J. Lupon

Bloodstream Amyloid-beta (1-40) Peptide, Cognition, and Outcomes in Heart Failure

INTRODUCTION AND OBJECTIVES In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF. METHODS Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death. RESULTS Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P < .001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P < .001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification. CONCLUSIONS Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging.

Extracellular vesicles do not contribute to higher circulating levels of soluble LRP1 in idiopathic dilated cardiomyopathy

Idiopathic dilated cardiomyopathy (IDCM) is a frequent cause of heart transplantation. Potentially valuable blood markers are being sought, and low‐density lipoprotein receptor‐related protein 1 (LRP1) has been linked to the underlying molecular basis of the disease. This study compared circulating levels of soluble LRP1 (sLRP1) in IDCM patients and healthy controls and elucidated whether sLRP1 is exported out of the myocardium through extracellular vesicles (EVs) to gain a better understanding of the pathogenesis of the disease. LRP1 α chain expression was analysed in samples collected from the left ventricles of explanted hearts using immunohistochemistry. sLRP1 concentrations were determined in platelet‐free plasma by enzyme‐linked immunosorbent assay. Plasma‐derived EVs were extracted by size‐exclusion chromatography (SEC) and characterized by nanoparticle tracking analysis and cryo‐transmission electron microscopy. The distributions of vesicular (CD9, CD81) and myocardial (caveolin‐3) proteins and LRP1 α chain were assessed in SEC fractions by flow cytometry. LRP1 α chain was preferably localized to blood vessels in IDCM compared to control myocardium. Circulating sLRP1 was increased in IDCM patients. CD9‐ and CD81‐positive fractions enriched with membrane vesicles with the expected size and morphology were isolated from both groups. The LRP1 α chain was not present in these SEC fractions, which were also positive for caveolin‐3. The increase in circulating sLRP1 in IDCM patients may be clinically valuable. Although EVs do not contribute to higher sLRP1 levels in IDCM, a comprehensive analysis of EV content would provide further insights into the search for novel blood markers.

Proteomic signature of circulating extracellular vesicles in dilated cardiomyopathy

Dilated cardiomyopathy (DCM) remains a major cause of heart failure and carries a poor prognosis despite important advances in recent years. Better disease characterization using novel molecular techniques is needed to refine its progression. This study explored the proteomic signature of plasma-derived extracellular vesicles (EVs) obtained from DCM patients and healthy controls using size-exclusion chromatography (SEC). EV-enriched fractions were analyzed by liquid chromatography-mass spectrometry (LC-MS/MS). Raw data obtained from LC-MS/MS were analyzed against the Uniprot human database using MaxQuant software. Additional analyses using Perseus software were based on the Intensity-Based Absolute Quantification (iBAQ) values from MaxQuant analyses. A total of 90.07 ± 21 proteins (227 different proteins) in the DCM group and 96.52 ± 17.91 proteins (183 different proteins) in the control group were identified. A total of 176 proteins (74.6%) were shared by controls and DCM patients, whereas 51 proteins were exclusive for the DCM group and 7 proteins were exclusive for the control group. Fibrinogen (α, β and γ chain), serotransferrin, α-1-antitrypsin, and a variety of apolipoprotein family members (C-I, C-III, D, H or β-2-glycoprotein, and J or clusterin) were clustered in SEC-EVs derived from DCM patients relative to controls (p < 0.05). Regarding Gene Ontology analysis, response to stress and protein activation-related proteins were enriched in DCM-EVs compared with controls. Thus, the present study reports the distinct proteomic signature of circulating DCM-EVs compared with control-EVs. Furthermore, we confirm that SEC obtains highly purified EV fractions from peripheral blood samples for subsequent use in determining disease-specific proteomic signatures.Extracellular vesicles (EVs) comprise a wide range of bilayer membrane-enclosed nanovesicles secreted by nearly all cell types and present in all human body fluids. In dilated cardiomyopathy, which is a frequent cause of heart transplantation, unraveling the specific combinations of cargo proteins within the EVs that peripherally circulate in patients hold promising potential for biomarker discovery.

Comorbidities, Fragility, and Quality of Life in Heart Failure Patients With Midrange Ejection Fraction

Objective To assess the effects of comorbidities, fragility, and quality of life (QOL) on long-term prognosis in ambulatory patients with heart failure (HF) with midrange left ventricular ejection fraction (HFmrEF), an unexplored area. Patients and Methods Consecutive patients prospectively evaluated at an HF clinic between August 1, 2001, and December 31, 2015, were retrospectively analyzed on the basis of left ventricular ejection fraction category. We compared patients with HFmrEF (n=185) to those with reduced (HFrEF; n=1058) and preserved (HFpEF; n=162) ejection fraction. Fragility was defined as 1 or more abnormal evaluations on 4 standardized geriatric scales (Barthel Index, Older Americans Resources and Services scale, Pfeiffer Test, and abbreviated-Geriatric Depression Scale). The QOL was assessed with the Minnesota Living with Heart Failure Questionnaire. A comorbidity score (0-7) was constructed. All-cause death, HF-related hospitalization, and the composite end point of both were assessed. Results Comorbidities and QOL scores were similar in HFmrEF (2.41±1.5 and 30.1±18.3, respectively) and HFrEF (2.30±1.4 and 30.8±18.5, respectively) and were higher in HFpEF (3.02±1.5, P<.001, and 36.5±20.7, P=.003, respectively). No statistically significant differences in fragility between HFmrEF (48.6%) and HFrEF (41.9%) (P=.09) nor HFpEF (54.3%) (P=.29) were found. In univariate analysis, the association of comorbidities, QOL, and fragility with the 3 end points was higher for HFmrEF than for HFrEF and HFpEF. In multivariate analysis, comorbidities were independently associated with the 3 end points (P≤.001), and fragility was independently associated with all-cause death and the composite end point (P<.001) in HFmrEF. Conclusion Comorbidities and fragility are independent predictors of outcomes in ambulatory patients with HFmrHF and should be considered in the routine clinical assessment of HFmrEF.

Impact of a ‘stent for life’ initiative on post-ST elevation myocardial infarction heart failure: a 15 year heart failure clinic experience: Impact of a ‘stent for life’ initiative on post-STEMI heart failure

Multidisciplinary heart failure (HF) clinics are a cornerstone of contemporary HF management. The stent‐for‐life (SFL) initiative improves mortality after ST elevation myocardial infarction (STEMI), but its impact in post‐STEMI HF is not well characterized. Here we assessed the impact of SFL among patients referred to a multidisciplinary HF clinic over a 15 year time period.

Idiopathic Dilated Cardiomyopathy: Molecular Basis and Distilling Complexity to Advance

Cardiomyopathies are heterogeneous diseases of the myocardium associated with abnormal findings of chamber size, wall thickness, and/or functional contractility. In particular, dilated cardiomyopathy (DCM) is mainly characterized by ventricular chamber enlargement with systolic dysfunction and normal left ventricular (LV) wall thickness. Although DCM is thought to be induced mainly by genetic or environmental factors, in the majority of cases, the cause is unknown. With an estimated prevalence of 1:2500 and an incidence of 1:18,000 per year in adults, DCM is the most frequent indication for heart transplantation, which represents an enormous cost burden on healthcare systems. These figures warrant greater accuracy in patient diagnosis and prognosis and further insight into the underlying basis of DCM. Here, we discuss past and recent findings on the molecular mechanisms involved in DCM. Dilated cardio‐ myopathy has been linked to the overactivation of extracellular signal‐regulated kinase (ERK1/2), which in turn is related to activation of low‐density lipoprotein receptor– related protein‐1 (LRP‐1). Moreover, a redistribution of LRP‐1 into cholesterol‐enriched plasma membrane domains (lipid rafts) and alterations in cardiac DNA methylation have been reported in failing hearts. In conclusion, more comprehensive analyses of myocardial lipid rafts and epigenetic mechanisms may advance our understanding of DCM causes and progression. In turn, this understanding may promote the develop‐ ment of innovative treatments.

Long-term mortality risk stratification in heart failure using classification and regression trees with a combination of biomarkers

Background: Mortality remains high in heart failure (HF). Several statistical models can be used in order to evaluate the additive usefulness of the combination of biomarkers reflecting different pathophysiological pathways. Objectives: To assess the performance of SPSS Classification and Regression trees (CART) for risk of death stratification using serum biomarkers. Patients and methods: We analyzed 876 consecutive outpatients (72% men, median age 70.4 years, main etiology of HF ischemic heart disease (52.7%), median LVEF 34%). A combination of biomarkers reflecting myocyte injury (hs-cTnT), myocardial stretch (NT-proBNP) and ventricular fibrosis and remodelling (ST2) was used. Results: During a median follow-up of 4 years, 370 patients died. Using semi-automatic CART (only selecting the minimum cases for parental (80) and filial (40) nodes), 12 nodes were obtained. At first step, hs-cTnT (cutoff point 16 ng/L) yielded 2 nodes with mortality rates of 18.4% (node 1) and 57.1% (node 2). At second step, ST2 (cut points 45 ng/L for low hs-cTnT and 91.6 ng/L for high hs-cTnT) yielded nodes with mortality rates of 13.9% (node 3), 35.7% (node 4), 54.2% (node 5), and 87.5% (node 6). At third step, hs-cTnT emerged again significant to further split node 3, and node 5 was divided by NTproBNP levels (cutoff point 1846.5 ng/L). The last step used again ST2 to split node 9. The mortality in the terminal branch nodes ranged from 3.3% (node 7) to 87.2% (node 6). Agreement between predicted and observed death was 70%. ![Figure][1] CART for total mortality Conclusions: Using a simple CART decision tree with the biomarkers hs-cTnT, ST2 and NTproBNP good stratification of risk of death was easily achieved in chronic HF outpatients. [1]: pending:yes

Evolution of Biochemical Diagnosis of Acute Coronary Syndrome – Impact Factor of High Sensitivity Cardiac Troponin Assays

In patients with acute thoracic pain and non-conclusive acute myocardial infarction electrocardiogram (non-STEMI), the biochemical diagnosis is an essential tool for its correct treatment. The study of the chosen biomarker for cardiac injury has raised interest during decades. The appearance of immunoassays to assess cardiac troponin I or T has reached great improvements in the diagnosis, evolution and prognosis of the Acute Coronary Syndrome (ACS), as well as in risk stratification of these patients and in patients with chronic cardiac diseases as heart failure or cardiomyopathies. Regarding the analytical sensitivity of the methods that evaluate cardiac troponin I or T these improvements have made possible to measure accurately very tiny seric concentrations of the protein (high sensitivity troponin) (hs-Tn). This fact, being positive in principle sometimes induces to reconsider if tiny seric concentrations of isolated troponin I or T are not due to acute myocardial infarction but to a less severe source which affects the myocardiocite, this will oblige us to assess the clinical presentation in depth.