Remnant cholesterol in atherosclerotic cardiovascular disease: A systematic review and meta-analysis.

BACKGROUND: Accumulating evidence suggests a substantial contribution of remnant cholesterol (RC) to residual risk for the development or relapse of atherosclerotic cardiovascular disease (ASCVD). We aimed to evaluate the association of RC levels with ASCVD risk by different risk categories and methods of RC assessment. We also assessed available evidence of the effects of lipid-lowering therapies (LLTs) on RC levels. METHODS: English-language searches of Medline, PubMed, and Embase (inception to 31 January 2023); ClinicalTrials.gov (October 2022); and reference lists of studies and reviews. Studies reporting on the risk of the composite endpoint [all-cause mortality, cardiovascular mortality, and major adverse cardiac events (MACE)] by RC levels were included. Moreover, we searched for studies reporting differences in RC levels after the administration of LLT(s). RESULTS: Among n = 29 studies with 257,387 participants, we found a pooled linear (pooled HR: 1.27 per 1-SD increase, 95% CI: 1.12-1.43, P < 0.001, I2 = 95%, n = 15 studies) and non-linear association (pooled HR: 1.59 per quartile increase, 95% CI: 1.35-1.85, P < 0.001, I2 = 87.9%, n = 15 studies) of RC levels and the risk of M ACE both in patients with and without established ASCVD. Interestingly, the risk of MACE was higher in studies with directly measured vs. calculated RC levels. In a limited number of studies and participants, LLTs reduced RC levels. CONCLUSION: RC levels are associated with ASCVD risk both in primary and secondary prevention. Directly measured RC levels are associated with ASCVD risk more evidently. Available LLTs tend to decrease RC levels, although the clinical relevance of RC decrease merits further investigation. PROSPERO REGISTRATION: CRD42022371346.

Endothelial dysfunction and immunothrombosis in sepsis.

Sepsis is a life-threatening clinical syndrome characterized by multiorgan dysfunction caused by a dysregulated or over-reactive host response to infection. During sepsis, the coagulation cascade is triggered by activated cells of the innate immune system, such as neutrophils and monocytes, resulting in clot formation mainly in the microcirculation, a process known as immunothrombosis. Although this process aims to protect the host through inhibition of the pathogen's dissemination and survival, endothelial dysfunction and microthrombotic complications can rapidly lead to multiple organ dysfunction. The development of treatments targeting endothelial innate immune responses and immunothrombosis could be of great significance for reducing morbidity and mortality in patients with sepsis. Medications modifying cell-specific immune responses or inhibiting platelet-endothelial interaction or platelet activation have been proposed. Herein, we discuss the underlying mechanisms of organ-specific endothelial dysfunction and immunothrombosis in sepsis and its complications, while highlighting the recent advances in the development of new therapeutic approaches aiming at improving the short- or long-term prognosis in sepsis.

Implementation of risk enhancers in ASCVD risk estimation and hypolipidemic treatment eligibility: A sex-specific analysis.

OBJECTIVE: Sex-specific data are limited regarding eligibility for hypolipidemic treatment. We aim to explore the sex-specific clinical utility of high-sensitivity C-reactive protein (hsCRP) and carotid ultrasound as risk modifiers for hypolipidemic treatment in primary prevention of atherosclerotic cardiovascular disease (ASCVD). METHODS: We aimed to explore these sex-specific trends in two pooled contemporary independent Greek cohorts (Athens Vascular Registry n = 698, 50.9% women and Menopause Clinic n = 373, 100% women) of individuals without overt ASCVD. Baseline ASCVD risk was estimated using the Systematic COronary Risk Evaluation-2 (SCORE2) tools. The presence of carotid plaque and hsCRP ≥2 mg/L were integrated as risk modifiers. RESULTS: Men had increased odds to achieve target LDL-C levels based on ASCVD risk (23.8% vs. 17.7%, OR: 1.45 95% CI: 1.05-2.00, p = 0.023, for men vs. women). Additionally, considering carotid plaque or high hsCRP levels did not change this association but reduced on-target LDL-C rate in both sexes. Women had decreased odds of being eligible for hypolipidemic treatment by ASCVD risk estimation (11.5% vs. 26.4%, p < 0.001) compared with men. The addition of carotid plaque presence or high hsCRP levels and their combination resulted in a higher relative increase in hypolipidemic treatment eligibility in women (from 11.5% to 70.9% vs. 26.4% to 61.4% for carotid plaque, from 11.5% to 38.5% vs. 26.4% to 50.8% for hsCRP and from 11.5% to 79.1% vs. 26.4% to 75% for their combination, all for women vs. men, pforinteraction < 0.001 for all) than men. CONCLUSIONS: Implementation of carotid plaque and hsCRP levels increases hypolipidemic treatment eligibility more prominently in women than in men. The impact on clinical outcomes in these untreated patients merits further investigation.

Remnant cholesterol and atherosclerotic disease in high cardiovascular risk patients. Beyond LDL cholesterol and hypolipidemic treatment.

BACKGROUND: Remnant cholesterol (RC) is an emerging factor contributing to residual risk for the development of atherosclerotic cardiovascular disease (ASCVD). We aimed to investigate the association of RC with ASCVD in high ASCVD risk patients. METHODS: RC was calculated in 906 participants (178 low/moderate-risk and 728 high-risk) consecutively recruited from a vascular registry. Subclinical carotid atherosclerosis was assessed by B-mode carotid ultrasonography. Maximal carotid wall thickness (maxWT) and carotid atherosclerotic burden (n ≥ 2 atherosclerotic plaques) were set as the vascular outcomes. An independent cohort of 87 consecutively recruited high-risk patients who were followed for their lipid profile for 3 months was also analyzed. RESULTS: RC was increased in the high-risk group as compared to controls (26 ± 17 vs. 21 ± 11 mg/dl, respectively, p < 0.001). Increased RC levels were independently associated with increased maxWT and carotid atherosclerotic burden (p < 0.05), after adjustment for traditional cardiovascular risk factors (TRF) and ASCVD. RC levels were associated with the presence of flow-limiting ASCVD and coronary artery disease (CAD) (p < 0.05), after adjustment for TRFs. These associations remained significant in those not receiving hypolipidemic treatment and in treated individuals achieving LDL-C<100 mg/dl. In the prospective cohort, there was no significant interaction between change in RC levels and hypolipidemic status, as contrasted to LDL-C levels (p < 0.001). CONCLUSION: In a high-risk population, RC was associated with subclinical and clinically overt ASCVD, particularly in patients with the most adverse lipid phenotype (untreated) or in treated patients with a low LDL-related risk profile. These findings support a residual pro-atherosclerotic role of RC in high-risk patients.

Carotid ultrasonography improves residual risk stratification in guidelines-defined high cardiovascular risk patients.

AIMS: The clinical value of carotid atherosclerosis markers for residual risk stratification in high atherosclerotic cardiovascular disease (ASCVD) risk patients is not established. We aimed to derive and validate optimal values of markers of carotid subclinical atherosclerosis improving risk stratification in guidelines-defined high ASCVD risk patients. METHODS AND RESULTS: We consecutively analysed high or very high ASCVD risk patients from a cardiovascular (CV) prevention registry (n = 751, derivation cohort) and from the Atherosclerosis Risk in Communities (ARIC) study (n = 2,897, validation cohort). Baseline ASCVD risk was defined using the 2021 European Society of Cardiology guidelines (clinical ESCrisk). Intima-media thickness excluding plaque, average maximal (avg.maxWT), maximal wall thickness (maxWT) and number of sites with carotid plaque were assessed. As primary endpoint of the study was defined the composite of cardiac death, acute myocardial infarction and revascularization after a median of 3.4 years in both cohorts and additionally for 16.7 years in the ARIC cohort. RESULTS: MaxWT > 2.00 mm and avg.maxWT > 1.39 mm provided incremental prognostic value, improved discrimination and correctly reclassified risk over the clinical ESCrisk both in the derivation and the validation cohort (P < 0.05 for net reclassification index, integrated discrimination index and Delta Harrell's C index). MaxWT < 0.9 mm predicted very low probability of CV events (negative predictive value = 97% and 92% in the derivation and validation cohort, respectively). These findings were additionally confirmed for very long-term events in the validation cohort. CONCLUSION: Integration of carotid ultrasonography in guidelines-defined risk stratification may identify patients at very high-risk in need for further residual risk reduction or at very low probability for events.

Insights to SARS-CoV-2 life cycle, pathophysiology, and rationalized treatments that target COVID-19 clinical complications.

BACKGROUND: Gaining further insights into SARS-CoV-2 routes of infection and the underlying pathobiology of COVID-19 will support the design of rational treatments targeting the life cycle of the virus and/or the adverse effects (e.g., multi-organ collapse) that are triggered by COVID-19-mediated adult respiratory distress syndrome (ARDS) and/or other pathologies. MAIN BODY: COVID-19 is a two-phase disease being marked by (phase 1) increased virus transmission and infection rates due to the wide expression of the main infection-related ACE2, TMPRSS2 and CTSB/L human genes in tissues of the respiratory and gastrointestinal tract, as well as by (phase 2) host- and probably sex- and/or age-specific uncontrolled inflammatory immune responses which drive hyper-cytokinemia, aggressive inflammation and (due to broad organotropism of SARS-CoV-2) collateral tissue damage and systemic failure likely because of imbalanced ACE/ANGII/AT1R and ACE2/ANG(1-7)/MASR axes signaling. CONCLUSION: Here we discuss SARS-CoV-2 life cycle and a number of approaches aiming to suppress viral infection rates or propagation; increase virus antigen presentation in order to activate a robust and durable adaptive immune response from the host, and/or mitigate the ARDS-related "cytokine storm" and collateral tissue damage that triggers the severe life-threatening complications of COVID-19.

Off-Target Effects of Antidepressants on Vascular Function and Structure.

Depression emerges as a risk factor for cardiovascular disease, and it is thought that successful antidepressant treatment may reduce such a risk. Therefore, antidepressant treatment embodies a potential preventive measure to reduce cardiovascular events in patients with depression. Accumulating evidence indicates that antidepressants have off-target effects on vascular dysfunction and in the early stages of atherosclerosis, which form the basis for cardiovascular disease (CVD) pathogenesis. In this context, we performed a thorough review of the evidence pertaining to the effects of different classes of antidepressant medications on hemodynamic and early atherosclerosis markers. The preclinical and clinical evidence reviewed revealed a preponderance of studies assessing selective serotonin reuptake inhibitors (SSRI), whereas other classes of antidepressants are less well-studied. Sufficient evidence supports a beneficial effect of SSRIs on vascular inflammation, endothelial function, arterial stiffening, and possibly delaying carotid atherosclerosis. In clinical studies, dissecting the hypothesized direct beneficial antidepressant effect of SSRIs on endothelial health from the global improvement upon remission of depression has proven to be difficult. However, preclinical studies armed with appropriate control groups provide evidence of molecular mechanisms linked to endothelial function that are indeed modulated by antidepressants. This suggests at least a partial direct action on vascular integrity. Further research on endothelial markers should focus on the effect of antidepressants on treatment responders versus non-responders in order to better ascertain the possible beneficial vascular effects of antidepressants, irrespective of the underlying course of depression.

Circulating Amyloid Beta 1-40 Is Associated with Increased Rate of Progression of Atherosclerosis in Menopause: A Prospective Cohort Study.

BACKGROUND: Accumulating evidence suggests that circulating amyloidß 1-40 (Αß1-40), a proatherogenic aging peptide, may serve as a novel biomarker in cardiovascular disease (CVD). We aimed to explore the role of plasma Αß1-40 and its patterns of change over time in atherosclerosis progression in postmenopausal women, a population with substantial unrecognized CVD risk beyond traditional risk factors (TRFs). METHODS: In this prospective study, Αß1-40 was measured in plasma by enzyme-linked immunosorbent assay and atherosclerosis was assessed using carotid high-resolution ultrasonography at baseline and after a median follow-up of 28.2 months in 152 postmenopausal women without history or symptoms of CVD. RESULTS: At baseline, high Αß1-40 was independently associated with higher carotid bulb intima-media thickness (cbIMT) and the sum of maximal wall thickness in all carotid sites (sumWT) (p < 0.05). Αß1-40 levels increased over time and were associated with decreasing renal function (p < 0.05 for both). Women with a pattern of increasing or persistently high Αß1-40 levels presented accelerated progression of cbIMT and maximum carotid wall thickness and sumWT (p < 0.05 for all) after adjustment for baseline Αß1-40 levels, TRFs, and renal function. CONCLUSION: In postmenopausal women, a pattern of increasing or persistently high Αß1-40 was associated with the rate of progression of subclinical atherosclerosis irrespective of its baseline levels. These findings provide novel insights into a link between Αß1-40 and atherosclerosis progression in menopause and warrant further research to clarify the clinical value of monitoring its circulating levels as an atherosclerosis biomarker in women without clinically overt CVD.

Cardiac arrest and drug-related cardiac toxicity in the Covid-19 era. Epidemiology, pathophysiology and management.

SARS-CoV-2 (Covid-19) infection has recently become a worldwide challenge with dramatic global economic and health consequences. As the pandemic is still spreading, new data concerning Covid-19 complications and related mechanisms become increasingly available. Accumulating data suggest that the incidence of cardiac arrest and its outcome are adversely affected during the Covid-19 period. This may be further exacerbated by drug-related cardiac toxicity of Covid-19 treatment regimens. Elucidating the underlying mechanisms that lead to Covid-19 associated cardiac arrest is imperative, not only in order to improve its effective management but also to maximize preventive measures. Herein we discuss available epidemiological data on cardiac arrest during the Covid-19 pandemic as well as possible associated causes and pathophysiological mechanisms and highlight gaps in evidence warranting further investigation. The risk of transmission during cardiopulmonary resuscitation (CPR) is also discussed in this review. Finally, we summarize currently recommended guidelines on CPR for Covid-19 patients including CPR in patients with cardiac arrest due to suspected drug-related cardiac toxicity in an effort to underscore the most important common points and discuss discrepancies proposed by established international societies.

Retinol-binding protein 4 is associated with arterial stiffness in early postmenopausal women.

OBJECTIVE: Recent evidence in postmenopausal women suggested lack of association between serum levels of retinol-binding protein 4 (RBP4) and subclinical atherosclerosis; however, associations with arterial stiffness in this population remain unexplored. We evaluated the association among RBP4 and cardiovascular risk factors, including homocysteine, a marker involved in retinoic acid synthesis, and indices of arterial stiffness, in a sample of apparently healthy postmenopausal women. METHODS: This cross-sectional study included 123 healthy postmenopausal women, not on hormone therapy, antihypertensive, or hypolipidemic treatment and with a menopausal age 10 years or less. We performed biochemical/hormonal assessment and sonographic evaluation, including carotid-femoral pulse wave velocity (PWV) and carotid artery stiffness index (SI). RESULTS: Univariate analysis showed that RBP4 values correlated with age, low-density lipoprotein-cholesterol and estradiol levels. There was a trend of association of SI and PWV with homocysteine and triglycerides. RBP4 differed according to PWV, using the median PWV value as cut-off (RBP4, PWV ≤8.1 vs >8.1 m/s: 10.09 ±â€Š2.05 vs 10.85 ±â€Š1.91 ng/mL, analysis of covariance P value 0.014 adjusted for age, menopausal age, estradiol, pulse pressure). Linear regression analysis showed that PWV was independently associated with RBP4, age, and pulse pressure, whereas SI was independently associated with RBP4. An increase of one standard deviation in RBP4 levels (2.54 ng/mL) was associated with an increase of 0.577 m/s in PWV. CONCLUSIONS: RBP4 serum levels are associated with arterial stiffness, in a sample of healthy postmenopausal women. If this association is causative, serum RBP4 levels could serve as a marker of arterial stiffness. Prospective studies are required to investigate the significance of our findings. : Video Summary:http://links.lww.com/MENO/A621.

Video Summary:http://links.lww.com/MENO/A621.