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CARDIAC CALCITROPES,MYOTROPES,MITOTROPES

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A new classification of drugs in heart failure based on the mechanism of action at molecular level

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CARDIAC CALCITROPES,MYOTROPES,MITOTROPES

  1. 1. CARDIAC CALCITROPES MYOTROPES MITOTROPES Dr. Praveen Nagula Mitchell A.Psotka et al
  2. 2. JACC May 14 2019 Volume 73, Issue 18, May 2019 DOI: 10.1016/j.jacc.2019.02.051
  3. 3. Introduction  Inotropes used in low cardiac output with cardiogenic shock  They improve the contractile function of the heart.  They exert action by modulating calcium signalling in the myocardium.  Their use associated with poor long term outcomes.  Need for newer molecules – break from calcium mediation and detrimental long term effects.
  4. 4. How do you assess the response ? The improvement in contractility from the conventional agents can be manifested by  1.increased LV systolic pressure generation per unit time (dp/dt)  2.augmented hemodynamic performance  3.increased stroke volume  4.increased cardiac output  5.increased LV EF on imaging  6.decreased cardiac biomarkers  7.decreased vascular tone – increased cardiac activity
  5. 5. Conventional inotrope agents Catecholamines Phosphodiesterase 3 inhibitors Na+ K+ ATP ase inhibitors Mixed mechanism – calcium sensitizers, phoshodiesterase 3 inhibitors  Alter myocardial energetics – decrease ATP/ADP ratio  Clinical outcomes – neutral to malignant arrhythmias  The underlying calcium centric mechanism may be detrimental.
  6. 6. Why term inotrope not to be used broadly? Currently used as an overly broad and ill defined concept to define therapies that improve the pumping function of the heart. “Detrimental long term effects of these agents on clinical outcomes for patients with HFrEF are a direct consequence of their mechanism of action and have sullied the term inotrope as a potential long term therapeutic option…”
  7. 7. Inotropy, contractility and contraction  Two attributes can increase the physical impulse produced  Force time product  Increased force  Increased duration of contraction time
  8. 8.  Typical definition of inotropy refers to the contraction of myocardial apparatus that is load independent.
  9. 9. Cardiac contractility  Conventionally manifested by accelerated myocardial fiber shortening that increase the rise in ventricular dp/dt and leads to an elevated peak tension.  Load independent  Ability of the myocardium to generate force per unit time.
  10. 10. Contraction  Measure of shortening of the underlying myocardial structure, the sarcomere.
  11. 11.  Increased contraction can occur because of augmented contractility.  Contraction can also increase independently of load or raise in dp/dt – by the mechanism that prolong the duration of contraction.  Vasodilation and decreased afterload – increased contraction speed with stable contractility.
  12. 12. Highlight points  LVEF by imaging and hemodynamically measured cardiac output is load dependent.  They are often conflated with contractility in clinical settings – and they fail to assess the isolated contractile status of the myocardium.  Although pure vasodilators – may improve LVEF or stroke volume they cannot be considered as inotropes.
  13. 13. Myocardial contractile apparatus and energetics  Available inotropic agents – alter ventricular systole performance by affecting the myocardial machinery 3 broad components of machinery are  1.contractile elements – myosin motor actin filaments regulatory proteins – troponin and tropomyosin complex  2.calcium cycling elements - storage and flux of myocardial calcium  3.energetic elements – ATP produced by mitochondria required for myosin activity.
  14. 14.  Myosin is the critical molecular motor that converts energy stored in as ATP to contractile force.  It is the active enzyme of the myocardial force producing structure – the sarcomere.  Sarcomeric myosin exists as thick filaments interdigitated between the thin filaments of actin on which it pulls to mediate contraction.  Actin associated troponin and tropomyosin enable the intracellular calcium status to regulate the myosin actin interaction.
  15. 15. Myosin mechanochemical cycle  Moves actin myofilament by approximately 10nm  Power stroke occurs during cardiac systole – following ECG QRS – correlate of calcium influx.  Resetting of molecular motor takes place during diastole – calcium efflux – T wave.  Substantial ATP is used within 1 minute.
  16. 16.  Intramyocardial power source responsible for providing energy to the myocardial contraction apparatus is mitochondria.  Intracellular processing of fatty acids, glucose – carrier molecules produced – delivers electrons to the mitochondrial electron transport chain – increased proton gradient – mitochondrial ATP synthase - ATP.  In normally functioning mitochondrion – fatty acids are the primary energy source.
  17. 17. Why the need of new agents ?  New pharmacological agents that alter the myocardial performance and contraction by novel means may be able to further improve myocardial energetics and clinical outcomes for patients with HFrEF.  They may have morbidity and mortality benefit without altering or increasing the cardiomyocyte calcium fluxes.  Direct contraction promoting agents
  18. 18.  A more novel, nuanced, holistic framework for drugs directly improve myocardial performance  To facilitate improved clinical and scientific communication  To augment pharmaceutical development  Enhance clinical care
  19. 19. Suggested schema  Mechanism of action  Hemodynamic consequences  Potential clinical benefits
  20. 20. Three myocardial mechanisms  Calcitropes – alters intracellular calcium concentrations  Myotropes – affects molecular motor and scaffolding  Mitotropes – influence energetics  Novel chemical entities can easily be incorporated into this structure, distinguishing themselves based on their mechanisms and clinical outcomes.
  21. 21. Traditional inotropes; cardiac calcitropes  The augmented calcium by these agents offsets the observed decrement of calcium in the SR of patients with HFREF caused by ryanodine receptor leak.  Because these agents act by altering calcium – cardiac calcitropes.  The calcitropes are defined by their direct myocardial action rather than their secondary effects on vascular tone and chronotropy – both of which may also alter cardiac performance.
  22. 22. PDE3 inhibitors  Act through cAMP  Blocks its degradation  Increases protein kinase A
  23. 23. Levosimendan
  24. 24.  Although cardiac glyosides do increase dp/dt they don’t markedly change cardiac output in clinical studies perhaps due to concomitant vasoconstriction and slowing of heart rate.
  25. 25. Istaroxime  Non glycoside  Na+K+ ATP ase inhibitor  Improved SERCA2a activity  Elevated cardiac output in phase 2 studies  Halted by manufacturer  HORIZON HF trial
  26. 26. Why inotropes have been detrimental ?  The unifying mechanism by which each of these agents enhance cardiac contractility is increased intracellular calcium – and this mechanism may be why they have been unable to improve long term survival of patients with HFrEF.
  27. 27. Cardiac myotropes  Independent of calcium dependent mechanisms  Calcium sensitizers acting on regulatory troponin and tropomyosin independently of calcium flux – cardiac myotropes.  Myosin is an attractive therapeutic target.  Omecamtiv mecarbil – directly activates cardiac myosin in a calcium independent manner by allosterically modulating its activity.
  28. 28.  Increased total amount of time spent in contraction  Increased systole time  No increase in dp/dt  Increased duration of ventricular systole  Increased Systolic ejection time  Increased Aortic blood flow  No greater oxygen consumption  Increased overall efficacy of mechanochemical system
  29. 29. GALACTIC – HF trial  Phase 3  Multicenter  RCT  Decreased NT proBNP  Decreased cardiac dimensions
  30. 30. Cardiac mitotropes  Drugs acting at the mitochondria  Primary oxidation substrates transition from fatty acid to glucose  Decreased myocardial ATP.  Perhexiline  Trimetazidine  Coenzyme Q10  Elamipretide
  31. 31. Calcitropes vs myotropes  Cardiac myotropes and cardiac calcitropes both increase the force time product  Calcitropes - increased force time  Myotropes – increased time of contraction
  32. 32. Classification of current HF medical therapy  B blockers – negative calcitropes,negative mitotropes  MRAs – negative calcitropes, positive myotropes  ACEI – negative calcitropes

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