RyR targets in HF

Question 1

Despite the controversies, there is a great potential for drugs that act to reduce the RyR mediated calcium leak and thus prevent arrhythmias, hypertrophic signalling and possibly contractile dysfunction

Answer 1

Several compounds are known as rycals

Question 2

Yano et al 2003

Answer 2

Identified a compound K201

It stabilised the RyR in the closed conformation, although whether or not this is mediated by calstabin is still highly controversial. An early study in a canine model of heart failure showed that JTV519 attenuated the PKA hyperphosphorylation of RyR, inhibited the SR leak and ultimately rescued LV function. Further studies by the same group suggest that rather than increasing calstabin binding, it is just restoring normal RyR interdomain interaction

Question 3

Kinura et al 1999

Answer 3

However, they suggest that they work by inhibiting ICa, INa and IK1 So might not be solely due to the stabilisation of the RyR2 channels

Question 4

Karl Toisser et al 2010

Answer 4

o Studied the effects of K201 on muscle preparations from failing human heart
o K201 improves both diastolic and systolic contractile function of failing human myocardium.
o Importantly, systolic improvement is confined to low concentrations of K201 as higher concentrations are clearly negatively inotropic

Question 5

Lenhart et al 2008

Answer 5

• New derivate of JTV519, S107
• More selective profile has been developed.
• S107 has been shown to increase the binding of calstabin to RyR, reduce abnormal diastolic Ca2+ release in arrhythmias, and attenuate HF progression

Question 6

S44121 (Adalorian)

Answer 6

o It is in phase 2 trial
o It is an oral medication and being
o Phase 2, placebo-controlled randomised trial being evaluated in patients with congestive heart failure

Question 7

Flecanide and tetracaine

Answer 7

o	Flecainide is a class Ic antiarrhythmic clinically used to treat atrial fibrillation. The drug has additionally been shown to inhibit the open-state of the RyR, and thus experimentally prevent Ca2+ waves and arrhythmias in both mice and human CPVT
o	However, this finding is controversial as Liu et al in 2011 found that flecainide prevented triggered activity in mice primarily by Na+ channel block, while Ca2+ homeostasis was minimally affected.
o	Tetracaine, on the other hand, is a closed-state blocker of RyR and could thereby reduce diastolic Ca2+ leak without interfering with the systolic Ca2+ release.