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Heart Failure) patients admitted with exacerbation of and vasodilators to receive either levosimendan or
systolic heart failure not requiring intravenous ino- dobutamine. An early reduction in mortality was not
tropic support were randomly assigned to receive sustained through 180 days, but levosimendan was
milrinone or placebo infusion. No difference was associated with a higher incidence of atrial fibrillation
found in the primary endpoint of days hospitalized and lower incidence of worsening heart failure com-
for cardiovascular causes within 60 days, but signif- pared with dobutamine.
icant increases in sustained hypotension and new
atrial arrhythmias were noted in the milrinone-treated NEWER INOTROPES
patients. In addition, a post hoc subgroup analysis Omecamtiv mecarbil
demonstrated increased mortality in patients with an
ischemic cause of heart failure who received milri- Formerly known as CK-1827452, omecamtiv mecarbil
none. This study reinforces the need for caution in [1]is a new potential therapy for heart failure. Ome-
selecting these agents for the treatment of patients camtiv mecarbil is the first selective cardiac myosin
with AHF. activator to be studied in humans. The development
of omecamtiv mecarbil showed that myocardial per-
Enoximone formance can be improved by prolonging systole
rather than increasing the velocity of fiber-shorten-
Enoximone also is a type IIIa PDE inhibitor. Dosing is ing, which is the usual mechanism typical of most
essentially one-tenth that of milrinone. It is extensive- positive inotropic agents. Omecamtiv mecarbil selec-
ly metabolized by the liver into renally cleared active tively activates the S1 domain of cardiac myosin and
metabolites, so doses should be reduced in the set- increases the rate of ATP turnover by accelerating
ting of either renal or hepatic insufficiency.
actin-dependent phosphate release and by slowing
the rate of adenosine 5′-diphosphate (ADP) release
Levosimendan leading to increased numbers of myosin molecules
Levosimendan is a novel agent that increases myo- bound to actin causing prolongation of the contrac-
cardial contractility and produces peripheral vasodila- tile force without increasing left ventricular pressure
tion. The main mechanism of action includes calcium development (dP/dt). The calcium transient remains
sensitization by calcium-dependent (systolic) tropo- unchanged in contrast to conventional inotropic
nin C binding and activation of vascular smooth mus- agents where there is an increase the calcium tran-
cle potassium channels. It also has some in vitro PDEI sient. By this mechanism, it appears that omecamtiv
activity and at high concentrations, PDE-3 inhibitor mecarbil does not increase the heart’s demand for
activity. Levosimendan has an active, acetylated me- energy; rather, it improves systolic performance by
tabolite with a half-life of over 80 hours, so that it can allowing the myocardium to make more efficient use
continue to exert its effect even days after discontin- of energy.
uation of the infusion. In clinical trials, levosimendan
has been shown to significantly increase cardiac out- The ATOMIC AHF (Acute Treatment with Omecamtiv
put, reduce PCWP and afterload, and decrease dys- Mecarbil to Increase Contractility–Acute Heart Failure
pnea. Initial clinical studies demonstrated reduced ar- showed that the drug appears to avoid the usual
rhythmias and improved survival with levosimendan adverse effects (e.g., tachycardia and arrhythmia) of
compared with placebo and dobutamine. REVIVE-II traditional inotropic agents. Early experience demon-
(Randomized multicenter EValuation of Intra- Venous strated an increase in LV ejection fraction and stroke
levosimendan Efficacy versus placebo in the short- volume with decreased end-systolic and end-diastolic
term treatment of decompensated heart failure), a re- volumes. At high plasma concentrations, chest pain,
cent study, demonstrated significant improvement in tachycardia, and myocardial ischemia were noted. In
clinical status, serial BNP levels, and hospital length a sense, omecamtiv mecarbil may not be an inotrope,
of stay with levosimendan treatment compared with but it does improve myocardial systolic performance.
standard care, but also documented more episodes
2+
of hypotension, atrial fibrillation, and ventricular ec- Sarcoplasmic Recticulum Ca - ATPase
topy, as well as a nonsignificant increase in early Modulation
deaths at 14 to 90 days.The SURVIVE (Survival of Sarcoplasmic reticulum Ca -ATPase (SERCA2a) is
2+
Patients with Acute Heart Failure in Need of Intrave- an enzyme responsible for both myocardial relax-
nous Inotropic Support) trial randomly assigned 1327 ation(by reuptake of calcium into the SR) and con-
patients with systolic dysfunction, evidence of low tractility (by controlling the amount of calcium in the
cardiac output, and dyspnea at rest despite diuretics SR). SERCA2a is usually downregulated in the fail-

GCDC 2017