Tag Archives: Heart

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.
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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.