[CRT-FORUM] 37E. Mcrocirculation in heart failure. Dr. Perez Riera

[CRT-INFO]

Dear Dr Cirill
The impact of contemporary drugs on microcirculation in HF Modern approach
to the treatment of decompensated HF.
Several groups of drugs are know: Ca2+ sensitizer, natriuretic peptides,
low intravenous infusion dose(33 microg/min) nitroglycerin and others.
Statins have emerged as drugs with cardioprotective properties, but more
randomized clinical trials are needed before routine administration. Medical
management should focus on improvements not only in the short-term but also
in the long-term.
The following are the main( experimental and clinical) new drugs in HF
treatment.

1) CALCIUM SENSITIZERS OR Ca2+ SENSITIZER: comprise a new drug class that
offers hemodynamic and symptomatic improvements without increasing cAMP and
intracellular Ca2+ concentrations. These agents enhance contractility
without a concurrent increase in the risk of cardiac events and thus
represent a significant improvement over classic positive inotropic agents.
The two most extensively studied Ca2+ sensitizers are levosimendan and
pimobendan. Levosimendan is the most potent Ca2+ sensitizer to date,
exhibiting a unique dual mechanism of action that combines a positive
inotropic action mediated via Ca2+ sensitization and a vasodilator property
via ATP-dependent potassium channels. Available clinical data suggest that
Ca2+ sensitizer agents represent a promising class of inotropic agents in a
field that has seen few advances in recent decades. In contrast to
epinephrine, levosimendan improves ventricular function without increasing
oxygen demand, thereby considerably improving external efficiency. Even
during epinephrine resistance in extremely dysfunctional hearts,
levosimendan successfully improves ventricular function.
levosimendan is a Ca2+ sensitiser used in the management of acutely
decompensated CHF. It increases the sensitivity of the heart to Ca2+, thus
increasing cardiac contractility without a rise in intracellular Ca2+.
levosimendan exerts its effect by increasing Ca2+- sensitivity of myocytes
by binding to cardiac troponin C in a Ca2+ -dependent manner. It also has a
vasodilatory effect, by opening adenosine triphosphate (ATP)-sensitive
potassium channels in vascular smooth muscle to cause smooth muscle
relaxation.

Mechanism of Action: Levosimendan appears to increase myofilament Ca2+
sensitivity by binding to cardiac troponin C in a Ca2+ -dependent manner.
This stabilizes the Ca2+ -induced conformational change of troponin C,
thereby changing actin-myosin cross-bridge kinetics apparently without
increasing the cycling rate of the cross-bridges or myocardial ATP
consumption, increasing the effects of Ca2+ on cardiac myofilaments during
systole and improving contraction at low energy cost. Ca2+ concentration
and, therefore, sensitization decline during diastole, allowing normal or
improved diastolic relaxation. Levosimendan also leads to vasodilation
through the opening of ATP-sensitive potassium channels. By these inotropic
and vasodilatory actions, levosimendan increases cardiac output without
increasing myocardial oxygen demand. Levosimendan also has a selective
phosphodiesterase (PDE)-III inhibitory action that may contribute to the
inotropic effect of this compound under certain experimental conditions. It
has been reported that levosimendan may act preferentially as a Ca2+
sensitizer at lower concentrations, whereas at higher concentrations its
action as a PDE-III inhibitor becomes more prominent in experimental animals
and humans.
Pharmacology: Levosimendan is a new Ca2+-sensitizing inotropic agent. Ca2+
sensitizers represent a new class of inotropic agents, which overcome the
disadvantages associated with currently available inotropic agents in as
they are not associated with an increased risk of arrhythmias, cell injury
and death due to Ca2+ overload in myocardial cells; they do not increase the
activation energy; and they have the potential to reverse contractile
dysfunction under pathophysiologic conditions, such as acidosis or
myocardial stunning.
Indication: For short term treatment of acutely decompensated severe CHF.
Also being investigated for use/treatment in heart disease.
Contraindications: The use of levosimendan is contraindicated in patients
with: moderate-to-severe renal impairment, severe hepatic impairment, severe
ventricular filling or outflow obstruction, severe hypotension and
tachycardia, and/or history of TdP.
Drug Interactions: Not Available No Important Interactions To Date
Levosimendan does not have clinically important pharmacokinetic interactions
with captopril, beta-blockers, felodipine, digoxin, warfarin, isosorbide
mononitrate, carvedilol, ethanol or itraconazole.

Drug Category: Anti-Arrhythmia Agents; Cardiotonic Agents; Phosphodiesterase
Inhibitors; Vasodilator Agents

Drug Type: Small Molecule; Approved; Investigational

Absorption: The bioavailability of oral levosimendan is 85 ± 6% in healthy
volunteers and 84 ± 4% in patients.

Protein Binding: 98% bound to plasma protein.

Biotransformation: Complete metabolism, with some active metabolites
(OR-1855 and OR-1896) possibly extending the drug's haemodynamic effects.

Half Life: Eliminination half-life is approximately 1 hour.


2) NATRIURETIC PEPTIDES Acute decompensated HF (ADHF) is a major public
health burden with significant mortality and morbidity. Nesiritide is a
recombinantly produced IV formulation of human B-type natriuretic peptide
that promotes vasodilation and increases salt and water excretion, which
results in reduced cardiac filling pressures. Prior studies have shown that
dyspnea is improved in patients with ADHF 3 hours after nesiritide infusion
with significant dose-related reductions in cardiac filling pressures and
systemic vascular resistance without significant arrhythmias. However, the
effect of nesiritide on dyspnea at 6 or 24 hours is unknown, and no clinical
outcome trials have been done to provide a reliable estimate of the effect
of nesiritide on morbidity and mortality. The Acute Study of Clinical
Effectiveness of Nesiritide in Decompensated Heart Failure trial (ASCEND-HF)
is a phase III study evaluating the efficacy and safety of nesiritide in
patients with ADHF. Patients hospitalized for HF will be randomly assigned
to receive either IV nesiritide or matching placebo for 24 hours to 7 days.
The 2 coprimary end points are (1) assessment of acute dyspnea at 6 or 24
hours and (2) death or rehospitalization for HF within 30 days. A total of
7,000 patients will be enrolled worldwide between 2007 and 2010.: The data
from the ASCEND-HF trial will establish whether nesiritide safely improves
acute dyspnea as well as morbidity and mortality at 30 days.

3) LOW INTRAVENOUS INFUSION DOSE (33 MICROG/MIN) NITROGLYCERIN (NTG)
improves microcirculatory perfusion in patients admitted for acute HF
because the drug significantly reduces cardiac filling pressures and
improves microvascular perfusion in patients admitted for acute HF(1).
Recent studies revealed an exceedingly high mortality with diastolic HF that
was previously regarded as relatively benign compared to systolic HF.
Prominent risk factors for diastolic HF are increasing age, hypertension and
diabetes. These risk factors are associated with coronary microvascular
rarefaction and resultant decreased coronary flow reserve, thereby rendering
the myocardium vulnerable to ischemia. The angiogenic gene programming in
preserv the coronary microvasculature, preserving cardiac function and
altering disease course.
The possible utility of therapies that activate hypoxia inducible factor-1
in preventing rarefaction of the coronary microvasculature and maintaining
cardiac diastolic function.


Reference
1)den Uil CA, Lagrand WK, Spronk PE, van der Ent M, Jewbali LS, Brugts JJ,
Ince C, Simoons ML.Low-dose nitroglycerin improves microcirculation in
hospitalized patients with acute heart failure. Eur J Heart Fail. 2009 Feb
10. [Epub ahead of print]

All the best
Andrés Ricardo Pérez Riera.MD
Chief of electrovectorcardiographic sector. ABC’s Medical School, ABC
Foundation, Santo André, São Paulo, Brazil Riera at uol.com.br
> Congratulate all participants!
> I have a question according to the Satellite Symposium concerning with 
> heart failure treatment.
> Dear doctors!
> What`s your opinion about the impact of contemporary drugs on 
> microcirculation in heart failure?
>
> All the best!
> Dr Cirill
> mihalevk at gmail.com
>


-- 
Dr. Sergio Dubner
President of Scientific Committee

Dr. Edgardo Schapachnik
President of Steering Committee