Lipoprotein Apheresis Acutely Reverses Coronary Microvascular Dysfunction in Patients With Severe Hypercholesterolemia

Abstract

Objectives: This 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] IU/s 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).

Keywords: apheresis; contrast ultrasound; familial hypercholesterolemia; myocardial contrast echocardiography.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Figures

FIGURE 1. Plasma Lipoprotein Lipid Measurements in Subjects Pre- and Post-Apheresis

Individual values are illustrated for patients on chronic apheresis (green) and those undergoing apheresis for the first time (pink). *p < 0.01 versus pre-apheresis. †p < 0.05 versus pre-apheresis. See text for mean values. HDL = high-density lipoprotein; LDL = low-density lipoprotein; OxPL-apoB = oxidized phospholipid on apolipoprotein B-100; VLDL = very low-density lipoprotein.

FIGURE 2. Blood Characteristics Influencing Microvascular Rheology

Mean ± SEM values for plasma viscosity are shown for rotational shear of (A) 75 s−1 and (B) 150 s−1. (C) Mean ± SEM values for erythrocyte deformability. *p < 0.05 versus pre-apheresis.

FIGURE 3. Skeletal Muscle Perfusion Imaging Data

Box-and-whisker plots for median (bar), 25% to 75% confidence interval (box), and range (whiskers) of values for resting skeletal muscle contrast-enhanced ultrasound data depicting: (A) microvascular blood flow, (B) blood flux rate or β, and (C) microvascular blood volume (MBV). Data from 1 outlying individual with extremely high resting β was removed after performing Grubb’s test for outliers. (D to F) Similar plots are illustrated for skeletal muscle during contractile exercise. p = NS for all pre- versus post-apheresis values. IU = video intensity units.

FIGURE 4. Myocardial Perfusion Imaging Data

Box-and-whisker plots are depicted for myocardial contrast echocardiography data on (A) microvascular blood flow, (B) blood flux rate or β, and (C) microvascular blood volume (MBV) in the myocardium at rest. Individual changes are provided in Online Figure 2. (D) Background-subtracted color-coded myocardial contrast echocardiography images obtained at each sequential end-systole (left to right) after a high-power pulse sequence, and (E) time-intensity data illustrating changes in resting myocardial perfusion from single subject who had a modest increase in perfusion after apheresis. IU = video intensity units.

FIGURE 5. Lipid Variables and Myocardial Blood Flow

Correlations are shown for (A) OxPL on apo B-100 lipoproteins or (B) LDL cholesterol with myocardial perfusion on myocardial contrast echocardiography expressed as the microvascular blood flux rate (β). Data are combined for pre-apheresis (green) and post-apheresis (pink) stages. SEE = standard error of the estimate; other abbreviations as in Figure 1.

FIGURE 6. Arterial Tension Assays and Endothelial NO Production

Tension assay dose-response curves illustrate degree of relaxation as a percentage of maximal tension (mean ± SEM) according to acetylcholine (Ach) concentration for the (A) coronary and (B) femoral branch arteries in a water bath containing pre- and post-apheresis plasma. For coronary analysis, p < 0.05 versus pre-apheresis by half maximal inhibitory concentration analysis. (C) Mean ± SEM values for 4,5-diaminofluorescein diacetate-2 (DAF-2) fluorescence over time, reflecting nitric oxide (NO) production, in cultured SVEC4–10 endothelial cells exposed to plasma from healthy volunteers or familial hypercholesterolemia patients pre- and post-apheresis. (D) Mean ± SEM area under the curve (AUC) for 10-min acquisition. *p < 0.05 versus healthy control subjects.