Author + information
- Received February 5, 2018
- Revision received April 23, 2018
- Accepted May 1, 2018
- Published online June 13, 2018.
- Melinda D. Wu, MDa,b,∗,
- Federico Moccetti, MDa,∗,
- Eran Brown, BSa,
- Brian P. Davidson, MDa,c,
- Tamara Atkinson, MDa,c,
- J. Todd Belcik, ACS, RDCSa,
- George Giraud, MD, PhDa,c,
- P. Barton Duell, MDa,
- Sergio Fazio, MD, PhDa,
- Hagai Tavori, PhDa,
- Sotirios Tsimikas, MDd and
- Jonathan R. Lindner, MDa,e,∗ ()
- aKnight Cardiovascular Institute, Oregon Health & Science University, Portland, Oregon
- bDoernbecher Children’s Hospital, Oregon Health & Science University, Portland, Oregon
- cPortland Veterans Administration Hospital, Oregon Health & Science University, Portland, Oregon
- dCardiovascular Division, University of California, San Diego, San Diego, California
- eOregon National Primate Research Center, Oregon Health & Science University, Portland, Oregon
- ↵∗Address for correspondence:
Dr. Jonathan R. Lindner, Cardiovascular Division, UHN-62, Oregon Health & Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239.
Objectives The study evaluated whether lipoprotein apheresis produces immediate changes in resting perfusion in subjects with severe hypercholesterolemia, and whether there is a difference in the response between peripheral and coronary microcirculations.
Background Lipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol.
Methods Quantitative contrast-enhanced ultrasound perfusion imaging of the myocardium at rest and skeletal muscle at rest and during calibrated contractile exercise was performed before and immediately after lipoprotein apheresis in 8 subjects with severe hypercholesterolemia, 7 of whom had a diagnosis of familial hypercholesterolemia. Myocardial perfusion imaging was also performed in 14 normal control subjects. Changes in myocardial work and left ventricular function were assessed by echocardiography. Ex vivo ovine coronary and femoral artery ring tension assays were assessed in the presence of pre- and post-apheresis plasma.
Results Apheresis acutely decreased low-density lipoprotein cholesterol (234.9 ± 103.2 mg/dl vs. 67.1 ± 49.5 mg/dl; p < 0.01) and oxidized phospholipid on apolipoprotein B-100 (60.2 ± 55.2 nmol/l vs. 47.0 ± 24.5 nmol/l; p = 0.01), and acutely increased resting myocardial perfusion (55.1 [95% confidence interval: 77.2 to 73.1] vs. 135 [95% confidence interval: 81.2 to 189.6] IU/s; p = 0.01), without changes in myocardial work. Myocardial longitudinal strain improved in those subjects with reduced pre-apheresis function. Skeletal muscle perfusion at rest and during contractile exercise was unchanged by apheresis. Acetylcholine-mediated dilation of ex vivo ovine coronary but not femoral arteries was impaired in pre-apheresis plasma and was completely reversed in post-apheresis plasma.
Conclusions Lipoprotein apheresis produces an immediate improvement in coronary microvascular function, which increases myocardial perfusion and normalizes endothelial-dependent vasodilation. These changes are not observed in the periphery. (Acute Microvascular Changes With LDL Apheresis; NCT02388633).
↵∗ Drs. Wu and Moccetti contributed equally to this work and are joint first authors.
Dr. Lindner is supported by grants R01-HL078610 and R01-HL120046 from the National Institutes of Health; and grant 14NSBRI1-0025 from the National Space Biomedical Research Institute (National Aeronautics and Space Administration). Dr. Wu is supported by grants T32-HL094294 and K08-HL133493 from the National Institutes of Health. Dr. Moccetti is funded by grant P2BSP3-158853 from the Swiss National Science Foundation. Dr. Fazio is supported by grant R01-132985 from the National Institutes of Health. Dr. Tsimikas is supported by the Fondation Leducq and National Institutes of Health grants R01-HL119828, R01-HL078610, R01-HL106579, R01 HL128550, R01 HL136098, P01 HL136275, and R35 HL135737. Dr. Duell has served as a consultant for Retrophin, Esperion, RegenxBio, Kastle, Daiichi-Sankyo, and Akcea; and has received institutional grant support from Regeneron, Retrophin, and Esperion. Dr. Fazio has served as a consultant for Kowa, Amgen, Amarin, and Aegerion. Dr. Tsimikas is a co-inventor and receives royalties from patents owned by the University of California, San Diego, on oxidation-specific antibodies and of oxidative biomarkers; and has a dual appointment at the University of California, San Diego, and as an employee of Ionis Pharmaceuticals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received February 5, 2018.
- Revision received April 23, 2018.
- Accepted May 1, 2018.
- 2018 American College of Cardiology Foundation
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