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Transcript

Greetings. Today I'm going to discuss some biomarkers of atherosclerotic risk, specifically ceramides and lipoprotein a. 

Introduction

My name is Vlad Vasile and I'm a cardiologist and a cardiovascular lab medicine co-director at Mayo Clinic in Rochester, Minnesota.

Disclosures

I have no financial disclosures. 

Ceramides and atherosclerotic risk

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

Cardiovascular mortality continues to increase despite advances in therapies and novel approaches as depicted here in light blue. 

ASCVD risk calculator

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/risk enhancers^1-3

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. 

Atherosclerotic plaque is initiated by lipids and propagated by inflammation

The atherosclerotic plaque is a very complex and dynamic structure. It is initiated by lipids and propagated by inflammation and thrombosis. 

Biomarkers of ASCVD risk

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. 

Ceramides are integral to cell function^4,5

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. 

Ceramide pathway

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. 

Mayo Clinic evaluation of plasma ceramides and atherosclerosis⁶

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. 

Ceramide score and survival⁶

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. 

Ceramides predict CV death in primary prevention – FINRISK study

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. 

Ceramide risk score predicts CV death alone and additively to hsCRP - FINRISK

In this study, the ceramide risk predicted cardiovascular death alone and in addition to an already established biomarker of atherosclerotic risk, high sensitivity CRP. 

Plasma ceramides are significantly lowered by aerobic exercise training

One important aspect of the ceramides and ceramide score is the fact that they are modifiable with certain interventions. 

Ceramide response to therapy^7,8

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. 

Ceramide score in primary prevention – Mayo Clinic experience

I also wanted to bring the Mayo Clinic experience here. We looked at a cohort of subjects that are very well characterized in the community population, followed longitudinally for approximately 16 years. And this is the Pavd cohort. 

Ceramide score in primary prevention at Mayo – Pavd

We examined the approximately 1100 individuals who had a risk profile very similar to a white, Caucasian U.S. population. 

Km curves for ceramide score by ASCVD

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. 

Dose-response curve

And there was a dose-response curve in the sense that the higher the ceramide score, the higher the atherosclerotic events. 

Mace and death adjusted for conventional risk factors for CAD

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. 

Ceramide score summary

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. 

Lipoprotein (a)

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. 

Lp(a) structure

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). 

Lp(a) pathophysiology

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). 

Lp(a) measurement and cutoffs used clinically

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 125 nmol/L. 

Guidelines – Screening

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. 

Screening

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 one-time, lifetime screening for Lp(a). 

Therapeutic approach

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). 

Lp(a) summary

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, one-time 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

Thank you very much for your interest and attention.

References

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2. Forbang NI, McClelland RL, Remigio-Baker RA, Allison MA, Sandfort V, Michos ED, Thomas I, Rifkin DE, Criqui MH. Associations of cardiovascular disease risk factors with abdominal aortic calcium volume and density: The Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis. 2016 Dec;255:54-58
3. Leber AW, Knez A, White CW, Becker A, von Ziegler F, Muehling O, Becker C, Reiser M, Steinbeck G, Boekstegers P. Composition of coronary atherosclerotic plaques in patients with acute myocardial infarction and stable angina pectoris determined by contrast-enhanced multislice computed tomography. Am J Cardiol. 2003 Mar 15;91(6):714-8
4. Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab. 2012 May 2;15(5):585-94
5. Lang, Elisabeth, et al. "Ceramide in the regulation of eryptosis, the suicidal erythrocyte death." Apoptosis 20.5 (2015): 758-767
6. Meeusen J, Donato L, Bryant S, et al: Plasma ceramides. Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1933-1939
7. Tarasov K, Ekroos K, Suoniemi M, et al: Molecular lipids identify cardiovascular risk and are efficiently lowered by simvastatin and PCSK9 deficiency. J Clin Endocrinol Metab. 2014 Jan;99(1):E45-52
8. Ng T, Ooi E, Watts G, et al: Dose-Dependent Effects of Rosuvastatin on the Plasma Sphingolipidome and Phospholipidome in the Metabolic Syndrome, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 11, 1 November 2014, E2335–E2340

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