Using Human Hearts to Study Arrhythmogenesis Igor R. Efimov, Ph.D., - - PowerPoint PPT Presentation

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Using Human Hearts to Study Arrhythmogenesis Igor R. Efimov, Ph.D., - - PowerPoint PPT Presentation

Oct 22, 2023 254 likes •856 views

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,

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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 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

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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

  • ther 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

  • f future advances?
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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

  • ther 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

  • f future advances?
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Jeanne M. Nerbonne, and Robert S. Kass Physiol Rev 2005;85:1205-1253

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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.”

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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

  • ther 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

  • f future advances?
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Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS

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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

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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.

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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

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Boineau et al., Am J Physiol, 1988

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37

SAN cells Atrial cells Connective tissue Coronary arteries

Fedorov, Circ Res, 2009

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Fedorov, JACC 2010

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Fedorov, JACC 2010

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Boineau et al., Am J Physiol, 1988 Fedorov, JACC 2010

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Fedorov, JACC 2010

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Kistler et al. P-Wave Morphology in Focal Atrial Tachycardia. J Am Coll Cardiol 2006;48:1010 –7.

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Mendez C, Moe GK. Circ Res. 1966;19:378–393

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Hucker, An. Rec. 2007

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Hucker, An. Rec. 2007

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Fedorov, Circ: EA, 2011

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Fedorov, Circ: EA, 2011

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Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS

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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)

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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.

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Laughner, AJP 2012 Gloschat, Sci Rep 2018

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Lou, AJP 2012 Qing Lou Lou, AJP 2012

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Qing Lou Lou, AJP 2012

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  • 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

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Kedar Aras Aras, Circ: A&E, 2018

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Kedar Aras Aras, Circ: A&E, 2018

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Kedar Aras

Wavelength volume: Vλ= λLongitudinal x λTransverse x λTransmural

Aras, Circ: A&E, 2018

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Kedar Aras

Wavelength volume: Vλ= λLongitudinal x λTransverse x λTransmural

Aras, Circ: A&E, 2018

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Kedar Aras

Endo L-trans R-trans Epi

Aras, Circ: A&E, 2018

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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

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Haissaguerre et al, Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death, Circ: A&E, 11(7), e006120

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Haissaguerre et al, Localized Structural Alterations Underlying a Subset of Unexplained Sudden Cardiac Death, Circ: A&E, 11(7), e006120

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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

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Basic electrophysiology: SA and AV nodes Pathophysiology: arrhythmia mechanisms Human heart disease OMICS

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Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.

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Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.

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Matkovich et al, Widespread Downregulation of Cardiac Mitochondrial and Sarcomeric Genes in Patients with Sepsis. Crit. Care Med. 2016.

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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.
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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.
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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.
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Novel promoters in FANTOM5

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Promoter-level heart transcriptome for ventricular remodeling studies

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Promoter-level heart transcriptome for ventricular remodeling studies

Deviatiiarov, unpublished 2019

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Deviatiiarov, unpublished 2019

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55 Overlapped regulatory features – 333 in our data vs 244 from Ensembl 6% upstream SNPs SNP 20% SNPs in heart-CAGE promoters Ensembl

promoters 204940

FANTOM5

enhancers 65420

GWAS

(heart SNPs 5104)

pro/enh

Heart CAGE: 1050/33 Ensembl: 431/17

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Disease-associated mutations:

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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

  • ther 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?

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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.

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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.