Significant pharmacologic, interventional and surgical strategies in the management of coronary syndromes, together with evolving surgical and non-surgical innovations for valvular disease and improved care of congenital heart disease, have ensured that patients live longer and better lives. With these advancing therapies for cardiac disease, the number of patients surviving to develop end-stage heart failure continues to increase exponentially. While the heart as an organ has evolved to demonstrate remarkable resilience in the setting of disease, death from cardiovascular causes remains the most common cause of death in many parts of the world. Given the significant morbidity and mortality associated with end-stage heart failure, the last half century has been notable for a concentrated effort on developing therapies for the failing heart.
In this issue, Professor Stephen Westaby (see https://doi.org/10.5837/bjc.2022.021) provides an insightful personal perspective on a laudable life-long pursuit in the development of mechanical circulatory support with the ultimate goal of a fully implantable device. His long career has been punctuated by a number of seminal achievements, which have led to incremental improvements in a challenging area.
The human heart has evolved over millennia whereby it is able to pump up to 20 litres per minute upon demand, it can adapt to work efficiently at altitudes of up to 30,000 feet and at high atmospheric pressures under sea. It is not surprising, therefore, that the first attempts at therapies for end-stage heart disease focused on orthotopic transplantation. Certainly, over the last 50 years since Barnard’s first heart transplant, significant advances in immunosuppression and post-transplant management have led to heart transplantation being the optimal long-term solution. One-year survival now exceeds 90% at many institutions (and a conditional median survival of 14 years), with 20% surviving beyond two decades.1 Such longevity has yet to be demonstrated for mechanical circulatory support. Additionally, heart transplantation affords unparalleled freedom with many patients remaining active and able to participate in endurance sports without the worry of remaining close to a power source.
Donor numbers increase
Lack of organ availability is a valid concern, but recent efforts at addressing this have resulted in significant progress. In the US more than half of available organs are not utilised2 and efforts are underway to improve on this. The acceptance of hearts for donation after circulatory death has expanded transplant volumes significantly, including in the UK, where volumes have surged by up to 48% with excellent outcomes.3 Other developments include the use of hepatitis C donors since the advent of direct-acting antiviral therapies.4 The development of organ preservation systems is now facilitating the use of organs with much longer ischaemic times.5 Hurdles of allosensitisation are being addressed by the development of desensitisation therapies, which are allowing the most immunologically challenging patients to undergo heart transplantation.6 An increasing number of young women after heart transplantation are now able to successfully complete pregnancy.7 Indeed, these benefits of transplantation and current limitations of mechanical circulatory support, have resulted in almost 50% of all heart transplants being performed in patients bridged with a mechanical device.1
Xenotransplantation has seen the slowest advance and Cambridge researchers may have backed the wrong horse. Two important advances in molecular technologies – cloning and gene editing – have again kick-started the field. The recent human xenotransplant attempt was so reminiscent of when Barney Clarke became the first recipient of a totally artificial heart.8 While many hurdles have seemingly been addressed, including elimination of porcine endogenous retroviruses and prevention of hyperacute rejection by elimination of carbohydrate antigens, there remain significant challenges, not least the concerning transmission of zoonotic infection, which may have contributed to the demise of the recipient two months after the xenotransplant.
Clearly, the demand for organs vastly outstrips the availability of donors despite the progress noted above. The development of mechanical circulatory support devices has thus provided a vital alternative therapy. Early challenges with pulsatile devices led to the development of continuous flow pumps, which are now the mainstay. The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM-3) demonstrated the remarkable progress that has been made with durable circulatory support outcomes comparable to those seen with heart transplantion, at least in the first few years.9 While patients on devices are not hampered by potential side effects of chronic immunosuppression, significant challenges remain, including ongoing complications relating to pump thrombosis, haemolysis, infection and bleeding. The long-term limitations of drivelines, with attendant complications, have been well outlined and the development of untethered systems will be a significant and promising advance in this field.
These advances are akin to many of the challenges seen in the evolution of the electric car, particularly pertaining to charging and ‘range anxiety’. Just as the talents of engineer David Saucier were leveraged to develop a continuous flow left ventricular assist device (LVAD) from his experience of designing hydrogen turbo pumps for the space shuttle, the significant resources allocated to developing charging technologies for the electric automotive will hopefully be translated to the LVAD arena. Another important priority is the development of biocompatible surfaces to minimise the need for anticoagulation.
The human heart is a formidable organ with remarkable adaptability and durability. The last few decades have seen remarkable efforts at developing a mechanical solution as an alternative or as a supplementary device through enduring and laudable efforts of pioneers in the field including Michael DeBakey, OH Frazier, John Kirklin and Stephen Westaby. The future for the field is bright with an appropriate focus on functionality, durability, adaptability to paediatric populations and, most importantly, cost.
Conflicts of interest
None declared.
Funding
None.
Editors’ note
Please see the article by Professor Stephen Westaby ‘Evolution of a circulatory support system with full implantability: personal perspectives on a long journey’ which can be found here: https://doi.org/10.5837/bjc.2022.021.
References
1. Khush KK, Cherikh WS, Chambers DC et al. The International Thoracic Organ Transplant Registry of the International Society for Heart and Lung Transplantation: Thirty-sixth adult heart transplantation report – 2019; focus theme: Donor and recipient size match. J Heart Lung Transplant 2019;38:1055–66. https://doi.org/10.1016/j.healun.2019.08.004
2. Khush KK, Menza R, Nguyen J, Zaroff JG, Goldstein BA. Donor predictors of allograft use and recipient outcomes after heart transplantation. Circ Heart Fail 2013;6:300–9. https://doi.org/10.1161/CIRCHEARTFAILURE.112.000165
3. Messer S, Cernic S, Page A et al. A 5-year single-center early experience of heart transplantation from donation after circulatory-determined death donors. J Heart Lung Transplant 2020;39:1463–75. https://doi.org/10.1016/j.healun.2020.10.001
4. Siddiqi HK, Schlendorf KH. Hepatitis C positive organ donation in heart transplantation. Curr Transplant Rep 2021;8:359–367. https://doi.org/10.1007/s40472-021-00350-1
5. Ardehali A, Esmailian F, Deng M et al. Ex-vivo perfusion of donor hearts for human heart transplantation (PROCEED II): a prospective, open-label, multicentre, randomised non-inferiority trial. Lancet 2015;385:2577–84. https://doi.org/10.1016/S0140-6736(15)60261-6
6. Patel JK, Coutance G, Loupy A et al. Complement inhibition for prevention of antibody-mediated rejection in immunologically high-risk heart allograft recipients. Am J Transplant 2021;21:2479–88. https://doi.org/10.1111/ajt.16420
7. Punnoose LR, Coscia LA, Armenti DP, Constantinescu S, Moritz MJ. Pregnancy outcomes in heart transplant recipients. J Heart Lung Transplant 2020;39:473–80. https://doi.org/10.1016/j.healun.2020.02.005
8. Mehra MR. Cardiac xenotransplantation: rebirth amidst an uncertain future. J Card Fail 2022;28:873–4. https://doi.org/10.1016/j.cardfail.2022.01.006
9. Mehra MR, Uriel N, Naka Y et al. A fully magnetically levitated left ventricular assist device – final report. N Engl J Med 2019;380:1618–27. https://doi.org/10.1056/NEJMoa1900486
