Gerard London – Fleury-Merogis, France
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Gerard London – Fleury-Merogis, France |
Prof Zoccali: Doctor London, you have been one of the main investigators that led us to believe that arterial rigidity is a fundamental determinant of cardiovascular risk. Traditionally investigators seem to privilege a biochemical and molecular approach to the identification of risk factors for disease. Your approach is based on a physical rather than a biochemical approach. How did you fall in love with the subject?
Prof London: Well, I think that it’s very difficult to dissociate what is the physical property of a system, the heart, the vessel from biochemical markers because actually, well, the problem actually is two slices. Some people are just interested in these biochemical markers and they don’t rely on these biochemical markers, which are finally able to modify the structure. Because the structure and the rigidity, which depends principally on the relationship between calcium content, collagen content, elastin content, smooth muscle activity, smooth muscle phenotype. Of course, these are the physical properties, which will influence what we are measuring, but these physical properties are influenced by many biochemical markers and so, you can modify the physical property modifying these biochemical markers. The problem is until now no one was really interested in the relationship between physical properties and biochemical properties and this is one of the challenges we are facing in the future and it’s up to us to try to analyse this relationship.
Prof Zoccali: Very good. Data are emerging like the CAFE study that you mentioned that demonstrates that considering central blood pressure may improve our understanding of the effect of drugs on solid outcome measures like mortality and cardiovascular events. Is there any other study based on antihypertensive drugs trying to replicate or extend the findings of the CAFE study?
Prof London: The CAFE study was a very large study because it included in this ancillary study to ASCOT and it included many patients. Many patients, I don’t exactly now remember the number but several hundreds even thousands of patients. There are studies, which were published two years ago in the same frame; the study is called Reason study. Of course, the number of patients in the Reason study which was published in Hypertension is much lower but already has shown in the past exactly the same results and in CAFE study very different effect on different antihypertensive classes on the central blood pressure in comparison with peripheral blood pressure, the effect of central blood pressure lowering, hypertrophy which is much more pronounced than what we observe from the brachial peripheral blood pressure. The problem is that the Reason study was a randomised and controlled study but with a very well, I would say maybe 120 patients nothing to do with the CAFE study which was a very large study and of course, the impact on a very large study implicating thousands, hundreds of patients is much higher but Reason study has already shown these differences. In patients with end-stage renal disease we also have but small study like usually in these patients. One of these studies was published if I remember well in Kidney International in 1996 by Olsen, which showed of course these differences between central and peripheral blood pressure. The problem is that this is related to stiffness and when stiffness increases, these differences between the brachial pressure and aortic central have a tendency to equalise to decrease because the stiffness and the transit times. So in patients with end-stage renal disease maybe it has not been done on a large scale to analyse these differences but maybe it could be less pronounced than in patients in the general population.
Prof Zoccali: Could you briefly tell us which relationship you envisage between arterial rigidity and the kidney?
Prof London: Well, yes but this is a very important point. We know today from several studies which were published in Kidney International, in Hypertension and so on that there is a tight relationship between aortic stiffness, principally aortic central or central artery stiffness and the progressive degradation of kidney function. This is not dependant on the mutual influence of age on kidney function and arterial stiffness and it’s also not dependant on the prevailing blood pressure. This tie exists and exists even in the normal population this trend from normal high GFR to low, which is accompanied by the stiffening of the aorta is real. The second problem is that concerning the CDK chronic kidney disease, a recent study has shown that if you analyse patients already with CDK stage 2, stage 3, stage 4, you have a trend to exactly the same consequences with a degradation of kidney function, the arterial system not only stiffens but only also changes its geometry becoming dilated and maybe this dilation is something which is observed in age because during aging the stiffness and dilation go together. Maybe it’s an adaptation to maintain the capacitive element more or less in the frame. So this is something, which occurs very frequently. The problem is that we don’t know I presently, I’m unable to tell you what is the reason. Maybe the increase in sympathetic activity tone which progresses with degradation, changes in many humoral biomarkers like ADMA, like many other systems which are increasing progressively with changes in kidney function but nobody has looked once again at the relationship between all these biomarkers of uraemic conditions or chronic kidney condition with these changes. But these changes exist. It’s let’s say an arterial renal syndrome.
Prof Zoccali: The study of arterial rigidity in central blood pressure could perhaps help us to a better understanding of early life cardiovascular risk build up. Is there any study going on in children and adolescents?
Prof London: Some small studies are already present and it has been shown that arterial stiffness in the siblings for example, of hypertensive patients is already abnormal. I know also about several genetic studies, which try to link some genetic markers of course, to the stiffening while this work is just in progress because it is of course, multifactorial, it’s not related to one gene but we know about monogenic diseases, which interfere with arterial stiffness, Marfan syndrome, Avlan Douglas syndrome and Gordon’s syndrome, which by a monogenic defect which are just implicated in the changes of stiffness but these are of course, easier to be analysed than these changes with aging. This is a phenomenon, aging is a phenomenon, it is the principal phenomenon in all these changes but what happens during the changes, during ageing to change for example, the relationship between collagen content which increases and elastin content which doesn’t? So where is the shift of these transcription factors? This another question but we know that there is a genetic trend.
Prof Zoccali: Which investigation area in the field of arterial physiology you consider still scarcely studied and in need to be properly investigated?
Prof London: Wow, this is a great question. Well, I will say that one of the problems which is still has not been resolved absolutely properly is the relationship between endothelial dysfunction and these functional changes. Endothelial dysfunction is principally characterised by decreased basal dilation, by decreased changes in the diameter of the artery but this is a conduit function, this is related to the conduit of blood not to the physical property. We know that it’s probably very tightly related. How to investigate? This is very difficult. One of my problems with the investigation of endothelial function is to analyse the signal and the response. The signal to vasodilation is change in shear stress and change in shear stress not only in flow because shear stress is shear rate and viscosity and the problem is that many of these studies just didn’t really analyse in a different patient category properly this relationship. Usually, you know, well in the patients, in central hypertensive patients or in the normal population it’s not a matter, it’s not a big problem, the problem is if you address specifically this question to patients with end-stage renal disease because in end-stage renal disease patients the primary signal, which is shear stress is low. So the signal is low the response is lower, so where is exactly the balance? So I think that for our patients with end stage renal disease, this problem has still not been solved. We know that there is antagonism, that ADMA is – we know all these biomarkers are much more precisely defined than the physical changes. So I think that in this field we need to analyse the relationship once again between function and structure.
Prof Zoccali: Which is the paper published in the last 2 or 3 years that you consider as of fundamental importance in the field of arterial function and arterial rigidity?
Prof London: I will tell you honestly Carmine that one of the most important papers are the results of ASCOT and CAFE study. Why? because in the past you could explain many times that the systolic blood pressure is not the same as the brachial artery and why is it so? Because of the different reflection effect and so on but this still was a theory just o.k. it’s maybe interesting and so what? But the CAFE study, which very carefully demonstrated that the survival and the incident rate of cardiovascular disease is very different in beta blocking group and ACE and calcium channel blocking group, it’s different why is this so? Because actually this difference in the pressure gradients is not just the fantasy, it’s an unexplained reality. So I think that this is a very important paper in my opinion because it’s not a very complicated paper but it’s a very clinical paper but maybe pointing out the importance of this phenomenon.
Prof Zoccali: A light question now. Which is the last film and the last book you read?
Prof London: The last, well, the last film, My God this is a good question. “Inside man” but not here, in Paris and the book I am still reading the book is ‘The History of Russia and its Empire’. It’s a huge book 800 pages, very interesting and if you want to understand what is Russia exactly even today, you have to go back to its history and analyse the genesis of this State and Empire.
Prof Zoccali: A few months ago in another interview you told us that you are fond of Pinot Noir.
Prof London: Yes.
Prof Zoccali: Which is the dish with which you accompany Pinot Noir?
Prof London: Pinot Noir, well venison, frequently venison. That’s strong cheese you know but Pinot Noir is the scale of taste with pinot noir is very huge and of course when I am speaking about pinot noir it’s French Burgundy because this is the origin of Pinot Noir and even in this area Pinot Noir, the wine from the north called the nuit is very different from Pinot Noir from la coute de bol which is lighter more fruity and in the north is more strong, more pronounced, it’s more sophisticated or flavours, so nevertheless the dish I prefer is probably is venison.
Prof Zoccali: Thank you very much.