Attribution: Kim Eagle, M.D., 2009

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Kim A. Eagle, M.D.Kim A. Eagle, M.D.Kim A. Eagle, M.D.Kim A. Eagle, M.D.

2008 and Beyond2008 and Beyond2008 and Beyond2008 and Beyond

FFRONTIERS IN RONTIERS IN CCARDIOVASCULAR ARDIOVASCULAR CCAREARE::

FFRONTIERS IN RONTIERS IN CCARDIOVASCULAR ARDIOVASCULAR CCAREARE::

Fall 2008Fall 2008

WWHAT HAT FFACTORS ACTORS WWILL ILL IIMPACTMPACTFFUTURE UTURE CCARE?ARE?

WWHAT HAT FFACTORS ACTORS WWILL ILL IIMPACTMPACTFFUTURE UTURE CCARE?ARE?

• Globalization of information / communicationGlobalization of information / communication

• Explosion of scientific knowledge / technologyExplosion of scientific knowledge / technology

• Global economyGlobal economy

• Genetic typingGenetic typing

• Globalization of information / communicationGlobalization of information / communication

• Explosion of scientific knowledge / technologyExplosion of scientific knowledge / technology

• Global economyGlobal economy

• Genetic typingGenetic typing

GGENERAL ENERAL CCARDIAC ARDIAC CCAREAREGGENERAL ENERAL CCARDIAC ARDIAC CCAREARE

• Increased emphasis on qualityIncreased emphasis on quality

• Electronic medical records and communicationElectronic medical records and communication

• Less emphasis on episodic care / more on Less emphasis on episodic care / more on

coordinated, cost-effective managementcoordinated, cost-effective management

• Clearer definition for end-of-line therapiesClearer definition for end-of-line therapies

• Increased emphasis on qualityIncreased emphasis on quality

• Electronic medical records and communicationElectronic medical records and communication

• Less emphasis on episodic care / more on Less emphasis on episodic care / more on

coordinated, cost-effective managementcoordinated, cost-effective management

• Clearer definition for end-of-line therapiesClearer definition for end-of-line therapies

PPREVENTIVE REVENTIVE CCARDIOLOGYARDIOLOGYPPREVENTIVE REVENTIVE CCARDIOLOGYARDIOLOGY

• Identification of new risk factors, particularly Identification of new risk factors, particularly geneticgenetic

• Development of both lifestyle and pharmacologic Development of both lifestyle and pharmacologic treatment menus tailored to genetic “fingerprint”treatment menus tailored to genetic “fingerprint”

• Worsening burden of coronary disease world Worsening burden of coronary disease world wide… “westernization” of fast foods and wide… “westernization” of fast foods and

smokingsmoking

• Identification of new risk factors, particularly Identification of new risk factors, particularly geneticgenetic

• Development of both lifestyle and pharmacologic Development of both lifestyle and pharmacologic treatment menus tailored to genetic “fingerprint”treatment menus tailored to genetic “fingerprint”

• Worsening burden of coronary disease world Worsening burden of coronary disease world wide… “westernization” of fast foods and wide… “westernization” of fast foods and

smokingsmoking

VVASCULAR ASCULAR DDISEASESISEASESVVASCULAR ASCULAR DDISEASESISEASES

• Computerized drug selection for hypertensive Computerized drug selection for hypertensive

managementmanagement

• Expanded use of gene therapyExpanded use of gene therapy

• Expanded use of percutaneous stent therapies Expanded use of percutaneous stent therapies

for occlusive disease in arterial beds for occlusive disease in arterial beds

• Computerized drug selection for hypertensive Computerized drug selection for hypertensive

managementmanagement

• Expanded use of gene therapyExpanded use of gene therapy

• Expanded use of percutaneous stent therapies Expanded use of percutaneous stent therapies

for occlusive disease in arterial beds for occlusive disease in arterial beds

NNON ON IINVASIVE NVASIVE IIMAGINGMAGINGNNON ON IINVASIVE NVASIVE IIMAGINGMAGING

• MRI and CT will reduce much of current-day MRI and CT will reduce much of current-day

angiographyangiography

• Endothelial imaging will allow identification of Endothelial imaging will allow identification of

“hot” areas… plaque, clot, etc.“hot” areas… plaque, clot, etc.

• Contrast echo in 3-D will emerge Contrast echo in 3-D will emerge

• MRI and CT will reduce much of current-day MRI and CT will reduce much of current-day

angiographyangiography

• Endothelial imaging will allow identification of Endothelial imaging will allow identification of

“hot” areas… plaque, clot, etc.“hot” areas… plaque, clot, etc.

• Contrast echo in 3-D will emerge Contrast echo in 3-D will emerge

IINVASIVE NVASIVE TTHERAPIESHERAPIESIINVASIVE NVASIVE TTHERAPIESHERAPIES

• More coronary intervention for acute MI… More coronary intervention for acute MI…

genetic fingerprint will influence choicegenetic fingerprint will influence choice

• Less coronary angiography for stable patients Less coronary angiography for stable patients

as medical / preventative therapies improveas medical / preventative therapies improve

• Local drug delivery on stentsLocal drug delivery on stents

• Smaller, slicker, safer cathetersSmaller, slicker, safer catheters

• More coronary intervention for acute MI… More coronary intervention for acute MI…

genetic fingerprint will influence choicegenetic fingerprint will influence choice

• Less coronary angiography for stable patients Less coronary angiography for stable patients

as medical / preventative therapies improveas medical / preventative therapies improve

• Local drug delivery on stentsLocal drug delivery on stents

• Smaller, slicker, safer cathetersSmaller, slicker, safer catheters

AARRHYTHMIA RRHYTHMIA TTHERAPIESHERAPIESAARRHYTHMIA RRHYTHMIA TTHERAPIESHERAPIES

• Expanded use of catheter based ablationExpanded use of catheter based ablation

• Expanded ability to map arrhythmic fociExpanded ability to map arrhythmic foci

• Smaller, cheaper, more widely used Smaller, cheaper, more widely used

defibrillators defibrillators

• Expanded use of catheter based ablationExpanded use of catheter based ablation

• Expanded ability to map arrhythmic fociExpanded ability to map arrhythmic foci

• Smaller, cheaper, more widely used Smaller, cheaper, more widely used

defibrillators defibrillators

SSCIENTIFIC CIENTIFIC EEMPHASISMPHASISSSCIENTIFIC CIENTIFIC EEMPHASISMPHASIS

• Genetic fingerprints - with ability to match best Genetic fingerprints - with ability to match best

therapy with genetic substratetherapy with genetic substrate

• Miniaturization of technology - defibrillators, Miniaturization of technology - defibrillators,

catheters, robotic surgery, etc.catheters, robotic surgery, etc.

• Vessel wall biology - why disease begins, how to Vessel wall biology - why disease begins, how to

stop it or treat itstop it or treat it

• Bioinformatics - the right information at the right timeBioinformatics - the right information at the right time

• Genetic fingerprints - with ability to match best Genetic fingerprints - with ability to match best

therapy with genetic substratetherapy with genetic substrate

• Miniaturization of technology - defibrillators, Miniaturization of technology - defibrillators,

catheters, robotic surgery, etc.catheters, robotic surgery, etc.

• Vessel wall biology - why disease begins, how to Vessel wall biology - why disease begins, how to

stop it or treat itstop it or treat it

• Bioinformatics - the right information at the right timeBioinformatics - the right information at the right time

SSPECIFIC PECIFIC DDISEASE ISEASE SSTATESTATESSSPECIFIC PECIFIC DDISEASE ISEASE SSTATESTATES

• Diabetes - keys to its’ malignant Diabetes - keys to its’ malignant

vascular diseasevascular disease

• Aging - better clarity of its’ causes and Aging - better clarity of its’ causes and

optimal therapyoptimal therapy

• Women and heart disease - further Women and heart disease - further

definition of optimal choicesdefinition of optimal choices

• Diabetes - keys to its’ malignant Diabetes - keys to its’ malignant

vascular diseasevascular disease

• Aging - better clarity of its’ causes and Aging - better clarity of its’ causes and

optimal therapyoptimal therapy

• Women and heart disease - further Women and heart disease - further

definition of optimal choicesdefinition of optimal choices

The Complexity of Genomics and The Complexity of Genomics and Cardiovascular MedicineCardiovascular Medicine

The Complexity of Genomics and The Complexity of Genomics and Cardiovascular MedicineCardiovascular Medicine

GenesGenes(3 Billion)(3 Billion)

↓↓Single Nucleotide Polymorphisms (SNP’s)Single Nucleotide Polymorphisms (SNP’s)

(10,000,000)(10,000,000)↓↓

Gene Expression Profiles (Transcriptomics)Gene Expression Profiles (Transcriptomics)(20,000)(20,000)

↓↓Protein Arrays of Specific Proteins (Proteomics)Protein Arrays of Specific Proteins (Proteomics)

(100,000)(100,000)↓↓

Metabolic Profiles (Metabolomics)Metabolic Profiles (Metabolomics)(1,000 – 10,000)(1,000 – 10,000)

Examples of Candidate Genes:Examples of Candidate Genes:CAD or MICAD or MI

Examples of Candidate Genes:Examples of Candidate Genes:CAD or MICAD or MI

• Apolipoprotein EApolipoprotein E• Tetrahydrofolate Tetrahydrofolate

Reductase Reductase • Angiotensin Converting Angiotensin Converting

EnzymeEnzyme• Apolipoprotein BApolipoprotein B• Plasminogen Activator Plasminogen Activator

InhibitorInhibitor• Fibrinogen B-ChainFibrinogen B-Chain• Endothelial Nitric OxideEndothelial Nitric Oxide• Connexin 37Connexin 37• Factor VIIFactor VII• ThrombopoetinThrombopoetin

• Apolipoprotein EApolipoprotein E• Tetrahydrofolate Tetrahydrofolate

Reductase Reductase • Angiotensin Converting Angiotensin Converting

EnzymeEnzyme• Apolipoprotein BApolipoprotein B• Plasminogen Activator Plasminogen Activator

InhibitorInhibitor• Fibrinogen B-ChainFibrinogen B-Chain• Endothelial Nitric OxideEndothelial Nitric Oxide• Connexin 37Connexin 37• Factor VIIFactor VII• ThrombopoetinThrombopoetin

• P-22P-22• StromelysinStromelysin• Lymphotoxin-alphaLymphotoxin-alpha• Alpha-adducinAlpha-adducin• Cholesterol Ester Transfer Cholesterol Ester Transfer

ProteinProtein• Paraxonase 1,2Paraxonase 1,2• Apolipoprotein C-IIIApolipoprotein C-III• 5-Lipoxygenase activating 5-Lipoxygenase activating

protein (FLAP)protein (FLAP)• Selectin-PSelectin-P• Thrombospondin 2,4Thrombospondin 2,4• Fibrinogen BFibrinogen B

Protein Biomarkers in CV DiseaseProtein Biomarkers in CV DiseaseProtein Biomarkers in CV DiseaseProtein Biomarkers in CV DiseaseClinical AreaClinical Area BiomarkerBiomarker Current StatusCurrent Status

In Clinical UseIn Clinical Use Emerging Clinical UseEmerging Clinical Use

Myocardial NecrosisMyocardial Necrosis• • Troponin I, TTroponin I, T XX• • Creatinine Kinase-MBCreatinine Kinase-MB XX• • MyoglobinMyoglobin XX

Hemodynamic StatusHemodynamic Status• • B-type natriuretic peptideB-type natriuretic peptide XX• • N-terminal pro-BNPN-terminal pro-BNP XX

IschemiaIschemia• • Unbound free fatty acidsUnbound free fatty acids XX• • Ischemia modified albuminIschemia modified albumin XX• • Whole blood cholineWhole blood choline XX• • BNPBNP XX

Inflammation/Inflammation/Plaque StabilityPlaque Stability • HS-CRP• HS-CRP X X

• • IL-6, 10, 18IL-6, 10, 18 XXXXXX• • CD-40 LigandCD-40 Ligand XX• • MyeloperoxidaseMyeloperoxidase XX• • MMP’sMMP’s XX

K. Eagle

Clinico-genomic Biosignatures to Predict Health, Clinico-genomic Biosignatures to Predict Health, Disease and Environmental Drug ResponseDisease and Environmental Drug Response

Clinico-genomic Biosignatures to Predict Health, Clinico-genomic Biosignatures to Predict Health, Disease and Environmental Drug ResponseDisease and Environmental Drug Response

Gene Expression ProfilesGene Expression Profiles

Clinical DataClinical DataTreatmentsTreatmentsFamily HistoryFamily HistoryDemographicsDemographicsEnvironmentalEnvironmental

Genomic DataGenomic DataSNPsSNPsGenome-scale sequenceGenome-scale sequence

ImagingImaging

Metabolic DataMetabolic DataProteomic DataProteomic Data

??

PatternsPatternsIntegrationIntegration

ModelsModels

Predictions:Predictions:RiskRisk

Individualized Prognosis & DiagnosisIndividualized Prognosis & DiagnosisDrug ResponseDrug Response

Environment (e.g. Diet) ResponseEnvironment (e.g. Diet) ResponseK. Eagle

What Genomics May BringWhat Genomics May Bringto Cardiovascular Medicineto Cardiovascular MedicineWhat Genomics May BringWhat Genomics May Bringto Cardiovascular Medicineto Cardiovascular Medicine

• Clinical use of genomic variation to predict health Clinical use of genomic variation to predict health and disease in individuals, communities, and and disease in individuals, communities, and whole populationswhole populations

• Incorporation of the complex interplay of genes Incorporation of the complex interplay of genes and the environment vis-and the environment vis-à-vis patient care, à-vis patient care, whether that environment be cellular, industrial or whether that environment be cellular, industrial or socioeconomicsocioeconomic

• Integration of precise phenotypic data with Integration of precise phenotypic data with equally precise genotypic data in a equally precise genotypic data in a comprehensive computationally robust clinical comprehensive computationally robust clinical frameworkframework

• Clinical use of genomic variation to predict health Clinical use of genomic variation to predict health and disease in individuals, communities, and and disease in individuals, communities, and whole populationswhole populations

• Incorporation of the complex interplay of genes Incorporation of the complex interplay of genes and the environment vis-and the environment vis-à-vis patient care, à-vis patient care, whether that environment be cellular, industrial or whether that environment be cellular, industrial or socioeconomicsocioeconomic

• Integration of precise phenotypic data with Integration of precise phenotypic data with equally precise genotypic data in a equally precise genotypic data in a comprehensive computationally robust clinical comprehensive computationally robust clinical frameworkframework

What Genomics May BringWhat Genomics May Bringto Cardiovascular Medicineto Cardiovascular MedicineWhat Genomics May BringWhat Genomics May Bringto Cardiovascular Medicineto Cardiovascular Medicine

• Development of state-of-the-art technologies that Development of state-of-the-art technologies that assess the activity of large portions of the genome, assess the activity of large portions of the genome, transcriptome, proteome, and metabolometranscriptome, proteome, and metabolome

• Utilization of genomic information to streamline drug Utilization of genomic information to streamline drug development and improve our understanding of drug development and improve our understanding of drug safety, tolerance and efficacysafety, tolerance and efficacy

• Discussion of the ethical, legal and policy issues Discussion of the ethical, legal and policy issues raised by the integration of the genome sciences into raised by the integration of the genome sciences into the practice of medicinethe practice of medicine

• Fundamentally alter the way in which health care is Fundamentally alter the way in which health care is delivered and practiced in order to optimize care and delivered and practiced in order to optimize care and reduce costs overallreduce costs overall

• Development of state-of-the-art technologies that Development of state-of-the-art technologies that assess the activity of large portions of the genome, assess the activity of large portions of the genome, transcriptome, proteome, and metabolometranscriptome, proteome, and metabolome

• Utilization of genomic information to streamline drug Utilization of genomic information to streamline drug development and improve our understanding of drug development and improve our understanding of drug safety, tolerance and efficacysafety, tolerance and efficacy

• Discussion of the ethical, legal and policy issues Discussion of the ethical, legal and policy issues raised by the integration of the genome sciences into raised by the integration of the genome sciences into the practice of medicinethe practice of medicine

• Fundamentally alter the way in which health care is Fundamentally alter the way in which health care is delivered and practiced in order to optimize care and delivered and practiced in order to optimize care and reduce costs overallreduce costs overall

CCHALLENGES HALLENGES YYOU’LL OU’LL FFACEACECCHALLENGES HALLENGES YYOU’LL OU’LL FFACEACE

• Ethics - genetic hair color… “bad person, Ethics - genetic hair color… “bad person,

good person”good person”

• End - of - life medical spendingEnd - of - life medical spending

• 2 - class health system2 - class health system

• Cost - widening gap between what we can Cost - widening gap between what we can

afford to give all citizens vs. what’s available afford to give all citizens vs. what’s available

to give one (wealthy) citizento give one (wealthy) citizen

• Ethics - genetic hair color… “bad person, Ethics - genetic hair color… “bad person,

good person”good person”

• End - of - life medical spendingEnd - of - life medical spending

• 2 - class health system2 - class health system

• Cost - widening gap between what we can Cost - widening gap between what we can

afford to give all citizens vs. what’s available afford to give all citizens vs. what’s available

to give one (wealthy) citizento give one (wealthy) citizen

CCHALLENGESHALLENGESCCHALLENGESHALLENGES

• Human cloningHuman cloning

• Organ cloningOrgan cloning

• Disease identification years before its developmentDisease identification years before its development

• Defining the degree of environmental influence on Defining the degree of environmental influence on diseasedisease

• ““Shaping human behavior: the cardiology - general Shaping human behavior: the cardiology - general has determined that has determined that french friesfrench fries are bad for your are bad for your health”health”

• Human cloningHuman cloning

• Organ cloningOrgan cloning

• Disease identification years before its developmentDisease identification years before its development

• Defining the degree of environmental influence on Defining the degree of environmental influence on diseasedisease

• ““Shaping human behavior: the cardiology - general Shaping human behavior: the cardiology - general has determined that has determined that french friesfrench fries are bad for your are bad for your health”health”

OOPPORTUNITIESPPORTUNITIESOOPPORTUNITIESPPORTUNITIES

• No generation has had more opportunity to No generation has had more opportunity to

change health care than yours willchange health care than yours will

• The new science, genomics, will allow The new science, genomics, will allow

“diagnostics and therapeutics of mind-boggling “diagnostics and therapeutics of mind-boggling

proportion”proportion”

• Globalization of science creates an opportunity Globalization of science creates an opportunity

for a kinder, more gentle worldfor a kinder, more gentle world

• No generation has had more opportunity to No generation has had more opportunity to

change health care than yours willchange health care than yours will

• The new science, genomics, will allow The new science, genomics, will allow

“diagnostics and therapeutics of mind-boggling “diagnostics and therapeutics of mind-boggling

proportion”proportion”

• Globalization of science creates an opportunity Globalization of science creates an opportunity

for a kinder, more gentle worldfor a kinder, more gentle world

EEPILOGUEPILOGUEEEPILOGUEPILOGUE

““The faculty consider it a great honor The faculty consider it a great honor

to participate in your education. Best to participate in your education. Best

wishes for your continued success. wishes for your continued success.

You will carry the work that we have You will carry the work that we have

started.”started.”

““The faculty consider it a great honor The faculty consider it a great honor

to participate in your education. Best to participate in your education. Best

wishes for your continued success. wishes for your continued success.

You will carry the work that we have You will carry the work that we have

started.”started.”

“There are those who just wander

about the wards and those who do

the doctoring. The difference is

having (and using) the data.”Eugene Stead, 1960’s

“There are those who just wander

about the wards and those who do

the doctoring. The difference is

having (and using) the data.”Eugene Stead, 1960’s

““Never doubt that a small group of thoughtful, Never doubt that a small group of thoughtful,

committed people can change the world. committed people can change the world.

Indeed, it is the only thing that ever has.”Indeed, it is the only thing that ever has.”

MeadMead

““Never doubt that a small group of thoughtful, Never doubt that a small group of thoughtful,

committed people can change the world. committed people can change the world.

Indeed, it is the only thing that ever has.”Indeed, it is the only thing that ever has.”

MeadMead

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Slide 15: K. EagleSlide 16: K. EagleSlide 15: K. EagleSlide 16: K. Eagle