Heart Failure with Preserved Ejection Fraction and Obstructive Sleep Apnea: A Novel Paradigm for Additional Cardiovascular Benefit of SGLT2 Inhibitors in Subjects With or Without Type 2 Diabetes.

After examining the complex interplay between heart failure (HF) in its various clinical forms, metabolic disorders like nonalcoholic fatty liver disease (NAFLD), and obstructive sleep apnea (OSA) syndrome, in this mini-review we described possible favorable effects of sodium-glucose cotransporter 2 inhibitors (SGLT2is) on HF with preserved (i.e., ≥ 50%) ejection fraction (HFpEF) through enhanced cardiorenal function and visceral-subcutaneous body fat redistribution. In greater detail, on the basis of pathophysiological mechanisms underlying OSA onset and the direct positive SGLT2i effect on renal function benefiting chronic kidney disease, we emphasized the promising role of SGLT2is in prevention, rehabilitation, and treatment of patients with OSA regardless of coexisting type 2 diabetes (T2DM). Indeed, SGLT2is enhance lipolysis and fatty acid beta-oxidation. These phenomena might prevent OSA by reducing the size of visceral and subcutaneous adipose tissue and, as proven in humans and animals with T2DM, counteract NAFLD onset and progression. The aforementioned mechanisms may represent an additional SGLT2i cardioprotective effect in terms of HFpEF prevention in patients with OSA, whose NAFLD prevalence is estimated to be over 50%.

Looking for a Tailored Therapy for Heart Failure: Are We Capable of Treating the Patient Instead of the Disease?

After almost a decade of stagnation in clinical research for HF treatment, five large randomized trials recently published have supported the use of four new classes of drugs, namely: angiotensin receptor/neprilysin inhibitor, sodium-glucose co-transporters 2 inhibitors, soluble guanylate cyclase modulators, and myosin activators. Each treatment has proved to be beneficial for both long-term outcomes and quality of life. Beside their clinical relevance, all these novel treatments have a different mechanism of action beyond the usual neuro-hormonal blockage. These different pathways, together with the unquestionable clinical evidence, advocate a re-thinking of HF treatment and of the appropriate drug to integrate with the existing standard therapy, according to different characteristics of HFrEF patients. This study aimed to offer a synthetic overview of the mechanisms of action of the new drugs and to propose a more personalized approach, considering patients' characteristics and safety profiles. To this end, we have identified seven profiles for patients with chronic heart failure with reduced ejection fraction and two for pre-discharge patients.

Possible Preventative/Rehabilitative Role of Gliflozins in OSA and T2DM. A Systematic Literature Review-Based Hypothesis.

Obstructive sleep apnoea (OSA) is characterized by frequent apnoea episodes during sleep due to upper airway obstruction. The present review summarizes current knowledge on inter-relationships between OSA and type 2 diabetes mellitus (T2DM) and suggests the former as a possible target for sodium-glucose co-transporter-2 inhibitors (SGLT-2i). Based on pathophysiological mechanisms underlying OSA onset and renal SGLT-2 effects, we suggest that SGLT-2i indications might expand beyond current ones, including glucose, lipids, uric acid, blood pressure, and body weight control as well as chronic heart failure and kidney disease prevention.

Differential Role of Circulating microRNAs to Track Progression and Pre-Symptomatic Stage of Chronic Heart Failure: A Pilot Study.

(1)Background: Chronic heart failure (CHF) contributes to the overall burden of cardiovascular disease. Early identification of at-risk individuals may facilitate the targeting of precision therapies. Plasma microRNAs are promising circulating biomarkers for their implications with cardiac pathologies. In this pilot study, we investigate the possible exploitability of circulating micro-RNAs (miRNAs) to track chronic heart failure (CHF) occurrence, and progression from NYHA class I to IV. (2)Methods: We screened 367 microRNAs using TaqMan microRNA Arrays in plasma samples from healthy controls (HC) and CHF NYHA-class I-to-IV patients (5/group). Validation was performed by singleplex assays on 10 HC and 61 CHF subjects. Differences in the expression of validated microRNAs were evaluated through analysis of covariance (ANCOVA). Associations between N-terminal pro-BNP (NT-proBNP), left ventricular end-diastolic volume (LVEDV) or peak oxygen uptake (VO2 peak) and plasma microRNA were assessed by multivariable linear regression analysis. (3)Results: Twelve microRNAs showed higher expression in CHF patients vs. HC. Seven microRNAs were associated with NT-proBNP concentration; of these, miR-423-5p was also an independent predictor of LVEDV. Moreover, miR-499-5p was a predictor of the VO2 peak. Finally, a cluster of 5 miRNAs discriminated New York Heart Association (NYHA) class-I from HC subjects. (4)Conclusions: Our data suggest that circulating miRNAs have the potential to serve as pathophysiology-based markers of HF status and progression, and as indicators of pre-symptomatic individuals.

Is heart failure misdiagnosed in hospitalized patients with preserved ejection fraction? From the European Society of Cardiology - Heart Failure Association EURObservational Research Programme Heart Failure Long-Term Registry.

AIMS: In hospitalized patients with a clinical diagnosis of acute heart failure (HF) with preserved ejection fraction (HFpEF), the aims of this study were (i) to assess the proportion meeting the 2016 European Society of Cardiology (ESC) HFpEF criteria and (ii) to compare patients with restrictive/pseudonormal mitral inflow pattern (MIP) vs. patients with MIP other than restrictive/pseudonormal. METHODS AND RESULTS: We included hospitalized participants of the ESC-Heart Failure Association (HFA) EURObservational Research Programme (EORP) HF Long-Term Registry who had echocardiogram with ejection fraction (EF) ≥ 50% during index hospitalization. As no data on e', E/e' and left ventricular (LV) mass index were gathered in the registry, the 2016 ESC HFpEF definition was modified as follows: elevated B-type natriuretic peptide (BNP) (≥100 pg/mL for acute HF) and/or N-terminal pro-BNP (≥300 pg/mL) and at least one of the echocardiographic criteria: (i) presence of LV hypertrophy (yes/no), (ii) left atrial volume index (LAVI) of >34 mL/m2 ), or (iii) restrictive/pseudonormal MIP. Next, all patients were divided into four groups: (i) patients with restrictive/pseudonormal MIP on echocardiography [i.e. with presumably elevated left atrial (LA) pressure], (ii) patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure), (iii) atrial fibrillation (AF) group, and (iv) 'grey area' (no consistent description of MIP despite no report of AF). Of 6365 hospitalized patients, 1848 (29%) had EF ≥ 50%. Natriuretic peptides were assessed in 28%, LV hypertrophy in 92%, LAVI in 13%, and MIP in 67%. The 2016 ESC HFpEF criteria could be assessed in 27% of the 1848 patients and, if assessed, were met in 52%. Of the 1848 patients, 19% had restrictive/pseudonormal MIP, 43% had MIP other than restrictive/pseudonormal, 18% had AF and 20% were grey area. There were no differences in long-term all-cause or cardiovascular mortality, or all-cause hospitalizations or HF rehospitalizations between the four groups. Despite fewer non-cardiac comorbidities reported at baseline, patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure) had more non-cardiovascular (14.0 vs. 6.7 per 100 patient-years, P < 0.001) and cardiovascular non-HF (13.2 vs. 8.0 per 100 patient-years, P = 0.016) hospitalizations in long-term follow-up than patients with restrictive/pseudonormal MIP. CONCLUSIONS: Acute HFpEF diagnosis could be assessed (based on the 2016 ESC criteria) in only a quarter of patients and confirmed in half of these. When assessed, only one in three patients had restrictive/pseudonormal MIP suggestive of elevated LA pressure. Patients with MIP other than restrictive/pseudonormal (suggestive of normal LA pressure) could have been misdiagnosed with acute HFpEF or had echocardiography performed after normalization of LA pressure. They were more often hospitalized for non-HF reasons during follow-up. Symptoms suggestive of acute HFpEF may in some patients represent non-HF comorbidities.

Plasma soluble HLA-G levels in a cohort of heart failure patients exposed to chemicals.

Heart failure (HF) is a syndrome caused by structural and/or functional cardiac abnormalities, resulting in a reduced cardiac output and/or elevated intracardiac pressures. Several studies reported a crucial role of immune activation and inflammation in the chronic heart failure (HF) pathogenesis, suggesting that pro-inflammatory and anti-inflammatory mediators could be predictive markers of the HF development and/or progression. Human Leukocyte Antigen-G (HLA-G), a tolerogenic and anti-inflammatory class I non-classical major histocompatibility complex molecule, was reported to be upregulated in patients diagnosed with HF, suggesting a tentative to regulate the inflammatory condition. We evaluated soluble (s)HLA-G plasmatic levels in patients with stable chronic heart failure at baseline visit and after 6 and 12 months. The 14 bp Insertion/Deletion polymorphisms of the HLA-G gene was also analyzed. We showed that in HF subjects, sHLA-G levels were higher in NYHA class II and III subjects (mild-severe symptoms) (6.11 ± 1.15 ng/ml; 8.25 ± 2.27 ng/ml, respectively) in comparison with NYHA class I subjects (no symptoms) (2.35 ± 0.43 ng/ml) (I vs II: p = 0.0156; I vs III: p = 0.0122). Moreover, the exposure to chemicals seems to affect sHLA-G levels, with higher sHLA-G levels in exposed patients (3.36 ± 5.12 ng/ml) in comparison with unexposed subjects (2.01 ± 2.84 ng/ml). The HLA-G 3'UTR 14 bp INS/DEL polymorphism correlated with sHLA-G, with the 14 bp INS/INS genotype associated with higher sHLA-G levels during the 12 months follow-up in unexposed subjects (p = 0.008). In conclusion, these results support a correlation between sHLA-G levels, genetics and HF disease in presence of work chemical exposition.

Echocardiographic Evaluation of Left Ventricular Output in Patients with Heart Failure: A Per-Beat or Per-Minute Approach?

BACKGROUND: Left ventricular (LV) output is a predictor of adverse outcome in patients with heart failure. It can be evaluated using a per-beat approach, measuring stroke volume index (SVI), or a per-minute approach, calculating cardiac index (CI). However, the prognostic value of these two approaches has never been compared. METHODS: A single-center retrospective observational study was conducted in 396 hospitalized patients who underwent echocardiography for suspected heart failure. In a group of 138 consecutive patients, SVI and CI cutoff values of 30 mL/m2 and 2.3 L/min/m2, respectively, were derived to separate normal from low LV forward flow conditions. Subsequently, the association of these values with all-cause mortality was compared in a group of 258 consecutive patients. Median follow-up duration was 2.6 years (interquartile range: 2-3.2 years). RESULTS: After adjustment for other outcome predictors, SVI <30 mL/m2 was independently associated with all-cause mortality with a hazard ratio of 2.67 (95% confidence interval, 1.74-4.1; P < .001), whereas CI was not. Additionally, three different subgroups of SVI (<30, 30-35, and >35 mL/m2) and CI (<1.8, 1.8-2.2, and ≥2.3 L/min/m2) were compared, and no incremental benefit of this risk stratification model was observed. CONCLUSIONS: Low LV output on the basis of a per-beat definition (SVI <30 mL/m2) is strongly associated with all-cause mortality in patients hospitalized with heart failure. A per-minute approach seems to add no further information to risk stratification. These findings may have implications for selecting the LV output index when evaluating prognosis in patients with heart failure.

Three-Year Hospitalization and Mortality in Elderly Smokers with Chronic Obstructive Pulmonary Disease or Chronic Heart Failure.

BACKGROUND: In elderly smokers, chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) usually present with dyspnoea. COPD and CHF are associated -almost invariably with concomitant chronic diseases, which contribute to severity and prognosis. OBJECTIVES: We investigated similarities and differences in the clinical presentation, concomitant chronic diseases and risk factors for -mortality and hospitalization at 3-year follow-up in elderly smokers/ex-smokers with a primary diagnosis of COPD or CHF recruited and followed in specialized centers. METHODS: We examined 144 patients with COPD and 96 with CHF, ≥65 years, ≥20 pack/years, and measured COPD Assessment Test (CAT) score, modified Medical Research Council, NYHA, and Charlson Index, routine blood test, estimated glomerular filtration rate, HRCT scan, 6-min walk test. In addition, in each patient we actively searched for CHF, COPD, peripheral vascular disease, and metabolic syndrome. RESULTS: COPD and CHF patients had mild to moderate disease, but the majority was symptomatic. Comorbidities were highly prevalent and often unrecognized in both groups. COPD and CHF patients had a similar risk of hospitalization and death at 3 years. Lower glomerular filtration rate, shorter 6MWT, and ascending aorta calcification score ≥2 were independent predictors of mortality in COPD, whereas previous 12 months hospitalizations, renal disease, and heart diameter were in CHF patients. Lower glomerular filtration rate value, higher CAT score, and lower FEV1/FVC ratio were associated with hospitalization in COPD, while age, lower FEV1% predicted, and peripheral vascular disease were in CHF. CONCLUSIONS: There are relevant similarities and differences between patients with COPD and CHF even when admitted to specialized outpatient centers, suggesting that these patients should be manage in multidisciplinary units.

Predicting return to work after acute myocardial infarction: Socio-occupational factors overcome clinical conditions.

OBJECTIVES: Return to work after acute myocardial infarction (AMI), a leading cause of death globally, is a multidimensional process influenced by clinical, psychological, social and occupational factors, the single impact of which, however, is still not well defined. The objective of this study was to investigate these 4 factors on return to work (RTW) within 365 days after AMI in a homogeneous cohort of patients who had undergone an urgent coronary angioplasty. PARTICIPANTS: We studied 102 patients, in employment at the time of AMI (88.24% of men), admitted to the Department of Cardiology of the University-Hospital of Ferrara between March 2015 to December 2016. Demographical and clinical characteristics were obtained from the cardiological records. After completing an interview on social and occupational variables and the Hospital Anxiety and Depression (HADS) questionnaire, patients underwent exercise capacity measurement and spirometry. RESULTS: Of the 102 patients, only 12 (12.76%) held a university degree, 68.63% were employees and 31.37% self-employed. The median number of sick-leave days was 44 (IQR 33-88). At day 30, 78.5% of all subjects had not returned to work, at day 60, 40.8% and at day 365 only 7.3% had not resumed working. At univariate analyses, educational degree (p = 0.026), self-employment status (p = 0.0005), white collar professional category (p = 0.020) and HADS depression score were significant for earlier return to work. The multivariate analysis confirms that having a university degree, being self-employed and presenting a lower value of HADS depression score increase the probability of a quicker return to work. CONCLUSIONS: These findings suggest that the strongest predictors of returning to work within 1 year after discharge for an acute myocardial infarction are related more to socio-occupational than to clinical parameters.

Breathlessness, but not cough, suggests chronic obstructive pulmonary disease in elderly smokers with stable heart failure.

Chronic obstructive pulmonary disease (COPD) is a common comorbidity of heart failure (HF), but remains often undiagnosed, and we aimed to identify symptoms predicting COPD in HF. As part of an observational, prospective study, we investigated stable smokers with a confirmed diagnosis of HF, using the 8-item COPD-Assessment-Test (CAT) questionnaire to assess symptoms. All the items were correlated with the presence of COPD, and logistic regression models were used to identify independent predictors. 96 HF patients were included, aged 74, 33% with COPD. Patients with HF and COPD were more symptomatic, but only breathlessness when walking up a hill was an independent predictor of COPD (odds ratio = 1.33, p = 0.0484). Interestingly, COPD-specific symptoms such as cough and phlegm were not significant. Thus, in elderly smokers with stable HF, significant breathlessness when walking up a hill is most indicative of associated COPD, and may indicate the need for further lung function evaluation.

[Latest news and perspectives in cardiogenetics]. / Attualità e nuove prospettive in tema di cardiogenetica.

In recent years, cardiogenetics is emerging as a major discipline for the study of many pathologies, with immediate clinical effects for patients who were previously managed by the cardiologist alone. Recent acquisitions have allowed significant improvements in terms of diagnostic characterization, prognostic stratification and guidance for treatment for both patients with genetic disease and their family members. At present, cardiogenetics has an important role for the clinical management of patients with cardiomyopathies and channelopathies. We present an updated review of the literature and a proposal of organizational model.

Cardiac resynchronization therapy guided by multimodality cardiac imaging.

AIMS: Up to 30-45% of implanted patients are non-responders to CRT. We evaluated the role of a 'CRT team' using cardiac magnetic resonance (CMR) and longitudinal myocardial strain to identify the target area defined as the most delayed and viable region for LV pacing. METHODS AND RESULTS: A total of 100 heart failure patients candidates for CRT divided into two groups were enrolled. Group 1 consisted of 50 consecutive patients scheduled for CRT and prospectively included. Group 2 (control) consisted of 50 patients with a CRT device implanted according to standard clinical practice and matched for age, sex, and LVEF with group 1. Patients were evaluated at baseline and at 6-month follow-up. In group 1, patients underwent two-dimensional speckle-tracking assessment of longitudinal myocardial strain and CMR imaging to identify the target area for LV lead pacing. A positive response to CRT was defined as a reduction of ≥15% of the LV end-systolic volume at 6-month follow-up. A total of 39 (78%) patients of group 1 were classified as responders to CRT whilst in group 2, only 28 (56%) were responders (P = 0.019). The 'CRT team' identified as target for LV pacing the lateral area in 30 (60%) patients, and the anterolateral or posterolateral areas in 12 (24%) patients. In 8 (16%) patients, the target was far from the lateral area, in the anterior or posterior areas. The patients with concordant position exhibited the highest positive response (93.1%) to CRT. CONCLUSIONS: Multimodality cardiac imaging as a guide for CRT implantation is useful to increase response rate.

Serum From Advanced Heart Failure Patients Promotes Angiogenic Sprouting and Affects the Notch Pathway in Human Endothelial Cells.

It is unknown whether components present in heart failure (HF) patients' serum provide an angiogenic stimulus. We sought to determine whether serum from HF patients affects angiogenesis and its major modulator, the Notch pathway, in human umbilical vein endothelial cells (HUVECs). In cells treated with serum from healthy subjects or from patients at different HF stage we determined: (1) Sprouting angiogenesis, by measuring cells network (closed tubes) in collagen gel. (2) Protein levels of Notch receptors 1, 2, 4, and ligands Jagged1, Delta-like4. We found a higher number of closed tubes in HUVECs treated with advanced HF patients serum in comparison with cells treated with serum from mild HF patients or controls. Furthermore, as indicated by the reduction of the active form of Notch4 (N4IC) and of Jagged1, advanced HF patients serum inhibited Notch signalling in HUVECs in comparison with mild HF patients' serum and controls. The circulating levels of NT-proBNP (N-terminal of the pro-hormone brain natriuretic peptide), a marker for the detection and evalutation of HF, were positively correlated with the number of closed tubes (r = 0.485) and negatively with Notch4IC and Jagged1 levels in sera-treated cells (r = -0.526 and r = -0.604, respectively). In conclusion, we found that sera from advanced HF patients promote sprouting angiogenesis and dysregulate Notch signaling in HUVECs. Our study provides in vitro evidence of an angiogenic stimulus arising during HF progression and suggests a role for the Notch pathway in it. J. Cell. Physiol. 231: 2700-2710, 2016. © 2016 Wiley Periodicals, Inc.

In vitro endothelial cell proliferation assay reveals distinct levels of proangiogenic cytokines characterizing sera of healthy subjects and of patients with heart failure.

Although myocardial angiogenesis is thought to play an important role in heart failure (HF), the involvement of circulating proinflammatory and proangiogenic cytokines in the pathogenesis and/or prognosis of HF has not been deeply investigated. By using a highly standardized proliferation assay with human endothelial cells, we first demonstrated that sera from older (mean age 52 ± 7.6 years; n = 46) healthy donors promoted endothelial cell proliferation to a significantly higher extent compared to sera obtained from younger healthy donors (mean age 29 ± 8.6 years; n = 20). The promotion of endothelial cell proliferation was accompanied by high serum levels of several proangiogenic cytokines. When we assessed endothelial cell proliferation in response to HF patients' sera, we observed that a subset of sera (n = 11) promoted cell proliferation to a significantly lesser extent compared to the majority of sera (n = 18). Also, in this case, the difference between the patient groups in the ability to induce endothelial cell proliferation correlated to significant (P < 0.05) differences in serum proangiogenic cytokine levels. Unexpectedly, HF patients associated to the highest endothelial proliferation index showed the worst prognosis as evaluated in terms of subsequent cardiovascular events in the follow-up, suggesting that high levels of circulating proangiogenic cytokines might be related to a worse prognosis.

Echocardiography, spirometry, and systemic acute-phase inflammatory proteins in smokers with COPD or CHF: an observational study.

Chronic obstructive pulmonary disease (COPD) and chronic heart failure (CHF) may coexist in elderly patients with a history of smoking. Low-grade systemic inflammation induced by smoking may represent the link between these 2 conditions. In this study, we investigated left ventricular dysfunction in patients primarily diagnosed with COPD, and nonreversible airflow limitation in patients primarily diagnosed with CHF. The levels of circulating high-sensitive C-reactive protein (Hs-CRP), pentraxin 3 (PTX3), interleukin-1ß (IL-1 ß), and soluble type II receptor of IL-1 (sIL-1RII) were also measured as markers of systemic inflammation in these 2 cohorts. Patients aged ≥ 50 years and with ≥ 10 pack years of cigarette smoking who presented with a diagnosis of stable COPD (n=70) or stable CHF (n=124) were recruited. All patients underwent echocardiography, N-terminal pro-hormone of brain natriuretic peptide measurements, and post-bronchodilator spirometry. Plasma levels of Hs-CRP, PTX3, IL-1 ß, and sIL-1RII were determined by using a sandwich enzyme-linked immuno-sorbent assay in all patients and in 24 healthy smokers (control subjects). Although we were unable to find a single COPD patient with left ventricular dysfunction, we found nonreversible airflow limitation in 34% of patients with CHF. On the other hand, COPD patients had higher plasma levels of Hs-CRP, IL1 ß, and sIL-1RII compared with CHF patients and control subjects (p < 0.05). None of the inflammatory biomarkers was different between CHF patients and control subjects. In conclusion, although the COPD patients had no evidence of CHF, up to one third of patients with CHF had airflow limitation, suggesting that routine spirometry is warranted in patients with CHF, whereas echocardiography is not required in well characterized patients with COPD. Only smokers with COPD seem to have evidence of systemic inflammation.

Plasma sRAGE and N-(carboxymethyl) lysine in patients with CHF and/or COPD.

BACKGROUND: Knowledge of the role of the receptor for advanced glycation end products (RAGE), particularly its soluble form (sRAGE), and of its advanced glycation end product (AGE) ligand, N-(carboxymethyl)lysine adducts (CML), is limited in chronic heart failure (CHF) and in chronic obstructive pulmonary disease (COPD). We evaluated whether the AGE/RAGE system is activated in stable CHF and COPD, and whether plasma sRAGE and CML levels are affected by clinical and functional parameters. MATERIALS AND METHODS: We measured plasma levels of sRAGE and CML using a sandwich enzyme-linked immunosorbent assay (ELISA) in 143 subjects, aged ≥ 65 years, divided into five groups: 58 with CHF, 23 with COPD, 27 with CHF+COPD and 35 controls (17 healthy smokers and 18 healthy nonsmokers). Individuals with diabetes were excluded from the study. RESULTS: Plasma levels of sRAGE and CML were higher in CHF patients than in controls [sRAGE: 0.48 (0.37-0.83) vs. 0.42 (0.29-0.52) ng/mL, P = 0.01; CML: 1.95 (1.58-2.38) vs. 1.68 (1.43-2.00) ng/mL, P = 0.01]. By contrast, sRAGE and CML were not different between both COPD and CHF+COPD patients and controls (P > 0.05). N-terminal pro-brain natriuretic peptide (Nt-pro BNP) correlated with sRAGE, but not with CML, in the patient groups: CHF (r = 0.43, P < 0.001), COPD (r = 0.77, P < 0.0001) and CHF/COPD (r = 0.43, P = 0.003). CONCLUSIONS: Plasma levels of sRAGE and CML are increased in CHF, but not in COPD patients. The robust association between NT-pro BNP, a diagnostic and prognostic marker in CHF, and sRAGE concentrations might suggest a possible BNP pathway of amplification of inflammation via the AGE/RAGE system.

CCL21 is associated with fatal outcomes in chronic heart failure: data from CORONA and GISSI-HF trials.

AIMS: Chronic heart failure (HF) is in part characterized by immune activation and inflammation, and factors that regulate lymphocyte trafficking and inflammation may contribute to the progression of this disorder. The homeostatic chemokine CCL21 is a potent regulator of T-cell migration into non-lymphoid tissue and may exert inflammatory properties and influence tissue remodelling. We therefore investigated CCL21 levels and association with fatal outcomes in patients with chronic HF. METHODS AND RESULTS: Plasma CCL21 was measured at randomization in 1456 patients enrolled in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) and in 1145 from the GISSI-HF trial. Association between CCL21 levels [given below as hazard ratio (HR) with 95% confidence interval (CI) for 1 SD increase] with all-cause (n = 741) or cardiovascular (CV) mortality (n = 576) was evaluated with multivariable Cox proportional hazard models, adjusting for clinical risk factors, C-reactive protein, and NT-proBNP. In multivariable Cox models, CCL21 was associated with higher risk of all-cause mortality (HR 1.16, 95% CI 1.02-1.32; P = 0.020) and CV mortality (HR 1.20, 95% CI 1.08-1.33; P < 0.001). When the two trials were analysed separately, CCL21 had a similar influence on risk prediction. Finally, CCL21 had a modest but significant impact on the discriminatory properties of the model (all-cause mortality, change in Harrell's C-statistic 0.004, P = 0.001; CV mortality, change in C-statistic 0.002, P = 0.002). CONCLUSION: Circulating CCL21 was associated with all-cause and CV mortality in two large populations of contemporary patients with chronic HF.