The Role of Metabolic Dysfunction in Heart
Failure
2013 Cardiac Physiome Workshop, Bar Harbor, ME
October 17, 2013
Scott M. Bugenhagen
MD/PhD student
Department of Physiology
Medical 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.
In heart failure:
Changes in metabolite pools lead
to diminished ATP hydrolysis
potential.
Wu et al. (2009) PNAS USA 106:7143-7148.
EDP <
15 mmHg
EDP >
15 mmHg
A Primer on Cardiac Energy Metabolism
Ca2+
K+
Na+
Na+
Na+
K+
Ca2+
OH-
HCO3-
Na+
HCO3-
Cl-
Na+
K+
Cl-
Pyr
Glycolysis
Glc
GLUT
FACoA
FACS
FFA
FATP
NADH
Subspace
MAS
Sacroplasmic
reticulum
Na+
Ca2+
H+
Na+
ATP
ATP
Ca2+
Ca2+
Mitochondria
NXB
NAD
Ca2+
Ca2+
Ca2+
ATP
ADP
+
AM2
Cytoplasm
Myofilaments



MgADP
Pi
H




o
GMgATP  GMgATP  RT ln
,
 MgATP 
Ca 2+ 
sr
 2 RT ln
,
2+
Ca 
i
J uptake  0 if GMgATP  GSERCA  0, else
J uptake  0
PXB
Pi
Ca2+
GSERCA
AM1
MgADP
ATP
Ca2+
MgATP
Pi
XBPreR
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.
___ __ ___ ____ __ _________ _______ __ _____
The Grand Vision
_______
image from wikipedia.org
Baroreflex and autonomic control of heart rate
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
800
800
600
600
400
200
0
2
t (seconds)
0
7
0
2
t (seconds)
0
20
60
40
20
200
100
0
2
t (seconds)
-0.25
-0.3
-0.35
0
2
t (seconds)
2
t (seconds)
Pao (mmHg)
0
0
2
t (seconds)
18.5
18
2
t (seconds)
80
40
20
0
-0.2
0
0.2
epsfsw (unitless)
-0.2
0
19
60
0
-0.2
0
0.2
epsflw (unitless)
2
t (seconds)
80
Ppv (mmHg)
30
2
t (seconds)
100
19.5
40
80
100
0
0
120
2
t (seconds)
50
7.5
2
t (seconds)
300
200
Prv (mmHg)
Plv (mmHg)
0
150
50
2
t (seconds)
400
0
3300
0
140
sigmafrw (kPa)
200
0
2
t (seconds)
Qsys (ml/s)
Qlvo (ml/s)
400
0
2
t (seconds)
8
200
600
0
8.5
3350
3250
2
t (seconds)
Qpul (ml/s)
Qrvi (ml/s)
0
Qrvo (ml/s)
Qlvi (ml/s)
200
0
0
800
400
0
2
t (seconds)
20
60
40
20
0
-0.5
0
0.5
epsfrw (unitless)
0.4
0.4
0.35
0.35
Cmrw (cm-1)
220
2
t (seconds)
600
0
260
240
0
50
160
40
Ppa (mmHg)
3500
0
100
3400
280
3550
3450
900
2
t (seconds)
300
Vpa (ml)
Vvc (ml)
3600
0
150
sigmafsw (kPa)
0
2
t (seconds)
950
60
Cmsw (cm-1)
0
50
Vpv (ml)
0
1000
Pvc (mmHg)
50
100
200
sigmaflw (kPa)
100
1050
Cmlw (cm-1)
Vrv (ml)
Vlv (ml)
150
150
Vao (ml)
200
0.3
0.25
0.2
0
2
t (seconds)
0.3
0.25
0.2
0
2
t (seconds)
Renal blood-volume control
Renal blood-volume control
___ __ ___ ____ __ _________ _______ __ _____
The Grand Vision
_______
image from wikipedia.org
___ __ ___ ____ __ _________ _______ __ _____
Cardiac energy metabolism
_______
From Wu et al. (2007) JBC 282:24525-24537
___ __ ___ ____ __ _________ _______ __ _____
Cardiac energy metabolism
_______
12
12
0.12
LVW / BW = 4.3´10-3
10
0.10
8
10
LVW / BW = 4.3´10-3
0.08
8
0.06
6
LVW / BW = 8.9 ´10-3
6
4
0.04
LVW / BW = 8.9 ´10-3
LVW / BW =12 ´10-3
4
LVW / BW =12 ´10-3
2
2
0.02
LVW / BW =12 ´10-3
0
0
2
H+
4
H+
H+
C(red)2+
C(ox)3+
H+
C(ox)3+
8
H+ H2PO4-
PIHt
ANT
NAD+
ADP3+ PI2-
PYR
ATP4-
ADP
ADP3-
PYRH+
COAS
NAD
1
NADH
GLUH+
CIT
2
3
MAL2HCIT2-
COAS
OAA
9
ICIT
NAD
NADH
GLU
11
NADH
MAL
CO2
AKG
ASP
COAS
NAD
NADH
CO2
SCOA
QH2
Q
COAS
6
7
GDP + PI
SUC
PI
PYR
CIT
AKG
PI2MAL2-
5
8
H+
AKG2MAL2-
4
NAD
FUM
ATP
AMP
CO2
ACCOA
K+
H+
10
CIV
NADH
COQ
CIII
QH2
ATP4- ADP3-
FoF1
CI
COQ
6
ASPHGLU0
SUC2MAL2-
MAL
SUC
ASP
GLU
GTP
10
ATP
ADP
12
0
0
2
4
6
8
10
12
0
0
LVW / BW
= 4.3´10-3
2
4
6
8
10
12
___ __ ___ ____ __ _________ _______ __ _____
Cardiac cell mechanics
_______
Components
Sympathetic nerve
1. Electrophysiology
2. Calcium handling
3. Signaling (CaMKII, β-AR,
others)
Norepinephrine
4. Cross-bridge
Ca2+
K+
Na+
Na+
Na+
K+
Ca2+
Cl-
Na+
K+
MAS
Diad space
Ca2+
Sacroplasmic
reticulum
Na+
HCO3-
Cl-
Pyr
Glycolysis
Glc
GLUT
FACoA
FACS
FFA
FATP
Mitochondria
NXB
NAD
Ca2+
Ca2+
ATP
ADP
+
MgATP
Pi
AM1
Pi
AM2
Ca2+
Cytoplasm
PXB
MgADP
ATP
CaMKII
Ca2+
OH-
HCO3-
NADH
Na+
Ca2+
H+
Na+
ATP
ATP
Ca2+
Ca2+
Myofilaments
XBPreR
___ __ ___ ____ __ _________ _______ __ _____
Cardiac cell mechanics
_______
Components
Sympathetic nerve
1. Electrophysiology
2. Calcium handling
3. Signaling (CaMKII, β-AR,
others)
Norepinephrine
4. Cross-bridge
Ca2+
Ca2+
ATP
Na+
Ca2+
fast
buffer
Ca2+
slow
buffer
Diad space
Ca2+
Sacroplasmic
reticulum
Ca2+
Ca2+
ATP
CaMKII
Myofilaments
Ca2+
Ca2+
Cytoplasm
___ __ ___ ____ __ _________ _______ __ _____
Cardiac cell mechanics
_______
___ __ ___ ____ __ _________ _______ __ _____
Electrophysiology
_______
40
control
20
Em (mV)
0
-20
-40
-60
-80
-100
0
0.05
0.1
t (seconds)
w/ 30nM isoprenaline
40
20
Em (mV)
0
-20
-40
-60
-80
-100
0
0.05
t (seconds)
0.1
___ __ ___ ____ __ _________ _______ __ _____
Calcium handling
_______
___ __ ___ ____ __ _________ _______ __ _____
Cross-bridge
_______
___ __ ___ ____ __ _________ _______ __ _____
Cross-bridge
_______
___ __ ___ ____ __ _________ _______ __ _____
Integrated HF model version 1.0 – Lumens/Smith/Wu/Tran
x 10
1
0
0
150
0.5
1
1.5
2
2.5
3
50
0
0
20
0.5
1
1.5
2
2.5
3
10
0
0
0.5
1
1.5
2
t (seconds)
2.5
3
Healthy resting conditions:
MVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM
[MgADP] ≈ 0.08 mM
[Pi] ≈ 0.2 mM
2
x 10
-3
1
0
0
150
P (mmHg)
100
P (mmHg)
P (mmHg)
-3
[Ca]i (mM)
2
0.5
1
1.5
2
2.5
3
0.5
1
1.5
2
2.5
3
0.5
1
1.5
2
2.5
3
100
P (mmHg)
[Ca]i (mM)
_______
50
0
0
20
10
0
0
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
x 10
1
0
0
150
0.5
1
1.5
2
2.5
3
50
0
0
20
0.5
1
1.5
2
2.5
3
10
0
0
0.5
1
1.5
2
t (seconds)
2.5
3
Healthy resting conditions:
MVO2 ≈ 3.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM
[MgADP] ≈ 0.08 mM
[Pi] ≈ 0.2 mM
2
x 10
-3
1
0
0
150
P (mmHg)
100
P (mmHg)
P (mmHg)
-3
[Ca]i (mM)
2
0.5
1
1.5
2
2.5
3
0.5
1
1.5
2
2.5
3
0.5
1
2
1.5
t (seconds)
2.5
3
100
P (mmHg)
[Ca]i (mM)
_______
50
0
0
20
10
0
0
HF resting conditions:
w/ Volume adjusted to 0.61 x control
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
x 10
2
0
0
150
0.2
0.4
0.6
0.8
1
1.2
1.4
50
0
0
20
0.2
0.4
0.6
0.8
1
1.2
1.4
10
0
0
0.2
0.4
0.6
0.8
t (seconds)
1
1.2
1.4
Healthy exercise conditions:
w/ Resistance adjusted to 0.33 x control
MVO2 ≈ 10.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 8 mM
[MgADP] ≈ 0.1 mM
[Pi] ≈ 2.5 mM
4
x 10
-3
2
0
0
150
P (mmHg)
100
P (mmHg)
P (mmHg)
-3
[Ca]i (mM)
4
0.2
0.4
0.6
0.8
1
1.2
1.4
0.2
0.4
0.6
0.8
1
1.2
1.4
0.2
0.4
0.6
0.8
t (seconds)
1
1.2
1.4
100
P (mmHg)
[Ca]i (mM)
_______
50
0
0
20
10
0
0
HF exercise conditions:
w/ Resistance adjusted to 0.25 x control
w/ Volume adjusted to 0.61 x control
MVO2 ≈ 10.5 μmol O2 min-1 (g tissue)-1
[MgATP] ≈ 1.5 mM
[MgADP] ≈ 0.04 mM
[Pi] ≈ 10 mM
___ __ ___ ____ __ _________ _______ __ _____
Acknowledgements
_______
Dissertation Committee
Daniel Beard (Advisor)
Brian Carlson
Paul Goldspink
Andrew Greene
Michael Widlansky
Jeff Saucerman
Funding
VPR - National Institute of Health Grant No. P50GM094503
Programs
Department of Physiology Graduate Program
Medical Scientist Training Program