Cardiomyocyte survivin protein expression is associated
with cell size and DNA content in the failing human heart
and is reversibly regulated after ventricular unloading
Jeremias Wohlschlaeger, MD,
a
Birgit Meier, MD,
a
Klaus Jürgen Schmitz, MD,
a
Atsushi Takeda, MD,
b
Nobuakira Takeda, MD,
c
Christian Vahlhaus, MD,
e
Bodo Levkau, MD,
d
Jörg Stypmann, MD,
e
Christof Schmid, MD,
f
Kurt Werner Schmid, MD,
a
and Hideo Andreas Baba, MD
a
a
Department of Pathology and Neuropathology, University Hospital Essen, University of Duisburg-Essen, Germany;
b
Faculty of
Health Science, School of Physical Therapy, Gumma Paz College, Gumma, Japan;
c
Department of Internal Medicine, Jikei
University, Tokyo, Japan;
d
Institute of Pathophysiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;
e
Department of Cardiology and Angiology, and
f
Department of Thoracic and Cardiovascular Surgery, University Hospital Münster,
Münster, Germany
BACKGROUND: Mechanical support in congestive heart failure (CHF) by a left ventricular assist device
(LVAD) is associated with decreased cardiac hypertrophy and altered cardiomyocyte molecular pathways.
Survivin initiates cell cycle progression by increased cyclinD1/cdk4 complexes by abrogation of the inhibitory
effect of p16
INK4a
on cdk4. Accordingly, the role of survivin in CHF and after unloading was explored.
METHODS: In 20 myocardial samples from patients with terminal CHF (before and after LVAD), the
protein expression of survivin, cyclin D1, cdk4, p16
INK4a
, and proliferating cell nuclear antigen (PCNA) was
immunohistochemically investigated and morphometrically quantified by calculating the percentage of positive
cardiomyocytes per visual field. These data were correlated with cardiomyocyte size and DNA content.
RESULTS: The mean percentage of cardiomyocytes immunoreactive against survivin, cyclin D1, cdk4,
p16
INK4a
, and PCNA was significantly increased in CHF compared with controls and significantly
decreased after unloading (57.6% to 26.6%, 42% to 18.3%, 45.4% to 15.3%, 73.0% to 60.5%, and
43.5% to 25.2%, respectively; p 0.05). All investigated parameters, in particular survivin and cyclin
D1, significantly correlated with cardiomyocyte diameters (r = 0.405; r = 0.563) and DNA content
(r = 0.430; r = 0.480), both in CHF (cardiac remodelling) and after unloading (p 0.05).
CONCLUSIONS: These data indicate that survivin is reversibly regulated by ventricular unloading and
might be involved in cell size/DNA content regulation and cardiomyocyte proliferation in cardiac remod-
elling during CHF. It is suggested that after ventricular unloading, decreased survivin protein expression
might contribute to cardiac hypertrophy decrease by lowering the number of cyclin D1/cdk4 complexes.
J Heart Lung Transplant 2010;29:1286 –92
© 2010 International Society for Heart and Lung Transplantation. All rights reserved.
KEYWORDS:
survivin;
cardiac hypertrophy;
cardiomyocyte DNA
content;
LVAD;
reverse cardiac
remodelling
In response to increased biomechanical stress induced by
various noxious stimuli, cardiomyocytes either compensate
for the increased workload by maladaptive hypertrophic
growth or undergo apoptosis, a process termed cardiac re-
modelling that eventually leads to congestive heart failure
(CHF).
1,2
In terminal CHF, prolonged ventricular unloading
by left ventricular assist devices (LVADs) provides pro-
found volume and pressure unloading of the LV and is
Reprint requests: Hideo Andreas Baba, MD, Institute of Pathology and
Neuropathology, University Hospital of Essen, University of Duisburg-
Essen, Hufelandstr 55, 45147 Essen, Germany. Telephone: 0049-201-723-
3577. Fax: 0049-201-723-3378.
E-mail address: hideo.baba@uk-essen.de
http://www.jhltonline.org
1053-2498/$ -see front matter © 2010 International Society for Heart and Lung Transplantation. All rights reserved.
doi:10.1016/j.healun.2010.06.015