Post-cardiac arrest temporal evolution of left ventricular function in a rat model: speckle-tracking echocardiography and cardiac circulating biomarkers.

Aims: There is little information from experimental studies regarding the evolution of post-resuscitation cardiac arrest [post-return of spontaneous circulation (post-ROSC)] myocardial dysfunction during mid-term follow-up. For this purpose, we assessed left ventricular (LV) function and circulating cardiac biomarkers at different time points in a rat model of cardiac arrest (CA). Methods and results: Rats were divided into two groups: control and post-ROSC rats. Eight minutes of untreated ventricular fibrillation were followed by 8 min of cardiopulmonary resuscitation. Conventional and speckle-tracking echocardiographic (STE) parameters and cardiac circulating biomarkers concentrations were assessed, at 3, 4, 72, and 96 h post-ROSC. At 3 and 4 h post-ROSC, LV systolic function was severely impaired, and high-sensitivity cardiac troponin T and N-terminal pro-atrial natriuretic peptide (NT-proANP) plasma concentrations were significantly increased, compared with control rats (P < 0.0001 for all). At 72 and 96 h post-ROSC, LV ejection fraction (LVEF) normalized. At 96 h, the following variables were significantly different from control rats: early trans-mitral peak velocity, 56.8 ± 3.1 vs. 87.8 ± 3.8 cm/s, P < 0.0001; late trans-mitral peak velocity, 50.6 ± 4.7 vs. 73.7 ± 4.2 cm/s, P < 0.0001; mean s' wave velocity, 4.6 ± 0.3 vs. 5.9 ± 0.3 cm/s, P < 0.0001, global longitudinal strain (GLS) -7.5 ± 0.5 and vs. -11 ± 1.2%, P < 0.01; GLS rate (GLSR) -0.9 ± 0.4 and -2.3 ± 0.2 1/s, P < 0.01; and NT-proANP concentration, 2.5 (0.2; 6.0) vs. 0.4 (0.01; 1.0) nmol/L, P < 0.01. Conclusion: s' velocity, GLS, and GLSR indicated that LV systolic function was still impaired 96 h post-ROSC. These findings agree with NT-proANP concentrations, which continue to be high. Normalization of LVEF supports the use of STE for its greater sensitivity for monitoring post-CA cardiac function. Further investigations are needed to provide evidence of the post-ROSC LV diastolic function pattern.

Characterization of the Cardiac Structure and Function of Conscious D2.B10-Dmdmdx/J (D2-mdx) mice from 16-17 to 24-25 Weeks of Age.

Duchenne muscular dystrophy (DMD) is the most common form of muscle degenerative hereditary disease. Muscular replacement by fibrosis and calcification are the principal causes of progressive and severe musculoskeletal, respiratory, and cardiac dysfunction. To date, the D2.B10-Dmdmdx/J (D2-mdx) model is proposed as the closest to DMD, but the results are controversial. In this study, the cardiac structure and function was characterized in D2-mdx mice from 16-17 up to 24-25 weeks of age. Echocardiographic assessment in conscious mice, gross pathology, and histological and cardiac biomarker analyses were performed. At 16-17 weeks of age, D2-mdx mice presented mild left ventricular function impairment and increased pulmonary vascular resistance. Cardiac fibrosis was more extended in the right ventricle, principally on the epicardium. In 24-25-week-old D2-mdx mice, functional and structural alterations increased but with large individual variation. High-sensitivity cardiac Troponin T, but not N-terminal pro-atrial natriuretic peptide, plasma levels were increased. In conclusion, left ventricle remodeling was mild to moderate in both young and adult mice. We confirmed that right ventricle epicardial fibrosis is the most outstanding finding in D2-mdx mice. Further long-term studies are needed to evaluate whether this mouse model can also be considered a model of DMD cardiomyopathy.

[Beta-blockers after myocardial infarction with preserved systolic function: useful or redundant?] / I betabloccanti nel post-infarto con funzione sistolica conservata: utili o ridondanti?

Given the lack of adequately sized randomized clinical trials (RCTs) testing the value of maintenance beta-blockers for post-myocardial infarction (MI) patients without reduced left ventricular ejection fraction and treated according to current standards, several observational studies have tried to address this highly relevant issue. However, results from observational studies have yielded opposite conclusions, with some suggesting that beta-blockers are associated with clinical benefit and others suggesting that they have no benefit. Due to the observational nature of these studies, the risk of bias is very high. In particular the existence of a confounding by indication factor is present when the prescription of the therapy is not random and is instead based on patients' clinical characteristics. Some randomness is needed to ensure that individuals with identical characteristics can be observed in both states (with or without beta-blockers). The only chance, therefore, to solve the question of benefits of beta-blockers is the execution of adequately sized RCTs. Currently, four large RCTs are ongoing in Europe, and, among them, the REBOOT-CNIC trial is already beyond three quarters of the expected cohort to be enrolled (6000/8648 revascularized MI patients without left ventricular dysfunction). An Italian cohort (1800 patients) will be included, enrolled by the Italian REBOOT Network. Enrollment is expected to be complete by the end of 2022, and the first results will become available by the end of 2025.

Transthoracic Echocardiography to Assess Post-Resuscitation Left Ventricular Dysfunction After Acute Myocardial Infarction and Cardiac Arrest in Pigs.

One of the main causes of out-of-hospital cardiac arrest is acute myocardial infarction (AMI). After successful resuscitation from cardiac arrest, approximately 70% of patients die before hospital discharge due to post-resuscitation myocardial and cerebral dysfunction. In experimental models, myocardial dysfunction after cardiac arrest, characterized by an impairment in both left ventricular (LV) systolic and diastolic function, has been described as reversible but very little data are available in cardiac arrest models associated with AMI in pigs. Transthoracic echocardiography is the first-line diagnostic test for the assessment of myocardial dysfunction, structural changes and/or AMI extension. In this pig model of ischemic cardiac arrest, echocardiography was done at baseline and 2-4 and 96 hours after resuscitation. In the acute phase, the examinations are done in anesthetized, mechanically ventilated pigs (weight 39.8 ± 0.6 kg) and ECG is recorded continuously. Mono- and bi-dimensional, Doppler and tissue Doppler recordings are acquired. Aortic and left atrium diameter, end-systolic and end-diastolic left ventricular wall thicknesses, end-diastolic and end-systolic diameters and shortening fraction (SF) are measured. Apical 2-, 3-, 4-, and 5-chamber views are acquired, LV volumes and ejection fraction are calculated. Segmental wall motion analysis is done to detect the localization and estimate the extent of myocardial infarction. Pulsed Wave Doppler echocardiography is used to record trans-mitral flow velocities from a 4-apical chamber view and trans-aortic flow from a 5-chamber view to calculate LV cardiac output (CO) and stroke volume (SV). Tissue Doppler Imaging (TDI) of LV lateral and septal mitral anulus is recorded (TDI septal and lateral s', e', a' velocities). All the recordings and measurements are done according to the recommendations of the American and European Societies of Echocardiography Guidelines.

Scientific and ethical issues in add-on designs for antidiabetic drugs.

This editorial describes the clinical trials related to antidiabetic drugs, most of them following an "add-on" design of where the new drug is added to metformin and the comparative arm is metformin plus placebo. Many drugs are already approved for therapy following this design; the authors believe that it is unethical to continue this trend because it makes it impossible to stratify the many antidiabetic drugs according to their efficacy and toxicity.

Cancer Incidence and Mortality According to Pre-Existing Heart Failure in a Community-Based Cohort.

Background: Studies assessing whether heart failure (HF) is associated with cancer and cancer-related mortality have yielded conflicting results. Objectives: This study assessed cancer incidence and mortality according to pre-existing HF in a community-based cohort. Methods: Among individuals ≥50 years of age from the Puglia region in Italy with administrative health data from 2002 to 2018, no cancer within 3 years before the baseline evaluation, and ≥5-year follow-up, the study matched 104,020 subjects with HF at baseline with 104,020 control subjects according to age, sex, drug-derived complexity index, Charlson comorbidity index, and follow-up duration. Cancer incidence and mortality were defined based on International Classification of Diseases-Ninth Revision codes in hospitalization records or death certificates. Results: The incidence rate of cancer in HF patients and control subjects was 21.36 (95% CI: 20.98-21.74) and 12.42 (95% CI: 12.14-12.72) per 1000 person-years, respectively, with the HR being 1.76 (95% CI: 1.71-1.81). Cancer mortality was also higher in HF patients than control subjects (HR: 4.11; 95% CI: 3.86-4.38), especially in those <70 years of age (HR: 7.54; 95% CI: 6.33-8.98 vs HR: 3.80; 95% CI: 3.44-4.19 for 70-79 years of age; and HR: 3.10; 95% CI: 2.81-3.43 for ≥80 years of age). The association between HF and cancer mortality was confirmed in a competing risk analysis (subdistribution HR: 3.48; 95% CI: 3.27-3.72). The HF-related excess risk applied to the majority of cancer types. Among HF patients, prescription of high-dose loop diuretic was associated with higher cancer incidence (HR: 1.11; 95% CI: 1.03-1.21) and mortality (HR: 1.35; 95% CI: 1.19-1.53). Conclusions: HF is associated with an increased risk of cancer and cancer-related mortality, which may be heightened in decompensated states.

Circulating levels and prognostic cut-offs of sST2, hs-cTnT, and NT-proBNP in women vs. men with chronic heart failure.

AIMS: To define plasma concentrations, determinants, and optimal prognostic cut-offs of soluble suppression of tumorigenesis-2 (sST2), high-sensitivity cardiac troponin T (hs-cTnT), and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in women and men with chronic heart failure (HF). METHODS AND RESULTS: Individual data of patients from the Biomarkers In Heart Failure Outpatient Study (BIOS) Consortium with sST2, hs-cTnT, and NT-proBNP measured were analysed. The primary endpoint was a composite of 1 year cardiovascular death and HF hospitalization. The secondary endpoints were 5 year cardiovascular and all-cause death. The cohort included 4540 patients (age 67 ± 12 years, left ventricular ejection fraction 33 ± 13%, 1111 women, 25%). Women showed lower sST2 (24 vs. 27 ng/mL, P < 0.001) and hs-cTnT level (15 vs. 20 ng/L, P < 0.001), and similar concentrations of NT-proBNP (1540 vs. 1505 ng/L, P = 0.408). Although the three biomarkers were confirmed as independent predictors of outcome in both sexes, the optimal prognostic cut-off was lower in women for sST2 (28 vs. 31 ng/mL) and hs-cTnT (22 vs. 25 ng/L), while NT-proBNP cut-off was higher in women (2339 ng/L vs. 2145 ng/L). The use of sex-specific cut-offs improved risk prediction compared with the use of previously standardized prognostic cut-offs and allowed to reclassify the risk of many patients, to a greater extent in women than men, and for hs-cTnT than sST2 or NT-proBNP. Specifically, up to 18% men and up to 57% women were reclassified, by using the sex-specific cut-off of hs-cTnT for the endpoint of 5 year cardiovascular death. CONCLUSIONS: In patients with chronic HF, concentrations of sST2 and hs-cTnT, but not of NT-proBNP, are lower in women. Lower sST2 and hs-cTnT and higher NT-proBNP cut-offs for risk stratification could be used in women.

Insulin treatment in patients with diabetes mellitus and heart failure in the era of new antidiabetic medications.

BACKGROUND: Coexistent heart failure (HF) and diabetes mellitus (DM) are associated with marked morbidity and mortality. Optimizing treatment strategies can reduce the number and severity of events. Insulin is frequently used in these patients, but its benefit/risk ratio is still not clear, particularly since new antidiabetic drugs that reduce major adverse cardiac events (MACEs) and renal failure have recently come into use. Our aim is to compare the clinical effects of insulin in a real-world setting of first-time users, with sodium-glucose cotransporter-2 inhibitor (SGLT-2i), glucagon-like peptide-1 receptor agonist (GLP-1RA) and the other antihyperglycemic agents (other-AHAs). METHODS: We used the administrative databases of two Italian regions, during the years 2010-2018. Outcomes in whole and propensity-matched cohorts were examined using Cox models. A meta-analysis was also conducted combining the data from both regions. RESULTS: We identified 34 376 individuals ≥50 years old with DM and HF; 42.0% were aged >80 years and 46.7% were women. SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin and particularly death from any cause (SGLT-2i, hazard ratio (95% CI) 0.29 (0.23 to 0.36); GLP-1RA, 0.482 (0.51 to 0.42)) and first hospitalization for HF (0.57 (0.40 to 0.81) and 0.67 (0.59 to 0.76)). CONCLUSIONS: In patients with DM and HF, SGLT-2i and GLP-1RA significantly reduced MACE compared with insulin, and particularly any cause of death and first hospitalization for HF. These groups of medications had high safety profiles compared with other-AHAs and particularly with insulin. The inadequate optimization of HF and DM cotreatment in the insulin cohort is noteworthy.

Cardiac biomarkers retain prognostic significance in patients with heart failure and chronic obstructive pulmonary disease.

AIMS: Chronic obstructive pulmonary disease (COPD) is a frequent comorbidity in patients with heart failure (HF). We assessed the influence of COPD on circulating levels and prognostic value of three HF biomarkers: N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), and soluble suppression of tumorigenesis-2 (sST2). METHODS: Individual data from patients with chronic HF, known COPD status, NT-proBNP and hs-TnT values (n = 8088) were analysed. A subgroup (n = 3414) had also sST2 values. RESULTS: Patients had a median age of 66 years (interquartile interval 57-74), 77% were men and 82% had HF with reduced ejection fraction. NT-proBNP, hs-TnT and sST2 were 1207 ng/l (487-2725), 17 ng/l (9-31) and 30 ng/ml (22-44), respectively. Patients with COPD (n = 1249, 15%) had higher NT-proBNP (P = 0.042) and hs-TnT (P < 0.001), but not sST2 (P = 0.165). Over a median 2.0-year follow-up (1.5-2.5), 1717 patients (21%) died, and 1298 (16%) died from cardiovascular causes; 2255 patients (28%) were hospitalized for HF over 1.8 years (0.9-2.1). NT-proBNP, hs-TnT and sST2 predicted the three end points regardless of COPD status. The best cut-offs from receiver-operating characteristics analysis were higher in patients with COPD than in those without. Patients with all three biomarkers higher than or equal to end-point- and COPD-status-specific cut-offs were also those with the worst prognosis. CONCLUSIONS: Among patients with HF, those with COPD have higher NT-proBNP and hs-TnT, but not sST2. All these biomarkers yield prognostic significance regardless of the COPD status.

Rationale and design of the pragmatic clinical trial tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT).

AIMS: There is a lack of evidence regarding the benefits of ß-blocker treatment after invasively managed acute myocardial infarction (MI) without reduced left ventricular ejection fraction (LVEF). METHODS AND RESULTS: The tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion (REBOOT) trial is a pragmatic, controlled, prospective, randomized, open-label blinded endpoint (PROBE design) clinical trial testing the benefits of ß-blocker maintenance therapy in patients discharged after MI with or without ST-segment elevation. Patients eligible for participation are those managed invasively during index hospitalization (coronary angiography), with LVEF >40%, and no history of heart failure (HF). At discharge, patients will be randomized 1:1 to ß-blocker therapy (agent and dose according to treating physician) or no ß-blocker therapy. The primary endpoint is a composite of all-cause death, non-fatal reinfarction, or HF hospitalization over a median follow-up period of 2.75 years (minimum 2 years, maximum 3 years). Key secondary endpoints include the incidence of the individual components of the primary composite endpoint, the incidence of cardiac death, and incidence of malignant ventricular arrhythmias or resuscitated cardiac arrest. The primary endpoint will be analysed according to the intention-to-treat principle. CONCLUSION: The REBOOT trial will provide robust evidence to guide the prescription of ß-blockers to patients discharged after MI without reduced LVEF.

Searching for Preclinical Models of Acute Decompensated Heart Failure: a Concise Narrative Overview and a Novel Swine Model.

PURPOSE: Available animal models of acute heart failure (AHF) and their limitations are discussed herein. A novel and preclinically relevant porcine model of decompensated AHF (ADHF) is then presented. METHODS: Myocardial infarction (MI) was induced by occlusion of left anterior descending coronary artery in 17 male pigs (34 ± 4 kg). Two weeks later, ADHF was induced in the survived animals (n = 15) by occlusion of the circumflex coronary artery, associated with acute volume overload and increases in arterial blood pressure by vasoconstrictor infusion. After onset of ADHF, animals received 48-h iv infusion of either serelaxin (n = 9) or placebo (n = 6). The pathophysiology and progression of ADHF were described by combining evaluation of hemodynamics, echocardiography, bioimpedance, blood gasses, circulating biomarkers, and histology. RESULTS: During ADHF, animals showed reduced left ventricle (LV) ejection fraction < 30%, increased thoracic fluid content > 35%, pulmonary edema, and high pulmonary capillary wedge pressure ~ 30 mmHg (p < 0.01 vs. baseline). Other ADHF-induced alterations in hemodynamics, i.e., increased central venous and pulmonary arterial pressures; respiratory gas exchanges, i.e., respiratory acidosis with low arterial PO2 and high PCO2; and LV dysfunction, i.e., increased LV end-diastolic/systolic volumes, were observed (p < 0.01 vs. baseline). Representative increases in circulating cardiac biomarkers, i.e., troponin T, natriuretic peptide, and bio-adrenomedullin, occurred (p < 0.01 vs. baseline). Finally, elevated renal and liver biomarkers were observed 48 h after onset of ADHF. Mortality was ~ 50%. Serelaxin showed beneficial effects on congestion, but none on mortality. CONCLUSION: This new model, resulting from a combination of chronic and acute MI, and volume and pressure overload, was able to reproduce all the typical clinical signs occurring during ADHF in a consistent and reproducible manner.

Total NT-proBNP, a novel biomarker related to recurrent atrial fibrillation.

BACKGROUND: Novel circulating biomarkers may help in understanding the underlying mechanisms of atrial fibrillation (AF), a challenge for AF management and prevention of cardiovascular (CV) events. Whether glycosylation affects the prognostic value of N-terminal pro-B type natriuretic peptide (NT-proBNP) in AF is still unknown. OBJECTIVES: To test how deglycosylated total NT-proBNP, NT-proBNP and a panel of biomarkers are associated with: (1) recurrent AF, (2) first hospitalization for CV reasons. METHODS: A total of 382 patients of the GISSI-AF trial in sinus rhythm with a history of AF, echocardiographic variables, total NT-proBNP, NT-proBNP and nine additional biomarkers [Total N-terminal pro-B type natriuretic peptide (Total NT proBNP), N-terminal pro-B type natriuretic peptide (NTproBNP), Angiopoietin 2 (Ang2), Bone morphogenic protein-10 (BMP10), Dickkopf-related protein-3 (DKK3), Endothelial cell specific molecule-1 (ESM1), Fatty acid-binding protein 3 (FABP3), Fibroblast growth factor 23 (FGF23), Growth differentiation factor-15 (GDF15), Insulin-like growth factor-binding protein-7 (IGFBP7) and Myosin binding protein C3 (MYPBC3)]. were assayed at baseline, 6 and 12 months under blind conditions in a laboratory at Roche Diagnostics, Penzberg, Germany. The associations between circulating biomarkers and AF at the 6- and 12-month visits, and their predictive value, were assessed in multivariable models with logistic regression analysis and Cox proportional hazards regression analysis. Biomarkers associations were modelled for 1SD increase in their level. RESULTS: Over a median follow-up of 365 days, 203/382 patients (53.1%) had at least one recurrence of AF and 16.3% were hospitalized for CV reasons. Total NT-proBNP, NT-proBNP, Ang2 and BMP10 showed the strongest associations with ongoing AF. Natriuretic peptides also predicted recurrent AF (total NT-proBNP: HR:1.19[1.04-1.36], p = 0.026; NT-proBNP: HR:1.19[1.06-1.35], p = 0.016; Ang2: HR:1.07[0.95-1.20], p = 0.283; BMP10: HR:1.09[0.96-1.25], p = 0.249) and CV hospitalization (total NT-proBNP: HR:1.57[1.29-1.90], p < 0.001 1.63], p = 0.097). CONCLUSIONS: The association of total NT-proBNP with the risk of AF first recurrence was similar to that of NT-proBNP, suggesting no influence of glycosylation. Analogous results were obtained for the risk of first hospitalization for CV reasons. Natriuretic peptides, Ang2 and BMP10 were associated with ongoing AF. Findings from the last two biomarkers point to a pathogenic role of cardiac extracellular matrix and cardiomyocyte growth in the myocardium of the right atrium and ventricle.

Brain Kynurenine Pathway and Functional Outcome of Rats Resuscitated From Cardiac Arrest.

Background Brain injury and neurological deficit are consequences of cardiac arrest (CA), leading to high morbidity and mortality. Peripheral activation of the kynurenine pathway (KP), the main catabolic route of tryptophan metabolized at first into kynurenine, predicts poor neurological outcome in patients resuscitated after out-of-hospital CA. Here, we investigated KP activation in hippocampus and plasma of rats resuscitated from CA, evaluating the effect of KP modulation in preventing CA-induced neurological deficit. Methods and Results Early KP activation was first demonstrated in 28 rats subjected to electrically induced CA followed by cardiopulmonary resuscitation. Hippocampal levels of the neuroactive metabolites kynurenine, 3-hydroxy-anthranilic acid, and kynurenic acid were higher 2 hours after CA, as in plasma. Further, 36 rats were randomized to receive the inhibitor of the first step of KP, 1-methyl-DL-tryptophan, or vehicle, before CA. No differences were observed in hemodynamics and myocardial function. The CA-induced KP activation, sustained up to 96 hours in hippocampus (and plasma) of vehicle-treated rats, was counteracted by the inhibitor as indicated by lower hippocampal (and plasmatic) kynurenine/tryptophan ratio and kynurenine levels. 1-Methyl-DL-tryptophan reduced the CA-induced neurological deficits, with a significant correlation between the neurological score and the individual kynurenine levels, as well as the kynurenine/tryptophan ratio, in plasma and hippocampus. Conclusions These data demonstrate the CA-induced lasting activation of the first step of the KP in hippocampus, showing that this activation was involved in the evolving neurological deficit. The degree of peripheral activation of KP may predict neurological function after CA.

LIPCAR Is Increased in Chronic Symptomatic HF Patients. A Sub-Study of the GISSI-HF Trial.

BACKGROUND: The long noncoding RNA LIPCAR (Long Intergenic noncoding RNA Predicting CARdiac remodeling) has emerged as a promising biomarker in cardiac disease and cardiac remodeling. To determine whether LIPCAR levels help for a molecular phenotyping of chronic heart failure (HF) patients, this study assessed the association of LIPCAR with severity of the disease and its progression, and with risk of death or hospitalization in HF patients. METHODS: LIPCAR was measured in plasma of 967 HF patients with symptomatic heart failure participating in the Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca - Heart Failure (GISSI-HF) biohumoral sub-study. RESULTS: Plasma levels of LIPCAR were significantly associated with functional impairment as assessed by the New York Heart Association (NYHA) class, kidney function as reflected by estimated glomerular filtration rate, and creatinine, hemoglobin and mitral insufficiency. In females, these associations were more marked as compared to males. LIPCAR plasma levels were significantly related to the two cardiac markers, N-terminal pro-B type natriuretic peptide and high-sensitivity cardiac troponin T, but not to inflammatory markers such as high sensitivity C-reactive protein and pentraxin-3, nor to patient reported outcomes such as depression and quality of life. HF patients with high LIPCAR levels univariately showed significantly higher incidence of cardiovascular hospitalizations but not of death; after adjusting for covariates, no significant effects of LIPCAR were found for cardiovascular hospitalizations. CONCLUSION: The circulating long noncoding RNA LIPCAR was increased in HF patients with higher NYHA class, impaired kidney function, and lower hemoglobin, which are indicators of patients' overall state.

NT-proBNP for Risk Prediction in Heart Failure: Identification of Optimal Cutoffs Across Body Mass Index Categories.

OBJECTIVES: The goal of this study was to assess the predictive power of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and the decision cutoffs in heart failure (HF) across body mass index (BMI) categories. BACKGROUND: Concentrations of NT-proBNP predict outcome in HF. Although the influence of BMI to reduce levels of NT-proBNP is known, the impact of obesity on prognostic value remains uncertain. METHODS: Individual data from the BIOS (Biomarkers In Heart Failure Outpatient Study) consortium were analyzed. Patients with stable HF were classified as underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5-24.9 kg/m2), overweight (BMI 25-29.9 kg/m2), and mildly (BMI 30-34.9 kg/m2), moderately (BMI 35-39.9 kg/m2), or severely (BMI ≥40 kg/m2) obese. The prognostic role of NT-proBNP was tested for the endpoints of all-cause and cardiac death. RESULTS: The study population included 12,763 patients (mean age 66 ± 12 years; 25% women; mean left ventricular ejection fraction 33% ± 13%). Most patients were overweight (n = 5,176), followed by normal weight (n = 4,299), mildly obese (n = 2,157), moderately obese (n = 612), severely obese (n = 314), and underweight (n = 205). NT-proBNP inversely correlated with BMI (ß = -0.174 for 1 kg/m2; P < 0.001). Adding NT-proBNP to clinical models improved risk prediction across BMI categories, with the exception of severely obese patients. The best cutoffs of NT-proBNP for 5-year all-cause death prediction were lower as BMI increased (3,785 ng/L, 2,193 ng/L, 1,554 ng/L, 1,045 ng/L, 755 ng/L, and 879 ng/L, for underweight, normal weight, overweight, and mildly, moderately, and severely obese patients, respectively) and were higher in women than in men. CONCLUSIONS: NT-proBNP maintains its independent prognostic value up to 40 kg/m2 BMI, and lower optimal risk-prediction cutoffs are observed in overweight and obese patients.

IGFBP7 and GDF-15, but not P1NP, are associated with cardiac alterations and 10-year outcome in an elderly community-based study.

BACKGROUND: Little is known about the clinical value of Insulin-like growth factor-binding protein-7 (IGFBP7), a cellular senescence marker, in an elderly general population with multiple co-morbidities and high prevalence of asymptomatic cardiovascular ventricular dysfunction. Inflammation and fibrosis are hallmarks of cardiac aging and remodelling. Therefore, we assessed the clinical performance of IGFBP7 and two other biomarkers reflecting these pathogenic pathways, the growth differentiation factor-15 (GFD-15) and amino-terminal propeptide of type I procollagen (P1NP), for their association with cardiac phenotypes and outcomes in the PREDICTOR study. METHODS: 2001 community-dwelling subjects aged 65-84 years who had undergone centrally-read echocardiography, were selected through administrative registries. Atrial fibrillation (AF) and 4 echocardiographic patterns were assessed: E/e' (> 8), enlarged left atrial area, left ventricular hypertrophy (LVH) and reduced midwall circumference shortening (MFS). All-cause and cardiovascular mortality and hospitalization were recorded over a median follow-up of 10.6 years. RESULTS: IGFBP7 and GDF-15, but not P1NP, were independently associated with prevalent AF and echocardiographic variables after adjusting for age and sex. After adjustment for clinical risk factors and cardiac patterns or NT-proBNP and hsTnT, both IGFBP7 and GDF-15 independently predicted all-cause mortality, hazard ratios 2.13[1.08-4.22] and 2.03[1.62-2.56] per unit increase of Ln-transformed markers, respectively. CONCLUSIONS: In a community-based elderly cohort, IGFBP7 and GDF-15 appear associated to cardiac alterations as well as to 10-year risk of all-cause mortality.

Esmolol during cardiopulmonary resuscitation reduces neurological injury in a porcine model of cardiac arrest.

Primary vasopressor efficacy of epinephrine during cardiopulmonary resuscitation (CPR) is due to its α-adrenergic effects. However, epinephrine plays ß1-adrenergic actions, which increasing myocardial oxygen consumption may lead to refractory ventricular fibrillation (VF) and poor outcome. Effects of a single dose of esmolol in addition to epinephrine during CPR were investigated in a porcine model of VF with an underlying acute myocardial infarction. VF was ischemically induced in 16 pigs and left untreated for 12 min. During CPR, animals were randomized to receive epinephrine (30 µg/kg) with either esmolol (0.5 mg/kg) or saline (control). Pigs were then observed up to 96 h. Coronary perfusion pressure increased during CPR in the esmolol group compared to control (47 ± 21 vs. 24 ± 10 mmHg at min 5, p < 0.05). In both groups, 7 animals were successfully resuscitated and 4 survived up to 96 h. No significant differences were observed between groups in the total number of defibrillations delivered prior to final resuscitation. Brain histology demonstrated reductions in cortical neuronal degeneration/necrosis (score 0.3 ± 0.5 vs. 1.3 ± 0.5, p < 0.05) and hippocampal microglial activation (6 ± 3 vs. 22 ± 4%, p < 0.01) in the esmolol group compared to control. Lower circulating levels of neuron specific enolase were measured in esmolol animals compared to controls (2[1-3] vs. 21[16-52] ng/mL, p < 0.01). In this preclinical model, ß1-blockade during CPR did not facilitate VF termination but provided neuroprotection.

Ventilation With Argon Improves Survival With Good Neurological Recovery After Prolonged Untreated Cardiac Arrest in Pigs.

Background Ventilation with the noble gas argon (Ar) has shown neuroprotective and cardioprotective properties in different in vitro and in vivo models. Hence, the neuroprotective effects of Ar were investigated in a severe, preclinically relevant porcine model of cardiac arrest. Methods and Results Cardiac arrest was ischemically induced in 36 pigs and left untreated for 12 minutes before starting cardiopulmonary resuscitation. Animals were randomized to 4-hour post-resuscitation ventilation with: 70% nitrogen-30% oxygen (control); 50% Ar-20% nitrogen-30% oxygen (Ar 50%); and 70% Ar-30% oxygen (Ar 70%). Hemodynamic parameters and myocardial function were monitored and serial blood samples taken. Pigs were observed up to 96 hours for survival and neurological recovery. Heart and brain were harvested for histopathology. Ten animals in each group were successfully resuscitated. Ninety-six-hour survival was 60%, 70%, and 90%, for the control, Ar 50%, and Ar 70% groups, respectively. In the Ar 50% and Ar 70% groups, 60% and 80%, respectively, achieved good neurological recovery, in contrast to only 30% in the control group (P<0.0001). Histology showed less neuronal degeneration in the cortex (P<0.05) but not in the hippocampus, and less reactive microglia activation in the hippocampus (P=0.007), after Ar compared with control treatment. A lower increase in circulating biomarkers of brain injury, together with less kynurenine pathway activation (P<0.05), were present in Ar-treated animals compared with controls. Ar 70% pigs also had complete left ventricular function recovery and smaller infarct and cardiac troponin release (P<0.01). Conclusions Post-resuscitation ventilation with Ar significantly improves neurologic recovery and ameliorates brain injury after cardiac arrest with long no-flow duration. Benefits are greater after Ar 70% than Ar 50%.