Sudden Cardiac Death in Heart Failure: A 20-Year Perspective From a Mediterranean Cohort.

BACKGROUND: The prediction of sudden cardiac death (SCD) in heart failure (HF) remains an unmet need. The aim of our study was to assess the prevalence of SCD over 20 years in outpatients with HF managed in a Mediterranean multidisciplinary HF Clinic, and to compare the proportion of SCD (SCD/all-cause death) to the expected proportional occurrence based on the validated Seattle Proportional Risk Model (SPRM) score. METHODS AND RESULTS: This prospective observational registry study included 2772 outpatients with HF admitted between August 2001 and May 2021. Patients were included when the cause of death was known and SPRM score was available. Over the 20-year study period, 1351 patients (48.7%) died during a median follow-up period of 3.8 years (interquartile range 1.6-7.6). Among these patients, the proportion of SCD out of the total of deaths was 13.6%, whereas the predicted by SPRM was 39.6%. This lower proportion of SCD was observed independently of left ventricular ejection fraction, ischemic etiology, and the presence of an implantable cardiac defibrillator. CONCLUSIONS: In a Mediterranean cohort of outpatients with HF, the proportion of SCD was lower than expected based on the SPRM score. Future studies should investigate to what extend epidemiological and guideline-directed medical therapy patterns influence SCD.

Long-term LVEF trajectories in patients with type 2 diabetes and heart failure: diabetic cardiomyopathy may underlie functional decline.

BACKGROUND: Left ventricular ejection fraction (LVEF) trajectories and functional recovery with current heart failure (HF) management is increasingly recognized. Type 2 diabetes mellitus (T2D) leads to a worse prognosis in HF patients. However, it is unknown whether T2D interferes with LVEF trajectories. The aim of this study was to prospectively assess very long-term (up to 15 years) LVEF trajectories in patients with and without T2D and underlying HF. METHODS: Ambulatory patients admitted to a multidisciplinary HF clinic were prospectively evaluated by scheduled two-dimensional echocardiography at baseline, 1 year, and then every 2 years afterwards, up to 15 years. Statistical analyses of LVEF change with time were performed using the linear mixed effects (LME) models, and locally weighted error sum of squares (Loess) curves were plotted. RESULTS: Of the 1921 patients, 461 diabetic and 699 non-diabetic patients with LVEF < 50% were included in the study. The mean number of echocardiography measurements performed in diabetic patients was 3.3 ± 1.6. Early LVEF recovery was similar in diabetic and non-diabetic patients, but Loess curves showed a more pronounced inverted U shape in diabetics with a more pronounced decline after 9 years. LME analysis showed a statistical interaction between T2D and LVEF trajectory over time (p = 0.009), which was statistically significant in patients with ischemic etiologies (p < 0.001). Other variables that showed an interaction between LVEF trajectories and T2D were male sex (p = 0.04) and HF duration (p = 0.008). CONCLUSIONS: LVEF trajectories in T2D patients with depressed systolic function showed a pronounced inverted U shape with a marked decline after 9 years. Diabetic cardiomyopathy may underlie the functional decline observed.

Initial experience with bosentan for the management of pulmonary hypertension after heart transplantation.

BACKGROUND: Pulmonary hypertension (PH) after heart transplantation (HT) is associated to right ventricular (RV) dysfunction and increased morbidity and mortality. We present our experience with bosentan for the treatment of PH after HT. METHODS: A retrospective evaluation of patients with PH receiving bosentan post-transplant was performed. Pulmonary hemodynamics before and after bosentan (BG) and clinical outcomes were assessed and compared to a historical control group (CG) not receiving bosentan. RESULTS: Between 2013 and 2016, 21 patients were treated post-transplant with bosentan. Twenty-four hours after bosentan initiation, there were significant decreases in systolic (42.5 ± 8 to 38.1 ± 8 mm Hg, P = 0.015), diastolic (21.4 ± 4 to 17.8 ± 6 mm Hg, P = 0.008) and mean (29.6 ± 5 to 25 ± 6 mm Hg, P = 0.001) pulmonary artery pressures (PAP), transpulmonary gradient (13.1 ± 3 to 9.7 ± 4 mm Hg, P < 0.001), diastolic gradient (5.2 ± 4 to 2.3 ± 3 mm Hg, P = 0.001) and pulmonary vascular resistance (PVR) (2.2 ± 1 to 1.6 ± 1WU, P = 0.015). This effect was maintained at day 3. Compared with CG, BG showed significantly more decrease in PVR (0.7 ± 0.9 vs 0.3 ± 1.7WU, P = 0.025) and mean PAP (4.6 ± 5.2 vs 1.5 ± 4.4 mm Hg, P = 0.040). RV function 7 days post-transplant was significantly better in BG compared to CG, P = 0.004. There were not clinically significant interactions between bosentan and immunosuppressive treatment. CONCLUSIONS: Bosentan, initiated early post-transplant, was associated with a significant decrease in PVR. Bosentan was well tolerated and did not interact with immunosuppressive treatment.

Clinical and prognostic implications of left ventricular dilatation in heart failure.

AIMS: To assess the agreement between left ventricular end-diastolic diameter index (LVEDDi) and volume index (LVEDVi) to define LV dilatation and to investigate the respective prognostic implications in patients with heart failure (HF). METHODS AND RESULTS: Patients with HF symptoms and LV ejection fraction (LVEF) < 50% undergoing cardiac magnetic resonance were evaluated retrospectively. LV dilatation was defined as LVEDDi or LVEDVi above the upper normal limit according to published reference values. Patients were followed up for the combined endpoint of cardiovascular death or HF hospitalization during 5 years. A total of 564 patients (median age 64 years; 79% men) were included. LVEDDi had a modest correlation with LVEDVi (r = 0.682, P < 0.001). LV dilatation was noted in 84% of patients using LVEDVi-based definition and in 73% using LVEDDi-based definition, whereas 20% of patients displayed discordant definitions of LV dilatation. During a median follow-up of 2.8 years, patients with both dilated LVEDDi and LVEDVi had the highest cumulative event rate (HR 3.00, 95% CI 1.15-7.81, P = 0.024). Both LVEDDi and LVEDVi were independently associated with the primary outcome (hazard ratio 3.29, 95%, P < 0.001 and 2.8, P = 0.009; respectively). CONCLUSION: The majority of patients with HF and LVEF < 50% present both increased LVEDDi and LVEDVi whereas 20% show discordant linear and volumetric definitions of LV dilatation. Patients with increased LVEDDi and LVEDVi have the worst clinical outcomes suggesting that the assessment of these two metrics is needed for better risk stratification.

Trajectories of Kidney Function in Heart Failure Over a 15-Year Follow-Up: Clinical Profiling and Mortality.

BACKGROUND: Limited data are available on the long-term trajectory of estimated glomerular filtration rate (eGFR) in patients with chronic heart failure. OBJECTIVES: The authors evaluated eGFR dynamics using the 2009 Chronic Kidney Disease Epidemiology Collaboration equation and its prognostic significance in a real-world cohort over a 15-year follow-up. METHODS: A prospective observational registry of ambulatory heart failure outpatients was conducted, with regular eGFR assessments at baseline and on a 3-month schedule for ≤15 years. Urgent kidney function assessments were excluded. Locally weighted error sum of squares curves were plotted for predefined subgroups. Multivariable longitudinal Cox regression analyses were conducted to assess associations with all-cause and cardiovascular death. RESULTS: A total of 2,672 patients were enrolled consecutively between August 2001 and December 2021. The average age was 66.8 ± 12.6 years, and 69.8% were men. Among 40,970 creatinine measurements, 28,634 were used for eGFR analysis, averaging 10.7 ± 8.5 per patient. Over the study period, a significant decline in eGFR was observed in the entire cohort, with a slope of -1.70 mL/min/1.73 m2 per year (95% CI: -1.75 to -1.66 mL/min/1.73 m2 per year). Older patients, those with diabetes, a preserved ejection fraction, a higher baseline eGFR, elevated hospitalization rates, and those who died during follow-up experienced more pronounced decreases in the eGFR. Moreover, the decrease in kidney function correlated independently with all-cause mortality and cardiovascular death. CONCLUSIONS: These findings highlight the sustained decline in eGFR over 15 years in patients with heart failure, with variations based on clinical characteristics, and emphasize the importance of regular eGFR monitoring in this population.

Prediction of Left Ventricular Reverse Remodeling and Outcomes by Circulating Collagen-Derived Peptides.

BACKGROUND: Myocardial fibrosis may increase vulnerability to poor prognosis in patients with heart failure (HF), even in those patients exhibiting left ventricular reverse remodeling (LVRR) after guideline-based therapies. OBJECTIVES: This study sought to characterize fibrosis at baseline in patients with HF with left ventricular ejection fraction (LVEF) <50% by determining serum collagen type I-derived peptides (procollagen type I C-terminal propeptide [PICP] and ratio of collagen type I C-terminal telopeptide to matrix metalloproteinase-1) and to evaluate their association with LVRR and prognosis. METHODS: Peptides were determined in 1,034 patients with HF at baseline. One-year echocardiography was available in 665 patients. Associations of peptides with 1-year changes in echocardiographic variables were analyzed by multivariable linear mixed models. LVEF was considered improved if it increased by ≥15% or to ≥50% or if it increased by ≥10% to >40% in patients with LVEF ≤40%. Cardiovascular death and HF-related outcomes were analyzed in all patients randomized to derivation (n = 648) and validation (n = 386) cohorts. RESULTS: Continuous associations with echocardiographic changes were observed only for PICP. Compared with high-PICP (≥108.1 ng/mL) patients, low-PICP (<108.1 ng/mL) patients exhibited enhanced LVRR and a lower risk of HF-related outcomes (P ≤ 0.018), with women and nonischemic patients with HF showing a stronger LVEF increase (interaction P ≤ 0.010). LVEF increase was associated with a better prognosis, particularly in low-PICP patients (interaction P ≤ 0.029). Only patients with both low PICP and improved LVEF exhibited a better clinical evolution than patients with nonimproved LVEF (P < 0.001). CONCLUSIONS: Phenotyping with PICP, a peptide associated with myocardial fibrosis, may be useful to differentiate patients with HF who are more likely to experience clinical myocardial recovery from those with partial myocardial improvement.

Evolocumab has no effects on heart failure with reduced ejection fraction injury biomarkers: The EVO-HF trial.

AIM: Patients with heart failure with reduced ejection fraction (HFrEF) have not been shown to benefit from statins. We hypothesized that, by limiting disease progression in stable HFrEF of ischaemic etiology, the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor evolocumab could reduce circulating troponin levels, a surrogate biomarker of myocyte injury and atherosclerosis progression. METHODS AND RESULTS: The EVO-HF multicentre prospective randomized trial compared evolocumab (420 mg/month administered subcutaneously) plus guideline-directed medical therapy (GDMT; n = 17) versus GDMT alone (n = 22) for 1 year in patients with stable coronary artery disease and left ventricular ejection fraction (LVEF) <40%, ischaemic aetiology, New York Heart Association class II, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥400 pg/ml, high-sensitivity troponin T (hs-TnT) >10 pg/ml, low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl. The primary endpoint was change in hs-TnT concentration. Secondary endpoints included NT-proBNP, interleukin-1 receptor-like 1 (ST2), high-sensitivity C-reactive protein (hs-CRP), LDL, low-density lipoprotein receptor (LDLR), high-density lipoprotein cholesterol (HDL-C), and PCSK9 levels at 1 year. Patients were mainly Caucasian (71.8%), male (79.5%), relatively young (mean age 68.1 ± 9.4 years), with a mean LVEF of 30.4 ± 6.5%, and managed with contemporary treatments. No significant changes in hs-TnT levels were observed in any group at 1 year. NT-proBNP and ST2 levels decreased in the GDMT plus evolocumab group (p = 0.045 and p = 0.008, respectively), without changes in hs-CRP, HDL-C, or LDLR. Total and LDL-C decreased in both groups, significantly higher in the intervention group (p = 0.003), and PCSK9 levels increased in the intervention group. CONCLUSIONS: This prospective randomized pilot trial, although with the limitation of the small sample size, does not support the benefit of evolocumab in reducing troponin levels in patients with elevated LDL-C levels, history of coronary artery disease, and stable HFrEF.

Fatty Acid Binding Proteins 3 and 4 Predict Both All-Cause and Cardiovascular Mortality in Subjects with Chronic Heart Failure and Type 2 Diabetes Mellitus.

Subjects with type 2 diabetes mellitus (T2D) are at increased risk for heart failure (HF). The cardiac-specific (FABP3) and adipose-tissue-specific (FABP4) types of the fatty acid binding proteins have been associated with both all-cause and cardiovascular (CV) mortality. The aim of this study was to explore the prognosis value of FABP3 and FABP4 in ambulatory subjects with chronic HF (CHF), with and without T2D. A prospective study involving 240 ambulatory CHF subjects was performed. Patients were followed-up for a mean of 5.78 ± 3.30 years and cause of death (if any) was recorded. Primary endpoints were defined as all-cause and CV death, and a composite endpoint that included CV death or hospitalization for HF was included as a secondary endpoint. Baseline serum samples were obtained and the serum FABP3 and FABP4 concentrations were assessed by sandwich enzyme-linked immunosorbent assay. Survival analysis was performed with multivariable Cox regressions, using Fine and Gray competing risks models when needed, to explore the prognostic value of FABP3 and FABP4 concentrations, adjusting for potential confounders. Type 2 diabetes mellitus was highly prevalent, accounting for 47.5% for total subjects with CHF. Subjects with T2D showed higher mortality rates (T2D: 69.30%; non-T2D: 50.79%, p = 0.004) and higher serum FABP3 (1829.3 (1104.9-3440.5) pg/mL vs. 1396.05 (820.3-2362.16) pg/mL, p = 0.007) and FABP4 (45.5 (27.6-79.8) ng/mL vs. 34.1 (24.09-55.3) ng/mL, p = 0.006) concentrations compared with non-T2D CHF subjects. In the whole study cohort, FABP3 was independently associated with all-cause death, and both FABP3 and FABP4 concentrations were associated with CV mortality. The predictive values of these two molecules for all-cause (FABP3: HR 1.25, 95% CI 1.09-1.44; p = 0.002. FABP4: HR 2.21, 95% CI 1.12-4.36; p = 0.023) and CV mortality (FABP3: HR 1.28, 95% CI 1.09-1.50; p = 0.002. FABP4: HR 4.19, 95% CI 2.21-7.95; p < 0.001) were only statistically significant in the subgroup of subjects with T2D. Notably, FABP4 (HR 2.07, 95% CI 1.11-3.87; p = 0.022), but not FABP3, also predicted the occurrence of the composite endpoint (death or hospitalization for HF) only in subjects with T2D. All these associations were not found in CHF subjects without T2D. Our findings support the usefulness of serum FABP3 and FABP4 concentrations as independent predictors for the occurrence of all-cause and CV mortality in ambulatory subjects with CHF with T2D.

Relationship of Circulating Vegetable Omega-3 to Prognosis in Patients With Heart Failure.

BACKGROUND: There is an urgent need for cost-effective strategies to promote quality of life in patients with heart failure (HF). Several studies reported benefits in HF prognosis for marine omega-3 fatty acids and plant-based dietary patterns. OBJECTIVES: The aim of this study was to explore whether dietary alpha-linolenic acid (ALA), the main plant omega-3, relates to a better HF prognosis. METHODS: ALA was determined in serum phospholipids (which reflect long-term dietary ALA intake and metabolism) by gas chromatography in 905 ambulatory patients with HF caused by different etiologies. RESULTS: After a median follow-up of 2.4 years (range: 0.02-3 years), 140 all-cause deaths, 85 cardiovascular (CV) deaths, and 141 first HF hospitalizations (composite of all-cause death and first HF hospitalization, n = 238) were documented. Using Cox regression analyses, we observed that, compared with patients at the lowest quartile of ALA in serum phospholipids (Q1), those at the 3 upper quartiles (Q2-Q4) exhibited a reduction in the risk of composite of all-cause death and first HF hospitalization (HR: 0.61; 95% CI: 0.46-0.81). Statistically significant reductions were observed for all-cause death (HR: 0.58; 95% CI: 0.41-0.82), CV death (HR: 0.51; 95% CI: 0.32-0.80), first HF hospitalization (HR: 0.58; 95% CI: 0.40-0.84), and the composite of CV death and HF hospitalization (HR: 0.58; 95% CI: 0.42-0.79). CONCLUSIONS: HF patients with bottom 25% ALA levels in serum phospholipids had a worse prognosis during a mid-term follow-up compared with those with the highest levels. This might be a target population in whom to test dietary ALA-rich interventions to promote quality of life.

Cause of Death in Heart Failure Based on Etiology: Long-Term Cohort Study of All-Cause and Cardiovascular Mortality.

We assessed differences in long-term all-cause and cardiovascular (CV) mortality in heart failure (HF) outpatients based on the etiology of HF. Consecutive patients admitted to the HF Clinic from August 2001 to September 2019 (N = 2587) were considered for inclusion. HF etiology was divided into ischemic heart disease (IHD), dilated cardiomyopathy (DCM), hypertensive heart disease, alcoholic cardiomyopathy, drug-induced cardiomyopathy (DICM), valvular heart disease, and hypertrophic cardiomyopathy. All-cause death and CV death were the primary end points. Among 2387 patients included in the analysis (mean age 66.5 ± 12.5 years, 71.3% men), 1317 deaths were recorded (731 from CV cause) over a maximum follow-up of 18 years (median 4.1 years, interquartile range (IQR) 2-7.8). Considering IHD as the reference, only DCM had a lower risk of all-cause death (adjusted hazard ratio (aHR) 0.68, 95% confidence interval (CI) 0.56-0.83, p < 0.001), and only DICM had a higher risk of all-cause death (aHR 1.47, 95% CI 1.02-2.11, p = 0.04). However, almost all etiologies had a significantly lower risk of CV death than IHD. Among the studied HF etiologies, DCM and DICM have the lowest and highest risk of all-cause death, respectively, whereas IHD has the highest adjusted risk of CV death.

GlycA and GlycB as Inflammatory Markers in Chronic Heart Failure.

The role of inflammation in heart failure (HF) has been extensively described, but it is uncertain whether inflammation exerts a different prognostic influence according to etiology. We aimed to examine the inflammatory state in chronic HF by measuring N-acetylglucosamine/galactosamine (GlycA) and sialic acid (GlycB), evolving proton nuclear magnetic resonance biomarkers of systemic inflammation, and explore their prognostic value in patients with chronic HF. The primary end point was a composite of all-cause death and HF readmission. A total of 429 patients were included. GlycB correlated with interleukin-1 receptor-like 1 in the whole cohort (r2 = 0.14, p = 0.011) and the subgroup of nonischemic etiology (r2 = 0.31, p <0.001). No association was found with New York Heart Association functional class or left ventricular ejection fraction. In patients with nonischemic HF (52.2%, n = 224), GlycA and GlycB exhibited significant association with the composite end point (hazard ratio [HR] 1.19, 95% confidence interval [CI] 1.06 to 1.33, p = 0.004 and HR 2.13, 95% CI 1.43 to 3.13, p <0.001; respectively) and GlycB with HF readmission after multivariable adjustment (HR 2.25, 95% CI 1.54 to 3.30, p <0.001). GlycB levels were also associated with a greater risk of HF-related recurrent admissions (adjusted incidence rate ratio 1.33, 95% CI = 1.07 to 1.65, p = 0.009). None of the markers were associated with the clinical end points in patients with ischemic HF. In conclusion, GlycA and GlycB represent an evolving approach to inflammation status with prognostic value in long-term outcomes in patients with nonischemic HF.

Global warming, renal function and heart failure over 20 years.

BACKGROUND: The impact of increasing temperatures on renal function in heart failure (HF) outpatients has never been specifically analyzed. METHODS: We retrieved creatinine and estimated glomerular filtration rate (eGFR) values of all HF outpatients followed at a HF clinic and temperature data from 2002 to 2021. For each patient and each year we averaged values of creatinine, eGFR and monthly temperatures during summer and the rest of the year. RESULTS: The study cohort included 2167 HF patients undergoing 25,865 elective visits, with a median of 14 visits for each patient (interquartile range 7-23). At the first visit, patients (70% men) had an age of 67 ± 13 years, and a left ventricular ejection fraction of 35 ± 14%. Creatinine was 1.25 ± 0.51 mg/dL, and eGFR was 65 ± 25 mL/min/1.73 m2. When pooling together all average values of creatinine and eGFR measured during summer or in the rest of the year, creatinine was significantly higher in summer (difference 0.04, 95% confidence interval [CI] 0.04 to 0.05, p < 0.001), and eGFR was slightly lower (difference - 2.0, 95% CI -2.3 to -1.8, p < 0.001). Temperature rise during summer increased from 2002 to 2021. The absolute (Δ) and percent (Δ%) elevation in temperature during summer displayed independent associations with Δ and Δ% creatinine and eGFR after adjusting for age, sex, plasma creatinine, and HF therapies. CONCLUSIONS: The magnitude of temperature elevation during summer has increased over 20 years. This elevation correlates with the decline in renal function during summer. This might be an example of how global warming is affecting human health.

Quality of life in patients with heart failure and improved ejection fraction: one-year changes and prognosis.

AIMS: The criteria for patients with heart failure (HF) and improved ejection fraction (HFimpEF) are a baseline left ventricular ejection fraction (LVEF) ≤40%, a ≥10-point increase from baseline LVEF, and a second LVEF measurement >40%. We aimed to (i) assess patients with HF and reduced LVEF (HFrEF) at baseline and compare quality of life (QoL) changes between those that fulfilled and those that did not fulfil the HFimpEF criteria 1 year later and (ii) assess the prognostic role of QoL in patients with HFimpEF. METHODS: We reviewed data from a prospective registry of real-world outpatients with HF that were assessed for LVEF and QoL at a first visit to the HF clinic and 1 year later. QoL was evaluated with the Minnesota Living with Heart Failure Questionnaire (MLWHFQ). The primary prognostic endpoint was the composite of all-cause death or HF hospitalization. RESULTS: Baseline and 1-year LVEF and MLWFQ scores were available for 1040 patients with an initial LVEF ≤40% (mean age, 65.2 ± 11.7 years; 75.9% men). The main aetiology was ischaemic heart disease (52.9%), and patients were mostly in New York heart Association Classes II (71.1%) and III (21.6%). At baseline, the mean LVEF was 28.5% ± 7.3, and the mean MLWHFQ score was 30.2 ± 19.5. After 1 year, the mean LVEF increased to 38.0% ± 12.2, and the MLWHFQ scores improved to 17.4 ± 16.0. In 361 patients that fulfilled the HFimpEF criteria (34.7%), significant improvements were observed in both LVEF (from 28.7% ± 6.6 to 50.9% ± 7.6, P < 0.001) and QoL (from 32.9 ± 20.6 to 16.9 ± 16.0, P < 0.001). Patients that did not fulfil the HFimpEF criteria also showed significant improvements in LVEF (from 28.4% ± 7.6 to 31.1% ± 7.9, P < 0.001) and QoL (from 28.7 ± 18.8 to 17.6 ± 15.9, P < 0.001). However, the QoL improvement was significantly higher in the HFimpEF group (-16.0 ± 23.8 vs. -11.1 ± 20.3, P = 0.001), despite the worse mean baseline MLWHFQ score, compared with the non-HFimpEF group (P = 0.001). The 1-year QoL was similar between groups (P = 0.50). The 1-year MLWHFQ score was independently associated with outcomes; the hazard ratio for the composite endpoint was 1.02 (95% CI: 1.01-1.03, P = 0.006). In contrast, the QoL improvement (with a cut-off ≥5 points) was not independently associated with the composite outcome. CONCLUSIONS: Patients with HFrEF showed improved QoL after 1 year, regardless of whether they met the HFimpEF criteria. The similar 1-year QoL perception between groups suggested that factors other than LVEF influenced QoL perception. The 1-year QoL was superior to the QoL change from baseline for predicting prognosis in patients with HFimpEF.

Sacubitril/valsartan affects pulmonary arterial pressure in heart failure with preserved ejection fraction and pulmonary hypertension.

AIMS: Prior studies have not fully characterized the haemodynamic effects of the angiotensin receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan in heart failure with preserved ejection fraction and pulmonary hypertension (HFpEF-PH). The aim of the Treatment of PH With Angiotensin II Receptor Blocker and Neprilysin Inhibitor in HFpEF Patients With CardioMEMS Device (ARNIMEMS-HFpEF) study is to assess pulmonary artery pressure (PAP) dynamics by means of implanted PAP monitors in patients with HFpEF-PH treated with sacubitril/valsartan. METHODS AND RESULTS: This single-arm, investigator-initiated, interventional study included 14 consecutive ambulatory symptomatic HFpEF-PH patients who underwent CardioMEMS implantation prior to enrolment [mean ejection fraction 60.4 ± 7.2%, baseline mean PAP (mPAP) 33.9 ± 7.6 mmHg]. Daily PAP values were examined during three periods: a 6 week period after CardioMEMS implantation and before sacubitril/valsartan treatment (pre-ARNI), a 6 week period with sacubitril/valsartan treatment (ARNI ON), and a 6 week period of sacubitril/valsartan withdrawal (ARNI OFF). The primary endpoint was change in mPAP with and without sacubitril/valsartan. Secondary endpoints included changes in 6 min walking distance, B-line sum in lung ultrasound, and quality of life (QoL). During the study period, 1717 mPAP measurements were recorded. Between pre-ARNI vs. ARNI ON, mPAP significantly declined by -4.99 mmHg [95% confidence interval (CI) -5.55 to -4.43]. Between ARNI ON vs. ARNI OFF, mPAP significantly increased by +2.84 mmHg [95% CI +2.26 to +3.42]. Between pre-ARNI vs. ARNI ON, we found an improvement in 6 min walking distance, B-lines, and QoL. Mean loop diuretic management did not differ between periods. CONCLUSIONS: Sacubitril/valsartan significantly reduced mPAP in patients with HFpEF-PH, independent of loop diuretic management, together with improvement in functional capacity, lung congestion, and QoL. Sacubitril/valsartan may be a therapeutic alternative in HFpEF-PH.

Mortality Risk Prediction Dynamics After Heart Failure Treatment Optimization: Repeat Risk Assessment Using Online Risk Calculators.

Objectives: Heart failure (HF) management has significantly improved over the past two decades, leading to better survival. This study aimed to assess changes in predicted mortality risk after 12 months of management in a multidisciplinary HF clinic. Materials and Methods: Out of 1,032 consecutive HF outpatients admitted from March-2012 to November-2018, 357 completed the 12-months follow-up and had N-terminal pro-B-type natriuretic peptide (NTproBNP), high sensitivity troponin T (hs-TnT), and interleukin-1 receptor-like-1 (known as ST2) measurements available both at baseline and follow-up. Three contemporary risk scores were used: MAGGIC-HF, Seattle HF Model (SHFM), and the Barcelona Bio-HF (BCN Bio-HF) calculator, which incorporates the three above mentioned biomarkers. The predicted risk of all-cause death at 1 and 3 years was calculated at baseline and re-evaluated after 12 months. Results: A significant decline in predicted 1-and 3-year mortality risk was observed at 12 months: MAGGIC ~16%, SHFM ~22% and BCN Bio-HF ~15%. In the HF with reduced ejection fraction (HFrEF) subgroup guideline-directed medical therapy led to a complete normalization of left ventricular ejection fraction (≥50%) in almost a third of the patients and to a partial normalization (41-49%) in 30% of them. Repeated risk assessment after 12 months with SHFM and BCN Bio-HF provided adequate discrimination for all-cause 3-year mortality (C-Index: MAGGIC-HF 0.762, SHFM 0.781 and BCN Bio-HF 0.791). Conclusion: Mortality risk declines in patients with HF managed for 12 months in a multidisciplinary HF clinic. Repeating the mortality risk assessment after optimizing the HF treatment is recommended, particularly in the HFrEF subgroup.

6-Month Outcomes of the TricValve System in Patients With Tricuspid Regurgitation: The TRICUS EURO Study.

BACKGROUND: Severe tricuspid regurgitation (TR) is frequently associated with significant morbidity and mortality; such patients are often deemed to be at high surgical risk. Heterotopic bicaval stenting is an emerging, attractive transcatheter solution for these patients. OBJECTIVES: The aim of this study was to evaluate the 30-day safety and 6-month efficacy outcomes of specifically designed bioprosthetic valves for the superior and inferior vena cava. METHODS: TRICUS EURO (Safety and Efficacy of the TricValve® Transcatheter Bicaval Valves System in the Superior and Inferior Vena Cava in Patients With Severe Tricuspid Regurgitation) is a nonblinded, nonrandomized, single-arm, multicenter, prospective trial that enrolled patients from 12 European centers between December 2019 and February 2021. High-risk individuals with severe symptomatic TR despite optimal medical therapy were included. The primary endpoint was quality-of-life (QOL) improvement measured by Kansas City Cardiomyopathy Questionnaire score and New York Heart Association (NYHA) functional class improvement at 6-month follow-up. RESULTS: Thirty-five patients (mean age 76 ± 6.8 years, 83% women) were treated using the TricValve system. All patients at baseline were in NYHA functional class III or IV. At 30 days, procedural success was 94%, with no procedural deaths or conversions to surgery. A significant increase in QOL at 6 months follow-up was observed (baseline and 6-month Kansas City Cardiomyopathy Questionnaire scores 42.01 ± 22.3 and 59.7 ± 23.6, respectively; P = 0.004), correlating with a significant improvement in NYHA functional class, with 79.4% of patients noted to be in functional class I or II at 6 months (P = 0.0006). The rates of 6-month all-cause mortality and heart failure hospitalization were 8.5% and 20%, respectively. CONCLUSIONS: The dedicated bicaval system for treating severe symptomatic TR was associated with a high procedural success rate and significant improvements in both QOL and functional classification at 6 months follow-up.

A new option for monitoring heart failure. First experience in Spain with CardioMEMS.

INTRODUCTION: The CardioMEMS device is inserted into the pulmonary artery and allows monitorization of pulmonary artery pressure in heart failure patients. Previous studies have shown a reduction in hospitalizations for heart failure and an improvement in quality of life in the group of patients monitored with the device. PATIENTS AND METHODS: Eleven patients managed in a multidisciplinary heart failure clinic implanted with the sensor were consecutively included from June 2019 to February 2020. This is the first experience with a cardioMEMS device published in Spain. RESULTS: The device was successfully implanted in all cases without severe complications or sensor failures, allowing precise adjustment of medical treatment that led to very few heart failure readmissions. DISCUSSION: Wireless pulmonary artery pressure monitoring will probably become an essential component in the management of selected HF patients.

Circulating neprilysin hypothesis: A new opportunity for sacubitril/valsartan in patients with heart failure and preserved ejection fraction?

BACKGROUND: Circulating Neprilysin (sNEP) has emerged as a potential prognostic biomarker in heart failure (HF). In PARAGON-HF benefit of sacubitril/valsartan was only observed in patients with left ventricular ejection fraction (LVEF) ≤57%. We aimed to assess the prognostic value of sNEP in outpatients with HF and LVEF >57%, in comparison with patients with LVEF ≤57%. METHODS: Consecutive HF outpatients were included from May-2006 to February-2016. The primary endpoint was the composite of all-cause death or HF hospitalization and the main secondary endpoint was the composite of cardiovascular death or HF hospitalization. For the later competing risk methods were used. RESULTS: sNEP was measured in 1428 patients (age 67.7±12.7, 70.3% men, LVEF 35.8% ±14), 144 of which had a LVEF >57%. sNEP levels did not significantly differ between LVEF groups (p = 0.31). During a mean follow-up of 6±3.9 years, the primary endpoint occurred in 979 patients and the secondary composite endpoint in 714 (in 111 and 84 of the 144 patients with LVEF >57%, respectively). sNEP was significantly associated with both composite endpoints. Age- and sex- adjusted Cox regression analyses showed higher hazard ratios for sNEP in patients with LVEF >57%, both for the primary (HR 1.37 [1.16-1.61] vs. 1.04 [0.97-1.11]) and the secondary (HR 1.38 [1.21-1.55] vs. 1.11 [1.04-1.18]) composite endpoints. CONCLUSIONS: sNEP prognostic value in patients with HF and LVEF >57% outperforms that observed in patients with lower LVEF. Precision medicine using sNEP may identify HF patients with preserved LVEF that may benefit from treatment with sacubitril/valsartan.

Decoding empagliflozin's molecular mechanism of action in heart failure with preserved ejection fraction using artificial intelligence.

The use of sodium-glucose co-transporter 2 inhibitors to treat heart failure with preserved ejection fraction (HFpEF) is under investigation in ongoing clinical trials, but the exact mechanism of action is unclear. Here we aimed to use artificial intelligence (AI) to characterize the mechanism of action of empagliflozin in HFpEF at the molecular level. We retrieved information regarding HFpEF pathophysiological motifs and differentially expressed genes/proteins, together with empagliflozin target information and bioflags, from specialized publicly available databases. Artificial neural networks and deep learning AI were used to model the molecular effects of empagliflozin in HFpEF. The model predicted that empagliflozin could reverse 59% of the protein alterations found in HFpEF. The effects of empagliflozin in HFpEF appeared to be predominantly mediated by inhibition of NHE1 (Na+/H+ exchanger 1), with SGLT2 playing a less prominent role. The elucidated molecular mechanism of action had an accuracy of 94%. Empagliflozin's pharmacological action mainly affected cardiomyocyte oxidative stress modulation, and greatly influenced cardiomyocyte stiffness, myocardial extracellular matrix remodelling, heart concentric hypertrophy, and systemic inflammation. Validation of these in silico data was performed in vivo in patients with HFpEF by measuring the declining plasma concentrations of NOS2, the NLPR3 inflammasome, and TGF-ß1 during 12 months of empagliflozin treatment. Using AI modelling, we identified that the main effect of empagliflozin in HFpEF treatment is exerted via NHE1 and is focused on cardiomyocyte oxidative stress modulation. These results support the potential use of empagliflozin in HFpEF.

Preload dependence of pulmonary haemodynamics and right ventricular performance.

AIMS: Systolic pulmonary artery pressure (SPAP) and right heart adaptation in relation to pre-existing preload are often disregarded. To determine volume-related changes in the pulmonary-right ventricle (RV) unit and the preload dependence of its components, we analysed pulmonary haemodynamics and right ventricular performance, taking advantage of the plasma volume removal associated to haemodialysis (HD). METHODS AND RESULTS: Fifty-three stable patients on chronic HD with LVEF > 50% and without heart failure were recruited (mean age 63.0 ± 12.4 years; 31.2% women; hypertension in 89% and diabetes in 53%) and evaluated just before and after HD (mean ultrafiltration volume 2.4 ± 0.7 l). SPAP from both times were available in 39 patients. After HD, SPAP decreased (42.2 ± 12.6 to 33.7 ± 11.6 mmHg, p < 0.001) without modification of non-invasive pulmonary vascular resistance (1.75 ± 0.44 to 1.75 ± 0.40 eWU, p = 0.94). Age and drop in the E/e' ratio were the variables associated with greater reduction in PASP (p = 0.022 and p = 0.049, respectively). A significant reduction of right chamber sizes was observed, along with a diminution in measures of RV contractility, excluding RV longitudinal strain. Functional tricuspid regurgitation (FTR) diminution was observed in 26% of patients, occurring in every case with more than mild FTR. On multivariate analyses, left atrial size was the only predictor of pulmonary hypertension (defined as SPAP > 40 mmHg) (OR 1.29 (1.07-1.56), p = 0.006). CONCLUSION: Rapid volemic changes may affect FTR grading, RV size and contractility, with RV longitudinal strain being less variable than conventional parameters. SPAP decreases after HD, and this reduction is related to age and greater diminution of the E/e' ratio.