Outcome of acute ST-segment elevation myocardial infarction in diabetics treated with fibrinolytic or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: Lessons from the GUSTO V trial

OBJECTIVES We studied the outcome of diabetics enrolled in the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) V trial to assess whether the combination of half-dose reteplase and abciximab provides any propitious benefits over standard fibrinolytic therapy in diabetic patients. BACKGROUND Diabetics with acute ST-segment elevation myocardial infarction (MI) have a worse outcome compared with nondiabetics. Higher-risk patients are usually more likely to benefit from advances in medical therapy. METHODS We analyzed diabetic patients enrolled in the GUSTO V trial to assess the outcome of those randomized to the combination of half-dose reteplase and abciximab versus those randomized to reteplase. We also evaluated whether any differences existed in presentation and outcome of MI among the diabetics versus the nondiabetics enrolled in the study. RESULTS The trial enrolled 13,782 nondiabetics and 2,633 diabetics. Compared to nondiabetics, diabetics had a significantly higher mortality at 30 days (8.5% vs. 5.1%, p < 0.001) and at 1 year (12.7% vs. 7.5%, p < 0.001). Among the diabetic subset, no significant difference existed in the incidence of 30-day (8.8% vs. 8.2%, p = 0.52) or 1-year mortality (13.0% vs. 12.4%, p = 0.62) among patients randomized to reteplase compared to those receiving combination of abciximab and reteplase. The incidence of reinfarction (2.5% vs. 4.3%, p = 0.013), recurrent ischemia (11.8% vs. 14.9%, p = 0.017), and urgent revascularization (10.9% vs. 13.3%, p = 0.055) at seven days was lower in diabetics treated with the combination therapy. CONCLUSIONS Compared to nondiabetics, diabetics continue to have a worse outcome with MI. Although combination therapy did not provide a survival benefit, nonfatal ischemic outcomes, including reinfarction, recurrent ischemia, and urgent revascularization, were substantially reduced

Intracoronary Injection of In Situ Forming Alginate Hydrogel Reverses Left Ventricular Remodeling After Myocardial Infarction in Swine

ObjectivesThis study sought to determine whether alginate biomaterial can be delivered effectively into the infarcted myocardium by intracoronary injection to prevent left ventricular (LV) remodeling early after myocardial infarction (MI).BackgroundAlthough injectable biomaterials can improve infarct healing and repair, the feasibility and effectiveness of intracoronary injection have not been studied.MethodsWe prepared a calcium cross-linked alginate solution that undergoes liquid to gel phase transition after deposition in infarcted myocardium. Anterior MI was induced in swine by transient balloon occlusion of left anterior descending coronary artery. At 4 days after MI, either alginate solution (2 or 4 ml) or saline was injected selectively into the infarct-related coronary artery. An additional group (n = 19) was treated with incremental volumes of biomaterial (1, 2, and 4 ml) or 2 ml saline and underwent serial echocardiography studies.ResultsExamination of hearts harvested after injection showed that the alginate crossed the infarcted leaky vessels and was deposited as hydrogel in the infarcted tissue. At 60 days, control swine experienced an increase in left ventricular (LV) diastolic area by 44%, LV systolic area by 45%, and LV mass by 35%. In contrast, intracoronary injection of alginate (2 and 4 ml) prevented and even reversed LV enlargement (p < 0.01). Post-mortem analysis showed that the biomaterial (2 ml) increased scar thickness by 53% compared with control (2.9 ± 0.1 mm vs. 1.9 ± 0.3 mm; p < 0.01) and was replaced by myofibroblasts and collagen.ConclusionsIntracoronary injection of alginate biomaterial is feasible, safe, and effective. Our findings suggest a new percutaneous intervention to improve infarct repair and prevent adverse remodeling after reperfused MI

Influence of anesthesia on hemodynamic assessment of mitral stenosis severity

Background: The treatment of choice for severe rheumatic mitral stenosis (MS) is balloon mitral valvuloplasty (BMV). Assessment of MS severity is usually performed by echocardiography. Before performing BMV, invasive hemodynamic assessment is also performed. The effect of anesthesia on the invasive assessment of MS severity has not been studied. The purpose of the present study was to assess changes in invasive hemodynamic measurement of MS severity before and after induction of general anesthesia. Methods: The medical files of 22 patients who underwent BMV between 2014 and 2020 were reviewed. Medical history, laboratory, echocardiographic and invasive measurements were collected. Anesthesia induction was performed with etomidate or propofol. Pre-procedural echocardiographic measurements of valve area using pressure half time, and continuity correlated well with invasive measurements using the Gorlin formula. Results: After induction of anesthesia the mean mitral valve gradient dropped by 2.4 mmHg (p = 0.153) and calculated mitral valve area (MVA) increased by 0.2 cm2 (p = 0.011). A wide variability in individual response was observed. While a drop in gradient was noted in 14 patients, it increased in 7. Gorlin derived MVA rose in most patients but dropped in 4. Assuming a calculated MVA of 1.5 cm2 and below to define clinically significant MS, 4 patients with pre-induction MVA of 1.5 cm2 or below had calculated MVA above 1.5 cm2 after induction. Conclusions: The impact of general anesthesia on the hemodynamic assessment of MS is heterogeneous and may lead to misclassification of MS severity

Left atrial size predicts long-term outcome after balloon mitral valvuloplasty

Background: The treatment of choice for severe rheumatic mitral stenosis is balloon mitral valvuloplasty (BMV). Numerous predictors of immediate and long-term procedural success have been described. The aims of this study were to describe our experience with BMV over the last decade and to evaluate predictors of long-term event-free survival.  Methods: Medical records were retrospectively analyzed of patients who underwent BMV between 2009 and 2021. The primary outcome was a composite endpoint of all-cause mortality, mitral valve replacement (MVR), and repeat BMV. Long-term event-free survival was estimated using the Kaplan-Meier curves. Logistic regression was used to create a multivariate model to assess pre-procedural predictors of the primary outcome. Results: A total of 96 patients underwent BMV during the study period. The primary outcome occurred in 36 patients during 12-year follow-up: 1 (1%) patient underwent re-BMV, 28 (29%) had MVR, and 8 (8%) died. Overall event-free survival was 62% at 12 years. On multivariate analysis, pre-procedural left atrial volume index (LAVI) &gt; 80 mL/m2 had a significant independent influence on event-free survival, as did previous mitral valve procedure and systolic pulmonary arterial pressure above 50 mmHg. Conclusion: Despite being a relatively low-volume center, excellent short and long-term results were demonstrated, with event-free survival rates consistent with previous studies from high-volume centers. LAVI independently predicted long-term event-free survival

Pseudo-discordance mimicking low-flow low-gradient aortic stenosis in transcatheter aortic valve replacement patients with severe symptomatic aortic stenosis

Background: While the combination of a small aortic valve area (AVA) and low mean gradient is frequently labeled ‘low-flow low-gradient aortic stenosis (AS)’, there are two potential causes for this finding: underestimation of mean gradient and underestimation of AVA. Methods: In order to investigate the prevalence and causes of discordant echocardiographic findings in symptomatic patients with AS and normal left ventricular (LV) function, we evaluated 72 symptomatic patients with AS and normal LV function by comparing Doppler, invasive, computed tomography (CT) LV outflow tract (LVOT) area, and calcium score (CaSc). Results: Thirty-six patients had discordant echocardiographic findings (mean gradient &lt; 40 mmHg, AV area ≤ 1 cm2). Of those, 19 had discordant invasive measurements (true discordant [TD]) and 17 concordant (false discordant [FD]): In 12 of the FD the mean gradient was &gt; 30 mmHg; technical pitfalls were found in 10 patients (no reliable right parasternal Doppler in 6). LVOT area by echocardiography or CT could not differentiate between concordants and discordants nor between TD and FD (p = NS). CaSc was similar in concordants and FD (p = 0.3), and it was higher in true concordants than in TD (p = 0.005). CaSc positive predictive value for the correct diagnosis of severe AS was 95% for concordants and 93% for discordants. Conclusions: Discordant echocardiographic findings are commonly found in patients with symptomatic AS. Underestimation of the true mean gradient due to technical difficulties is an important cause of these discrepant findings. LVOT area by echocardiography or CT cannot differentiate between TD and FD. In the absence of a reliable and compete multi-window Doppler evaluation, patients should undergo CaSc assessment

Transcatheter edge-to-edge mitral valve repair in patients with acute decompensated heart failure due to severe mitral regurgitation

Background: Transcatheter edge-to-edge mitral valve repair (TEER) has been established as a therapy for severe symptomatic mitral regurgitation (MR) in stable patients, and it has recently emerged as a reasonable option for acutely ill patients. The aim of this study was to evaluate the safety and efficacy of TEER in hospitalized patients with acute decompensated heart failure (ADHF) and severe MR that was deemed to play a major role in their deterioration. Methods: We included 31 patients who underwent emergent TEER for MR ≥ 3+ from 2012 to 2022 at Sheba Medical Center. Outcomes included procedural safety, procedural success, all-cause mortality, heart failure readmission, and functional improvement. Outcomes were evaluated at 3 months and at 1 year. Data were obtained retrospectively by chart review. Results: Implantation of a TEER device was achieved in 97% of patients, and reduction in MR severity of at least two grades and final MR ≤ 2+ at discharge was achieved in 74%. No intra-procedural mortality or life-threatening complications were noted. Mortality at 30 days was 23%. No excess mortality occurred beyond 6 months, with a total mortality of 41%. At 1 year all survivors had MR ≤ 2+, all were free of heart failure hospitalizations, and 88% were at New York Heart Association class ≤ II. Conclusions: Mitral valve TEER for patients with ADHF and significant MR is safe, feasible, and achieves substantial reduction in MR severity. Despite high early mortality, procedural success is associated with good long-term clinical outcomes for patients surviving longer than 6 months

New insights into the genetic etiology of Alzheimer's disease and related dementias

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele

Multiancestry analysis of the HLA locus in Alzheimer’s and Parkinson’s diseases uncovers a shared adaptive immune response mediated by HLA-DRB1*04 subtypes

Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson’s disease (PD) and Alzheimer’s disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues