Jaski_Wagnersubbed 21/4/09 9:05 am Page 48
Heart Failure
Figure 2: Effect on Survival by Increasing
SERCA2a gene transfer is accompanied by a reversal of the ‘fetal gene
Contractility Through SERCA2a Gene Transfer
program’ induced by heart failure, as studied in a rodent model.
26
In
versus Inotropic Agents
30,31
this study, 1,300 genes appeared specifically dysregulated after the
induction of heart failure, and 251 transcripts were found differentially
100
Sham
expressed by at least 1.2-fold during heart failure versus normal. Of
these 251 transcripts, 51 returned to normal levels by the restoration
80
Failing + Ad.SERCA2a
of a single enzyme via gene transfer. The normalization of multiple
transcriptional elements can potentially be explained by the fact that
60
normalization of SERCA2a activity results in restoration of Ca
2+
homeostasis, and that intracellular Ca
2+
is the most universal signal
survival
% 40
Failing
20
+ Dobutamine
Failing + Ad.GP
One of the most important beneficial
0
0 5 10 15 20 25 30
aspects of restoring SERCA2a levels in
Days
heart failure relates to the correction of
Gene transfer
the abnormal mitochondrial energetics.
Downstream regulators of the enzyme include phospholamban, a
key regulatory protein of SERCA2a activity. Kinases and phosphatases,
which regulate phospholamban phosphorylation, also influence
SERCA2a activity.
17
Unphosphorylated phospholamban inhibits
SERCA2a activity, while the phosphorylated protein does not. The used by living organisms to convey information to many different
regulation of SERCA2a activity via phosphorylation of phospholamban cellular processes. A number of proteins have been identified that
is one of the key pathways responsible for an increase in cardiac sense intracellular Ca
2+
and decode the key elements in the nucleus
performance to beta-adrenergic stimulation. Unfortunately, sustained to regulate the activity of various transcriptional networks.
27
beta-adrenergic stimulation leads to a profound alteration of the
response to circulating catecholamines, including a reduction in In addition to correction of contraction and relaxation defects, one of
SERCA2a that ultimately contributes to the progression of heart the most important beneficial aspects of restoring SERCA2a levels in
failure syndrome.
18
heart failure relates to the correction of the abnormal mitochondrial
energetics. Cardiac excitation–contraction coupling consumes vast
Pioneering work by Roger Hajjar, MD, has demonstrated that amounts of cellular energy, most of which is produced in mitochondria
increasing the level of SERCA2a using gene transfer results in by oxidative phosphorylation. In order to adapt the constantly varying
significant improvements in cardiac function in pre-clinical models of workload of the heart to energy supply, tight coupling mechanisms are
heart failure in rodents,
19–21
pigs,
22
and sheep,
23
even when the essential to maintain cellular pools of adenosine triphosphate (ATP),
underlying pathophysiology or insult (e.g. mitral valve rupture or phosphocreatine, and nicotinamide adenine dinucleotide, reduced
pacing induced heart failure) is not corrected. Since calcium (NADH). The most important regulators of oxidative phosphorylation
homeostasis has been implicated in ventricular dysrhythmias, are adenosine diphosphate (ADP), inorganic phosphates (Pi), and Ca
2+
.
Ca
2+
signals in cardiac myocytes have an impact on energy supply and
demand matching.
28
Calcium regulation in cardiac myocytes
Defects in excitation–contraction coupling in chronic heart failure may
acts as a nodal control point in cardiac
adversely affect mitochondrial Ca
2+
uptake and energetics, initiating a
vicious cycle of contractile dysfunction and energy depletion. The
electrical activity, excitation–contraction
importance of this process is highlighted by the experience with
coupling, energetics, and excitation–
inotropic agents. The use of inotropic agents has been regarded as a
logical approach to treat depressed left-ventricular contractility
transcription coupling.
associated with heart failure. Despite this conceptual framework,
inotropic intervention is associated with an increase in the energetic
cost of contractility, with consequences including excessive mortality.
29
restoring Ca
2+
homeostasis has potential to correct the contractile However, unlike inotropic agents, which improve contractile function
and relaxation deficits in patients with heart failure.
24
Reduction in at the expense of increased mortality and worsening metabolism,
ventricular arrhythmias after overexpression of SERCA2a has been gene transfer of SERCA2a improves contractility but, most importantly,
demonstrated after ischemia followed by reperfusion in rats
21
and also improves survival (see Figure 2) and reduces the oxygen cost of
pigs.
25
The resulting restoration of Ca
2+
homeostasis following contractility in animal models of heart failure.
30,31
Thus, the replacement
48 US CARDIOLOGY
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