Angiotensin II receptor blockers and cardiovascular protection: Focus on left ventricular hypertrophy regression and atrial fibrillation prevention

Left ventricular hypertrophy (LVH) and atrial fibrillation (AF) are strong predictors of cardiovascular (CV) morbidity and mortality, independently of blood pressure levels and other modifiable and nonmodifiable risk factors. The actions of circulating and tissue angiotensin II, mediated by AT1 receptors, play an important role in the development of a wide spectrum of cardiovascular alterations, including LVH, atrial enlargement and AF. Growing experimental and clinical evidence suggests that antihypertensive drugs may exert different effects on LVH regression and new onset AF in the setting of arterial hypertension. Since a number of large and adequately designed studies have found angiotensin II receptor blockers (ARBs) to be more effective in reducing LVH than beta-blockers and data are also available showing their effectiveness in preventing new or recurrent AF, it is reasonable to consider this class of drugs among first line therapies in patients with hypertension and LVH (a very high risk phenotype predisposing to AF) and as adjunctive therapy to antiarrhythmic agents in patients undergoing pharmacological or electrical cardioversion of AF

Effects of antihypertensive drugs on carotid intima-media thickness: Focus on angiotensin II receptor blockers. A review of randomized, controlled trials

Carotid intima-media thickness (IMT) and plaques have been shown to have a strong continuous relationship with cardiovascular (CV) morbidity and mortality; therefore, carotid atherosclerosis, as assessed by ultrasonography, can be regarded as a reliable surrogate end-point for therapeutic interventions. In this survey, we report the results of 16 double blind, randomized, controlled studies comparing: 1) antihypertensive drugs versus placebo/no treatment (five trials including 3,215 patients); 2) different active antihypertensive drug regimens (five trials including 4,662 patients); 3) angiotensin-II receptor blockers (ARBs) versus other antihypertensive agents (six trials including 841 patients). Our main findings can be summarized as follows: I) Long-term antihypertensive treatment has a blunting effect on carotid IMT progression, regardless of types of drugs. II) Calcium-channel blockers (CCBs) are more effective than other antihypertensive drugs including diuretics, beta-blockers, and angiotensin converting-enzyme (ACE)-inhibitors in this blunting effect; III) the effect of ARBs compared to other antihypertensive regimens (mostly based on atenolol) on carotid atherosclerosis progression needs to be further elucidated, as a protective effect was demonstrated by some, but not all studies examined. Thus, further studies are needed to clarify the role of ARBs in this therapeutic area

Left ventricular geometry and diastolic function in the hypertensive heart : impact of age

Background and aim. The impact of aging on the relationship between left ventricular (LV) mass/geometry and diastolic function as assessed by updated echocardiographic methods, such as tissue Doppler, is poorly defined. We investigated this issue in a cohort of hypertensive patients. Methods. A total of 660 hypertensives (mean age 65±13 years, 48% men) with preserved LV systolic function underwent a comprehensive echo-Doppler examination for routine clinical indications. For the present analysis, the subjects have been divided in two age groups (<65 or ≥65 years). Results. Overall, 61% of subjects fulfilled the criteria for LVH, 18% for left atrial (LA) enlargement and 11% for altered LV filling index. Concentric LV geometry was 1.4-fold higher in older hypertensives than in younger counterparts; also the prevalence of LA enlargement and altered LV filling was 2.0- and 1.9-fold higher in the former group, respectively. In older hypertensives, at variance from younger ones, neither LV mass nor relative wall thickness (RWT), a continuous index of LV geometry, were independently correlated to conventional as well as tissue Doppler LV diastolic indexes. Conclusions. Our findings suggest the relationship between cardiac hypertrophy and diastolic function in hypertensive subjects is affected by aging-associated factors unrelated to the amount of LV mass as assessed by standard echocardiography. © 2013 Scandinavian Foundation for Cardiovascular Research

Metabolic syndrome and multiple organ damage in essential hypertension

Aim. We investigated the prevalence of the metabolic syndrome (MS) in hypertensive patients categorized according to the number of markers of organ damage (OD) in order to assess the value of a systematic search for cardiac and extra-cardiac OD in the MS setting. Methods. A total of 3119 untreated and treated essential hypertensives included in the Evaluation of Target Organ Damage in Hypertension (ETODH), an observational registry of hypertension-related OD, were considered for this analysis. All patients underwent extensive investigation for left ventricular hypertrophy (LVH) or LV concentric remodeling (cardiac OD), carotid plaques and/or intima-media thickening (vascular OD) and microalbuminuria (MA) and/or increased serum creatinine (renal OD). Subjects were classified as: positive for none (group 0), one (group I), two (group II) or three markers (group III) of OD. Results. MS prevalence rates progressively rose across the groups stratified according to the OD score, reaching a 2.3-fold increase in group III compared with their MS counterparts in group 0. The distribution of subjects with and without the MS across the groups was 15% vs 29% (group 0), 32% vs 38% (group I), 39% vs 26% (group II) and 14% vs 7% (group III), respectively. Thus, subjects having two or three markers of OD were 53% among those with MS and 33% (p<0.01) among those without it. Conclusion. Our findings indicate a strong association between the MS and OD by showing that a clustering of two or three markers of OD is the prevalent cardiovascular phenotype in MS hypertensives referred to a specialist center and call for a systematic evaluation of cardiac and extracardiac OD in this setting

Metabolic syndrome, left ventricular hypertrophy and carotid atherosclerosis in hypertension: a gender-based study.

Background. The influence of gender on the association between metabolic syndrome (MS) and subclinical organ damage (OD) has been poorly investigated. The aim of this study was to investigate whether the risk of developing left ventricular hypertrophy (LVH) and carotid atherosclerosis is different in men and women with MS. Methods. A total of 3752 untreated and treated hypertensive patients (mean age 53.3 ± 12.6, 52.7% men) were considered for this analysis. All patients underwent standard ultrasonographic investigations searching for LVH and carotid atherosclerosis. The MS was defined according to ATP III criteria. Results. LVH was more prevalent in women and men with the MS compared with their counterparts (58% vs 34% and 48% vs 33%, respectively, p < 0.001). This was also the case for carotid plaque prevalence (61% vs 42% and 57% vs 44%, p < 0.001). The prevalence of OD was not different between men and women with MS, after adjusting for confounders. In multivariate analysis, abdominal obesity was the most important MS component independently related to LVH in both genders, followed by blood pressure. As for carotid plaques, blood pressure, hyperglycemia and hypertriglyceridemia turned out to be independent correlates regardless of gender. Conclusions. Our data indicate that MS is associated with a higher risk of LVH and carotid atherosclerosis irrespective of gender; these findings do not support a gender influence in the association between MS and subclinical OD. © 2013 Scandinavian Foundation for Cardiovascular Research

Discovery and characterization of non-canonical E2 conjugating enzymes

E2 conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation is fundamental for maintaining cellular homeostasis and impacts almost all cellular process. By interacting with multiple E3 ligases, E2s direct the ubiquitylation landscape within the cell. Since its discovery, ubiquitylation has been regarded as a post-translational modification that specifically targets lysine side chains (canonical ubiquitylation). We used MALDI-TOF Mass Spectrometry to discover and characterize a family of E2s that are instead able to conjugate ubiquitin to serine and/or threonine. We employed protein modelling and prediction tools to identify the catalytic determinants that these E2s use to interact with ubiquitin as well as their substrates. Our results join a stream of recent literature that challenges the definition of ubiquitylation as an exquisitely lysine-specific modification and provide crucial insights into the missing E2 element responsible for non-canonical ubiquitylation.<br/

Frequency of positive antiphospholipid antibodies in pregnant women with SARS-CoV-2 infection and impact on pregnancy outcome: A single-center prospective study on 151 pregnancies

Background: At the beginning of the SARS-CoV-2 pandemic, there was a lack of information about the infection’s impact on pregnancy and capability to induce de novo autoantibodies. It soon became clear that thrombosis was a manifestation of COVID-19, therefore the possible contribution of de novo antiphospholipid antibodies (aPL) raised research interest. We aimed at screening SARS-CoV-2 positive pregnant patients for aPL. Methods: The study included consecutive pregnant women who were hospitalized in our Obstetric Department between March 2020 and July 2021 for either a symptomatic SARS-CoV-2 infection or for other reasons (obstetric complications, labour, delivery) and found positive at the admission nasopharyngeal swab. All these women underwent the search for aPL by means of Lupus Anticoagulant (LA), IgG/IgM anti-cardiolipin (aCL), IgG/IgM anti-beta2glycoprotein I (aB2GPI). Data about comorbidities, obstetric and neonatal complications were collected. Results: 151 women were included. Sixteen (11%) were positive for aPL, mostly at low titre. Pneumonia was diagnosed in 20 women (5 with positive aPL) and 5 required ICU admission (2 with positive aPL). Obstetric complications occurred in 10/16 (63%) aPL positive and in 36/135 (27%) negative patients. The occurrence of HELLP syndrome and preeclampsia was significantly associated with positive aPL (p=0,004). One case of maternal thrombosis occurred in an aPL negative woman. aPL positivity was checked after at least 12 weeks in 7/16 women (44%): 3 had become negative; 2 were still positive (1 IgG aB2GPI + IgG aCL; 1 IgM aB2GPI); 1 remained positive for IgG aCL but became negative for aB2GPI; 1 became negative for LA but displayed a new positivity for IgG aCL at high titre. Conclusions: The frequency of positive aPL in pregnant women with SARS- CoV-2 infection was low in our cohort and similar to the one described in the general obstetric population. aPL mostly presented as single positive, low titre, transient antibodies. The rate of obstetric complications was higher in aPL positive women as compared to negative ones, particularly hypertensive disorders. Causality cannot be excluded; however, other risk factors, including a full-blown picture of COVID-19, may have elicited the pathogenic potential of aPL and contributed themselves to the development of complications

Discovery and characterization of noncanonical E2-conjugating enzymes

E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation, is required to maintain cellular homeostasis and affects almost all cellular process. By interacting with multiple E3 ligases, E2s dictate the ubiquitylation landscape within the cell. Since its discovery, ubiquitylation has been regarded as a posttranslational modification that specifically targets lysine side chains (canonical ubiquitylation). We used Matrix-Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry to identify and characterize a family of E2s that are instead able to conjugate ubiquitin to serine and/or threonine. We used structural modeling and prediction tools to identify the key activity determinants that these E2s use to interact with ubiquitin as well as their substrates. Our results unveil the missing E2s necessary for noncanonical ubiquitylation, underscoring the adaptability and versatility of ubiquitin modifications.</p

Discovery and characterization of noncanonical E2-conjugating enzymes

E2-conjugating enzymes (E2s) play a central role in the enzymatic cascade that leads to the attachment of ubiquitin to a substrate. This process, termed ubiquitylation, is required to maintain cellular homeostasis and affects almost all cellular process. By interacting with multiple E3 ligases, E2s dictate the ubiquitylation landscape within the cell. Since its discovery, ubiquitylation has been regarded as a posttranslational modification that specifically targets lysine side chains (canonical ubiquitylation). We used Matrix-Assisted Laser Desorption/Ionization-Time Of Flight Mass Spectrometry to identify and characterize a family of E2s that are instead able to conjugate ubiquitin to serine and/or threonine. We used structural modeling and prediction tools to identify the key activity determinants that these E2s use to interact with ubiquitin as well as their substrates. Our results unveil the missing E2s necessary for noncanonical ubiquitylation, underscoring the adaptability and versatility of ubiquitin modifications.</p

Measurement of the correlation between the polar angles of leptons from top quark decays in the helicity basis at √s = 7 TeV using the ATLAS detector

A measurement of the correlations between the polar angles of leptons from the decay of pair-produced t and t̄ quarks in the helicity basis is reported, using proton-proton collision data collected by the ATLAS detector at the LHC. The dataset corresponds to an integrated luminosity of 4.6  fb−¹ at a center-of-mass energy of √s = 7  TeV collected during 2011. Candidate events are selected in the dilepton topology with large missing transverse momentum and at least two jets. The angles θ1 and θ2 between the charged leptons and the direction of motion of the parent quarks in the tt̄ rest frame are sensitive to the spin information, and the distribution of cosθ1 ⋅ cosθ2 is sensitive to the spin correlation between the t and t̄ quarks. The distribution is unfolded to parton level and compared to the next-to-leading order prediction. A good agreement is observed