Greetings.
Today I'm going to discuss about some biomarkers of atherosclerotic risk, specifically ceramides
and lipoprotein a.
My name is Vlad Vasile and I'm a cardiologist and a cardiovascular lab medicine co-director
at Mayo Clinic in Rochester, Minnesota.
I have no financial disclosures.
To start with, I'm going to talk about ceramides and their atherosclerotic risk.
I'm going to define ceramides, talk about when we should test for ceramides, as well
as touch on the topic about ceramides in primary prevention.
Cardiovascular mortality continues to increase despite advances in therapies and novel approaches
as depicted here in light blue.
The ASCVD or atherosclerotic risk calculator is the only current American Heart Association/American
College of Cardiology calculator endorsed by the guidelines for assessment of atherosclerosis.
However, this calculator has some limitations, and these are related to discrimination of
risk in sex, different ethnic or racial groups as well as socioeconomic groups and diabetes.
Some experts consider in pre-hoc analysis the ASCVD calculator as a simple flip of a
coin.
Therefore, emphasizing the need for more robust biomarkers of cardiovascular risk.
Patients at intermediate risk or patients presenting with risk enhancers.
The current guidelines recommend further risk stratification of these patients by using
different tests such as high sensitivity CRP, or the coronary calcium scoring of which the
most widespread method is the Agatston method.
However, this method is not without limitations.
There are important limitations related to reproducibility.
Certain calcium densities in certain populations.
And we expectedly know that the calcium density will increase when we start patients on statins.
Again, emphasizing how importantly we need more robust biomarkers of cardiovascular risk.
The atherosclerotic plaque is a very complex and dynamic structure.
It is initiated by lipids and propagated by inflammation and thrombosis.
When we talk about biomarkers of atherosclerotic risk, we talk about biomarkers that pertain
to the lipid pathway, such as the reputed LDL-C, biomarkers that pertain to the inflammation
pathway, such as high sensitivity CRP or biomarkers that belong to both, as well as biomarkers
that pertain to the thrombosis pathway.
Ceramides are central biomarkers that play roles in all three pathways, in the lipid
pathway, inflammation pathway and thrombosis pathway.
And it is my opinion that these biomarkers are very comprehensive and assess the atherosclerotic
risk much more comprehensive than biomarkers pertaining to specific pathways.
What are ceramides?
They're integral to cell function that are ubiquitously expressed in all cell membranes,
but they're not just simple inert molecules, they're signaling molecules that accumulate
with caloric excess, hyperlipidemia, inflammation, and ischemic injury.
The ceramide pathway is a very complex pathway.
Suffice to say that certain ceramide species, such as 16:0, 18:0, and 24:1, have been implicated
in atherosclerotic events, particularly in cohorts of patients with established coronary
artery disease.
At Mayo Clinic, we have validated and implemented in clinical practice the ceramide score approximately
three years ago.
This score consists of four ceramides of which three are of medical interest and the fourth
is used for normalization.
For validation purposes, we use the cohort of patients with established coronary artery
disease by coronary angiogram.
As you can appreciate here, if the score is 0 to 2 the cardiovascular atherosclerotic
risk is considered to be low, while a score of 10 to 12 confers a very high risk for these
patients.
How about ceramides in primary prevention?
While there are not that many studies that look at ceramides in primary prevention, the
majority of these studies have been conducted in Northern European population, such as the
FINRISK study presented here.
In this study, the ceramide risk predicted cardiovascular death alone and in addition
to an already established biomarker of atherosclerotic risk, high sensitivity CRP.
One important aspect of the ceramides and ceramide score is the fact that they are modifiable
with certain interventions.
They are modifiable with the Mediterranean diet, with aerobic exercise training and with
statins, and more recently with PCSK9 inhibitors, all measures that we extensively use in preventive
cardiology.
I also wanted to bring the Mayo Clinic experience here.
We looked at a cohort of subjects that they are very well characterized in the community
population followed longitudinally for approximately 16 years.
And this is the Pavd cohort.
We examined the approximately 1100 individuals who had a risk profile very similar to a white
Caucasian US population.
As you can appreciate here, there was a clear association between the ceramide score and
atherosclerotic events with a hazard ratio of 1.63 for the second quartile and 2.63 for
the fourth quartile.
And there was a dose-response curve in the sense that the higher the ceramide score,
the higher the atherosclerotic events.
We also wanted to see how good of a test the ceramide score was, and we obtained a C-statistic
of 0.67, which I know doesn't sound impressive, but if you think that coronary artery disease
is such a multi-factorial disease, a C-statistic of 0.67 becomes important.
If you compared that to the C-statistic of the ASCVD risk calculator, which is a 0.5,
clearly the ceramide score becomes significant.
To summarize, the ceramide score is a robust biomarker of atherosclerotic risk for primary
and secondary prevention which I encourage you to adopt in clinical practice.
It is a reproducible test.
It is useful to assess response to intervention or interventions.
And it motivates patients to continue the intervention because you show them the ceramide
score before and after the intervention and this score should decrease in parallel with
the decrease in atherosclerotic risk.
There is no radiation involved and it's a very cost-effective test.
Results are very easy to interpret by us providers.
Simple numbers that place the patient in buckets of atherosclerotic risk.
And if your patient has financial concerns, you can reassure them that the test has been
recently approved for reimbursement.
And with this I'm going to change gears and talk about another biomarker of atherosclerotic
risk, lipoprotein a or Lp(a).
What is Lp(a)?
When should we check for Lp(a)?
As well as what measures we have to mitigate the atherosclerotic risk associated with Lp(a)
elevation.
What is Lp(a)?
Simply put, Lp(a) is a particle that associates with the cholesterol complex.
It has two components, an LDL particle and an apo (a) particle.
The apo (a) particle becomes important because it contains the so-called cringles of various
sizes that are attached to the core.
LDL particle contributes to plaque formation by facilitating cholesterol deposition in
the intima.
At the same time, the apo (a) particle has structural homology with plasminogen and inhibits
fibrinolysis.
In animal models, the apo (a) particle is thrombogenic.
The apo (a) particle has variable sizes, which is important for the particle size, but also
for assay binding sites.
We know that assays are better if the antibodies target the non-repeating subunit of apo (a).
From a pathophysiologic perspective, Lp(a) elevation has been independently associated
with atherosclerotic cardiovascular events in a dose-response manner.
It has also been associated with valvular disease such as aortic stenosis.
It has a very strong genetic component and we know that one in five individuals walking
on the street will have elevated Lp(a) and the majority of these individuals will be
missed.
The cardiovascular risk increases in parallel with the level of Lp(a).
Some aspects related to Lp(a) measurement and cutoffs that we use clinically.
First of all, the measurement is not standardized nor harmonized.
The units are either nanomole per liter (nmol/L) or milligrams per deciliter (mg/dL).
There is an isoform dependent bias.
There is no need to do adjustments for age, sex, ethnicity, or co-morbidities.
We know that the risk increases at a value of 30 mg/dL, however, the guidelines endorse
increased risk at 50 mg/dL.
And there is significantly increased risk when the value exceeds a 125 nmol/L.
How about guidelines?
Who should be screened for Lp(a)?
The American Heart Association/American College of Cardiology recommend screening for patients
with familial hypercholesterolemia with a IIa level of confidence.
If you look at other American societal guidelines, such as the National Lipid Association, their
recommendations are much more extensive.
The Europeans recommend a one time, lifetime testing as a universal screening in everybody.
So, with all these guidelines, who should we screen for Lp(a)?
Well, for sure patients with familial hypercholesterolemia, patients with a personal or family history
of premature coronary artery disease, or patients that are deemed at intermediate risk by the
ASCVD risk calculator.
Or patients with established atherosclerotic cardiovascular disease, be that vascular cardiovascular
or cerebrovascular.
Patients with aortic stenosis.
Patients with minimal or no response to statin therapy, or patients that have progressive
atherosclerotic events despite adequately controlled risk factors.
And one important recommendation which is frequently missed is to screen all first-degree
relatives of patients with elevated Lp(a).
I also wanted to bring here my personal practice.
In my practice, I tend to follow the European Society of Cardiology guidelines which recommend
that everybody gets a onetime, lifetime screening for Lp(a).
Now that we know what Lp(a) is, the atherosclerotic risk inferred by Lp(a) elevation, we should
discuss about therapeutic options that we have to mitigate the atherosclerotic risk
associated with this elevation.
Unfortunately, to date there is no etiologic treatment.
Some medications reduce the Lp(a) level such as niacin, but studies have failed to show
a survival benefit of patients with Lp(a) reduction due to niacin.
Taking that into consideration, significant side effects associated with niacin, we do
not recommend niacin to reduce Lp(a).
Estrogen also reduces Lp(a) by approximately 10%.
But again, given the pharmacologic profile of estrogen, we do not recommend that to reduce
Lp(a).
We do use apheresis.
We have two positive trials.
But we should always keep in mind that there are complications related to LDL-C lowering.
More recently, in the FOURIER trial, the PCSK9 inhibitors, as well as small interfering RNA
inhibitors, such as Inclisiran, these are promising pharmacologic options for patients
with elevated Lp(a).
However, they do need more clinical validation before implementing in clinical practice.
So how do we treat these patients?
The treatment is threefold.
First of all, we aggressively address lifestyle and risk factor modification.
We have a low target for LDL-C.
We strongly consider initiation of a statin and low dose aspirin in these patients.
And we always screen all first-degree relatives of patients with elevated Lp(a).
To summarize, Lp(a) bares independent risk of cardiovascular atherosclerotic events in
a dose dependent manner.
We should screen all patients with familial hypercholesterolemia.
Consider screening patients at intermediate cardiovascular risk, patients with a personal
or family history of premature coronary artery disease, and patients with atherosclerotic
disease.
We should consider a universal, onetime lifetime screening, as our European colleagues do.
We should aggressively treat patients with elevated Lp(a) by reducing the risk factors
and recommending healthy lifestyle choices.
We should consider initiation of statin and baby aspirin in these patients, and recommend
that all first-degree relatives of patients with elevated Lp(a) be screened for Lp(a).
You can also discuss with your patients that future pharmacologic interventions may be
possible but warrant further clinical validation before implementing into clinical practice.
Thank you very much for your interest and attention.