Cardiovascular Research in Dogs & Humans : The Clinicians - - PowerPoint PPT Presentation

Cardiovascular Research in Dogs & Humans: The Clinician’s Perspective

Scott A. Bernstein MD

Clinical Cardiac Electrophysiology Assistant Professor of Medicine Leon H Charney Division of Cardiology NYU School of Medicine Bellevue Hospital Manhattan VA Hospital March 27th, 2019

Outline

• Perspective on the state of cardiovascular disease clinical research

and the translation to human health improvements; how much has research in dogs contributed to improvements in human cardiac health?

• How likely is it that first-in-human studies could replace the use of

dogs in cardiovascular disease research?

• What are the current or near-term cardiovascular human health

needs/gaps for which additional research is needed?

How have canines contributed to human cardiovascular medicine?

How have canines contributed?

• Dogs have played an incalculable

role in advancement of knowledge in all areas of cardiovascular medicine and surgery

• At almost every major milestone
• f development of modern

cardiovascular care, dogs have been involved

Cardiovascular Care

• Judkins & Dotter; Andreas Gruentzig (1977 - first angioplasty)
• Stents, Drug-Eluting Stents
• Diagnostic electrophysiology
• Interventional electrophysiology
• Congenital Heart Surgery
• Development of bypass pump; CABG, Valve Surgery, Robotic Surgery, TAVR
• Transplant
• Cardiac Rhythm Device therapy
• Pacemakers
• Defibrillators
• Biventricular pacing
• Hypertension
• Prevention
• Peripheral Vascular Disease
• Cardiac Rehab

How have canines contributed?

• Dr Dotter was among the first of

what would eventually become known as interventional radiologists

• Performed the first angiography of

the coronary arteries after first performing the procedure in dogs in the early 1950s (Dotter CT, Frische LH. Visualization of the coronary circulation by occlusion aortography: a practical method. Radiology 1958;71:503-23)

Charles Dotter, MD (1920-1985)

Tex Heart Inst J. 2001; 28(1): 28–38. Charles Theodore Dotter: The Father of Intervention

How have canines contributed?

• Dr Dotter was among the first of what

would eventually become known as interventional radiologists

• Performed the first angiography of the

coronary arteries after first performing the procedure in dogs in the early 1950s (Dotter CT, Frische LH. Visualization of the coronary circulation by occlusion aortography: a practical method. Radiology 1958;71:503-23)

• Also performed the first transluminal

angioplasty (lower extremity)

Selective coronary arteriogram in a normal dog by Charles Dotter in 1950’s. Dotter CT, Frische LH. Visualization of the coronarycirculation by occlusion aortography: a practical

• method. Radiology 1958;71:503-23

Development of the ICD

• Pacemakers had been invented in the

1950s to treat bradyarrhythmias (slow heart rates)

• However it was realized that many

patients, especially with coronary artery disease, died suddenly from dangerous ventricular tachyarrhythmias

• Medical therapies, such as anti-

arrhythmic drugs, turned out to cause more harm than benefit

• Dr Michel Morowski was inspired by a

mentor who suffered from Ventricuar Tachycardia and eventually designed the first implantable cardiac defibrillator

Drs Morton Mower and Michel Morowski in 1985 (Kastor, JA. Americal Journal of Cardiology, Vol 63;1989)

Development of the ICD

• By 1975 Dr Mirowski’s team had constructed a

model small enough to be implanted in a dog

• The first ICD was implanted in a human in 1980, in

a young girl suffering from severe ventricular arrhythmias

• Longer term 3-year studies were carried out in 25
• dogs. Seals were improved, toxicity tests were

performed, and eventually the FDA approved the device for humans (Morowski et al, Circulation 1978;58:90-94)

• By 1988 over 5,000 had been implanted
• In the 1990’s and 2000’s multiple randomized

clinical trials proved the mortality benefit of ICDs in high-risk patients, adding years to their lives at little relative cost.

• Now are implanted annually in the US

Development of the ICD

Valvular Heart Disease

• Open heart surgery for valve

replacement was rarely performed prior to the advent of cardiopulmonary bypass

• The ability to support the

patient while the heart was

• pened and repaired led to rapid

development in all areas of cardiac surgery in the 1950’s until today

Valvular Heart Disease

• Minimally invasive techniques were

developed in several animal models, including canines

• Minimally invasive endoscopic

surgery is associated with decreased morbidity and decreased recovery time for patients in many procedures

• Further refinements in minimally

invasive techniques include robotoc-assisted surgery and catheter-based techniques

*Pompili et al, Port Access Mitral Valve Replacement in Dogs. The Journal of Thoracic and Cardiovascular Surgery Volume 112, Number 5; 1996

Valvular Heart Disease

• TAVR is safe in low-risk patients with symptomatic

severe aortic stenosis, with

• low procedural complication rates,
• short hospital length of stay, zero mortality, and zero

disabling stroke at 30 days. Subclinical leaflet thrombosis was observed in a minority of TAVR patients at 30 days

• 200 low-risk patients with

symptomatic severe aortic stenosis at 11 centers to underwent TAVR.

• At 30 days, there was zero all-cause mortality

in the TAVR group versus 1.7% mortality in the SAVR group. There was zero in-hospital stroke in the TAVR group versus 0.6% stroke in the SAVR group.

• (Waksman et al, Aortic Valve Replacement in Low-Risk Patients With

Symptomatic Severe Aortic Stenosis. J Am Coll Cardiol. 2018 Oct 30;72(18):2095-2105)

Atrial Fibrillation

• Atrial Fibrillation affects millions

worldwide

• Mechanism of AF still poorly

understood

• Current ablation therapies not

always effective

• New techniques utilizing currently-

available technologies can be studied in humans

• Development of novel catheter or
• ther interventions/tools best

addressed in animal models in the pre-clinical phase

Atrial Fibrillation

• Mechanism of AF still poorly

understood

• Current ablation therapies not

always effective

• New techniques utilizing currently-

available technologies can be studied in humans

• Development of novel catheter or
• ther interventions/tools best

addressed in animal models in the pre-clinical phase

• The initial surgical techniques (ie:

Cox Maze procedure) were developed after some of the mechanisms of atrial arrhythmias were described in dogs

• Natural and evoked atrial flutter

due to circus movement in dogs: Role of abnormal atrial pathways, slow conduction, nonuniform refractory period distribution and premature beats (Boineau et al. Journal of the Americal College of

• Cardiology. June 1980. Vol 45)

Atrial Fibrillation

Dog and human studies suggested electrical isolation could eliminate AF First described… Often done at the time of cardiac surgery for other indication

Boineau et al. Journal of the Americal College of Cardiology. June 1980. Vol 45

Atrial Fibrillation

The first catheter ablation in humans was performed by Dr. Melvin Scheinman in 1981, using high energy DC shocks. The basic concept of pulmonary vein isolation from the surgical Cox Maze procedure was adapted for use with RF ablation catheters and transeptal puncture, described in 1998 by Michele Haisaguerre in Bordeaux, France.

Atrial Fibrillation

Haisseguerre, 1998 NYU, 2019

Atrial Fibrillation

Kunihiro Nishida, Tomás Datino, Laurent Macle and Stanley Nattel Journal of the American College of Cardiology Atrial Fibrillation Ablation: Translating Basic Mechanistic Insights to the Patient. Vol 64, Issue 8; 2014

Although we have learned much about pathophysiology of AF and how to ablate it, there is still much we do not understand about this common arrhythmia. Many patients have recurrence after ablation.

Atrial Fibrillation

• Although therapeutic options

have progressed significantly in recent years, AF is still the most common arrhythmia

• AF associated with very high cost

and morbidity

• Many animal models exist
• Thyrotoxic

Pericarditis

• Tachy-pacing

Heart Failure

• Mice, Dogs, Pigs, Goats, Sheep

Heart Rhythm, Sept 2012

Atrial Fibrillation

• Although therapeutic options

have progressed significantly in recent years, AF is still the most common arrhythmia

• AF associated with very high cost

and morbidity

• Many animal models exist
• Thyrotoxic

Pericarditis

• Tachy-pacing

Heart Failure

• Mice, Dogs, Pigs, Goats, Sheep

Heart Rhythm, Sept 2012

Can first-in-human studies replace the use of dogs in cardiovascular disease research?

First to Human?

Rune Elmqvist developed the first implantable pacemaker at the prompting of

• Dr. Åke Senning, a surgeon at the Karolinska Institute in Stockholm, in
• 1958. It had a pulse amplitude of 2 volts and a pulse width of 1.5

milliseconds, at a constant rate of 70-80 impulses a minute. The first implant was on October 8, 1958, into a patient named Arne Larsson who lived until December 28, 2001. Arne had about two dozen pacemakers in his extended

• lifetime. This device went straight from the workbench to the patient.

First to Human?

• Letter published in the Annals of

Thoracic and Cardiovascular Surgery 1986;34:204-6

• First reported mitral valve

replacement in 1955

• The valve was designed by

cardiac surgeon and car enthusiast Judson T Chesterton who designed the valve based

• n his knowledge of automobile

engine valves

First to Human?

• Hand made by a pathology

technician on a lathe in the hospital’s mechanical shop from Perspex plastic

• Polished by hand with a silk

handkerchief while watching movies at a local theater

• The valve was placed in the

patient, a 34 year old man with mitral stenosis, through a lateral thoracotomy - not on bypass

• The patient survived 14 hours

First to Human?

• Humans subjects are commonly

used for cardiovascular disease research

• Clinical observations are often

hypothesis-generating

• Certain clinical questions can only

be answered in human subjects or in large population-based clinical studies

• Smaller human studies often used

for refinement of clinical tools/techniques and/or prove efficacy

First to Human in 2019?

• Stringent FDA requirements
• Liability concerns without

adequate pre-clinical/animal testing

• Limitations in existing non-animal

and small animal models to provide sufficient data and experience

• Practical limitations of alternative

animal models

*Class III devices support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential, unreasonable risk of injury

• Novel (FDA-unapproved)

medical devices require Pre- Market Approval by the FDA*

• Can be a long, difficult process
• Iterations of existing, approved

devices may be streamlined via the 501(k) designation if the FDA judges the device to be “substantially similar” to existing devices

First to Human in 2019?

• New devices begin with a concept

which prompts a design by a physician, designer, and/or engineer*

• Prototypes built; patents obtained
• Preliminary bench testing followed

by animal testing

• Testing, re-testing, investment

* Class III devices support or sustain human life, are of substantial importance in preventing impairment of human health, or present a potential, unreasonable risk of injury

• Novel (FDA-unapproved)

medical devices require Pre- Market Approval by the FDA*

• Can be a long, difficult process
• Iterations of existing, approved

devices may be streamlined via the 501(k) designation if the FDA judges the device to be “substantially similar” to existing devices

First to Human?

• Class III devices require IDE prior

to initiation of human studies

• Human studies usually start with

first-in-man and/or small group studies followed by large clinical trials which support the use of the device

• In the current process, direct

from bench to bedside is unlikely

• Dogs vs. alternative animal

model

What are the current or near-term cardiovascular human health needs/gaps for which additional research is needed?

Canine Models

It’s 2019, why are we still doing research on large animals/dogs? An astute observer may ask “It’s 2019, why are not doing more research on large animals/dog?”

Canine Alternative – porcine/murine

Similar physiology and anatomy to humans Can use same/similar instrumentation Legacy data Fully grown can approximate human adult, depending on breed Practical for long-term/survival studies Other animals (Pigs, goats, sheep) may be too pig for standard instrumentation or animal growth rate less practical for survival studies Smaller animals more practical for genetic modification, greater ’n’ Improvements in miniaturization <3F EP catheters Suitable pacemakers Microsurgical techniques Small MRI, optical voltage mapping Canine, and larger animals, very expensive and very labor intensive Greater regulation for large animals requires more time for study approval (appropriately so)

Current Gaps in Knowledge/Clinic Care

• Sudden Cardiac Death
• Prevention
• Indentification of at-risk populations
• Coronary Artery Disease
• Prevention
• Treatment of Acute MI
• Recurrent Events
• Chronic Angina
• PCI vs Surgery
• Congestive Heart Failure
• Valvular Heart Disease
• TAVR vs SAVR
• Stroke/Cerebrovascular Disease
• Peripheral Vascular Disease
• Sudden Death in Atheletes
• Transplant/Artificial Hearts
• Cardiac Rhythm Devices
• Leadless pacemakers
• Lead Management
• New Technologies, power sources
• Device Recalls

Canine Models

It’s 2019, why are we still doing research on large animals/dogs? An astute observer may ask “It’s 2019, why are not doing more research on large animals/dog?”

• Could additional testing have detected

potential problems with cardiac rhythm devices?

• Accufix
• Sprint Quattro Fidelis
• Riata
• Ball & cage valve – Silastic Ball Variance

Ball variance in a Harken mitral prosthesis. Echocardiographic and phonocardiographic features.

• L. Samuel Wann, H J Pyhel, +2 authors Harvey B Feigenbaum
• Published in Chest 1977

Canine Models

It’s 2019, why are we still doing research on large animals/dogs? An astute observer may ask “It’s 2019, why are not doing more research on large animals/dog?” Characteristics of Sprint Fidelis lead failure

The Future – Increasing Incidence

Incidence of Sudden Cardiac Death

Martinez et al. Increasing incidence of non-valvular atrial fibrillation in the UK from 2001 to 2013. BMJ. Vol 101, Issue 21

Incidence of Atrial Fibrillation