Cox Regression Research Articles

Equitable Access, Lasting Results: The Influence of Socioeconomic Environment on Bariatric Surgery Outcomes.

Low socioeconomic status (SES) correlates with higher obesity rates and challenges in accessing treatments like bariatric surgery (BS). This study aims to assess SES's influence on medium-term BS outcomes in a setting of universal healthcare, ensuring equitable treatment access. We conducted a retrospective analysis of 193 BS patients (1997-2018) at a tertiary care hospital. Weight loss was expressed as change in % total weight loss (%TWL) and excess body weight (EBW) loss. Successful BS was defined as > 50% EBW loss. SES was gauged using quartiles of the Spanish Deprivation Index. A multivariable Cox regression model evaluated SES impact on BS success over follow-up. The mean follow-up was 6.9 ± 4.6years; patients averaged 43.9 ± 11.8years, with 29.7% men. Preoperative BMI was 48.2 ± 8.2kg/m2. At follow-up, BMI was 33.9 ± 6.6kg/m2, with 29.3 ± 12.02% of %TWL. No SES quartile differences in BS success were noted at follow-up (log rank p = 0.960). Cox regression revealed no SES disparities in BS outcomes post-adjustment. However, female sex (HR 1.903; p = 0.009) and diabetes mellitus (HR = 0.504; p = 0.010) correlated with weight-related outcomes. In a universal healthcare system with equitable treatment access, medium-term BS outcomes remain consistent irrespective of patients' socioeconomic status.

Evolution and prognostic impact of left ventricular myocardial work indices after transcatheter aortic valve replacement in patients with severe aortic stenosis

Abstract Introduction Left ventricular myocardial work (LVMW) is an echocardiographic-based technique to evaluate LV function using pressure-strain loops and therefore correcting for the left ventricular (LV) afterload. LVMW indices have been shown to be of prognostic importance in patients with aortic stenosis (AS) before transcatheter aortic valve replacement (TAVR), but no data is available on the evolution and the prognostic value of these parameters after TAVR. Purpose To measure LVMW indices before and after TAVR in patients with severe AS and explore the association with outcome. Methods As previously validated, LV global longitudinal strain (GLS) and LV systolic pressure (as the sum of the brachial arterial blood pressure and mean aortic valve gradient before TAVR and as brachial arterial blood pressure after TAVR) were incorporated to build pressure-strain loops and to calculate the following LVMW indices: global work index (LV GWI), global constructive work (LV GCW), global wasted work (LV GWW) and global work efficiency (LV GWE). The endpoint was all-cause mortality. Results A total of 255 patients were included with a median age of 82 years (IQR 77-85); 51% were men and 67% presented with NYHA class III/IV. After TAVR, LVEF and LV GLS remained in average unchanged (from 56 to 55%, p=0.470 and from 13.6 to 13.2%, p=0.068). While LV GWW remained unchanged after TAVR (from 247 to 258mmHg%, p=0.080), LV GWI, LV GCW and LV GWE significantly decreased (from 1882 to 1291mmHg%, p <0.001, from 2248 to 1671mmHg%, p <0.001 and from 89 to 85%, p <0.001 respectively). During a median follow-up of 59 months (IQR 40-72), 129 patients died. Univariable Cox regression analysis identified an association between all-cause mortality and male sex, diabetes mellitus, chronic obstructive pulmonary disease (COPD), renal function, atrial fibrillation, Charlson comorbidity index, pacemaker implantation, and post-TAVR LV GLS, LV GWI and LV GCW. These clinical parameters were used as a basal multivariable Cox regression model of which on top either post-TAVR LV GLS, LV GWI or LV GCW were added. All these parameters of post-TAVR LV systolic function showed an independent association with all-cause mortality, but LV GWI demonstrated the highest increase in model predictivity (Figure 1). Given the prognostic relevance of post-TAVR LV GWI, the population was divided into LV GWI tertiles. The group with the lowest LV GWI tertile showed a significantly higher proportion of male patients, higher prevalence of atrial fibrillation and also worse pre-TAVR LVEF, LV GLS, LV GWI, LV GCW and LV GWE. Kaplan Meier survival analysis confirmed the worse survival in the group with the lowest LV GWI compared to the highest tertile (log-rank ꭓ2: 8,224, p 0.016, Figure 2). Conclusion LVMW indices change after TAVR and post-TAVR LV GLS, LV GWI, LV GCW are independently associated with all-cause mortality. Among these parameters, LV GWI yielded the highest prognostic value.

Long-term clinical outcomes informed by artificial intelligence-enabled single-lead ECG detection of reduced ejection fraction

Abstract Background * Reduced left ventricular ejection fraction (LVEF) is linked to poor clinical outcomes (1, 2). * Despite its increasing prevalence, reduced LVEF is often undetected due to resource-limited echocardiography and lack of suitable point-of-care diagnostic tools. * Previous studies have shown that an artificial intelligence-enabled electrocardiogram (AI-ECG) algorithm can accurately identify patients with reduced LVEF, but may also offer novel insights on long-term prognosis (3, 4). Purpose We aimed to determine if an AI-ECG algorithm designed for detecting reduced LVEF can also independently predict 2-year major adverse cardiovascular events (MACE) and all-cause mortality. Method * A retrospective multicentre observational study investigating the ability of AI-ECG to predict long-term clinical outcomes (i.e. over two years' follow up). * Analysis included a total of 1,007 consecutive unselected patients attending for routine echocardiography, with a single-lead ECG recording performed at the same time. * An AI-ECG algorithm, designed to identify impaired LVEF, was applied to each single-lead ECG. * Occurrence of MACE and all-cause mortality associated with AI-ECG results (Figure 1) was investigated using Cox regression; evaluating performance of AI-ECG results as a classifier (0 or 1) and as a probability score (0 to 1). * The study was approved by the UK Health Research Authority (reference 21/LO/0051). Results * The mean age was 62.3 years. 52.4% of patients were male and 57.5% of patients were White. * Appropriately, patients with a positive AI-ECG had a higher MACE rate compared to those with a negative AI-ECG (34.2% vs. 11.9%; adjusted hazard ratio (aHR) 2.02; 95% CI, 1.46 – 2.81; p < 0.005), primarily driven by increased mortality (23% vs. 9.6%; p < 0.0001; aHR 1.65; 95% CI, 1.12 – 2.43) and heart failure hospitalization (14.5% vs. 1%; p < 0.0001) – Figure 2. * AI-ECG probability score (per 10% increase) was significantly associated with MACE (aHR 1.17; 95% CI, 1.09 – 1.25; p < 0.005) and all-cause mortality (aHR 1.11; 95% CI, 1.02 – 1.20; p = 0.01). * Importantly, sub-analysis of AI-ECG for those who have a normal LVEF (i.e. ≥50%) continued to show association between positive AI-ECG and MACE (27.2% vs. 11.9%; p < 0.0001; aHR 1.70, 95% CI 1.17 – 2.48) and all-cause mortality (20.4% vs. 9.6%; p < 0.0001; aHR 1.53, 95% CI 1.00 – 2.36). Conclusion An AI-ECG algorithm designed to identify impaired LVEF can identify patients at risk of MACE and all-cause mortality from single-lead ECG screening – regardless of their LVEF. Such results may enable further risk stratification for cardiovascular investigations through the simple addition of single-lead ECG recording.

Adjustment of the SMART risk score by bioactive adrenomedullin enables a more accurate prediction of mortality in patients with ASCVD

Abstract Background Bioactive adrenomedullin 1-52 (bio-ADM) is a dynamic blood biomarker for real-time assessment of endothelial function. Bio-ADM was recently shown to be a prognostic marker in patients with acute heart failure and cardiogenic shock. The SMART (Second Manifestations of Arterial Disease) score is a validated tool for risk assessment in patients with established atherosclerotic cardiovascular disease (ASCVD). The aim of this study was to assess whether measurement of bio-ADM adds incremental value to the SMART score in stable patients with ASCVD. Methods Circulating bio-ADM levels were assessed in n=695 stable patients with ASCVD in an all-comer cohort. Endpoints evaluated were all-cause mortality and cardiovascular mortality; follow up was 3 years. Results Bio-ADM was higher in non-survivors (all-cause death: n=54, median 33.1 pg/mL) compared to survivors (n=641, median 17.9 pg/mL; p<0.0001). Univariable Cox regression analyses showed bio-ADM to be associated with adverse outcome [standardized hazard ratio (HR) of bio-ADM values: All-cause death: 2.4, 95% confidence interval (CI): 2.0-2.9; p<0.001, cardiovascular death: 2.5, 95% CI: 1.9-3.3; p<0.001]. This association remained significant in various multivariable Cox regression models. Bio-ADM was found to be a strong marker for mortality (c-index: 0.80, Chi²: 54.1) and proved to be superior to other markers including hs-Troponin T (c-index: 0.61, Chi²: 2.0) and eGFR CKD-EPI 2021 (c-index: 0.687, Chi²: 33.5). Addition of bio-ADM to the SMART score significantly improved model performance in predicting mortality (SMART score: c-index: 0.717, Chi²: 24.73; SMART score + bio-ADM: c-index: 0.832, Chi²: 63.24; Delta c-index: 0.115; Delta Chi²: 38.51; all p<0.001) and showed net reclassification improvement in risk categorization with 11.6% in the group of survivors and 9.8% for non-survivors. Conclusion Bio-ADM provides incremental added value (improved discrimination, calibration and reclassification) on top of the SMART risk score in patients with ASCVD.

Prognostic value of follow-up hemodynamics after initial treatment in pulmonary arterial hypertension

Abstract Background Hemodynamic variables such as right atrial pressure (RAP), cardiac index (CI) and mixed venous oxygen saturation (SvO2) have consistently been associated with survival in pulmonary arterial hypertension (PAH). The prognostic importance of hemodynamics after treatment initiation seems to be superior to baseline evaluation and stroke volume index (SVI) emerged as an independent prognostic parameter. New PAH treatments are, however, able to improve exercise capacity without increasing CI or SVI. Purpose The aim of this work was to define the prognostic role of follow-up hemodynamic parameters in a population of patients with idiopathic, hereditary, drug-induced PAH (I/H/D-PAH) and PAH associated with connective tissue disease (CTD-PAH) and congenital heart disease (CHD-PAH). Methods Treatment naïve PAH patients were assessed at baseline and at 1st follow-up (3-4 months after starting PAH-specific therapy; 1st F-UP) with 6-minute walk distance (6MWD), World Health Organization functional class (WHO-FC) and right heart catheterization (RHC). Collected hemodynamic parameters were: RAP, systolic, diastolic and mean pulmonary artery pressure (s/d/mPAP), CI, SVI, SvO2, pulmonary vascular resistance (PVR), pulmonary arterial compliance (PAC), cardiac efficiency (CE), pulmonary arterial elastance (Ea), resistance–compliance product (RC), right ventricular (RV) power, and RV stroke work index (RVSWI). The primary outcome was all cause death. We used stepwise Cox regression to assess variables obtained at baseline and at 1st F-UP. Results 794 patients with PAH were enrolled (54% I/H/D, 28% CTD, 18% CHD). A primary outcome occurred in 54% of patients over a median follow-up duration of 5.8 (2.4–11) years. In a multivariable model considering only baseline variables, no hemodynamic variables independently predicted prognosis but RAP. At first follow-up RHC (n=706), WHO-FC, 6-minute walk distance, RAP, and Ea were independently associated with death, adjusted for age, gender, and etiology of PAH. Because hemodynamic variables were highly correlated, we compared multivariable Cox regression models adding only variables with a correlation coefficient <0.6. In these models, RAP, Ea, PAC, CE, PVR, SvO2, CI, and SVI at follow-up RHC were independent predictors of death (Table). Conclusions Ea and right atrial pressure were the hemodynamic variables independently associated with death at 1st F-UP RHC after initial PAH treatment. These findings suggest that beyond improving RV function, RV afterload reduction can be considered a further treatment target.Table

Can the presence of aortic or coronary artery calcifications in the standard of care baseline CT or PET-CT scan of patients with Hodgkin or non-Hodgkin lymphoma be used as a predictor of MACE?

Abstract Background Major adverse cardiovascular events (MACE), commonly defined as acute myocardial infarction, acute coronary syndrome/ischemic heart disease requiring revascularization, stroke, and heart failure, represent a significant cause of mortality among patients with cancer. With increased rates of both cancer and cancer survivorship, the identification of new predictive markers for the development of MACE in this population is crucial for implementing effective preventive and risk-mitigation strategies. Purpose To determine whether the presence of calcifications in the coronary arteries (CAC) or aorta (CA) of lymphoma patients, as reported in standard-of-care PET-CT (Positron Emission Tomography-Computed Tomography) or chest CT (Computed Tomography) scan, can predict the occurrence of MACE. Methods A Retrospective analysis was conducted on a cohort of patients diagnosed with Hodgkin or non-Hodgkin lymphoma and treated with anthracycline-based chemotherapy. Patients were diagnosed from January 1, 2013, and followed through to June 30, 2023. The reference point for the study was the radiologist’s report of the PET-CT or chest CT conducted before the initiation of anthracycline therapy. Patients who did not undergo a PET-CT or CT before the start of treatment, and/or developed MACE before treatment initiation were excluded. Univariate and multivariate adjusted Cox regression models were employed to assess whether the presence of CA and CAC was associated with the development of MACE. Associations with outcomes were evaluated using the Kaplan-Meier method and Cox regression. Results 326 patients were included with a mean age of 55 years (range: 52-60), predominantly male 201 (61%) and white 314 (96%), CAC was reported in 75 patients (23%) and CA in 18 (6%). In the univariate regression model, a statistically significant association was found between the presence of both CA and CAC with the risk of MACE. CAC showed a stronger association with the development of MACE than CA (HR: 3.7 [1-7.9], p=0.0005 vs HR: 2.9 [1- 8.5], p=0.050). In multivariable analysis CAC emerged as the strongest predictor of MACE (HR: 2.9 [1.3 – 6.4], p=0.01), after accounting for hypertension, diabetes, dyslipidemia, and GFR <60 (Table 1), while the association with CA attenuated (HR: 2.01 [0.7-6.5], p=0.2010) and was no longer significant (Table 2). Conclusion CAC in the standard-of-care PET/-CT scans was a predictor of MACE in lymphoma patients treated with anthracyclines, while the association with CA weakened in multivariable analyses and was likely underpowered given the small number of patients with CA. If replicated, this finding warrants closer surveillance of this group of patients and can be considered as a non-invasive cardiovascular risk marker.

Mechanical right ventricular involvement is independent of right coronary arterial bed and has a prognostic impact in acute myocardial infarction complicated by cardiogenic shock

Abstract Background In Acute Myocardial Infarction complicated by Cardiogenic Shock(AMI-CS), understanding the implications of right ventricular involvement (RVi) is crucial for refining risk stratification and optimizing management. Purpose Distinguish the prognosis in RVi at baseline(RVB) and persistent(RVP) in AMI-CS Methods 357 patients with AMI-CS+PAC serial measures at 0, 6, 12, 24h. RVi was defined as the presence of all 4 criteria PAPI<1; RVSWi≤4.08; RAP≥15 mmHg; and PVC/PCP≥0.86 and persistent as the presence of the 4 criteria at 4 time points. For hemodynamic measures, repeated measures ANOVA; and KM curves and Cox regression were performed. Results 300 without vs 57 with RVB. Additionally, 344 without vs 13 had RVP. Killip-Kimball classification showed a higher significant association with both RVB(P=0.042). A higher percentage of RVB received vasopressin(P=0.008), and there was a significant association with levosimendan use(P=0.009) in RVP. The higher MODS score, RVB(P=0.017) and RVP(P=0.029). The number of vasoactives was higher in RVB(P=0.031) RVP(P=0.009). Finally, the phenotypic characterization revealed a significant association with RVB(P=0.001) and RVP(P=0.032) more cardio-metabolic. The SCAI-CSWG classification indicated a higher proportion in the E category for both RVB(P=0.046) and not significant in RVP(P=0.405). Overall, mortality rates did not differ significantly between in RVB(P=0.174) or RVP(P=0.117), although there was a trend towards higher mortality in patients with RVi. Age, sex, DM, HTN, previous MI, PCI, CABG, stroke, and type of MI, primary reperfusion, LVEF, and laboratory parameters did not differ. RVB had higher heart rate(P=0.036), RAP, PASP(both P<0.001), lower SBP(P=0.049), cardiac output(P=0.004), index(P=0.001), power(P=0.012), power index(P=0.002), CPI(RAP), perfusion pressure, PAPi(both P<0.001), Stroke volume(SV, P=0.001), SVi(P<0.001), LVSWi(P=0.001), and RVSWi(P<0.001). RVP higher RAP(<0.001), and lower cardiac output(P=0.008), index(P=0.005), power(P=0.034), power index(P=0.029), CPI(RAP)(P=0.002), perfusion pressure(P=0.035), PAPi(P<0.001), SV(P=0.018), SVi(P=0.011), LVSWi(P=0.034) RVSWi(P<0.001). Importantly interaction between group*time was found in RVB in RAP(P<0.001), mPAP(P=0.038), perfusion pressure(P=0.002) and RVSWi(P<0.001) and in RVP in SV(P=0.014), SVi(P=0.013) and LVSWi(P=0.028) suggest that RVi had different hemodynamic response. For RVB a reduction of -4.16 days in survival time (-7.79, -0.54, P=0.024); Logrank P=0.035. Similarly, for RVP demonstrated a significant reduction of -7.27 days (-14.08, -0.47, P=0.036); Logrank P=0.017. No significant of the culprit artery in RVB, RVP (P>0.05) was observed. RVB and RVP was strongly associated with a higher prevalence of RVi (STe-V3/4R) on ECG (35.1 vs. 11.7%, and 61.5 vs. 13.7%, P<0.001). Conclusion In AMI-CS, RVi, whether baseline or persistent, is associated with distinct hemodynamic profiles and a trend toward higher mortality.Figure 1.Hemodynamics of RVB(A-C) & RVP(D-F)Figure 2.Survival of RVB, RVP (A, B) & HR(C)

Time-varying cox model for heart failure prediction in phospholamban p.(Arg14del)-positive individuals

Abstract Background Phospholamban (PLN) p.(Arg14del)-positive individuals are at risk for developing severe heart failure (HF), yet a comprehensive risk model for this outcome is missing. Our PLN registry contains longitudinal data which enables us to capture dynamic changes in covariables over time, while prior prediction models rely on baseline clinical information which may change over time. Using this longitudinal clinical information will enhance the accuracy of HF prediction and may aid patients selection for future (gene)therapy. Purpose The aim of this study is to develop a dynamic HF risk prediction model for PLN p.(Arg14del)-positive individuals. Method Data were collected of 594 PLN p.(Arg14del)-positive individuals who had no documented history of HF or myocardial infarction at time of the first echocardiography. We incorporated two time-dependent covariates in our time-varying Cox regression model: longitudinal individual predicted left ventricular ejection fraction (LVEF) and longitudinal individual predicted relative risk for major ventricular arrhythmia (VA). Predicted LVEF values were derived using observed LVEF values in a linear mixed-effect model, while the relative risk for major VA was predicted using a Cox regression model with major VA as the outcome. These time-dependent covariates were included in the time-varying Cox regression along with baseline covariables age at inclusion and previous major VA. The results were validated using 5-fold cross-validation. Results Over a median follow-up period of 3.6 years (interquartile range 1.4-6.8), 77 (13%) individuals developed HF, defined as a composite endpoint of HF hospitalisation, implantation of left ventricular assist device, heart transplantation and HF-related mortality. Our time-varying Cox regression model demonstrated a robust 5-year mean C-statistic of 0.904 (95% CI 0.901-0.908). The hazard ratio for time-dependent LVEF predictions was 0.89 per % LVEF increase (95% CI 0.87-0.91, p <0.001) and for time-dependent relative major VA risk predictions 3.59 (95% CI 1.49-8.69, p = 0.005). Regarding baseline covariates, age at inclusion had a hazard ratio of 1.01 (95% CI 0.99-1.03, p = 0.47) and previous major VA 0.48 (95% CI 0.21-1.1, p = 0.08). Combining the hazard ratios of time-dependent predicted relative risk for major VA and major VA in history results in a hazard ratio of 1.73. Conclusion Our study introduces a novel time-varying Cox regression model for the individual prediction of heart failure events in PLN p.(Arg14del)-positive individuals which may aid patient selection for future (gene)therapy. Results demonstrate robust predictive performance (C-statistic of 0.904, 95% CI 0.901-0.908), highlighting the significance of incorporating longitudinal data for enhanced prediction accuracy.

Heart rate response and recovery in bicycle exercise testing - reference values and association with mortality

Abstract Introduction Chronotropic incompetence and impaired heart rate (HR) recovery are related to mortality. Guidelines lack specific recommendations for reference values on HR recovery assessment. Purpose To define normal values for HR response and recovery in individuals referred for a bicycle exercise stress test and to relate these factors to risk of mortality. Methods We included 9,917 subjects (46% females) aged 18–85 years who performed a bicycle exercise test. We defined age- and sex-specific reference equations for peak HR, HR reserve, and HR recovery at 1 and 2 minutes (HRR1 and HRR2) using a subgroup of individuals without apparent cardiovascular (CV) risk nor comorbidities (N=2,774). Associations between blunted HR indices (<5thpercentile) and mortality were analysed using Cox regression in all subjects and in individuals with normal exercise capacity (N=8,070). Results All HR indices were age-dependent. The 5th percentiles of HR reserve, HRR1, and HRR2 correlated weakly with previously reported reference values. During median follow-up of 8.6 years 1,110 (11%) died. HR recovery variables were the strongest predictors of all-cause (HRR1, hazard ratio 1.66 (95% confidence interval, 1.45–1.90)) and CV mortality (HRR2, 1.59 (1.26–2.00)) after adjustments for potential confounders. Blunted HR response (peak HR) increased risk of all-cause (1.32 (1.14–1.53)) and CV mortality (1.41 (1.09–1.83)). Combined blunted HRR1 and HRR2 or HR response and HRR1 further increased risk of all-cause (1.92 (1.64–2.24) and 1.85 (1.55–2.22), respectively) and CV mortality (1.95 (1.50–2.54) and 1.94 (1.42–2.65), respectively). HR recovery variables (HRR1, 1.97 (1.63–2.39) and HRR2, 1.76 (1.46–2.12)) remained stronger predictors of mortality than peak HR (1.38 (1.10–1.72)) in individuals with normal exercise capacity. Conclusions All HR variables were age-dependent and associated with mortality. Blunted HR recovery was more strongly related to mortality than chronotropic incompetence, and their combination added prognostic value. Furthermore, blunted HR recovery variables, rather than blunted HR response, remained strongly associated with mortality even in the presence of normal exercise capacity.

Metformin is associated with lower risks of incident cancers compared to sulphonylurea use: a population-based study with competing risk analyses

Abstract Objective To investigate the effects of sulphonylurea compared to metformin on the risks new-onset cancers and mortality in patients with type 2 diabetes mellitus. Methods This is a retrospective population-based cohort study of patients with type 2 diabetes mellitus between 1st January and 31st December 2009 with follow-up until 31st December 2019. Propensity score matching (1:2 ratio) between metformin and sulphonylurea users was performed. The primary outcome is new diagnosis of any cancer. The secondary outcomes are cancer, cardiovascular, or all-cause mortality. Cox regression was used to identify significant predictors. Competing risks were considered using cause-specific or subdistribution hazard models. Propensity score stratification, inverse probability weighting, and high-dimensional propensity score adjustment were also used. Results In the matched cohort, 36487 sulphonylurea and 71306 metformin users were included. Univariable Cox regression showed that compared to metformin users, sulphonylurea users had a higher risks of any new cancer diagnosis (hazard ratio [HR]: 2.26, 95% confidence interval [CI]: 2.18-2.34, P<0.0001), including pancreatic (HR: 4.03 [3.37, 4.82], P<0.0001), colorectal (HR: 2.12 [1.97, 2.27], P <0.0001), genitourinary (HR: 1.73 [1.57, 1.90], P<0.0001), breast (HR: 1.36 [1.22, 1.51], P<0.0001) and lung cancer (HR: 3.37 [3.11, 3.65], P<0.0001) cancers. Sulphonylurea users also had higher risks of cancer-related (HR: 2.38, 95% CI: 1.87-3.03; P<0.0001) and all-cause mortality (HR: 1.92, 95% CI: 1.78 -2.08; P<0.0001). Conclusion Metformin use was associated with lower risks of new diagnosis of any cancer, cancer-related and all-cause mortality in patients with type 2 diabetes mellitus.Figure 1.Study flow diagram.FIgure 2.New diagnosis of cancer.

The impact of targeted bleeding source treatment on the risk of recurrent bleeding after percutaneous coronary intervention among patients with a history of prior bleeding

Abstract Background Prior bleeding is one of the strongest predictors for bleeding after percutaneous coronary intervention (PCI). Whether targeted treatment of the prior bleeding site affects the risk of bleeding after PCI is unknown to date. Methods From an all-comers population undergoing PCI between 2009-2019, patients with BARC 2-4 bleeding prior to index PCI were identified. Among those, the recurrence of BARC 2-5 bleeding at the same bleeding site, any BARC 2-5 bleeding, and mortality were compared throughout 1 year after PCI between patients with vs. without targeted treatment at the prior bleeding site. Targeted treatment was defined as medical, interventional, or surgical therapy targeted to cure the cause of bleeding. Adjusted hazard ratios (HRadj) were extracted from Cox regressions. Inverse probability weights were computed from a logistic regression with targeted treatment as dependent variable, and the following covariates: ARC-HBR variables associated with ≥4% 1-year bleeding risk in this registry (including oral anticoagulation), aspirin, potent P2Y12 inhibitor treatment, and prior bleeding site. Results Out of 18’510 patients enrolled from 2009-2019, 845 (4.6%) had a history of prior BARC 2-4 bleeding before PCI. Mean age was 71.6 years, 25% were female, and 52% presented with acute coronary syndrome. Patients with targeted treatment were significantly younger (70.3 vs. 72.5 years, p=0.005) and had more frequently malignancies (25% vs. 18%, p=0.012). 26/344 (7.6%) of patients with targeted treatment vs. 31/501 (6.2%) of patients without targeted treatment experienced recurrent BARC 2-5 bleeding at the same bleeding site (HRadj 1.35, 95% CI 0.79-2.30, p=0.268). 45/344 (13.1%) of patients with targeted treatment vs. 59/501 (11.8%) of patients without targeted treatment experienced any recurrent BARC 2-5 bleeding (HRadj 1.16, 95% CI 0.78-1.72, p=0.473). The rate of mortality was also similar between the groups (targeted treatment 13.7% vs. no targeted treatment 12.4%, HRadj 1.13, 95% CI 0.76-1.67, p=0.549). Conclusions Among patients with a bleeding history before PCI, half of the recurrent bleeding events throughout 1-year after PCI occurred at the same bleeding site, regardless of whether the bleeding source underwent targeted treatment. These findings imply that targeted treatment is not protective for recurrent bleeding events after PCI and that prior bleeding represents rather a systemic than local bleeding risk.Frequency of bleeding sitesKaplan Meier curves

Efficacy of diet with low glycemic index on coronary artery disease

Abstract Background Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide, with dietary factors playing a significant role in its pathogenesis. The glycemic index (GI) of foods has been implicated in cardiovascular health, with low GI diets hypothesized to reduce the risk of CAD and improve outcomes [1]. However, the efficacy of low glycemic index diets in patients with established CAD remains uncertain. Objective This study aimed to assess the efficacy of a low glycemic index diet on coronary artery disease by evaluating changes in cardiovascular biomarkers and major adverse cardiovascular events (MACE) using Kaplan-Meier analysis and Cox regression models. Material and Methods A randomized controlled trial was conducted involving 156 patients with established coronary artery disease (Aged 43-75 years, mean age 62.4±12.7 years, male=57%). Participants were randomized to either a low glycemic index diet group or a control group receiving standard dietary advice. Changes in cardiovascular biomarkers, including lipid profiles, inflammatory markers, and glycemic control parameters, were assessed at baseline and follow-up visits. Major adverse cardiovascular events, including myocardial infarction, stroke, and cardiovascular death, were recorded over a median follow-up period of 6.2±2.4 years. Kaplan-Meier analysis and Cox regression models were used to evaluate the association between adherence to a low glycemic index diet and MACE. Results Preliminary analysis demonstrated significant improvements in cardiovascular biomarkers, including reductions in LDL cholesterol, triglycerides, and inflammatory markers, in the low glycemic index diet group compared to the control group (p < 0.05). Kaplan-Meier analysis revealed a lower incidence of MACE in patients adherent to the low glycemic index diet compared to non-adherent patients (log-rank p < 0.05). Cox regression analysis confirmed the independent association between adherence to a low glycemic index diet and reduced risk of MACE after adjusting for confounding factors (hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.60-0.95; p < 0.001). Conclusion Our findings suggest that a low glycemic index diet may be efficacious in reducing cardiovascular risk and improving outcomes in patients with coronary artery disease. Adherence to a low glycemic index diet was associated with favorable changes in cardiovascular biomarkers and a reduced risk of major adverse cardiovascular events. Further research is warranted to confirm these findings and elucidate the mechanisms underlying the cardioprotective effects of low glycemic index diets.

Prognostic impact of the concept of late gadolinium enhancement granularity in non-ischaemic dilated cardiomyopathy

Abstract Background The prognostic stratification of non-ischaemic dilated cardiomyopathy (DCM) to predict the risk of death is mainly driven by the left ventricular ejection fraction (LVEF). Indeed, LVEF<35% is currently the only indication for primary prevention with implantable cardioverter-defibrillator (ICD) in these patients. Beyond LVEF, several cardiac magnetic resonance imaging (MRI) studies have suggested the strong prgnostic impact of late gadolinium enhancement (LGE), and particularly its extent and location. Therefore, we assumed that a more granular approach combining detailed LGE findings including extent, location and pattern could improve risk stratification in this population. Purpose To assess the additional prognostic value of the concept of "Late Gadolinium Enhancement (LGE) Granularity" that includes extent, location, and pattern in non-ischaemic dilated cardiomyopathy (DCM) patients to predict all-cause death. Methods Between 2008-2021, all consecutive patients with DCM without ICD or history of sustained ventricular arrythmia referred for cardiac MRI were included in two French centres. In line with the current ESC and AHA guidelines, DCM was defined by the LV dilation and LVEF< 50% using cardiac MRI. All patients with history of coronary artery disease or clinical history of myocarditis were excluded. The primary outcome was all-cause death using the French National Registry of Death. Cox regressions were performed to determine the prognostic value of each LGE findings. The additional prognostic value of the LGE granularity was assessed by the C-statistic increment, the continuous net reclassification improvement (NRI), and the integrative discrimination index (IDI). Results Of 1,668 DCM patients (age 52±8 years, 54% males), 268 (16%) died after a median (interquartile range) follow-up of 9 (7-12) years. With a median LVEF value of 39% (30-46), 472 (28%) patients had non-ischemic LGE. Using survival curves, patients with LVEF>35% but the LGE septal location showed a higher risk of death compared to all patients with LVEF≤35% with or without LGE (except for the septal location, all p<0.001). In DCM patients with LGE (N=472), LGE extent (adjusted HR: 4.27, 95% CI: 2.22-8.22), septal location (HR: 5.74, 95% CI: 3.35-9.85) and multiple areas of LGE (HR: 4.38, 95% CI: 2.08-9.22; all p<0.001) were all independently associated with death after adjustment for prognosticators. The concept of "LGE granularity" combining all these LGE features showed the best improvement in model discrimination and reclassification over traditional prognosticators including LVEF (C-statistic improvement: 0.14; net reclassification improvement=64.3%; integrative discrimination index=29.0%; all p<0.05). Conclusion In a large cohort of DCM patients, the concept of "LGE granularity" combining LGE extent, location and the presence of multiple areas had an additional prognostic value above traditional prognosticators including LVEF to predict all-cause death.

Left ventricular apical aneurysms and outcomes in hypertrophic cardiomyopathy

Abstract Background/Introduction The presence of left ventricular apical aneurysm (LVAA) has been shown to be associated with increased risk of adverse events in patients with hypertrophic cardiomyopathy (HCM). However, the between LVAA size and outcomes is uncertain. Purpose To explore associations between baseline LVAA diameter and progressive changes in LVAA size over time and poor outcomes in HCM patients. Methods Our HCM multimodality imaging database (transthoracic echocardiography (TTE) or cardiac magnetic resonance (CMR)) was retrospectively assessed for studies reporting LVAA, defined as one or more akinetic or dyskinetic apical segments. LVAA size (widest systolic diameter in millimetres in the transverse plane) was recorded at two time points: earliest identification and most recent imaging, with LVAA size progression (mm/year) calculated. Patients’ electronic records were reviewed for composite outcome including stroke, apical thrombus, death, and appropriate therapy from implantable cardioverter defibrillator (ICD). Continuous variables are presented as mean ± standard deviation (SD), categorical data numerically or as percentages. Comparisons between groups were made using Wilcoxon ranks sum and Fischer exact test for continuous and binary variables, respectively. Cox regression was used to assess independent associations with composite outcomes. A p value of <0.05 was considered statistically significant. Results A total of 106 patients were identified with LVAA and clinical follow-up (mean age 64.7±11.4 years, 70% male). Mean follow-up duration was 6.5±3.0 years. Baseline LVAA was confirmed by CMR and TTE in 70 and 30% of cases respectively. Mean LVAA size at baseline was 16.2±7.6 mm (range 6-56 mm). During multivariate Cox analysis, baseline LVAA size in mm was independently associated with the composite outcome (HR 1.04, 95% CIs 1.0 to 1.08, p=0.04). Mean duration between baseline and maximal LVAA size scan was 5.4±3.0 years. Median progression in LVAA size was 1.0 (IQR 0.6 to 1.8) mm per annum (range 0.0 to 8.1 mm). During multivariate analysis, LVAA progression rate in mm per year was independently associated with the composite outcome (HR 1.4 95% CIs 1.11 to 1.7, p=0.002). Conclusion(s) These data support the association between LVAA size and poor outcomes in HCM patients. We also demonstrate the progressive nature of LVAAs and indicate those more rapidly increasing in size are at highest risk of adverse events, with potential implications for management strategies.

Relationship of serum vitamin D levels with atrial fibrillation incidence: The HUNT Study

Abstract Background Evidence on the association between serum vitamin D levels and incidence of atrial fibrillation (AF) was inconclusive. To elucidate the nature of the association, we studied the relationship between serum 25-hydroxyvitamin D (25(OH)D) levels and AF incidence in the Norwegian Trøndelag Health (HUNT) Study using both conventional observational and Mendelian Randomization (MR) approaches. Methods 3394 adult participants without AF diagnoses were followed up from HUNT3 (2006-2008) to 2021 in a prospective cohort. Average serum 25(OH)D levels over ten years between HUNT2 (1995-1997) and HUNT3 were calculated and categorized into <50 and ≥50 nmol/L as exposure. AF diagnoses were retrieved from hospital registers and validated by medical doctors. Cox regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI). Furthermore, a one-sample MR was conducted among 36,554 adults who participated in both HUNT2 and HUNT3. An externally weighted genetic risk score based on 19 vitamin D-related genetic variants, chosen for their clear biological functions in serum vitamin D transport, synthesis and metabolism, was used as instrument. We applied the Wald ratio method to assess the causal effect. Results During a median 13-year follow-up, 303 AF cases were diagnosed in the prospective cohort. Serum 25(OH)D level <50.0 nmol/L was associated with a 26% reduced incidence of AF (HR 0.74, 95% CI 0.58 to 0.95), compared to serum 25(OH)D ≥50 nmol/L after adjustment for confounders. Genetically determined 10 nmol/L decrease in serum 25(OH)D level was associated with a 7% reduced incidence of AF (HR 0.93, 95% CI 0.86 to 1.00) in the MR analysis. Sensitivity analyses supported this positive association. Conclusions We found a consistent positive association between serum 25(OH)D level and AF incidence in the Norwegian HUNT population using both observational and MR approaches. Key messages • Serum vitamin D levels appeared to be positively associated with the incidence of AF. • Vitamin D supplementation should be prescribed with caution, especially for people at high risk for AF.

Cardiovascular events risk in office-masked nocturnal hypertension defined by home blood pressure monitoring: the J-HOP nocturnal blood pressure study

Abstract Background Elevated nocturnal home blood pressure (BP) has been reported to be associated with increased risk for cardiovascular disease (CVD). Masked hypertension defined by home BP monitoring is also a strong risk factor for adverse CVD outcomes. However, no study has investigated the association between office-masked nocturnal hypertension defined by home BP monitoring and CVD events risk. Purpose This study aimed to examine the association between office-masked nocturnal hypertension defined by home BP monitoring and CVD events risk in a clinical practice-based population. Methods This was a prospective observational study including Japanese participants with CVD or high risk of CVD. Three office BPs were taken on two different occasions. Nocturnal home BP was measured three times per night for two weeks. The association between office-masked nocturnal hypertension and incident total CVD events (including fatal and non-fatal stroke and coronary heart disease) was examined using Cox regression. Results 2,545 participants were followed for the mean of 7.1 years (18,116 person-years), during which 152 (6.0%) CVD events occurred. Mean age (standard deviation) was 63.3 (10.3) years; 49.0% were male; 82.6% took antihypertensive medications. The proportions of participants with normotension (office BP <140/90 mmHg and nocturnal home BP <120/70 mmHg), white-coat hypertension (office BP ≥140/90 mmHg and nocturnal home BP <120/70 mmHg), office-masked nocturnal hypertension (office BP <140/90 mmHg and nocturnal home BP ≥120/70 mmHg), and sustained hypertension (office BP ≥140/90 mmHg and nocturnal home BP ≥120/70 mmHg) were 25.3%, 14.4%, 23.2%, and 37.1%, respectively. The office-masked nocturnal hypertensive group and sustained hypertensive group had higher incidence rates of total CVD events compared with the normotensive group. Relative to normotension, those with both office-masked nocturnal hypertension (adjusted hazard ratio [aHR] 1.72, 95% confidence interval [CI] 1.01–2.92) and sustained hypertension (aHR 1.75, 95%CI 1.03–2.96) had similarly increased CVD risk, even after adjustment for daytime home BP values. Conclusions Screening for office-masked nocturnal hypertension with home BP monitoring identifies a potentially important group of patients with increased risk for incident CVD events for whom additional preventative measures may be appropriate.

Comprehensive machine learning models for prediction of heart failure in 476,393 women and men from the UK Biobank reveal sex differences and underutilized risk factors

Abstract Background Machine learning (ML) models provide potential advantage over ‘traditional’ regression models in heart failure (HF) prediction. Objective To compare performances of Cox PH models and ML survival models for incident HF in men and women without prevalent ischemic heart disease (IHD). We also aimed to identify potential high-risk precursors otherwise ignored by conventional survival models, and to investigate differences between sex-specific models. Methods We included 476,393 participants (55.6% women) from the UK Biobank, after excluding participants with a history of HF or IHD, and defined sex-specific datasets. We predicted incident HF events using over 400 baseline characteristics. We constructed multivariable Cox PH models, which included all predictor variables and subsequently only those remaining after LASSO stability selection. We also developed two supervised ML models (Random Survival Forest (RSF), eXtreme Gradient Survival Boosting (XGBoost)). We identified the 15 most important sex-specific predictors in each model and performances were compared using the C-index. Models were validated using hold-out sets. Results During 12.3 ± 1.9 years of follow-up, 4680 (1.76%) women and 6631 (3.14%) men developed incident HF. XGBoost showed the best performance during model training (C-index, training: 0.89 in men, 0.97 in women; validation 0.77 in men, 0.80 in women). The multivariable Cox model performed second-best (C-index, training: 0.78 in men, 0.82 in women; validation: 0.76 in men, 0.78 in women). RSF performed slightly worse (C-index, training: 0.75 in men, 0.79 in women; validation: 0.75 in men, 0.79 in women) but did not show performance drop during validation. LASSO stability selection performed similar to RSF. Age, self-reported lifetime treatments and medications, cystatin-C, waist circumference and FEV1-scores were identified as strong risk factors in all models for both sexes. Reduced albumin levels and elevated HbA1c were more strongly associated with high risk in men, while elevated systolic BP showed higher importance in women. Traditional Cox models observed CRP as important only in men, while the ML models identified CRP as important for both sexes. Neutrophil count was considered a strong risk factor in both sexes in the traditional Cox models, yet it was not among the most important predictors in both ML models. Presence of other heart disease (which included a.o. pericardial disease, valve disorders and arrhythmias) was an important predictor variable only in the ML models. Conclusion ML models showed similar performance to Cox PH models for HF prediction. Despite this, differences in predictor importance were identified between models. Sex-specific risk predictors were found, and FEV1 score, which is not commonly included in existing models, was identified as an important risk factor. These results suggest that ML models may reveal additional insights that would otherwise remain unnoticed.

Validation of the HFA-ICOS risk assessment tool with real-world data from a prospective cohort of breast cancer patients in treatment with anthracyclines and trastuzumab

Abstract Background The increasing prevalence of cancer therapy-related cardiovascular toxicity (CTRCD) poses a significant challenge to patient management, necessitating accurate risk assessments. Previous methodologies have struggled with precise risk stratification, partly due to varying definitions of CTRCD and the specificity of cancer treatments. Purpose This study aimed to evaluate the assessment tool proposed by the Heart Failure Association and the International Cardio-Oncology Society (HFA-ICOS) in predicting the risk of CTRCD in patients undergoing anthracycline and trastuzumab treatment for breast cancer at a national reference center. Methods A prospective cohort study was conducted, encompassing 172 patients treated from January 2022 to July 2023. Patients were assessed at baseline, three months, and six months post-treatment initiation, with exclusion criteria including baseline left ventricular ejection fraction (LVEF) <50%, history of heart failure, and stage IV breast cancer. The study utilized the HFA-ICOS tool for risk stratification and CTRCD was defined with the current criteria of the European Society of Cardiology guideline. Descriptive statistics were calculated, and incidence rates and Cox proportional-hazards models were developed according to the risk category. Results In our study, 138 (80.2%) patients were classified as low risk, 23 (13.4%) as moderate risk and 11 (6.4%) as high risk. We identified 81 (47.1%) patients that developed CTRCD in follow-up. Descriptive characteristics can be found in Table 1. The global incidence rate for CTRCD in our cohort was of 2.4 new cases per 1000 person-days, however no differences in incidence rates were found when stratifying by risk category (Figure 1A). Moreover, patients with moderate to high risk according to the HFA-ICOS tool did not show a significantly increased hazard ratio for cardiotoxicity (HR 0.41, 95%CI 0.15-1.12, p=0.082 and HR 1.39, 95%CI 0.50-3.86, p=0.5, respectively) as shown in Figure 1B. Conclusion While the HFA-ICOS tool provides a structured framework for assessing cardiotoxicity risk, its predictive value in this cohort was limited. The findings underscore the complexity of cancer therapy-related cardiotoxicity and the need for enhanced, individualized risk assessment tools. Future research should focus on refining risk prediction models, incorporating broader clinical and genetic factors to improve patient outcomes in cardio-oncology.Table 1.Clinical CharacteristicsFigure 1.Incidence rates and Cox models

Impact of new definition on the prognosis of patients with pulmonary hypertension compared to classic definition

Abstract Background The recent European Society of Cardiology (ESC)/European Respiratory Society (ERS) 2022 pulmonary hypertension (PH) guidelines have updated the definition of PH from a mean pulmonary arterial pressure (mPAP) ≥ 25mmHg to > 20mmHg, and the pulmonary vascular resistance (PVR) threshold for pre-capillary PH (Pre-PH) from > 3 wood units (WU) to > 2 WU. Little is known regarding the implication of this new criteria in all PH subgroups in Asia. Purpose In this study, we aim to evaluate the impact of the new PH definition on the prevalence and prognosis of PH subgroups in as Asian cohort. Methods A retrospective analysis of a single-center RHC registry (April 2016 - July 2023) was conducted. 314 patients (median age 62.5, 50.3% men) were included. Patients were categorized into PH subgroups as defined by both the classic and new criteria. The primary outcome included cardiovascular mortality or heart failure hospitalizations, assessed over a maximum follow-up period of 5 years. Clinical outcomes of different PH subgroups using the classic and new definitions were compared using Kaplan-Meier methods, log-rank tests, and Cox proportional hazards models. Continuous parameters were analyzed using restrictive cubic splines within Cox models. Results Based on the new cutoffs (mPAP > 20mmHg, PVR > 2 WU), 76 patents (24.2%) were reclassified. PH increased to 233 (+ 41, +13.1%), Pre-PH increased to 92 (+ 30, +9.6%), Ipc-PH decreased to 27 (- 21, -6.7%), and Cpc-PH increased to 108 (+33, +10.5%). Over a median follow-up of 238.5 days, 65 primary outcomes occurred. Under the new PH definition, 5-year survival rates for Pre-PH, Ipc-PH, and Cpc-PH are 73.2%, 57.5%, and 47.0%, improved from 67.0%, 53.3%, and 44.3% in the classic definition. In the Cox regression analysis, using the Non-PH as a reference, the risk of primary outcome for PH subgroups was lower in the new definition compared to the classic definition (Table 1). Using the classic mPAP cut-off [<25 vs. ≥25 mmHg], patients with PH had a significantly higher risk for primary outcome (HR 2.25, 95% CI 1.26-4.00, p=0.006) compared with patients without PH. However, using the new mPAP cut-off [<20 vs. ≥20 mmHg], it didn’t show significant difference between two groups (HR 1.62, 95% CI 0.86-3.04, p=0.132). Spline analyses suggested a linear relation between the risk of primary outcome and mPAP considering mPAP between 20 and 45mmHg, and a plateau of events for mPAP values over 45mmHg. In patients with PVR > 2 WU, we observed a linear relation between PVR and events for values and a plateau of events for PVR values over 7.5 WU (Figure 1). Conclusion The new definition increased the diagnosis of PH, particularly in Pre-PH and Cpc-PH. This definition faciliates earlier diagnosis, encompassing milder disease states, and demonstrated better prognosis in PH subgroups. However, it dose not identify additional patients at increased risk of primary outcomes.Table 1Figure 1

Safety of beta-blocker discontinuation in patients after acute coronary syndromes and preserved left ventricular ejection fraction: long-term clinical outcomes from the SPUM-ACS cohort

Abstract Background While beta-blockers have been shown to improve outcomes after acute coronary syndromes (ACS), most trials predate the advent of reperfusion therapy and modern secondary prevention. Recent trial data in the reperfusion era found no all-cause or cardiovascular mortality benefit in patients with a left ventricular ejection fraction (LVEF) >40%, while myocardial infarction and angina were reduced. We hypothesized that, in patients who receive optimal contemporary treatment following ACS and who have an LVEF >40%, beta-blocker discontinuation within 1 year after ACS is safe and non-inferior to beta-blocker continuation in terms of the 5-year incidence of major adverse cardiovascular events (MACE). Purpose We assessed the safety of beta-blocker discontinuation within 12 months following ACS in patients with an LVEF >40% at discharge, compared to continued long-term beta-blocker therapy, with respect to the 5-year incidence of MACE. Methods Data was derived from the Swiss Special Program University Medicine – Inflammation in ACS (SPUM-ACS) cohort (N=3,762), a multicenter prospective cohort of patients hospitalized for invasive management of ACS between 2009-2017. We included patients with an LVEF >40%, beta-blockers at discharge, and who completed the 5-year follow-up. Patients who continued beta-blockers at one year were compared with those who discontinued beta-blockers at any time throughout the first year after ACS using a target trial emulation design. Adjusted hazard ratios (aHR) were obtained with a Cox model using an inverse probability weighting adjustment for baseline characteristics including demographic parameters, comorbidities, and concomitant medication. The primary endpoint was 5-year MACE (cardiovascular death, myocardial infarction, stroke or transient ischemic attack, unplanned coronary revascularization, and hospitalization for unstable angina). Results Of 2,077 patients with an LVEF >40% and beta-blockers at discharge, 1,758 (85%) continued beta-blockers and 319 (15%) had discontinued beta-blocker therapy at one year. The 5-year risk between the discontinuation and continuation group was similar for the primary endpoint (14.5% vs 14.3%, respectively, aHR 1.00, 95%CI 0.73-1.36, p=0.98). All-cause mortality (aHR 1.08, 95%CI, 0.64-1.81, p=0.79) did not differ between both groups. In a subgroup analysis, there was no effect modification by LVEF, but some evidence for a higher risk of primary endpoint with beta-blocker discontinuation in STEMI (aHR 1.50, 95%CI 1.02-2.21) compared with NSTEMI (aHR 0.69, 95%CI 0.40-1.19, P interaction = 0.022). Conclusion Beta-blocker discontinuation within 12 months following ACS in patients with an LVEF >40% was not associated with an increased risk of MACE at 5 years, compared to long-term continuation of beta-blocker therapy. In the absence of a dedicated randomized controlled trial, beta-blocker discontinuation may be safe, especially after NSTEMI.Kaplan-Meier plot: probability of MACE