Could increased axial wall stress be responsible for the development of atheroma in the proximal segment of myocardial bridges?

<p>Abstract</p> <p>Background</p> <p>A recent model describing the mechanical interaction between a stenosis and the vessel wall has shown that axial wall stress can considerably increase in the region immediately proximal to the stenosis during the (forward) flow phases, so that abnormal biological processes and wall damages are likely to be induced in that region. Our objective was to examine what this model predicts when applied to myocardial bridges.</p> <p>Method</p> <p>The model was adapted to the hemodynamic particularities of myocardial bridges and used to estimate by means of a numerical example the cyclic increase in axial wall stress in the vessel segment proximal to the bridge. The consistence of the results with reported observations on the presence of atheroma in the proximal, tunneled, and distal vessel segments of bridged coronary arteries was also examined.</p> <p>Results</p> <p>1) Axial wall stress can markedly increase in the entrance region of the bridge during the cardiac cycle. 2) This is consistent with reported observations showing that this region is particularly prone to atherosclerosis.</p> <p>Conclusion</p> <p>The proposed mechanical explanation of atherosclerosis in bridged coronary arteries indicates that angioplasty and other similar interventions will not stop the development of atherosclerosis at the bridge entrance and in the proximal epicardial segment if the decrease of the lumen of the tunneled segment during systole is not considerably reduced.</p

Mortality Risk Prediction by an Insurance Company and Long-Term Follow-Up of 62,000 Men

Background: Insurance companies use medical information to classify the mortality risk of applicants. Adding genetic tests to this assessment is currently being debated. This debate would be more meaningful, if results of present-day risk prediction were known. Therefore, we compared the predicted with the observed mortality of men who applied for life insurance, and determined the prognostic value of the risk assessment. Methods: Long-term follow-up was available for 62,334 male applicants whose mortality risk was predicted with medical evaluation and they were assigned to five groups with increasing risk from 1 to 5. We calculated all cause standardized mortality ratios relative to the Dutch population and compared groups with Cox's regression. We compared the discriminative ability of risk assessments as indicated by a concordance index (c). Results: In 844,815 person years we observed 3,433 deaths. The standardized mortality relative to the Dutch male population was 0.76 (95 percent confidence interval, 0.73 to 0.78). The standardized mortality ratios ranged from 0.54 in risk group 1 to 2.37 in group 5. A large number of risk factors and diseases were significantly associated with increased mortality. The algorithm of prediction was significantly, but only slightly better than summation of the number of disorders and risk factors (c-index, 0.64 versus 0.60, P,0.001). Conclusions: Men applying for insurance clearly had better survival relative to the general population. Readily available medical evaluation enabled accurate prediction of the mortality risk of large groups, but the deceased men could not have been identified with the applied prediction method

Insights into the pathogenesis of vein graft disease: lessons from intravascular ultrasound

The success of coronary artery bypass grafting (CABG) is limited by poor long-term graft patency. Saphenous vein is used in the vast majority of CABG operations, although 15% are occluded at one year with as many as 50% occluded at 10 years due to progressive graft atherosclerosis. Intravascular ultrasound (IVUS) has greatly increased our understanding of this process. IVUS studies have shown that early wall thickening and adaptive remodeling of vein grafts occurs within the first few weeks post implantation, with these changes stabilising in angiographically normal vein grafts after six months. Early changes predispose to later atherosclerosis with occlusive plaque detectable in vein grafts within the first year. Both expansive and constrictive remodelling is present in diseased vein grafts, where the latter contributes significantly to occlusive disease. These findings correlate closely with experimental and clinicopathological studies and help define the windows for prevention, intervention or plaque stabilisation strategies. IVUS is also the natural tool for evaluating the effectiveness of pharmacological and other treatments that may prevent or slow the progression of vein graft disease in clinical trials

17β-Estradiol Prevents Early-Stage Atherosclerosis in Estrogen Receptor-Alpha Deficient Female Mice

Estrogen is atheroprotective and a high-affinity ligand for both known estrogen receptors, ERα and ERβ. However, the role of the ERα in early-stage atherosclerosis has not been directly investigated and is incompletely understood. ERα-deficient (ERα−/−) and wild-type (ERα+/+) female mice consuming an atherogenic diet were studied concurrent with estrogen replacement to distinguish the actions of 17β-estradiol (E2) from those of ERα on the development of early atherosclerotic lesions. Mice were ovariectomized and implanted with subcutaneous slow-release pellets designed to deliver 6 or 8 μg/day of exogenous 17β-estradiol (E2) for a period of up to 4 months. Ovariectomized mice (OVX) with placebo pellets (E2-deficient controls) were compared to mice with endogenous E2 (intact ovaries) and exogenous E2. Aortas were analyzed for lesion area, number, and distribution. Lipid and hormone levels were also determined. Compared to OVX, early lesion development was significantly (p < 0.001) attenuated by E2 with 55–64% reduction in lesion area by endogenous E2 and >90% reduction by exogenous E2. Compared to OVX, a decline in lesion number (2- to 4-fold) and lesser predilection (~4-fold) of lesion formation in the proximal aorta also occurred with E2. Lesion size, development, number, and distribution inversely correlated with circulating plasma E2 levels. However, atheroprotection was independent of ERα status, and E2 athero-protection in both genotypes was not explained by changes in plasma lipid levels (total cholesterol, triglyceride, and high-density lipoprotein cholesterol). The ERα is not essential for endogenous/exogenous E2-mediated protection against early-stage atherosclerosis. These observations have potentially significant implications for understanding the molecular and cellular mechanisms and timing of estrogen action in different estrogen receptor (ER) deletion murine models of atherosclerosis, as well as implications to human studies of ER polymorphisms and lipid metabolism. Our findings may contribute to future improved clinical decision-making concerning the use of hormone therapy

Genome-wide association study identifies genetic factors that modify age at onset in Machado-Joseph disease

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences

Multicenter, Prospective Validation of a Phenotypic Algorithm to Guide Carbapenemase Testing in Carbapenem-Resistant Pseudomonas aeruginosa Using the ERACE-PA Global Surveillance Program

Background Carbapenemase-producing, carbapenem-resistant Pseudomonas aeruginosa (CP-CRPA) is a global challenge. However, detection efforts can be laborious because numerous mechanisms produce carbapenem resistance. A minimum inhibitory concentration-based algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) was proposed to identify the isolates most likely to harbor a carbapenemase; however, prospective validation in geographies displaying genotypic diversity and varied carbapenemase prevalence is warranted. Methods CRPA isolates were collected during the Enhancing Rational Antimicrobials for P. aeruginosa (ERACE-PA) global surveillance program from 17 sites in 12 countries. Isolates underwent susceptibility testing following local standards to ceftazidime, cefepime, and ceftolozane/tazobactam. Isolates underwent initial phenotypic carbapenemase screening followed by molecular testing if positive. The primary algorithm criteria were applied, and results were compared with phenotypic carbapenemase results to assess the performance of the algorithm. A secondary criterion, the algorithm criterion or imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible, was assessed. Results A total of 807 CRPA were assessed, and 464 isolates met the algorithm criteria described above. Overall, testing was reduced by 43% compared with testing all CRPA. Carbapenemase-positive isolates missed by the algorithm were largely driven by Guiana extended spectrum (GES). Addition of the criterion of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible decreased the number of CP-CRPA missed by the algorithm (21 vs 40 isolates, respectively), reducing number of isolates tested by 39%. Conclusions Application of the initial algorithm (imipenem- or meropenem-resistant plus ceftazidime-nonsusceptible plus cefepime-nonsusceptible) performed well in a global cohort, with 33% phenotypically carbapenemase-positive isolates. The addition of imipenem- or meropenem-resistant plus ceftolozane/tazobactam-nonsusceptible reduced the number of phenotypically carbapenemase-positive isolates missed and may be useful in areas with a prominence of GES

The ERACE-PA Global Surveillance Program: Ceftolozane/tazobactam and Ceftazidime/avibactam in vitro Activity against a Global Collection of Carbapenem-resistant Pseudomonas aeruginosa

The cephalosporin-beta-lactamase-inhibitor-combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have revolutionized treatment of carbapenem-resistant Pseudomonas aeruginosa (CR-PA). A contemporary assessment of their in vitro potency against a global CR-PA collection and an assessment of carbapenemase diversity are warranted. Isolates determined as CR-PA by the submitting site were collected from 2019-2021 (17 centers in 12 countries) during the ERACE-PA Global Surveillance Program. Broth microdilution MICs were assessed per CLSI standards for ceftolozane/tazobactam, ceftazidime/avibactam, ceftazidime, and cefepime. Phenotypic carbapenemase testing was conducted (modified carbapenem inactivation method (mCIM)). mCIM positive isolates underwent genotypic carbapenemase testing using the CarbaR, the CarbaR NxG, or whole genome sequencing. The MIC50/90 was reported as well as percent susceptible (CLSI and EUCAST interpretation). Of the 807 isolates, 265 (33%) tested carbapenemase-positive phenotypically. Of these, 228 (86%) were genotypically positive for a carbapenemase with the most common being VIM followed by GES. In the entire cohort of CR-PA, ceftolozane/tazobactam and ceftazidime/avibactam had MIC50/90 values of 2/ > 64 and 4/64 mg/L, respectively. Ceftazidime/avibactam was the most active agent with 72% susceptibility per CLSI compared with 63% for ceftolozane/tazobactam. For comparison, 46% of CR-PA were susceptible to ceftazidime and cefepime. Against carbapenemase-negative isolates, 88 and 91% of isolates were susceptible to ceftolozane/tazobactam and ceftazidime/avibactam, respectively. Ceftolozane/tazobactam and ceftazidime/avibactam remained highly active against carbapenem-resistant P. aeruginosa, particularly in the absence of carbapenemases. The contemporary ERACE-PA Global Program cohort with 33% carbapenemase positivity including diverse enzymology will be useful to assess therapeutic options in these clinically challenging organisms with limited therapies