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Abstract Background NT-proBNP levels are associated with disease severity and outcomes in patients with HF across the spectrum of LVEF. Recently, it has been suggested that the effectiveness of certain treatments may vary by NT-proBNP level with greater benefit from omecamtiv mecarbil, and smaller benefit from vericiguat, in patients with higher NT-proBNP levels. We examined the benefit of sacubitril/valsartan on outcomes across the range of NT-proBNP levels in patients with HFrEF/HFmrEF/HFpEF. Purpose To evaluate clinical outcomes, and the efficacy of sacubitril/valsartan, according to NT-proBNP levels, in patients with HFrEF/HFmrEF/HFpEF, using the pooled dataset of participants in the PARADIGM-HF and PARAGON-HF trials. Methods The PARADIGM-HF (n=8399) and PARAGON-HF (n=4822) trials enrolled patients with HF, functional limitation, and elevated NT-proBNP levels. Patients with LVEF ≤40% were randomized to sacubitril/valsartan 200 mg twice daily or enalapril 10mg twice daily in PARADIGM-HF, and those with LVEF ≥45% to sacubitril/valsartan 200 mg twice daily or valsartan 160mg twice daily in PARAGON-HF. Patients were categorized by quintiles of NT-proBNP level and using NT-proBNP as a continuous variable, analysed using restricted cubic splines. The primary outcome in the present study was the composite of cardiovascular death or HF hospitalization. Results Among the 13195 patients in the pooled PARADIGM-HF and PARAGON-HF dataset, 13142 (99.6%) patients with baseline NT-proBNP were analysed. Patients with higher NT-proBNP levels were more often male, had lower body mass index and LVEF, worse New York Heart Association functional class, worse kidney function, and more atrial fibrillation, while age was similar across NT-proBNP levels. The rate of the primary outcome (per 100 person-years) increased with NT-proBNP level: quintile 1, 5.9 (95%CI 5.3-6.5); quintile 2, 7.5 (95%CI 6.9-8.2); quintile 3, 9.0 (95%CI 8.2-9.7); quintile 4, 12.0 (95%CI 11.1-12.9); and quintile 5, 20.8 (95%CI 19.6-22.2) (Figure 1). Similar trends were observed for other outcomes. The benefit of sacubitril/valsartan was consistent across NT-proBNP levels: the hazard ratio for the primary outcome in NT-proBNP quintile 1 was 0.79 (95%CI 0.65-0.96); quintile 2, 0.87 (95%CI 0.72-1.04); quintile 3, 0.79 (95%CI 0.66-0.93); quintile 4, 0.85 (95%CI 0.73-0.99); and quintile 5, 0.86 (95%CI 0.76-0.97), P-interaction=0.86. The consistent benefit of sacubitril/valsartan was also seen when NT-proBNP was analysed as a continuous variable (Figure 2). The absolute benefit was greatest in quintile 5 of NT-proBNP; the number needed to treat for quintile 5 was 16 versus 37 for the quintile 1 for the primary endpoint. Conclusions Patients with higher NT-proBNP had worse outcomes, but the benefits of sacubitril valsartan were consistent across the range of NT-proBNP levels of participants in PARADIGM-HF and PARAGON-HF.Kaplan-Meier curvesEffect of sac/val across NT-proBNP range

Abstract Background Patients with heart failure possess an increased risk for adverse outcomes with noncardiac surgery (1). While bariatric surgery is frequently performed in patients with obesity, there remains a limited understanding of the impact of bariatric surgery in obese patients with heart failure. Purpose The purpose of this study was to compare outcomes of bariatric surgery versus nonsurgical management in obese patients with heart failure. Methods We searched PubMed, EMBASE, and the Cochrane Library, through February 2024, for studies evaluating outcomes in obese patients with heart failure who underwent bariatric surgery compared to nonsurgical management. Outcomes assessed were postoperative atrial fibrillation, all-cause mortality, and hospital readmission. We used a fixed-effect model to calculate hazard ratios (HR) with 95% confidence intervals (CI) in R studio for outcomes assessed. In outcomes where significant heterogeneity was found (P< 0.05 and I2 > 60%), a random effects model was used. Results A total of 3 studies were identified, consisting of 260,186 patients. Compared to nonsurgical management, bariatric surgery was associated with a significant reduction in postoperative atrial fibrillation (HR 0.72; 95% CI: 0.62-0.84), all-cause mortality (HR 0.50; 95%CI 0.35-0.72), and hospital readmission (HR 0.73; 95% CI 0.69-0.78) in obese patients with heart failure. Conclusion Our study suggests that bariatric surgery significantly reduces post-operative atrial fibrillation, mortality, and hospital readmission among obese patients with heart failure.Our findings demonstrate that bariatric surgery should be considered as a viable intervention in obese patients with heart failure. Further studies are warranted to confirm our findings.Forest Plots of Outcomes Assessed

Abstract Background Hypercontractile phenotype of the left ventricle (LV) is an actionable therapeutic target in patients with chronic coronary syndromes (CCS), but its clinical recognition remains elusive. Purpose To assess the clinical variables associated with the hypercontractile phenotype of the LV, identified with supernormal values of an index of LV contractility such as LV force, also known as ventricular elastance. Methods In a prospective, observational, multicenter study, we recruited 5,122 patients (age 65± 11.1 years, 2974 males, 58%) with CCS referred for resting transthoracic echocardiography with technically successful volumetric echocardiography in 17 accredited laboratories. We measured systolic blood pressure (SBP) with a cuff sphygmomanometer. We assessed semi-quantitatively wall motion score index (WMSI), and quantitatively LV end-diastolic volume (EDV), end-systolic volume (ESV), ejection fraction (EF), force (SBP/ESV), stroke volume (SV), arterial elastance (SBP/SV), ventricular-arterial coupling (VAC, as SV/ESV), and cardiac output (CO = SV*heart rate).Univariable and multivariable logistic regression analysis assessed independent factors associated with the highest force sextile. Odds ratios (ORs) with the corresponding 95% confidence interval (CI) were estimated. Results For all the studied patients, EF was 59±11%. Force was 4.51±2.11 mmHg/ml, with reference sextile = 3.50-4.26 mmHg/ml, lowest sextile (Group 1) <2.60 mmHg/ml and highest sextile (Group 6) > 6.36 mmHg/ml. The correlation between the log of EF and the log of Force was significant with linear regression (r = 0.73, p < 0.001). Patients in the highest sextile of force showed lower values of WMSI, SV, EDV, and ESV, and higher values of arterial elastance and VAC (Table). By multivariable logistic regression model, the highest sextile of force was associated with age > 71 years (OR 4.35, 95% CI 3.06-6.18, p < 0.001), female sex (OR 4.48, 95% CI 3.62-5.54, p < 0.001), absence of beta-blocker therapy (OR 1.56, 95% CI 1.27-1.91), rest SBP> 159 mmHg (OR 6.86, 95% CI 5.03-9.35, p < 0.001), high heart rate (OR 1.03, 95% CI 1.02-1.04, p < 0.001), absence of prior MI (OR 1.31, 95% CI 1-1.72, p = 0.049), and higher LV EF at rest (OR 1.24, 95% CI 1.22-1.26, p < 0.001). Conclusions A hypercontractile phenotype of the LV with high force is associated with a small heart, reduced SV, and higher arterial elastance. It was clinically associated with advanced age, female sex, history of hypertension, absence of beta-blocker therapy, and high resting SBP.

Abstract Background Abnormal (<50%) ejection fraction (EF) is a cornerstone of risk stratification and therapy, but also an imperfect proxy of left ventricular (LV) cardiac pump function, better assessed with stroke volume (SV). Aim To assess the value of SV in stratifying risk of patients with abnormal EF. Methods In a prospective, observational, multicenter study, we recruited 746 patients (age 66± 11 years, 536 males, 72%, 359 with previous myocardial infarction, 48%) with chronic coronary syndromes (CCS) and EF <50% referred for resting transthoracic echocardiography with technically successful 2-dimensional volumetric echocardiography in 17 accredited laboratories. We quantitatively assessed LV end-diastolic volume (EDV) and end-systolic volume (ESV) by Simpson’s biplane method. EF (EDV-ESV/EDV) and SV (EDV-ESV) were calculated from LV volumes. The outcome end-point was all-cause death. Results EF was 39±9%, SV 48±20 ml. There were 100 all-cause deaths during a median follow-up of 796 days (interquartile range 420-1286 days). Receiver-operating curve analysis identified SV≤31.4 ml/b as the best cut-off for predicting mortality. At multivariable analysis, after adjustment for age and prior myocardial infarction, EF <40% and SV ≤31.4 ml/b were significantly associated with decreased survival (HR 2.09, 95%, confidence intervals 1.09-4.01, p=0.024). The annual mortality was lowest (3.19%) in the group with mildly reduced (40-49%) EF and normal (>31.4 ml) SV, and highest (8.30%) in patients with both reduced EF and abnormal SV: see figure. Conclusion Patients with CCS and abnormal EF are a prognostically heterogeneous group, and the mortality rate is almost 3-times worse in patients with reduced EF and abnormal SV compared to patients with mildly reduced EF and normal SV. A simple resting volumetric two-dimensional echocardiography can offer an efficient risk stratification, beyond EF, with no extra imaging or analysis time.Figure

Abstract Background Concerns have been raised about the appropriateness of use and safety of beta-blockers (BBs) in patients with heart failure and mildly reduced (HFmrEF) and preserved ejection fraction (HFpEF). However, randomized trial evidence is still lacking. Purpose To perform an observational analysis of the association between BB use and clinical outcomes in a large dataset of patients with HFmrEF and HFpEF. Methods We pooled individual patient data from four large HFmrEF/HFpEF trials (I-Preserve, TOPCAT, PARAGON-HF, and DELIVER). The associations between baseline BB use and outcomes were analyzed. The primary outcome was the composite of cardiovascular death or HF hospitalization. Results Among the 16,951 patients included, the mean left ventricular ejection fraction (LVEF) was 56.8%, and 13,400 (79.1%) had HFpEF (LVEF ≥50%). Overall, 12,812 patients (75.6%) received a BB. The median bisoprolol-equivalent dose of BB was 5.0 (Q1-Q3: 2.5-5.0) mg with BB continuation rates of 95.1% at 1 year and 93.1% at 2 years (in patients who survived more than 1 and 2 years, respectively). Overall, the hazard ratio (HR) for the primary outcome did not differ between BB users and non-users (HR: 0.98 [95% CI: 0.91-1.05]) but among patients with HFmrEF, BB users had a lower HR (0.84 [95% CI 0.71-0.98]), whereas in HFpEF the HR was similar BB users and non-users (0.99 [95% CI 0.92-1.08]). However, after comprehensive adjustment for known prognostic variables, including NT-proBNP, BB use was associated with a better outcome in the overall cohort (HR 0.81 [0.74-0.88]), and this association was maintained across the range of LVEF (Figure 1). In subgroup analyses, the risk of the primary outcome was similar in BB users and non-users with or without a history of myocardial infarction, with or without a history of hypertension, or with or without a baseline heart rate <70 bpm. By contrast, a better outcome with BB use was seen in patients with atrial fibrillation compared to those without atrial fibrillation (Figure 2). Conclusions Although this is an observational analysis of non-randomized treatment, there was no suggestion that BB use was associated with worse HF outcomes even after extensive adjustment for other prognostic variables. Figure Legends Figure 1. Association between beta-blocker use and outcomes across the range of LVEF. Risk in beta-blocker users versus non-users is shown as an adjusted continuous hazard ratio Figure 2. Association between beta-blocker use and non-use in the overall population and clinically relevant patient subgroups, shown as an adjusted hazard ratio (HR). The outcome analyzed was the composite of CV death or HF hospitalization (primary outcome)Figure 1Figure 2

Abstract Background Excess fat, particularly visceral fat, plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Sodium glucose cotransporter-2 inhibitors improve hemodynamics, reduce symptom severity, and decrease risk of hospitalization, but their impact on body composition, as well as potential relationships between changes in body composition and hemodynamic effects, are unknown in HFpEF. Purpose Evaluate the effect of dapagliflozin on body and blood composition and examined the potential correlation of such changes on cardiac hemodynamics. Methods The CAMEO-DAPA trial, a single-center, double-blind, randomized, placebo-controlled study, showed that 24 weeks of dapagliflozin reduced resting and exercise pulmonary capillary wedge pressures (PCWP) in patients with HFpEF. This prespecified secondary analysis reports the effects of dapagliflozin on body composition using dual energy x-ray absorptiometry (DEXA), blood composition (radiolabeled iodinated albumin), and cardiac hemodynamics using high-fidelity micromanometers. Analysis was performed based on the intention-to-treat. Relative change was calculated by dividing the absolute change on the baseline value. Results Overall, 37 patients (67 years, 65% women, 70% with obesity, 27% overweight) completed the trial. As compared with baseline, dapagliflozin decreased total body fat compared with placebo [mean (SD) absolute change: -2.29 (2.94) kg vs -0.32 (1.84) in placebo, p=0.03; relative change: -4.6% (5.4) vs -0.8% (4.3), p=0.02], Figure 1. This was primarily due to greater loss of upper body trunk fat [absolute change: -1.53 (1.70) kg vs +0.31 (0.99) in placebo, p<.001; relative change: -5.2% (5.6) vs +1.1% (4.1), p<.001], Figure 1. Reductions in trunk fat were correlated with decreases in PCWP (r=0.41, p=0.03), Figure 2. Total body fat-free mass (FFM) tended to decrease in the dapagliflozin group [absolute change: -0.63 (1.85) kg vs +0.34 (1.76), p=0.12]; reductions in leg, android, and gynoid FFM were all greater than placebo (p<0.05). Dapagliflozin reduced plasma volume [absolute change: -170 (343) ml vs +112 (346), p=0.02] compared with placebo, and the decrease in plasma volume was correlated with the reduction in FFM (r=0.47, p=0.006), Figure 2. Treatment with dapagliflozin had no effect on resting metabolic rate but was associated with modest reduction in bone mineral content [-16 (47) g vs +26 (61), p=0.03]. Conclusions In patients with HFpEF, dapagliflozin decreases body fat, particularly trunk fat, suggesting greater effect on visceral adipose, which is correlated with favorable hemodynamic effects. Dapagliflozin also tends to reduce FFM, which may relate to reduction in total body water with or without reduction is muscle mass, in tandem with modest decreases in bone mineral content.Figure 1:Relative change in fat massFigure 2

Abstract Background/Introduction Cardiac stress tests are carried out in populations with a low probability of ischemic heart disease (IHD) much more frequently than in the past. Stress ECG remains a frequently used modality for the diagnosis of IHD in vast areas of the world with limited facilities. Purpose To assess the diagnostic value of stress ECG for diagnosing IHD using inducible regional wall motion abnormalities (RWMA) on stress echocardiography (SE) as the gold standard method of diagnosis. Methods The 12-lead ECG response was retrospectively analyzed in 4317 patients (age 64±13 years, 59.6% males) undergoing SE for chronic coronary syndromes who were prospectively recruited from 39 cardiac centers between March 2021 and February 2024. Exclusion criteria were left bundle branch block or pacemaker rhythm. ECG response was considered ischemic according to standard criteria (if ST-segment deviated >1.0 mm from baseline in ≥2 contiguous leads at 80 ms from J point) during an exercise (n=2980, 69.8%), dobutamine (n = 766, 18.0%), or vasodilator (n=519, 12.2%) SE. All patients underwent a comprehensive SE protocol with an assessment of wall motion score index (WMSI), B-lines (4-site simplified score), left ventricular contractile reserve (LVCR) based on force, coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending artery (LAD), and heart rate reserve (HRR). Results ECG changes occurred in 641 patients (14.8%, Group 1) for the overall studied population. Compared to patients without ECG changes (Group 2, n=3676, 85.2%), patients with ECG changes showed higher values of peak WMSI and lower values of CFVR and LVCR (see table).Amongst patients without inducible RWMA (n=3553), there were 392 (11%) patients with an ischemic ECG at stress (89% specificity). Of 764 patients with inducible RWMA during SE, 249 had an ischemic ECG trace (sensitivity 33%). In patients without inducible RWMA, those with ischemic ECG changes showed similar abnormal stress B-lines (23% vs. 21%, p=0.719), LVCR (61% vs. 63%, p=0.602), CFVR (31% vs 33%, p=0.607) and HRR (37% vs 41%, p=0.097) compared to those without ECG changes. Amongst patients with inducible RWMA and ECG changes, CFVR was significantly lower in patients with ECG changes (39.2% and 60.8%, respectively, p<0.001). Conclusions Simple standard stress ECG diagnostic value in the current era in populations with a low probability of IHD seems to be low. However, during SE, stress-induced ischemic ECG changes are associated with more extensive RWMA and blunted global LVCR, with reduced CFVR in the LAD. Therefore, analysis of ST segment changes during stress imaging studies can offer additional, significant information.

Abstract Background Patients with lower extremity peripheral arterial disease (PAD) have a higher risk of cardiovascular events. Stress echocardiography (SE) based on regional wall motion abnormality (RWMA) is imperfect for risk stratification in PAD, but it can be complemented with an assessment of coronary flow velocity reserve (CFVR) in the mid-distal left anterior descending coronary artery. Purpose To assess the value of SE with RWMA and CFVR to predict survival in PAD. Methods In a retrospective analysis of prospectively acquired data in an observational, multicenter study, we recruited 359 patients (age 69±8 years, 240 [67%] males) with PAD referred for dipyridamole SE in 3 accredited laboratories. We assessed RWMA and CFVR (abnormal value <2.0). All patients were followed up for a median of 4.7 (interquartile range: 2.0 to 8.2 years). All-cause death was the outcome end-point. Results The positivity rate was 37/359 (10%) for RWMA and 159/359 (44%) for CFVR. During follow-up, 97 (27%) deaths were registered. At multivariable analysis, inducible RWMA and/or CFVR <2.0 (HR 2.58, 95% CI 1.65-4.04; p<0.0001), age ≥70 years, diabetes, dialysis treatment, and ejection fraction ≤50% were associated with decreased survival. The annual mortality was 7.4% in patients with RWMA and/or CFVR <2.0 and 2.7% in those with no RWMA and CFVR >2.0 (Figure, p<0.0001). Conclusion In patients with PAD, SE shows more than 4-fold higher prevalence of abnormal CFVR compared to RWMA. The prognostic value of CFVR outperforms RWMA, showing the importance of coronary microvascular dysfunction and diffuse, subcritical coronary atherosclerosis in determining the outcome.

Abstract Background In severely symptomatic patients with obstructive hypertrophic cardiomyopathy (HCM), the VALOR-HCM phase 3 randomized, double-blind, placebo-controlled clinical trial demonstrated that mavacamten, a cardiac myosin inhibitor, reduces the eligibility for septal reduction therapy with sustained improvement in left ventricular (LV) outflow tract gradients and symptoms. Mavacamten also resulted in favorable cardiac remodeling, including improvement in left atrial volume index (LAVI), LV diastolic function, and biomarkers (NT-proBNP and troponin T). However, the impact of mavacamten on LA function is not known. Objective We sought to assess serial changes in LA strain measures in patients enrolled in the VALOR-HCM trial. Methods VALOR-HCM included 112 symptomatic obstructive HCM patients (mean age 60 years, 51% male). Patients assigned to mavacamten at baseline (n=56) continued therapy for 56 weeks and those assigned to placebo crossed over to mavacamten (n=52) from week 16-56 (40-week exposure). Echocardiographic LA strain assessment was performed according to the current American and European guideline recommendations, using a vendor-neutral post processing software. For assessment of LA strain components (reservoir, conduit, and contraction), the non-foreshortened apical 4-chamber view was utilized. The zero reference was set at end-diastole. Results Serial changes in LAVI and all components of mean LA strain from baseline to week 56 are shown in the Figure. At baseline, LAVI and all mean LA strain values were worse than reported normal mean thresholds. There was a continued and significant improvement in all 3 LA strain values, from baseline to week 56, along with a significant reduction in LAVI. Improvement in LAVI was seen earlier than improvements in LA strain. There was a significant inverse correlation between change in mean LAVI and LA reservoir strain from baseline to week 56 (r= -0.42, p<0.001). Conclusions In the VALOR-HCM trial, average LAVI and baseline LA strain values were significantly worse than reported normal thresholds. Treatment with mavacamten resulted in an improvement in LAVI and LA strain values from baseline through week 56 suggesting a sustained favorable impact on cardiac remodeling. The advantageous cardiac remodeling associated with long-term treatment with mavacamten may in turn have a favorable impact on the observed high burden of atrial tachyarrhythmias in HCM.Serial changes in LA strain in VALOR-HCM