Table Of ContentBiological and Medical Physics, Biomedical Engineering
R. John Solaro
Jil C. Tardiff Editors
Biophysics of
the Failing
Heart
Physics and Biology of Heart Muscle
BIOLOGICAL AND MEDICAL PHYSICS,
BIOMEDICAL ENGINEERING
Thefieldsofbiologicalandmedicalphysicsandbiomedicalengineeringarebroad,multidisciplinaryand
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Editor-in-Chief:
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Editorial Board:
MasuoAizawa,DepartmentofBioengineering, MarkS.Humayun,DohenyEyeInstitute,LosAngeles,
TokyoInstituteofTechnology,Yokohama,Japan California,USA
OlafS.Andersen,DepartmentofPhysiology, PierreJoliot,InstitutedeBiologiePhysico-Chimique,
Biophysics&MolecularMedicine,CornellUniversity, FondationEdmonddeRothschild,Paris,France
NewYork,USA
LajosKeszthelyi,InstituteofBiophysics,Hungarian
RobertH.Austin,DepartmentofPhysics,Princeton AcademyofSciences,Szeged,Hungary
University,Princeton,NewJersey,USA
RobertS.Knox,DepartmentofPhysicsandAstronomy,
JamesBarber,DepartmentofBiochemistry,Imperial UniversityofRochester,Rochester,NewYork,USA
CollegeofScience,TechnologyandMedicine,London,
AaronLewis,DepartmentofAppliedPhysics,Hebrew
England
University,Jerusalem,Israel
HowardC.Berg,DepartmentofMolecular
StuartM.Lindsay,DepartmentofPhysicsand
andCellularBiology,HarvardUniversity,Cambridge,
Astronomy,ArizonaStateUniversity,Tempe,
Massachusetts,USA
Arizona,USA
VictorBloomfield,DepartmentofBiochemistry,
DavidMauzerall,RockefellerUniversity,NewYork,
UniversityofMinnesota,St.Paul,Minnesota,USA
NewYork,USA
RobertCallender,DepartmentofBiochemistry,Albert
EugenieV.Mielczarek,DepartmentofPhysics
EinsteinCollegeofMedicine,Bronx,NewYork,USA
andAstronomy,GeorgeMasonUniversity,Fairfax,
StevenChu,LawrenceBerkeleyNationalLaboratory, Virginia,USA
Berkeley,California,USA
MarkolfNiemz,MedicalFacultyMannheim,
LouisJ.DeFelice,DepartmentofPharmacology, UniversityofHeidelberg,Mannheim,Germany
VanderbiltUniversity,Nashville,Tennessee,USA
V.AdrianParsegian,PhysicalScienceLaboratory,
JohannDeisenhofer,HowardHughesMedicalInstitute, NationalInstitutesofHealth,Bethesda,Maryland,USA
TheUniversityofTexas,Dallas,Texas,USA
LindaS.Powers,UniversityofArizona,Tucson,
GeorgeFeher,DepartmentofPhysics,University Arizona,USA
ofCalifornia,SanDiego,LaJolla,California,USA
EarlW.Prohofsky,DepartmentofPhysics,Purdue
HansFrauenfelder,LosAlamosNationalLaboratory, University,WestLafayette,Indiana,USA
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AndrewRubin,DepartmentofBiophysics,Moscow
IvarGiaever,RensselaerPolytechnicInstitute,Troy, StateUniversity,Moscow,Russia
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For furthervolumes:
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R. John Solaro (cid:129) Jil C. Tardiff
Editors
Biophysics of the Failing
Heart
Physics and Biology of Heart Muscle
Editors
R.JohnSolaro JilC.Tardiff
DepartmentofPhysiology UniversityofArizona
andBiophysics Tucson,AZ,USA
CenterforCardiovascularResearch
UniversityofIllinoisatChicago
Chicago,IL,USA
ISSN1618-7210
ISBN978-1-4614-7677-1 ISBN978-1-4614-7678-8(eBook)
DOI10.1007/978-1-4614-7678-8
SpringerNewYorkHeidelbergDordrechtLondon
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Contents
IntroductiontotheBiophysicsoftheFailingHeart................... 1
R.JohnSolaroandJilC.Tardiff
SarcoplasmicReticulumCaHomeostasisandHeartFailure........... 5
AlekseyV.ZimaandDmitryTerentyev
Ca-HomeostasisandHeartFailure:FocusontheBiophysics
ofSurfaceMembraneCa-Fluxes..................................... 37
KathrinBanach
BiophysicsofMembraneCurrentsinHeartFailure................... 63
ManLiu,VikramMaddikuntaBrahmanandam,
andSamuelC.DudleyJr.
BiophysicalMechanismsfortheMetabolicComponent
ofImpairedHeartFunction......................................... 91
E.DouglasLewandowski
CytoskeletalNuclearLinksintheCardiomyocyte..................... 123
ElizabethMcNally
BiophysicalForcesModulatetheCostamereandZ-Disc
forSarcomereRemodelinginHeartFailure.......................... 141
AllenM.Samarel,YevgeniyaKoshman,ErikR.Swanson,
andBrendaRussell
HeartFailure:TheFinalFrontierforBiophysics
inCardiovascularMedicine?........................................ 175
LuisF.Santana
Arrhythmogenesis,HeartFailure,andtheBiophysics
ofZ-BandProteinNetworks......................................... 183
M.VattaandR.JohnSolaro
v
vi Contents
BiophysicsofTitininCardiacHealthandDisease.................... 201
BrianR.AndersonandHenkL.Granzier
SarcomeresandtheBiophysicsofHeartFailure...................... 225
JillianN.Simon,JilC.Tardiff,andBeataM.Wolska
Index............................................................... 249
Introduction to the Biophysics
of the Failing Heart
R.JohnSolaroandJilC.Tardiff
Introduction
Perusalofthecontentsofanybasictextbookinphysicsgivesalistofthetopicsthat
are ofrelevance tobiological processes andin the examplesgiven inthis bookto
theheartinhealthandinfailure.Thebreakdownfallsalongthelinesofmechanics,
electricity,magnetism,thermodynamics,sound,andoptics.Inonewayoranother,
each of these topics in physics comes into play in the biophysics of the heart.
Chaptersinthisvolumeprovidestrongevidenceofthesignificanceofbiophysical
principlesinourunderstandingofthenormalmechanical,energetic,andelectrical
aspects of how the heart functions normally and how it fails in this function in
responsetodiverseformsofstress.Thephysicalprinciplesofsoundandopticsare,
of course, inextricably tied to the use of biophysical principles to determine
functional, structural, and mechanistic aspects of the heart. Here we provide an
overviewofthetopicscoveredandhoweachofthetopicsrepresentsunderpinning
biophysicalprinciples.Theemphasisandfocusisonworkingcardiacmyocytesin
theventricle,althoughwewishtopointoutthatothercelltypesarepresentinthe
heartandcontributesubstantiallytohomeostaticmechanisms.Theworkingcardiac
myocyteprovidesanexcellentexampleofthemarriageofbiology,chemistry,and
physicsinacellthatundergoeslifelongchangesinelectricalstate,forcegeneration,
energy turnover, and length with every beat of the heart. The homeostasis of this
continually active cell involves maintenance of a range of electrical, mechanical,
andenergeticactivities,whichareregulatedtomeettothedemandsofexerciseand
R.J.Solaro(*)
DepartmentofPhysiologyandBiophysics,CenterforCardiovascularResearch,
UniversityofIllinoisatChicago,Chicago,IL60611,USA
e-mail:[email protected]
J.C.Tardiff
UniversityofArizona,1656EastMabelStreet,MRB312,MS#245217,
Tucson,AZ85724-5217,USA
R.J.SolaroandJ.C.Tardiff(eds.),BiophysicsoftheFailingHeart:PhysicsandBiology 1
ofHeartMuscle,BiologicalandMedicalPhysics,BiomedicalEngineering,
DOI10.1007/978-1-4614-7678-8_1,©SpringerScience+BusinessMedia,LLC2013
2 R.J.SolaroandJ.C.Tardiff
externalstressorsofnormallife.Whatisapparentfromthestudiespresentedhereis
that when these systems operate outside this range of homeostatic activity, the
systementersintoadisorderedstateleadinginsomecasestoaslowprocesstoward
deathandinotherstosuddendeath.
Cytoskeletal, Electrical, Metabolic, and Mechanical
Elements in the Initiation of Progression to Heart Failure
Whatdistinguishesphysicsfrombiophysics?Amajordifferencebetweenthetwois
thatsprings,levers,fulcrums,andscrewsareinprincipleinanimate,andthisisnot
the case with the proteins that make up the electrical and mechanical elements of
thecardiacmyocytes.Inproteins,leverlengths,thepointsaboutwhichtheypivot
(fulcrum),andtheirpointofcontactwithneighborsarevariablesandthevariability
ofthesephysicalpropertiesmaybeadaptivetothestressesofnormallife,ormaybe
maladaptive as the stresses exceed the capability of the system to cope. An
excellent example is the chapter by Anderson and Granzier “Biophysics of Titin
inCardiacHealthandDisease.”Titin,thebiggestproteininourbodies,hasallthe
mechanical properties described above. It has spring elements that determine
resting tension in the cardiac myocyte and are therefore a major determinant of
diastolictensionandpressure.Titinisaleverwithevidencethatwhenitstretchesit
moves cross-bridges away from the thick filament proper. It is also likely that
rotationalmovementsofelementsintitinactlikeascrew.What’sfascinatingisthat
all these properties are variables subject to adaptation important in maintaining
normalcardiacfunctionbypost-translationmodifications.Moreover,unlikephysi-
calmachines,biophysicalmachinescanchangepartsbydispensingwithmotifsand
replacing them to form isoforms with different properties. This happens with the
development of the heart and in response to the variations in hemodynamic load.
The fine-tuning required in maintaining function is remarkable in that when
mutatedgenesinduceinappropriatesubstitutionsofaminoacidsintitin,thereisa
progression toward various states of maladaptive cardiac growth, often ending in
sudden death. The linkage of mutations in a biological spring to cardiac growth
indicatesthatthemechanicalstateofthecellismonitoredbysensors,whichsetinto
motioneffectorsthatadjusttothealteredmechanicalstate,andremodeltheheart.
Thismayoccurphysiologicallyaswithchronicexercise,orpathologicallyaswith
inheritedmutationsinproteinssuchastitinorwithstressesontheheartasoccurs
withhypertensionandmyocardialinfarction.
The conceptualization of a mechanical system as a regulator of cell growth is
considered in the chapter by Samarel et al. “Biophysical Forces Modulate the
CostamereandZ-DiscforSarcomereRemodelinginHeartFailure.”Theyempha-
sizetheideathat“mechanicalforcesdrivethegrowthofheartcells.”Theyreview
key cellular elements in the sensing of mechanical strain in the form of the
costameres (the “rib cage” of the cell) and the Z-disc, which not only contain
IntroductiontotheBiophysicsoftheFailingHeart 3
an array of mechano-sensors but also an array of proteins, which influence
transcription, translation, and post-translational modification of cells as well as
assemblyofsarcomeresintheremodelingprocess.Althoughnotfullyunderstood,
itisevidentthatthephysicsofthesystemismodifiedasamechanismtoconverta
mechanicalstatetoanalteredbiochemicalstate.Theversatilityofthesystemand
the long range communications from the extracellular matrix to the nucleus are
amazing examples of how biology employs physics to accomplish regulation.
As with every mechanism discussed in the book, there is a range of homeostatic
adaptivemodificationsandarangeofmaladaptivemodifications.
Electrophysiology provides another example of the application of physical
principles to biological processes. The physics of electricity has been a mainstay
inbiologybeginningmostsignificantlywiththeworkofLuigiGalvani,whoaround
1780cametotherealizationthatafrog’slegisabletoconductelectricitytometal.
Galvani was a practicing physician with an interest in “medical electricity” and
certainlycouldbeconsideredoneofthefirstbiophysicists.Theconceptsofvoltage,
current,resistance,andcapacitanceretaintheirsignificanceandapplicabilityinion
flows. Yet, the proteins that form the channels through which the ions move
demonstrate remarkable abilities to respond to signals that alter their physical
properties so that conductance and voltage changes dramatically via biological
processes and the voltage changes serve as signals for propagation of activation
among cells. In the chapter “Biophysics of Membrane Currents in Heart Failure”
Liu et al. focus on active and passive processes that maintain gradients of ions
across the cell membrane and establish the transmembrane potential, which
depends on the conductance ofan array of channels to various ions including Na,
K,Cl,andCa.Biophysicalmeasurementsprovidehighfidelityread-outsofchannel
activity; patch clamping, in fact, permitted the accurate measurement of current
throughsinglechannels.Againchannelporesareconceptualizedintermsoflevers
andgates,whicharemodifiedbybiologicalprocesses.“Ballandchain”modelsof
thegatingofionchannelsprovideagraphicexampleofthisconceptualization.
Thepassageoftheionsthroughthesechannels,inparticularCa-channels,serves
tosignalmultipleanddiverseeventsinthemyocytes.Mostprominentistheability
ofCacurrentstotriggercontractionbypromotingthereleaseofCafromstoresin
thesarcoplasmicreticulum.ThemechanismsareconsideredinthechapterbyZima
and Terentyev “Sarcoplasmic Reticulum Ca Homeostasis and Heart Failure,” and
thechapterbyBanach“Ca-homeostasisandHeartFailure:FocusontheBiophysics
of Surface Membrane Ca-Fluxes.” A thread running through these and other
chapters is the critical dependence of control of intracellular Ca with regard to
the electrical stability of the cardiac cells. Minor modifications in the fluxes
promote inappropriate changes in membrane potential that trigger and promote
arrhythmias. The chapter by Vatta and Solaro “Arrhythmogenesis, Heart Failure,
andtheBiophysicsofZ-bandProteinNetworks”explicitlyrelatestheactivityofK
andCa-channelstothestrainsinthenetworkofproteinsintheZ-disccytoskeletal
network. Maladaptive mutations in these proteins that lead to sudden death are
thoughttoalterthebiophysicalpropertiesofthenetworks.
