electrophysiologic aspects of cell transplant saeed oraii md, cardiologist interventional...

Electrophysiologic Electrophysiologic AspectsAspects

of of Cell TransplantCell Transplant

Saeed Oraii Saeed Oraii MD,MD, CardiologistCardiologist

Interventional electrophysiologistInterventional electrophysiologist

Tehran Arrhythmia ClinicTehran Arrhythmia Clinic

Tehran Arrhythmia CenterTehran Arrhythmia Center

StatisticsStatistics

Cardiovascular disease affects approximately Cardiovascular disease affects approximately 58.8 million people in the United States.58.8 million people in the United States.

About 400,000 new cases of congestive heart About 400,000 new cases of congestive heart failure occur each year. failure occur each year.

More than 2,600 deaths occur each day from More than 2,600 deaths occur each day from cardiovascular disease -- 1 death every 33 cardiovascular disease -- 1 death every 33 seconds. seconds.

Currently the most effective treatment Currently the most effective treatment strategies include lifestyle, medication and strategies include lifestyle, medication and devices.devices.


Cell TransplantCell TransplantThe adult heart was once thought of as a post-mitotic The adult heart was once thought of as a post-mitotic and terminally differentiated organ.and terminally differentiated organ.

This dogma is being challenged by recent findings This dogma is being challenged by recent findings that the adult heart contains cardiomyocytes that that the adult heart contains cardiomyocytes that undergo proliferation.undergo proliferation.

““new paradigm sees heart as new paradigm sees heart as a highly dynamic organa highly dynamic organ in which old, poorly functioning myocytes & vascular in which old, poorly functioning myocytes & vascular smooth muscle cells replaced by activation & smooth muscle cells replaced by activation & commitment of resident Cardiac Stem Cells”commitment of resident Cardiac Stem Cells”

Limited cardiac regeneration through either Limited cardiac regeneration through either recruitment of stem cell populations from the bone recruitment of stem cell populations from the bone marrow or through the activation of resident cardiac marrow or through the activation of resident cardiac progenitor cells has been suggested.progenitor cells has been suggested.


Regenerating HeartRegenerating Heart

Old dogma for last 30 years: “the heart is a post-mitotic organIncapable of regenerating parenchymal cells…Cardiomyocytes can undergo cellular hypertrophy, but cannotbe replaced”“… you have so many beats of your heart, so use it wisely”

In other words, the heart cells you have at birth is it!!When they are damaged, or die – that’s it!! Why the change?•Observation of male cells in female hearts transplanted intoa male (progeny of primitive cells in the heart, or migrated fromelsewhere – bone)

Anversa P, Kajstura J, Leri A, Bolli R. Life and death of cardiac stem cells: a paradigm shift in cardiac biology. Circulation. 2006 Mar 21;113(11):1451-63.


New ParadigmNew Paradigm

Heart is viewed as a Heart is viewed as a self-renewing organself-renewing organ (cell # controlled by (cell # controlled by stem cell compartment)stem cell compartment)

Primitive cells may represent Primitive cells may represent 2%2% of cells of cells

Clustered in atria, apex & throughout ventricular myocardiumClustered in atria, apex & throughout ventricular myocardium

Entire cell population of heart re-populated every Entire cell population of heart re-populated every 4.5 years4.5 years

Old concept Old concept falsefalse - parenchymal cells do not live as long - parenchymal cells do not live as long as the organism (approx. 80 years)as the organism (approx. 80 years)

Stem cells within infarcted area also dieStem cells within infarcted area also die

Do not migrate from healthy myocardium to infarcted area to Do not migrate from healthy myocardium to infarcted area to replace dead cellsreplace dead cells


NewNew ParadigmParadigmIntense myocyte formation in non-infarcted tissue, and Intense myocyte formation in non-infarcted tissue, and acute & chronic heart failureacute & chronic heart failure

11 fold higher than normal physiological turnover11 fold higher than normal physiological turnover

Myocardial aging – telomere dysfunction, decrease pool of Myocardial aging – telomere dysfunction, decrease pool of competent stem cells.competent stem cells.

View of aging & heart failure from perspective of stem cell View of aging & heart failure from perspective of stem cell disorder.disorder.

““new paradigm sees heart as a new paradigm sees heart as a highly dynamic organhighly dynamic organ in in which old, poorly functioning myocytes & vascular smooth which old, poorly functioning myocytes & vascular smooth muscle cells replaced by activation & commitment of muscle cells replaced by activation & commitment of resident Cardiac Stem Cells”resident Cardiac Stem Cells”


Implications for Cardiac Implications for Cardiac RehabilitationRehabilitation

Awareness of trials for stem cell implantation Awareness of trials for stem cell implantation

Potential for arrhythmiasPotential for arrhythmias

Tracking other side effectsTracking other side effects

Sense of hope for CR patientsSense of hope for CR patients

There is a healing capacity of the heartThere is a healing capacity of the heart

What is the effect of our interventions (exercise, dietary, stress What is the effect of our interventions (exercise, dietary, stress management) on stem cell regenerationmanagement) on stem cell regeneration

Exercise – when to start and how much from the perspective of Exercise – when to start and how much from the perspective of stem cell healthstem cell health

e.g. effects of ischemia on stem cell healthe.g. effects of ischemia on stem cell health


Arrhythmias in Heart Arrhythmias in Heart FailureFailure

The failing heart is prone to ventricular The failing heart is prone to ventricular tachyarrhythmias.tachyarrhythmias.

Ventricular arrhythmias are common in patients with Ventricular arrhythmias are common in patients with CHF. CHF.

During 24- to 48-hour period, 5% to 10% of patients During 24- to 48-hour period, 5% to 10% of patients have runs of sustained (>30 seconds) VT and 40% have runs of sustained (>30 seconds) VT and 40% to 80% have nonsustained VT.to 80% have nonsustained VT.

Of the annual mortality of up to 50% in severe heart Of the annual mortality of up to 50% in severe heart failure, about half the deaths are sudden and failure, about half the deaths are sudden and presumably arrhythmic.presumably arrhythmic.

Zalmen Blanck, MD Nicholas D. Georgakopoulos, MD Marcie Berger, MD et al. Electrical Therapy in Patients with Congestive Heart Failure. Current Problems in Cardiology Volume 27 Number 2 February 2002


Mechanism of ArrhythmiasMechanism of Arrhythmias

Reentry due to fibrosisReentry due to fibrosis

Myocardial ischemiaMyocardial ischemia

Enhanced automaticityEnhanced automaticity

Dispersion of repolarizationDispersion of repolarization

Electrolyte abnormalitiesElectrolyte abnormalities


Transmural HeterogeneityTransmural Heterogeneity

Normal cardiac cells exhibit significant Normal cardiac cells exhibit significant transmural heterogeneity of action potential transmural heterogeneity of action potential duration. duration.

A delicate balance has to be maintained to A delicate balance has to be maintained to prevent arrhythmia. prevent arrhythmia.

When abnormal shortening or prolongation of When abnormal shortening or prolongation of action potential duration in some, but not all, of action potential duration in some, but not all, of the myocardial cells, disturbs this balance, the the myocardial cells, disturbs this balance, the incidence of arrhythmia increases.incidence of arrhythmia increases.


Cell Regenerative Cell Regenerative TherapiesTherapies

Many of the cell therapy strategies under Many of the cell therapy strategies under investigation will themselves be applied in investigation will themselves be applied in a patchy or regional distribution, which a patchy or regional distribution, which may or may not be targeted to the areas may or may not be targeted to the areas of greatest contractile dysfunction.of greatest contractile dysfunction.

One important question that this raises is One important question that this raises is whether this approach will suppress an whether this approach will suppress an arrhythmic tendency, by restoring greater arrhythmic tendency, by restoring greater uniformity of healthy tissue architecture uniformity of healthy tissue architecture and function, or whether it will further add and function, or whether it will further add to the heterogeneity, thereby enhancing to the heterogeneity, thereby enhancing any arrhythmic tendency.any arrhythmic tendency.


EXAMPLES OF NATURALLY EXAMPLES OF NATURALLY OCCURRING STEM CELLSOCCURRING STEM CELLS

ADAPTED FROM WWW.NIH.GOV/NEWS/STEMCELL/FIG2.GIF

TOTIPOTENTCELL (ZYGOTE)

PLURIPOTENTSTEM CELLS(EMBRYONIC STEM CELLS)

OTHER COMMITTEDSTEM CELLS (Myoblast, ETC.)

WHITE BLOODCELLSPLATELETS

RED BLOODCELLS

SPECIALIZED CELLS:

BLOOD STEM CELLS

“ADULT”STEM CELLS

Tehran Arrhythmia Center

Which Cell Type?Which Cell Type?

Tissue-specific stem cells:

Germ-line


Skeletal MyoblastsSkeletal Myoblasts

Skeletal myoblasts are one of the Skeletal myoblasts are one of the earliest cell types that have been earliest cell types that have been tested as a regenerative agent for tested as a regenerative agent for structural heart disease. structural heart disease.

Myoblasts are derived from Myoblasts are derived from skeletal muscle satellite cells that skeletal muscle satellite cells that normally lie quiescent under the normally lie quiescent under the basal membrane of skeletal basal membrane of skeletal muscle fibers. muscle fibers.

They are harvested by muscle They are harvested by muscle biopsy, expanded in culture, and biopsy, expanded in culture, and then injected into the heart of the then injected into the heart of the same patient.same patient.


Skeletal MyoblastsSkeletal Myoblasts

From a clinical perspective, they are attractive for the From a clinical perspective, they are attractive for the following reasons: following reasons:

They are easily obtained by muscle biopsyThey are easily obtained by muscle biopsy

They are autologous, circumventing any They are autologous, circumventing any histocompatibility concerns histocompatibility concerns

They have a high proliferative potential in vitro They have a high proliferative potential in vitro

They have commitment to a well-differentiated myogenic They have commitment to a well-differentiated myogenic lineagelineage

They have high resistance to ischemia, which is an They have high resistance to ischemia, which is an advantage given the hypovascular nature of post-infarct advantage given the hypovascular nature of post-infarct scarsscars


First Cell TransplantsFirst Cell Transplants

Autologous myoblast transplantation was first performed Autologous myoblast transplantation was first performed by Taylor et al in rabbit hearts following cryoinjury in by Taylor et al in rabbit hearts following cryoinjury in 1996. 1996.

Skeletal myoblasts were the first cell type tested in Skeletal myoblasts were the first cell type tested in humans for cellular cardiomyoplasty by Menasche’s humans for cellular cardiomyoplasty by Menasche’s group.group.

Menasche P, Hagege AA, Vilquin JT, et al. Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction. J Am Coll Cardiol 2003;41:1078–83.


Gap JunctionsGap Junctions

Although transplantation of skeletal myoblasts Although transplantation of skeletal myoblasts was demonstrated to improve myocardial was demonstrated to improve myocardial performance in animal models, gap junctions performance in animal models, gap junctions and functional coupling were not observed and functional coupling were not observed between grafted and host tissues.between grafted and host tissues.

Yet even the presence of such gap junctions Yet even the presence of such gap junctions between host and donor cardiomyocyte tissues, between host and donor cardiomyocyte tissues, as observed in some studies, does not as observed in some studies, does not guarantee functional integration.guarantee functional integration.


Arrhythmogenic RiskArrhythmogenic Risk

The second important electrophysiological The second important electrophysiological consideration relates to the possible consideration relates to the possible arrhythmogenic risk of these procedures.arrhythmogenic risk of these procedures.

In the skeletal myoblast trials, a disturbingly high In the skeletal myoblast trials, a disturbingly high incidence of ventricular arrhythmias was noted incidence of ventricular arrhythmias was noted in the initial stages of clinical follow-up.in the initial stages of clinical follow-up.

10 out of the first 22 patients undergoing skeletal 10 out of the first 22 patients undergoing skeletal myoblast transplantation experienced ventricular myoblast transplantation experienced ventricular arrhythmias.arrhythmias.


Ventricular ArrhythmiasVentricular ArrhythmiasOne of the five patients had sustained episodes of One of the five patients had sustained episodes of ventricular tachycardia and required implantable ventricular tachycardia and required implantable cardioverter-defibrillator placement. cardioverter-defibrillator placement.

The investigators also describe a subsequent unpublished The investigators also describe a subsequent unpublished experience of two sudden deaths and three serious experience of two sudden deaths and three serious ventricular arrhythmias in eight additional patients. ventricular arrhythmias in eight additional patients.

These data seem to correspond to the Menasche et al. These data seem to correspond to the Menasche et al. experience in which 4 of 10 patients required ICD experience in which 4 of 10 patients required ICD implantation for ventricular arrhythmias after open chest implantation for ventricular arrhythmias after open chest autologous myoblast transplantation.autologous myoblast transplantation.

Smits PC, van Geuns R-J, Poldermans D, et al. Catheter-based intramyocardial injection of autologous skeletal myoblasts as a primary treatment of ischemic heart failure: clinical experience with six-month follow-up. J Am Coll Cardiol 2003;42:2063–9.

Menasche P, Hagege AA, Scorsin M, et al. Myoblast transplantation for heart failure. Lancet 2001;357:279–80.


Potential Hazards of Skeletal Potential Hazards of Skeletal MyoblastsMyoblasts

Itsik Ben-Dor, Shmuel Fuchs and Ran Kornowski. Cell Transplantation Protocols for Ischemic Myocardial Syndrome J. Am. Coll. Cardiol. 2006;48;1519-1526


Time CourseTime Course

The time course of these events appear to The time course of these events appear to show a peak at 11–30 days post cell show a peak at 11–30 days post cell transplantation. transplantation.

There is also a hint from the pooled There is also a hint from the pooled findings that there may be an early period findings that there may be an early period following cell transplantation, possibly following cell transplantation, possibly extending for the first 20–30 days, during extending for the first 20–30 days, during which there is enhanced arrhythmic which there is enhanced arrhythmic tendency.tendency.


Why?Why?

In the case of skeletal myoblasts, the generated In the case of skeletal myoblasts, the generated myotubes have completely different myotubes have completely different physiological properties than host myocytes physiological properties than host myocytes (extremely short APD). (extremely short APD).

Moreover, due to their lack of gap junctions, Moreover, due to their lack of gap junctions, these myotubes are completely uncoupled to the these myotubes are completely uncoupled to the surrounding ventricular myocytes and may surrounding ventricular myocytes and may therefore act as anatomical obstacles, therefore act as anatomical obstacles, increasing tissue inhomogeneity, slowing increasing tissue inhomogeneity, slowing conduction, and increasing the likelihood for the conduction, and increasing the likelihood for the formation of reentrant arrhythmias.formation of reentrant arrhythmias.


Cell Therapy ProarrhythmiaCell Therapy Proarrhythmia

Proarrhythmia after stem cell therapy might be Proarrhythmia after stem cell therapy might be attributed to one or more of the following attributed to one or more of the following reasons: reasons:

Heterogeneity of action potentials between the Heterogeneity of action potentials between the native and the transplanted stem cellsnative and the transplanted stem cells

Intrinsic arrhythmic potential of injected cellsIntrinsic arrhythmic potential of injected cells

Increased nerve sprouting induced by stem cell Increased nerve sprouting induced by stem cell injectioninjection

Local injury or edema induced by Local injury or edema induced by intramyocardial injectionintramyocardial injection


Slow Conduction ZonesSlow Conduction Zones

This hypothesis was recently demonstrated This hypothesis was recently demonstrated experimentally. experimentally.

Co-culturing of human skeletal myoblasts with Co-culturing of human skeletal myoblasts with primary rat cardiomyocyte cultures resulted in primary rat cardiomyocyte cultures resulted in the formation of slow conduction zones that led the formation of slow conduction zones that led to the generation of spiral (reentrant) wave in to the generation of spiral (reentrant) wave in this this in vitro in vitro model.model.

Interestingly, genetic modification of the Interestingly, genetic modification of the myoblasts to express the major gap junction myoblasts to express the major gap junction protein, Cx43, improved conduction and protein, Cx43, improved conduction and decreased the tendency for arrhythmiasdecreased the tendency for arrhythmias


Different Cell TypesDifferent Cell TypesThe nature of the injected cell may have the most impact on The nature of the injected cell may have the most impact on arrhythmogenesis after transplantation. arrhythmogenesis after transplantation.

Myoblasts and stem cells differ in their inherent Myoblasts and stem cells differ in their inherent electrophysiologic properties and in their ability to couple electrophysiologic properties and in their ability to couple electromechanically both among themselves and with host electromechanically both among themselves and with host cardiomyocytes. cardiomyocytes.

Limited clinical data available thus far suggest that arrhythmias Limited clinical data available thus far suggest that arrhythmias are more likely to occur after myoblast than after stem cell are more likely to occur after myoblast than after stem cell transplantation. transplantation.

Finally, limited clinical experience suggests that proarrhythmic Finally, limited clinical experience suggests that proarrhythmic effects of cell therapy may be transient. effects of cell therapy may be transient.

Nonetheless, because the occurrence of cardiac arrhythmia is Nonetheless, because the occurrence of cardiac arrhythmia is highly unpredictable, long-term follow-up studies of cell highly unpredictable, long-term follow-up studies of cell transplant recipients would seem to be essential for transplant recipients would seem to be essential for understanding the natural course of myoblast and stem cell understanding the natural course of myoblast and stem cell induced arrhythmogenesis.induced arrhythmogenesis.


Potential Antiarrhythmic Potential Antiarrhythmic EffectEffect

Although cell grafting could theoretically increase the Although cell grafting could theoretically increase the potential for arrhythmias, the opposite may also occur. potential for arrhythmias, the opposite may also occur.

Cardiomyocyte transplantation in the infarct border zone Cardiomyocyte transplantation in the infarct border zone may facilitate the emergence of new reentrant ventricular may facilitate the emergence of new reentrant ventricular arrhythmias by generating slow conduction channels in arrhythmias by generating slow conduction channels in this area. this area.

The same strategy, on the other hand, may also be The same strategy, on the other hand, may also be utilized as a novel antiarrhythmic strategy. Thus, if utilized as a novel antiarrhythmic strategy. Thus, if cardiomyocyte transplantation will result in efficient cardiomyocyte transplantation will result in efficient regeneration of the infarct, existing slow conduction regeneration of the infarct, existing slow conduction pathways within the scar may be eliminated, reducing pathways within the scar may be eliminated, reducing the arrhythmogenic risk in these patients.the arrhythmogenic risk in these patients.


Border or CenterBorder or Center

Soliman et reported more frequent and polymorphic Soliman et reported more frequent and polymorphic premature ventricular contractions, couplets, triplets, premature ventricular contractions, couplets, triplets, longer post-PAC pauses, and bradycardiac death longer post-PAC pauses, and bradycardiac death following injection of myoblasts in the infarct border zone following injection of myoblasts in the infarct border zone compared with central scar injection in a rabbit model.compared with central scar injection in a rabbit model.

One might expect that myoblast injection into the border One might expect that myoblast injection into the border zone, but not scar, may be proarrhythmic. zone, but not scar, may be proarrhythmic.

Because functional improvement is independent of Because functional improvement is independent of electrical integration of the injected myoblasts, injection electrical integration of the injected myoblasts, injection of myoblasts into regions of scar may improve of myoblasts into regions of scar may improve hemodynamics via a paracrine mechanism without the hemodynamics via a paracrine mechanism without the potential proarrhythmic consequences.potential proarrhythmic consequences.


Cell SpecificitiesCell Specificities

This mechanism may be specific for This mechanism may be specific for transplanted myoblasts, because embryonic transplanted myoblasts, because embryonic stem cells have been reported to differentiate stem cells have been reported to differentiate into a spontaneously contracting functional into a spontaneously contracting functional syncytium with gap junctions distributed along syncytium with gap junctions distributed along the cell borders.the cell borders.

Kehat I, Gepstein A, Spira A, Itskovitz-Eldor J, Gepstein L. Highresolution electrophysiological assessment of human embryonic stem cell-derived cardiomyocytes: a novel in vitro model for the study of conduction. Circ Res 2002;91:659–61.


Arrhythmias With Other Cell TypesArrhythmias With Other Cell Types

Itsik Ben-Dor, Shmuel Fuchs and Ran Kornowski. Cell Transplantation Protocols for Ischemic Myocardial Syndrome J. Am. Coll. Cardiol. 2006;48;1519-1526


And we draw conclusions: And we draw conclusions: what do we learn by what do we learn by examining the evidence?examining the evidence?

And we draw conclusions: And we draw conclusions: what do we learn by what do we learn by examining the evidence?examining the evidence?


Factors Affecting RiskFactors Affecting Risk

Current data suggest that the risk of arrhythmia occurring Current data suggest that the risk of arrhythmia occurring after myocardial cell transplantation may be increased by after myocardial cell transplantation may be increased by several factors: several factors:

The type of cell injectedThe type of cell injected

The local myocardial milieu and electrical properties of The local myocardial milieu and electrical properties of the recipient tissuethe recipient tissue

The presence of global and regional left ventricular The presence of global and regional left ventricular function; function;

The ex vivo cell expansion technique; and The ex vivo cell expansion technique; and

The timing of the transplantation relative to the ischemic The timing of the transplantation relative to the ischemic or infarction eventsor infarction events


We Need More Basic Research on Stem We Need More Basic Research on Stem Cells to Define Antiarrhythmic or Cells to Define Antiarrhythmic or

Proarrhythmic PotentialsProarrhythmic Potentials

??


ConclusionConclusionOne implication of this clinical One implication of this clinical observation may be a observation may be a requirement for a prophylactic requirement for a prophylactic ICD implantation in all patients ICD implantation in all patients participating in these trials.participating in these trials.

Another implication is the need Another implication is the need for a clinical electrophysiologist for a clinical electrophysiologist to be actively involved in the to be actively involved in the designing and execution of designing and execution of these trials. these trials.

This latter would allow better This latter would allow better patient selection and better patient selection and better understanding of the nature, understanding of the nature, prevention, and treatment of prevention, and treatment of the arrhythmia episodes.the arrhythmia episodes.

1997: Dolly, a Cloned Mammal1997: Dolly, a Cloned Mammal


Cell Therapy for Cardiac ArrhythmiasCell Therapy for Cardiac Arrhythmias

Cardiac arrhythmias represent one of the Cardiac arrhythmias represent one of the most common causes of worldwide most common causes of worldwide morbidity and mortality and result in a morbidity and mortality and result in a major burden on the health care systems. major burden on the health care systems.

The possible applications of these The possible applications of these emerging technologies is establishing emerging technologies is establishing novel antiarrhythmic therapeutic novel antiarrhythmic therapeutic paradigms.paradigms.


Cell Therapy for Cardiac ArrhythmiasCell Therapy for Cardiac Arrhythmias

LIOR YANKELSON and LIOR GEPSTEIN. From Gene Therapy and Stem Cells to Clinical Electrophysiology. PACE 2006; 29:996–1005


Implanted PacemakersImplanted PacemakersImplanted pacemakers have become a highly Implanted pacemakers have become a highly effective and safe treatment modality. effective and safe treatment modality.

Nevertheless, these devices are not without Nevertheless, these devices are not without limitations.limitations. The need for a surgical procedure with its associated The need for a surgical procedure with its associated

small but existing riskssmall but existing risks The requirement of repeated procedures for battery The requirement of repeated procedures for battery

replacementreplacement The inability to adjust heart rate and the resulting The inability to adjust heart rate and the resulting

electrical activation sequence in the same electrical activation sequence in the same effectiveness as the native pacemaker and cardiac effectiveness as the native pacemaker and cardiac conduction system.conduction system.


Biological PacemakersBiological Pacemakers

In recent years, a number of novel gene and cell therapy In recent years, a number of novel gene and cell therapy approaches have emerged as experimental platforms for approaches have emerged as experimental platforms for the creation of biological pacemakers.the creation of biological pacemakers.


Avenues for Creating Biological Avenues for Creating Biological PacemakersPacemakers

To manipulate autonomic control;To manipulate autonomic control;

To manipulate ion channel number, structure, To manipulate ion channel number, structure, and/or function in order to create a nidus of and/or function in order to create a nidus of pacemaker cells; pacemaker cells;

or or

To create the SA or AV node “from scratch.”To create the SA or AV node “from scratch.”


Cell TherapyCell TherapyBoth embryonic and adult mesenchymal stem cells have Both embryonic and adult mesenchymal stem cells have been used in attempts to fabricate biological been used in attempts to fabricate biological pacemakers.pacemakers.

With With embryonic stem cellsembryonic stem cells (pluripotent), the general (pluripotent), the general strategy is to direct the cells down a lineage that will strategy is to direct the cells down a lineage that will incorporate pacemaker properties in its own right, couple incorporate pacemaker properties in its own right, couple to adjacent myocytes, and be integrated as a new sinus to adjacent myocytes, and be integrated as a new sinus node cell.node cell.

With With adult mesenchymal stem cellsadult mesenchymal stem cells (multipotent), the (multipotent), the strategy is to use the cells as platforms to carry genes of strategy is to use the cells as platforms to carry genes of interest to regions of the heart where the cells would interest to regions of the heart where the cells would need to couple with adjacent myocytes.need to couple with adjacent myocytes.


Embryonic Stem CellsEmbryonic Stem Cells

Human embryonic stem cells provide a rich Human embryonic stem cells provide a rich source of material for regenerating myocardium source of material for regenerating myocardium and initiating electrical activity in heart. and initiating electrical activity in heart.

The possibility that their use requires The possibility that their use requires immunosuppressive treatment remains an issue.immunosuppressive treatment remains an issue.


Human Embryonic Stem Cell LinesHuman Embryonic Stem Cell Lines

LIOR YANKELSON and LIOR GEPSTEIN. From Gene Therapy and Stem Cells to Clinical Electrophysiology. PACE 2006; 29:996–1005


Mesenchymal Stem CellsMesenchymal Stem Cells

Hyperpolarization-activated, Cyclic Nucleotide-gated (HCN) channel (If current)

Michael R. Rosen, MD. Biological pacemaking: In our lifetime? Heart Rhythm, Vol 2, No 4, April 2005


Mesenchymal Stem CellsMesenchymal Stem Cells

Michael R. Rosen, MD. Biological pacemaking: In our lifetime? Heart Rhythm, Vol 2, No 4, April 2005


LimitationsLimitations

In the case of the engineered Mesenchymal Stem Cells In the case of the engineered Mesenchymal Stem Cells it is not clear whether the transfected cells will eventually it is not clear whether the transfected cells will eventually discontinue expressing the channel or whether these discontinue expressing the channel or whether these multipotent cells may differentiate into unwanted cell multipotent cells may differentiate into unwanted cell types such as bone and cartilage.types such as bone and cartilage.

The genetically engineered cells only partially The genetically engineered cells only partially recapitulate the phenotype of the SA nodal cells. recapitulate the phenotype of the SA nodal cells.

In the case of the hESC-derived cells, it is not clear In the case of the hESC-derived cells, it is not clear whether these early stage cardiomyocytes, that display whether these early stage cardiomyocytes, that display some pacemaker like properties, will eventually mature some pacemaker like properties, will eventually mature into adult ventricular-like cells and lose their capabilities into adult ventricular-like cells and lose their capabilities for spontaneous automaticity.for spontaneous automaticity.


Challenge: Knowledge ExplosionChallenge: Knowledge Explosion

““We are drowning in We are drowning in information but starved information but starved for knowledge.”—Naisbitt, ‘82for knowledge.”—Naisbitt, ‘82

electrophysiologic aspects of cell transplant saeed oraii md, cardiologist interventional...

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