[BLITZ-AF Cancer study: an international observational research project on patients with atrial fibrillation and cancer]. / Studio BLITZ-AF Cancer: un progetto di ricerca osservazionale internazionale sui pazienti con fibrillazione atriale e cancro.

BACKGROUND: Cancer is an important condition associated with the development of atrial fibrillation (AF). The objectives of the BLITZ-AF Cancer study were to collect real-life information on the clinical profile and use of antithrombotic drugs in patients with AF and cancer to improve clinical management, as well as the evaluation of the association between different antithrombotic treatments (or their absence) and the main clinical events. METHODS: European multinational, multicenter, prospective, non-interventional study conducted in patients with AF (electrocardiographically confirmed) and cancer occurring within 3 years. The CHA2DS2-VASc and the HAS-BLED scores were calculated in all enrolled patients. RESULTS: From June 2019 to July 2021, 1514 patients were enrolled, 36.5% women, from 112 cardiology departments in 6 European countries (Italy, Belgium, the Netherlands, Spain, Portugal and Ireland). Italy enrolled 971 patients in 77 centers. Average age of patients was 74 ± 9 years, of which 20.9% affected by heart failure, 18.1% by ischemic heart disease, 9.8% by peripheral arterial disease and 38.5% by valvular diseases; 41.5% of patients had a CHA2DS2-VASc score ≥4. The most represented cancer sites were lung (14.9%), colorectal tract (14.1%), prostate (8.8%), or non-Hodgkin's lymphoma (8.1%). Before enrollment, 16.6% of patients were not taking antithrombotic therapy, while 22.7% were on therapy with antiplatelet agents and/or low molecular weight heparin. After enrollment these percentages decreased to 7.7% and 16.6%, respectively and, at the same time, the percentage of patients on direct oral anticoagulant (DOAC) therapy increased from 48.4% to 68.4%, also to the detriment of those on vitamin K antagonist therapy. CONCLUSIONS: The BLITZ-AF Cancer study, which enrolled patients diagnosed with AF and cancer, highlights that the use of DOACs by cardiologists in this clinical context has increased, even though the guidelines on AF do not give accurate indications about oral anticoagulant therapy in patients with cancer.

Circulating miRNA in functional tricuspid regurgitation. Unveiling novel links to heart failure: A pilot study.

AIM: Severe functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, particularly heart failure (HF) and mortality. MicroRNAs (miRNAs) have been recently identified as novel biomarkers in different cardiovascular conditions, but no studies have focused on FTR. We sought to (1) to identify and validate circulating miRNAs as regulators of FTR and (2) to test association of miRNA with heart failure and mortality in FTR. METHODS AND RESULTS: Consecutive patients with isolated severe FTR (n = 100) evaluated in the outpatient Heart Valve Clinic and age- and gender-matched subjects with no TR (controls, n = 50) were prospectively recruited. The experimental design included (1) a screening phase to identify candidate miRNA differentially expressed in FTR (n = 8) compared with controls (n = 8) through miRNA array profiling of 192 miRNAs using quantitative reverse transcription PCR arrays [qRT-PCR]) and (2) a validation phase in which candidate miRNAs identified in the initial screening were selected for further validation by qRT-PCR in a prospectively recruited cohort of FTR (n = 92) and controls (n = 42). Bioinformatics analysis was used to predict their potential target genes and functional pathways elicited. A combined endpoint of hospital admission due to heart failure (HF) and all-cause mortality was defined. Initial screening identified 16 differentially expressed miRNAs in FTR compared with controls, subsequently confirmed in the validation phase (n = 16 were excluded due to significant haemolysis). miR-186-5p, miR-30e-5p, and miR-152-3p identified FTR with high predictive value [AUC of 0.93 (0.88-0.97), 0.83 (0.75-0.91) and 0.84 (0.76-0.92), respectively]. During a median follow-up of 20.4 months (IQR 8-35 months), 32% of FTR patients reached the combined endpoint. Patients with low relative expression of miR-15a-5p, miR-92a-3p, miR101-3p, and miR-363-3p, miR-324-3p, and miR-22-3p showed significantly higher rates of events (log-rank test for all P < 0.01). Both miR-15a-5p [hazard ratio: 0.21 (0.06-0.649, P = 0.007) and miR-92a-3p (0.27 (0.09-0.76), P = 0.01] were associated with outcomes after adjusting for age, gender, and New York Heart Association functional class. CONCLUSIONS: Circulating miRNAs are novel diagnostic and prognostic biomarkers in severe FTR. The quantification of miR-186-5p, miR-30e-5p, and miR-152-3p held strong diagnostic value, and the quantification of miR-15a-5p and miR-92a-3p are independently associated with outcomes. The recognition of specific miRNAs offers a novel perspective for TR evaluation.

Remote Dielectric Sensing Before and After Discharge in Patients With ADHF: The ReDS-SAFE HF Trial.

BACKGROUND: Incomplete treatment of congestion often leads to worsening heart failure (HF). The remote dielectric sensing (ReDS) system is an electromagnetic energy-based technology that accurately quantifies changes in lung fluid concentration noninvasively. OBJECTIVES: This study sought to assess whether an ReDS-guided strategy during acutely decompensated HF hospitalization is superior to routine care for improving outcomes at 1 month postdischarge. METHODS: ReDS-SAFE HF (Use of ReDS for a SAFE discharge in patients with acute Heart Failure) was an investigator-initiated, multicenter, single-blind, randomized, proof-of-concept trial in which 100 patients were randomized to a routine care strategy, with discharge criteria based on current clinical practice, or an ReDS-guided decongestion strategy, with discharge criteria requiring an ReDS value of ≤35%. ReDS measurements were performed daily and at a 7-day follow-up visit, with patients and treating physicians in the routine care arm blinded to the results. The primary outcome was a composite of unplanned visits for HF, HF rehospitalization, or death at 1 month after discharge. RESULTS: The mean age was 67 ± 14 years, and 74% were male. On admission, left ventricular ejection fraction was 37% ± 16%, and B-type natriuretic peptide was 940 pg/L (Q1-Q3: 529-1,665 pg/L). The primary endpoint occurred in 10 (20%) patients in the routine care group and 1 (2%) in the ReDS-guided strategy group (log-rank P = 0.005). The ReDS-guided strategy group experienced a lower event rate, with an HR of 0.094 (95% CI: 0.012-0.731; P = 0.003), and a number of patients needed to treat of 6 to avoid an event (95% CI: 3-17), mainly resulting from a decrease in HF readmissions. The median length of stay was 2 days longer in the ReDS-guided group vs the routine care group (8 vs 6; P = 0.203). CONCLUSIONS: A ReDS-guided strategy to treat congestion improved 1-month prognosis postdischarge in this proof-of-concept study, mainly because of a decrease of the number of HF readmissions. (Use of ReDS for a SAFE discharge in patients with acute Heart Failure [ReDS-SAFE HF]; NCT04305717).

Pupil reflex as a marker of activity and prognosis in heart failure: a longitudinal and prospective study.

AIMS: Compensatory mechanisms in heart failure (HF) are triggered to maintain adequate cardiac output. Among them, hyperactivation of the sympathetic nervous system (SNS) is one of the main ones and carries a worse prognosis. The pupillary reflex depends on the SNS, and we can evaluate it through pupillometry. The aim of the study was to compare the differences in pupillary reflex between patients with acute HF and controls and to analyse whether these differences in pupillary reflex may offer a new and easy prognostic factor in such patients. METHODS AND RESULTS: We prospectively and consecutively included 107 patients admitted with decompensated HF. Quantitative pupillometry was performed with the NeuroOptics pupillometry during the first 24 h after admission and prior to discharge. The results were compared with those of a group of 100 healthy volunteers who also underwent pupillometry. The maximum baseline pupil size (MBPS) and the minimum pupil diameter (MPD) were measured. Patients with decompensated HF have a higher MBPS (3.64 ± 0.81) and higher MPD (2.60 ± 0.58) than HF patients at discharge and in the control group (P-value = 0.01 and 0.01, respectively). Also, HF patients presented an improvement in pupillometric values at discharge [MBPS (3.47 ± 0.79) and MPD (2.51 ± 0.58)] and showed no differences compared with the control group [MBPS (3.34 ± 0.82) and MPD (2.40 ± 0.53)] (P-value = 0.19 and 0.14, respectively). In addition, MBPS provides a good independent predictor of in-hospital and 1 month mortality in patients admitted with HF. Six patients (5.61%) died during hospital admission, and 11 patients (10.2%) died in the first month after discharge. Also, four patients (3.74%) were readmitted within 1 month of discharge. The receiver operating characteristic (ROC) curve for predicting in-hospital mortality through MBPS was 0.823. No patient with an MBPS < 3.7 mm died. The ROC curve for predicting combined mortality or readmission within the first month for MBPS was 0.698. CONCLUSIONS: Pupillometry may be a new, non-invasive, and simple tool to determine the status of SNS, help in the prognostic stratification of acute HF patients, and improve therapeutic management.

Advances in heart failure management. / Avances en insuficiencia cardiaca.

Heart failure is a pathological condition characterized by substantial prevalence and mortality, particularly in the Western world. Over recent decades, both pharmacological and non-pharmacological interventions have emerged, significantly enhancing patient survival and overall quality of life. Moreover, advancements in diverse imaging modalities facilitate precise diagnosis and comprehensive investigation into the fundamental etiology, enabling the development of more precise therapeutic approaches. Nonetheless, discernible gaps persist in comprehending specific facets of this condition, albeit persistent research endeavors seek to elucidate these inquiries.

Subjective identification and ablation of drivers improves rhythm control in patients with persistent atrial fibrillation. The CHAOS-AF study.

INTRODUCTION AND OBJECTIVES: The optimal approach for persistent atrial fibrillation (AF) ablation remains unknown. In patients with persistent AF, we compared an ablation strategy based on pulmonary vein isolation (PVI) plus ablation of drivers (PVI+D), with a conventional PVI-only approach performed in a 1:1 propensity score-matched cohort. METHODS: Drivers were subjectively identified using conventional high-density mapping catheters (IntellaMap ORION, PentaRay NAV or Advisor HD Grid), without dedicated software, as fractionated continuous or quasicontinuous electrograms on 1 to 2 adjacent bipoles, which were ablated first; and as sites with spatiotemporal dispersion (the entire cycle length comprised within the mapping catheter) plus noncontinuous fractionation, which were only targeted in patients without fractionated continuous electrograms, or without AF conversion after ablation of fractionated continuous electrograms. Ablation included PVI plus focal or linear ablation targeting drivers. RESULTS: A total of 50 patients were included in each group (61±10 years, 25% women). Fractionated continuous electrograms were found and ablated in 21 patients from the PVI+D group (42%), leading to AF conversion in 7 patients. In the remaining 43 patients, 143 sites with spatiotemporal dispersion plus noncontinuous fractionation were targeted. Globally, AF conversion was achieved in 21 patients (42%). The PVI+D group showed lower atrial arrhythmia recurrences at 1 year of follow-up (30.6% vs 48%; P=.048) and at the last follow-up (46% vs 72%; P=.013), and less progression to permanent AF (10% vs 40%; P=.001). CONCLUSIONS: Subjective identification and ablation of drivers, added to PVI, increased 1-year freedom from atrial arrhythmia and decreased long-term recurrences and progression to permanent AF.

NOS3 prevents MMP-9, and MMP-13 induced extracellular matrix proteolytic degradation through specific microRNA-targeted expression of extracellular matrix metalloproteinase inducer in hypertension-related atherosclerosis.

BACKGROUND: Endothelial nitric oxide synthase (NOS3) elicits atheroprotection by preventing extracellular matrix (ECM) proteolytic degradation through inhibition of extracellular matrix metalloproteinase inducer (EMMPRIN) and collagenase MMP-13 by still unknown mechanisms. METHODS: C57BL/6 mice lacking ApoE , NOS3, and/or MMP13 were fed with a high-fat diet for 6 weeks. Entire aortas were extracted and frozen to analyze protein and nucleic acid expression. Atherosclerotic plaques were detected by ultrasound imaging, Oil Red O (ORO) staining, and Western Blot. RNA-seq and RT-qPCR were performed to evaluate EMMPRIN, MMP-9, and EMMPRIN-targeting miRNAs. Mouse aortic endothelial cells (MAEC) were incubated to assess the role of active MMP-13 over MMP-9. One-way ANOVA or Kruskal-Wallis tests were performed to determine statistical differences. RESULTS: Lack of NOS3 in ApoE null mice fed with a high-fat diet increased severe plaque accumulation, vessel wall widening, and high mortality, along with EMMPRIN-induced expression by upregulation of miRNAs 46a-5p and 486-5p. However, knocking out MMP-13 in ApoE/NOS3 -deficient mice was sufficient to prevent mortality (66.6 vs. 26.6%), plaque progression (23.1 vs. 8.8%), and MMP-9 expression, as confirmed in murine aortic endothelial cell (MAEC) cultures, in which MMP-9 was upregulated by incubation with active recombinant MMP-13, suggesting MMP-9 as a new target of MMP-13 in atherosclerosis. CONCLUSION: We describe a novel mechanism by which the absence of NOS3 may worsen atherosclerosis through EMMPRIN-induced ECM proteolytic degradation by targeting the expression of miRNAs 146a-5p and 485-5p. Focusing on NOS3 regulation of ECM degradation could be a promising approach in the management of atherosclerosis.

The Reproductive Biology of Puye (Galaxias maculatus) under Experimental Culture.

This study determines the reproductive patterns of puye (Galaxias maculatus) under culture conditions. A population of 567 wild fish was caught in the Cautín River, Chile, and held in captivity for four years. Mortality, sex ratio, gonadosomatic index (GSI), sexual maturity stages, spawning period, type and frequency of spawning, and fecundity were measured. The fish grew throughout the experimental period, with the fastest rate during the first half of the first year of life. The highest mortality occurred during the first three months of the experiment and during the spawning season. The sex ratio was almost 1:1 (female:male). First sexual maturity was reached at one year of age, with an average weight of 0.85 ± 0.01 g, total length of 4.85 ± 0.16 cm, and condition factor 0.0074. The highest GSI in both females (12.14 ± 0.74) and males (17.7 ± 2.70) was recorded in August. Nevertheless, the females spawned 3 to 10 times between September and February, with the highest reproductive peak between September and October. The number of embryos per female per day varied from 1 to 429, while the total number of embryos per female during the entire season evaluated varied from 163 to 1044. There was a high correlation (r = 0.82) between absolute fecundity and body weight. Although further studies are needed in this field, these results are basic for establishing future reproductive programs in captivity as a strategy for sustainable fisheries and aquaculture management.

TRI-SCORE and benefit of intervention in patients with severe tricuspid regurgitation.

BACKGROUND AND AIMS: Benefit of tricuspid regurgitation (TR) correction and timing of intervention are unclear. This study aimed to compare survival rates after surgical or transcatheter intervention to conservative management according to a TR clinical stage as assessed using the TRI-SCORE. METHODS: A total of 2,413 patients with severe isolated functional TR were enrolled in TRIGISTRY (1217 conservatively managed, 551 isolated tricuspid valve surgery, and 645 transcatheter valve repair). The primary endpoint was survival at 2 years. RESULTS: The TRI-SCORE was low (≤3) in 32%, intermediate (4-5) in 33%, and high (≥6) in 35%. A successful correction was achieved in 97% and 65% of patients in the surgical and transcatheter groups, respectively. Survival rates decreased with the TRI-SCORE in the three treatment groups (all P < .0001). In the low TRI-SCORE category, survival rates were higher in the surgical and transcatheter groups than in the conservative management group (93%, 87%, and 79%, respectively, P = .0002). In the intermediate category, no significant difference between groups was observed overall (80%, 71%, and 71%, respectively, P = .13) but benefit of the intervention became significant when the analysis was restricted to patients with successful correction (80%, 81%, and 71%, respectively, P = .009). In the high TRI-SCORE category, survival was not different to conservative management in the surgical and successful repair group (61% and 68% vs 58%, P = .26 and P = .18 respectively). CONCLUSIONS: Survival progressively decreased with the TRI-SCORE irrespective of treatment modality. Compared to conservative management, an early and successful surgical or transcatheter intervention improved 2-year survival in patients at low and, to a lower extent, intermediate TRI-SCORE, while no benefit was observed in the high TRI-SCORE category.

Bicaval TricValve Implantation in Patients With Severe Symptomatic Tricuspid Regurgitation: 1-Year Follow-Up Outcomes.

BACKGROUND: Several orthotopic transcatheter strategies have been developed to treat severe tricuspid regurgitation (TR); however, many patients are deemed unsuitable. Caval valve implantation with the TricValve system addresses this unmet need. OBJECTIVES: This study sought to determine the impact of TricValve on systemic congestion and quality of life (QOL) at 1 year. METHODS: The TRICUS (Safety and Efficacy of the TricValve® Transcatheter Bicaval Valves System in the Superior and Inferior Vena Cava in Patients With Severe Tricuspid Regurgitation) and TRICUS EURO studies were prospective, nonblinded, nonrandomized, single-arm trials representing the early-in-man experience of the TricValve system in NYHA functional class III or IV severe TR patients, optimally medicated and ineligible for open heart surgery, with significant caval backflow. The primary endpoint was QOL metrics and functional status. The 1-year results of the combined cohort are described here. RESULTS: Forty-four patients were included. Mean age was 76.2 ± 7.5 years, 81.0% were women, and the TRISCORE (risk score model for isolated tricuspid valve surgery) was 5.3 ± 1.3. Clinical improvement at 1 year was achieved in 42 (95.5%) patients, measured by (at least 1 of) an increase in ≥15 points from baseline in 12-item Kansas City Cardiomyopathy Questionnaire score, improvement to NYHA functional class to I or II, or an increase ≥40 m in the 6-minute walk test. There were 3 (6.8%) deaths at 1-year follow-up (1 cardiovascular), and the heart failure rehospitalization rate was 29.5%. Stent fracture, conduction system disturbances, or clinically significant leaflet thrombosis were not detected. Abolished hepatic vein backflow was achieved and persisted in 63.8% of the patients, contributing towards a reduction in congestive symptoms, N-terminal pro-B-type natriuretic peptide levels (P = 0.032), and diuretic treatment. CONCLUSIONS: Caval valve implantation with the TricValve system associated with meaningful 1-year clinical improvements in terms of QOL along with relatively low mortality rates. (TRICUS Study - Safety and Efficacy of the TricValve® Device; NCT03723239).

Tricuspid valve disease and cardiac implantable electronic devices.

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers.

Epidemiology, pathophysiology, diagnosis and management of chronic right-sided heart failure and tricuspid regurgitation. A clinical consensus statement of the Heart Failure Association (HFA) and the European Association of Percutaneous Cardiovascular Interventions (EAPCI) of the ESC.

Right-sided heart failure and tricuspid regurgitation are common and strongly associated with poor quality of life and an increased risk of heart failure hospitalizations and death. While medical therapy for right-sided heart failure is limited, treatment options for tricuspid regurgitation include surgery and, based on recent developments, several transcatheter interventions. However, the patients who might benefit from tricuspid valve interventions are yet unknown, as is the ideal time for these treatments given the paucity of clinical evidence. In this context, it is crucial to elucidate aetiology and pathophysiological mechanisms leading to right-sided heart failure and tricuspid regurgitation in order to recognize when tricuspid regurgitation is a mere bystander and when it can cause or contribute to heart failure progression. Notably, early identification of right heart failure and tricuspid regurgitation may be crucial and optimal management requires knowledge about the different mechanisms and causes, clinical course and presentation, as well as possible treatment options. The aim of this clinical consensus statement is to summarize current knowledge about epidemiology, pathophysiology and treatment of tricuspid regurgitation in right-sided heart failure providing practical suggestions for patient identification and management.

Determinants of Tricuspid Regurgitation Progression and Its Implications for Adequate Management.

BACKGROUND: Tricuspid regurgitation (TR) is associated with an increased mortality. Previous studies have analyzed predictors of TR progression and the clinical impact of baseline TR. However, there is a lack of evidence regarding the natural history of TR: the pattern of change and clinical impact of progression. OBJECTIVES: The authors sought to evaluate predictors of TR progression and assess the prognostic impact of TR progression. METHODS: A total of 1,843 patients with at least moderate TR were prospectively followed up with consecutive echocardiographic studies and/or clinical evaluation. All patients with less than a 2-year follow-up were excluded. Clinical and echocardiographic features, hospitalizations for heart failure, and cardiovascular death and interventions were recorded to assess their impact in TR progression. RESULTS: At a median 2.3-year follow-up, 19% of patients experienced progression. Patients with baseline moderate TR presented a rate progression of 4.9%, 10.1%, and 24.8% 1 year, 2 years, and 3 years, respectively. Older age (HR: 1.03), lower body mass index (HR: 0.95), chronic kidney disease (HR: 1.55), worse NYHA functional class (HR: 1.52), and right ventricle dilation (HR: 1.33) were independently associated with TR progression. TR progression was associated with an increase in chamber dilation as well as a decrease in ventriculoarterial coupling and in left ventricle ejection fraction (P < 0.001). TR progression was associated with an increased cardiovascular mortality and hospitalizations for heart failure (P < 0.001). CONCLUSIONS: Marked individual variability in TR progression hindered accurate follow-up. In addition, TR progression was a determinant for survival regardless of initial TR severity.

STREI: a new index of right heart function in isolated severe tricuspid regurgitation by Speckle tracking Echocardiography.

AIMS: Right ventricular (RV) performance determines clinical management in severe tricuspid regurgitation (TR). Right atrial (RA) function complements RV assessment in TR. This study aimed to design a novel index by Speckle-tracking echocardiography (STREI index) integrating RA and RV strain information and to evaluate the clinical utility of combining RV and RA strain for prediction of cardiovascular (CV) outcomes. METHODS AND RESULTS: Consecutive patients with at least (≥) severe TR evaluated in the Heart Valve Clinic (n = 300) were prospectively included. An additional independent TR cohort was included for external validation (n = 50). STREI index was developed with the formula: [2 * RV-free wall longitudinal strain (RV-FWLS)] + Reservoir RA strain (RASr). The composite endpoint included hospital admission due to HF and all cause-mortality. 176 patients with ≥ severe TR were finally included. STREI index identified a higher percentage of patients with RV dysfunction compared to conventional parameters. After a median follow-up of 2.2 years (IQR: 12-41 months), 38% reached the composite endpoint. STREI values were predictors of outcomes independently of TR severity and RV dimensions. The combination of prognostic cut-off values of RASr (<10%) and RV-FWLS (>-20%) (STREI stratification) stratified 4 different groups of risk independently of TR severity, RV dimensions and clinical status (adj HR per stratum 1.89 (1.4-2.34), p < 0.001). Pre-defined cut-off values achieved similar prognostic performance in the validation cohort (n = 50). CONCLUSION: STREI index is a novel parameter of RV performance that independently predicts CV events. The combination of RA and RV strain stratifies better patients' risk, reflecting a broader effect of TR on right heart chambers.

Predictive capacity of a genetic risk score for coronary artery disease in assessing recurrences and cardiovascular mortality among patients with myocardial infarction.

Aim: This study aimed to evaluate the capacity of a genetic risk score (GRS) for coronary artery disease (CAD) independent of classical cardiovascular risk factors to assess the risk of recurrence in patients with first myocardial infarction. The secondary aim was to determine the predictive value of this GRS. Methods: We performed a meta-analysis of individual data from three studies, namely, a prospective study including 75 patients aged <55 years, a prospective study including 184 patients with a mean age of 60.5 years, and a case-control study (77 cases and 160 controls) nested in a cohort of patients with first myocardial infarction. A GRS including 12 CAD genetic variants independent of classical cardiovascular risk factors was developed. The outcome was a composite of cardiovascular mortality and recurrent acute coronary syndrome. Results: The GRS was associated with a higher risk of recurrence [hazard ratio = 1.24; 95% confidence interval (CI): 1.04-1.47]. The inclusion of the GRS in the clinical model did not increase the model's discriminative capacity (change in C-statistic/area under the curve: 0.009; 95% CI: -0.007 to 0.025) but improved its reclassification (continuous net reclassification index: 0.29; 95% CI: 0.08-0.51). Conclusion: The GRS for CAD, independent of classical cardiovascular risk factors, was associated with a higher risk of recurrence in patients with first myocardial infarction. The predictive capacity of this GRS identified a subgroup of high-risk patients who could benefit from intensive preventive strategies.

The compound YK 3-237 promotes pig sperm capacitation-related events.

Before fertilization of the oocyte, the spermatozoa must undergo through a series of biochemical changes in the female reproductive tract named sperm capacitation. Spermatozoa regulates its functions by post-translational modifications, being historically the most studied protein phosphorylation. In addition to phosphorylation, recently, protein acetylation has been described as an important molecular mechanism with regulatory roles in several reproductive processes. However, its role on the mammal's sperm capacitation process remains unraveled. Sirtuins are a deacetylase protein family with 7 members that regulate protein acetylation. Here, we investigated the possible role of SIRT1 on pig sperm capacitation-related events by using YK 3-237, a commercial SIRT1 activator drug. SIRT1 is localized in the midpiece of pig spermatozoa. Protein tyrosine phosphorylation (focused at p32) is an event associated to pig sperm capacitation that increases when spermatozoa are in vitro capacitated in presence of YK 3-237. Eventually, YK 3-237 induces acrosome reaction in capacitated spermatozoa: YK 3-237 treatment tripled (3.40 ± 0.40 fold increase) the percentage of acrosome-reacted spermatozoa compared to the control. In addition, YK 3-237 induces sperm intracellular pH alkalinization and raises the intracellular calcium levels through a CatSper independent mechanism. YK 3-237 was not able to bypass sAC inhibition by LRE1. In summary, YK 3-237 promotes pig sperm capacitation by a mechanism upstream of sAC activation and independent of CatSper calcium channel.