Populations Are Different; So Is Their Lp(a)!

LONDON — Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death globally despite many advances in its diagnosis and management. Improving the understanding of the disease has been one of the main research interests of cardiologist Zhenyue Chen, MD, PhD, chief physician at Ruijin Hospital, Shanghai Jiao Tong University of Medicine, in China. 
As both a clinical and basic science researcher, Chen has been at the forefront of some important discoveries concerning the pathologic mechanisms underlying atherosclerosis, cardiomyopathy, and heart failure. Her work covers a range of activities, from looking at the mechanisms of regeneration at the molecular level to the development of therapeutic strategies. 
Chen’s work has been recognized internationally, including receipt of a Young Investigator Award from the American College of Cardiology. She has participated in clinical trials and was involved in writing multiple Chinese guidelines and expert consensus statements for the management of dyslipidemia and ASCVD prevention. 
In an interview here at the European Society of Cardiology (ESC) Congress, Professor Chen discussed some of her work in the cardiology field. Starting with what inspired her to enter the specialty in the first place and ending with a discussion on her involvement in recent updates to lipid management guidelines in China, Chen gives an overview of her life as a cardiologist working in China.
It was my parents. My mom would always tell me that doctors can help people and save lives, and it’s [a] noble [profession]. “That’s tremendous!” [she would say]. 
At the very beginning, I think I wanted a challenge. I wanted to be a surgeon initially, but I decided to look at internal medicine after advice from senior doctors. I think cardiology was the most interesting to me because the heart is so important to the human body and contains a lot of subspecialties, and I can pick one that I am most interested in. 
I don’t think sex or gender is a barrier to being a cardiologist. People may assume that being a man is good for laborious tasks, such as major surgeries, but thinking is the most important priority. You need to be able to think about the problem, analyze it, and then resolve it. I don’t think it’s a kind of physical thing. It’s believing in yourself and saying that you can do this no matter if you are male or female.
There are two different areas. One is clinical research, mainly about coronary artery disease, atherosclerosis, and lipid metabolism. Another is basic science. It’s kind of related to the clinical research, but I am working on drug screening using zebrafish, and setting up some disease-specific models to explore the mechanisms of disease. As a doctor, I think translational medicine is very important. We can’t do research just for research’s sake. We should think about why we do it. We do it for patients, right? It’s like a bench-to-bedside and bedside-to-bench approach. 
ASCVD is the most highly prevalent disease in the world. We need to know the mechanisms behind it in order to discover and explore possible new targets for treating patients. 
I focus on lipid metabolism and major parameters, such as LDL-C [low-density lipoprotein cholesterol] and Lp(a) [lipoprotein (a)], in both humans and in some disease models, to explore how to reverse the formation and progression of atherosclerotic plaques. This is important because if the plaque does rupture, patients may develop an acute coronary syndrome such as a myocardial infarction. In my research we try to figure out how to deal with that and try to find new targets in the lipid metabolism pathway. We are also using some patient tissue and blood samples to clarify that. 
I have had a major focus on this for years and try to do some things that may help set up some new strategy, like reducing temperature to protect cardiomyocytes by either adjusting surrounding temperature or turning on some related gene expression, or we use some small molecules to target a new pathway and try to cure the disease. Right now, we are working on this in animal models and we try to set up a system that’s safe and effective; then we will go back to the clinical setting.
I was at the Mayo Clinic for nearly 3 years. There, I set up some disease models for heart failure and cardiomyopathy to explore some mechanisms. We used the zebrafish, which is a very small fish — just 1 cm in size — at an adult stage, and I generated ECGs and echocardiographs in this disease model. At that time, I found different gene subunits in the same family related to cardiomyopathy that express different phenotypes through different pathways. That’s interesting, because it is just like two brothers from one family but who show different personalities. I published a paper showing that different genes [express a] different personality, especially on the phenotype of cardiac function: One affected the systolic function and another affected the diastolic function. 
When I returned to China, I set up my own fish facility and cardiovascular zebrafish lab, not only in cardiomyopathy and heart failure, but also in the atherosclerosis field and lipid metabolism. We feed fish with a high-fat diet to generate a model of atherosclerosis, for example. When these fish are in the embryonic stage or are very young (within 1 week) , they are almost transparent. So you can directly look at the fish body, vessels, and heart under the microscope. That’s unique. We can also label them using some needles.
Because zebrafish are very small, we cannot see plaques in zebrafish vessels. The advantage of using a zebrafish model is that there is a high consistency with human genetics, and it’s a high-throughput screening method. It’s cheap; 1000 fish vs 1000 mice is a totally different price. If you have some data from zebrafish then you translate that into other, bigger animal models and it will be cost-effective.
Lp(a) is an independent risk factor for CVD and is defined as a risk enhancer for ASCVD as well. It has been known to be a risk factor for a long time but it has a skewed distribution in the general population, and there is no specific medicine targeting it. It’s not like LDL-C as a primary target for managing ASCVD. 
The particle of Lp(a) is like the LDL particle , with a specific extra structure called apo(a) [apolipoprotein a], which is prothrombotic. Lp(a) also has a high loading of oxidized phospholipids, which is proinflammation. So Lp(a) is really a bad guy; one molar of Lp(a) is worse than one molar of LDL-C. 
Right now, people focus on LDL-C because it has a normal distribution and covers more of the population at risk. Since Lp(a) has kind of a skewed distribution, only up to 20%-30% of people have elevated Lp(a). But Lp(a) definitely cannot be ignored because it can also harm your vessels and aortic valve. 
We have some new drugs on the way that will specifically target Lp(a). Maybe in 1 or 2 years we will have these medicines for Lp(a) to resolve the problem. For now, the strategy for elevated Lp(a) is to improve lifestyle and control overall risk factors of ASCVD, including reducing LDL-C intensively, to dilute the CV risk derived from Lp(a).
In the general population. T here are two different cutoffs for Lp(a): One is the cutoff for increased CV risk and the other is the cutoff for being a risk enhancer of ASCVD.
The most common cutoff for increased CV risk is about 50 mg/dL. But in China, it is 30 mg/dL, based on existing local data. 
If we need to define the patient in terms of risk stratification , Lp(a) beyond 50 mg/dL will be considered as an enhancer of risk for ASCVD. But the cutoff for elevated CV risk or defining an enhancer is not the cutoff for initiating treatment. We are waiting for some results coming from a [CV outcomes trial]. The baseline Lp(a) level for inclusion of a secondary prevention population is about 70 mg/dL, and there is a subgroup setting of 90 mg/dL. If either one of these two Lp(a) levels is associated with positive results — achieves a CV benefit — for the investigational drug, then 70 or 90 mg/dL will be the cutoff for initiating the treatment.
Lp(a) is basically determined by the genetic background rather than lifestyle; more than 90% of Lp(a) is determined by genetics. The Chinese population has lower Lp(a) than other populations. African populations have the highest levels and Western populations are in the middle. But I always say that the lower median Lp(a) doesn’t mean the less harm to your vessels. 
It’s difficult because we don’t have a dedicated treatment for Lp(a). In China, Lp(a) is measured as part of the lipid profiles in most of the tier 2-3 hospitals in big cities. When patients’ lipid test reports show that the Lp(a) level is elevated, they will see their doctors and require some explanation and treatment. Usually, we tell them they will have to wait for a new medicine to become available and that they need to control their overall risk for ASCVD, including with intensive reduction of LDL-C, to dilute the risk from Lp(a) at present. You definitely need to manage the risk instead of ignoring it , because Lp(a) is a causative risk factor, for sure. 
Some interesting dialogue from Chinese physicians has been : “If we don’t test, we don’t need to explain.” But I’d like to say that if you don’t know the level of Lp(a), you cannot consider the patient’s overall CV risk and how to manage their risk comprehensively. It’s like a puzzle without a piece. 
In China, Lp(a) testing can be reimbursed by the government in most provinces. The cost in China is not a barrier, because it is relatively cheap — less than US$5 per test. But in some countries, it is expensive and there are many restrictions on administering it.
I think generating awareness of Lp(a) is very important. For patients, I would say that if you think you have elevated Lp(a), go and see your cardiologist to check your history and clinical status. If you also have elevated LDL-C, that’s one plus one but more than two, which is going to be more harmful to your vessels. If you also have hypertension or other CV risk or a history of ASCVD and/or early onset of ASCVD, elevated Lp(a) is a risk enhancer and you need to pay more attention to it. If you have elevated Lp(a), you need to check your carotid or coronary artery to determine whether you already have atherosclerosis. Atherosclerosis sometimes is subclinical, with stable or unstable plaques. If you don’t get treated, the risk for myocardial infarction will increase in the future. Education is important for doctors and patients, and the general population.
I participate in multiple guidelines and expert consensus statements. For the guidelines, the most recent one is the 2023 Chin a guideline for lipid management, which is the most important lipid management guideline in China. It is an update from the version published in 2016. It has been 7 years, so there are a lot of changes in this updated version.
We have a different CV risk classification [to Western guidelines], including low, moderate, high, very high, and extremely high risk [categories]. We initiate with moderately intensive statin treatment. It’s not like the start with highly intensive statins or maximum tolerated statin dose recommended by Western countries. This is because the Chinese population has a lower tolerance to statins and there is no evidence showing that a benefit can be achieved by using high, intensive statin [dosing]. 
The goal for LDL-C is also different. In Europe, very high-risk patients need to bring their LDL-C level below 1.4 mmol/L, with a 50% reduction from baseline, according to ESC guidelines. In China, however, only patients in the extremely high-risk category need to have an LDL-C under 1.4 mmol/L and 50% reduction from baseline, and those at very high risk need to keep it under 1.8 mmol/L with a 50% reduction from baseline. We cannot say that ESC guidelines are more aggressive and Chinese guidelines are more conservative. It is just based on the local data and the different genetic background [of the local populations].
Then there are the special populations. The prevalence of hypertension and stroke is very high in the Chinese population. We emphasize some recommendations for managing people with hypertension. Meanwhile, we also pay attention to patients with chronic kidney disease, women during pregnancy, children and adolescents, familial hypercholesterolemia, and the elderly population, and give some specific recommendations based on local evidence. 
We also have the first Chinese guidelines for primary prevention of CVD, the first Lp(a) expert statement published in 2021, followed by an English version published in JACC: Asia in 2022. 
This interview has been edited for length and clarity. Chen reports no relevant financial relationships. 
Sara Freeman is a medical journalist and writer based in London, United Kingdom. She is a regular contributor to Medscape and other specialist healthcare media outlets.