Sex-dependent alterations of Ca2+ cycling in human cardiac hypertrophy and heart failure.
OBJECTIVE
Clinical studies have shown differences in the propensity for malignant ventricular arrhythmias between women and men suffering from cardiomyopathies and heart failure (HF). This is clinically relevant as it impacts therapies like prophylactic implantable cardioverter-defibrillator implantation but the pathomechanisms are unknown. As an increased sarcoplasmic reticulum (SR) Ca(2+) leak is arrhythmogenic, it could represent a cellular basis for this paradox.


RESULTS
We evaluated the SR Ca(2+) leak with respect to sex differences in (i) afterload-induced cardiac hypertrophy (Hy) with preserved left ventricular (LV) function and (ii) end-stage HF. Cardiac function did not differ between sexes in both cardiac pathologies. Human cardiomyocytes isolated from female patients with Hy showed a significantly lower Ca(2+) spark frequency (CaSpF, confocal microscopy, Fluo3-AM) compared with men (P < 0.05). As Ca(2+) spark width and duration were similar in women and men, this difference in CaSpF did not yet translate into a significant difference of the calculated SR Ca(2+) leak between both sexes at this stage of disease (P = 0.14). Epifluorescence measurements (Fura2-AM) revealed comparable Ca(2+) cycling properties (diastolic Ca(2+) levels, amplitude of systolic Ca(2+) transients, SR Ca(2+) load) in patients of both sexes suffering from Hy. Additionally, the increased diastolic CaSpF in male patients with Hy did not yet translate into an elevated ratio of cells showing arrhythmic events (Ca(2+) waves, spontaneous Ca(2+) transients) (P = 0.77). In the transition to HF, both sexes showed an increase of the CaSpF (P < 0.05) and the sex dependence was even more pronounced. Female patients had a 69 ± 10% lower SR Ca(2+) leak (P < 0.05), which now even translated into a lower ratio of arrhythmic cells in female HF patients compared with men (P < 0.001).


CONCLUSIONS
These data show that the SR Ca(2+) leak is lower in women than in men with comparable cardiac impairment. Since the SR Ca(2+) leak triggers delayed afterdepolarizations, our findings may explain why women are less prone to ventricular arrhythmias and confirm the rationale of therapeutic measures reducing the SR Ca(2+) leak.
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Thomas H
TH
Fischer
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Jonas
J
Herting
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Jörg
J
Eiringhaus
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Steffen
S
Pabel
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Nico H
NH
Hartmann
Institut für Medizinische Statistik, Georg-August-Universität Göttingen, Göttingen, Germany.
David
D
Ellenberger
Abt. Thorax-, Herz- und Gefäßchirurgie, Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany.
Martin
M
Friedrich
Abt. Thorax-, Herz-, Gefäßchirurgie, Herz- und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany.
André
A
Renner
Abt. Thorax-, Herz-, Gefäßchirurgie, Herz- und Diabeteszentrum Nordrheinwestfalen, Bad Oeynhausen, Germany.
Jan
J
Gummert
Klinik und Poliklinik für Innere Medizin II, Universitätsklinikum Regensburg, Regensburg, Germany.
Lars S
LS
Maier
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Göttingen, Germany.
Markus
M
Zabel
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Göttingen, Germany.
Gerd
G
Hasenfuss
Klinik für Kardiologie und Pneumologie/Herzzentrum, Georg-August-Universität Göttingen, Göttingen, Germany Deutsches Zentrum für Herz-Kreislauf-Forschung (DZHK), Standort Göttingen, Germany ssossalla@med.uni-goettingen.de.
Samuel
S
Sossalla
D000328:Adult; D000368:Aged; D001145:Arrhythmias, Cardiac / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D020013:Calcium Signaling; D006332:Cardiomegaly / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D006339:Heart Rate; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D012737:Sex Factors; D013997:Time Factors; D016277:Ventricular Function, Left
Arrhythmias; Calcium cycling; Heart failure; SR calcium leak; Sex/gender