On Causality and the Problem of Aneurysms

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                      Notes for a lecture
    M. David Tilson
    Ailsa Mellon Bruce Professor of Surgery
    Columbia University and the St. Luke's/Roosevelt Hospital 
    1000 Tenth Avenue, New York, New York, 10019.
    Phone: 212-523-7779; Fax: 212-523-6495
    Internet address: [email protected]
         I believe that the term "atherosclerotic aneurysm" has been very 
    unfortunate, because it has given us the notion that we have identified
    the necessary cause, the same as we have in the case of "syphlitic"
    aneurysm.  In what follows, I will make the argument that atherosclerosis
    does not provide an informative explanation of aneurysm disease.
         Arguably the most incisive contemporary philosopher on the subject 
    of causality is Paul Humphreys at the University of Virginia 
    (Charlottesville).  He presupposes an ontology where things are presumed 
    to be real and where causal relationships exist among things that are 
    discoverable by experimental methods.  This ontically-oriented metaphysics 
    enables him to avoid the difficulties of Hume, who was unable to discriminate 
    causal from non-causal relationships among observable regularities.  I will 
    return to this idea later when we consider joint observable effects at the 
    root of the fallacy of spurious causation.  And, eschewing linguistic models 
    that articulate rather sterile notions of causality (in my opinion), 
    Humphreys uses the concept of probability to avoid the problems inherent in 
    formulations that fail to deal adequately with the situation of chance 
         Reduced to simplest terms, his view is that we can properly assert 
    that X causes Y if the existence of X increases the probability of the 
    existence of Y.  This is a useful notion. The classical concepts of necessity 
    and sufficiency are the boundary conditions, where the probability factor is 
    either zero or 100%.  X is a sufficient cause of Y, if the existence of X 
    makes Y inevitable.  X is a necessary cause of Y, if in the absence of X, 
    Y will never occur. I will argue in what follows that zero and 100% are 
    imaginary numbers in science.
         Let us see how these ideas work out when applied to the causation of 
    various forms of aneurysm disease.  Among the most intuitive cases under 
    discussion today for a necessary and sufficient cause is mutation of a 
    recently discovered gene for a metal-transporting-ATPase at the mottled 
    locus of the Brindled mouse, which is closely related to the Blotchy.  The 
    Blotchy mutation is sufficient in the sense that 100% of the males carrying 
    the mutation will develop aneurysms, if they do not die of other causes 
    before six months of age.  It is necessary in the sense that the phenotype 
    does not occur in the absence of the mutation.  You get a perfectly normal 
    C57BL6 black laboratory mouse.  
         However, sufficiency fails under the condition of a negative 
    contributing cause.  We have found that propranolol reduces the probability 
    to 70 % at six months.  Nor can we be sure that only one gene will satisfy 
    the requirement for necessity, since one cannot a priori rule out the 
    possibility that a new mutation may arise that causes identical phenotypic 
    effects.  Since we cannot be sure that a cause is absolutely necessary or 
    absolutely sufficient until the world is over, I will henceforth use the 
    terms in a less formal sense, when I intend to imply that their presence or 
    absence makes the existence of the respective effect highly probable.  
         The example of the broad-breasted-white (BBW) turkey allows further 
    exposition of probabilistic causality and enables us to examine an example 
    that has multiple causal influences.  The broad-breasted-bronze (BBB) turkey 
    does not get spontaneous aortic aneurysms, so we may infer that some feature 
    of the genome of the BBW-turkey is a necessary cause, in the sense that if 
    this feature were not present, the aneurysms would not occur.  However, the 
    genetic factor is not a sufficient cause, since some BBW-turkeys do not 
    develop aneurysms.  The  case of multiple causal influences applies because 
    there are well-defined positive and negative contributing causes.  If the 
    BBW-turkey is treated with the lathyrogen, beta-amino-proprionitrile (BAPN), 
    the probability of aneurysm development increases substantially.  If the 
    BBW-BAPN turkey is treated with the negative contributing cause, propranolol, 
    the probability is reduced.The example of the BBW-turkey also allows us to 
    introduce the notion of a chain of causal events.  What is the intermediate 
    step between administration of propranolol and a reduced probability of 
    aneurysms?  The hypothesis that propranolol achieves its status as a negative 
    contributing cause through its antihypertensive properties is defeated by 
    the fact that other antihypertensives are not effective, even though a 
    similar hemodynamic response is achieved.  It now appears that propranolol 
    is a negative contributing cause, both in the BBW-turkey and in the Blotchy 
    mouse, because of an effect that stimulates crosslinking in connective 
                   NON-HUMAN PRIMATES
         Now consider the examples of the non-human primates.  As in the 
    BBW-turkey, genetic considerations apply.  Aneurysms are thirteen times 
    more common among cynomolgus monkeys than rhesus monkeys.  Among cynomolgus 
    monkeys that develop aneurysms, it would be extremely interesting to know 
    if they comprise a kinship, of brothers, fathers, and/or monkeys' uncles.  
         Zarins has reported aortic ectasia in four of six monkeys subjected 
    to a regimen of atherogenesis and regression.  The monkeys were fed a 2% 
    cholesterol / 25% peanut oil diet for 6 months, and their mean serum 
    cholesterol reached 788 mg%.  They were then fed a 0.25% cholesterol / 
    15% corn oil diet for 6 months.  There was less than a 50% increase in the 
    mean aortic radius, by comparison to the 6 month atherogenic diet controls.  
    The authors claim that one animal had a "manifest" aneurysm on the basis of 
    a three-fold increase in lumen area.  From data provided in the paper, one 
    can calculate that this animal had an increase of approximately 65% in 
    aortic diameter.  Using one conventional criterion of a 50% increase in 
    diameter to define an aneurysm, this animal makes the cut, but not by much.  
         Controls were not reported for the regression diet alone.  The 
    information at hand does not rule out the possibility that the regression 
    diet caused an aneurysm in one monkey.  Suppose that there had been an 
    appropriate control group.  Would one positive monkey in six be statistically 
    different than no positive monkeys in six?  By Fishers Exact Test of a 2 x 
    2 contingency table, the one-tailed probability value = 0.50.  It would take 
    about 20 animals in each group to avoid a Type I error.
         Was hypercholesterolemia a contributing cause in this experiment?  
    Perhaps, reserving judgement until there is more than one monkey on which to 
    base an opinion and until there are additional controls.
                     THE HUMAN CONDITION
         Finally, we come to the species of greatest interest.  A mutation 
    in the gene for fibrillin on chromosome 15 (Fib-15) is a necessary and 
    sufficient cause for Marfan's Syndrome.  Certain mutations in the gene make 
    the phenotype inevitable.  Also, so far, no case of the Marfan phenotype 
    has been shown to have two normal genes for Fib-15.  The case of the 
    abdominal aortic aneurysm (AAA) could turn out to be as decisive, if a 
    similarly definitive single major locus were discovered to be the necessary 
    cause.  It would then be left to determine whether the gene satisfies the 
    condition for sufficiency, if an affected individual lives long enough to 
    pass through the window of peak risk.  My hunch is that things may not be so 
    simple, since the AAA may be a disease of greater clinical and molecular 
         Vascular surgeons from time to time see patients with ordinary 
    non-specific AAA's, who have normal cholesterols and minimal systemic 
    atherosclerosis.  Thus, atherosclerosis is not a necessary cause for 
    aneurysm disease in man.  Is it a sufficient cause?  Absolutely not.
         From the point of view of risk factor analysis in the AAA, it 
    appears that smoking is a contributing cause, insofar as the presence of 
    the risk factor increases the probability of the disease.  But smoking is 
    neither necessary nor sufficient.  Smoking is also a contributing cause for 
    atherosclerosis.  The aneurysmal aorta has features that are different from 
    the atherosclerotic occlusive aorta, specifically adventitial inflammation 
    and weakening of the structural integrity of adventitial collagen, which 
    permits ballooning.   Atherosclerosis, on the other hand, is primarily a 
    disease of the subendothelium, associated with the migration and 
    proliferation of cells that may lead to stenosis of the lumen. 
         Consider the hypothesis that the mechanisms by which smoking 
    increases the probability of both diseases are different.  Smoking inhibits 
    the activity of alpha-1-antitrypsin, which may contribute a positive causal 
    influence for aneurysms, by interference with the mechanisms of defense 
    against enzymatic destruction of connective tissue.  Smoking may also result 
    in the exposure of subintimal smooth muscle cells to mitogens absorbed from 
    burning tobacco, which may contribute a positive causal influence for 
    atherosclerosis.  If a person has a genetic susceptibility for both diseases, 
    one would predict that both aneurysmal dilatation and atherosclerosis will 
    develop.  This analysis can be extended by analogy to overlapping Venn 
    diagrams in the field of a common contributing cause.  
         Correlation of joint effects of a common cause can lead to the 
    fallacy of spurious causation.2  To borrow an analogy from Humphreys, we may 
    observe that when the water in an old-fashioned barometer spout rises, a 
    storm often follows.  To say that rising water in the device causes the 
    storm is the fallacy of spurious causation.  However, it is informative 
    scientifically to say that falling barometric pressure has the joint 
    observable effects of water rising in the spout and rain falling.  A similar 
    analysis applies not only to smoking but also to possible joint effects of 
    other factors like hypertension and hypercholesterolemia in aneurysm disease.  
    The occurence of joint effects may permit accurate predictions, but joint 
    effects do not provide informative causal explanations.2
         Pyeritz has observed that Marfan described the syndrome that bears 
    his name in the late 19th century, but it was not until about 1950 that 
    skeptics were convinced that there was a necessary cause (in the sense of a 
    single major locus).  Appreciation of the need to postulate a necessary 
    cause for the AAA was even more delayed, in large part (I believe) because 
    of the unproven dogma that the disease is caused by atherosclerosis.  One of 
    my students, Anil Hingorani, has searched for the first historical 
    attribution of the disease to atherosclerosis, and he found that it is 
    traceable to the translation into English of a book by the Italian surgeon, 
    Scarpa, in the early 19th century.  Although the notion of a difference in 
    atherosclerotic stenosing versus atherosclerotic dilating processes had been 
    raised before, I believe that my paper in 1980 was the first systematic 
    challenge to the idea that atherosclerosis is causal.  Once the ground was 
    broken, seeds quickly sprouted in many laboratories in the United States and 
    around the world.  It is astonishing how long the disease had been neglected, 
    simply because it was so widely presumed that atherosclerosis was an 
    informative explanation.  The old dogma has been passionately defended by 
    the faithful, sometimes with religious fervor, against attacks by the 
    blasphemers; but that has not stemmed a dramatic crescendo of new knowledge 
    on the subject.
         As Humphreys observes, scientific explanations are progressively 
    discovered.  And, in complex situations, the matter of timing can lead to 
    confusion.  He makes the following argument to illustrate a case of 
    sequential overdetermination. If I light a long fuse leading to a bomb, and 
    you then light a much shorter fuse, which ignites the bomb first, it was you 
    and your fuse that caused the explosion, not me and mine.  "One must work 
    backward in the completed process that leads from cause to effect in order 
    to arrive at the correct attribution." 2
         Working backwards, I have advocated the notion that mechanical 
    failure of the collagen is very proximate to the aneurysm effect.  Since 
    the time that I wrote a chapter with a subsection entitled  "Why collagen 
    must fail in aneurysm disease," this idea has gained support.  The evidence 
    for increased collagen turnover and collagenolysis is impressive. We have 
    shown the presence of collagenase in soluble extracts of aneurysmal aorta 
    and also shown that it is detectable immunohistochemically in mesenchymal 
    cells and occasionally endothelial cells.  Gelatinase-B (also known as 
    Matrix MetalloProteinase 9 or Type IV Collagenase) and stromelysin-1 are 
    also present and localize to macrophages.25    In addition, plasmin and the 
    plasminogen activators are present.   
         The complex interrelationships of the contributing causes, including 
    the several types of cells present, the immunoglobulin response, the 
    cytokinetic signals,  and the biochemistry of the enzymes, will all be 
    discovered in due course by the scientific method.  And, so will the 
    necessary cause, which I still hypothesize to have a genetic basis. 
                   IN CONCLUSION
         The most extreme iconoclastic position would be that the present 
    evidence supports a stronger argument that aneurysms cause atherosclerosis 
    than the other way around.  Consider the subclavian artery aneurysm that 
    begins as a post-stenotic dilatation caused by a cervical rib.  In due 
    course it will develop atherosclerosis.  Rob once reported calcification 
    of a post-stenotic dilatation of the aorta distal to a coarctation.  
    Bauer Sumpio and I found that there are boundary layer separations, 
    turbulence, and reversal of flow on the surface of a glass model aneurysm 
    of the human aorta.  These conditions at the flow surface have been shown 
    by many workers to stimulate the development of atherosclerotic lesions.  
    It should not be surprising that Reed and coworkers found a large portion 
    of the flow surface of an aneurysm to be affected by atherosclerosis.13
         I remain skeptical that primary attribution of aneurysm disease 
    to atherosclerosis has been particularly helpful in the search for a 
    necessary cause, and I feel that I have been very fortunate to see some of 
    my ideas serve as a propaedeutic that has brought many talented young 
    investigators into the aneurysm research field.  A natural scientist cannot 
    rest until there is an informative explanation for a biological event.