Coronary endothelial dysfunction is an established driver for the development of coronary atherosclerosis, and abnormal coronary endothelial function (CEF) is an independent predictor of adverse cardiovascular events. Advances in magnetic resonance imaging make it possible to quantify CEF by measuring changes in the coronary cross-sectional area in response to isometric handgrip exercise, an endothelial-dependent stressor. Healthy coronaries respond by vasodilatation and thus an increase in cross-sectional area is measured; no change or paradoxical vasoconstriction is seen in the presence of endothelial dysfunction.1 This non-invasive method allows assessment of the effectiveness of interventions that may improve CEF.
Human immunodeficiency virus (HIV) infection is associated with accelerated atherosclerosis. Both elevated LDL-C (LDL-cholesterol) and Lp(a) (lipoprotein[a]) are independently associated with cardiovascular risk and are reduced following PCSK9 (proprotein convertase subtilisin/kexin type 9 inhibition).2 We previously reported that PCSK9 inhibition with the monoclonal antibody evolocumab improved CEF in people with HIV (REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03500302).3 Here, we investigated 15 of the 19 people with HIV in this study for whom we had stored serum samples and measured Lp(a) and LDL-C to examine the association of the changes in Lp(a) and LDL-C with the changes in CEF.
The data, and methods used in the analysis, and materials used to conduct the research that support the findings of this study are available from the corresponding author upon reasonable request. The study was approved by the Johns Hopkins Medicine Institutional Review Board and all participants provided informed written consent. Magnetic resonance imaging scans for CEF were performed before and six weeks following the initiation of evolocumab, 420 mg subcutaneously, every 4 weeks. All participants were on antiretroviral therapy and had a plasma HIV RNA of ≤27copies/mL. Statistical analysis was performed using GraphPad Prism 9.5.0 and SAS 9.4. Categorical variables were compared using the Fisher exact test. Data were tested for normality using the Shapiro-Wilk test. Parametric and nonparametric tests were used for normally distributed and skewed data, respectively, to compare paired Lp(a), LDL-C, and CEF measures at baseline before PCSK9 inhibition, and at follow-up. Generalized estimation equation analysis was used to assess the longitudinal correlation between CEF and Lp(a) and between CEF and LDL-C.
The mean (±SD) age was 54 (±9) years, 20% were women and 80% were Black participants. At baseline, median Lp(a) was 46 (12–127) nmol/L, LDL-C was 112 (87–126) mg/dL and the coronary cross-sectional area response to isometric handgrip exercise was −5.5% (±11.2%). Lp(a) decreased from 46 (12–127) to 38 (10–61) nmol/L at six weeks following PCSK9 inhibition (P<0.001). Lp(a) did not increase in any of the participants, with a median change of −26 (−39 to −1) nmol/L and a maximum change of −73 nmol/L. The coronary cross-sectional area response to isometric handgrip exercise improved from −5.5% (±11.2%) to +3.8% (±8.5%; P=0.002; Figure [A] through [D]), and the improvement was significantly correlated with the decrease in Lp(a); regression coefficient, −0.6673; SE, 0.2512; and 95% CI, −1.159 to −0.175; P=0.008. Despite a significant decrease in LDL-C, from 112 (87–126) to 27 (18–48) mg/dL (P<0.001), there was no correlation between this decrease and the improvement in CEF (P=0.47). The decreases in Lp(a) and LDL-C are plotted against the change in CEF in Figure [E].
Figure:
Representative magnetic resonance imaging images of the right coronary artery (RCA) in a person with HIV and correlation of the changes in CEF with the changes in Lp(a) and LDL-C in the study participants. A scout scan of the RCA is shown in A along with the location for cross-sectional imaging (yellow line). A view of the RCA cross-section is shown (yellow box) in B that is perpendicular to image (A). The yellow box in B is magnified to show a cross-sectional image of the RCA (red circles) at rest and during isometric handgrip exercise before (C) and following (D) initiation of the PCSK9 inhibitor. E, Correlation analysis showing the 6-week changes in coronary endothelial function (CEF) plotted against the changes in Lp(a) (lipoprotein[a]) and in LDL-cholesterol (LDL-C). There is a significant correlation between the change in CEF and the change in Lp(a) (blue symbols; regression coefficient, −0.6673; SE, 0.2512 [95% CI, −1.159 to −0.175]; P=0.008), but no association between the change in CEF and the change in LDL-C (red symbols; P=0.47). LA indicates left atrium; LV, left ventricle; RA, right atrium; and RV, right ventricle.
We previously reported that elevated serum PCSK9 was associated with impaired CEF in people with HIV1 and that administering a PCSK9 inhibitor rapidly improved CEF.3 We now report a clear correlation between Lp(a) reduction and a rapid improvement in CEF following the initiation of a PCSK9 antibody. Nitric oxide bioavailability is a key mediator of normal coronary vascular function and nonenzymatic lipid oxidation reactions can directly scavenge nitric oxide, alter the activity of the nitric oxide synthase enzyme, and convert nitric oxide to prooxidant species, such as peroxynitrite.4 As Lp(a), rather than LDL-C, is the major carrier of oxidized phospholipids, the correlation of the rapid improvement of CEF with the decrease in Lp(a) may therefore be due to an early reduction in oxidized phospholipids. However, there is some uncertainty as to whether PCSK9i decreases oxidized phospholipids.5 Although there was no correlation with the decrease in LDL-C, it is possible that there would be a relationship with a longer follow-up period and a larger sample size. A larger sample size would also allow assessment of the reliability and reproducibility of the correlations we observed. Although the median Lp(a) levels at baseline and at 6-weeks are within the reference range of healthy, non-HIV-infected individuals, the decrease was statistically significant. Assessing the impact of reducing Lp(a) with specific compounds such as pelacarsen or olpasiran would be more informative, but these interventions, to our knowledge, are not presently available for coronary vascular function research studies.
The correlation of the extent of Lp(a) reduction and the improvement of CEF was not previously reported. These results indicate that a potential benefit of reducing Lp(a) in patients with, or at risk for, coronary disease is improved CEF, dysfunction of which is a driver of atherosclerosis. Studies of CEF may inform the identification and assess the effectiveness of emerging pharmacotherapies that specifically target Lp(a).
Sources of Funding:
Amgen provided the evolocumab for this study. Amgen had no role in the design of the study, the collection, management or interpretation of the data, or the statistical analysis. Amgen reviewed the first submitted version of the article but was not involved in the writing or approval of the article or the decision to submit the article for publication.
Disclosures:
Dr Leucker reports a research grant from Amgen. Dr Brown has served as a consultant to Merck, ViiV Healthcare, Gilead Sciences, Janssen, and Theratechnologies. The other authors report no conflicts.
References:
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