Cardiac contractility I. Cardiomyocyte contractility, Ca 2+ - - PowerPoint PPT Presentation

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Cardiac contractility I. Cardiomyocyte contractility, Ca 2+ - - PowerPoint PPT Presentation

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Cardiac contractility I. Cardiomyocyte contractility, Ca 2+ availability vs. Ca 2+ sensitivity ZOLTN PAPP Muscle Biophysics PhD Summer School Thursday, 30 August, 2018, Budapest 8:30 9:30 Division of Clinical Physiology, Department of

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Cardiac contractility I. Cardiomyocyte contractility, Ca2+ availability vs. Ca2+ sensitivity

Division of Clinical Physiology, Department of Cardiology University of Debrecen Hungary

ZOLTÁN PAPP

Muscle Biophysics PhD Summer School Thursday, 30 August, 2018, Budapest 8:30 – 9:30

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Division of Clinical Physiology, Department of Cardiology University of Debrecen Hungary

Cardiac contractility I. Cardiomyocyte contractility, Ca2+ availability vs. Ca2+ sensitivity

ZOLTÁN PAPP

Muscle Biophysics PhD Summer School Thursday, 30 August, 2018, Budapest 8:30 – 9:30

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Cardiac contractions and relaxations form the basis of cardiac function

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SLIDE 4

Cardiac contractility depends on cardiomyocytes

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SLIDE 5

What makes a cardiomyocyte work? cardiomyocyte

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SLIDE 6

sarcomere

Sarcomeric structure in the heart is similar to that of skeletal myofibres

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SLIDE 7

Force generation depends on actin and myosin

Fatty acids Glucose

FA-CoA Pyruvate

ATP Contraction/ Relaxation Ca2+

CPT1/2

-Oxi- dation

NADH

Acetyl-CoA

Krebs Cycle

PDH

Ca2+ + ROS ETC

Fe3+

+ + Fatty acids Glucose

FA-CoA Pyruvate

ATP Contraction/ Relaxation Ca2+

CPT1/2

-Oxi- dation

NADH

Acetyl-CoA

Krebs Cycle

PDH

Ca2+ + ROS ETC

Fe3+

+ +

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SLIDE 8

deGoma et al., J Am Coll Cardiol 2006;48:2397–409

The actin and myosin cross-bridge cycle

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SLIDE 9

Frank-Starling mechanism: ventricular end-diastolic volume regulates force of contraction

Ernest Henry Starling 1866-1927

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SLIDE 10

The Frank-Starling-mechanism and the length-tension relationship

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2,2 1 1,8 1,4 2,6 3,0 Sarcomere-

length (m) Force (%)

100

Cardiac muscle

The Frank-Starling-mechanism and the length-tension relationship

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SLIDE 12

2,2 1 1,8 1,4 2,6 3,0 Sarcomere-

length (m)

100

Cardiac muscle Skeletal muscle

The Frank-Starling-mechanism and the length-tension relationship

Force (%)

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SLIDE 13

Cardiomyocyte

What makes a cardiomyocyte work? Answer 1: myofilaments

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Excitation-contraction coupling and Ca2+ transport

Sarcolemma

NCX Ca2+ ATPase SERCA

SR

T-tubule

NCX Ca2+ Channel RyR PLB Myofilaments

Adapted from Sjaastad et al., 2003

AP [Ca2+]i Contraction

200 ms

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SLIDE 15

K+ Na+ Na+ Ca2+ ICa-L

[Ca2+]i 

Ca2+ transients regulate cardiac contractile force

Cardiomyocyte

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SLIDE 16

Positive staircase

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SLIDE 17

Positive staircase in human heart

Tension Ca2+

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Ca2+ movements are frequency dependent

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SLIDE 19

K+ Na+ Na+ Ca2+ ICa-L

[Ca2+]i 

cardiomyocyte What makes a cardiomyocyte work? Answer 2: Ca2+

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SLIDE 20

 - adrenergic regulation of contractility

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SLIDE 21

Sarcoplasmic Reticulum

T-tubule

RyR2 LTCC Ca2+

Serca2

Ca2+ Ca2+

nucleus myofilaments

in

  • ut

PLB

-AR

cAMP

Gs

ATP

AC PKA PKA PKA PKA

Cardiac  contractility

CREB

 - adrenergic regulation of contractility

Fischmeister et al.,

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SLIDE 22

PDE4B PDE3 Gs Gi

T-tubule

RyR2 2-AR 1-AR Ca2+

Serca2

PDE2 Ca2+ Ca2+

nucleus myofilaments

in

  • ut

cAMP

Gs

PLB

AC AKAP18δ LTCC Sarcoplasmic Reticulum

Cyclic nucleotide mycrodomains in cardiomyocytes

Fischmeister et al.,

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PDE3B PI3Kγ PDE4B PDE3 PDE4D3 PDE3A Gs Gi

T-tubule

RyR2 2-AR 1-AR

AKAP15

Ca2+ mAKAP CST2 PP2A PP1

Serca2

PDE2 Ca2+ Ca2+

nucleus

CREB

cAMP

mAKAP Epac1 ICER PDE3A ERK5 PDE4D3

myofilaments

in

  • ut

cAMP

PKA myomegalin PDE4D3 Gs

AKAP79

arrestin PDE4D5

PLB

AC

AKAP79

AKAP18δ PDE3A PDE1 LTCC Sarcoplasmic Reticulum PDE8 AKAP-lbc PKD PKC sGC pGC PDE5 PDE2

cGMP cGMP

Fischmeister et al.,

Cycic nucleotide mycrodomains in cardiomyocytes

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SLIDE 24

K+ Na+ Na+ Ca2+

β1R AC

Gs

cAMP PDE 5’-AMP ATP PKA

ICa-L

[Ca2+]i 

cardiomyocyte What makes a cardiomyocyte work? Answer 3: signaling mechanisms

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SLIDE 25

K+ Na+ Na+ Ca2+ ICa-L

[Ca2+]i  cardiomyocyte

ATP

Myocardial contractility = Ca2+-availibility + Ca2+-sensitivity

+ preignition

  • preignition
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[Ca2+] time systole diastole contraction

Ca2+-sensitivity and contractile force under steady-state conditions

Force Force

Ca2+-sensitivity

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[Ca2+] systole diastole

Ca2+-sensitivity

Force contraction Force time

Ca2+-sensitivity and contractile force under steady-state conditions

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Ca2+-sensitivity is increased in chronic heart failure

van der Velden J, et al. Cardiovasc Res 57,37-47, 2003

0.0 0.2 0.4 0.6 0.8 1.0 4.5 5.0 5.5 6.0

Donor Heart failure

pCa Relative force

pCa50 = 0.26

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SLIDE 29

0.0 0.2 0.4 0.6 0.8 1.0 4.5 5.0 5.5 6.0

Donor

pCa50 = 0,26

0.0 0.2 0.4 0.6 0.8 1. 4.5 5.0 5.5 6.0

Donor PKA Heart faiure PKA

pCa50 = 0,01

Phosphorylation deficit in chronic heart failure

proteinkinase A P protein Relative force pCa

Heart failure

van der Velden J, et al. Cardiovasc Res 57,37-47, 2003

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The  - adrenergic system during chronic heart failure

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SLIDE 31
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Metabolic changes impair contractile performance during acute heart failure (e.g. ischaemia)

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Intracellular acidosis decreases Ca2+-sensitivity of force production

Metzger et al., Journal of Physiology (1996), 492.1, pp. 163-172 pH: 7.0 pH: 6.2 cTnC cTnI

Robertson…Sykes, Arch Biochem Biophys. 2013 Dec 12. doi: 10.1016/j.abb.2013.12.003.

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Kentish J. J Physiol.1986;370,585-604.

Pi

Inorganic phosphate (Pi) decreases contractile force in permeabilized cardiac trabeculae of the rat

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Motor

Force transducer

70 µm 70 µm

width height

Force measurements in isolated cardiomyocytes

Measured parameters: Force (F) turnover rate of the actin-myosin cycle (ktr)

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25 kN/m

2

9 4,82 Length Force pCa passive force 20 sec active force

Ca2+- contracture in a single cardiomyocyte

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Determination of the Ca2+-sensitivity of force production

Ca2+-sensitivity (pCa50)

Maximal Ca2+-activated force (Fo)

nHill

Force (rel.)

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SLIDE 38

Measuring the turnover rate of actin-myosin cycle in cardiomyocytes

25 kN/m

2

10 4.75

Length Force pCa

P passive 20 sec

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SLIDE 39

25 kN/m

2

10 4.75

Length Force pCa

P passive 20 sec ktr

1 sec 25 kN/m2

Hossz Erő Force Length

Measuring the turnover rate of actin-myosin cycle in cardiomyocytes

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SLIDE 40

6 5 1 ktr (1/sec) pCa 6 5 1 Force (relative) pCa

Isometric force and ktr are both Ca2+-dependent

A B C pCa:

10 6.5 6.2 6.0 5.8 5.6 5.4 4.82

1 sec

0.5 P0 (relative unit)

A

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SLIDE 41

time

contractile force ventricular volume

time

Frank-Starling mechanism and Ca2+-sensitivity of force production

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SLIDE 42

time

contractile force sarcomere length ventricular volume

time

1,9 µm 2,3 µm

Frank-Starling mechanism and Ca2+-sensitivity of force production

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SLIDE 43

time [Ca2+]

contractile force sarcomere length ventricular volume Ca2+ -sensitivity

time [Ca2+]

1,9 µm 2,3 µm

Frank-Starling mechanism and Ca2+-sensitivity of force production

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SLIDE 44

sarcomere length Ca2+-sensitivity crossbridge kinetics ? ?

(SL) (pCa50) (ktr)

myosin heavy chain

Ca2+-sensitivity and sarcomere length

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7 6 5 1

pCa Sertés Normalizált erő Egér Humán

7 6 5 1

pCa

7 6 5 1

pCa

SL: 2.3 m SL: 1.9 m

pCa50: ~0,1

Édes IF.,…Papp Z.

  • Am. J. Physiol. 293: R20-R29, 2007

Length dependent Ca2+-sensitisation is conservative in mammalians

Human Mouse Pig Normalized force

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SLIDE 46

7 6 5 3 6 9

Humán pCa ktr (s-1)

7 6 5 3 6 9

Egér pCa

7 6 5 3 6 9

S L : 2 .3 m S L : 1 .9 m

pCa Sertés

Édes IF.,…Papp Z.

  • Am. J. Physiol. 293: R20-R29, 2007

Human Mouse Pig

ktr is species dependent, but does not depend on sarcomere length

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SLIDE 47

Length dependent Ca2+-sensitisation does not depend

  • n ktr
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ktr = fapp + gapp

Length dependent Ca2+-sensitisation does not depend

  • n ktr
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Blocked state Closed state Open state Actin Tropomyosin Myosin head

Length dependent Ca2+-sensitisation is compatible with SL dependent cross-bridge recruitment

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Summary

1. Cardiomyocyte contractions and relaxations are controlled by interactions between myoplasmic Ca2+ and myofilament proteins. 2. The Frank-Starling mechanism is the function of sarcomere length. 3. The force-frequency relationship is governed by cardiomyocyte Ca2+ homeostasis. 4. Cardiomyocyte signaling mechanisms affect Ca2+-availability and Ca2+- sensitivity of force production. 5. The Frank-Starling mechanism involves changes in Ca2+-sensitivity of force production.

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THANK YOU FOR YOUR ATTENTION!