Progression of aortic stenosis after an acute myocardial infarction

Background Myocardial infarction (MI) has been shown to induce fibrotic remodelling of the mitral and tricuspid valves. It is unknown whether MI also induces pathological remodelling of the aortic valve and alters aortic stenosis (AS) progression. We thus compared AS progression after an acute MI and in patients with/without history of MI, and assessed post-MI pathobiological changes within the aortic valve leaflets in a sheep model. Methods Serial echocardiograms in human patients with AS were retrospectively analysed and compared between 3 groups: (1) acute MI at baseline (n=68), (2) prior history of MI (n=45) and (3) controls without MI (n=101). Annualised progression rates of AS severity were compared between these 3 groups. In addition, aortic valves were harvested from 15 sheep: (1) induced inferior MI (n=10) and (2) controls without MI (n=5), for biological and histological analyses. Results In humans, the acute MI, previous MI and control groups had comparable baseline AS severity. Indexed aortic valve area (AVAi) declined faster in the acute MI group compared with controls (−0.07±0.06 vs −0.04±0.04 cm²/m²/year; p=0.004). After adjustment, acute MI status was significantly associated with faster AVAi progression (mean difference: −0.013 (95% CI −0.023 to −0.003) cm²/m²/year, p=0.008). In the post-MI experimental animal model, aortic valve thickness and qualitative/quantitative expression of collagen were significantly increased compared with controls. Conclusions The results of this study suggest that AS progression is accelerated following acute MI, which could be caused by increased collagen production and thickening of the aortic valve after the ischaemic event

Epitaxial monolayers of the magnetic 2D semiconductor FeBr2 grown on Au(111)

Magnetic two-dimensional (2D) semiconductors have attracted a lot of attention because modern preparation techniques are capable of providing single-crystal films of these materials with precise control of thickness down to the single-layer limit. It opens up a way to study a rich variety of electronic and magnetic phenomena with promising routes toward potential applications. We have investigated the initial stages of epitaxial growth of the magnetic van der Waals semiconductor FeBr2 on a single-crystal Au(111) substrate by means of low-temperature scanning tunneling microscopy (STM), low-energy electron diffraction (LEED), X-ray photoemission spectroscopy (XPS), low-energy electron emission microscopy (LEEM), and X-ray photoemission electron microscopy (XPEEM). Magnetic properties of the one- and two-layer thick films were measured via X-ray absorption spectroscopy (XAS) and X-ray magnetic circular dichroism (XMCD). Our findings show a striking difference in the magnetic behavior of the single layer of FeBr2 and its bulk counterpart, which can be attributed to the modifications in the crystal structure due to the interaction with the substrate.C.G.-O. and M.P.-D. acknowledge funding of the Ph.D. fellowship from the MPC Foundation. S.E.H. thanks the whole AG Kuch and in particular J. Gördes for help during the BESSY measurements and also the local IT/electronics workshop/fine mechanics workshop teams for their continuous support. In particular, he is very thankful for the possibility to perform some last STM measurements at the PEARL beamline at SLS thanks Dr. Matthias Muntwiler. J.N. thanks the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) for his funding under project 277101999 - CRC 183. S.T. acknowledges financial support by BMBF through project VEKMAG (BMBF 05K19KEA). P.G. acknowledges funding from PID2020-116181RB-C32 and FlagEraSOgraphMEM PCI2019-111908-2 (AEI/FEDER). D.G.O. acknowledges funding by the Spanish MCIN/AEI/10.13039/501100011033 and by the European Union “NextGenerationEU”/PRTR (PID2019-107338RB-C63 and TED2021-132388B–C43). C.R., M.I., C.G.-O., and M.P.-D. acknowledge funding by the European Union’s Horizon 2020 research and innovation program (grant agreement No 800923), the Spanish MCIN/AEI/10.13039/501100011033 (PID2020-114252GB-I00, PID2019-107338RB-C63, TED2021-130292B–C42), the Basque Goverment IT1591-22, and by the IKUR Strategy under the collaboration agreement between Ikerbasque Foundation and MPC on behalf of the Department of Education of the Basque Government. C.R., M.I., C.G.-O., and S.E.H. are very thankful for the help during the XMCD and STM measurements of Samuel Kerschbaumer, Andrea Aguirre Baños, and Amitayush Jha Thakur.Peer reviewe

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Effects of cyproheptadine on mitral valve remodeling and regurgitation after myocardial infarction

BACKGROUND Ischemic mitral regurgitation (MR) is primarily caused by left ventricle deformation, but leaflet thickening with fibrotic changes are also observed in the valve. Increased levels of 5-hydroxytryptamine (5-HT; ie, serotonin) are described after myocardial infarction (MI); 5-HT can induce valve fibrosis through the 5-HT type 2B receptor (5-HT2BR). OBJECTIVES This study aims to test the hypothesis that post-MI treatment with cyproheptadine (5-HT2BR antagonist) can prevent ischemic MR by reducing the effect of serotonin on mitral biology. METHODS Thirty-six sheep were divided into 2 groups: inferior MI and inferior MI treated with cyproheptadine (0.5 mg/kg/d). Animals were followed for 90 days. Blood 5-HT, infarct size, left ventricular volume and function, MR fraction and mitral leaflet size were assessed. In a complementary in vitro study, valvular interstitial cells were exposed to pre-MI and post-MI serum collected from the experimental animals. RESULTS Increased 5-HT levels were observed after MI in nontreated animals, but not in the group treated with cyproheptadine. Infarct size was similar in both groups (11 ± 3 g vs 9 ± 5 g; P = 0.414). At 90 days, MR fraction was 16% ± 7% in the MI group vs 2% ± 6% in the cyproheptadine group (P = 0.0001). The increase in leaflet size following MI was larger in the cyproheptadine group (+40% ± 9% vs +22% ± 12%; P = 0.001). Mitral interstitial cells overexpressed extracellular matrix genes when treated with post-MI serum, but not when exposed to post-MI serum collected from treated animals. CONCLUSIONS Cyproheptadine given after inferior MI reduces post-MI 5-HT levels, prevents valvular fibrotic remodeling, is associated with larger increase in mitral valve size and less MR

Echocardiographic variables associated with transvalvular gradient after a transcatheter edge-to-edge mitral valve repair

Background: Transcatheter edge-to-edge mitral valve repair may lead to a reduction in mitral valve area (MVA) and elevated mean transmitral gradient (TMG). The objectives of this study were to assess the value of baseline MVA by different imaging methods and to explore the associations between MVA indexed to body surface area or left ventricular forward stroke volume and postprocedural TMG. Methods: Preprocedural echocardiographic images from 76 consecutive patients were retrospectively reviewed. MVA planimetry from two-dimensional (2D) transthoracic echocardiography (MVATTE), 2D transesophageal echocardiography in the transgastric view (MVA₂D TEE), and three-dimensional (3D) transesophageal echocardiography (MVA₃D) were measured. Postprocedural TMGs were assessed at 1 to 3 months and all-cause mortality at 1 year. Results: Postprocedural mean TMG > 5 mm Hg was associated with a 3.42-fold (95% confidence interval [CI], 1.08–10.87; P = .04) increased risk for 1-year all-cause mortality. Patients with postprocedural TMG > 5 mm Hg (25% [19 of 76]) had significantly smaller preprocedural MVA3D (3.9 ± 0.8 vs 5.2 ± 1.3 cm2 , P 5 mm Hg were, respectively, 3.9 cm² (area under the curve [AUC] = 0.80; 95% CI, 0.66–0.94; sensitivity 62%, specificity 87%) and 4.6 cm² (AUC = 0.68; 95% CI, 0.54–0.82; sensitivity 53%, specificity 80%). MVA₃D indexed to body surface area and to stroke volume showed overall the best associations with postprocedural mean TMG > 5 mm Hg, with optimal thresholds, respectively, of 2.5 cm² /m² (AUC = 0.88; 95% CI, 0.77–0.98; sensitivity 92%, specificity 74%) and 95 cm² /L (AUC = 0.87; 95% CI, 0.77–0.97; sensitivity 85%, specificity 82%). Conclusions: Elevated TMG following transcatheter edge-to-edge mitral valve repair was associated with increased mortality. The present results indicate that MVA₃D, MVA₃D indexed to body surface area, and MVA₃D indexed to stroke volume may be considered potential predictors of postprocedural TMG > 5 mm Hg and could help optimize patient selection, while the use of 2D methods for valve area were poorly associated with TMG

1,2,4-Triazole-3-thione analogues with an arylakyl group at position 4 as metallo-β-lactamase inhibitors

International audienceMetallo-β-lactamases (MBLs) represent an increasingly serious threat to public health because of their increased prevalence worldwide in relevant opportunistic Gram-negative pathogens. MBLs efficiently inactivate widely used and most valuable β-lactam antibiotics, such as oxyiminocephalosporins (ceftriaxone, ceftazidime) and the last-resort carbapenems. To date, no MBL inhibitor has been approved for therapeutic applications. We are developing inhibitors characterized by a 1,2,4-triazole-3-thione scaffold as an original zinc ligand and few promising series were already reported. Here, we present the synthesis and evaluation of a new series of compounds characterized by the presence of an arylalkyl substituent at position 4 of the triazole ring. The alkyl link was mainly an ethylene, but a few compounds without alkyl or with an alkyl group of various lengths up to a butyl chain were also synthesized. Some compounds in both sub-series were micromolar to submicromolar inhibitors of tested VIM-type MBLs. A few of them were broad-spectrum inhibitors, as they showed significant inhibitory activity on NDM-1 and, to a lesser extent, IMP-1. Among these, several inhibitors were able to significantly reduce the meropenem MIC on VIM-1- and VIM-4- producing clinical isolates by up to 16-fold. In addition, ACE inhibition was absent or moderate and one promising compound did not show toxicity toward HeLa cells at concentrations up to 250 μM. This series represents a promising basis for further exploration. Finally, molecular modelling of representative compounds in complex with VIM-2 was performed to study their binding mode

Detection of the elusive Dwarf sperm whale (Kogia sima) using environmental DNA at Malpelo island (Eastern Pacific, Colombia)

Monitoring large marine mammals is challenging due to their low abundances in general, an ability to move over large distances and wide geographical range sizes. The distribution of the pygmy (Kogia breviceps) and dwarf (Kogia sima) sperm whales is informed by relatively rare sightings, which does not permit accurate estimates of their distribution ranges. Hence, their conservation status has long remained Data Deficient (DD) in the Red list of the International Union for Conservation of Nature (IUCN), which prevent appropriate conservation measures. Environmental DNA (eDNA) metabarcoding uses DNA traces left by organisms in their environments to detect the presence of targeted taxon, and is here proved to be useful to increase our knowledge on the distribution of rare but emblematic megafauna. Retrieving eDNA from filtered surface water provides the first detection of the Dwarf sperm whale (Kogia sima) around the remote Malpelo island (Colombia). Environmental DNA collected during oceanic missions can generate better knowledge on rare but emblematic animals even in regions that are generally well sampled for other taxa