Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis.
OBJECTIVE
Gap junctions (GJ) are important determinants of conduction. In advanced heart failure alterations of the major ventricular GJ protein, connexin 43 (Cx43) are found. However, changes in Cx43 expression during the progression from compensated cardiac hypertrophy to heart failure, especially in humans, have not been studied extensively. The aim of the present study was to investigate changes in Cx43 expression and distribution in compensated and decompensated left ventricular (LV) hypertrophy in pressure-overloaded human hearts with valvular aortic stenosis (AS).


METHODS
We measured Cx43 levels by Western blot and quantitative immunoconfocal microscopy of LV septum biopsies from three groups of patients with AS (group I (n=9): ejection fraction (EF)>50%; group II (n=12): EF 30-50%; group III (n=9): EF<30%). LV biopsies from six patients with mitral valve stenosis and two donor hearts served as controls.


RESULTS
Only the early phase of LV hypertrophy (AS-I) was characterized by extensive Cx43 lateral staining. As compared to controls, the AS-I group showed a 44.3% increase in Cx43 protein, which was reflected in an augmented number of GJs per 100 microm(2) intercalated disc area (control: 62.5+/-6.4 vs. AS-I: 79.8+/-4, p<0.001) and an increased GJ surface density (control: 0.00547 vs. AS-I: 0.00724 microm(2)/microm(3), p<0.01). Decompensated LV hypertrophy (AS-III) was specified by reduced percentage of the Cx43 signal per myocyte area (control: 1.74% vs. AS-III: 1.31%, p<0.01) or per intercalated disc (control: 18.3% vs. AS-III: 11.3%, p<0.005). Mean GJ area and GJ number per intercalated discs in the AS-III group were decreased significantly by, respectively, 42.5% and 36.4% as compared to control. In addition, decompensated LV myocardium showed a markedly heterogeneous spatial distribution of Cx43.


CONCLUSIONS
The quantity and spatial distribution of Cx43 differs markedly between compensated and decompensated LV hypertrophy in human patients with AS. Upregulation of Cx43 in compensated hypertrophy may represent the immediate adaptive response to increased load, whereas diminished and heterogeneous Cx43 distribution in decompensated hypertrophy may play maladaptive roles culminating in heart failure and ventricular arrhythmias.
Kostin
Sawa
S
Department of Experimental Cardiology, Max-Planck-Institute, Benekestr. 2D-61231, Bad Nauheim, Germany. skostin@kerckhoff.mpg.de
Dammer
Sebastian
S
Hein
Stefan
S
Klovekorn
Wolf P
WP
Bauer
Erwin P
EP
Schaper
Jutta
J
D000368:Aged; D001024:Aortic Valve Stenosis / Q000150:complications* / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D016022:Case-Control Studies; D018031:Connexin 43 / Q000032:analysis*; D005260:Female; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000150:complications* / Q000378:metabolism; D008297:Male; D018613:Microscopy, Confocal; D009206:Myocardium / Q000378:metabolism*; D020257:Ventricular Remodeling
D018031:Connexin 43