Progress towards the development of a HIV-1 gp41-directed vaccine

The HIV-1 gp41 envelope glycoprotein mediates fusion of the viral and cellular membranes. The core of the gp41 ectodomain undergoes a receptor-triggered conformational transition forming a trimeric, alpha-helical coiled-coil structure. This trimer-of-hairpins species facilitates insertion of the viral envelope protein into the host cell membrane promoting viral entry. The prefusogenic conformation of gp41 is capable of stimulating a neutralizing antibody immune response and is therefore an attractive therapeutic target. Several broadly neutralizing HIV-1 monoclonal antibodies which bind to gp41 have been characterized and include 4E10, Z13 and 2F5. A conserved segment of gp41 (residues 661-684) has been identified as the epitope for the HIV-1 neutralizing antibody 2F5 (MAb 2F5). MAb 2F5 has attracted considerable attention because of the highly conserved recognition epitope and the ability to neutralize both laboratory-adapted and primary viral isolates. Antibodies which recognize the immunodominant regions of gp41 may provide protection against HIV infection if elicited at appropriate concentrations. Here we review the rational design, structure-activity relationships and conformational features of both linear and constrained peptide immunogens incorporating variants of both the 2F5 epitope and the gp41 ectodomain. This review describes a rational design approach combining structural characterization with traditional SAR to optimize MAb 2F5 antibody affinities of gp41-based peptide immunogens. The immunogens are shown to stimulate a high titer, peptide-specific immune response; however, the resulting antisera were incapable of viral neutralization. The implication of these findings with regard to structural and immunological considerations is discussed.     

Aortic elasticity and size in bicuspid aortic valve syndrome.

AIMS: To investigate the relation between aortic elastic properties and size in bicuspid aortic valves (BAVs). METHODS AND RESULTS: 127 BAV outpatients (121 males; age 23 +/- 10 years) with no or mild valvular impairment, were recruited with 114 control subjects comparable for age, gender, and body size. Aortic distensibility (DIS) and stiffness index (SI) were derived by M-mode evaluation of the aortic root together with blood pressure measured by cuff sphygmomanometer. BAVs vs. controls had increased aortic diameter (P < 0.0001), higher systolic (P = 0.02) and pulse (P = 0.04) pressures. DIS was lower in BAVs than in controls (4.71 +/- 3.67 vs. 7.44 +/- 3.94 10(-6) cm(2)dyne(-1), respectively; P < 0.0001) and SI was greater in BAVs (7.21 +/- 4.93 vs. 3.57 +/- 1.88, respectively; P < 0.0001). Definite impairment in aortic elasticity was present in 53 (42%) BAVs. Both DIS and SI were related (P < 0.0001) to aortic size in BAVs and controls. After adjusting for aortic size and blood pressure, the regression relations between SI and aortic diameter of BAVs were significantly different from controls (P = 0.0052). CONCLUSION: Abnormal aortic elasticity is a common finding in BAVs with no or mild aortic valve impairment. However, impaired aortic stiffness is not due to aortic dilation. Simple assessment of aortic size may thus fail to identify early abnormal load bearing characteristics of the aortic wall in BAVs.     

Initial experience of three-minute freeze cycles using the second-generation cryoballoon ablation: acute and short-term procedural outcomes

Background

The second-generation cryoballoon (CB-A) (Arctic Front Advance, Cryocath, Medtronic, MN, USA) might significantly improve procedural outcome with respect to the first-generation balloon. These technological improvements might also question the current recommendation of the need a 4-min freeze to achieve durable pulmonary vein isolation (PVI).

Objective

The main aim of the study was to analyze the procedural efficacy of a 3-min freeze–thaw cycles with the CB-A balloon in the terms of rates of acute PVI and 6-month outcome.

Methods

Patients having undergone CB-A for PAF or early persistent AF, with 3-min freeze–thaw cycles were consecutively included in our analysis. Acute procedural success was measured in terms of the rate of PVI. Short-term follow-up was evaluated by the means of 24-h Holters and clinical examinations at regular intervals.

Results

Fifty-two consecutive patients (35 male (67 %); mean age, 59.8?±?10.5) were included. Mean procedure and fluoroscopy times were 96?±?15 and 13.2?±?8.3 min, respectively. Mean time from groin puncture to catheter extraction was 60.4?±?20 min. After a mean of 1.5 freeze cycles per vein of 3 min in duration, all 208 (100 %) PVs could be isolated with the CB-A. A total 192 (91 %) veins were isolated during the first freeze. At a mean of 5.7-month follow-up, 82 % of patients were free of AF.

Conclusion

CB-A is effective in producing PVI by using 3-min-duration freeze cycles. After a mean of 1.5 freeze per vein, freedom from AF was achieved in 82 % of patients at 6-month follow-up.     

Cardiac and arrhythmic complications in patients with COVID‐19

In December 2019, the world started to face a new pandemic situation, the severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). Although coronavirus disease (COVID‐19) clinical manifestations are mainly respiratory, major cardiac complications are being reported. Cardiac manifestations etiology seems to be multifactorial, comprising direct viral myocardial damage, hypoxia, hypotension, enhanced inflammatory status, ACE2‐receptors downregulation, drug toxicity, endogenous catecholamine adrenergic status, among others. Studies evaluating patients with COVID‐19 presenting cardiac injury markers show that it is associated with poorer outcomes, and arrhythmic events are not uncommon. Besides, drugs currently used to treat the COVID‐19 are known to prolong the QT interval and can have a proarrhythmic propensity. This review focus on COVID‐19 cardiac and arrhythmic manifestations and, in parallel, makes an appraisal of other virus epidemics as SARS‐CoV, Middle East respiratory syndrome coronavirus, and H1N1 influenza.     

Coronary cardiac allograft vasculopathy versus native atherosclerosis: difficulties in classification

Cardiac allograft vasculopathy is regarded as a progressive and diffuse intimal hyperplastic lesion of arteries and veins that leads to insidious vessel narrowing and to allograft ischemic disease, such as acute myocardial infarction or sudden cardiac death. The coronary lesions in transplanted hearts are considered as a particular type of arteriosclerosis with many similarities but also significant differences compared to native coronary atherosclerosis. It is particularly difficult for pathologists to systematically classify the lesions and to elucidate their origins, since over time, the allograft immune responses cause vascular pathology characterized by not only the onset of de novo fibrocellular lesions but also remodeling of already-existing native atherosclerotic lesions in the donor heart. Intraplaque hemorrhages, which result from newly formed leaky microvessels, may cause rapid increase of stenosis and generate a substrate for plaque destabilization. Comparing cardiac allograft vasculopathy from explanted hearts at autopsy with native coronary atherosclerosis from hearts removed at transplantation has revealed that ongoing intraplaque hemorrhages are also an important feature of cardiac allograft vasculopathy and may be important factors in the rapid progression of cardiac allograft vasculopathy.