contractility modulation Flashcards
how do conventional inotropics work?
- Work indirectly to improve contractility by activating second messenger signalling cascades that increase intracellular Ca in cardiomyocytes
- Catecholamines (dobutamine, dopamine) -> ↑cAMP
Phosphodiesterase inhibitors (milrinone) -> ↑cAMP by preventing its degradation
cAMP-mediated inotropic agents affect cardaic function by increasing the rate ofLV dP/dt and decreasing systolic ejection time.
major limitations of conventional inotropics?
○ Increase in tachyarrhythmias
○ Desensitisation leading to increasing dose requirement
○ Downstream effect of ↑Ca →↑demand for energy (ATP) to actively transport Ca out of the cytoplasm
cardiac myosin activators mechanism
work directly on sarcomeric proteins within cardiomyocytes
A sarcomere contains numerous myosin molecules that cat as independent force generators, however, only a small subset of myosin heads participate in force generation during each cardiac cycle.
Myosin heaad contains ATPase which uses chemical energy to generate mechanical force. Myosin binds and hydrolyses ATP, weakly binds to actin via Ca-sensitive mechanism and then releases phosphate, thus forming a strong bond with actin, which is followed by a powerful force-generating stroke.the enzymatic and mechanical cycles are tightly coupled.
• The rate limiting step in the cross-bridge cycle is the transition from the weakly bound (actin-myosin-ADP-Pi complex) to the strongly bound (actin-myosin-ADP complex) configuration, accompanied by a force producing power stroke.
► Cardiac myosin activators, specifically omecamtiv mecarbil, directly activate the sarcomere by accelerating the rate-limiting step, ie. The transition from weakly bond to the strongly bound state when the phosphate is released, in myocyte contraction and reducing nonproductive ATP hydrolysis.#
· OM is a cardiac selective, allosteric activator of the myosin S1 domain (head), a domain that allows the medication to modulate both enzymatic and mechanical properties of the cardiac myosin.
Accelerating this step results in faster cycling of actin-myosin cross-bridge formation, which in turn increases the amount of myosin heads interacting with actin. The latter is responsible for generation of a stronger contractile force because normally only a small subset of myosin heads interct with acting during each cycle
the bottom line of cardiac myosin activators mechanism of action?
► Cardiac myosin activators, specifically omecamtiv mecarbil, directly activate the sarcomere by accelerating the rate-limiting step, ie. The transition from weakly bond to the strongly bound state when the phosphate is released, in myocyte contraction and reducing nonproductive ATP hydrolysis.#
· OM is a cardiac selective, allosteric activator of the myosin S1 domain (head), a domain that allows the medication to modulate both enzymatic and mechanical properties of the cardiac myosin.
Accelerating this step results in faster cycling of actin-myosin cross-bridge formation, which in turn increases the amount of myosin heads interacting with actin.
what are the functional effects of cardiac myosin activators?
OM has been shown to improve cardiac contractility by means of prolonging systolic ejection time without altering myocardial oxygen consumption, myocyte calcium levels or the rate of LV pressure development (LV dP/dt). While OM may increase ATP turnover at the level of the sarcomere, it does not appear to increase overall myocardial oxygen consumption. Any potential increase in ATP turnover in the sarcomere appears to be balanced by other decreases in myocardial energy consumption, most likely related to decreases in myocardial wall stress and heart rate.
how is calcium handling affected by cardiac myosin activators?
they do NOT affect the calcium transients.
early clinical trial for cardiac myosin activators did what and showed what?
A double-blind placebo controlled phase I trial involving 6-hour infusion of OM in 34 healthy men was performed to determine the max tolerable dose. There was evidence od dose-dependent increases in cardiac dunction as measured by EF, systolic ejection time, fractional shortening, stroke volume, however there was not enough participants to meet the defined criteria for max tolerated dose.
in another study: The effects of OM on cardiac function peristed for 72 hours, indicating the absence of desensitisation.
what relative side effect was found in another trial (cardiac myosin activators)
In a study performed by Cleland et al, there was noted to be a small reduction in diastolic duration. However, OM treatmetn resulted in increased atrial contractile duration and function, which may have attenuated the effects of decreased diastolic filling time.
