59 results on '"Eric J Topol"'
Search Results
2. Lateral flow test engineering and lessons learned from COVID-19
- Author
-
Jobie Budd, Benjamin S. Miller, Nicole E. Weckman, Dounia Cherkaoui, Da Huang, Alyssa Thomas Decruz, Noah Fongwen, Gyeo-Re Han, Marta Broto, Claudia S. Estcourt, Jo Gibbs, Deenan Pillay, Pam Sonnenberg, Robyn Meurant, Michael R. Thomas, Neil Keegan, Molly M. Stevens, Eleni Nastouli, Eric J. Topol, Anne M. Johnson, Maryam Shahmanesh, Aydogan Ozcan, James J. Collins, Marta Fernandez Suarez, Bill Rodriguez, Rosanna W. Peeling, and Rachel A. McKendry
- Published
- 2023
3. Multimodal biomedical AI
- Author
-
Julián N. Acosta, Guido J. Falcone, Pranav Rajpurkar, and Eric J. Topol
- Subjects
General Medicine ,General Biochemistry, Genetics and Molecular Biology - Published
- 2022
4. Self-supervised learning in medicine and healthcare
- Author
-
Rayan Krishnan, Pranav Rajpurkar, and Eric J. Topol
- Subjects
Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Computer Science Applications ,Biotechnology - Abstract
The development of medical applications of machine learning has required manual annotation of data, often by medical experts. Yet, the availability of large-scale unannotated data provides opportunities for the development of better machine-learning models. In this Review, we highlight self-supervised methods and models for use in medicine and healthcare, and discuss the advantages and limitations of their application to tasks involving electronic health records and datasets of medical images, bioelectrical signals, and sequences and structures of genes and proteins. We also discuss promising applications of self-supervised learning for the development of models leveraging multimodal datasets, and the challenges in collecting unbiased data for their training. Self-supervised learning may accelerate the development of medical artificial intelligence.
- Published
- 2022
5. Smartphone apps in the COVID-19 pandemic
- Author
-
Jay A. Pandit, Jennifer M. Radin, Giorgio Quer, and Eric J. Topol
- Subjects
Biomedical Engineering ,Molecular Medicine ,Bioengineering ,Applied Microbiology and Biotechnology ,Biotechnology - Published
- 2022
6. Author Correction: Long COVID: major findings, mechanisms and recommendations
- Author
-
Hannah E. Davis, Lisa McCorkell, Julia Moore Vogel, and Eric J. Topol
- Subjects
Infectious Diseases ,General Immunology and Microbiology ,Microbiology - Published
- 2023
7. The digital phenotype of vaccination
- Author
-
Giorgio Quer, Eric J. Topol, and Steven R. Steinhubl
- Subjects
Biomedical Engineering ,Molecular Medicine ,Bioengineering ,Applied Microbiology and Biotechnology ,Biotechnology - Published
- 2022
8. Inter-individual variation in objective measure of reactogenicity following COVID-19 vaccination via smartwatches and fitness bands
- Author
-
Giorgio Quer, Matteo Gadaleta, Jennifer M. Radin, Kristian G. Andersen, Katie Baca-Motes, Edward Ramos, Eric J. Topol, and Steven R. Steinhubl
- Subjects
Health Information Management ,Medicine (miscellaneous) ,Health Informatics ,Article ,Computer Science Applications - Abstract
The ability to identify who does or does not experience the intended immune response following vaccination could be of great value in not only managing the global trajectory of COVID-19 but also helping guide future vaccine development. Vaccine reactogenicity can potentially lead to detectable physiologic changes, thus we postulated that we could detect an individual’s initial physiologic response to a vaccine by tracking changes relative to their pre-vaccine baseline using consumer wearable devices. We explored this possibility using a smartphone app-based research platform that enabled volunteers (39,701 individuals) to share their smartwatch data, as well as self-report, when appropriate, any symptoms, COVID-19 test results, and vaccination information. Of 7728 individuals who reported at least one vaccination dose, 7298 received an mRNA vaccine, and 5674 provided adequate data from the peri-vaccine period for analysis. We found that in most individuals, resting heart rate (RHR) increased with respect to their individual baseline after vaccination, peaked on day 2, and returned to normal by day 6. This increase in RHR was greater than one standard deviation above individuals’ normal daily pattern in 47% of participants after their second vaccine dose. Consistent with other reports of subjective reactogenicity following vaccination, we measured a significantly stronger effect after the second dose relative to the first, except those who previously tested positive to COVID-19, and a more pronounced increase for individuals who received the Moderna vaccine. Females, after the first dose only, and those aged
- Published
- 2022
9. Passive detection of COVID-19 with wearable sensors and explainable machine learning algorithms
- Author
-
Steven R. Steinhubl, Eric J. Topol, Vik Kheterpal, Matteo Gadaleta, Katie Baca-Motes, Giorgio Quer, Jennifer M. Radin, and Edward Ramos
- Subjects
Coronavirus disease 2019 (COVID-19) ,business.industry ,Computer applications to medicine. Medical informatics ,Decision tree ,R858-859.7 ,Wearable computer ,Medicine (miscellaneous) ,Health Informatics ,Predictive analytics ,Asymptomatic ,Article ,Computer Science Applications ,Health Information Management ,Feature (computer vision) ,Cohort ,Medicine ,Infectious diseases ,Gradient boosting ,medicine.symptom ,business ,Algorithm ,Biomarkers - Abstract
Individual smartwatch or fitness band sensor data in the setting of COVID-19 has shown promise to identify symptomatic and pre-symptomatic infection or the need for hospitalization, correlations between peripheral temperature and self-reported fever, and an association between changes in heart-rate-variability and infection. In our study, a total of 38,911 individuals (61% female, 15% over 65) have been enrolled between March 25, 2020 and April 3, 2021, with 1,118 reported testing positive and 7,032 negative for COVID-19 by nasopharyngeal PCR swab test. We propose an explainable gradient boosting prediction model based on decision trees for the detection of COVID-19 infection that can adapt to the absence of self-reported symptoms and to the available sensor data, and that can explain the importance of each feature and the post-test-behavior for the individuals. We tested it in a cohort of symptomatic individuals who exhibited an AUC of 0.83 [0.81-0.85], or AUC=0.78 [0.75-0.80] when considering only data before the test date, outperforming state-of-the-art algorithm in these conditions. The analysis of all individuals (including asymptomatic and pre-symptomatic) when self-reported symptoms were excluded provided an AUC of 0.78 [0.76-0.79], or AUC of 0.70 [0.69-0.72] when considering only data before the test date. Extending the use of predictive algorithms for detection of COVID-19 infection based only on passively monitored data from any device, we showed that it is possible to scale up this platform and apply the algorithm in other settings where self-reported symptoms can not be collected.
- Published
- 2021
10. Variant-proof vaccines — invest now for the next pandemic
- Author
-
Dennis R. Burton and Eric J. Topol
- Subjects
0301 basic medicine ,2019-20 coronavirus outbreak ,Multidisciplinary ,Coronavirus disease 2019 (COVID-19) ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,digestive, oral, and skin physiology ,05 social sciences ,food and beverages ,AIDS Vaccines ,Virology ,03 medical and health sciences ,030104 developmental biology ,0502 economics and business ,Pandemic ,Business ,050207 economics ,Prevention control ,health care economics and organizations ,Disaster planning - Abstract
COVID’s evolution signals the importance of rational vaccine design based on broadly neutralizing antibodies. COVID’s evolution signals the importance of rational vaccine design based on broadly neutralizing antibodies.
- Published
- 2021
11. Welcoming new guidelines for AI clinical research
- Author
-
Eric J. Topol
- Subjects
0301 basic medicine ,Computer science ,media_common.quotation_subject ,Interpretation (philosophy) ,Clinical study design ,MEDLINE ,Translational research ,General Medicine ,Data science ,General Biochemistry, Genetics and Molecular Biology ,Field (computer science) ,Clinical trial ,03 medical and health sciences ,Presentation ,030104 developmental biology ,0302 clinical medicine ,Clinical research ,030220 oncology & carcinogenesis ,media_common - Abstract
With only a limited number of clinical trials of artificial intelligence in medicine thus far, the first guidelines for protocols and reporting arrive at an opportune time. Better protocol design, along with consistent and complete data presentation, will greatly facilitate interpretation and validation of these trials, and will help the field to move forward.
- Published
- 2020
12. We were warned what to expect in the pandemic, shows health-care league table
- Author
-
Eric J. Topol
- Subjects
Economic growth ,Multidisciplinary ,business.industry ,League table ,Political science ,Pandemic ,Health care ,Health insurance ,business ,Ranking (information retrieval) - Abstract
Germany and Taiwan top a ranking drawn up pre-crisis by architect of US Affordable Care Act; United States trails behind. Germany and Taiwan top a ranking drawn up pre-crisis by architect of US Affordable Care Act; United States trails behind.
- Published
- 2020
13. Mechanical activation of noncoding-RNA-mediated regulation of disease-associated phenotypes in human cardiomyocytes
- Author
-
Eric J. Topol, Yang-Hsun Hou, Aditya Kumar, Stephanie Thomas, Valentina Lo Sardo, Kevin Tenerelli, Kirsten C. Wong, Jesse K. Placone, Ali Torkamani, William C. Ferguson, Adam J. Engler, Kristin K. Baldwin, and Daniel S Cheah
- Subjects
0301 basic medicine ,Gene isoform ,Cardiac fibrosis ,Biomedical Engineering ,Medicine (miscellaneous) ,Bioengineering ,Biology ,Cardiovascular ,Regenerative Medicine ,Article ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Genetics ,medicine ,2.1 Biological and endogenous factors ,Allele ,Induced pluripotent stem cell ,Gene ,Stem Cell Research - Induced Pluripotent Stem Cell ,Stem Cell Research - Induced Pluripotent Stem Cell - Human ,Kinase ,Human Genome ,Stem Cell Research ,medicine.disease ,Non-coding RNA ,Phenotype ,Computer Science Applications ,Cell biology ,Heart Disease ,030104 developmental biology ,030217 neurology & neurosurgery ,Biotechnology - Abstract
How common polymorphisms in noncoding genome regions can regulate cellular function remains largely unknown. Here we show that cardiac fibrosis, mimicked using a hydrogel with controllable stiffness, affects the regulation of the phenotypes of human cardiomyocytes by a portion of the long noncoding RNA ANRIL, the gene of which is located in the disease-associated 9p21 locus. In a physiological environment, cultured cardiomyocytes derived from induced pluripotent stem cells obtained from patients who are homozygous for cardiovascular-risk alleles (R/R cardiomyocytes) or from healthy individuals who are homozygous for nonrisk alleles contracted synchronously, independently of genotype. After hydrogel stiffening to mimic fibrosis, only the R/R cardiomyocytes exhibited asynchronous contractions. These effects were associated with increased expression of the short ANRIL isoform in R/R cardiomyocytes, which induced a c-Jun N-terminal kinase (JNK) phosphorylation-based mechanism that impaired gap junctions (particularly, loss of connexin-43 expression) following stiffening. Deletion of the risk locus or treatment with a JNK antagonist was sufficient to maintain gap junctions and prevent asynchronous contraction of cardiomyocytes. Our findings suggest that mechanical changes in the microenvironment of cardiomyocytes can activate the regulation of their function by noncoding loci.
- Published
- 2019
14. Toward superhuman SARS-CoV-2 immunity?
- Author
-
Eric J. Topol and Dennis R. Burton
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,Immunity ,business.industry ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,Medicine ,General Medicine ,business ,Virology ,General Biochemistry, Genetics and Molecular Biology - Published
- 2020
- Full Text
- View/download PDF
15. Has SARS-CoV-2 reached peak fitness?
- Author
-
Eric J. Topol, Roberto Burioni, Burioni, R., and Topol, E. J.
- Subjects
2019-20 coronavirus outbreak ,Coronavirus disease 2019 (COVID-19) ,SARS-CoV-2 ,Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ,COVID-19 ,General Medicine ,Biological evolution ,Biology ,Biological Evolution ,Virology ,General Biochemistry, Genetics and Molecular Biology ,Mutation ,Host-Pathogen Interactions ,Mutation (genetic algorithm) ,Humans ,Immune Evasion - Published
- 2021
16. Stop the privatization of health data
- Author
-
Eric J. Topol and John Wilbanks
- Subjects
020205 medical informatics ,050801 communication & media studies ,Patient Advocacy ,02 engineering and technology ,Public administration ,Patient advocacy ,0508 media and communications ,Health care ,0202 electrical engineering, electronic engineering, information engineering ,Civil Rights ,Data Mining ,Electronic Health Records ,Humans ,media_common.cataloged_instance ,Confidentiality ,European Union ,European union ,Health policy ,Monitoring, Physiologic ,media_common ,Patient Access to Records ,HRHIS ,Multidisciplinary ,Information Dissemination ,business.industry ,05 social sciences ,United States ,Health promotion ,Harm ,Government Regulation ,business ,Algorithms - Abstract
Tech giants moving into health may widen inequalities and harm research, unless people can access and share their data, warn John T. Wilbanks and Eric J. Topol.
- Published
- 2016
17. With an eye to AI and autonomous diagnosis
- Author
-
Eric J. Topol and Pearse A. Keane
- Subjects
Preventive medicine ,medicine.medical_specialty ,business.industry ,010102 general mathematics ,Medicine (miscellaneous) ,Health Informatics ,lcsh:Computer applications to medicine. Medical informatics ,01 natural sciences ,Computer Science Applications ,law.invention ,03 medical and health sciences ,Editorial ,0302 clinical medicine ,Health Information Management ,Randomized controlled trial ,law ,Randomized controlled trials ,Physical therapy ,medicine ,lcsh:R858-859.7 ,030212 general & internal medicine ,0101 mathematics ,business ,Preventive healthcare - Published
- 2018
18. From reproduction to the right to die: bioethics now
- Author
-
Eric J. Topol
- Subjects
Right to die ,Government ,Multidisciplinary ,Political science ,Law ,Reproduction (economics) ,Field (Bourdieu) ,Bioethics - Abstract
Eric J. Topol weighs up a book on a field sprinting to keep up with biotechnology. Eric J. Topol weighs up a book on a field sprinting to keep up with biotechnology.
- Published
- 2019
19. Unpatients—why patients should own their medical data
- Author
-
Eric J. Topol and Leonard J. Kish
- Subjects
Medical education ,Extramural ,Biomedical Engineering ,MEDLINE ,Bioengineering ,Digital medicine ,Health records ,Personal autonomy ,Applied Microbiology and Biotechnology ,Molecular Medicine ,Confidentiality ,Personal health ,Psychology ,Biotechnology - Abstract
For the benefits of digital medicine to be fully realized, we need not only to find a shared home for personal health data but also to give individuals the right to own them.
- Published
- 2015
20. A skin patch for sensing blood pressures
- Author
-
Eric J. Topol and Steven R. Steinhubl
- Subjects
ComputerSystemsOrganization_COMPUTERSYSTEMIMPLEMENTATION ,Transdermal patch ,ComputingMethodologies_IMAGEPROCESSINGANDCOMPUTERVISION ,Biomedical Engineering ,Transdermal Patch ,Medicine (miscellaneous) ,Wearable computer ,Blood Pressure ,Bioengineering ,030204 cardiovascular system & hematology ,01 natural sciences ,law.invention ,03 medical and health sciences ,0302 clinical medicine ,law ,Humans ,Medicine ,Monitoring, Physiologic ,Skin ,Blood pressure monitors ,business.industry ,010401 analytical chemistry ,Continuous monitoring ,Ultrasound ,Intensive care unit ,Blood Pressure Monitors ,0104 chemical sciences ,Computer Science Applications ,Skin patch ,business ,Biotechnology ,Biomedical engineering - Abstract
A wearable ultrasound patch enables the continuous monitoring of cardiovascular performance outside the intensive care unit.
- Published
- 2018
21. Blood, sweat and tears in biotech — the Theranos story
- Author
-
Eric J. Topol
- Subjects
body regions ,030213 general clinical medicine ,03 medical and health sciences ,0302 clinical medicine ,Multidisciplinary ,parasitic diseases ,education ,0502 economics and business ,05 social sciences ,Art history ,Tears ,human activities ,050203 business & management - Abstract
Eric Topol extols a gripping account of the rise and fall of the US medical-testing company. Eric Topol extols a gripping account of the rise and fall of the US medical-testing company.
- Published
- 2018
22. Pharmacogenomics in clinical practice and drug development
- Author
-
Eric J. Topol and Andrew R. Harper
- Subjects
Biomedical Engineering ,Bioengineering ,Genome-wide association study ,Bioinformatics ,Applied Microbiology and Biotechnology ,Article ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Medical prescription ,Exome ,business.industry ,Chromosome Mapping ,Sequence Analysis, DNA ,Odds ratio ,Clopidogrel ,Drug development ,Pharmacogenetics ,Drug Design ,Pharmacogenomics ,Molecular Medicine ,business ,Biotechnology ,medicine.drug - Abstract
Genome-wide association studies (GWAS) of responses to drugs, including clopidogrel, pegylated-interferon and carbamazepine, have led to the identification of specific patient subgroups that benefit from therapy. However, the identification and replication of common sequence variants that are associated with either efficacy or safety for most prescription medications at odds ratios (ORs) >3.0 (equivalent to >300% increased efficacy or safety) has yet to be translated to clinical practice. Although some of the studies have been completed, the results have not been incorporated into therapy, and a large number of commonly used medications have not been subject to proper pharmacogenomic analysis. Adoption of GWAS, exome or whole genome sequencing by drug development and treatment programs is the most striking near-term opportunity for improving the drug candidate pipeline and boosting the efficacy of medications already in use.
- Published
- 2012
23. The importance of phase information for human genomics
- Author
-
Eric J. Topol, Vikas Bansal, Ali Torkamani, Ryan Tewhey, and Nicholas J. Schork
- Subjects
Genetics ,Comparative genomics ,Genomics ,Genome project ,Computational biology ,Biology ,ENCODE ,Genome ,Article ,Human genome ,Molecular Biology ,Functional genomics ,Genetics (clinical) ,Personal genomics - Abstract
Contemporary sequencing studies often ignore the diploid nature of the human genome because they do not routinely separate or ‘phase’ maternally and paternally derived sequence information. However, many findings — both from recent studies and in the more established medical genetics literature — indicate that relationships between human DNA sequence and phenotype, including disease, can be more fully understood with phase information. Thus, the existing technological impediments to obtaining phase information must be overcome if human genomics is to reach its full potential.
- Published
- 2011
24. Common variants in KCNN3 are associated with lone atrial fibrillation
- Author
-
Gerhard Steinbeck, John Barnard, Dan M. Roden, Tamara B. Harris, Calum A. MacRae, Moritz F. Sinner, David R. Van Wagoner, Lenore J. Launer, Seiko Makino, Eric J. Topol, Siegfried Perz, Thomas J. Wang, Aravinda Chakravarti, Ke Wang, Kathryn L. Lunetta, Markus M. Nöthen, Mina K. Chung, Elsayed Z. Soliman, Stefan Kääb, David J. Milan, Mari Nelis, Stanley L. Hazen, Arne Pfeufer, Thomas Meitinger, Daniel Levy, Dawood Darbar, Susanne Moebus, Andres Metspalu, Jacqueline C.M. Witteman, Vilmundur Gudnason, Jonathan D. Smith, Albert Hofman, Anna Köttgen, Susan R. Heckbert, Paul I.W. de Bakker, Emelia J. Benjamin, Kenneth Rice, Britt-M. Beckmann, Ramachandran S. Vasan, Charlotte van Noord, Eric Boerwinkle, Stefan Möhlenkamp, Martina Mueller, Bruce M. Psaty, Alvaro Alonso, Dan E. Arking, H.-Erich Wichmann, Christopher Newton-Cheh, Man Li, Nicole L. Glazer, André G. Uitterlinden, Georg Ehret, Tõnu Esko, Bruno H. Stricker, Nicholas L. Smith, W. H. Linda Kao, Albert V. Smith, Steven A. Lubitz, Jerome I. Rotter, Patrick T. Ellinor, Renate B. Schnabel, Ervin R. Fox, Epidemiology, and Internal Medicine
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Heart disease ,Small-Conductance Calcium-Activated Potassium Channels ,Medizin ,Genome-wide association study ,Biology ,Polymorphism, Single Nucleotide ,Article ,Cohort Studies ,Young Adult ,Meta-Analysis as Topic ,Polymorphism (computer science) ,Internal medicine ,Atrial Fibrillation ,Genetics ,medicine ,Humans ,Aged ,Genetic association ,Case-control study ,Atrial fibrillation ,Odds ratio ,Middle Aged ,medicine.disease ,Introns ,Endocrinology ,Case-Control Studies ,Cardiology ,Female ,Genome-Wide Association Study ,Cohort study - Abstract
Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.
- Published
- 2010
25. Microdroplet-based PCR enrichment for large-scale targeted sequencing
- Author
-
Masakazu Nakano, Kelly A. Frazer, Michael L. Samuels, Jonathan W. Larson, Martina Medkova, Eric J. Topol, J. Brian Hutchison, Brian Libby, Ryan Tewhey, Darren R. Link, Olivier Harismendy, Jeff Olson, Michael P. Weiner, Jason Warner, Patricia H David, and Steve K. Kotsopoulos
- Subjects
Microfluidics ,Biomedical Engineering ,Bioengineering ,02 engineering and technology ,Biology ,Polymerase Chain Reaction ,Applied Microbiology and Biotechnology ,Genome ,Article ,law.invention ,03 medical and health sciences ,chemistry.chemical_compound ,law ,Genetic variation ,Humans ,Gene ,Polymerase chain reaction ,030304 developmental biology ,Genetics ,0303 health sciences ,Base Sequence ,Reproducibility of Results ,Sequence Analysis, DNA ,Amplicon ,021001 nanoscience & nanotechnology ,chemistry ,Mutation ,Molecular Medicine ,Human genome ,0210 nano-technology ,DNA ,Biotechnology - Abstract
Targeted sequencing of specific loci of the human genome is a promising approach for maximizing the efficiency of second-generation sequencing technologies for population-based studies of genetic variation. Here we describe microdroplet PCR, which performs 1.5 million separate amplifications in parallel, as an approach for enriching targeted sequences in the human genome. We initially designed primers to 435 exons of 47 genes that were selected for having a broad spectrum of sequence characteristics. Using this primer set we amplified the same six samples by both microdroplet and traditional singleplex PCR and sequenced the products using the Illumina GAII demonstrating that both methods generate similarly high quality data; 84% of the uniquely mapping reads fell within the targeted sequences, uniform coverage of ~90% of the targeted bases, greater than 99% accuracy in sequence variant calls, and high reproducibility between different samples (r2=0.9). We next scaled the microdroplet PCR to 3976 amplicons totaling 1.49 Mb of sequence, sequenced the resulting sample on both the Illumina GAII and Roche 454 platforms, and obtained data with equally high specificity and sensitivity quality. Our results demonstrate that microdroplet technology is well suited for processing DNA for massively parallel amplification of specific subsets of the human genome for targeted sequencing.
- Published
- 2009
26. Human genetic variation and its contribution to complex traits
- Author
-
Kelly A. Frazer, Eric J. Topol, Nicholas J. Schork, and Sarah S. Murray
- Subjects
Genetics ,Base Sequence ,Genotype ,Genome, Human ,Molecular Sequence Data ,Genetic Variation ,Genome-wide association study ,Single-nucleotide polymorphism ,Human genetic variation ,Phenotypic trait ,Biology ,Polymorphism, Single Nucleotide ,Phenotype ,Linkage Disequilibrium ,Evolutionary biology ,Genetic variation ,Trait ,Humans ,Genetic Predisposition to Disease ,Genetic variability ,Molecular Biology ,Genetics (clinical) ,Genome-Wide Association Study - Abstract
The last few years have seen extensive efforts to catalogue human genetic variation and correlate it with phenotypic differences. Most common SNPs have now been assessed in genome-wide studies for statistical associations with many complex traits, including many important common diseases. Although these studies have provided new biological insights, only a limited amount of the heritable component of any complex trait has been identified and it remains a challenge to elucidate the functional link between associated variants and phenotypic traits. Technological advances, such as the ability to detect rare and structural variants, and a clear understanding of the challenges in linking different types of variation with phenotype, will be essential for future progress.
- Published
- 2009
27. The use of high-sensitivity assays for C-reactive protein in clinical practice
- Author
-
Richard A. Lange, Milind Y. Desai, Ty J. Gluckman, Valentin Fuster, Brian G. Kral, James T. Willerson, Roger S. Blumenthal, Samia Mora, Kiran Musunuru, Catherine Y. Campbell, Michael H. Davidson, and Eric J. Topol
- Subjects
Male ,Oncology ,medicine.medical_specialty ,Cost-Benefit Analysis ,Disease ,Risk Assessment ,Sensitivity and Specificity ,Asymptomatic ,Article ,Diabetes Complications ,Predictive Value of Tests ,Risk Factors ,Internal medicine ,Secondary Prevention ,Humans ,Medicine ,cardiovascular diseases ,Aged ,Metabolic Syndrome ,Aspirin ,biology ,business.industry ,C-reactive protein ,nutritional and metabolic diseases ,Cholesterol, LDL ,General Medicine ,Middle Aged ,Clinical Practice ,C-Reactive Protein ,Cardiovascular Diseases ,Predictive value of tests ,Hypertension ,biology.protein ,Physical therapy ,Female ,Hydroxymethylglutaryl-CoA Reductase Inhibitors ,Inflammation Mediators ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Inflammatory biomarker ,Risk assessment ,Risk Reduction Behavior ,Biomarkers ,medicine.drug - Abstract
Measurement of the inflammatory biomarker high sensitivity C-reaction protein (hsCRP) has been proposed for assessment of risk for cardiovascular disease (CVD). It remains unclear which patient populations would benefit from and should be targeted for hsCRP testing. Current data indicate that hsCRP levels are independently associated with risk of CVD, including both coronary events and stroke, in various asymptomatic populations; add predictive power to current coronary risk scores for some intermediate risk individuals; and are associated with clinical outcomes in high risk individuals treated with statin therapy. HsCRP levels are also associated with incident diabetes and CVD outcomes in patients with the metabolic syndrome. There is a growing body of evidence to support recommendations for measurement of hsCRP in selected asymptomatic individuals deemed to be at intermediate risk of CVD according to traditional risk factor assessment and who do not already warrant treatment with chronic aspirin and statin therapy, and selected secondary CVD prevention patients for further risk stratification in combination with LDL cholesterol.
- Published
- 2008
28. The genetics of health
- Author
-
Eric J. Topol and Joseph H. Nadeau
- Subjects
Genetics ,Drug-Related Side Effects and Adverse Reactions ,Genetics, Medical ,Incidence (epidemiology) ,Genetic Variation ,Disease ,Biology ,Biological Evolution ,Pharmacogenetics ,Humans ,Genetic Predisposition to Disease ,Selection, Genetic ,Allele ,Modifier Genes - Abstract
Recent experience with several high-profile drugs demonstrates the great challenges in developing effective and safe therapeutics. A complementary approach to the popular paradigm of disease genetics is based on inherited factors that reduce the incidence and severity of disease among individuals who are genetically predisposed to disease. We propose testing specifically for modifier genes and protective alleles among at-risk individuals and studying the efficacy of therapeutics based on the genetics of health.
- Published
- 2006
29. Assessing the impact of population stratification on genetic association studies
- Author
-
Stacey Gabriel, Laurence N. Kolonel, Matthew L. Freedman, David Altshuler, Michele T. Pato, Eric J. Topol, Andre A. Mignault, Pamela Sklar, Carlos N. Pato, Gavin J. McDonald, Brian E. Henderson, Nick Patterson, Tracey L. Petryshen, Joel N. Hirschhorn, Jordan W. Smoller, David Reich, Eric S. Lander, and Kathryn L. Penney
- Subjects
Genetics ,Mutation, Missense ,Population genetics ,Disease ,Biology ,Population stratification ,Polymorphism, Single Nucleotide ,Stratification (mathematics) ,Cohort Studies ,Genetics, Population ,Genetic marker ,Case-Control Studies ,Humans ,Genotyping ,Allele frequency ,Genetic association ,Demography - Abstract
Population stratification refers to differences in allele frequencies between cases and controls due to systematic differences in ancestry rather than association of genes with disease. It has been proposed that false positive associations due to stratification can be controlled by genotyping a few dozen unlinked genetic markers. To assess stratification empirically, we analyzed data from 11 case-control and case-cohort association studies. We did not detect statistically significant evidence for stratification but did observe that assessments based on a few dozen markers lack power to rule out moderate levels of stratification that could cause false positive associations in studies designed to detect modest genetic risk factors. After increasing the number of markers and samples in a case-cohort study (the design most immune to stratification), we found that stratification was in fact present. Our results suggest that modest amounts of stratification can exist even in well designed studies.
- Published
- 2004
30. The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke
- Author
-
Anna Helgadottir, Helga Jonsdottir, Eric J. Topol, Jesus Sainz, Halldor Johannsson, Stefan E Matthiasson, Gudmundur Thorgeirsson, Olof Gudmundsdottir, Unnur Thorsteinsdottir, Jeffrey R. Gulcher, Gudmar Thorleifsson, Michael L. Frigge, Gudmundur Gudmundsson, Vilmundur Gudnason, Augustine Kong, Solveig Gretarsdottir, Nilesh J. Samani, Hakon Hakonarson, Einar M. Valdimarsson, Mark E. Gurney, Struan F.A. Grant, Margret B. Andresdottir, Kari Stefansson, Andrei Manolescu, Margret Thorhallsdottir, and Sigurlaug Sveinbjörnsdóttir
- Subjects
Leukotriene B4 ,5-Lipoxygenase-Activating Proteins ,Leukotriene Production ,Myocardial Infarction ,Locus (genetics) ,Inflammation ,Biology ,Polymorphism, Single Nucleotide ,Pathogenesis ,chemistry.chemical_compound ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,cardiovascular diseases ,Myocardial infarction ,5-lipoxygenase-activating protein ,Chromosomes, Human, Pair 13 ,Haplotype ,Chromosome Mapping ,Membrane Proteins ,medicine.disease ,Stroke ,chemistry ,Immunology ,biology.protein ,medicine.symptom ,Carrier Proteins ,Microsatellite Repeats - Abstract
We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13. A four-marker single-nucleotide polymorphism (SNP) haplotype in this locus spanning the gene ALOX5AP encoding 5-lipoxygenase activating protein (FLAP) is associated with a two times greater risk of myocardial infarction in Iceland. This haplotype also confers almost two times greater risk of stroke. Another ALOX5AP haplotype is associated with myocardial infarction in individuals from the UK. Stimulated neutrophils from individuals with myocardial infarction produce more leukotriene B4, a key product in the 5-lipoxygenase pathway, than do neutrophils from controls, and this difference is largely attributed to cells from males who carry the at-risk haplotype. We conclude that variants of ALOX5AP are involved in the pathogenesis of both myocardial infarction and stroke by increasing leukotriene production and inflammation in the arterial wall.
- Published
- 2004
31. Scientific and therapeutic advances in antiplatelet therapy
- Author
-
Eric J. Topol and Deepak L. Bhatt
- Subjects
Blood Platelets ,medicine.medical_treatment ,Platelet Glycoprotein GPIIb-IIIa Complex ,Pharmacology ,Revascularization ,Bioinformatics ,Polymorphism, Single Nucleotide ,law.invention ,Mediator ,Randomized controlled trial ,law ,Drug Discovery ,medicine ,Animals ,Humans ,Platelet ,Aspirin ,business.industry ,General Medicine ,medicine.disease ,Thrombosis ,Adenosine Diphosphate ,Cardiovascular Diseases ,business ,Platelet Aggregation Inhibitors - Abstract
Over the past decade, the platelet has emerged as a pivotal entity in cardiovascular diseases. Indeed, the 'preeminence of the platelet' has spawned a variety of drugs that have been shown in large-scale randomized trials to improve patient outcomes in acute coronary syndromes and percutaneous revascularization procedures. Although the platelet was initially viewed only as a bystander in haemostasis, it is now evident that the platelet is in fact a key mediator of thrombosis as well as of inflammation. New insights at the cellular and genomic levels will probably generate novel drugs to inhibit platelet function more effectively and safely than previously possible.
- Published
- 2003
32. Glycoprotein IIb/IIIa antagonists - from bench to practice
- Author
-
Eric J. Topol and Ivan P. Casserly
- Subjects
Blood Platelets ,Acute coronary syndrome ,Platelet Aggregation ,Protein Conformation ,Apoptosis ,Receptors, Cell Surface ,Platelet Glycoprotein GPIIb-IIIa Complex ,Pharmacology ,Cellular and Molecular Neuroscience ,medicine ,Humans ,Platelet ,Angina, Unstable ,Myocardial infarction ,Receptor ,Molecular Biology ,Stroke ,Clinical Trials as Topic ,business.industry ,Thrombosis ,Cell Biology ,medicine.disease ,Toxicity ,Immunology ,Molecular Medicine ,Glycoprotein IIb/IIIa ,business ,Platelet Aggregation Inhibitors ,Signal Transduction - Abstract
The central role played by the alphaIIb beta3 receptor in platelet aggregation, and hence in platelet thrombosis, has led to the development of a number of parenteral and oral glycoprotein (GP) IIb/IIIa inhibitors for use in cardiovascular disease states, such as acute coronary syndromes and stroke. The predominant effect of these agents is to inhibit platelet aggregation, although studies of alphaIIb beta3 receptor function and various GP IIb/IIIa inhibitors have demonstrated the potential for these agents to produce effects on other aspects of platelet function, in addition to non-platelet effects. Overall, clinical studies have demonstrated an impressive beneficial effect for parenteral agents in reducing ischemic complications following percutaneous intervention, and a more modest beneficial effect in the treatment of patients with acute coronary syndromes. Trials with oral GP IIb/IIIa inhibitors in similar patient populations have demonstrated toxicity, manifested by an increased mortality in treated patients. Increased understanding of molecular aspects of both alphaIIb beta3 receptor function and the effects of GP IIb/IIIa inhibition may help explain some of the inconsistency in recently reported clinical studies with parenteral agents, and the frank toxicity of oral agents. Such studies may also hold the key to the development of newer agents with enhanced therapeutic benefit.
- Published
- 2002
33. [Untitled]
- Author
-
L. Kristin Newby, Robert A. Harrington, Manjushri V. Bhapkar, Frans Van de Werf, Judith S. Hochman, Christopher B. Granger, R. John Simes, Catherine G. Davis, Eric J. Topol, Robert M. Califf, David J. Moliterno, and null for the PARAGON A Investigators
- Subjects
medicine.medical_specialty ,Chemotherapy ,medicine.diagnostic_test ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Anticoagulant ,Follow up studies ,Hematology ,Heparin ,Coronary disease ,Coronary heart disease ,Internal medicine ,medicine ,Cardiology ,Cardiology and Cardiovascular Medicine ,Intensive care medicine ,business ,circulatory and respiratory physiology ,medicine.drug ,Partial thromboplastin time - Abstract
Background: Intravenous unfractionated heparin remains a cornerstone of anticoagulation therapy for patients with acute coronary syndromes, but regulation to a target aPTT is challenging. We assessed unfractionated heparin infusion regulation by bedside, whole-blood aPTT testing and computerized, algorithmic infusion adjustment, and further evaluated the relationship of achieving the target aPTT with clinical outcomes.
- Published
- 2002
34. [Untitled]
- Author
-
Venu Menon, Eric J. Topol, Christopher B. Granger, Andreas U. Wali, Trevor D. Thompson, Scott D. Berkowitz, Robert M. Califf, Judith S. Hochman, and Michael S. Lee
- Subjects
medicine.medical_specialty ,education.field_of_study ,Acute coronary syndrome ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,medicine.medical_treatment ,Population ,Anticoagulant ,Context (language use) ,Hematology ,Heparin ,Thrombolysis ,medicine.disease ,Surgery ,Anesthesia ,medicine ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,education ,circulatory and respiratory physiology ,medicine.drug ,Partial thromboplastin time - Abstract
Context: Unfractionated heparin remains widely utilized in the treatment of acute coronary syndromes (ACS). However, limited data exist on optimal dosing and range of activated partial thromboplastin time (aPTT) in this setting. A large trial of thrombolysis for acute myocardial infarction has reported an association between longer aPTTs and adverse outcomes. Objectives: Estimate the optimal heparin-dosing regimen in achieving early therapeutic aPTTs (50 to 75 seconds) and determine the association of aPTT and death, reinfarction, and bleeding in population with ACS. Design: Subgroup analysis within a randomized, controlled trial of 5861 patients given unfractionated heparin who had aPTTs at 6, 12, or 24 hours, with outcome analyses by weight categories. Setting: In 373 hospitals in 13 countries from May 1994 to October 1995. Patients: A total of 12,142 patients admitted for ACS, stratified by the presence (n = 4131) or absence (n = 8011) of ST-segment elevation, and randomized to 72 hours of unfractionated heparin. Results: In a simulated weight-adjusted model, based on retrospective grouping by weight, a simulated dose of 60-U/kg bolus and 12-U/kg/h infusion resulted in the highest proportion of therapeutic aPTTs. After adjustment for baseline variables, longer 12-hour aPTT was associated with the composite of 30-day death or reinfarction in patients not treated with thrombolytic therapy (odds ratio, 1.10; 95% CI, 1.00 to 1.22; P = 0.047). Longer aPTT at 6 hours was associated with increased moderate or severe bleeding for the entire cohort. There was also a significant, nonlinear correlation of the 12-hour aPTT with moderate or severe bleeding in thrombolysis-treated patients. Conclusions: For ACS patients who are treated with heparin, aPTT is highly associated with body weight. Longer aPTT within the first 12 hours is associated with adverse outcomes in ACS. Heparin dosing for ACS should be weight based.
- Published
- 2002
35. Cocaine use is associated with a number of life-threatening cardiovascular complications that require careful treatment
- Author
-
J. Bauman, H. Rodier, I. Hahn, Robert S. Hoffman, R. Tharratt, J. Grawe, L. D. Hillis, A. Sharma, O. Obel, Larry S. Green, Robert W. Derlet, K. Phillips, G. DiSciascio, A. Luk, M. Scheinman, S. Hamwi, K. Kuczkowski, S. Ellahham, C. Blomstrom-Lundqvist, J. McCord, A. Om, J. Rashid, H. Jneid, E. Aliot, Richard A. Lange, Jonathan L. Burstein, Jeffrey L. Anderson, R. Naseem, T. Henry, J. Chen, A. Winecoff, R. Shih, G. Soor, Eric J. Topol, Judd E. Hollander, M. Eisenberg, Timothy E Albertson, and N. Garg
- Subjects
medicine.medical_specialty ,business.industry ,Anesthesia ,medicine ,Cocaine use ,Pharmacology (medical) ,Intensive care medicine ,business - Published
- 2010
36. [Untitled]
- Author
-
J D Talley, Kristina N. Sigmon, Erik Magnus Ohman, R P Tracy, Michael M. Kitt, Diane Joseph, Eric J. Topol, Neal S. Kleiman, and Robert M. Califf
- Subjects
medicine.medical_specialty ,Glycoprotein IIb/IIIa Antagonist ,business.industry ,medicine.medical_treatment ,Hematology ,Heparin ,Pharmacology ,Tissue plasminogen activator ,Surgery ,Thrombin ,Fibrinolysis ,medicine ,Eptifibatide ,Cardiology and Cardiovascular Medicine ,business ,Glycoprotein IIb/IIIa ,TIMI ,medicine.drug - Abstract
Thrombin activity has been implicated as a mechanism for failed reperfusion and reocclusion following thrombolysis. Aggregating platelets provide a phospholipid surface on which prothrombin is cleaved to form thrombin. We examined markers of thrombin generation and activity in patients enrolled in a randomized, placebo-controlled, dose escalating trial of the platelet glycoprotein IIb-IIIa inhibitor eptifibatide (Integrilintrade mark) administered concomitantly with tissue plasminogen activator for the treatment of myocardial infarction. Measurements were obtained at baseline, at 90 minutes, and at 6, 12, and 24 hours after starting therapy. Eptifibatide inhibited platelet aggregation in response to 20 microM ADP. Levels of fibrinopeptide A (FPA), thrombin-antithrombin complexes (TAT), and prothrombin fragment 1.2 (F1.2) were not lower in patients treated with eptifibatide than in the control group. In the course of dose escalation, two groups of patients received the same 135 microg/kg bolus of eptifibatide, one with and one without a heparin bolus. FPA levels were dramatically lower in the heparin-treated patients. Levels of FPA, TAT, and F1.2 were not higher in patients with than in those without recurrent ischemia, or in patients without than in those with Thrombolysis in Myocardial Infarction (TIMI) grade 3 angiographic flow at 90 minutes. These data suggest that thrombin generation and activity persist following thrombolysis, despite inhibition of platelet aggregation, and that treatment with inhibitors of thrombin activity may be required even when glycoprotein IIb-IIIa inhibitors are used.
- Published
- 2000
37. [Untitled]
- Author
-
Eric J. Topol and Steven R. Steinhubl
- Subjects
Regimen ,medicine.medical_specialty ,Aspirin ,Hematology ,business.industry ,Internal medicine ,Cardiology ,Medicine ,Cardiology and Cardiovascular Medicine ,business ,Clopidogrel ,medicine.drug - Published
- 1999
38. Warfarin Pharmacogenomics: A big step forward for individualized medicine: enlightened dosing of warfarin
- Author
-
Darlene J. Elias and Eric J Topol
- Subjects
medicine.medical_specialty ,business.industry ,Pharmacogenomics ,Genetics ,Warfarin ,Medicine ,Dosing ,Personalized medicine ,Pharmacology ,business ,Intensive care medicine ,Genetics (clinical) ,medicine.drug - Abstract
Warfarin Pharmacogenomics: A big step forward for individualized medicine: enlightened dosing of warfarin
- Published
- 2008
39. [Untitled]
- Author
-
Eric J. Topol
- Subjects
medicine.medical_specialty ,Hematology ,business.industry ,Angioplasty ,medicine.medical_treatment ,Internal medicine ,medicine ,Cardiology ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Published
- 1998
40. [Untitled]
- Author
-
Eric J. Topol and Todd L. Johnson
- Subjects
medicine.medical_specialty ,Myocardial reperfusion ,business.industry ,Hematology ,Gold standard (test) ,medicine.disease ,Infarct size ,Clinical trial ,medicine.anatomical_structure ,Clinical investigation ,Internal medicine ,Cardiology ,Medicine ,cardiovascular diseases ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,Artery - Abstract
Early clinical trials of thrombolytic therapy in the setting of acute myocardial infarction (AMI) demonstrated that early angiographic reperfusion correlated with improved survival. This supported the open-artery hypothesis that early reperfusion decreases infarct size, improves left ventricular function, and improves survival. Two subsequent comparative thrombolytic trials showed no difference in left ventricular function or survival between agents with different rates of reperfusion. Additionally, reduction in mortality was demonstrated without improvement in left ventricular function and with the late administration of thrombolytic therapy. Therefore, there was a real question as to the importance of infarct vessel patency, and its relation to clinical outcome. This article discusses the various markers of coronary artery patency, their relation to clinical outcome, and how they reflect perfusion at the tissue level. The coronary angiogram gives a snapshot view of the infarct-related artery (IRA) that does not reflect the dynamic process of vessel reocclusion and recanalization. The patent artery is therefore "open" at only a given time frame, and may undergo cyclic or complete reocclusion. Angiographically characterized flow has been demonstrated to be more clinically meaningful. The GUSTO-I trial was designed to test the open-artery hypothesis. This trial confirmed that improved early IRA patency and optimal (TIMI-3) flow correlated with improved survival. The presence of TIMI-3 flow in the IRA has consistently demonstrated significant improvement in patient morbidity and mortality, and conversely, less than optimal, but still "patent" (TIMI-2) flow in the IRA correlates with clinical outcomes observed in patients with occluded infarct vessels. Even TIMI-3 flow in the IRA does not always confirm perfusion of the myocardium at risk. Therefore, the "patent" IRA can be subsequently compromised by intermittent patency, reocclusion, less than TIMI-3 flow, and a "no-reflow" effect at the tissue level. The development of accurate, reliable non-invasive markers of IRA patency is crucial. This would allow a more selective application of invasive and interventional techniques to restore patency to the IRA. The merits and faults of these noninvasive markers are discussed. The ideal gold standard for establishing the adequacy of therapy in AMI is one that could detect rapid, complete, and sustained coronary reperfusion with adequate myocardial perfusion. Current technologic achievements allow an approach to this ideal; however, as of 1997, the coronary angiogram demonstrating TIMI-3 flow represents the clinically proven standard of optimal therapeutic efficacy.
- Published
- 1997
41. Randomized, placebo-controlled study of Lamifiban with thrombolytic therapy for the treatment of acute myocardial infarction: Rationale and design for the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) study
- Author
-
Eric J. Topol, David J. Moliterno, Robert M. Califf, Robert A. Harrington, and Hans J. Rapold
- Subjects
medicine.medical_specialty ,Aspirin ,business.industry ,medicine.medical_treatment ,Placebo-controlled study ,Hematology ,Thrombolysis ,medicine.disease ,Clinical trial ,Internal medicine ,Anesthesia ,medicine ,Cardiology ,Clinical endpoint ,Platelet activation ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,TIMI ,medicine.drug - Abstract
The benefits of thrombolytic therapy in the treatment of acute myocardial infarction are incontrovertible. Large-scale studies combining angiographic and clinical end-points have demonstrated a perfusion-mortality relationship, with the highest survival rate among patients with early restoration of TIMI grade 3 coronary arterial flow. Despite advances in thrombolytic strategies, a substantial number of patients fail to rapidly achieve and maintain adequate coronary perfusion with thrombolysis. Conjunctive therapy with aspirin has proven useful in thrombolytic regimens, likely countering the heightened platelet activity central to acute coronary syndromes. The antiplatelet effect of aspirin is relatively weak compared with that of glycoprotein IIb/IIIa platelet receptor antagonists, which block the final common pathway of platelet aggregation. Lamifiban is a nonpeptide glycoprotein IIb/IIIa receptor antagonist. In early experimental studies, Lamifiban in combination with thrombolytic therapy has been shown to effectively restore coronary arterial patency, and phase I and phase II data have shown its use to be safe. To determine the optimal dose with regard to safety and efficacy of Lamifiban to be used with thrombolytic therapy in a large-scale trial, a phase II study is underway. The Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) study is a randomized, placebo-controlled study of Lamifiban in 400 patients receiving thrombolysis as treatment for acute myocardial infarction. By studying 90-minute angiography, platelet aggregation, continuous electrocardiography, and clinical outcome in PARADIGM, important insights will be obtained to determine the optimal dose of Lamifiban for phase III study. We provide the background and rationale for the study of Lamifiban in PARADIGM and other ongoing studies in acute coronary syndromes.
- Published
- 1995
42. Metabolic imaging by positron emission tomography early after myocardial infarction as a predictor of recovery of myocardial function after reperfusion
- Author
-
Ronald J.L. Dick, Jeffrey J. Popma, Eric J. Topol, Pierre G. Melon, Victor Kalff, Rodney J. Hicks, Markus Schwaiger, and Edwin R. Wolfe
- Subjects
Adult ,Male ,medicine.medical_specialty ,Myocardial Infarction ,Myocardial Reperfusion ,Coronary Angiography ,Chest pain ,Internal medicine ,Humans ,Medicine ,Thrombolytic Therapy ,Radiology, Nuclear Medicine and imaging ,Carbon Radioisotopes ,Myocardial infarction ,Aged ,Ejection fraction ,medicine.diagnostic_test ,business.industry ,Electrocardiography in myocardial infarction ,Metabolism ,Blood flow ,Middle Aged ,medicine.disease ,Myocardial Contraction ,Positron emission tomography ,Cardiology ,Female ,medicine.symptom ,Cardiology and Cardiovascular Medicine ,business ,Perfusion ,Tomography, Emission-Computed - Abstract
Myocardial ischemia leads to alterations in myocardial substrate metabolism that have been shown to reflect severity of ischemic injury. The purpose of this study was to correlate oxidative metabolism with recovery of contractile function in patients with acute myocardial infarction.Regional blood flow and oxidative metabolism were assessed by dynamic positron emission tomography early after myocardial infarction treated with thrombolytic therapy in 18 patients. The extent of myocardial perfusion abnormally (carbon 11-labeled acetate uptake; relative amplitudeor = 50%) was inversely correlated with the ejection fraction obtained within 8 hours of the onset of chest pain (r = -0.81; p - 0.01) but not clearly with that at follow-up 1 week later (r = 0.64; p = 0.09). Oxidative metabolism (carbon 11-labeled acetate; monoexponential clearance) was higher in periinfarct territories with early or late recovery of contractile function than in those without, but there was a large overlap in absolute values limiting the predictive power of a single measurement. Relatively preserved oxidative metabolism compared with perfusion in low-flow areas was predictive of early (day 1 to 1 week) and delayed (week 1 to beyond 1 month) recovery. Normal resting perfusion with regionally decreased oxidative metabolism predicted early recovery of contractile function.Thus in patients studied with positron emission tomography early after myocardial infarction, comparison of regional perfusion and oxidative metabolism was more predictive of recovery in contractile function than was assessment of either one alone.
- Published
- 1994
43. Thrombolytic Therapy for Acute Myocardial Infarction
- Author
-
Christopher B. Granger, Robert M. Califf, and Eric J. Topol
- Subjects
Urokinase ,medicine.medical_specialty ,business.industry ,Streptokinase ,Myocardial Infarction ,Infarction ,medicine.disease ,Tissue plasminogen activator ,Thrombosis ,Anistreplase ,Internal medicine ,medicine ,Cardiology ,Humans ,Thrombolytic Agent ,Thrombolytic Therapy ,Pharmacology (medical) ,Myocardial infarction ,business ,medicine.drug - Abstract
In the past 10 years, thrombolytics have become standard therapy for acute myocardial infarction. Although the ability of streptokinase to lyse clot was first recognised in the 1930s, thrombolytic therapy was not used to treat acute myocardial infarction until the early 1980s, when the importance of thrombosis in the pathogenesis of acute infarction was fully recognised. In addition to streptokinase and urokinase, recombinant human tissue plasminogen activator (tPA) and anistreplase were developed and widely used in the 1980s. Saruplase (prourokinase) and BM-06022 (recombinant plasminogen activator) have also undergone human clinical studies. All of these agents are effective at achieving clot lysis and coronary patency. Large, randomised clinical trials have demonstrated that thrombolytic therapy reduces mortality in patients with ST elevation treated within the first 6 to 12 hours of acute infarction, with an approximately 0.5% risk of intracranial haemorrhage. Recent data have more clearly identified which patients benefit from thrombolytic therapy. Efforts have been made to improve the speed of reperfusion, decrease reocclusion, simplify administration and reduce adverse effects. The characteristics of fibrin specificity and more rapid clot lysis with tissue plasminogen activator have not yet been translated into overall clinical benefit compared with the less expensive streptokinase. The lack of close association of improved early patency and improved global left ventricular function with improved survival challenges the very paradigm which led to the use of thrombolytic therapy for acute myocardial infarction. The need for development of additional methods for evaluation of new thrombolytic agents is evident.
- Published
- 1992
44. [Untitled]
- Author
-
David B. Brieger and Eric J. Topol
- Subjects
medicine.medical_specialty ,Unstable angina ,business.industry ,Streptokinase ,Hirudin ,Infarction ,Hematology ,Heparin ,medicine.disease ,Internal medicine ,medicine ,Clinical endpoint ,Cardiology ,Myocardial infarction ,Cardiology and Cardiovascular Medicine ,business ,TIMI ,medicine.drug - Abstract
Two large multicenter clinical trials comparing heparin with hirudin in the management of patients with acute coronary syndromes have recently been completed. Direct thrombin inhibition was reported to result in only a modest reduction in the incidence of primary endpoint in GUSTO IIb, and to be of no demonstrable benefit in TIMI 9b. However, closer examination of the performance of hirudin in these trials suggests it to have been harshly judged. Hirudin provided a consistently more reliable anticoagulant effect than heparin, was associated with a comparable risk of bleeding and minimal risk of allergy. Furthermore, direct thrombin inhibition was more effective in preventing events in patients with unstable angina and non-Q wave infarction, and resulted in a significant reduction in the incidence of reinfarction among all facets of the acute coronary syndromes. There was in addition a striking benefit of combining hirudin with streptokinase in patients with acute myocardial infarction. Based on these data, there is little doubt that hirudin rather than heparin should form the foundation on which to base future strategies for management of the acute coronary syndromes.
- Published
- 1997
45. Point-of-care genetic testing—a new frontier explored
- Author
-
Eric J. Topol and Paddy M. Barrett
- Subjects
medicine.medical_specialty ,business.industry ,CYP2C19 ,Clopidogrel ,Point-of-care genetic testing ,Surgery ,Platelet reactivity ,Medicine ,In patient ,cardiovascular diseases ,Cardiology and Cardiovascular Medicine ,business ,Intensive care medicine ,Genotyping ,Pharmacogenetics ,medicine.drug - Abstract
Much debate surrounds the utility of CYP2C19*2 genotyping in patients receiving clopidogrel after coronary artery stenting. The effectiveness of its use in a point-of-care setting has now been examined and, given the substantial incremental suppression of platelet reactivity achieved, its routine use might soon be a reality.
- Published
- 2012
46. The next phase in human genetics
- Author
-
Eric J. Topol, Vikas Bansal, Nicholas J. Schork, and Ryan Tewhey
- Subjects
Disease susceptibility ,Evolutionary biology ,Haplotype ,Biomedical Engineering ,Molecular Medicine ,Bioengineering ,Sequence variation ,Biology ,Applied Microbiology and Biotechnology ,Phenotype ,Genome ,Human genetics ,Biotechnology - Abstract
Experimental haplotyping of whole genomes is now feasible, enabling new studies aimed at linking sequence variation to human phenotypes and disease susceptibility.
- Published
- 2011
47. Catapulting clopidogrel pharmacogenomics forward
- Author
-
Eric J. Topol and Nicholas J. Schork
- Subjects
Antiplatelet drug ,business.industry ,medicine.medical_treatment ,Amino acid substitution ,General Medicine ,Clopidogrel ,Bioinformatics ,medicine.disease ,Thrombosis ,General Biochemistry, Genetics and Molecular Biology ,Pharmacotherapy ,Pharmacogenomics ,Medicine ,cardiovascular diseases ,business ,circulatory and respiratory physiology ,medicine.drug - Abstract
The antiplatelet drug clopidogrel helps prevent stent-associated thrombosis, but the antiplatelet effects are quite variable and the clinical consequences can be serious. New findings show that the variability in clopidogrel efficacy is affected by the enzyme paraoxonase-1 (PON1), which is required for clopidogrel bioactivation (pages 110–116 ).
- Published
- 2011
48. Is there a genetic basis for acute coronary syndrome?
- Author
-
Bradley A. Patay and Eric J. Topol
- Subjects
Acute coronary syndrome ,medicine.medical_specialty ,business.industry ,Internal medicine ,medicine ,Cardiology ,General Medicine ,Cardiology and Cardiovascular Medicine ,medicine.disease ,business - Published
- 2007
49. The resequencing imperative
- Author
-
Kelly A. Frazer and Eric J. Topol
- Subjects
Genetics ,education.field_of_study ,Plasma triglyceride ,Population ,Quantitative trait locus ,Biology ,education ,Gene ,Multiethnic population - Abstract
The possibility of deep population resequencing of genes has generated excitement over its potentially promising role in understanding complex human traits. A new study has now demonstrated the utility of this approach, reporting the resequencing of a lipid metabolism gene in a large multiethnic population and definitively showing that coding variants in the gene are associated with plasma triglyceride levels.
- Published
- 2007
50. Cholesterol, racial variation and targeted medicines
- Author
-
Eric J. Topol
- Subjects
Genetics ,medicine.medical_specialty ,Apolipoprotein B ,biology ,Cholesterol ,business.industry ,PCSK9 ,General Medicine ,Familial hypercholesterolemia ,medicine.disease ,General Biochemistry, Genetics and Molecular Biology ,Stop codon ,chemistry.chemical_compound ,Endocrinology ,chemistry ,Internal medicine ,LDL receptor ,biology.protein ,medicine ,Missense mutation ,lipids (amino acids, peptides, and proteins) ,business ,Lipoprotein - Abstract
Only a year or so ago we thought we understood the primary determinants of low-density lipoprotein, 'bad' cholesterol in the bloodstream--apolipoprotein B and the LDL receptor. But since 2003, a flurry of human genetic studies have emphasized a new player, the gene encoding proprotein convertase subtilisin/kexin type 9, PCSK9. Abifadel and colleagues identified two missense mutations in PCSK9 to account for a form of autosomal dominant hypercholesterolemia in French families1. Soon thereafter, a third missense mutation was found in unrelated pedigrees in Utah and Norway2,3. Beyond monogenic disorders associated with the LDL receptor and apolipoprotein B, gain-of-function mutations in PCSK9 quickly emerged as the third cause of familial hypercholesterolemia. Cohen et al. have now taken the genetics of PCSK9 further4. Using the Dallas Heart Study cohort of 3,553 multiethnic patients, they genoomically screened 128 individuals who had markedly reduced choleesterol levels. Although almost all previous studies have focused on high levels of LDL cholesterol tied to coronary artery disease, this was a clever way to further probe PCSK9 protein's potential impact on blood LDL cholesterol levels. Two nonsense, loss-of-function PCSK9 mutations were identified, occurring in 2% of African Americans and less than 0.1% of European Americans and Hispanics. Both mutations introduce a stop codon and are predicted to result in a truncated protein.
- Published
- 2005
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.