US009 161952B2

(12) United States Patent (10) Patent No.: US 9,161,952 B2 Matheny et al. (45) Date of Patent: Oct. 20, 2015

(54) METHOD FORTREATMENT OF (52) U.S. Cl. CARDOVASCULARDISORDERS CPC ...... A61K 35/35 (2013.01) (58) Field of Classification Search (71) Applicant: CORMATRIX CARDIOVASCULAR, CPC ...... A61K 35/34: A61K 35/36; A61 K35/12: INC., Roswell, GA (US) A61L 2300/236; A61L 2300/41: A61 L (72) Inventors: Robert G Matheny, Norcross, GA (US); i. A61L, 3. A61L E. Anna Fallon, Woodstock, GA (US) A61L 27/00; A61L 27/3633; A61L 27/3637; A61L 27/3683; A61L 27/3839; A61L 27/54; (73) Assignee: CORMATRIX CARDIOVASCULAR, A61L 27/56; A61L 27/58: A61M 5/14 INC., Roswell, GA (US) See application file for complete search history. (*) Notice: Subject to any disclaimer, the term of this (56) References Cited patent is extended or adjusted under 35 U.S.C. 154(b) by 0 days. U.S. PATENT DOCUMENTS 2005/0031691 A1 2/2005 McGurk et al...... 424/484 (21) Appl. No.: 13/915,203 2005/0058688 A1* 3/2005 Boerger et al...... 424/426 2005, 0169960 A1* 8, 2005 Hunter et al...... 424/423 (22) Filed: Jun. 11, 2013 2005/0182465 A1 8/2005 Ness ...... 607,116 2007/0014773 A1* 1/2007 Matheny et al...... 424.93.21 (65) Prior Publication Data OTHER PUBLICATIONS US 2015/OO17254A1 Jan. 15, 2015 Krishnamani et al. Nature Reviews Cardiology 7, 71-76 Feb. 2010.* Related U.S. Application Data (60) Division of application No. 13/782,115, filed on Mar. k cited. by examiner 1, 2013, and a continuation-in-part of application No. war. ?hri continuation-in-part13/573,569, filed ofon applicationSep. 24, No.2012, 1 1/334,631, and a CfiO,SSIS OF EXOFife —(i. oug aS whiite filed on Jan. 18, 2006, and a continuation-in-part of (74) Attorney, Agent, or Firm — Francis Law Group application No. 1 1/182,551, filed on Jul. 15, 2005, now Pat. No. 8,568,761. (57) ABSTRACT Methods for treating a cardiovascular disorder comprising (51) Int. Cl. concomitant administration of one or more extracellular CI2N5/00 (2006.01) matrix (ECM) based compositions directly to damaged or A6F 2/00 (2006.01) diseased cardiovascular tissue associated with the cardiovas A 6LX 35/37 (2015.01) cular disorder, and provision of Ventricular assistance. In a A6 IK35/38 (2015.01) preferred embodiment, the ECM based compositions include CI2N 5/071 (2010.01) an ECM material derived from a mammalian source. CI2N 5/02 (2006.01) A 6LX 35/35 (2015.01) 4 Claims, 4 Drawing Sheets

U.S. Patent Oct. 20, 2015 Sheet 1 of 4 US 9,161,952 B2

U.S. Patent Oct. 20, 2015 Sheet 2 of 4 US 9,161,952 B2

U.S. Patent Oct. 20, 2015 Sheet 3 of 4 US 9,161,952 B2

U.S. Patent Oct. 20, 2015 Sheet 4 of 4 US 9,161,952 B2

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06 US 9,161,952 B2 1. 2 METHOD FOR TREATMENT OF ods for treating ischemic heart disease have thus been devel CARDOVASCULARDISORDERS oped. Such methods include systemic delivery of various pharmacological agents. CROSS-REFERENCES TO RELATED Several additional methods for treating ischemic heart dis APPLICATIONS ease are directed to re-establishing blood flow to the ischemic area. Such methods include stimulation of angiogenesis and This application is a division of U.S. application Ser. No. Surgical intervention, e.g. bypass Surgery or angioplasty. 13/782,115, which is a continuation-in-part of U.S. applica Other methods include the use of lasers to bore holes through tion Ser. No. 13/573,569, filed on Sep. 24, 2012, which is a theischemic area(s) to promote blood flow. As one can readily continuation-in-part of U.S. application Ser. No. 1 1/334,631, 10 appreciate, there are numerous incumbent risks associated with the noted methods. filed on Jan. 18, 2006, which is a continuation of application A further method for treating ischemic heart disease is the Ser. No. 12/371,158, filed on Feb. 13, 2009, now abandoned, direct delivery of bioactive or pharmacological agents to the which is a continuation of application Ser. No. 1 1/747.018, ischemic area. Illustrative is the delivery of extracellular filed on May 10, 2007, now abandoned. 15 matrix (ECM) based compositions directly to cardiovascular FIELD OF THE INVENTION tissue disclosed in Co-pending application Ser. No. 13/573, 569. More recently, ventricular assist devices (VADs) have been The present invention relates to methods for treating car employed as treatment platforms for various pharmacologi diovascular disorders. More particularly, the present inven cal therapies, e.g. stem cell administration, which have been tion relates to methods for treating cardiovascular disorders developed to treat cardiovascular disorders, including comprising concomitant administration of an extracellular ischemic heart disease. VADS are designed to Support (or matrix (ECM) composition and Ventricular assistance. augment) the function of either the right (RVAD) or left (LVAD) ventricle, or both at once (BiVAD). The type of VAD BACKGROUND OF THE INVENTION 25 employed depends primarily on the underlying cardiovascu lar disorder, and the pulmonary arterial resistance that deter As is well known in the art, heart failure can be caused by mines the load on the right ventricle. a diverse array of cardiovascular disorders that reduce the Although the direct delivery of bioactive or pharmacologi efficiency of the myocardium, including ischemic heart dis cal agents; particularly, the ECM based compositions dis ease, coronary artery disease, and a defective or diseased 30 closed in Co-pending application Ser. No. 13/573,569, and heart Valve. Among the noted disorders, ischemic heart dis other treatment therapies employing ventricular assistance ease, which commonly presents as a myocardial infarction, is have been found effective to treat cardiovascular disorders the leading cause of heart failure. and, thereby, heart failure, there remains a need to provide Indeed, in 2004 alone, the World Health Organization esti even more effective means for treating cardiovascular disor mated that 12.2% of worldwide deaths occurred as a result of 35 ders. ischemic heart disease. Ischemic heart disease was also It is therefore an object of the present invention to provide deemed the leading cause of death in middle to high income improved methods for treating cardiovascular disorders. countries and second only to respiratory infections in lower It is another object of the present invention to provide income countries. The Global Burden of Disease. World methods for treating cardiovascular disorders that include Health Organization 2004 Update, Geneva (2008). World 40 concomitant administration of an ECM based composition wide more than 3 million people present with a ST elevation and Ventricular assistance. myocardial infarction (STEMI) and 4 million people present It is another object of the present invention to provide with a non-ST elevation myocardial infarction (NSTEMI) a methods for treating cardiovascular disorders that include year. White, et al., Acute Myocardial Infarction, Lancet 372 concomitant administration of (i) an ECM based composi (9638), pp. 570-84 (August 2008). 45 tion, which, when delivered to damaged biological tissue; Rates of death from ischemic heart disease have slowed or particularly, cardiovascular tissue, induces neovasculariza declined in most high income countries, although cardiovas tion, host tissue proliferation, bioremodeling, and regenera cular disease still accounted for 1 in 3 of all deaths in the USA tion of cardiovascular tissue and associated structures with in 2008. Roger, et al., Executive summary: Heart Disease and site-specific structural and functional properties, and (ii) Ven Stroke Statistics 2012 update. A report from the American 50 tricular assistance to augment heart function. Heart Association, Circulation 125 (1), pp. 188-97 (January 2012). SUMMARY OF THE INVENTION In contrast, ischemic heart disease is becoming a more common cause of death in the developing world. For example The present invention is directed to methods and systems in India, ischemic heart disease had become the leading cause 55 for treating cardiovascular disorders. In a preferred embodi of death by 2004; accounting for 1.46 million deaths (14% of ment of the invention, the methods comprise concomitant total deaths). Deaths in India due to ischemic heart disease administration of one or more ECM based compositions to were also expected to double during 1985-2015. Gupta, et al., damaged or diseased cardiovascular tissue, and provision of Epidemiology and Causation of Coronary Heart Disease and Ventricular assistance. Stroke in India, Heart 94(1), pp. 16-26 (January 2008). 60 In a preferred embodiment of the invention, one or more Globally, it is predicted that disability adjusted life years ECM based compositions are administered directly to the (DALYs) lost to ischemic heart disease will account for 5.5% cardiovascular tissue. of total DALYs in 2030, making it the second most important In some embodiments, the cardiovascular tissue comprises cause of disability (after unipolar depressive disorder), as myocardium tissue. well as the leading cause of death by this date. 65 In a preferred embodiment, the ECM based compositions Ischemic heart disease often occurs when myocardial tis include at least one ECM material derived from a mammalian Sue is no longer receiving adequate blood flow. Various meth tissue source. US 9,161,952 B2 3 4 In some embodiments, the mammalian tissue source is preferred embodiments of the invention, as illustrated in the selected from the group comprising Small intestine Submu accompanying drawings, and in which like referenced char cosa (SIS), urinary bladder submucosa (UBS), stomach sub acters generally refer to the same parts or elements through mucosa (SS), central nervous system tissue, epithelium of out the views, and in which: mesodermal origin, i.e. mesothelial tissue, dermal extracel lular matrix, Subcutaneous extracellular matrix, gastrointes FIG. 1 is a depiction of a normal heart; tinal extracellular matrix, i.e. large and Small intestines, tissue FIG. 2 is a of a heart having an ischemic infracted region; Surrounding growing bone, placental extracellular matrix, FIG. 3A is an exploded perspective view of one embodi ornamentum extracellular matrix, cardiac extracellular ment of a multi-needle injection apparatus that is suitable for matrix, e.g., pericardium and/or myocardium, kidney extra direct administration of ECM compositions to biological tis cellular matrix, pancreas extracellular matrix, lung extracel 10 Sue, e.g. cardiovascular tissue, in accordance with the inven lular matrix, and combinations thereof. tion; In a preferred embodiment, the mammalian tissue source FIG. 3B is an assembled perspective view of the multi comprises mesothelial tissue. needle injection apparatus shown in FIG. 3A, in accordance In some embodiments, the ECM compositions further with the invention; include one or more additional biologically active compo 15 FIG. 4 is a front perspective view of a prior art ventricular nents to facilitate treatment of the damaged cardiovascular assist device (VAD): tissue and/or the tissue regenerative process. FIG. 5 is a simplified, fragmentary representation of a In some embodiments, the biologically active component human heart, showing the VAD illustrated in FIG. 4 comprises a pharmacological agent or composition. implanted within the left ventricle of the heart, in accordance In some embodiments of the invention, the biologically with the invention; and active component comprises an anti-inflammatory agent or FIG. 6 is a graphical illustration of ejection fraction as a composition. function of time for porcine samples Subjected to three car In some embodiments of the invention, the biologically diovascular treatments, i.e. Ventricular assist (VAD) only, active component comprises a statin. administration of an extracellular matrix (ECM) composi In Some embodiments, the statin is selected from the group 25 comprising atorvastatin, cerivastatin, fluvastatin, lovastatin, tion, and VAD plus administration of an ECM composition, in mevastatin, pitavastatin, pravastatin, rosuvastatin, and simv accordance with the invention. astatin. In some embodiments of the invention, the biologically DETAILED DESCRIPTION OF THE PREFERRED active component comprises chitosan. EMBODIMENT In some embodiments of the invention, the biologically 30 active component comprises a growth factor selected from Before describing the present invention in detail, it is to be the group comprising a platelet derived growth factor understood that this invention is not limited to particularly (PDGF), epidermal growth factor (EGF), transforming exemplified apparatus, systems, compositions or methods as growth factor alpha (TGF-alpha), transforming growth factor Such may, of course, vary. Thus, although a number of sys beta (TGF-beta), fibroblast growth factor-2 (FGF-2), basic 35 tems, compositions and methods similar or equivalent to fibroblast growth factor (bFGF), vascular epithelial growth those described herein can be used in the practice of the factor (VEGF), hepatocyte growth factor (HGF), insulin-like present invention, the preferred systems, compositions and growth factor (IGF), nerve growth factor (NGF), platlet methods are described herein. derived growth factor (PDGF), tumor necrosis factor alpha It is also to be understood that, although a preferred method (TNA-alpha), and placental growth factor (PLGF). 40 of delivering an ECM based composition of the invention to In some embodiments of the invention, the biologically biological tissue comprises direct injection into the tissue. active component comprises an antiarrhythmic agent selected The delivery of an ECM based composition is not limited to from the group comprising quinidine, procainamide, disopy direct injection. According to the invention, an ECM based ramide, lidocaine, phenytoin, mexiletine, flecainide, pro composition of the invention can be delivered to biological pafenone, moricizine, propranolol, esmolol, timolol, meto 45 prolol, atenolol, amiodarone, Sotalol, ibutilide, dofetilide, tissue by other conventional means, including topical admin Verapamil, diltiazem, adenosine and digoxin. istration. In some embodiments of the invention, the biologically It is further to be understood that the terminology used active component comprises a protein. herein is for the purpose of describing particular embodi In some embodiments of the invention, the ECM based ments of the invention only and is not intended to be limiting. compositions are formulated to facilitate injection of the 50 Unless defined otherwise, all technical and scientific terms ECM based compositions to damaged or diseased tissue (i.e. used herein have the same meaning as commonly understood injectable ECM compositions). by one having ordinary skill in the art to which the invention In some embodiments of the invention, Ventricular assis pertains. tance is provided by a mechanical circulatory support (MCS) Further, all publications, patents and patent applications device. 55 cited herein, whether supra or infra, are hereby incorporated In some embodiments of the invention, Ventricular assis by reference in their entirety. tance is provided by a left ventricular assist device (LVAD). Finally, as used in this specification and the appended In some embodiments of the invention, Ventricular assis claims, the singular forms “a, “an and “the include plural tance is provided by a right ventricular assist device (RVAD). referents unless the content clearly dictates otherwise. Thus, In some embodiments of the invention, Ventricular assis 60 for example, reference to “an anti-inflammatory' includes tance is provided by a left and right ventricular assist device two or more Such agents and the like. (BiVAD). DEFINITIONS BRIEF DESCRIPTION OF THE DRAWINGS 65 The terms “cardiovascular disorder” and “heart failure' are Further features and advantages will become apparent used interchangeably herein, and mean and include any from the following and more particular description of the abnormal function of the heart; particularly, abnormal func US 9,161,952 B2 5 6 tions or deficiency of the myocardium. The terms “cardiovas submucosa (SIS), urinary bladder submucosa (UBS), stom cular disorder” and “heart failure' thus include, without limi ach Submucosa (SS), central nervous system tissue, epithe tation, ischemic heart disease, coronary artery disease, a lium of mesodermal origin, i.e. mesothelial tissue, dermal defective or diseased heart valve, myocarditis, an inflamma extracellular matrix, Subcutaneous extracellular matrix, gas tory disease, cardiomyopathy and amyloidosis. trointestinal extracellular matrix, i.e. large and Small intes The term “ventricular assistance', as used herein, means tines, tissue Surrounding growing bone, placental extracellu and includes any means of providing circulatory assistance to lar matrix, ornamentum extracellular matrix, cardiac a heart and/or supporting the function of a heart. According to extracellular matrix, e.g., pericardium and/or myocardium, the invention, “ventricular assistance' can be provided by a kidney extracellular matrix, pancreas extracellular matrix, variety of conventional ventricular assist devices, including, 10 lung extracellular matrix, and combinations thereof. The without limitation, a left ventricular assist device (LVAD), ECM material can also comprise collagen from mammalian right ventricular assist device (RVAD), left and right ventricu SOUCS. lar assist device (BiVAD), and other mechanical circulatory The terms “urinary bladder submucosa (UBS)”, “small support (MCS) devices. intestine submucosa (SIS) and “stomach submucosa (SS)” The term “concomitant, as used herein in connection with 15 also mean and include any UBS and/or SIS and/or SS material the administration of an ECM based composition of the that includes the tunica mucosa (which includes the transi invention and ventricular assistance, means that the ECM tional epithelial layer and the tunica propria), Submucosal based composition and Ventricular assistance are adminis layer, one or more layers of muscularis, and adventitia (a tered (or provided) concurrently at a defined point in time. loose connective tissue layer) associated therewith. Thus, in some embodiments of the invention, ventricular The ECM material can also be derived from basement assistance is initially provided followed by the administration membrane of mammalian tissue/organs, including, without of an ECM based composition. In some embodiments, an limitation, urinary basement membrane (UBM), liver base ECM based composition is initially administered and ven ment membrane (LBM), and amnion, chorion, allograft peri tricular assistance is provided thereafter. cardium, allograft acellular dermis, amniotic membrane, The terms “cardiovascular tissue damage.” “cardiac tissue 25 Wharton's jelly, and combinations thereof. damage.” and "cardiac tissue injury' and are used inter Additional Sources of mammalian basement membrane changeably herein, and mean and include any area of abnor include, without limitation, spleen, lymph nodes, salivary mal tissue in the cardiovascular system or heart caused by a glands, prostate, pancreas and other secreting glands. disease, disorder, injury or damage, including damage to the The ECM material can also be derived from other sources, epicardium, endocardium and/or myocardium. 30 including, without limitation, collagen from plant sources As is well known in the art, cardiovascular tissue damage and synthesized extracellular matrices, i.e. cell cultures. most often involves damage or injury to the myocardium and, According to the invention, ECM material can comprise, in therefore, for the purposes of this disclosure, myocardial whole or in part, just the basement membrane (or transitional damage or injury is equivalent to cardiovascular tissue dam epithelial layer) with the Subadjacent tunica propria, the age. 35 tunica Submucosa, tunica muscularis, and tunica serosa. The The terms “prevent' and “preventing are used inter extracellular matrix component of the ECM material can thus changeably herein, and mean and include reducing the fre contain any or all of these layers or only the basement mem quency or severity of a disease, condition or disorder. The brane portion, excluding the Submucosa. term does not require an absolute preclusion of the disease, The term “chamber remodeling, as used herein, means condition or disorder. Rather, this term includes decreasing 40 and includes a series of events (which may include changes in the chance for disease occurrence. gene expression, molecular, cellular and interstitial changes) The terms “treat' and “treatment” are used interchange that result in changes in size, shape and function of biological ably herein, and mean and include medical management of a tissue following stress or injury. As is well known in the art, patient with the intent to cure, ameliorate, stabilize, or prevent remodeling can occur after a myocardial infarction, pressure a disease, pathological condition or disorder. The terms 45 overload (e.g., aortic Stenosis, hypertension), Volume over include “active treatment’, i.e. treatment directed specifically load (e.g., valvular regurgitation), inflammatory heart disease toward the improvement of a disease, pathological condition (e.g., myocarditis), or in idiopathic cases (e.g., idiopathic or disorder, and “causal treatment’, i.e. treatment directed dilated cardiomyopathy). toward removal of the cause of the associated disease, patho The term “angiogenesis', as used herein, means a physi logical condition or disorder. 50 ologic process involving the growth of new blood vessels The terms “treat' and “treatment' further include “pallia from pre-existing blood vessels. tive treatment’, i.e. treatment designed for the relief of symp The term “neovascularization', as used herein, means and toms rather than the curing of the disease, pathological con includes the formation of functional vascular networks that dition or disorder, “preventative treatment’, i.e. treatment can be perfused by blood or blood components. Neovascu directed to minimizing or partially or completely inhibiting 55 larization includes angiogenesis, budding angiogenesis, the development of the associated disease, pathological con intus Suceptive angiogenesis, Sprouting angiogenesis, thera dition or disorder, and “supportive treatment’, i.e. treatment peutic angiogenesis and Vasculogenesis. employed to Supplement another specific therapy directed The terms “pharmacological agent”, “pharmacological toward the improvement of the associated disease, pathologi composition' and “biologically active agent, as used herein, cal condition or disorder. 60 mean and include an agent, drug, compound, composition of The terms “extracellular matrix”, “ECM’ and “ECM mate matter or mixture thereof, including its formulation, which rial” are used interchangeably herein, and mean and include a provides some therapeutic, often beneficial, effect. This collagen-rich Substance that is found in between cells in includes any physiologically or pharmacologically active mammalian tissue, and any material processed therefrom, Substance that produces a localized or systemic effect or e.g. decellularized ECM. According to the invention, the 65 effects in animals, including warm blooded mammals, ECM material can be derived from a variety of mammalian humans and primates; avians; domestic household or farm tissue sources, including, without limitation, Small intestine animals, such as cats, dogs, sheep, goats, cattle, horses and US 9,161,952 B2 7 8 pigs; laboratory animals, such as mice, rats and guinea pigs, The terms “pharmacological agent” and “biologically fish; reptiles; Zoo and wild animals; and the like. active agent' further include, without limitation, the follow The terms “pharmacological agent' and “biologically ing steroids: andranes (e.g., testosterone), cholestanes, cholic active agent” thus mean and include, without limitation, anti acids, corticosteroids (e.g., dexamethasone), estraenes (e.g., biotics, anti-arrhythmic agents, anti-viral agents, analgesics, estradiol) and pregnanes (e.g., progesterone). steroidal anti-inflammatories, non-steroidal anti-inflamma The terms “pharmacological agent” and “biologically tories, anti-neoplastics, anti-spasmodics, modulators of cell active agent' further include, without limitation, the follow extracellular matrix interactions, proteins, hormones, growth ing narcotic analgesics: morphine, codeine, heroin, hydro factors, matrix metalloproteinases (MMPS), enzymes and morphone, levorphanol, meperidine, methadone, oxycodone, enzyme inhibitors, anticoagulants and/or antithrombic 10 propoxyphene, fentanyl, methadone, naloxone, buprenor agents, DNA, RNA, modified DNA and RNA, NSAIDs, phine, butorphanol, nalbuphine and pentazocine. inhibitors of DNA, RNA or protein synthesis, polypeptides, The terms “pharmacological agent” and “biologically oligonucleotides, polynucleotides, nucleoproteins, com active agent' further include, without limitation, the follow pounds modulating cell migration, compounds modulating ing anesthetics: esters, such as benzocaine, chloroprocaine, proliferation and growth of tissue, and vasodilating agents. 15 cocaine, cyclomethycaine, dimethocaine/larocaine, piper The terms “pharmacological agent' and “biologically ocaine, propoxycaine, procaine/novacaine, proparacaine, and active agent” accordingly include, without limitation, atro tetracaine/amethocaine. Local anesthetics can also include, pine, tropicamide, dexamethasone, dexamethasone phos without limitation, amides, such as articaine, bupivacaine, phate, betamethasone, betamethasone phosphate, predniso cinchocaine/dibucaine, etidocaine, levobupivacaine, lone, triamcinolone, triamcinolone acetonide, fluocinolone lidocaine/lignocaine, mepivacaine, prilocaine, ropivacaine, acetonide, anecortave acetate, budesonide, cyclosporine, and trimecaine. Local anesthetics can further include combi FK-506, rapamycin, ruboxistaurin, midostaurin, flurbipro nations of the above from either amides or esters. fen, Suprofen, ketoprofen, diclofenac, ketorolac, nepafenac, The terms “pharmacological agent” and “biologically lidocaine, neomycin, polymyxin b, bacitracin, gramicidin, active agent' further include, without limitation, the follow gentamicin, oyXtetracycline, ciprofloxacin, ofloxacin, tobra 25 ing cytotoxic anti-neoplastic agents and chemotherapy mycin, amikacin, Vancomycin, cefazolin, ticarcillin, agents: alkylating agents, cisplatin, carboplatin, oxaliplatin, chloramphenicol, miconazole, itraconazole, trifluridine, mechlorethamine, cyclophosphamide, chlorambucil, and Vidarabine, ganciclovir, acyclovir, cidofovir, ara-amp, foscar ifosfamide. Chemotherapy agents can also include, without net, idoxuridine, adefovir dipivoxil, methotrexate, carbopl limitation, antimetabolites, such as purine analogues, pyrimi atin, phenylephrine, epinephrine, diplivefrin, timolol, 6-hy 30 dine analogues, and antifolates, plant alkaloids, such as Vin droxydopamine, betaxolol, pilocarpine, carbachol, cristine, vinblastine, Vinorelbine, Vindesine, podophyllo physostigmine, demecarium, dorzolamide, brinzolamide, toxin, etoposide and teniposide, taxanes, such as paclitaxel latanoprost, sodium hyaluronate, insulin, Verteporfin, pegap and docetaxel, topoisomerase inhibitors, such as irinotecan, tanib, ranibizumab, and other antibodies, antineoplastics, topotecan, amsacrine, etoposide, etoposide phosphate and AntiVGEFs, ciliary neurotrophic factor, brain-derived neu 35 teniposide, cytotoxic antibiotics. Such as actinomyocin, bleo rotrophic factor, bFGF, Caspase-1 inhibitors, Caspase-3 mycin, plicamycin, mytomycin and anthracyclines, such as inhibitors, C-Adrenoceptors agonists, NMDA antagonists, doxorubicin, daunorubicin, valrubicin, idarubicin, epirubi Glial cell line-derived neurotrophic factors (GDNF), pigment cin, and antibody treatments, such as abciximab, adamli epithelium-derived factor (PEDF), and NT-3, NT-4, NGF, mumab, alamtuzumab, basiliximab, belimumab, bevaci IGF-2. 40 Zumab, brentuximab vedotin, canakinumab, cetuximab, According to the invention, the terms “pharmacological certolizumab pego, daclizumab, denosumab, eculizumab, agent” and “biologically active agent' further include, with efalizumab, gemtuzumab, golimumab, ibritumomab tiuX out limitation, the following growth factors: platelet derived etan, infliximab, ipilimumab, muromonab-CD3, natali growth factor (PDGF), epidermal growth factor (EGF), trans Zumab. ofatumumab, omalizumab, palivizumab, panitu forming growth factor alpha (TGF-alpha), transforming 45 mumab, ranibizumab, rituximab, tocilizumab (atlizumab), growth factor beta (TGF-beta), fibroblast growth factor-2 to sittimomab and trastuzumab. (FGF-2), basic fibroblast growth factor (bfGF), vascular epi The terms “pharmacological agent” and “biologically thelial growth factor (VEGF), hepatocyte growth factor active agent' further include, without limitation, the follow (HGF), insulin-like growth factor (IGF), nerve growth factor ing anti-inflammatories: alclofenac, alclometasone dipropi (NGF), platlet derived growth factor (PDGF), tumor necrosis 50 onate, algestone acetonide, alpha amylase, amcinafal, factor alpha (TNA-alpha), and placental growth factor amcinafide, amfenac sodium, amiprilose hydrochloride, (PLGF). anakinra, anirolac, anitraZafen, apaZone, balsalazide diso The terms “pharmacological agent' and “biologically dium, bendazac, benoxaprofen, benzydamine hydrochloride, active agent' further include, without limitation, the follow bromelains, broperamole, budesonide, carprofen, ciclopro ing Class I-Class V antiarrhythmic agents: (Class Ia) quini 55 fen, cintaZone, cliprofen, clobetasol propionate, clobetaSone dine, procainamide and disopyramide: (Class Ib) lidocaine, butyrate, clopirac, cloticasone propionate, cormethasone phenytoin and mexiletine; (Class Ic) flecainide, propafenone acetate, cortodoxone, decanoate, deflazacort, delatestry1. and moricizine; (Class II) propranolol, esmolol, timolol. depo-testosterone, desonide, desoximetaSone, dexametha metoprolol and atenolol; (Class III) amiodarone, Sotalol, Sone dipropionate, diclofenac potassium, diclofenac sodium, ibutilide and dofetilide: (Class IV) Verapamil and diltiazem) 60 diflorasone diacetate, diflumidone sodium, diflunisal, diflu and (Class V) adenosine and digoxin. prednate, diftalone, dimethyl sulfoxide, drocinonide, end The terms “pharmacological agent' and “biologically rysone, enlimomab, enolicam Sodium, epirizole, etodolac, active agent' further include, without limitation, the follow etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fen ing antiobiotics: aminoglycosides, cephalosporins, chloram clorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, phenicol, clindamycin, erythromycins, fluoroquinolones, 65 flufenamic acid, flumizole, flunisolide acetate, flunixin, macrollides, azolides, metronidazole, penicillins, tetracy flunixin meglumine, fluocortin butyl, fluorometholone clines, trimethoprim-sulfamethoxazole and Vancomycin. acetate, fluguaZone, flurbiprofen, fluretofen, fluticaSone pro US 9,161,952 B2 10 pionate, furaprofen, furobufen, halcinonide, halobetasol pro interchangeably herein, and mean and include a “pharmaco pionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen logical agent” (or “biologically active agent”) optionally in aluminum, ibuprofen piconol, illonidap, indomethacin, combination with one or more pharmaceutically acceptable indomethacin Sodium, indoprofen, indoxole, intrazole, isof carriers and/or additional inert ingredients. According to the lupredone acetate, isoxepac, isoxicam, ketoprofen, lofemi invention, the formulations can be either in solution or in Zole hydrochloride, lomoxicam, loteprednol etabonate, Suspension in the carrier. meclofenamate Sodium, meclofenamic acid, meclorisone The term “pharmacological composition', as used herein, dibutyrate, mefenamic acid, mesalamine, meseclaZone, mes means and includes a composition comprising a “pharmaco terolone, methandrostenolone, methenolone, methenolone logical agent” and/or “biologically active agent' and/or acetate, methylprednisolone Suleptanate, momiflumate, 10 nabumetone, nandrolone, naproxen, naproxen Sodium, “pharmacological agent formulation' and/or any additional naproxol, nimaZone, olSalazine sodium, orgotein, orpanoxin, agent or component identified herein. Oxandrolane, Oxaprozin, oxyphenbutaZone, oxymetholone, The term “therapeutically effective', as used herein, means paranyline hydrochloride, pentosan polysulfate Sodium, that the amount of the “pharmacological composition' and/or phenbutaZone sodium glycerate, pirfenidone, piroxicam, 15 “biologically active agent” and/or “active agent formulation' piroXicam cinnamate, piroXicam olamine, pirprofen, pred administered is of Sufficient quantity to ameliorate one or nazate, prifelone, prodolic acid, produaZone, proxazole, more causes, symptoms, or sequelae of a disease or disorder. proxazole citrate, rimexolone, romazarit, salcolex, Salnace Such amelioration only requires a reduction or alteration, not din, Salsalate, Sanguinarium chloride, seclaZone, Sermetacin, necessarily elimination, of the cause, symptom, or sequelae stanozolol, Sudoxicam, Sulindac, Suprofen, talmetacin, talni of a disease or disorder. flumate, talosalate, tebufelone, tenidap, tenidap Sodium, The terms “delivery” and “administration” are used inter tenoxicam, tesicam, tesimide, testosterone, testosterone changeably herein, and mean and include providing a “phar blends, tetrydamine, tiopinac, tiXocortol pivalate, tolmetin, macological composition' or “biologically active agent” or tolimetin Sodium, triclonide, triflumidate, Zidometacin, and “active agent formulation' to a treatment site, e.g., damaged Zomepirac sodium. 25 tissue, through any method appropriate to deliver the func The term “biologically active agent' further includes, tional agent or formulation or composition to the treatment without limitation, organisms that have the potential to induce site. Non-limiting examples of delivery methods include modulating proliferation, and/or growth and/or regeneration direct injection, percutaneous delivery and topical applica of tissue. The terms “biologically active agent” thus includes, tion at the treatment site. without limitation, the following cells: human embryonic 30 stem cells, fetal cardiomyocytes, myofibroblasts, mesenchy The term "percutaneous', as used herein, means and mal stem cells, autotransplated expanded cardiomyocytes, includes any penetration through the skin of a patient or adipocytes, totipotent cells, pluripotent cells, blood stem Subject, whether in the form of a small cut, incision, hole, cells, myoblasts, adult stem cells, bone marrow cells, mesen cannula, tubular access sleeve or port or the like. chymal cells, embryonic stem cells, parenchymal cells, epi 35 The terms “patient' and “subject' are used interchange thelial cells, endothelial cells, mesothelial cells, fibroblasts, ably herein, and mean and include warm blooded mammals, osteoblasts, chondrocytes, exogenous cells, endogenous humans and primates; avians; domestic household or farm cells, stem cells, hematopoietic stem cells, bone-marrow animals, such as cats, dogs, sheep, goats, cattle, horses and derived progenitor cells, myocardial cells, skeletal cells, fetal pigs; laboratory animals, such as mice, rats and guinea pigs, cells, undifferentiated cells, multi-potent progenitor cells, 40 fish; reptiles; Zoo and wild animals; and the like. unipotent progenitor cells, monocytes, cardiac myoblasts, The term “comprise' and variations of the term, such as skeletal myoblasts, macrophages, capillary endothelial cells, “comprising and "comprises.” means “including, but not Xenogenic cells, allogenic cells, and post-natal stem cells. limited to' and is not intended to exclude, for example, other According to the invention, the terms “pharmacological additives, components, integers or steps. agent” and “biologically active agent can further include the 45 The following disclosure is provided to further explain in following active agents (referred to interchangeably hereinas an enabling fashion the best modes of performing one or more a “protein', 'peptide' and “polypeptide'): collagen (types embodiments of the present invention. The disclosure is fur I-V), proteoglycans, glycosaminoglycans (GAGS), glycopro ther offered to enhance an understanding and appreciation for teins, growth factors, cytokines, cell-Surface associated pro the inventive principles and advantages thereof, rather than to teins, cell adhesion molecules (CAM), angiogenic growth 50 limit in any manner the invention. The invention is defined factors, endothelial ligands, matrikines, cadherins, immuo globins, fibril collagens, non-fibrallar collagens, basement solely by the appended claims including any amendments membrane collagens, multiplexins, Small-leucine rich pro made during the pendency of this application and all equiva teoglycans, decorins, biglycans, fibromodulins, keratocans, lents of those claims as issued. lumicans, epiphycans, heparin Sulfate proteoglycans, perle 55 As indicated above, the present disclosure is directed to cans, agrins, testicans, Syndecans, glypicans, Serglycins, methods and systems for treating cardiovascular disorders. In selectins, lecticans, aggrecans, versicans, neurocans, brev a preferred embodiment of the invention, the methods com icans, cytoplasmic domain-44 (CD-44), macrophage stimu prise concomitant administration of one or more ECM based lating factors, amyloid precursor proteins, heparins, chon compositions to damaged or diseased cardiovascular tissue, droitin sulfate B (dermatan sulfate), chondroitin sulfate A, 60 and provision of Ventricular assistance. heparin Sulfates, hyaluronic acids, fibronectins, tenascins, As also indicated above and discussed in detail herein, the elastins, fibrillins, laminins, nidogen/enactins, fibulin I, finu term “concomitant’ means that an ECM based composition lin II, integrins, transmembrane molecules, thrombospon and Ventricular assistance are administered (or provided) dins, ostepontins, and angiotensin converting enzymes concurrently at a defined point in time. (ACE). 65 Thus, in some embodiments of the invention, ventricular The terms “active agent formulation”, “pharmacological assistance is initially provided followed by the administration agent formulation' and "agent formulation', are also used of an ECM based composition. US 9,161,952 B2 11 12 According to the invention, the pre-ECM delivery time lar matrix portions that support cell development and differ period can promptly after administering Ventricular assis entiation and tissue regeneration. tance to, minutes, hours or days after administering ventricu According to the invention, the ECM based compositions lar assistance. can comprise mixed liquids, mixed emulsions, mixed gels, In some embodiments, an ECM based composition is ini mixed pastes, or mixed solid particulates. Suitable ECM tially administered and Ventricular assistance is provided based compositions are set forth in Co-pending application thereafter. Ser. Nos. 11/182,551, 1 1/448,351, 1 1/334,631, 13/033,053, In a preferred embodiment of the invention, the ECM based 13/573,569 and 13/732,943; which are incorporated herein in compositions include at least one extracellular matrix (here their entirety. 10 According to the invention, the ECM based compositions inafter “ECM material'). of the invention can further include one or more pharmaco According to the invention, the ECM material can be logical agents or compositions, and/or one or more bioactive derived from various mammalian tissue sources and methods agents or components that aid in the treatment of damaged for preparing same, such as disclosed in U.S. Pat. Nos. 7.550, tissue and/or facilitate the tissue regenerative process. 004, 7,244444, 6,379,710, 6,358,284, 6,206,931, 5,733,337 15 In some embodiments, the ECM based compositions thus and 4,902,508 and U.S. application Ser. No. 12/707.427: include at least one pharmacological agent or composition, which are incorporated by reference herein in their entirety. which can comprise, without limitation, antibiotics or anti The mammalian tissue sources include, without limitation, fungal agents, anti-viral agents, anti-pain agents, anesthetics, small intestine submucosa (SIS), urinary bladder submucosa analgesics, steroidal anti-inflammatories, non-steroidal anti (UBS), stomach submucosa (SS), central nervous system inflammatories, anti-neoplastics, anti-spasmodics, modula tissue, epithelium of mesodermal origin, i.e. mesothelial tis tors of cell-extracellular matrix interactions, proteins, hor Sue, dermal extracellular matrix, Subcutaneous extracellular mones, enzymes and enzyme inhibitors, anticoagulants and/ matrix, gastrointestinal extracellular matrix, i.e. large and or antithrombic agents, DNA, RNA, modified DNA and Small intestines, tissue Surrounding growing bone, placental RNA, NSAIDs, inhibitors of DNA, RNA or protein synthesis, extracellular matrix, ornamentum extracellular matrix, car 25 polypeptides, oligonucleotides, polynucleotides, nucleopro diac extracellular matrix, e.g., pericardium and/or myocar teins, compounds modulating cell migration, compounds dium, kidney extracellular matrix, pancreas extracellular modulating proliferation and growth of tissue, and vasodilat matrix, lung extracellular matrix, and combinations thereof. ing agents. The ECM material can also comprise collagen from mamma Suitable pharmacological agents and/or compositions lian Sources. 30 accordingly include, without limitation, atropine, tropicam The ECM material can also be derived from basement ide, dexamethasone, dexamethasone phosphate, betametha membrane of mammalian tissue/organs, including, without sone, betamethasone phosphate, prednisolone, triamcino limitation, urinary basement membrane (UBM), liver base lone, triamcinolone acetonide, fluocinolone acetonide, ment membrane (LBM), and amnion, chorion, allograft peri anecortave acetate, budesonide, cyclosporine, FK-506, rapa cardium, allograft acellular dermis, amniotic membrane, 35 mycin, ruboxistaurin, midostaurin, flurbiprofen, Suprofen, Wharton's jelly, and combinations thereof. ketoprofen, diclofenac, ketorolac, nepafenac, lidocaine, neo Additional Sources of mammalian basement membrane mycin, polymyxin b, bacitracin, gramicidin, gentamicin, include, without limitation, spleen, lymph nodes, salivary oyXtetracycline, ciprofloxacin, ofloxacin, tobramycin, ami glands, prostate, pancreas and other secreting glands. kacin, Vancomycin, cefazolin, ticarcillin, chloramphenicol, The ECM material can also be derived from other sources, 40 miconazole, itraconazole, trifluridine, Vidarabine, ganciclo including, without limitation, collagen from plant sources Vir, acyclovir, cidofovir, ara-amp, foscarnet, idoxuridine, ade and synthesized extracellular matrices, i.e. cell cultures. fovir dipivoxil, methotrexate, carboplatin, phenylephrine, According to the invention, the ECM compositions of the epinephrine, diplivefrin, timolol, 6-hydroxydopamine, betax invention can also comprise ECM material from two or more olol, pilocarpine, carbachol, physostigmine, demecarium, mammalian Sources. Thus, for example, the composition can 45 dorzolamide, brinzolamide, latanoprost, sodium hyaluronate, comprise ECM material combinations from Such sources as, insulin, Verteporfin, pegaptainib, ranibizumab, and other anti for example, but not limited to, Small intestine Submucosa, bodies, antineoplastics, Anti VGEFs, ciliary neurotrophic liver basement membrane, stomach submucosa, urinary blad factor, brain-derived neurotrophic factor, bFGF, Caspase-1 der Submucosa, placental basement membrane, pancreatic inhibitors, Caspase-3 inhibitors, C.-Adrenoceptors agonists, basement membrane, large intestine Submucosa, lung inter 50 NMDA antagonists, Glial cell line-derived neurotrophic fac stitial membrane, respiratory tract submucosa, heart ECM tors (GDNF), pigment epithelium-derived factor (PEDF), material, dermal matrix, and, in general, ECM material from and NT-3, NT-4, NGF, IGF-2. any mammalian fetal tissue. The ECM material sources can According to the invention, the amount of a pharmacologi also comprise different mammalian animals or an entirely cal agent added to an ECM composition of the invention will, different species of mammals. 55 of course, vary from agent to agent. For example, in one The ECM material can also be used in whole or in part, so embodiment, wherein the pharmacological agent comprises that, for example, an ECM material can contain just the base diclofilenac (VoltarenR), the amount of diclofilenac included ment membrane (or transitional epithelial layer) with the in the ECM composition is preferably in the range of 10 ug-75 Subadjacent tunica propria, the tunica Submucosa, tunica ng. muscularis, and tunica serosa. The ECM material component 60 In some embodiments of the invention, the pharmacologi of the composition can contain any or all of these layers, and cal agent specifically comprises an anti-inflammatory agent. thus could conceivably contain only the basement membrane According to the invention, Suitable anti-inflammatory agents portion, excluding the Submucosa. However, generally, and include, without limitation, alclofenac, alclometasone dipro especially since the Submucosa is thought to contain and pionate, algestone acetonide, alpha amylase, amcinafal, Support the active growth factors and other proteins necessary 65 amcinafide, amfenac sodium, amiprilose hydrochloride, for in vivo tissue regeneration, the ECM or matrix composi anakinra, anirolac, anitraZafen, apaZone, balsalazide diso tion from any given Source will contain the active extracellu dium, bendazac, benoxaprofen, benzydamine hydrochloride, US 9,161,952 B2 13 14 bromelains, broperamole, budesonide, carprofen, ciclopro Anti-Inflammatory Properties/Actions fen, cintaZone, cliprofen, clobetasol propionate, clobetaSone Statins have numerous favorable effects on vascular wall butyrate, clopirac, cloticasone propionate, cormethasone cells and the cardiovascular system. One specific example is acetate, cortodoxone, decanoate, deflazacort, delatestry1. that statins facilitate the reduction of the G-Protein-Coupled depo-testosterone, desonide, desoximetaSone, dexametha Receptor, thromboxane A2 (TXA), which lowers the platelet Sone dipropionate, diclofenac potassium, diclofenac sodium, activation and aggregation, and augmentation of adhesion diflorasone diacetate, diflumidone sodium, diflunisal, diflu molecules and chemokines. prednate, diftalone, dimethyl sulfoxide, drocinonide, end Statins further impact vascular wall cells and the cardio rysone, enlimomab, enolicam sodium, epirizole, etodolac, vascular system by blocking ras homilog gene family, mem 10 ber A (RhoA) activation. Blocking RhoA activation further etofenamate, felbinac, fenamole, fenbufen, fenclofenac, fen impacts numerous systems, such as macrophage growth, tis clorac, fendosal, fenpipalone, fentiazac, flazalone, fluazacort, Sue plasminogen activators (t-PA), plasminogen activator flufenamic acid, flumizole, flunisolide acetate, flunixin, inhibitor type 1 (PAI-1), smooth muscle cell (SMC) prolif flunixin meglumine, fluocortin butyl, fluorometholone eration, nitric oxide (NO) production, endothelins, and angio acetate, flucuaZone, flurbiprofen, fluretofen, fluticasone pro 15 tensin receptors. pionate, furaprofen, furobufen, halcinonide, halobetasol pro Macrophage growth reduced by blocking RhoA activation pionate, halopredone acetate, ibufenac, ibuprofen, ibuprofen results in the reduction of matrix metalloprotinases (MMPs) aluminum, ibuprofen piconol, illonidap, indomethacin, and tissue factors (TF). Lowered MMPs also results in a indomethacin Sodium, indoprofen, indoxole, intrazole, isof lowered presence of thrombi, as the MMPs attach to ECM lupredone acetate, isoxepac, isoxicam, ketoprofen, lofemi present in thrombi or damaged ECM at wound sites. Zole hydrochloride, lomoxicam, loteprednol etabonate, Fibrinolysis Properties/Actions meclofenamate Sodium, meclofenamic acid, meclorisone Blocking RhoA activation also affects the presence of tis dibutyrate, mefenamic acid, mesalamine, meseclaZone, mes Sue plasminogen activators (t-PA) and plasminogen activator terolone, methandrostenolone, methenolone, methenolone inhibitor type 1 (PAH), which is the principal inhibitor of acetate, methylprednisolone Suleptanate, momiflumate, 25 fibrinolysis. With t-PA presence raised and PAI-1 diminished nabumetone, nandrolone, naproxen, naproxen Sodium, from the blocking of RhoA activation induced by statins, a naproxol, nimaZone, olSalazine sodium, orgotein, orpanoxin, reduced thrombotic effect is realized due to reduced oppor Oxandrolane, Oxaprozin, oxyphenbutaZone, oxymetholone, tunity for fibrin to form the polymeric mesh of a hemostatic paranyline hydrochloride, pentosan polysulfate Sodium, plug. phenbutaZone sodium glycerate, pirfenidone, piroxicam, 30 NO Regulation Properties/Actions piroxicam cinnamate, piroxicam olamine, pirprofen, pred Blocking RhoA activation also affects the presence of Nitric Oxide (NO) in the cardiovascular system. NO contrib nazate, prifelone, prodolic acid, produaZone, proxazole, utes to vessel homeostasis by inhibiting vascular Smooth proxazole citrate, rimexolone, romazarit, salcolex, Salnace muscle contraction and growth, platelet aggregation, and leu din, Salsalate, Sanguinarium chloride, seclaZone, Sermetacin, 35 kocyte adhesion to the endothelium. stanozolol, Sudoxicam, Sulindac, Suprofen, talmetacin, talni RhoA Activation Blocking Properties/Actions flumate, talosalate, tebufelone, tenidap, tenidap Sodium, The administration of statins can also enhance the presence tenoxicam, tesicam, tesimide, testosterone, testosterone of endothelins and angiotensin receptors. Endothelins and blends, tetrydamine, tiopinac, tiXocortol pivalate, tolmetin, angiotensin receptors can also be affected by the Subsequent tolimetin Sodium, triclonide, triflumidate, Zidometacin, and 40 blocking of RhoA activation associated with statin adminis Zomepirac sodium. tration. According to the invention, the amount of an anti-inflam There are three isoforms of endothelins; ET-1, ET-2, and matory added to an ECM composition of the invention can ET-3, with ET-1 being the isoform primarily affected by similarly vary from anti-inflammatory to anti-inflammatory. statins and RhoA activation blocking. Secretion of ET-1 from For example, in one embodiment of the invention, wherein 45 the endothelium signals vasoconstriction and influences local the pharmacological agent comprises ibuprofen (AdvilR), cellular growth and survival. the amount of ibuprofen included in the ECM composition is Angiotensin receptors are protein coupled receptors that preferably in the range of 100 ug-200 mg. are responsible for the signal transduction of the vasocon In some embodiments of the invention, the ECM based stricting stimulus of the main effector hormone angiotensin compositions include a statin, i.e. a HMG-CoA reductase 50 II. Angiotensin Receptor II Type I (AT-1) is the angiotensin inhibitor. According to the invention, Suitable statins include, receptor primarily affected by statin administration and without limitation, atorvastatin (Lipitor R), cerivastatin, flu RhoA activation blocking. AT-1 mediates vasocontraction, vastatin (LescolR), lovastatin (Mevacor R. Altocorr, Alto cardiac hypertrophy, vascular Smooth muscle cell prolifera prev(R), mevastatin, pitavastatin (Livalo(R), PitavaR), pravas tion, interalia. tatin (PravacholR), Selektine(R), Lipostat(R), rosuvastatin 55 C-Reactive Protein Reduction Properties/Actions (Crestor(R), and simvastatin (Zocor R, LipexR). Several C-Reactive Proteins (CRP) are also reduced by statins. actives comprising a combination of a statin and another CRPs are found in the blood; the levels of which deviate in agent, such as eZetimbe/simvastatin (VytorinR), are also Suit response to differing levels of inflammation. able. Adhesion Molecule Reduction Properties/Actions Applicant has found that the noted statins exhibit numer 60 Statins also reduce the presence of adhesion molecules on ous beneficial properties that provide several beneficial bio the endothelium. Adhesion molecules are proteins that are chemical actions or activities. Several significant properties located on the cell surface and are involved with inflammation and beneficial actions resulting therefrom are discussed in and thrombin formation in vascular endothelial cells. detail below. Additional properties and beneficial actions are Rac-1 Reduction Properties/Actions set forth in Co-Pending application Ser. No. 13/373,569, filed 65 The expression of Rac-1 is also reduced by statins. Rac-1 is on Sep. 24, 2012; which is incorporated by reference herein in a protein found in human cells, which plays a central role in its entirety. endothelial cell migration, tubulogenesis, adhesion, and per US 9,161,952 B2 15 16 meability. The decrease in the presence of Rac-1 also results domain-44 (CD44), macrophage stimulating factor, amyloid in the decrease of reactive oxygen species (ROS). precursor protein, heparin, chondroitin Sulfate B (dermatan According to the invention, the amount of a statin added to Sulfate), chondroitin Sulfate A, heparan Sulfate, hyaluronic an ECM composition of the invention is preferably less than acid, fibronectin (Fn), tenascin, elastin, fibrillin, laminin, 20 mg, more preferably, less than approximately 10 mg. nidogen?entactin, fibulin I, fibulin II, integrin, a transmem In some embodiments of the invention, the ECM based brane molecule, platelet derived growth factor (PDGF), epi compositions include 100 ug-5 mg of a statin. In some dermal growth factor (EGF), transforming growth factor embodiments of the invention, the ECM based compositions alpha (TGF-alpha), transforming growth factor beta (TGF include 500 ug-2 mg of a statin. beta), fibroblast growth factor-2 (FGF-2) (also called basic In some embodiments of the invention, the ECM based 10 fibroblast growth factor (bFGF)), thrombospondin, osteopon compositions include chitosan. As also set forth in detail in tin, angiotensin converting enzyme (ACE), and vascular epi Co-Pending application Ser. No. 13/573.569, chitosan also thelial growth factor (VEGF). exhibits numerous beneficial properties that provide several According to the invention, the pharmacological and bio beneficial biochemical actions or activities. active agents referenced above can comprise any form. In According to the invention, the amount of chitosan added 15 Some embodiments of the invention, the agents, e.g. simvas to an ECM based composition of the invention is preferably tatin and/or chitosan, comprise microcapsules that provide less than 50 ml, more preferably, less than approximately 20 delayed delivery of the agent contained therein. ml. Referring now to FIG. 1, there is shown a depiction of a In some embodiments of the invention, the ECM based normal human heart 100. The heart wall 102 consists of an compositions include a growth factor. According to the inven inner layer of simple squamous epithelium, referred to as the tion, Suitable growth factors include, without limitation, a endocardium. The endocardium overlays the myocardium (a platelet derived growth factor (PDGF), epidermal growth variably thick heart muscle) and is enveloped within a multi factor (EGF), transforming growth factor alpha (TGF-alpha), layer tissue structure referred to as the pericardium. The transforming growth factor beta (TGF-beta), fibroblast innermost layer of the pericardium, referred to as the visceral growth factor-2 (FGF-2), basic fibroblast growth factor 25 pericardium or epicardium, covers the myocardium. An out (bFGF), vascular epithelial growth factor (VEGF), hepato ermost layer of the pericardium, referred to as the fibrous cyte growth factor (HGF), insulin-like growth factor (IGF), pericardium, attaches the parietal pericardium to the sternum, nerve growth factor (NGF), platlet derived growth factor the great vessels and the diaphragm. (PDGF), tumor necrosis factor alpha (TNA-alpha), and pla Referring now to FIG. 2, there is shown a depiction of a cental growth factor (PLGF). 30 heart 200 having an ischemic infarcted region 202, and a In some embodiments of the invention, the ECM based peri-infarcted region 204 that is surrounded by healthy non compositions include an antiarrhythmic agent. According to ischemic myocardium tissue 206. the invention, Suitable antiarrhythmic agents include, without As indicated above, the ischemic infarcted region 202 (or limitation, quinidine, procainamide, disopyramide, myocardial infarction) can, and in many instances will trigger lidocaine, phenytoin, mexiletine, flecainide, propafenone, 35 a cascading sequence of myocellular events. In many moricizine, propranolol, esmolol, timolol, metoprolol. instances, the myocellular events lead to deterioration inven atenolol, amiodarone, Sotalol, ibutilide, dolfetilide, Verapamil, tricular function and heart failure. diltiazem, adenosine and digoxin. As discussed in detail in Co-pending application Ser. No. In some embodiments of the invention, the ECM based 13/573,569, the effects of an ischemic infarcted region can be compositions include a cell. According to the invention, Suit 40 ameliorated or eliminated by delivering an ECM based com able cells include, without limitation, a human embryonic position of the invention directly to the infarcted cardiovas stem cell, fetal cell, fetal cardiomyocyte, myofibroblast, mes cular tissue. In most instances, the based ECM compositions enchymal stem cell, autotransplanted expanded cardiomyo will induce neovascularization, host tissue proliferation, cyte, adipocyte, totipotent cell, pluripotent cell, blood stem bioremodeling, and regeneration of new cardiac tissue struc cell, myoblast, adult stem cell, bone marrow cell, mesenchy 45 tures with site-specific structural and functional properties. mal cell, embryonic stem cell, parenchymal cell, epithelial According to the invention, the ECM based compositions cell, endothelial cell, mesothelial cell, fibroblast, myofibro can be delivered to infarcted cardiovascular tissue, as well as blast, osteoblast, chondrocyte, exogenous cell, endogenous other damaged or diseased biological tissue, by various con cell, stem cell, hematopoetic stem cell, pluripotent stem cell, ventional means. In some embodiments, a multi-needle injec bone marrow-derived progenitor cell, progenitor cell, myo 50 tion system, such as disclosed in U.S. Application No. cardial cell, skeletal cell, undifferentiated cell, multi-potent 61/704,634, filed Sep. 24, 2012 and illustrated in FIGS. 3A progenitor cell, unipotent progenitor cell, monocyte, cardi and 3B is employed to deliver one or more ECM based com omyocyte, cardiac myoblast, skeletal myoblast, macrophage, positions to damaged or diseased cardiovascular tissue. capillary endothelial cell, Xenogenic cell and allogenic cell. Applicants herein have further found that the noted cardio In some embodiments of the invention, the ECM based 55 vascular disorder, i.e. ischemic heart disease, as well as other compositions include a protein. According to the invention, cardiovascular disorders can be effectively treated by the the protein can comprise, without limitation, a growth factor, administration of an ECM based composition (and/or a collagen, proteoglycan, glycosaminoglycan (GAG) chain, device formed therefrom, e.g. an ECM based patch or glycoprotein, cytokine, cell-surface associated protein, cell endograft) in conjunction with Ventricular assistance. adhesion molecule (CAM), angiogenic growth factor, endot 60 According to the invention, Ventricular assistance can be helial ligand, matrikine, matrix metalloprotease, cadherin, provided by a variety of conventional ventricular assist immunoglobin, fibril collagen, non-fibrillar collagen, base devices, including, without limitation, a left ventricular assist ment membrane collagen, multiplexin, Small-leucine rich device (LVAD), right ventricular assist device (RVAD), left proteoglycan, decorin, biglycan, fibromodulin, keratocan, and right ventricular assist device (BiVAD), and other lumican, epiphycan, heparan Sulfate proteoglycan, perlecan, 65 mechanical circulatory support (MCS) devices. agrin, testican, Syndecan, glypican, Serglycin, selectin, lecti In some embodiments of the invention, Ventricular assis can, aggrecan, Versican, nuerocan, brevican, cytoplasmic tance is provided by a left ventricular assist device (LVAD), US 9,161,952 B2 17 18 Such as the HeartWare HVADTM device illustrated in FIG. 4. cates what percentage of blood is ejected from the heart with As illustrated in FIG.4, the HVAD device includes a pump 10 each beat and, hence, is a seminal cardiovascular perfor having an elongated inlet 12 and an impeller casing or Volute mance factor. A normal ejection fraction is 50%. 14. A discharge tube 16 also extends through the pump hous As illustrated in FIG. 6, there was a progressive improve ing to communicate with the interior of the impeller casing ment in cardiovascular performance after 60 days between 14. the porcine groups; with the combined therapy of VAD and Referring now to FIG. 5, in some applications, the inlet ECM composition administration being the greatest. tube 12, which serves as an inflow cannula, is preferably The improvement with ECM composition administration placed into the apex of the left ventricle 208. An arterial graft alone was also substantial in view of a lower starting point, 212 is connected on one end to discharge tube 16 and on the 10 other end to the aorta 210 through an end-to-end anastomosis. having no evidence after infarct of improvement. As illustrated in FIG. 5, the pump 10 further includes a Without departing from the spirit and scope of this inven driveline (cable) 26 that connects the implanted pump 10 to tion, one of ordinary skill can make various changes and an externally worn controller 28. The controller 28, which modifications to the invention to adapt it to various usages and includes a battery pack 30, regulates the pump 10 and pro 15 conditions. As such, these changes and modifications are vides the patient with visual and audible indications regard properly, equitably, and intended to be, within the full range ing the operation of the system. of equivalence of the following claims. There is thus provided herein methods for treating a car diovascular disorder comprising concomitant administration What is claimed is: of (i) an ECM based composition directly to damaged or 1. A method of treating a cardiovascular disorder in a diseased cardiovascular tissue associated with the cardiovas Subject in need thereof, comprising: cular disorder, and (ii) Ventricular assistance. administering to said subject a mesothelial composition There is also provided herein a system for treating a car comprising acellular bioremodelable mesothelial tissue, diovascular disorder comprising (i) means for delivering an said mesothelial tissue comprising endogenous pro ECM based composition directly to damaged or diseased 25 teoglycans, transforming growth factor-B (TGF-B) and cardiovascular tissue associated with the cardiovascular dis vascular endothelial growth factor (VEGF), said order, and (ii) means for providing ventricular assistance or mesothelial tissue further comprising an exogenously Support for the underlying cardiovascular system. added anti-arrhythmic agent selected from the group consisting of quinidine, procainamide, disopyramide, EXAMPLES 30 lidocaine, phenytoin, mexiletine, flecainide, pro pafenone, moricizine, propranolol, esmolol, timolol, The following examples are provided to enable those metoprolol, atenolol, amiodarone, Sotalol, ibutilide, skilled in the art to more clearly understand and practice the dofetilide, Verapamil, diltiazem, adenosine and digoxin; present invention. They should not be considered as limiting providing a Ventricular assist device; and the scope of the invention, but merely as being illustrated as 35 simultaneously providing ventricular assistance to said representative thereof. Subject by administering said ventricular assist device Example 1 and said mesothelial composition to damaged cardio vascular tissue associated with said cardiovascular dis order. Three groups of porcine samples were subjected to three 40 cardiovascular treatments, i.e. Ventricular assist (VAD) only, 2. The method of claim 1, wherein said mesothelial com administration of an extracellular matrix (ECM) composition position is administered directly to said cardiovascular tissue. of the invention, and VAD plus administration of the ECM 3. The method of claim 1, wherein said ventricular assist composition after inducing an infarct. device comprises a left ventricular assist device (LVAD). 4. The method of claim 1, wherein said ventricular assist Referring now to FIG. 6, there is shown a graphical illus 45 tration of ejection fraction as a function of time for the porcine device comprises a right ventricular assist device (RVAD). samples. AS is well known in the art, ejection fraction indi k k k k k