US 20090306027A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0306027 A1 Worcel et al. (43) Pub. Date: Dec. 10, 2009 (54) GENETIC RISK ASSESSMENT IN HEART (86). PCT No.: PCT/US2O07/OO8426 FAILURE IMPACT OF THE GENETIC VARATION OF G-PROTEIN BETA3 S371 (c)(1), SUBUNIT POLYMORPHISM (2), (4) Date: Jun. 25, 2009 Related U.S. Application Data (75) Inventors: Manuel Worcel, Boston, MA (US); (60) Provisional application No. 60/790,555, filed on Apr. Michael Sabolinski, Franklin, MA 10, 2006. (US); Sang W. Tam, Dover, MA (US); Dennis M. McNamara, Publication Classification Venetia, PA (US) (51) Int. Cl. A6II 3/56 (2006.01) Correspondence Address: A6II 3/34 (2006.01) WILMERHALEANTROMED A63L/502 (2006.01) 1875 PENNSYLVANIAAVE, NW (52) U.S. Cl. .......................... 514/171; 514/470; 514/248 WASHINGTON, DC 20006 (US) (57) ABSTRACT The invention provides methods for treating various indica (73) Assignees: NitoMed, Inc., Lexington, MA tions and diseases in a patient in need thereof, wherein the (US); Unversity of Pittsburgh of patient has a C825T polymorphism in the G protein beta3 the Commonwealth System of the Subunit (GNB3), comprising administering to the patient (i) Higher Education, Pittsburgh, PA at least one antioxidant compound or a pharmaceutically (US) acceptable salt thereof; (ii) at least one nitric oxide enhancing compound; and (iii) optionally the best current therapy for the treatment of cardiovascular diseases. In one embodiment the (21) Appl. No.: 12/296,630 antioxidant is a hydralazine compound or a pharmaceutically acceptable salt thereof and the nitric oxide enhancing com (22) PCT Filed: Apr. 4, 2007 pound is isosorbide dinitrate and/or isosorbide mononitrate. Patent Application Publication Dec. 10, 2009 Sheet 1 of 4 US 2009/0306027 A1 Figure 1 SO 50 - 40 32227 genotype so20 k. s 2 TTTC og 2 -4tal-rzazar Blacks Blacks Whites (A-HeFT) (GRACE) (GRACE) Patent Application Publication Dec. 10, 2009 Sheet 2 of 4 US 2009/0306027 A1 Figure 2 I-H = fixed dose combination of isosorbide dinitrate and hydraiazine hydrochloride GNB3TT Subjects: Event-free Survival, I-H vs. Placebo 100 2s :O e i 70 so ---- l ir Place 50 P = 0.047 AO O 10 200 300 400 500 Patent Application Publication Dec. 10, 2009 Sheet 3 of 4 US 2009/0306027 A1 Figure 3 A 0.8 D Placebo ISDN-HYD -O.2 GNB3 TT only GNB3 TC+CC p=0.016, n=184 p=0.871, n=166 Patent Application Publication Dec. 10, 2009 Sheet 4 of 4 US 2009/0306027 A1 Figure 3 B O.8 Placebo ISDN-HYD GNB3 TT only GNB3 TC+CC "p=0.039, n=184 p=0.563, n=166 US 2009/03 06027 A1 Dec. 10, 2009 GENETIC RISKASSESSMENT IN HEART from oxidative stress; (p) treating endothelial dysfunctions; FAILURE IMPACT OF THE GENETIC (q) treating diseases caused by endothelial dysfunctions; (r) VARATION OF G-PROTEIN BETA3 treating cardiovascular diseases; in a patient in need thereof, SUBUNIT POLYMORPHISM wherein the patient has a a C825T polymorphism in the G protein beta3 subunit, comprising administering to the patient RELATED APPLICATIONS (i) at least one antioxidant compound or pharmaceutically 0001. This application claims priority under 35 USC S119 acceptable salt thereof; (ii) at least one nitric oxide enhancing to U.S. Application No. 60/790,555 filed Apr. 10, 2006; the compound; and (iii) optionally at least one compound disclosure of which is incorporated by reference herein in its selected from the group consisting of an angiotensin convert entirety. ing enzyme inhibitor, a B-adrenergic antagonist, an angio tensin II antagonist, an aldosterone antagonist, a cardiac gly FIELD OF THE INVENTION coside and a diuretic compound or a combination of two or 0002 The invention provides methods for (a) reducing more thereof. In another embodiment the patient has at least mortality associated with heart failure; (b) improving oxygen one polymorphism in an endothelial nitric oxide synthase consumption; (c) treating heart failure; (d) treating hyperten (NOS3) gene and/or at least one polymorphism in a beta 1 sion; (e) improving the quality of life in a heart failure patient; adrenergic receptor gene and/or at least one polymorphism in (f) inhibiting left ventricular remodeling; (g) reducing hospi an aldosterone synthase CYP11B2 gene. In another embodi talizations related to heart failure; (h) improving exercise ment, the patient is categorized as New York Heart Associa tolerance; () increasing left Ventricular ejection fraction; (k) tion heart failure functional classification I, II, III or IV. In yet decreasing levels of B-type natriuretic protein; (1) treating another embodiment, the patient is categorized as New York renovascular diseases; (m) treating end-stage renal diseases; Heart Association heart failure functional classification II, III (n) reducing cardiomegaly; (O) treating diseases resulting or IV. In yet another embodiment the patient is a blackpatient. from oxidative stress; (p) treating endothelial dysfunctions; In one embodiment the antioxidant is a hydralazine com (q) treating diseases caused by endothelial dysfunctions; or pound or a pharmaceutically acceptable salt thereof and the (r) treating cardiovascular diseases; in a patient in need nitric oxide enhancing compound is isosorbide dinitrate and/ thereof, wherein the patient has a C825T polymorphism in the or isosorbide mononitrate. The antioxidants, nitric oxide G proteinbeta3 subunit (GNB3), comprising administering to enhancing compounds and/or additional compounds can be the patient (i) at least one antioxidant compound or a phar administered separately or as components of the same com maceutically acceptable salt thereof; (ii) at least one nitric position in one or more pharmaceutically acceptable carriers. oxide enhancing compound; and (iii) optionally the best cur 0006. The invention provides methods for (a) reducing rent therapy for the treatment of cardiovascular diseases. In mortality associated with heart failure; (b) improving oxygen one embodiment the antioxidant is a hydralazine compound consumption; (c) treating heart failure; (d) treating hyperten or a pharmaceutically acceptable salt thereof and the nitric sion; (e) improving the quality of life in a heart failure patient; oxide enhancing compound is isosorbide dinitrate and/or (f) inhibiting left ventricular remodeling; (g) reducing hospi isosorbide mononitrate. talizations related to heart failure: (h) improving exercise tolerance; () increasing left Ventricular ejection fraction; (k) BACKGROUND OF THE INVENTION decreasing levels of B-type natriuretic protein; (1) treating renovascular diseases; (m) treating end-stage renal diseases; 0003 Genetic background appears to influence outcomes (n) reducing cardiomegaly; (O) treating diseases resulting for patients with congestive heart failure. The G protein beta from oxidative stress; (p) treating endothelial dysfunctions; 3-subunit (GNB3) plays an important role in alpha adrenergic (q) treating diseases caused by endothelial dysfunctions; (r) signaling. A common polymorphism (C825T) exists in exon treating cardiovascular diseases; in a patient in need thereof, 10 (i.e. G-protein beta3 subunit (GNB3) C825T polymor wherein the patient has a C825T polymorphism in the G phism). The T haplotype is linked to a splicing variant of protein beta3 subunit, comprising administering to the patient GNB3 which results in enhanced alpha adrenergic tone and is (i) at least one antioxidant compound or pharmaceutically more prevalent in African Americans than in white cohorts. acceptable salt thereof; (ii) at least one nitric oxide enhancing The Thaplotype has also been linked to the risk of hyperten compound; (iii) analdosterone antagonist; and (iv) optionally Sion, and may affect the response to angiotensin converting at least one compound selected from the group consisting of enzyme inhibitors. an angiotensin converting enzyme inhibitor, a B-adrenergic 0004. There is a need in the art for the determination of a antagonist, an angiotensin II antagonist, a cardiac glycoside patient's genetic variation and for the treatment of heart fail and a diuretic compound or a combination of two or more le. thereof. In another embodiment the patient has at least one polymorphism in an endothelial nitric oxide synthase (NOS3) SUMMARY OF THE INVENTION gene and/or at least one polymorphism in a beta 1 adrenergic 0005. The invention provides methods for (a) reducing receptor gene and/or at least one polymorphism in an aldos mortality associated with heart failure; (b) improving oxygen terone synthase CYP11B2 gene. In one embodiment the anti consumption; (c) treating heart failure; (d) treating hyperten oxidant is a hydralazine compound or a pharmaceutically sion; (e) improving the quality of life in a heart failure patient; acceptable salt thereof and the nitric oxide enhancing com (f) inhibiting left ventricular remodeling; (g) reducing hospi pound is isosorbide dinitrate and/or isosorbide mononitrate. talizations related to heart failure; (h) improving exercise In these embodiments of the invention, the methods can tolerance; () increasing left Ventricular ejection fraction; (k) involve (i) administering the hydralazine compound or a decreasing levels of B-type natriuretic protein; (1) treating pharmaceutically acceptable salt thereof, and at least one of renovascular diseases; (m) treating end-stage renal diseases; isosorbide dinitrate and/or isosorbide mononitrate, and an (n) reducing cardiomegaly; (O) treating diseases resulting aldosterone antagonist or (ii) administering the hydralazine US 2009/03 06027 A1 Dec. 10, 2009 compound