Clinical Management Research Articles

Subgroup analysis of diabetes in COVID-positive revascularized patients: implications for clinical management

Abstract Background The management of revascularized patients with COVID-19, particularly in the presence of diabetes mellitus (DM), presents significant challenges. Understanding the clinical outcomes in this subgroup is essential for optimizing patient care during the pandemic. Purpose This study aimed to investigate the clinical outcomes of revascularized COVID-positive patients with and without DM, focusing on revascularization methods, hospitalization rates, mechanical ventilation requirement, mortality, stroke incidence, and presentation of acute coronary syndrome (ACS) subtypes. Methods A retrospective analysis was conducted on the cohort of 620 COVID-positive revascularized patients. Among them, 267 patients had diabetes mellitus (DM), while 353 patients did not. Data on revascularization methods, hospitalization rates, mechanical ventilation requirement, mortality, stroke incidence, and ACS presentation were collected and compared between the two groups. Statistical analysis was performed to assess the significance of differences observed. Results Among the 620 COVID-positive revascularized patients, 267 (43.1%) had diabetes mellitus, while 353 (56.9%) did not. Demographic analysis revealed that 299 (84.7%) of the COVID-positive patients with diabetes mellitus were male, compared to 181 (67.8%) of those without diabetes mellitus. This difference in gender distribution between the two groups was statistically significant (p < 0.001). Additionally, smoking was more prevalent among COVID-positive patients without diabetes mellitus (38.8%) compared to those with diabetes mellitus (22.5%), with a significant difference observed (p < 0.001) (Table 1). Among the revascularized patients, a higher proportion of patients with diabetes mellitus underwent coronary artery bypass grafting (CABG) compared to those without DM (32.6% vs. 24.1%, p = 0.019). Patients with diabetes exhibited significantly higher hospitalization rates (27.0% vs. 15.6%, p = 0.001) and a trend towards increased mechanical ventilation requirement (11.1% vs. 3.6%, p = 0.121). However, mortality rates, stroke incidence, and ACS presentation did not significantly differ between the two groups (Table2). Conclusion This study underscores the heightened vulnerability of revascularized COVID-positive patients with DM, as evidenced by higher hospitalization rates and a trend towards increased mechanical ventilation requirement. These findings emphasize the importance of tailored management strategies for this high-risk subgroup to optimize patient outcomes during the ongoing COVID-19 pandemic.Table 1Table 2

Laboratory Testing for ADAMTS13 for Thrombotic Thrombocytopenia Purpura and Beyond.

ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), also called von Willebrand factor (VWF) cleaving protease, acts as a moderator of VWF activity. ADAMTS13 cleaves VWF multimers, thereby reducing VWF activity in blood. When ADAMTS13 is absent (e.g., in patients with TTP [thrombotic thrombocytopenia purpura]), accumulation of VWF in plasma can occur, particularly as "ultra-large" VWF multimers, with this leading to adverse outcomes such as thrombosis. Relative ADAMTS13 deficiencies also occur in several other conditions, including secondary thrombotic microangiopathies (TMA), cancer, and with severe infections such as in COVID-19 (coronavirus disease 2019). These situations might therefore be accompanied with relative loss of ADAMTS13, thereby potentially also leading to pathological VWF accumulation, with this then generating a prothrombotic milieu, thus contributing to enhance the risk of thrombosis. Laboratory testing for ADAMTS13 can aid in the diagnosis of such disorders (i.e., TTP, TMA), and help guide their management, with testing now accomplished using various assays. As most presentations of TTP reflect an acquired condition due to anti-ADAMTS13 antibodies, there may also be a need to test for these, as this will also influence clinical management. We herein provide an overview of TTP, note other conditions in which low levels of ADAMTS13 may be present, and then detail laboratory testing for both ADAMTS13 and associated inhibitors.

Exercise stress echocardiography detects patients with paroxysmal/persistent atrial fibrillation

Abstract Background Atrial fibrillation (AF) is the most prevalent atrial tachyarrhythmia, affecting an estimated 2-4% of adults worldwide. AF is a well-recognized and treatable risk factor for stroke, but it often remains asymptomatic or subclinical, leading to underdiagnosis. This study aimed to identify distinguishing signs during exercise stress echocardiography (ESE) among patients in sinus rhythm (SR), with and without history of paroxysmal/persistent AF (PAF). Methods An international prospective cohort comprising 1035 consecutive patients was initially considered from 12 cardiology institutions. These patients were referred for clinically-driven ESE as part of the Stress Echo 2020-2030 study network. All patients underwent comprehensive ESE with the ABCDE protocol, which included assessment of B-lines, left ventricle contractile reserve (LVCR), ECG-based heart rate reserve (HRR), LV ejection fraction (EF), LV end-diastolic volume, E/e’, pulmonary artery systolic pressure estimation, tricuspid annular plane sytolic excursion (TAPSE), left atrium volume index (LAVi) and left atrium reservoir phase strain (LASr) at rest and with exercise. Results After excluding 89 patients who were in AF during the ESE, 946 patients in SR were included as the main study cohort (101 with and 845 without a history of PAF). A scoring system was then constructed using all independent variables that differentiate the two groups (those with and without history of PAF). Presence of systemic hypertension, rest LAVI>31ml/m2, rest |LASr|< 21%, stress LAVI >29 ml/m2, stress |LASr| <24%, stress E/e’ >7, ∆TAPSE <4.5 mm, HRR<1.87, and LVCR<1.6 were identified as the discriminators between patients with and without PAF. The composite score, summing all 9 items (with a total score range from 0 to 9), yielded a score of >4 as the best balance between sensitivity (87%) and specificity (60%) in predicting those with PAF. The receiver operating characteristic curve analysis of the scoring model showed an AUC of 0.79 (p-value <0.0001), Figure. Conclusion ESE evaluation can be a valuable adjunct for identifying patients in SR with history of PAF. This multifaceted approach enhances the potential for more accurate detection and clinical management of individuals in SR at risk for AF, who could be considered for aggressive monitoring programs to prevent the development of new onset AF and subsequent increase in cardiovascular risk.

Accelerated hazard prediction based on age time-scale for women diagnosed with breast cancer using a deep learning method

Breast cancer is the most common cancer in women. Previous studies have investigated estimating and predicting the proportional hazard rates and survival in breast cancer. This study deals with predicting accelerated hazards (AH) rate based on age categories in breast cancer patients using deep learning methods. The AH has a time-dependent structure whose rate changes according to time and variable effects. We have collected data related to 1225 female patients with breast cancer at the Mandarin University of Medical Sciences. The patients' demographic and clinical characteristics including family history, age, history of tobacco use, hysterectomy, first menstruation age, gravida, number of breastfeeding, disease grade, marital status, and survival status have been recorded. Initially, we dealt with predicting three age groups of patients: ≤ 40, 41–60, and ≥ 61 years. Then, the prediction of accelerated risk value based on age categories for each breast cancer patient through deep learning and the importance of variables using LightGBM is discussed. Improving clinical management and treatment of breast cancer requires advanced methods such as time-dependent AH calculation. When the behavioral effect is assumed as a time scale change between hazard functions, the AH model is more appropriate for randomized clinical trials. The study results demonstrate the proper performance of the proposed model for predicting AH by age categories based on breast cancer patients' demographic and clinical characteristics.

Long-term prognostic value of multiple circulating biomarkers for ventricular arrhythmias in patients with left ventricular hypertrabeculation

Abstract Background Left ventricular hypertrabeculation (LVHT) is a rare morphologic phenotype of the heart with heterogeneous manifestations and variable prognosis [1,2]. Ventricular arrhythmia (VA) has been recognized as an independent risk factor that significantly impacts the mortality of LVHT patients [1,3]. However, knowledge regarding the prognosis and risk stratification of VAs in LVHT is currently limited. Purpose To explore the long-term predictive value of multiple circulating biomarkers reflecting cardiac function, endothelial function, inflammation, and oxidative stress for the development of VAs in LVHT patients. Methods This longitudinal cohort study consecutively enrolled morphologically diagnosed LVHT patients between January 2012 and December 2020 at a national-level medical center. All participants possessed thorough profiles of multiple biomarkers [N-terminal pro-brain natriuretic peptide, big endothelin-1 (big ET-1), high-sensitivity C-reactive protein, uric acid and free fatty acid] and had no previously documented ventricular arrhythmic events. The cohort were followed annually until October 2022. VA was defined as a composite of non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, and appropriate therapy of implantable cardioverter defibrillator. Potential predictors for VAs in the LVHT cohort were evaluated by multivariable Cox regression. Restricted cubic spline (RCS) analysis was employed to explore the nonlinear association between plasma big ET-1 and clinical outcomes. Differences in the cumulative incidence of VAs according to big ET-1 levels and/or the extent of hypertrabeculation were analyzed by Kaplan-Meier curves. Results A total of 265 morphologically diagnosed LVHT patients (44.2 ± 17.0 years, 65.7% male) were included in this study. Over a median follow-up of 4.34 years, 82 (30.9%) patients experienced ventricular arrhythmic events. Multivariable Cox regression analysis identified that baseline levels of big ET-1 (hazard ratio 1.513, 95% confidence interval 1.136-2.013) and isolated hypertrabeculation in left ventricular lateral wall (LVLW) (hazard ratio 1.810, 95% confidence interval 1.023-3.202) were independently associated with the occurrence of VAs. RCS analysis illustrated that the susceptibility to VAs was remarkably raised with the increase of big ET-1 levels. LVHT patients with higher plasma big ET-1 suffered from more severe cardiac dysfunction and remodeling. Individuals who displayed elevated concentrations of big ET-1 and isolated LVLW hypertrabeculation were at a significantly greater risk of developing VAs. Conclusions Introducing routine assessments for plasma big ET-1 and the extent of hypertrabeculation at baseline can offer valuable support in the risk stratification and clinical management of ventricular arrhythmic events in patients with LVHT.Prognositc value of big ET-1 for VAsbig ET-1/LVLW hypertrabeculation & VAs

Comparative Analysis of Osteoarthritis Therapeutics: A Justification for Harnessing Retrospective Strategies via an Inverted Pyramid Model Approach

In this review, we seek to explore two distinct approaches to the clinical management of OA: a prospective approach, addressing primarily one’s genetic predisposition to OA and generating early intervention options, and the retrospective approach, aimed at halting or reversing OA progression post-symptom onset. The clinical management of OA remains challenging, largely due to the limited availability of preventative treatments and failure of existing therapies to modify or reverse the underlying pathophysiology. The prospective approach involves the identification of genetic markers associated with OA and utilizes in vitro and in vivo models to characterize the underlying disease mechanism. Further, this approach focuses on identifying genetic predispositions and unique molecular subtypes of OA to develop individualized treatment plans based on patient genotypes. While the current literature investigating this strategy has been notable, this approach faces substantial challenges, such as extensive time burdens and utilization of extensive genetic testing that may not be economically feasible. Additionally, there is questionable justification for such extensive investigations, given OA’s relatively low mortality rates and burden when contrasted with diseases like specific forms of cancer, which rely heavily on the prospective approach. Alternatively, the retrospective approach primarily focuses on intervention following symptom onset and aims to utilize novel therapeutics to slow or reverse the inflammatory cascade typically seen in disease progression. These treatments, like Hippo pathway inhibitors, have shown initial promise in halting OA progression and alleviating OA symptomology by modulating cellular processes to preserve articular cartilage. In comparison to the prospective approach, the retrospective strategy is likely more cost-effective, more widely applicable, and does not necessitate thorough and invasive genetic screening. However, this approach must still be weighed against the typical natural history of disease progression, which frequently results in total knee arthroplasty and unacceptable outcomes for 15–20% of patients. From a comparative analysis of these two approaches, this review argues that the retrospective strategy, with ideally lower time and economic burden and greater accessibility, offers a more reasonable and effective solution in the context of OA management. Using a similar approach to other management of chronic diseases, we suggest an “Inverted Pyramid” model algorithm, a structured research and development regimen that prioritizes generating widely effective therapies first, with subsequent refinement of treatments based on the development of patient resistance to these therapies. We argue that this strategy may reduce the need for total knee arthroplasty while improving patient outcomes and accessibility.

Role of common variants and new genes associated with arrhythmogenic cardiomyopathy

Abstract Introduction Arrhythmogenic Cardiomyopathy (ACM) is an inherited cardiac disease, predominantly affecting males, characterized by fibro-fatty myocardial replacement mainly in the right ventricle. It leads to 5% sudden cardiac death in affected young adults (<25 yo) without an implantable cardioverter defibrillator. Early diagnosis is crucial for appropriate clinical management to reduce mortality and prevent disease progression. Rare variants in desmosomal genes (PKP2,DSC2,DSG2,DSP and JUP) are found in 50% of cases. However, challenges persist since we observe a low penetrance in relatives (28-58%) and a high variability in expressivity and severity annihilating any preventive strategy. Objective We aim to decipher the genetic architecture of ACM by investigating the role of common variants in disease susceptibility/severity and to idendify new genes associated to ACM. Method A Genome Wide Association Study (GWAS) was performed on 1079 ACM index patients and 7305 controls, followed by conditional analysis. New candidate genes were knocked out (KO) in Zebrafish and/or hiPSC using CRISPR/Cas9. Impedance and external field potential measurements were performed on hiPSC derived cardiomyocytes (CM-hiPSC). Results The GWAS identified 5 significant loci (Figure 1, P<5.10-8), including 2 desmosomal genes (PKP2 a n d DSG2) and 3 new candidates (KLF12, CTNNA3, and ARL17B/WNT3). Conditional analysis revealed 3 additional loci with suggestive p-values (P<1.10-6), highlighting 3 new susceptible loci. Among them, we uncovered key non-coding regulatory regions near desmosomal genes (DSC2 and DSG2). Initial findings in PKP2-KO zebrafish present hearts with structural defects, while CM-hiPS KLF12-KO(-/-) exhibited altered interbeat interval and relaxation time compared to isogenic controls. Conclusion Our findings reveal ACM's complex genetic architecture, implicating common variants in disease susceptibility. A polygenic risk score will be implemented to improve patient risk stratification. Three novel loci/genes for ACM as well as specific regulatory regions of desmosomal genes have been highlighted. Their functional studies in isogenic hiPSC and Zebrafish models will offer new insights in ACM underlying molecular mechanism and potential therapeutic targets.

Prospective evaluation of an AI algorithm for real-time LVEF assessment in acute coronary syndrome using left coronary angiograms: the CathEF multicenter study

Abstract Background Acute assessment of Left Ventricular Ejection Fraction (LVEF) is critical at time of percutaneous coronary intervention to optimize clinical management. The CathEF artificial intelligence algorithm offers a novel approach for real-time, intra-procedural LVEF assessment using routinely obtained left coronary artery angiograms without additional dye use[1]. Our objective was to evaluate the real-time application of the CathEF algorithm for LVEF measurement during coronary angiogram procedures in patients with acute coronary syndrome (ACS) and to compare its performance with transthoracic echocardiography (TTE) and left ventriculography. Methods The CathEF study is a prospective multi-center study that recruited ACS patients undergoing coronary angiography at two institutions from July 2022 to July 2023. Using the CathEF algorithm and the PACS-AI software, we analyzed 2 to 4 left coronary angiogram videos per procedure for LVEF assessment to compare to ventriculography (if indicated) and echocardiography performed during the same hospitalization. Operators were blinded to the CathEF AI-generated results. The primary measure was the algorithm's area under the receiving-operating characteristic curve (AUC) in identifying LVEF <40% or ≥40% compared to TTE-LVEF. Results 240 patients (32% female, average age 66 ± 12 years) were enrolled, with 207 undergoing TTE during index hospitalization (coronary angiogram to TTE mean delay of 0.8±6.3 days). The CathEF algorithm analyzed 881 coronary angiogram videos, averaging 3.12±1.66 per patient. Indications for angiography included unstable angina (18%), NSTEMI (47%), and STEMI (35%). The algorithm took under one minute to apply. CathEF’s performance yielded an AUC of 0.90 (95% CI, 0.840-0.96) and an MAE of 6.81% ± 0.43, with a Spearman correlation of 0.52. Conclusions This study provides proof-of-concept for prospective deployment of an AI algorithm at point-of-care with reliable LVEF measurement in real-time during ACS. This innovation holds the potential to ensure all ACS patients can receive prompt and appropriate care based on their LVEF.CathEF algorithm applied to an angiogramPACS-AI : Platform used to apply CathEF

Clinical reality and challenges with familial hypercholesterolemia patients management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

Abstract Background HeFH is one of the most prevalent genetic diseases significantly increasing the risk of CVD events and mortality. Despite new achievements with earlier diagnosis and new effective drugs, most of heFH patients do not achieve LDL-C goal and are still on residual CVD risk. Purpose We aimed to present the most recent data from the regional FH registry in Poland to show the challenges and reality of everyday clinical management with FH patients. Methods The registry is conducted at the RCRD in the 2nd largest, supraregional hospital in Poland. The main inclusion criteria were being phenotypically or genetically diagnosed with FH. Nonadherence was investigated based on detailed interview, monitoring the treatment’s effects and purchasing prescribed medications. For this analysis we investigated only adult FH patients from the registry. Due to small number of cases (n=5), patients treated with inclisiran were not included in this analysis. Results We included 142 consecutive heFH patients at mean age 45,8±14,9 years (min/max 18-75 years; 60% women). Mean BMI was 29.6±5.52 kg/m2, mean baseline TC was 282.9±80 mg/dl (the highest observed was 600 mg/dl), LDL-C 204.2±72.5 mg/dL (the highest observed -762 mg/dl), TG - 151.1±123.4 mg/dl, Lp(a) 37.6±41.5 mg/dl and HDL-C - 52.3±14.2 mg/dl. Most patients were diagnosed with LDLR (72%) or APOB (24%) mutations. High intensity statin therapy was used in 74.3% of patents, ezetimibe (mostly as a part of combination LLT) in 47.2%, and PCSK9 inhibitors in all those that met the reimbursement criteria – 25.6% of FH patients. Non-adherence to statin therapy and ezetimibe in the follow up of 2 years was 27%. In patients treated with statin therapy and ezetimibe mean achieved LDL-C was 153.6±82.82 mg/dl and on triple therapy - 64.5±43.73 mg/dl. Mean achieved LDL-C in the investigated population was 87.9±55.5 mg/dl. LDL-C goal was achieved in 39% of patients – in those treated with triple therapy with PCSK9 inhibitors it was 57.14%, and in those on statins and ezetimibe only 27.1%. Combination therapy of statins and ezetimibe did not significantly change baseline Lp(a) level (p=0.109), but when PCSK9 inhibitors were introduced the mean Lp(a) reduction by 34.2% (p=0.049) was observed. Based on the multivariable regression analysis, the following factors played the most important role for FH patients to be on LDL-C target: DLCN total score (OR 1.21, 95%CI: 1.04-1.40; p=0.013), DLCN category (10.39, 1.43-75.29; p=0.021), ezetimibe use (4.78, 1.15-19.92; p=0.031), and PCSK9 inhibitors use (4.56; 1.40-14.86; p=0.012). Conclusions FH patients in Poland are diagnosed definitely too late (45 years) and most of them are still not on LDL-C goal. Double and especially triple therapy significantly, even 5 times, increase the chance of achieving LDL-C goal, therefore PCSK9 inhibitors should be available for all FH patients, without the limitations existing currently e.g., within B101 drug program in Poland.

Developing a multi-center registry of peripheral artery disease using natural language processing: unlocking the power of the electronic health record

Abstract Background Although peripheral artery disease (PAD) is common and associated with a high risk of mortality, contemporary PAD research remains limited due to poor accuracy of diagnosis codes in the electronic health record (EHR). We previously developed and validated a novel natural language processing (NLP) algorithm that can extract ankle brachial index (ABI) and toe-brachial index (TBI) values from clinical documents and identify patients with PAD with high accuracy (positive predictive value 92.4%). Purpose Scale the NLP system for developing a nationwide registry of PAD in the Veterans Health Administration (VHA), the largest integrated health system in the U.S. that provides care to ~9 million Veterans across 130 sites. Describe the baseline characteristics and mortality outcomes among participants and identify predictors of long-term mortality. Methods A total of 1,182,025 documents from vascular and radiology procedures during 2013-2020 were processed by the NLP system. After excluding non-ABI vascular studies, patients with a known diagnosis of PAD prior to 2015, patients younger than 40 years of age, and those who do not regularly follow-up in the VHA, we identified 107,711 patients with newly diagnosed PAD during 2015-2020. Patients were followed longitudinally using the VA’s electronic health record data. The primary outcome was all-cause mortality. We used Cox proportional hazards regression to examine predictors of long-term mortality. Results The mean age was 70.5 years; 97.3% were males, and 18.5% were of Black race. The mean ABI value was 0.78 (SD: 0.26) and the mean TBI value was 0.51 (SD: 0.19). There was a high prevalence of hypertension (83.6%), heart failure (20.8%), diabetes (53.6%), renal failure (22.1%) and chronic obstructive pulmonary disease (32.4%, Table 1). At 1-year, 9.6% of patients had died and this proportion increased to 25.4% at 3 years. Although nearly all patient variables were significantly associated with mortality, older age, severe PAD at diagnosis, diabetes, heart failure, renal failure and COPD were the strongest predictors of long-term mortality. Black race was associated with lower hazard of long-term mortality. Conclusions Using a previously validated novel NLP algorithm that extracts ABI and TBI values from clinical documents, we have successfully developed a registry of newly diagnosed PAD in the VHA. Ongoing studies from our cohort will yield important insights into the association between clinical management of PAD and clinical outcomes, with the goal of identifying opportunities for improving care.

Improved prognosis prediction of idiopathic pulmonary arterial hypertension using targeted plasma proteomics in disease management

Abstract Background Idiopathic pulmonary arterial hypertension (IPAH), a special subgroup of PAH with unclear etiology, is characterized by rapid progression and poor prognosis underscoring the need for optimization of IPAH management and the accurate prediction of prognosis. However, it is disappointing that specific plasma biomarkers for IPAH management and prognosis are lacking in clinical practice. Up to date, the plasma biomarkers used for assessment of IPAH severity and prognosis are relied solely on indicators such as N-terminal prohormone of brain natriuretic peptide, or brain natriuretic peptide, which could reflect cardiac function but fail to promptly response to the dynamic change of disease condition due to the complexity of IPAH pathogenesis. Purpose We evaluated the prognostic value of plasma proteins in addition to current clinical predictors for prognosis prediction of IPAH. Methods Olink Immune-Response panel was used to measure 92 plasma proteins in a prospective IPAH cohort with 169 patients and a mean follow-up period of 2.4 ± 0.9 years. Six machine learning methods were used to construct predictive models, including plasma proteins-based Olink models, clinical parameters-based clinical models, and integrative models. Results A total of 18 proteins showed differential expression between patients with or without adverse clinical outcomes. Three proteins (STC1, CXADR, and IL6) were strongly correlated with clinical indicators of IPAH severity and their concentrations showed upward trends along with increased risk stratification. Elevated levels of STC1, CXADR, and IL6 are all associated with an increased risk of adverse clinical events, indicated by survival analysis, restricted cubic splines, and multivariable Cox regression analysis (STC1 HR=3.474, 95%CI: 1.129-10.692, P=0.030; CXADR: HR=1.602, 95%CI: 1.074-2.387, P=0.021; IL6: HR=1.883, 95%CI: 1.376-2.576, P<0.001). The inclusion of these three proteins into the predictive model could significantly increase the predictive power on the basis of the clinical model (AUC: 0.746 vs 0.626). Conclusions High levels of STC1, CXADR, and IL6 in plasma were associated with severe clinical phenotype and increased risk of adverse clinical events in patients with IPAH. These plasma proteins could significantly improve the prognostic performance of pre-existing clinical models, facilitating the clinical management of IPAH patients.The predictive efficient of models

Increased adoption of IL-1 pathway inhibition and the steroid-sparing paradigm shift: temporal trends in recurrent pericarditis treatment from the RESONANCE patient registry

Abstract Background Recurrent pericarditis (RP) is a chronic autoinflammatory disease mediated by IL-1 that requires long-term treatment. While the 2015 European Society of Cardiology Guidelines position IL-1 pathway inhibition only after corticosteroids, complications associated with long-term steroid use underscore the importance of steroid-sparing strategies. Rilonacept, an IL-1α and IL-1β cytokine trap, is the only FDA-approved treatment for RP (available since April 2021). RESONANCE, an ongoing 5-year non-interventional US registry of patients (pts) with RP, has collected real-world data from pts cared for by cardiologists with a focus on pericardial disease, with a goal of informing contemporary RP clinical management. Purpose Analysis of temporal trends in RP management from RESONANCE. Methods From a database cut-off (DCO) on 21 December 2023, patient demographics and disease characteristics are reported for 242 active RP pts (excluding RHAPSODY prior participants) at 20 US sites (median [Q1:Q3] 2.1 [1.5:2.6] years and 556 patient-years [PY] of observation). Complete medication class use data were available for 239 pts (total 546 PY). Proportional medication class use prior to initiating rilonacept was analyzed annually across the observation period. Results Mean (standard deviation) age at DCO was 50.2 (16.6) years; 58.1% were female. Median [Q1:Q3] disease duration at DCO from index pericarditis episode was 3.1 [2.2:5] years. Median [Q1:Q3] number of prior recurrences at enrollment was 3 [2:5]. Prior to rilonacept availability, NSAIDs/Colchicine/Aspirin represented the highest proportion of treatment (73% of PY); steroid use was 9% of PY, IL-1 pathway inhibition (anakinra) was 13% of PY, and conventional synthetic disease modifying antirheumatic drugs (csDMARDs) were 0.46% PY (no RP-specific treatment was 5% of PY) (Fig 1). In the years since rilonacept availability, proportional IL-1 pathway inhibition use has increased, from 13% of PY in 2020-21 to 26% of PY in 2023, driven by an increase in rilonacept use (6%, 13%, 16% of PY in 2021, 2022, and 2023, respectively). Over that same period, proportional NSAIDs/Colchicine/Aspirin use (57%-63% of PY) has been consistently 6-times more than proportional steroid use (10%-11% of PY). Among pts who initiated rilonacept (n=81), similar proportions transitioned from NSAIDs/Colchicine/Aspirin as from corticosteroids (Fig 2), a robust trend observed each year. Of those pts transitioning from corticosteroids, 1/3 had used corticosteroids for <30 days and 1/3 for >6 months. Conclusions Real-world data from the RESONANCE registry reveal a temporal shift in RP management in US centers with RP-focused cardiologists, with increased proportional IL-1 pathway inhibition use since rilonacept availability in 2021. Advancing beyond 2015 guideline recommendations, IL-1 pathway inhibition is often being used as steroid-sparing treatment, i.e., after colchicine instead of chronic corticosteroids.

The admission inflammatory biomarkers profile of elderly hip fractures and its association with one-year walking independence and mortality: a prospective study.

Immune response plays an important role in the regulation of elderly hip fracture. This study aims to analyze the relationship between systemic inflammatory markers including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), systemic immune-inflammation index (SII), and systemic inflammation response index (SIRI) and mortality and walking independence, providing valuable references for the postoperative management of geriatric hip fracture. A retrospective analysis of prospective data on elderly patients who have undergone hip surgery and have been followed for at least one year. The receiver operating characteristic (ROC) curves and the optimum cutoff value were calculated. Univariate analysis and multivariate logistic regression analysis were used to identify the associations between admission four systemic inflammatory markers and one-year mortality and locomotion recovery. During the study period, respiratory disease was the most common cause of death, followed by cardiovascular disease. Multivariate analysis identified NLR (OR, 1.13; 95%CI: 1.09-1.17), SIRI(OR, 1.18; 95%CI: 1.08-1.28) and advanced age (OR, 1.06; 95%CI: 1.01-1.11) as independent risk factors for one-year mortality. In addition, 89 (rate, 31.8%) survivors had poor walking independence within one year. NLR (OR, 1.37; 95%CI: 1.26-1.50), SII(OR, 1.00; 95%CI: 1.001-1.003), SIRI(OR, 1.36; 95%CI: 1.18-1.57) and advanced age (OR, 1.08; 95%CI: 1.02-1.13) were associated with postoperative locomotion recovery. In summary, admission NLR and SIRI are correlated with a high risk of one-year walking independence and mortality, providing a basis for the clinical management of geriatric hip fractures.

Association of cardiac amyloidosis with cardiovascular outcomes after aortic valve replacement in patients with severe aortic stenosis: a systematic review and meta-analysis

Abstract Introduction Aortic stenosis (AS) and cardiac amyloidosis (CA) frequently coexist and is commonly observed in older individuals referred for aortic valve replacement (AVR). However, the association of CA with adverse outcomes after AVR has not been well established. Purpose This meta-analysis aimed to evaluate the association of CA with adverse cardiovascular outcomes in patients with severe AS after undergoing AVR. Methods A literature search was performed for studies evaluating patients with severe AS undergoing AVR, comparing clinical endpoints on follow-up for patients with and without CA. The clinical endpoints included all-cause mortality and heart failure (HF) hospitalization. Databases searched included Ovid MEDLINE, Embase, and Web of Science. Subgroup analysis was performed for short term (<30 days) and long term (>30 days) mortality. The search was not restricted to time or publication status. Results Five studies including 1,105 patients with severe AS (111 with concurrent CA, 904 without CA) met inclusion criteria. The mean follow-up duration was 24.6 months, mean age was 81.2 years and 55.4% were men. Mean echocardiographic aortic valve parameters included valve area of 0.715cm2, mean gradient of 41.8 mmHg, and peak velocity of 4.2m/s. The mean left ventricular ejection fraction was 58%. All except 1 study included only patients with ATTR CA while excluding other causes of CA. There was no statistically significant difference in all-cause mortality between patients with and without CA following AVR, both in short-term (OR 0.94; 95% CI 0.17-5.31; p=0.95) and long-term (OR 1.72; 95% CI 0.75-3.91; p=0.20) follow-up. However, patients without CA demonstrated a significantly lower risk of heart failure hospitalization post-AVR compared to those with CA (OR 2.49; 95% CI 1.18–5.23; p = 0.02). Conclusion In the context of patients with severe AS undergoing AVR, the presence of CA does not appear to significantly impact short-term or long-term all-cause mortality. Notably, patients without CA exhibited a lower risk of heart failure hospitalization following AVR. These findings underscore the importance of considering cardiac amyloidosis in the clinical management of severe AS and highlight potential differences in outcomes based on its presence or absence. Additional studies are needed to elucidate outcome differences for CA patients who undergo surgical versus transcatheter AVR.Figure 1

Lesion-like effect of gliosis secondary to deep brain stimulation electrode infection: illustrative case.

Deep brain stimulation (DBS) is commonly used to treat Parkinson's disease (PD) and other movement disorders when other treatments fail. Although DBS can significantly improve motor symptoms, it carries risks such as infections, which can require multiple surgeries and prolonged antibiotic therapy. Research on the long-term neurological effects of DBS-related infections is limited. A 58-year-old man with a 13-year history of PD, refractory to optimized clinical management, underwent subthalamic nucleus (STN) DBS after previous contralateral lesioning of the posterior subthalamic area. Postoperatively, the DBS lead migrated upward and was repositioned, but he developed perielectrode cerebritis 5 days later. The DBS system was completely removed, and he underwent a 28-day course of intravenous antibiotics. Initially, his motor symptoms remained unchanged, but 4 months later, he experienced a significant and sustained motor symptom improvement that continued until the last follow-up assessment (40 months). Magnetic resonance imaging performed 2 years after the explantation showed gliosis and hemosiderin deposition in the STN, suggesting that the infection-induced gliosis had a lesion-like effect, leading to the observed clinical improvement. This case suggests that infection-induced gliosis from DBS complications can unexpectedly result in long-term motor symptom improvements, potentially influencing future management strategies for similar cases. https://thejns.org/doi/10.3171/CASE24502.

Clinical coordination in cancer diagnosis: healthcare stakeholders’ viewpoints in Latin America

Abstract Background Delays in diagnosis contribute to increasing cancer mortality rates in Latin American countries due to, among others, highly fragmented healthcare systems. The objective of this study, part of a larger research project (EquityCancer-LA), was to analyze cross-level coordination during cancer diagnosis and factors influencing it from healthcare stakeholders’ perspectives in Chile, Colombia, and Ecuador. Methods This descriptive-interpretative qualitative study was based on 114 semi-structured individual interviews in 2022-23 using a criterion sample of health professionals from primary care (PC) (n = 40) and secondary care (SC) (n = 44) as well as managers and policy makers (n = 30) from two public healthcare networks in each country. Sample reached saturation. A thematic analysis was conducted first by country and then comparatively, guided by the theoretical framework of clinical coordination. Results In all countries, informants highlighted limited cross-level exchange of information and limited coordination of clinical management, delays in referral, and long waiting times after referral, leading to diagnostic delays. Factors hindering coordination differed across countries: structural (insufficient personnel, access to diagnostic tests in PC); organizational (limited/inadequate coordination mechanisms, e.g. shared clinical records; poor working conditions); and health professional characteristics (limited knowledge and skills among PC doctors). Direct feedback was emphasized to facilitate coordination of cancer diagnosis: virtual joint clinical conferences in Chile, co-location of PC and SC in Colombia, and informal networks (based on personal contacts) in Ecuador. Conclusions The findings underscore the critical coordination problems contributing to delays in cancer diagnosis. Addressing these challenges requires strategic interventions aimed at strengthening primary care and fostering cross-level coordination. Key messages • Cancer diagnosis in Latin America suffers from coordination deficits due to structural, organizational, and professional factors. • Strengthening primary care and cross-level coordination is needed.

Association of PCSK6 rs1531817(C/A) polymorphism with the prognosis and coronary stenosis in premature myocardial infarction patients: a prospective cohort study

Abstract Background An increasing proportion of younger patients are currently hospitalized for acute myocardial infarction. Exploring the factors affecting coronary artery lesions and prognosis in patients with premature myocardial infarction (PMI) from a genetic perspective is of great significance to clinical management. Proprotein convertase subtilisins/kexins 6(PCSK6), a member of the PCSK family, functions in protein hydrolytic cleavage. It has been shown that PCSK6 polymorphisms are associated with carotid atherosclerosis. Purpose This research intended to evaluate the relationship between the PCSK6 rs1531817 polymorphism and the prognosis of PMI patients and their coronary stenosis. Methods This study was a prospective cohort study, which consecutively included 605 patients with PMI who underwent emergency PCI from January 2017 to August 2022 at X Hospital. Using the Massarray technique, the single nucleotide polymorphisms(SNPs) of PCSK6 rs1531817 were identified, and the patients underwent follow-up for 12 to 72 months, with major adverse cardiovascular events (MACEs) as the outcome. Analyze the relationship between patients' SNPs, Gensini score(GS), Triple vessel diseases(TVD), and MACEs. Results In PMI patients with PCSK6 rs1531817 CA+AA genotypes, ApoA1/ApoB levels were higher than in patients with CC genotype, and TC/HDL levels were lower (p < 0.05). Logistic regression analysis showed that the PCSK6 rs1531817 polymorphism (Dominant model: CA+AA vs.CC) was significantly correlated with the GS (high vs. low GS, adjOR=0.297, 95%CI:0.139-0.632, p=0.002; high vs. medium GS, adjOR=0.449, 95%CI:0.211-0.956, p=0.038), and it was correlated with the number of coronary artery lesions (TVD vs. SVD, adjOR=0.420, 95%CI:0.226-0.782, p=0.006; TVD vs. DVD, adjOR=0.406, 95%CI:0.214-0.773, p=0.006). According to multivariate Cox regression analysis, the PCSK6 rs1531817 dominant model was associated with the MACEs in PMI patients (adjHR=0.454, 95%CI:0.269-0.766, p=0.003). The mediation effect results showed that ApoA1/ApoB played a partially mediating role in the association between PCSK6 rs1531817 polymorphism and the severity of coronary stenosis (the effect leading to high GS and TVD accounted for 14.6% and 8.3% respectively), TC/HDL and TVD partially parallel mediated the association between PCSK6 rs1531817 polymorphism and MACEs (effect proportions were 8.1% and 17.1%, respectively). Conclusion Carrying the PCSK6 rs1531817 mutant A allele is an independent protective predictor of severe coronary stenosis and long-term prognosis in patients with PMI. Patients with the PCSK6 CA+AA genotypes have milder coronary stenosis partially because they have higher levels of ApoA1/ApoB; in addition, these patients have a better long-term prognosis partially because they have lower TC/HDL levels and fewer TVD patients.Figure 1.ApoA1/ApoB and TC/HDL were compareFigure 2.Correlation of PCSK6 rs1531817 pol

A practical nomogram and risk stratification system for predicting in-hospital mortality of patients with non-acute myocardial infarction related cardiogenic shock

Abstract Background The morbidity and mortality of Cardiogenic Shock(CS) remain high despite the advance in management these years1.As acute myocardial infarction (AMI) is considered to be the most common reason for cardiogenic shock,Non-AMI related CS is excluded from the majority of CS studies and remains largely understudied2. Considering its inherent complexity and hemodynamically multiplicity, it is needed to focusing on these patients to identify specific risk factors, which may be conducive to the promotion of critically CS patients with early decision and timely intervention. Purpose In this study,we sought to investigate the variables which are predictive of in hospital mortality in non AMI related CS patients, developed and validated a practical nomogram for risk quantification. Methods 1298 patients and 548 patients with cardiogenic shock from the MIMIC-IV (version 1.0) and MIMIC-III(version1.4) databaes were included in the study after excluding acute myocardial infarction. We used in-hospital death and 30 day survival as the end points. Lasson and logistic regression analysis were used to identify statistically significant predictors which were finally involved in the nomogram. The predictive performance of the nomogram was evaluated by Harrell’s concordance index (C-index) and calibration after comparing with commonly used ICU scores for in-hospital death.Lastly, we plotted Kaplan-Meier curves of three subgroup classified by the identified cutoff values of the nomogram to further assess the discriminative ability of the prognosis. Results The in-hospital mortality of patients with non-AMI related CS is about 36.6%.After the analysis of regression, age, heart rate, wbc, albumin, lactic acid, GCS score, urine volume, using vasopressor were identified as the most critical factors for the in-hospital death. Based on the these results, a nomogram for predicting in-hospital death was established.The calibration plot also shows good consistency between nomogram prediction and actual in-hospital mortality.In addition, compared with other scores, the AUC value of nomogram was 0.806 (95% CI = 0.799-0.831) in the training queue, 0.814 (95% CI = 0.771-0.852) in the internal validation queue and 0.730 (95% CI = 0.690-0.767) in the external validation set, which was significantly higher than other commonly used ICU scoring systems(SAPSII, APSIII and SOFA).Also, three risk subgroups were created using two boundary points (303 and 339) of the nomogram score and the survival curve shows that there were significant differences in the 30 day survival of each subgroup. Conclusion A prognostic nomogram and risk stratification system of non-AMI related CS were established and verified, which can provide a practical tool for individualized clinical management of patients.Workflow of the study.Nomogram for non-AMI related CS patients

Genotype predicts heart failure independent of left ventricular ejection fraction and NT-proBNP levels in hypertrophic cardiomyopathy

Abstract Background/Introduction Hypertrophic cardiomyopathy (HCM) is a myocardial disease associated with progression to heart failure. In around 40% of cases, the disease is caused by variants in genes encoding sarcomere proteins. Purpose To evaluate the role of genotype in predicting heart failure (HF) outcomes. Methods In this observational single-centre cohort study, consecutive patients with HCM were assessed for heart failure clinically stratified by genetic status into genotype-elusive which included those with no significant variants (G-) or variants of unknown significance (VUS) and genotype-positive (G+) with pathogenic/likely pathogenic (LP/P) variants. Heart failure endpoint was defined as left ventricular assist device implantation, heart transplantation or heart-failure-related death. The incidence of HF endpoint was compared between genotypes during follow-up using a time-to-event analysis. Results 474 patients (50.9 ±14.5 years, 67.3 males) with HCM (25% with left ventricular (LV) outflow obstruction) were followed for 10.9 years (IQR 5.1-13.5). G+ LP/P patients (201/474 (42.4%)) were younger (45.8. ±14.0 years) compared to G- (225/474 (47.5%), 55.2 ±13.4 years) and VUS (48/474 (10.1%), 52.0 ± 15 years); 29/474 (6.1%) reached the heart failure endpoint. The incidence of heart failure endpoints was 12.4% (25/201) in the G+ LP/P group compared to 1.5% (4/273) in the gene elusive group. A multivariate Cox proportional hazards model including NT-proBNP and LV ejection fraction (LVEF) and genetic status showed that G+ LP/P was associated with increased risk of heart failure outcomes (HR: 5.11, 95% CI: 1.43–18.25, p=0.012). Every 100-unit rise in NT-proBNP was associated with a 41% increase in risk (HR: 1.41, 95% CI: 1.20–1.66, p<0.0001). A one-unit (1%) reduction in LVEF correlated with a 10% increase in heart failure risk (HR: -0.90, 95% CI: 0.87–0.93, p<0.0001). Conclusion(s) Genetic status is a predictor of heart failure outcomes independent of LVEF and NT-proBNP levels in HCM. This underscores the importance of genetic testing in the clinical management of HCM.

Utilizing cluster analysis of biomarkers alongside echocardiographic deformation parameters to forecast the outcome of atrial fibrillation post-ablation

Abstract Background Atrial fibrillation (AF) management often involves catheter ablation, but its recurrence necessitates careful clinical management and potential adjustments in medication or further ablation procedures. This study aims to investigate the predictive value of biomarkers and echocardiographic parameters for early AF recurrence. Methods In the prospective study, we enrolled patients with symptomatic paroxysmal or persistent atrial fibrillation undergoing catheter ablation. Pulmonary vein isolation was performed in every index procedure, with additional ablation or substrate modification as per physician preference. Blood samples were collected from both the atrium and peripheral vein to assess levels of tumor endothelial marker 1 (TEM1), galectin 3, connective tissue growth factor (CTGF), transforming growth factor-beta (TGF-β), C-terminal propeptide of procollagen type I (PICP), and Smad3. Pre-procedural echocardiographic parameters, including the E/e’ ratio, peak atrial longitudinal strain (PALS), and peak atrial contractile strain (PACS), were recorded. Clustering models with sparse canonical association analysis (CCA) were employed to develop predictive models integrating biomarker and echocardiographic data for early atrial fibrillation recurrence. Results Out of 80 prospectively enrolled patients, 68 completed the study, with six cases of early atrial fibrillation recurrence observed. Following dimension reduction and clustering, we found that the combined use of biomarkers and echocardiography significantly predicted atrial fibrillation recurrence (HR: 9.44, p=0.05, 95% CI: 1.0-88.9). Notably, among these parameters, TEM1 biomarker sampled from the peripheral vein (p=0.02), left atrium dimension (p=0.07), and left ventricle dimension (p=0.02) exhibited the most significant predictive power. Conclusions Our study highlights the effectiveness of integrating biomarkers and echocardiography parameters in predicting early recurrence of atrial fibrillation post-ablation in patients undergoing catheter ablation.main_figure