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Investigation of structural and electrophysiologic remodeling at the
cellular level has largely been performed on ventricular myocytes, mainly from rat heart. Nonetheless, the
lessons learned from this work are applicable, at least in a general sense, to atrium. Perhaps most important
is the effect of altered stress on myocyte cultures to induce release of humoral substances. For example,
Sadoshima and colleagues demonstrated that myocyte cultures subjected to altered patterns of stretch
synthesized increased amounts of angiotensin II3,4. There are conflicting data regarding the relative
contributions of myocyte and connective tissue elements to the synthesis of hormone, but the net result –
the increased availability of a hypertrophic stimulus – is consistent.
Application of this information to the intact heart would suggest that intervening to alter stress/strain
relationships on the myocardium will increase synthesis of angiotensin II, with its attendant effects on
structure and function. There is clinical evidence in dogs that this in fact occurs. In a model where altered
ventricular activation led to stress/strain changes and T waves characteristic of cardiac memory,
administration of an ACE inhibitor or an angiotensin II receptor blocker prevented these changes from
occurring5. That altered activation can induce structural changes as well has been demonstrated in young
dogs subjected to three weeks of ventricular pacing. Here, myofibrillar protein synthesis was altered, and
the myofibrils deviated from their normal stepwise arrangement to follow a pattern influenced by the
abnormally propagating waveform6.
With respect to cellular electrophysiology, altering the pathway of activation in isolated samples of canine
ventricular myocardium induces changes in action potential contour that last long after the return to normal
activation7,8. Given that the voltage-time course of repolarization is an important determinant of
refractoriness, this suggests the remodeling process extends to factors that influence the expression of
cardiac arrhythmias. This alteration in repolarization is attendant upon molecular changes in ion channels.
For example, the transient outward current, Ito, in canine epicardial ventricular myocytes is reduced in
density by about 1/3, and shows a 10-fold prolongation in recovery from inactivation as compared to
controls, while message levels for Kv4.3, the gene product responsible for Ito, are also reduced by
1/39.
Controlling the pathway of electrical activation also has profound effects on the expression, density and
orientation of gap junctional proteins as was shown in neonatal rat ventricular myocytes in culture, by
Kleber and associates10. This, too, has a reflection in the intact heart:
Patel et al11 demonstrated that
in dogs paced from the left ventricle for three weeks, there is a 20% decrease in connexin43 (the primary
gap junctional protein in ventricle) density within several centimeters of the pacing site as well as a
reorientation of the connexins such that they lie much more on the lateral margins of the myocytes, rather
than in their usual position at the ends of the myocytes.
The lessons of this and related work with respect to remodeling in the atrium are as follows: it is clear that
altering the site of impulse initiation and thereby altering propagation changes stress/strain relationships
and can induce release of hypertrophic factors such as angiotensin II. It is clear as well that proteins that
affect both impulse propagation (connexins) and contraction (myofibrils) are also modified by changing the
site of impulse initiation and propagation. As a result, aberrant impulses, especially if delivered repetitively
and at rapid rates, would induce the electrophysiologic and structural changes considered under the general
term of atrial remodeling. That this is indeed the case has been demonstrated in preliminary studies of
memory in atrium12,13. Here, pacing to alter the pathway of impulse initiation for 1-2 hours altered the
morphology of the Ta wave for at least 30 min after the cessation of pacing. The behavior of the Ta waves in
this setting was identical to that seen with ventricular T wave memory on cessation of pacing. As we unravel
the mechanistic determinants of this effect of activation on repolarization in atrium, we should evolve a
better understanding of the reason whereby atria remodel and “atrial fibrillation begets atrial fibrillation”.
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