Platelet activation and endothelial dysfunction biomarkers in acute coronary syndrome: the impact of PCSK9 inhibition.

AIMS: Platelet activation and endothelial dysfunction contribute to adverse outcomes in patients with acute coronary syndromes (ACS). The goals of this study were to assess the impact of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on markers of platelet activation and endothelial dysfunction in ACS patients and the interaction among PCSK9, platelets, and endothelial cells (ECs) on left internal mammary artery (LIMA) vascular endothelium using specimens obtained during coronary artery bypass surgery (CABG). METHODS AND RESULTS: Acute coronary syndromes patients enrolled in the Evolocumab in ACS trials were randomized to placebo or a single dose of 420 mg evolocumab within 24 h of hospitalization. Serum samples for analysis of platelet factor 4 (PF4) and P-selectin, markers of platelet activation, and von Willebrand factor (vWF), a marker of endothelial dysfunction, were obtained at baseline and 30 days. Additionally, LIMA segments obtained during CABG from patients who were and were not receiving evolocumab were immunostained with PCSK9; CD61, a platelet-specific marker; and CD31, an endothelial cell-specific marker. Forty-six participants were randomized to placebo or to evolocumab. Controlling for baseline levels, PF4 and vWF were significantly lower in the evolocumab, than in the placebo, group at 30 days. Immunostaining of LIMA specimens from twelve participants undergoing CABG revealed colocalization of PCSK9, CD61, and CD31 at the vascular endothelium. Administration of evolocumab was associated with decreased overlap of PCSK9, CD61, and CD31. CONCLUSIONS: Proprotein Convertase Subtilisin/Kexin 9 inhibition decreases markers of platelet activation and endothelial dysfunction in ACS patients. PCSK9 is associated with platelets and vascular ECs in LIMA segments and PCSK9 inhibition decreases that interaction.

Lipoprotein(a) concentrations in acute myocardial infarction patients are not indicative of levels at six month follow-up.

Aims: Lipoprotein(a) [Lp(a)] levels are generally constant throughout an individual's lifetime, and current guidelines recommend that a single measurement is sufficient to assess the risk of coronary artery disease (CAD). However, it is unclear whether a single measurement of Lp(a) in individuals with acute myocardial infarction (MI) is indicative of the Lp(a) level six months following the event. Methods and results: Lp(a) levels were obtained from individuals with non-ST-elevation myocardial infarction (NSTEMI) or ST-elevation myocardial infarction (STEMI) (n = 99) within 24 h of hospital admission and after six months, who were enrolled in two randomized trials of evolocumab and placebo, and in individuals with NSTEMI or STEMI (n = 9) who enrolled in a small observation arm of the two protocols and did not receive study drug, but whose levels were obtained at the same time points. Median Lp(a) levels increased from 53.5 nmol/L (19, 165) during hospital admission to 58.0 nmol/L (14.8, 176.8) six months after the acute infarction (P = 0.02). Subgroup analysis demonstrated no difference in the baseline, six-month, or change between the baseline and six-month Lp(a) values between the STEMI and NSTEMI groups and between the group which received evolocumab and the group that did not. Conclusion: This study demonstrated that Lp(a) levels in individuals with acute MI are significantly higher six months after the initial event. Therefore, a single measurement of Lp(a) in the peri-infarction setting is not sufficient to predict the Lp(a)-associated CAD risk in the post-infarction period. Registration: Evolocumab in Acute Coronary Syndrome Trial [EVACS I] NCT03515304, Evolocumab in Patients with Acute Myocardial Infarction [EVACS II], NCT04082442.

Adult Cancer-Related Emergency Department Utilization: An Analysis of Trends and Outcomes From Emergency Departments in Maryland and New York.

PURPOSE: To explore emergency department (ED) visits by adults with cancer and to estimate associations between inpatient admissions through the ED and mortality with sociodemographic and clinical factors within this cohort. METHODS: We conducted a retrospective, pooled, cross-sectional analysis of the Healthcare Cost and Utilization State Emergency Department Databases and State Inpatient Databases for Maryland and New York from January 2013 to December 2017. We examined inpatient admissions through the ED and mortality using frequencies. Among patients with cancer, multivariable regressions were used to estimate sociodemographic and clinical factors associated with inpatient admissions and outpatient ED and inpatient mortality overall. RESULTS: Among 22.7 million adult ED users, 1.3 million (5.7%) had at least one cancer-related diagnosis. ED visit rates per 100,000 population increased annually throughout the study period for patients with cancer and were 9.9% higher in 2017 compared with 2013 (2013: 303.5; 2017: 333.6). Having at least one inpatient admission (68.7% v 20.5%; P < .001) and inpatient or ED mortality (6.5% v 1.0%; P < .001) were higher among ED users with cancer compared with those without. Among patients with cancer, being uninsured (adjusted odds ratio, 0.52; 95% CI, 0.44 to 0.62) compared with having Medicare coverage and non-Hispanic Black (adjusted odds ratio, 0.86; 95% CI, 0.80 to 0.92) compared with non-Hispanic White were associated with decreased odds of inpatient admissions. In contrast, patients with cancer without health insurance, non-Hispanic Black patients, and residents of nonlarge metropolitan areas and of areas with lower household incomes had increased odds of mortality. CONCLUSION: High inpatient admissions through the ED and mortality among adult patients with cancer, coupled with an increase in cancer-related ED visit rates and observed disparities in outcomes, highlight the need to improve access to oncologic services to contain ED use and improve care for patients with cancer.

Lipoprotein (a) Levels and Abdominal Aortic Aneurysm. A Systematic Review and Meta-analysis.

BACKGROUND: Several studies have linked high Lipoprotein (a) (Lp(a)) concentrations to cardiovascular events, including the formation of Abdominal Aortic Aneurysms (AAA). We review and meta-analyze existing evidence on the association of Lp(a) levels with AAA. METHODS: Studies evaluating the link of Lp(a) with AAA, up to December 27th 2021, were identified by a systematic search of PubMed, SCOPUS, and Web of Science databases. The results were qualitatively and quantitatively synthesized according to PRISMA guidelines. Results are presented as standardized mean differences (SMD) with 95% confidence intervals (CI). RESULTS: A total of 5,078 subjects (1,637 patients with AAA vs. 3,441 controls) from 11 studies were included in the meta-analysis, with a mean age of 69.9 years and a male sex prevalence of 85.8%. Based on the qualitative synthesis, high Lp(a) concentrations are linked to abdominal aortic wall degradation and extracellular matrix disarrangement. Moreover, despite the considerable variability among races, high Lp(a) levels are related to increased AAA risk, independently of race differences. Accordingly, patients with AAA displayed significantly higher Lp(a) levels compared to controls (SMD: 0.86, 95% CI: 0.55-1.17, p < 0.001). The outcome was not affected in a sensitivity analysis excluding three outlying studies (SMD: 0.40, 95% CI: 0.22-0.58, p < 0.001). CONCLUSION: This meta-analysis indicates the association between high Lp(a) levels and the presence of AAA, although existing literature presents high heterogeneity. Further studies are needed to standardize Lp(a) measurements and to conclude whether Lp(a) can be used as a sensitive biomarker of early presymptomatic AAA diagnosis.

The Trajectory of Lipoprotein(a) During the Peri- and Early Postinfarction Period and the Impact of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibition.

Lipoprotein(a), or Lp(a), levels and the effect of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition on Lp(a) during the peri-infarction and early postinfarction period are not well characterized. This study aimed to describe the trajectory of Lp(a), as well as the effect of PCSK9 inhibition on that trajectory during the peri-infarction and early postinfarction period. Lp(a) levels were obtained within 24 hours of hospital admission as well as within 24 hours of hospital discharge and at 30 days from 74 participants who presented with a NSTEMI (troponin I >5 ng/ml) or with a STEMI and were enrolled in 2 randomized, double-blind trials of evolocumab and placebo (Evolocumab in Acute Coronary Syndrome [EVACS I]; ClinicalTrials.gov, NCT03515304 and Evolocumab in Patients With STEMI [EVACS II]; ClinicalTrials.gov Identifier: NCT04082442). There was a significant increase from the pretreatment level in the placebo-treated patients, from 64 (41,187) nmol/L to 80 (47, 172) nmol/L at hospital discharge and to 82 (37, 265) at 30 days. This was primarily driven by the results from participants with high Lp(a) at hospital admission (>75 nmol/L) in whom the median increase was 28% as compared with a 10% increase in those with pretreatment Lp(a) of <75 nmol/L. In contrast, there was no significant change from the pretreatment level in the evolocumab-treated patients regardless of pretreatment Lp(a) levels. In conclusion, Lp(a) rises during the peri-infarction and early postinfarction period in patients with acute myocardial infarction. The increase was prevented by a single dose of subcutaneous evolocumab given within 24 hours of hospital admission.

Comparison of Ticagrelor Versus Clopidogrel on Cerebrovascular Microembolic Events and Platelet Inhibition during Transcatheter Aortic Valve Implantation.

The impact of the antiplatelet regimen and the extent of associated platelet inhibition on cerebrovascular microembolic events during transcatheter aortic valve implantation (TAVI) are unknown. Our aim was to evaluate the effects of ticagrelor versus clopidogrel and of platelet inhibition on the number of cerebrovascular microembolic events in patients undergoing TAVI. Patients scheduled for TAVI were randomized previous to the procedure to either aspirin and ticagrelor or to aspirin and clopidogrel. Platelet inhibition was expressed in P2Y12 reaction units (PRU) and percentage of inhibition. High intensity transient signals (HITS) were assessed with transcranial Doppler (TCD). Safety outcomes were recorded according to the VARC-2 definitions. Among 90 patients randomized, 6 had an inadequate TCD signal. The total number of procedural HITS was lower in the ticagrelor group (416.5 [324.8, 484.2]) (42 patients) than in the clopidogrel group (723.5 [471.5, 875.0]) (42 patients), p <0.001. After adjusting for the duration of the procedure, diabetes, extra-cardiac arteriopathy, BMI, hypertension, aortic valve calcium content, procedural ACT, and pre-implantation balloon valvuloplasty, patients on ticagrelor had on average 256.8 (95% CI: [-335.7, -176.5]) fewer total procedural HITS than patients on clopidogrel. Platelet inhibition was greater with ticagrelor 26 [10, 74.5] PRU than with clopidogrel 207.5 (120 to 236.2) PRU, p <0.001, and correlated significantly with procedural HITS (r = 0.5, p <0.05). In conclusion, ticagrelor resulted in fewer procedural HITS, compared with clopidogrel, in patients undergoing TAVI, while achieving greater platelet inhibition.

The role of Lipoprotein(a) in cardiovascular disease: Current concepts and future perspectives.

High lipoprotein(a) [Lp(a)] levels are associated with the development of atherosclerotic cardiovascular disease (ASCVD) and with calcific aortic valve stenosis (CAVS) both observationally and causally from human genetic studies. The mechanisms are not well characterized but likely involve its role as a carrier of oxidized phospholipids (OxPLs), which are known to be increased in pro-inflammatory states, to induce pro-inflammatory changes in monocytes leading to plaque instability, and to impair vascular endothelial cell function, a driver of acute and recurrent ischemic events. In addition, Lp(a) itself has prothrombotic activity. Current lipid-lowering strategies do not sufficiently lower Lp(a) serum levels. Lp(a)-specific-lowering drugs, targeting apolipoprotein(a) synthesis, lower Lp(a) by up to 90% and are being evaluated in ongoing clinical outcome trials. This review summarizes the current knowledge on the associations of Lp(a) with ASCVD and CAVS, the current role of Lp(a) assessment in the clinical setting, and emerging Lp(a)-specific-lowering therapies.