Out of Pandora's Box

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Rami Khouzam, MD
Out of Pandora's Box
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DISCLOSURE

• The Impossible Dream

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INDEX CASE

• 64 y/o WM presented with left- sided CP for 3
  weeks
• sharp, continuous, radiating down his left arm,
  not exacerbated by exertion
• NTG SL some relief
• diaphoresis and palpitations
• (Similar episode 3 months prior)

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Past Medical History

• HTN
• Diverticulosis, AVMs, Multiple GI bleeds
• Hyperlipidemia
• Hypothyroidism
• Cerebellar stroke1996
• Fe. Deficiency anemia
• Aortic insufficiency
• Atrial fibrillation

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• Family History
• CAD, HTN in father
• Colon cancer in uncle
• Social History
• Tobacco ETOH (), quit after CVA

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Medications

• Aspirin 81 mg
• Plavix 75 mg
• Ferrous sulfate 325 mg bid
• Synthroid 0.05 mg
• Lisinopril 20 mg
• Nitroglycerin 0.4 mg SL prn
• Omeprazole 20 mg

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PE

• Gen Pale
• Neck JVD 12 cm
• CV S1 S2 S4 Irregular irregularity
• 3/6 early diastolic murmur LSB? apex
• Lungs Fine bilat. basal crackles
• Abdom BS
• Ext Trace edema bilat.

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Labs (pertinent)

• HGB 11.8 ?
• HCT 37.2 ?
• MCV ?
• Ferritin ?
• TIBC ?

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• Dipsesta (3 months earlier)
• No evidence of ischemia
• EF 35. Cardiomyopathy
• Cardiac catheterization
• Normal coronary arteries
• Aortic root 3-4 AI

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• 2D- Echo
• Dilated aortic root with moderate to severe
  aortic insufficiency
• LV Diastole 70 mm
• TEE
• Dilated aortic root at the sinuses of Valsalva
  maximun diameter 6.3 cm
• 3-4 AI
• Mild global hypokinesis. EF 45-50

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• CT of Chest/ Abdomen/ Pelvis
• Dilated aortic root with ectatic descending
  thoracic and abdominal aorta
• No ascending aortic aneurysm identified beyond
  the root

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Aortic Aneurysms

• Incidence (thoracic) 5.9 per 100,000
  person-years
• Lifetime probability of rupture 75-80
• 5-year untreated survival rates 10-20

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• Size matters
• risk of rupture within 1 year
• lt 5 cm 4
• ? 6 cm 43
• ? 8 cm 80

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PATHOPHYSIOLOGY

• Aneurysm localized or diffuse aortic dilatation
  gt 50 normal diameter
• Weakness or defect in the aortic wall
• Cystic medial degeneration ? progressive
  dilatation
• Atherosclerosis associated but not enough
• Other factors CTD

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CONDITIONS ASSOCIATED WITH ANEURYSMS

• ADPKD
• FMD (Fibromuscular Dysplasia)
• AVM
• CTD Ehlers-Danlos type IV, Marfans syndrome,
  pseudoxanthoma elasticum
• Coarctation of the aorta
• Osler-Weber-Rendu syndrome
• Bacterial endocarditis

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SURGICAL TREATMENT

• Aortic valve or graft replacement or both,
  depends on patient presentation
• 1970s and 1980s No longer was any portion of the
  aorta beyond reach of the cardiovascular surgeon
• Cooley, Debakey, and others...

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• Michael E. DeBakey, M.D., is the oldest of five
  children born to Lebanese immigrants
• Born in 1908, in Lake Charles, LA
• While still a medical student, he devised a pump
  that became one of the essential components of
  the heart-lung machine, which made open-heart
  surgery possible
• Has performed more than 60,000 cardiovascular
  procedures
• First to perform successful excision and graft
  replacement of arterial aneurysms

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• A pioneer in the development of an artificial
  heart, he was the first to use a heart pump
  successfully in a patient
• He also conceived the idea of lining a bypass
  pump and its connections with Dacron velour
• DeBakey is currently working with NASA to develop
  a self-contained, miniaturized artificial heart
• His DeBakey-Raytheon-ITS telemedicine system uses
  satellites to electronically link remote sites of
  the world to the Texas Medical Center for medical
  training and treatment

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• Aortic insufficiency causes
• A) Damage of the aortic valve leaflets
• Rheumatic endocarditis
• Trauma
• Bicuspid aortic valve
• Rheumatoid arthritis
• Myxomatous degeneration
• Ankylosing spondylitis
• Marfans syndrome
• Phenfluramine-phenteramine

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• B) Distortion or dilation of the aortic root and
  ascending aorta
• Aortic root dilatation
• Systemic hypertension
• Syphilis
• Reiters syndrome
• Ankylosing spondylitis
• Trauma
• Dissecting aneurysm
• Elhers-Danlos syndrome
• Osteogenesis imperfecta
• Pseudoxanthoma elasticum
• Inflammatory bowel disease
• Annuloaortic ectasia

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• Severe valvular lesions...
• Until the early 1980s ONLY surgery
• 1985 Percutaneous aortic valvuloplasty (PAV) was
  described by Cribier et al

Circulation, April 2004
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Results

• Reduces tight stenosis to moderate
• final valve area between 0.7 and 1.1 cm2
• (clearly inferior to a valvular prosthesis
  usually valve area gt1.5 cm2)

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Risks

• Hospital mortality from 3.5-13.5 within 24
  hours, 20-25 of the patients at least 1 serious
  complication

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Long-Term Results

• Benefit decreases and finally disappears after a
  few months
• It is now recognized that PAV alone does not
  change the natural course of the disease

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• New Frontiers
• Or
• New Dead-Ends???

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Percutaneous Valve Replacement Repair

• Mid 1960s first experiments started
• 1992 Andersen et al
• porcine bioprosthetic valve attached to a wire
  stent in pigs chest
• Followed by other animal models

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• 2000 percutaneous pulmonary valve replacement
  started in humans with the report by Bonhoeffer
  et al
• (bovine jugular vein sutured into a stent)
• Lutter et al similar experiments with a porcine
  aortic valve mounted into a self-expandable
  nitinol stent

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• Satisfactory durability of the devices for a
  period up to 2 years
• Late 2002 First percutaneous aortic valve
  implantation in humans, performed by Cribier, in
  a 57 yo man with severe aortic stenosis,
  cardiogenic shock and contraindications for
  surgery

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• Good valve function AVA 1.6 cm2
• However, the patient died of severe extracardiac
  complications 4 months later
• Since then, 6 other such procedures have been
  performed

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JACC, March 2004
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• Prolonged life expectancy, aging population,
  increased number of patients with degenerative
  calcific aortic stenosis
• who NEED Surgical AVR
• A subset of patients, elderly with declining
  health status or life-threatening comorbidities
• AVR too high risk or contraindicated

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• Limited therapeutic options
• ? interest in the development of percutaneously
  delivered bioprosthetic aortic heart valve

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• Apr. 2002- Aug. 2003 6 patients 5 males and 1
  female
• Each patient declined for surgery by cardiac
  surgeon
• 3 in cardiogenic shock. All in (NYHA) class IV
• Balloon valvuloplasty previously attempted in 4
  cases

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• Aspirin (160 mg) and Plavix (300 mg) the day
  before the procedure
• Trans-septal catheterization from the right
  femoral vein, heparin 5,000 IV
• A 7-F flotation balloon catheter for anterograde
  crossing of the aortic valve

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• Transseptal puncture dilated with a 10-mm balloon
  catheter, 23 mm balloon catheter advanced from
  the right femoral vein to predilate the native
  aortic valve
• Through a 24-F sheath PHV advanced over the wire,
  across the interatrial septum within the stenotic
  native valve

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• In 2 patients, rapid cardiac pacing (200 to 220
  beats/min) of the right ventricle during PHV
  delivery to decrease aortic blood flow and
  prevent the risk of PHV migration during balloon
  inflation
• Post-procedural treatment included aspirin (160
  mg), plavix (75 mg)
• No COUMADIN needed

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• ? in AVA from 0.49 ? 0.8 cm2 to 1.66 ? 0.13 cm2
  (plt0.04)
• ? in transvalvular gradient from 38 ? 11 mm Hg to
  5.6 ? 3.4 mm Hg (plt0.04)
• Mean duration of the procedure was 134 ? 23 min.
  Mean fluoroscopy time was 28 ? 14 min

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Clinical Course

• Dramatic clinical improvement
• The initial 3 patients who survived the procedure
  (patients 1, 3 4) died of non-cardiac
  complication at 18, 4 and 2 weeks respectively

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• Causes of death
• complications of leg amputation due to
  long-standing PVD (patient 1)
• abdominal syndrome (patient 3)
• hemorrhage from rectal carcinoma (patient 4)
• The most recent 2 patients were discharged at
  days 12 and 15. Clinically stable at 8 weeks with
  no symptoms of heart failure

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• Why the anterograde trans-septal approach?
• Several advantages over the retrograde approach
  to reach the aortic valve
• Allows percutaneous insertion of the PHV through
  a 24-F sheath in the femoral vein under local
  anesthesia
• Eliminates the risk of arterial thrombosis,
  dissection or rupture
• Offers more predictable valve delivery (since the
  PHV crosses the less diseased myocardial surface
  of the aortic leaflets and is coincident with the
  direction of blood flow)

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• AVA 1.7 cm2 obtained in all successful cases
• gt 3-fold improvement ? consistently associated
  with a striking early improvement of the left
  ventricular function
• Results significantly better than those obtained
  after balloon aortic valvuloplasty which rarely
  provides ? in valve area above 0.8 cm2

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• Survival Outcome ??
• In this selected population of severe aortic
  stenosis associated with multiple potentially
  fatal comorbidities, prolonged survival is
  unlikely
• Paravalvular aortic regurgitation noted in all
  patients post-PHV implantation

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• Advantages
• Bioprosthetic valve with stainless steel stent
• No NEED for long-term anticoagulation
• ASA Plavix enough
• I-REVIVE study Ongoing pilot clinical trial will
  allow further refinement of the technique and
  assessment of short and long-term clinical
  outcomes

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JACC, March 2004
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• The technique that will be adopted by the
  majority of cardiologists has to be
• Safe
• Very low risk of mortality morbidity
• Easy to perform
• The Valve has to be
• Ideal
• Biocompatible with no long-term morbidity
• Should last preferably for a lifetime but at
  least 7-10 years
• Expandable (child)
• Economical

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• EXCITING new era for percutaneous cardiac
  intervention
• If such valves and procedures are proved safe and
  effective
• Hundreds of thousands of patients with calcific
  aortic stenosis thousands of patients with
  pulmonic insufficiency may benefit
• ? Maybe alsoAI

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Conclusions

• At the present stage, there are more questions
  than answers
• How can we prevent the obstruction of coronary
  ostia and paravalvular leaks in asymmetric
  calcified orifices?
• What will be the ideal material?
• Jugular bovine veins are limited in size, their
  outcome in the systemic circulation is unknown
• Valves made of polymer or biological material are
  to be designed and evaluated

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• Lessons from the past suggest that in this field,
  a close collaboration between interventionists
  and surgeons is of utmost importance
• First applications of percutaneous aortic valve
  replacement in humans opens a new era for
  research and potential clinical application for
  the percutaneous treatment of acquired valve
  disease

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• Zeus made Pandora, the first mortal woman,
  because he was mad at Prometheus who had had
  given the mortals special gifts, so he decided to
  give them one more Pandora
• Each god gave her something to make her perfect.
  Venus gave her beauty, Mercury gave her
  persuasion, Apollo gave her music, Hephaestus
  gave her voice, Hermes gave her pettiness in her
  tiny brain, etc. Finally she was ready for Earth

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• Zeus gave her to Epimetheus (Prometheus' brother)
• Prometheus had said to Epimetheus not to take
  anything from the Olympians, especially Zeus
• Epimetheus was about to decline, but as soon as
  he looked at her and saw her beauty, he accepted
  Zeus' gift
• Epimetheus gave Pandora a box that she was
  forbidden to open

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• Every day Pandora wondered what was in the box
• She knew she mustn't open it, but she was
  extremely curious and could not bear not to know
  its contents
• As soon as she pulled the cover off, all of the
  evil and mistrust flew out into the world
• When Pandora looked at the bottom of the box, she
  saw that the only thing left was hope to Comfort
  mankind

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From a DREAM..
To a REALITY ??
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