# US 12,491,364 B2 · Monitoring of neuromodulation using biomarkers

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- Number: US 12,491,364 B2
- Document ID: US12491364B2
- Status: Granted
- Kind: B2
- Application number: 17/717,958
- Filed: 2022-04-11
- Published: 2022-09-22
- Granted: 2025-12-09
- Earliest claimed: 2012-03-08
- Assignees: Medtronic Ireland Manufacturing Unlimited Company
- Applicants: Medtronic Ireland Manufacturing Unlimited Company
- Inventors: Ayala Hezi-Yamit; Rudy A. Beasley; Susan Thornton Edwards; Lori Garcia; Michele Lee Silver; Christopher W. Storment; Carol M. Sullivan; Joseph A. Traina; Stefan Stoyanov Tunev
- Web page: https://patentgrep.com/patent/US12491364B2

## CPC

- A61N 1/3606: {adapted for a particular treatment}
- A61B 5/14503: {invasive, e.g. introduced into the body by a catheter or needle or using implanted sensors (A61B5/1459, A61B5/1464, A61B5/1473, A61B5/1482, A61B5/14865 take precedence)}
- A61B 5/14546: {for measuring analytes not otherwise provided for, e.g. ions, cytochromes}
- A61B 5/15003: {for venous or arterial blood}
- A61B 5/201: {Assessing renal or kidney functions}
- A61B 5/6852: {Catheters}
- A61B 5/6853: {with a balloon}
- A61B 18/1492: {having a flexible, catheter-like structure, e.g. for heart ablation (A61B18/1477 takes precedence)}
- A61N 1/36121: {Production of neurotransmitters; Modulation of genes expression}
- A61B 5/1405: {Devices for taking blood samples (devices for taking samples of other body liquids A61B10/0045)}
- A61B 5/15: Devices for taking samples of blood
- A61B 5/150229: {Pumps for assisting the blood sampling}
- A61B 5/150992: {Blood sampling from a fluid line external to a patient, such as a catheter line, combined with an infusion line; Blood sampling from indwelling needle sets, e.g. sealable ports, luer couplings or valves}
- A61B 5/157: {Devices} characterised by integrated means for measuring characteristics of blood
- A61B 5/20: for measuring urological functions {restricted to the evaluation of the urinary system (A61B5/4375 takes precedence)}
- A61B 5/4035: {Evaluating the autonomic nervous system}
- A61B 5/4836: {Diagnosis combined with treatment in closed-loop systems or methods (A61B5/0036 takes precedence)}
- A61B 5/4848: {Monitoring or testing the effects of treatment, e.g. of medication}
- A61B 5/6858: {with a distal basket, e.g. expandable basket}
- A61B 10/0045: {Devices for taking samples of body liquids}
- A61B 10/007: {for taking urine samples (measuring urological functions A61B5/20; genital receptacles A61F5/451; urinals for bed-ridden persons A61G9/006)}
- A61B 2018/00166: {Multiple lumina}
- A61B 2018/00214: {Expandable means emitting energy, e.g. by elements carried thereon}
- A61B 2018/00232: {having an irregular shape}
- A61B 2018/00279: {deployable}
- A61B 2018/00345: {Vascular system}
- A61B 2018/00404: {Blood vessels other than those in or around the heart}
- A61B 2018/00434: {Neural system}
- A61B 2018/00511: {Kidney}
- A61B 2018/00577: {Ablation}
- A61B 2018/00642: {with feedback, i.e. closed loop control}
- A61B 2018/0212: {using an instrument inserted into a body lumen, e.g. catheter}
- A61N 1/05: for implantation or insertion into the body, e.g. heart electrode (A61N1/06 takes precedence)
- A61N 1/0551: {Spinal or peripheral nerve electrodes}
- A61N 1/32: alternating or intermittent currents {(applying electric fields by inductive or capacitive coupling A61N1/40; microwave apparatus A61N5/02)}
- A61N 1/3605: {Implantable neurostimulators for stimulating central or peripheral nerve system}
- A61N 1/36135: {using physiological parameters}
- G01N 2800/347: Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- A61B: DIAGNOSIS; SURGERY; IDENTIFICATION (usefulness limited to only animals A61D)
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Provided herein are methods, devices, compositions, and kits for monitoring neuromodulation efficacy based on changes in the level or activity of one or more target biomarkers. A method can include transluminally delivering a distal portion of an elongated shaft of a catheter to a target renal blood vessel and at least partially inhibiting sympathetic neural activity of a renal nerve. The method includes determining a post-neuromodulation level of one or more biomarkers after at least partially inhibiting the sympathetic neural activity of the renal nerve, wherein the level of the one or more biomarkers directly or indirectly correlates with sympathetic nervous activity in the patient. The method can include comparing the post-neuromodulation level to a predetermined level for the one or more biomarkers, wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs from the predetermined level.

## Claims

### Claim 1

A method of assessing efficacy of a renal neuromodulation procedure, the method comprising:
transluminally delivering a distal portion of an elongated shaft of a catheter to a target renal blood vessel of a patient;
at least partially inhibiting sympathetic neural activity of a renal nerve of the patient via a therapy delivered by a neuromodulation assembly carried by the distal portion of the elongated shaft;
wherein an analyzer that is operatively coupled to the elongated shaft receives bodily fluid having a post-neuromodulation level of one or more biomarkers,
determining the post-neuromodulation level of the one or more biomarkers in the bodily fluid using the analyzer that is operatively coupled to the elongated shaft, wherein upon receiving the bodily fluid, the analyzer determines the post-neuromodulation level of the one or more biomarkers by at least interacting with the bodily fluid, wherein the bodily fluid is collected from the patient and received by the analyzer after at least partially inhibiting the sympathetic neural activity of the renal nerve, and wherein the post-neuromodulation level of the one or more biomarkers directly or indirectly correlates with sympathetic nervous activity in the patient; and
comparing the post-neuromodulation level to a predetermined level for the one or more biomarkers,
wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs at least about 1% from the predetermined level.

### Claim 2 (depends on 1)

The method of claim 1, wherein one or more of the biomarkers comprise one or more of epinephrine, dopamine, neuropeptide Y, vasopressin, aldosterone, a secreted catecholamine metabolite, or a combined level of norepinephrine and a metabolite thereof.

### Claim 3 (depends on 1)

The method of claim 1, wherein the bodily fluid comprises plasma and the one or more biomarkers includes a component of a renin-angiotensin aldosterone system in the plasma, and wherein the component of the renin-angiotensin aldosterone system is selected from a group consisting of aldosterone, angiotensin, angiotensin converting enzyme (ACE), kalakrein B1 (KLKB1), and natriuretic peptide B (BNP).

### Claim 4 (depends on 1)

The method of claim 1, wherein the bodily fluid comprises plasma or urine collected from the patient within about 5 minutes to about 14 days after at least partially inhibiting the sympathetic neural activity of the renal nerve.

### Claim 5 (depends on 1)

The method of claim 1, wherein the predetermined level is an upper limit of a normal range of level for the one or more biomarkers.

### Claim 6 (depends on 1)

The method of claim 1, wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs at least about 5% from the predetermined level.

### Claim 7 (depends on 1)

The method of claim 1, wherein at least partially inhibiting sympathetic neural activity of the renal nerve via the therapy delivered by the neuromodulation assembly comprises delivering at least one of radiofrequency (RF) energy, pulsed RF energy, microwave energy, laser light energy, optical energy, ultrasound energy, high-intensity focused ultrasound energy, magnetic energy, direct heat energy, and cryotherapeutic energy to tissue of the patient.

### Claim 8 (depends on 1)

The method of claim 1, wherein at least partially inhibiting sympathetic neural activity of the renal nerve via the therapy delivered by the neuromodulation assembly comprises delivering thermal energy to tissue of the patient.

### Claim 9 (depends on 1)

The method of claim 1, wherein at least partially inhibiting sympathetic neural activity of the renal nerve via the therapy delivered by the neuromodulation assembly comprises delivering a chemical to tissue of the patient.

### Claim 10 (depends on 1)

The method of claim 1, further comprising intravascularly obtaining a volume of the bodily fluid using the catheter within 30 minutes after delivery of the therapy by the neuromodulation assembly, wherein determining the post-neuromodulation level of the one or more biomarkers comprises determining the post-neuromodulation level of the one or more biomarkers in the volume of the bodily fluid.

### Claim 11 (depends on 1)

The method of claim 1, wherein at least partially inhibiting sympathetic neural activity in the renal nerve of the patient via the therapy delivered comprises delivering electrically-induced, thermally-induced, or chemically-induced neuromodulation therapy to tissue of the patient.

### Claim 12 (depends on 1)

The method of claim 1, wherein at least partially inhibiting sympathetic neural activity of the renal nerve via the therapy comprises at least partially ablating neural fibers via the therapy.

### Claim 13 (depends on 1)

The method of claim 1, wherein the predetermined level is derived from a standard value for the one or more biomarkers across a population.

### Claim 14 (depends on 1)

The method of claim 1, wherein comparing the post-neuromodulation level to the predetermined level for the one or more biomarkers includes using the analyzer, the analyzer being configured to compare the post-neuromodulation level to the predetermined level.

### Claim 15 (depends on 1)

The method of claim 1, wherein the catheter includes a handle configured to remain extracorporeal to the patient, and wherein the handle includes the analyzer.

### Claim 16 (depends on 1)

The method of claim 1, wherein the analyzer is configured to output an indication of whether the renal neuromodulation procedure is classified as at least partially successful.

### Claim 17 (depends on 1)

The method of claim 1, wherein the analyzer includes a memory, and wherein the predetermined level for the one or more biomarkers is stored in the memory.

### Claim 18

A method of assessing efficacy of a renal neuromodulation procedure in a patient, the method comprising:
transluminally positioning an energy delivery element of a catheter within a target renal blood vessel of the patient and adjacent to target neural fibers innervating a kidney of the patient;
at least partially ablating the target neural fibers via the energy delivery element;
wherein an analyzer that is operatively coupled to an elongated shaft of the catheter receives bodily fluid having a post-neuromodulation level of one or more biomarkers,
determining the post-neuromodulation level for the one or more biomarkers in the bodily fluid using the analyzer that is operatively coupled to the elongated shaft of the catheter, wherein upon receiving the bodily fluid, the analyzer determines the post-neuromodulation level of the one or more biomarkers by at least interacting with the bodily fluid, wherein the bodily fluid is collected from the patient and received by the analyzer after at least partially ablating the target neural fibers, and wherein the post-neuromodulation level of the one or more biomarkers directly or indirectly correlates with sympathetic nervous activity in the patient; and
comparing the post-neuromodulation level to a predetermined level for the one or more biomarkers,
wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs at least about 1% from the predetermined level, and
wherein one or more of the biomarkers are selected from the group consisting of epinephrine, dopamine, neuropeptide Y, vasopressin, aldosterone, a catecholamine metabolite, or a combined level of norepinephrine and a metabolite thereof.

### Claim 19 (depends on 18)

The method of claim 18, wherein the bodily fluid comprises plasma or urine collected from the patient within about 5 minutes to about 14 days following the renal neuromodulation procedure.

### Claim 20 (depends on 18)

The method of claim 18, wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs at least about 10% from the predetermined level.

### Claim 21

A method of assessing efficacy of a renal neuromodulation procedure, the method comprising:
transluminally delivering a distal portion of an elongated shaft of a catheter to a target renal blood vessel of a patient;
at least partially inhibiting sympathetic neural activity of a renal nerve of the patient via a therapy delivered by a neuromodulation assembly carried by the distal portion of the elongated shaft;
intravascularly obtaining a volume of fluid including one or more biomarkers using the catheter within 30 minutes after delivery of the therapy by the neuromodulation assembly;
wherein an analyzer that is operatively coupled to the elongated shaft of the catheter receives the volume of fluid having a post-neuromodulation level of the one or more biomarkers,
determining the post-neuromodulation level of the one or more biomarkers in the volume of fluid using the analyzer operatively coupled to the elongated shaft, wherein upon receiving the volume of fluid, the analyzer determines the post-neuromodulation level of the one or more biomarkers by at least interacting with the volume of fluid, and wherein the post-neuromodulation level of the one or more biomarkers directly or indirectly correlates with sympathetic nervous activity in the patient; and
comparing the post-neuromodulation level to a predetermined level for the one or more biomarkers,
wherein the renal neuromodulation procedure is classified as at least partially successful if the post-neuromodulation level differs at least about 1% from the predetermined level.

### Claim 22 (depends on 21)

The method of claim 21, wherein the predetermined level is an upper limit of a normal range of level for the one or more biomarkers.

### Claim 23 (depends on 21)

The method of claim 21, wherein at least partially inhibiting sympathetic neural activity in the renal nerve of the patient via the therapy delivered comprises delivering electrically-induced, thermally-induced, or chemically-induced neuromodulation therapy to tissue of the patient.