(Circulation. 1999;100:155-163.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Subunit Expression of the Cardiac L-Type Calcium Channel Is Differentially Regulated in Diastolic Heart Failure of the Cardiac Allograft
From the Department of Internal Medicine I (R.H., F.A., J.H., P.B.), University Hospital Großhadern, Munich, Germany, and Department of Pharmacology (A.L.), Technical University, Munich, Germany.
Correspondence to Roger Hullin, MD, Department of Internal Medicine I, University Hospital Großhadern, Marchioninistraße 15, 81 377 München, Germany. E-mail roger.hullin{at}med1.med.uni-muenchen.de
Background—Left
ventricular diastolic dysfunction is a major
cause of cardiac allograft failure. Multimeric L-type calcium
channels (
1-, 2/
-, and ß-subunits)
are essential for excitation/contraction coupling in the heart.
Their gene expression was studied in allografts that developed
diastolic heart failure.
Methods and Results—mRNA levels of calcium channel subunits were
measured by competitive reverse transcriptase–polymerase chain
reaction in microbiopsy samples from the interventricular
septum. Size and tissue variabilities between biopsy samples were
assessed by determination of cardiac calsequestrin mRNA levels. In the
cardiac allografts studied, mRNA levels in microbiopsy samples were
considered to represent left ventricular gene
expression, because septal and left ventricular gene
expression in Northern blots was equivalent, and left ventricles
contracted homogeneously. Biopsy samples (n=72) were taken
from allografts with normal left ventricular
end-diastolic pressure (LVEDP; 8 to 13 mm Hg; n=30),
moderately elevated LVEDP (14 to 18 mm Hg; n=26), and elevated
LVEDP (19 to 28 mm Hg; n=16). Increased LVEDP was related to
slowed diastolic relaxation determined by the time constant
(r2=0.86), whereas systolic
performance (dP/dt; ejection fraction) was preserved. With
increasing LVEDP, mRNA levels of the pore-forming
1c-subunit (n=15) and of the regulatory
2/-subunit (n=17) remained unchanged but decreased
exponentially (r2=-0.83) for the regulatory
ß-subunit (n=40). Compared with cardiac allografts with normal LVEDP
(n=15), ß-subunit mRNA level was reduced by 75% at elevated LVEDP
(n=9; P=0.012). In an explanted,
diastolically failing cardiac allograft, ß-subunit
expression was reduced correspondingly by 72% and 76% on the mRNA
level in septal and left ventricular myocardium
and by 80% on the protein level.
Conclusions—The downregulated expression of the calcium channel ß-subunit might contribute to altered calcium handling in diastolically failing cardiac allografts.
Key Words: calcium channels • diastolic heart failure
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