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Evolocumab, a PCSK9-Monoclonal Antibody, Rapidly Reverses Coronary Artery Endothelial Dysfunction in People Living With HIV and People With Dyslipidemia.

ABSTRACT: Background PCSK9 (proprotein convertase subtilisin/kexin type 9) is well recognized for its important role in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies (PCSK9i) lowers cardiovascular events in patients with coronary artery disease. PCSK9 levels are also elevated in people living with HIV (PLWH) and those with dyslipidemia. Because increased PCSK9 in PLWH is associated with impaired coronary endothelial function, a barometer of coronary vascular health, we tested the hypothesis that PCSK9i improves impaired coronary endothelial function in dyslipidemia without coronary artery disease and in PLWH with nearly optimal/above goal low-density lipoprotein cholesterol levels. Methods and Results We performed a single-center study in 19 PLWH and 11 with dyslipidemia to evaluate the effects of the PCSK9i evolocumab on coronary endothelial function using cine 3T MRI to noninvasively measure coronary endothelial function, assessed as the changes in coronary cross-sectional area and coronary blood flow from rest to that during isometric handgrip exercise, a known endothelial-dependent vasodilator. Before evolocumab, there was a decrease or no coronary vasodilation and no increase in coronary blood flow (the normal responses) to isometric handgrip exercise in either group. Following 6 weeks of evolocumab, 480 mg q4 weeks, the % cross-sectional area changes from rest to isometric handgrip exercise were +5.6±5.5% and +4.5±3.1% in the PLWH and dyslipidemia groups, respectively, both P<0.01 versus baseline. Improved cross-sectional area was paralleled by a significant coronary blood flow improvement in both groups. Conclusions To our knowledge, these data represent the first evidence that PCSK9 inhibition improves coronary artery health in PLWH and people with dyslipidemia. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT03500302.

SUBMITTER: Leucker TM

PROVIDER: S-EPMC7660736 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Evolocumab, a PCSK9-Monoclonal Antibody, Rapidly Reverses Coronary Artery Endothelial Dysfunction in People Living With HIV and People With Dyslipidemia.

Leucker Thorsten M TM Gerstenblith Gary G Schär Michael M Brown Todd T TT Jones Steven R SR Afework Yohannes Y Weiss Robert G RG Hays Allison G AG

Journal of the American Heart Association 20200717 14

Background PCSK9 (proprotein convertase subtilisin/kexin type 9) is well recognized for its important role in cholesterol metabolism. Elevated levels are associated with increased cardiovascular risk and inhibition with PCSK9 antibodies (PCSK9i) lowers cardiovascular events in patients with coronary artery disease. PCSK9 levels are also elevated in people living with HIV (PLWH) and those with dyslipidemia. Because increased PCSK9 in PLWH is associated with impaired coronary endothelial function, ...[more]

PMID: 32674634

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Project description:D-amphetamine induces emergence from sevoflurane and propofol anesthesia in rats. Dexmedetomidine is an α2-adrenoreceptor agonist that is commonly used for procedural sedation, whereas ketamine is an anesthetic that acts primarily by inhibiting NMDA-type glutamate receptors. These drugs have different molecular mechanisms of action from propofol and volatile anesthetics that enhance inhibitory neurotransmission mediated by GABAA receptors. In this study, we tested the hypothesis that d-amphetamine accelerates recovery of consciousness after dexmedetomidine and ketamine. Sixteen rats (Eight males, eight females) were used in a randomized, blinded, crossover experimental design and all drugs were administered intravenously. Six additional rats with pre-implanted electrodes in the prefrontal cortex (PFC) were used to analyze changes in neurophysiology. After dexmedetomidine, d-amphetamine dramatically decreased mean time to emergence compared to saline (saline:112.8 ± 37.2 min; d-amphetamine:1.8 ± 0.6 min, p < 0.0001). This arousal effect was abolished by pre-administration of the D1/D5 dopamine receptor antagonist, SCH-23390. After ketamine, d-amphetamine did not significantly accelerate time to emergence compared to saline (saline:19.7 ± 18.0 min; d-amphetamine:20.3 ± 16.5 min, p = 1.00). Prefrontal cortex local field potential recordings revealed that d-amphetamine broadly decreased spectral power at frequencies <25 Hz and restored an awake-like pattern after dexmedetomidine. However, d-amphetamine did not produce significant spectral changes after ketamine. The duration of unconsciousness was significantly longer in females for both dexmedetomidine and ketamine. In conclusion, d-amphetamine rapidly restores consciousness following dexmedetomidine, but not ketamine. Dexmedetomidine reversal by d-amphetamine is inhibited by SCH-23390, suggesting that the arousal effect is mediated by D1 and/or D5 receptors. These findings suggest that d-amphetamine may be clinically useful as a reversal agent for dexmedetomidine.

Project description:ObjectivePeople living with HIV (PLWH) have an increased risk of pulmonary vascular disease and pulmonary hypertension. Endothelial cell dysfunction is thought to contribute, but human studies have been limited by the invasive nature of conventional measures of pulmonary artery endothelial function (PAEF). We report here a noninvasive MRI approach to measure nitric oxide mediated PAEF by quantifying changes in pulmonary artery area and blood flow during isometric handgrip exercise (IHE), an endothelial nitric oxide dependent stressor. We used this to test the hypothesis that PLWH have impaired PAEF, even before development of pulmonary hypertension.DesignA prospective cohort study.MethodsWe enrolled 25 HIV-positive viral-suppressed individuals on stable antiretroviral therapy without known or suspected pulmonary hypertension and 19 matched seronegative control individuals (HIV-negative). Pulmonary artery area and blood flow changes in response to IHE were measured with noncontrast MRI. Data previously collected during nitric oxide-synthase inhibition were analysed to determine the role of nitric oxide in the pulmonary artery response to IHE.ResultsSeronegative individuals exhibited the anticipated PA vasodilatory response to IHE, but this was completely absent in HIV-positive individuals who exhibited an impaired area change (-1.1 ± 1.2 vs. +7.7 ± 2.2%, HIV-positive vs. HIV-negative, mean ± SEM, respectively, P = 0.002) and blood flow response (0.2 ± 2.3 vs. 13.5 ± 4.8%, P = 0.005). The pulmonary artery vasodilatory effect of IHE in healthy individuals was fully blocked by nitric oxide-synthase, demonstrating this pulmonary artery response is predominantly nitric oxide mediated.ConclusionUsing noninvasive MRI methods to quantify PAEF, we observed significantly impaired PAEF in PLWH compared with matched HIV-negative controls. Noninvasive PAEF testing may be useful in evaluating early HIV-related pulmonary vascular disease.

Dataset Information

Evolocumab, a PCSK9-Monoclonal Antibody, Rapidly Reverses Coronary Artery Endothelial Dysfunction in People Living With HIV and People With Dyslipidemia.

Publications

Evolocumab, a PCSK9-Monoclonal Antibody, Rapidly Reverses Coronary Artery Endothelial Dysfunction in People Living With HIV and People With Dyslipidemia.

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