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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
EngineeringNational 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
37
SAN cells Atrial cells Connective
tissue
Coronary
arteries
Fedorov, Circ Res, 2009
Fedorov, JACC 2010
Fedorov, JACC 2010
Boineau et al., Am J Physiol, 1988Fedorov, 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)
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 /Ihuman, where
I is evaluated from Equation 1, and Ihuman 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.
Effective size (L) of the tissue: L = D/λ, D - the size of the tissue; λ - the wavelength.
Laughner, AJP 2012 Gloschat, Sci Rep 2018
Lou, AJP 2012
Qing Lou
Lou, AJP 2012
Qing Lou
Lou, AJP 2012
• 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 cm2
• WSA(Blebbistatin) = 39-60 cm2
• Ventricular epicardial surface area = 39.4+/-1.8 cm2
Qing Lou
Lou, AJP 2012
Kedar Aras
Aras, Circ: A&E, 2018
Kedar Aras
Aras, Circ: A&E, 2018
Kedar Aras
Wavelength volume: Vλ= λLongitudinal x λTransverse x λTransmural
Aras, Circ: A&E, 2018
Kedar Aras
Wavelength volume: Vλ= λLongitudinal x λTransverse x λTransmural
Aras, Circ: A&E, 2018
Kedar Aras
Endo
L-trans
R-trans
Epi
Aras, Circ: A&E, 2018
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
Superimposed 252 egms in VF
****
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
Deviatiiarov, unpublished 201953
Deviatiiarov, unpublished 2019
55
Overlapped regulatory features – 333 in our data vs 244 from Ensembl
6% upstream SNPsSNP
20%
SNPs in heart-CAGE
promoters
Ensemblpromoters 204940
FANTOM5enhancers 65420
GWAS(heart SNPs 5104)
pro/enhHeart CAGE: 1050/33
Ensembl: 431/17
Disease-associated
mutations:
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?
The canine model is the closest to human in terms of normal
and pathological electrophysiology.
Translational therapy development for chronic atrial and
ventricular arrhythmias requires large animal models prior to
human trials, with the canine model preferable.
Human heart is the best model for Omics studies due to genetic
differences.
A national program is needed to utilize widely available for
research donor human hearts which are rejected for
transplantation, and not used.
Acknowledgments:
- Oleg Gusev, Riken Institute, Yokohama, Japen
- Washington Regional Transplant Community, Mid-America Transplant Services
- US National Heart, Lung, and Blood Institute, NIH, R01HL114395, R01HL085369, R01HL141470,
R21EB023106…
- Leducq Foundation Transatlantic Network of Excellence RHYTHM.
