Continuous mechanical aspiration thrombectomy performs equally well in main versus branch pulmonary emboli: A subgroup analysis of the EXTRACT-PE trial.

INTRODUCTION: The EXTRACT-PE trial evaluated the safety and performance of the Indigo Aspiration System (Penumbra Inc.) with an 8F continuous mechanical aspiration thrombectomy system for the treatment of pulmonary embolism (PE). This subgroup analysis evaluates performance outcomes of patients with main pulmonary artery (PA) emboli versus discrete unilateral or bilateral PA emboli without main PA involvement. METHODS: The EXTRACT-PE trial was a prospective, single-arm, multicenter trial that enrolled 119 patients with acute submassive PE. Emboli location was collected at the time of enrollment, CT obstruction was measured and assessed by a Core Lab, and patients were grouped on whether emboli involved the main PA (with or without branch vessels) or not (branch vessels alone). Procedural device time, changes in the right ventricle to left ventricle (RV/LV) ratio, and systolic PA pressure from pre-and posttreatment were compared between the two groups. RESULTS: Out of the 119 patients enrolled, 118 had core lab-assessed clot locations. Forty-five (38.1%) had emboli that involved the main PA and 73 (61.9%) had only branch emboli. No significant difference was observed between these groups for 30-day mortality, procedural device time, changes in RV/LV ratio, reduction in CT Obstruction Index, or for systolic PA pressure from pre-and posttreatment. The mean absolute reduction in clot burden was significant in both groups. CONCLUSION: Continuous mechanical aspiration thrombectomy with the 8F Indigo Aspiration System was effective at improving clinical outcomes for submassive PE patients regardless of emboli location, and clot burden was significantly reduced in both groups.

Sex-specific risk factors for cardiovascular disease in women-making cardiovascular disease real.

PURPOSE OF REVIEW: Sex-specific differences in pathophysiology, prevalence, and impact of cardiovascular disease (CVD) risk factors may explain the high cardiovascular mortality rates in women. RECENT FINDINGS: We review the sex differences in traditional risk factors (dyslipidemia, hypertension, diabetes, and smoking) and nontraditional risk factors (menopause and hormones, pregnancy, inflammation and autoimmune diseases, anemia, depression, and migraines) and their prognostic and therapeutic implications. SUMMARY: Recent research indicates that with respect to traditional risk factors such as dyslipidemia, hypertension, diabetes, and smoking, women appear to have a similar risk of CVD when compared to men. The risk is accelerated after menopause, possibly because of vascular and lipid profile changes. Pregnancy offers a unique opportunity and window to screen otherwise healthy women who may be at an increased risk of CVD in the future. Clinicians should be aware of other novel risk factors including inflammation, anemia, migraines, and depression, and further studies are warranted in order to identify therapeutic implications for these conditions and CVD risk.

Prolonged corrected QT interval in the donor heart: Is there a risk?

BACKGROUND: Assessing the QT interval in donors is important to exclude long QT syndrome as the cause of death. A donor heart with a corrected QT (QTc ) >500 milliseconds is often concerning. We sought to evaluate first year outcomes for donors with a QTc interval >500 milliseconds. METHODS: Between 2010 and 2014, we assessed 257 donor hearts for QTc interval >500 milliseconds. Post-transplant outcomes included 1-year survival, 1-year freedom from any-treated rejection, 1-year freedom from cardiac allograft vasculopathy (CAV) defined as stenosis ≥30% by angiography, and 1-year freedom from nonfatal major adverse cardiac events. RESULTS: Patients with QTc interval >500 milliseconds had a significantly lower 1-year freedom from CAV development. There were no significant differences for other outcomes. A significantly higher percentage of donors with QTc >500 milliseconds had a stroke or subarachnoid hemorrhage. Multivariate analysis found that donor QTc >500 milliseconds was associated with a 6.7-fold increased risk of developing CAV (P=.029, 95% CI 1.21-36.6) after adjusting for other known risk factors. CONCLUSION: QTc >500 milliseconds in the donor heart appears to be an independent risk factor for the development of early CAV after heart transplantation possibly due to a higher immunological risk.

Intravenous Hydration for Management of Medication-Resistant Orthostatic Intolerance in the Adolescent and Young Adult.

Orthostatic intolerance (OI) is common in teenagers (T) and young adults (A). Despite treatment with oral fluids, medication, and exercise, a significant number have symptoms from multiple organ systems and suffer low quality of life (QOL). Previous studies showed that acute intravenous (IV) hydration (IH) could help restore orthostatic tolerance; however, no data are available about the intermediate-term effects of IH. We therefore studied the efficacy of IH to improve QOL and manage medication-refractory OI patients. Our study population consisted of 39 patients (mean age = 16.1 ± 3.3) years; thirty-two were female. Average number of medications failed = 3.1. Average QOL score on self-reported OI questionnaire was 4.2 (normal QOL = 10). IV hydration consisted of normal saline (1-2 l/day, 3-7 days/week). 1) Orthostatic testing revealed Postural Orthostatic Tachycardia (24), Neurally Mediated Hypotension (14) or OI (1). 2) Average orthostatic change in heart rate was 48 ± 18 bpm. 3) IH was performed via intermittent IV access (10), PICC line (22), and Port (7). 4) Duration of IH varied from 1 week to 3.8 years (mean = 29 ± 47 weeks). 5) Overall, 79 % (n = 31) demonstrated clinically improved self-reported QOL. 6) Six patients who discontinued IH requested to restart treatment. (7) Complications consisted of upper extremity deep vein thrombosis (n = 3) and infection (n = 4). IH is an effective therapy to improve QOL in T&A with medication-resistant OI. Most patients continued to report improved QOL once IH was discontinued. IH should be considered a therapeutic option in medication-resistant OI patients with low QOL.

A bis(PCN) palladium pincer complex with a remarkably planar 2,5-diarylpyrazine core.

A bimetallic Pd complex of a bis(pincer) with a diarylpyrazine core has been prepared. The complex demonstrates near-perfect coplanarity of the aromatic core, is fluorescent under UV irradiation, and displays two quasi-reversible reduction events.

Synthesis of fluorinated aminium cations coupled with carborane anions for use as strong one-electron oxidants.

Synthesis of a series of hydrocarbon-soluble triarylamines bearing F, CF3, and Br substituents showing quasi-reversible redox events in the 0.59-1.32 V range is reported. Chemical oxidation of the amines was carried out with 0.5PhI(OAc)2/Me3SiX/Na[RCB11Cl11] (X = Cl or OTf, R = H or Me), and a few aminium salts were isolated as pure solids.

Low-Intensity vs. High-Intensity Antithrombotic Therapy After Transcatheter Aortic Valve Replacement: Meta-Analysis of Randomized Controlled Trials.

Background: The optimal antithrombotic therapy after transcatheter aortic valve replacement (TAVR) is controversial. We performed a systematic review and meta-analysis of randomized controlled trials comparing high-intensity vs. low-intensity antithrombotic therapy after TAVR in the absence of an established indication for anticoagulation. Methods: The primary efficacy and safety endpoints were a composite of death or thromboembolic events and Valve Academic Research Consortium 2-defined significant bleeding, respectively. All analyses were by intention to treat. Risk ratios (RRs) were calculated using the inverse variance random-effects model. Results: Four studies comprising 3358 patients (mean age 81 years, mean Society of Thoracic Surgery score 3.3%) were identified. Two studies compared anticoagulation vs. antiplatelet therapy after TAVR; the other 2 trials compared dual-antiplatelet therapy vs. mono-antiplatelet therapy after TAVR. The incidence of death or thromboembolic events (RR 0.66 [95% confidence interval (CI) 0.55-0.80], p < 0.0001, I2 = 0%), death (RR 0.68 [95% CI 0.51-0.92], I2 = 11%, p = 0.01), and Valve Academic Research Consortium 2-defined major bleeding (RR 0.69 [95% CI 0.48 - 1.00], p = 0.003, I2 = 44%) was significantly lower in patients on low-intensity antithrombotic therapy than in those on high-intensity antithrombotic therapy. Conclusions: In an elderly patient population undergoing TAVR, routine initiation of a high-intensity antithrombotic therapy in the absence of a clinical indication for anticoagulation was associated with increased risk of death or thromboembolic complications, increased risk of death, and increased risk of significant bleeding. Routine initiation of an anticoagulation therapy or dual-antiplatelet therapy after TAVR in the absence of an established indication for anticoagulation may not be advisable.

Implementation of an Electronic Health Records-Based Safe Contrast Limit for Preventing Contrast-Associated Acute Kidney Injury After Percutaneous Coronary Intervention.

BACKGROUND: Contrast-associated acute kidney injury (CA-AKI) after percutaneous coronary intervention is associated with increased mortality. We assessed the effectiveness of an electronic health records safe contrast limit tool in predicting CA-AKI risk and reducing contrast use and CA-AKI. METHODS: We created an alert displaying the safe contrast limit to cardiac catheterization laboratory staff prior to percutaneous coronary intervention. The alert used risk factors automatically extracted from the electronic health records. We included procedures from June 1, 2020 to October 1, 2021; the intervention went live February 10, 2021. Using difference-in-differences analysis, we evaluated changes in contrast volume and CA-AKI rates after contrast limit tool implementation compared to control hospitals. Cardiologists were surveyed prior to and 9 months after alert implementation on beliefs, practice patterns, and safe contrast estimates for example patients. RESULTS: At the one intervention site, there were 508 percutaneous coronary interventions before and 531 after tool deployment. At 15 control sites, there were 3550 and 3979 percutaneous coronary interventions, respectively. The contrast limit predicted CA-AKI with an accuracy of 64.1%, negative predictive value of 93.3%, and positive predictive value of 18.7%. After implementation, in high/modifiable risk patients (defined as having a calculated contrast limit <500ml) there was a small but significant -4.60 mL/month (95% CI, -8.24 to -1.00) change in average contrast use but no change in CA-AKI rates (odds ratio, 0.96 [95% CI, 0.84-1.10]). Low-risk patients had no change in contrast use (-0.50 mL/month [95% CI, -7.49 to 6.49]) or CA-AKI (odds ratio, 1.24 [95% CI, 0.79-1.93]). In assessing CA-AKI risk, clinicians heavily weighted age and diabetes but often did not consider anemia, cardiogenic shock, and heart failure. CONCLUSIONS: Clinicians often used a simplified assessment of CA-AKI risk that did not include important risk factors, leading to risk estimations inconsistent with established models. Despite clinician skepticism, an electronic health records-based contrast limit tool more accurately predicted CA-AKI risk and was associated with a small decrease in contrast use during percutaneous coronary intervention but no change in CA-AKI rates.

Canadian Cardiovascular Society-Canadian Heart Failure Society Focused Clinical Practice Update of Patients With Differing Heart Failure Phenotypes.

A number of societies produce heart failure (HF) management guidelines, comprising official recommendations on the basis of recent research discoveries, but their applicability to specific situations encountered in daily practice might be difficult. In this clinical practice update we aim to provide responses to fundamental questions that face health care providers, like appropriate timing for the introduction and optimization of different classes of medication according to specific patient phenotypes, when second-line therapies and valvular interventions should be considered, and management of difficult clinical scenarios such as cardiorenal syndrome and frailty. A consensus-based methodology was used. Approaches to 5 different phenotypes are presented: (1) The wet HF phenotype is the easiest to manage, decongestion being performed alongside introduction of guideline-directed medical therapy (GDMT); (2) The de novo HF phenotype requires the introduction of the 4 pillars of GDMT, personalizing the order on the basis of the individuals' biological and physiological characteristics; (3) The worsening HF phenotype is a marker of poor prognosis, and therefore should motivate optimization of GDMT, start second-line therapies, and/or reevaluate goals of care/advanced HF therapies; (4) The cardiorenal phenotypes require correct volume assessment, because renal function usually improves with decongestion; and (5) The frail HF phenotype require special attention, careful drug titration, and consideration of cardiac rehabilitation programs. In conclusion, specific common HF phenotypes call for a personalized approach to improve adoption of the HF guidelines into clinical practice.

Probing in vivo trafficking of polymer/DNA micellar nanoparticles using SPECT/CT imaging.

Successful translation of nonviral gene delivery to therapeutic applications requires detailed understanding of in vivo trafficking of the vehicles. This report compares the pharmacokinetic and biodistribution profiles of polyethylene glycol-b-polyphosphoramidate (PEG-b-PPA)/DNA micellar nanoparticles after administration through intravenous infusion, intrabiliary infusion, and hydrodynamic injection using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Nanoparticles were labeled with (111)In using an optimized protocol to retain their favorable physicochemical properties. Quantitative imaging analysis revealed different in vivo trafficking kinetics for PEG-b-PPA/DNA nanoparticles after different routes of administration. The intrabiliary infusion resulted in the highest liver uptake of micelles compared with the other two routes. Analysis of intrabiliary infusion by the two-compartment pharmacokinetic modeling revealed efficient retention of micelles in the liver and minimal micelle leakage from the liver to the blood stream. This study demonstrates the utility of SPECT/CT as an effective noninvasive imaging modality for the characterization of nanoparticle trafficking in vivo and confirms that intrabiliary infusion is an effective route for liver-targeted delivery of DNA-containing nanoparticles.

String-like micellar nanoparticles formed by complexation of PEG-b-PPA and plasmid DNA and their transfection efficiency.

PURPOSE: To investigate the gene delivery efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver after intravenous injection and intrabiliary infusion. METHODS: PEG-b-PPA/DNA micellar nanoparticles were prepared in aqueous solution through spontaneous self-assembly between plasmid DNA and PEG(10K)-b-PPA(4K) or PEG(10K)-b-PP(13K) polymer. The stability of these micellar nanoparticles in different physiological media was evaluated by monitoring the particle size change of micellar nanoparticles with dynamic light scattering (DLS). The transfection efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver was examined and compared with that of PPA/DNA nanoparticles after intravenous and intrabiliary infusion. RESULTS: These PEG-b-PPA/DNA micellar nanoparticles exhibited unique string-like morphology under TEM. The stability of these string-like nanoparticles in salt-, serum- or bile- containing media was significantly improved compared with PPA/DNA nanoparticles. More importantly, these PEG-b-PPA/DNA nanoparticles mediated 10-fold higher transfection efficiency than PPA/DNA nanoparticles in rat liver when delivered via intrabiliary infusion. In addition, histopathological data revealed that the PEG-b-PPA/DNA nanoparticles induced minimal level of liver toxicity or damage. CONCLUSIONS: These string-like PEG-b-PPA/DNA micelles can mediate efficient transgene expression in the liver after bile duct infusion, and they have great potential to be used as effective gene carriers for liver-targeted gene delivery.

Delayed repolarization and ventricular tachycardia in patients with heart failure and preserved ejection fraction.

Sudden death is the most common mode of mortality in patients with heart failure and preserved ejection fraction (HFpEF). Ventricular arrhythmias (VA) have been suspected as the etiology but the supporting evidence in patients with HFpEF is scarce. We sought to investigate VA prevalence, and to determine if VA are associated with prolonged repolarization, in patients with HFpEF. In a retrospective case-control study design, Cedars-Sinai patients who underwent prolonged ambulatory electrocardiographic monitoring (Zio Patch) between 2016 and 2018 were screened for a clinical diagnosis of HFpEF. Patients with normal diastolic and systolic function who underwent Zio Patch monitoring were also reviewed as controls. Multivariable logistic regression was used to compare the prevalence of rhythm disturbances in patients with and without HFpEF. Ventricular tachycardia (VT) was more prevalent in patients with HFpEF (37% vs. 16% in controls, p = 0.001). Most episodes were non-sustained except for one case of sustained VT in a patient with HFpEF. Covariate-adjusted logistic regression including HFpEF diagnosis, age, sex, body mass index, and the presence of comorbidities revealed that only HFpEF was associated with increased risk of VT (relative risk 2.86, p = 0.023). Subgroup-analyses revealed an association between increased QTc interval and risk of VT (460 ± 38 ms in HFpEF patients with VT vs. 445 ± 28 ms in HFpEF patients without VT, p = 0.03). Non-sustained VT was more prevalent in patients with HFpEF compared to patients without HFpEF, and QTc interval prolongation was associated with VT in HFpEF.

Risk factors for heart failure in women with ischemia and no obstructive coronary artery disease.

Study objective: Women with ischemia and no obstructive coronary artery disease (INOCA) are at increased risk for heart failure (HF) hospitalizations, which is predominantly HF with preserved ejection fraction (HFpEF). We aimed to identify predictors for the development of heart failure HF in a deeply phenotyped cohort of women with INOCA and long-term prospective follow-up. Design setting and participants: Women enrolled in the NHLBI-sponsored Women's Ischemia Syndrome Evaluation (WISE) were evaluated for baseline characteristics including clinical history, medications, physical exam, laboratory data and angiographic data. Using a multivariate Cox analysis, we assessed the association between baseline characteristics and the occurrence of HF hospitalizations in 493 women with evidence of ischemia but no obstructive coronary disease, no prior history of HF, and available follow-up data. Results: During a median follow-up of 6-years, 18 (3.7%) women were hospitalized for HF. Diabetes mellitus and tobacco use were associated with HF hospitalization. In a multivariate analysis adjusting for known HFpEF predictors including age, diabetes, hypertension, tobacco use, and statin use, novel predictive variables included higher resting heart rate, parity and IL-6 levels and lower coronary flow reserve (CFR) and poor functional status. Conclusions: There is a considerable incidence of HF hospitalization at longer term follow-up in women with INOCA. In addition to traditional risk factors, novel risk variables that independently predict HF hospitalization include multi-parity, high IL-6, low CFR, and poor functional status. These novel risk factors may be useful to understand mechanistic pathways and future treatment targets for prevention of HFpEF.

Heart Failure: A Palliative Medicine Review of Disease, Therapies, and Medications With a Focus on Symptoms, Function, and Quality of Life.

Despite significant advances in heart failure (HF) treatment, HF remains a progressive, extremely symptomatic, and terminal disease with a median survival of 2.1 years after diagnosis. HF often leads to a constellation of symptoms, including dyspnea, fatigue, depression, anxiety, insomnia, pain, and worsened cognitive function. Palliative care is an approach that improves the quality of life of patients and their caregivers facing the problems associated with life-threatening illness and therefore is well suited to support these patients. However, historically, palliative care has often focused on supporting patients with malignant disease, rather than a progressive chronic disease such as HF. Predicting mortality in patients with HF is challenging. The lack of obvious transition points in disease progression also raises challenges to primary care providers and specialists to know at what point to integrate palliative care during a patient's disease trajectory. Although therapies for HF often result in functional and symptomatic improvements including health-related quality of life (HRQL), some patients with HF do not demonstrate these benefits, including those patients with a preserved ejection fraction. Provision of palliative care for patients with HF requires an understanding of HF pathogenesis and common medications used for these patients, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes HF and current targeted therapies and their effects on symptoms, hospital admission rates, exercise performance, HRQL, and survival. Pharmacological interactions with and precautions related to commonly used palliative care medications are reviewed. The goal of this review is to equip palliative care clinicians with information to make evidence-based decisions while managing the balance between optimal disease management and patient quality of life.