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The Role of Metabolic Dysfunction in Heart Failure
2013 Cardiac Physiome Workshop, Bar Harbor, ME October 17, 2013
Scott M. BugenhagenMD/PhD studentDepartment of PhysiologyMedical College of Wisconsin
What is heart failure?
“heart failure: inability of the heart to maintain cardiac output sufficient to meet the body's needs” -Dorland’s Medical Dictionary, 2007
Dx involves various algorithms (Framingham, European Society of Cardiology, others) based on criteria from medical history, physical examination, laboratory tests, response to therapy, etc.
image from wikipedia.org
___ __ ___ ____ __ _________ _______ __ _____ _______ What causes heart failure?
Adapted from Beard, Examination of the “Dominant Role of the Kidneys in Long-Term Regulation of Arterial Pressure and in Hypertension”, Physiology Seminar 2013
What causes heart failure?
Adapted from McKinsey, T.A. and Olson, E.N. (2005) J Clin Invest 115, 538-46.
???
A Primer on Cardiac Energy Metabolism
Physiological control:
In vitro (purified mitochondria) and in vivo data are consistent with the hypothesis that cardiac energy metabolism is primarily regulated through feedback of substrates for oxidative phosphorylation.
EDP < 15 mmHg
EDP > 15 mmHg
In heart failure:
Changes in metabolite pools lead to diminished ATP hydrolysis potential.
Wu et al. (2009) PNAS USA 106:7143-7148.
A Primer on Cardiac Energy Metabolism
MitochondriaSacroplasmicreticulum
Cytoplasm Myofilaments
PXBAM1
XBPreRAM2
NXB
MgATP
MgADPPi
ATP ADP Pi+
Ca2+ Na+
Ca2+ Na+
K+
Na+
Ca2+
Ca2+
Ca2+
Ca2+
Ca2+
Na+ K+
ATP
Ca2+
ATP
K+
Na+
Ca2+
ATP
Ca2+
Subspace
GLUTGlc
FATPFFA
Glycolysis
FACS
Pyr
FACoA
H+
Na+ Cl-
HCO3- OH-
Cl-
HCO3-Na+
MAS
NAD
NADH
oMgATP MgATP
2+
SERCA 2+
uptake MgATP SERCA
uptake
MgADP Pi Hln ,
MgATP
Ca2 ln ,
Ca
0 if 0, else
0
sr
i
G G RT
G RT
J G G
J
Can energy failure cause heart failure?
Goal: To develop a mathematical model linking cardiac energy metabolism with cell- and organ-level cardiac mechanics and whole-body cardiovascular dynamics in order to test the hypothesis that energy failure alone provides a sufficient explanation for the mechanical changes observed in heart failure.
Cardiovascular hemodynamics
from Lumens J, Arts T, et al. Ann Biomed Eng. 2009 Nov;37(11):2234-55
from Smith BW, JG Chase , et al. Medical Engineering & Physics. 2004 Mar;26(2):131-39
Cardiovascular hemodynamics
0 20
50
100
150
200
t (seconds)
Vlv
(m
l)
0 20
50
100
150
t (seconds)
Vrv
(m
l)
0 2900
950
1000
1050
t (seconds)
Vao
(m
l)0 2
3450
3500
3550
3600
t (seconds)
Vvc
(m
l)
0 2220
240
260
280
300
t (seconds)
Vpa
(m
l)
0 23250
3300
3350
3400
t (seconds)
Vpv
(m
l)
0 20
50
100
150
200
t (seconds)
Plv
(m
mH
g)
0 20
20
40
60
t (seconds)
Prv
(m
mH
g)
0 280
100
120
140
160
t (seconds)
Pao
(m
mH
g)
0 27
7.5
8
8.5
t (seconds)
Pvc
(m
mH
g)
0 220
30
40
50
t (seconds)
Ppa
(m
mH
g)
0 218
18.5
19
19.5
t (seconds)
Ppv
(m
mH
g)
0 20
200
400
600
t (seconds)
Qlv
i (m
l/s)
0 20
200
400
600
800
t (seconds)
Qlv
o (m
l/s)
0 250
100
150
200
t (seconds)
Qsy
s (m
l/s)
0 20
200
400
600
800
t (seconds)
Qrv
i (m
l/s)
0 20
200
400
600
800
t (seconds)
Qrv
o (m
l/s)
0 20
100
200
300
t (seconds)
Qpu
l (m
l/s)
-0.2 0 0.20
20
40
60
80
epsflw (unitless)
sigm
aflw
(kP
a)
-0.2 0 0.20
20
40
60
epsfsw (unitless)
sigm
afsw
(kP
a)
-0.5 0 0.50
20
40
60
80
epsfrw (unitless)
sigm
afrw
(kP
a)
0 2-0.35
-0.3
-0.25
-0.2
t (seconds)
Cm
lw (
cm-1
)
0 20.2
0.25
0.3
0.35
0.4
t (seconds)
Cm
sw (
cm-1
)
0 20.2
0.25
0.3
0.35
0.4
t (seconds)
Cm
rw (
cm-1
)
___ __ ___ ____ __ _________ _______ __ _____ _______ Cardiac energy metabolism
From Wu et al. (2007) JBC 282:24525-24537
___ __ ___ ____ __ _________ _______ __ _____ _______ Cardiac energy metabolism
ADP
ATP
AMP
PI
MAL
PYR
AKG
SUC
ASP
GLU
CIT
PYR-
H+
GLU-
H+
MAL2-
HCIT2-
AKG2-
MAL2-
PI2-
MAL2-
ASP-
HGLU0
ACCOA CIT
COAS
ICIT
AKG
SCOA
SUC
FUM
MAL
OAA
CO2 NADH
NAD
NADH
NAD
CO2 QH2
Q
NADH
NAD
2 3
4
5
6 7
8
9
COAS
GDP + PI
GTP
11
COAS ASP
GLU
1
PYR
COAS
NADH
NAD
CO2
10 ATP
ADP
SUC2-
MAL2-
K+
H+
H+
K+
H+
H+
COQ QH2
COQ
NADH NAD+
C(ox)3+ C(red)2+
H+ H+
C(ox)3+
H+
ADP3-
+ PI2-ATP4-
ATP4- ADP3-
ADP3-
AN
T
Fo F
1
CIV
CIII
CI
H+
PIH
t
H+ H2PO4-
COQ QH2
COQ
NADH NAD+
C(ox)3+ C(red)2+
H+ H+
C(ox)3+
H+
ADP3-
+ PI2-ATP4-
ATP4- ADP3-
ADP3-
AN
T
Fo F
1
CIV
CIII
CI
H+
PIH
t
H+ H2PO4-
2 4 6 8 10 120 2 4 6 8 10 120 2 4 6 8 10 120
2
4
6
8
10
12
0
0.02
0.04
0.06
0.08
0.10
0.12
0
2
4
6
8
10
12
0
___ __ ___ ____ __ _________ _______ __ _____ _______ Cardiac cell mechanics
Mitochondria
Sacroplasmicreticulum
Cytoplasm Myofilaments
PXBAM1
XBPreRAM2
NXB
MgATP
MgADPPi
ATP ADP Pi+
Ca2+ Na+
Ca2+ Na+
K+
Na+
Ca2+
Ca2+
Ca2+
Ca2+
Na+ K+
ATP
Ca2+
ATP
K+
Na+
Ca2+
ATP
Ca2+
Diad space
GLUTGlc
FATPFFA
Glycolysis
FACS
Pyr
FACoA
H+
Na+ Cl-
HCO3- OH-
Cl-
HCO3-Na+
MAS
NAD
NADH
Sympathetic nerve
Ca2+
Components
1. Electrophysiology
2. Calcium handling
3. Signaling (CaMKII, β-AR, others)
4. Cross-bridge Norepinephrine
CaMKII
___ __ ___ ____ __ _________ _______ __ _____ _______ Cardiac cell mechanics
Cytoplasm
slow buffer
Na+
Ca2+
Ca2+
Ca2+
Ca2+
ATP
Ca2+
Ca2+
ATP
Ca2+
Ca2+
fast buffer
Sacroplasmicreticulum
Diad space
Ca2+
CaMKII
Sympathetic nerve
Norepinephrine
Components
1. Electrophysiology
2. Calcium handling
3. Signaling (CaMKII, β-AR, others)
4. Cross-bridge
Myofilaments
___ __ ___ ____ __ _________ _______ __ _____ _______ Electrophysiology
control
w/ 30nM isoprenaline
0 0.05 0.1-100
-80
-60
-40
-20
0
20
40
t (seconds)
Em
(m
V)
0 0.05 0.1-100
-80
-60
-40
-20
0
20
40
t (seconds)
Em
(m
V)
___ __ ___ ____ __ _________ _______ __ _____ _______ Integrated HF model version 1.0 – Lumens/Smith/Wu/Tran
0 0.5 1 1.5 2 2.5 30
1
2x 10
-3
[Ca
] i (m
M)
0 0.5 1 1.5 2 2.5 30
50
100
150
P (
mm
Hg
)
0 0.5 1 1.5 2 2.5 30
10
20
t (seconds)
P (
mm
Hg
)
Healthy resting conditions:MVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM [MgADP] ≈ 0.08 mM[Pi] ≈ 0.2 mM
0 0.5 1 1.5 2 2.5 30
1
2x 10
-3
[Ca
] i (m
M)
0 0.5 1 1.5 2 2.5 30
50
100
150
P (
mm
Hg
)
0 0.5 1 1.5 2 2.5 30
10
20
P (
mm
Hg
)
t (seconds)
HF resting conditions:MVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 1.5 mM [MgADP] ≈ 0.01 mM[Pi] ≈ 0.8 mM
___ __ ___ ____ __ _________ _______ __ _____ _______ Integrated HF model version 1.0 – Lumens/Smith/Wu/Tran
0 0.5 1 1.5 2 2.5 30
1
2x 10
-3
[Ca
] i (m
M)
0 0.5 1 1.5 2 2.5 30
50
100
150
P (
mm
Hg
)
0 0.5 1 1.5 2 2.5 30
10
20
t (seconds)
P (
mm
Hg
)
Healthy resting conditions:MVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM [MgADP] ≈ 0.08 mM[Pi] ≈ 0.2 mM
HF resting conditions:w/ Volume adjusted to 0.61 x controlMVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 1.5 mM [MgADP] ≈ 0.01 mM[Pi] ≈ 0.8 mM
0 0.5 1 1.5 2 2.5 30
1
2x 10
-3
[Ca
] i (m
M)
0 0.5 1 1.5 2 2.5 30
50
100
150
P (
mm
Hg
)
0 0.5 1 1.5 2 2.5 30
10
20
P (
mm
Hg
)
t (seconds)
___ __ ___ ____ __ _________ _______ __ _____ _______ Integrated HF model version 1.0 – Lumens/Smith/Wu/Tran
Healthy exercise conditions:w/ Resistance adjusted to 0.33 x controlMVO2 ≈ 10.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM [MgADP] ≈ 0.1 mM[Pi] ≈ 2.5 mM
HF exercise conditions:w/ Resistance adjusted to 0.25 x controlw/ Volume adjusted to 0.61 x controlMVO2 ≈ 10.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 1.5 mM [MgADP] ≈ 0.04 mM[Pi] ≈ 10 mM
0 0.2 0.4 0.6 0.8 1 1.2 1.40
2
4x 10
-3
[Ca
] i (m
M)
0 0.2 0.4 0.6 0.8 1 1.2 1.40
50
100
150
P (
mm
Hg
)
0 0.2 0.4 0.6 0.8 1 1.2 1.40
10
20
P (
mm
Hg
)
t (seconds)
0 0.2 0.4 0.6 0.8 1 1.2 1.40
2
4x 10
-3
[Ca
] i (m
M)
0 0.2 0.4 0.6 0.8 1 1.2 1.40
50
100
150
P (
mm
Hg
)
0 0.2 0.4 0.6 0.8 1 1.2 1.40
10
20
P (
mm
Hg
)
t (seconds)
___ __ ___ ____ __ _________ _______ __ _____ _______ Acknowledgements
Dissertation CommitteeDaniel Beard (Advisor)Brian CarlsonPaul GoldspinkAndrew GreeneMichael WidlanskyJeff Saucerman
FundingVPR - National Institute of Health Grant No. P50-GM094503
ProgramsDepartment of Physiology Graduate ProgramMedical Scientist Training Program