Prognostic implication of lung ultrasound in heart failure: pooled analysis of international cohorts.

BACKGROUND: Lung ultrasound (LUS) is often used to assess congestion in heart failure (HF). In this study, we assessed the prognostic role of LUS in HF patients at admission and hospital discharge, and in an out-patient setting and explored whether clinical factors (age, sex, left ventricular ejection fraction (LVEF) and atrial fibrillation) impact the prognostic value of LUS findings. Further, we assessed the incremental prognostic value of LUS on top of AHEAD and MAGGIC clinical risk scores. METHODS AND RESULTS: We pooled data of patients hospitalized for HF or followed-up in out-patient clinics from international cohorts. We enrolled 1,947 patients, at admission (n=578), discharge (n=389) and in out-patient clinic (n=980). Total LUS B-line count was calculated for the 8-zone scanning protocol. The primary outcome was a composite of re-hospitalization for HF and all-cause death. Compared to those in the lower tertiles of B-lines, patients in the highest tertile were older, more likely to have signs of HF and higher NT-proBNP levels. A higher number of B-lines was associated with increased risk of primary outcome at discharge (Tertile3 vs Tertile1: adjustedHR= 5.74 (3.26- 10.12), p<0.0001) and in out-patients (Tertile3 vs Tertile1: adjustedHR= 2.66 (1.08- 6.54), p=0.033). Age and LVEF did not influence the prognostic capacity of LUS in different clinical settings. Adding B-line count to MAGGIC and AHEAD scores improved net reclassification significantly in all three clinical settings. CONCLUSION: A higher number of B-lines in patients with HF was associated with increased risk of morbidity and mortality, regardless of the clinical setting.

Assessing the impact of haemodynamic monitoring with CardioMEMS on heart failure patients: a cost-benefit analysis.

AIMS: The objective of this study was to perform a cost-benefit analysis of the CardioMEMS HF System (Abbott Laboratories, Abbott Park, IL, USA) in a heart failure (HF) clinic in Spain by evaluating the real-time remote monitoring of pulmonary artery pressures, which has been shown to reduce HF-related hospitalizations and improve the quality of life for selected HF patients. Particularly, the study aimed to determine the value of CardioMEMS in Southern Europe, where healthcare costs are significantly lower and its effectiveness remains uncertain. METHODS AND RESULTS: This single-centre study enrolled all consecutive HF patients (N = 43) who had been implanted with a pulmonary artery pressure sensor (CardioMEMS HF System); 48.8% were females, aged 75.5 ± 7.0 years, with both reduced and preserved left ventricular ejection fraction; 67.4% of them were in New York Heart Association Class III. The number of HF hospitalizations in the year before and the year after the sensor implantation was compared. Quality-adjusted life years gained based on a literature review of previous studies were calculated. The rate of HF hospitalizations was significantly lower at 1 year compared with the year before CardioMEMS implantation (0.25 vs. 1.10 events/patient-year, hazard ratio 0.22, P = 0.001). At the end of the first year, the usual management outperformed the CardioMEMS HF System. By the end of the second year, the CardioMEMS system is estimated to reduce costs compared with usual management (net benefits of €346). CONCLUSIONS: Based on the results, we suggest that remote monitoring of pulmonary artery pressure with the CardioMEMS HF System represents a midterm and long-term efficient strategy in a healthcare setting in Southern Europe.

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.

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 (CMR) 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). CONCLUSIONS: 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.

Heart failure risk scores in advanced heart failure patients: insights from the LEVO-D registry.

AIMS: The prevalence of advanced heart failure (HF) is increasing due to the growing number of patients with HF and their better treatment and survival. There is a scarcity of data on the accuracy of HF web-based risk scores in this selected population. This study aimed to assess mortality prediction performance of the Meta-Analysis Global Group in Chronic HF (MAGGIC-HF) risk score and the model of the Barcelona Bio-HF Risk Calculator (BCN-Bio-HF) containing N terminal pro brain natriuretic peptide in HF patients receiving intermittent inotropic support with levosimendan as destination therapy. METHODS AND RESULTS: Four hundred and three advanced HF patients from 23 tertiary hospitals in Spain receiving intermittent inotropic support with levosimendan as destination therapy were included. Discrimination for all-cause mortality was compared by area under the curve (AUC) and Harrell's C-statistic at 1 year. Calibration was assessed by calibration plots comparing observed versus expected events based on estimated risk by each calculator. The included patients were predominantly men, aged 71.5 [interquartile range 64-78] years, with reduced left ventricular ejection fraction (27.5 ± 9.4%); ischaemic heart disease was the most prevalent aetiology (52.5%). Death rate at 1 year was 26.8%, while the predicted 1-year mortality by BCN-Bio-HF and MAGGIC-HF was 17.0% and 22.1%, respectively. BCN-Bio-HF AUC was 0.66 (Harrell's C-statistic 0.64), and MAGGIC-HF AUC was 0.62 (Harrell's C-statistic 0.61). CONCLUSIONS: The two evaluated risk scores showed suboptimal discrimination and calibration with an underestimation of risk in advanced HF patients receiving levosimendan as destination therapy. There is a need for specific scores for advanced HF.

A new FGF15/19-mediated gut-to-heart axis controls cardiac hypertrophy.

FGF15 and its human orthologue, FGF19, are members of the endocrine FGF family and are secreted by ileal enterocytes in response to bile acids. FGF15/19 mainly targets the liver, but recent studies indicate that it also regulates skeletal muscle mass and adipose tissue plasticity. The aim of this study was to determine the role(s) of the enterokine FGF15/19 during the development of cardiac hypertrophy. Studies in a cohort of humans suffering from heart failure showed increased circulating levels of FGF19 compared with control individuals. We found that mice lacking FGF15 did not develop cardiac hypertrophy in response to three different pathophysiological stimuli (high-fat diet, isoproterenol, or cold exposure). The heart weight/tibia length ratio and the cardiomyocyte area (as measures of cardiac hypertrophy development) under hypertrophy-inducing conditions were lower in Fgf15-null mice than in wild-type mice, whereas the levels of the cardiac damage marker atrial natriuretic factor (Nppa) were up-regulated. Echocardiographic measurements showed similar results. Moreover, the genes involved in fatty acid metabolism were down-regulated in Fgf15-null mice. Conversely, experimental increases in FGF15 induced cardiac hypertrophy in vivo, without changes in Nppa and up-regulation of metabolic genes. Finally, in vitro studies using cardiomyocytes showed that FGF19 had a direct effect on these cells promoting hypertrophy. We have identified herein an inter-organ signaling pathway that runs from the gut to the heart, acts through the enterokine FGF15/19, and is involved in cardiac hypertrophy development and regulation of fatty acid metabolism in the myocardium. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Left-to-right ventricular volume ratio and outcome in heart failure with preserved ejection fraction.

BACKGROUND: Age-specific and gender-specific reference values for left ventricular (LV) and right ventricle volumes are available. The prognostic implications of the ratio between these volumes in heart failure and preserved ejection fraction (HFpEF) have never been evaluated. METHODS: We examined all HFpEF outpatients undergoing a cardiac magnetic resonance from 2011 to 2021. The left-to-right ventricular volume ratio (LRVR) was defined as the ratio between the LV and right ventricle end-diastolic volume indexes (LVEDVi/RVEDVi). RESULTS: Among 159 patients [median age 58 years (interquartile range 49-69), 64% men, LV ejection fraction 60% (54-70%)] the median LRVR was 1.21 (1.07-1.40). Over 3.5 years (1.5-5.0), 23 patients (15%) experienced all-cause death or heart failure hospitalization, and 22 (14%) cardiovascular death or heart failure hospitalization. The risk of all-cause death or heart failure hospitalization increased with an LRVR less than 1.0 or at least 1.4. An LRVR less than 1.0 was associated with a higher risk of all-cause death or heart failure hospitalization [hazard ratio 5.95, 95% confidence interval (CI) 1.67-21.28; P = 0.006] and cardiovascular death or heart failure hospitalization (hazard ratio 5.68, 95% CI 1.58-20.35; P = 0.008) as compared with LRVR 1.0-1.3. Furthermore, an LRVR at least 1.4 was associated with a higher risk of all-cause death or heart failure hospitalization (hazard ratio 4.10, 95% CI 1.58-10.61; P = 0.004) and cardiovascular death or heart failure hospitalization (hazard ratio 3.71, 95% CI 1.41-9.79; P = 0.008) as compared with LRVR 1.0-1.3. These results were confirmed in patients without dilation of either ventricle. CONCLUSION: LRVR values less than 1.0 or at least 1.4 are associated with worse outcomes in HFpEF. LRVR may become a valuable tool for risk prediction in HFpEF.

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.

Performance analysis of a STEMI network: prognostic impact of the type of first medical contact facility.

INTRODUCTION AND OBJECTIVES: Prognosis in ST-elevation myocardial infarction (STEMI) is determined by delay in primary percutaneous coronary intervention (PPCI). The impact of first medical contact (FMC) facility type on reperfusion delays and mortality remains controversial. METHODS: We performed a prospective registry of primary coronary intervention (PCI)-treated STEMI patients (2010-2020) in the Codi Infart STEMI network. We analyzed 1-year all-cause mortality depending on the FMC facility type: emergency medical service (EMS), community hospital (CH), PCI hospital (PCI-H), or primary care center (PCC). RESULTS: We included 18 332 patients (EMS 34.3%; CH 33.5%; PCI-H 12.3%; PCC 20.0%). Patients with Killip-Kimball classes III-IV were: EMS 8.43%, CH 5.54%, PCI-H 7.51%, PCC 3.76% (P <.001). All comorbidities and first medical assistance complications were more frequent in the EMS and PCI-H groups (P <.05) and were less frequent in the PCC group (P <.05 for most variables). The PCI-H group had the shortest FMC-to-PCI delay (median 82 minutes); the EMS group achieved the shortest total ischemic time (median 151 minutes); CH had the longest reperfusion delays (P <.001). In an adjusted logistic regression model, the PCI-H and CH groups were associated with higher 1-year mortality, OR, 1.22 (95%CI, 1.00-1.48; P=.048), and OR, 1.17 (95%CI 1.02-1.36; P=.030), respectively, while the PCC group was associated with lower 1-year mortality than the EMS group, OR, 0.71 (95%CI 0.58-0.86; P <.001). CONCLUSIONS: FMC with PCI-H and CH was associated with higher adjusted 1-year mortality than FMC with EMS. The PCC group had a much lower intrinsic risk and was associated with better outcomes despite longer revascularization delays.

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.

Mechanical complications in STEMI: prevalence and mortality trends in the primary PCI era. The Ruti-STEMI registry.

INTRODUCTION AND OBJECTIVES: Mechanical complications confer a dreadful prognosis in ST-elevation myocardial infarction (STEMI). Their prevalence and prognosis are not well-defined in the current era of primary percutaneous coronary intervention (pPCI) reperfusion networks. We aimed to analyze prevalence and mortality trends of post-STEMI mechanical complications over 2 decades, before and after the establishment of pPCI networks. METHODS: Prospective, consecutive registry of STEMI patients within a region of 850 000 inhabitants over 2 decades: a pre-pPCI period (1990-2000) and a pPCI period (2007-2017). We analyzed the prevalence of mechanical complications, including ventricular septal rupture, papillary muscle rupture, and free wall rupture (FWR). Twenty eight-day and 1-year mortality trends were compared between the 2 studied decades. RESULTS: A total of 6033 STEMI patients were included (pre-pPCI period, n=2250; pPCI period, n=3783). Reperfusion was supported by thrombolysis in the pre-pPCI period (99.1%) and by pPCI in in the pPCI period (95.7%). Mechanical complications developed in 135 patients (2.2%): ventricular septal rupture in 38 patients, papillary muscle rupture in 24, and FWR in 73 patients. FWR showed a relative reduction of 60% in the pPCI period (0.8% vs 2.0%, P<.001), without significant interperiod changes in the other mechanical complications. After multivariate adjustment, FWR remained higher in the pre-pPCI period (OR, 1.93; 95%CI, 1.10-3.41; P=.023). At 28 days and 1 year, mortality showed no significant changes in all the mechanical complications studied. CONCLUSIONS: The establishment of regional pPCI networks has modified the landscape of mechanical complications in STEMI. FWR is less frequent in the pPCI era, likely due to reduced transmural infarcts.

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.

Preclinical scenario of targeting myocardial fibrosis with chimeric antigen receptor (CAR) immunotherapy.

Fibrosis is present in an important proportion of myocardial disorders. Injury activates cardiac fibroblasts, which deposit excess extracellular matrix, increasing tissue stiffness, impairing cardiac function, and leading to heart failure. Clinical therapies that directly target excessive fibrosis are limited, and more effective treatments are needed. Immunotherapy based on chimeric antigen receptor (CAR) T cells is a novel technique that redirects T lymphocytes toward specific antigens to eliminate the target cells. It is currently used in haematological cancers but has demonstrated efficacy in mouse models of hypertensive cardiac fibrosis, with activated fibroblasts as the target cells. CAR T cell therapy is associated with significant toxicities, but CAR natural killer cells can overcome efficacy and safety limitations. The use of CAR immunotherapy offers a potential alternative to current therapies for fibrosis reduction and restoration of cardiac function in patients with myocardial fibrosis.