Slide 1

Mr Chairman, Ladies and Gentlemen it’s my pleasure to talk about atrial volume and cardiac biomarkers in CKD patients. Just before starting, I don’t want to say I’m a cardiologist, I’m just a nephrologist explaining some cardiac problems to nephrologists. So it would be, I would say a nice approach for the nephrologist ---- introducing the cardiology aspects.

Slide 2

So the question that I want to cover today, --- the first question is, of course, what is a risk stratification factor? Why and how to measure the left atrial volume? Which is an interesting factor for us. What could be the clinical significance? If left atrial volume is increased, does it mean it’s a risk factor? We will have a lot of information from the general population and we will see that it applies also to the kidney disease population and what could be the consequences.

Slide 3

This is the menu.

Slide 4

First, risk stratification is coming and you know that from the Framingham study, 1961.So risk stratification is a very important factor that appears from this population analysis over 40 years. First identifying the risk factors, so this is a way of stratifying patients. If you can apply a modification to this risk, then you can apply and see what happens to the outcome of the patient. So this is risk stratification for major outcomes and this is a foundation of modern cardiovascular medicine. It was a way of preventing and defining preventive paradigm I would say for the medical care applying to the CKD and of course, you can extend to CKD patients. So this is the basic thing that we know coming from the Framingham study.

Slide

So why and how to measure the left atrial volume?

Slide 6

I just want to say that assessment of cardiac dysfunction in CKD we get a lot of parameters from the clinic, from the chest x-ray, EKG, echocardiography and new imaging coming from the CT-MRI and of course, cardiac biomarkers. So we get a lot of parameters and CKD will be affected by one of these parameters and of course, I will concentrate on echocardiography and cardiac biomarkers, I don’t want to talk about MRI.

Slide 7

So why measure this left atrial volume?

Slide 8

And what sort of measurement can be provided by cardiologists? And of course, analyze the volume and just appreciate it in terms of surfaces, area and volume.

Slide 9

So the question, of course, is to have a nice methodology and so looking at the literature you have to remember that the American Society of Echocardiography Guidelines provides you all the parameters. I don’t want to go into the details but you just have to remember that by a two dimensional measurement you can calculate the volume according to this formula which is very simple. I don’t want to go into the details so after that you get left atrial volume which is in ml and of course, you have to index this to the body mass and usually you will affect on the m2. So these are 2 which is very simple volume and this is volume.

Slide 10

So what is the clinical significance and what are the causes?

Slide 11

I’ll just summarise. If you accept mitral regurgitation which is the first cause of increased left atrial volume, in kidney disease you have 2 causes; one is hypervolemia and the second one which is more important should be related to left ventricular diastolic dysfunction. So this is a perfect link between atrial volume and diastolic dysfunction. If you see the patient starting dialysis, I would say 80% of cardiologists say you get diastolic dysfunction. This is, of course, because the left ventricle is fibrosed so you get fibrosis, you get hypertrophy, so the left ventricle is losing the compliance and of course, increased upstream left atrial pressure. So just remember that left atrial volume is reflecting I would say left ventricular dysfunction. Of course, there are a lot of associations.

Slide 12

This is coming from cardiology in the general population not on a CKD patient but just look, left atrial volume indexes as compared to the diastolic abnormality from normal to grade III or IV and you see there is a perfect linearity between the grade of dysfunction and the volume. So, we have a nice marker which is a mechanical marker of left ventricular abnormality.

Slide 13

Of course, when you look at the left atrium biomarkers, you get a lot of information. This is focused on left atrial volume. You get and you know from the physiology that blood is the transporting chamber but this is not ---. You get volume sensor of the heart and this is very important and you will know that natriuretic peptides and just reflex from tachycardia coming from this – sensor, you get mechanical sensors and this is a transistor which is affecting, enlarging and remodelling the heart and of course, it’s a marker of sustained I would say increase of left ventricular like diabetics have haemoglobin glycosylated. So you have time exposure to the risk factors so left atrial size or volume is really reflecting a long time exposure. So just remember that this window is very important for analysis.

Slide 14

So is left atrial volume a risk factor?

Slide 15

We will cover the general population and the kidney disease population.

Slide 16

Of course, when you look at the general literature as just selected from Tsang and there the prediction of cardiovascular outcome just made with this left atrial size. This is more than1500 general population with cardiac disease.

Slide 17

And you see that if you split according to sinus rhythm or atrial fibrillation, you can see that the left atrial volume is something which is associated with the cardiovascular event. Small volume or small index volume is not associated with high increase of cardiovascular risk which is not the case. Cardiovascular event in sinus rhythm population as you can see, is exposed with large volume. Of course, if you move to the atrial patients, you get more. You see the size and the volume of the left atrium is completely different. So it’s a marker of risk and it’s a marker of atrial fibrillation. Of course, if you look at sensitivity and specificity, you see that volume is better than area and dimension. So you can have a two dimension but for left atrial volume this curve is better. You see that the sensitivity ROC curve is better. So volume calculation is better than just having signs from the area of the dimension.

Slide 18

Of course, if you look at this volume and the cardiovascular event in a population not with atrial fibrillation, as you can see normal volume very few events. Large volume or severely enlarged volume, a lot of events within 5 years. So left atrial volume is associated with cardiovascular risk in a non-arrhythmic population.

Slide 19

Again, if you look at this patient with sinus rhythm, I just want to eliminate atrial fibrillation as you can see, you can see that the risk of developing cardiovascular events is completely related to the size of the volume. The risk could be multiplied by a factor of 6 or 7 if you want a severe increase. So we have nice indicators and they are very strong predictors.

Slide 20

Again this is another study but just comparing the validity of diastolic dysfunction and left atrial volume. So comparing diastolic dysfunction and atrial volume in terms of surviving of the patient. You can see there is a perfect I would say relationship so the left atrial volume in terms of quartiles is significantly associated with diastolic dysfunction. So you have to consider that the left atrial volume is associated with diastolic dysfunction.

Slide 21

Now, does it apply to the kidney disease population?

Slide 22

We get a lot of information. This is coming from Verma in the Journal of American Cardiology. Just showing that the problem of the atrial volume starts early in the kidney disease before dialysis. This is the general population coming from the VALIANT Echostudy so nothing to do with dialysis, just looking at the GFR coming from a virtual normal GFR to a low GFR. You see the left ventricular mass, left ventricular hypertrophy and the volume and you can see that according to the loss of kidney disease you have a regular increase of the left atrial volume meaning that it starts very early in kidney disease and you can just consider that 60 ml is a first starting point for increasing the volume of the atrium. So meaning that there are some diastolic dysfunctions associated.

Slide 23

Of course, when you look at the left ventricular mass on the left and the left atrial volume on the right, you see that there is a nice correlation between the two markers. So you have now two markers; left atrial volume and the left ventricular mass which are identical in terms of I would say the prognosis.

Slide 24

So this is just to remind you that looking at the prediction of risk you see that moving from 60 ml to less than 45 ml the risk of cardiovascular events is multiplied by a factor of 2. So starting very early in the kidney disease.

Slide 25

Now what happens in a patient on dialysis? This is coming from the Tripepi the Italian group of course the famous group. They looked at a cohort of about 250 patients on dialysis and they compared different I would say un-indexed left atrial volume, indexed on BSA and indexed on the height that does not matter you have an index. Comparing dialysis population to healthy subjects and you can see just at a first glance that of course, atrial volume is completely different as compared to the general population but these are patients on dialysis and now looking at different parameters.

Slide 26

This is left atrial volume compared to the geometry, left ventricular remodelling, concentric left ventricular hypertrophy or eccentric hypertrophy and this is with different parameters. It does not matter you can see that left atrial volume is perfectly correlated with a lot of abnormalities from the left ventricle. So meaning that left atrial volume is reflecting what is going on the left ventricle.

Slide 27

Coming from Brazil. This is a very nice study from the Archives of Brazilian Cardiology in dialysis population you know relatively small numbers of patients, 118 on regular dialysis and what did they observe?

Slide 28

Clearly they looked at the cardiovascular events and they looked prospectively at the cardiovascular events, so meaning without cardiovascular event or with cardiovascular events and they looked at dilation.

Slide 29

Again you see that there is a completely different volume in terms of left atrial volume, as you can see and this is very significant at any time and if you index or you don’t index, you have very significant prognosis factors. Again, if you apply to the survival of the patient in terms of endpoint free survival, in terms of cardiovascular risk, you see that low volume is associated with low risk. High volume is associated with high risk.

Slide 30

Again, from the Tripepi group same analysis you see remember the population. This is interesting because there are two points one starting point and one control point after 1-2 years. So there is one visit and a second visit meaning that you have a trend over time. I don’t want to go into detail but just to show left atrial volume comparing from the first visit and the second visit you see an increase and again, you can have different I would abnormalities associated with the left ventricular mass again showing the same trend increase of volume is associated with an increase in left ventricular mass.

Slide 31

This is an important point indexes on height, not on the surface but that does not matter. You can see that over a one-year period there is an increase of the volume even in dialysis patients.

Slide 32

Of course if you just look at the impact on the survival fatal cardiovascular events according to the left atrial volume and the left ventricular mass selecting two groups with a low left ventricular mass and a high or low left change in atrial volume, you can see that change in atrial volume is very important in defining risk of death.

Slide 33

So this is I would say in non-hypertrophic patients you see that the change in the left atrial volume is very sensitive. Now, if you select the other group with the left ventricular mass increase which is very important, you see that you get worse results with a change in the left atrial volumes.

Slide 34

So atrial volume is a marker but the change is very important in terms of prediction.
Again, this is just showing in terms of --- risk and you can see that the change you can multiply by a factor of 3 the risk of developing cardiovascular events.

Slide 35

So what do we know? Of course left atrial volume is a volume sensor and it will be the starting point of the BNP, proBNP and other cardiac biomarkers.

Slide 36

I don’t want to go into detail because it will be covered in the next presentation but just to show that there is some relationship between left atrial volume of course and these cardiac biomarkers just showing that if you look again with glomerular filtration before dialysis you see that the increase of cardiac failure is very important as you see the percentage of course but there is some association particularly in a patient with cardiac heart failure and kidney disease.

Slide 37

You can see that there are a lot of abnormalities in the diastolic dysfunction. So meaning it’s again proved by the BNP, proBNP and the cardiac biomarkers.

Slide 38

Of course, you know this slide GFR declining there is an increase of the BNP, proBNP or different markers.

Slide 39

Again, this is another form. There is a nice relationship between the increase of kidney disease and the increase of BNP.

Slide 40

Again this is a very sensitive way. So the ROC curve is perfect, as you can see, you can use indifferently the NT-proBNP or the BNP other markers.

Slide 41

And of course this is a nice way of analyzing.

Slide 42

Different markers I don’t want to go into detail but another marker of hypervolemia is adrenomedullin and you can see that in a dialysis population when you dry your patient, you just change the blood volume and you can change the adrenomedullin.

Slide 43

So we have another marker just to evaluate the volume. We have another marker showing that the patients on dialysis are very I would say activated in terms of sympathetic nervous system. This the marker of neuropeptide Y.

Slide 44

Just neuropeptide is correlated with norepinephrine meaning that in the patient on dialysis there is activation. Of course this is important since I would say cardiovascular events are associated with this neuropeptide Y increase. So we have a lot of information.

Slide 45

So what are the consequences?

Slide 46

Of course, we know that the patient on dialysis gets a lot of trouble cardiovascular risk, other cause of increased left ventricular volume is of course arrhythmia. I showed you that in a normal population, it’s true in a dialysis population and you can get a lot of complications, thromboemboli events or different I would say abnormalities. Of course, how do you explain sudden death? Since we know that sudden death in patients is very frequent particularly because you associate hemodynamic changes, hypovolemia, coronary hypoperfusion, potassium gradient and different things that can affect.

Slide 47

This is left atrial volume is an important marker of death in the general population.

Slide 48

Again, if you plot I would say all the different parameters, clinical, atrial dimension and atrial dimension and volume, you have a very important risk of death.

Slide 49

And these are just factors of increase of the relative risk which is about 30-40%.

Slide 50

So this is now and what we know also from the dialysis is sudden death. If you remember this very nice work, you have to remember that the risk of death is about 70% in the 12 hours just following the dialysis session. So meaning that there are a lot of events coming from the atrial volume, atrial I would say excitability or atrial fibrillation or different events coming in the period just after dialysis.

Slide 51

I just want to end my talk by showing that we need a multimarker approach of cardiovascular risk, cardiobiomarkers are very important but the left atrial volume should be one of the best.

Slide 52

I’ll just end my presentation showing that there is a link between heart and kidney and this is just by the left atrial volume with very strong indicators of diastolic dysfunction is a strong marker of cardiovascular events and could be considered eye witness of cardiovascular events in the CKD patient. Thank you very much.

Chairman: Thank you.