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Aim: Phenylacetylglutamine (PAGln) is a phenylalanine‐derived metabolite produced by gut microbiota with mechanistic links to heart failure (HF)‐relevant phenotypes. We sought to investigate the prognostic value of PAGln in patients with stable HF. Methods and results: Fasting plasma PAGln levels were measured by stable‐isotope‐dilution liquid chromatography–tandem mass spectrometry (LC‐MS/MS) in patients with stable HF from two large cohorts. All‐cause mortality was assessed at 5‐year follow‐up in the Cleveland cohort, and HF, hospitalization, or mortality were assessed at 3‐year follow‐up in the Berlin cohort. Within the Cleveland cohort, median PAGln levels were 4.2 (interquartile range [IQR] 2.4–6.9) μM. Highest quartile of PAGln was associated with 3.09‐fold increased mortality risk compared to lowest quartile. Following adjustments for traditional risk factors, as well as race, estimated glomerular filtration rate, amino‐terminal pro‐B‐type natriuretic peptide, high‐sensitivity C‐reactive protein, left ventricular ejection fraction, ischaemic aetiology, and HF drug treatment, elevated PAGln levels remained predictive of 5‐year mortality in quartile comparisons (adjusted hazard ratio [HR] [95% confidence interval, CI] for Q4 vs Q1: 1.64 [1.07–2.53]). In the Berlin cohort, a similar distribution of PAGln levels was observed (median 3.2 [IQR 2.0–4.8] μM), and PAGln levels were associated with a 1.92‐fold increase in 3‐year HF hospitalization or all‐cause mortality risk (adjusted HR [95% CI] for Q4 vs Q1: 1.92 [1.02‐3.61]). Prognostic value of PAGln appears to be independent of trimethylamine N‐oxide levels. Conclusion: High levels of PAGln are associated with adverse outcomes independent of traditional cardiac risk factors and cardio‐renal risk markers. [ABSTRACT FROM AUTHOR]

Aim: To identify distinct phenotypic subgroups in a highly-dimensional, mixed-data cohort of individuals with heart failure (HF) with preserved ejection fraction (HFpEF) using unsupervised clustering analysis.Methods and Results: The study included all Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) participants from the Americas (n = 1767). In the subset of participants with available echocardiographic data (derivation cohort, n = 654), we characterized three mutually exclusive phenogroups of HFpEF participants using penalized finite mixture model-based clustering analysis on 61 mixed-data phenotypic variables. Phenogroup 1 had higher burden of co-morbidities, natriuretic peptides, and abnormalities in left ventricular structure and function; phenogroup 2 had lower prevalence of cardiovascular and non-cardiac co-morbidities but higher burden of diastolic dysfunction; and phenogroup 3 had lower natriuretic peptide levels, intermediate co-morbidity burden, and the most favourable diastolic function profile. In adjusted Cox models, participants in phenogroup 1 (vs. phenogroup 3) had significantly higher risk for all adverse clinical events including the primary composite endpoint, all-cause mortality, and HF hospitalization. Phenogroup 2 (vs. phenogroup 3) was significantly associated with higher risk of HF hospitalization but a lower risk of atherosclerotic event (myocardial infarction, stroke, or cardiovascular death), and comparable risk of mortality. Similar patterns of association were also observed in the non-echocardiographic TOPCAT cohort (internal validation cohort, n = 1113) and an external cohort of patients with HFpEF [Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial cohort, n = 198], with the highest risk of adverse outcome noted in phenogroup 1 participants.Conclusions: Machine learning-based cluster analysis can identify phenogroups of patients with HFpEF with distinct clinical characteristics and long-term outcomes. [ABSTRACT FROM AUTHOR]

Aims: Prior cohorts demonstrating the importance of serum chloride levels in heart failure either excluded or had partial representation of patients with heart failure with preserved ejection fraction (HFpEF). We aimed to examine the relationship between serum chloride concentration and outcomes in HFpEF.Methods and Results: We included participants from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist Trial (TOPCAT) who met the following criteria: met inclusion by the natriuretic peptide stratum, had recorded serum chloride levels, and were from the Americas (n = 942). Multivariable Cox proportional hazards models tested the association of serum chloride with clinical outcomes, and mixed effects modelling tested the association of spironolactone or loop diuretic on serial serum chloride levels. The median serum chloride level was 102 [25th-75th percentile 100-105 mmol/L (range 84-114 mmol/L)]. After multivariable adjustment, every standard deviation decrease in serum chloride (4.05 mmol/L) was associated with ∼50% increased risk for cardiovascular death [hazard ratio (HR) 1.51, 95% confidence interval (CI) 1.11-2.06, P = 0.008] and ∼30% increased risk for all-cause death (HR 1.29, 95% CI 1.02-1.62, P = 0.04), but not with the primary composite endpoint or heart failure hospitalization (P > 0.3 for both). There were no significant interactions between spironolactone use and the serum chloride-risk relationship (P > 0.1) for each endpoint. Spironolactone was not (P = 0.33) but loop diuretic use was associated with lower serial serum chloride levels (P < 0.001).Conclusion: Lower serum chloride was independently associated with increased risk of cardiovascular and all-cause death in HFpEF. Loop diuretic use, but not spironolactone, lead to a decrease in serum chloride levels over time. [ABSTRACT FROM AUTHOR]

Aims: Decreased arylesterase (ArylE) activity of paraoxonase-1, a HDL-associated protein with anti-inflammatory and antioxidant properties, has been associated with increased risk of cardiac events in patients with ischaemic heart failure (HF). We aim to investigate the prognostic significance of changes in serum ArylE activity over time.Methods and Results: We examined the association between baseline and follow-up serum ArylE activity and HF outcomes (death, cardiac transplantation, or ventricular assist device implantation) in 299 patients with HF enrolled in a prospective cohort study from January 2008 to July 2009, with 145 patients having available follow-up levels at 1 year. A significant drop in ArylE activity on follow-up was defined as a drop of ≥25% vs. baseline levels. Mean baseline and follow-up ArylE activity levels were 110.6 ± 29.9 µmol/min/mL and 106.2 ± 29.9 µmol/min/mL, respectively. After a mean follow-up of 2.8 ± 1.1 years, low baseline ArylE activity was associated with increased risk of adverse HF events [hazard ratio (HR; lowest vs highest tertile) 2.6, 95% confidence interval (CI) 1.3-5.5, P = 0.01] and HF-related hospitalization [incidence rate ratio (lowest vs. highest tertile) 2.1, 95% CI 1.2-4.1, P = 0.016], which remained significant after adjustment for age, male gender, systolic blood pressure, diabetes, creatinine clearance, CAD, and HDL-cholesterol levels. Patients who had a significant drop in ArylE activity on follow-up (n = 18) had a significantly increased risk of HF events (HR 4.9, 95% CI 1.6-14.6, P = 0.005), even after adjustment for baseline levels of ArylE activity.Conclusions: Reduced baseline ArylE activity and decreased levels on follow-up are associated with adverse outcomes in stable outpatients with HF. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) can be associated with a higher resting heart rate (HR), and an elevated HR is associated with adverse long-term events. However, the mechanistic and causal role of HR in HF is unclear. This study aimed to investigate changes in HR during hospitalization, and the association between discharge HR and clinical outcomes as well as an interaction with beta-blocker therapy in patients with acute decompensated HF (ADHF).Methods and Results: We studied 2906 patients with an LVEF ≤35%, without AF, who were enrolled in the ASCEND-HF trial. A total of 2492 (85.8%) patients had a HR ≥70 b.p.m. at baseline and 1580 (54.4%) patients were on beta-blocker treatment. Although HR was gradually reduced from baseline to discharge (85.5 ± 15.9 b.p.m. at baseline, 81.7 ± 14.1 b.p.m. at 24 h from treatment initiation, and 79.1 ± 12.2 b.p.m. at discharge), 80.2% of the patients still had a HR ≥70 b.p.m. at discharge. Patients with a HR ≥70 b.p.m. at discharge had significantly lower survival rates than those with a HR <70 b.p.m. (adjusted hazard ratio 1.02, 95% confidence interval 1.01-1.04, P = 0.002). Moreover, HR at discharge had a curvilinear association with mortality, and had no significant interaction effect with beta-blocker therapy at discharge (P = 0.82).Conclusions: Despite current beta-blocker therapy, many patients with hospitalized ADHF with reduced LVEF have relatively high discharge HR, and discharge HR is associated with higher mortality. Further studies are warranted to determine the optimal strategy for HR control to improve outcomes. [ABSTRACT FROM AUTHOR]

Aims: Hyponatraemia is strongly associated with adverse outcomes in heart failure. However, accumulating evidence suggests that chloride may play an important role in renal salt sensing and regulation of neurohormonal and sodium-conserving pathways. Our objective was to determine the prognostic importance of hypochloraemia in patients with heart failure.Methods and Results: Patients in the BEST trial with baseline serum chloride values were evaluated (n = 2699). Hypochloraemia was defined as a serum chloride ≤96 mmol/L and hyponatraemia as serum sodium ≤135 mmol/L. Hypochloraemia was present in 13.0% and hyponatraemia in 13.7% of the population. Chloride and sodium were only modestly correlated (r = 0.53), resulting in only 48.7% of hypochloraemic patients having concurrent hyponatraemia. Both hyponatraemia and hypochloraemia identified a population with greater disease severity; however, renal function tended to be worse and loop diuretic doses higher with hypochloraemia. In univariate analysis, lower serum sodium or serum chloride as continuous parameters were each strongly associated with mortality (P < 0.001). However, when both parameters were included in the same model, serum chloride remained strongly associated with mortality [hazard ratio (HR) 1.3 per standard deviation decrease, 95% confidence interval (CI) 1.18-1.42, P < 0.001], whereas sodium was not (HR 0.97 per standard deviation decrease, 95% CI 0.89-1.06, P = 0.52).Conclusion: Serum chloride is strongly and independently associated with worsened survival in patients with chronic heart failure and accounted for the majority of the risk otherwise attributable to hyponatraemia. Given the critical role of chloride in a number of regulatory pathways central to heart failure pathophysiology, additional research is warranted in this area. [ABSTRACT FROM AUTHOR]

Background Over the years, several methods have been developed to reliably quantify functional capacity in patients with heart failure. Few studies have investigated the prognostic value of these assessment tools beyond cardiorenal prognostic biomarkers in stable patients with chronic heart failure. Methods and Results We administered the Duke Activity Status Index (DASI) questionnaire, a self-assessment tool comprising 12 questions for estimating functional capacity, to 1,700 stable nonacute coronary syndrome patients with history of heart failure who underwent elective diagnostic coronary angiography with 5-year follow-up of all-cause mortality. In a subset of patients (n = 800), B-type natriuretic peptide (BNP) was measured. In our study cohort, the median DASI score was 26.2 (interquartile range [IQR] 15.5–42.7). Low DASI score provided independent prediction of a 3.3-fold increase in 5-year mortality risk (quartile 1 vs quartile 4: hazard ratio [HR] 3.33, 95% confidence interval [CI] 2.57–4.36; P < .0001). After adjusting for traditional risk factors, BNP, and estimated glomerular filtration rate, low DASI score still conferred a 2.6-fold increase in mortality risk (HR 2.57, 95% CI 1.64–4.15; P < .0001). Conclusions A simple self-assessment tool of functional capacity provides independent and incremental prognostic value for mortality prediction in stable patients with chronic heart failure beyond cardiorenal biomarkers. [ABSTRACT FROM AUTHOR]

Prediction Rule to Identify Patients at High Risk for Early Demise Following CRT Background In patients with advanced heart failure, the decision of whether to pursue cardiac resynchronization therapy (CRT) or to proceed directly to advanced heart failure therapies can be challenging. We sought to create a prediction rule to identify patients with advanced systolic heart failure at heightened risk of rapid deterioration despite receiving CRT. Methods Clinical data were collected on consecutive patients with advanced heart failure presenting for a new CRT device at the Cleveland Clinic between February 12, 2002 and July 8, 2008. Early demise was defined as death, left ventricular assist device, or heart transplant within 6 months following CRT implant. Using a multivariate model, variables associated with early demise were identified and a prediction rule created. Results A total of 879 patients were included of whom 47 met criteria for early demise. Using forward stepwise regression followed by a bootstrapping analysis, the final model included: left ventricular end-diastolic diameter ≥6.5 cm (OR 3.23 [1.72-6.06 g], P < 0.001), the presence of a non-left bundle branch block (non-LBBB) morphology (OR 2.18 [1.18-4.04, P = 0.013]), creatinine ≥1.5 mg/dL (OR 2.98 [1.52-5.49], P < 0.001), and lack of or intolerance to β-blocker use (OR 2.80 [1.46-5.39], P = 0.002). The specificity for ≥2 and ≥3 risk factors was 72.6% and 94.6%, respectively. Conclusions Left ventricular dilatation, the presence of a non-LBBB morphology, renal dysfunction, and lack of or intolerance to β-blockers are associated with early demise following CRT. In patients with at least 3 of these factors, bypassing CRT with early adoption of advanced heart failure therapies may be considered given the high specificity for rapid decline. [ABSTRACT FROM AUTHOR]

Objectives: We sought to assess the diagnostic accuracy and incremental prognostic value of delayed hyper-enhancement cardiac magnetic resonance (DHE-CMR) compared with electrocardiographic and transthoracic echocardiographic (TTE) parameters in such patients. Background: Utility of DHE-CMR in the diagnosis of patients with suspected cardiac amyloidosis (CA) has recently been demonstrated, but its incremental prognostic utility is unclear. Methods: Forty-seven consecutive patients (mean age 63 years, 70% men, 55% New York Heart Association functional class >II) with suspected CA who underwent electrocardiography (ECG), TTE, DHE-CMR, and biopsy (38 endomyocardial, 9 extracardiac) were studied. Low voltage on ECG was defined as S-wave in lead V1 + R-wave in lead V5 or V6 <15 mm. TTE parameters, including deceleration time, E/E′ ratio, and diastolic grade were recorded. CMR was considered positive with diffuse DHE of the subendocardium extending to adjacent myocardium. All-cause mortality was ascertained. Results: In the study population, 59% had low voltage on ECG, 30% had abnormal deceleration time ≤150 ms, 38% had E/E′ ratio >15, and 47% had advanced (pseudonormal or restrictive) diastology. The diagnostic accuracy of DHE-CMR in patients undergoing endomyocardial biopsy was as follows: sensitivity 88%, specificity 90%, positive predictive value 88%, and negative predictive value 90%. On multivariable logistic regression testing of the diagnostic ability of various noninvasive imaging parameters, only DHE-CMR was significant (Wald chi-square statistic 9.6, p < 0.01). At 1-year post-biopsy, there were 9 (19%) deaths. On Cox proportional hazards analysis, only positive DHE-CMR was a predictor of 1-year mortality (Wald chi-square statistic 4.91, p = 0.03). Conclusions: A characteristic DHE-CMR pattern is more accurate for diagnosis and is a stronger predictor of 1-year mortality in patients with suspected CA as compared with other noninvasive parameters. [Copyright &y& Elsevier]

Objectives: We hypothesized that an integrated assessment of arginine with its catabolic products might better predict cardiovascular risks than arginine levels alone. Background: Arginine is the sole nitrogen source for nitric oxide (NO) synthesis. The major catabolic products of arginine are ornithine and citrulline. Methods: Plasma levels of free arginine, ornithine, citrulline, and the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) were measured with liquid chromatography coupled with tandem mass spectrometry. We examined the relationship of global arginine bioavailability ratio (GABR) (defined as arginine/[ornithine + citrulline]) versus arginine and its catabolic metabolites to prevalence of significantly obstructive coronary artery disease (CAD) and incidence of major adverse cardiovascular events (MACE) (death, myocardial infarction, stroke) over a 3-year follow-up in 1,010 subjects undergoing elective cardiac catheterization. Results: Patients with significantly obstructive CAD had significantly lower GABR (median [interquartile range]: 1.06 [0.75 to 1.31] vs. 1.27 [0.96 to 1.73], p < 0.001) and arginine levels [mean: 68 ± 20 μmol/l vs. 74 ± 24 μmol/l, p < 0.001) than those without significantly obstructive CAD. After adjusting for Framingham risk score, C-reactive protein, and renal function, lower GABR (but not arginine levels) and higher citrulline levels remained significantly associated with both the prevalence of significantly obstructive CAD (adjusted odds ratio: 3.93, p < 0.001, and 5.98, p < 0.001, respectively) and 3-year risk for the incidence of MACE (adjusted hazard ratio: 1.98, p = 0.025, and 2.40, p = 0.01, respectively) and remained significant after adjusting for ADMA. Conclusions: GABR might serve as a more comprehensive concept of reduced NO synthetic capacity compared with systemic arginine levels. Diminished GABR and high citrulline levels are associated with both development of significantly obstructive atherosclerotic CAD and heightened long-term risk for MACE. [Copyright &y& Elsevier]

Objectives: The aim of this study was to determine the relationship between right atrial volume index (RAVI) and right ventricular (RV) systolic and diastolic function, as well as long-term prognosis in patients with chronic systolic heart failure (HF). Background: RV dysfunction is associated with poor prognosis in patients with HF, although echocardiographic assessment of RV systolic and diastolic dysfunction is challenging. The ability to visualize the RA allows a quantitative, highly reproducible assessment of the RA volume that can be indexed to body surface area. Methods: The ADEPT (Assessment of Doppler Echocardiography for Prognosis and Therapy) trial enrolled 192 subjects with chronic systolic HF (left ventricular ejection fraction [LVEF] ≤35%). The RA volume was calculated by Simpson''s method using single-plane RA area and indexed to body surface area (RAVI). RV systolic function was graded as normal, mild, mild-moderate, moderate, moderately severe, or severe dysfunction. Results: In our study cohort, the mean RAVI was 28 ± 15 ml/m2, and increased with worsening RV systolic dysfunction, LVEF, and LV diastolic dysfunction (Spearman''s r = 0.61, r = 0.26, and r = 0.51, respectively; p < 0.001 for all). RAVI correlated modestly with echocardiographic estimates of RV diastolic dysfunction, including tricuspid early/late velocities ratio (Spearman''s r = 0.34, p < 0.0001), hepatic vein systolic/diastolic ratio (Spearman''s r = −0.26, p < 0.001) but not tricuspid early/tricuspid annular early velocities ratio (E/Ea) (Spearman''s r = 0.12, p = 0.11). Increasing tertiles of RAVI were predictive of death, transplant, and/or HF hospitalization (log-rank p = 0.0002) and remained an independent predictor of adverse clinical events after adjusting for age, B-type natriuretic peptide, LV ejection fraction, RV systolic dysfunction, and tricuspid E/Ea ratio (hazard ratio: 2.00, 95% confidence interval: 1.15 to 3.58, p = 0.013). Conclusions: In patients with chronic systolic HF, RAVI is a determinant of right-sided systolic dysfunction. This quantitative and reproducible echocardiographic marker provides independent risk prediction of long-term adverse clinical events. [Copyright &y& Elsevier]

Abstract: Background: The influence of myocardial function on plasma levels of cystatin C (CysC), a sensitive marker of renal function, in chronic systolic heart failure (HF) has not been well established. Methods: We prospectively identified 139 subjects with stable, chronic HF (left ventricular ejection fraction ≤ 35%) and measured plasma levels of CysC. We prospectively tracked patients'' long-term adverse clinical outcomes (death, cardiac transplantation, and HF hospitalizations). Results: Plasma levels of CysC were elevated in 41% of patients with preserved renal function and directly correlated with N-terminal prohormone brain natriuretic peptide (r = 0.57, P < .0001). There was a significant association between CysC and mitral E/septal E'' ratio (r = 0.34, P < .001), right ventricular systolic dysfunction severity (r = 0.30, P < .001), and mitral regurgitation severity (r = 0.31, P < .001), but not left ventricular ejection fraction. At the cutoff of 1.23 mg/dL, CysC remains a significant independent risk factor for adverse clinical outcomes (hazard ratio 1.88, 95% confidence interval 1.15–3.09, P = .012) after adjusting for estimated glomerular filtration rate, left ventricular ejection fraction, and E/septal E''. Conclusion: CysC is associated with more advanced left ventricular diastolic dysfunction and right ventricular systolic dysfunction and remains an independent predictor of long-term prognosis in chronic systolic HF after adjusting for myocardial factors. [Copyright &y& Elsevier]

Objectives: The purpose of this study was to explore the relationship between myeloperoxidase (MPO) and cardiac structure, performance, and prognosis. Background: Myeloperoxidase is an inflammatory marker that is elevated in patients with heart failure (HF) and cardiac dysfunction, with mechanistic links to plaque vulnerability and left ventricular (LV) remodeling. Methods: We evaluated plasma MPO levels (CardioMPO, PrognostiX, Inc., Cleveland, Ohio) in 140 patients with chronic systolic HF (LV ejection fraction <35%) and examined the plasma MPO levels’ relationships with echocardiographic indexes of systolic and diastolic performance, as well as long-term clinical outcomes (death, cardiac transplantation, or HF hospitalization). Results: Within the overall cohort, increasing plasma MPO levels were associated with increasing likelihood of more advanced HF (restrictive diastolic stage, right ventricular systolic dysfunction ≥3+, and tricuspid regurgitation area ≥1.8 cm2). Plasma MPO levels were predictive of long-term clinical outcomes (risk ratio [95% confidence interval] = 3.35 [1.52 to 8.86]), even after adjustment for age, LV ejection fraction, plasma B-type natriuretic peptide (BNP), creatinine clearance, or diastolic stage. In receiver-operator characteristic curve analyses, addition of MPO to BNP testing augmented the predictive accuracy of future adverse clinical events (area under the curve 0.66 for BNP only [chi-square test = 12.9, p = 0.0003], and 0.70 for BNP plus MPO [chi-square test = 15.87, p = 0.0004]). Conclusions: In chronic systolic HF, elevated plasma MPO levels are associated with an increased likelihood of more advanced HF. Moreover, elevated plasma MPO levels within a HF subject seem to be predictive of increased adverse clinical outcomes. [Copyright &y& Elsevier]

The LHFRS is a simple score derived from three factors (history of hypertension, history of coronary artery disease/myocardial infarction, and red blood cell distribution width) deployed for the risk stratification of AHF in Greek population. This study aimed to validate the Larissa Heart Failure Risk Score (LHFRS) in patients with acute heart failure (AHF) in a Japanese population. We performed post-hoc analysis of 1670 consecutive patients enrolled in the REALITY-AHF. In all, 964 patients were finally enrolled. Exclusion criteria included patients with anemia, malignancies and sepsis. The primary outcome was defined as a composite of all-cause mortality and/or heart failure readmission, and the secondary outcome was defined as all-cause mortality. The median admission LHFRS value was 1 (interquartile range [IQR]: 0–2). During a median follow-up of 365 (IQR: 161–365) days, the primary and secondary outcomes were observed in 321 and 157 patients, respectively. LHFRS was an independent predictor of both the primary (adjusted hazard ratio per 1-point increase, 95% confidence interval: 1.17 [1.04–1.32], p = 0.011), and the secondary outcomes (1.31 [1.12–1.55], p = 0.001). Patients with higher LHFRS scores (≥2) exhibited significantly worse outcomes than those with lower scores (<2) both for the primary outcome (1.40 [1.07–1.83], p = 0.014) and the secondary outcome (1.60 [1.09–2.34], p = 0.015). Additionally, LHFRS revealed an excellent goodness of fit (observed versus predicted outcomes) for predicting both the primary and the secondary outcomes (p > 0.99 and p = 0.99, respectively). The simple LHFRS was proved as a reliable predictor of outcomes in patients with AHF. • Risk stratification is important during hospitalization for acute heart failure (AHF). • The Larissa Heart Failure Risk Score (LHFRS) is a simple score that easily and reliably risk stratifies AHF patients. • Close monitoring of high risk AHF patients is warranted. [ABSTRACT FROM AUTHOR]

Background: Diabetes is associated with abnormalities in cardiac remodeling and high risk of heart failure (HF).Objectives: The purpose of this study was to evaluate the prevalence and prognostic implications of diabetes with cardiomyopathy (DbCM) among community-dwelling individuals.Methods: Adults without prevalent cardiovascular disease or HF were pooled from 3 cohort studies (ARIC [Atherosclerosis Risk In Communities], CHS [Cardiovascular Health Study], CRIC [Chronic Renal Insufficiency Cohort]). Among participants with diabetes, DbCM was defined using different definitions: 1) least restrictive: ≥1 echocardiographic abnormality (left atrial enlargement, left ventricle hypertrophy, diastolic dysfunction); 2) intermediate restrictive: ≥2 echocardiographic abnormalities; and 3) most restrictive: elevated N-terminal pro-B-type natriuretic peptide levels (>125 in normal/overweight or >100 pg/mL in obese) plus ≥2 echocardiographic abnormalities. Adjusted Fine-Gray models were used to evaluate the risk of HF.Results: Among individuals with diabetes (2,900 of 10,208 included), the prevalence of DbCM ranged from 67.0% to 11.7% in the least and most restrictive criteria, respectively. Higher fasting glucose, body mass index, and age as well as worse kidney function were associated with higher risk of DbCM. The 5-year incidence of HF among participants with DbCM ranged from 8.4%-12.8% in the least and most restrictive definitions, respectively. Compared with euglycemia, DbCM was significantly associated with higher risk of incident HF with the highest risk observed for the most restrictive definition of DbCM (HR: 2.55 [95% CI: 1.69-3.86]; least restrictive criteria HR: 1.99 [95% CI: 1.50-2.65]). A similar pattern of results was observed across cohort studies, across sex and race subgroups, and among participants without hypertension or obesity.Conclusions: Regardless of the criteria used to define cardiomyopathy, DbCM identifies a high-risk subgroup for developing HF. [ABSTRACT FROM AUTHOR]

Cardiorenal syndrome encompasses a spectrum of disorders involving both the heart and kidneys in which acute or chronic dysfunction in 1 organ may induce acute or chronic dysfunction in the other organ. It represents the confluence of heart-kidney interactions across several interfaces. These include the hemodynamic cross-talk between the failing heart and the response of the kidneys and vice versa, as well as alterations in neurohormonal markers and inflammatory molecular signatures characteristic of its clinical phenotypes. The mission of this scientific statement is to describe the epidemiology and pathogenesis of cardiorenal syndrome in the context of the continuously evolving nature of its clinicopathological description over the past decade. It also describes diagnostic and therapeutic strategies applicable to cardiorenal syndrome, summarizes cardiac-kidney interactions in special populations such as patients with diabetes mellitus and kidney transplant recipients, and emphasizes the role of palliative care in patients with cardiorenal syndrome. Finally, it outlines the need for a cardiorenal education track that will guide future cardiorenal trials and integrate the clinical and research needs of this important field in the future. [ABSTRACT FROM AUTHOR]

Objective: The objective was to study whether the temporal pattern of transient hyponatremia development in acute heart failure might provide insight into its pathophysiology and prognostic relevance.Methods: A post hoc analysis of the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) and Diuretic Optimization Strategies Evaluation in Acute Heart Failure (DOSE AHF) studies was performed (n = 716). Patients were stratified according to the temporal pattern of hyponatremia development: (1) no hyponatremia, (2) persistent hyponatremia, (3) decompensation hyponatremia disappearing with decongestive treatment, and (4) treatment-induced hyponatremia.Results: Transient decompensation versus no hyponatremia was associated with significantly elevated blood urea nitrogen/creatinine ratio (P < .001), plasma renin activity (P < .001), and plasma aldosterone levels (P < .001) at baseline. Disease severity characteristics of such patients were intermediate between no and persistent hyponatremia. In contrast, patients with treatment-induced versus no hyponatremia had similar baseline characteristics and comparable natriuretic peptide levels, and both groups had little neurohumoral activation at baseline. Diuretic efficacy, defined as net fluid balance (milliliters) per 40 mg furosemide-equivalent dose administered, was lower in patients with persistent or treatment-induced hyponatremia versus decompensation hyponatremia or no hyponatremia, respectively. The former versus latter groups also had more pronounced neurohumoral activation with decongestive treatment. The risk for all-cause mortality (hazard ratio, 2.50; 95% confidence interval, 1.50-4.19; P < .001) and death or heart failure readmission (hazard ratio, 2.18; 95% confidence interval, 1.60-2.97; P < .001) was significantly elevated in patients with persistent versus no hyponatremia, with the risk of decompensation and treatment hyponatremia situated in between.Conclusions: Transient hyponatremia is prognostically relevant, but it has a heterogeneous cause according to its temporal pattern of development. [ABSTRACT FROM AUTHOR]

Background: Cardiac dysfunction influences candidate selection for kidney transplantation. There is a paucity of data regarding predictors of myocardial recovery following kidney transplantation and long-term outcomes.Objectives: The purpose of this study was to identify the extent of reverse remodeling in our kidney transplant population and the predictors of such changes, and to assess outcomes in these patients.Methods: We reviewed 232 patients who underwent kidney transplantation at the Cleveland Clinic from 2003 to 2013 and who had baseline and post-transplant echocardiograms; patients with simultaneous heart transplantation were excluded.Results: Post-transplantation mean left ventricular ejection fraction (LVEF) improved in those with LV dysfunction (increased from 41% to 50%; p < 0.0001; n = 66). There was significant improvement in other parameters, including diastolic function, LV end-diastolic dimension, LV mass, and right ventricular systolic pressure. After adjusting for multiple clinical variables, increased hemoglobin following transplantation was associated with an improved LVEF (odds ratio: 1.50; 95% confidence interval [CI]: 1.07 to 2.14; p = 0.016) and reduced mortality (hazard ratio [HR]: 0.65; 95% CI: 0.49 to 0.87; p = 0.004). An improved LVEF ≥10% predicted survival independently of a pre-transplantation LVEF (HR: 0.46; 95% CI: 0.21 to 0.93; p = 0.031).Conclusions: Kidney transplantation is associated with improved cardiac structure and function. A rise in post-transplantation hemoglobin was a significant factor associated with such changes, in addition to conferring a survival advantage. [ABSTRACT FROM AUTHOR]

Background Cardiac troponin (cTn) levels offer prognostic information for patients with heart failure. Highly sensitive assays detect levels of cTn much lower than the 99th percentile of standard cTn assays. We hypothesize that cardiac troponin levels measured by a high-sensitivity assay provide better prognostic value compared with cTn levels measured by a standard assay in patients with chronic heart failure. Methods We measured high-sensitivity cTnT (hs-cTnT) and standard cardiac troponin I (cTnI) levels, as well as amino-terminal pro B-type natriuretic peptide (NT-proBNP) in 504 sequential stable patients with a history of heart failure who underwent elective coronary angiography, without acute coronary syndrome, and with 5-year follow-up of all-cause mortality. Results The median hs-cTnT level was 21.2 (interquartile range 12.3-40.9) ng/L and 170 subjects died over 5 years. In a head-to-head overall comparison, hs-cTnT provided increased prognostic utility compared with cTnI (area under the curve [AUC] 66.1% and AUC 69.4%, respectively, P = .03; 9.0% integrated discrimination improvement, P < .001; and 13.6% event-specific reclassification, P < .001), and was independent of NT-proBNP and renal function. Even within the subset of patients where cTn levels by both assays were above the limit of quantification, higher hs-cTnT is associated with a 2-fold increase in 5-year mortality risk after adjusting for traditional risk factors (tertile 1 vs 3: hazard ratio [95% confidence interval] 2.0 [1.3-3.2]; P = .0002). Conclusion Cardiac troponin can be detected by the high-sensitivity assay in more patients with chronic heart failure than the standard assay, and may yield independent and better prognostic accuracy for mortality prediction than standard assay. [ABSTRACT FROM AUTHOR]

Objectives: This study sought to examine the ability of left ventricular (LV) global longitudinal strain (GLS) to assess disease severity in patients with chronic systolic heart failure (HF). Background: Left ventricular GLS is a sensitive measure of LV mechanics. Its relationship with standard clinical markers and long-term adverse events in chronic systolic HF is not well established. Methods: In 194 chronic systolic HF patients, we performed comprehensive echocardiography with assessment of GLS by velocity vector imaging averaged from apical 4-chamber and 2-chamber views. Death, cardiac transplantation, and HF hospitalization were tracked for 5 years. Results: In our study cohort (age 57 ± 14 years, left ventricular ejection fraction [LVEF] 26 ± 6%, median N-terminal pro-B-type natriuretic peptide [NT-proBNP] 1,158 pg/ml), the mean GLS was −7.1 ± 3.3%. The GLS worsened with increasing New York Heart Association functional class (rank-sum p < 0.0001) and higher NT-proBNP (r = 0.42, p < 0.0001). The GLS correlated with LV cardiac structure (LV mass index: r = 0.35, p < 0.0001; LV end-diastolic volume index: r = 0.43, p < 0.0001) and LVEF (r = −0.66, p < 0.0001). A lower magnitude of GLS was associated with worsening LV diastolic function (E/e'' septal: r = 0.33, p < 0.0001), right ventricular (RV) systolic function (RV s'': r = −0.30, p < 0.0001), and RV diastolic function (RV e''/a'': r = 0.16, p = 0.033). GLS predicted long-term adverse events (hazard ratio: 1.55, 95% confidence interval: 1.21 to 2.00; p < 0.001). Worsening strain (GLS ≥−6.95%) predicted adverse events after adjustment for age, sex, ischemic etiology, E/e'' septal, and NT-proBNP (hazard ratio: 2.04, 95% confidence interval: 1.09 to 3.94; p = 0.025) and age, sex, ischemic etiology, and LVEF (hazard ratio: 2.15, 95% confidence interval: 1.19 to 4.02; p = 0.011). Conclusions: In chronic systolic HF, worsening LV GLS is associated with more severe LV diastolic dysfunction and RV systolic and diastolic dysfunction, and provides incremental prognostic value to LVEF. [Copyright &y& Elsevier]