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

1. CARDIAC CALCITROPES
MYOTROPES
MITOTROPES
Dr. Praveen Nagula
Mitchell A.Psotka et al

2. JACC May 14 2019
Volume 73, Issue 18, May 2019
DOI: 10.1016/j.jacc.2019.02.051

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. 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. 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. 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. Inotropy, contractility and contraction
 Two attributes can increase the physical impulse produced
 Force time product
 Increased force
 Increased duration of contraction time

8.  Typical definition of inotropy refers to the contraction of
myocardial apparatus that is load independent.

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. Contraction
 Measure of shortening of the underlying myocardial
structure, the sarcomere.

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. 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. 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.  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.

16. 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.

17.  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.

18. 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

19.  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

20. Suggested schema
 Mechanism of action
 Hemodynamic consequences
 Potential clinical benefits

21. 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.

22. 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.

37. PDE3 inhibitors
 Act through cAMP
 Blocks its degradation
 Increases protein kinase A

38. Levosimendan

40.  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.

41. Istaroxime
 Non glycoside
 Na+K+ ATP ase inhibitor
 Improved SERCA2a activity
 Elevated cardiac output in phase 2 studies
 Halted by manufacturer
 HORIZON HF trial

43. 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.

44. 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.

46.  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

50. GALACTIC – HF trial
 Phase 3
 Multicenter
 RCT
 Decreased NT proBNP
 Decreased cardiac dimensions

52. Cardiac mitotropes
 Drugs acting at the mitochondria
 Primary oxidation substrates transition from fatty acid to
glucose
 Decreased myocardial ATP.
 Perhexiline
 Trimetazidine
 Coenzyme Q10
 Elamipretide

58. Calcitropes vs myotropes
 Cardiac myotropes and cardiac calcitropes both
increase the force time product
 Calcitropes - increased force time
 Myotropes – increased time of contraction

60. Classification of current HF medical therapy
 B blockers – negative calcitropes,negative mitotropes
 MRAs – negative calcitropes, positive myotropes
 ACEI – negative calcitropes