METHODS FOR DIAGNOSING BRUGADA SYNDROME USING AN AEROSOL

1 . A method of evaluating a subject in need thereof comprising: administering an aerosol of a sodium channel blocker to said subject, and assessing cardiac activity of said subject, wherein said cardiac activity is indicative of Brugada syndrome.

2 . The method of claim 1 , wherein said aerosol comprises a microdose of said sodium channel blocker per breath.

3 . The method of claim 1 or 2 , wherein said aerosol comprises at most about 1000 micrograms of said sodium channel blocker per breath.

4 . The method of claim 3 , wherein said aerosol comprises at least about 10 micrograms of said sodium channel blocker per breath.

5 . The method of claim 3 , wherein said aerosol comprises at least about 100 micrograms of said sodium channel blocker per breath.

6 . The method of claim 3 , wherein said aerosol comprises at least about 500 micrograms of said sodium channel blocker per breath.

7 . The method of claim 1 or 2 , wherein said aerosol comprises at most about 10 milligrams of said sodium channel blocker per breath.

8 . The method of claim 1 or 2 , herein said aerosol comprises at least about 20 milligrams of said sodium channel blocker per breath.

9 . The method of claim 1 or 2 , wherein said aerosol comprises at least about 50 milligrams of said sodium channel blocker per breath.

10 . The method of claim 1 or 2 . wherein said aerosol comprises at least about 100 milligrams of said sodium channel blocker per breath.

11 . The method of claim 1 or 2 , wherein said aerosol comprises about 100 micrograms to about 500 micrograms of said sodium channel blocker.

12 . The method of any one of claims 1 to 11 , wherein said aerosol comprises liquid droplets or dry powder, or an evaporative or condensation aerosol.

13 . The method of any one of claims 1 to 12 , further comprising producing said aerosol by a nebulizer, a metered dose inhaler, or a dry powder inhaler.

14 . The method of claim 13 , wherein said nebulizer is a vibrating mesh nebulizer or a jet nebulizer.

15 . The method of claim 13 , wherein said dry powder inhaler is an active dry powder inhaler or a passive dry powder inhaler.

16 . The method of any one of claims 1 to 15 , wherein said assessing cardiac activity of said subject comprises conducting an electrocardiogram (ECG) test on said subject.

17 . The method of claim 16 , wherein said ECG test is performed with a Holter monitor.

18 . The method of claim 16 , wherein said ECG test is a 12-lead ECG test.

19 . The method of claim 16 , wherein said ECG test measures at least one right precordial lead.

20 . The method of claim 16 , wherein said ECG test measures V1, V2, or V3 lead.

21 . The method of any one of claims 1 to 20 , wherein said administering of said sodium channel blocker elicits an ECG change in said subject.

22 . The method of claim 21 , wherein said ECG change appears within 60 minutes of said administering of said sodium channel blocker.

23 . The method of claim 21 , wherein said ECG change appears within 30 minutes of said administering of said sodium channel blocker.

24 . The method of claim 21 , wherein said ECG change appears within 10 minutes of said administering of said sodium channel blocker.

25 . The method of claim 21 , wherein said ECG change appears within 5 minutes of said administering of said sodium channel blocker.

26 . The method of any one of claims 1 to 25 , wherein said administering of said sodium channel blocker unmasks an ECG phenotype of Brugada syndrome in said subject.

27 . The method of claim 26 , wherein said ECG phenotype of Brugada syndrome is a Type 1, Type 2, or Type 3 Brugada syndrome ECG pattern.

28 . The method of claim 26 , wherein said ECG phenotype of Brugada syndrome comprises a J wave amplitude of >2 mm or 0.2 mV in more than one right precordial lead.

29 . The method of claim 26 , wherein said Type 1 Brugada syndrome ECG pattern comprises a negative T-wave following said J wave.

30 . The method of claim 29 , wherein said Type 1 Brugada syndrome ECG pattern comprises a coved ST-T configuration.

31 . The method of claim 29 or 30 , wherein said Type 1 Brugada syndrome ECG pattern comprises a descending terminal portion of ST segment.

32 . The method of any one of claims 21 to 31 , wherein said administering of said sodium channel blocker converts a normal ECG pattern without said sodium channel blocker to a Type 1, Type 2, or Type 3 Brugada syndrome ECG phenotype in said subject.

33 . The method of any one of claims 21 to 31 , wherein said administering of said sodium channel blocker converts a Type 2 Brugada syndrome ECG pattern without said sodium channel blocker to a Type 1 Brugada syndrome ECG pattern in said subject.

34 . The method of claim 33 , wherein said Type 2 Brugada syndrome ECG pattern comprises a J wave amplitude of >2 mm or 0.2 mV in more than one right precordial lead.

35 . The method of claim 34 , wherein said Type 2 Brugada syndrome ECG pattern comprises a positive or biphasic T-wave following said J wave.

36 . The method of any one of claims 33 to 35 , wherein said Type 2 Brugada syndrome ECG pattern comprises a saddleback ST-T configuration.

37 . The method of any one of claims 33 to 36 , wherein said Type 2 Brugada syndrome ECG pattern comprises a terminal portion of ST Segment that is elevated for at least about 1 mm or 0.1 mV.

38 . The method of any one of claims 21 to 31 , wherein administering of said sodium channel blocker converts a Type 3 Brugada syndrome ECG pattern without said sodium channel blocker to a Type 1 Brugada syndrome ECG pattern in said subject.

39 . The method of claim 38 , wherein said Type 3 Brugada syndrome ECG pattern comprises a J wave amplitude of >2 mm in more than one right precordial lead.

40 . The method of claim 38 , wherein said Type 3 Brugada syndrome ECG pattern comprises a positive T-wave following said J wave.

41 . The method of any one of claims 38 to 40 , wherein said Type 3 Brugada syndrome ECG pattern comprises a saddleback ST-T configuration.

42 . The method of any one of claims 38 to 41 , wherein said Type 3 Brugada syndrome ECG pattern comprises a terminal portion of ST Segment that is elevated for less than 1 mm or 0.1 mV.

43 . The method of any one of claims 1 to 42 , wherein said administering of said aerosol of said sodium channel blocker is repeated at least once to confirm a presence or absence of Brugada syndrome.

44 . The method of claim 43 , wherein said administering of said aerosol of said sodium channel blocker is repeated two to five times to confirm the presence or absence of Brugada syndrome.

45 . The method of any one of claims 1 to 44 , wherein said administering of said aerosol of said sodium channel blocker is performed in a hospital or a physician clinic setting.

46 . The method of any one of claims 1 to 45 , wherein said sodium channel blocker is a Class I antiarrhythmic agent.

47 . The method of claim 46 , wherein said sodium channel blocker is a Class Ic anti-arrhythmic agent.

48 . The method of any one of claims 1 to 45 , wherein said sodium channel blocker comprises flecainide or salt thereof.

49 . The method of any one of claims 1 to 45 , wherein said sodium channel blocker comprises flecainide acetate.

50 . The method of any one of claims 1 to 45 , wherein said sodium channel blocker is selected from the group consisting of: ajmaline, pilsicainide, flecainide, procainamide, salt and solvate thereof.

51 . The method of any one of claims 1 to 50 , wherein said subject has one or more of the following: (a) documented ventricular fibrillation; (b) self-terminating polymorphic ventricular tachycardia; (c) a family history of sudden cardiac death; (d) coved-type ECGs in family members; (d) electrophysiologic inducibility; or (e) syncope or nocturnal agonal respiration.

52 . The method of any one of claims 1 to 51 , wherein said subject has one or more genetic mutations associated with Brugada syndrome.

53 . The method of any one of claims 1 to 52 , further comprising performing genetic testing of said subject's genome for one or more genetic mutations associated with Brugada syndrome.

54 . A unit dose comprising: a composition that comprises a sodium channel blocker in a microdose that is sufficient to elicit an ECG change that unmasks an ECG phenotype of Brugada syndrome in a subject, and a pharmaceutically acceptable excipient.

55 . The unit dose of claim 54 , wherein said composition comprises a solution.

56 . The unit dose of claim 55 , wherein said composition comprises an aqueous solution.

57 . The unit dose of claim 55 , wherein said composition comprises a non-aqueous solution.

58 . The unit dose of any one of claims 54 to 57 , wherein said composition comprises a pH buffer.

59 . The unit dose of claim 58 , wherein said composition comprises a pH buffer selected from the group consisting of: citrate, phosphate, phthalate, acetate, and lactate.

60 . The unit dose of claim 54 , wherein said composition consists essentially of said sodium channel blocker and water.

61 . The unit dose of claim 54 , wherein said composition consists essentially of said sodium channel blocker, water, and a pH buffer.

62 . The unit dose of any one of claims 54 to 61 , wherein the composition has a pH ranging from 3.5 to 8.0.

63 . The unit dose of any one of claims 54 to 62 , wherein said sodium channel blocker comprises a class Ic antiarrhythmic.

64 . The unit dose of any one of claims 54 to 62 , wherein said sodium channel blocker is selected from the group consisting of ajmaline, pilsicainide, flecainide, procainamide, salt and solvate thereof.

65 . The unit dose of any one of claims 54 to 64 , comprising at most about 1000 micrograms of said sodium channel blocker.

66 . The unit dose of claim 65 . comprising at least about 10 micrograms of said sodium channel blocker.

67 . The unit dose of claim 65 , comprising at least about 100 micrograms of said sodium channel blocker.

68 . The unit dose of claim 65 , comprising at least about 500 micrograms of said sodium channel blocker.

69 . The unit dose of any one of claims 54 to 64 , comprising about 100 micrograms to about 500 micrograms of said sodium channel blocker.

70 . The unit dose of any one of claims 54 to 69 , comprising a unit dose receptacle that contains the composition.

71 . A kit comprising: the unit dose of any one of claims 54 to 70 , and instructions for use of the unit dose for evaluating a presence or absence of Brugada syndrome in a subject in need thereof.

72 . An aerosol comprising particles having a mass median aerodynamic diameter less than 10 μm, wherein said particles comprise: a sodium channel blocker in a microdose that is sufficient to elicit an ECG change that unmasks an ECG phenotype of Brugada syndrome in a subject, and a pharmaceutically acceptable excipient.

73 . The aerosol of claim 72 . wherein said particles comprise a nebulized solution.

74 . The aerosol of claim 72 , wherein said particles comprise a nebulized aqueous solution.

75 . The aerosol of any one of claims 72 to 74 , wherein the particles comprise a pH buffer.

76 . The aerosol of any one of claims 72 to 74 , wherein said particles comprise a pH buffer selected from the group consisting of: citrate, phosphate, phthalate, acetate, and lactate.

77 . The aerosol of claim 72 , wherein said particles consist essentially of said sodium channel blocker and water.

78 . The aerosol of claim 72 , wherein said particles consist essentially of said sodium channel blocker, water, and a pH buffer.

79 . The aerosol of any one of claims 72 to 78 , wherein said particles have a pH ranging from 3.5 to 8.0.

80 . The aerosol of any one of claims 72 to 79 , wherein said sodium channel blocker comprises a class Ic antiarrhythmic.

81 . The aerosol of any one of claims 72 to 80 , wherein said sodium channel blocker is selected from the group consisting of: ajmaline, pilsicainide, flecainide, procainamide, salt and solvate thereof.

82 . The aerosol of any one of claims 72 to 81 , comprising at most about 1000 micrograms of said sodium channel blocker.

83 . The aerosol of claim 82 , comprising at least about 10 micrograms of said sodium channel blocker.

84 . The aerosol of claim 83 , comprising at least about 100 micrograms of said sodium channel blocker.

85 . The aerosol of claim 83 , comprising at least about 500 micrograms of said sodium channel blocker.

86 . The aerosol of any one of claims 72 to 81 , comprising about 100 micrograms to about 500 micrograms of said sodium channel blocker.

87 . A kit, comprising: a container containing a sodium channel blocker in a microdose that is sufficient to elicit an ECG change that unmasks an ECG phenotype of Brugada syndrome in a subject; and an aerosolization device.

88 . The kit of claim 87 , wherein the aerosolization device comprises a nebulizer.

89 . The kit of claim 87 , wherein the aerosolization device comprises a vibrating mesh nebulizer or a jet nebulizer.

90 . The kit of claim 87 , wherein the aerosolization device comprises a dry powder inhaler.

91 . The kit of claim 87 , wherein the aerosolization device comprises an active dry powder inhaler or a passive dry powder inhaler,

92 . The kit of claim 87 , wherein the aerosolization device comprises a metered dose inhaler.

93 . The kit of any one of claims 87 to 92 , wherein said sodium channel blocker comprises a class Ic antiarrhythmic.

94 . The kit of any one of claims 87 to 92 , wherein said sodium channel blocker is selected from the group consisting of: ajmaline, pilsicainide, flecainide, procainamide, salt and solvate thereof.

95 . The kit of any one of claims 87 to 94 , wherein said container comprises at most about 1000 micrograms of said sodium channel blocker.

96 . The kit of claim 95 , wherein said container comprises at least about 10 micrograms of said sodium channel blocker.

97 . The kit of claim 95 , wherein said container comprises at least about 100 micrograms of said sodium channel blocker.

98 . The kit of claim 95 , wherein said container comprises at least about 500 micrograms of said sodium channel blocker.

99 . The kit of any one of claims 87 to 94 , wherein said container comprises about 100 micrograms to about 500 micrograms of said sodium channel blocker.