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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).

SUBMITTER: Wu MD

PROVIDER: S-EPMC6458098 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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

Wu Melinda D MD Moccetti Federico F Brown Eran E Davidson Brian P BP Atkinson Tamara T Belcik J Todd JT Giraud George G Duell P Barton PB Fazio Sergio S Tavori Hagai H Tsimikas Sotirios S Lindner Jonathan R JR

JACC. Cardiovascular imaging 20180619 8 Pt 1

<h4>Objectives</h4>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.<h4>Background</h4>Lipoprotein apheresis is used in patients with severe hypercholesterolemia to reduce plasma levels of low-density lipoprotein cholesterol.<h4>Methods</h4>Quantitative contrast-enhanced ultrasound perfusion imaging of ...[more]

PMID: 29909101

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Project description:Aging is associated with blunted coronary microvascular vasodilatory function. Previously, systemically administered adipose stromal vascular fraction (SVF) therapy reversed aging-induced attenuation of β1-adrenergic- and flow-mediated dilation dependent on reducing mitochondrial reactive oxygen species. We hypothesized that SVF-mediated recovery of microvascular dilatory function is dependent on recovery of mitochondrial function, specifically by reducing mitochondrial hyperfission. Female Fischer-344 rats were allocated into young control, old control, and old + SVF therapy groups. Pressure myography, immunofluorescent staining, Western blot analysis, and RNA sequencing were performed to determine coronary microvascular mitochondrial dynamics and function. Gene and protein expression of fission-mediator DRP-1 was enhanced with aging but reversed by SVF therapy. SVF facilitated an increase in fusion-mediator MFN-1 gene and protein expression. Mitochondrial morphology was characterized as rod-like and densely networked in young controls, isolated circular and punctate with aging, and less circularity with partially restored mitochondrial branch density with SVF therapy. Decreased mitochondrial membrane potential and ATP bioavailability in aged animals at baseline and during flow-mediated dilation were reversed by SVF and accompanied with enhanced oxygen consumption. Dilation to norepinephrine and flow in young controls were dependent on uninhibited mitochondrial fusion, whereas inhibiting fission did not restore aged microvessel response to norepinephrine or flow. SVF-mediated recovery of β-adrenergic function was dependent on uninhibited mitochondrial fusion, whereas recovery of flow-mediated dilation was dependent on maintained mitochondrial fission. Impaired dilation in aging is mitigated by SVF therapy, which recovers mitochondrial function and fission/fusion balance.NEW & NOTEWORTHY We elucidated the consequences of aging on coronary microvascular mitochondrial health as well as SVF's ability to reverse these effects. Aging shifts gene/protein expression and mitochondrial morphology indicating hyperfission, alongside attenuated mitochondrial membrane potential and ATP bioavailability, all reversed using SVF therapy. Mitochondrial membrane potential and ATP levels correlated with vasodilatory efficiency. Mitochondrial dysfunction is a contributing pathological factor in aging that can be targeted by therapeutic SVF to preserve microvascular dilative function.

Dataset Information

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

Publications

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

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