Virtual Issue: Lipoprotein (a): Many strides made, yet there is a long road ahead

Assembled by Gissette Reyes-Soffer

Reyes-Soffer

Gissette Reyes-Soffer is Herbert Irving assistant professor of medicine at Columbia University Irving Medical Center and a junior associate editor for the Journal of Lipid Research. Her research is centered on examining the regulation and metabolism of lipoprotein (a).

In producing this virtual issue of the JLR, we searched our archives to rediscover the exciting work by a diverse group of authors who are moving the field of lipoprotein (a), or Lp(a), research forward. We chose manuscripts that highlight the past, present, and future status of Lp(a) research. We celebrate the accomplishments of team science and spotlight early career members of these teams by providing their current career status, areas of research and some personal life facts.

Large epidemiological studies, Mendelian randomized studies, and genome-wide association studies have suggested that elevated plasma Lp(a) levels are a heritable, independent, and key causal risk factor for atherosclerotic cardiovascular disease (ASCVD). High levels of Lp(a) promote atherosclerosis, inflammation, and thrombosis. Current guidelines recommend that plasma Lp(a) levels should be measured for patients with an intermediate to high risk of cardiovascular disease, familial hypercholesterolemia, a family history of early cardiovascular disease, an elevated Lp(a), or progressive ASCVD despite receiving optimal therapy.

Lipoprotein (a) is encoded by the LPA gene on chromosome 6. Depending on the individual, the encoded protein contains 2-43 copies of kringle IV type 2 (KIV-2) domains. Most individuals express two isoforms that vary in size based on their KIV-2 repeat number. In most cases, a large isoform size (high number of KIV-2 repeats) is associated with low serum Lp(a) concentrations and these have been linked to increase risk of cardiovascular disease and type 2 diabetes mellitus. Lp(a) has also been linked to development of calcific aortic stenosis (AS), which is the most common form of valvular disease in North America.

There are currently no FDA approved treatments that specifically lower Lp(a). Various lipid lowering drugs have provided reductions in Lp(a) levels; one of these, the PCSK9 inhibitor Alirocumab, induced reduction of Lp(a), independent of isoform size. Lipoprotein apheresis has also been shown to lower Lp(a) concentrations. There are also promising targeting strategies in development, such as an Lp(a) antisense.

Currently, we don’t have a clear understanding how Lp(a) and its two main proteins apo(a) and apoB100 are assembled and secreted. Novel methods in mass spectrometry have allowed various teams to investigate the pathways that regulate its levels. These methods may also aid in providing more specific Lp(a) plasma measurements. There is currently no standardized method for measuring plasma Lp(a) levels with most assays utilizing different standardization methodology. This has made it difficult to interpret large combined cohort data and provide risk stratification. In addition, clearance mechanisms of the particle are in question. It’s time to develop scientifically rigorous studies that can link currently available data and uncover missing pathways in Lp(a) pathophysiology. Such studies will help to identify the populations at risk and accelerate the development of targeted therapies that can decrease disease states and mortality.

Cover Image

The cover art depicts the Lp(a) particle following the steps of a walking path, increasing in size as the road goes into infinity. Artwork by Luciana Giono.

Special thanks to Henry Ginsberg for assisting with the production of this issue.

Featured research and reviews

Effects of mipomersen, an apolipoprotein B100 antisense,
on lipoprotein (a) metabolism in healthy subjects

Renu Nandakumar, Anastasiya Matveyenko, Tiffany Thomas, Marianna Pavlyha, Colleen Ngai, Stephen Holleran, Rajasekhar Ramakrishnan, Henry N. Ginsberg, Wahida Karmally, Santica M. Marcovina and Gissette Reyes-Soffer
First Published on October 7, 2018

Marianna Pavlyha

Marianna Pavlyha is currently in postgraduate year one of her residency at David Geffen School of Medicine at UCLA Division of Vascular Surgery in Los Angeles, California. Marianna in interested in studying vascular pathology and cardiovascular disease, was born in Ukraine and likes to play the piano.

The roles of apo(a) size, phenotype, and dominance pattern
in PCSK9-inhibition-induced reduction in Lp(a) with alirocumab

Byambaa Enkhmaa, Erdembileg Anuurad, Wei Zhang, Kun Yue, Ching-Shang Li and Lars Berglund
First Published on August 10, 2017

Byambaa Enkhmaa

Enkhmaa Byambaa is an associate professor in the department of internal medicine at the UC Davis School of Medicine in Sacramento, California. Her current scientific interests include risk factors for cardiovascular disease, lipids and lipoproteins (lipoprotein (a) in particular), inflammation and women’s cardiovascular health. She enjoys driving at sunset with her kids, doing yoga and making rhubarb pie from scratch.

PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab:
an analysis of 10 clinical trials and the LDL receptor’s role

Frederick J. Raal, Robert P. Giugliano, Marc S. Sabatine, Michael J. Koren, Dirk Blom, Nabil G. Seidah, Narimon Honarpour, Armando Lira, Allen Xue, Padmaja Chiruvolu, Simon Jackson, Mei Di, Matthew Peach, Ransi Somaratne, Scott M. Wasserman, Rob Scott and Evan A. Stein
First Published on April 21, 2016

Frederick J. Raal

In addition to being a professor, Derick Raal is Head of the Division of Endocrinology and Metabolism and Director of the Carbohydrate and Lipid Metabolism Research Unit at the University of the Witwatersrand in Johannesburg, South Africa. There, he studies novel drug therapies for familial hypercholesterolemia, with a particular interest in homozygous familial hypercholesterolemia. For fun, Raal enjoys hitting a rubber ball around the squash court.

Lipoprotein apheresis to treat elevated lipoprotein (a)

Elisa Waldmann and Klaus G. Parhofer
First Published on February 17, 2016

Elisa Waldmann

Elisa Waldmann is board certified in internal medicine and a fellow in endocrinology at the Medical Department II-Grosshadern at Ludwig Maximilians University Munich in Munich, Germany. She is interested in studying postprandial lipids, PCSK-9-inhibition and continuous glucose monitoring. In most of her free time, Waldmann plays beach volleyball.

Multiplexed peptide analysis for kinetic measurements of
major human apolipoproteins by LC/MS/MS

Mikaël Croyal, Fanta Fall, Véronique Ferchaud-Roucher, Maud Chétiveaux, Yassine Zaïr, Khadija Ouguerram, Michel Krempf and Estelle Nobécourt
First Published on January 15, 2016

Mikaël Croyal

Mikaël Croyal is a technical manager at the Mass Spectrometry Core Facility of West Human Nutrition Research Center in Nantes, France. He is interested in studying lipoprotein metabolism and apolipoprotein turnovers in metabolic diseases by using stable isotope tracers and mass spectrometry-based approaches. More specifically, Croyal wants to uncover the functional impacts of single-nucleotide and post-translational polymorphisms of apolipoproteins. Every weekend, Croyal sails to brainstorm and search for new research ideas.

Lipoprotein (a) in calcific aortic valve disease:
from genomics to novel drug target for aortic stenosis

George Thanassoulis
First Published on December 18, 2015

Chen

Hao Yu Chen is a doctoral student co-supervised by George Thanassoulis and James C. Engert at McGill University in Montreal, Canada. Her research is focused on understanding the genetic contributors to aortic stenosis, the most prevalent clinical heart valve disease in industrialized nations. The LPA gene and lipoprotein (a) are important aspects of her research given their contributions to aortic stenosis risk. Chen enjoys canicross running with her dog Ghost.

LPA kringle IV type 2 is associated with type 2 diabetes
in a Chinese population with very high cardiovascular risk

Di-Li-Da-Er Mu-Han-Ha-Li, Tian-Yu Zhai, Yan Ling and Xin Gao
First Published on March 6, 2018

A genome-wide association meta-analysis on lipoprotein (a) concentrations
adjusted for apolipoprotein (a) isoforms

Salome Mack, Stefan Coassin, Rico Rueedi, Noha A. Yousri, Ilkka Seppälä, Christian Gieger, Sebastian Schönherr, Lukas Forer, Gertraud Erhart, Pedro Marques-Vidal, Janina S. Ried, Gerard Waeber, Sven Bergmann, Doreen Dähnhardt, Andrea Stöckl, Olli T. Raitakari, Mika Kähönen, Annette Peters, Thomas Meitinger, Konstantin Strauch, KORA-Study Group, Ludmilla Kedenko, Bernhard Paulweber, Terho Lehtimäki, Steven C. Hunt, Peter Vollenweider, Claudia Lamina and Florian Kronenberg
First Published on May 16, 2017

Population and assay thresholds for the predictive value of lipoprotein (a) for coronary artery disease: the EPIC-Norfolk Prospective Population Study

Rutger Verbeek, S. Matthijs Boekholdt, Robert M. Stoekenbroek, G. Kees Hovingh, Joseph L. Witztum, Nicholas J. Wareham, Manjinder S. Sandhu, Kay-Tee Khaw and Sotirios Tsimikas
First Published on January 31, 2016

Antisense inhibition of apolipoprotein (a) to lower plasma lipoprotein (a) levels in humans

Mark J. Graham, Nick Viney, Rosanne M. Crooke and Sotirios Tsimikas
First Published on November 4, 2015