Independent Predictor Of Outcome Research Articles

Three dimensional biatrial expansion index as an independent predictor of outcome in dilated cardiomyopathy

Abstract Background Left atrial expansion index (LAEI) is a marker of left ventricular (LV) diastolic dysfunction and an outcome predictor in heart failure (HF). However, the role of the right atrial expansion index (RAEI) in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the left, right and combined bi-atrial expansion index (BAEI) with three-dimensional (3D) echocardiography in a cohort of patients with dilated cardiomyopathy (DCM) and to assess their prognostic role. Methods We enrolled 121 consecutive patients (mean age 59±14 years, 74% men) with DCM in sinus rhythm, who underwent 3D echocardiography and were prospectively followed for 19±11 months for an endpoint of death, nonfatal cardiac arrest and HF hospitalization. As previously described, for the left atrium (LA), LAEI was measured as (3D LA Vmax – 3D LA Vmin) x 100/3D LA Vmin, where Vmax was the maximal end-systolic atrial volume and Vmin was the minimal end-diastolic atrial volume. For the right atrium (RA), RAEI was calculated as (3D RA Vmax – 3D RA Vmin) x 100/3D RA Vmin. BAEI was defined as the sum of LAEI and RAEI. Results 55 patients (46%) reached the endpoint: there were 27 deaths, 5 nonfatal cardiac arrests and 23 readmissions for HF. Patients with adverse outcome had lower LAEI (52±25 vs. 63±36, p=0.047), lower RAEI (57±29 vs. 70±32, p=0.02), lower BAEI (108±46 vs. 133±55, p=0.008). In univariate Cox regression, all three expansion indices were predictors of adverse events: HR=3.23 [95% CI, 1.45-7.20], p=0.004 for LAEI, HR=2.12 [95% CI, 1.24-3.61], p=0.006 for RAEI, HR=3.99 [95% CI, 1.70-9.36], p=0.001 for BAEI. We constructed a multivariable model with well-established event predictors in DCM and one expansion index at a time. After adjustment for age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure, all three expansion indices remained independent predictors of the composite endpoint: HR=2.75 [95% CI, 1.18-6.38], p=0.02 for LAEI, HR=1.86 [95% CI, 1.04-3.31], p=0.04 for RAEI, HR=3.53 [95% CI, 1.46-8.51], p=0.005 for BAEI. BAEI yielded the highest incremental prognostic power (likelihood ratio chi2 test=14, p=0.03) on top of the baseline model consisting of age, left ventricular ejection fraction, mitral regurgitation severity and pulmonary artery systolic pressure (likelihood ratio chi2 test=9). Conclusion In DCM, 3D atrial expansion indices are significantly lower in patients with major adverse events, reflecting a more impaired atrial reservoir dysfunction. Both LAEI, RAEI and BAEI were independent outcome predictors in patients with DCM. Combining the left and right atrial expansion indices might improve risk stratification, since BAEI had the highest predictive value after adjustment for confounders.

Left atrioventricular coupling index: association with diastolic dysfunction and prognostic implications in heart failure patients

Abstract Background Left atrioventricular coupling index (LACI), an index coupling left atrial (LA) to left ventricular (LV) volume at end-diastole (Figure 1), showed to be associated with prognosis in different clinical settings. However, the relation between LACI and LV diastolic dysfunction (DD) remains to be established. Purpose The present study aimed to investigate the association between LACI and LV DD and to assess its prognostic value in patients with heart failure (HF). Methods We retrospectively analyzed 1158 stable HF patients (mean age 66±12 years, 75% men) on optimal medical therapy (derivation cohort). Clinical and echocardiographic features were characterized across LACI tertiles. The independent prognostic value of LACI (endpoint: all-cause death/HF-hospitalization) was assessed by Cox regression and spline curve analyses. Results were validated in an external cohort of 242 HF patients. Results In the derivation cohort, the median LACI value was 0.29 (IQR:0.19-0.42). Patients in the third tertile (LACI>0.36) were older and presented with more advanced HF symptoms. While prevalence of grade-1 DD (ASE/EACVI classification) progressively decreased across LACI tertiles, the prevalence of grade-3 DD significantly increased (8%,23%, and 46% respectively, P<0.0001). A cut-off value ³0.26 identified moderate-to-severe DD with an area-under the-curve of 0.75. During follow-up (median 28 months, IQR:11-53), 407 (35%) patients reached the endpoint. On multivariable analysis, LACI was independently associated with outcomes (HR for 1-unit-increase 2.34; 95%CI 1.35-4.03; P=0.002 – Figure 2), showing incremental predictive value over the DD grading system (net reclassification improvement=0.150, P<0.0001). The prognostic value of LACI was consistent in the external validation cohort. Conclusions LACI is associated with DD severity and is an independent predictor of outcomes in HF patients.How to assess LACIPrognostic value of LACI in HF

Quality of life in patients with heart failure and improved ejection fraction: one-year follow-up with ARNI and SGLT2i

Abstract Introduction A baseline Heart Failure (HF) with reduced Ejection fraction (HFrEF) <=40% that improved for >=10 points and a second measured left ventricle ejection fraction (LVEF) >40%, can be considered as HF with improved ejection fraction (HFimpEF). The novel therapy for HFrEF and HFimpEF are sacubitril/valsartan (ARNI- angiotensin receptor/neprilysin inhibitor) and Sodium-glucose cotransporter-2 inhibitors (SGLT2i). Purpose Our study aimed to evaluate ARNI and SGLT2i therapy on the health status of HFrEF patients, as well as the prognostic impact of HFimpEF in terms of quality of life and outcomes (mortality and rehospitalization due to HF) during a one-year follow-up. Methods In this prospective study, we included 376 hospitalized HFrEF patients, in whom ARNI and SGLT2i were initiated into regular therapy. A 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12) was performed at discharge and after one year. The primary prognostic endpoints were all-cause mortality and HF rehospitalization. Results Initially, about two-thirds of the study population were men (71%), mean age of 61.0±11.5 years, mean LVEF 27.5±5.2 % and mean KCCQ overall summary (KCCQ-OS) score of 48.5±12.5, while quality of life KCCQ-QoL 37.4±10.2. After one year LVEF was increased by 35.6±7.1 %. The total number of 143 patients (38%) met the criteria for HFimpEF, with the improvement of mean LVEF (45.2±8.6 %., p<0.001). Overall, HFimpEF patients experienced an average 5.3 ± 18.6-point improvement in the KCCQ-OS compared with 2.5 ± 17.4 points for non-HFimpEF group (differences in mean changes of 2.9 [95% CI: 1.4 to 4.7). This is largely due to improvements in the domain of KCCQ-QoL (5.8 ± 29.7 points vs. 2.9 ± 22.2 points, respectively). During one year of follow-up, combined SGLT2i + ARNI therapy was represented statistically significantly more in HFimpEF compared to the non-HFimpEF group (86% vs. 34%, p<0.0005), where 45% took only one medicine and 21% none. The HFimpEF group had a significantly better outcome in terms of all-cause mortality (2.8% vs. 18.9%, p<0.005) and HF rehospitalization (3.5% vs. 40%, p<0.0001). The one-year KCCQ-12 was independently associated with outcomes; the hazard ratio for the integrated endpoints (mortality and HF rehospitalization) was 1.08 (95% CI: 1.05–1.11, p = 0.005). Conclusions In routine clinical practice, initiation of the ARNI and SGLT2i therapy was associated with significant improvements in the health status of HFrEF patients, but also change to HFimpEF. The one-year quality of life in patients with heart failure and improved ejection fraction was superior to baseline and compared to the non-HFimpEF group. HFimpEF was associated with a better outcome. All HF patients should undergo KCCQ-12 because it is an independent predictor of outcome.

Clinical and angiographic features of patients experiencing exercise-induced out-of-hospital cardiac arrest

Abstract Background Out-of-hospital cardiac arrest (OHCA) is a devastating condition that exhibits significant clinical heterogeneity. Previous studies have reported coronary artery disease (CAD) as the most common cause of OHCA. Possible causes of exercise-induced OHCA in patients with CAD include ST-elevation myocardial infarctions (STEMI), exercise-induced myocardial ischaemia and other triggers. We investigated whether there are differences in the clinical and angiographic features between 'exercise-induced (EX)' and 'non-exercise-induced (non-EX)' OHCA secondary to CAD. Methods In total, resuscitated 2300 patients (from 72 institutions) with OHCA due to CAD were registered within our regional CCU network database between 2010 and 2021. The population of the coverage area is 16.8 million during the day and 14.1 million at night. Patients with a trigger were grouped based on their triggering event: at rest, sleeping, eating, drinking, watching television, bathing, excretion, mild physical activity, driving, exercise and other activity. We classified the patients into 2 groups based on their triggering event as exercise: exercise (EX) group(n=169) and Non-Ex group(n=2131). The primary clinical outcome of interest was favorable 30-day neuroprognosis. Results Baseline characteristics was shown in the Table (below). Acute coronary syndrome (ACS) was the most common type of clinical presentation in each group. In ACS, the EX group had less ST elevation and/or left bundle branch block in electrocardiogram (57% vs. 68%; P=0.01), and initial good flow (TIMI grade 3) of culprit lesion in coronary artery was more frequently seen in the EX group than in the Non-EX group (23% vs. 12%; P< 0.01). A Kaplan-Meier survival curve analysis showed that EX group had favorable clinical outcome compared with Non-EX group (71% vs 58%, p<0.001:log-rank test). Multivariate analysis demonstrated that exercise-related trigger for OHCA was an independent predictor of favorable outcome (OR:0.59, 95%CI:0.38-0.90; P=0.015). Conclusion EX-OHCA had favorable clinical outcome compared with non-EX-OHCA. Reason may be that these patient present with culprit lesion that has good blood flow, possibly leading to fewer STEMI events.Baseline charactaristicComparison in Patients with ACS

Echocardiographic predictors of cardiovascular outcome in heart failure with preserved ejection fraction

Abstract Background The optimal echocardiographic predictors of cardiovascular outcome in heart failure with presereved ejection fraction (HFpEF) are unknown. Purpose We aimed to identify independent echocardiographic predictors of cardiovascular outcome in patients with HFpEF. Methods Systematic literature search of three electronic databases was conducted from date of inception until November 2022. Hazard ratios (HRs) and their 95% confidence intervals (CIs) for echocardiographic variables from multivariate prediction models for the composite primary endpoint of cardiovascular death and heart failure (HF) hospitalization were pooled using a random effects meta-analysis. Specific subgroup analyses were conducted for studies that enrolled patients with acute versus chronic HF, and for those studies that included E/e’, pulmonary artery systolic pressure (PASP), renal function, natriuretic peptides and diuretic use in multivariate models. Results Forty-six studies totalling 20,056 patients with HFpEF were included. Three echocardiographic parameters emerged as independent predictors in all subgroup analyses: Decreased left ventricular (LV) global longitudinal strain (HR 1.24, 95% CI 1.10-1.39 per 5% decrease), decreased left atrial (LA) reservoir strain (HR 1.30, 95% CI 1.13-1.1.50 per 5% decrease) and lower tricuspid annular plane systolic excursion (TAPSE) to PASP ratio (HR 1.17, 95% CI 1.07-1.25) per 0.1 unit decrease). Other independent echocardiographic predictors of the primary endpoint were a higher E/e’, moderate to severe tricuspid regurgitation, LV mass index and LA ejection fraction, although these variables were less robust. Conclusion Impaired LV global longitudinal strain, lower LA reservoir strain and lower TAPSE/PASP ratio predict cardiovascular death and HF hospitalization in HFpEF and are independent of filling pressures, clinical characteristics and natriuretic peptides. These echocardiographic parameters reflect key functional changes in HFpEF, and should be incorporated in future prospective risk prediction models.

The gut-microbiome derived phenylacetylglutamine predicts adverse events in patients with acute coronary syndromes

Abstract Background and Introduction The gut microbiota-derived metabolite phenylacetylglutamine (PAG) is associated with incident cardiovascular events(1). Acute coronary syndromes (ACS) present a major health challenge, especially as population ages(2). Data from our group show increased PAG levels during aging in humans. However, the predictive potential of PAG for mortality and major adverse cardiovascular events (MACE) in patients (pts) with ACS is unknown. Purpose Here, we investigated the potential of PAG to predict ischemic and fatal events in pts with acute coronary syndromes (ACS). We also compared the predictive potential of PAG to another relevant gut-microbiota derived metabolite involved in CVD, namely Trimethylaminoxyde, (TMAO), and we evaluated their cumulative risk potential. Methods A total of 1’848 patients were enrolled in Cohort I of the SPUM-ACS study – a multi-center prospective ACS cohort study from Switzerland. Overall survival and incident MACE after 1 year follow-up were analyzed using Kaplan-Meier (KM) estimates and compared by log-rank test after patient stratification into PAG tertiles. Uni- and multivariable Cox-regression models were fit to calculate the hazard ratios for 1-year MACE in a crude model and adjusted model (adjusted for established confounders). Healthy controls served as additional controls. PAG plasma levels were quantified using LC-HRMS. Results The median PAG plasma level in the healthy control group was 1.76µM, whereas for the whole ACS patient population it was 1.92µM (Table 1). Pts in the third PAG tertile had a two times higher MACE rate and a four times higher mortality rate compared to pts in the first PAG tertile (p<0.001). (Table 2). PAG levels were significantly higher in pts who presented with MACE (2.63µM) or died (3.1µM) within the 1-year follow-up compared to the healthy control subjects (p<0.0001) (Figure 1A). Spearman correlation analysis revealed that plasma PAG levels were positively associated with age (r=0.43, p<0.0001), while a negative association with eGFR was observed (r=-0.51, p<0.0001) (Figure 1B). KM estimates indicated that pts in the highest PAG tertile had significantly higher 1-year MACE risk relative to those with low levels (Figure 1C; p<0.001 log rank). Following multivariable adjustment, PAG remained an independent predictor for MACE at 1-year follow-up with a hazard ratio (HR) of 1.8 (95% CI, 1.1–3.2, p=0.048) (Figure 1D). KM estimates of both, high levels of PAG and high levels of TMAO together, indicate that the combination of these two detrimental metabolites leads to an even higher risk of 1-year MACE relative to lower levels (Figure 1E). Conclusion PAG is a novel and independent predictor of adverse outcomes in patients with ACS. This study indicates the role of the gut-microbiome and its metabolites in predicting ischemic and fatal outcomes of pts with established CVD.

Mid-regional pro-adrenomedullin is an independent predictor of cardiovascular outcomes in cardiac surgery, a prospective cohort study in 500 patients

Abstract Background MR-proADM (mid-regional pro-adrenomedullin) is a stable pro-peptide of Adrenomedullin, which is expressed in various cell types such as heart, lung, and renal tissue. It is a prognostic parameter for heart failure (HF) and sepsis as well as all-cause and cardiovascular (CV) mortality. Purpose Considering the characteristics of MR-proADM as a reliable biomarker for adverse events, we aimed to investigate the prognostic impact of MR-proADM in patients undergoing elective cardiac surgery. Methods We prospectively enrolled patients undergoing elective cardiac bypass and/or valve surgery at the department of cardiac surgery between May 2013 and August 2018. Blood samples were taken one day prior to surgery. MR-proADM was measured using an automated immunofluorescence assay. Patients were followed prospectively until endpoints were reached. The primary endpoint was the composite of hospitalization for heart failure (HHF) or CV mortality, the secondary endpoint was postoperative atrial fibrillation (POAF). The multivariate regression model was adjusted for age, sex, NT-proBNP, type of surgery, and CRP-level at baseline. Results A total of 500 patients (146 female [29.2%]; median age 69.8 years [IQR 60.6-75.5]) were followed over a median of 4.6 years (IQR 3.0–5.8). Valve surgery was performed in 214 (42.8%) patients, 160 (32%) underwent a bypass operation and 126 (25.2%) a combined valve and bypass surgery. The median MR-proADM value of the entire study population was 0.58 nmol/L (IQR: 0.44-0.79 nmol/L). Patients were stratified in risk categories based on their MR-proADM values (Low Risk ≤0.63nmol/L, Intermediate Risk 0.63-0.83nmol/L, High Risk >0.84nmol/L). Patients in the highest category presented with higher rates of diabetes mellitus (p <0.001), COPD (p <0.001), HF (p=0.009) and either bypass surgery (p=0.039) or the combination of bypass and valve surgery (p=0.008), compared to patients in the lowest tertile. We observed a significant increase in 5-year’s event rates for HHF/ CV Mortality in patients in higher risk groups (Low Risk 8.6% vs High Risk 37.7%, p <0.001, Figure 1). The adjusted Cox regression model found that MR-pro ADM was independently associated with a risk increase for HHF/ CV Mortality (adjusted HR of 4.45, 95% CI 2.55-8.09; p<0.001, Figure 2) comparing the High Risk to the Low Risk Group. A comparable risk increase could be observed in POAF, with an adjusted HR of 2.61 (High Risk Group vs Low Risk Group, 95% CI 1.46-4.67, p<0.001). Conclusion Within the prospective investigation, MR-pro ADM was found to be an independent predictor for HHF and CV mortality in patients undergoing cardiac bypass and/or valve surgery. Furthermore, there was a consistent predictive potential for POAF. In the era of personalized medicine, preoperative MR-pro ADM levels could help to identify patients at risk for serious adverse events, in order to apply intensified secondary prevention and reduce mortality and morbidity.

Impact of coronary revascularization on clinical outcomes of post-acute myocardial infarction patients with left ventricular thrombus

Abstract Background Left ventricular thrombus (LVT) is an uncommon, but dangerous complication seen in post-acute myocardial infarction (AMI). With advances in percutaneous coronary intervention (PCI) techniques, the incidence of post-AMI LVT has declined in the contemporary era. However, a minority of patients do not undergo coronary revascularisation due to medical contraindications or patient preference. This study aimed to evaluate the clinical characteristics and outcomes of post-AMI LVT patients treated with and without coronary revascularisation. Methods This was a retrospective study of 263 consecutive post-AMI patients diagnosed with LVT from November 2012 to January 2021, retrieved from a echocardiography database. Patients were stratified by the presence or absence of revascularisation treatment. Baseline clinical characteristics, treatment and outcomes data were collected and analysed. Results The median follow-up duration was 2.9 years (IQR: 0.9 – 4.7). A majority of post-AMI LVT patients underwent revascularisation via PCI (71.5%, n = 188), CABG (4.2%, n = 11) or thrombolysis (0.4%, n = 1). Unrevascularised patients (24.0%, n = 63) were older (p <0.001), more likely to be female (p <0.001), and had more co-morbidities such as previous stroke (p <0.001), heart failure (p = 0.001), chronic kidney disease (p = 0.020), and malignancy (p = 0.021). More unrevascularised patient had NSTEMI (p < 0.001), and significantly fewer were treated with triple therapy (p < 0.001). Incidence of LVT resolution was lower (p < 0.001) while all-cause mortality was higher (p < 0.001) for unrevascularised patients on univariate survival analyses. On multivariable Cox regression, revascularisation status was not an independent predictor of LVT resolution, bleeding, stroke, or all-cause mortality outcomes. Conclusion While unrevascularised post-AMI LVT patients had poorer outcomes compared to revascularised patients overall, revascularisation status itself was not independently associated with poorer clinical outcomes. Optimising medical therapy such as triple therapy remains a key treatment goal for post-AMI LVT patients.

Right atrio-ventricular strain as a predictor of death in left-sided heart failure

Abstract Background Right ventricular (RV) strain is an established outcome predictor in heart failure (HF). However, the role of right atrial (RA) strain in the setting of left-sided HF is incompletely understood. Purpose We sought to evaluate the RV, RA and combined right atrio-ventricular (RAV) strain using speckle-tracking echocardiography in a cohort of patients with left-sided HF and to assess their prognostic role. Methods 121 consecutive patients (mean age 59±14 years, 74% men) with HF with reduced ejection fraction (HFrEF) referred to our echocardiography department were prospectively enrolled. The main endpoint was all-cause death. RV strain was measured as the average longitudinal strain of the basal, mid, and apical segments of the RV free wall and was reported as a positive value, thus a lower RV strain reflecting a greater longitudinal dysfunction. RA strain was defined as the maximal longitudinal displacement of the atrial wall at end-systole, corresponding to atrial reservoir function. RAV strain was defined as the sum of RV strain and RA strain. Results During a median follow-up of 19±11 months, 26 patients (21%) died. Patients who reached the endpoint had lower left ventricular ejection fraction (LVEF) (21±7% vs. 26±7%, p=0.001), lower tricuspid annular plane systolic excursion (16±3 vs. 18±5, p=0.02) and lower RA strain (13± 10% vs. 18±11%, p=0.03). In univariable Cox regression, RV, RA and RAV strain were all predictors of death: HR=1.05 [95% CI, 1.00-1.11], p=0.045 for RV strain, HR=0.95 [95% CI, 0.91-0.99], p=0.02 for RA strain, HR=0.97 [95% CI, 0.94-0.99], p=0.01 for RAV strain. We constructed a multivariable model with well-established event predictors in HFrEF and one strain index at a time. After adjustment for LVEF, maximal left atrial volume, tricuspid regurgitation severity and pulmonary artery systolic pressure, only RAV strain remained an independent predictor of death (HR=0.97 [95% CI, 0.94-1.00], p=0.04), while RV strain and RA strain did not (p=0.07 for both). LVEF did not emerge as a predictor of death in multivariable regression (p=0.57). Conclusion In left-sided HF, RV and RA strain were predictors of death. Combining the longitudinal strain of both right heart chambers might improve risk stratification, since RAV strain remained the only independent predictor of adverse outcome after adjustment for confounders.

Comparison between coronary calcium score and segment involvement score when used in clinical routine

Abstract Data from a nationwide registry on coronary computer tomography angiography. Background The Coronary Artery Calcium Score (CACS) and segment involvement score (SIS) are crucial factors in assessing the severity of coronary artery disease (CAD) and determining the likelihood of future cardiovascular events. However, there are few large multicenter studies comparing the predictive value of CACS and SIS when used in the clinical routine. Objectives To compare CACS and SIS ability to predict cardiovascular outcomes when used in the clinical routine. Methods This retrospective cohort study included patients who underwent Coronary Computed Tomography Angiography (CCTA) for CAD evaluation between 2006-2022 in 29 different centers in Sweden. CACS was calculated using the Agatston method, and SIS was determined based on the number of coronary segments exhibiting plaque. For SIS, patients were categorized into SIS=0, SIS=1, SIS=2, SIS=3, SIS³4, for CACS patients were categorized into CACS=0, CACS=1-9, CACS=10-99, CACS=100-299, CACS³300. Patients were followed regarding the primary outcome of death or myocardial infarction. Multivariable Cox proportional hazards models were used for adjusting for potential confounders. Results A total of 23034 patients underwent CCTA and were followed for up to ten years. Median age (IQR) was 58 (49–67) years, 50% were women, 9% had diabetes mellitus, 42% had hypertension, 25% had hyperlipidemia, 5% had previously known CAD. There were 955 patients (4.1%) with myocardial infarction (MI) and 409 patients (2.2%) died during follow up. There was an increase in cardiovascular events with increasing SIS. When comparing SIS and presence of obstructive stenosis, SIS was a better predictor of outcome (Figure 1). There was also an increase cardiovascular events with increasing CACS (Figure 2). When adjusted for age, sex, risk factors, previous cardiovascular disease and intervention, both SIS and CACS were independently associated with outcome. When SIS and CACS were compared in a receiver operating characteristic curve, CACS had significantly larger AUC than SIS, (0.70[0.67-0.73] vs 0.62[0.60-0.63]). Conclusion Our findings show that both CACS and SIS are important and independent predictors of cardiovascular outcomes thereby offering a valuable tool for personalized risk stratification and management in clinical settings. When used in the clinical routine, CACS appears to be more strongly associated with outcome than SIS.Figure1 Survival SISFigure 2 Survival CACS

The associations of triglyceride glucose and its derived indexes with 10-year cardiovascular disease risk in a Chinese community-based population

Abstract Background The triglyceride-glucose (TyG) index has been regarded as a reliable surrogate marker of insulin resistance and an independent predictor of cardiovascular outcomes. However, the associations of the derived TyG indexes with incident CVD risk are controversial, and that the relevant data are sparse for the Chinese population studies. Objectives We aimed to investigate the association of TyG index and its derived indexes with incident CVD risk and to compare their predictive capacity in the Chinese community-based population. Methods We conducted a prospective cohort study on subjects from a Beijing community in China who were free of prevalent stroke or myocardial infarction at baseline. The primary endpoint was a new-onset major adverse cardiovascular event (MACE), defined as a composite of cardiovascular death, first non-fatal stroke, and first non-fatal acute myocardial infarction. Cox proportional-hazards regression analyses and time-dependent receiver operator characteristic curve analyses were performed. Results A total of 8,806 participants were included. The mean age was 56.51 ± 8.93 years, and 5,679 (64.5%) were female. The median value of TyG index, TyG-BMI, TyG-WC, and TyG-WHtR were 8.71 (8.34-9.12), 226.37 (201.02-252.87), 720.80 (653.52-791.03), and 4.47 (4.07-4.90), respectively. During a mean 9.7-year follow-up, a total of 877 (10%) cases of MACE were recorded. The Kaplan–Meier curves showed significant differences in cumulative hazards of new-onset MACE among tertiles of abovementioned indexes (Log rank P < 0.0001) (Figure 1). Multivariable Cox regression analyses revealed that TyG index, TyG-BMI, TyG-WC, and TyG-WHtR were positively associated with the hazards of MACE. Compared with tertile 1, the multivariable adjusted HRs (95% CIs) of incident CVD for tertile 3 were 1.26 (1.01-1.56), 1.57 (1.15-2.14), 1.54 (1.19-2.00), and 1.81 (1.40-2.33) for TyG, TyG-BMI, TyG-WC, and TyG-WHtR, respectively (Figure 2). There are no significant differences in the Harrell's C indexes among the various indexes compared to the TyG index (TyG index: 0.758 [0.743-0.774], TyG-BMI: 0.758 [0.743-0.773], TyG-WC: 0.758 [0.743-0.774], and TyG-WHtR: 0.760 [0.745-0.775]). Conclusions Higher TyG and its derived indexes are significantly associated with an increased risk of 10-year MACE. Our results suggest that TyG and its derived indexes may serve as a useful marker for stratifying CVD risk in the general population.

The CT-derived fat-free muscle fraction is associated with inflammation and predicts outcome in patients with aortic stenosis undergoing TAVR

Abstract Background The ESC guidelines underscore the importance of objective risk stratification in making patient-centered decision for valve interventions. However, they primarily rely on surgical risk scores, not considering essential factors such as frailty. Computed tomography (CT) is a routine part of the pre-interventional workup in patients undergoing TAVR and allows for body composition analysis, including the assessment of fat-free muscle fraction (FFMF) as an indicator of muscle quality. Purpose This study aimed to assess the correlation between FFMF and both inflammation and endocrine disorders, and to investigate the predictive value of FFMF in patients with aortic stenosis undergoing TAVR. Methods The study included 789 patients undergoing TAVR between 2017 and 2019. Evaluations involved CT scans to assess body composition. Using densitometric thresholds, the skeletal muscle area at L3/L4 level was separated into fatty and lean muscle to calculate the FFMF. The cohort was divided into tertiles of high, medium, and low FFMF, Figure 1. Results The study population was 45.5% female with a mean age of 81.2±6.0 years. Overall, 261 (33.1%) patients had a high FFMF, 293 (37.1%) had a medium FFMF, and 235 (29.8%) had a low FFMF. Patients with a low FFMF were older (82.3±5.9 vs 81.6±5.6 vs 79.8±6.2 years, p<0.01) and had higher rates of atrial fibrillation (52 vs 43 vs 37%, p<0.01), compared to those with a medium and high FFMF. Regarding body composition, low FFMF patients had a higher percentage of body fat (28.7±11.2 vs 26.8±9.1 vs 24.2±9.6%, p=0.01) and a lower percentage of body muscle (30.9±5.3 vs 31.3±4.2 vs 32.7±4.4%, p=0.03). Moreover, a low FFMF was associated with inflammation, as indicated by increased levels of C-reactive protein (6.3 vs 4.2 vs 3.1 mg/l, p<0.01) and procalcitonin (0.06 vs 0.05 vs 0.05 µg/l, p=0.01). Endocrinological assessment revealed lower levels of estradiol (6.8 vs 14.7 vs 15.0 pg/ml, p=0.02) and testosterone (0.18 vs 0.48 vs 2.35 ng/ml, p<0.01) as well as higher levels of cortisol (8.9 vs 7.7 vs 7.6μg/dl, p=0.05) in low FFMF patients. Regarding clinical outcomes, low FFMF was associated with increased one-year mortality (23.4%) compared to medium (11.6%) or low FFMF (3.8%, p<0.01), Figure 2A. This difference persisted over five years (p<0.01), Figure 2B. ROC curve analysis showed that FFMF had the strongest association with one-year mortality (AUC 0.75, p<0.01) and was superior to the STS-PROM (AUC 0.65) and EuroSCORE II (AUC 0.64). Multivariate analysis revealed that low FFMF was independently associated with mortality following TAVR (OR: 3.19 [CI: 1.64 – 6.22], p<0.01). Conclusion The CT-derived FFMF is associated with inflammation and endocrinological disorder in patients undergoing TAVR. Importantly, a low FFMF is a strong and independent predictor of dismal outcomes. FFMF assessment can seamlessly integrate into routine pre-interventional CTs, offering a promising objective parameter for outcome prediction.

Association between CMR derived hepatic T1 times, tricuspid regurgitation severity, and outcomes

Abstract Background Hepatic T1 times have been shown to predict adverse clinical outcomes. However, up to date, the various causes contributing to changes in hepatic T1 times are not fully understood. So far, strong correlations with liver congestion and hepatic fibrosis have been demonstrated. Valvular heart disease, especially tricuspid regurgitation (TR), can lead to congestive hepatopathy (CH) and might significantly increase liver T1 values. In contrast, hepatic steatosis – commonly present in patients with cardiovascular disease - would result in lower T1 values. Currently, no studies are investigating the relationship between hepatic T1 times and TR. Methods We retrospectively measured hepatic T1-times, displayed on standard cardiac T1-maps, in an all-comer CMR cohort. Only patients, who underwent a comprehensive transthoracic echocardiogram within three weeks of CMR were included. Results 1029 participants (67±17 y/o, 44% female) had mean hepatic T1-times of 605±79ms. Overall, 41% (417) presented with non/trace, 38% (391) mild, 13% (135) moderate, 8% (85) severe, massive, and torrential tricuspid regurgitation. Liver T1 times were significantly correlated with TR severity (no/trace: 586±72ms; mild: 601±74ms; moderate: 634±84ms; severe/massive/torrential: 665±83ms; r= 0.25, p<0.001). Additionally, when adjusted for higher NT-proBNP levels, and right ventricular function in a linear regression model, TR severity was associated with hepatic T1 times (p<0.001). During follow-up (mean 53±36months), a total of 326 (32%) events occurred. Patients with higher T1 times and more severe tricuspid regurgitation were more likely to suffer events (adj.HR 1.44 [95%CI:1.23-1.69] per 100ms increase, p<0.001). Conclusion Tricuspid regurgitation exerts a notable influence on hepatic T1 times which is likely attributable to hepatic congestion. Importantly, hepatic T1 times were associated with outcomes even after adjustment for NTproBNP, LVEF, and RVEF. This underscores the importance of hepatic T1 times as both a marker of tricuspid regurgitation and an independent predictor of clinical outcomes.

Association between left atrial dysfunction and adverse outcomes after tricuspid valve surgery for atrial functional tricuspid regurgitation

Abstract Objectives To identify factors associated with clinical outcomes in patients undergoing tricuspid valve (TV) surgery for atrial functional tricuspid regurgitation (AF- TR). Methods Among 1,670 patients who underwent TV surgery between January 2000 and December 2020, we included 83 AF-TR patients (69.1±9.2 years, 50 women) who had severe TR without any cause other than atrial fibrillation. A comprehensive analysis of right ventricular (RV) and left atrial (LA) function on preoperative and postoperative echocardiography was performed. LA function was evaluated by LA emptying fraction (LAEF), LA reservoir strain, and LA stiffness index. The primary outcome was a composite of all-cause death and heart failure hospitalization during follow up after surgery. Results For a median of 39.9 (interquartile range 19.9 to 55.8) months, the primary outcome occurred in 20 (24.1%) patients. Patients with a primary outcome showed significantly lower LAEF (9.7±7.3 vs. 21.8±6.7 %, p<0.001) and LA reservoir strain, and higher LA stiffness index than those without. However, there was no difference in RV chamber size and functional parameters according to the occurrence of a primary outcome. The restricted cubic spline plot exhibited a significant relationship between LAEF and primary outcome. The low baseline LAEF (<17%) group showed a poorer outcome than the high LAEF group (log rank p<0.001). In the Cox regression analysis, the low LAEF (<17%) was independent predictor for primary outcome (adjusted hazard ratio 13.5, 95% confidence interval 3.1–58.6). Conclusion In patients undergoing TV surgery with AF-TR, preoperative LA dysfunction was independently associated with adverse outcomes.Figure1

Prognostic implications of right and left atrial strain in diabetes mellitus without coronary artery diseases

Abstract Background 2D- speckle-tracking echocardiography (2D-STE) has recently be used to assess subclinical myocardial dysfunction, however its utility in diabetes mellitus (DM) has been specifically focusing on the longitudinal systolic function of the left ventricle (LV). Aim To assess the prognostic relation between left (LA) and right (RA) systolic and diastolic strain parameters with clinical outcome in patients with DM. Methods Of the initial 1721 diabetic patients screened for this study only 502 consecutive patients with DM were eligible and retrospectively enrolled, and 2D-STE strain parameters assessed on the 2D-TTE images. All patients were prospectively followed for development of new outcome/cardiac events which included hospitalization for acute HF, CVS-related death, new onset AF/AFI, stroke, heart transplantation, or need for ventricular assist device implantation. The 2D-STE analysis was used to measure the peak LA (longitudinal, radial and circumferential) and RA (longitudinal) strain. The long-term outcomes were evaluated for all-cause CVS outcomes and recurrent hospitalization. Results For the 502 eligible patients [mean age:58±4; 58 % male sex], 221 reached the combined endpoint. Mean follow-up was 1.1±0.6years. Both LA and RA strain parameters were significantly impaired compared to normal standard references (p<.0001), the RA was more impaired than LA strain parameters. The best performance parameters predictive of CVS (combined outcomes) events were for LA>RA systolic and diastolic strain, global RA systolic and diastolic strain (AUC: 0.74 and 70) and global LA longitudinal systolic and diastolic strain (AUC: 0.86 and 0.77). The strongest association between the degree of atrial myocardial mechanical dysfunction and risk of cardiovascular events was more evident for LA strain (free wall > global strain) and lesser extend to RA strain. More myocardial mechanical strain impairments were demonstrated in those with higher left atrial volume index (LAVI), NYHA ≥II class, significantly impaired diastolic function, lower strain values (LA, LV, RV), and tricuspid annular plane systolic excursion (TAPSE), p<.001). The LA (free wall) strain impairment was the independent predictors of combined outcome (including survival) after multiple adjustments using different models. Conclusion Patients with DM, LA strain parameters are stronger predictors of outcome than RA and other conventional parameters and should be included for regular clinical screening DM patients as these parameters provide a stronger prognostic stratification.

Impact of the lower extremity arterial calcification score on clinical outcomes after drug-coated balloon angioplasty for de novo femoropopliteal artery disease

Abstract Background Severe calcification, assessed using the peripheral artery calcification scoring system (PACCS), is associated with poor clinical outcomes after endovascular treatment (EVT) for de novo femoropopliteal lesions. However, the PACCS classification is a qualitative assessment performed in the angiographic room, and there are no established indicators for the quantitative assessment of calcification prior to treatment. Purpose We aimed to investigate the impact of the lower extremity arterial calcification score (LEACS) calculated using non-contrast lower limb computed tomography on clinical outcomes after drug-coated balloon angioplasty for de novo femoropopliteal artery disease. Methods We retrospectively analyzed the clinical outcomes of 141 consecutive patients treated at our center for de novo femoropopliteal artery disease using a drug-coated balloon between April 2018 and December 2022. Patients who did not undergo lower limb computed tomography before EVT were excluded from the analyses. LEACS was determined based on the method used to calculate the Agatston score for the coronary arteries. Each patient’s score consisted of a sum of calcification scores from ostium of superficial artery to the popliteal artery at the knee joint of treated limb. The primary and secondary outcomes measured were primary patency and clinically-driven target vessel revascularization (CD-TVR) at 1 year. Cox proportional hazards analysis was used to explore independent predictors of clinical outcomes. The study population was divided into higher and lower LEACS groups based on the cut-off value (1750), which best discriminated patency, and the outcomes were compared between the two groups. Results In the higher and lower LEACS groups, the mean age was 75.1 ± 9.1 years and 75.5 ± 11.0 years (p = 0.87) and the mean lesion length was 170.3±102.8 mm and 157.7±112.1 mm (p = 0.64), respectively. The higher LEACS group showed significantly lower 1-year patency than the lower LEACS group (53.5% vs. 84.3%, log-rank, p = 0.041). In addition, freedom from 1-year CD-TVR was significantly lower in the higher LEACS group than in the lower LEACS group (66.8% vs. 93.7%, p = 0.047). The Cox proportional hazard analysis showed that the higher LEACS group was an independent predictor of 1-year restenosis (odds ratio: 2.80, 95% confidence interval: 1.24–8.84, p=0.037), along with a small (< 5 mm) reference vessel diameter (odds ratio: 3.55, 95% confidence interval: 1.44–9.53, p=0.028). Conclusion Higher LEACS scores were independently associated with clinical outcomes after drug-coated balloon angioplasty for de novo femoropopliteal artery disease. Non-contrast lower limb computed tomography is an acceptable and feasible option for predicting the outcomes in patients with de novo femoropopliteal artery disease prior to treatment.

Single-cell and bulk transcriptomic datasets enable the development of prognostic models based on dynamic changes in the tumor immune microenvironment in patients with hepatocellular carcinoma and portal vein tumor thrombus

BackgroundHepatocellular carcinoma (HCC) patients exhibiting portal vein tumor thrombosis (PVTT) face a high risk of rapid malignant progression and poor outcomes, with this issue being compounded by a lack of effective treatment options. The integration of bulk RNA-sequencing (RNA-seq) and single-cell RNA-seq (scRNA-seq) datasets focused on samples from HCC patients with PVTT has the potential to yield unprecedented insight into the dynamic changes in the tumor microenvironment (TME) and associated immunological characteristics in these patients, providing an invaluable tool for the reliable prediction of disease progression and treatment responses.MethodsscRNA-seq data from both primary tumor (PT) and PVTT cells were downloaded from the Gene Expression Omnibus (GEO) database, while the International Cancer Genome Consortium (ICGC) and Cancer Genome Atlas (TCGA) databases were used to access bulk RNA-seq datasets. scRNA-seq, clustering, GSVA enrichment, mutational profiling, and predictive immunotherapeutic treatment analyses were conducted using these data with the goal of systematically assessing the heterogeneity of PT and PVTT cells and establishing a model capable of predicting immunotherapeutic and prognostic outcomes in patients with HCC.ResultsThese analyses revealed that PVTT cells exhibited patterns of tumor proliferation, stromal activation, and low levels of immune cell infiltration, presenting with immune desert and immune rejection-like phenotypes. PT cells, in contrast, were found to exhibit a pattern of immunoinflammatory activity. Core PVTT-associated genes were clustered into three patterns consistent with the tumor immune rejection and immune desert phenotypes. An established clustering model was capable of predicting tumor inflammatory stage, subtype, TME stromal activity, and patient outcomes. PVTT signature genes were further used to establish a risk model, with the risk scores derived from this model providing a tool to evaluate patient clinicopathological features including clinical stage, tumor differentiation, histological subtype, microsatellite instability status, and tumor mutational burden. These risk scores were also able to serve as an independent predictor of patient survival outcomes, responses to adjuvant chemotherapy, and responses to immunotherapy. In vitro experiments were used to partially validate the biological prediction results.ConclusionThese results offer new insight into the biological and immunological landscape of PVTT in HCC patients, By utilizing individual patient risk scores, providing an opportunity to guide more effective immunotherapeutic interventional efforts.

Elevated mitral valve pressure gradient following transcatheter edge-to-edge repair is independently associated with inferior outcomes in atrial, but not in ventricular secondary mitral regurgitation

Abstract Background In transcatheter mitral valve edge-to-edge repair (M-TEER), the goal of optimizing post-procedural residual mitral regurgitation inadvertently carries the risk of generating relevant mitral stenosis, resulting in an elevated mean mitral valve pressure gradient (MPG). In patients with primary mitral regurgitation, an elevated post-procedural MPG has been found to independently predict impaired outcomes. However, the effect of elevated post-procedural MPG on outcome after M-TEER in patients with secondary mitral regurgitation (SMR) has yet to be fully elucidated. This study investigated the impact of elevated MPG on outcome in the EuroSMR registry, a large, multi-center real-world cohort of patients with SMR. Methods This retrospective study included patients who underwent M-TEER for SMR between 2009 and 2021 in 12 centers. Patients were stratified into two groups based on SMR etiology: (1) ventricular SMR (vSMR), and (2) atrial SMR (aSMR). The etiology was considered as vSMR in patients with a left ventricular ejection fraction (LV-EF) <50% and aSMR in subjects with preserved left ventricular function (LV-EF ≥50%) and a markedly dilated left atrium (Left Atrial Volume Index [LAVi] ≥40ml/m2). According to the proposed M-VARC threshold, post-procedural MPG was assessed by discharge transthoracic echocardiography and was considered elevated if >5 mmHg. The primary endpoint was all-cause mortality after 5 years, with statistical analysis conducted using Kaplan-Meier and uni- and multivariable Cox Regression analysis. Results Among the 1703 patients in the study (vSMR: n=1420; aSMR: n=283), elevated post-procedural MPG was observed in 9.4% (n=133) of vSMR and 19.1% (n=54) of aSMR patients. Atrial fibrillation was significantly more prevalent in aSMR (78.4% vs. 57.1%, p<0.001). Patients with vSMR had a higher median surgical risk assessed by the EuroScore II (aSMR vs. vSMR: 7.0% [IQR 4.0, 13.1] vs. 4.9% [IQR 2.9, 8.5], p<0.001). Kaplan-Meier analyses for all-cause mortality after 5 years demonstrated significant differences in aSMR patients (low vs. elevated MPG: 48.9% vs. 69.8%, log-rank p<0.01), while there was no difference in vSMR patients (55.7% vs. 60.8%, log-rank p=0.66) (Figure 1). This observed effect remained significant even after accounting for common confounding factors: elevated MPG was an independent predictor for all-cause mortality in aSMR patients (HR=1.86; 95%-CI: 1.14-3.02, p=0.013) but not in vSMR patients (HR=1.00; 95%-CI: 0.74-1.35, p=0.99). Conclusion Our findings suggest that elevated post-procedural MPG is an independent predictor of adverse outcomes in patients with aSMR, but not in those with vSMR. This effect may partially be explained by a reduced left atrial function and higher rates of atrial fibrillation.Figure 1.Study flowchart

Mortality based right ventricle functional echocardiographic cutoffs in patients with compared to without tricuspid regurgitation

Abstract Introduction Tricuspid-annular-plane-systolic-excursion (TAPSE) and peak-lateral-tricuspid-annular-systolic-velocity (S’) are frequently used echocardiographic indices of right-ventricle (RV) function. Tricuspid regurgitation (TR) is present in 70-90% of the general population, and while trivial or mild TR may not have prognostic implications, several studies have demonstrated that ≥moderate TR is an independent predictor of adverse outcomes, and that increasing TR severity incurs an increased risk of mortality. The abnormality thresholds for TAPSE and S' are based on published mean and standard deviation data obtained from healthy adults, but not on outcome data. The effect of significant TR on the abnormality threshold of TAPSE and S’ prime is currently unknown. Purpose We aimed to re-examine the abnormality thresholds for TAPSE and S' based on their association with mortality in consecutive patients, stratified to with, or without, significant tricuspid regurgitation (TR). Methods We performed a retrospective analysis of consecutive patients undergoing echocardiography between 2011-2021 in a large tertiary center. TR was assessed using a semi-quantitative method. Cut-off values associated with excess mortality were assessed using spline curves in univariate, and multivariate Cox logistic regression analyses. Results A total of 24717 subjects were included in the current analysis with a median (interquartile range) follow up of 1321 (581-1902) days. 1143 (4.6%) subjects had clinically significant (≥moderate) TR. In the entire cohort, TAPSE<20.9 mm and S’ <10.9 cm/s were associated with excess mortality. In sub-group analysis, among subjects with significant TR, TAPSE<18.0 mm and S'<10.0 cm/s was the cutoff associated with excess mortality, while subjects without TR had a higher cutoff of TAPSE<21.5 mm and S'<10.9 cm/s. In a multivariate model adjusted for the presence of TR and baseline characteristics, TAPSE<20.9 mm (HR 1.20, 95% CI 1.14-1.27; p<0.001) and S’<10.9 cm/s (HR 1.07, 95% CI 1.01-1.13; p=0.015) were independent predictors for mortality. A sensitivity analysis, which included 14,664 patients with additional echocardiographic indices, demonstrated that low TAPSE remained an independent predictor of mortality (aOR=1.15; 95% CI: 1.07-1.24; p<0.001) Conclusion TAPSE and S’ thresholds associated with excess mortality are higher than those previously reported in healthy adults. The TAPSE and S' cutoffs associated with excess mortality were lower in patients with significant TR compared to patients without, suggesting that a personalized approach for their interpretation is needed.Central illustration

Different right ventricular mechanics in atrial and ventricular secondary tricuspid regurgitation and their prognostic role. A multicentric three-dimensional echocardiography study

Abstract Background/Introduction Secondary tricuspid regurgitation (STR) can develop from markedly different etiologies. Both progressive dilation and dysfunction of the right atrium (atrial phenotype, ASTR), and adverse right ventricular (RV) remodeling (ventricular phenotype, VSTR) may result in STR. RV function is a major determinant of outcome in patients with STR. However, data about how RV function adapts to ASTR and VSTR are scarce, and the prognostic implications of RV mechanics in ASTR and VSTR remain to be clarified. Purpose Accordingly, we aimed to investigate the RV mechanical patterns in ASTR and VSTR and to examine their prognostic role using three-dimensional (3D) echocardiography. Methods We enrolled 192 patients with STR (60% women) who underwent clinically indicated transthoracic echocardiography in a multicentric prospective observational study. The primary outcome was defined as a composite of heart failure hospitalization or cardiac death. STR etiology was assessed based on the TVARC criteria (ventricular STR n=134, atrial STR n=58). STR severity was categorized using STR effective regurgitant orifice area according to current guidelines. We assessed RV function by measuring the tricuspid annular plane systolic excursion (TAPSE) by M-mode echocardiography and RV ejection fraction (EF) by 3D echocardiography. In addition, we imported the 3D RV meshes into the ReVISION software package (Argus Cognitive, Inc, Lebanon, USA) to quantify the relative contribution of the longitudinal (LEFi), radial (REFi), and anteroposterior motion components (AEFi) to total RV EF. Results ASTR and VSTR patients had comparable TAPSE (17±5 mm vs. 18±5 mm, p=0.10), while RV EF was significantly higher in ASTR (54±7% vs. 47±10% p<0.001). Although LEFi (0.37±0.08 vs. 0.38±0.10, p=0.95) and AEFi (0.45±0.08 vs. 0.44±0.11, p=0.53) were comparable between ASTR and VSTR, REFi was significantly lower in VSTR (0.52±0.09 vs. 0.47±0.12, p<0.01). RF EF was comparable among STR severity grades (mild vs. moderate vs. severe: 50±11 vs. 49±9 vs. 50±10%, respectively, p=0.85). Conversely, LEFi was significantly higher in mild and moderate STR vs severe STR (0.39±0.08 vs. 0.39±0.09 vs. 0.35±0.10, respectively, p=0.04). Using multivariable Cox regression based on variables significant in the univariate analysis, REFi was a significant independent predictor of outcome in the entire cohort (hazard ratio: 0.978 [CI, 0.959-0.999], p= 0.037). Conclusions Using 3D echocardiographic assessment, ASTR and VSTR patients demonstrated significant differences in the RV mechanical pattern, with a lower contribution of the radial contraction in the case of ventricular STR etiology. While RV EF was comparable between STR severity grades, the relative importance of the longitudinal motion significantly differed. Notably, the relative contribution of radial motion to RV function demonstrated independent prognostic value in patients with STR.RV mechanics in STR severity stages