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 27 th , 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 of 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 Selective coronary arteriogram in a normal dog by Charles 1958;71:503-23) Dotter in 1950’s. Dotter CT, Frische LH. Visualization of the coronarycirculation by occlusion aortography: a practical • Also performed the first transluminal method. Radiology 1958;71:503-23 angioplasty (lower extremity)
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 opened 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 *Pompili et al, Port Access Mitral catheter-based techniques 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 other interventions/tools best addressed in animal models in the pre-clinical phase
Atrial Fibrillation • Mechanism of AF still poorly • The initial surgical techniques (ie: understood Cox Maze procedure) were developed after some of the • Current ablation therapies not mechanisms of atrial arrhythmias always effective were described in dogs • New techniques utilizing currently- • Natural and evoked atrial flutter available technologies can be due to circus movement in dogs: studied in humans Role of abnormal atrial pathways, • Development of novel catheter or slow conduction, nonuniform other interventions/tools best refractory period distribution and addressed in animal models in the premature beats (Boineau et al. pre-clinical phase 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.
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