Using Human Hearts to Study Arrhythmogenesis Igor R. Efimov, Ph.D., F.A.I.M.B.E., F.A.H.A., F.H.R.S. The Alisann and Terry Collins Professor & Chairman, Department of Biomedical Engineering National Academies of Science, Engineering, Medicine: Public Workshop on the Uses of Dogs in Biomedical Research National Academies Keck Center Building. 500 5th St. NW Washington, DC 20001 March 27-28, 2019
Present on the state of the science for using human hearts in cardiovascular disease research. What accomplishments/advancements have been made in the recent past (last 5 – 10 years) in cardiovascular disease through the use of human hearts in research? Could any of these accomplishments/advancements have been achieved in other species? From your perspective, what is the likelihood of in vitro models replacing dogs as the preferred model for cardiovascular disease going forward? What would be the tradeoffs in doing so? Would replacing dogs with another species compromise the quality or timelines of future advances?
Present on the state of the science for using human hearts in cardiovascular disease research. What accomplishments/advancements have been made in the recent past (last 5 – 10 years) in cardiovascular disease through the use of human hearts in research? Could any of these accomplishments/advancements have been achieved in other species? From your perspective, what is the likelihood of in vitro models replacing dogs as the preferred model for cardiovascular disease going forward? What would be the tradeoffs in doing so? Would replacing dogs with another species compromise the quality or timelines of future advances?
Jeanne M. Nerbonne, and Robert S. Kass Physiol Rev 2005;85:1205-1253
Jeff Robbins (Circ. Res., 2011): “What have we learned in the past 20 years? Although the pace of data acquisition and subsequent definition of multiple signaling pathways, gene function, and normal and pathogenic mechanisms has been exhilarating, we cannot help but be humbled by the relatively tiny impact of these data on human health in general and cardiovascular disease specifically. Our “wet bench” advances have not, with rare exceptions, been translated to the bedside. Although this failure is due at least in part to our inability to effectively apply what we have learned to drug development, it also reflects remaining, serious deficits in understanding the mechanisms that drive cell and organ function.”
Present on the state of the science for using human hearts in cardiovascular disease research. What accomplishments/advancements have been made in the recent past (last 5 – 10 years) in cardiovascular disease through the use of human hearts in research? Could any of these accomplishments/advancements have been achieved in other species? From your perspective, what is the likelihood of in vitro models replacing dogs as the preferred model for cardiovascular disease going forward? What would be the tradeoffs in doing so? Would replacing dogs with another species compromise the quality or timelines of future advances?
Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS
Human heart No. 136. The two-year old child heart. v=musculature of the atrial septum; k=node; m=anterior mitral leaflet; s=the atrioventricular fibrous septum; t=septal leaflet of the tricaspid valve; h=initial portion of the ventricular bundle; r & l= the right and the left bundle brunches of the conduciton system; sf=a tendinous fiber of the septal leaflet of the tricuspid valve; km=musculature of the ventricular septum. Tawara S, Das Reizleitungssystem Des Saugetierherzens, Gustav Fischer, Jena, 1906
Keith A, Flack M. The form and nature of the muscular connections between the primary divisions of the vertebrate heart. J Anat Physiol 1907; 41:172 – 189.
Lewis T, Meakins J, White PD. The Excitatory Process in the Dog's Heart. Part I. The Auricles. Philosophical Transactions of the Royal Society of London. Series B, Vol. 205, (1914), pp. 375-420
Boineau et al., Am J Physiol, 1988
Connective Coronary SAN cells Atrial cells tissue arteries Fedorov, Circ Res, 2009 37
Fedorov, JACC 2010
Fedorov, JACC 2010
Boineau et al., Am J Physiol, 1988 Fedorov, JACC 2010
Fedorov, JACC 2010
Kistler et al. P-Wave Morphology in Focal Atrial Tachycardia. J Am Coll Cardiol 2006;48:1010 – 7.
Mendez C, Moe GK. Circ Res. 1966;19:378 – 393
Hucker, An. Rec. 2007
Hucker, An. Rec. 2007
Fedorov, Circ: EA, 2011
Fedorov, Circ: EA, 2011
Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS
George R. Mines, On Dynamic Equilibrium of the Heart. J. Physiol., 1913, XLVI, 349-383 Wavelength λ = Refractory Period x Conduction velocity Reentry is possible only if wavelength < pathlength (1D) George R. Mines (1886-1914)
Effective size (L) of the tissue: L = D/λ, D - the size of the tissue; λ - the wavelength. Figure 1. a: Spiral wave using the TNNP human ventricular cell model (bottom panel) and the Luo-Rudy phase 1 model for gs (conductance of the slow inward current) = 0 (top panel). The medium size is 25 × 25 cm and 5 × 5 cm. The effective size of both patterns is L = 2.5. b: The relative effective size of the heart S vs heart mass. Here S = I /I human , where I is evaluated from Equation 1, and I human is I for the human heart. Panfilov AV, Is heart size a factor in ventricular fibrillation? Or how close are rabbit and human hearts? Heart Rhythm, 2006, 3(7):862-4.
Laughner, AJP 2012 Gloschat, Sci Rep 2018
Qing Lou Lou, AJP 2012 Lou, AJP 2012
Qing Lou Lou, AJP 2012
Qing Lou • Wavelength = conduction velocity x action potential duration (refractory period) • WSA (Wavelength surface area) = longitudinal wavelength * transverse wavelengths • Arrhythmia can be sustained only is WSA < Ventricular surface area: • WSA(BDM) = 19-34 cm 2 • WSA(Blebbistatin) = 39-60 cm 2 • Ventricular epicardial surface area = 39.4+/-1.8 cm 2 Lou, AJP 2012
Kedar Aras Aras, Circ: A&E, 2018
Kedar Aras Aras, Circ: A&E, 2018
Kedar Aras Wavelength volume: V λ = λ Longitudinal x λ Transverse x λ Transmural Aras, Circ: A&E, 2018
Kedar Aras Wavelength volume: V λ = λ Longitudinal x λ Transverse x λ Transmural Aras, Circ: A&E, 2018
Kedar Aras Endo R-trans Epi L-trans Aras, Circ: A&E, 2018
Superimposed 252 egms in VF 1 - Early (‘organized’) VF versus disorganized VF is associated with different characteristics of drivers **** 2- VF mainly driven by reentrant activity (~88% wavefronts) 3- Focal breakthroughs- dominant origin from RV Haissaguerre et al, Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death, Circ: A&E, 11(7), e006120
Haissaguerre et al, Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death, Circ: A&E, 11(7), e006120
Small animal models are necessary to develop the experimental tools and scientific vocabulary to conduct research of the mechanisms of ventricular fibrillation Human heart research is needed to determine human specific mechanisms of VT/VF
Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS
Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.
Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.
Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.
Hemerich et al., Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes. Circ Genom Precis Med. 2019 Feb; 12(2):e002328.
Hemerich et al., Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes. Circ Genom Precis Med. 2019 Feb; 12(2):e002328.
Hemerich et al., Integrative Functional Annotation of 52 Genetic Loci Influencing Myocardial Mass Identifies Candidate Regulatory Variants and Target Genes. Circ Genom Precis Med. 2019 Feb; 12(2):e002328.
Novel promoters in FANTOM5 51
Promoter-level heart transcriptome for ventricular remodeling studies 52
Promoter-level heart transcriptome for ventricular remodeling studies 53 Deviatiiarov, unpublished 2019
Deviatiiarov, unpublished 2019
6% upstream SNPs SNP 20% SNPs in heart-CAGE promoters Overlapped regulatory features – 333 in our data vs 244 from Ensembl Ensembl promoters 204940 FANTOM5 enhancers 65420 GWAS (heart SNPs 5104) pro/enh Heart CAGE: 1050/33 Ensembl: 431/17 55
Disease-associated mutations:
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