US 2013 02374.39A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0237439 A1 Stolen et al. (43) Pub. Date: Sep. 12, 2013

(54) SYSTEMIS AND METHODS USING Publication Classification BOMARKERPANEL, DATA (71) Applicants: Craig M. Stolen, New Brighton, MN (51) Int. Cl. (US); Timothy E. Meyer, North Oaks, GOIN33/68 (2006.01) MN (US); Milan Seth, Minneapolis, MN (52) U.S. Cl. (US); Francis G. Spinale, Blythewood, CPC ...... G0IN33/6893 (2013.01) SC (US); Nicholas David Wold, Arden USPC ...... 506/9; 435/7.92 Hills, MN (US) (72) Inventors: Craig M. Stolen, New Brighton, MN (US); Timothy E. Meyer, North Oaks, (57) ABSTRACT MN (US); Milan Seth, Minneapolis, MN (US); Francis G. Spinale, Blythewood, SC (US); Nicholas David Wold, Arden Embodiments of the disclosure are related to systems and Hills, MN (US) methods for utilizing biomarker panel data with respect to (73) Assignees: MEDICAL UNIVERSITY OF medical devices and methods, amongst other things. In an SOUTH CAROLINA, CHARLESTON, embodiment, the disclosure can include a method of predict SC (US); CARDIAC PACEMAKERS, ing the likelihood of response to CRT therapy. The method INC., ST. PAUL, MN (US) can include quantifying levels of one or more biomarkers in a (21) Appl. No.: 13/756,129 biological sample of a patient, analyzing the quantified levels to determine response to CRT therapy, wherein a panel of (22) Filed: Jan. 31, 2013 biomarkers includes at least two selected from the group Related U.S. Application Data consisting of CRP, SGP-130, SIL-2R, STNFR-II, IFNg, BNP (60) Provisional application No. 61/593,037, filed on Jan. sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. Other 31, 2012. embodiments are also included herein. Patent Application Publication Sep. 12, 2013 Sheet 1 of 7 US 2013/02374.39 A1

Quantifying Levels of Biomarkers

Analyzing the Quantified Levels

FIG. 1

Quantifying Levels Of Biomarkers

Placing the Patient into a Category

FIG. 2 Patent Application Publication Sep. 12, 2013 Sheet 2 of 7 US 2013/02374.39 A1

Quantifying Levels of Biomarkers

Analyzing the Quantified Levels

Adjusting Therapy

FIG. 3 Patent Application Publication Sep. 12, 2013 Sheet 3 of 7 US 2013/02374.39 A1

350 Patient With DOCumented Heart Failure

352 Curren

F Medications and Guideline 354 Met? Biomarker Up-Titrate? Add 368

Panel Medications. Using Analysis AHA IACC Guidelines

370 Follow-Up

372

Up-Tirate HF tandard of 360 Care Met? 358 Medications

362 Schedule Patient for CRT Device Follow-Up Referral for Implant Advanced HF

Biomarker Treatment Panel Analysis

FIG. 4 Patent Application Publication Sep. 12, 2013 Sheet 4 of 7 US 2013/02374.39 A1

Z2 Patent Application Publication Sep. 12, 2013 Sheet 5 of 7 US 2013/02374.39 A1

0//

?ETTONLNOO

06/G9/09/GG/

èJETTONLNOO G0/ Patent Application Publication Sep. 12, 2013 Sheet 6 of 7 US 2013/02374.39 A1

872

WENTRICULAR CHANNEL INTERFACE

MCROPROCESSOR CHANNEL NTERFACE

SHOCK PULSE GENERATOR

TELEMETRY INTERFACE

FIG. 7

US 2013/0237439 A1 Sep. 12, 2013

SYSTEMS AND METHODS USING from the group consisting of CRP, SGP-130, sIL-2R, STNFR BOMARKERPANEL, DATA II, IFNg, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. In some embodiments, the method can include 0001. This application claims the benefit of U.S. Provi quantifying levels of one or more of a panel of biomarkers in sional Application No. 61/593,037, filed Jan. 31, 2012, the a biological sample of a patient, and using the quantified content of which is herein incorporated by reference in its levels to place the patient into one of a set of categories, the set entirety. of categories including CRT therapy responders, wherein the panel of biomarkers includes at least two selected from the TECHNICAL FIELD group consisting of CRP, SGP-130, SIL-2R, STNFR-II, IFN 0002 This disclosure relates generally to medical devices y, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. and methods, and more particularly, to systems and methods 0008. An embodiment can include a method of identifying for utilizing biomarker panel data with respect to medical patients that are unlikely to respond to CRT therapy. The devices and methods, amongst other things. method can include quantifying levels of one or more of a panel of biomarkers in a biological sample of a patient, and BACKGROUND OF THE INVENTION analyzing the quantified levels to determine likelihood of 0003 Implantable medical devices (IMDs) are commonly response to CRT therapy, wherein the panel of biomarkers used to provide treatment to patients. Some types of implant includes at least two selected from the group consisting of able medical devices deliver electrical stimuli to a target CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP tissue via a lead wire (“stimulation lead') or catheter having 2, MMP-9, TIMP-1, TIMP-2, TIMP-4. one or more electrodes disposed in or about the target tissue. 0009. An embodiment can include a method of determin In the context of cardiac rhythm management devices, the ing prognosis of a patient receiving CRT therapy. The method electrical stimulican be delivered in the form of pacing pulses can include selecting a patient that is receiving CRT therapy, to pace the heart and/or relatively high energy defibrillation quantifying levels of one or more of a panel of biomarkers in shocks or cardioversion shocks to terminate arrhythmias. a biological sample of the patient, and analyzing the quanti 0004. The American College of Cardiology/American fied levels to determine prognosis, wherein the panel of biom Heart Association Guidelines for the Evaluation and Manage arkers includes at least two selected from the group consisting ment of Chronic Heart Failure in the Adult defines heart of CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP sST2, failure as a “complex clinical syndrome that can result from MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. any structural or functional cardiac disorder that impairs the 0010. An embodiment can include a method of treating a ability of the ventricle to fill with oreject blood'. Heart failure patient. The method can include quantifying levels of one or has various adverse hemodynamic and circulatory conse more of a panel of biomarkers in a biological sample of the quences. Signs and symptoms of heart failure include sys patient, analyzing the quantified levels, and adjusting therapy temic and pulmonary fluid accumulation, reduced activity for the patient based at least in part on the analysis results, levels and exercise tolerance, and poor kidney and cerebral/ wherein the panel of biomarkers includes at least two selected cognitive function, amongst others. Over time, patients with from the group consisting of CRP, SGP-130, sIL-2R, STNFR heart failure typically experience further declines in cardiac II, IFNg, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, pump function which is accompanied by increased fluid accu TIMP-4. In some embodiments, the method can include mulation, continued decline in activity/exercise tolerance, selecting a patient that is receiving CRT therapy, quantifying further decline in kidney and cerebral/cognitive function. levels of one or more of a panel of biomarkers in a biological 0005 Cardiac resynchronization therapy (CRT) is used to sample of the patient, analyzing the quantified levels to deter treat the delay in ventricular contractions of the heart that mine an expected response to CRT therapy, comparing the occur in some people with advanced heart failure. A delay expected response to CRT therapy to the patient’s actual between the contraction of the right and left ventricles often response to CRT therapy, and adjusting parameters of the occurs with heart failure, leading to biomechanically ineffi CRT therapy if the patients actual response to CRT therapy is cient heart contractions and reduced cardiac output. Cardiac worse than the expected response to CRT therapy, wherein the resynchronization therapy aims to address this problem panel of biomarkers includes at least two selected from the through stimulation of multiple chambers of the heart in order group consisting of CRP, SGP-130, SIL-2R, STNFR-II, IFNg, to resynchronize contraction of the right and left ventricles. BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. 0006 Biomarkers, or biological markers, are substances 0011. An embodiment can include a method of monitoring that can be used as an indicator of a biological state. Biom a patient receiving CRT therapy. The method can include arkers can include Small molecules, proteins, nucleic acids, quantifying levels of one or more of a panel of biomarkers in carbohydrates, lipids, and combinations thereof. a biological sample of the patient, and analyzing the quanti fied levels to determine status. In some embodiments the SUMMARY OF THE INVENTION method can include quantifying levels of one or more of a 0007 Embodiments of the disclosure are related to sys panel of biomarkers in a biological sample of the patient, and tems and methods for utilizing biomarker panel data and analyzing the change in quantified levels overtime to perform related medical devices and methods, amongst other things. one or more selected from the group consisting of analyzing An embodiment can include a method of predicting the like response to therapy changes and monitoring disease progres lihood of response to CRT therapy. The method can include S1O. quantifying levels of one or more of a panel of biomarkers in 0012. An embodiment can include an assay including a biological sample of a patient, analyzing the quantified probes to quantify levels of one or more of a panel of biom levels to determine likelihood of response to CRT therapy, arkers in a biological sample of a patient, wherein the panel of wherein the panel of biomarkers includes at least two selected biomarkers includes at least two selected from the group US 2013/0237439 A1 Sep. 12, 2013

consisting of CRP, SGP-130, SIL-2R, STNFR-II, IFNg, BNP 0025. In various embodiments, a plasma biomarker panel sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, TIMP-4. is included that predicts (including prior to CRT implant) 0013 This summary is an overview of some of the teach those HF patients that would demonstrate a functional ings of the present disclosure and is not intended to be an response to CRT. In various embodiments, a biomarker pro exclusive or exhaustive treatment of the present Subject mat file is included that can be used to differentiate a functional ter. Further details are found in the detailed description and response in HF patients following CRT placement. appended claims. Other aspects will be apparent to persons 0026. In some embodiments, a peripheral, non-invasive skilled in the art upon reading and understanding the follow diagnostic test quantifying a specific combination of biomar ing detailed description and viewing the drawings that form a kers, taken at the time of CRT evaluation, but prior to CRT part thereof, each of which is not to be taken in a limiting placement, can predict those patients that will have HF and sense. The scope of the present invention is defined by the MACE risk reduced, or conversely identify those patients that appended claims and their legal equivalents. will not have these indices of cardiovascular risk effectively reduced. BRIEF DESCRIPTION OF THE DRAWINGS 0027. In some embodiments, prediction algorithms, and/ or devices executing the same, can predict and/or stratify 0014. The disclosure may be more completely understood those patients that will demonstrate improved cardiac perfor in connection with the following drawings, in which: mance following CRT and thereby slow the progression of 0015 FIG. 1 is a flow chart of some steps of methods in HF and reduce the risk of MACE. accordance with various embodiments herein. 0028. In some embodiments, a specific test of a biological 0016 FIG. 2 is a flow chart of some steps of methods in sample (such as a blood test) for a specific set of biomarkers accordance with various embodiments herein. can be used to assess the response of patients after placement 0017 FIG. 3 is a flow chart of some steps of methods in of CRT. Such embodiments can be advantageous because accordance with various embodiments herein. identifying the relative response to CRT, particularly early 0018 FIG. 4 is a flow chart of some steps of methods in following CRT placement can be difficult and often requires accordance with various embodiments herein. complex imaging and functional studies. As such, in accor 0019 FIG. 5 is a schematic diagram of an exemplary sys dance with some embodiments herein, a specific peripheral, tem consistent with various embodiments herein. diagnostic test can provide diagnostic information on those 0020 FIG. 6 is a schematic diagram of various compo patients that are responding to CRT, and inversely identify nents of an external device in accordance with some embodi those patients that are not responding to CRT as would be ments of the disclosure. predicted. Such embodiments can serve to provide early 0021 FIG. 7 is a schematic diagram of various compo warning information that can then be used to initiate early and nents of an implantable device in accordance with some more aggressive workup of these patients including, but not embodiments of the disclosure. limited to, reprogramming a CRT (cardiac resynchronization 0022 FIG. 8 is a graph showing absolute change from therapy) device, altering medications, performing additional baseline at 3 and 6 months for CRT responders versus non imaging and invasive functional studies. responders for 12 biomarkers. 0029. It will be understood then that some embodiments 0023. While the disclosure is susceptible to various modi herein include systems and methods for utilizing biomarker fications and alternative forms, specifics thereof have been panel data in order to perform various tasks such as predicting shown by way of example and drawings, and will be response to CRT therapy, identifying patients that are described in detail. It should be understood, however, that the unlikely to respond to CRT therapy, determine the prognosis disclosure is not limited to the particular embodiments of patients received CRT therapy, treat patients with CRT described. On the contrary, the intention is to cover modifi therapy, adjust CRT therapy treatment, and monitor patients cations, equivalents, and alternatives falling within the spirit receiving CRT therapy, amongst others. Also included herein and scope of the disclosure. are biomarker assay kits. 0030. As used herein, the term “biomarker” shall include measurable Substances that can be used as an indicator of a DETAILED DESCRIPTION biological State including, without limitation, Small mol 0024 Cardiac resynchronization therapy (CRT) is a rec ecules, proteins, nucleic acids, carbohydrates, lipids, and ognized device driven therapy for heart failure (HF) second combinations thereof. It will be appreciated that reference to ary to severe LV dysfunction. However, outcomes in these HF specific biomarkers herein shall include reference to precur patients following CRT can be variable as defined by clinical sors, proforms, isoforms, mature form variants, and degraded course and/or LV functional improvement. Studies have iden forms thereof including but not limited to metabolites thereof tified that there is a proportion of patients with cardiac dys unless the context dictates otherwise. function that do not respond to cardiac resynchronization 0031. It will be appreciated that many different types of therapy (CRT) as would be expected, and as such, there is a biomarkers can be utilized in embodiments herein. Biomar subset of patients that receive CRT but the progression to HF kers used in various embodiments herein can include, but are (heart failure) and risk of MACE (major adverse cardiovas not limited to adiponectin, adrenomedullin, midregion proa cular events including but not limited to hospitalization for drenomedullin, angiotensin II, apelin, BNP BNP1-32, heart failure, myocardial infarction or cardiogenic shock, NTproBNP1-76, caspase-3, connexin-43, copeptin, C-reac stroke or thromboembolic event, and death) is unaffected. At tive protein (CRP), dihydropyridine receptor, epidermal present, there is no validated approach to predict those HF growth factor (EGF), endoglin, endothelin, endothelin-1, big patients that would yield a functional benefit from CRT. endothelin, eotaxin, fibroblast growth factor-2 (FGF-2), Moreover, early differentiation of those patients that will not fibronectin, Flt-3 ligand, fractalkine, galectin 3 (Gal-3), optimally respond to CRT remains a clinical challenge. G-CSF, GDF-15, GM-CSF, GRO, ICTP, IFNa2, IFN-gamma, US 2013/0237439 A1 Sep. 12, 2013

IGF-1, IL-1, IL-1a, IL-1b, IL-1 ra, IL-2, IL-3, IL-4, IL-5, IL-6, in Subcombinations to indicate the status of a human Subject IL-7, IL-8, IL-9, IL-10, IL-12 (p40), IL-12 (p70), IL-13, with respect to a condition, status, or state of being of the IL-15, IL-17, IP-10, L-type calcium channel alpha subunit, human subject. The biomarkers within the panel of biomar MCP-1, MCP-3, MDC, MIP-1a, MIP-1b, miR-1, miR-21, kers can include those biomarkers discussed above. It will be miR-29, miR-30, miR-133, miR-208, miR-486, miR-760, appreciated that the specific identity of biomarkers within the MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, panel and the number of distinct biomarkers within the panel MMP-12, MMP-13, MPO, osteopontin, PAI-I, PDGF-AA, can depend on the particular use to which the biomarker panel PDGF-AB/BB, PIIINP, PINP PRA-plasma rennin, is put and the Stringency that the results of panel must meet for RANTES, RNU 44, RNU 6B, SCD30, SCD40L, SBGFR, the particular application. sE-selectin, sgp130, SICAM-I, SIL-1Rib, sIL-1RII, SIL-2Ra, 0038. In some embodiments, the panel includes at least SIL-4R, SIL-6R, sRAGE, ST2, sST2, STNF RI, STNF RII, two distinct biomarkers selected from CRP, SGP-130, SIL sVCAM-I, sVEGFR1, SVEGFR2, SVEGFR3, TGFa, TGF bl, 2R, STNFR-II, IFN-y, BNP, sST2, MMP-2, MMP-9, TIMP-1, TGF b|I, TGF b|II, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TIMP-2, and TIMP-4. In other embodiments, the panel TNFa. TNFb, TROPONIN-I, VEGF, ANP NTproANP, includes at least three distinct biomarkers selected from CRP, midregion pro-ANPSERCA2a, ryanodine receptor, carboxy SGP-130, SIL-2R, STNFR-II, IFN-y, BNP, sST2, MMP-2, terminal propeptide of procollagen type I (PICP), C-type MMP-9, TIMP-1, TIMP-2, and TIMP-4. In other embodi natriuretic peptides (CNP, NTproCNP), aldosterone, epi ments, the panel includes at least four distinct biomarkers nephrine, arginine vasopressin (AVP), copeptin, urocortins I, selected from CRP, SGP-130, sIL-2R, STNFR-II, IFN-y, II, III, Fas(APO-1), slas, FasL, IL-18, oxidized low-density BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP lipoproteins, myeloperoxidase, urine biopyrrins, urine and 4. In other embodiments, the panel includes at least five plasma isoprostanes, plasma malondialdehyde, carbonyl pro distinct biomarkers selected from CRP, SGP-130, SIL-2R, teins, cardiac troponins I and T. myosin light-chain kinase I. sTNFR-II, IFN-y, BNP, sST2, MMP-2, MMP-9, TIMP-1, heart fatty acid binding protein, creatine kinase MB fraction, TIMP-2, and TIMP-4. In other embodiments, the panel ischemia modified albumin, osteoprotegerin, coenzyme Q10. includes at least six distinct biomarkers selected from CRP, sGp130, STNFr-II, VAP-1, sVCAM-1, M-CSF, GM-CSF, and SGP-130, SIL-2R, STNFR-II, IFN-y, BNP, sST2, MMP-2, analogues thereof. MMP-9, TIMP-1, TIMP-2, and TIMP-4. In other embodi 0032. In some embodiments, biomarkers can include, but ments, the panel includes at least seven distinct biomarkers are not limited to, heart failure markers, inflammatory biom selected from CRP, SGP-130, sIL-2R, STNFR-II, IFN-y, arkers, and/or remodeling biomarkers. In some embodi BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP ments, biomarkers can include, but are not limited to, biom 4. In other embodiments, the panel includes at least eight arkers of inflammation, bioactive biomarkers, and/or distinct biomarkers selected from CRP, SGP-130, SIL-2R, proteolytic biomarkers. sTNFR-II, IFN-y, BNP, sST2, MMP-2, MMP-9, TIMP-1, 0033. It will be appreciated that a relatively diverse set of TIMP-2, and TIMP-4. In other embodiments, the panel biomarkers can be relevant in terms of indicating inflamma includes at least nine distinct biomarkers selected from CRP, tion. Specific biomarkers of inflammation in various embodi SGP-130, SIL-2R, STNFR-II, IFN-y, BNP, sST2, MMP-2, ments herein can include, but are not limited to, CRP (C-re MMP-9, TIMP-1, TIMP-2, and TIMP-4. In other embodi active protein), SGP-130 (soluble glycoprotein 130), sIL-2R ments, the panel includes at least ten distinct biomarkers (soluble interleukin-2 receptor), STNFR-II (soluble tumor selected from CRP, SGP-130, sIL-2R, STNFR-II, IFN-y, necrosis factor receptor-II), IFN-Y (), SST2 BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP (soluble Suppressor of tumorigenicity-2), and fragments of 4. In other embodiments, the panel includes at least eleven any of these. distinct biomarkers selected from CRP, SGP-130, SIL-2R, 0034 Bioactive biomarkers can include, but are not lim sTNFR-II, IFN-y, BNP, sST2, MMP-2, MMP-9, TIMP-1, ited to, BNP (brain natriuretic peptide) and fragments thereof. TIMP-2, and TIMP-4. In other embodiments, the panel CRP, 0035. Proteolytic biomarkers can include, but are not lim SGP-130, SIL-2R, STNFR-II, IFN-y, BNP, sST2, MMP-2, ited to, MMPs and TIMPs. Matrix metalloproteinases MMP-9, TIMP-1, TIMP-2, and TIMP-4. (MMPs) are zinc-dependent endopeptidases. Synthesized as 0039. In some embodiments, the panel includes at least pro-enzymes, most MMPs are secreted before conversion to CRP, SST2, TIMP1, and TIMP2. In some embodiments, the their active form. MMPs are capable of degrading extracel panel includes at least CRP, BNP, and TNFR-II. In some lular matrix proteins in addition to processing a number of embodiments, the panel includes at least CRP and BNP. bioactive molecules. MMPs play an important role in break 0040. Because the biomarkers within a particular biomar ing down components of the extracellular matrix (ECM). ker panel can include a heterogeneous group in terms of their Specific MMPs for use as proteolytic biomarkers in various underlying biological function, it will be appreciated that embodiments herein can include, but are not limited to, each biomarker included within a panel may have a different MMP-2: MMP-9; and fragments of any of these. normal biological concentration and therefore each biomar 0036 Tissue inhibitors of metalloproteinases (TIMPs) ker included within a panel may have a different concentra function by suppressing MMPs. Structurally, TIMPs contain tion or concentration threshold that is significant for indicat two domains. The N-terminal domain binds to the active site ing a particular biological status. By way of example, normal of mature metalloproteases via a 1:1 non-covalent interac serum concentrations of CRP (C-reactive protein) are differ tion, blocking access of Substrates to the catalytic site. Spe ent from normal serum concentrations of IL-2, and therefore cific TIMPs for use as proteolytic biomarkers in various analyzing their concentrations for application in the context embodiments herein can include, but are not limited to, of a panel of biomarkers may require accounting for different TIMP-1, TIMP-2, TIMP-4; and fragments of any of these. inherent magnitudes in concentrations between the two. 0037. As used herein, the term “biomarker panel shall 0041. In some embodiments each individual biomarker is refer to a set of biomarkers that can be used alone, together, or assessed according to normal values (or reference normal US 2013/0237439 A1 Sep. 12, 2013 values) for that biomarker in patient populations. In other atrial volume less than 40 mL/mi). Use of such other types of words, each individual biomarker can be assessed as either data can include their use as binary variable or continuous being higher than normal, normal, or lower than normal. In variables where appropriate. some embodiments, the reference normal levels are deter 0045. In some embodiments, the data used can include mined based on a group of healthy patients. In other embodi ST2, CRP, TIMP1, TIMP2, and one, two, three, or more of ments, the group is patients with heart failure. In other LVESV at baseline, age at baseline, sex, systolic blood pres embodiments, the group is patients with heart failure who sure at baseline, QRS duration at baseline, PR interval at have received CRT therapy devices. In still other embodi baseline, ischemic status at baseline, and ACE (angiotensin ments, the group is made up of patients with heart failure who converting enzyme inhibitors)/ARB (angiotensin II receptor are responders to CRT therapy. In some embodiments, the blockers) use at baseline. group is made up of patients with heart failure who are not 0046. In some embodiments, the data used can include CRP BNP, and one, two, three, or more of LVESV at baseline, responders to CRT therapy. age at baseline, sex, systolic blood pressure at baseline, pres 0042 Analysis of the biomarker panel can result in a posi ence of left bundle branch block at baseline, renal disease at tive result, a negative result, or an indeterminate result. In baseline, ischemic status at baseline, and beta blocker use at Some embodiments, a positive biomarker panel result can be baseline. defined based on all of the biomarkers within the panel 0047. In some embodiments, the data used can include exceeding a threshold value. In other embodiments, a positive CRP BNP, and one, two, three, or more of LVESV at baseline, biomarker panel result can be defined based on a majority of age at baseline, sex, systolic blood pressure at baseline, QRS the biomarkers within the panel exceeding a threshold value. duration at baseline, PR interval at baseline, ischemic status at In some embodiments, the threshold value can be a unique baseline, beta blocker use at baseline, and ACE/ARB use at quantitative concentration for that particular biomarker. In baseline. other embodiments, the threshold value can be more qualita 0048. In some embodiments, the data used can include tively assessed as either normal or abnormal; or higher than BNP, CRP, TNFR-II, and one, two, three, or more of LVESV normal, normal, or lower than normal. at baseline, age at baseline, sex, systolic blood pressure at baseline, QRS duration at baseline, presence of left bundle 0043. Various embodiments herein can include quantify branch block at baseline, ischemic status at baseline, and ing levels of one or more of a panel of biomarkers in a renal disease at baseline. biological sample of a patient. In some embodiments, quan 0049. It will be appreciated that various samples can be tifying levels can be conducted in vitro. In some embodi used as the biological sample for testing in accordance with ments, quantifying levels can be conducted in vivo. It will be various embodiments herein. By way of example, Samples appreciated that many different techniques exist for quanti can include, but are not limited to fluid samples (such as fying levels of biomarkers, depending of course on the nature plasma, blood, blood serum, interstitial fluid, bodily filtrates, of the specific biomarker. For example, in the context of pleural fluid, lymph fluids, cerebrospinal fluid, mucus, peri identifying proteins or fragments thereof methods used can toneal fluid, saliva, Sweat, tears, urine, as well as other secre include, but are not limited to, ELISA (enzyme linked immu tions, and the like) as well as tissue samples. In various nosorbent assay), western blotting, other types of electro embodiments, the method can further include the step of phoretic analytic assays, immunohistochemical staining, taking a biological sample of a patient. affinity chromatography, mass spectrometry, and the like. In 0050. In some embodiments herein, assay kits are Some embodiments, quantifying levels of one or more biom included. Assay kits can include materials in order to facili arkers can include quantifying levels of other compounds that tate quantifying levels of one or more of a panel of biomarkers would be indicative of those levels. By way of example, in the in a biological sample of a patient. The specific components context of quantifying levels of a particular protein, detection of an assay kit can depend on the technique used to quantify of mRNA coding for the protein or precursors thereof can be the biomarkers. By way of example, in Some embodiments, used in order to quantify Such levels. As such, in various the kit can include probes specific to one or more of a panel of embodiments, techniques can be used including northern biomarkers. In some embodiments, the kit can include probes blotting, RT-PCR (polymerase chain reaction), serial analysis exhibiting binding specificity to one or more of the panel of of gene expression (SAGE), microarray assays, and the like. biomarkers. For example, in some embodiments, the kit can In the context of quantifying levels of particular proteins, include antibodies exhibiting binding specificity to one or other compounds that are indicative of those levels can more of the panel of biomarkers. In some embodiments, the include precursors, proforms, isoforms, mature form vari probes can be hybridization probes. In some embodiments, ants, and degraded forms including but not limited to metabo the probes themselves can include proteins, nucleic acids, and lites thereof. It will be appreciated, however, that many other the like. In some embodiments, the probes can be attached to techniques exist that can be used to detect and/or quantify a Substrate, such as probes attached to a coated glass slide or levels of biomarkers. a gene chip. 0044. In some embodiments, other types of data can be 0051 Referring now to FIG. 1, in some embodiments, used in conjunction with biomarker data for methods herein. methods can include quantifying levels of one or more of a By way of example, data can includebut is not limited to, data panel of biomarkers 102 in a biological sample of a patient. regarding patient gender, ischemic or non-ischemic origin of Quantification of the levels of the biomarkers in the panel can heart failure, the presence or absence of left bundle branch be performed in various ways, such as through the use of block, QRS width (such as QRS width greater than or equal to various techniques described above. In some embodiments, 150 milliseconds), information on prior hospitalizations, left the quantification is an absolute value of the biomarker or ventricular end-diastolic volume (LVEDV) (such as LVEDV panel of biomarkers. In some embodiments, the quantifica greater than 125 mL/m, and left atrial volume (such as left tion is a relative value with respect to values for other mark US 2013/0237439 A1 Sep. 12, 2013 ers, genomic or proteomic targets, or reference values. In still selecting the patient can be based on the patient being indi other embodiments, the quantification may reflect a change in cated for CRT therapy. In some embodiments, selecting the levels over a time period (such as the time period between patient can be based on the patient suffering from heart fail follow-up visits to a clinician or the time period between ure, but not being indicated for CRT therapy. implant of a device and a follow-up visit to a clinician). In 0056. In some embodiments, methods can further include Some embodiments, the change can be a change in absolute determining whether the patient is unlikely to respond to CRT values. In other embodiments, the change can be measured therapy. relative to another piece of data regarding the patient, or 0057. Some methods can include placing the patient into a change of specific biomarkers as measured relative to other category. For example, referring now to FIG. 2, methods can biomarkers. In some embodiment, data regarding biomarker include quantifying levels of biomarkers 202 and placing the levels for a particular patient can be tracked over an extended patient into a category 204. Some embodiments are directed period of time including measurements at a plurality (e.g., to a method of predicting the likelihood of response to CRT 2-100 or more) of time points and an overall profile of therapy including quantifying levels of one or more of a panel changes can be determined. of biomarkers in a biological sample of a patient and using the 0.052. In some embodiments, measurements of biomark quantified levels to place the patient into one of a set of ers can be made prior to a patient receiving a CRT device. In categories. Categories can include, but are not limited to, one other embodiments, measurements of biomarkers can be or more of CRT therapy responders, non-responders, Super made after a patient has received a CRT device. In some responders (e.g., those predicted to respond to a larger than embodiments, measurements of biomarkers can be made average degree amongst responders), negative responders, both prior to and after a patient receiving a CRT device. patients who would likely die regardless of CRT therapy, 0053 Methods can also include analyzing the quantified indeterminate responders, and the like. In some embodi levels 104. For example, method can include analyzing the ments, the set of categories can include at least two catego quantified levels to determine response to CRT therapy. Ana ries. In some embodiments, the set of categories can include lyzing the quantified levels can include various operations. In at least three categories. In some embodiments, the set of Some embodiments, analyzing the quantified levels includes categories can include at least four categories. In some comparing quantified levels to reference normal levels to embodiments, the set of categories can include at least five determine likelihood of response to CRT therapy. The refer categories. ence normal levels can be determined in various ways. In 0058. In some embodiments, placement into a category some embodiments, the reference normal levels are deter can be based on the difference between quantified levels of mined based on a group of patients. In some embodiments, one or more of the panel of biomarkers and reference normal the group is made up of healthy patients. In other embodi levels for one or more of the panel of biomarkers. In some ments, the group is patients with heart failure. In other embodiments, different biomarkers receive equal weighting. embodiments, the group is patients with heart failure who In other embodiments, different biomarkers received differ have received CRT therapy devices. In still other embodi ent weighting. ments, the group is made up of patients with heart failure who 0059. In various embodiments, a method of identifying are responders to CRT therapy. In some embodiments, the patients that are unlikely to respond to CRT therapy is group is made up of patients with heart failure who are not included. The method can include quantifying levels of one or responders to CRT therapy. more of a panel of biomarkers in a biological sample of a 0054. In some embodiments, analyzing the quantified lev patient and analyzing the quantified levels to determine like els includes calculating an aggregate score that represents the lihood of response to CRT therapy. In some embodiments, the deviations of quantified levels from reference normal levels method can further include the step of selecting the patient. for the panel of biomarkers. Positive or negative deviations By way of example, the method can include the step of select from reference normal levels can be indicative of likelihood ing the patient based on the patient being indicated for CRT of response to CRT therapy. In some embodiments, the spe therapy. In some embodiments, the method can further cific degree of positive or negative deviations from reference include the step of selecting the patient based on the patient normal levels can be indicative of likelihood of response to suffering from heart failure, but not being indicated for CRT CRT therapy. In some embodiments, such as where reference therapy. normal levels are derived based on a group of patients with 0060. In some embodiments, a method of determining heart failure who are responders to CRT therapy, non-devia prognosis of a patient receiving CRT therapy is included. The tion from reference normal levels can be indicative of likeli method can include selecting a patient that is receiving CRT hood of response to CRT therapy. In some embodiments, therapy, quantifying levels of one or more of a panel of analyzing the quantified levels comprises comparing quanti biomarkers in a biological sample of the patient, and analyZ fied levels to threshold levels to determine likelihood of ing the quantified levels to determine prognosis. In some response to CRT therapy. embodiments, prognosis can be determined based on com 0055. In some embodiments, methods can further include paring quantified levels to reference normal levels. As with selecting a patient. In some embodiments, the patient can be the above, the reference normal levels can be determined in selected on the basis of symptoms. For example, selecting the various ways. In some embodiments, the reference normal patient can be done on the basis of heart failure symptoms. In levels are determined based on a group of patients. In some Some embodiments, the symptoms can include Subjective embodiments, the group is made up of healthy patients. In symptoms. In other embodiments, the symptoms can include other embodiments, the group is patients with heart failure. In objective symptoms. In still other embodiments, the Symp Some embodiments, the group is made up of patients with toms can include combinations of Subjective and objective heart failure are responders to CRT therapy. In some embodi symptoms. In some embodiments, selecting the patient can be ments, the group is made up of patients with heart failure who based on what the patient is indicated for. By way of example, are not responders to CRT therapy. Also, as with the above, US 2013/0237439 A1 Sep. 12, 2013 analyzing the quantified levels can include calculating an Again, exemplary parameters of CRT therapy can include, aggregate score that represents the deviations of quantified but are not limited to, A-V delay, V-V delay, stimulation levels from reference normal levels for the panel of biomar vector, and the like. kers in Some embodiments. Positive or negative deviations 0064. In some embodiments, a method of monitoring a from reference normal levels can be indicative of patient patient receiving CRT therapy is included herein. The method prognosis. In some embodiments, the specific degree of posi can include quantifying levels of one or more of a panel of tive or negative deviations from reference normal levels can biomarkers in a biological sample of the patient and analyzing be indicative of patient prognosis. In some embodiments, the quantified levels to determine status of the patient. Ana non-deviation from reference normal levels can be indicative lyzing the status of the patient can include classifying the of likelihood of response to CRT therapy. In some embodi patient into one of a set of possible status indicators. The set ments, analyzing the quantified levels comprises comparing of possible status indicators can include one or more of quantified levels to threshold levels to determine patient prog improving condition, worsening condition, or maintaining status quo. In an embodiment, a method of monitoring a OS1S. patient receiving CRT therapy includes quantifying levels of 0061. In some embodiments, data regarding biomarkers one or more of a panel of biomarkers in a biological sample of can be used as a companion diagnostic or theragnostic. One the patient, and analyzing the change in quantified levels over unique impact of Such a theragnostic is that a peripheral time to determine response to therapy changes or to monitor sample can be easily obtained and analyzed and provide rapid disease progression. turn-around information in order to guide the utilization of 0065 Referring now to FIG. 4, a flow chart of some steps medical devices, and thereby provide a significant improve of methods in accordance with various embodiments herein is ment over current diagnostics in that it will provide a predic shown. Specifically, FIG. 4 shows one example of a multi tion of CRT response and responsiveness, and thereby can variate biomarker profiling and decision algorithm for aiding improve medical resource utilization. in the determination of whether cardiac resynchronization therapy (CRT) would be beneficial in patients with signs and 0062. In some embodiments, a method of treating a patient symptoms of heart failure (HF). In some embodiments, is included. Referring now to FIG. 3, in some embodiments, patients are considered if they have signs and symptoms of methods herein can include quantifying levels of biomarkers systolic heart failure. Using the total biomarker panel or a 302, analyzing the quantified levels 304, and adjusting subset of these biomarkers, a high level of prediction (for therapy being received by a patient 306, based at least in part example, AUC-0.80 in some embodiments) can be achieved on the analysis results. Adjusting therapy can include various which will identify those patients with HF and the greatest steps. In some embodiments, adjusting therapy for the patient probability of response. In some embodiments the biomarker includes at least one selected from the group consisting of panel can achieve an AUC-0.60. In some embodiments the initiating the administration of CRT therapy to the patient biomarker panel can achieve an AUC-0.70. In some embodi with an implanted medical device and changing the param ments the biomarker panel can achieve an AUCD0.80. In the eters of CRT therapy administered to the patient. Exemplary method (or algorithm) of FIG. 4 in operation 350, patients that parameters of CRT therapy can include, but are not limited to, have documented HF would be considered. The patients A-V delay, V-V delay, stimulation vector, and the like. In would then be evaluated in operation 352 to determine if they Some embodiments, adjusting therapy can be performed as have been treated according to current American Heart Asso part of a closed-loop process. In some embodiments, changes ciation/American College of Cardiology (AHA/ACC) guide to the parameters of CRT therapy can be made by an lines. If they have, then in operation 354 biomarker panel implanted device automatically. In some embodiments, analysis would be conducted. Then, in operation 356, it would changes to the parameters of CRT therapy can be made by an be determined whether or not the biomarker profile for the external device and then programmed into an implanted patient is above the prediction set point limit based on the device. In other embodiments, adjusting therapy can include AUC (area under the curve in ROC analysis) of the biomarker Suggesting changes in therapy to a clinician through an alert profile as implemented. In some embodiments, the set point notice or other display on an external device. limit is a greater than 60 percent likelihood of non-response. 0063. In some embodiments, a method of treating a patient In some embodiments, the set point limit is a greater than 70 receiving CRT therapy is included. The method can include percent likelihood of non-response. In some embodiments, selecting a patient that is receiving CRT therapy, quantifying the set point limit is a greater than 80 percent likelihood of levels of one or more of a panel of biomarkers in a biological non-response. In some embodiments, the set point limit is a sample of the patient, analyzing the quantified levels to deter greater than 90 percent likelihood of non-response. If the mine an expected response to CRT therapy, comparing the biomarker profile results are below the set point limit, then in expected response to CRT therapy to the patient’s actual operation 358 the patient can be referred for CRT device response to CRT therapy, and adjusting parameters of the implant, or at least referred for further consideration of the CRT therapy if the patient’s actual response to CRT therapy is same. However, if the biomarker profile results are above the worse than the expected response to CRT therapy. Whether or set point limit (meaning for example, that there is a greater not the response to CRT therapy is worse than the expected than 80% chance of non-response) then in operation 360 response can be determined subjectively by a clinician or can various steps can be taken including up-titrating heart failure be objectively determined through techniques including medications. Then, after a time period, a follow-up 362 with analysis based on responses of comparison populations of the patient can be conducted. For example, a follow-up visit patients. In some embodiments, whether heart failure is can take place after three months. Then, in operation 364 worse can be determined according to cardiac pump function, biomarker panel analysis can be repeated. Then, in operation amount of fluid accumulation, activity/exercise tolerance, 356, it can be again determined whether or not the biomarker kidney and cerebral/cognitive function, amongst others. profile for the patient is above the prediction set point limit. If US 2013/0237439 A1 Sep. 12, 2013

the biomarker profile results are below the set point limit, then 414. However, in other embodiments, communication can be in operation 358 the patient can be referred for CRT device carried out via radiofrequency transmission, acoustically, or implant, or at least referred for further consideration of the the like. same. However, if the biomarker profile results are above the 0069. The external medical device 416 can include a video set point limit then in operation 374 the patient can be referred output device, such as a display Screen 418 for displaying for other advanced heart failure treatment. Video output. In some embodiments, the external medical 0066 Referring back to operation 352, if it is determined device 416 can be configured to process the gathered data. that the patient has not been treated according to current The external medical device 416 can also include a user input American Heart Association/American College of Cardiol device 420, such as keys. The external medical system 416 ogy (AHA/ACC) guidelines, then in operation 368 medica can be for example, a programmer/recorder/monitor device, a tions can be titrated and/or added or dropped in according to computer, an advanced patient management system, or a per AHA and/or ACC guidelines. Then, after a time period, a Sonal digital assistant (PDA). Exemplary programmer/re follow-up 370 with the patient can be conducted. For corder/monitor devices include the Model 3120 Programmer, example, a follow-up visit can take place after three months. available from Boston Scientific Corporation, Natick, Mass. Then in operation 372 it can be determined whether the stan 0070. In some embodiments the implantable medical dard of care is being met. If the answer is yes, then biomarker device 414 can include one or more implantable sensors in panel analysis can be performed according to operation 354. order to gather data regarding the patient 412. By way of If not, then the patient can be referred for other advanced heart example, the medical device 414 can include an implantable failure treatment in operation 374. sensor in order to sense concentrations of a predictive marker. 0067. Some embodiments can include systems and/or In some embodiments, the implantable sensor can sense con devices. However, it will be appreciated that embodiments centrations of CRP in vivo. Exemplary implantable sensors related to biomarkers herein are not limited to implementa are described in U.S. Publ. Pat. Appl. No. 2007/0270675, the tion through devices or systems. FIG. 5 is a schematic view of content of which is herein incorporated by reference in its Some system 400 components, consistent with various entirety. embodiments herein. FIG. 5 schematically illustrates a biom arker diagnostic test being run and the values being commu (0071. In some embodiments, concentrations of biomark nicated with a server as well as a device programmer (external ers can be measured using an in vitro assay. By way of medical device) and an implantable medical device. In some example, in some embodiments, an external assay device 428 embodiments, the programmer can communicate with the can be used to measure concentrations of a biomarker Such as device and based on the biomarker values reprogram the CRP. The patient 412 can provide an assayable quantity of device settings as appropriate. Some embodiments can blood or other bodily fluid to the external assay device 428 include all of the components shown in FIG. 5, while other and the device can measure the amount of the biomarker embodiments include only some of the components. Data can present and then report back regarding concentration data pass from various specific components to other components either directly to the implantable medical device 414 or within the system as indicated by the arrows. However, it will through the external medical device 416. be appreciated that communication is not restricted to Such 0072. In some embodiments, the system 400 can include a pathways and that communication of data between devices server 430. The server 430 can be located remotely from other can take place in various ways including automatically or components of the system 400 but can be in communication through manual data input processes. The system 400 can Such as through a network, Such as a packet Switched net include an implantable medical device 414. Methods work. The server 430 can be in communication with one or described herein, or portions thereof, can be executed by the more of the implantable medical device 414, the external implantable medical device 414. The implantable medical medical device 416, and the external assay device 428, when device 414 can be disposed within a patient 412. The implant such components are part of the system 400. The server 430 able medical device 414 can be of various types such as, for can include standard server components such as processor, example, a pacemaker, a cardioverter-defibrillator, a cardiac memory, input/output interfaces, and the like. In some resynchronization device, or the like. In some embodiments, embodiments, the server 430 can further be in communica the implantable medical device 414 is specifically a cardiac tion with a database (not shown). Methods described herein, resynchronization device. One example of an implantable or portions thereof, can be executed by the server 430. medical device is disclosed in commonly assigned U.S. Pat. 0073. In some embodiments, one or more operations, No. 4.562,841, the content of which is herein incorporated by methods described herein, orportions thereof can be executed reference in its entirety. In some embodiments, the implant by an external device. Exemplary external devices, such as able medical device 414 can include one or more leads 422 programmer/recorder/monitors, can include components disposed in or near the patient’s heart 426. The leads can common to many computing devices. Referring now to FIG. include a plurality of electrodes, such as ring and/or tip elec 6, a diagram of various components is shown in accordance trodes. In some embodiments, leads 422 can be positioned in with some embodiments. The external system includes a cen both the left ventricle and the right ventricle of the heart. tral processing unit (CPU) 705 or processor, which may 0068. The implantable medical device 414 can be in com include a conventional microprocessor, random access munication with an external medical device 416 (or device memory (RAM) 710 for temporary storage of information, programmer). Methods described herein, or portions thereof, and read only memory (ROM) 715 for permanent storage of can be executed by the external medical device 416. In some information. A memory controller 720 is provided for con embodiments, communication between the implantable trolling system RAM 710. A bus controller 725 is provided medical device 414 and the external medical device 416 can for controlling data bus 730, and an interrupt controller 735 is be via inductive communication through a wand held on the used for receiving and processing various interrupt signals outside of the patient 412 near the implantable medical device from the other system components. US 2013/0237439 A1 Sep. 12, 2013

0074. In some embodiments mass storage can be provided output pulses, change the pacing pulse amplitude, and adjust by diskette drive 741, which is connected to bus 730 by the gain and threshold values for the sensing amplifiers. It will controller 740, CD-ROM drive 746, which is connected to be appreciated that in some embodiments some of the ele bus 730 by controller 745, and hard disk drive 751, which is ments of the controller module 872 shown in FIG.7 may be connected to bus 730 by controller 750. User input to the omitted. programmer system may be provided by a number of devices. 0078. A shock pulse generator 874 can also be interfaced For example, a keyboard and mouse can connected to bus 730 to the microprocessor for delivering defibrillation shocks to by keyboard and mouse controller 755. DMA controller 760 the heart via a separate pair of electrodes 876, 878. In some is provided for performing direct memory access to system embodiments, electrodes 876 and 878 can be disposed along RAM 710. A visual display is generated by a video controller stimulation lead 830 and stimulation lead 828 respectively. In 765 or video output, which controls video display 770. The Some embodiments, one or more of these components may be external system can also include a telemetry interface 790 or omitted. By way of example, if the implantable medical telemetry circuit which allows the external system to inter device is a pacemaker, then it may not include a shock pulse face and exchange data with an implantable medical device or generator 874. Similarly, depending on the type of the device an external device. In some embodiments, the external system and its configuration, it may have a greater or lesser number of can include a network interface. The external programmer electrodes and channels. device can be configured to receive data regarding levels of 0079. It should be noted that, as used in this specification one or more of a panel of biomarkers in a biological sample of and the appended claims, the singular forms “a” “an and a patient. This description of elements is only provided by “the include plural referents unless the content clearly dic way of example and it will be appreciated that some embodi tates otherwise. It should also be noted that the term 'or' is ments may lack various elements illustrated in FIG. 6. For generally employed in its sense including “and/or unless the example, some embodiments of external devices may lack a content clearly dictates otherwise. diskette drive 741. 0080. It should also be noted that, as used in this specifi 0075. In some embodiments, one or more operations, cation and the appended claims, the phrase “configured methods described herein, orportions thereof can be executed describes a system, apparatus, or other structure that is con by an implantable medical device. Referring now to FIG. 7, structed or configured to perform a particular task or adopt a some components of an exemplary implantable device 800 particular configuration. The phrase “configured’ can be used are schematically illustrated. The implantable medical device interchangeably with other similar phrases such as 800 can include a controller module 872 coupled to one or “arranged”, “arranged and configured”, “constructed and more stimulation leads 830 and 828. The controller module arranged', 'constructed, “manufactured and arranged, and 872 can include a microprocessor 848 (or processor) that the like. communicates with a memory circuit (module) 846 via a I0081. One of ordinary skill in the art will understand that bidirectional data bus. The memory circuit 846 can include the modules, circuitry, and methods shown and described ROM or RAM for program storage and ROM (such as herein with regard to various embodiments can be imple EEPROM) or RAM for data storage. The controller module mented using Software, hardware, and combinations of Soft 872 can be configured to execute various operations such as ware and hardware. As such, the illustrated and/or described processing of signals and execution of methods or portions modules and circuitry are intended to encompass Software thereofas described herein. For example, the controller mod implementations, hardware implementations, and Software ule can be configured to process data regarding the levels of and hardware implementations. one or more of a panel of biomarkers. A telemetry interface I0082 All publications and patent applications in this 864 or communication circuit is also provided for communi specification are indicative of the level of ordinary skill in the cating with an external unit, such as a programmer device or art to which this disclosure pertains. All publications and a patient management system. The communication circuit patent applications are herein incorporated by reference to the can be configured to receive data regarding levels of one or same extent as if each individual publication or patent appli more of the panel of biomarkers. cation was specifically and individually indicated by refer 0076. The controller module 872 can include one or more CCC. Ventricular sensing and pacing channels including sensing I0083. This application is intended to cover adaptations or amplifier 852, output circuit 854, and a ventricular channel variations of the present subject matter. It is to be understood interface 850 which communicates bidirectionally with a port that the above description is intended to be illustrative, and of microprocessor 848. Further, in some embodiments, addi not restrictive. The scope of the present subject matter should tional elements may be included. The Ventricular sensing and be determined with reference to the appended claims, along pacing channel can be in communication with stimulation with the full scope of equivalents to which such claims are lead 830 and electrode 834. entitled. 0077. The controller module 872 can include one or more atrial sensing and pacing channels including sensing ampli EXAMPLES fier858, output circuit 860, and an atrial channel interface 856 which communicates bidirectionally with a port of micropro Example 1 cessor 848. Theatrial sensing and pacing channel can be in communication with stimulation lead 828 and electrode 832. Biomarkers Relevant to CRT Response For each channel, the same lead and electrode can be used for I0084 Plasma was collected at baseline (during CRT both sensing and pacing. The channel interfaces 850 and 856 evaluation, but prior to CRT implant), at 3 and 6 months can include analog-to-digital converters for digitizing sens post-CRT placement in a prospective fashion, from patients ing signal inputs from the sensing amplifiers and registers with heart failure enrolled in a trial (n=764). See Ellenbogen which can be written to by the microprocessor in order to et al., Primary results from the SmartDelay determined AY US 2013/0237439 A1 Sep. 12, 2013

optimization: a comparison to other AV delay methods used in as sST2 and sTNFR-II (31219+980 vs 35435+1120, and cardiac resynchronization therapy (SMART-AV) trial. Circu 8839+497 vs. 9145+281 pg/mL, p<0.05, respectively). lation 2010; 122:2660-2668. The trial established a pre-speci I0089 More importantly, including the baseline measure fied endpoint of a reduction in LV end-systolic volume of 15 ments of all 12 biomarkers in a multivariable regression mL at 6 months post-CRT as a functional response and this model yielded a significant AUC (0.60, p<0.05) for the pre definition was utilized in this biomarker profiling study. The diction of CRT response at 6 months. In addition, a significant initial goal of the trial was to compare 3 different modes of and differential biomarker profiles occurred as a function of CRT atrioventricular (A-V) delay, which following random time, between responders and non-responders to CRT (Fig ization demonstrated relative equivalency for the primary ure). For example, at 3 months post-CRT significant and endpoint, and therefore these patients were pooled for the directional changes in BNP MMP-2, TIMP-2 and TIMP-4 present analysis. occurred between responders/non-responders (p<0.05), and a 0085 Specifically, peripheral venous blood samples were multivariable analysis of all 12 biomarkers at 3 months pre collected from patients with heart failure who meet standard dicted 6 month response (AUC-0.64, p<0.05). FIG. 8 is a indications for CRT in the United States and Europe. Samples graph showing absolute change from baseline at 3 and 6 were collected by standard Venipuncture in two (2) ethylene months for CRT responders versus non-responders for the 12 diamine tetraacetic acid (EDTA, 18 mg purple top) tubes (BD selected biomarkers. However, it will be appreciated that Vacutainer, 366643). Centrifugation was done at room tem relative changes can also be considered in various embodi perature for 10 minutes at high speed (recommended to be mentS. 23,000 revolutions per minute (RPM) or >1300 g (relative 0090 The new and unique findings from this prospec centrifugal force=RCF-g)). The plasma from each blood tively designed plasma profiling study include that a specific sample tube was decanted into two separate and properly biomarker panel can Successfully predict CRT response in labeled polypropylene tubes. The plasma was kept on ice until patients with HF indicated for a device (NYHA Class III/IV, it is transferred to a storage freezer. Plasma samples were EFs35%, QRS duration>120 ms), as well as be utilized to frozen as soon as possible following centrifugation. The monitor functional response following CRT. It will be appre plasma sample were then stored in a -20° C. freezer until ciated, however, that embodiments herein are not limited to shipment. Samples were shipped to the analysis facility patients with that specific indication. Thus, plasma biomarker within 72 hours from enrolling centers. profiling can provide prognostic utility when evaluating I0086 90 candidate plasma proteins which spanned func patients with HF for CRT as well as an adjunctive diagnostic tional domains Such as signaling, inflammation, myocyte/ tool for monitoring functional response in the early period matrix structure for extraction efficiency, detection thresh following CRT placement. olds, and variability in referent non-device patients (n=25). 0091 Multivariate logistic regression modeling was per This was followed by a validation phase of 18 candidate formed to assess positive responders (defined as change in biomarkers in a second subset of the SMART-AV patient LVESV (left ventricular end-systolic volume) from base samples (n=25/25; responder/non-responder). For example, lines-15 ml) versus neutral/negative responders (defined as IFN-gamma was analyzed using an array (Millipore Cytokine death within first 6 months or LVESV change from base Panel); SIL-2RA, and STNF-RII were analyzed using an array line-15 ml). The following biomarker and clinical covari (Millipore Panel), SVCAM-1 was ana ates included in the final multivariate model were selected lyzed using an array (Millipore HCVD1 Panel); MMP-2 using 10-fold cross validation methodology: ST2 (continuous (LMP902: Rn D Systems) and MMP-9 (LMP911; RnD Sys variable), CRP (continuous variable), TIMP1 (continuous tems) were analyzed using an MMP Multiplex Array Panel variable), TIMP2 (continuous variable), LVESV at baseline (RnD Systems Cat #LMP000); TIMP-1 was analyzed using (continuous variable), age at baseline (continuous variable), TIMP Array Panel (Cat #LKT003: RnlD Systems); CRP was sex (binary variable), systolic blood pressure at baseline (con analyzed using an ELISA assay (Cat #DCRP00; RnD Sys tinuous variable). QRS duration at baseline (continuous vari tems), BNP was analyzed using an ELISA assay (Cat #04 able), PR interval at baseline (continuous variable), ischemic BI-20852. ALPCO Immunoassays); ST2 was analyzed using status at baseline (binary variable). ACE (angiotensin-con an ELISA assay (Cat #DST200; RnlD Systems). verting enzyme inhibitors)/ARB (angiotensin II receptor 0087. Using logistic regression and area under the curve blockers) use at baseline (binary variable). Area under the (AUC), a final set of 12 biomarkers were analyzed by inter curve (AUC) obtained via cross-validation for the final set of nally validated, robotic assisted, high sensitivity multiplex covariates equaled 0.731: AUC obtained by fitting the model Suspension array on the entire prospectively collected sample on the entire dataset equaled 0.754. set (>2200 samples) where at 6 months, through independent 0092 Multivariate logistic regression modeling was per review, 338 patients were defined as responders and 376 formed to assess negative responders (defined as death within defined as non-responders. first 6 months or LVESV change from baseline220 ml) ver 0088. The 12 biomarkers represented several domains: sus positive/neutral responders (defined as LVESV change inflammatory (C-reactive protein: CRP soluble glycoprotein from baseline.<20 ml). The following biomarker and clinical 130: SGP-130, soluble interleukin-2 receptor: sIL-2R, covariates included in the final multivariate model were soluble tumor necrosis factor receptor-II: STNFR-II, inter selected using 10-fold cross validation methodology: CRP feron gamma: IFNg), bioactive (brain natriuretic peptide: (continuous variable), BNP (continuous variable), LVESV at BNP soluble suppressor of tumorgenicity-2:SST2), and pro baseline (continuous variable), age at baseline (continuous teolytic (matrix metalloproteinase-2 and -9: MMP-27-9, tis variable), sex (binary variable), systolic blood pressure at sue inhibitors of MMP. TIMP-1, -2, -4). Significant differ baseline (continuous variable), presence of left bundlebranch ences in absolute values for several of these prospectively block at baseline (binary variable), renal disease at baseline collected biomarkers occurred at baseline between those (binary variable), ischemic status at baseline (binary vari defined as responders and non-responders at 6 months. Such able), beta blocker use at baseline (binary variable). Area US 2013/0237439 A1 Sep. 12, 2013

under the curve (AUC) obtained via cross-validation for the consisting of CRP, SGP-130, SIL-2R, STNFR-II, IFNg, BNP final set of covariates equaled 0.676: AUC obtained by fitting sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. The the model on the entire dataset equaled 0.715. device can further be configured to modulate therapy based 0093 Multivariate logistic regression modeling was per on the data regarding levels of the one or more of the panel of formed to assess positive responders (defined as change in biomarkers. In an embodiment, the panel of biomarkers LVESV from baselines-15 ml) versus negative responders includes at least three selected from the group consisting of (defined as death within first 6 months or LVESV change CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP from baseline-20 ml). The following biomarker and clinical 2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. In an embodi covariates included in the final multivariate model were ment, the panel of biomarkers includes at least four selected selected using 10-fold cross validation methodology: CRP from the group consisting of CRP, SGP-130, sIL-2R, STNFR (continuous variable), BNP (continuous variable), LVESV at II, IFNg, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, baseline (continuous variable), age at baseline (continuous and TIMP-4. The implantable medical device can be config variable), sex (binary variable), systolic blood pressure at ured to change the parameters of CRT therapy administered to baseline (continuous variable). QRS duration at baseline the patient based on the data regarding the levels of one or (continuous variable), PR interval at baseline (continuous more of the panel of biomarkers. variable), ischemic status at baseline (binary variable), beta 0097. In an embodiment, a medical system is included. blocker use at baseline (binary variable). ACE/ARB use at The medical system can include an external programmer baseline (binary variable). Area under the curve (AUC) device and an implantable medical device. The implantable obtained via cross-validation for the final set of covariates medical device can be configured to communicate with the equaled 0.739; AUC obtained by fitting the model on the programmer through a telemetry interface. The external pro entire dataset equaled 0.765. grammer device can be configured to receive data regarding 0094 Multivariate cumulative logistic regression model levels of one or more of a panel of biomarkers in a biological ing was performed to assess response as a three level out sample of a patient; the panel of biomarkers including at least come: positive responders (defined as change in LVESV from one selected from the group consisting of CRP, SGP-130, baselines-15 ml), neutral responders (defined as LVESV sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP-2, MMP-9, change from baseline-15 ml and <20 ml), and negative TIMP-1, TIMP-2, and TIMP-4. The external programmer responders (defined as death within first 6 months or LVESV device can be configured to process the data regarding the change from baseline220 ml). The following biomarker and levels of one or more of the panel of biomarkers. The external clinical covariates included in the final multivariate model programmer device can be configured to send programming were selected using 10-fold cross validation methodology: instructions regarding CRT therapy to the implantable device BNP (continuous variable), CRP (continuous variable), based on the data regarding the levels of one or more of the TNFR-II (continuous variable), LVESV at baseline (continu panel of biomarkers. ous variable), age at baseline (continuous variable), sex (bi What is claimed is: nary variable), systolic blood pressure at baseline (continuous 1. A method of predicting response to CRT therapy com variable). QRS duration at baseline (continuous variable), prising: presence of left bundle branch block at baseline (binary vari quantifying levels of one or more of a panel of biomarkers able), ischemic status at baseline (binary variable), renal dis in a biological sample of a patient; ease at baseline (binary variable). Area under the curve analyzing the quantified levels to determine response to (AUC) obtained via cross-validation for the final set of cova CRT therapy: riates equaled 0.681; AUC obtained by fitting the model on wherein the panel of biomarkers includes at least two the entire dataset equaled 0.696. selected from the group consisting of CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP-2, MMP-9, Additional Embodiments TIMP-1, TIMP-2, and TIMP-4. 0095. In an embodiment, an assay kit is included. The 2. The method of claim 1, wherein analyzing the quantified assay kit can include probes to quantify levels of one or more levels comprises comparing quantified levels to threshold of a panel of biomarkers in a biological sample of a patient; levels to determine likelihood of response to CRT therapy. wherein the panel of biomarkers includes at least two selected 3. The method of claim 1, wherein the panel of biomarkers from the group consisting of CRP, SGP-130, sIL-2R, STNFR includes at least three selected from the group consisting of II, IFNg, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP and TIMP-4. In an embodiment, the panel of biomarkers 2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. includes at least three selected from the group consisting of 4. The method of claim 1, wherein the panel of biomarkers CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP sST2, MMP includes at least CRP, STNFR-II, and BNP. 2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. In an embodi 5. The method of claim 1, wherein the panel of biomarkers ment, the panel of biomarkers includes at least four selected includes at least CRP, SST2, TIMP-1 and TIMP-2. from the group consisting of CRP, SGP-130, sIL-2R, STNFR 6. The method of claim 1, further comprising selecting the II, IFNg, BNP, sST2, MMP-2, MMP-9, TIMP-1, TIMP-2, patient on the basis of heart failure symptoms. and TIMP-4. 7. The method of claim 1, further comprising using the 0096. In an embodiment, an implantable medical device is quantified levels to place the patient into one of a set of included. The implantable medical device can include a pro categories, the set of categories including at least one of CRT cessor, and a communication circuit operably connected to therapy responders, CRT therapy non-responders, and inde the processor. The communication circuit can be configured terminate response. to receive data regarding levels of one or more of a panel of 8. The method of claim 1, further comprising the step of biomarkers in a biological sample of a patient; the panel of selecting the patient based on the patient being indicated for biomarkers including at least one selected from the group CRT therapy. US 2013/0237439 A1 Sep. 12, 2013

9. The method of claim 1, further comprising the step of 15. The method of claim 14, further comprising adjusting selecting the patient based on the patient Suffering from heart therapy for the patient based at least in part on the analysis failure but not being indicated for CRT therapy. results. 10. A method of determining prognosis of a patient receiv 16. The method of claim 15, wherein adjusting therapy for ing CRT therapy: the patient includes at least one selected from the group Selecting a patient that is receiving CRT therapy; consisting of initiating the administration of CRT therapy to quantifying levels of one or more of a panel of biomarkers the patient with an implanted medical device and changing in a biological sample of the patient; the parameters of CRT therapy administered to the patient. analyzing the quantified levels to determine prognosis: wherein the panel of biomarkers includes at least two 17. The method of claim 14, further comprising selecting a selected from the group consisting of CRP, SGP-130, patient that is receiving CRT therapy. sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP-2, MMP-9, 18. The method of claim 14, further comprising analyzing TIMP-1, TIMP-2, and TIMP-4. the quantified levels to determine an expected response to 11. The method of claim 10, wherein the panel of biomar CRT therapy; comparing the expected response to CRT kers includes at least three selected from the group consisting therapy to the patient’s actual response to CRT therapy; and of CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP, sST2, adjusting parameters of the CRT therapy if the patients actual MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. response to CRT therapy is worse than the expected response 12. The method of claim 10, wherein the panel of biomar to CRT therapy. kers includes at least CRP, STNFR-II, and BNP. 19. The method of claim 14, wherein the panel of biomar 13. The method of claim 10, wherein the panel of biomar kers includes at least three selected from the group consisting kers includes at least CRP, SST2, TIMP-1 and TIMP-2. of CRP, SGP-130, sIL-2R, STNFR-II, IFNg, BNP sST2, 14. A method of evaluating a patient: MMP-2, MMP-9, TIMP-1, TIMP-2, and TIMP-4. quantifying levels of one or more of a panel of biomarkers in a biological sample of the patient; and 20. The method of claim 14, further comprising analyzing analyzing the quantified levels to determine status; the change in quantified levels over time to perform one or wherein the panel of biomarkers includes at least two more selected from the group consisting of analyzing selected from the group consisting of CRP, SGP-130, response to therapy changes and monitoring disease progres sIL-2R, STNFR-II, IFNg, BNP, sST2, MMP-2, MMP-9, S1O. TIMP-1, TIMP-2, and TIMP-4.