Treatments targeting inotropy

Abstract

Acute heart failure (HF) and in particular, cardiogenic shock are associated with high morbidity and mortality. A therapeutic dilemma is that the use of positive inotropic agents, such as catecholamines or phosphodiesterase-inhibitors, is associated with increased mortality. Newer drugs, such as levosimendan or omecamtiv mecarbil, target sarcomeres to improve systolic function putatively without elevating intracellular Ca2+. Although meta-analyses of smaller trials suggested that levosimendan is associated with a better outcome than dobutamine, larger comparative trials failed to confirm this observation. For omecamtiv mecarbil, Phase II clinical trials suggest a favourable haemodynamic profile in patients with acute and chronic HF, and a Phase III morbidity/mortality trial in patients with chronic HF has recently begun. Here, we review the pathophysiological basis of systolic dysfunction in patients with HF and the mechanisms through which different inotropic agents improve cardiac function. Since adenosine triphosphate and reactive oxygen species production in mitochondria are intimately linked to the processes of excitation-contraction coupling, we also discuss the impact of inotropic agents on mitochondrial bioenergetics and redox regulation. Therefore, this position paper should help identify novel targets for treatments that could not only safely improve systolic and diastolic function acutely, but potentially also myocardial structure and function over a longer-term.

Keywords: Acute decompensated heart failure; Adrenergic receptors; Calcium; Cardiogenic shock; Contractility; Energetics; Excitation–contraction coupling; Heart failure; Inotropes; Levosimendan; Mitochondria; Nitroxyl; Omecamtiv mecarbil; Sarcomeres.

Figure 1

The physiology of excitation–contraction coupling and how this is altered in systolic heart failure. AR, adrenergic receptor; cAMP, cyclic adenosine monophosphate; ETC, electron transport chain; I_Ca and I_Na, Ca²⁺ and Na⁺ currents; NCX; Na⁺/Ca²⁺-exchanger; NKA, Na⁺/K⁺-ATPase; PDE, phosphodiesterase; PKA, protein kinase A; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; SERCA, SR Ca²⁺ ATPase; T-tubule, transversal tubule. Red arrows (_↑↓) indicate the direction of change in heart failure.

Figure 2

Signal transduction of β₁-adrenergic stimulation in cardiac myocytes and its impact on inotropy, but also arrhythmias, hypertrophy, and apoptosis. 5’-AMP, 5’ adenosine monophosphate; AC, adenylyl cyclase; ADR, adrenaline; AR, adrenergic receptor; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; cAMP, cyclic adenosine monophosphate; EPAC, exchange protein directly activated by cAMP; GRK2, G-protein coupled receptor kinase 2; NA, noradrenaline; PDE, phosphodiesterase; PKA, protein kinase A; α, β, γ, α-, β- and γ-subunits of the stimulatory G-protein.

Figure 3

Interplay between EC coupling and mitochondrial energetics. Krebs cycle activity is controlled by Ca²⁺, and mitochondrial Ca²⁺ uptake is diminished in heart failure by changes in cytosolic Ca²⁺ and Na⁺ handling. This provokes an energetic deficit and oxidative stress, which further impairs EC coupling and aggravates systolic and diastolic function. AR, adrenergic receptor; ATPase, F₁F_o-ATP synthase; CaMKII, Ca²⁺/calmodulin-dependent protein kinase II; CK, creatine kinase; Cr, creatine; ETC, electron transport chain; IDP_m, isocitrate dehydrogenase; late I_Na, late Na⁺ current; MCU, mitochondrial Ca²⁺ uniporter; Mn-SOD, mitochondrial superoxide dismutase; NCLX, mitochondrial Na⁺/Ca²⁺-exchanger; Nnt, nicotinamide nucleotide transhydrogenase; PCr, phosphocreatine; RyR, ryanodine receptor; SERCA, SR Ca²⁺ ATPase. Red arrows (_↑↓) indicate the direction of change in heart failure.

Figure 4

Mechanisms of action of cardiotonic glycosides (CTG) and istaroxime (ISTA). I_Ca and I_Na, Ca²⁺ and Na⁺ currents; NCLX, mitochondrial Na⁺/Ca²⁺-exchanger; NCX, Na⁺/Ca²⁺-exchanger; NKA, Na⁺/K⁺-ATPase; ROS, reactive oxygen species; RyR, ryanodine receptor; SERCA, SR Ca²⁺ ATPase; SR, sarcoplasmic reticulum; TCA, tricarboxylic acid (Krebs) cycle. Red arrows (_↑↓) indicate the direction of change in response to CTG.

Figure 5

Mode of action of levosimendan and its active metabolite OR-1896. Both Ca²⁺-sensitization and PDE3-inhibition at nanomolar concentrations (nM) contribute to their inotropic and lusitropic effects. Activation of mitochondrial K_ATP (mitoK_ATP) channels at micromolar concentrations (_µM) may provide protection against ischaemia/reperfusion. AR, adrenergic receptor; cAMP, cyclic adenosine monophosphate; ETC, electron transport chain; I_Ca and I_Na, Ca²⁺ and Na⁺ currents; NCX, Na⁺/Ca²⁺-exchanger; NKA, Na⁺/K⁺-ATPase; PDE, phosphodiesterase; PKA, protein kinase A; RyR, ryanodine receptor; SERCA, SR Ca²⁺ ATPase; SR, sarcoplasmic reticulum; T-tubule, transversal tubule. Red arrows (_↑↓) indicate the direction of change in heart failure, while green arrows (_↑↓) indicate the direction induced by levosimendan.

Figure 6

Mechanism of action and effects of omecamtiv mecarbil. (A) The mechanochemical cycle of myosin. Yellow indicates myosin weakly bound to actin, while red indicates the myosin strongly bound to actin. Omecamtiv mecarbil (OM) accelerates the transition rate of myosin into the strongly actin-bound force-generating state. (B) Representative tracings showing that OM (200 nM) increases the time and amplitude of myocyte shortening without any effect on the cytosolic Ca²⁺ transient. In contrast, the β-AR agonist isoproterenol increases myocyte shortening through increasing cytosolic Ca²⁺ transients. Fractional systolic sarcomere shortening and diastolic cell length (C) as well as time to peak and maximal relaxation velocity (D) in isolated rat cardiac myocytes in response to escalating concentrations of OM. (A–D) are from Malik et al. with permission. (E) Impact of OM (20 min infusion at a dose that prolonged SET by 20%) on LV pressure-volume loops in a pig model of myocardial stunning (termed ‘post-ischaemic’ heart). The volumes indicate LV stroke volume and end-diastolic volume, of which EF is calculated. Taken from Bakkehaug et al. with permission. (F) The impact of OM at 0.1 or 1 µM on normalized isometric force in response to increasing Ca²⁺ concentrations (decreasing pCa) in skinned rat cardiac myocytes. Taken from Nagy et al. with permission.

Figure 7

Mechanisms of action of nitroxyl (HNO) in HF. HNO affects redox-sensitive residues of various proteins involved in myocyte Ca²⁺ handling. In particular, HNO increases SERCA activity and sensitizes myofilaments to Ca²⁺. In concert, these properties increase SR Ca²⁺ load, systolic Ca²⁺ transients and contraction. Red arrows (↑↓) indicate the direction of change in heart failure, while green arrows (↑↓) indicate the direction induced by HNO.

Figure 8

Known and hypothesized bioenergetic consequences of inotropic interventions that either increase cytosolic Ca²⁺ or myofilament Ca²⁺ sensitivity. ECC, excitation–contraction coupling; ETC, electron transport chain; MCU, mitochondrial Ca²⁺ uptake.

Take home figure

Mechanisms of excitation-contraction coupling, known defects in heart failure and which targets inotropic compounds have. In systolic HF, contractile dysfunction is primarily related to attenuated increases in cytosolic Ca²⁺ during systole. This is the result of decreased activity of the sarcoplasmic reticulum (SR) Ca²⁺ ATPase (SERCA) and leaky ryanodine receptors (RyR). Maximal contractility is further limited by decreased adenosine triphosphate (ATP) production in mitochondria. Dobutamine and norepinephrine activate β₁-adrenergic receptors (β₁-AR), increasing cAMP which phosphorylates protein kinase A (PKA). PKA in turn phosphorylates proteins involved in EC coupling and thereby accelerates the kinetics and amounts of cytosolic Ca²⁺ during systole. The phosphodiesterase 3 (PDE3) inhibitors enoximone and milrinone potentiate β-AR-induced cAMP elevations and therefore, have similar effects on inotropy as dobutamine, increasing Ca²⁺ fluxes. Digitalis inhibits the Na⁺/K⁺-ATPase (NKA) and thereby elevates intracellular Na⁺, which in turn elevates Ca²⁺ by hampering cytosolic Ca²⁺ export via the forward mode Na⁺/Ca²⁺ exchanger (NCX) and may increase reverse mode NCX-mediated Ca²⁺ influx during the early phase of the action potential. Istaroxime has similar effects as digitalis but also activates SERCA to accelerate diastolic Ca²⁺ uptake into the SR. SERCA2a gene therapy increases the mRNA and protein levels of SERCA and thereby, potentiates SR Ca²⁺ uptake and release. Nitroxyl (HNO) activates SERCA activity and increases myofilament Ca²⁺ sensitivity. Levosimendan increases the affinity of troponin C to Ca²⁺ and thereby, increases force generation for any given cytosolic Ca²⁺ concentration. In addition, levosimendan inhibits PDE3, which elevates cAMP and PKA activity with subsequent effects on Ca²⁺ handling as described above for catecholamines and PDE-inhibitors. Omecamtiv mecarbil is a myosin activator that prolongs actin–myosin interaction and thereby, results in a prolongation (but not acceleration) of contraction. Elamipretide (also known as Bendavia or MTP-131) binds to cardiolipin in the inner mitochondrial membrane, increasing ATP production and reducing the generation of reactive oxygen species (ROS). Trimetazidine and perhexiline optimize substrate utilization and thereby, improve cardiac energetics. Iron restores iron deficiency and thereby, may improve function of Krebs cycle enzymes and possibly, the electron transport chain (ETC).