Slide 1

Dear Colleagues, Mr President thank you to the organisers of giving me the opportunity of sharing with you some data and analyses concerning arterial stiffness and its relation with the kidney.

Slide 2

I will be speaking of methodological considerations first. Second on findings in end stage renal disease patients, third the relations of arterial stiffness with moderate renal insufficiency, the gap of risk assessment strategy to risk reduction strategies and after we will conclude together on the necessity of using arterial stiffness in usual care.

Slide 3

Ok, let’s speak of methodological considerations on arterial stiffness.

Slide 4

I’ll try to be perhaps more accessible to colleagues that are not specialists in haemodynamics. Part of my speech will be based on these documents which are documents that have been published in the European Heart Journal very recently and these documents are focused on colleagues that are not specialised in haemodynamic stuff.

Slide 5

The first point in this document is exactly the topic of Gerard London. Brachial and central pulse pressure, because of pulse pressure amplification between central and peripheral arteries, it is inaccurate to use brachial pulse pressure as a surrogate for aortic or carotid pulse pressure, particularly in young subjects.

Slide 6

We know now that the blood pressure is not the same in the aorta and in the brachial artery, we have know this data for a long time but it has come back to the clinical knowledge recently, for example, with the CAFÉ ASCOT substudy and the REASON study.

Slide 7

The second point is that brachial systolic blood pressure and pulse pressure should not be confounded with central systolic and pulse most often measured at the carotid site. Brachial and systolic hand pulse overestimate always central systolic end pulse especially in young subjects.

Slide 8

Gerard London told us that it was sometimes difficult to analyse the data we get, namely with amplification index and reflected waves. I think that it’s also very important to be very careful in performing haemodynamic assessments. There are many, many points that are important to consider.

Slide 9

These are the main points but remember that if you wish to perform haemodynamic measurements you have to be very, very careful on the measurement conditions. It begins to be a little bit tough. We can assess local arterial rigidity, local arterial stiffness with ultrasound. With echographic parameters we can assess the diastolic diameter and we can assess the systolic diameter and then if we have the difference in the diameter between systole and diastole, we can with the level of blood pressure, of local blood pressure that is to say, for example carotid systolic blood pressure and carotid diastolic blood pressure, we can have the relation between volume that is to say cross-sectional area and pressure that is systolic minus diastolic that is pulse pressure. With this equation we can have distensibility that is the inverse of rigidity.

Slide 10

We have many, many haemodynamic data for local haemodynamic assessments. We have the stroke change in diameter that is a change in diameter during systole. The change in lumen area, that is to say the wall cross-sectional area and we have the elastic properties of the artery that can be the cross-sectional distensibility, the cross-sectional compliance and the modulus, either the Peterson elastic modulus or the Young’s elastic modulus or incremental elastic properties. That is to say that with those two parameters, diameter local pulse pressure and thickness of the artery, you can combine all those elements.

Slide 11

The local arterial stiffness is now assessed with echotracking systems. They provide optimal conditions for a precise determination of local arterial stiffness which is directly determined and requires no assumption from models of circulation.
The local arterial stiffness should be determined from measurements of stroke changes in diameter and local pulse pressure. The term local is very important because if you make an echography of the carotid artery, for example, and you use brachial pulse pressure, you will have discrepancies that could be very important.
Echotracking systems additionally provide precise measurements of intima-media thickness which allows calculation of the modulus.
Determination of both carotid stiffness and thickness is optimal and I think the last point is very important, local measurements of arterial stiffness are indicated for mechanistic analyses in pathophysiology, pharmacology and therapeutics rather than for epidemiological studies. That is to say that I think that for clinical care these assessments should not be performed in this moment.

Slide 12

Pulse wave velocity.
Pulse wave velocity is very easy to perform, it’s not very expensive and it’s quite reliable. You have just to capture a pressure curve here at the site of the aorta or at the site of the carotid artery and to capture at the same time, a pressure curve at the site of the femoral artery and if you have the Δ time between the two beginnings of the curve, you can have the pulse wave velocity.

Slide 13

The pulse wave velocity is considered as a ‘gold standard’ measurement of arterial stiffness.

Slide 14

There are many, many papers relating to the degree of pulse wave velocity on one hand and the cardiovascular and general prognostics on the other hand. Those papers have been performed in different populations, in hypertensive populations, in elderly populations and also in ESRD populations. The population of Gerard London, the population of Doctor Shoji from Japan and a German population from Doctor Barenbrock.

Slide 15

I won’t come back on pulse wave analysis. I think that we now all know what is augmentation pressure. I completely agree with Gerard London with the difficulty to interpret results of pulse wave analysis.

Slide 16

Central pulse wave analysis should be optimally obtained at a central level that is to say the site of the carotid artery or the ascending aorta and either directly recorded or computed from the radial artery waveform using a transfer function, as Gerard showed us with the sphygmomanometry. Pulse wave should be analysed through 3 major parameters: central pulse pressure, central systolic and augmentation index.

Slide 17

The use of central pressure, augmentation index and pulse wave velocity cannot be used interchangeably as indexes of arterial stiffness. In contrast to pulse wave velocity which is a direct measurement of arterial stiffness central pressure and the augmentation index are only indirect surrogate measures of arterial stiffness. However, they provide additional information concerning wave reflections. Central pulse wave analysis should be optimally coupled with the measurements of aortic pulse wave velocity to determine the contribution of aortic stiffness to wave reflections. I think that this last point is very important, if we wish to correctly analyse our data.

Slide 18

We have some data which are coming now concerning central blood pressure and cardiovascular and all cause mortality in longitudinal studies. It has been made in the population of Gerard London still in ESRD and now in the population of the CAFÉ substudy with Doctor Williams.

Slide 19

Slide 20

What are the findings in ESRD patients concerning aortic pulse wave velocity?

Slide 21

We published a paper 8 years ago now in Circulation concerning a cohort of 241 patients with ESRD. You well know these patients.

Slide 22

These patients have quite low HDL cholesterol, quite high triglycerides, they have increased parathyroid hormone, they have increased systolic and decreased diastolic blood pressure and their aortic pulse wave velocity is quite high, 11 m/s and one out of 4 of these patients were in secondary cardiovascular prevention.

Slide 23

We have shown that for these patients the pulse wave velocity was closely related to prognosis that is to say that the tertile of patients with the increased aortic pulse wave velocity had an increased risk of cardiovascular events morbid or later on.

Slide 24

The results are exactly the same for overall survival but you know that those ESRD patients die very frequently from cardiovascular causes. Then, it’s I think very important for this marker of aortic pulse wave velocity to demonstrate in different populations that is to say in ESRD populations but also in the hypertensive populations and I think also in general populations that it is a good predictor for the occurrence of cardiovascular events and for cardiovascular mortality.

Slide 25

Why is pulse wave velocity increased in this ESRD population? There are many, many papers relating calcifications, I mean vascular calcification and increased arterial stiffness in those populations.

Slide 26

This very recent paper published in Kidney International showed that pulse wave velocity was related to coronary artery calcium, to thoracic aortic calcium and to abdominal artery calcium and perhaps also to the calcium deposits on the cardiac valves.

Slide 27

I think that pulse wave velocity is not a synonym of aortic calcifications. We know that calcification is a very powerful predictor for cardiovascular death. We have known that for many, many years because there are very old papers showing that the presence of aortic calcification of the abdominal aorta was related to cardiovascular prognosis.

Slide 28

But I think that arterial stiffness is not only calcification. I’m not sure I understand very well this slide. I have stolen it from Gerard London. What I understand is that it’s a very complicated business and probably that increased arterial stiffness in this population is heterogeneous.

Slide 29

Let’s come back to other haemodynamic measurements. We have shown this is a paper signed by Michel Safar, we have shown that the central pulse pressure was also related to mortality in this ESRD population, that it’s true also for augmentation index and that it’s true for pulse pressure amplifications. That means that all those central haemodynamic parameters are related to cardiovascular prognosis and to cardiovascular risk.

Slide 30

We tried to differentiate the strengths

Slide 31

and the incremental added value of all these parameters.

Slide 32

It’s interesting to see that in crude analysis all these parameters except mean blood pressure are related to prognosis that is the area under the ROC curve that is the crude hazard rate and that is the adjusted hazard rate and adjustment has been made on confounders that is to say age, cardiovascular risk factors, anaemia etc. You can see that after multi adjustments only 3 parameters were independent predictors of cardiovascular prognosis. That was carotid pulse pressure that is to say central pulse pressure because you know that carotid pulse pressure is very close to aortic pulse pressure. The amplification of pulse pressure between central and peripheral arteries and the level of aortic pulse wave velocity. All the other parameters did not stay in the multivariate models.

Slide 33

Is all this information valid only for ESRD patients?

Slide 34

No, really not. We showed 9 years ago that in the hypertensive population the plasma creatinine was strongly and independently related to the level of aortic pulse wave velocity.

Slide 35

In this paper we had a third of the patients that had moderate chronic renal insufficiency with creatinine over 130 micromole.

Slide 36

In this other paper it is I think much more further because in this paper you can see that the third of the patients had a normal creatinine clearance and that a third of the patients had a very small decrease in creatinine clearance and even with this level of renal insufficiency you can see that the aortic pulse wave velocity is different between the 3 groups and this difference is statistically significant.

Slide 37

Further it is interesting to see that in the independent determinant of aortic pulse wave velocity GFR is a very important determinant both in the aortic pulse wave velocity and in the peripheral pulse wave velocity.

Slide 38

Then aortic pulse wave velocity is related to renal function not only at the stage of ESRD but also with a very small decrease in GFR. There is, I think one major paper which relates pulse wave velocity to prognosis in terms of risk reduction strategies.

Slide 39

This paper was published by Alain Guérin 6 years ago in Circulation. It begins with a therapeutic trial, a therapeutic trial in 150 patients with ESRD undergoing haemodialysis. These patients had, of course, haemodialysis plus ultrafiltration. The second step in terms of anti-hypertensive treatment was a randomised choice between ACE inhibitor and calcium channel antagonist. The third step was an intervention in case of bad tolerance. The fourth step was the association of a beta-blocker and the fifth step was all the drugs together to the same patient.

Slide 40

That is the characteristic of the patients at inclusion. You can see that those patients were dialysed for around 5-6 years. 43% had previous cardiovascular events and they had, of course, left ventricular hypertrophy as most of the dialysis patients.

Slide 41

Systolic blood pressure was 169 mmHg at the entry 151 mmHg at the target blood pressure time and 148 mmHg at the end of the follow up and you can see that diastolic blood pressure was normal.

Slide 42

That is the Cox model of all-cause mortality and you can see that there are 4 predictors of the mortality of the patients. First, of course, the age, second the increase in left ventricular mass index. Third, the increase in pulse wave velocity and fourth, the randomisation to ACE inhibitors in first treatment in comparison to calcium channel antagonist.

Slide 43

For cardiovascular mortality age has been replaced by the presence of cardiovascular disease and there is also left ventricular mass index increase. Pulse wave velocity increase, and ACE inhibitor at randomisation.

Slide 44

In this cartoon you can see on the left the patients who ended the therapeutic trial and you can see on the right the patients who died before the end of the follow up. You can see that mean blood pressure that is here in yellow on the figure, mean blood pressure decreased to the same level in the two groups of patients but you can see that the element that differentiates those two populations is the evolution of aortic pulse wave velocity in red. In the survivors aortic pulse wave velocity decreased at the beginning and after had a very small increase but you can see that in the patients who died during the therapeutic trial aortic pulse wave velocity did not stop to increase during all the trial that is to say that in the patients on the right the aortic pulse wave velocity does not respond to the anti-hypertensive therapy, it increases also blood pressure decreases.

Slide 45

Are we ready for large clinical use? My last point.

Slide 46

We tried to build pulse wave velocity index and we published that with Gerard London 3 years ago in Kidney International and we tried to mix two populations, two very different populations.

Slide 47

The first one was a population of hypertensives we had in the Broussais hospital and the second one was a population of ESRD that Gerard London had in the Manhès hospital.

Slide 48

Then we made a model, a multivariate model explaining the aortic pulse wave velocity in those two populations and we tried to define a theoretical pulse wave velocity which was dependant on age, on mean pressure, on heart period and on gender.

Slide 49

We have shown that using this pulse wave velocity index, there were the patients that were over this index and those patients had a cardiovascular risk increased compared to the patients that had a pulse wave velocity index under the theoretical pulse wave velocity. The problem is that this index is very complicated to use in the clinical practice and I think that for the moment the problem is that 12 m/sec is a very high pulse wave velocity in a young normotensive patient. It is an increased pulse wave velocity but 12 m/sec is not so high in an old hypertensive patient and the problem is that this index per se is not sufficient to take a clinical decision.

Slide 50

Then other conclusions generally I speak to cardiologists and I say to cardiologists that renal insufficiency is a cardiovascular condition but today I will not give you the same message, I will tell you that arterial stiffening is a nephrologic disease but I believe that those 2 concepts are finally the same one. Thank you for your attention.

Slide 51

Chiarman: Thank you Doctor Blacher. Now, the presentation is open for discussion for one quick question. Professor----?

Question: I wonder if there is any study or if you have experience of the use of statins in the prevention of arterial rigidity in uremic subjects?

Prof. Blacher: I have no personal data on this subject but there is the very well performed paper in the April issue of the American Journal of Kidney Disease and it is a randomised trial between statins and gemfibrosil and the primary end point is arterial rigidity and there is an effect on arterial function of the statin but no effect of gemfibrosil. Then I believe that arterial function is probably sensitive not only to anti-hypertensive drugs.

Question: Michel Jadoul, Brussels. Congratulations for a very good talk like the former speaker and for a nice large body of work on that difficult topic. I have a very simple question. As you know, in ESRD heart failure is very common, so my question is does that interfere with the measurement, the prognostic value, the way we should interpret it etc? Thanks. If known.

Prof. Blacher: I think it is an important clinical question. I believe that until a very late stage of cardiac insufficiency, the level of arterial stiffness reflects the arterial stiffness but I think that for very advanced patients with cardiac insufficiency when ejection fraction goes under, for example, 20%, I think that it is very difficult to measure arterial stiffness and I’m not sure we know exactly what we measure. Is arterial stiffness related to prognosis? In this very interesting population cardiac insufficiency plus renal insufficiency I really don’t know.

Chairman: Thank you Doctor Blacher.