Cardiovascular effects of histone deacetylase inhibitors epigenetic therapies: Systematic review of 62 studies and new hypotheses for future research

Differences in Functional Expression of Connexin43 and NaV1.5 by Pan- and Class-Selective Histone Deacetylase Inhibition in Heart

“…With the phase 3 clinical trial class I HDAC inhibitor, entinostat, we observed no change in ventricular g j , peak I Na density, or the V ½ for V m -dependent activation and inactivation at the class-selective concentration of 1 μM. The lack of these effects may help explain the safer record of entinostat pertaining to cardiotoxicity, especially considering that this concentration is still more than three times the therapeutic dose used in clinical trials [7,18]. The phase 1–2 clinical trial class IIb HDAC inhibitor, ricolinostat, also had minor effects on ventricular g j and I Na electrophysiological properties.…”

“…Furthermore, hundreds of HDAC inhibitors are undergoing clinical trials (). However, HDAC inhibitor-related severe cardiotoxic side effects, especially QT interval prolongation, ventricular arrhythmia and unexpected sudden cardiac death, necessitated clinical trial termination or dose readjustments of numerous promising non-selective HDAC inhibitors [4,5,6,7]. In addition, panobinostat, the most potent pan-HDAC inhibitor, carries a black box warning for severe cardiac abnormalities on its prescription label [31].…”

“…Encouragingly, the development of the Class I HDAC inhibitor entinostat has enabled this goal. Entinostat combined with exemestane increased overall survival and progression-free survival in patients with advanced hormone receptor (HR)-positive breast cancer without adverse cardiac toxicity events [7,11]. But the mechanisms for the reduced arrhythmogenic cardiotoxicities observed with pan-HDAC inhibitors remains essentially unknown.…”

“…HDACs have been suggested to be overexpressed in tumor cells and alter the expression and function of many tumor suppressor genes like p53 [2,3]. However, the four U. S. Food and Drug Administration (FDA) approved pan-HDAC inhibitors are limited to non-solid tumors and have been reported to cause serious cardiotoxicities such as QT interval prolongation, ventricular arrhythmia and unexpected sudden cardiac death [4,5,6,7]. In order to improve their effectiveness on solid tumors as well as to minimize their cardiac side effects, a new generation of HDAC inhibitors, class-selective HDAC inhibitors were designed and developed [8].…”

“…These functional reductions in rapid depolarization and electrical coupling likely contribute to decreased excitability and slowed conduction, thereby increasing the vulnerability to reentrant arrhythmias. Since entinostat (MS-275), a class I selective HDAC inhibitor, apparently causes minimal cardiotoxic effects [7,8,18], we hypothesize that class-selective HDAC inhibition does not cause the functional downregulation of the cardiac I Na or gap junction conductance (g j ) observed with the first two FDA-approved pan-HDAC inhibitors, vorinostat (VOR, Zolinza ® ) and romidepsin (FK228, Istodax ® ) [13,14]. In this study, we examine the effects of another FDA-approved HDAC inhibitor, panobinostat (LBH589, Farydak ® ), and two clinical trial class-selective HDAC inhibitors, entinostat (MS-275, HDAC class I selective), and ricolinostat (ACY-1215, HDAC class IIb selective), on Cx43-mediated cardiac gap junction coupling and excitatory cardiac sodium current density mediated primarily by Na V 1.5.…”