external electronics.

It is another object of the present invention to provide the method as defined above, further comprising the step of storing at least one selected from the group consisting of said at least one bio-impedance waveform, said at least one parameter P, correlation of P and LVEDP and any combination thereof.

It is another object of the present invention to provide the method as defined above, further comprising the step of displaying said at least one bio-impedance waveform, said at least one parameter P, said change in at least one parameter P, LVEDP, said change in LVEDP and any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said method is carried out by a wearable device.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded at 20 KHz and 90 KHz.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded in AC, DC or both. It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said electrodes are placed along the sternum, with a proximal pair of electrodes near the neck and a distal pair near the xiphoid process.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded as CSV files.

It is another object of the present invention to provide the method as defined above, wherein said CSV files are analyzed by mathematical programs MATLAB.

It is another object of the present invention to provide the method as defined above, wherein said change of LVEDP is determined on the order of 1-2 mmHg.

It is another object for the present invention to provide a computer-implemented system for non-invasively monitoring change in hemodynamic status of a subject's heart, comprising:

a. means adapted to acquire at least one bio-impedance waveform of said subject, said bio-impedance waveform is defined as the change of bio-impedance during at least one cardiac cycle of said subject;

b. a processor in communication with said means, configured to (a) analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance waveform; (b) calculate either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; wherein said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter .P.

It is another object for the present invention to provide the system as defined above, wherein change in said at least one impedance waveform parameter P is correlated with change in left ventricular end-diastolic pressure (LVEDP) such that an estimated value of change in LVEDP is determined. additionally comprising alerting means.

wherein said alerting means are configured to alert if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 2 mmHg. wherein said alerting means are configured to alert if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 10%..

It is another object for the present invention to provide the system as defined above, wherein said at least one parameter P is defined as:

p area of average waveform

absolute area of average waveform'

where average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.

It is another object for the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P =0 and fully positive area is 1.

It is another object for the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through quadratic polynomial fit of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object for the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through at least one fitting function selected from a group consisting of Log, Ln, Linear, Parabolic, Exponent, Polynomial and any combination thereof; of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object for the present invention to provide the system as defined above, wherein said estimated value of change in LVEDP is determined from said change in said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object for the present invention to provide the system as defined above, wherein said estimated value of said LVEDP is determined from said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object for the present invention to provide the system as defined above, wherein said at least one parameter P is morphology of said bioimpedance waveform selected from the group consisting of timing of critical point, shape of said waveforms, slope, relative area and any combination thereof.

It is another object for the present invention to provide the system as defined above, wherein said means adapted to measure impedance waveform comprises a plurality of electrodes placed on said subject's chest.

It is another object for the present invention to provide the system as defined above, wherein said system further comprising a device adapted to measure ECG of said subject.

It is another object for the present invention to provide the system as defined above, wherein said cardiac cycle is determined by ECG signal of said subject via synchronizing measurement of said bio-impedance waveform to R wave of ECG such that the accurate start point of each of said waveform in said cardiac cycle is determined.

It is another object for the present invention to provide the system as defined above, further comprising a transmitter configured to transmit at least one bio-impedance waveform in wired or wireless manner to external electronics.

It is another object for the present invention to provide the system as defined above, further comprising at least one recording device configured to store at least one selected from the group consisting of said at least one bio-impedance waveform, said at least one parameter P, correlation of P and LVEDP and any combination thereof.

It is another object for the present invention to provide the system as defined above, further comprising at least one display configured to show said at least one bio-impedance waveform, said at least one parameter P, said change in at least one parameter P, LVEDP, said change in LVEDP and any combination thereof.

It is another object for the present invention to provide the system as defined above, wherein said system is configured to be wearable.

It is another object for the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded at 20 KHz and 90 KHz.

It is another object for the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded in AC, DC or both.

It is another object for the present invention to provide the system as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.

It is another object for the present invention to provide the system as defined above, wherein said electrodes are placed along the sternum, with a proximal pair of electrodes near the neck and a distal pair near the xiphoid process.

It is another object for the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded as CSV files.

It is another object for the present invention to provide the system as defined above, wherein said CSV files are analyzed by mathematical programs MATLAB.

It is another object for the present invention to provide the system as defined above, wherein said change of LVEDP is determined on the order of 1-2 mmHg.

It is one object of the present invention to provide a system for non-invasively monitoring change in hemodynamic status of a subject's heart, comprising:

a. means adapted to acquire at least one bio-impedance waveform of said subject, said bio-impedance waveform is defined as the change of bio-impedance during at least one cardiac cycle of said subject;

b. a processor in communication with said means, configured to analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance waveform; wherein said at least one impedance waveform parameter P is correlated with left ventricular end-diastolic pressure (LVEDP) such that an estimated value of said LVEDP is determined from said impedance waveform parameter P

c. alerting means adapted to alter the user if said LVEDP is above a predetermined threshold.

It is another object of the present invention to provide the system as defined above, wherein said system is in communication with a database adapted to store at least one selected from a group consisting of (i) said LVEDP; (ii) said change in said LVEDP; and any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein change in said at least one impedance waveform parameter P is correlated with change in left ventricular end-diastolic pressure (LVEDP) such that an estimated value of change in LVEDP is determined

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P is defined as:

p area of average waveform

absolute area of average waveform'

where average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P =0 and fully positive area is 1.

It is another object of the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through quadratic polynomial fit of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through at least one fitting function selected from a group consisting of Log, Ln, Linear, Parabolic, Exponent, Polynomial and any combination thereof; of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said estimated value of change in LVEDP is determined from said change in said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said estimated value of said LVEDP is determined from said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P is morphology of said bioimpedance waveform selected from the group consisting of timing of critical point, shape of said waveforms, slope, relative area and any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said means adapted to measure impedance waveform comprises a plurality of electrodes placed on said subject's chest.

It is another object of the present invention to provide the system as defined above, wherein said system further comprising a device adapted to measure ECG of said subject.

It is another object of the present invention to provide the system as defined above, wherein said cardiac cycle is determined by ECG signal of said subject via synchronizing measurement of said bio-impedance waveform to R wave of ECG such that the accurate start point of each of said waveform in said cardiac cycle is determined.

It is another object of the present invention to provide the system as defined above, further comprising a transmitter configured to transmit at least one bio-impedance waveform in wired or wireless manner to external electronics.

It is another object of the present invention to provide the system as defined above, further comprising at least one recording device configured to store at least one selected from the group consisting of said at least one bio-impedance waveform, said at least one parameter P, correlation of P and LVEDP and any combination thereof.

It is another object of the present invention to provide the system as defined above, further comprising at least one display configured to show said at least one bio-impedance waveform, said at least one parameter P, said change in at least one parameter P, LVEDP, said change in LVEDP and any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said system is configured to be wearable.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded at 20 KHz and 90 KHz.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded in AC, DC or both.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said electrodes are placed along the sternum, with a proximal pair of electrodes near the neck and a distal pair near the xiphoid process.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded as CSV files.

It is another object of the present invention to provide the system as defined above, wherein said CSV files are analyzed by mathematical programs MATLAB.

It is another object of the present invention to provide the system as defined above, wherein said change of LVEDP is determined on the order of 1-2 mmHg.

It is another object of the present invention to provide a system for non-invasive ly monitoring hemodynamic status of a subject's heart, comprising:

a. means adapted to acquire at least one bio-impedance waveform of said subject, said bio-impedance waveform is defined as the change of bio-impedance during at least one cardiac cycle of said subject;

b. a processor in communication with said means, configured to analyze said bio-impedance waveform and extract at least one parameter P from said at least one bio-impedance l O waveform; wherein said at least one impedance waveform parameter P is correlated with either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; such that an estimated value of either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; is determined from said impedance waveform parameter P;

c. alerting means adapted to alter the user if either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; is above a predetermined threshold.

It is another object of the present invention to provide the system as defined above, wherein said threshold is above ± 2 mmHg.

It is another object of the present invention to provide the system as defined above, wherein said threshold is above ± 10%.

It is another object of the present invention to provide the system as defined above, wherein said system is in communication with a database adapted to store at least one selected from a group consisting of (i) said LVEDP; (ii) said change in said LVEDP; and any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P is defined as:

p area of average waveform

absolute area of average waveform'

where average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P =0 and fully positive area is 1.

It is another object of the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through quadratic polynomial fit of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through at least one fitting function selected from a group consisting of Log, Ln, Linear, Parabolic, Exponent, Polynomial and any combination thereof; of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said estimated value of change in LVEDP is determined from said change in said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said estimated value of said LVEDP is determined from said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object of the present invention to provide the system as defined above, wherein said at least one parameter P is morphology of said bioimpedance waveform selected from the group consisting of timing of critical point, shape of said waveforms, slope, relative area and any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said means adapted to measure impedance waveform comprises a plurality of electrodes placed on said subject's chest.

It is another object of the present invention to provide the system as defined above, wherein said system further comprising a device adapted to measure ECG of said subject.

It is another object of the present invention to provide the system as defined above, wherein said cardiac cycle is determined by ECG signal of said subject via synchronizing measurement of said bio-impedance waveform to R wave of ECG such that the accurate start point of each of said waveform in said cardiac cycle is determined.

It is another object of the present invention to provide the system as defined above, further comprising a transmitter configured to transmit at least one bio-impedance waveform in wired or wireless manner to external electronics.

It is another object of the present invention to provide the system as defined above, further comprising at least one recording device configured to store at least one selected from the group consisting of said at least one bio-impedance waveform, said at least one parameter P, correlation of P and LVEDP and any combination thereof.

It is another object of the present invention to provide the system as defined above, further comprising at least one display configured to show said at least one bio-impedance waveform, said at least one parameter P, said change in at least one parameter P, LVEDP, said change in LVEDP and any combination thereof. It is another object of the present invention to provide the system as defined above, wherein said system is configured to be wearable.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded at 20 KHz and 90 KHz.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded in AC, DC or both.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.

It is another object of the present invention to provide the system as defined above, wherein said electrodes are placed along the sternum, with a proximal pair of electrodes near the neck and a distal pair near the xiphoid process.

It is another object of the present invention to provide the system as defined above, wherein said bio-impedance waveform is recorded as CSV files.

It is another object of the present invention to provide the system as defined above, wherein said CSV files are analyzed by mathematical programs MATLAB.

It is another object of the present invention to provide the system as defined above, wherein said change of LVEDP is determined on the order of 1-2 mmHg.

It is another object of the present invention to provide a method of non-invasively monitoring hemodynamic status of a subject's heart, comprising steps of:

a. acquiring at least one bio-impedance waveform of said subject, said bio-impedance waveform is the change of bio-impedance during at least one cardiac cycle of said subject; b. analyzing said at least one bio-impedance waveform and extracting at least one waveform parameter P;

c. monitoring said hemodynamic status;

wherein said step of monitoring is provided by correlating said at least one impedance waveform parameter P with either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; and calculating an estimated value of either (i) estimated value of said LVEDP; (ii) change in left ventricular end-diastolic pressure (LVEDP); (iii) any combination thereof; from said impedance waveform parameter .P. It is another object of the present invention to provide the method as defined above, additionally comprising step of alerting if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 2 mmHg.

It is another object of the present invention to provide the method as defined above, additionally comprising step of alerting if said change in left ventricular end-diastolic pressure (LVEDP) is above ± 10%.

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P is defined as:

p area of average waveform

absolute area of average waveform'

where average waveform is median of a plurality of said bio-impedance waveforms acquired in a predetermined time period and superimposed thereof.

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P ranges from -1 to 1, where fully negative area is -1, negative area equals to positive area P =0 and fully positive area is 1.

It is another object of the present invention to provide the method as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through quadratic polynomial fit of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the method as defined above, wherein correlation of said at least one impedance waveform parameter P and said LVEDP is established through at least one fitting function selected from a group consisting of Log, Ln, Linear, Parabolic, Exponent, Polynomial and any combination thereof; of said parameter P to the measured LVEDP thereby acquiring predictive algorithm.

It is another object of the present invention to provide the method as defined above, wherein said estimated value of change in LVEDP is determined from said change in said at least one impedance waveform parameter P via acquired predictive algorithm.

It is another object of the present invention to provide the method as defined above, wherein said estimated value of said LVEDP is determined from said at least one impedance waveform parameter P via acquired predictive algorithm

It is another object of the present invention to provide the method as defined above, wherein said at least one parameter P is morphology of said bio-impedance waveform selected from the group consisting of timing of critical point, shape of said waveforms, slope, relative area and any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said acquiring bio-impedance waveform is via a plurality of electrodes placed on said subject's chest.

It is another object of the present invention to provide the method as defined above, further comprising the step of measuring ECG of said subject.

It is another object of the present invention to provide the method as defined above, wherein said cardiac cycle is determined by ECG signal of said subject via synchronizing measurement of said bio-impedance waveform to R wave of ECG such that the accurate start point of each of said waveform in said cardiac cycle is determined.

It is another object of the present invention to provide the method as defined above, further comprising the step of transmitting acquired at least one bio-impedance waveform in wired or wireless manner to external electronics.

It is another object of the present invention to provide the method as defined above, further comprising the step of storing at least one selected from the group consisting of said at least one bio-impedance waveform, said at least one parameter P, correlation of P and LVEDP and any combination thereof.

It is another object of the present invention to provide the method as defined above, further comprising the step of displaying said at least one bio-impedance waveform, said at least one parameter P, said change in at least one parameter P, LVEDP, said change in LVEDP and any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said method is carried out by a wearable device.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded at 20 KHz and 90 KHz.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded in AC, DC or both.

It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is whole thoracic impedance waveform, trans-thoracic impedance waveform or any combination thereof.

It is another object of the present invention to provide the method as defined above, wherein said electrodes are placed along the sternum, with a proximal pair of electrodes near the neck and a distal pair near the xiphoid process. It is another object of the present invention to provide the method as defined above, wherein said bio-impedance waveform is recorded as CSV files.

It is another object of the present invention to provide the method as defined above, wherein said CSV files are analyzed by mathematical programs MATLAB.

It is another object of the present invention to provide the method as defined above, wherein said change of LVEDP is determined on the order of 1-2 mmHg.

BRIEF DESCRIPTION OF THE FIGURES

In order to better understand the invention and its implementation in practice, a plurality of embodiments will now be described, by way of non-limiting example only, with reference to the accompanying drawings, wherein

Figure 1 schematically illustrates Wiggers diagram of the cardiac physiology with the bio-impedance waveform integrated into the theoretical diagram;

Figure 2 schematically illustrates the system (100) according to a preferred embodiment of the present invention;

Figure 3 schematically illustrates the system (200) according to a preferred embodiment of the present invention;

Figure 4 schematically illustrates the high-level overview of the method (400) according to a preferred embodiment of the present invention;

Figure 5 illustrates waveform analysis tool panel showing individual cycles and mean waveform;

Figure 6 illustrates relationship of extravascular Lung Water (EVLW) and resistivity (the present invention) during controlled volume infusion in the sheep model;

Figure 7 shows Spearman's correlation coefficient between Resistivity and EVLW;

Figure 8A shows changes in resistivity occurs concomitantly with changes in LVEDP;

Figure 8B shows changes in resistivity lags behind changes in ITBV but precedes changes in pulmonary congestion defined by EVLW;

Figure 9 shows precision of Resistivity measurement;

Figure 10 shows typical waveforms during baseline, congestion and decongestion. Baseline and decongestion LVEDP and waveform parameter P values were identical, despite significant change in heart rate;

Figure 11 shows measured vs. estimated LVEDP in a sheep;

Figure 12 shows estimated vs. measured LVEDP during early Congestion in a sheep;

Figure 13 shows combined data for estimated vs measured LVEDP using waveform parameter P;

Figure 14 shows combined data for estimated vs measured LVEDP using transthoracic resistance;

Figure 15A illustrates high quality 11 mmHg LVEDP recordings in a human subject;

Figure 15B illustrates low quality 11 mmHg LVEDP recordings in a human subject;

Figure 16 shows the LVEDP measurements and their quality in the 7 evaluable subjects;

Figure 17 shows waveform analysis panel showing individual cycles (upper panel) and mean waveforms (lower panel) captured during one recording cycle in a human subject;

Figure 18A shows superimposed individual wave measurements in a human subject;

Figure 18B shows composite median measurements in a human subject;

Figure 19 shows normalized median waveforms in each human subject showing the change between 'high' and 'low';

Figure 20 shows differences between the mean waveforms. The red curve is the difference curve between the blue ('low' LVEDP) and green ('high' LVEDP) curves;

Figure 21 shows LVEDP and corresponding waveform parameter which is expressed as a numerical parameter; and

Figure 22 shows Bio-impedance waveform parameter - ALVEDP relationships in 7 human subjects. DETAILED DESCRIPTION OF THE PREFERRED EMB ODIEMNTS

The following description is provided, alongside all chapters of the present invention, so as to enable any person skilled in the art to make use of said invention and sets forth the best modes contemplated by the inventor of carrying out this invention. Various modifications, however, will remain apparent to those skilled in the art, since the generic principles of the present invention have been defined specifically to provide an early detection device, using bio-impedance waveform algorithm analysis that identifies an increase in estimated left ventricular end diastolic pressure (LVEDP) and enables preventive therapeutic interventions aimed to reduce hospitalization rates and healthcare system costs of chronic heart failure management.

The term 'subject' hereinafter refers to any human or animal that has heart conditions.

The term 'bio-impedance' hereinafter refers to the response of a living organism (or a portion thereof, such as a body part, organ, tissue, or the like) to an externally applied electric current. It is a measure of the opposition to the flow of that electric current through the tissues. The measurement of the bio-impedance (or bioelectrical impedance) has proved useful as a non-invasive method for measuring various parameters of the body such as blood flow (often referred to as bioimpedance plethymography) and body composition (known as bioelectrical impedance analysis or simply BIA). According to some preferred embodiments, the measurement of bio-impedance in the presentation is via adhesive electrodes applied to the skin of a subject, and a tiny alternating current at a frequency of 10-100 kHz is applied (typically a few milli-Amperes, and up to 9mA). The Ohmic power dissipated is sufficiently small and diffused over the body to be easily handled by the body's thermoregulatory system - certainly below the threshold at which they would cause stimulation of nerves. The frequency of the alternating current is sufficiently high not to give rise to electrolytic effects in the body (lower frequency current may increase electrode impedances, cause other noise factors, and risk the patient with an electric shock), but low enough for neglecting of displacement currents in the calculations.

The term 'thoracic region' hereinafter refers to the region between the abdomen and neck wherein the ribs are located.

The term 'waveform' hereinafter refers to a curve showing the shape of a wave at a given time.

The term 'bio-impedance waveform' hereinafter refers to change of bio-impedance according to time during at least one cardiac cycle.

The term 'pre-load' hereinafter refers to the amount of myocardial fiber stretch at the end of diastole, it also refers to the amount of volume in the ventricle at the end of this phase. It is clinically acceptable to measure the pressure required to fill the ventricles as an indirect assessment of ventricular preload. Left atrial filling pressure or pulmonary artery wedge pressure is used to assess left ventricular preload. End diastolic left ventricular pressure and volume are also common surrogates for preload. Preload increases with greater circulating volume, venoconstriction, exercise, arterioventricular fistulae, increased ventricular compliance, increased ventricular filling time, left ventricular systolic failure. Preload decreases with volume depletion, decreased venous return, impaired atrial contraction, tricuspid or mitral stenosis, less compliant ventricles. Cardiac preload is a semi-quantitative composite assessment that is variously described in different cardiovascular physiology texts and articles as end-diastolic myocardial fiber tension, end-diastolic myocardial fiber length, ventricular end-diastolic volume, and ventricular end-diastolic filling pressure. There is a general recognition that preload is not synonymous with any one of these measurable parameters, but is rather a physiological concept that encompasses all of the factors that contribute to passive ventricular wall stress at the end of diastole. A number of techniques have been developed which enables monitoring of volumetric parameters. These parameters include: global end-diastolic volume (GEDV) and intrathoracic blood volume (ITBV). Transpulmonary thermodilution enables the assessment of intrathoracic blood volume (ITBV) and global end diastolic volume (GEDV). ITBV comprises the volume of all four cardiac chambers and the pulmonary circulation whereas GEDV only comprises the cardiac volumes in end-diastole. From a physiological point of view, ITBV is a surrogate parameter for the central blood volume which serves as the fluid reservoir for the left ventricle. So, at least in theory a severe hypovolemia should be reflected by a decrease in ITBV and GEDV. In clinical studies, it has been demonstrated that both ITBV and GEDV are more sensitive than CVP and PAOP and comparable to echocardiographically determined LVEDA. As pressures (CVP or PAWP) are inaccurate indicators of left and right ventricular filling, volume indices (such as intrathoracic blood volume (ITBV) and global end-diastolic volume (GEDV) may form a physiological point of view, better estimate left ventricular preload.

The term 'conductivity' hereinafter refers to the ability of a certain tissue to conduct electricity, the conductance of a unit cube of tissue. Conductivity σ (Greek: sigma) is expressed in Siemens per meter (S/m) and it is defined as the inverse of resistivity, where resistivity is expressed in Ohm*meter (Ω -m). Alternatively, this ability is measured in the form of impedivity, the impedance of a unit cube of tissue. The impedivity is the sum of resistivity and reactivity and is expressed in Ohm*meter (Ω-m) or Ohm*cm (Ω-cm). Both conduction and displacement currents are generated in tissues when applying an electromagnetic field. In most biological tissues the conduction currents dominate in lower frequencies (<100 kHz). At high frequencies (>50 kHz) the displacement currents are dominant.

The term 'impedance cardio raphy' hereinafter refers to an application of the plethysmography technique used to detect the properties of the blood flow in the thorax. According to some preferred embodiments, the placement of four dual disposable sensors on the neck and chest are used to transmit and detect electrical and impedance changes in the thorax, which are used to measure and calculate hemodynamic parameters. Bioimpedance has being widely used to detect cardiac output (CO) and its derivatives. Another parameters typically measured by ICG systems is the Thoracic Fluid Content (TFC) or Trans-Thoracic Impedance, defined as the electrical conductivity of the chest cavity. TFC is primarily determined by the intravascular, interstitial and intraalveolar fluids in the thorax and therefore responds to changes in lung fluids. The TFC decreases as the amount of fluid in the lungs increases.

The term 'Systolic dysfunction' refers to impaired ventricular contraction. In chronic heart failure, this is most likely due to changes in the signal transduction mechanisms regulating cardiac excitation-contraction coupling. The loss of cardiac inotropy (i.e., decreased contractility) causes a downward shift in the Frank-Starling curve. These results in a decrease in stroke volume and a compensatory rise in preload (often measured as ventricular end-diastolic pressure or pulmonary capillary wedge pressure). The rise in preload is considered compensatory because it activates the Frank- Starling mechanism to help maintain stroke volume despite the loss of inotropy. If preload did not rise, the decline in stroke volume would be even greater for a given loss of inotropy. Depending upon the precipitating cause of the heart failure, there will be ventricular hypertrophy, dilation, or a combination of the two. The effects of a loss of intrinsic inotropy on stroke volume, and end-diastolic and end-systolic volumes, are best depicted using ventricular pressure-volume loops (Figure 3). Loss of intrinsic inotropy decreases the slope of the end-systolic pressure-volume relationship (ESPVR). This leads to an increase in end-systolic volume. There is also an increase in end-diastolic volume (compensatory increase in preload), but this increase is not as great as the increase in end-systolic volume.

The term "diastolic dysfunction" hereinafter refers to changes in ventricular diastolic properties that have an adverse effect on stroke volume. About 50% of heart failure patients have diastolic dysfunction, with or without normal systolic function as determined by normal ejection fractions. Ventricular function is highly dependent upon preload as demonstrated by the Frank-Starling relationship. Therefore, if ventricular filling (preload) is impaired, this will lead to a decrease in stroke volume.

Currently, there are established methods for diagnosing and monitoring hemodynamic congestions. Invasive left heart catheterization for the measurement of (LVEDP) is performed either by Pigtail catheter (Fluid-Filled Catheters) or by a Millar Mikro-Cath™ pressure catheter (electronic pressure sensor). While adequate to monitor a patient's state, pressure waveforms from fluid-filled catheters can be unreliable for diagnostic purposes. The disposable Mikro-CathTM (Millar Inc., Germany) pressure catheter produces a more complete and accurate representation of cardiovascular waveforms, making it the gold standard for clinical applications. Pulmonary capillary wedge pressure (PCWP) is measured during right diagnostic cardiac catheterization using a Swan-Ganz catheter. Intermittent pulmonary artery pressure is measured using a sphygmomanometer. Another method of measurement is of pulmonary artery pressure monitoring is done by permanent implant called CardioMEMS™ HF System (St. Jude Medical, USA). The CardioMEMS™ HF System provides ambulatory pulmonary artery (PA) pressure monitoring using a small pressure sensor, permanently implanted in the distal pulmonary artery via a safe right heart catheterization procedure. Patient-initiated sensor readings are wirelessly transmitted to an external electronics unit and stored in a secure website for clinicians to access and review. Directly monitoring PA pressure not only enables early detection of worsening heart failure, but also allows the titration of medications for proactive and personalized patient management. The CardioMEMS™ HF System is the first and only FDA-approved heart failure (HF) monitor proven to significantly reduce HF hospital admissions and improve quality of life in NYHA class III patients. When used by clinicians to manage HF, the CardioMEMS HF System is safe and reliable, clinically proven, proactive and personalized.

The present invention provides an early detection device, using bio-impedance waveform algorithm analysis that identifies an increase in estimated left ventricular end diastolic pressure (LVEDP) and enables preventive therapeutic interventions aimed to reduce hospitalization rates and healthcare system costs of chronic heart failure management. The present invention provides a waveform technique, in which a whole cardiac cycle is measured, is inferred from surface electrical (bio-impedance) measurements. The waveform technology expands the usefulness of simple bio-impedance measurement by enabling the tracking of changes in LVEDP. The physiological foundation for this measurement is based on the concept of preload which is a composite assessment of cardiac filling that represents the primary determinant of cardiac output. Both end diastolic left ventricular pressure (LVEDP) and volume are common surrogates for preload.

The present invention provides the system and method for evaluating the dynamic changes in the cardiac cycle on a beat-to-beat basis. It provides the aimed information by focusing on the heart and major vessels in the chest, rather than on the lungs. It is designed to detect and track small changes in preload (compared with changes in LVEDP). The technology is less sensitive to changes in electrodes position and their contact with the chest wall than transthoracic bio-impedance since the bioimpedance waveform morphology is less sensitive to changes than the amplitude measured by other methods. The raw signals are expressed as changes of the waveform over time as compared to baseline measurements. These changes (including systolic and diastolic components, as defined by simultaneous ECG recording - see Figure 1) are fed into the proprietary algorithm and translated to numeric parameters which provide the estimate of the changes in LVEDP.

Reference is now made to Figure 2, which illustrates the system (100) for non-invasively monitoring change in hemodynamic status of a subject's (102) heart according to a preferred embodiment of the present invention. The system comprises a means (110) to acquire bio-impedance waveform of the subject (102). According to a preferred embodiment, the measurement means comprises a plurality of electrodes 110a, 110b, 110c and llOd. According to a preferred embodiments, the electrodes are placed on a desecrate slim wearable patch, wire free and water resistant. According to some preferred embodiment, the electrodes are placed far away from the heart and the great vessels. It can be worn on the thorax for 30 days, acquiring the impedance waveform. According to another preferred embodiment, the electrodes, which is integrated into one wearable patch, are placed near the heart in order to facilitate the shortest (electrical) path to the heart and the great vessels. Due to the fact that impedance waveform is measured, the position of electrodes is not so critical to the accuracy of the results.

According to another preferred embodiment, the system (100) further comprise a transmitter (120) in communication with the electrodes configured to transmit acquired bio-impedance waveform to an external electronics (e.g. a mobile phone, a cloud, a monitoring center) and acquired bio-impedance waveform can be analyzed via a processor ( 130) using dedicated algorithm assessing the changes in LVEDP and presenting them via a display (140) to a trained physician/nurse assisting them to guide the patient about required changes in his or her therapy.

Reference is now made to Figure 3, which illustrates the system (200) for non-invasively monitoring change in hemodynamic status of a subject with chronic heart failure according to a preferred embodiment of the present invention. The system (200) applies a tiny currents using 4 skin surface electrodes (210) placed around the subject's chest and measures the resulting potential (voltage) on the body surface, thus, determining the body's bio-impedance. It then measures the bio-impedance resistance of the lungs, and the bio-impedance waveform from the heart and large vessels.

According to some preferred embodiments, the system (200) further comprises ECG monitor applied with 3 ECG electrodes for Lead II tracing. The ECG signal is required as an input for the definition of the cardiac cycle systolic and diastolic components and for application of algorithm calculation of changes in LVEDP.

According to a preferred embodiment, the system (200) further comprises a display configured to show resistance values in Ohm (Qand the bio , (-impedance waveform graphs represented and expressed as the waveform parameter (P). This information is displayed in real-time and the recorded numeric values and graphical trends will allow physicians to continuously monitor the status of chronic heart failure patients. The system (200) is not a life-supporting device. It does not have any real-time alarms. The displayed information is intended only to serve as a supplementary source of data. This additional information does not titute in any way diagnosis or treatment subs approaches based upon standard medical practice.

The user affixes on the subject's chest four standard pre-wired ECG electrodes which are provided with the system. The four electrodes set (210) is designated for bio-impedance measurement. The connector at the end of the electrodes wires is connected with the patient cable (220), which in turn connected to the monitor unit (240). The user also affixes three standard ECG monitoring electrodes (RA, LA, N) and connect them with the snap on connector to the ECG cable (250). The user connects the Monitor Unit USB cable (230) to a processor (e.g. a computer) configured to recognize the system with the S/N. The processor fully controls the measurement, its settings and recordings. At the end of the monitoring session, the user can download a CVS file contains the all measurement, to a storage device, such as standard USB portable memory stick.

According to a preferred embodiment, the monitoring unit (240) comprises a bio-impedance card and ECG card in a single enclosure, integrated USB cable and connector (230) for power supply and communication transfer, connector for patient cables (260) and connector for ECG cables (270). The monitoring unit (240) is designed to be placed on a table or stroller.

According to a preferred embodiment, the processing unit, e.g. a Laptop, is installed with "Cardio Sampler" software, and is used for viewing, recording and re-running recorded measurements. According to a preferred embodiment, the processing unit further comprises a micro Simulator configured to check the bio-impedance signal of the monitor unit.

According to a preferred embodiment, the patient cable (220) is multiple use and non-sterile, it serves as extension from the monitor unit (240) to the bio-impedance electrodes (210). According to a preferred embodiment, the patient cable (220) is IP-D317 adapter cable used for IP-D316 electrodes (CE Mark, FDA cleared). According to another preferred embodiment, it is a generic ECG monitoring electrodes adapter cable.

According to a preferred embodiment, the ECG Cable (250) is multiple use and non-sterile, it serves as extension from the monitor unit (240) to the ECG electrodes (not shown). It is a generic ECG monitoring electrodes adapter cable with snap-on connector.

According to a preferred embodiment, the bio-impedance electrodes (210) are CE Marked and FDA cleared. They are non-sterile and for single use. Usually the bio-impedance electrodes (210) comprise 4 electrodes. They are either integral process pre-wired electrodes or generic ECG Electrodes.

According to a preferred embodiment, the ECG electrodes are CE Marked and FDA cleared. They are non-sterile and for single use. Usually the ECG electrodes comprise 3 electrodes. They are generic ECG Electrodes.

According to a preferred embodiment, the system is packaged with reusable use packaging and/or durable case. According to some preferred embodiments, transportation of the system (200) is in a single package at the first shipping to the site following electrodes and placement accessories can be shipped upon request.

According to a preferred embodiment, during a monitoring session, the Monitor Unit (240) and the processing unit shall be connected by the USB cable. Monitoring control is done through the processing unit. The monitoring result is saved in a designated storage unit. At the end of the session the file can be downloaded to a standard USB portable memory stick.

Reference is now made to Figure 4, the method (400) for non-invasively monitoring change in hemodynamic status of a subject with chronic heart failure according to a preferred embodiment of the present invention. The method (400) start with acquiring at least one bio-impedance waveform of the subject (410), via bio-impedance electrodes as described above. The acquired bio-impedance waveform is then received by a processor (420). The processor analyze the bio-impedance waveform (430) and extract at least one waveform parameter P (440). The change in the impedance waveform parameter P is then correlated with change in left ventricular end-diastolic pressure (LVEDP) (450) such that an estimated value of change in LVEDP is provided (460).

Example 1: WAVEFORM ANALYSIS TOOL. PARAMETER DEFINITION AND THE PREDICTIVE ALGORITHM

The analysis tool is a MATLAB program that loads CSV measurement files containing bio-impedance waveform. The program looks for repetitive data in order to determine the heart rate in each measurement, and 'break' the input data into heart rate cycles. According to some preferred embodiment, real-time ECG input is used to synchronize the beginning of each cycle to the peak of the ECG R wave.

Figure 5 shows the individual cycles, which include small red circles (502) at the time of the peak of the R wave that separate each cycle from the next one. The lower graph shows in grey all the superimposed cycles and in red their average value. The spread of the grey lines (504) around the red average (506) is a measure of the variation of waveform shape during the measurement. The main contributor to the variation in waveform shape was the respiratory cycle.

From the average waveform a large set of parameters that are related to the waveform shape, area, and morphology can be derived. In the sheep study we used a simple calculation of the area of the average waveform divided by the absolute area of the same waveform: area of average waveform

P = - absolute area of average waveform

This gives a normalized unit less P that depends only on the waveform morphology. For a fully negative waveform P = -\, while for a fully positive waveform P = \. We get P = 0 when the area of the positive and negative parts are equal. The parameter does depend on proper determination of the waveform start time. Synchronization to the R wave of the ECG helps in accurately determining the waveform start point.

In order to see the correlation between P and physiological measures, a quadratic scaling vs. LVEDP is carried out for each subject. The scaling was calculated by quadratic polynomial fit of the calculated P to the measured LVEDP.

In human, more sophisticated algorithm is used. In the development of predictive algorithm, multiple factors and parameters need to be evaluated in a thorough quantitative manner. Even fairly simple predictive algorithms will have a number of variables that might have direct impact on the overall performance of the algorithm. Therefore, the ability to determine what components and associated settings result in the best overall predictive performance is a critical step in the development of high-performing and predictive algorithm.

Example 2: Initial Animal Studies in Sheep

To evaluate in a sheep model of acute progressive pulmonary congestion the accuracy of pEI in quantifying pulmonary congestion compared to established invasive measurements, animal experiments are conducted in order to provide solid evidence of the performance of the device under controlled hemodynamic condition. The accuracy of congestion detection was assessed in comparison with invasive pressure catheters (Pigtail catheter or Millar) and Transpulmonary Thermodilution technique (EV1000 - Edwards Lifescience) which are the gold standards for assessment of filling pressure and volumes in the cardiovascular system and lungs.

Methods: Eleven sheep were instrumented and progressive lung congestion was induced by infusion of saline combined with a volume expander and Noradrenaline (as shown in Figure 6). Standard pressure measurements and volumetric parameters of Intra Thoracic Vascular Blood Volume (ITBV) and Extravascular Lung Water (EVLW) measured by invasive Single Transpulmonary Thermodilution (EV1000 Edward Lifescience) were compared with Resistivity (Ohm*cm) obtained by the pEI method. Measurements were performed every 15 minutes. Mild to moderate congestion (defined as <30% increase in EVLW) was induced in 5 and severe congestion (>30% increase in EVLW) in 6 sheep.

Results: Resistivity measurements show good correlation with LVEDP, (mean r= -0.91, p<0.0001, SD=0.06), ITBV (mean r= -0.89, pO.0001, SD=0.08) and EVLW (mean r=-0.92, p<0.0001, SD=0.07) in both groups of mild and severe congestion (Figure 7).

Changes in resistivity occurred concomitantly with changes in LVEDP (Figure 8A); lagged behind changes in ITBV but preceded changes in pulmonary congestion defined by EVLW (Figure 8B), presents %change from baseline, %BL).

The repeatability of Resistivity (Figure 9) as measured by the coefficient of variation of repeated measurements was 1.6% at baseline and 2.6% during pulmonary congestion. Precision of Resistivity measurement was evaluated by comparing repeated measurements (N = 330) of Resistivity taken under identical conditions over a short time interval (repeated measures ANOVA with Random Effect). The measurements were found highly repeatable and the results can be applied to the general sheep population (due to the statistical model used).

In this animal model, a novel pEI noninvasive technology was highly reproducible and exhibited good correlation with different levels of pulmonary congestion defined by EVLW. pEI detected congestion already in its early, hemodynamic phase, prior to accumulation of fluids in the lung tissue.

Example 3: Revised Animal studies

The animal studies is revised to overcome the well-known phenomena of poor signal/noise ratio when the subjects are human. The revised method would be more stable and could serve as surrogate for changes in LVEDP during early congestion and also decongestion in heart failure. The objective is to evaluate the accuracy of the present invention in estimating LVEDP in an animal model of gradual pulmonary congestion and decongestion.

Method: The study design similar to the previous described animal studies (first study) with new five sheep. We induced progressive lung congestion infusion of saline combined with a volume expander and Noradrenaline in the first phase of the study. In the second phase of the study, fluid administration was stopped and high dose of diuretic (Fusid) was administered for achieving gradual decongestion. The experiment lasted on average 12 hours (3 hours instrumentation + 9hours experiment). The rate of infusion was 450ml fluids/15 min, about 1800-2000 ml/hour. The first 3 sheep were used for proof of concept of the feasibility of the Waveform measurements for predicting LVEDP. In these animals measurements were performed every 15 minutes, and each sheep averaged -40 documented cycles. In the last 2 sheep we focused on the threshold of detection of increase in LVEDP. Therefore, measurements were performed every 4-5 minutes (administration of 120-150 ml of fluid) during the congestion period in order to document EARLY CONGESTION. Thereafter, measurements continued every 15 minutes, similar to the previous protocol.

Results: Figure 10 presents typical waveforms during baseline, congestion and decongestion. The waveforms morphology and P (-0.900 and -0.903) were very similar during baseline and decongestion, with identical LVEDP (9mmHg), despite the fact that heart rate during baseline was 103/min and after decongestion 165/min. The P and LVEDP during congestion cycle were -0.334 and 29 mmHg, respectively (taken from recordings of sheep no 2).

For each sheep, the calculated waveform parameter P for estimation of LVEDP is carried out by quadratic fit over the full experiment duration. The following graph (Figure 11) shows the measured vs. estimated LVEDP for the five sheep.

In two sheep (4 & 5) the early congestion period included almost continuous measurements every 4- 5 minutes. Zooming in on the early congestion period in these two sheep results Figure 12.

The standard deviations of difference between the estimated and actual LVEDP for the early congestion period in the two sheep are 2.2 mmHg and 1.1 mmHg.

The standard deviations of the difference between the estimated and actual LVEDP in five sheep (excluding sheep 4 decongestion period) are: 2.7 mmHg, 3.5 mmHg, 2.8 mmHg, 3.0 mmHg and 2.3 mmHg.

The combined data points for estimated vs. measured LVEDP for five sheep are shown in Figure 13.

The linear fit shows an almost unity slope and high correlation (R ² > 0.8). TThe full thoracic impedance (TR) is also measured. The correlation of TR with LVEDP is good for the congestion period, with R ² > 0.9. During the decongestion period TR stays at almost the same level and does not follow decreasing LVEDP. The correlation over the full experiment duration falls to R ² ~ 0.2. Thus, full thoracic impedance is overall a poor candidate to estimate and track LVEDP changes. Figure 14 shows estimated vs. measured LVEDP based on TR.

Measuring the bio-impedance waveform and tracking the change in waveform morphology provides a sensitive measure of LVEDP changes in the five sheep included in the study. Although in the example, only a single waveform parameter is presented to show the correlation with LVEDP changes, but additional waveform morphology measures can also correlates to LVEDP - such as timing of critical points, slopes, relative areas, etc.

The animal experiments show the waveform changes are significant and repeatable in all phases of the study: baseline - congestion - decongestion, with estimation error in the range of 3 mm Hg of measured LVEDP for the overall study (congestion and decongestion periods). The waveform parameter serves as a surrogate measure of LVEDP with good correlation - R ² > 0.8.

Continuous measurement during the early congestion period, where small increments in cardiac filling pressures (LVEDP) are caused by administration of small amounts of fluids show very high sensitivity to congestion onset, on the order of 1-2 mmHg. These findings provide a firm basis to design human tests with a similar approach - measuring bio-impedance waveform and correlating changes in morphology to measured LVEDP or PCWP changes.

Example 4: Clinical feasibility studies

The clinical feasibility studies were preformed to explore the feasibility of bio-impedance methodology to detect changes in LVEDP in patients undergoing diagnostic left heart cardiac catheterization. The pilot phase of the study was planned in advance to be based on analysis of the data in the first 5-10 subjects.

Study Design: This was an observational, single-center, prospective, opened label, non-randomized, and comparative clinical investigation. The study was conducted in the catheterization laboratory of Hadassah Hebrew University Hospital, Jerusalem, Israel, during routine elective diagnostic left heart catheterization procedures.

During the catheterization procedure, the investigational non-invasive measurements were recorded simultaneously with the invasive LVEDP measurements. The LVEDP measurements served as the gold standard to the investigational bio-impedance measurements. LVEDP was measured with high fidelity Mikro-Cath ^tm (Millar Inc., USA). The Mikro-Cath™ disposable pressure catheters use pressure sensor technology to record precise measurements of LVEDP, which is not affected by motion artifacts or body position.

Data were collected simultaneously from both the investigational device and the reference device at baseline and following predefined physiological or pharmacological procedures which aimed to induce changes in LVEDP. The physiological maneuvers included hand grip, leg rising and the Valsalva procedure. The planned pharmacological procedure consisted of intravenous administration of nitroprusside. It could be performed only when clinically indicated, in patients with elevated LVEDP and possibly pulmonary hypertension, were information on reversibility of the elevated pressures had to be evaluated. Each recording was repeated 3-4 times.

In this study, each subject served as his/her own control.

Primary endpoint: The primary and only predefined end point was the correlation between the bio-impedance waveform measured by the investigational device and changes in LVEDP measured by the Millar catheter.

Subject Recruitment and Screening: Subjects were recruited from patients scheduled for diagnostic left heart catheterization in the catheterization laboratory. Subjects were screened for eligibility.

Inclusion Older than 21 years

Criteria Able to have at least one of the provocative maneuvers which alter the

LVEDP during the diagnostic heart catheterization procedure

Capable and willing to give informed consent

Exclusion Patients undergoing urgent catheterization, in unstable or life Criteria threatening conditions

Any electrical Implanted Electronic Device (cardiac or non-cardiac)

If echocardiogram was not performed during the last 12 months or there was a change in the clinical condition of the patient since the last available echocardiogram.

Known hypersensitivity or allergies to standard ECG electrode gel or adhesive or skin lesions that prohibit adequate electrode placement

Breast implants

Unable or unwilling to participate in study procedures

Women known to be pregnant

Mentally handicapped, prisoners, or legally incompetent

Any reasons making the patient a poor candidate in the opinion of the investigator Number of Subjects and Groups: An interim analysis was planned to be done after the first 5-10 subjects. In total 30 evaluable subjects were planned to be enrolled in the completed study The enrollment of the subjects was guided by the principle of having 3 possibly similar sized groups, based on clinically/echo cardiographically expected values of LVEDP. Group 1 n=10 subjects with LVEDP > 15 mmHg and predominantly systolic dysfunction (LVEF<45%) undergoing diagnostic left and possibly right heart catheterization Group 2 n=10 subjects with LVEDP > 15 mmHg and with a normal/preserved systolic function (LVEF>45%) undergoing diagnostic left and possibly right heart catheterization Group 3 n=10 subjects with normal LVEDP <\2 mmHg undergoing diagnostic left and possibly right heart catheterization

Investigational Procedure: The bio-impedance investigational device and its disposable ECG electrodes were connected to the subject during the preparations for the cardiac catheterization procedure.

Initially, a baseline measurement was recorded simultaneously by the investigational device and LVEDP was measured using the high fidelity catheter (repeated 3 times).

A second simultaneous measurement was done following raising the legs of the participant on a 25° triangular mattress (repeated 3 times). Alternatively, a second simultaneous measurement was done following a hand grip of both hands (repeated 3 times). A third simultaneous measurement was done during Valsalva maneuver performed by the participant (repeated 3 times). The LVEDP tracing were recorded on paper kept as a source document. The bio-impedance recordings were saved as a CSV files in the computer and analyzed with MATLAB software. Interpretable recordings (LVEDP and waveforms) were required to show at least 10-20 consecutive stable morphology and values. The quality of both LVEDP and waveforms was classified as high, medium and low.

Bio-impedance measures voltage between electrodes. Since the applied current is kept constant, the measured voltage is a measure of body impedance, or resistance. The measured waveform is the temporal change of this resistance during a cardiac cycle. Hence the individual waveforms have 'resistance' as the vertical axis. Calculated waveform parameter is the integral of resistance overtime divided by another integral of resistance over time.

Statistical Methodology: It was estimated that a sample size of 30 subjects will enable the detection of a correlation coefficient of 0.85 or higher with 90% power at a 5% level of significance. Statistical analyses were performed using SAS® v9.3 or higher (SAS Institute, Cary NC, USA).

The required significance level of findings was equal to or lowers than 5%. Where confidence limits were appropriate, the confidence level was 95%. Baseline values were defined as the last valid value prior to study start. All statistical analyses of safety and performance measures were descriptive in nature. Continuous variables will be summarized by a mean, standard deviation, minimum, median and maximum, and categorical variables by a count and percentage. Relationships between two continuous variables will be assessed with a correlation coefficient. If multiple measurements were taken in a single subject, statistics were appropriately modified to accommodate the within subject correlation.

Results:

Patients and procedures

There were 15 candidates to be enrolled in the study. Of these, 8 did not have a simultaneous LVEDP/investigational device measurement: 2 subjects were screen failures, in 1 subject the catheterization was prematurely terminated due to arrival of a patient with acute infarction who required the attention of the team, in 4 subjects the low quality of LVEDP recording did not fulfill the technical criteria for inclusion in the study and in 1 patient the investigational device malfunctioned. Therefore the results of the pilot study are based on analysis of recordings in 7 subjects.

LVEDP Measurements

The LVEDP recordings (see Figure 15A) were interpreted for numerical value and quality of the recording, by three independent reviewers. The quality of the LVEDP recordings was classified as high (H), medium (M) and low (L) based on the stability, the length and the uniformity in morphology of the pressure waves. The quality of the pressure recordings was influenced by the intra-cardiac position of the catheter, presence or absence of VPBs and the compliance of the subject with holding his/her breathing for 10 to 20 seconds, as well as with the right performance of the physiological maneuver (hand grip and Valsalva) during the procedure. We found that there was a good correlation between the quality of the bio-impedance waveforms and the quality of the LVEDP recordings. We learned that bio-impedance waveforms which were recorded concomitantly with medium and low quality pressure waves were also of low quality. An example of high quality LVEDP tracing is presented in Figure 15A. In the same subject, an example of poor quality LVEDP tracing is shown in Figure 15B. Both recordings were performed during leg raising (LR).

Figure 16 summarizes the LVEDP values and their quality in the 7 subjects. In each state (baseline, legs up, Valsalva) we took three consecutive repeated recordings of about 10 to 20 seconds and had between them short time intervals of approximately 1 minute. In few cases the PI decided to perform 4 measurements. Only high quality LVEDP measurements were included in the analysis. Waveform Analysis

The bio-impedance waveform recordings were recorded and saved as CSV files as described in Example 1. The waveform data collection and analysis tool used was a MATLAB program that loads CSV measurement files. The bio-impedance waveform and the ECG were recorded simultaneously. The program identified the peaks of the R waves timing from the ECG and separated the bio-impedance waveform into individual cardiac cycles.

When reviewing the bio-impedance waveforms we can see a systolic phase and a diastolic phase, similarly to the appearance of pressure waves and ventricular volume curves (as shown in Figure 1).

Figure 17 shows the individual cycles recorded, which is similar as shown in the example 1. The small red circles mark the peak of the R wave that separates each cycle from the next one. The lower graph shows in grey all the superimposed cycles acquired during one episode of data recording and in red their average value. The spread of the grey lines around the red average is a measure of the variation of waveform shape during the measurement period. The main contributors to the variation in waveform shape were the respiratory cycle and arrhythmias (i.e. VPBs). These were also the major reasons for exclusion of certain waveform recordings from analysis. In the example given, the mild variation due to changes in chest volume was considered to be acceptable of amplitude and the waveform recording was included in analysis.

For each measurement cycle the collected waveforms were reviewed and outliers were manually filtered out of the average waveform calculation. The review included identification of periods where the subject held his/her breath, and also constancy of concomitant LVEDP recordings. Each measurement session lasted for 10 - 20 seconds.

Following exclusion from analysis of the handgrip and of the Valsalva recordings, changes between bio-impedance waveforms from baseline to legs up were correlated with changes in LVEDP measurements (mmHg) during the same manoeuver.

The following graphs show the SUPERIMPOSED INDIVIDUAL RECORDINGS for each of the 7 evaluated subjects. During each individual measurement cycle (for example, 3 baseline measurements) approximately 10 to 20 waveforms are continuously recorded. Each measurement cycle is graphically presented by 2 consecutive waveforms which represent the overlay of all beats recorded during that specific measurement cycle. Each measurement cycle provided one median LVEDP measurement which appears in the upper part of the waveform graph.

The measurement cycles are organized in three horizontal rows. The first row shows the 3 baseline, the second the 3 legs up and the third shows the 3 Valsalva maneuver recordings. Empty graphs indicate the exclusion of that measurement from analysis due to inadequate quality of LVEDP, waveform or both measurements.

The second series of graphs represent the overlay of the COMPOSITE MEDIAN OF THE RECORDINGS of the same cycles of measurements (i.e. in Subject 5: 3 baselines, 3 legs up, and 3 Valsalva procedures). The corresponding LVEDP values measured during each recording appears in the box situated on the right upper area of the graphs.

This paired graphic presentation (e.g. Figures 18A and 18B in Subject 5) allows a person to appreciate the reproducibility and qualitative changes in waveforms morphology with different LVEDP values. Changes in LVEDP were minor during the legs up maneuver but were very significant during Valsalva. Concomitantly, only subtle changes occurred between the baseline and the legs up waveforms' morphology but the changes were dramatic during the Valsalva maneuver. It is also noticeable that in cases where there was no change in LVEDP during the legs-up maneuver, there was no change in the shape of the waveforms.

After calculating the median for each measurement cycle to generate a representative waveform, all these mean representative waveforms were collected and normalized each one of them (Y = -1 to +1, mean = 0). In the next step, they are divided by the corresponding LVEDP into "low" and "high" LVEDP groups, and created two median waveforms for each subject ("Low"; usually baseline, appears in the graph in blue, and "high" usually post maneuver measurements appear in green) (Figure 19).

Then the differences between the waveforms is further analyzed. The end result of this calculation was coined as the 'waveform parameter' . This gives a measure that is between 0 - no difference between waveforms - to 1, the waveforms differ substantially.

This technique enables one to QUANTIFY THE CHANGE IN WAVEFORM MORPHOLGY as a numerical value and correlate it with its corresponding change in LVEDP value (see Figure 20 and 21). A Pearson Correlation of 0.879 with p=0.009 is found.

In Figure 22 each point on the graph represents one evaluable subject. X axis: represents the change in the LVEDP (Δ) (the lower LVEDP measurement value was subtracted from the higher LVEDP measurement value). Y axis: The bio-impedance waveform parameter. This analysis reveals that LVEDP change as low as 2 mmHg was detected by our system and methodology.

The initial clinical feasibility pilot studies includes 7 patients who underwent routine cardiac catheterization. The investigational device detected even small changes in LVEDP, in the range of 2-7mmHg. These results provide a proof of concept of the utility of the bio-impedance waveform in detecting changes in LVEDP. More subtle changes in LVEDP is the focus as found during the legs up maneuver. This was achieved by elevating the legs on a triangular mattress at 25°. No subject's cooperation was required during this maneuver. Assuming that there was no or there was very little influence on the chest anatomy of the subject, therefore this maneuver is reliable and independent of the collaboration of the evaluated subjects.

The main findings of this initial feasibility pilot study in humans were:

waveform measurements were repeatable in the same measurement cycle, in recurrent measurements cycles, at different time intervals, in the same subject, during the same maneuver;

small changes in LVEDP corresponded with small changes in waveform morphology on quantitative analysis; on the other hand lack of change in LVEDP showed good reproducibility of the waveform under different conditions in the same subject;

changes as small as 2mmHg in LVEDP induced detectable and measurable changes in the bio-impedance waveform morphology;

the changes in waveform morphology were similar at identical LVEDP change (Δ), regardless of the initial value of LVEDP (baseline LVEDP ranged from 11 to 23mmHg in the 7 patients).

It should be apparent from the foregoing that an invention having significant advantages has been provided. While the invention is shown in only a few of its forms, it is not just limited but is susceptible to various changes and modifications without departing from the spirit thereof.