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Circulation, Volume 148, Issue 25, Page 2073-2073, December 19, 2023.
Circulation, Volume 148, Issue Suppl_1, Page A18737-A18737, November 6, 2023. Introduction:The 2022 USPSTF guidelines issued a grade C recommendation for aspirin in patients aged 40-59 and recommended against its use in patients ≥ 60 years. We sought to assess if coronary artery calcium (CAC) would allow for personalized allocation of aspirin.Methods:Using MESA, aspirin naïve participants without high-risk bleeding features were identified. Participants were grouped by age into
Circulation, Volume 148, Issue Suppl_1, Page A18867-A18867, November 6, 2023. Introduction:Atrial arrhythmias, including atrial fibrillation (AF), contribute to significant morbidity and mortality. However, the lack of suitable tissue models in small animals hampers our understanding of the underlying mechanisms. Optogenetic actuators offer precise and reversible stimulation with high spatiotemporal resolution, presenting a unique opportunity to investigate atrial arrhythmias.Hypothesis:Our aim was to develop a light-sensitive ex-vivo anatomical model in rats for studying atrial arrhythmias and to utilize this model for optimizing optogenetic stimulation and cardioversion strategies.Methods:We injected purified AAV particles containing the transgenic light-sensitive channel (CoChR) into 5-day-old Wistar rats, followed by an 8-10 week period for atrial growth. The atria were then isolated, flattened, and affixed to a custom-made silicon plate. Superfusion with oxygenated Tyrode’s solution and loading with Di-4-ANBDQBS allowed for high-resolution optical mapping. Atrial arrhythmias were induced through targeted tachypacing combined with carbamylcholine treatment. Additionally, we compared different optical and pharmacological treatment strategies to evaluate their efficacy in modulating atrial arrhythmias.Results:Immunostaining confirmed atrial expression of CoChR. Optical mapping revealed a functional syncytium with sinus node activation and propagation throughout the atria. Pacing at increasing frequencies resulted in a relatively flattened action potential duration restitution curve. Successful induction of reentrant arrhythmias was achieved. Additionally, we demonstrated the feasibility of optogenetic actuators for atrial pacing, modulation of spontaneous activity, and optical termination of arrhythmias.Conclusions:The developed optogenetic superfused atria model provides a valuable platform for studying atrial electrophysiology and modeling reentrant arrhythmias. Furthermore, it enables the optimization of optogenetic stimulation and cardioversion strategies. This integrated approach enhances our understanding of atrial arrhythmias and holds promise for the development of novel therapeutic interventions.
Circulation, Volume 148, Issue Suppl_1, Page A12850-A12850, November 6, 2023. Introduction:The potentially unlimited number of cardiomyocyte (CMs) derived from human induced pluripotent stem cells (hiPSCs) facilitates high throughput applications like cell transplantation, disease modelling, and cardiotoxicity testing during drug development. Despite promising progress in these areas, a major disadvantage that limits the use of hiPSC derived CMs (hiPSC-CMs) is their immaturity.Hypothesis:Ascorbic acid (AA) can promote ventricular myosin light chain-2 (MLC-2v) expression and maturation of hiPSC-CMs.Methods:Three hiPSC lines (PCBC-hiPSC, DP3-hiPSCs, and MLC2v-mEGFP-hiPSC) were differentiated into CMs (PCBC-CMs, DP3-CMs,a nd MLC2v-CMs, respectively) with or without retinoic acid (RA). hiPSC-CMs were either maintained up to day 30 of contraction (D30C), or D60C, or purified using lactate acid and used for experiments. Purified hiPSC-CMs were cultured in basal maturation medium (BMM) or BMM supplemented with AA for 14 days. The AA treated and non-treated hiPSC-CMs were characterized for sarcomeric proteins (MLC2v, TNNI3, and MYH7), ion channel proteins (Kir2.1, Nav1.5, Cav1.2, SERCA2a, and RyR), mitochondrial membrane potential, metabolomics, and action potential. Bobcat339, a selective and potent inhibitor of DNA demethylation, was used to determine whether AA promoted hiPSC-CM maturation through modulating DNA demethylation.Results:AA significantly increased MLC2v expression in PCBC-CMs, DP3-CMs, MLC2v-CMs, and RA induced atrial-like PCBC-CMs. AA treatment significantly increased mitochondrial mass, membrane potential, and amino acid and fatty acid metabolism in PCBC-CMs. Patch clamp studies showed that AA treatment induced PCBC-CMs and DP3-CMs adaptation to a ventricular-like phenotype. Bobcat339 inhibited MLC2v protein expression in AA treated PCBC-CMs and DP3-CMs. DNA demethylation inhibition was also associated with reduced TET1 and TET2 protein expressions and reduced accumulation of the oxidative product, 5 hmC, in both PCBC-CMs and DP3-CMs, in the presence of AA.Conclusions:Ascorbic acid promoted MLC2v protein expression and maturation of hiPSC-CMs. The effect of AA on hiPSC-CM was attenuated with inhibition of TET1/TET2 mediated DNA demethylation.
Circulation, Volume 148, Issue Suppl_1, Page A12465-A12465, November 6, 2023. Background:Light-chain amyloidosis (AL) is a rare, multisystem disease with a varied presentation, and significant morbidity and mortality. Diagnostic delay can result in poor survival, particularly in patients with cardiac involvement.Aim:To understand the path to diagnosis for patients with AL using US-based claims data.Methods:We conducted a retrospective cohort study of adults (age ≥18 years) with AL using IQVIA PharMetrics Plus data (Jan 1, 2016-Sep 30, 2022). Patients with ≥2 AL diagnosis codes (index is date of second diagnosis; ICD-10: E85.81), ≥24 months’ continuous coverage pre-index, and ≥6 months follow-up were included. Results are reported using descriptive statistics.Results:A total of 1276 patients (58% male, mean age 62 years, 64% treatment naïve) met inclusion criteria at index. In the 2 years pre-index, patients saw the highest number of cardiologists (mean 4.1) compared with hematologist/oncologists (mean 1.8) and nephrologists (mean 1.7). Cardiovascular (CV) symptoms were experienced by 87% of patients within 2 years prior to index; 55% experienced their first CV symptom >1 year prior to index. 71% of patients with CV symptoms had features suggestive of renal involvement, eg, proteinuria. Almost a quarter (23%) of patients had at least 1 emergency room (ER) visit and a third (31%) had at least one inpatient hospitalization (IP) over the 6-month follow-up period. Over half of the ER visits and IP stays were due to CV-related symptoms. Among patients whose diagnosis of AL was delayed (with early onset of CV symptoms >1 year pre-index) compared with those who did not, the crude unadjusted odds of experiencing a CV related ER visit were 53% higher (OR 1.53, 95% CI: 1.09, 2.14; p=0.01).Conclusions:Cardiologists are a key part of the AL diagnostic pathway, as the most visited specialty prior to diagnosis. CV symptoms are the most common experienced by patients with AL and account for the largest proportion of IP stays and ER visits. Patients with delayed AL diagnosis from their first CV symptoms experienced significantly more CV-related ER visits than those without delayed diagnosis. Prompt diagnosis may help prevent a decline and the presence of heart failure symptoms with proteinuria or monoclonal gammopathy should raise suspicion of AL.
Circulation, Volume 148, Issue Suppl_1, Page A17025-A17025, November 6, 2023. Introduction:Vascular retinopathy is a leading cause of preventable blindness in diabetes and retinopathy of prematurity. While most studies focus on individual neural or vascular structures, there remains a knowledge gap in understanding the retinal neurovascular interactions after injury and during repair (Fig. 1A). We seek to demonstrate 3-D neurovascular interactions with a multi-view light-sheet imaging system.Methods and Results:Intact 3-D retinas from 2-month-old mice were fixed and permeabilized followed by the optical clearance (CytoVista). Retinal vessels were stained with biotinylated isolectin B4 for microvasculature and Alexa Fluor 488-conjugated streptavidin (Fig. 1B-C) for labeling, while bipolar cells were stained with anti-PKCα (rabbit host) for neurons and Alexa Fluor Plus 555-conjugated goat anti-rabbit IgG for labeling. Refractive index matching was performed to 1.53. Multi-view light-sheet imaging was performed at 5 different angles followed by 3-D registration and reconstruction. The point spread function (PSF) demonstrates a spatial resolution of less than 5 μm (Fig. 1B, inlet). This enabled 3-D co-registration of the vasculature (Fig. 1D, in green) in relation to the bipolar cells (Fig. 1D, in red) for visualization.Conclusion:We revealed the 3-D neuro-microvascular network providing both deep tissue penetration and high spatial resolution for investigating hyperoxia and diabetes-associated vascular retinopathy.
Circulation, Volume 148, Issue Suppl_1, Page A11748-A11748, November 6, 2023. Introduction:Light chain (AL) and transthyretin amyloidosis are the most common forms of cardiac amyloidosis. Despite having similar presentation, the prognosis and treatment pathways are distinct, placing importance on accurate diagnosis.Aim:Assess the real-world diagnostic workup for AL in patients with AL, wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM), or both (AL+ATTRwt-CM).Methods:A retrospective study of Optum EHRs from Jan 2019-Dec 2021. Diagnostic workups in the 24 months prior to first diagnosis (index date) were assessed in mutually exclusive patient cohorts (aged ≥18 years) with AL (ICD10: E85.81 not E85.82), ATTRwt-CM (ICD10: E85.82 not E85.81), or AL+ATTRwt-CM (both ICD10 codes).Results:Of 49,466,996 patients in the database, 996, 526, and 31 met criteria for the AL, ATTRwt-CM, and AL+ATTRwt-CM cohorts, respectively (Table). Notable proportions of patients had no relevant workups (40%, 24%, and 23%) or no AL workups (40%, 29%, and 23%). Across cohorts, 54% (AL), 35% (ATTRwt-CM), and 61% (AL+ATTRwt-CM) received a workup for AL only, and >60% had 1-3 types of AL workup. Among patients tested with the serum-free AL assay (n=681), serum (n=460), or urine (n=286) immunofixation (IF) methods, ≥60% were in the AL cohort; ≤36% were in the ATTRwt-CM cohort and ≤4% in the AL+ATTRwt-CM cohort (Figure).Conclusions:In Optum EHRs, >20% of patients diagnosed with ATTRwt-CM or AL+ATTRwt-CM, and 40% with AL, had no relevant workups. Due to clinical urgency, it is critical to rule out AL in patients with cardiac amyloidosis using the AL assay or IF. These findings highlight the need for better diagnostic pathways for patients with suspected AL or ATTRwt-CM.
Circulation, Volume 148, Issue Suppl_1, Page A15484-A15484, November 6, 2023. A 42-year-old female patient was admitted for lower limb edema. Laboratory tests showed nephrotic proteinuria (2.76g/24h). Serum-free λ light chains were 84.9 mg/L, with a κ/λ ratio of 0.12. Bone marrow examination detected 6% immature clonal plasma cells. Amyloid deposition was identified in a renal biopsy. Cardiac magnetic resonance (CMR) revealed normal left ventricular ejection fraction (LVEF), left ventricular circumferential late gadolinium enhancement (LGE), and elevated myocardial T1 value (1459ms) and extracellular volume (47.4%). She was diagnosed with AL amyloidosis and classed as IIIa by the Mayo Stage 2004. A hematologic complete response (CR) was achieved and sustained after treatment with sequencing cyclophosphamide, bortezomib, dexamethasone (CyBorD) and daratumumab regimen. The follow-up CMRs were underwent at 6, 12, and 18 months after starting chemotherapy, which monitored cardiac changes in reponse to CR. Unfortunately, there was no alleviation of cardiac involvement. CMR re-examination (at 42 months) revealed severe cardiac function impairment (LVEF 28%), and dramatically increased extracellular volume (66.2%). Then, she underwent heart transplantation (HTx) evaluated by the heart transplantation multidisciplinary team. Three months later, she was doing well, CMR demonstrated stable cardiac allograft function. Repeated endomyocardial biopsies showed no amyloid deposits. This case illustrates that cardiac amyloid deposition might be a dynamic process in AL amyloidosis and highlights the value of CMR in long-term monitoring and identifying the patients reached CR who need HTx.
Circulation, Volume 148, Issue Suppl_1, Page A208-A208, November 6, 2023. Introduction:The assessment of serum biomarkers, specifically Neuron-Specific Enolase, S-100B protein, and Neurofilament Light Chain, at 24 hours post-cardiac arrest is under investigation for its ability to predict brain injury.Aim:This study aims to evaluate the accuracy of serum biomarkers NSE, S-100B protein, and NFL predicting post-cardiac arrest neurological outcomes.Methods:A systematic search up to December 2022 across PubMed, Embase, and Scopus identified studies examining the association between 24-hour serum levels of NSE, S-100B protein, or NFL and neurological outcomes post-cardiac arrest. Statistical analyses were conducted using R software with mada package to pool sensitivity, specificity, false-positive rates, diagnostic odds ratios, and positive and negative likelihood ratios; each expressed with a 95% Confidence Interval.Results:We incorporated 3 studies, with 759 patients in S-100B protein group, 753 in NSE group, and 799 in NFL group. At 24 hours post-cardiac arrest, NSE showed a pooled sensitivity of 37.7% (95% CI: 24.4-53.2%, I2=85.7%) and specificity of 85.5% (95% CI: 81.6-88.7%, I2=0%). S-100B protein demonstrated a pooled sensitivity of 54.7% (95% CI: 32.1-75.5%, I2=94.8%) and specificity of 81% (95% CI: 66.9-90.1%, I2=82.3%). NFL exhibited a pooled sensitivity of 88.1% (95% CI: 47.7-98.4%, I2=93.8%) and specificity of 93.6% (95% CI: 85.4-97.3%, I2=77.7%). The diagnostic odds ratios were 3.57 (95% CI: 1.79-7.15) for NSE, 5.15 (95% CI: 1.55-17.14) for S-100B protein, and 108.65 (95% CI: 11.02-1071.24) for NFL. The positive Likelihood Ratios were 2.61 (95% CI: 1.64-4.14) for NSE, 2.88 (95% CI: 1.37-6.06) for S-100B protein, and 13.87 (95% CI: 5.64-33.69) for NFL, while the negative Likelihood Ratios were 0.73 (95% CI: 0.57-0.93) for NSE, 0.19 (95% CI: 0.9-0.33) for S-100B protein, and 0.06 (95% CI: 0.03-0.15) for NFL.Conclusion:Brain biomarkers NSE, S-100B protein, and NFL, especially NFL, with its superior sensitivity and specificity, are promising in predicting neurological outcomes post-cardiac arrest, aiding clinicians in patient management and family communication. The limited number of studies and heterogeneity in results necessitate further validation and research of their predictability.
Circulation, Volume 148, Issue Suppl_1, Page A15527-A15527, November 6, 2023. Introduction:The clinical value of cardiac magnetic resonance (CMR) imaging-derived first-pass perfusion parameters in patients with light-chain (AL) amyloidosis remains unknown.Methods:This prospective study included 226 patients with biopsy-proven AL amyloidosis who underwent CMR between November 2011 to June 2021, with 43 healthy volunteers as normal controls. pulmonary transit time (PTT), Corrected PTT (PTTc), and pulmonary transit beats (PTB) were quantified and calculated from first-pass perfusion image. All-cause mortality was defined as the primary endpoint. Receiver operating characteristic curve, Kaplan-Meier analysis and Cox regression were used for statistical analyses.Results:PTT [area under the curve (AUC) 0.84], p
Circulation, Volume 148, Issue Suppl_1, Page A11740-A11740, November 6, 2023. Introduction:Cardiac amyloidosis (CA) is the key determinant of survival in systemic AL amyloidosis.Hypothesis:To assess (i) the differences between serum biomarkers, echocardiography and CMR with ECV mapping in characterising cardiac involvement, (ii) their independent prognostic role, and (iii) the role of ECV mapping to guide treatment strategies.Methods:Consecutive patients newly diagnosed with systemic AL amyloidosis between 2015-2021 who underwent echocardiography, cardiac biomarkers, and CMR with ECV mapping at the time of diagnosis were included. Haematological response (HR) at 1 and 6 months was defined according to validated criteria. The primary outcome was mortality.Results:Five-hundred sixty AL patients were included. The different approaches produced different results in terms of presence and severity of cardiac infiltration (CA present from 48.2% to 93%). Over 40.5 months [IQR 9-58], only ECV was independently associated with mortality (p< 0.001). In the landmark analysis at 1 month, patients with ECV < 0.30 and with ECV 0.31-0.40 had an excellent long-term survival regardless of the achieved HR (p=0.92 and p=0.08, respectively), whilst in patients with ECV > 0.40 survival was dependent on the depth of the HR (p< 0.001). In the landmark analysis at 6 months, patients with ECV < 0.30 had excellent survival regardless of the achieved HR and patients with ECV 0.31-0.40 had excellent survival if achieving at least a PR (inter-group p=0.006 in NR vs PR). In ECV 0.41-0.50 and ECV > 0.50, long-term survival was excellent only among patients achieving CR (inter-group p< 0.05 in CR vs VGPR). Reaching a deep HR at 1 month vs 6 months was associated with better survival in ECV > 0.40 (p< 0.05), but not in ECV < 0.40.Conclusions:ECV mapping in systemic AL amyloidosis is the only independent predictor of prognosis. ECV mapping can define optimal depth and rapidity of the HR for each patient and inform treatment strategies.
Circulation, Volume 148, Issue Suppl_1, Page A12234-A12234, November 6, 2023. Background:AL amyloidosis is a rare disorder characterized by organ infiltration of unstable misfolded light chain proteins. Diagnosis requires a high degree of suspicion, and cardiac involvement has poor outcomes. Anthracycline-based regimens are preferred for treating abdominal leiomyosarcoma (LMS) but pose a challenge in the presence of cardiac AL amyloidosis.Case:A 66-year-old male presented with bilateral leg edema and underwent evaluation for new heart failure. Echocardiography revealed preserved left ventricle ejection fraction (LVEF) with mild hypertrophy, increased interventricular septum thickness, and diastolic dysfunction. Due to concern for cardiac amyloidosis, the patient underwent nuclear scintigraphy scan, which was negative. Ongoing clinical suspicion prompted endomyocardial biopsy, which was positive for Congo Red staining, and serum studies revealed monoclonal lambda spike with increased free light chains. PET-CT was done to assess the lung nodule, revealing abdominal LMS. While Anthracycline is the drug of choice for LMS, its potential cardio-toxic effect in the presence of heart failure need be addressed. Treatment decisions involved a multidisciplinary team, resulting in bortezomib for AL amyloidosis, gemcitabine/paclitaxel for LMS, and symptomatic heart failure management.Decision-making:Anthracycline therapy was avoided due to potential cardiotoxicity. Daratumumab was added to expedite light chain reduction and minimize cardiotoxic effects. Individualized treatment considered the patient’s clinical presentation and comorbidities.Conclusion:Diagnosing cardiac amyloidosis requires a high index of suspicion. Concurrent AL amyloidosis and LMS is extremely rare and presents a therapeutic dilemma, necessitating personalized management. Further research is needed to assess the potential cardio-toxic effect of anthracycline in the presence of cardiac AL amyloidosis.
New England Journal of Medicine, Volume 389, Issue 16, Page 1523-1525, October 2023.
Introduction
The objective is to investigate the effect of antimicrobial photodynamic therapy (aPDT) mediated by erythrosine and a blue light-emitting diode (LED) in the reduction of bacteria in dental biofilm.
Methods and analysis
This clinical trial will be conducted with 30 patients who have biofilm, but without the presence of periodontal pockets, and who are being treated at the Dental Clinic of Universidade Metropolitana de Santos. A split-mouth model will be used (n=30), with group 1 control (conventional treatment) and group 2 (conventional treatment and aPDT). The bicarbonate jet will be used to remove dental biofilm in both groups. The treatment will be carried out in one session. aPDT will be performed before cleaning/prophylaxis, only in group 2. Participants will rinse with the photosensitiser erythrosine (diluted to 1 mM) for 1 min of pre-irradiation time, so that the drug can stain all the bacterial biofilm. Then, the D-2000 LED (DMC) will be applied, emitting at a wavelength of =470 nm, radiant power of 1000 mW, irradiance of 0.532 W/cm2 and radiant exposure of 63.8 J/cm2. Irradiation will be performed until the biofilm of the cervical region is illuminated for 2 min/point (4 cm2). The microbiological examination will be performed from samples of supragingival biofilm collected from the gingival sulcus. Collection will be performed in each experimental site before irradiation, immediately after the irradiation procedure and after the prophylaxis. Colony-forming units will be counted and the data will be submitted for statistical analysis for comparison of pretreatment and post-treatment results and between groups (conventional X aPDT).
Ethics and dissemination
This study has been approved by the Ethics Committee of Universidade Metropolitana de Santos under process number 66984123.0.0000.5509. Results will be published in peer-reviewed journals and will be presented at conferences.
Trial registration number
NCT05805761.
Tra i sintomi nei giovani bruciore, prurito e secchezza
Introduction
Evaporative dry eye (EDE) is common and can lead to ocular pain, decreased visual quality and reduced quality of life. Intense pulsed light (IPL) and 3% diquafosol ophthalmic solution have been found to be beneficial in reducing signs and symptoms of dry eye.
Methods and analysis
A randomised clinical trial will be performed at He Eye Specialist Hospital in Shenyang. 360 dry eye disease patients will be equally divided randomly into the IPL group, DQS group (3% diquafosol ophthalmic solution eye-drops) and IPL+group (IPL combined with 3% diquafosol eye-drops). All groups will be followed up for 4 weeks. The primary outcome measures will be the non-invasive tear break-up time and the Ocular Surface Disease Index change from the baseline. The secondary outcome measures willincludeconjunctival and cornea staining with fluorescein and lissamine, meibomian gland function and secretion quality, tear film lipid layer score, tear meniscus height, conjunctival hyperemia (redness score) changes . Adverse events also will be monitored and documented.
Discussion
This study aimed to assess whether the combination of IPL with 3% diquafosol ophthalmic solution (study group), IPL+ (study group), is more effective than IPL (active control group) or DQS (active control group) in participants with EDE.
Ethics and dissemination
Management of dry eye with IPL combined with 3% diquafosol ophthalmic solution, registered on 23 January 2023. Ethics approval number: IRB (2022) K029.01. The study’s findings will be shared regardless of the effect’s direction.
Trial registration number
NCT05694026.
