Association of Lipoprotein(a) with arterial stiffness: A Mendelian randomization study.

BACKGROUND: In this study we used Mendelian randomization (MR) to investigate the potential causal association of lipoprotein (a) [Lp(a)] levels with pulse wave velocity (PWV). METHODS: Genetic variants associated with Lp(a) were retrieved from the UK Biobank GWAS (N = 290,497). A non- overlapping GWAS based on a European cohort (N = 7,000) was used to obtain genetic associations with PWV (outcome) and utilized two different measures for the same trait, brachial-ankle (baPWV) and carotid-femoral (cfPWV) PWV. We applied a two-sample MR using the inverse variance weighting method (IVW) and a series of sensitivity analyses for 170 SNPs that were selected as instrumental variables (IVs). RESULTS: Our analyses do not support a causal association between Lp(a) and PWV for neither measurement [ßiwv(baPWV) = -.0005, p = .8 and ßiwv(cfPWV) = -.006, p = .16]. The above findings were consistent across sensitivity analyses including weighted median, mode-based estimation, MR-Egger regression and MR-PRESSO. CONCLUSION: We did not find evidence indicating that Lp(a) is causally associated with PWV, the gold standard marker of arterial stiffness.

Clinical implications of vascular dysfunction in acute and convalescent COVID-19: A systematic review.

BACKGROUND: Accumulating evidence suggests that endothelial dysfunction is implicated in the pathogenesis and severity of coronavirus disease 2019 (COVID-19). In this context, vascular impairment in COVID-19 might be associated with clinical manifestations and could refine risk stratification in these patients. METHODS: This systematic review aims to synthesize current evidence on the frequency and the prognostic value of vascular dysfunction during acute and post-recovery COVID-19. After systematically searching the MEDLINE, clinicaltrials.gov and the Cochrane Library from 1 December 2019 until 05 March 2022, we identified 24 eligible studies with laboratory confirmed COVID-19 and a thorough examination of vascular function. Flow-mediated dilation (FMD) was assessed in 5 and 12 studies in acute and post-recovery phase respectively; pulse wave velocity (PWV) was the marker of interest in three studies in the acute and four studies in the post-recovery phase. RESULTS: All studies except for one in the acute and in the post-recovery phase showed positive association between vascular dysfunction and COVID-19 infection. Endothelial dysfunction in two studies and increased arterial stiffness in three studies were related to inferior survival in COVID-19. DISCUSSION: Overall, a detrimental effect of COVID-19 on markers of endothelial function and arterial stiffness that could persist even for months after the resolution of the infection and provide prognostic value was congruent across published studies. Further research is warranted to elucidate clinical implications of this association.

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia.

Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia.

Psychiatric manifestations of anti-NMDA receptor encephalitis: neurobiological underpinnings and differential diagnostic implications.

OBJECTIVE: Anti-N-methyl-d-aspartate receptor (NMDA-R) encephalitis is a recently discovered disorder with prominent psychiatric manifestations that is often misdiagnosed. The objective of this review is to raise awareness of the disorder among psychiatrists and to expand upon the diagnostic considerations that arise in the context of the neurobiology and symptomatology of this disorder. We also aim to examine the similarities in terms of symptoms and underlying neurobiology between anti-NMDA-R encephalitis and schizophrenia-spectrum illnesses. METHODS: The information presented will reflect a review of the literature of the symptomatology and pathophysiology of anti-NMDA-R encephalitis and the role of the NMDA-R in both anti-NMDA-R encephalitis and schizophrenia-spectrum illnesses. RESULTS: The studies reviewed highlight the role of the NMDA-R in both anti-NMDA-R encephalitis and schizophrenia in terms of symptom presentation and neurobiology. Studies have also begun to identify involvement of NMDA-R antibodies in patients diagnosed with schizophrenia. CONCLUSIONS: There is an increasing need for psychiatrists to become aware of the disorder and consider it in their differential diagnosis, as they are often the first to be consulted on patients with anti-NMDA-R encephalitis. The similarities identified between anti-NMDA-R encephalitis and schizophrenia-spectrum illnesses also raise questions about a common underlying pathophysiology particularly in regard to the NMDA-R.

Impact of Diabetes and Glycemia on Cardiac Improvement and Adverse Events Following Mechanical Circulatory Support.

BACKGROUND: Type 2 diabetes is prevalent in cardiovascular disease and contributes to excess morbidity and mortality. We sought to investigate the effect of glycemia on functional cardiac improvement, morbidity, and mortality in durable left ventricular assist device (LVAD) recipients. METHODS AND RESULTS: Consecutive patients with an LVAD were prospectively evaluated (n=531). After excluding patients missing pre-LVAD glycated hemoglobin (HbA1c) measurements or having inadequate post-LVAD follow-up, 375 patients were studied. To assess functional cardiac improvement, we used absolute left ventricular ejection fraction change (ΔLVEF: LVEF post-LVAD-LVEF pre-LVAD). We quantified the association of pre-LVAD HbA1c with ΔLVEF as the primary outcome, and all-cause mortality and LVAD-related adverse event rates (ischemic stroke/transient ischemic attack, intracerebral hemorrhage, gastrointestinal bleeding, LVAD-related infection, device thrombosis) as secondary outcomes. Last, we assessed HbA1c differences pre- and post-LVAD. Patients with type 2 diabetes were older, more likely men suffering ischemic cardiomyopathy, and had longer heart failure duration. Pre-LVAD HbA1c was inversely associated with ΔLVEF in patients with nonischemic cardiomyopathy but not in those with ischemic cardiomyopathy, after adjusting for age, sex, heart failure duration, and left ventricular end-diastolic diameter. Pre-LVAD HbA1c was not associated with all-cause mortality, but higher pre-LVAD HbA1c was shown to increase the risk of intracerebral hemorrhage, LVAD-related infection, and device thrombosis by 3 years on LVAD support (P<0.05 for all). HbA1c decreased from 6.68±1.52% pre-LVAD to 6.11±1.33% post-LVAD (P<0.001). CONCLUSIONS: Type 2 diabetes and pre-LVAD glycemia modify the potential for functional cardiac improvement and the risk for adverse events on LVAD support. The degree and duration of pre-LVAD glycemic control optimization to favorably affect these outcomes warrants further investigation.

Pathophysiologic Vasodilation in Cardiogenic Shock and Its Impact on Mortality.

BACKGROUND: Cardiogenic shock (CS) mortality remains near 40%. In addition to inadequate cardiac output, patients with severe CS may exhibit vasodilation. We aimed to examine the prevalence and consequences of vasodilation in CS. METHODS: We analyzed all patients hospitalized at a CS referral center who were diagnosed with CS stages B to E and did not have concurrent sepsis or recent cardiac surgery. Vasodilation was defined by lower systemic vascular resistance (SVR), higher norepinephrine equivalent dose, or a blunted SVR response to pressors. Threshold SVR values were determined by their relation to 14-day mortality in spline models. The primary outcome was death within 14 days of CS onset in multivariable-adjusted Cox models. RESULTS: This study included 713 patients with a mean age of 60 years and 27% females; 14-day mortality was 28%, and 38% were vasodilated. The median SVR was 1308 dynes•s•cm-5 (interquartile range, 870-1652), median norepinephrine equivalent was 0.11 µg/kg per minute (interquartile range, 0-0.2), and 28% had a blunted pressor response. Each 100-dynes•s•cm-5 decrease in SVR below 800 was associated with 20% higher mortality (adjusted hazard ratio, 1.23; P=0.004). Each 0.1-µg/kg per minute increase in norepinephrine equivalent dose was associated with 15% higher mortality (adjusted hazard ratio, 1.12; P<0.001). A blunted pressor response was associated with a nearly 2-fold mortality increase (adjusted hazard ratio, 1.74; P=0.003). CONCLUSIONS: Pathophysiologic vasodilation is prevalent in CS and independently associated with an increased risk of death. CS vasodilation can be identified by SVR <800 dynes•s•cm-5, high doses of pressors, or a blunted SVR response to pressors. Additional studies exploring mechanisms and treatments for CS vasodilation are needed.

Cardiac Reverse Remodeling Mediated by HeartMate 3 Left Ventricular Assist Device: Comparison to Older Generation Devices.

Currently, the fully magnetically levitated left ventricular assist device (LVAD) HeartMate 3 (HM3) is the only commercially available device for advanced heart failure (HF) patients. However, the left ventricular (LV) functional and structural changes following mechanical unloading and circulatory support (MCS) with the HM3 have not been investigated. We compared the reverse remodeling induced by the HM3 to older generation continuous-flow LVADs. Chronic HF patients (n = 405) undergoing MCS with HeartWare Ventricular Assist Device (HVAD, n = 115), HM3 (n = 186), and HeartMate II (HM2, n = 104) at four programs were included. Echocardiograms were obtained preimplant and at 1, 3, 6, and 12 months following LVAD implantation. There were no differences in the postimplant serial LV ejection fraction (LVEF) between the devices. The postimplant LV internal diastolic diameter (LVIDd) was significantly lower for HM2 at 3 and 6 months compared with HVAD and HM3. The proportion of patients achieving "cardiac reverse remodeling responder" status (defined as LVEF improvement to ≥40% and LVIDD ≤5.9 cm) was 11.9%, and was similar between devices. HeartMate 3 appears to result in similar cardiac reverse remodeling as older generation CF-LVADs, suggesting that the fully magnetically levitated device technology could provide an effective platform to further study and promote cardiac reverse remodeling.

Therapeutic inertia in rhythm control strategies in hospitalized patients with fibrillation: Insights from Hellenic Cardiorenal Morbidity Snapshot (HECMOS) study.

BACKGROUND: Current guidelines recommend a rhythm control strategy in patients with symptomatic atrial fibrillation (AF) while catheter ablation has been shown to be a safer and more efficacious approach than antiarrhythmic medications. METHODS: HECMOS was a nationwide snapshot survey of cardiorenal morbidity in hospitalized cardiology patients. In this sub-study, we included 276 cases who had a history of AF, particularly on the rhythm strategy, and catheter ablation procedures had been performed before the index admission. RESULTS: Among 276 AF patients (mean age: 76.4 ±â€¯11.5 years, 58 % male), 60.9 % (N = 168) had persistent AF and 39.1 % (N = 108) had paroxysmal AF. Heart failure was the main cause of admission in 54.3 % (N = 145) of the patients, while 14.1 % (N = 39) were admitted due to paroxysmal AF, 7.3 % (N = 20) due to bradyarrhythmic reasons, and 6.5 % (N = 18) suffered from acute coronary syndrome. Most importantly, heart failure with reduced ejection fraction was present in 76 (27 %) patients. Only 10 patients out of the total (3 %, mean age 59.7 years) had undergone AF ablation while electrical cardioversion had been attempted in 37 (13.4 %) patients. Interestingly, in this AF population with heart failure, 3.6 % (N = 10) had a defibrillator implanted (4 single-chamber), and only 1.5 % (N = 4) had a cardiac resynchronization therapy defibrillator (CRT-D). CONCLUSION: High prevalence of persistent AF was detected in hospitalized patients, with heart failure being the leading cause of admission and main co-morbidity. Rhythm control strategies are notably underused, along with CRT-D implantation in patients with AF and heart failure.

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.

PCSK9 Inhibition in Atherosclerotic Cardiovascular Disease.

Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) represent a novel class of hypolipidemic drugs, providing an additional therapeutic option over conventional hypolipidemic treatments. Given the constantly lowering recommended LDL-C goals, low goal achievement rate and low compliance with treatment, new hypolipidemic drug classes may substantially contribute to residual risk reduction for atherosclerotic cardiovascular disease (ASCVD). This review aims to summarize contemporary evidence on the clinical role of PCSK9i in ASCVD prevention. PubMed and MEDLINE databases were searched for keywords in studies on PCSK9i and ASCVD. Approved PCSK9i are the monoclonal antibodies (Mabs), evolocumab and alirocumab, targeting PCSK9, and inclisiran, a small interfering RNA inhibiting PSCK9 synthesis. Overall, PCSK9i effectively reduced LDL-C and other atherogenic lipoproteins, including apolipoprotein B and lipoprotein( a) primarily. PSCK9i Mabs improved imaging markers reflecting coronary atherosclerotic plaque vulnerability and reduced ASCVD events in high-risk patients after short-term treatment (< 3 years follow-up). They are currently indicated as a third-line treatment for secondary prevention and primary prevention in patients with familial hypercholesterolemia at high risk of not achieving their LDL-C goals. Patients with higher baseline ASCVD risk receive greater benefits from PCSK9i. Recent evidence suggests that evolocumab was effective and safe after long-term treatment. Ongoing trials investigate new therapeutic indications for PCSK9i while their cost-effectiveness is still being considered. PCSK9i is a novel hypolipidemic drug class currently indicated for reducing residual risk in secondary ASCVD prevention and high-risk patients.

Glycemia is associated with subclinical atherosclerosis through renal function in nondiabetic apparently healthy adults: a mediation analysis.

The causative associations between glycemia and early alterations in renal and vascular function remain unclear. To examine the interplay among glycemia, renal function, and markers of subclinical atherosclerosis in apparently healthy subjects. Nondiabetic (30-60 years old) individuals (n = 205) without chronic kidney disease or cardiovascular disease were consecutively recruited from a cardiovascular prevention clinic. All subjects underwent arterial stiffness assessment by measuring the carotid-femoral pulse wave velocity (cfPWV). Glomerular filtration rate (GFR) was estimated by CKD-EPI equation. Study procedures were identical in the two visits (median follow-up 66 months). We employed structural equation modeling (SEM) analysis to investigate the directionality of associations. Baseline fasting plasma glucose (FPG) was independently and inversely associated with GFR (p = 0.008). GFR was significantly associated with cfPWV (p < 0.001) at baseline. By SEM analysis decreasing baseline GFR directly correlated with increasing cfPWV (p = 0.003) whereas FPG correlated with cfPWV indirectly through GFR (mediation) (P = 0.032). FPG did not mediate the effect of GFR on cfPWV (P = 0.768). SEM analysis of longitudinal data revealed bidirectional correlations between changes in FPG and GFR (P < 0.001). Alterations in GFR were directly related to changes in cfPWV (p < 0.001) whereas FPG only indirectly correlated with cfPWV through GFR changes (P = 0.002). In apparently healthy nondiabetic subjects, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status. These findings provide the first clinical evidence supporting the directionality between kidney function and glycemia in nondiabetic subjects leading to vascular dysfunction. In apparently healthy nondiabetic subjects, without cardiovascular disease or chronic kidney disease, the association between baseline or longitudinal glycemia levels and arterial stiffening was indirect, consistently mediated by renal function status.

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.

Effector T cell chemokine IP-10 predicts cardiac recovery and clinical outcomes post-myocardial infarction.

Background and aims: Preclinical data suggest that activation of the adaptive immune system is critical for myocardial repair processes in acute myocardial infarction. The aim of the present study was to determine the clinical value of baseline effector T cell chemokine IP-10 blood levels in the acute phase of ST-segment elevation myocardial infarction (STEMI) for the prediction of the left ventricular function changes and cardiovascular outcomes after STEMI. Methods: Serum IP-10 levels were retrospectively quantified in two independent cohorts of STEMI patients undergoing primary percutaneous coronary intervention. Results: We report a biphasic response of the effector T cell trafficking chemokine IP-10 characterized by an initial increase of its serum levels in the acute phase of STEMI followed by a rapid reduction at 90min post reperfusion. Patients at the highest IP-10 tertile presented also with more CD4 effector memory T cells (CD4 TEM cells), but not other T cell subtypes, in blood. In the Newcastle cohort (n=47), patients in the highest IP-10 tertile or CD4 TEM cells at admission exhibited an improved cardiac systolic function 12 weeks after STEMI compared to patients in the lowest IP-10 tertile. In the Heidelberg cohort (n=331), STEMI patients were followed for a median of 540 days for major adverse cardiovascular events (MACE). Patients presenting with higher serum IP-10 levels at admission had a lower risk for MACE after adjustment for traditional risk factors, CRP and high-sensitivity troponin-T levels (highest vs. rest quarters: HR [95% CI]=0.420 [0.218-0.808]). Conclusion: Increased serum levels of IP-10 in the acute phase of STEMI predict a better recovery in cardiac systolic function and less adverse events in patients after STEMI.

Cardiac mechanics in response to proteasome inhibition: a prospective study.

AIM: Ubiquitin-Proteasome System (UPS) is of paramount importance regarding the function of the myocardial cell. Consistently, inhibition of this system has been found to affect myocardium in experimental models; yet, the clinical impact of UPS inhibition on cardiac function has not been comprehensively examined. Our aim was to gain insight into the effect of proteasome inhibition on myocardial mechanics in humans. METHODS AND RESULTS: We prospectively evaluated 48 patients with multiple myeloma and an indication to receive carfilzomib, an irreversible proteasome inhibitor. All patients were initially evaluated and underwent echocardiography with speckle tracking analysis. Carfilzomib was administered according to Kd treatment protocol. Follow-up echocardiography was performed at the 3rd and 6th month. Proteasome activity (PrA) was measured in peripheral blood mononuclear cells.At 3 months after treatment, we observed early left ventricular (LV) segmental dysfunction and deterioration of left atrial (LA) remodelling, which was sustained and more pronounced than that observed in a cardiotoxicity control group. At 6 months, LV and right ventricular functions were additionally attenuated (P < 0.05 for all). These changes were independent of blood pressure, endothelial function, inflammation, and cardiac injury levels. Changes in PrA were associated with changes in global longitudinal strain (GLS), segmental LV strain, and LA markers (P < 0.05 for all). Finally, baseline GLS < -18% or LA strain rate > 1.71 were associated with null hypertension events. CONCLUSION: Inhibition of the UPS induced global deterioration of cardiac function.

Modification of the GRACE Risk Score for Risk Prediction in Patients With Acute Coronary Syndromes.

Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury. Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury. Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023. Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE). Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event. Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056). Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.

Links between childhood physical abuse and intimate partner aggression: the mediating role of anger expression.

Research linking childhood physical abuse (CPA) and adult intimate partner aggression (IPA) has focused on individuals without sufficient attention to couple processes. In this study, 109 couples reported on histories of CPA, IPA, and anger expression. Actor-partner interdependence model (APIM) was used to examine links between CPA and revictimization and perpetration of IPA, with anger suppression as a potential mediator. Women's CPA histories were associated with more physical aggression towards and more revictimization by partners. Men's CPA histories were only associated at the trend level with their revictimization. Anger suppression fully mediated the link between women's CPA and both revictimization and perpetration of IPA. Findings suggest that women with CPA histories are more prone to suppress anger, which leaves them at greater risk for revictimization and perpetration of IPA.

A systematic review and meta-analysis on the effect of selective serotonin reuptake inhibitors on endothelial function.

AIMS: Depression and atherosclerotic cardiovascular disease (ASCVD) are commonly clustered in affected patients. Endothelial dysfunction is an early marker of ASCVD while also reported in patients with depression. Emerging evidence suggests that selective serotonin receptor inhibitors (SSRIs) may improve endothelial function. However, clinical studies assessing flow-mediated dilation (FMD), the gold-standard method to evaluate conduit artery endothelial function, in response to SSRIs treatment included limited number of patients and did not provide consistent results. In the present study we aim to evaluate the effect of SSRIs treatment on endothelial function assessed by longitudinal changes in FMD. METHODS AND RESULTS: We performed a systematic review to retrieve and subsequently meta-analyze eligible studies in patients with depression who received SSRIs and had available measurements of FMD change before and after treatment. In 5 studies and 323 individuals in total, SSRIs were associated with increased FMD at the end of follow-up compared to baseline measurement (pooled mean change 1.97 %, 95 % CI 0.17, 3.77, P = 0.032, I2 = 87.4 %). These results did not substantially change when analysis was restricted to patients with history of atherosclerotic cardiovascular disease (ASCVD). Similarly, FMD changes were higher in individuals receiving SSRIs compared to not-treated subjects (pooled mean difference 2.5 %. 95 % CI 0.7, 4.2, P < 0.001, I2 = 82.7 %). LIMITATIONS: Substantial heterogeneity regarding with respect to follow-up duration, demographics, and SSRIs agents. CONCLUSION: SSRIs significantly improve FMD, the gold-standard marker of endothelial function. Further investigation is warranted for the role of FMD as a possible therapeutic biomarker in patients with depression and established or subclinical ASCVD. PROSPERO REGISTRATION: CRD42021252241.

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.