Elisabetta Cerbai*, Roberto
Pino*, Laura Sartiani*, Guido Sani°, Gianfranco Lisi#, Federico Bizzarri#, Giuseppe
Vaccari#, Alessandro Mugelli*.
*Department of Pharmacology, University of Florence, °Cardiosurgery, University
of Cagliari, #Thoracic Cardiosurgery, University of Siena, Italy
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The last decade has seen an explosive increase in our
knowledge of the electrophysiology of cardiac cells. The variety and complex interactions
of the ionic currents which cross the cell membrane have been largely clarified. This
insight has been gained by the development of modern methods of investigation such as the
patch clamp technique. In addition, molecular biology is providing an increasingly deeper
level of understanding. This work has been almost exclusively carried out using animal
cells. However this knowledge is now on the way to be extended to human cells. This is
particularly important because significant differences exist in cellular behavior between
different mammalian species. In the past the cellular electrophysiological investigation
of human cardiac tissues has been performed mainly on small pieces of atrial or
ventricular myocardium excised from the heart of patients undergoing corrective open heart
surgery or cardiac transplantation. Enzymatic procedures for cell isolation have been
extended to human atrial and ventricular preparations and it is now possible to record
action potentials and ionic currents in single myocytes using patch-clamp techniques. It
is now increasingly recognized that the electrophysiologic behavior of the heart may be
altered in disease, presumably as a consequence of disease-related changes in individual
ionic currents and/or disease-induced activation of ion channels not expressed or inactive
under physiological conditions. Recent studies have documented that the
electrophysiological properties of cardiac cells are altered in terminal heart failure
compared to control myocytes obtained from normal hearts not utilised for transplantation
for technical reasons. Since the "control" hearts are fortunately rarely
available, it is obviously necessary to continuously verify the results obtained in human
studies with those derived from significant and possible predictive animal models of
cardiac failure. The spontaneous hypertensive rat (SHR) is a widely used model for human
hypertension1. SHR develops left ventricular
hypertrophy in response to pressure overload, through a process which evolves continuously
during the life of the animal2,3. At 2 to 3 months of
age, SHR presents a mild degree of myocardial hypertrophy4,5,
with the myocyte dimension only slightly increased compared to normotensive rats4,5. At 18 months of age, SHR develops severe left
ventricular hypertrophy, the myocytes manifesting the highest value of cross sectional
area2. Between the ages of 18 and 24 months, 57% of
male SHRs have evidence of cardiac decompensation and only 13% survive to 24 months
without evidence of heart failure6.
Action potentials of ventricular myocytes isolated from patients with congestive
cardiomyopathy are prolonged7. The underlying ionic
mechanism appears to be a decrease in transient outward current Ito8. Prolongation of action potential duration and reduction
of Ito have been reported in hypertrophied myocytes isolated from the heart of
SHR9. The similarities of the alterations found led us
to consider the SHR a useful and predictive model for cardiac hypertrophy due to pressure
overload and for its transition to failure9,10. In more
than 90% of myocytes isolated from the left ventricle of old SHR (ie heart with severe
hypertrophy) we have previously demonstrated the presence of a time-dependent inward
current, activated by hyperpolarization and having the properties of the pacemaker current
If11. The pacemaker current If is
a cesium-sensitive, barium-insensitive inward current generally thought to be present only
in primary or secondary pacemakers, where it might contribute to diastolic depolarization12. More recently we found that If density in
ventricular myocytes can be linearly related to the severity of cardiac hypertrophy 10. In
SHR with signs of heart failure the amplitude of If was even larger13. Furthermore, If amplitude was increased by
ß-adrenergic stimulation by shifting its activation curve toward less negative potentials10. Since our previous results were suggestive of a
contribution of If to the increased propensity for ventricular arrhythmias of
the hypertrophied and failing (rat) heart, we assessed the presence of If in
human ventricular myocytes. We found that a current with the electrophysiological
properties of If is consistently present in human ventricular myocytes isolated
from patients with post-ischemic dilatative cardiomyopathy undergoing heart
transplantation14. Here we report that the amplitude of
If is larger in human ventricular myocytes isolated from failing hearts than
from normal hearts; the possible mechanism by which If may contribute to
arrhythmogenesis in heart failure is described.
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