Novel epigenetic-based therapies useful in cardiovascular medicine

Table 1 Interventional and randomized ongoing clinical trials on the use of hydralazine and procainamide in cardiovascular diseases

No.	Status	Condition	No. of enrolled patients	Intervention
NCT00684489	Completed	Hypertension	52	Hydralazine and other drugs
NCT02305095	Not open for participant recruitment	Heart failure	500 (estimated enrollment)	Hydralazine in combination with isosorbide dinitrate
NCT00661895	Completed	Hypertension	99	Hydralazine and other drugs
NCT00599235	Completed	Hypertension	30	Hydralazine, sildenafil, and placebo
NCT00223717	Recruiting participants	Hypertension	160 (estimated enrollment)	Hydralazine and other drugs
NCT01255475	Completed	Heart failure, cardiac failure, and congestive heart failure	21	Hydralazine/amlodipine and placebo
NCT01516346	Recruiting participants	Heart failure and congestive heart failure	54 (estimated enrollment)	Hydralazine, isosorbide dinitrate, and placebo
NCT01822808	Recruiting participants	Acute heart failure and left ventricular dysfunction	500 (estimated enrollment)	Hydralazine, isosorbide dinitrate, and placebo
NCT00000499	Completed	Cardiovascular diseases, heart diseases, hypertension, and vascular diseases	Not provided	Hydralazine, reserpine, chlorthalidone, and metoprolol
NCT02050529	Recruiting participants	Hypertension, Pregnancy induced	180 (estimated enrollment)	Hydralazine, labetalol
NCT01538875	Completed	Hypertension, Pregnancy induced	261	Hydralazine, labetalol
NCT00383799	Unknown	Ventricular tachycardia	302 (estimated enrollment)	Procainamide, amiodarone
NCT00000464	Completed	Arrhythmia, Cardiovascular diseases	115	Procainamide, quinidine, disopyramide, and other drugs
NCT00702117	Completed	Atrial fibrillation, tachycardia	123	Procainamide, ajmaline, flecainide
NCT00589303	Terminated	Atrial fibrillation, heart failure	27	Rhythm control drugs: Procainamide and other drugs
NCT00000556	Completed	Arrhythmia, atrial fibrillation, cardiovascular diseases	4060	Procainamide and other drugs
NCT01205529	Recruiting	Atrial fibrillation	750 (estimated enrollment)	Procainamide

Table 2 Histone modifications and therapeutic targets involved in cardiovascular diseases

Target	Epigenetic mechanisms	Condition	Organism/in vitro, in vivo	Effects	Ref.
TSA	Inhibition of HDAC4	Ischemic injury	Mouse, in vitro and in vivo	HDACi would be predicted to have a beneficial effect in the context of active ischemia	Granger et al[28] (2008)
TSA/VPA	Class I HDACs	Cardiac hypertrophy	Mouse, in vitro and in vivo	Therapeutic target for preventing or reversing cardiac hypertrophy and subsequent heart failure	Kee et al[29] (2006)
TSA	Inhibition of HDACs	Atrial fibrosis and arrhythmias	Mouse, in vitro and in vivo	Reversed myocardial fibrosis	Liu et al[30] (2008)
TSA	Inhibition of HDACs	Acute myocardial ischemia and reperfusion injury	Mouse, in vitro and in vivo	Improved cardiac functional recovery and antagonized myocardial remodeling in chronic myocardial infarction	Zhang et al[31] (2012)
TSA/SAHA	HDAC inhibitor	Myocardial infarct	Mouse, rabbit, in vivo	Reduced infarct size in a large animal model	Xie et al[35] (2014)
SAHA/sodium valproate	Inhibition of HDACs	Ischemic injury	Mouse, in vitro and in vivo	Potential therapeutic strategy for restoring compromised cardiac proteostasis	Wang et al[36] (2011)
VPA or tributyrin	Inhibition of HDACs	Infarct	Rat, in vitro	Attenuated ventricular remodeling after infarction	Lee et al[37] (2007)
MS-275A	Inhibition of class I/II HDACs	Infarct	Rat, in vivo	Significant reduction of infarct area observed	Aune et al[39] (2014)
Apicidin	Inhibition of class I HDACs	Cardiac hypertrophy and heart failure	Rat pups, in vitro Mouse, in vivo	Preserved cardiac function in the long-term	Gallo et al[42] (2008)
Curcumin	p300 HAT inhibitor	Heart failure	Rat, in vitro	Prevented deterioration of systolic function and heart failure	Morimoto et al[45] (2008)

TSA: Trichostatin A; HDAC: Histone deacetylases; HDACi: Inhibitors of histone deacetylases; SAHA: Suberoylanilide hydroxamic acid; VPA: Valproic acid.

Table 3 Recent evidence investigating the role of circulating miRNAs as biomarkers in several cardiovascular diseases

miRNAs	Sources	Conditions	Ref.
↑miR-339-5p, miR-483-3p ↓miR-139-5b	Plasma	LVI	Saddic et al[64] (2015)
↓miR-145	Plasma	AMI	Gao et al[65] (2015)
↑miR-122, miR-140-3p, miR-720, miR-2861, miR-3149	Plasma	ACS, AMI	Li et al[66] (2015)
↑Let-7e, miR-15a, miR-196b ↓miR-411	Plasma	AAA, Atherosclerosis	Stather et al[67] (2015)
↓ miR-125b, miR-320b	Plasma	AMI, CAD	Huang et al[68] (2014)
↓miR-21	Serum	CAD	Fan et al[69] (2014)
↓miR-31	Plasma	CAD	Wang et al[70] (2014)
↑miR-146a, miR-186, miR-208b, miR-499	Serum	ACS, Stable CAD, CV risk	Wu et al[71] (2014)
↑miR-210	PBMC	HF	Endo et al[72] (2013)
↑miR-21, miR-25, miR-92a, miR-106b, miR-126, miR-451, miR-590-5p	Plasma	AP, UA	Ren et al[73] (2013)
↔ miR-1, miR-208a, miR-423-5p	Plasma	AMI, CAD	Nabialek et al[74] (2013)
↑miR-30a, miR-210	Serum	HF	Zhao et al[75] (2013)
↑miR-337-5p, miR-433, miR-485-3p, miR-1, miR-122, miR-126, miR-133a/b, miR-199a ↔miR-17-5p, miR-92a, miR-145, miR-155, miR-208a, miR-375, miR-799-5p	Plasma	AP, UA	D’Alessandra et al[76] (2013)
↓miR-103, miR-142-3p, miR-30b, miR-342-3p	Plasma	HF	Ellis et al[77] (2013)
↑miR-122, miR-200b, miR-520d-5p, miR-622	WB and serum	HF	Vogel et al[78] (2013)
↓miR-558
↑miR-21, miR-133a, miR-423-5p, miR-499-5p	Plasma	HF, NSTEMI	Olivieri et al[79] (2013)
↔miR-1, miR-208a
↑miR-133a	Plasma	AMI, AP	Wang et al[80] (2013)
↓miR-214	Plasma	AMI, AP, UA	Lu et al[81] (2013)

AAA: Abdominal aortic aneurysm; ACS: Acute coronary syndrome; AMI: Acute myocardial infarction; AP: Angina pectoris; CAD: Coronary artery disease; CV: Cardiovascular; HF: Heart failure; LVI: Left ventricular ischemia; NSTEMI: Non-ST-elevation myocardial infarction; PBMC: Peripheral blood mononuclear cells; UA: Unstable angina; WB: Whole blood.