MYOCARDIAL DYSFUNCTION IN HYPERTROPHIC CARDIOMYOPATHY: PRIMARY
EFFECTS OF SARCOMERIC MUTATIONS VERSUS SECONDARY EC-COUPLING
REMODELLING.
Raffaele Coppini1, Cecilia Ferrantini2, Francesca Gentile2, Luca
Mazzoni1, Benedetta Tosi2, Manuel J. Pioner1, Beatrice Scellini2,
Nicoletta Piroddi2, Jil C. Tardiff3, Chiara Tesi2, Elisabetta
Cerbai1, Corrado Poggesi2. 1University of Florence, Firenze, Italy
2University of Arizona, Tucson, USA.
In cardiac muscle from HCM patients primary changes in
myofilament function, related to the presence of disease-causing
mutations in sarcomeric proteins, are always associated with
secondary abnormalities due to adverseremodeling of cardiomyocyte
EC-coupling(Coppini et al,Circulation 2013). The latter are likely
major contributorsof the mechanical dysfunction and
arrhythmogeneity of HCM human hearts. Here we characterize the
changes insarcomere function and EC-coupling that occur in two HCM
mouse models carrying different mutations in cTnT(R92Q and E163R).
Echocardiography showed LV hypertrophy, enhanced contractility,
diastolic dysfunction andenlarged left atria in both HCM models;
the phenotype was more pronounced in the R92Q mice. In
E163Rventricular myofibrils, in spite of a significant increase in
the rate of the initial isometric slow phase of relaxation,overall
relaxation from maximal activation was impaired and prolonged vs WT
and R92Q myofibrils that exhibitedsimilar relaxation kinetics.
Resting tension was higher in the E163Q compared to WT and R92Q
myofibrils.Isometric ATPase both at rest and at maximal
Ca2+-activation and the energy cost of tension generation
wereincreased in E163R vs WT and R92Q skinned trabeculae.
Myofilament Ca2+-sensitivity was increased in bothmutant lines
compared to WT; the change was larger in the R92Q preparations.
R92Q intact cardiomyocytes andtrabeculae compared to WT and E163R
preparations showed blunted response to inotropic interventions,
reducedamplitude and slower decay of Ca2+-transients with reduced
SERCA function. Twitch kinetics were prolonged inboth HCM mouse
models, despite Ca2+-transient kinetics was faster and SERCA
function unchanged in theE163R mice. Intact preparations of both
HCM mouse models showed increased probability of
arrhythmogenicbehavior that increased in response to isoproterenol.
The results suggest that similar HCM phenotypes can begenerated
through different pathogenic pathways. Grant Telethon-GGP13162.
ABSTRACTIntact trabeculae mechanics
Intracellular Calcium Fluxes
BACKGROUND AND AIM
RESULTS
METHODS
We aimed to characterize changes in sarcomere function and in
E-Ccoupling in two HCM mouse models carrying two different cTnT
mutations.
SUMMARY and CONCLUSIONSThe cardiac phenotypes of R92Q and E163R
cTnT mouse models areessentially similar and recapitulate the
features of the human HCM.
In E163 mice the mutant protein is associated with major
impairment ofmyofilament function (increased CB dissociation rate
& increased energeticcost of tension generation, impaired
mechanism that switches contraction off& impaired sarcomere
relaxation) that can be directly related to themechanical
dysfunction of the in vivo heart.
In R92Q mice no major changes in myofilament function (a part
from theincreased Ca2+-sensitivity) are observed suggesting that
additionalpathogenic mechanisms may be involved in the mechanical
dysfunction of thein vivo heart.
In R92Q mice increased myofilament Ca2+ sensitivity is
associated with alarge spectrum of E-C coupling changes which
appear to be the majorcontributor to the observed mechanical
dysfunction and arrhythmogeneicityresembling the advanced human
disease (Coppini et al., Circulation 2013).
In E163R mice impairment of myofilament function appears to be
theleading element determining mechanical abnormalities. In the
absence ofmajor E-C coupling changes, the increased
arrhythmogeneicity in E163Rmyocardium may be a direct consequence
of the increased myofilament Ca2sensitivity.
ACKNOWLEDGEMENTS
Telethon Italy grant 13162Gileas Sciences Inc.
Ca2+sensitivity ATP
consumed
Altered CB mechanics& kinetics
Impairedcontractionswitch-off
PLB
Sarcoplasmic reticulum
ATPase
Na+overload
Sarcomere Mutation
ATPconsumedCa2+ sensitivity
RyR
SERCA
Sarcolemma
T
-
t
u
b
u
l
e
ROS
ATP produced
Na/K ATPase
Ca2+overload
Ca2+ Ca2+
Ca2+
Ca2+
Na+
Na+
K+
-receptor
Primary sarcomere changes Secondary E-C coupling remodeling
Invivo
1
0
m
N
/
m
m
2
F
/
F
o
1 s
Ca2+ transients
1s
IsometrictensionThin intact
trabeculae
Cardiomyocytes
Skinnedtrabeculae
SingleMyofibrils
Sarcomerekinetics
Invitro
Echocardiography Systolic/diastolic function
Tension/ATPase
R92Q E163R
Manning, Tardiff et al. J Mol Biol. 2012
~30micepergroup,810months
KITransgenicMice
Coppini R. et al, Circulation 2013Ferrantini C. et al. J
Cardiovasc Trasl Res 2009
Echocardiography
Volumes andsystolic function
Diastolic Volume Systolic Volume0
20
40
60
80
L
V
V
o
l
u
m
e
(
L
)
WT R92Q E163R
Ejection Fraction Wall thickening40
50
60
70
%
Stroke Volume Cardiac Output10
20
30
40
50
S
.
V
.
(
L
)
-
C
.
O
.
(
m
l
/
m
i
n
)
*
*
* **
NS
NS
NS
NS
* **
#
*
0
2
4
6
8
A
r
e
a
s
(
m
m
2
)
Left Atrium
***
Diast. Septum Syst. Septum0,5
1,0
1,5
S
e
p
t
a
l
T
h
i
c
k
n
e
s
s
(
m
m
) WT R92Q E163R
**
#
**
Septal Thickness
LALA
LA
R92QWT
E163R
EA
E A E A
E/A0,0
0,4
0,8
1,2
1,6
E
/
A
R
a
t
i
o
WT R92Q E163R
***
Means S.E.from14WT,11R92Qand8E163Rmice.*=p
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