What does Om mean in cardiology
Omecamtiv mecarbil (OM) is a new substance with potential for treating heart failure. It works myotropically without increasing the cytosolic calcium concentration. Clinical studies are still ongoing until the end of the year, the results of which are eagerly awaited.
Heart failure (HI) is particularly caused by age-related diseases such as diabetes and hypertension. The prevalence of HI increases with age, but also that of diseases of other organ systems. Comorbidities have an unfavorable influence on the prognosis of HI, and
conversely, a HI increases the risk of comorbidities such as kidney failure, diabetes, depression or tumors.
Heart failure as a systemic disease
Therefore, HI should not be viewed as an isolated organ disease, but as a systemic disease. What systems do organs use to communicate with one another?
Three main ones are neuroendocrine activation, inflammation and metabolism. While current HI therapy is predominantly aimed at blocking neuroendocrine activation, newer therapies target inflammation and metabolic processes.
There are more and more therapy options
Antibody to interleukin-1b (canakinumab) or the inhibition of interleukin-1b production with colchicine reduced cardiovascular endpoints in patients after myocardial infarction. Canakinumab also lowered hospitalizations for HI.
SGLT2 inhibitors reduce the prognosis in patients with diabetes who are hospitalized for HI, and in the DAPA-HF study, dapagliflozin improved the prognosis in HI patients with reduced ejection fraction (HFrEF) even without diabetes. Further
Studies with empagliflozin and dapagliflozin in patients with cardiac and renal insufficiency are ongoing.
Thus, the therapeutic horizons for HI could soon expand beyond the neuroendocrine axis.
Few therapies target the heart only. Ivabradine inhibits the “pacemaker channel current” (If) of the heart. The heart rate reduction achieved in this way differs from b-blockers in that they do not
has negative inotropic effects (caused by b-blockade) and in patients with HI the left ventricular (LV) stroke volume even increases acutely, because in HI the myocardial contractility decreases at a higher heart rate. Thus, the hemodynamic effects of ivabradine in the acute phase are complementary to b-blockers and smaller studies suggest that the early addition of ivabradine facilitates the titration of b-blockers.
New drug works directly on the heart
Omecamtiv mecarbil (OM) is a new type of drug that also acts directly on the heart, that is, "myotropically" on the sarcomeres. The effect of OM is currently being tested on 8,256 patients with HI and HFrEF in the GALACTIC-HF study, the results of which are expected by the end of 2020.
But how does OM work exactly? With electromechanical coupling, the influx of calcium (Ca2 +) via L-type Ca2 + channels triggers an even greater Ca2 + release from the sarcoplasmic reticulum (SR; Fig. 1).
This Ca2 + binds to the myofilaments and initiates the contraction via an actin-myosin interaction. In the diastole, Ca2 + diffuses from myosin again and is pumped back into the SR via the SR-Ca2 + -ATPase (SERCA)
or exported from the cell via the Na + / Ca2 + exchanger.
In HFrEF, reduced cytosolic Ca2 + transients cause the reduced contraction, which is due to a reduced SERCA activity and thus SRCa2 + loading. The SERCA deficit also slows down Ca2 + re-uptake into SR and thus relaxation, which explains why every HFrEF patient also has a diastolic deficit.
Fig. 1:The systolic dysfunction in HI is based on dysregulated electromechanical coupling and energetics (arrows up / down). Mechanisms of action for stimulation (+) or inhibition (–I).
NCX: Na + / Ca2 + exchanger; NKA: Na + / K + -ATPase; PDE: phosphodiesterase;
PKA: protein kinase A; AR: adrenoceptor; SR: sarcoplasmic reticulum; SERCA: SR calcium ATPase.
Difference from other drugs
Previous drugs that acutely increase inotropy act primarily by increasing the cytosolic Ca2 + concentrations, in particular through
Activation of b-adrenergic signal transduction and cAMP production, such as dobutamine or phosphodiesterase (PDE) inhibitors (Fig. 1). Indeed
they cause excess mortality, as they trigger arrhythmias and favor the chronic activation of the b-adrenergic system, maladaptive remodeling, hypertrophy and cell death.
Omecamtiv acts as a Ca2 + sensitizer
To avoid this, “Ca2 + sensitizers” were developed, which increase the affinity of the myofilaments for Ca2 +. This increases the contraction without increasing the Ca2 + concentrations, but at the same time worsens the relaxation, since the diffusion of Ca2 + from the myofilaments is slowed down.
Levosimendan increases the binding of Ca2 + to myosin-binding protein C and is therefore a Ca2 + sensitizer, but the substance also potent inhibits PDE3 (Fig. 1), which explains why levosimendan increases contraction without worsening relaxation. The PDE3 inhibition could explain why levosimendan did not improve the prognosis compared to dobutamine or placebo in any (single) study.
Myotropy prolongs contraction
OM binds as a “small molecule” to the catalytic domain of myosin-ATPase and thus favors the actin-binding, force-generating conformation of myosin without influencing the cytosolic Ca2 + concentration.
This lengthens the “power stroke”, which causes the contraction to be lengthened, but not accelerated.
This type of inotropy increase is called "myotropy" in order to reduce the
To distinguish the mechanism of action from conventional inotropes, which mostly work by increasing the Ca2 + concentration (calcitropic).
Echocardiographically, the OM effect can be documented by increasing the systolic ejection time (SET), which is shortened in HFrEF patients.
Previous study results
In healthy volunteers, OM increased LV stroke volume and blood pressure. In the ATOMIC-HF study on 606 patients with acute heart failure, intravenous OM increased the SET and blood pressure, but reduced the end-systolic LV volume and heart rate. The latter is most likely due to a reflex withdrawal of endogenous sympathetic activation. Although OM in ATOMIC-HF did not lead to a reduction in dyspnoea, this was the case in a pre-specified subgroup with a higher OM dose.
The COSMIC-HF study examined the effect of oral OM in 448 outpatients with chronic HFrEF. Compared to placebo, OM extended the SET after 20 weeks, increased the stroke volume and reduced end-systolic and -diastolic LV volumes, heart rate and NTproBNP-
Phase III study GALACTIC-HF
These results enabled the Phase III GALACTIC-HF study in patients
with HFrEF (LVEF basal 27%). A special feature of this study is that 25% of the patients were hospitalized due to an HI when randomized. The patients are optimally treated with medication, 19% with sacubitril / valsartan, but only 3% with SGLT2 inhibitors.
Two aspects require special discussion: By lengthening the systole under OM, the diastole is automatically shortened. In a few subjects with very high plasma concentrations (1,200 ng / ml), angina and troponin secretion occurred in early studies, which was presumably due to a compromised diastolic coronary flow. Lower OM doses and plasma concentrations are therefore used in HI patients (in COSMIC: 318 ng / ml).
There was also a very slight increase in troponin levels under OM, but
this did not correlate with the OM plasma concentrations. The reason for this is currently unclear. The fact that OM NT-proBNP values and also end-diastolic LV volumes were reduced in COSMIC-HF speaks against the myocardial damaging effects of the substance.
In a smaller safety study on patients with ischemic HFrEF, OM did not lead to increased angina symptoms or adverse events even under exercise. In addition, it is currently not entirely clear whether OM in a therapeutic dose reduces the oxygen consumption of the heart
increases. In a study on heart failure dogs, OM increased cardiac output, but oxygen consumption remained unchanged despite the lowering of the heart rate. This could mean that although OM moderately increases the oxygen consumption per contraction, this is compensated for by reduced endogenous sympathetic activation and the resulting decrease in heart rate.
If the data from the GALACTIC-HF study are positive, further mechanistic studies could answer the open questions
- How common is depression in CEOs
- Why do teens hate poetry
- Is a male Lama la Lama
- Recycling of MAC addresses
- How WeChat Money works
- How does autopilot get buggy
- Should Twitter implement a like function
- Did your midwives respect your birth plan?
- Is rubber mulch harmful to the environment
- You can refuse a catheter during surgery
- How common are unicellular eukaryotes
- Are weed pens legal to travel
- How to say sweat in Korean
- What philosophies did Napoleon follow
- Who is CrazyRussianHacker on YouTube
- Can you share your After Holi picture
- Which programming languages does Github support
- What is an MS publisher
- What is Elton John's Rocket Man about
- Where did medieval tournaments take place
- Is rubber sproede or ductile material
- What operating system in Jio phone
- What kind of knowledge gives power
- What is the MI Note 10