Tag Archives: Heart

50 Year Anniversary of the First Human Heart Transplant: Lessons for Today

On 3 December we commemorated the 50 year anniversary of the world’s first heart transplant. The operation took place in the early hours of a Saturday morning at the Groote Schuur hospital in Cape Town, South Africa. Christiaan Barnard sutured Denise Darvall’s donated heart into the chest of the recipient, Louis Washkansky. Barnard restarted the new heart with an electric shock and then tried to wean the recipient off the heart and lung machine. But the new heart could not take the strain and Washkansky had to go back on the machine. The second attempt also failed, but when the heart and lung machine was turned off for the third time the recipient’s blood pressure started to climb. It kept on climbing, and soon Denise Darvall’s small heart had taken over the perfusion of Louis Washkansky’s large frame. Later that morning the world woke to the news of the world’s first heart transplant. Looking back over fifty years what should we make of Barnard’s achievement?

The transplant in an historical perspective

The two decades preceding the heart transplant have sometimes been referred to as the golden age of medical discovery.[1] The transplant can be ‘fitted’ retrospectively as the culmination of this golden age just as Neil Armstrong’s moon walk, two years later, can be seen as the crowning achievement of the space race. They belong to a number of technical achievements, including the first “test tube” baby and the first man in space, which are emblematic of human progress. They generate great public interest and media attention, but differ from more fundamental intellectual discoveries, such as the double helix in DNA or Higgs boson, that are rewarded with Nobel prizes.

The heart transplant in the ‘heroic’ medical age

In his book ‘One Life’ Barnard provides an interesting cameo of the power and autonomy of the medical profession in his time.[2] He recalls writing up the routine operation note that must follow any surgical procedure. The anaesthetist, ‘Oz’, suggested that Dr Jacobus Burger, the hospital superintendent, should be informed. Barnard asked whether he should wake him so early in the morning, but Oz replied that the night’s events warranted such an intrusion. At first the befuddled Dr Burger, aware if work in the animal lab, thought that he was being informed about another heart transplant in dogs. However, even when he learned that the transplant involved a human heart, he cryptically thanked the surgeon and replaced the receiver. Nowadays, the idea of carrying out a procedure of such novelty, cost and risk without formal sanction would be unfathomable. The vignette from the doctor’s tearoom vividly illustrates how the relationship between the medical profession and the broader society has changed over one generation. Rene Amalberti argues [3] that many professions progressed through a heroic age in the twentieth century before gradually becoming more formalised and regulated – aviation followed a similar trajectory following Charles Lindbergh’s dramatic flight across the Atlantic in 1927.

Gradually changing ethical norms

The ethics of heart transplants relate mainly to organ donation. In ‘One Life’ Barnard describes the tense atmosphere in the operating room as the team waited for the donor heart to stop after turning off Darvall’s ventilator. In fact, they did not wait, and Barnard’s brother Marius has stated he persuaded Christiaan to stop the donor heart by injecting a concentrated dose of potassium in order to give Washkansky the best chance of survival. Today two different doctors need to independently carry out tests to confirm the donor is brain stem dead before the heart can be removed, as opposed to waiting for death by the whole-body standard, i.e. when there is brain death and the heart has stopped beating.

Public views of heart transplants, then and now

Following the operation the exhausted Barnard went home for a sleep. In the afternoon he returned to the hospital where he was surprised to find his route obstructed by a large crowd of reporters. He had unleashed a tide of publicity and acclaim that resonated for many decades, but dissenting voices were also heard. Some, notably Malcolm Muggeridge, the editor of Punch magazine, attacked the operation on the basis of a near mystical reverence for the human heart and to this Barnard had a succinct response: “it’s merely a pump.” Others worried about the allocation of scarce resources to such a high-tech solution when people were dying from malnutrition and malaria. Defence of the procedure came, albeit years later, from the economics profession when it was shown that the operation has a highly favourable cost-to-benefit ratio (at least in a high-income country).[4] The procedure not only extends life by many years on average, but greatly improves the quality of that life. In fact, patients feel much better from the moment they regain consciousness after the operation despite pain from the sternotomy. The operation is now uncontroversial and is performed routinely in high-income countries. It was long predicted that a mechanical pump would supplant the need for transplantation. Mechanical hearts have improved,[5] but they are largely seen as a bridge to transplantation, rather than a better alternative.

If Christiaan Barnard had not performed his operation, heart transplants would have developed anyway (the second transplant was carried out independently by Adrian Kantrowitz in the USA on 6 December). I was a school boy with hopes of getting into medical school when Washkansky received his new heart. I was among the many millions who were swept up in the wonder of the event and it still stirs my imagination half a century later. And my family knows that I wish to donate my own heart if the circumstances arise.

— Richard Lilford, CLAHRC WM Director

References:

  1. Lilford RJ. Future Trends in NHS. NIHR CLAHRC West Midlands. 25 November 2016.
  2. Barnard C & Pepper CB. One Life. Toronto, Canada: Macmillan; 1969.
  3. Amalberti R. The paradoxes of almost totally safe transportation systems. Saf Sci. 2001; 37(2-3): 109-26.
  4. O’Brien BJ, Buxton MJ, Ferguson BA. Measuring the effectiveness of heart transplant programmes: Quality of life data and their relationship to survival analysis. J Chron Dis. 1987; 40(s1): s137-53.
  5. Girling AJ, Freeman G, Gordon JP, Poole-Wilson P, Scott DA, Lilford RJ. Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapyInt J Technol Assess Health Care. 2007; 23(2): 269-77.
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More on Mendelian Randomisation

News Blog readers know that the CLAHRC WM Director loves Mendelian randomisation studies, originally proposed by his erstwhile colleagues, Gray and Whitley.[1] The method has been used to crack open the story regarding lipids and coronary artery disease.[2] Everyone knows that low density lipoproteins are bad news – these fats clog up arteries. The association is confirmed by Mendelian studies. But what about those two old chestnuts, high density lipoproteins (HDLs) and triglycerides? In observational studies HDLs are consistently associated with reduced risk of coronary disease.[3] While triglyceride levels are associated with increased coronary risk, this effect disappears once confounders have been controlled in multi-variable analysis.[3] However, Mendelian randomisation tells a completely different story – HDLs are not associated with coronary risk, while triglycerides are.[4] [5] What is going on here? That is to say, why do the observational studies and the Mendelian studies give such different answers with respect to HDLs and triglycerides? More curious still, why does the association between triglyceride and coronary artery disease confirmed by Mendelian randomisation disappear after controlling for confounders? This is not entirely clear, but as HDL levels drop, so triglycerides tend to rise. Hence controlling for triglyceride levels when examining HDLs, and vice-versa, will give the wrong result. This may be yet another example of ‘over controlling’ but including in a multi-variable analysis / logistic regression variables that have a causal interaction with the explanatory variable of interest.[6]

— Richard Lilford, CLAHRC WM Director

References:

  1. Gray R & Wheatley K. How to avoid bias when comparing bone marrow transplantation with chemotherapy. Bone Marrow Transplant. 1991;7(s3):9-12.
  2. Emdin CA, Khera AV, Kathiresan S. Mendelian Randomization. JAMA. 2017; 318(19): 1925-6.
  3. Di Angelantonio E, Sarwar N, Perry P, et al.; Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA. 2009; 302(18): 1993-2000.
  4. Do R, Willer CJ, Schmidt EM, et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet. 2013; 45(11): 1345-52.
  5. Frikke-Schmidt R, Nordestgaard BG, Stene MCA, et al. Association of loss-of-function mutations in the ABCA1 gene with high-density lipoprotein cholesterol levels and risk of ischaemic heart disease. JAMA. 2008; 299(21): 2524-32.
  6. Lilford RJ. A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease. NIHR CLAHRC West Midlands News Blog. 10 November 2017.

A Very Interesting Paper Using Mendelian Randomisation to Determine the Effect of Extra Years of Education on Heart Disease

It turns out that there are a number of genes, all associated with aspects of neurodevelopment, that predict how many years a person will spend in formal education.[1] It is already very well established that more years of education are associated with large reductions in coronary heart disease (CHD) (mediated by behaviour such as lower calorie intake, less smoking, more exercise).[2] So the authors of a recent well-written and most interesting BMJ paper did the obvious thing.[3] [4] They related the (random) presence or absence of educational propensity genes to CHD. Bingo, they measured a large effect (the genes that predispose to larger durations of formal education associate with reduced CHD). Now, the thing with Mendelian randomisation is that the genotype must not be linked to the outcome (CHD in this case), other than through the putative explanatory variable (duration of education in this case). The authors are aware that it is quite possible that education genes are linked to the outcome (CHD), net of (any) effect on education. To deal with this possibility they perform sensitivity analyses. They examine the association of genetic variates associated with education and the behaviours that lead to CHD. If the effects on education and on CHD behaviours are similar across the genetic variates this suggests that the effect on CHD is through education and not through another variable. And so it was. They also looked to see whether genetic variants already known to be associated with CHD (genes for high cholesterol, etc.) were also associated with education. If the genes associated with education do not associate with these other risk factors, then that favours a cause and effect explanation. There was no association. However, such an association would only be expected if there was a ‘massive’ effect of ‘education genes’ that bypassed education.

This all falls short of proof. Since the educational genes lead to education through mental processes, it is reasonable to suppose that almost all genetic variates that affect education also affect behaviour. Thus, they would affect CHD, even if there was no extra education. The authors say that their conclusion is strongly supported by identical twin studies where one twin stayed longer in education than the other, but this too ignores the fact that these twins are different, for all that their inherited genotype is the same, and so these differences could be the cause of both increased education and decrease in the behaviours that lead to heart disease.

One more point ­– even if years of education really are causative, this might well apply only to people genetically predisposed to more education and may not apply among those not so predisposed – there may be an interaction between the genes that predisposes to education and response to that education. After all, why would one persist in the classroom if you were not predisposed to benefit from the experience? People not predisposed would find being coerced to do so most unpalatable, and such an approach could even have a perverse effect. This is an excellent article and is beautifully presented. But I am a little more sceptical than the authors. I would like to see a debate on the issues.

— Richard Lilford, CLAHRC WM Director

References:

  1. Okbay A, Beauchamp JP, Fontana MA, et al. Genome-wide association study identifies 74 loci associated with educational attainment. Nature. 2016; 533(7604): 539–42.
  2. Veronesi G, Ferrario MM, Kuulasmaa K, et al. Educational class inequalities in the incidence of coronary heart disease in EuropeHeart. 201635895865.
  3. Tillmann T, Vaucher J, Okbay A, et al. Education and coronary heart disease: Mendelian randomisation study. BMJ. 2017; 358: j3542.
  4. Richards JB & Evans DM. Back to School to Protect Against Coronary Heart Disease? BMJ. 2017; 358: j3849.

So What About Oxygen for Heart Attacks Then?

A heart attack is caused by blockage of one of the arteries that supplies oxygen to the heart muscle. When this happens some of the heart muscle dies quickly and, as with stroke, this area of necrosis is surrounded by a penumbra where the heart muscle cells are damaged but not dead. Oxygen administered through a face-mask results in an increase in the amount of oxygen dissolved in the blood. Surely then, oxygen makes sense in people who are having a heart attack? Such therapy has been standard since my days as a medical student.

Well, it turns out that while oxygen therapy does no harm in heart attack victims, it also does no good whatsoever. This is the result of a randomised trial of over 6600 patients.[1] Death rates, a test for heart cell damage, and re-hospitalisation rates were almost identical across the two groups. The null result was consistent across all pre-specified subgroups of patients.

A picture is starting to emerge: oxygen therapy does not limit tissue loss in patients with acute ischemic injury.

It is quite difficult to improve on the bodies evolutionary adaptations to injury as the following report will further reinforce.

— Richard Lilford, CLAHRC WM Director

Reference:

  1. Hoffman R, James SK, Jernberg T, et al. Oxygen Therapy in Suspected Acute Myocardial Infarction. New Engl J Med. 2017; 337: 1240-9.

Brain Activity and Heart Disease – a New Mechanism

The amygdala is a key component in the ‘salience network’ of the brain. This network is activated in conditions of fear and stress. A recent elegant paper in Lancet [1] examined the relationship, first, between amygdala activation (measured by PET scanning) and cardiovascular outcomes, and second, between activation of the amygdala and certain mediators of cardiovascular disease concerned with stimulation of bone marrow to produce inflammatory cells and with arterial inflammation. They showed positive correlations in all cases. I am interested in causal modelling,[2] [3] and I was therefore provoked by the authors’ ‘mediation model’, which I take to be a form of structural equation modelling. This suggested that only half of the amygdala’s ‘effect’ on cardiovascular disease could be explained by the two mechanisms proposed above (production of inflammatory cells and arterial inflammation). This paper represents a potential step change in understanding brain-body interactions, but I await replication with interest.

— Richard Lilford, CLAHRC WM Director

References:

  1. Tawakol A, Ishai A, Takx RAP, et al. Relation between resting amygdalar activity and cardiovascular events: a longitudinal and cohort study. Lancet. 2017; 389: 834-45.
  2. Lilford RJ, Girling AJ, Sheikh, et al. Protocol for evaluation of the cost-effectiveness of ePrescribing systems and candidate prototype for other related health information technologies. BMC Health Serv Res. 2014; 14: 314.
  3. Watson SI & Lilford RJ. Essay 1: Integrating multiple sources of evidence: a Bayesian perspective. In: Challenges, solutions and future directions in the evaluation of service innovations in health care and public health. Southampton (UK): NIHR Journals Library, 2016.

A Device for Failing Hearts

Back in 2005 I was approached by Sally Davies, then languishing as deputy director general of Research and Development, and asked to evaluate the utility of a trial of left ventricular assist devices (LVADs) for heart failure. We elicited a Bayesian prior from a chapter of surgeons from the American Society of Heart Surgeons. This prior was the basis for a value of information study,[1] which suggested that expensive LVAD technology might be a bridge too far for the hard-pressed NHS. Anyway, the world moves on and the New England Journal of Medicine has recently carried out a trial comparing two different LVADs, one more sophisticated (type 3) than the original version we studied (type 2).[2] The latest version had less problems with clotting up of the device, but survival free of a serious stroke at six months was similar, at over 80% in both groups – quite high considering how sick these patients were. The article has some extremely good diagrams explaining the devices. These devices are sometimes used to rest the heart, for example in a case of inflammation of the heart muscle. Most often they are used when the heart muscle packs up permanently, say as a result of heart attacks. In that case LVADs can be used to keep a person alive until a match can be found for a heart transplant, so called ‘bridge to transplant’, or as a permanent solution. However, I think the devices are themselves a bridge to a more subtle regenerative medicine approach based on stem cells.

— Richard Lilford, CLAHRC WM Director

References:

  1. Girling AJ, Freeman G, Gordon JP, Poole-Wilson P, Scott DA, Lilford RJ. Modeling payback from research into the efficacy of left-ventricular assist devices as destination therapy. Int J Technol Assess Health Care. 2007; 23(2): 269-77.
  2. Mehrea MR, Naka Y, Uriel N, et al. A Fully Magnetically Levitated Circulatory Pump for Advanced Heart Failure. New Engl J Med. 2017; 376: 440-50.