Combined Endpoint Research Articles

Combined Assessment of Function and Survival to Demonstrate the Effect of Treatment on Progressive Supranuclear Palsy.

Progressive supranuclear palsy (PSP) is a rare and fatal neurodegenerative disorder for which there are currently no disease-modifying treatments. Recent trials of potential therapies had durations of 12 months, which may be insufficient because of nonrandom missingness due to death. Longer durations, incorporating PSP Rating Scale and survival, can reduce the potential for type II error. Selecting efficacy measures more sensitive to disease modification may facilitate identification of treatment effect. The objective of this study was to evaluate the simulated phase 3 PSP trial assessing the effect of disease-modifying intervention on a novel combined primary endpoint comprising function (PSP Rating Scale) and survival, the Combined Assessment of Function and Survival (CAFS), and to determine operating characteristics of the CAFS. To simulate PSP progression in the trial population, we developed models of PSP Rating Scale and survival using data from published clinical studies. These models were used to define operating characteristics of the CAFS for use in a phase 3 trial. The sample size determined (N = 384; 1:1 randomization) would provide >80% power to detect significant treatment effects on the CAFS compared with placebo. The CAFS provides good operating characteristics and increased power to detect moderate treatment effects on the PSP Rating Scale. We propose a trial design allowing potential detection of treatment effects at a preplanned interim analysis after participants complete 12 months of treatment, with assessment of effects of treatment (≤24 months) on survival. Use of the CAFS could provide a comprehensive and robust estimate of the clinical benefit of future therapies. © 2024 UCB. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Characteristics and outcomes of patients with a history of cancer enrolled in our prospective HFpEF registry

Abstract Background Along with the aging population, the incidence of concomitant heart failure with preserved ejection fraction (HFpEF) and cancer, is increasing. However, little is known about the typical characteristics of patients with both HFpEF and a history of oncologic disease. Aim We aimed to characterize the distinctive characteristics and outcomes of patients with a history of cancer within a prospective HFpEF registry. Methods We analyzed data from 491 unselected HFpEF patients from our tertiary university center between 2010 and 2022 and followed the patients until 2023. Laboratory parameters and comorbidities were assessed. Patients were categorized into those with and without a history of cancer, including various malignancies, survivors of childhood cancer, radiation therapy, with or without chemotherapy. Kaplan-Meier estimates were used to explore the association between cancer history, as well as previous radiotherapy, and a combined endpoint of heart failure hospitalization and/or all-cause death. Results In this analysis of 491 HFpEF patients, a total of 101 patients (21%); had a history of cancer [mean age 74±7 years; female 72 (72%), male 29 (29%)]. The median time from cancer diagnosis to the initial HFpEF visit was 7.0 years (IQR 13-0.5 years). The most prevalent primary cancer sites included the chest wall (32%) comprising 4 adenocarcinomas of the lung and 28 cases of breast cancer, followed by the gastric (28%), urogenital system (18%), hematologic and lymphatic system (16%), cancers located at the head and neck (5%) and endocrine malignancies (1%). Radiotherapy (39%) and chemotherapy (26%) were common. Notably, no significant differences were observed, between patients with or without a history of cancer, in terms of median NT-proBNP levels [1037 (IQR 416-2075) vs. 1060 pg/ml (IQR 462-2013)] and the frequency of key cardiovascular comorbidities (all p>0.05, see Table 1). Over the study period [median follow-up 50 months (IQR 18-76)], 64 (64%) of cancer patients met the combined endpoint, with no statistically significant difference in outcomes between HFpEF patients with and without a cancer history (log-rank p=0.222, see Figure 1). Furthermore, there was no significant difference in the combined endpoint between patients who had undergone radiotherapy and those without (log-rank p=0.162). Conclusion Our findings highlight a high coexistence of cancer and HFpEF, which can frequently occur after oncology therapies. The data suggest that the presence of a history of cancer or previous radiotherapy did not significantly impact overall outcomes in HFpEF patients compared to those without cancer during the study period. Further research is needed to characterize patients with both disease entities in detail. Due to modern cardiovascular therapy in a university and cardio-oncology clinic setting, outcomes for cancer patients appear better than expected.

HFpEF is associated with a higher risk of hospitalization or death in men undergoing transcatheter edge-to-edge tricuspid valve repair

Abstract Aims There are fundamental differences between women and men regarding the pathophysiology and etiology of tricuspid regurgitation (TR) as well as underlying comorbidities. The aim of this study was to analyze differences between female and male patients undergoing transcatheter edge-to-edge tricuspid valve repair for TR (T-TEER) and to identify gender-specific predictors of adverse outcome. Methods and Results In this monocentric study 197 consecutive patients (96 women and 101 men) undergoing T-TEER at our university heart center were included. Prevalence of heart failure with preserved ejection (HFpEF) was higher in women than in men (63% vs. 37.3%; p=0.001) whereas men more often had heart failure with reduced ejection fraction (HFrEF; 62.7% vs. 37%; p=0.001). Women had more severe symptoms (86.2% in New York Heart Association (NYHA) class III-IV vs. 72.3% in men; p=0.022). Device success rates (p=0.64), procedural characteristics (e.g. number of clips, p=0.17) and postprocedural results (TR grade post clip, p=0.1) were comparable. One-year mortality did not differ between genders (5.9% in women, 8.6% in men; p=0.53). Likewise, no significant difference could be found with regard to heart failure hospitalizations within one year after T-TEER (20.3% in women, 18.8% in men, p=0.82). Strikingly, prevalence of HFpEF was substantially higher than of HFrEF in men that reached the combined endpoint of one-year mortality or rehospitalization for heart failure (61.5% vs. 38.5%; p = 0.08). In women, no relevant difference could be found (27.0% vs. 32.4%; p=0,623). To identify gender-specific predictors of the combined endpoint, a cox regression analysis was performed. In men, HFpEF emerged as an independent predictor (HR 2.703; 95% CI 1.069 – 6.837; p = 0.036). In women, NYHA functional class proved to be an independent risk factor (Hazard Ratio (HR) 3.362; 95% confidence interval (CI) 1.085 – 10.415; p=0.036) for the combined endpoint whereas HFpEF was not associated with adverse outcome (HR 0.865, 95% CI 0.259 – 2.885, p=0.81). Conclusions Women undergoing T-TEER were more symptomatic and had higher prevalence of HFpEF compared to men. Nevertheless, HFpEF emerged as an independent predictor of the combined endpoint of one-year mortality or rehospitalization for heart failure only in men. NYHA functional class independently predicted adverse outcome in women.

Right ventricular-pulmonary artery coupling and clinical outcomes after mitral transcatheter edge-to-edge repair: A meta-analysis

Abstract Introduction Mitral transcatheter edge-to-edge repair (TEER) has gained prominence in the realm of cardiovascular care, as it has been proven to improve patient prognosis and quality of life. While the primary focus of such interventions is the mitral valve itself, understanding the broader impact of right ventricular function and pulmonary artery dynamics is crucial for a comprehensive assessment of clinical efficacy and patient outcomes. A newly recognized index, right ventricular-pulmonary artery (RV-PA) coupling, reflects the RV's ability to handle pulmonary afterload and is associated with adverse outcomes. Purpose This meta-analysis consolidates findings from diverse studies to systematically evaluate the association between RV-PA coupling parameters and the success of mitral TEER. Methods We conducted a systematic literature search for studies assessing RV-PA coupling indices at baseline in patients undergoing mitral TEER. We recorded the year of publication, method of RV-PA assessment, and the proposed cutoffs. The primary outcome of interest was the combined primary endpoint of included studies at maximal follow-up and the adjusted hazard ratios of RV-PA uncoupling were extracted if they were available. Secondary outcomes included mortality and post-operative mitral regurgitation at follow-up. Pooling of the hazard ratios was conducted according to a random effects model. I2 was chosen as the measure of between-study heterogeneity, with values exceeding 50% being significant. Results We identified a total of 316 studies, of which 8 were ultimately selected for data extraction and inclusion in the meta-analysis after screening of title/abstract/full-text. All but one study utilized the Tricuspid Annular Plane Systolic Excursion/Pulmonary artery systolic pressure (TAPSE/PASP) as the method of RV-PA assessment. According to the results of the meta-analysis, the presence of baseline RV-PA uncoupling was associated with a 2.3-fold increased risk of facing the combined primary endpoint at maximal follow-up (Figure, Panel A). All-cause mortality was also approximately 2.2-fold higher in cases of RV-PA uncoupling (Figure, Panel B). Finally, post-operative MR was 1.4-fold higher in cases of RV-PA uncoupling (Figure, Panel C). Significant between-study heterogeneity was detected in all the examined endpoints. Conclusion: This meta-analysis indicates that RV-PA uncoupling at baseline represents an important prognostic marker in patients undergoing mitral TEER.Figure

The prognostic impact of tricuspid regurgitation improvement after left-sided valvular interventions

Abstract Background Tricuspid regurgitation is a common bystander in patients with left-sided valvular heart disease such as mitral regurgitation (MR) or aortic stenosis (AS). Data on the prognostic impact of potential TR improvement after interventions for left sided valvar disease is scarce. Objectives This study aimed to assess incidence and prognostic value of TR improvement after left-sided valvular interventions (M-TEER and TAVI) using merged data from two prospective single-center registries. Methods The merged database included all consecutive patients with symptomatic left-sided valvular heart disease (MR or AS) undergoing either M-TEER or TAVI from 2008 until 2023. The prognostic impact of baseline TR severity and TR improvement was assessed using Kaplan-Meier estimates and stepwise Cox regression. TR improvement was defined as a reduction in TR severity at discharge by at least one grade compared to baseline in patients with ≥moderate TR at baseline. Results A total of 4,461 patients undergoing left-sided valvular interventions (M-TEER: N=663; TAVI: N=3,798) were eligible for study inclusion (age 81.0 years [IQR 76.2-84.7], 52.7% male). TR severity at baseline was none or mild in 70.9% (N=3,161), moderate in 19.4% (N=864), and severe in 9.8% (N=436). Patients with ≥moderate TR at baseline showed significantly higher rates of all-cause mortality (p<0.001) and of the combined endpoint after 3 years (p<0.001), compared to patients with none or mild TR. This finding was consistent for the M-TEER and TAVI subgroups. Among patients with ≥moderate TR at baseline (N=1,300), 499 patients (38.4%) showed TR improvement by at least one grade following left-sided valvular intervention, while TR did not improve in 801 patients (61.6%). In the overall study population, patients with TR improvement showed lower rates of all-cause mortality (p<0.001) and the combined endpoint after 3 years (p=0.006) (Figure 1A, 1B). This finding was consistent only in the subgroup of patients undergoing M-TEER (p=0.013 and p=0.003), but not for patients undergoing TAVI (p=0.12 and 0.62) (Figure 2A, 2B). Following stepwise Cox regression (incl. adjustment for treatment), TR ≥moderate at baseline was independently associated with death (p=0.0019) and combined death or HF rehospitalization (p=0.0068) 3 years after intervention (Figure 3A,3B). TR improvement was independently associated with survival (p=0.015) and combined survival or absent HF rehospitalization (p=0.032) 3 years after intervention (Figure 4A, 4B). Conclusions Patients with TR improvement after left sided valvular interventions showed significantly better clinical outcomes compared to those without. These results reinforce the need for assessment for TR assessment before and after left-sided valvular interventions and may identify patients that qualify for subsequent TR intervention.

Left atrial cardiomyopathy predicts stroke recurrence and atrial fibrillation

Abstract Background Markers of atrial cardiomyopathy, encompassing both left atrial (LA) structure and function, have been linked to an increased long-term risk of ischemic stroke and atrial fibrillation (AF). However, the short-term risk associated with these markers in patients with stroke without previously known or detected AF during stroke workup remains insufficiently characterized. Purpose To investigate the association between functional and structural markers of atrial cardiomypathy using cardiac magnetic resonance (CMR) with late gadolinium enhancement (LGE) in patients with stroke of either i) undetermined etiology or ii) small or large-vessel stroke and the recurrence of stroke or new-onset AF. Methods Between 2019 and 2021 we consecutively included 91 patients with a recent stroke (<30 days) without known or detected AF during at least 48-hours of continuous monitoring. All patients had CMR with LGE to determine LA emptying fraction, LA volumes, and LA fibrosis. The primary endpoint was a composite of stroke recurrence or new-onset AF. Results Baseline characteristics are presented in Table 1. Over a median follow-up of 2.3 years, fourteen patients (15%) reached the combined endpoint of stroke or new-onset AF. Multivariable cause specific regression analysis demonstrated that a lower LA emptying fraction was associated with the primary endpoint (hazard ratio [HR], 1.41 per 5% decrease [95% CI, 1.09–1.82]). LA volumes and LA fibrosis did not show any associations with the combined endpoint (Table 2). Subgroup analysis indicated that the results were predominantly driven by new-onset AF in patients with stroke of undetermined etiology Conclusion Our results suggests that LA emptying fraction, measured using CMR, may serve as a prognostic indicator for stroke recurrence or new-onset atrial fibrillation in patients without detected AF, especially in those with stroke of undetermined etiology. Surprisingly, LA fibrosis was not associated with either recurrence of stroke or new-onset AF.

Mortality and heart failure in patients with severe tricuspid regurgitation. Impact of RV volumes and function by CMR.

Abstract Background Beyond symptoms, right ventricle (RV) dilatation and dysfunction are established criteria for intervention in patients with significant tricuspid regurgitation (TR); however defined thresholds to support intervention are lacking. As a result, the optimal timing for intervention remains controversial and it is commonly undertaken at a late stage. Purpose To describe prognostic cut-off values of RV size and function by Cardiac Magnetic Resonance in a multicentre cohort of patients with at least severe TR. Methods The study enrolled patients with at least severe TR assessed by 2D echocardiography who underwent a contemporary cardiac magnetic resonance (CMR) study. Conventional parameters of biventricular volume and function were assessed in all patients. A combined endpoint of hospital admission due to heart failure (HF) and all-cause mortality was defined. Results 318 patients with severe TR recruited from 5 tertiary care hospitals were included in this study (70 ± 11 years, 67% female, 73% NYHA I or II). Regarding the etiology, 10% were primary TR, 1% CIED-related TR, 46 % atrial secondary TR and 43% ventricular secondary TR. After a median follow-up of 28 months (IQR: 10-54 months), 42% of the patients (n=134) experienced the combined endpoint (n=113 were admitted due to HF, n=61 died). After adjusting for age, NYHA class, comorbidities, type of TR and LVEF in a multivariate Cox proportional model (LR Chi-Square: 88.01, p<0.001), RV-EDV and RVEF were independently associated with all-cause mortality and heart failure (adjusted HR for RV-EDV per ml/m2 =1.008 [1.005-1.012], p<0.001 and RVEF HR per 1%=0.961 [0.942-0.981], p<0.001). Thresholds of RV-EDV ≥ 93 ml/m2, RV-ESV ≥ 39 ml/m2 and RVEF ≤ 58% held the best accuracy to predict outcomes (figure). In multivariable analysis, prognostic cut-off values of RV-EDV, RV-ESV and RVEF was associated with 1.91, 2.03, and 1.76-fold increased risk of HF or all-cause mortality respectively (RV-EDV HR: 1.91 [1.34-2.71], p<0.001, RV-ESV HR 2.03 [1.42-2.89], p<0.001 and RVEF HR1.76 [1.25-2.49], p=0.001). Conclusion RV size and function are crucial for determining optimal timing for TR intervention. CMR remains the gold standard to assess RV remodeling. Cut-off values of RV volume and function by CMR are defined in a multicentre cohort of patients based on outcome data; proposed thresholds differ from those previously established by echocardiography.Kaplan Meier curves

Do CYP2D6 polymorphisms affect the efficacy and toxicity of flecainide? A cohort study

Abstract Background The CYP2D6 enzyme, coded by the CYP2D6 gene, is the primary metabolic pathway for flecainide.(1,2) Over the years, studies on how different variants of this gene affect flecainide metabolism and efficacy have yielded contradictory results.(3–7) This is likely due to the fact that CYP2D6 pharmacogenetic classifications were not standardized until 2017.(8,9) Purpose To date, there has been no published study using a standardized classification to assess the efficacy and toxicity of flecainide across different CYP2D6 phenotypes; therefore, we decided to study this. Methods We conducted a cohort study with data collected through indirect methods, blinding all parties involved except the statistician. We identified patients with flecainide prescriptions (100 mg/12 h) and follow-up in our health area (n=450,136 people) between 2017 and 2021. A primary combined endpoint composed of initial inefficacy and early toxicity was pre-set, and a secondary combined endpoint of toxicity or inefficacy during follow-up. Results 104 patients met the criteria and agreed to participate: 38 (36.5%) intermediate metabolizers, 52 (50%) normal metabolizers, 2 (1.9%) could not be classified with certainty (compatible with intermediate or normal metabolizers), 7 (6.7%) poor metabolizers, 4 (3.8%) ultra-rapid metabolizers, and 1 (1%) possible hybrid. Intermediate and normal metabolizers showed an almost superimposable incidence of the primary endpoint (28,9% vs 28,8%, p=0.99), early inefficacy (21,6% vs 17,4%, p=0.97) and early toxicity (13,2% vs 13,3%, p=0.72). No significant differences were observed in multivariate analysis (p=0.76, picture 1) or in a combined endpoint of toxicity or inefficacy during follow-up (p=0.58, Kaplan-Meier in picture 2). Differences were seen in the primary endpoint when comparing poor metabolizers to the rest of the sample, although they did not reach statistical significance (p=0.07), likely due to the small number of patients in this group (n=7, absolute risk reduction -32%; 95% confidence interval: -41% to -23%). Conclusions Using the standardized classification for CYP2D6 pharmacogenetics, no statistically significant differences were detected between the two largest groups, intermediate and normal metabolizers. It is possible that better results are achieved in poor metabolizers. Based on these results, it is worth questioning whether, in an attempt to minimize the risk of flecainide toxicity, doses that are subtherapeutic in all groups except slow metabolizers have been used unknowingly.

Effective RV ejection fraction by CMR: a new index of RV function in patients with severe TR

Abstract Background Right ventricle (RV) dysfunction represent an formal indication for intervention in patients with significant tricuspid regurgitation (TR). RV ejection fraction (RVEF) by Cardiac Magnetic Resonance (CMR) is considered the gold standard of RV function; however it is influenced by changes of preload conditions and may remain unaffected until late stages in severe TR. Effective RV ejection fraction (eRVEF) is corrected by the amount of TR and may reflect an earlier parameter of RV dysfunction. Purpose To compare the prognostic impact of both indices of RV function: RVEF and eRVEF in a multicentre cohort of patients with severe TR. Methods Patients with at least severe TR assessed by 2D echocardiography with a contemporary cardiac magnetic resonance (CMR) study were included in this study. In addition to conventional parameters of biventricular volume and function, eRVEF was assessed in all patients. eRVEF was calculated according to the formula: eRVEF=net pulmonary forwardflow/RV− EDV (figure). A combined endpoint of hospital admission due to right heart failure and cardiovascular mortality was defined. Results 271 patients with severe TR recruited from 5 tertiary care hospitals were included in this study (age 71 ± 11 years, 67% female, 83% NYHA I or II). Regarding the etiology, 10% were primary TR, 1% CIED-related TR, 46 % atrial secondary TR and 43% ventricular secondary TR. After a median follow-up of 27 months (IQR: 10-53 months), 41% of the patients (n=112) experienced the combined endpoint (n=97 were admitted due to HF, n=49 died). After adjusting for age, NYHA class, comorbidities, type of TR and LVEF in multivariate Cox proportional models, both RVEF and eRVEF were independently associated with all-cause mortality and heart failure (adj HR for RVEF HR per 1%=0.96 [0.94-0.98], p<0.001 and for eRVEF per 1%=0.98 [0.96-0.99], p<0.001). A value of eRVEF of ≤37% were associated with impaired prognosis (figure). eRVEF identified higher rates of RV dysfunction compared to RVEF (49% vs 38%, p<0.001). eRVEF was superior to RVEF to predict outcomes (higher AUC 0.70 [0.63-0.76] vs 0.66 [0.59-0.73, p<0.001; Δ C-statistic 0.139 [0.040-0.237], p=0.05). Conclusion RV function is crucial for determining optimal timing for TR intervention. eRVEF is corrected by the amount of TR and identify higher rates of RV dysfunction in severe TR. eRVEF held stronger association with outcome compared to RVEF.eRVEF calculationKaplan Meier Curves

Prognostic value of left atrial and ventricular strain in moderate atrial and ventricular secondary mitral regurgitation

Abstract Background Secondary mitral regurgitation (SMR) is associated with increased morbidity and mortality. In these patients, left ventricular global longitudinal strain (LVGLS) and left atrial reservoir strain (LARS) have been proposed to improve risk stratification. However their prognostic value was shown to be inconsistent when considering the SMR etiology (i.e. atrial or ventricular), possibly due to be the influence of atrial fibrillation (AF) on these measures and specifically LARS. Moreover, data focusing on moderate SMR is lacking. Aim To investigate the prognostic value of LVGLS and LARS in patients with SMR stratified according to etiology, and to identify optimal threshold for both measures. Methods Patients (n=1061; age 68±11years , 59% male) with moderate SMR were retrospectively included and classified as ASMR or VSMR, and further subdivided into "sinus rhythm (SR) subgroup" (ASMR-SR: n=68 , VSMR-SR: n=435) or as "AF subgroup" (ASMR-AF: n=284 , VSMR-AF: n=274), if patients had history of AF. The endpoint was a composite of heart failure events and all-cause mortality. Threshold values for LVGLS and LARS were defined based on spline curve analysis. Results As compared to VSMR, ASMR patients were more frequently female (61% vs. 35%, p<0.001), had less comorbidities and were less symptomatic (i.e. NYHA functional class III-IV in 11% of ASMR vs. 24% of VSMR, p<0.001). For the echocardiographic characteristics, VSMR patients showed lower LV ejection fraction and LVGLS, as compared to ASMR patients. For both ASMR and VSMR, patients in the AF subgroups had larger LA volume index, lower LARS and more severe tricuspid regurgitation (Figure 1). During a median follow-up of 78 (IQR: 44-111) months, 27% of ASMR-SR, 37% of ASMR-AF, 50% of VSMR-SR and 72% of VSMR-AF group reached the combined endpoint. Separated multivariable cox regression analyses were performed in ASMR and VSMR patients (Table 1): for both etiologies, LARS and LVGLS were independently associated with the endpoint after correcting for other significant variables at the univariate analysis, including the SR or AF group and the interventions during follow-up. In addition, a stepwise addition of LVGLS and LARS to a basic model led to a significant difference in the likelihood ratio for both groups. The thresholds of LVGLS and LARS associated with an increased risk of the combined endpoint differed per etiology. For LVGLS the threshold was <16% for ASMR, and <12% for VSMR. When considering LARS assessment, different thresholds were identified according to the SR or AF group: <18% in ASMR-SR; <15% in ASMR-AF; <17% in VFMR-SR and <12% in VFMR-AF. Conclusion In moderate SMR patients, LVGLS and LARS are independently associated with outcomes both in ASMR and VSMR and could be considered to improve risk stratification. However, lower threshold for both parameters should be considered based on etiology and on the presence of AF.

Sex differences in aortic prognosis in Marfan patients, a retrospective longitudinal study from the REPAG registry

Abstract Introduction Previous studies(1-4) have suggested a more favourable aortic outcome among women with Marfan syndrome (MFS), although the precise underlying mechanism remains not completely understood. In this retrospective longitudinal study, we aim to evaluate sex differences in aortic events in a large cohort of Marfan patients seen in 11 tertiary centres in Spain. Methods Patients with diagnosis of Marfan syndrome (MFS) were included. Data on aortic events (AE) including elective aortic surgeries, acute aortic syndrome or death were incorporated. Survival free of the combined endpoint of death or first aortic event (elective aortic surgery or acute aortic syndrome) was compared between male and female by the Kaplan-Meier curves, log-rank test and subsequent Cox regression analysis. Results A total of 442 patients with MFS where included, 48.2% female and 56.2% index cases. Although systemic score and proband proportion was not different between both sexes, the diagnosis was earlier in males (p=0.01) (Table). Furthermore, among adult patients, males exhibited greater height, weight, and body surface area (BSA). Absolute aortic root diameter at baseline was greater in males, but not BSA-indexed diameters or z-scores. Combined endpoint of death or aortic event was observed in 192 patients (120 male, 72 female, p=<0.00001). Female sex had better survival free of the combined endpoint in a multivariable Cox analysis (HR 0.41 95% CI=0.30–0.55) with a mean survival free of the combined endpoint of 41.3yrs in male and 61.4 years in females (p<0.0001) (Figure).Although a higher proportion of elective aortic interventions as first event was observed in males (66.7% vs 52.8%), the proportion of type A dissections was similar between both sexes (26.7 vs 26.4%) with increased frequency of type B dissections in females as first aortic event (4.2 vs 15.3%) (p=0.026) Conclusions Male patients with MFS present higher aortic root diameters but similar BSA-indexed and zscores than females. Survival free of first aortic event or death is reduced in male with MFS, with greater frequency of elective aortic intervention. Although this last is driven by absolute aortic diameter, no increase on type A dissection was observed in women. These findings might suggest a potentially less aggressive manifestation of proximal aortic disease in women with MFS.Table:Comparison male and female Marfan

Prognostic value of cardiac magnetic resonance global circumferential strain assessed by feature tracking techniques in asymptomatic patients with significant aortic regurgitation

Abstract Introduction Cardiac magnetic resonance feature tracking (CMR-FT) deformation techniques have gained significant interest in recent years. They provide a comprehensive evaluation of myocardial function and improve the reproducibility of echocardiography strain techniques. Purpose The aim of this study was to evaluate whether CMR-FT deformation parameters play a role predicting worse clinical evolution in patients with chronic significant aortic regurgitation (AR) not meeting guidelines intervention criteria. Methods We included 85 patients with significant AR (moderate, moderate/severe, and severe) referred for CMR. Only asymptomatic patients with preserved left ventricle ejection fraction (LVEF) were considered for inclusion. Other concomitant myocardiopathies were excluded. Conventional functional left chambers parameters as well as myocardial deformation were evaluated, including global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS). A composite clinical major outcome was assessed, including admission heart failure admission, need for aortic valvule replacement and all-cause mortality. Results The mean age of the sample was 62 years old. One third of the patients were females. Other clinical baseline characteristics were not significantly different between groups when compared with Chi-squared and T-test statistical analysis. Mean follow-up was 42 months (±31). 21 patients presented with the composited outcome previously described. End-diastolic and end-systolic volumes did not differ between groups. Mean end-diastolic volume (EDV) was 196 ± 6.1 mL and mean end-systolic volume (ESV) was 88 ± 3.4 mL. Mean values of CMR-FT GLS, GCS and GRS were -14.1%, 22.8% and -16.9% respectively. GCS was selected as the best predictor for the combined endpoint point, with and area under the ROC curve of 0.67. A GCS value <-17% was selected as the optimal cut-off point. This value predicted events as is shown in Kaplan-Meier curves (HR 3.6, CI 95% 1.42 - 9.02, p = 0.007). A multivariate analysis showed that this association was independent of left ventricle (LV) ejection fraction, LV volumes and left atrial (LA) volume. Conclusion CMR-FT deformation parameters are impaired in significant AR patients even if intervention criteria are not met. A value of GCS < -17% in this population could predict a worse clinical evolution and emerges as a promising new tool helping clinical decision making in this challenging population.Kaplan-Meier curve free-event survival

Long-term prognostic value of microvascular obstruction by cardiac magnetic resonance in ST-segment elevation myocardial infarction

Abstract Background Microvascular obstruction (MVO) has been associated with a higher risk of cardiac remodelling and adverse events following ST-segment elevation myocardial infarction (STEMI). However, long-term prognostic implications of MVO in STEMI beyond five years of follow-up have not been assessed to date. Purpose To investigate the relation of MVO with all-cause mortality and recurrent ischemic events at long-term follow-up after STEMI. Methods This is a pooled analysis of three observational studies including 876 prospectively enrolled reperfused first STEMI patients, who underwent cardiac magnetic resonance imaging with late gadolinium enhancement, between 2003-2019, from four university medical centers in the Netherlands and Spain. Median follow-up duration was 6.3 (IQR 3.6-9.3) years. The primary outcome was all-cause mortality. The secondary outcome was a combined endpoint of all-cause mortality and recurrent ischemic events (i.e. myocardial infarction or stroke). We performed Cox regression analyses with a time-dependent covariate. Model 1 included correction for clinical covariates only, i.e. age, sex, smoking, diabetes mellitus, hypertension, and LAD culprit artery. Model 2 included imaging characteristics, i.e. infarct size and left ventricular ejection fraction, in addition to the clinical covariates. Results The study population consisted of 876 patients, mean age 59 years ± 12, 720 men (82%). MVO was present in 499 patients (58%). The presence of MVO was significantly associated with all-cause mortality up to six years post-STEMI, independent from clinical characteristics (Hazard Ratio [HR] 2.23, 95% CI 1.09-4.57, p=0.029), but not after six years post-STEMI (HR 0.98, 95% CI 0.45-2.12, p=0.958). Presence of MVO was not significantly associated with a combined endpoint of all-cause mortality and recurrent ischemic events before or after six years of follow-up (HR 1.27, 95% CI 0.81-1.99, p=0.294 and HR 0.68, 95% CI 0.35-1.31, p=0.244, respectively). All other traditional prognosticators, except age, also lacked predictive value at long-term follow-up beyond six years. Conclusions In STEMI patients, the presence of MVO by cardiac magnetic resonance imaging is associated with a more than two-fold higher risk of all-cause mortality up to six years after the index event. This relation seems to dissipate beyond this time period. Furthermore, presence of MVO was not associated with recurrent ischemic events at long-term follow-up post-STEMI.

Left atrioventricular coupling index is an independent associate of new-onset AF and stroke in hypertrophic cardiomyopathy: a CMR study

Abstract Background Left atrial (LA) dysfunction is an important marker of disease progression in hypertrophic cardiomyopathy (HCM). LA volumes and functional parameters are associated with new-onset atrial fibrillation (AF) and its complications including stroke. The association between left atrioventricular coupling (LACI), a parameter reflecting the contribution of the left ventricular and LA remodeling to LA dysfunction, with the occurrence of new-onset AF and stroke has not been evaluated. Aim To investigate the association between LACI and the occurrence of new-onset AF or stroke in patients with HCM. Methods In patients with an established diagnosis of HCM and cardiac magnetic resonance (CMR) data, LACI was calculated as the ratio between the LA and the LV end-diastolic volumes. New-onset AF or occurrence of stroke comprised the primary combined endpoint. Cumulative event-free survival rates for the occurrence of the primary endpoint were estimated with the population divided according to a LACI cut-off value of 40%. The association between clinical and CMR variables and the primary endpoint was assessed with univariable and multivariable Cox proportional hazard regression models. Results Of 114 patients with HCM, (mean age 54±16 years, 33 (29%) female, LV ejection fraction 67.0±8.4%), 71 patients (49%) had a LACI > 40% (left atrioventricular uncoupling). During a median follow-up of 4.1 (1.8-6.4) years, 19 (16.7%) patients experienced new-onset AF or stroke. Patients with preserved left atrioventricular coupling (LACI ≤ 40%) had a lower cumulative rate of events compared to those with left atrioventricular uncoupling (log-rank p=0.031, Fig. 1). LACI was independently associated with new-onset AF or stroke after adjusting by the presence of late gadolinium enhancement (LGE) sex and age (HR=23.27, p=0.016). Conclusions In patients with HCM, the presence of left atrioventricular uncoupling is independently associated with the occurrence of new-onset AF or stroke.

Beating the clock: the impact of heart failure duration on CRT efficacy

Abstract Background Cardiac Resynchronization Therapy (CRT) stands as an established intervention for selected patients with heart failure (HF) presenting with a wide QRS complex. The optimal timing for CRT implantation remains uncertain. Current evidence suggests superior outcomes post-CRT in patients who have not been previously hospitalised for HF and those receiving the implant during their initial hospitalisation for HF.1 Purpose The primary objective of this study is to investigate the long-term clinical outcomes following CRT implantation relative to the duration of HF previous to the implant. It was analysed in a cohort of consecutive patients from a HF Unit who met the criteria for CRT as recommended by the ESC guidelines (QRS duration ≥150ms, left bundle branch block morphology, and left ventricular ejection fraction (LVEF) ≤35% despite optimal medical therapy). Methods We evaluated all patients who received CRT from January 2011 through September 2022. Follow-up ended in September 2023. Patients with CRT indicated for ventricular pacing due to high-degree atrioventricular block were excluded. Patients were categorized into two groups based on the duration of HF progression prior to CRT implantation: more than 3 years and 3 years or less. The primary outcome was all-cause mortality (ACM). Secondary outcomes included a composite of ACM and HF hospitalisation and the proportion of patients who demonstrated a significant improvement in LVEF (defined as an increase of ≥10% from baseline and a subsequent measurement of LVEF ≥40%). Results The cohort consisted of 127 patients, mean age 65.8±10.7 years, 23.6% were women, mean LVEF was 28.4±8.6% and 36.2% had ischaemic aetiology (Table 1). 62 patients either died or were hospitalized for HF. Mean follow-up was 4.9±2.7 years. After adjusting for age, sex and baseline LVEF, patients with HF for more than three years before CRT implantation had a worse prognosis: HRs of 2.31 for ACM (p=0.016) and 2.13 for the combined endpoint of ACM+HFH (p=0.010) (Figure 1). The proportion of patients with improved LVEF after CRT was significantly higher in the group with shorter HF duration (68.25%) compared to the group with longer HF duration (25%), p <0.001. Conclusions Our findings reveal that patients with a shorter history of HF (less than three years) prior to CRT implantation exhibit significantly better clinical outcomes. These results highlight the role of early intervention with CRT in patients with HF, suggesting that shorter HF duration prior to CRT may lead to more favourable long-term outcomes.

Prognostic impact of symptom relief under low and normal physical performance in patients hospitalized for worsening heart failure

Abstract Background Subjective symptoms, represented by the New York Heart Association (NYHA) class, are well-established prognostic indicators and treatment goals of heart failure (HF). However, older patients may be less likely to develop subjective symptoms due to an impaired physical performance. Purpose To evaluate the prognostic impact of symptom relief under low and normal physical performance in patients hospitalized for worsening HF. Methods We carried out a sub-analysis of FRAGILE-HF, a prospective multicenter study, including 1272 consecutive older (>=65 years) hospitalized patients with HF (median age 80; 57.2% male; left ventricular ejection fraction 46±17%). NYHA class and gait speed were documented before discharge. The patients were prospectively followed-up for two years after discharge. Results At the time of discharge, 715 patients (56%) remained symptomatic (NYHA2-4) whereas 557 patients (44%) were asymptomatic (NYHA1). Patients were classified into 4 groups according to symptom relief and physical performance represented by slow (<0.8 m/s) or normal (>=0.8 m/s) gait speed: 279 slow-asymptomatic, 278 normal-asymptomatic, 402 slow-symptomatic, and 313 normal-symptomatic patients, respectively. During the follow-up period, 266 patients (20.9%) died. Slow-asymptomatic (hazard ratio (HR) 1.72[1.09-2.72], p=0.019 in comparison with normal-asymptomatic patients as a reference) and slow-symptomatic (HR 1.85[1.21-2.82], p=0.004) status was associated with high mortality in a Cox regression analysis adjusted for the Meta-analysis Global Group in Chronic Heart Failure score and B-type natriuretic peptide level (Figure). Furthermore, the combined endpoint of HF rehospitalization and all-cause death within 90 days were more frequently observed in slow-asymptomatic (HR 1.94[1.05-3.60], p=0.034), normal-symptomatic (HR 1.89[1.06-3.36], p=0.031), and slow-symptomatic (HR 1.97[1.10-3.52], p=0.022) patients than normal-asymptomatic patients (Figure). Conclusions Symptom relief achieved at the time of discharge was not associated with a lower mortality in patients with low physical performance, for whom careful follow-up may be needed especially in the early period after discharge because the symptoms may be masked due to low physical performance.

Prognostic value of MELD-XI score and hemodynamic parameters in patients undergoing transcatheter tricuspid valve intervention

Abstract Background Hepatorenal dysfunction is a strong prognostic predictor in patients with tricuspid regurgitation. Patients are often hospitalized with acute heart failure due to volume overload and peripheral hypoperfusion. End-organ dysfunction is associated with the development of right ventricular failure related to hemodynamic changes such as low cardiac output and passive congestion from increased right ventricular filling pressures. Purpose This study aimed to investigate the prognostic value of hepatorenal dysfunction using the Model for End-stage Liver Disease (MELD) Score, the modified version of the score, MELD-XI, and of parameters determined during right-heart catheterization in patients undergoing transcatheter tricuspid valve intervention. Methods In this single-center prospective cohort study, data from patients undergoing edge-to-edge repair or heterotopic minimal invasive tricuspid valve repair were analyzed. Serum creatinine, INR and bilirubin were measured and the MELD score as well as the MELD XI score was calculated. All patients underwent right heart catheterization before the intervention. Receiver operator characteristics with calculation of the area under the curve (AUC) were performed to determine the predictive value of MELD (XI) score and hemodynamic parameters for the combined endpoint of rehospitalization due to decompensated heart failure and mortality within 3 months. Results Data from 36 consecutive patients were analyzed. 28 patients underwent edge-to-edge repair and 8 patients heterotopic minimal invasive tricuspid valve repair. Mean age of patients was 80.2 ± 5.9 years; 33.3% (12/36) were male. Baseline characteristics are shown in table 1. Rehospitalization due to decompensated heart failure occurred in 9/36 patients (25%). Mortality within the first 3 months was 11% (4/36). The predictive value for the composite endpoint of the modified MELD IX score was AUC 0.82 (95 % CI 0.63-0.99; p=0.009), while the conventional MELD score had an AUC of 0.77 (95 % CI 0.55-0.99; p = 0.059) (figure 1). RV pressure (AUC 0.84, 95% CI 0.66-1.00, p= 0.012) and RA pressure (AUC 0.83, 95% CI 0.67-0.98, p=0.016) showed a good predictive value for the composite endpoint (figure 2). The combination of MELD XI (at admission) and RV or PA pressure improved the AUC (MELD XI + RV: AUC 0.85; MELD XI + PA: AUC 0.84). Conclusion In this pilot-study, the modified MELD XI score, as indicator of hepatorenal dysfunction, was identified as a potential marker for short-term outcome after interventional tricuspid valve treatment.

Prognostic value of exercise right ventricular-pulmonary arterial coupling in primary mitral regurgitation

Abstract Background Exercise-induced pulmonary hypertension (mPAP/CO slope >3mmHg/L/min) was recently associated with worse outcome in >moderate PMR. However, the prognostic value of right ventricle to pulmonary artery coupling (RVPAc) is unknown. Purpose Assess the prognostic value of RVPAc; determine the additional value of exercise over rest RVPAc and compare these findings to the mPAP/CO slope. Methods Cohort study including consecutive pts submitted to CPET-echo with >moderate PMR, no/discordant symptoms, preserved LV function and without >moderate concomitant valvular disease or atrial fibrillation (AF). Thorough assessment of RV systolic function and RVPAc (TAPSE/sPAP ratio) was obtained by echocardiography using a dedicated RV window. mPAP and CO were obtained by Doppler echocardiography. Primary outcome was the composite of all-cause mortality, cardiovascular hospitalization (CVH), new-onset AF and valvular intervention; secondary outcome was the composite of CVH and new-onset AF. Results A total of 128 consecutive pts (64±11 years, 61% men) underwent CPET-echo. Event-free survival rate was 55% and 46% at 1 and 2 years. Pts that reached the primary combined endpoint were significantly older, had larger left atrium indexed volumes (LAVi), higher proportion of grade 4 MR, lower absolute and normalized peak VO2, and a significantly higher mPAP/CO slope (2,1±0,8 vs.3,7±2,6). They had a significantly lower rest and exercise TAPSE/sPAP, RV global and free wall longitudinal strain, rest and exercise TAPSE and exercise RV free wall S’. Rest and low exercise TAPSE/sPAP scored the highest accuracy in predicting the primary combined endpoint among variables statistically significant in the univariate analysis and therefore were used in the multivariate model. Sequentially adding rest and low exercise TAPSE/sPAP significantly improved the baseline predictive model (age, LAVi and MR grade). Low exercise TAPSE/sPAP and LAVi remained as significant independent variables in the multivariate model. They also correlated with new-onset AF and CVH; with rest and low exercise TAPSE/sPAP constituting significant steps (Fig 2). Replacing low exercise TAPSE/sPAP for mPAP/CO slope in the proposed model only slightly improved its accuracy in predicting the primary and secondary composite outcomes. Adding predicted peak VO2 (≥80% vs <80%) did not significantly improve the accuracy of any of the multivariate models. Low exercise TAPSE/sPAP and mPAP/CO slope both correlated well with peak VO2 and VE/VCO2 slope. Conclusion Decreased rest or exercise TAPSE/sPAP are single point measures of RVPAc, associated with adverse outcome in pts with >moderate PMR and no/discordant symptoms. Low exercise TAPSE/sPAP has independent additional value over rest TAPSE/sPAP in predicting adverse events, with a similar accuracy as mPAP/CO slope. Low exercise TAPSE/sPAP is a potential alternative to mPAP/CO slope in this population and it may be simpler to adopt in clinical practice.Central Illustration

Unveiling the prognostic journey: renal function trajectories in 'de novo' heart failure with reduced ejection fraction - insights from a cohort study and their impact on patient outcomes

Abstract Background HFrEF poses significant clinical challenges globally. Renal dysfunction frequently coexists with HF, exacerbating prognosis. However, the dynamic trajectory of renal function in 'de novo' HFrEF patients and its prognostic implications remain understudied. Methods We conducted a prospective cohort study involving 370 'de novo' HFrEF patients. Renal function was initially assessed upon admission and re-evaluated at the end of the titration period. The CKD-EPI formula was used for renal function assessment. Patients were followed up for a median of 15 months. Statistical analyses were performed to evaluate predictors of adverse outcomes. Results Baseline renal function significantly influenced outcomes, with eGFR < 45 ml/min associated with higher mortality and heart failure readmissions. Among patients with available renal function data at discharge (n=354), 87 (24.6%) had eGFR < 45 ml/min, while 267 (72.2%) ≥ 45 ml/min. Patients with eGFR < 45 ml/min exhibited older age, higher prevalence of comorbidities, lower haemoglobin levels, and higher creatinine and NT-proBNP levels, both at admission and discharge. Furthermore, they were less likely to receive certain heart failure medications at discharge. During follow-up, 46 deaths (13.0%) and 105 events of combined all-cause death and readmission due to heart failure (29.6%) occurred. Patients with eGFR ≥ 45 ml/min exhibited a lower overall mortality (HR: 0.29, p < 0.001) and all-cause death and heart failure readmissions (HR: 0.32, p < 0.001) both in univariate and multivariate analysis (HR: 0.63, p = 0.028 for mortality; HR: 0.53, p = 0.038 for combined endpoint). See Figure 1. Among patients with available renal function data at follow-up (n=304), 240 (78.9%) had eGFR ≥ 45 ml/min (stabilization or improvement), and 64 (21.1%) had eGFR < 45 ml/min (deterioration or previously < 45 ml/min). Patients with eGFR < 45 ml/min at follow-up exhibited older age, lower BMI, higher prevalence of comorbidities, lower haemoglobin levels, and higher NTproBNP levels at admission and discharge. They were also less likely to receive certain crucial heart failure medications at discharge and follow-up (Table 1). During follow-up, 31 deaths (10.1%) and 87 events of combined death and readmission due to heart failure (38.6%) occurred. In univariate analysis, patients with eGFR ≥ 45 ml/min exhibited a lower overall mortality (HR: 0.27, p < 0.001) and admissions (HR: 0.30, p < 0.001), which remained significant in multivariate analysis (HR: 0.43, p = 0.048 for mortality; HR: 46, p = 0.014 for admissions). See Figure 1. Conclusion Our findings underscore the importance of integrated heart-kidney care in 'de novo' HFrEF patients. Continuous monitoring of renal function and interventions to prevent deterioration are crucial for optimizing outcomes. Further research is needed to validate these findings and explore targeted therapeutic strategies for renal protection in HFrEF.

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.