Class III-IV Research Articles

Relationship between clinical congestion and worsening renal function after intravenous initiation of furosemide in patients with acute heart failure.

To investigate if worsening renal function (WRF) appearing in some patients with acute heart failure (AHF) after intravenous furosemide initiation is influenced by severity of congestion. We conducted a retrospective secondary analysis of consecutive patients diagnosed with AHF and prospectively included in 10 Spanish emergency departments (EDs) for whom serum creatinine at ED arrival and after 2-7days of intravenous furosemide initiation were available. Congestion was clinically evaluated by identification of 7 signs/symptoms and by chest X-ray. The outcome was WRF, defined as a delta-creatinine ≥ 0.3mg/dL. Risk of WRF according to congestion was estimated in models adjusted by patient baseline characteristics and vitals at ED arrival, and interaction was also investigated. We included 3027 patients (median age 82years, 56% women), and 657 (21.7%) presented WRF after intravenous furosemide initiation. When signs/symptoms were individually considered, only lower limbs edema was associated with decreased risk of WRF (20.1% vs. 24.8%; OR = 0.76, 95%CI = 0.64-0.91). After adjustment, lower limbs edema persisted inversely associated with WRF (aOR = 0.78, 95%CI = 0.65-0.94), with significant lower risk for patients ≤ 80years and without chronic kidney disease, functional limitation, and hypoxemia (p for interaction 0.01, 0.04, 0.02 and 0.03, respectively). Neither degree of clinical congestion (number of signs/symptoms of congestion) nor radiological congestion in chest X-ray were related to WRF. Worsening renal function was associated with a higher 1-year all-cause mortality (40.1% vs 34.6%; HR = 1.27, 1.10-1.46; aHR = 1.331, 1.151-1.540). In patients with WRF, liver cirrhosis, chronic treatment with loop diuretics and renin-angiotensin system inhibitors, age (> 80years), dementia, heart valve disease and NYHA class III-IV were associated with higher mortality. Intravenous furosemide initiation in patients with AHF without lower limbs edema must be cautious, as they are at increasing risk of developing WRF during the next following days, which in turn is associated with a higher 1-year mortality.

Smaller intrinsic QRS area and smaller reduction of QRS area during cardiac resynchronisation therapy are associated with higher risk of ventricular arrhythmias and appropriate ICD therapy

Abstract Background Cardiac resynchronisation therapy (CRT) patients are at high risk for ventricular arrhythmias (VAs), and little is known about which characteristics are associated with an increased risk for arrhythmic events. Purpose To investigate the association between QRS area parameters and the risk for VAs in patients with heart failure undergoing primary preventive CRT with defibrillator (CRT-D) implantation. Methods All patients receiving CRT-D between 2015 and 2020 at a large-volume tertiary care center were retrospectively evaluated. Digital 12-lead electrocardiograms (ECGs) were collected before and after CRT implantation. Patients were included if they had native LBBB and were implanted with a primary preventive CRT-D. Kors’ regression transformation was used to derive vectorcardiographic QRS area from the 12-lead ECGs. QRS area parameters were analysed in relation to a primary endpoint of first appropriate ICD therapy, i.e., ATP or shock therapy. Results 177 patients with LBBB (68.9 years [60.7–73.8]; 21.5% female; 52.9% New York Heart Association (NYHA) class III-IV; LVEF 25.9±6.3%) were followed over a median follow-up time of 2.5 years [1.6–3.0] after CRT-D implantation. 27 patients reached the primary endpoint. The median pre-CRT QRS area was 134.5 μVs [102.3–163.8]. Multivariable Cox regression identified a small pre-CRT QRS area (HR, per 10 μVs decrease, 1.30; [1.12–1.51]; p=<.001) and a small post-CRT reduction in QRS area (HR, per 10 μVs decrease, 1.30; [1.13–1.49]; p=<.001) as independent predictors of an increased risk of appropriate ICD therapy. In analyses with a scoring variable combining pre-CRT QRS area and QRS area reduction both above or below median, the combination of a small pre-CRT QRS area and a small QRS area reduction was strongly associated with an increased risk of reaching the endpoint (HR, per point increase, 2.47; [1.2–4.9]; p=0.01). Conclusion A small intrinsic QRS area, by itself or in combination with a small reduction of post-CRT QRS area, was strongly associated with a higher risk of ventricular arrhythmias in this cohort of CRT-D treated patients. In conjunction with other parameters, further risk stratification for arrhythmic events could be achieved by assessing QRS area data pre- and post-CRT.Figure 1.K-M pre-CRT QRS area quartilesFigure 2.K-M QRS area score

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

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

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.

Coronary microvascular dysfunction in patients with heart failure with reduced and mildly reduced ejection fraction: results from the PANACEA study

Abstract Aims Coronary microvascular dysfunction (CMD) is common and associated with impaired survival in patients with heart failure with preserved ejection fraction (HFpEF). In patients with heart failure with reduced ejection fraction (HFrEF) and mildly reduced ejection fraction (HFmrEF) the impact of CMD is not fully known. Purpose We aimed to investigate the prevalence of CMD and its association with phenotype, biomarkers, endothelial function and echocardiographic measurements in patients with HFrEF or HFmrEF. Method A prospective, exploratory bi-center study in patients with chronic stable heart failure, New York Heart Association (NYHA) Class II-IV, and ejection fraction (EF) <50% was performed. Study procedures included echocardiography, adenosine-based transthoracic Doppler echocardiography to assess coronary flow reserve (CFR), physical examination, fasting blood and urine sample, pulse wave velocity (PWV) and hemodynamic measurements. The cutoff of CFR<2.5 was used to diagnose CMD. A multivariable linear regression analysis with CFR as dependent variable, adjusted for age, sex, body mass index, smoking, atrial fibrillation and left ventricular mass, was performed to explore biomarkers, endothelial function, and echocardiographic measurements associated with CMD. Results Of 112 included patients, 87 (78%) were men, with a mean age of 73.3 (±7.5) years. Among patients with a successful CFR measurement (n=62), CMD was present in 40 (65%), mean age of 75.4 (±5.8) years (Table 1). Patients with CMD had higher N-terminal pro B-type natriuretic peptide (NTproBNP) and Troponin T (p<0.05), and more often HFrEF ( p=0.06). Patients with CMD had larger ventricles with greater left ventricular mass and larger end-diastolic volumes (p<0.05). In a linear regression analysis CMD was associated with higher NTproBNP, lower EF, PWV and global strain (table 2). Conclusion CMD was common and present in two thirds of patients with HFrEF or HFmrEF. Further CMD was associated with markers of more severe heart failure and systemic endothelial dysfunction indicating that CMD may be an important predictor of outcome in patients with HFrEF and HFmrEF.

Impact of dapagliflozin on cardiometabolic outcomes after myocardial infarction according to baseline left ventricular ejection fraction: a DAPA-MI substudy

Abstract Background Dapagliflozin improved cardiometabolic outcomes compared with placebo following acute myocardial infarction (MI) in participants without prior diabetes mellitus (DM) or chronic heart failure (HF) in the DAPA-MI trial. Purpose Cardiometabolic outcomes were assessed in the DAPA-MI trial according to left ventricular ejection fraction (EF) at randomisation. Methods Participants were categorised according to whether baseline EF was ≥50 or <50%. Those without a baseline EF result and those who did not receive a dose of study drug were excluded. The primary objective was to determine the clinical effect of dapagliflozin 10 mg versus placebo assessed using a hierarchical composite outcome and analysed by the win ratio method. The primary outcome was the hierarchical composite, by order of perceived clinical importance, of death, hospitalization for HF (HHF), nonfatal MI, atrial fibrillation/flutter event, new diagnosis of type 2 DM, NYHA functional class at the last trial visit, and body weight decrease of ≥5% from baseline to the last trial visit. Time to first event of NYHA class II-IV or HHF and time to first event of NYHA class III-IV or HHF were assessed as endpoints of special interest. Hazard ratios (HR) with 95% confidence intervals (CI) were determined using Cox proportional hazards models. The main subgroup variable (baseline EF ≥50 or <50) and its interaction with treatment (P int) were included. Results 838 participants had EF≥50 and 2913 had EF<50 at baseline. The primary hierarchical composite outcome resulted in a win ratio for those with EF≥50 of 1.32 (CI 1.00-1.73) and 1.38 for those with EF<50 (CI 1.21-1.57; P int 0.8) (Figures). There were no significant interactions by EF for any of the secondary outcomes. In those with EF<50, a first event of NYHA class II-IV or HHF occurred in 435 (29.4%) participants in the dapagliflozin group and 485 (33.8%) in the placebo group (absolute risk difference [ARD] 4.4%; HR 0.83, CI 0.73-0.94, P<0.01). In those with EF≥50, this occurred in 81 (19.7%) and 93 (21.8%), respectively (ARD 2.1%; HR 0.96, CI 0.65-1.41, P=0.7; P int 0.47). In those with EF<50, a first event of NYHA class III-IV or HHF occurred in 77 (5.2%) in the dapagliflozin and 115 (8.0%) in the placebo groups (ARD 2.2%; HR 0.64, CI 0.48-0.85, P<0.01). In those with EF≥50, this occurred in 14 (3.4%) and 19 (4.4%), respectively (ARD 1.0%; HR 0.80, CI 0.40-1.60, P=0.5; P int 0.55). There was no significant effect of dapagliflozin on death/MI/stroke in either subgroup (EF<50: HR 0.96, CI 0.65-1.41; EF≥50: HR 0.83, CI 0.38-1.84; P int 0.75). Dapagliflozin increased the incidence of 5% weight loss in both of the EF subgroups with no significant interaction. Conclusions Dapagliflozin resulted in significant benefit in cardiometabolic outcomes compared with placebo regardless of baseline EF. The absolute reduction in HF symptoms or HHF with dapagliflozin, compared with placebo, was greatest in those with baseline EF<50.Figures

Impact of dapagliflozin on cardiometabolic outcomes after myocardial infarction according to baseline glycaemic status and body mass index: a DAPA-MI substudy

Abstract Background Dapagliflozin improved cardiometabolic outcomes compared with placebo following acute myocardial infarction (MI) in participants without prior diabetes mellitus (DM) or chronic heart failure (HF) in the DAPA-MI trial. Purpose To assess cardiometabolic outcomes in the DAPA-MI trial according to glycaemic status and body mass index (BMI) at randomisation (baseline). Methods Participants were categorised, according to their baseline HbA1c, as normoglycaemic (<5.7% [39 mmol/mol]) or having pre-DM (5.7-<6.5% [48 mmol/mol]). Those with HbA1c >6.5%, diagnosis of DM during hospitalisation, or missing HbA1c result were excluded. New-onset DM during follow-up was defined as either investigator-reported DM diagnosis or HbA1c >6.5%. Time to first occurrence of new-onset DM was assessed according to randomised treatment with dapagliflozin or placebo over median 11.6 months. Incidences of hospitalisation for HF (HHF), cardiovascular death/MI/stroke (MACE), first occurrence of NYHA class III or IV, and weight reduction >5% were assessed according to baseline HbA1c subgroup. Hazard ratios with 95% confidence intervals (CI) were determined using Cox proportional hazards models, stratified by country (UK and Sweden), including randomized treatment as covariate. Similar analyses were performed according to baseline BMI ranges <25, >25-<30, and >30 kg/m2. Results 3,425 out of 4,017 (85.3%) participants met the inclusion criteria, of whom 1,926 (56.2%) were normoglycemic and 1,499 (43.8%) had pre-DM at baseline. In those with normoglycaemia, new-onset DM during follow-up occurred in 6 (0.6%) and 15 (1.6%) participants assigned to dapagliflozin and placebo, respectively (HR 0.40, CI 0.15-1.03; P=0.06); in those with pre-DM, this outcome occurred in 77 (10.1%) and 97 (13.1%) participants, respectively (HR 0.74, CI 0.55-0.99; P<0.05), without significant interaction between the subgroups (P int=0.23)(Figure). A similar pattern was seen for new-onset DM during follow-up according to the BMI subgroup (P int=0.22), with greater absolute risk reduction seen in patients with obesity (5.0% vs. 9.8%, HR 0.52, 0.32-0.82; P<0.01)(Figure). There was no significant treatment effect or interaction according to baseline HbA1c for incidences of HHF or MACE, whereas first occurrence of NYHA class III or IV was reduced more with dapagliflozin versus placebo in the pre-DM subgroup (HR 0.38, CI 0.23-0.61; P<0.001) compared with the normoglycaemia subgroup (HR 0.87, CI 0.58-1.30; P=0.50; P int<0.01). Dapagliflozin increased the incidence of >5% weight loss in both HbA1c subgroups and all BMI subgroups with no significant interactions. Conclusions Dapagliflozin, compared with placebo, reduces the occurrence of new-onset DM following MI, regardless of baseline HbA1c or BMI and with greater absolute risk reduction in those with pre-DM or obesity. Dapagliflozin has a greater beneficial effect on HF symptom burden (NYHA class III-IV) in those with pre-DM versus normoglycaemia.

Left ventricular dilatation in patients with significant aortic regurgitation: association with mortality

Abstract Background In aortic regurgitation (AR), left ventricular (LV) dilatation occurs as a response to volume and pressure overload. Current guidelines recommend the use of LV end-systolic diameter index (LVESDi) to give indication for intervention, but recent studies suggested that volumetric measures may be more accurate in identifying LV remodeling in AR as compared to linear dimensions. Purpose To characterize LV dilatation in patients with significant AR (≥moderate), based on linear and volumetric dimensions, and to determine their prognostic value. Methods A total of 1070 patients (56 ± 18 years,65% male) were included. Cut-off values of 20 mm/m2 for LVESDi and 45 ml/m2 for end-systolic volume index (LVESVi) were used to identify the following LV remodeling patterns: No-significant LV dilatation (N=485), when both LVESDi and LVESVi were below the cut-off values; Discordant LV dilatation (N=279) if only one positive criterion was present; and Concordant LV dilatation (N=306) when both LVESDi and LVESVi were enlarged (Figure 1). The primary endpoint was all-cause mortality. Results Baseline characteristics differed across the 3 LV dilatation groups. Compared to patients with no-significant or discordant LV dilatation, those with concordant LV dilatation were more likely to be men, had a lower prevalence of systemic arterial hypertension and were more symptomatic. Concerning the echocardiographic characteristics, patients with concordant LV dilatation showed more severe AR, worse LV systolic function and larger left atrial volumes compared to the other two LV dilatation groups. During a median follow-up of 89 (IQR,54-132) months, 168 (16%) patients died and 484 (45%) underwent aortic valve surgery (AVS). Patients with concordant LV dilatation had worse 10-year survival (72%) compared to the groups (Figure 2), but benefited more from AVS based on a landmark analysis (p=0.001). In multivariable analysis, a significant association with the risk of all-cause mortality was observed for the presence of discordant (HR 1.645, 95%CI 1.077-2.513;p=0.021) or concordant LV dilatation (HR 2.695, 95% CI 1.710 to 4.249;p<0.001) after adjusting for the variables significant in the univariate analysis such as, age, male gender, NYHA class III-IV, AVS as a time-dependent covariate and LV ejection fraction (LVEF) ≤55%. Moreover, the addition of LV dilatation groups to a basal model including the above mentioned clinical and echocardiographic variables led to a significant increase in the predictivity of the model (Chi-square difference=21.1,p<0.001). Conclusion In patients with significant AR, LV dilatation detected by linear and/or volumetric measures was independently associated with increased mortality. Combining both methods for assessment of LV remodeling may improve risk stratification of these patients.

Sex differences in left ventricular dilatation in patients with significant aortic regurgitation: prognostic implications

Abstract Background Left ventricular (LV) dilatation is a strong indicator of adverse outcome in patients with aortic regurgitation (AR). Accordingly, current guidelines recommend the use of LV end-systolic diameter index (LVESDi) as one of the criteria to trigger aortic valve surgery (AVS) in patients with severe AR, but with the same threshold regardless of gender. Purpose To assess sex differences in LV remodeling using both volumetric and linear measurements in a large cohort of patients with significant AR (moderate or greater) and to investigate their prognostic implications. Methods A total of 1070 patients (56 ± 18 years, 691 men) were included. The primary outcome was all-cause mortality. Results Women presented with older age (58 ± 19 vs. 55 ± 17, p=0.023) and more advanced heart failure (HF) symptoms than men (NYHA class III-IV 12% vs. 9%, p=0.017). Men showed significantly larger LVESDi (21 ± 5 vs. 20 ± 5 mm/m2, p=0.013) and LV end-systolic volume index (LVESVi 37 ± 28 vs. 26 ± 17 ml/m2 p<0.001). During a median follow-up of 89 (IQR, 54-132) months, 168 patients died. Women had lower survival rates at 3, 5, and 10 years of follow-up compared to men (92% vs. 94.3%; 85% vs. 89.7% and 75.3% vs. 84.1%, p=0.005) (Figure 1). Spline curve analysis revealed that the threshold of LVESDi associated with an increased risk of mortality was 20 mm/m2 for both sexes. In turn, the threshold for LVESVi was 40 ml/m2 for women and 45 ml/m2 for men. Univariable Cox regression models were constructed separately for men and women. The variables associated with all-cause mortality were age, NYHA class III-IV, and AVS as time-dependent covariate in women, and age, diabetes, AVS as time-dependent covariate, and LAVI (left atrial volume index) in men. These parameters were used as a basal multivariable Cox regression model on top of which LVESDi >20 mm/m2 (Model 1), LVESVi >40 ml/m2 for women and 45 ml/m2 for men (Model 2) were added (Table 1A). LVESVi >40 ml/m2 was not a significant univariate predictor in men. In women, LVESDi >20 mm/m2 (HR: 2.046, 95%CI 1.244-3.419; p=0.006) and LVESVi >40 ml/m2 (HR 1.758, CI 1.095-2.825; p=0.020) showed an independent association with all-cause mortality among other factors (Table 1A). In men, death was independently associated with LVESDi >20 mm/m2 (HR 1.979, 95%CI 1.255-3.121; p=0.003) and LVESVi >45 ml/m2 (HR 2.388, 1.522-3.746; p<0.001), among other factors (Table 1A). Moreover, when added to a basal model that included clinical and echocardiographic variables associated with prognosis, LV dilatation based on volumetric LV enlargement resulted in a greater discriminatory power for both genders (Table 1B). Conclusion Men and women have a similar LVESDi threshold of 20 mm/m2, which is associated with an increased risk of death. However, their respective cut-off values for LVESVi differ, with the optimal threshold for women being 40 ml/m2 and for men 45 ml/m2.

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.

Effect of remote monitoring on the management of heart failure patients with cardiac amyloidosis

Abstract Objective The primary objective was to assess the characteristics of heart failure (HF) patients with cardiac amyloidosis (CA) monitored remotely with our program. The secondary objective was to evaluate the discrimination of alerts by remote monitoring for HF in this specific population. Methods The entire multicentre cohort of HF patients monitored remotely with our program from August 2018 to December 2023 were included in the analysis. Results A total of 13,933 patients, including 346 (2.5%) with CA and 13,587 (97.5%) without cardiac amyloidosis (no-CA), had a median follow-up of 14 months. CA patients were more often male (78.6% vs 63.8%), over 80 years of age (69.9% vs 40.4%), with left ventricular ejection fraction >40% (78.6% vs 56.5%), more often NYHA class III-IV (26.6% vs 16.2%), more atrial fibrillation (54.0% vs 40.9%) but less myocardial infarction (8.4% vs 27.9%), diabetes (16.5% vs 28.1%), smoking (2.9% vs 13.4%), p<0.001 for all. There was no difference in the rate of renal failure (21.7% vs. 20.3%), obstructive sleep apnea (15.9% vs. 14.9%) or stroke (10.7% vs. 9.4%). Remote monitoring identified a total of 57,624 alerts, including 1240 in the CA group vs 56,384 in the no-CA group (i.e. 3.58 alerts per CA patient vs 4.15 alerts per no-CA patient). Of the alert resolutions in the CA group vs no-CA group, 22.4% vs 38.9% had a low probability of cardiac decompensation, 34.0% vs 35.4% had a moderate probability, 43.6% vs 25.7% had a high probability of cardiac decompensation (global Chi-square p<0.001). Conclusion Despite an elderly population with different comorbidities, remote monitoring with this program in CA patients identifies correct relevance for discrimination of cardiac decompensation.

Characterizing disease burden and health care resource utilization in patients with hypertrophic cardiomyopathy: a nationwide real-world study in Finland

Abstract Background Hypertrophic cardiomyopathy (HCM) is an often hereditary myocardial disease with an estimated prevalence of 1:500 in the general population. Purpose This study aimed to investigate healthcare resource utilization (HCRU) and associated costs in patients diagnosed with HCM (and the associated subtypes: obstructive or non-obstructive) in a nationwide cohort in Finland. Methods This retrospective, registry-based cohort study included all Finnish patients diagnosed with HCM between 2000 and 2021, who were 12+ years old at the time of diagnosis, as identified from the national care registers for healthcare. HCRU data were collected between 2014 and 2021 from the Finnish national care registers for health care and the social insurance institution. Data pertaining to New York Heart Association (NYHA) classification were collected from three Finnish university hospitals. Results The study cohort comprised 5,834 patients with an HCM diagnosis; obstructive HCM accounted for 34% of cases. Mean per patient-year costs were €6638, 95% confidence interval (CI) €6472-€7415, and €6112, 95% CI €5957-€6560 for those with obstructive and non-obstructive HCM respectively. All-cause hospitalizations at specialized care were the most prominent cost associated with patients with obstructive and non-obstructive HCM equating to 46.3% and 46.1% of the total cost respectively (Fig 1.). Comorbidity burden, as measured by Charlson comorbidity index (CCI) score, was greater in patients with the obstructive than non-obstructive phenotype of the disease (CCI ≥4: 2.2 and 1.8, p<0.01, respectively). The highest utilization of invasive procedures was found for patients with NYHA class III-IV. Conclusion This population-based study, utilizing real-world data, provides novel insights into HCRU and related costs among Finnish patients with HCM (and associated subtypes). HCRU appears to be primarily driven by hospitalizations at specialized care. Furthermore, the data indicate that patients with obstructive HCM are likely to have a more severe disease, with higher comorbidity burden and requiring more invasive procedures than patients with the non-obstructive form of the disease. However, there were no statistically significant differences in health care costs between those with obstructive and non-obstructive HCM.

Early Intervention in Patients With Asymptomatic Severe Aortic Stenosis and Myocardial Fibrosis

Development of myocardial fibrosis in patients with aortic stenosis precedes left ventricular decompensation and is associated with an adverse long-term prognosis. To investigate whether early valve intervention reduced the incidence of all-cause death or unplanned aortic stenosis-related hospitalization in asymptomatic patients with severe aortic stenosis and myocardial fibrosis. This prospective, randomized, open-label, masked end point trial was conducted between August 2017 and October 2022 at 24 cardiac centers across the UK and Australia. Asymptomatic patients with severe aortic stenosis and myocardial fibrosis were included. The final date of follow-up was July 26, 2024. Early valve intervention with transcatheter or surgical aortic valve replacement or guideline-directed conservative management. The primary outcome was a composite of all-cause death or unplanned aortic stenosis-related hospitalization in a time-to-first-event intention-to-treat analysis. There were 9 secondary outcomes, including the components of the primary outcome and symptom status at 12 months. The trial enrolled 224 eligible patients (mean [SD] age, 73 [9] years; 63 women [28%]; mean [SD] aortic valve peak velocity of 4.3 [0.5] m/s) of the originally planned sample size of 356 patients. The primary end point occurred in 20 of 113 patients (18%) in the early intervention group and 25 of 111 patients (23%) in the guideline-directed conservative management group (hazard ratio, 0.79 [95% CI, 0.44-1.43]; P = .44; between-group difference, -4.82% [95% CI, -15.31% to 5.66%]). Of 9 prespecified secondary end points, 7 showed no significant difference. All-cause death occurred in 16 of 113 patients (14%) in the early intervention group and 14 of 111 (13%) in the guideline-directed group (hazard ratio, 1.22 [95% CI, 0.59-2.51]) and unplanned aortic stenosis hospitalization occurred in 7 of 113 patients (6%) and 19 of 111 patients (17%), respectively (hazard ratio, 0.37 [95% CI, 0.16-0.88]). Early intervention was associated with a lower 12-month rate of New York Heart Association class II-IV symptoms than guideline-directed conservative management (21 [19.7%] vs 39 [37.9%]; odds ratio, 0.37 [95% CI, 0.20-0.70]). In asymptomatic patients with severe aortic stenosis and myocardial fibrosis, early aortic valve intervention had no demonstrable effect on all-cause death or unplanned aortic stenosis-related hospitalization. The trial had a wide 95% CI around the primary end point, with further research needed to confirm these findings. ClinicalTrials.gov Identifier: NCT03094143.

The mortality implications of increasing and decreasing sST2 levels during acute decompensated heart failure

Abstract Introduction Soluble Suppressor of Tumorigenicity (sST2), a marker of cardiac remodelling and fibrosis, has demonstrated promises in prognostication of heart failure (HF) and therefore recommended as an additional test for risk stratification of HF in the 2017 ACC/AHA/HFSA guidance. It is well investigated as single measurements in acute and ambulatory settings. Data regarding sST2 level changes during acute decompensated heart failure (ADHF) and its potential in providing additional prognostic information is however sparse. We therefore sought to evaluate changes in sST2 and its prognostic implications in hospitalized patients during ADHF. Methods Between December 2019 and February 2022, consecutive patients with ADHF and reduced ejection fraction (EF<50%) presenting to our University Hospital were recruited as part of the Investigating the soluble ST2 biomarker in addition to Natriuretic peptides in managing patients with Heart Failure and a Reduced Ejection Fraction (INST2ANT-HF) study (REC Reference: 19/EE/0269). Serum samples were taken at clinician determined decompensation and recompensation in all participants, who were then followed up for one year post discharge. The study primary end point was all-cause mortality at one year. A 2x2 contingency table was constructed to display the relationship between the frequency of unchanged/increased or decreased sST2 levels at recompensation and the frequency of mortality at one year (Table 1). A Kaplan-Meier curve was plotted to display the survival probability of the two groups during one-year follow up (Figure 1), and log-rank test applied to evaluate for significant difference in the survival distributions. Results In 169 patients with paired sST2 samples, median age (IQR) was 72 (62-80.8), 39 (23.2%) were female and 160 (95.2%) were ethnically white. 158 (94.1%) presented with NYHA class II-IV and the median (IQR) EF was 26% (17.5-32.5). Median (IQR) length of stay in hospital was 8 days (5-13). Median (IQR) sST2 level at decompensation and recompensation were 60ng/ml (40-93.3) and 39.5ng/ml (24-64.8) respectively. At clinician determined recompensation, sST2 level decreased in 136 (81%) patients while 32 (19%) had unchanged/increased sST2 levels. One-year mortality was 37.5% in patients with unchanged or increasing sST2 levels during ADHF, compared to 16.2% in those with decreased sST2 levels. The mean (SE) survival time was 332 (7) days for patients with unchanged/increasing sST2, and 274 (22.5) days for patients with decreasing sST2 at HF recompensation (p=0.003). Conclusion Our data demonstrates that there was a downward trend in sST2 in most patients during recovery from an ADHF episode. Importantly, a static or increasing sST2 level from HF decompensation to recompensation was associated with a significantly higher risk of mortality at one year. Further research may ascertain if the mortality risk is also dependent on the percentage changes in sST2 concentrations.Table 1:2x2 contingency tableFigure 1:Kaplan-Meier curve

Comparison of ultrasound-assisted thrombolysis and mechanical thrombectomy in patients with intermediate-high-risk pulmonary embolism

Abstract Background Pulmonary embolism (PE) can cause right heart failure and is associated with a high mortality. Early risk stratification is critical for individualized management. In patients with intermediate-high-risk PE, guidelines recommend to consider a percutaneous catheter-directed treatment (CDT). While different techniques are available, comparisons between treatments regarding right heart function and outcome are still scarce. Purpose To compare changes in right heart function as well as outcome in patients with intermediate-high-risk PE after catheter-directed treatment with ultrasound-assisted thrombolysis as compared to mechanical thrombectomy. Methods This is a retrospective, single-center study in intermediate-high-risk PE. According to the ESC guidelines, all patients had PESI class III-V, RV dysfunction and elevated cardiac troponin levels, but were hemodynamically stable. PE was confirmed by CT angiography. All patients underwent a catheter-directed treatment. One group received an ultrasound-assisted thrombolysis (USAT), while the other had a large-bore mechanical thrombectomy (MT). Right heart function (RV-Diameter, RV-/LV-Ratio, TAPSE) assessed via transthoracic echocardiography before and after CDT as well as interventional characteristics and postinterventional hospital stay were compared. Results From June 2022 to January 2024, 27 patients (43% female; aged 62 ± 14 years) were diagnosed with pulmonary embolism with intermediate-high-risk and underwent a catheter-directed treatment. Most patients (89%) had bilateral pulmonary embolisms. 15 patients (55%) received an ultrasound-assisted thrombolysis. 12 patients (45%) had a mechanical thrombectomy via a large-bore aspiration system. The mean procedural time was 41 ± 19 minutes for USAT and 106 ± 33 minutes for MT (p < 0.001). Right ventricular / left ventricular ratio reduction was -0.48 ± 0.25 in the USAT group (p < 0.001) and -0.34 ± 0.14 in the MT group (p < 0.001) (between group difference p = 0.2). TAPSE increased by 8 mm ± 4.4 mm in the USAT group (p < 0.001) and by 8.7mm ± 3.8 mm in the MT group (p < 0.001) (between group difference p = 0.7). The median postinterventional hospital stay was 7 days for the USAT patients and 7 days for the MT patients (between group difference p = 1). Conclusions In patients with intermediate-high-risk PE both ultrasound-assisted thrombolysis and large-bore mechanical thrombectomy lead to an improved right heart function with both interventions leading to a similar length of postprocedural hospital stay. Further randomized data have to discriminate differential impact of novel tools for the treatment of intermediate risk PE.

Effect of empagliflozin on epicardial adipose tissue volume in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF)

Abstract Background Epicardial adipose tissue (EAT) is postulated to be linked to the pathophysiology of heart failure with reduced ejection fraction (HFrEF), acting both as a biomarker and a potential therapeutic target. Investigating changes in EAT volume following treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor could provide valuable mechanistic insights. Purpose This posthoc substudy of the SUGAR-DM-HF trial aimed to assess the effect of the SGLT2 inhibitor empagliflozin on EAT volume. Methods Within a multicentre, randomised, double-blind, placebo-controlled trial, the effects of empagliflozin were evaluated in patients with HFrEF (New York Heart Association functional class II-IV, left ventricular ejection fraction (LVEF) ≤40%), and type 2 diabetes or prediabetes. Patients with atrial fibrillation/flutter were excluded to avoid image degradation. Patients were randomly assigned 1:1 to empagliflozin 10mg daily or placebo. EAT volume was quantified using cardiovascular magnetic resonance (CMR) cine imaging at baseline and week 36, and reported as: (a) total EAT volume (mL); (b) EAT volume indexed to body surface area (mL/m2); (c) % change from baseline. Observers were blinded to subject identification, scan date, clinical data, and randomization arm. Scans with major artefacts were not analysed. Results One hundred five patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% (9.8%). Baseline EAT volume was available in 101 patients (median [IQR] 85 [67-104] mL and 41 [34-52] mL/m2). Paired baseline and 36-week EAT volume was available in 90 patients. Higher baseline total EAT volume was associated with male gender, higher body mass index, coronary artery disease, elevated serum creatinine, higher left ventricular end-diastolic volume, and higher left ventricular mass (TABLE). EAT volume changed by -2.7 mL / -1.3 mL/m2 / -3.1% in the empagliflozin group versus 0.3 mL / 0.3 mL/m2 / 1.5% in the placebo group (between-group difference -3.4 mL, 95% CI -6.7 to -0.1; p=0.045 and -1.7 mL/m2, 95% CI -3.4 to -0.04; p=0.045) at 36 weeks (FIGURE). The beneficial reduction in left ventricular end-systolic volume indexed to body surface area observed with empagliflozin treatment was not modified by baseline total or indexed EAT volumes (p interaction=0.31 and 0.45, respectively). Conclusion Empagliflozin treatment significantly reduced EAT volume. This may represent an additional benefit of SGLT2 inhibition in HFrEF.

PROFILE OF PATIENTS WITH SLEEP COMPLAINTS IN A SECONDARY CARE HEALTH INSTITUTION IN THE CITY OF CAMPINAS, SÃO PAULO STATE

Objective: We report data of the profile of patients who sought our outpatient clinic for sleep disorders of the Faculty of Medicine of São Leopoldo Mandic Medical School, during the Week of Sleep, that took place in March, 2022. Methods: All participants responded to a form designed by the researcher, as well as to commonly used questionnaires in Sleep Research, such as the Epworth Sleepiness Scale (ESS), the Insomnia Severity Index (ISI), the Hospital Anxiety and Depression Scale, the STOP-BANG questionnaire for screening of apnea, and the WHO Quality of Life abbreviated questionnaire (WHOQOL-BREF). Results: 30 patients were evaluated, mean age 51.8 (± 14), 63% women. Main complaints were insomnia (63%), snore/apnea (23%) and excessive daytime sleepiness (10%). ESS scores were significantly higher among men, daytime nappers and alarm clock users. ISI scores were importantly associated with those who woke 2 or more times per night, while physically active, non-obese, normotensive people and those with Modified Mallampatti (MM) classes I and II scored significantly less in STOP-BANG. Obese, MM classes III-IV and people with abnormal cervical and abdominal circumferences performed markedly worse in Domain 1, while women, older people and alarm clock users went worse in Domain 4 of WHOQOL-BREF. Discussion: One or more sleep disturbances were detected in all seekers of Sleep Care, emphasizing the importance of these types of action.

Assessment of safety profile of ivabradine in real-world scenario using FDA adverse event reporting system database

ABSTRACT Background Ivabradine is primarily indicated for patients with sinus rhythm and a heart rate ≥ 75 beats/min, who have NYHA class II-IV chronic heart failure with systolic dysfunction. There is currently a lack of large-scale, real-world studies concerning its drug adverse reactions. Research design & methods This research assesses the side effects of ivabradine by analyzing reports of adverse events (AEs) from the FDA’s Adverse Event Reporting System (FAERS) database. To evaluate the importance of these AEs, four sequential analytic strategies were utilized. Results In total, 2,701 ivabradine-related AE reports were identified in the FAERS database. We identified 26 ivabradine-induced AEs, each with more than 20 reports, including some significant AEs not mentioned on the product label. The timing of AEs was also analyzed, with the majority of AEs occurring within the first month of ivabradine use. Gender-specific analysis indicates that female have a higher risk of AEs, such as off-label use, tachycardia, drug effectiveness for unapproved indications, and rash compared to male. Conclusion This study provides important information for maximizing the usage of ivabradine, increasing its efficacy, and reducing any possible negative effects. The actual clinical use of the medication will be greatly aided by this knowledge.

The value of blood flow velocity and pressure gradient in differentiating patients with different types of heart failure.

Patients with different types of heart failure (HF) exhibit varying rates of blood flow through cardiac chambers and pressure gradients across the aortic valve, attributed to differing degrees of myocardial contractility. Assessment of these dynamics offers insights into early HF diagnosis. This study aimed to analyze left ventricular outflow tract (LVOT) blood flow parameters, specifically peak blood flow velocity and pressure gradient derived from four-dimensional flow cardiovascular magnetic resonance (4D flow CMR), and to evaluate 4D flow CMR's utility in distinguishing HF types. This prospective cross-sectional study recruited 115 HF patients from January 2019 to May 2022 at the General Hospital of Ningxia Medical University, classified by the New York Heart Association Cardiac Function Classification of Heart Failure as class II-IV, alongside a control group (n=30). Participants underwent cardiovascular magnetic resonance (CMR), including 4D flow. HF patients were categorized into heart failure with reduced ejection fraction (HFrEF, n=55), heart failure with mildly reduced ejection fraction (HFmrEF, n=30), and heart failure with preserved ejection fraction (HFpEF, n=30), based on ejection fraction. The cardiac functional parameters and aortic valve flow indices were measured using Circle Cardiovascular Imaging. LVOT 4D flow data were obtained 3 mm below the junction of the aortic valve leaflets, assessing peak velocities above and below the valve. Differences in cardiac function and blood flow parameters between groups were analyzed using one-way analysis of variance (ANOVA). The accuracy of these parameters in identifying subgroups was assessed using the receiver operating characteristic (ROC) curve. Analysis of conventional cardiac function parameters revealed that left ventricular ejection fraction (LVEF) was significantly lower in the HFrEF and HFmrEF groups compared to the HFpEF and control groups (P<0.01). Additionally, end-diastolic volume and end-systolic volume were significantly higher in the HFrEF and HFmrEF groups than in the HFpEF and control groups (P<0.01). However, there were no significant differences in cardiac function parameters between the HFpEF and control groups (P>0.05). Significant differences were observed in aortic valve peak pressure gradients (Supra-APGmax) among the four study groups (5.01±1.09 vs. 6.23±2.94 vs. 7.63±1.81 vs. 8.89±2.97 mmHg, P<0.05). Aortic valve peak velocities in the HFrEF group differed significantly from the HFpEF and control groups (111.31±12.05 cm/s vs. 137.2±16 vs. 147.15±24.55 cm/s, P<0.001). The ROC curve for the pressure gradient below the aortic valve had an area under the curve (AUC) of 0.728 [95% confidence interval (CI): 0.591-0.864, P=0.002], with an optimal threshold of 4.72 mmHg (sensitivity: 0.8, specificity: 0.7, Youden index: 0.5). HF patients exhibit reduced pressure gradients across the aortic valve during systole, indicative of altered intracardiac blood flow dynamics. Combining aortic valve velocities and pressure gradients can aid in distinguishing different types of HF, including HFpEF patients.

Clinicopathological and prognostic significance of stromal cell derived factor 2 in the patients with gastric cancer

BackgroundThe stromal cell derived factor 2 (SDF2) relates closely to the occurrence and development of several kind of cancers. There are few studies to investigate the clinicopathological and prognostic significance of SDF2 in gastric cancer (GC) patients.MethodsWe detected SDF2 expression in GC and normal gastric tissues using bioinformatics, western blot and immunohistochemistry. Furthermore, we tested the relationship between SDF2 expression and clinicopathological characteristics and prognosis of GC patients.ResultsBioinformatics, western blot and immunohistochemistry results showed that SDF2 expression in GC tissue was higher than that in normal gastric tissue (P < 0.01). SDF2 expression was associated with Borrmann classification III-IV (χ2 = 6.484, P = 0.011), depth of infiltration T3-T4 (χ2 = 9.140, P = 0.003), positive lymph node metastasis (χ2 = 24.945, P = 0.000) and TNM III-IV stage (χ2 = 9.945, P = 0.002) of GC patients. The Cox regression analysis indicated that distant metastasis M1 stage (HR = 6.026, 95% CI: 1.880-19.318, P = 0.003), TNM III-IV (HR = 1.833, 95% CI: 1.023–3.287, P = 0.042) and SDF2 high expression (HR = 2.091, 95% CI: 1.064–4.108, P = 0.032) were independent risk factors for OS of GC patients. Kaplan-Meier test showed that the OS of GC patients with SDF2 high expression was much poorer than that of GC patients with SDF2 low-expression (χ2 = 22.925, P = 0.000).ConclusionSDF2 expression is high in GC tissue and is correlated with Borrmann classification III-IV, tumor infiltration depth, positive lymph node metastasis and TNM III-IV stage of GC patients. GC patients with SDF2 high-expression have significantly poor OS.