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Aims: Acetazolamide, an inhibitor of proximal tubular sodium reabsorption, leads to more effective decongestion in acute heart failure (AHF). It is unknown whether acetazolamide alters serum sodium and potassium levels on top of loop diuretics and if baseline values modify the treatment effect of acetazolamide. Methods and results: This is a pre‐specified sub‐analysis of the ADVOR trial that randomized 519 patients with AHF and volume overload in a 1:1 ratio to intravenous acetazolamide or matching placebo on top of standardized intravenous loop diuretics. Mean potassium and sodium levels at randomization were 4.2 ± 0.6 and 139 ± 4 mmol/L in the acetazolamide arm versus 4.2 ± 0.6 and 140 ± 4 mmol/L in the placebo arm. Hypokalaemia (<3.5 mmol/L) on admission was present in 44 (9%) patients and hyponatraemia (≤135 mmol/L) in 82 (16%) patients. After 3 days of treatment, 44 (17%) patients in the acetazolamide arm and 35 (14%) patients in the placebo arm developed hyponatraemia (p = 0.255). Patients randomized to acetazolamide demonstrated a slight decrease in mean potassium levels during decongestion, which was non‐significant over time (p = 0.053) and had no significant impact on hypokalaemia incidence (p = 0.061). Severe hypokalaemia (<3.0 mmol/L) occurred in only 7 (1%) patients, similarly distributed between the two treatment arms (p = 0.676). Randomization towards acetazolamide improved decongestive response irrespective of baseline serum sodium and potassium levels. Conclusions: Acetazolamide on top of standardized loop diuretic therapy does not lead to clinically important hypokalaemia or hyponatraemia and improves decongestion over the entire range of baseline serum potassium and sodium levels. [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]

Background QRS duration (QRSd) may be impacted by both left ventricular (LV) dilatation and conduction delay. It is possible therefore that the same QRSd may portend significantly different amounts of LV activation delay in patients with small versus large left ventricles. We hypothesized that LV size modifies the effect of QRSd on predicting outcomes in patients undergoing CRT implant. Methods We extracted data on consecutive patients presenting for initial CRT implant. In patients with a follow-up echocardiogram, response was defined as an absolute improvement in LV ejection fraction ≥5%. Multivariate models were created to determine if left ventricular end-diastolic diameter (LVEDD) modified the effect of QRSd on its association with both long-term survival free of left ventricular assist device (LVAD) and heart transplant and echocardiographic response. Results 464 patients met inclusion criteria. At a mean follow-up of 4.9 ± 2.6 years, there were 210 deaths, 13 heart transplants, and 12 LVAD placements. There was a weak but significant correlation between baseline QRSd and LVEDD (Spearman's Rho 0.106, P < 0.001). In a multivariate analysis, there was no evidence of effect modification of LVEDD on QRSd (LVEDDi*QRS interaction term HR 1.0 [0.995-1.006], P = 0.94). Note that 305 patients had a follow-up echocardiogram, of whom 193 met the criteria for response. In a multivariate analysis, there was no evidence of effect modification of LVEDD on QRSd (LVEDDi*QRS interaction term odds ratio 0.998 (0.988-1.008), P = 0.65). Conclusion LV size does not modify the effect of QRSd and its association with outcomes following CRT. The correlation between LV size and QRSd in patients with a QRSd ≥ 120 ms is weak. [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: The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up-titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF).Methods and Results: Medical records of 147 consecutive ADHF patients who underwent placement of a pulmonary artery catheter and received intravenous vasodilator therapy were reviewed. Intravenous sodium nitroprusside and sodium nitroglycerin as first-line agent for those with preserved blood pressures were utilized in 143 and 32 patients, respectively. Sixty-one percent of patients were converted to oral HYD/ISDN combination therapy through a standardized conversion protocol. These patients had a significantly higher admission mean pulmonary arterial wedge pressure compared with patients not converted (28 ± 7 vs. 25 ± 8 mmHg, respectively; P-value 0.024). Beneficial haemodynamic response to decongestive therapy, defined as low cardiac filling pressures and cardiac index ≥2.20 L/min/m(2) without emergent hypotension, was achieved in 32% and 29% of patients who did or did not receive oral HYD/ISDN, respectively (P-value 0.762). HYD/ISDN dosing was progressively and consistently decreased up to the moment of hospital discharge and during outpatient follow-up, primarily due to incident hypotension.Conclusion: The use of a standardized haemodynamically guided up-titration protocol for conversion from intravenous to oral vasodilators may warrant subsequent dose reductions upon stabilization. [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]

Aims Cardiac resynchronization therapy (CRT) leads to reverse ventricular remodelling, improved functional capacity, and better clinical outcome in patients with advanced chronic heart failure, reduced ejection fraction, and evidence of ventricular conduction delay, who are under optimal medical therapy. This study investigated whether these benefits can be extrapolated to older patients, typically not included in randomized clinical trials. Methods and results Consecutive patients who received a CRT device between October 2008 and June 2011, including optimization afterwards in a dedicated clinic, were stratified into 3 pre-specified groups, according to age: <70 years (n = 76); 70–79 years (n = 95); and ≥80 years (n = 49). Left ventricular remodelling, functional capacity, heart failure hospitalization, and mortality data were assessed during follow-up. Reverse left ventricular remodelling and improvement in New York Heart Association functional class were similar in all groups at 6 months after implantation. During mean follow-up of 20 months, 32 patients died and 66 were admitted for heart failure. Annualized mortality rates were significantly higher in elderly patients (6% vs. 8% vs. 15% in all groups, respectively; P < 0.001), but time to death or first heart failure admission was similar among age groups (P = 0.531). Progressive pump failure was the major cause of death (50%), with co-morbidity-related deaths also being frequent (41%). Conclusion Reverse left ventricular remodelling and functional capacity improvement after CRT are sustained at advanced age. Moreover, time to all-cause mortality or heart failure admission was similar, irrespective of age, in a context of maximized optimization including optimal medical therapy. [ABSTRACT FROM PUBLISHER]

Aims We examined the prognostic importance of cardiac troponin I (cTnI) in a cohort of patients enrolled in the ASCEND-HF study of nesiritide in acute decompensated heart failure (ADHF). Circulating troponins are a prognostic marker in patients with ADHF. Contemporary assays with greater sensitivity require reassessment of the significance of troponin elevation in HF. Methods and results Cardiac troponin I was measured in a core laboratory in 808 ADHF patients enrolled in the ASCEND-HF biomarkers substudy using a sensitive assay (VITROS Trop I ES, Ortho Clinical Diagnostics) with a lower limit of detection of 0.012 ng/mL and a 99th percentile upper reference limit (URL) of 0.034 ng/mL. Patients with clinical evidence of acute coronary syndrome or troponin >5× the URL were excluded. Multivariable modelling was used to assess the relationship between log(cTnI) and in-hospital and post-discharge outcomes. Baseline cTnI was undetectable in 22% and elevated above the 99th percentile URL in 50% of subjects. cTnI levels did not differ based on HF aetiology. After multivariable adjustment, higher cTnI was associated with worsened in-hospital outcomes such as length of stay (P = 0.01) and worsening HF during the index hospitalization (P = 0.01), but was not associated with worsened post-discharge outcomes at 30 or 180 days. The relationship between cTnI and outcomes was generally linear and there was no evidence of a threshold effect at any particular level of cTnI. Conclusion cTnI is elevated above the 99th percentile URL in 50% of ADHF patients and predicts in-hospital outcome, but is not an independent predictor of long-term outcomes. [ABSTRACT FROM AUTHOR]

Background: Worsening renal function (WRF) in the setting of aggressive diuresis for acute heart failure treatment may reflect renal tubular injury or simply indicate a hemodynamic or functional change in glomerular filtration. Well-validated tubular injury biomarkers, N-acetyl-β-d-glucosaminidase, neutrophil gelatinase-associated lipocalin, and kidney injury molecule 1, are now available that can quantify the degree of renal tubular injury. The ROSE-AHF trial (Renal Optimization Strategies Evaluation-Acute Heart Failure) provides an experimental platform for the study of mechanisms of WRF during aggressive diuresis for acute heart failure because the ROSE-AHF protocol dictated high-dose loop diuretic therapy in all patients. We sought to determine whether tubular injury biomarkers are associated with WRF in the setting of aggressive diuresis and its association with prognosis.Methods: Patients in the multicenter ROSE-AHF trial with baseline and 72-hour urine tubular injury biomarkers were analyzed (n=283). WRF was defined as a ≥20% decrease in glomerular filtration rate estimated with cystatin C.Results: Consistent with protocol-driven aggressive dosing of loop diuretics, participants received a median 560 mg IV furosemide equivalents (interquartile range, 300-815 mg), which induced a urine output of 8425 mL (interquartile range, 6341-10 528 mL) over the 72-hour intervention period. Levels of N-acetyl-β-d-glucosaminidase and kidney injury molecule 1 did not change with aggressive diuresis (both P>0.59), whereas levels of neutrophil gelatinase-associated lipocalin decreased slightly (-8.7 ng/mg; interquartile range, -169 to 35 ng/mg; P<0.001). WRF occurred in 21.2% of the population and was not associated with an increase in any marker of renal tubular injury: neutrophil gelatinase-associated lipocalin (P=0.21), N-acetyl-β-d-glucosaminidase (P=0.46), or kidney injury molecule 1 (P=0.22). Increases in neutrophil gelatinase-associated lipocalin, N-acetyl-β-d-glucosaminidase, and kidney injury molecule 1 were paradoxically associated with improved survival (adjusted hazard ratio, 0.80 per 10 percentile increase; 95% confidence interval, 0.69-0.91; P=0.001).Conclusions: Kidney tubular injury does not appear to have an association with WRF in the context of aggressive diuresis of patients with acute heart failure. These findings reinforce the notion that the small to moderate deteriorations in renal function commonly encountered with aggressive diuresis are dissimilar from traditional causes of acute kidney injury. [ABSTRACT FROM AUTHOR]

Background: Among various cardiac autoantibodies (AAbs), those recognizing the β1-adrenergic receptor (β1AR) demonstrate agonist-like effects and induce myocardial damage that can be reversed by β-blockers and immunoglobulin G3 (IgG3) immunoadsorption.Objectives: The goal of this study was to investigate the role of β1AR-AAbs belonging to the IgG3 subclass in patients with recent-onset cardiomyopathy.Methods: Peripheral blood samples were drawn at enrollment in patients with recent-onset cardiomyopathy (left ventricular ejection fraction [LVEF] ≤0.40; <6 months). The presence of IgG and IgG3-β1AR-AAb was determined, and echocardiograms were assessed, at baseline and 6 months. Patients were followed up for ≤48 months.Results: Among the 353 patients who had blood samples adequate for the analysis, 62 (18%) were positive for IgG3-β1AR-AAbs (IgG3 group), 58 (16%) were positive for IgG but not IgG3 (non-IgG3 group), and the remaining were negative. There were no significant differences in baseline systolic blood pressure, heart rate, or LVEF among the groups at baseline. Left ventricular end-diastolic and end-systolic diameters were significantly larger in the non-IgG3 group compared with the other groups (left ventricular end-diastolic diameter, p < 0.01; left ventricular end-systolic diameter, p = 0.03). At 6 months, LVEF was significantly higher in the IgG3 group (p = 0.007). Multiple regression analysis showed that IgG3-β1AR-AAb was an independent predictor of LVEF at 6 months and change in LVEF over 6 months, even after multivariable adjustment (LVEF at 6 months, β = 0.20, p = 0.01; change in LVEF, β = 0.20, p = 0.008). In patients with high New York Heart Association functional class (III or IV) at baseline, the IgG3 group had a lower incidence of the composite endpoint of all-cause death, cardiac transplantation, and hospitalization due to heart failure, whereas the non-IgG3 group had the highest incidence of the composite endpoint.Conclusions: IgG3-β1AR-AAbs were associated with more favorable myocardial recovery in patients with recent-onset cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Patients with moderate-to-severe chronic kidney disease (CKD) are poorly represented in clinical trials of cardiac resynchronization therapy (CRT).Objectives: This study sought to assess the real-world comparative effectiveness of CRT with defibrillator (CRT-D) versus implantable cardioverter-defibrillator (ICD) alone in CRT-eligible patients with moderate-to-severe CKD.Methods: We conducted an inverse probability-weighted analysis of 10,946 CRT-eligible patients (ejection fraction <35%, QRS >120 ms, New York Heart Association functional class III/IV) with stage 3 to 5 CKD in the National Cardiovascular Data Registry (NCDR) ICD Registry, comparing outcomes between patients who received CRT-D (n = 9,525) versus ICD only (n = 1,421). Outcomes were obtained via Medicare claims and censored at 3 years. The primary endpoint of heart failure (HF) hospitalization or death and the secondary endpoint of death were assessed with Cox proportional hazards models. HF hospitalization, device explant, and progression to end-stage renal disease were assessed using Fine-Gray models.Results: After risk adjustment, CRT-D use was associated with a reduction in HF hospitalization or death (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.78 to 0.91; p < 0.0001), death (HR: 0.85; 95% CI: 0.77 to 0.93; p < 0.0004), and HF hospitalization alone (subdistribution HR: 0.84; 95% CI: 0.76 to 0.93; p < 0.009). Subgroup analyses suggested that CRT was associated with a reduced risk of HF hospitalization and death across CKD classes. The incidence of in-hospital, short-term, and mid-term device-related complications did not vary across CKD stages.Conclusions: In a nationally representative population of HF and CRT-eligible patients, use of CRT-D was associated with a significantly lower risk of the composite endpoint of HF hospitalization or death among patients with moderate-to-severe CKD in the setting of acceptable complication rates. [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]

Despite improvement in morbidity and mortality with cardiac resynchronization therapy (CRT), disease progression continues to affect a subset of patients and there is limited effort to identify contributing factors. Our objective was to investigate if a protocol-driven approach incorporated in a management strategy of heart failure immediately after implantation would provide incremental benefits beyond usual care after implantation. We reviewed 114 consecutive patients with CRT implanted from 2005 through 2009 who received usual care after implantation or underwent protocol-driven CRT care after implantation. Preimplantation characteristics in patients receiving usual versus protocol-driven care were similar in left ventricular (LV) dimension (LV internal diastolic diameter 6.2 ± 0.8 vs 6.4 ± 1.0 cm), LV ejection fraction (26 ± 8% vs 25% ± 8%), QRS width, and medication usage. Major adjustments during the protocol-driven approach were uptitration of neurohormonal blockers (64%), echocardiographically guided atrioventricular optimization (50%), heart failure education (42%), arrhythmia management (19%), and LV lead repositioning (7%). Although positive LV remodeling was noted in the 2 groups at 6 months, extent was significantly greater in the protocol-driven approach compared to usual care (change in LV internal diastolic diameter 0.7 ± 0.6 cm vs 0.2 ± 1.2 cm, p = 0.01; change in LV ejection fraction 11 ± 7% vs 7 ± 9%, p = 0.01), which was associated with fewer major adverse events (14% vs 53%, p <0.001). In conclusion, a protocol-driven approach for patients with CRT started immediately after implantation is associated with incremental favorable effects on reverse remodeling and fewer adverse events compared to usual care after implantation. These effects appeared to be driven not only by changes in device settings and arrhythmia management but also by concomitant medication optimization and heart failure education. [Copyright &y& Elsevier]

Background: Choline is a dietary precursor to the gut microbial generation of the prothrombotic and proatherogenic metabolite trimethylamine-N-oxide (TMAO). Eggs are rich in choline, yet the impact of habitual egg consumption on TMAO levels and platelet function in human subjects remains unclear.Methods: Healthy volunteers (41% male, 81% Caucasian, median age 28 years) with normal renal function (estimated glomerular filtration rate >60) were recruited and assigned to 1 of 5 daily interventions for 4 weeks: 1) hardboiled eggs (n = 18); 2) choline bitartrate supplements (n = 20); 3) hardboiled eggs + choline bitartrate supplements (n = 16); 4) egg whites + choline bitartrate supplements (n = 18); 5) phosphatidylcholine supplements (n = 10). Fasting blood and urine samples were collected for quantification of TMAO, its precursors, and platelet aggregometry.Results: Participants' plasma TMAO levels increased significantly in all 3 intervention arms containing choline bitartrate (all P < .0001), but daily ingestion of 4 large eggs (P = .28) or phosphatidylcholine supplements (P = .27) failed to increase plasma TMAO levels. Platelet reactivity also significantly increased in the 3 intervention arms containing choline bitartrate (all P < .01), but not with eggs (P = .10) or phosphatidylcholine supplements (P = .79).Conclusions: Despite high choline content in egg yolks, healthy participants consuming 4 eggs daily showed no significant increase in TMAO or platelet reactivity. However, choline bitartrate supplements providing comparable total choline raised both TMAO and platelet reactivity, demonstrating that the form and source of dietary choline differentially contributes to systemic TMAO levels and platelet responsiveness. [ABSTRACT FROM AUTHOR]