Long-term Failure Research Articles

Immunosuppressant nonadherence profile in kidney transplant recipients and the impact of medication adherence on transplant outcomes

BackgroundDespite the fact that 1-year graft and recipient survival rates are above 90% in most transplant centers, improving long-term graft survival remains an important challenge. Immunosuppressant nonadherence has been recognized as one of the important risk factors for long-term graft failure. Understanding the modifiable correlates and risk factors for medication non-adherence is essential to develop interventions to improve adherence and thus long-term transplantation outcomes.MethodsThis study conducted a questionnaire survey on 431 renal transplant recipients who were followed up in the outpatient clinic between January 2022 and January 2023, and 409 valid questionnaires were returned. The BAASIS questionnaire was used to assess the prevalence of nonadherence to immunosuppressive therapy (implementation phase) in Chinese renal transplant recipients and to explore the multilevel correlates of immunosuppressive nonadherence. The BAASIS questionnaire was used to categorize renal transplant recipients into adherent (n = 239) and non-adherent (n = 170) groups, and a prospective cohort study with a 1-year follow-up was conducted to explore the impact of immunosuppressant non-adherence on clinical outcomes.ResultsThe prevalence of nonadherence to immunosuppressant therapy in renal transplant recipients in this study was as high as 41.6%. The number of years post-transplant (OR: 1.240, 95% CI: 1.136–1.353, p < 0.001) and the frequency of twice-daily dosing (OR: 5.145, 95% CI: 2.690–9.840, p < 0.001) were positively correlated with immunosuppressive nonadherence. There was a significant difference in TAC IPV (Intra-individual Variability) between the adherent and nonadherent groups (22.7 ± 8.7 vs. 25.4 ± 11.6, p = 0.010). Renal function remained stable during the follow-up period in the recipients in the adherence group and tended to decrease in the recipients in the non-adherence group (F = 4.932, p = 0.001). The rates of graft loss (7.1% vs. 1.7%, p = 0.006) and rejection (12.4% vs. 4.2%, p = 0.002) were higher in the nonadherent group than in the adherent group.ConclusionLonger time post-transplant and higher frequency of immunosuppressive dosing were positively associated with nonadherence to immunosuppressives medication. Immunosuppressant nonadherence was associated with adverse graft outcomes.

Percutaneous versus surgical catheter insertion for peritoneal dialysis: a systematic review and meta-analysis of randomized controlled trials.

Peritoneal dialysis (PD) is used as a kidney replacement therapy for patients with kidney failure. Institutional practices vary considerably, and the optimal technique for insertion of PD catheters is unknown. This study compared the efficacy and safety of surgical versus percutaneous approaches to PD catheter insertion for patients with end-stage kidney disease. Electronic databases (MEDLINE, Embase, CENTRAL) were systematically searched and analysed for relevant randomized controlled trials (RCTs). Eligible RCTs for inclusion were those that compared surgical versus percutaneous approaches to catheter insertion for patients undergoing PD dialysis. Outcomes of interest were patient- and catheter-related complications. In this study risk of bias was assessed using the Cochrane Risk of Bias Tool for RCTs. The certainty of the evidence was evaluated using the Grading of Recommendations Assessment and Evaluation (GRADE) approach. Four studies (397 participants) were included. With regards to surgical approaches, only one study evaluated laparoscopic insertion; all other studies reported on open surgical techniques. Percutaneous insertion techniques varied significantly between the studies. No difference in patient mortality was found (RR = 0.82, 95% CI = 0.43-1.57, I2 = 0%). Percutaneous techniques were associated with lower rates of early peritonitis (RR = 0.34, 95% CI = 0.12-0.91, I2 = 0%) and long-term catheter failure (RR = 0.69, 95% CI = 0.47-1.00, I2 = 0%) than surgical approaches. Percutaneous catheter insertion was also associated with reduced late peri-catheter leak rates (RR = 0.35, 95% CI = 0.12-0.98, I2 = 0%) and peri-procedural complications (RR = 0.25, 95% CI = 0.07-0.90, I2 = 0%). The overall risk of bias was moderate, and certainty of evidence was low or very low. Whilst percutaneous PD insertion techniques may have lower early and late complications compared to surgical technique, there was a lack of high-quality evidence comparing outcomes between contemporary percutaneous and surgical PD catheter insertion techniques. Future RCTs are required to compare the safety and efficacy of modern percutaneous with laparoscopic techniques.

Moisture dependent bending mechanical properties of Chinese fir

ABSTRACT Predicting the long-term deformation and failure of wood under varying environmental conditions is challenging due to the complex rheological behaviour of wood. In this study, the bending failure mechanism and moisture-dependent viscoelastic creep behaviours of Chinese fir (Cunninghamia lanceolata [Lamb.] Hook.) were explored. The digital image correlation technique was used to monitor strain field changes during the bending process. The results revealed that wood in a dry state was more brittle than in a moist state. Strain field variations showed that the tensile load on the tension side primarily governs bending failure. There are distinct differences between tension and compression regions by fracture morphology analysis. The study further developed the time-moisture-stress superposition principle to integrate the effects of time, moisture, and stress on wood's creep behaviour in bending. These findings provide critical insights into how moisture affects wood’s mechanical behaviour, guiding more efficient design and manufacturing practices for long-term structural performance in the timber-construction industry.

Anterior Cruciate Ligament Reconstruction in Patients Older Than 50 Years: A Descriptive Study With Minimum 10-Year Follow-up

Background: Anterior cruciate ligament (ACL) reconstruction is increasingly being performed in patients >50 years old; however, the long-term outcomes are unclear. Purpose: To analyze the functional results, osteoarthritic progression, reoperation rate, and failure rate at minimum 10-year follow-up in patients >50 years old who have undergone primary ACL reconstruction. Study Design: Case series; Level of evidence, 4. Methods: Included in this study were patients >50 years old who underwent primary ACL reconstruction and had at least 10 years of follow-up data. All patients had instability with limitation of their activities, indicating the necessity of surgical intervention. Patients with revision surgeries, ACL repairs, and nonoperative treatment were excluded. Failure was defined as the presence of revision, high-grade Lachman, positive pivot shift (2+), or subjective instability. The Knee injury and Osteoarthritis Outcome Score (KOOS), subjective and objective functional scores, and osteoarthritic progression were analyzed at final follow-up. Results: A total of 38 patients were identified. The mean age at surgery was 56.8 ± 5.7 years (range, 50.6-70 years). The mean clinical follow-up was 16.2 ± 4.3 years (range, 10.9-23.3 years). The failure rate was 10.5% (4/38): 1 of the 4 patients had a recurrence of instability at 13 years postoperatively and underwent revision with a modified Lemaire extra-articular tenodesis, 1 patient had a positive pivot shift (2+) without subjective instability, and 2 patients underwent total knee arthroplasty. The overall KOOS was 74.2 ± 22.2, and 91.4% of patients were satisfied or very satisfied with the results of the procedure. Radiographic osteoarthritis was identified in 88.5% of patients at final follow-up; however, there was no statistical significance on clinical outcomes ( P > .05). Concomitant partial medial meniscectomy ( P < .01) and meniscal repair ( P < .01) were associated with the presence of Ahlbäck grade 3 or 4 osteoarthritic manifestations. Conclusion: In patients over the age of 50 years who underwent primary ACL reconstruction, there was a low long-term failure rate and a high level of patient satisfaction, despite osteoarthritic progression in 88.5% of cases. Concomitant meniscal procedures were associated with more severe osteoarthritic progression.

Transplant-associated TMA: the conundrum of diagnosis and treatment.

Transplant-associated thrombotic microangiopathy (TA-TMA) after hematopoietic cell transplantation is characterized by microangiopathic hemolytic anemia (MAHA) with persistent schistocytosis, elevated markers of hemolysis, thrombocytopenia, and microvascular thrombosis leading to ischemic injuries in the kidneys and other organs. The initial evaluation of the disease requires confirmation of non-immune MAHA and careful examination of known secondary causes of TMA. Due to increased likelihood of long-term renal failure and overall mortality, a rapid diagnosis and treatment of the underlying trigger is needed. However, the diagnostic criteria proposed to define TA-TMA remain insufficient. sC5b9, the soluble form of the membrane attack complex of the terminal complement pathway, is the most studied prognostic biomarker for the disease, though its sensitivity and specificity remain suboptimal for clinical use. Current evidence does not support the cessation of calcineurin inhibitors without cause or the use of therapeutic plasma exchange. Many recent single-arm studies targeting the complement pathway inhibition have been reported, and larger randomized controlled trials are ongoing. This review aims to provide an evidence-based discussion from both adult and pediatric perspectives on the advances and conundrums in TA-TMA diagnosis and treatment.

Bariatric Surgery in Adolescent Age Group

Obesity in children is a problematic condition which interfere with physical and mental health. It is a complicated disorder with interwoven environmental, genetic, biological components, developmental, and behavioral. A combination of medical treatment and behavioral and lifestyle modifications was typically what causes poor short-term weight loss and long-term failure. For this reason, adolescents who suffer from moderate to severe obesity and have attempted lifestyle interventions in the past but had no success should think about having bariatric surgery. Specifically, laparoscopic sleeve gastrectomy is thought to be the most often carried out bariatric procedure globally. The technique is safe and doable. It has been demonstrated that this surgical weight loss procedure is effective in young patients. However, there are obstacles that need to be removed at the levels of patients, providers, and the healthcare system. Above all, for ensuring successful long-term treatment and permit healthy growth, more should be done to stop the nutritional status decline that frequently follows bariatric surgery, as well as to prevent insufficient weight loss and weight regain. With a focus on LSG, nutritional management, and the resolution of metabolic comorbidities, we examined the clinical indications, surgical treatment options, and outcomes in adolescents with severe obesity in this narrative review.

Surrogate Endpoints in APOL1-Associated Kidney Disease: Evaluation in Three Cohorts.

Surrogate endpoints for the clinical outcome of kidney failure have been accepted by the United States Food and Drug Administration. However, they have not been specifically evaluated in Apolipoprotein L1 (APOL1)-associated kidney disease. This random-effects meta-analysis included African-American participants in the Atherosclerosis Risk in Communities (ARIC) study (N=3071), the Chronic Renal Insufficiency Cohort (CRIC; N=998), and the African American Study of Kidney Disease and Hypertension (AASK; N=609). Surrogate endpoints included three-year 30% and 40% decline in glomerular filtration rate (GFR), doubling of urine protein-to-creatinine ratio (UPCR), and >3 ml/min/1.73 m2 per year decline in GFR. Clinical outcomes included kidney failure requiring kidney replacement therapy, heart failure, cardiovascular disease, and death after three years.Results: 22% in AASK, 18% in CRIC, and 13% in ARIC had the APOL1 high risk genotype. Participants with the APOL1 high-risk genotype had higher risk of all three-year GFR outcomes but not doubling of UPCR, as well as kidney failure after three years. The three-year outcomes were strongly associated with kidney failure, with weaker but statistically significant associations with the development of heart failure, cardiovascular disease, and mortality. There were no differences in associations between short-term and long-term clinical outcomes by APOL1 risk status. Individuals with the APOL1 high risk genotype were more susceptible to three-year GFR-related endpoints and long-term kidney failure than individuals with the APOL1 low-risk genotype. There was no consistent difference in short-term-clinical outcome associations by APOL1 genotype, supporting the use of surrogates in APOL1-associated kidney disease.

Anterior Cruciate Ligament Reconstruction With The Rectus Femoris Autograft – Results From The First 80 Patients

Objectives To report on the clinical outcomes and complications following anterior cruciate ligament (ACL) reconstruction using a novel rectus femoris autograft, including its clinical efficacy and safety. Methods Retrospective case series of patients undergoing isolated primary anatomic ACL reconstruction, with an outside-in technique, using a novel a rectus femoris autograft. Non-inclusion criteria consisted of partial tears; prior ipsilateral knee surgery; concomitant ligament, meniscus or cartilage procedures; follow-up shorter than 6 months. The primary clinical outcome measure was Lysholm score, including the percentage of patients achieving a previously published patient acceptable symptom state (PASS). Secondary outcomes included the observed rates for complications, as well as graft failure rate. Results 80 patients (53% male; mean age 28.95 ± 8,04 years) were included, with a mean follow up of 18.03 months (± 6,94; min 6, max 28). The mean postoperative Lysholm was 97.08 (± 2.63; min 90, max 100), with 100% of patients achieving PASS. There were three instances of graft amputation during harvest (3/83 = 3.61%), all of which occurred within the first 10 cases. An overall post-operative complication rate of 6.25% was observed, with 4 instances of hematoma at the graft harvest site (4/80 = 5%), one infection (1/80 = 1.25%) and no instances of graft failure (0/80 = 0%) at final follow-up. Conclusion The rectus femoris autograft is a suitable graft option for ACL reconstruction, with demonstrated clinical efficacy and safety in this initial case series. Potential benefits include a minimally invasive harvest technique without the need for additional instruments, and an observed length of around 30cm, which can be tailored to multiligament or revision cases. Longer follow-up and comparative studies are needed in the future in order to assess the long-term efficacy and failure rates.

Comparative analysis of post-PCI fractional flow reserve and quantitative flow ratio in predicting long-term Target Vessel Failure and hard endpoints

Abstract Background The role of functional assessment after angiographically acceptable post-PCI result is debatable. Purpose We sought to investigate the correlation between Fractional Flow Reserve measured directly after drug eluting stent (DES) implantation (post-PCI FFR) and post-PCI Quantitative Flow Ratio (post-PCI QFR), clarify their relationship with clinical parameters, and long-term target vessel failure (TVF: cardiac death (CD), non-fatal target vessel myocardial infarction (MI) and target vessel revascularisation (TVR)), and a composite of CD and MI (CD/MI). Method Coronary arteries that underwent post-PCI FFR measurement at our centre between 2012 and January 2021 were consecutively included in this registry. Post-PCI QFR was calculated blinded to the post-PCI FFR value. We analysed the influence of LAD vs. (non-LAD) location, gender, age, hypertension, diabetes mellitus, hyperlipidemia, indication (acute (ACS) vs. chronic coronary syndrome), stent diameter, in-stent restenosis (ISR) vs. de novo lesion category, estimated glomerular filtration rate, proximal vs. distal lesions, severe aortic stenosis, atrial fibrillation during the procedure (AF), and prior myocardial infarction in the supply area (prior MI) on post-PCI FFR and QFR. Optimal cut-off was determined by ROC curves. Results A total of 400 coronary arteries were analysed. LAD location (p<0.001), male gender (p=0.0029) and smaller stent diameter (p=0.0073) proved to be predictors of a lower post-PCI FFR. LAD location (p=0.001), ISR (p=0.02), distal location (p=0.0019), AF (p=0.042) and prior MI (p=0.029) were predictors of a lower post-PCI QFR. There was a systematic bias in post-PCI QFR compared to post-PCI FFR (bias 0.0614, 95% CI, 0.053 - 0.069). During a median follow-up of 45 months, 31 CD, 20 MI and 35 TVR occurred. Follow-up was complete in 100%. There was a significant inverse correlation between post-PCI FFR and TVF (p<0.001) as well as between post-PCI QFR and TVF (p=0.045). In-stent restenosis (p=0.014) and prior MI (p=0.002) were also predictors of higher TVF rate. The predictors of CD/MI were lower post-PCI FFR (p<0.001), smaller stent diameter (p=0.03), higher age (p=0.031) and ACS indication (p=0.048), whereas post-PCI QFR was not. The best post-PCI FFR cut-off to predict TVF was 0.87 (p<0.0001). There was no single optimal post-PCI QFR cut-off to predict TVF. Conclusion Post-PCI QFR shows a systematic bias compared to post-PCI FFR. Post-PCI FFR is a significant predictor of TVF as well as CD/MI, whereas post-PCI QFR predicts TVF. No significant correlation between post-PCI QFR and CD/MI could be demonstrated. Our findings underscore the importance of considering multiple clinical parameters in predicting long-term outcomes. The best post-PCI FFR cut-off to predict TVF was 0.87. However, there was no single, universally applicable post-PCI QFR threshold to predict TVF.

Long-term heart failure risk after atrial septal defect closure in elderly

Abstract Background There is concern that atrial septal defect (ASD) closure will unmask underlying diastolic dysfunction or left heart disease in elderly causing heart failure. It is controversial whether fenestrated devices should be used in elderly patients. Purpose To assess the long-term heart failure risk after ASD closure in elderly and risk factors associated with heart failure hospitalization in a single centre. Method From 2003-2023, all elderly patients aged more that 60 years old who had ASD closure performed successfully in this centre were retrospectively studied. Baseline demographics, underlying risk factors and survival without heart failure hospitalization were analyzed. Result From 2003-2023, 73 patients aged more than 60 years old underwent successful ASD closure in our centre. None of these patients had balloon occlusion test for assessment of left atrial pressure. Median age was 66 years old (60-84) at operation and 27 (37.0%) of them were male. Common risk factors included diabetes (n=9, 12.3%), hypertension (n=31, 42.5%) and ischaemic heart disease (n=8, 11%). Thirty-nine (53.4%) patients had pre-existing atrial fibrillation and 17 (23.3%) of them had moderate to severe left sided valvular lesions. Heart failure symptoms were present in 31 (42.5%) of them (Figure 1). During a median follow-up time of 4 years (1-15 years), 80.8% of patients did not experience heart failure hospitalization (Figure 2). Pre-existing atrial fibrillation and left-sided valvular lesions were associated with higher risk of heart failure hospitalization (OR 4.06, 95% CI 1.03-16.06 p=0.036 and OR 4.9, 95% CI 1.41-17.09 p=0.009). Conclusion In a median follow-up time of 4 years, patients aged more than 60 years old had low rate of heart failure hospitalization after ASD closure. Pre-existing atrial fibrillation and left-sided moderate to severe valvular lesions were associated with higher risk of heart failure admission. Further studies should be conducted on ASD closure in these group of patients.Figure 1Figure 2

Heart failure hospitalization reduction and long-term safety with remote pulmonary artery pressure monitoring: results of the CardioMEMS HF System OUS Post-Market Study

Abstract Background Heart failure (HF) is increasing in prevalence and is responsible for frequent hospitalization and readmissions, despite current guideline recommended therapies. Hemodynamic guided HF management using frequently remotely obtained pulmonary artery (PA) pressure information using a permanently implanted PA sensor (CardioMEMSTM HF System, Abbott) consistently reduced HF hospitalizations (HFH) in multiple healthcare settings. The safety and efficacy of the CardioMEMS HF System has been shown previously in several clinical studies, which reported significant reductions in HFH compared to a control (CHAMPION: 33%, 18M; GUIDE-HF: 28%, 1 yr; and MONITOR-HF: 44%, 1 yr) and longitudinally (MEMS-HF: 62%, 1 yr; and CardioMEMS US PAS: 57%, 1 yr) across varying health systems. Purpose The CardioMEMS HF System OUS Post-Market Study (COAST) aimed to evaluate the safety and effectiveness of hemodynamic guided HF management in patients with NYHA Class III HF in varying health systems across Europe and Australia. Methods COAST is a prospective, multi-centre, open-label clinical trial that consented 321 patients at 38 European and Australian centres. The primary endpoint is a combination of safety (freedom from DSRCs and freedom from pressure sensor failure at 2 years after implant) and efficacy endpoints (annualized HFH rate at 1-year vs the HFH rate in the year prior to enrolment). In this analysis we report these primary results of the study. Results Out of 321 consented patients, 17 subjects were withdrawn before implant, while the PA sensor was implanted successfully in 299 out of 304 patients who underwent the procedure (98.3% success rate). Seventy-three percent (73%) of the patients were male, the mean age was 68.4±11.7 years with ischemic cardiomyopathy in 45.4%. At baseline, all patients had NYHA Class III symptoms and an average EQ-5D-5L VAS score of 60.0±21.6. After 2 years follow-up there was 100% freedom from DSRCs and 99.7% freedom from pressure sensor failure. The annualized HFH rate after 1 year decreased by 69%, from 1.586 (pre-implant) to 0.488 (post-implant) (p<0.0001). The patient’s quality of life (EQ-5D-5L VAS) increased 8.1 units (68.2 ± 20.1, p=0.0008). Conclusion The COAST Study demonstrated that hemodynamic-guided remote HF management using PA pressure information is both safe and effective, with consistent implant safety and low risk for long-term sensor failure. At 1 year post implant, HFH were significantly reduced and quality of life improved. These results are also consistent with long-term clinical follow-up (2 yr) in other geographies with no late-stage adverse events or adverse events from sensor implant, demonstrating the generalizability of this type of hemodynamic-guided HF management.

Left ventricular dysfunction, pulmonary congestion, or both and cardiovascular risk after acute myocardial infarction

Abstract Background Patients with acute myocardial infarction (AMI) complicated by left ventricular systolic dysfunction (LVSD), pulmonary congestion, or both are at increased risk for adverse cardiovascular events, including long-term heart failure. The EMPACT-MI trial studied the efficacy and safety of early initiation of a sodium-glucose cotransporter-2 inhibitor (SGLT2i) in this population. We set out to evaluate the contemporary real-world risk associated with AMI presenting with LVSD and/or congestion and the projected impact of implementing early SGLT2i post-MI across the spectrum of risk. Purpose To evaluate the independent risk of presenting with LVSD, congestion, or both in patients with AMI. We will further explore the potential impact of the implementation of early initiation of SGLT2i in real-world clinical practice. Methods We conducted a retrospective population-based cohort study in Ontario, Canada, analyzing AMI hospitalizations from April 2009 to March 2022, emulating the EMPACT-MI trial cohort. Patients that survived to hospital discharge were stratified by baseline presentation with LVSD (defined as LVEF<50%), signs or symptoms of congestion or both and compared with a referent group without either risk factor (none). Exclusion criteria were previously established heart failure, prior SGLT2i use, eGFR < 20 ml/min/1.73m2 or chronic dialysis. The primary outcome was a composite of HF hospitalization or all-cause mortality at 30 days and 1 year. We used a multivariable logistic regression model to report an odds ratio (OR) and 95% confidence intervals (CI) adjusted for clinical risk factors. Results Among 36,837 AMI patients, 3% presented with congestion, 55% with LVSD, 10% with both, and 32% with none. Age/sex-adjusted 30-day event rates for the primary endpoint were 30%, 22%, 57%, and 7%, respectively. The corresponding adjusted ORs were 3.34 (95% CI: 2.05-5.46) for congestion, 3.58 (95% CI: 2.72-4.71) for LVSD, and 7.01 (95% CI: 5.09-9.65) for both, versus the reference group (none) (Figure 1). At year 1, a similar pattern of risk was observed (Figure 2). Based on the results of the EMPACT-MI trial being reported at the ACC conference in April 2024, relative and absolute risk differences in outcomes with implementation of early initiation of SGLT2i post-MI in real-world clinical practice across the spectrum of presentation will be reported. Conclusion Patients presenting with pulmonary congestion and/or LVSD remain at high risk of adverse cardiovascular events following AMI. This high-risk group represents an unmet need with a potential impact for improvement with novel interventions such as SGLT2i.

Systematic review and meta-analysis on the effects of physical activity-based interventions on frailty status and clinical outcomes in adults with long-term cardiac conditions

Abstract Introduction Frailty is common in patients with long-term cardiac conditions and is associated with poor clinical outcomes, but limited treatment options are available. Previous studies investigating interventions for frailty have shown positive results with physical activity interventions, however, these studies were largely based on general elderly populations. Aim To assess the impact of physical activity-based interventions on frailty and clinical outcomes in frail patients with long-term cardiac conditions. Methods A systematic review and meta-analysis was conducted based on the PRISMA guideline, using Medline, Embase, CENTRAL, PEDro, CINAHL electronic databases for articles published between 2000 and 2023. Studies which recruited adults >18 years with long-term cardiac conditions (including angina, acute coronary syndrome (ACS), valve disease, heart failure (HF), atrial fibrillation, cardiac surgery and congenital heart disease) who underwent physical activity-based interventions were included. The primary outcome was change in frailty (measured using a validated tool) post intervention. We also assessed the effect of interventions on mortality and hospitalisation. Results We screened 2697 records and reviewed 91 full-text articles; 12 studies (14 articles) were included, involving 1394 patients. Median age of participants ranged from 64 to 82 years. Five studies recruited participants with HF, 3 evaluated participants post transaortic valve implantation, 3 recruited cardiac surgical patients and 1 study evaluated participants post ACS. Physical activity-based interventions were multi-domain, including a mixture of aerobic, strength, balance, endurance and respiratory muscle training; the majority (N=10) had individualised exercise prescription. Meta-analysis of 8 randomised controlled trials (RCTs) showed statistically significant improvement in frailty associated with physical activity-based interventions compared to controls [pooled standardised mean difference (95% CI) = -0.34 (-0.59 to -0.08), p = 0.01, I2 = 48%]. Seven RCTs evaluated change in frailty by short physical performance battery (SPPB). Meta-analysis of these studies showed a statistically significant improvement in SPPB associated with physical activity-based interventions compared to controls [pooled mean difference (95% CI) = 0.83 (0.31-1.34), p = 0.002, I2 = 49%]. (Figure) The magnitude of improvement in SPPB exceeded the minimally clinically significant improvement of 0.5. Three studies evaluated the effect of physical activity-based intervention on clinical outcomes, all of which showed neutral effect on mortality and hospitalisation. Conclusion Physical activity-based interventions in patients with frailty and long-term cardiac conditions were associated with significant improvement in frailty status, with neutral effect on mortality and hospitalisation. Figure: Meta-analysis of 7 RCTs assessing effect of physical activity-based interventions on SPPB

Long-term outcomes after transcatheter aortic valve implantation: derivation and validation of the long-TAVI prediction model

Abstract Background Identification of high-risk individuals after transcatheter aortic valve implantation (TAVI) is essential to personalized care. Established risk models require a plethora of variables, fail to account for biomarker dynamics and imaging parameters, mostly focus on the short term, and offer limited predictive performance. Purpose We aimed to develop an easily applicable prediction model for long-term mortality or heart failure (HF) admission following TAVI. Methods Patients undergoing TAVI at a high-volume university centre in the United Kingdom (n = 990) were recruited into a prospective cohort study. Enrolled patients were divided into a development cohort (07/2007 – 12/2016) and a validation cohort (01/2017 – 11/2018) and followed for up to 15.1 (median 5.3, interquartile range [IQR] 2.8 – 7.4) years. Patient characteristics along with pre- and post-procedural imaging results and brain natriuretic peptide (BNP) levels before the procedure and at 3 months were recorded. A clinical risk score for long-term mortality and HF admission (i.e., Long-TAVI risk score) was derived using Cox regression and evaluated using time-dependent area under the receiver operating characteristics curve (AUC). Results Age at presentation was 79.8 (standard deviation [SD] 8.9) years, 961 (99.0%) patients had signs of heart failure, left ventricular ejection fraction was 52 (SD 11.2), and pre-TAVI BNP levels were 298.0 (interquartile range [IQR] 159.0 – 571.5) pg/mL. High BNP levels at presentation (higher vs. lower than 400 pg/mL: HR 1.50, 95% CI 1.17 – 1.92, P < 0.001) and dynamic changes in BNP with the first 3 months (low/high vs. low/low: 2.61, 95% CI 1.17 – 5.86, P = 0.020; high/high vs. low/low: 2.41, 95% CI 1.26 – 4.64, P = 0.008) were independent predictors mortality or HF admission. The simple 8-item Long-TAVI score accounts for periprocedural BNP dynamics and shows good discrimination (AUC 0.76, 95% CI 0.72 – 0.79) and calibration in the development cohort performing similarly well in the external validation cohort (AUC 0.70, 95% CI 0.63 – 0.77). Long-TAVI significantly outperformed the logistic EURO score (AUC 0.56, 95% CI 0.52 – 0.59, P < 0.001). Conclusion Both pre-TAVI BNP levels and periprocedural BNP trajectories are independently associated with long-term outcomes after TAVI. Accounting for clinical characteristics, imaging parameters, and circulating BNP levels, the newly developed Long-TAVI risk score achieves high performance and provides the first prediction model for long-term mortality or HF admission. Long-TAVI represents a novel tool for personalized risk assessment in patients undergoing TAVI.Correlation at baseline A) and FUP B)Score performance A) and risk groups B)

Postoperative atrial fibrillation following noncardiac surgery is associated with long-term heart failure: insights from a nationwide cohort

Abstract Background Atrial fibrillation (AF) is associated with the development of heart failure (HF). Whether postoperative AF (POAF) also confers a greater risk of HF is unclear. Purpose To investigate the long-term rate of incident HF in patients developing new-onset POAF after noncardiac surgery relative to patients who did not develop POAF after noncardiac surgery. Methods In this cohort study, the Danish nationwide registries were used to identify all patients aged ≥30 years who developed POAF following noncardiac, nonobstetric surgery from 1996 to 2020. These patients were matched in a 1:3 ratio by age, sex, type of surgery, selected comorbidities, and year of inclusion with patients without POAF after noncardiac surgery. The primary outcome was incident HF. Secondary outcomes were HF hospitalization and all-cause mortality. Results A total of 2,270 patients with POAF were matched with 6,810 patients without POAF (median age: 75 years [25th-75th percentile: 67-82 years]; 53.5% females). The median follow-up was 7.2 years. Compared with patients without POAF, those with POAF had a higher associated long-term rate of incident HF (2.6 versus 1.2 events per 100 person-years; HR 2.39 [95% CI 2.06-2.78]]), HF hospitalization (2.2 versus 1.0 events per 100 person-years; HR 2.33 [95% CI 1.97-2.74]), and all-cause mortality (9.8 versus 7.4 events per 100-person-years; HR 1.55 [95% CI 1.45-1.66]) (Figure 1). Conclusions Patients with new-onset postoperative atrial fibrillation following noncardiac surgery had a higher associated long-term rate of incident heart failure compared to those without postoperative atrial fibrillation following noncardiac surgery. These findings highlight the importance of increased awareness among physicians of the risk of adverse outcomes, including heart failure, in patients with postoperative atrial fibrillation after noncardiac surgery. Closer postoperative follow-up and monitoring, as well as aggressive treatment of cardiovascular risk factors, may be warranted to reduce the risk of adverse outcomes in these patients.

A larger reduction of spatial mean QRS-T angle during cardiac resynchronisation therapy is associated with a lower risk of mortality and heart failure hospitalisation

Abstract Background Predicting clinical outcome in heart failure patients undergoing cardiac resynchronization therapy (CRT) remains challenging, necessitating improved risk stratification for CRT recipients. Previous studies have shown an association between large spatial peak and mean QRS-T angles and cardiovascular disease. Little is known, however, about their relation to clinical outcome following CRT. Purpose To investigate the association between spatial peak and mean QRS-T angles and long-term clinical outcome following CRT initiation. Methods All patients with native LBBB receiving CRT at a large-volume tertiary care center between 2015 and 2020 were retrospectively evaluated. Spatial peak and mean QRS-T angles were derived from digital pre- and post-CRT 12-lead ECGs that were processed using Glasgow algorithm and Kors’ regression transformation. The QRS-T angles and their change after CRT were analyzed in relation to the primary composite endpoint of heart failure hospitalisation or all-cause mortality using Cox regression analysis adjusted for clinical covariates (age, gender, CRT-P or CRT-D, secondary ICD indication, ischemic etiology, NYHA class, LVEF, diabetes, atrial fibrillation, baseline QRS duration, NT-proBNP, and eGFR). Results The study group comprised 250 patients (a median age [Q1–Q3] of 72.2 years [64.5–76.3]; 22% female; 58% New York Heart Association (NYHA) class III-IV; LVEF 27% [22–30]) who were followed over a median follow-up time of 4.5 years [3.2–5.8] after CRT implantation. The median post-CRT spatial peak and mean QRS-angles were 142° [116–160] and 152° [127–166], and the median angle was decreased by 16° [-0.6–41] and 14° [-0.4–38], respectively. Both a larger post-CRT mean QRS-T angle (HR 1.20, 95%CI 1.08-1.33, p=<.001) and peak QRS-T angle (HR 1.08, 95%CI 1.01-1.17, p=0.046) were associated with the primary endpoint. A larger reduction of mean QRS-T angle, but not peak QRS-T angle, was associated with a risk reduction (HR 0.87, 95%CI 0.79-0.95, p<0.003). In Kaplan-Meier analysis, patients with a post-CRT mean QRS-T angle above median had a higher risk of reaching the endpoint (log-rank p=0.002, Figure 1). Conclusion Our results show that a larger magnitude of the post-CRT spatial peak and mean QRS-T angles, and a larger reduction of the latter, are associated with long-term heart failure hospitalisation and death. These findings suggest that spatial QRS-T angle may have a potential role in refined risk stratification of CRT patients.Figure 1.K-M curve spatial mean QRS-T

Late Survival Benefits of Concomitant Surgical Ablation for Atrial Fibrillation During Cardiac Surgery: A Systematic Review and Meta-Analysis

The long-term survival benefits after surgical ablation for atrial fibrillation (AF) during cardiac surgery were not confirmed in previous randomized controlled trials or meta-analyses. This study aimed to investigate the long-term efficacy of surgical ablation in patients with AF. MEDLINE, EMBASE, and CENTRAL were searched to identify studies comparing concomitant surgical AF ablation with no surgical ablation during cardiac surgery. The primary outcome was long-term all-cause mortality. Secondary outcomes were stroke, heart failure rehospitalization, major bleeding, freedom from AF, and permanent pacemaker implantation during follow-up. To minimize confounding, only adjusted outcomes were used from observational studies. A total of 38 studies met the inclusion criteria. Of those, 9 randomized controlled trials and 15 observational studies with 41,678 patients (surgical ablation: n = 19,125; no surgical ablation: n = 22,553) were analyzed for all-cause mortality, with a weighted median follow-up of 62.0 months. Surgical ablation was associated with decreased risks of long-term mortality (hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.71 to 0.84), stroke (HR 0.60, 95% CI 0.48 to 0.76), heart failure rehospitalization (HR 0.92, 95% CI 0.87 to 0.96), and more freedom from AF during follow-up (relative risk 1.93, 95% CI 1.50 to 2.49), whereas surgical ablation was associated with a higher risk of permanent pacemaker implantation during follow-up (HR 1.35, 95% CI 1.03 to 1.77). There was no significant difference in major bleeding during follow-up between the 2 groups. In patients with AF who underwent cardiac surgery, surgical ablation was associated with decreased risks of long-term mortality, stroke, and heart failure rehospitalization compared with patients with untreated AF. Given that the survival benefits were predominantly observed in observational studies, further randomized trials are necessary to confirm these findings.

Competing and Noncompeting Risk Models for Predicting Kidney Allograft Failure.

Prognostic models are becoming increasingly relevant in clinical trials as potential surrogate endpoints, and for patient management as clinical decision support tools. However, the impact of competing risks on model performance remains poorly investigated. We aimed to carefully assess the performance of competing risk and noncompeting risk models in the context of kidney transplantation, where allograft failure and death with a functioning graft are two competing outcomes. We included 11,046 kidney transplant recipients enrolled in 10 countries. We developed prediction models for long-term kidney graft failure prediction, without accounting (i.e., censoring) and accounting for the competing risk of death with a functioning graft, using Cox, Fine-Gray, and cause-specific Cox regression models. To this aim, we followed a detailed and transparent analytical framework for competing and noncompeting risk modelling, and carefully assessed the models' development, stability, discrimination, calibration, overall fit, clinical utility, and generalizability in external validation cohorts and subpopulations. More than 15 metrics were used to provide an exhaustive assessment of model performance. Among 11,046 recipients in the derivation and validation cohorts, 1,497 (14%) lost their graft and 1,003 (9%) died with a functioning graft after a median follow-up post-risk evaluation of 4.7 years (IQR 2.7-7.0). The cumulative incidence of graft loss was similarly estimated by Kaplan-Meier and Aalen-Johansen methods (17% versus 16% in the derivation cohort). Cox and competing risk models showed similar and stable risk estimates for predicting long-term graft failure (average mean absolute prediction error of 0.0140, 0.0138 and 0.0135 for Cox, Fine-Gray, and cause-specific Cox models, respectively). Discrimination and overall fit were comparable in the validation cohorts, with concordance index ranging from 0.76 to 0.87. Across various subpopulations and clinical scenarios, the models performed well and similarly, although in some high-risk groups (such as donors over 65 years old), the findings suggest a trend towards moderately improved calibration when using a competing risk approach. Competing and noncompeting risk models performed similarly in predicting long-term kidney graft failure.

TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia

Hypoglycemia triggers autonomic and endocrine counter-regulatory responses to restore glucose homeostasis, a response that is impaired in patients with diabetes and its long-term complication hypoglycemia-associated autonomic failure (HAAF). We show that insulin-evoked hypoglycemia is severely aggravated in mice lacking the cation channel proteins TRPC1, TRPC4, TRPC5, and TRPC6, which cannot be explained by alterations in glucagon or glucocorticoid action. By using various TRPC compound knockout mouse lines, we pinpointed the failure in sympathetic counter-regulation to the lack of the TRPC5 channel subtype in adrenal chromaffin cells, which prevents proper adrenaline rise in blood plasma. Using electrophysiological analyses, we delineate a previously unknown signaling pathway in which stimulation of PAC1 or muscarinic receptors activates TRPC5 channels in a phospholipase-C-dependent manner to induce sustained adrenaline secretion as a crucial step in the sympathetic counter response to insulin-induced hypoglycemia. By comparing metabolites in the plasma, we identified reduced taurine levels after hypoglycemia induction as a commonality in TRPC5-deficient mice and HAAF patients.

Association between Respiratory Virus Infection and Development of De Novo Donor-Specific Antibody in Lung Transplant Recipients.

Chronic lung allograft dysfunction (CLAD) is the most common cause of long-term lung allograft failure. Several factors, including respiratory virus infection (RVI), have been associated with CLAD development, but the underlying mechanisms of these associations are not well understood. We hypothesize that RVI in lung transplant recipients elicits the development of donor-specific antibodies (DSAs), thus providing a mechanistic link between RVI and CLAD development. To test this hypothesis, we retrospectively evaluated for the presence of HLA antibodies in a cohort of lung transplant recipients with symptomatic RVI within the first four months post-transplant using sera at two time points (at/directly after the transplant and following RVI) and time-matched controls without RVI (post-transplant). We found a trend toward the development of de novo DSAs in those with symptomatic RVI versus controls [6/21 (29%) vs. 1/21 (5%), respectively, p = 0.09]. No cases or controls had DSA at baseline. We also found increased rates of CLAD and death among those who developed class II DSA versus those who did not (CLAD: 5/7 (71.4%) vs. 19/34 (54.3%), death: 5/7 (71.4%) vs. 17/35 (48.6%)). Prospective studies evaluating the temporal development of DSA after RVI in lung transplant patients and the subsequent outcomes are warranted.