Slide 1

Almost all previously pulblished study in hypertension were based on the measure of brachial blood pressure. We know today that this pressure does not represent the Systolic and pulse pressure in the aorta which is the real pressure impacting on the heart.

Slide 2

The differences in aortic and brachial blood pressure could account for differences in the the outcomes associated with cardiac disorders and also for different impacts of cardiovascular drugs since we shall show that they don't have the same effect on the differences between aortic and brachial pressures.

Brachial pressure is not the pressure which is facing the left ventricle and the aorta. The brachial blood pressure is completely different from the blood pressure in the aorta and in the central arteries. You also know that while diastolic blood pressure, mean blood pressure which is the product of cardiac output and peripheral resistances is almost constant within the arterial tree, blood pressure systolic and pulse pressure are amplified progressively in young subjects from the aorta to the peripheral artery. The pressure we measure in the brachial artery which is about this distant from this aorta is absolutely not, at least in young age and middle-aged subjects, what is facing the heart.

Slide 3

We also know that all drugs have not exactly the same effect on brachial pressure and on aortic pressure.

Slide 4

In the control subjects if you measure the aortic pressure and the pressure in the brachial artery and you apply now nitrate to these patients, you will have a profound effect on the aortic blood pressure.

Slide 5

Which is principally due to the decrease in what we call the intensity in wave reflection.

Slide 6

While in the brachial artery wave reflection will decrease but it has no impact on the normal systolic pressure and in the aorta the final results have no effect on the brachial pressure and an important effect on the aortic pressure.

Slide 7

So, this is just an illustration that all these drugs have not the same effect, if you measure pressure in the brachial or in the aorta.

Slide 8

The best example is the recently published CAFE study which is a substudy of ASCOT and if you analyse for example, the pulse pressure in the brachial artery with atenolol or amlodipine/perindopril, we have almost the same results in the brachial artery but if you look at the aortic pulse pressure, systematically aortic pulse pressure is lower than amlodipine/perindopril, of course and it could explain why these two associations have a completely different impact on the outcome because actually we know that the outcome with amlodipine/perindopril is much better but this could be due not to pleiotropic effect of ACE inhibition but normally only to a much better effect of this drug on aortic and central blood pressure.

Slide 9

We also know that in end stage renal disease patients usually the aortic pulse pressure, the relationship between aortic pulse pressure and end organ damage is stronger than the association between, for example, carotid intima-media thickness as an end organ damage and systolic blood pressure. Of course the two are associated but the degree of association and the degree of the strength of the relationship is much higher and always better, if you analyse this relationship with aortic pulse pressure.

Slide 10

How about the survival? We all know and you all know that pulse pressure is an independent factor associated with survival in a general population and in patients with end stage renal disease. If you look at the survival according to peripheral brachial pulse pressure, of course you find that patients with lower than 55 mmHg of brachial pulse pressure have a better survival but do not exactly differentiate the other categories.

Slide 11

If you analyse the same relationship taking into consideration the carotid pulse pressure or aortic pulse pressure, you will be able to differentiate the effect of this pressure on survival. Of course, this is just another illustration that it’s much stronger to analyse aortic pressure or central like carotid pressure and the relationship with end organ damage and survival.

Slide 12

If you want now to analyse, for example, several blood pressure indices with a survival for a cardiovascular survival, the better index is of course carotid pulse pressure. The brachial pulse pressure is a good prognostic marker but not so important. Diastolic blood pressure is usually associated with a better survival and of course, mean blood pressure has absolutely no prognostic value in this population because it’s due to cardiac output and peripheral resistances.

Slide 13

Now, if you look at the Cox regression comparing the relative risk of cardiovascular mortality  and brachial versus aortic systolic blood pressure in this population, brachial systolic blood pressure has no predictive value in this population while aortic systolic blood pressure even after adjustment for other parameters like age, cholesterol, diabetes keeps its predictive value. This is very understandable because aortic pressure is the pressure facing the left ventricle in the heart.

Slide 14

All these problems and these discrepancies are due to the phenomenon called wave reflection. What is wave reflection? You all know from school house that if you have a fixed end rope and if you create reflection, ondulatory movement, this is propagated to the fixed end and it creates a wave which is travelling in the opposite direction. Of course, these two waves from time to time, well not from time to time are travelling in the opposite direction and at one point of the rope they merge creating a new wave with a completely different shape and completely different amplitude. This is exactly what happens in the arterial system.

Slide 15

In the arterial system during left ventricular ejection depending on the stiffness of the aorta and injected volume you create in the red the incident primary pressure wave. This pressure wave is propagated at a pulse wave velocity which depends on the stiffness and generates like in the rope its own reflection in green at what we call the reflecting sites. At reflecting sites these two waves merge completely together, they are in phase and the final result is that you obtain this wave of a different shape and different amplitude. But this reflected wave travels in the opposite direction, this reflected wave and gets back to the aorta but it takes such a long time to come back, so these two waves are not exactly in phase. The overlap is not total and according to the overlap, finally normally these reflected waves return in the late systole or diastole actually changing the shape with this abnormal boosting which is called augmentation index but finally of course you have this normal amplification and the difference is due to the different overlap between these two waves.

Slide 16

If you want to analyse the aortic pressure wave, you have to analyse several parameters. One parameter is the so well known augmentation index which is the part due to wave reflection for the total pulse pressure. You should also analyse two other parameters which will determine the overlap of these two waves, left ventricular ejection time which is the slot during creation of the incident pressure wave but also the slot for the reception of the reflected wave and time to shoulder which is the time taken from the incident pressure wave to travel to reflecting sites and back. So these are important parameters to analyse, if you really want to analyse in detail what happens.

Slide 17

What is the influence of aortic stiffness which means pulse wave velocity on this aortic pressure wave? If you take a young subject with a slow pulse wave velocity, let’s say 8 m/sec, it takes a lot time to come back at low velocity from reflecting sites back to the aorta. This reflected wave comes back usually after the closure of aortic valves or during very late systole. It is a natural counter procession which didn’t change the systolic pressure in the aorta and left ventricle but has this nice boosting counter procession effect on the perfusion of the coronary system. If you have a stiff aorta in the calcified aorta in old subjects, the pulse wave velocity increases and the reflected wave comes back very early. Still during the left ventricular ejection and time is very short and this case you have a large overlap. Here the overlap is small, there the overlap is much higher and in this condition this reflected wave appears already in the systole changing the aortic pressure and unfortunately the counter procession with this nice boosting effect on the diastolic pressure has disappeared. You have high systolic pressure, high pressure load on the left ventricle and poor coronary perfusion.

Slide 18

The problem is that this time to shoulder, time taken to wave reflection and back which will determine the overlap depends on the time to shoulder and time to shoulder depends on the two properties, pulse wave velocity, of course, when the speed of wave propagation is fast, the time decreases and the second problem is that it increases with the length of the arterial system.

Slide 19

The wave has to travel and this is tightly associated with body height. If you are a tall guy or a tall girl it takes a longer time for any given pulse wave velocity to come back from the reflecting site back and in this condition the amplification of the pressure from the aorta to the systole will be, of course, higher.

Slide 20

Just an example, low pulse wave velocity takes a long time to come back from this reflected wave, comes back to the systole with coronary perfusion and nothing happens to worsen systolic function. The speed is much higher, it comes during the systolic ejection, still during the creation of this pressure wave, high augmentation, low diastolic boosting effect and principally the equalisation of central systolic pressure and peripheral with disappearance of this natural amplification.

Slide 21

Just an example, young subjects, middle-aged, old subjects, high pulse wave velocity, high rigidity. Low pulse wave velocity, low rigidity. Completely different aortic and peripheral blood pressures.

Slide 22

The second problem which plays a role in this amplification is heart rate. But not heart rate as such, the duration of left ventricular ejection time. This is very easy to understand. If you have everything the same but you change left ventricular ejection time, if the left ventricular ejection time is very short, the overlap will be very high. Here you have a left ventricular ejection time. When you decrease, when you increase left ventricular ejection time high low high left ventricular ejection time, it gives much more time for the reflected wave to come back and to be manifested. If you shorten the left ventricular ejection time, you don’t have time for the reflected wave to appear during the systole. It means that in acute conditions, if you increase heart rate, you can shift this curve with positive augmentation index to this one because actually the left ventricular ejection time which is time open for the reception of wave reflection is too short and wave reflection occurs after the closure. So wave reflection and the intensity at which wave reflection appears depends also on the heart rate but it doesn’t mean that wave reflection, the intensity has changed, only the timing of incident and reflected wave has changed and the central aortic pressure has changed. This is one of the reasons, for example, if you have beta-blocking drugs and you have a long cardiac, low cardiac interval with a long left ventricular ejection time, you will have higher augmentation index and higher central pulse pressure than if you have other drugs that do not change heart rate and do not change left ventricular ejection time. Of course, time to shoulder could be changed not by changing the height of the subject and body size but by changing pulse wave velocity which actually could be obtained with many drugs, many antihypertensive drugs.

Slide 23

The second problem which is very important is that augmentation index, the index I have just shown, is not an index of stiffness, it’s just an index which indicates the proportion of pulse pressure which is due to wave reflection but wave reflection by itself depends on the coefficient of reflection, the amount, the acoustic property of the arterial system and the ability of the arterial system to create this reflection. This is another index which is important. The things are a little bit complicated. I will try to make the things simple.

Slide 24

The reflection coefficient, the intensity of reflection depends on the relationship between peripheral resistance and so-called characteristic impedance. In simple words it depends on the heterogeneity, acoustic heterogeneity of the arterial system. In young subjects the characteristic impedance is very low because you have a large aorta and very slow pulse wave velocity. The rest of the arterial system is characterised by a decrease in the dimension and increase in the stiffness and wave reflection like in all acoustic systems are created by the discrepancies between the different segments in which the pulse is propagated. This heterogeneity is very much marked in young subjects, 6 metres of the stiffness, 10 meters, tapering of the aorta, large aortic diameter. It means that the reflection is intense and it’s closer to the heart but it’s propagated at slow velocity. Near to the heart slow velocity, low impact. It means that the peripheral arterial system by this dampening of the intensity of the pressure wave is relatively protected, the pressure which impacts on the periphery is relatively protected. In old subjects you change the properties of this arterial acoustic system. First, pulse wave velocity is equal in the aorta and peripheral arteries, so the heterogeneity has disappeared. Aortic tapering has disappeared, aorta has dilated everywhere which means that the reflections are lower they are lower but propagated at a high velocity, so nevertheless having this effect on central pressure but the reflecting sites are not in this position but much closer to the terminal arterial system and the pressure which is directly impacting on the peripheral tissues is not protected anymore by this heterogeneity and of course, with a direct impact on the peripheral vessels and on the microcirculation and this is creating probably the possibility why the microcirculation in this condition, for example, rarefaction of the vessels is present.

Slide 25

The fact that aorta is not aging at the same speed as the peripheral artery is a well known fact illustrated in these slides, work by Alberto Avolio when aging aortic pulse wave velocity increases, it doesn’t impact on the brachial artery and in aged patients you have a homogenisation of the arterial system.

Slide 26

Finally, everything depends on age and the reflection coefficient decreases with age.

Slide 27

The impact of reflection due to pulse wave velocity which is higher still plays a negative role but the intensity of reflection decreases with age.

Slide 28

So, aortic systolic pressure and many of you are probably interested and the measurement of this very modern parameter depends on the amplitude of forward incident pressure wave which depends on the aortic volume and aortic stiffness and it depends on the amplitude of reflected wave which depends on the reflected coefficients but principally on the overlap between these two pressure waves. The overlap is influenced by the left ventricular ejection time and the travelling distance, travelling time of pressure wave to and from reflecting sites, so called time to shoulder, which depends on the pulse wave velocity and this tends to reflect from the site.

Slide 29

So this is just an illustration for all of you if you are interested in these works that it’s a complex business and should always be analysed very strictly. So now just a few examples to document the importance of these changes. If you look at the results of trials on the left ventricular hypertrophy regression, atenolol, perindopril/indapamide, the effect is much more pronounced with drugs including ACE inhibitors and diuretics than atenolol.

Slide 30

But you have also to know that if you analyse the systolic blood pressure effect of these two drugs in the aorta, there is a tremendous difference between aortic systolic blood pressure in these two drugs while brachial is exactly the same.

Slide 31

Finally, this difference is not due to changes in the overlap and travelling time because pulse wave velocity decreases to the same extent with these two drugs.

Slide 32

The difference is due to changes in the reflection, the reflection coefficients and this was of course, adjusted to changes in left ventricular ejection time with atenolol, so this is the effect of these drugs, principally ACE inhibitors on the coefficient of reflection and distance of reflecting sites.

Slide 33

Another example how different drugs could change completely this aortic systolic blood pressure also called augmentation index placebo, nitrates, eprosartan and captopril. So you can see that all these drugs have a very different impact.

Slide 34

These measurements could be done non-invasively today.

Slide 35

You have several possibilities one is so-called sphygmomanometry using transfer function which from radial artery pressure could re-sensitise aortic pressure and with a little sophisticated program you can differentiate incident and reflected pressure wave and maybe something which is also very useful is another system which analyzes only the pressure wave reflection in peripheral arteries. They are non-invasive, very useful but interpretation must be very careful and really very tough. Thank you for your attention.

Slide 36

Chairman: Thank you very much Doctor London. The presentation is open for discussion. We have time for a couple of burning questions.

Question: Maybe I can start while you’re waiting for another question. Professor London you have explained to us a lot of things which are consequence like pulse wave velocity, pulse pressure or augmentation index and these consequences are because of the wide range of different factors which belong to different demographies as you said. Metabolic changes for calcium and phosphate and specific changes like fluid overload in ERSD patients. What do you think you can submit as an additional advice to our audience, how they can prevent our patients from having these unwilling consequences?

Prof. London: Well, the principal thing when you analyse, when you are interested in all these subjects is really to understand what is behind. One of the biggest mistakes which is usually made concerns augmentation index. I tried to explain augmentation index is only the visible part of the effect of wave reflection on the central pressure. It depends completely on the overlap. It’s not an index of stiffness, the overlap is influenced by pulse wave velocity and of course, duration of left ventricular ejection. In the peripheral arteries when the wave reflection is very high, you don’t have any augmentation index because you have a total overlap and you cannot identify this point of the secondary wave. If you have a very high pulse wave velocity like in old subjects, the overlap even in the aorta will be total and you will not be able to analyse a reflection point. Once again, the augmentation index will disappear. So please when you study these parameters, augmentation index is not an index of stiffness, it’s influenced by pulse wave velocity and overlap. Now, back to your question. The best parameter in my opinion to be analysed in these subjects is pulse wave velocity. Pulse wave velocity is a composite index which depends on the elastic modulus of the artery, it means on the structure of the material, of the biomaterial and depends on the geometry, the relationship between diameter and thickness. So it’s easy to be measured, it’s not so expensive and it’s probably and Jacques Blacher will show it to you, the best predictive cardiovascular index including intima-media thickness, left ventricular hypertrophy to predict the outcome in the general population and in our patients. Pulse wave velocity is influenced by age, you must know that it’s influenced by operating blood pressure. So it must be always referred to blood pressure and it’s influenced by the intrinsic property of biomaterials and in patients with end stage renal disease principally by the presence of heavy calcification.

Chairman: We just have time for a very short question please.

Question: Yes, a very short question. Coen from Rome. I read a recent paper giving an importance to ADMA and nitric oxide in the rebound of the wave, the rebound wave. Do you agree with that? Do you think we can in anyway pharmacologically modify the reflected wave?

Prof. London: First, there is a very good relationship between abnormalities in large arteries like expressed by pulse wave velocity and microcirculation and arterial flow mediated dilation, so the relationships are very, very close. The problem of wave reflection. Nitrates are able and I have shown the slide to decrease tremendously the intensity of wave reflection because actually what they do they change the property of the peripheral resistance of the relationship between characteristic impedance and peripheral resistant changes and the intensity of reflection changes. The problem is that reflection are a good phenomenon, the existence of reflection when they are well-timed and they come back to diastole is very useful. So one of the questions is if I decrease the intensity of reflection, my god it may not be so useful the problem is that with nitrates you decrease the intensity of reflection but to decrease the systolic pressure which decreases the oxygen consumption and you also have a direct effect on the coronary arteries. So you compensate largely with nitrates, it’s not true with all drugs. Another drug which has a very good impact on wave reflection at least on the timing and the intensity are ACE inhibitors and ARBs. Everybody’s accusing beta-blocking drugs of being nasty drugs because as in CAFE studies they are associated with the worst outcome but this is not true for all beta-blocking drugs, this is true for atenolol because the left ventricular ejection is long, so it gives a long time, plenty of time for this poorly reflected wave to come back and to manifest herself. If you have other drugs like visprolol for example, with beta-blocking drugs with vasodilating properties they don’t have absolutely the same effect as atenolol. So we cannot accuse beta-blocking drugs, all beta-blocking drugs of being so nasty.

Question: A very short question to Gerard. Since many patients are invited to self-monitor their blood pressure is what you say also extended to brachial and radial blood pressure in self-measurement devices which address to the brachial artery and to the wrist artery?

Prof. London: Well, the problem is how to measure continuously, how to have ambulatory measurement of this stiffness. Stassen has developed recently a stiffness index which is 24-hour blood pressure recordings and the stiffness is actually just the relationship between diastolic pressure and is the slope relating to diastolic, to systolic blood pressure over 24 hours but actually it has exactly the same meaning as pulse pressure but the difference is that it is 24-hour recording. Concerning self-measurements I would say that all these problems relating to difference in aortic and brachial pressure are principally observed in young and middle-aged subjects. This amplification exists even in older subjects but it’s very low. So the difference between aortic and brachial pressure in patients 75-80 years old is not exactly, the discussion is not appropriate so much as in young and middle-aged subjects. So this is the main thing but it is important to know because the difference exists too. But the problem is in pharmacology don’t accuse all drugs of being very nasty because even in the same class they don’t have the same effect.

Chairman: Doctor London thank you very much I’m sure that we would have a lot of questions but we have to move forward.