Effectiveness and safety of injectable PCSK9 inhibitors in dyslipidaemias’ treatment and cardiovascular disease prevention: An overview of 86 systematic reviews and a network metaanalysis / Eficacia y seguridad de los inyectables inhibidores de la PCSK9 en el tratamiento de dislipidemias y la prevención de enfermedades cardiovasculares: una visión general de 86 revisiones sistemáticas y un metaanálisis en red

Objective Multiple systematic reviews (SR) have been performed on the effects of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), often providing conflicting findings. This overview and network meta-analysis (NMA) aimed to summarize SR findings on the efficacy and safety of PCSK9i and provide an updated NMA. Materials and methods MEDLINE (Pubmed), Scopus, Cochrane, Epistemonikos and Google Scholar were searched from inception to September 21, 2023 for SRs of randomized controlled trials (RCTs) and from January 1, 2020 to September 21, 2023 for additional RCTs. Double-independent study selection, data extraction and quality assessment were performed. Qualitative analysis was performed for SRs and a frequentist random-effects model NMA was performed for RCTs. Results Totally, 86 SRs and 76 RCTs were included. Alirocumab (77/86 [90%]) and evolocumab (73/86 [85%]) were mostly analyzed. Associations from SRs (35/42 [83%]) and the updated NMA indicated PCSK9i benefit on major adverse cardiovascular events (MACEs). Reductions were also noted for cerebrovascular events (47/66 [71%]), coronary revascularization (29/33 [88%]) and myocardial infarction (41/63 [65%]). Alirocumab was associated with reductions on all-cause mortality (RR=0.82, 95%CI [0.72,0.94]). Data on any CV event reduction were conflicting (7/16 [44%]). Inclisiran appeared effective only on MACEs (RR=0.76, 95%CI [0.61,0.94]). No reductions in heart failure were observed (0/16). No increases were identified between PCSK9i and any (0/35) or serious adverse events (0/52). However, PCSK9i were associated with injection-site reactions (20/28 [71%]). Conclusion PCSK9i appeared to be effective in CV outcomes and their clinical application was generally safe. (AU)

Objetivo Las revisiones sistemáticas (RS) sobre los efectos de los inhibidores de la proproteína convertasa subtilisina/kexina tipo 9 (PCSK9i), presentan resultados contradictorios. Esta revisión general y metaanálisis en red (MER) tiene como objetivo resumir los hallazgos sobre la eficacia y seguridad de los PCSK9i. Materiales y métodos Se realizaron búsquedas en MEDLINE (PubMed), Scopus, Cochrane, Epistemonikos y Google Scholar desde sus inicios hasta el 21 de septiembre de 2023 para las RS de ensayos controlados aleatorios (ECA) y desde el 1 de enero de 2020 hasta 21 de septiembre de 2023 para los ECA adicionales. La selección de estudios, extracción de datos y evaluación de calidad se llevaron a cabo de manera doble e independiente. Se realizó un análisis cualitativo de las SR y un modelo de efectos aleatorios frecuentistas MER para los ECA. Resultados En total, se incluyeron 86 SR y 76 RCT. Alirocumab (77/86 [90%]) y evolocumab (73/86 [85%]) fueron los más analizados. Se reconocieron beneficios de los PCSK9i en eventos cardiovasculares adversos mayores (ECVAM), reducción de eventos cerebrovasculares (47/66 [71%]), revascularización coronaria (29/33 [88%]) e infartos de miocardio (41/63 [65%]). Alirocumab redujo la mortalidad por todas las causas (RR: 0,82; IC del 95%: 0,72-0,94). Los resultados sobre la reducción de cualquier evento cardiovascular (CV) fueron contradictorios (7/16 [44%]). Inclisiran pareció ser efectivo solo en la reducción de ECVAM (RR: 0,76; IC del 95%: 0,61-0,94). No se observaron reducciones en insuficiencia cardíaca (0/16) o relación con eventos adversos serios (0/52). Sin embargo, se asociaron con reacciones en el lugar de la inyección (20/28 [71%]). (AU)

Effectiveness and safety of injectable PCSK9 inhibitors in dyslipidaemias' treatment and cardiovascular disease prevention: An overview of 86 systematic reviews and a network metaanalysis.

OBJECTIVE: Multiple systematic reviews (SR) have been performed on the effects of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i), often providing conflicting findings. This overview and network meta-analysis (NMA) aimed to summarize SR findings on the efficacy and safety of PCSK9i and provide an updated NMA. MATERIALS AND METHODS: MEDLINE (Pubmed), Scopus, Cochrane, Epistemonikos and Google Scholar were searched from inception to September 21, 2023 for SRs of randomized controlled trials (RCTs) and from January 1, 2020 to September 21, 2023 for additional RCTs. Double-independent study selection, data extraction and quality assessment were performed. Qualitative analysis was performed for SRs and a frequentist random-effects model NMA was performed for RCTs. RESULTS: Totally, 86 SRs and 76 RCTs were included. Alirocumab (77/86 [90%]) and evolocumab (73/86 [85%]) were mostly analyzed. Associations from SRs (35/42 [83%]) and the updated NMA indicated PCSK9i benefit on major adverse cardiovascular events (MACEs). Reductions were also noted for cerebrovascular events (47/66 [71%]), coronary revascularization (29/33 [88%]) and myocardial infarction (41/63 [65%]). Alirocumab was associated with reductions on all-cause mortality (RR=0.82, 95%CI [0.72,0.94]). Data on any CV event reduction were conflicting (7/16 [44%]). Inclisiran appeared effective only on MACEs (RR=0.76, 95%CI [0.61,0.94]). No reductions in heart failure were observed (0/16). No increases were identified between PCSK9i and any (0/35) or serious adverse events (0/52). However, PCSK9i were associated with injection-site reactions (20/28 [71%]). CONCLUSION: PCSK9i appeared to be effective in CV outcomes and their clinical application was generally safe.

Preventative Imaging with Coronary Computed Tomography Angiography.

PURPOSE OF REVIEW: Coronary computed tomography angiography (CCTA) is the diagnostic modality of choice for patients with stable chest pain. In this review, we scrutinize the evidence on the use of CCTA for the screening of asymptomatic patients. RECENT FINDINGS: Clinical evidence suggests that CCTA imaging enhances cardiovascular risk stratification and prompts the timely initiation of preventive treatment leading to reduced risk of major adverse coronary events. Visualization of coronary plaques by CCTA also helps patients to comply with preventive medications. The presence of non-obstructive plaques and total plaque burden are prognostic for cardiovascular events. High-risk plaque features and pericoronary fat attenuation index, enrich the prognostic output of CCTA on top of anatomical information by capturing information on plaque vulnerability and coronary inflammatory burden. Timely detection of atherosclerotic disease or coronary inflammation by CCTA can assist in the deployment of targeted preventive strategies and novel therapeutics to prevent cardiovascular disease.

Stem Cell-based Therapies in Cardiovascular Diseases: From Pathophysiology to Clinical Outcomes.

Over 20 years of intensified research in the field of stem cells brought about unprecedented possibilities in treating heart diseases. The investigators were initially fascinated by the idea of regenerating the lost myocardium and replacing it with new functional cardiomyocytes, but this was extremely challenging. However, the multifactorial effects of stem cell-based therapies beyond mere cardiomyocyte generation, caused by paracrine signaling, would open up new possibilities in treating cardiovascular diseases. To date, there is a strong body of evidence that the anti-inflammatory, anti-apoptotic, and immunomodulatory effects of stem cell therapy may alleviate atherosclerosis progression. In the present review, our objective is to provide a brief overview of the stem cell-based therapeutic options. We aim to delineate the pathophysiological mechanisms of their beneficial effects in cardiovascular diseases especially in coronary artery disease and to highlight some conclusions from important clinical studies in the field of regenerative medicine in cardiovascular diseases and how we could further move onwards.

Interleukin-6 Signaling in Atherosclerosis: From Molecular Mechanisms To Clinical Outcomes.

Interleukin-6 (IL-6) is a cytokine centrally involved in several immune responses and it has been recognized as a driver of enhanced atherothrombotic risk. Immunity and inflammation are intrinsically involved in atherosclerosis progression. This generated 'inflammation hypothesis', which is now validated in large-scale clinical trials. Abundant evidence supports the distinctive role of IL-6 in coronary artery disease. The focus on this cytokine stems from epidemiological studies linking high plasma concentrations of IL-6 with greater risk for adverse cardiovascular events, genetic studies which implicate a causative role of IL-6 in atherosclerosis and murine data which support the involvement of IL-6 in various pathophysiological cascades of atherothrombosis. The fact that high IL-6 levels are equivalent to increased cardiovascular risk created an unmet need to address those who are at 'residual inflammatory risk'. Moreover, the opposing effects of IL-6 underlined the importance of deciphering specific signaling cascades, which may be responsible for different effects. Finally, murine data and some small clinical trials highlighted the possibility of reversing the pro-atherogenic effects of IL-6 by directly targeting it. While IL-1 blockage was proved effective, it is reasonable to examine if moving more downstream in the inflammation cascade could be more selective and effective than other anti-inflammatory therapies. In the present review, we examine the role of IL-6 as a biomarker of 'residual inflammatory risk', its vital role in the pathophysiology of atherosclerosis progression and the possibility of targeting it to stall coronary artery disease progression.

Oxidative Stress Biomarkers in Coronary Artery Disease.

Oxidative stress plays a central role in atherogenesis, implicated in endothelial dysfunction, coronary plaque formation, and destabilization. Therefore, identifying oxidative stress in the vascular wall by reliable biomarkers could aid in early diagnosis and better coronary artery disease (CAD) prognostication. Because of the short half-life of reactive oxygen species, the current approach is to measure stable products generated by the oxidation of macromolecules in plasma or urine. Most popular oxidative stress biomarkers are oxidized low-density lipoprotein, myeloperoxidase and lipid peroxidation biomarkers, such as malondialdehyde and F2-isoprostanes. Oxidative protein modification biomarkers and oxidized phospholipids have also been studied and discussed in the present review. Most of these biomarkers are associated with the presence and extent of CAD, are elevated in patients with acute coronary syndromes, and may predict outcomes independent of traditional CAD risk factors. However, further standardization of measurement methods and assessment in large randomized clinical trials are required to integrate these biomarkers into clinical practice. In addition, evidence that these biomarkers detect oxidative stress in the vascular wall lacks and more specific biomarkers should be developed to identify vascular oxidative stress. Consequently, several oxidative stress biomarkers have been developed, most of which can be associated with the presence and extent of CAD and event prognosis. However, they still have significant limitations that hinder their integration into clinical practice.

High-Sensitivity Troponin (hs-Tn) for Cardiovascular Risk Prognostication: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic low-grade inflammation is involved in coronary atherosclerosis progression whereas recent research efforts suggest that preventative methods should be tailored to the "residual inflammatory risk". As such, modalities for the early identification of the risk have to be investigated. METHODS: We performed a systematic review and meta-analysis according to the PRISMA guidelines. Any study that presented the prognostic value of high sensitivity troponin (hs-cTn) of vascular inflammation in stable patients without known cardiac heart disease was considered to be potentially eligible. The Medline (PubMed) database was searched up to April 22, 2021. The main endpoint was the difference in c-index (Δ[c-index]) with the use of hs-cTn for major adverse cardiovascular events (MACEs), cardiovascular and all-cause mortality. We calculated I² to test heterogeneity. RESULTS: In total, 44 studies and 112,288 stable patients without known coronary heart disease were included in this meta-analysis. The mean follow-up duration of the whole cohort was 6.8 ± 1.1 years. 77,004 (68.5%) of the patients presented with low cardiovascular risk while 35,284 (31.5%) in high. The overall pooled estimate of Δ[c-index] for MACE was 1.4% (95%CI: 0.7-2.1, I2=0%) and for cardiovascular death 1.3% (95%CI: 0.3-2.3, I2=0%). Finally, the overall pooled estimate of Δ[c-index] for all-cause mortality was 3% (95%CI: 1.9-3.9, I2=86%), while high heterogeneity was observed between the studies. CONCLUSION: The predictive usefulness of changes in hs-cTn measures in stable individuals with either high or low cardiovascular risk, demonstrates that assessing vascular inflammation in addition to clinical risk factors enhances risk prediction for cardiovascular events and all-cause mortality. Further prospective studies are necessary to confirm these findings and assist clinical decision-making regarding the most optimal prevention strategy.

Lipoprotein(a) and inflammation- pathophysiological links and clinical implications for cardiovascular disease.

The role of lipoprotein(a) (Lp[a]) as a significant and possibly causal cardiovascular disease (CVD) risk factor has been well established. Many studies, mostly experimental, have supported inflammation as a mediator of Lp(a)-induced increase in CVD risk. Lp(a), mainly through oxidized phospholipids bound to its apolipoprotein(a) part, leads to monocyte activation and endothelial dysfunction. The relationship between Lp(a) and inflammation is bidirectional as Lp(a) levels, besides being associated with inflammatory properties, are regulated by inflammatory stimuli or anti-inflammatory treatment. Reduction of Lp(a) concentration, especially by potent siRNA agents, contributes to partial reversion of the Lp(a) related inflammatory profile. This review aims to present the current pathophysiological and clinical evidence of the relationship between Lp(a) and inflammation.

Granulocyte Colony-Stimulating Factor Ameliorates Endothelial Activation and Thrombotic Diathesis Biomarkers in a Murine Model of Hind Limb Ischemia.

Novel therapies in peripheral arterial disease, such as granulocyte colony-stimulating factor (GCSF) administration, might result in anti-atherosclerotic effects. In this study, we used 10-week-old male ApoE-/- mice, which were fed an atherosclerosis-inducing diet for four weeks. At the end of the four weeks, hind limb ischemia was induced through left femoral artery ligation, the atherosclerosis-inducing diet was discontinued, and a normal diet was initiated. Mice were then randomized into a control group (intramuscular 0.4 mL normal saline 0.9% for 7 days) and a group in which GCSF was administrated intramuscularly in the left hind limb for 7 days (100 mg/kg). In the GCSF group, but not in the control group, we observed significant reductions in the soluble adhesion molecules (vascular cell adhesion molecule-1 (sVCAM-1) and intercellular adhesion molecule-1 (sICAM-1)), sE-Selectin, and plasminogen activator inhibitor (PAI)-1 when they were measured through ELISA on the 1st and the 28th days after hind limb ischemia induction. Therefore, GCSF administration in an atherosclerotic mouse model of hind limb ischemia led to decreases in the biomarkers associated with endothelial activation and thrombosis. These findings warrant further validation in future preclinical studies.

Biomarkers of Vascular Inflammation for Cardiovascular Risk Prognostication: A Meta-Analysis.

OBJECTIVES: The purpose of this study was to systematically explore the added value of biomarkers of vascular inflammation for cardiovascular prognostication on top of clinical risk factors. BACKGROUND: Measurement of biomarkers of vascular inflammation is advocated for the risk stratification for coronary heart disease (CHD). METHODS: We systematically explored published reports in MEDLINE for cohort studies on the prognostic value of common biomarkers of vascular inflammation in stable patients without known CHD. These included common circulating inflammatory biomarkers (ie, C-reactive protein, interleukin-6 and tumor necrosis factor-a, arterial positron emission tomography/computed tomography and coronary computed tomography angiography-derived biomarkers of vascular inflammation, including anatomical high-risk plaque features and perivascular fat imaging. The main endpoint was the difference in c-index (Δ[c-index]) with the use of inflammatory biomarkers for major adverse cardiovascular events (MACEs) and mortality. We calculated I2 to test heterogeneity. This study is registered with PROSPERO (CRD42020181158). RESULTS: A total of 104,826 relevant studies were screened and a final of 39 independent studies (175,778 individuals) were included in the quantitative synthesis. Biomarkers of vascular inflammation provided added prognostic value for the composite endpoint and for MACEs only (pooled estimate for Δ[c-index]% 2.9, 95% CI: 1.7-4.1 and 3.1, 95% CI: 1.8-4.5, respectively). Coronary computed tomography angiography-related biomarkers were associated with the highest added prognostic value for MACEs: high-risk plaques 5.8%, 95% CI: 0.6 to 11.0, and perivascular adipose tissue (on top of coronary atherosclerosis extent and high-risk plaques): 8.2%, 95% CI: 4.0 to 12.5). In meta-regression analysis, the prognostic value of inflammatory biomarkers was independent of other confounders including study size, length of follow-up, population event incidence, the performance of the baseline model, and the level of statistical adjustment. Limitations in the published literature include the lack of reporting of other metrics of improvement of risk stratification, the net clinical benefit, or the cost-effectiveness of such biomarkers in clinical practice. CONCLUSIONS: The use of biomarkers of vascular inflammation enhances risk discrimination for cardiovascular events.

Machine learning of native T1 mapping radiomics for classification of hypertrophic cardiomyopathy phenotypes.

We explored whether radiomic features from T1 maps by cardiac magnetic resonance (CMR) could enhance the diagnostic value of T1 mapping in distinguishing health from disease and classifying cardiac disease phenotypes. A total of 149 patients (n = 30 with no heart disease, n = 30 with LVH, n = 61 with hypertrophic cardiomyopathy (HCM) and n = 28 with cardiac amyloidosis) undergoing a CMR scan were included in this study. We extracted a total of 850 radiomic features and explored their value in disease classification. We applied principal component analysis and unsupervised clustering in exploratory analysis, and then machine learning for feature selection of the best radiomic features that maximized the diagnostic value for cardiac disease classification. The first three principal components of the T1 radiomics were distinctively correlated with cardiac disease type. Unsupervised hierarchical clustering of the population by myocardial T1 radiomics was significantly associated with myocardial disease type (chi2 = 55.98, p < 0.0001). After feature selection, internal validation and external testing, a model of T1 radiomics had good diagnostic performance (AUC 0.753) for multinomial classification of disease phenotype (normal vs. LVH vs. HCM vs. cardiac amyloid). A subset of six radiomic features outperformed mean native T1 values for classification between myocardial health vs. disease and HCM phenocopies (AUC of T1 vs. radiomics model, for normal: 0.549 vs. 0.888; for LVH: 0.645 vs. 0.790; for HCM 0.541 vs. 0.638; and for cardiac amyloid 0.769 vs. 0.840). We show that myocardial texture assessed by native T1 maps is linked to features of cardiac disease. Myocardial radiomic phenotyping could enhance the diagnostic yield of T1 mapping for myocardial disease detection and classification.

Plasma signature of apoptotic microvesicles is associated with endothelial dysfunction and plaque rupture in acute coronary syndromes.

OBJECTIVE: Circulating microvesicles (MV) are surrogate biomarkers of atherosclerosis. However, their role in acute coronary syndromes (ACS) has not been fully elucidated yet. We sought to examine the association of circulating apoptotic MVs with ACS pathophysiology. APPROACH AND RESULTS: One hundred and fifty-three patients (n = 153) were included in the study; 49 patients with ST-elevation myocardial infarction (STEMI), 35 with non-STEMI (NSTEMI), 38 with unstable angina, 15 with stable coronary artery disease and 16 control individuals. Flow cytometry analysis was used to quantify circulating apoptotic/non-apoptotic (phospatidyloserine+/phospatidyloserine-) endothelial cell (EMV), red blood cell (RMV) and platelet (PMV) derived MV. Flow-mediated dilatation (FMD) of the brachial artery was assessed by ultrasound to estimate endothelial function. The inflammatory profile was assessed by serum C-reactive protein (hsCRP) levels. Apoptotic only (but not non-apoptotic) MV were increased in patients with ACS (EMV, P = 2.32 × 10-9; RMV, P = .0019; PMV, P = .01). Hierarchical clustering of the total population of ACS patients (n = 122) by circulating levels of phospatidyloserine+ EMV, RMV and PMV identified two discreet clusters of patients without any differences in traditional risk factors, but significant differences in brachial FMD (5.2% (2.5) vs. 4.1% (2.3), P < .05) that remained significant after adjustment for co-variates. The prevalence of STEMI, a surrogate for plaque rupture and vessel thrombotic occlusion, was significantly higher in the patient cluster with impaired endothelial function (60% vs 32%, P = .016, adjusted odds ratio for STEMI, 3.041, 95%CI, 1.160 to 7.968, p = .024). CONCLUSION: Our findings indicate that the circulating levels of apoptotic MV are increased in ACS patients and their plasma profiles associate with endothelial dysfunction and thrombotic complications in ACS patients.

The role of kisspeptin system in cancer biology.

Kisspeptins are a family of neuropeptides that are known to be critical in puberty initiation and ovulation. Apart from that kisspeptin derived peptides (KPs) are also known for their antimetastatic activities in several malignancies. Herein we report recent evidence of the role of kisspeptins in cancer biology and we examine the prospective of targeting the kisspeptin pathways leading to a better prognosis in patients with malignant diseases.

Mitochondria and cardiovascular diseases-from pathophysiology to treatment.

Mitochondria are the source of cellular energy production and are present in different types of cells. However, their function is especially important for the heart due to the high demands in energy which is achieved through oxidative phosphorylation. Mitochondria form large networks which regulate metabolism and the optimal function is achieved through the balance between mitochondrial fusion and mitochondrial fission. Moreover, mitochondrial function is upon quality control via the process of mitophagy which removes the damaged organelles. Mitochondrial dysfunction is associated with the development of numerous cardiac diseases such as atherosclerosis, ischemia-reperfusion (I/R) injury, hypertension, diabetes, cardiac hypertrophy and heart failure (HF), due to the uncontrolled production of reactive oxygen species (ROS). Therefore, early control of mitochondrial dysfunction is a crucial step in the therapy of cardiac diseases. A number of anti-oxidant molecules and medications have been used but the results are inconsistent among the studies. Eventually, the aim of future research is to design molecules which selectively target mitochondrial dysfunction and restore the capacity of cellular anti-oxidant enzymes.