A method of treating a patient having heart failure and a method of selecting a patient for a splanchnic ablation procedure

Abstract

Techniques for selecting and / or treating patients with heart failure, such as heart failure with preserved ejection fraction (HFpEF) are provided. Diagnostic tests are used to determine whether a patient is preload sensitive or preload dependent based on metrics such as delta pulse pressure (dPP) and delta heart rate (dHR). Patients may be selected for treatment based on such a determination.

Description

A METHOD OF TREATING A PATIENT HAVING HEART FAILURE AND A METHOD OF SELECTING A PATIENT FOR A SPLANCHNIC ABLATION PROCEDUREINCORPORATION BY REFERENCE

[0001] This application claims priority to U.S. Provisional Application No. 63 / 703,530, Filed October 4, 2024, the entire contents being hereby incorporated by reference.

[0002] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0003] This disclosure is related by subject matter to U.S. Pub. Nos. US2019 / 0175912, US2019 / 0183569, US2021 / 0220043, Patents US 10,376,308, US 10,207,110, US1 1672595B1 , App. Nos. 16 / 510,503, 62 / 836,720, 62 / 837,090, 62 / 864,093, PCT / US2019 / 15400, PCT / US2020 / 038934, PCT / US2021 / 014001 , and PCT Pub. Nos. WO201 8 / 023132, WO2019 / 1 18976, WO / 2020 / 257763, and WO2022 / 261022 all of which are incorporated herein by reference in their entirety for all purposes.FIELD

[0004] The inventions herein relate to medical diagnosis or identification of a patient who may benefit from a medical procedure. In particular, the inventions relate to diagnosis or identification of a patient who may benefit from a medical procedure having an effect (e.g., increasing splanchnic venous capacitance) on shifting blood volume distribution to treat heart failure or hypertension. For example, the medical procedure may include blocking or ablating a thoracic splanchnic nerve (e.g., greater splanchnic nerve, lesser splanchnic nerve, least splanchnic nerve, or their roots, herein referred to as GSN Ablation) with an interventional procedure to treat heart failure or hypertension or their symptoms, examples of which are in publications listed in the Incorporation by Reference section.

[0005] Medical procedures such as GSN ablation, or similar procedures, may benefit a large population suffering from disease. There remains a need for techniques to identify patients who may best benefit from such procedures so that procedural outcomes may be improved and patients may be better served.- I of 30 -BRIEF DESCRIPTION OF THE DRAWINGS

[0006] FIGURE 1 shows results of the responder assignment scores after 6 months for lead-in, sham and treatment groups. Table A demonstrates that the percentage of responders and super responders is higher in included lead-in and treatment subgroups compared to the sham group. Table B demonstrates the distribution of subjects in all responder score groups.

[0007] FIGURE 2 are histograms showing distribution of responder score at 6 months compared to baseline score.

[0008] FIGURE 3 is a flow chart of patient selection criteria to be classified as a good responder to GSN ablation.

[0009] FIGURE 4 is a Venn diagram representation of the patient selection criteria to be classified as a good responder to GSN ablation.

[0010] FIGURE 5 is the distribution of responder scores for preload sensitive patients in relation to dBP.

[0011] FIGURE 6 is the distribution of responder scores for preload dependent patients in relation to dBP.DETAILED DESCRIPTION

[0012] Disclosed herein are systems, devices, and / or methods for medical diagnosis or identification of patients who may benefit from a GSN ablation or blocking procedure.Physics of load on body when standing

[0013] When a healthy patient transitions from a supine or sitting to standing position, gravity pools blood in the legs and abdomen through both veins and arteries. This results in a decrease in blood pressure (BP) and venous return of blood to the heart, ultimately leading to reduced cardiac stroke volume (SV) and cardiac output (CO). The baroreceptors in the carotid and aortic walls detect the BP reduction through stretch. This signals the activation of the sympathetic system to increase heart rate (HR), contractility and vasoconstriction.

[0014] This disclosure includes characterizing physiological changes, such as a change in pulse pressure (PP), due to the stress of assuming an upright position from a sittingor lying position as a potential identifier of a good or bad responder to greater splanchnic nerve (GSN) ablation.Cardiac loading

[0015] Cardiac preload is the amount of ventricular stretch at the end of diastole. In other words, it is the ventricles getting ready for the next contraction during systole. Cardiac afterload is the amount of resistance the heart has to overcome to open the aortic valve and push blood through systemic circulation.Heart failure disease progression and patient phenotypes

[0016] The splanchnic bed is a crucial circulatory reservoir. It modulates how blood is stored at rest to take stress off the heart and has the capability to recruit more blood when needed, such as during physiological stress or exercise. The GSN modulates preload via splanchnic venous compliance, and can be disrupted as a result of GSN hyperactivity. Hyperactive GSN activity leads to too much venous blood return to the heart, resulting in the heart muscle working too hard. When the cardiac muscle is overworked, it can become thicker and stiffer which results in reduced CO. Additionally the loss of splanchnic compliance can reduce the body’s ability to recruit blood when blood is needed by the body to respond to physiological stress due to the limited capacity of the heart.

[0017] There are two main patient phenotypes. The first is preload sensitive patients who experience over shifting of blood volume during physiological stress. These patients can still utilize compensatory mechanisms to augment CO during physiological stress and pool blood in the splanchnic bed. The second patient phenotype includes those who are preload dependent. These are patients with compensatory mechanism loss and have more difficulty augmenting CO. These patients experience chronic venoconstriction, are unable to pool blood in the splanchnic bed and thus have a limited reservoir to recruit blood volume. They are more dependent on heart rate and contractility to augment CO, while experiencing more significant structural changes in the cardiac muscle.

[0018] The progression of GSN hyperactivation starts with preload sensitive patients experiencing transient GSN hyperactivity. Eventually, these patients can experiencechronic venoconstriction and lose splanchnic compliance due to the GSN being chronically activated. These patients then progress to preload dependent patients, where the heart experiences remodeling due to the increased blood volume and inability to augment CO.GSN ablation goals

[0019] GSN ablation or blocking in heart failure (HF) patients can change the preload and take the load off the heart. The hypothesis is that by selectively reducing sympathetic nervous system (SNS) activity to splanchnic reservoir by blocking the GSN, there will be a reversal of both chronic and acute venoconstriction. Ultimately, by blocking the right GSN and preserving the left GSN, patients will benefit from improved vascular compliance and lower pulmonary and cardiac filling pressures at rest and with exercise. The result would be improved exercise tolerance, quality of life, cardiac remodeling, and reduction in HF hospital admissions, providing a clinical benefit for patients with HFpEF. However, only specific heart failure with preserved ejection fraction (HFpEF) patients can benefit from GSN ablation.

[0020] GSN ablation or blocking procedures may include decreasing or preventing nerve signal transmission through one or more thoracic splanchnic nerves (e.g., greater, lesser or least splanchnic nerve or their roots). This may involve blocking or ablating a thoracic nerve on only one side of the patient, or both sides. Blocking of the nerve may include any action the temporarily or permanently decreases or prevents nerve signal transmission, for example, electrically blocking of a nerve with electrical signals delivered by electrodes (e.g., implanted electrodes, surgically implanted electrodes, transvascular electrodes positioned in an intercostal vein or azygos vein, electrodes positioned on or near a thoracic splanchnic nerve with a thoracoscopic procedure, implanted electrodes powered by an implantable power and control source). Blocking of the nerve may include stunning the nerve with temperature (e.g., cooling the nerve below body temperature or below a nerve blocking threshold such as 10 degrees Celsius or lower), mechanically fatiguing the nerve, or chemical nerve inhibition). The nerve may be ablated to decrease or prevent nerve signal transmission. For example, a nerve ablation procedure may include a percutaneously delivered RF ablation probe, a transvascular ablation catheter, a thoracoscopically delivered ablation probe. Examplesof transvascular ablation catheters may include those disclosed in the publications listed in the Incorporation by Reference section, such as catheters that deliver an ablation energy from within an intercostal vein, within and azygos vein, or that penetrates a vessel wall and positions an extravascular ablation element near a target nerve. Ablation energy modalities may include radiofrequency, electroporation, cryogenic, ultrasound, thermal, chemical, or laser for example.

[0021] Preload sensitive patients experience heart decongestion and have the ability for SV increase on standing, which is concurrent with the classical description for standing HF patients. These patients benefit from gravity pooling blood into the abdomen, thus demonstrating a more compliant splanchnic system. Preload sensitive patients benefit from GSN ablation because they are functional shifters. GSN ablation can restore the normal function of the splanchnic bed and reduce overshift with exercise.

[0022] Preload dependent patients have advanced structural disease, and / or severe congestion with the inability to increase splanchnic capacity to accommodate blood with standing. These patients experience a decrease in SV when standing. Ultimately, preload dependent patients who cannot increase HR do not benefit from GSN ablation because they cannot augment CO.

[0023] Delta pulse pressure (dPP) is the change in pulse pressure a patient experiences when they go from laying down to standing. An orthostatic hypotension measurement is assessed to analyze the cardiovascular system’s response to the physiological stress as an indication of the disease state. The orthostatic hypotension measurement is taken by a non-invasive BP cuff. The patient is instructed to lie down for five minutes before the first BP recording is taken. The BP cuff measures and records the patients’ systolic pressure, diastolic pressure and HR measurement. The patient then sits briefly before standing for one minute. After one minute of standing, the BP cuff takes a second recording. The patient then stands for three minutes and the BP cuff takes the third and final recording.

[0024] dPP provides a composite index of several variables such as neurogenic / autonomic function, chronotropic competence, measure of peripheral resistance, measure of arterial stiffness and preload sensitivity. These variables give insight into how a particular patient responds to changes in preload and afterload. Fromthis analysis, dPP provides a reliable way to determine the phenotype of the patient, and therefore predict whether GSN ablation would be beneficial or harmful.

[0025] Patients who are preload sensitive experience a widening pulse pressure on standing and a subsequent positive dPP (dPP>0). These patients experience a systolic pressure increase that is more than the diastolic pressure increase. This indicates that even if the diastolic pressure increased when the patient stood, the heart was able to pump more to increase stroke volume and recruit more blood. Further, the left ventricle (LV) was well functioning. The LV in these patients is able to deal with the preload increase and output more blood, indicating that these patients would be good responders to GSN ablation due to their ability to augment CO.

[0026] Patients who are preload dependent experience a narrowing of pulse pressure on standing and a subsequent negative dPP (dPP<0). The key drivers of symptoms for these patients are structural cardiac muscle changes and progression of diastolic dysfunction. Additionally, these patients experience a diastolic pressure increase that is more than the systolic pressure increase. This indicates that the aortic valve is closed for longer in these patients, resulting in an increased back pressure. As such, the left atrium (LA) is unable to fill the LV. Subsequently, SV is reduced with each heartbeat and CO decreased on standing, indicating that these patients would not be good responders to GSN ablation due to their inability to augment CO. It is key to note however that if preload dependent patients have adequate chronotropic competence, they could increase their HR to augment CO instead. As such, chronotropic competence or delta heart rate (dHR) is a crucial predictor of response for preload dependent patients.Human StudyMethods

[0027] A randomized study examined a total of 185 human subjects with heart failure with preserved ejection fraction (HFpEF). The purpose of the study was to assess the safety and initial effectiveness of catheter-based unilateral ablation of the right GSN in subjects having HFpEF. A total of 150 subjects were divided into sham (control) and treatment groups with a 1 :1 randomization scheme. The sham procedure was utilized to understand any potential placebo effect. A third group of 35 subjects, known as thelead-in, were also given treatment with no sham effect. Each subject was assessed with the following tests, in addition to an orthostatic hypotension assessment as described in earlier. Refer to the example below in table 3 for a detailed protocol synopsis. Subjects were assessed with three main methods before the trial to determine a baseline score, and then at subsequent follow-up periods after 1 month, 3 months, 6 months, 12 months. The tests were the Kansas City Cardiomyopathy Questionnaire (KCCQ), Six Minute Walk test (6MWT) and N-Terminal Pro-B-Type Natriuretic Peptide (NTProBNP) test. Responder assignment to determine the subjects’ response to the trial was subsequently based on the sum of the KCCQ, 6MWT and NTproBNP responder scores.Kansas City Cardiomyopathy Questionnaire (KCCQ)

[0028] The KCCQ assessment is a 23-item self-administered questionnaire used to measure a subject’s perception of their own health status. This test includes questions about HF symptoms, social and physical function and quality of life. The score is tracked over time. The subjects were given the questionnaire before the trial and at 4 follow-up periods throughout the trial to assess their response. Every 10-point increase in KCCQ score for a subject over time yields 1 positive responder score point, while every 10-point decrease in KCCQ score for a subject over time yields 1 negative responder score point. The clinical threshold for success is for a subject to show a 5% improvement of scores over time. For the trial in question, the sham group saw an average 15-point increase over time. Therefore, the first 20-points recorded by subjects in the trial do not indicate any improvement. In other words, a subject needs to show at least a 20 point improvement to get 1 positive point. Reference Table 1 , below, for a summary of the responder score point system.Six Minute Walk Test (6MWT)

[0029] The 6MWT is a distance measurement to analyze how far a subject can walk in a 6-minute period. To qualify for the trial in question, the subject had to be able to walk between 150 m and 450 m. If a subject could walk farther than 450 m in 6 minutes, the subject was considered ‘not sick enough’ and was excluded from the trial. On the other hand, if participants walked less than 150 m in the 6 minute time interval, the participant was considered ‘too sick’ and was excluded from the trial. The score is tracked overtime. The subjects were given the questionnaire before the trial and at 4 follow-up periods throughout the trial to assess their response. Participants needed to demonstrate at least a 25 m change in distance to receive a responder score point. Every 25 m increase in distance for a subject over time yields 1 positive responder score point, while every 25 m decrease in distance for a subject over time yields 1 negative responder score point. Reference Table 1 , below, for a summary of the responder score point system.N-Terminal Pro-B-Type Natriuretic Peptide (NTProBNP) Test

[0030] The NTProBNP test measures levels of N-terminal pro-B-type natriuretic peptide in the blood, and is often used for diagnosing acute decompensated heart failure. Pro- B-type natriuretic peptide (proBNP) is secreted by cardiomyocytes in response to increased volume and pressure, and is cleaved into two fragments, the active C- terminal BNP and the inert N-terminal pro-BNP. Therefore, NTProBNP is a common marker of stretch. With increased volume, the body experiences an increase in NTProBNP levels. Higher NTProBNP levels may be a sign of heart failure. The score is tracked over time. The subjects were given the test before the trial and at 4 follow-up periods throughout the trial to assess their response. Participants needed to demonstrate at least a 20% change in NTProBNP levels to receive a responder score point. Every 20% decrease in NTProBNP levels for a subject over time yields 1 positive responder score point, while every 20% increase in NTProBNP levels for a subject over time yields 1 negative responder score point. Reference Table 1 , below, for a summary of the responder score point system.B031]Table 1 is a summary of the responder score point system for the KCCQ, 6MWT and NTproBNP assessments.Responder Score

[0032] Responder assignment was subsequently based on the sum of the KCCQ, 6MWT and NTproBNP responder scores. Negative responders with a summed response score of less than or equal to -2 represented subjects who were feeling worse, walking less and had high NTProBNP levels after the trial compared to their baseline score. Non-responders with a summed response score of -1 to 1 represented subjects who fundamentally did not change after the trial compared to their baseline score. For example, these subjects either experienced an unchanged score in all three assessments or they experienced an increase in KCCQ score but an equal decrease in 6MWT score. Responders with a summed response score of 2 to 4 represented subjects who had clinically significant improvement in KCCQ and 6MWT, with lower NTProBNP levels after the trial compared to their baseline score. Super responders with a summed response score of greater than or equal to 5 represented subjects whoexperienced a substantial increase in KCCQ scores, were walking significantly further and had a large decrease in NTProBNP levels after the trial compared to their baseline score. Reference Table 2, below, for a summary of the sum of responder score points.

[0033] Table 2 is a summary of the sum of responder score points corresponding to the four responder classifications, negative responder, non-responder, responder and super responder. Responder assignment is based on a sum of KCCQ, 6MWT and NTproBNP responder scores from table 1 .Results of study

[0034] Each of the three groups, lead-in, sham and treatment, were further separated into two groups, included and excluded, based on the inclusion and exclusion criteria outlined in table 3 below.

[0035] The hypothesis behind GSN ablation is that by blocking the right GSN and preserving the left GSN, patients will benefit from improved vascular compliance and lower pulmonary and cardiac filling pressures at rest and with exercise. The result would be improved exercise tolerance, quality of life, and cardiac remodeling. Thus, these results can be used to examine the clinical efficacy of the Axon system by comparing baseline and follow-up KCCQ, 6MWT and NTproBNP responder scores.

[0036] Results of the responder assignment scores after 6 months showed a higher percentage of responders and super responders in the included subgroup for lead-in and treatment groups versus the sham group. This is demonstrated in Figure 1 . Comparing the distribution of responder scores after 6 months to the baseline scores, there was a noticeable treatment effect in the ‘included’ subgroup as seen in Figure 2.

[0037] In general, the patients that responded to GSN ablation seemed to have an improved or maintained response score over time. There were few cases of response scores declining.Data analysis

[0038] Analysis was retroactively conducted on the study data to assess correlations between patient’s response to treatment and various parameters associated with their pre-treatment condition.

[0039] Firstly, E / A ratio, TAPSE and RVFAC were examined as these are known indicators of diastolic dysfunction and commonly used prognosis values. The E / A ratio is a marker of the function of the left ventricle of the heart, where E represents the passive filling wave from LA to LV and A represents the filling wave as atria contract. Tricuspid Annular Plane Systolic Excursion (TAPSE) is a measure (in millimeters) of how much the ring of the tricuspid valve moves up and down with each heartbeat on an echocardiogram. Right Ventricular Fractional Area Change (RVFAC) represents the change in cross sectional area of the RV per beat on an echocardiogram.

[0040] Empirical analysis found a significant correlation that indicated that patients who responded well (as defined by the rating system shown in Figure 1 ) in the included subgroup, had E / A ratio 0.5 < E / A < 2, TAPSE > 1 .2 and RVFAC > 25%, and conversely subjects who did not respond well had E / A > 2, TAPSE < 1 .2 cm and RVFAC < 25%. The assessments are the first set of inclusion criteria a participant has to meet in order to be classified as a potential responder as seen in Figure 3.

[0041] Secondly, analysis of dPP and dHR between responders and non-responders were conducted. The analysis revealed a discovery that dPP was significantly different between the two patient groups. An empirical analysis revealed a threshold of -10% between the groups and a statistical analysis indicated a threshold of -7%. Although the lower range began at -7%, in order to accommodate any margin for error and be conservative, -10% was the selected threshold for dPP. Patients can be divided into two groups, dPP < -10% (excluded non-responder) and dPP > -10% (included responder).

[0042] Additionally, preload dependent patients (dPP<0) with adequate chronotropic competence, can increase their HR to pump at a faster beat per minute (BPM) to augment CO. These patients can be further divided into two groups, dHR < 15 BPM (excluded non-responders) and > 15 BPM (included responders) after an empirical analysis of the responder vs non-responder data. These patient selection criteria to be classified as a responder to GSN ablation are summarized in Figure 4.Treatment Group Outcomes

[0043] Once the subgroup only included patients meeting E / A (E / A < 2, optionally, 0.5 E / A < 2), TAPSE (> 1 .2) and RVFAC (> 25%) requirements, dPP and dHR were examined. As described in a previous section, patients can be preload sensitive (dPP>0) or preload dependent (dPP<0).

[0044] In preload sensitive patients (dPP>0), E / A, TAPSE and RVFAC screened out 9 / 18 treatment patients. These criteria alone were sufficient to screen out the negative responders with a positive PP, regardless of dBP. Of the remaining 9 patients, 8 were responders and 1 was a non-responder. There were no negative responders in this group. Data for the preload dependent patients is in Figure 5.

[0045] In the preload dependent patients (dPP<0), E / A, TAPSE and RVFAC screened out 9 / 25 treatment patients. These criteria alone were not sufficient to screen out the negative responders with an increase in dBP. Of the remaining 16 patients, 9 were responders, 6 were negative responders and 1 was a non-responder. Of the 9 responders, 6 had a dPP greater than -10 and 3 had dPP less than -10. 2 of the responders with dPP less than -10 had a dHR of 15. All the negative responders experienced dPP less than -10. The non-responder had a dPP less than -10 and a dHR less than 15. Data for the preload dependent patients is in Figure 6.

[0046] Based on these 4 groups and the data in Figure 5 and 6, it is clear that the criteria seemed to work well with the exception of the PP<0 with DdBP >0. It is in this analysis where the PP<-10 with change in HR becomes evident.

[0047] Overall, the retroactive statistical analysis led to the generation of a patient selection equation to indicate E / A, TAPSE RVFAC, dHR and dPP requirements as summarized in Equation 1 , optionally, the E / A requirement may be further refined as in Equation 2, wherein patients that meet these requirements may be selected for treatment with a GSN ablation procedure, and / or patients that do not meet these requirements may be rejected for treatment with a GSN ablation procedure.Equation 1.

[0048] E / A < 2 & TAPSE > 1 .2 cm & RVFAC > 25% & ((dPP < -10% & HR > 15 bpm) || dPP > -10%)Equation 2.

[0049] 0.5 > E / A < 2 & TAPSE > 1 .2 cm & RVFAC > 25% & ((dPP < -10% & HR > 15 bpm) || dPP > -10%)

[0050] An alternative method of selecting patients for GSN ablation may include excluding patients who present as orthostatic hypotensive or orthostatic hypertensive. For example, orthostatic hypertension may be defined as a sustained increase in systolic blood pressure of at least 20 mmHg and / or diastolic blood pressure of at least 10 mmHg within 3 minutes of transitioning from a sitting or supine position to an upright position, which may be assessed with a tilt table test; and orthostatic hypotension may be defined as a systolic blood pressure decrease of at least 20 mm Hg or a diastolic blood pressure decrease of at least 10 mm Hg within 3 minutes of transitioning from a sitting or supine position to an upright position, which may be assessed with a tilt table test. Patients who do not present as orthostatic hypertensive or hypotensive may be selected for a GSN ablation procedure.

[0051] The following is a Human Trial Protocol Synopsis. This study was conducted in compliance with the World Medical Association Declaration of Helsinki, ISO 14155:2020, ICH-GCP Guidelines, and FDA regulations, 21 CFR Parts 11 , 50, 54, 56, 812.

[0052] The following are examples that may be implemented in accordance with one or more embodiments.

[0053] In a first embodiment, a method of patient selection and treating one or more symptoms of heart failure, the method comprising: performing one or more tests on a patient; determining if the patient is preload sensitive or preload dependent based atleast partially on the results of the one or more tests; in response to determining that the patient is preload sensitive and not preload dependent, selecting the patient for a treatment to treat the one or more symptoms of heart failure; and performing a treatment procedure on the selected patient to treat the one or more symptoms of heart failure.

[0054] In a second embodiment according to the first embodiment, wherein performing the treatment comprises ablating a greater splanchnic nerve (GSN) of the patient, optionally only one of a right GSN and left GSN and leaving unablated the remaining right or left GSN of the patient.

[0055] In a third embodiment according to the second embodiment, wherein ablating the GSN comprises intravascularly delivering an ablation apparatus to an intercostal vein (ICV), optionally a T9-T1 1 ICV.

[0056] In a fourth embodiment according to the third embodiment, wherein ablating the GSN comprises delivering an ablation device through a wall of the ICV, examples of which are described in U.S. Patent 11672595B1 .

[0057] In a fifth embodiment according to the third embodiment, wherein ablating the GSN does not include delivering an ablation device through a wall of the ICV.

[0058] In a sixth embodiment according to any of the first to fifth embodiment, wherein performing one or more tests on a patient comprises obtaining blood pressure readings when the patient is sitting or lying down and when upright, and wherein determining if the patient is preload sensitive or preload dependent comprises calculating a delta pulse pressure (dPP), optionally by a computer executable method, based at least partially on the blood pressure readings, and determining that the patient is preload sensitive if the calculated dPP is above a threshold dPP.

[0059] In a seventh embodiment according to the sixth embodiment, wherein the threshold dPP is within a range of -10 to 0, and optionally -10 to -5, and optionally -10.

[0060] In an eight embodiment according to any of the first to seventh embodiments, further comprising, in response to determining that the subject is preload dependent and not preload sensitive, selecting the patient for the treatment to treat the one or more symptoms of HFpEF if the patient has a delta heart rate (dHR), between sitting or lying down and being upright, that is above a preset threshold.

[0061] In a ninth embodiment according to the eighth embodiment, wherein the preset threshold is in a range from 10 -20, optionally from 12-18, and optionally greater than or equal to 15.

[0062] In a tenth embodiment, a method of patient selection and treating one or more symptoms of HFpEF, the method comprising: performing one or more tests on a patient, including obtaining heart rate when the patient is lying down and standing; calculating a change in heart rate (dHR) of the patient between lying and standing; determining if the patient is preload sensitive or preload dependent based at least partially on the results of the one or more tests; in response to determining that the subject is preload dependent and not preload sensitive, selecting the patient for a treatment to treat the one or more symptoms of HFpEF if the dHR is above a present threshold dHR; and performing a treatment procedure on the selected patient to treat the one or more symptoms of HFpEF.

[0063] In an eleventh embodiment according to the 10thembodiment, wherein the preset threshold is in a range from 10 - 20, optionally from 12-18, and optionally greater than or equal to 15.

[0064] In 12thembodiment according to the 10thor 11thembodiment, wherein performing the treatment comprises ablating a greater splanchnic nerve (GSN) of the patient, optionally only a right GSN and leaving unablated a left GSN of the patient.

[0065] In a 13thembodiment according to the 12,hembodiment, wherein ablating the GSN comprises intravascularly delivering an ablation apparatus to an intercostal vein (ICV), optionally a T9-T1 1 ICV.

[0066] In a 14thembodiment according to the 13thembodiment, wherein ablating the GSN comprises delivering an ablation device through a wall of the ICV, examples of which are described in U.S. Patent 11672595B1 .

[0067] In a 15thembodiment according to the 13thembodiment, wherein ablating the GSN does not include delivering an ablation device through a wall of the ICV.

[0068] In a 16thembodiment, a method of patient selection for treating one or more symptoms of HFpEF, the method comprising: obtaining one or more patient metrics when the patient is lying down and when standing; calculating a change in pulse pressure (dPP) between lying down and standing, and determining if a patient ispreload sensitive (PS) or preload dependent (PD) if the calculated dPP is above a preset threshold; in response to determining that the subject is preload sensitive and not preload dependent, selecting the patient for a treatment to treat the one or more symptoms of HFpEF; and ablating the subject’s GSN if the patient is PS based on the calculated dPP.

[0069] In a 17thembodiment according to the 16thembodiment, wherein calculating the dPP comprises using blood pressure readings from when the patient is lying down and when standing.

[0070] In an 18,hembodiment according to the 16thor 17thembodiment, wherein the threshold dPP is within a range of -10 to 0, and optionally -10- -5, and optionally -10.

[0071] In a 19thembodiment according to any of the 16thto 18thembodiments, wherein ablating the GSN comprises intravascularly delivering an ablation apparatus to an intercostal vein (ICV), optionally a T9-T11 ICV.

[0072] In a 20thembodiment according to the 19thembodiment, wherein ablating the GSN comprises delivering an ablation device through a wall of the ICV, examples of which are described in U.S. Patent 11672595B1 .

[0073] In a 21stembodiment according to the 19thembodiment, wherein ablating the GSN does not include delivering an ablation device through a wall of the ICV.

[0074] In a 22ndembodiment, A method of GSN ablation, the method comprising: receiving instructions that the patient is preload sensitive, or preload dependent with a dHR above a preset threshold, and has thus been selected for a GSN ablation procedure; and in response to receiving instructions that the patient is selected, performing an ablation on the subject’s greater splanchnic nerve to ablate the GSN, optionally only a right GSN of the patient and leaving a patient’s left GSN unablated.

[0075] In a 23rdembodiment according to the 22ndembodiment, wherein ablating the GSN comprises intravascularly delivering an ablation apparatus to an intercostal vein (ICV), optionally a T9-T1 1 ICV.

[0076] In a 24thembodiment according to the 23rdembodiment, wherein ablating the GSN comprises delivering an ablation device through a wall of the ICV, examples of which are described in U.S. Patent US11672595B1 .

[0077] In a 25thembodiment according to the 23rdembodiment, wherein ablating the GSN does not include delivering an ablation device through a wall of the ICV, mere examples of which are shown and described in references incorporated by reference herein, such as U.S. Pub. Nos. US2019 / 0183569, US2021 / 0220043, and Patent US 10,376,308, which are completely incorporated by reference herein for all purposes.

[0078] In a 26thembodiment A method of selecting a patient for treating one or more symptoms of HFpEF, the method comprising: performing one or more tests on a patient; determining if the patient is preload sensitive or preload dependent with a dHR above a preset threshold, based at least partially on the results of the one or more tests; in response to determining that the patient is preload sensitive or preload dependent with a dHR above a preset threshold, selecting the patient for a treatment to treat the one or more symptoms of HFpEF; and outputting instructions indicative that the patient is selected for and / or will likely be responsive to the treatment.

[0079] In a 27thembodiment according to the 26thembodiment, wherein performing one or more tests on a patient comprises obtaining blood pressure readings when the patient is lying down and when standing, and wherein determining if the patient is preload sensitive or preload dependent with a dHR above a preset threshold comprises calculating a delta pulse pressure (dPP), optionally by a computer executable method, based at least partially on the blood pressure readings, and determining that the patient is preload sensitive if the calculated dPP is above a threshold dPP.

[0080] In a 28thembodiment according to the 27thembodiment, wherein the threshold dPP is within a range of -10 to 0, and optionally -10- -5, and optionally -10.

[0081] In a 29thembodiment according to the 26thembodiment further comprising, in response to determining that the subject is preload dependent and not preload sensitive, selecting the patient for the treatment to treat the one or more symptoms of HFpEF if the patient has a dHR, between lying down and standing, that is above a preset threshold.

[0082] In a 30thembodiment according to the 29thembodiment, wherein the preset threshold is in a range from 10 -20, optionally from 12-18, and optionally greater than or equal to 15.

[0083] In a 31stembodiment, A method of patient selection and treating one or more symptoms of heart failure, the method comprising: performing one or more tests on a patient; determining if the patient is not orthostatic hypotensive or orthostatic hypertensive based at least partially on the results of the one or more tests; in response to determining that the patient is not orthostatic hypotensive or orthostatic hypertensive, selecting the patient for a treatment to treat the one or more symptoms of heart failure; and performing a treatment procedure on the selected patient to treat the one or more symptoms of heart failure.

[0084] In a 32ndembodiment according to the 31stembodiment, wherein performing the treatment comprises ablating a greater splanchnic nerve (Than) of the patient, optionally only one of a right GSN and left GSN and leaving unablated the remaining right or left GSN of the patient.

[0085] In a 33rdembodiment according to the 32ndembodiment, wherein ablating the GSN comprises intravascularly delivering an ablation apparatus to an intercostal vein (ICV), optionally a T9-T1 1 ICV.

[0086] In a 34thembodiment according to the 33rdembodiment, wherein ablating the GSN comprises delivering an ablation device through a wall of the ICV, examples of which are described in U.S. Patent 11672595B1 .

[0087] In a 35thembodiment according to the 33rdembodiment, wherein ablating the GSN does not include delivering an ablation device through a wall of the ICV.

[0088] In a 36thembodiment, A non-transitory, computer-readable storage media with executable instructions executed by a processor to perform a method, the method comprising: receiving as input one or more patient metrics; calculating if the patient is preload sensitive, or preload dependent with a dHR above a preset threshold, based at least partially on the received one or more patient metrics; and in response to calculating that the patient is preload sensitive or preload dependent with a dHR above a preset threshold, outputting instructions indicative of the patient being preload sensitive or preload dependent with a dHR above a preset threshold.

[0089] In a 37thembodiment according to the 36thembodiment, wherein receiving as input one or more patient metrics comprises receiving as input blood pressure readings when the patient is lying down and when standing, and wherein calculating if the patientis preload sensitive or preload dependent with a dHR above a preset threshold comprises calculating a delta pulse pressure (dPP), based at least partially on the blood pressure readings.

[0090] In a 38thembodiment according to the 37thembodiment, wherein outputting instructions comprises outputting instructions indicative that the patient is preload sensitive if dPP is above a preset dPP threshold.

[0091] In a 39thembodiment according to the 38thembodiment, wherein the dPP threshold is within a range of -10 to 0, and optionally -10- -5, and optionally -10.

[0092] In a 40thembodiment according to any of the 36thto 39thembodiments, if the dPP is not above the preset threshold, calculating a dHR and calculating if the dHR is above a preset threshold.

[0093] In a 41stembodiment according to the 40thembodiment, wherein outputting instructions comprises outputting instructions if the dHR is above the preset threshold.

[0094] In a 42ndembodiment according to the 41stembodiment, wherein the preset threshold is in a range from 10 - 20, optionally from 12-18, and optionally greater than or equal to 15.

[0095] Each or any of the steps of a method may be embodied on a non-transitory computer readable storage medium and / or executed by the hardware processor.

Claims

CLAIMSWhat is claimed is:1 . A computer executable method executable by a processor, the method comprising: receiving as input one or more patient metrics; calculating if the patient is preload sensitive, or preload dependent with a dHR above a preset threshold, based at least partially on the received one or more patient metrics; and in response to calculating that the patient is preload sensitive or preload dependent with a dHR above a preset threshold, outputting instructions indicative that the patient is preload sensitive or preload dependent with a dHR above a preset threshold.

2. The computer executable method of claim 1 , wherein receiving as input one or more patient metrics comprises receiving as input blood pressure readings when the patient is lying down and when standing, and wherein calculating if the patient is preload sensitive or preload dependent with a dHR above a preset threshold comprises calculating a delta pulse pressure (dPP), based at least partially on the blood pressure readings.

3. The computer executable method of Claim 2, wherein outputting instructions comprises outputting instructions indicative that the patient is preload sensitive if dPP is above a preset dPP threshold.

4. The computer executable method of Claim 3, wherein the dPP threshold is within a range of -10 to 0, and optionally -10 to -5, and optionally -10.

5. The computer executable method of any of Claims 1 to 4, wherein, if the dPP is not above the preset threshold, calculating a dHR and calculating if the dHR is above a preset threshold.

6. The computer executable method of Claim 5, wherein outputting instructions comprises outputting instructions if the dHR is above the preset threshold.

7. The computer executable method of Claim 6, wherein the preset threshold is in a range from 10 - 20, optionally from 1 -18, and optionally greater than or equal to 15.

8. The computer executable method of any one of claims 1 to 7, wherein the one or more patient metrics include an E / A ratio.

9. The computer executable method of any one of claims 1 to 8, wherein the one or more patient metrics include a tricuspid annular plane systolic excursion (TAPSE) measurement.

10. The computer executable method of any one of claims 1 to 9, wherein the one or more patient metrics include a right ventricular fractional area change (RVFAC).1 1 . The computer executable method of any one of claims 1 to 10, wherein the one or more patient metrics include a delta pulse pressure (dPP) measurement.

12. The computer executable method of Claim 11 , further comprising: outputting instructions that identifies the target patient for treatment for a GSN ablation treatment based on the 1 ) E / A ratio, 2) the TAPSE measurement, 3) the RVFAC, 4) the dPP, and 5) the dHR.

13. The computer executable method of Claim 11 , wherein the instructions are output based on: 1 ) the E / A ratio being < 2, 2) the TAPSE being > 1 .2 cm, 3) the RVFAC being > 25%, and 4) ((dPP < -10% & HR > 15 bpm) or dPP > -10%).

14. A computer executable method executable by a processor for identifying a patient for a GSN ablation treatment, the patient identified as having heart failure with preserved ejection fraction (HFpEF), the method comprising: obtaining, for a target patient, an E / A ratio; obtaining, for the target patient, a tricuspid annular plane systolic excursion (TAPSE) measurement; obtaining, for the target patient, a right ventricular fractional area change (RVFAC);obtaining a delta pulse pressure (dPP) measurement of the target patient obtaining a delta heart rate (dHR) of the target patient; and outputting instructions that identifies the target patient for treatment based on the1 ) E / A ratio, 2) the TAPSE measurement, 3) the RVFAC, 4) the dPP, and 5) the dHR of the target patient.

15. The computer executable method of claim 14, wherein the instructions that identifies the target patient for treatment are output based on: 1 ) the E / A ratio being < 2,2) the TAPSE being > 1.2 cm, 3) the RVFAC being > 25%, and 4) ((dPP < -10% & HR > 15 bpm) or dPP > -10%).

16. The computer executable method of claim 15, wherein the instructions that identifies the target patient for treatment are further based on the E / A ratio for the target patient being > 0.5.

17. The computer executable method of any one of claims 1 to 16, wherein the method is stored on a computing device in non-transitory media.

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