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.

___ __ ___ ____ __ _________ _______ __ _____ _______ 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

0 20

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t (seconds)

Vlv

(m

l)

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Vrv

(m

l)

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l)0 2

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t (seconds)

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l)

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l)

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mH

g)

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mH

g)

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(m

mH

g)

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t (seconds)

Pvc

(m

mH

g)

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30

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t (seconds)

Ppa

(m

mH

g)

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t (seconds)

Ppv

(m

mH

g)

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t (seconds)

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i (m

l/s)

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Qlv

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l/s)

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s (m

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Qrv

o (m

l/s)

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t (seconds)

Qpu

l (m

l/s)

-0.2 0 0.20

20

40

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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

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80

epsfrw (unitless)

sigm

afrw

(kP

a)

0 2-0.35

-0.3

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-0.2

t (seconds)

Cm

lw (

cm-1

)

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0.25

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t (seconds)

Cm

sw (

cm-1

)

0 20.2

0.25

0.3

0.35

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t (seconds)

Cm

rw (

cm-1

)

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

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

___ __ ___ ____ __ _________ _______ __ _____ _______ Cardiac cell mechanics

___ __ ___ ____ __ _________ _______ __ _____ _______ Electrophysiology

control

w/ 30nM isoprenaline

0 0.05 0.1-100

-80

-60

-40

-20

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20

40

t (seconds)

Em

(m

V)

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-80

-60

-40

-20

0

20

40

t (seconds)

Em

(m

V)

___ __ ___ ____ __ _________ _______ __ _____ _______ Calcium handling

___ __ ___ ____ __ _________ _______ __ _____ _______ Cross-bridge

___ __ ___ ____ __ _________ _______ __ _____ _______ Cross-bridge

___ __ ___ ____ __ _________ _______ __ _____ _______ 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

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P (

mm

Hg

)

0 0.5 1 1.5 2 2.5 30

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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)

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P (

mm

Hg

)

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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

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150

P (

mm

Hg

)

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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

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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