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Alzheimer's disease (AD) and related dementias constitute an important global health challenge. Detailed understanding of the multiple molecular mechanisms underlying their pathogenesis constitutes a clue for the management of the disease. Kallikrein-related peptidases (KLKs), a lead family of serine proteases, have emerged as potential biomarkers and therapeutic targets in the context of AD and associated cognitive decline. Hence, KLKs were proposed to display multifaceted impacts influencing various aspects of neurodegeneration, including amyloid-beta aggregation, tau pathology, neuroinflammation, and synaptic dysfunction. We propose here a comprehensive survey to summarize recent findings, providing an overview of the main kallikreins implicated in AD pathophysiology namely KLK8, KLK6 and KLK7. We explore the interplay between KLKs and key AD molecular pathways, shedding light on their significance as potential biomarkers for early disease detection. We also discuss their pertinence as therapeutic targets for disease-modifying interventions to develop innovative therapeutic strategies aimed at halting or ameliorating the progression of AD and associated dementias., (Copyright © 2024 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.)

Background: Clinical characteristics and outcomes of patients with transthyretin amyloidosis cardiomyopathy (ATTR-CM) vary by region, necessitating the acquisition of country-specific evidence for proper management., Methods: This is an observational study including sequential patients presenting in the Amyloidosis Reference Center of Greece, from 01/2014 to 12/2022. ATTR-CM was diagnosed by positive scintigraphy and exclusion of light-chain amyloidosis or positive biopsy typing. Genetic testing was performed in all cases., Results: In total, 109 ATTR-CM patients were included (median age, 81 years) of which 15 carried TTR mutations (27% Val30Met). Most patients (82%) presented with heart failure and 59% with atrial fibrillation, while 10% had aortic stenosis. Importantly, 78 (71.6%) had clinically significant extracardiac manifestations (45% musculoskeletal disorder, 40% peripheral neuropathy, and 33% gastrointestinal symptoms). Sixty-five (60%) received disease-specific treatment with tafamidis. Estimated median survival was 48 months; advanced NYHA class, National Amyloidosis Center stage, eGFR<45 ml/kg/1.73 m 2 , NT-pro-BNP>5000 pg/mL were associated with worse survival, while tafamidis treatment was associated with improved survival in patients with IVS≥ 12 mm., Discussion: These are the first data describing the characteristics, management, and outcomes of patients with ATTR-CM in Greece, which could influence local guidelines., Competing Interests: Declaration of competing interest GG has received research support from Pfizer. KS has received research support from Pfizer. EK has received honoraria from Amgen, Genesis Pharma, Janssen, Takeda, Pfizer, GSK, and research support from Amgen, Janssen, and Pfizer. The rest of authors declare no conflict of interest., (Copyright © 2023 Hellenic Society of Cardiology. Published by Elsevier Inc. All rights reserved.)

Background/Objectives: This study aims to create a strong binary classifier and evaluate the performance of pre-trained convolutional neural networks (CNNs) to effectively distinguish between benign and malignant ovarian tumors from still ultrasound images. Methods: The dataset consisted of 3510 ultrasound images from 585 women with ovarian tumors, 390 benign and 195 malignant, that were classified by experts and verified by histopathology. A 20% to80% split for training and validation was applied within a k-fold cross-validation framework, ensuring comprehensive utilization of the dataset. The final classifier was an aggregate of three pre-trained CNNs (VGG16, ResNet50, and InceptionNet), with experimentation focusing on the aggregation weights and decision threshold probability for the classification of each mass. Results: The aggregate model outperformed all individual models, achieving an average sensitivity of 96.5% and specificity of 88.1% compared to the subjective assessment's (SA) 95.9% sensitivity and 93.9% specificity. All the above results were calculated at a decision threshold probability of 0.2. Notably, misclassifications made by the model were similar to those made by SA. Conclusions: CNNs and AI-assisted image analysis can enhance the diagnosis and aid ultrasonographers with less experience by minimizing errors. Further research is needed to fine-tune CNNs and validate their performance in diverse clinical settings, potentially leading to even higher sensitivity and overall accuracy.

Aims: Complete haematologic response to treatment for light chain cardiac amyloidosis (AL-CA) may lead to improvement of myocardial function and better outcomes. We sought to evaluate the effect of response to treatment for AL-CA on echocardiographic indices of myocardial deformation and work and their prognostic significance., Methods and Results: Sixty-one patients treated for AL were enrolled and underwent echocardiographic assessment at baseline and at 1 year. Patients were stratified according to haematologic response as complete or not complete responders. A significant reduction in median N-terminal pro-brain natriuretic peptide (NT-proBNP) (2771-1486 pg/mL; P < 0.001) and posterior wall thickness (13-12 mm; P = 0.002) and an increase in global work index (GWI) (1115-1356 mmHg%; P = 0.018) was observed at 1 year. Patients with complete response (CR) had a more pronounced decrease in intraventricular septum thickness (14.2-12.0 mm; P = 0.006), improved global longitudinal strain (GLS) (-11.6 to -13.1%; P for interaction = 0.045), increased global constructive work (1245-1436 mmHg%; P = 0.008), and GWI (926-1250 mmHg%, P = 0.002) compared with non-CR. Furthermore, deltaGLS (ρspearman = 0.35; P < 0.001) and deltaGWI (ρspearman = -0.32; P = 0.02) correlated with delta NT-proBNP. Importantly, patients with GLS and GWI response had a better prognosis (log-rank P = 0.048 and log-rank P = 0.007, respectively). After adjustment for Mayo stage, gender, and response status, deltaGLS [hazard ratio (HR) = 1.404, P = 0.046 per 1% increase] and deltaGWI (HR = 0.996, P = 0.042 per 1mmHg% increase) were independent predictors of survival., Conclusion: Complete haematologic response to treatment is associated with improved left ventricular myocardial work indices, and their change is associated with improved survival in AL-CA., Competing Interests: Conflict of interest: E.K. has received honoraria from Janssen, Pfizer, and GSK and research support (E.K.’s institution) from Janssen, GSK, and Pfizer. The other authors have no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Patients with cardiac light chain amyloidosis and Mayo stage 3b disease define a high-risk population with very poor prognosis. Here, we report treatment outcomes of 80 consecutive patients with newly diagnosed AL and Mayo 3b who received novel regimens. Early mortality (<1 month) rate was 12.5%. On intention-to-treat, overall hematologic response rate was 40%, with complete response (CR)/very good partial response (VGPR) in 25% and partial response (PR) in 15%. At 1- and 3- month landmark analysis CR or VGPR/PR rates were 25%/23.5% and 34%/25.5%, respectively. Among patients that were treated with daratumumab-based therapies, 52.6% and 85.7% achieved at least VGPR within one 1 and 3 months, respectively. Three-month cardiac response rate was 11.3% and 6-month was 18.8%. At least hemVGPR at 3 months was associated with cardiac response at 6 months (p = 0.034). Median overall survival (OS) was 6.3 months. At 1-month landmark at least hemPR was associated with better median OS (24.1 vs. 4.9 months, p = 0.017) and at 3-month landmark, at least hemVGPR was associated with a median OS of 40.7 versus 17 months for hemPR and 7.4 months for those without hematologic response (p = 0.028). Cardiac response at 3 months was associated with longer median OS (59.7 vs. 10.9 months, p = 0.044). Factors associated with poorer survival were κ-light chain amyloidosis (median OS 2.9 vs. 7.4 months, p = 0.028), peripheral nerve involvement (3.4 vs. 10.45 months, p = 0.024), systolic blood pressure <90 mmHg (2 vs. 8 months, p = 0.002), baseline LVEF <55% (median OS 3.4 vs. 32 months, p = 0.29) and New York Heart Association (NYHA) class (2.7 months for NYHA 3B-4 vs. 8 months for NYHA 2-3A, p = 0.02). Twenty-one patients (26.3%) received salvage therapy and ORR was 57.1%. Median OS for patients who received second line therapy was 24 months. In conclusion, patients with Mayo 3b disease benefit from early hematologic response but cardiac response rates remain low., (© 2023 John Wiley & Sons Ltd.)

Competing Interests: The authors have no conflicts of interest to declare.

Background: We have previously shown that chronic exposure of adult male mice to low doses of di(2-ethylhexyl) phthalate (DEHP) altered male sexual behavior and induced down-regulation of the androgen receptor (AR) in the neural circuitry controlling this behavior., Objectives: The cellular mechanisms induced by chronic exposure of adult male mice to low doses of DEHP alone or in an environmental phthalate mixture were studied., Methods: Two-month-old C57BL/6J males were exposed orally for 8 wk to DEHP alone (0, 5, or 50 μ g / kg / d ) or to DEHP ( 50 μ g / kg / d ) in a phthalate mixture. Behavior, dendritic density per 50 - μ m length, pre-/postsynaptic markers, synapse ultrastructure, and bioenergetic activity were analyzed., Results: Mice exposed to DEHP either alone or in a phthalate mixture differed in mating, emission of ultrasonic vocalizations, and the ability to attract receptive females in urinary preference tests from control mice. Analyses in the medial preoptic area, the key hypothalamic region involved in male sexual behavior, showed lower dendritic spine density and protein levels of glutamate receptors and differences in other postsynaptic components and presynaptic markers between the treated groups. Ultrastructural observation of dendritic synapses by electron microscopy showed comparable morphology between the treated groups. Metabolic analyses highlighted differences in hypothalamic metabolites of males exposed to DEHP alone or in a phthalate mixture compared to control mice. These differences included lower tryptophan and higher NAD + levels, respectively, a precursor and end product of the kynurenine pathway of tryptophan metabolism. The protein amounts of the xenobiotic aryl hydrocarbon receptor, one of the targets of this metabolic pathway and known negative regulator of the AR, were higher in the medial preoptic area of exposed male mice., Discussion: Differences in behavior of male mice exposed to environmental doses of phthalates were associated with differences in neural structure and metabolism, with possibly a key role of the kynurenine pathway of tryptophan metabolism in the effects mediated by these substances. https://doi.org/10.1289/EHP11514.

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., (© 2023. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

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., Competing Interests: Conflict of interest: E.K. Janssen: consultancy, honoraria, other: travel/accommodations/expenses, research funding; Pfizer: consultancy; Genesis Pharma: consultancy, honoraria, other: travel/accommodations/expenses; Amgen: consultancy, honoraria, research funding; Takeda: consultancy, honoraria, other: travel/accommodations/expenses. E.T. Janssen: honoraria, other: travel expenses, research funding; Takeda: honoraria, other: travel expenses, research funding; Celgene: honoraria; Medison: honoraria; Amgen: honoraria, research funding; Genesis: honoraria, other: travel expenses, research funding. K.S. Amgen: honoraria. M.-A.D. BMS: consultancy, membership on an entity's Board of Directors or advisory committees, other: personal fees; Celgene: consultancy, honoraria, membership on an entity's Board of Directors or advisory committees, other: personal fees, speakers bureau; Takeda: consultancy, honoraria, membership on an entity's Board of Directors or advisory committees, other: personal fees, research funding, speakers bureau; Janssen: consultancy, honoraria, membership on an entity's Board of Directors or advisory committees, other: personal fees, research funding, speakers bureau; Amgen: consultancy, honoraria, membership on an entity's Board of Directors or advisory committees, other: personal fees, research funding, speakers bureau. The remaining authors have nothing to disclose., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

We recently showed that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture altered blood brain barrier integrity and induced an inflammatory profile in the hippocampus. Here, we investigate whether such exposure alters hippocampus-dependent behavior and underlying cellular mechanisms. Adult C57BL/6 J male mice were continuously exposed orally to the vehicle or DEHP alone (5 or 50 μg/kg/d) or to DEHP (5 μg/kg/d) in a phthalate mixture. In the Morris water maze, males showed reduced latencies across days to find the platform in the cue and spatial reference memory tasks, regardless of their treatment group. In the probe test, DEHP-50 exposed males displayed a higher latency to find the platform quadrant. In the temporal order memory test, males exposed to DEHP alone or in a phthalate mixture were unable to discriminate between the most recently and previously seen objects. They also displayed reduced ability to show a preference for the new object in the novel object recognition test. These behavioral alterations were associated with a lowered dendritic spine density and protein levels of glutamate receptors and postsynaptic markers, and increased protein levels of the presynaptic synaptophysin in the hippocampus. Metabolomic analysis of the hippocampus indicated changes in amino acid levels including reduced tryptophan and L-kynurenine and elevated NAD + levels, respectively, a precursor, intermediate and endproduct of the kynurenine pathway of tryptophan metabolism. Interestingly, the protein amounts of the xenobiotic aryl hydrocarbon receptor, a target of this metabolic pathway, were elevated in the CA1 area. These data indicate that chronic exposure of adult male mice to environmental doses of DEHP alone or in a phthalate mixture impacted hippocampal function and structure, associated with modifications in amino acid metabolites with a potential involvement of the kynurenine pathway of tryptophan metabolism., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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 &gt; 2.00 mm and avg.maxWT &gt; 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 &lt; 0.05 for net reclassification index, integrated discrimination index and Delta Harrell's C index). MaxWT &lt; 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., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Cardiopulmonary exercise testing (CPET) has been widely used for the functional evaluation of patients with heart failure. Patients with amyloidosis and cardiac involvement typically present with heart failure with preserved or mildly reduced ejection fraction. We sought to evaluate the use of CPET parameters in patients with AL amyloidosis for the assessment of disease severity and prognosis and their association with cardiac imaging findings. Methods: A single-center prospective analysis was conducted, which included 23 consecutive ambulatory patients with AL amyloidosis with cardiac involvement, not requiring hospitalization or intravenous diuretics. Patient evaluation included CPET, laboratory testing, echocardiography and cardiac MRI. The cohort was divided according to the presence of high-risk CPET characteristics (below median peak VO2 and above median VE/VCO2). Results: Patients with AL amyloidosis and cardiac involvement (median age was 60 years (56.5% males) had median peak relative VO2 (VO2/kg) of 17.8 mL/kg/min, VE/VCO2 slope of 39.4 and circulatory power of 2362.5 mmHg⋅mL/kg/min. Peak relative VO2 gradually declined across Mayo stages (p = 0.046) and exhibited a significant inverse correlation with NT-proBNP levels (r = −0.52, p = 0.01). Among imaging parameters, peak VO2 positively correlated with global work efficiency (r = 0.61, p < 0.001), and global work index (r = 0.45, p = 0.04). The group of patients with high-risk CPET findings showed evidence of more advanced disease, such as higher NT-proBNP levels (p = 0.007), increased septal and posterior left ventricular wall thickness (p = 0.043 and p = 0.033 respectively) and decreased global work efficiency (p = 0.027) without substantial differences in cardiac MRI parameters. In this group of patients, peak VO2 and VE/VCO2 were not associated significantly with overall survival and cardiac response at one year. Conclusion: In patients with AL amyloidosis, evaluation of exercise capacity with CPET identified a group of patients with more advanced cardiac involvement. The potential of CPET as a risk stratification tool in AL amyloidosis with cardiac involvement warrants further research.

Background: The impact of wild-type transthyretin-related cardiac amyloidosis (ATTRwt) on functional and structural peripheral vascular measures is unknown. In the present study, we explored patterns of vascular dysfunction in patients with ATTRwt in comparison to diseases with similar cardiac phenotype., Methods: Treatment-naïve patients with ATTRwt (n = 32) were compared to: 1. Age-and sex-matched reference population without amyloidosis (n = 32), 2. Age-and sex-matched patients with systemic AL amyloidosis (n = 32), and 3. patients with cardiac AL amyloidosis (AL-HF, n = 23) or elderly patients with heart failure with preserved ejection fraction (HFpEF) (n = 16). All subjects underwent peripheral vascular assessment using carotid artery ultrasonography, brachial artery flow-mediated dilation (FMD), measurement of arterial stiffness and aortic hemodynamics including heart rate-adjusted time of return of reflected waves (Tr/HR)., Results: After adjustment for traditional cardiovascular risk factors and coronary artery disease (core model), peripheral and aortic blood pressures (BP) were lower in patients with ATTRwt (p < 0.05) whereas other vascular markers were preserved compared to the reference non-amyloidosis group. ATTRwt was independently associated with lower BP and longer Tr/HR compared to AL. Compared to AL-HF, FMD was lower in ATTRwt (p = 0.033). ATTRwt patients had lower BP and higher Tr/HR than HFpEF (p < 0.05). By ROC analysis, Tr/HR discriminated ATTRwt vs. AL-HF (sensitivity 93%, specificity 75%) and HFpEF (sensitivity 100%, specificity 94%) and lower FMD increased the likelihood for ATTRwt at low Tr/HR values., Conclusion: ATTRwt patients present a distinct peripheral vascular fingerprint which is different from AL-HF or HFpEF, consisting of lower peripheral and aortic BP, prolonged Tr/HR and FMD at reference-population range., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Senescence is a well-characterized cellular state associated with specific markers such as permanent cell proliferation arrest and the secretion of messenger molecules by cells expressing the senescence-associated secretory phenotype. The senescence-associated secretory phenotype composition depends on many factors such as the cell type or the nature of the stress that induces senescence. Because the skin constitutes a barrier with the external environment, it is particularly subjected to different types of stresses and consequently prone to premature cellular aging. The dicarbonyl compounds glyoxal (GO) and methylglyoxal are precursors of advanced glycation end products, whose presence marks normal and pathological aging. In this study, we show that GO treatment provokes oxidative stress by increasing ROS and advanced glycation end-products levels and induces senescence in human keratinocytes. Furthermore, GO-induced senescence bears a unique molecular progression profile: an early-stage senescence when protein kinase B‒FOXO3a-p27 KIP1 pathway mediates cell cycle arrest and a late-stage senescence maintained by the p16 INK4 /pRb pathway. Moreover, we characterized the resulting secretory phenotype during early-stage senescence by mass spectrometry. Our study provides evidence that GO can affect keratinocyte functions and act as a driver of human skin aging. Hence, senotherapeutics aimed at modulating GO-associated senescence phenotype hold promising potential., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 Hellenic Society of Cardiology. Published by Elsevier B.V. All rights reserved.)

Background: The utilization and clinical impact of beta-blockers (BBs) in cardiac amyloidosis (CA) is largely unexplored., Methods: We conducted a retrospective, single-center analysis of indications, timing of initiation, types and doses of BB used, reasons to discontinue BB and association between BB tolerance and outcomes in a cohort of patients with immunoglobulin light chain amyloidosis (AL)., Results: We reviewed 236 patients with AL CA and identified 53 patients taking BB (22.5%). Most patients presented in New York Heart Association Class (NYHA) II or III (74.5%) and 24% presented in Mayo stage IIIB. The most frequent indications for BB initiation were atrial fibrillation (AF) and coronary artery disease (CAD). In most cases (59%) BB was started before the diagnosis of CA. The median duration of BB treatment was 9 months (interquartile range [IQR] 3-24 months). Among patients receiving BB, 28 tolerated BB during follow-up whereas 25 patients discontinued BB. The main causes of BB discontinuation were hypotension and heart failure (HF) exacerbation. Patients intolerant to BB presented with more advanced NYHA class, worse performance status and lower median left ventricular ejection fraction (LVEF) at baseline. At median follow-up duration of 17.7 months, patients who did not tolerate BB had a poor survival., Conclusions: Although some patients with CA may have indications for treatment with BB, their use is uncommon and those with more advanced disease tolerate BB poorly. Intolerance to BB in patients with cardiac AL is an indicator of poorer outcome.