Biomedical Engineering Reference
In-Depth Information
on cardiac contractility and has potential for therapeutic use in patients with
coronary artery disease (CAD). A large-scale, multicenter clinical trial (BEAUTI
F
UL:
the morBidity-mortality EvAlUaTion of the
I
f
inhibitor ivabradine in patients with
coronary disease and left ventricular dysfunction) has evaluated the efficacy of
ivabradine at reducing morbidity/mortality in patients with impaired left ventricular
function [
85
,
86
]. In these patients with a heart rate
70 bpm, ivabradine signifi-
cantly reduces important coronary events such as myocardial infarction (MI) (by
36%) and coronary revascularisation (by 30%). Moreover, in a subgroup of patients
with limited angina, the BEAUTI
F
UL study showed that ivabradine (Procoralan)
reduced the risk of the combination of primary endpoint-cardiovascular death,
hospitalization for acute MI, or new or worsening heart failure by 24% in all angina
patients, and by 31% in those with a heart rate
70 bpm. More recently, the Systolic
Heart Failure Treatment with the If inhibitor ivabradine Trial (SHIFT) study has
confirmed that high heart rate is a risk factor in heart failure, and the results support
the importance of heart rate reduction with ivabradine for improvement of clinical
outcomes in heart failure [
87
,
88
]. Other ongoing clinical trials (SIGNI
F
Y and
VIVI
F
Y) will allow a more precise analysis of the therapeutic action of ivabradine
in CAD and acute coronary syndrome.
Although the f-current is the main ionic mechanism involved in the genesis and
regulation of the spontaneous activity of SA node cells under physiological
conditions, overexpression of pacemaker channels can be observed in pathological
situations such as thyrotoxicosis, leading to sinus tachycardia [
52
,
53
].
Overexpression of f-channels is also observed in rat hypertrophied myocytes [
89
]
and in failing human heart [
90
]. Under these pathological conditions,
I
f
could be
interacting with other mechanisms and thus contribute to the appearance of ven-
tricular arrhythmias. In this way, we have reported that ivabradine inhibits the
I
f
current in atrial myocytes isolated from human right appendages with
characteristics similar to those described previously in rabbit sinus node cells. In
this human atrial tissue, the major HCN gene subtype detected was HCN2. The
action of ivabradine could be beneficial in limiting the genesis of ectopic atrial
arrhythmias, in which
I
f
may be involved [
91
].
Ivabradine could thus offer a new therapeutic strategy (or be a good candidate) to
reduce these arrhythmias.
6.4 ZD 7288
ZD 7288 [4-(
N
-ethyl-
N
-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium
chloride] (see chemical structure in Fig.
3
), originally named ICI D7288, has been
shown to reduce the
I
f
current in many different physiological preparations. In the
heart, at concentrations lower than 1
M, ZD 7288 was reported to decrease
the spontaneous beating rate of guinea-pig isolated right atria with no effect on the
contractile force of paced left atria [
92
]. This effect was attributed to a strong
and specific inhibition of
I
f
at concentrations less than 1
m
M[
93
]. ZD 7288 was
m
