1. An Equal Opportunity University Charles Hoopes MD Jason Alexander Gill Professor in Thoracic Surgery Section Chief, Heart and Lung Transplant/Mechanical Circulatory Support Director, UK Comprehensive Transplant Center University of Kentucky Lexington, KY Evolution of Mechanical Circulatory Support – From the Balloon Pump to the Destination Ventricular Assist Device

2. An Equal Opportunity University Evolution of Mechanical Circulatory Support – From the Balloon Pump to the Destination Ventricular Assist Device Charles Hoopes MD Jason Gill Professor in Thoracic Surgery Section Chief, Cardiopulmonary Transplant/Mechanical Circulatory Support Director, UK Transplant Center University of Kentucky I have no financial disclosures I have no financial relationship with any of the technologies discussed I will not discuss any off label use of current technologies Objectives: Discuss the history of mechanical circulatory support devices from the balloon pump to the first artificial hearts and destination VADs. Describe the evolution of the mechanical assist device from early conception to today’s current technology in successful treatment of advanced heart therapy. Describe the clinical implications for implantation of devices and recovery and what issues future devices may solve.

3. Conceptual eras of mechanical circulatory support.. Etienne-Jules Marey (Paris,1881) – physician, inventor.. the 1 st “artificial heart 1812 Le Gallois “parts of the body may be preserved by external perfusion” Guillotined head of a dog in perfusion experiments of Brukhonenko and Tchetchuline. This preparation relied on gas exchange from a second donor dog's lungs. Diaphragm-like pumps pumped blood into the recipient dog's carotid arteries. Dog heads perfused in this manner remained functional for a few hours. (Reprinted from Brukhonenko S, Tchetchuline S. Experiences avec la tete isolee du chien.1.Technique et conditions des experiences. J Physiol Pathol Gen 1929;27:42)..a “biological oxygenator”

4. “Experimentally, it is possible to completely replace the heart with an artificial heart, and animals have been known to survive as long as 36 hours. This idea, I am sure, could be reached to full fruition if we had more funds to support more work, particularly in the bioengineering area” DeBakey (1963) Senator Lister Hill’s Subcommittee on Health Intellectual origins of “mechanical assist” and “circulatory support”… May 1965 In Jan of 1964 James Hardy consented the sister of Boyd Rush – a 68 yo comatose deaf mute with ischemic heart failure and lower extremity gangrene – for “the insertion of a suitable heart transplant if such should be available. Rush decompensated and was placed on cardiopulmonary bypass. In the absence of a viable donor Hardy transplanted the heart of a 45 kg chimpanzee. The heart provided hemodynamic support for 90 minutes… “..surgeons at Baylor hailed the Jackson transplant. The Baylor surgeons say there are two solutions for support of the failing heart..transplants from humans or animals and artificial hearts. The Baylor group is concentrating its efforts on developing an artificial heart.” Associated Press, 25 Jan 1964

5. Ann Review Med 1966 Physiologic basis… “..mechanical pumping of blood to viscera previously inadequately perfused … reducing the workload and oxygen consumption of the myocardium”

6. 1936 19651969 1981 1968 As socio-political history… 1982 Evolution of Mechanical Circulatory Support…

7. As medical technology … Evolution of Mechanical Circulatory Support … HeartWare Thoratec Abiomed

8. Historical context oxygenators and pumps, biological and mechanical Application (why are you doing this and what do you want) “moratorium of decision” (non-durable ) “bridge to recovery” (non-durable and durable) “bridge to transplant” (non-durable and durable) “destination therapy” (durable) Deployment (how do we do it and when do we try) Problems (general, device specific, and evolving) Evolution of Mechanical Circulatory Support… As clinical medicine…

9. Historical “truisms” in mechanical circulatory support (MCS)… Deployment of MCS technologies in the context of medical futility results in futile deployment of technology… MCS is capable of resuscitation, not reanimation MCS technology restores hemodynamics (>86%) but may not alter survival depending upon the specifics of deployment “Unnecessary surgery” performed well has excellent outcomes… device technology should be deployed based upon clinical trajectory and the natural history of the disease process Physiology always trumps engineering.. MCS can support patients awaiting good clinical decision making but is ineffective in supporting bad clinical decisions

10. 3 October 1930 “..at 8AM respirations ceased and the blood pressure could not be obtained. Within 6 min and 30 sec Dr. Churchill opened the chest, incised the pulmonary artery, extracted a large pulmonary embolus, and closed the incised wound..” “the idea occurred to me if it were possible to remove continuously some of the blue blood from the patient’s swollen veins, put oxygen into the blood and allow carbon dioxide to escape from it, and then to inject continuously the now red blood back into the patients arteries, we might have saved her life. We would have bypassed the obstructing embolus and performed part of the work of the patients heart and lungs outside the body.” JH Gibbon Gibbon JH Jr (1939) The maintenance of life during experimental occlusion of the pulmonary artery followed by survival. Surg Gynecol Obstet 69:604

11. The original “TandemHeart ”… Dennis et al (1962) Ann Surg 156:623

12. Pre pLVADPost pLVAD Cardiac index, l/(min·m2) 0.52 (0.8) 3.0 (0.9) SBP, mm Hg 75 (15) 100 (15) DBP, mm Hg 30 (20) 65 (20) MAP, mm Hg 45 (20) 81 (15) HR, beats/min 105. 118.0 SVO2, % 49 (11.5) 69.29 (10) PCWP, mm Hg 31.52 17.29 PAP mm Hg 39.16 26.70 Lactic acid, mg/dl 24.5 (74.25) 11.0 (12) LDH, U/dl 602 (630) 416.5 (335) pH 7.22 0.14 7.44 0.06 Urine output, ml/day 70.3 1200 Hemoglobin 11 10.25 The Percutaneous Ventricular Assist Device in Severe Refractory Cardiogenic Shock Kar et al (2011) JACC 57:688 Cardiogenic shock: SBP<90mmHg, CI<2 L/min, inadequate end organ perfusion with IABP/pressor support 88 ischemic, 37 non-ischemic (9 myocarditis) pLVAD (TandemHeart): SVO2>70%, MAP>60mmHg, AoV DOS 5.8 days…MSOF(n=31),CVA(n=8)

13. “Pumping improved two patients' circulatory status; one survived. Two patients died before pumping could begin; in another, an abdominal aortic aneurysm prevented insertion of the pump… Kantrowitz et al (1968) JAMA 203:135

14. RETROSPECTIVE ANALYSIS OF 286 PATIENTS REQUIRING CIRCULATORY SUPPORT WITH THE INTRAAORTIC BALLOON PUMP Device function must match patient need… preservation of end organ perfusion (survival) and capacity for functional myocardial recovery The timing of implantation is critical to patient survival… Mechanical circulatory support (MCS) as a clinical program, not an isolated procedure “From 1972 through 1974, we implanted the pump in 34 patients. Of those patients, only 2 (1 in 1973 and 1 in 1974) survived until explantation, and only 1 (the patient in 1974) survived to discharge. Yet the intraaortic balloon pump remains essentially unchanged today, and survival rates of 70% to 80% can be expected when the device is implanted in appropriately selected patients … This experience emphasizes the danger of premature randomized studies, which can expose technology to errors that are manmade rather than inherent.” OH Frazier (2005) Tex Heart Inst J 32:60 Johnson et al (1977) Cardiovasc Dis 4(4):428–436.

15. Cardiac power is the strongest hemodynamic correlate of mortality in cardiogenic shock: A report from the SHOCK trial registry Fincke (2004) JACC 44:340 0.53 CPO: MAP x CO/451 Hemodynamic instability: CI 18 FiO2/PaO2<300, “high” inotropy “Escalation therapy” criteria and MCS application…and deployment

16. Ben Roe and the UCSF “artificial heart” circa 1970 post LVAD

17. Heartware (impellar) Heartmate II (axial flow ) AbioCor TAH Syncardia TAH Left ventricular assist vs. biventricular replacement… Durable vs non-durable applications

18. I II III Evolution of implantable mechanical cardiac assist technologies… …

19. The complexity of mechanical circulatory support technologies represents… epidemiology…a significant clinical need…cardiogenic shock is highly morbid and frequently lethal (>55%) absence of a common effective therapy… anecdotal experience not supported by clinical trials pkVO2 12-16 ml/kg/min variability of clinical application… “Crash and burn” will get bridge to durable device Ongoing RCT in low risk pts with pkVO2 12-16 ml/kg/min Inotrope dependent 1. Critical cardiogenic shock 2. Progressive decline 3. Stable inotrope dependent 4. Recurrent advanced disease 5. Exercise intolerant 6. Exercise limited 7. Advanced NYHA class III

20. Risk factors for death in patients with an implantable mechanical circulatory support device: older patient age at the time of implant (relative risk [RR] = 1.41, p < 0.001); assignment to INTERMACS Level 1 category characterized by cardiogenic shock with life-threatening hypoperfusion (RR = 1.59, p = 0.02); indicators of severe right ventricular failure, such as ascites and hyperbilirubinemia, which are clinically evident at the time of implant Pagani et al (2009) J Heart Lung Transpl

21. Months after Device Implant Competing Outcomes – Level 1: Critical Cardiogenic Shock (n=186) Transplanted 40% Dead 29% Alive 26% Recovery 5% Proportion of patients Transplanted Dead Alive Competing Outcomes – Level 2: Progressive Decline (n=148) Months after Device Implant Proportion of patients Competing Outcomes – Level 3: Stable but Inotrope Dependent (n=35) Transplanted Alive Dead Months after Device Implant Proportion of patients INTERMACS

22. Evolution of mechanical circulatory support…ventricular assist devices Slaughter M (2010) Will destination therapy be limited to large transplant centers? Texas Heart Inst J 37(5):562 Moratorium of decision Bridge to recovery Bridge to transplant Destination (CMS) Are VADs an operation…or part of an integrated heart failure program?

23. No device has ever saved or killed a patient … good physicians using good devices have done both No device program has everything … effective device programs have everything they need Device technology accomplishes nothing but facilitates everything The evolution of mechanical cardiopulmonary support … the “learning curve”

24. May ‘08 Dec ‘08 LVAD induced remodeling: Basic science and clinical implications for recovery BNP inotropes LVAD pod1 Explant pod1 Explant pod7(103) Pre- explant(12) Inotrope dependent Feb ‘09 s/p LVAD LVAD Dec ‘08 * biomarkers of recovery (genetic,structural,metabolic) * therapeutic intervention (pre,post,and peri) * etiology of CHF (sequential tissue) Leftward shift of the EDPVR (structural “reverse remodeling”) Time dependent reduction in heart size (EDP of 30 mmHg, V 30 ) Regression of cellular hypertrophy

25. May ‘08 Dec ‘08 LVAD induced remodeling: Basic science and clinical implications for recovery Inotrope dependent Feb ‘09 s/p LVAD LVAD Dec ‘08 Leftward shift of the EDPVR (structural “reverse remodeling”) Time dependent reduction in heart size (EDP of 30 mmHg, V 30 ) Regression of cellular hypertrophy