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Aims: Patients with sleep apnoea (SA) and heart failure (HF) are less sleepy than SA patients without HF. HF and SA both increase sympathetic nervous system activity (SNA). SNA can augment alertness. We previously showed that in HF patients, the degree of daytime sleepiness was not related to the severity of SA but was inversely related to SNA. Elevated SNA is associated with increased mortality in HF. Therefore, we hypothesized that in HF patients with SA, the degree of daytime sleepiness will be inversely related to mortality., Methods and Results: In a prospective cohort study, 218 consecutive patients with systolic HF had overnight polysomnography. Among them, 80 subjects with SA (apnoea-hypopnoea index ≥15) were followed for a mean of 28 months to determine all-cause mortality rate. Subjective daytime sleepiness was assessed by the Epworth Sleepiness Scale (ESS). During follow-up, 20 patients died. The 5 year death rate in patients with ESS less than 6 (i.e. less sleepy) was significantly higher than in patients with an ESS at or above the median of 6 (i.e. sleepier) [21.3 deaths/100 patient-years vs. 6.2 deaths/100 patient-years, unadjusted hazard ratio (HR) 2.94, 95% confidence interval (CI) 1.20 to 7.20, P = 0.018]. After adjusting for confounding factors that included sex, history of hypertension, and mean arterial oxyhaemoglobin saturation, compared with the sleepier patients, less sleepy patients had greater risk of mortality (HR 2.56, 95% CI 1.01 to 6.47, P = 0.047). As a continuous variable, ESS scores were inversely related to mortality risk (HR 0.86, 95% CI 0.75 to 0.98, P = 0.022)., Conclusions: In patients with HF and SA, the degree of subjective daytime sleepiness is inversely related to the mortality risk, suggesting that among HF patients with SA, those with the least daytime sleepiness are at greater risk of death. They may therefore have greater potential for mortality benefit from therapy of SA than those with greater daytime sleepiness., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background and Aims: Potassium-wasting (loop diuretics [LD]) and potassium-sparing (spironolactone) medications used for heart failure (HF) may alter renal potassium handling and confound the use of twenty-four-hour (24-h) urine collections as a surrogate marker for potassium intake, an effect that has been observed with dietary sodium assessment. The objective was to determine the strength of association between 24-h urine collections and weighed food records in assessing potassium intake in HF patients stratified by LD usage and spironolactone usage., Methods and Results: Stable outpatients with HF simultaneously completed two 24-h urine collections and two weighed food records on consecutive days. Analyses compared patients stratified by LD and/or spironolactone use. Pearson's correlation and the Bland-Altman method of agreement assessed the relationship between the techniques. Overall, 109 patients (61 ± 11 yrs, 74% male) were included. The mean difference in dietary potassium estimated between 24-h urine collections and food records was -353 ± 1043 mg (p < 0.01) for all patients, with no differences between measures among subgroups. The association between the two methods was r = 0.551 (95% CI, 0.373 to 0.852, p < 0.001) for LD users; r = 0.287 (95% CI, 0.01 to 0.570, p = 0.050) for LD non-users; r = 0.321 (95% CI, 0.13 to 0.798, p = 0.043) for spironolactone users, and; r = 0.534 (95% CI, 0.331 to 0.747, p < 0.001) for spironolactone non-users. There were no significant mean biases identified as part of the Bland-Altman analysis., Conclusion: Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake., Competing Interests: Declaration of Competing Interest All the authors confirmed that they have no conflicts of interest., (Copyright © 2020 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Sodium restriction is the primary dietary therapy for heart failure (HF) patients. Currently, it is unknown if changing diets to reduce dietary sodium in HF causes secondary changes to the intake of other nutrients in this patient population already at nutritional risk., Methods and Results: HF patients (n = 16; 52 ± 12 years old; 78% male) followed a sodium-restricted diet for 1 week. Nutritional changes were documented at baseline and after a <2,000 mg/d sodium-restricted diet, as measured by food records before baseline and each day during the study. After a 49% reduction in dietary sodium (3,626 ± 956 to 1,785 ± 696 mg/d), we observed a significant reduction in calorie (2,467 ± 748 to 1,931 ± 388 kcal/d; P < .016), carbohydrate (293 ± 108 to 232 ± 56 g/d; P = .013), calcium (995 ± 496 to 609 ± 208 mg/d; P < .004), thiamine (2.0 ± 0.8 to 1.5 ± 0.8 mg/d; P = .020), and folate (412 ± 192 to 331 ± 172 μg/d; P = .019) intakes. There was a decrease in saturated fat (32 ± 18 to 21 ± 6 g/d; P = .032) and a trend to lower total fat (89 ± 34 to 68 ± 19 g/d; P = .066) and higher potassium (1,262 ± 328 to 1,405 ± 268 mg/1,000 kcal; P = .055) intakes., Conclusions: We found multiple unintentional nutritional consequences with dietary sodium reduction in HF patients. These findings highlight the need to consider the whole diet when counseling HF patients to lower sodium intake., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: We previously showed in heart failure (HF) patients that obstructive respiratory events during sleep and generation of negative intrathoracic pressure during Mueller manoeuvres, mimicking obstructive apneas, acutely reduced stroke volume (SV). We also showed that treating obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) increased left ventricular ejection fraction over a 1-month period. We therefore hypothesized that, in HF patients, those with OSA would have greater overnight declines in SV and cardiac output (CO) than in those without sleep apnea, and that therapy of OSA using CPAP would prevent these declines., Methods: We examined overnight percent change in SV and CO in 32 HF patients with and 28 without OSA using digital photoplethysmography. Among patients with OSA, we also examined changes in SV and CO during a CPAP titration study., Results: During the baseline polysomnogram SV and CO decreased more overnight in those with OSA than in those without sleep apnea (-12.6 ± 7.7% vs -3.2 ± 6.8%; P < 0.001 and -16.2 ± 9.9% vs -3.7 ± 8.3%; P < 0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index (r = -0.551; P < 0.001 and r = -0.522; P < 0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 ± 21.4 to 15.0 ± 16.0 (P < 0.001) in association with attenuation of the overnight reduction of SV (from -14.0 ± 7.9% to -3.4 ± 9.8%; P = 0.002) and CO (from -17.2 ± 9.0% to -9.7 ± 10.7%; P = 0.042)., Conclusions: In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP., (Copyright © 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.)

Purpose: The prognostic implications of blood glucose on a wide range of outcomes including early mortality, hospitalizations, and incident diabetes diagnoses have not been fully elucidated in acute heart failure syndromes (AHFS)., Methods: In a population-based cohort of 16 524 AHFS patients presenting to the emergency department (ED) in Ontario, Canada between 2004 and 2007, we performed a competing risk analysis for 30-day mortality, new diabetes diagnoses, and hospitalization outcomes. Presentation blood glucose concentrations were categorized as follows: 3.9-6.1 [referent], >6.1-7.8, >7.8-9.4, >9.4-11.1, and >11.1 mmol/L., Results: Among AHFS patients without diabetes presenting to the ED (n = 9275), blood glucose >6.1 mmol/L (n = 5252, 56.6%) was associated with increased risks of all-cause death [hazard ratio (HR) range: 1.26 (95% CI 1.05-1.50) to 1.50 (95% CI 1.11-2.02)], and cardiovascular death [HR range: 1.28 (95% CI 1.03-1.59) to 1.64 (95% CI 1.16-2.33)]. Among AHFS patients with diabetes (n = 7249), presenting blood glucose >11.1 mmol/L (n = 2286, 31.5%) was associated with increased risks of all-cause death (HR 1.48, 95% CI 1.10-2.00) and diabetes-related hospitalizations (HR 1.39, 95% CI; 1.20-1.61). Presentation blood glucose >9.4 mmol/L was associated with increased risks of hospitalization for HF or cardiovascular causes [HR range: 1.09 (95% CI 1.02-1.17) to 1.15 (95% CI 1.07-1.24)] in all patients. With higher presentation blood glucose, the risk of incident diabetes diagnosis increased, with adjusted HRs of 1.61 (>6.1-7.8 mmol/L) to 3.61 (>11.1 mmol/L) among those without the condition at baseline (all P < 0.001)., Conclusions: Mildly elevated presentation blood glucose was associated with early death, future diabetes, and hospitalizations for diabetes, HF, and cardiovascular causes among patients with AHFS., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Heart failure (HF) is associated with a high burden of morbidity and mortality. Hospital discharge is an opportunity for identification of modifiable prognostic factors in the transition to chronic HF., Methods and Results: We examined the association of discharge heart rate with 30-day and 1-year mortality and hospitalization outcomes in a cohort of 9097 patients with HF discharged from hospital. Discharge heart rate was categorized into predefined groups: 40 to 60 (n=1333), 61 to 70 (n=2170), 71 to 80 (n=2631), 81 to 90 (n=1700), and >90 bpm (n=1263). There was a significant increase in all-cause 30-day mortality with adjusted odds ratios of 1.59 (95% confidence interval [CI], 1.18-2.14; P=0.003) for discharge heart rates 81 to 90 bpm and 1.56 (95% CI, 1.13-2.16; P=0.007) for heart rates>90 bpm when compared with the reference group (heart rates, 61-70 bpm). Cardiovascular death risk at 30 days was also higher with adjusted odds ratio 1.59 (discharge heart rates, 81-90 bpm; 95% CI, 1.09-2.33; P=0.017) and 1.65 (discharge heart rates, >90 bpm; 95% CI, 1.09-2.48; P=0.017). One-year all-cause mortality (adjusted odds ratio, 1.41; 95% CI, 1.16-1.72; P<0.001) and cardiovascular death (adjusted odds ratio, 1.47; 95% CI, 1.12-1.92; P=0.005) were higher with discharge heart rates>90 bpm when compared with the reference group (heart rates, 40-60 bpm). Readmissions for HF (adjusted hazard ratio, 1.26; 95% CI, 1.04-1.54; P=0.021) and cardiovascular disease (adjusted hazard ratio, 1.29; 95% CI, 1.08-1.54; P=0.004) within 30 days were also higher with discharge heart rates>90 bpm., Conclusions: Higher discharge heart rates were associated with greater risk of all-cause and cardiovascular mortality≤1-year follow-up and an elevated risk of 30-day readmission for HF and cardiovascular disease.

Background: In men with heart failure, nocturnal rostral fluid shift is associated with an overnight increase in the neck circumference (NC) and with severity of obstructive sleep apnea. Because the prevalence of obstructive sleep apnea is lower in women than in men with heart failure, we hypothesized that less fluid would shift into the neck in association with less severe obstructive sleep apnea in women than in men with heart failure., Methods and Results: In 35 men and 30 women with heart failure, we assessed overnight changes in NC (ΔNC) and leg fluid volume before and after polysomnography. The severity of obstructive sleep apnea was assessed by the apnea-hypopnea index. Although the changes in leg fluid volume did not differ significantly between men and women (-131 ± 90 versus -180 ± 132 mL, P=0.081), in women, ΔNC was smaller (P<0.001) than in men. Furthermore, although in men, changes in leg fluid volume correlated inversely with ΔNC (r=-0.755, P<0.001) and apnea-hypopnea index (r=-0.765, P<0.001), it did not in women., Conclusions: Despite no difference in overnight displacement of fluid from the legs compared with in men, in women, less of this fluid reached the neck, and unlike men, there was no relationship between changes in leg fluid volume and either ΔNC or apnea-hypopnea index. These findings suggest a differing relationship between overnight fluid shift from the legs and severity of obstructive sleep apnea in women than in men with heart failure.

Background: Heart failure contributes to millions of emergency department (ED) visits, but hospitalization-versus-discharge decisions are often not accompanied by prognostic risk quantification., Objective: To derive and validate a model for acute heart failure mortality applicable in the ED., Design: Clinical data abstraction with development of a broadly applicable multivariate risk index for 7-day death using initial vital signs, clinical and presentation features, and readily available laboratory tests., Setting: Multicenter study of 86 hospitals in Ontario, Canada., Patients: Population-based random sample of 12 591 patients presenting to the ED from 2004 to 2007., Measurements: Death within 7 days of presentation., Results: In the derivation cohort (n = 7433; mean age, 75.4 years [SD, 11.4]; 51.5% men), mortality risk increased with higher triage heart rate (adjusted odds ratio [OR], 1.15 [95% CI, 1.03 to 1.30] per 10 beats/min) and creatinine concentration (OR, 1.35 [CI, 1.14 to 1.60] per 1 mg/dL [88.4 µmol/L]), and lower triage systolic blood pressure (OR, 1.52 [CI, 1.31 to 1.77] per 20 mm Hg) and initial oxygen saturation (OR, 1.16 [CI, 1.01 to 1.33] per 5%). Nonnormal serum troponin levels (OR, 2.75 [CI, 1.86 to 4.07]) were associated with increased mortality risk. Areas under the receiver-operating characteristic curves of the multivariate model were 0.805 for the derivation data set (bootstrap-corrected, 0.811) and 0.826 for validation data set (n = 5158; mean age, 75.7 years [SD, 11.4]; 51.6% men). In the derivation cohort, a multivariate index score stratified 7-day mortality with rates of 0.3%, 0.3%, 0.7%, and 1.9% in quintiles 1 to 4, respectively. Mortality rates in the 2 highest risk groups were 3.5% and 8.2% in deciles 9 and 10, respectively., Limitation: Left ventricular ejection fraction was not included in the model., Conclusion: A multivariate index comprising routinely collected variables stratified mortality risk with high discrimination in a broad group of patients with acute heart failure presenting to the ED., Primary Funding Source: Canadian Institutes of Health Research.

Objectives: The purpose of this study was to test the hypothesis that severity of sleep apnea (SA), assessed by frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]), is related to sodium intake in patients with heart failure (HF)., Background: Dependent edema and overnight rostral fluid shift from the legs correlate with the AHI in patients with HF in whom excessive sodium intake can cause fluid retention., Methods: Sodium intake was estimated by food recordings in 54 HF patients who underwent overnight polysomnography., Results: Thirty-one of the 54 patients had SA, and their mean sodium intake was higher than that in those without SA (3.0 ± 1.2 g vs. 1.9 ± 0.8 g, p < 0.001). There was a significant correlation between the AHI and sodium intake (r = 0.522, p < 0.001). Multivariate analysis showed that the significant independent correlates of the AHI were sodium intake, male sex, and serum creatinine level., Conclusions: These findings suggest that in patients with HF, sodium intake plays a role in the pathogenesis of SA., (Copyright © 2011 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Twenty-four-hour urine collections are considered the optimal method for sodium intake assessment. Whether a diagnosis of heart failure (HF) or the use of loop diuretic (LD) therapy for HF compromises the validity of 24-h urine collections as a surrogate marker for sodium intake is unknown., Objective: The objective was to determine the strength of association between 24-h urine collections and food records for sodium intake assessment in non-HF cardiac patients and in HF patients stratified by LD usage., Design: Food records and 24-h urine collections were simultaneously completed for 2 consecutive days. Correlation coefficients and the Bland-Altman method of agreement described the relation between the techniques., Results: Non-HF cardiac patients (n = 96; mean ± SD age: 65 ± 11 y), HF patients who were not taking an LD (n = 47; 62 ± 11 y), and HF patients who were taking an LD (n = 62; age: 60 ± 12 y) were included. Correlation coefficients for sodium intake between food records and urine collections were r = 0.624 (P < 0.001) for non-HF cardiac patients and r = 0.678 (P < 0.001) for HF patients who were not taking an LD. However, no significant association (r = 0.132, P = 0.312) was observed for HF patients who were taking LDs. The 95% limits of agreement between the non-HF cardiac patients and the HF patients who were not taking LDs were similar but were ≈50% wider for HF patients who were taking LDs., Conclusions: For the assessment of sodium intake, food records agree well with 24-h urine collections in non-HF patients with cardiovascular disease and in HF patients who are not receiving LD but not for HF patients who are taking LDs. Therefore, food records may provide a better estimate of sodium intake in HF patients who are receiving LD therapy.

Background: Clinical outcomes for cardiovascular syndromes such as heart failure differ between men and women., Objective: To seek phenotypic evidence for sex-differences in cardiac-specific sympathetic nervous system activation, as abnormal sympathetic nervous system activation is a key pathophysiological mechanism in heart failure (HF)., Methods: Patients who underwent evaluation of cardiac norepinephrine spillover (CNESP) using radiotracer methodology were identified retrospectively, and included in the analysis if they met criteria for either a normal left ventricular (NLV) function group, or systolic HF group, defined as an LV ejection fraction <40% and NYHA class II-III symptoms. Within each group a matched cohort analysis, identifying two control men for each woman, was performed., Results: 166 subjects were identified, 48 within the NLV function group and 118 within the HF group. In the NLV function group, 12 women were matched for age to 24 men. Women had significantly higher NE concentrations in coronary sinus plasma. When normalised to total body NE spillover (CNESP:TBNESP), women had significantly higher values than men (CNESP:TBNESP, 6±3% in women vs 3±3% in men, p<0.05). In the HF group, 20 women were matched for age, date of study and presence of coronary disease to 39 men. There were no differences in comorbidities, drugs or haemodynamic measurements. Both CNESP and CNESP:TBNESP were significantly higher in women with HF than in men (CNESP 264±191 in women vs 182±110 in men, CNESP:TBNESP 9±6% in women vs 4±2% in men, p<0.05 for both)., Conclusion: In patients with and without HF, women exhibit increased cardiac-specific sympathetic activation. Sexual dimorphism in cardiac autonomic physiology and its relationship to disease merits further investigation.

Background: A low-sodium diet is an accepted treatment of patients with heart failure (HF), although minimal evidence exists on the appropriate amount of sodium intake for this population. Certain HF guidelines have liberalized dietary sodium recommendations, which actually exceed guidelines for healthy adults., Objectives: We tested the hypothesis that high sodium intake is related to acute decompensated HF (ADHF) in ambulatory HF patients. Secondary outcomes included all-cause hospitalization and mortality., Design: We prospectively enrolled medically stable, ambulatory patients with systolic HF (n = 123; mean ± SD age: 60 ± 13 y) from 2 outpatient HF clinics from 2003 to 2007. Baseline estimates of dietary sodium and other nutrient intakes were obtained from two 3-d food records., Results: The median follow-up time was 3.0 y. Mean (±SD) sodium intakes were 1.4 ± 0.3, 2.4 ± 0.3, and 3.8 ± 0.8 g Na/d in the lower, middle, and upper tertiles, respectively. Cumulative ADHF event rates at 3 y were 12 ± 6%, 15 ± 7%, and 46 ± 11% in the low, middle, and upper tertiles, respectively (log-rank P = 0.001). For ADHF, the upper tertile was associated with an adjusted hazard ratio of 2.55 (95% CI: 1.61, 4.04; P < 0.001). Time-to-event probabilities were significant for mortality (log-rank P = 0.022) but not for all-cause hospitalization (log-rank P = 0.224). The high-sodium tertile was associated with an adjusted hazard ratio of 1.39 (95% CI: 1.06, 1.83; P = 0.018) for all-cause hospitalization and 3.54 (95% CI: 1.46, 8.62; P = 0.005) for mortality., Conclusions: To our knowledge, this study provides the first prospective evidence that ambulatory HF patients who consume higher amounts of sodium are at greater risk of an ADHF event. These data provide support for more stringent sodium intake guidelines than those currently recommended for HF patients.

Background: Muscle sympathetic nerve firing rate increases as chronic heart failure (CHF) progresses, yet its oscillation, particularly within the frequency range encompassing 0.13 Hz, diminishes. The current study tested the hypothesis that chronic therapy with lipophilic β-adrenoceptor antagonists augments the modulation of muscle sympathetic nerve activity variability (MSNAV) at this frequency range., Methods and Results: In 21 CHF angiotensin converting enzyme (ACE) inhibitor-treated patients (age: 53 ± 2, ejection fraction: 20 ± 2%), MSNA was recorded before and after 4 months of β-blockade with either metoprolol (up to 50mg b.i.d.) or carvedilol (up to 25mg b.i.d.). Harmonic MSNAV was assessed by coarse graining spectral analysis. Both drugs lowered heart rate similarly (-13 ± 2 beats/min; P < 0.001) but neither affected MSNA burst frequency (-7 ± 4 bursts/min, not significant). Before β-blockade, harmonic MSNA power in the region encompassing 0.13 Hz was essentially absent. Beta-blockade increased the mean values for total power (from 0.00 to 0.50 Hz; 5.2 ± 0.8 to 6.8 ± 1.2U(2); P < 0.001) and for harmonic MSNA spectral power across the 0.1-0.22 Hz frequency range (from 0.48 ± 0.10 to 1.50 ± 0.32 U(2), F = 12.2; P < 0.001). Both carvedilol and metoprolol had a similar effect., Conclusions: In patients with CHF receiving ACE inhibitors, adding a β-adrenoceptor antagonist restores low and high frequency harmonic oscillations in MSNA. Beta-1 antagonism is sufficient to achieve this response. Augmented modulation of sympathetic outflow could contribute to the beneficial effects of β-blockade in CHF on sudden death and disease progression.

Objectives: Generic triage risk assessments are widely used in the emergency department (ED), but have not been validated for prediction of short-term risk among patients with acute heart failure (HF). Our objective was to evaluate the Canadian Triage Acuity Scale (CTAS) for prediction of early death among HF patients., Methods: We included patients presenting with HF to an ED in Ontario from Apr 2003 to Mar 2007. We used the National Ambulatory Care Reporting System and vital statistics databases to examine care and outcomes., Results: Among 68,380 patients (76±12 years, 49.4% men), early mortality was stratified with death rates of 9.9%, 1.9%, 0.9%, and 0.5% at 1-day, and 17.2%, 5.9%, 3.8%, and 2.5% at 7-days, for CTAS 1, 2, 3, and 4-5, respectively. Compared to lower acuity (CTAS 4-5) patients, adjusted odds ratios (aOR) for 1-day death were 1.32 (95%CI; 0.93-1.88; p = 0.12) for CTAS 3, 2.41 (95%CI; 1.71-3.40; p<0.001) for CTAS 2, and highest for CTAS 1: 9.06 (95%CI; 6.28-13.06; p<0.001). Predictors of triage-critical (CTAS 1) status included oxygen saturation <90% (aOR 5.92, 95%CI; 3.09-11.81; p<0.001), respiratory rate >24 breaths/minute (aOR 1.96, 95%CI; 1.05-3.67; p = 0.034), and arrival by paramedic (aOR 3.52, 95%CI; 1.70-8.02; p = 0.001). While age/sex-adjusted CTAS score provided good discrimination for ED (c-statistic = 0.817) and 1-day (c-statistic = 0.724) death, mortality prediction was improved further after accounting for cardiac and non-cardiac co-morbidities (c-statistics 0.882 and 0.810, respectively; both p<0.001)., Conclusions: A semi-quantitative triage acuity scale assigned at ED presentation and based largely on respiratory factors predicted emergent death among HF patients.

Background: The array of outcomes according to longitudinal furosemide doses in heart failure (HF) have not been evaluated. We examined the relationship of dynamic furosemide dose with mortality and hospitalizations for cardiovascular disease and renal dysfunction., Methods: Among elderly patients with HF (>or=65 years) newly discharged from hospital, dynamic furosemide exposure was determined by examining dose fluctuations up to 5 years of follow-up using the Ontario Drug Benefit pharmacare database. Dynamic furosemide exposures were classified as low dose (LD; 1-59 mg/d), medium dose (MD; 60-119 mg/d), or high dose (HD; >or=120 mg/d). Outcomes were assessed by modeling furosemide exposure as a time-dependent covariate., Results: Among 4,406 patients (78.4 +/- 7.0 years; 50.5% male), 46% changed furosemide dose categories within 1 year, and 63% changed dose categories over the follow-up period. High-dose furosemide patients were younger, were mostly male, and exhibited more ischemic or valvular disease, diabetes, atrial fibrillation, hypotension, hyponatremia, and higher baseline creatinine than LD. Compared with LD, MD exposure was associated with increased mortality with adjusted hazard ratio 1.96 (95% CI 1.79-2.15), whereas HD exposure conferred greater mortality risk with hazard ratio 3.00 (95% CI 2.72-3.31) after multiple covariate adjustment (both P < .001). Adjusted risks of hospitalization for HF (MD: 1.24 [95% CI 1.12-1.38] and HD: 1.43 [95% CI 1.26-1.63]), renal dysfunction (MD: 1.56 [95% CI 1.38-1.76] and HD: 2.16 [95% CI 1.88-2.49]), and arrhythmias (MD: 1.15 [95% CI 1.03-1.30] and HD: 1.45 [95% CI 1.27-1.66]) were also higher with increasing furosemide exposure., Conclusion: Exposure to higher furosemide doses is associated with worsened outcomes and is broadly predictive of death and morbidity., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: Obstructive sleep apnea (OSA) and central sleep apnea are common in patients with heart failure. We hypothesized that in such patients, severity of OSA is related to overnight rostral leg fluid displacement and increase in neck circumference, severity of central sleep apnea is related to overnight rostral fluid displacement and to sleep Pco(2), and continuous positive airway pressure alleviates OSA in association with prevention of fluid accumulation in the neck., Methods and Results: In 57 patients with heart failure (ejection fraction or=50% of apneas and hypopneas obstructive) and a central-dominant group (>50% of events central). Patients with OSA received continuous positive airway pressure. In obstructive-dominant patients, there were inverse relationships between overnight change in leg fluid volume and both the overnight change in neck circumference (r=-0.780, P<0.001) and the apnea-hypopnea index (r=-0.881, P<0.001) but not transcutaneous Pco(2). In central-dominant patients, the overnight reduction in leg fluid volume correlated inversely with the apnea-hypopnea index (r=-0.919, P<0.001) and the overnight change in neck circumference (r=-0.568, P=0.013) and directly with transcutaneous Pco(2) (r=0.569, P=0.009). Continuous positive airway pressure alleviated OSA in association with prevention of the overnight increase in neck circumference (P<0.001)., Conclusions: Our findings suggest that nocturnal rostral fluid shift is a unifying concept contributing to the pathogenesis of both OSA and central sleep apnea in patients with heart failure.

Sodium restriction is the primary nutritional strategy in heart failure; however, other diet-related concerns may also occur. We characterized dietary intake among stable patients with heart failure and a non-heart-failure cardiac control group to quantify and determine prevalence of inadequate micronutrient intake. Two 3-day food records were completed by 123 patients with heart failure and 58 controls. A subset of each group provided two 24-hour urine collections. Mean intake of sodium (2,540+/-1,122 vs 2,596+/-1,184 mg/day) and potassium (3,190+/-980 vs 3,114+/-828 mg/day) was similar between the heart failure and control groups. Prevalence of inadequate potassium intake was 94% among patients with heart failure and 91% among controls. More than 50% in each group had inadequate intakes of calcium, magnesium, folate, and vitamins D and E. In stable patients with heart failure, sodium intake was not excessive. However, we demonstrated widespread dietary inadequacies of other vitamins and minerals. These findings highlight the importance of diet beyond that of sodium restriction.

Background: Higher blood pressure in acute heart failure has been associated with improved survival; however, the relationship between blood pressure and survival in stabilized patients at hospital discharge has not been established., Methods and Results: In 7448 patients with heart failure (75.2+/-11.5 years; 49.9% men) discharged from the hospital in Ontario, Canada, we examined the association of systolic blood pressure (SBP) and diastolic blood pressure with long-term survival. Parametric survival analysis was performed, and survival time ratios were determined according to discharge blood pressure group. A total of 25 427 person-years of follow-up were examined. In those with left ventricular ejection fraction < or =40%, median survival was decreased by 17% (survival time ratio, 0.83; 95% CI, 0.71 to 0.98; P=0.029) when discharge SBP was 100 to 119 mm Hg and decreased by 23% (survival time ratio, 0.77; 95% CI, 0.62 to 0.97; P=0.024) when discharge SBP was <100 mm Hg, compared with those in the reference range of 120 to 139 mm Hg. Survival time ratios were 0.75 (95% CI, 0.60 to 0.92; P=0.007) and 0.75 (95% CI, 0.53 to 1.07; P=0.12) when discharge SBPs were 140 to 159 and > or =160 mm Hg, respectively. In those with left ventricular ejection fraction >40%, survival time ratios were 0.69 (95% CI, 0.51 to 0.93), 0.83 (95% CI, 0.71 to 0.99), 0.95 (95% CI, 0.80 to 1.14), and 0.76 (95% CI, 0.61 to 0.95) for discharge SBPs <100, 100 to 119, 140 to 159, and > or =160 mm Hg, respectively., Conclusions: In this long-term population-based study of patients with heart failure, the association of discharge SBP with mortality followed a U-shaped distribution. Survival was shortened in those with reduced or increased values of discharge SBP.

Background: Previous studies reported high prevalences of obstructive and central sleep apnea (OSA and CSA, respectively) in patients with heart failure (HF). However, these preceded widespread use of beta-blockers and spironolactone that might have reduced their prevalences. We therefore determined, in patients with HF, prevalences and predictors of OSA and CSA and the influence of changes in HF therapy on prevalences., Methods and Results: A total of 218 HF patients with left ventricular ejection fraction (LVEF) or=15 hours of sleep, either OSA or CSA), or mild to no sleep apnea. The prevalence of moderate to severe OSA was 26% and of CSA was 21%. Predictors of OSA were older age, male sex, and greater body mass index, and of CSA were older age, male sex, atrial fibrillation, hypocapnia, and diuretic use. Between 1997 and 2004, the prevalences of OSA and CSA did not change significantly (P(trend) =.460, P(trend) =.211, respectively) despite increased use of beta-blockers and spironolactone (P(trend) < .001, P(trend) < .001, respectively), and an increase in LVEF (P(trend)=.005)., Conclusions: OSA and CSA remain common in patients with HF, despite increases in beta-blocker and spironolactone use.

Background: Women with systolic heart failure (HF) demonstrate better survival than men. Whether sex differences occur in hemodynamics or measures of left ventricular (LV) function is not well understood., Methods: We retrospectively analyzed a cohort who underwent evaluation by right heart catheterization +/- micromanometer-tipped catheterization of the LV. Two groups, defined at the time of catheterization, were studied: normal LV (NLV) function or HF (LV ejection fraction <35%, New York Heart Association II-III symptoms). For each female, we identified 2 male controls matched for age and LV ejection fraction in the HF group., Results: In the NLV group, we matched 73 men (56 +/- 10 years) to 39 women (56 +/- 10 years). In the HF group, we matched 71 men (57 +/- 10 years) to 36 women (57 +/- 10 years). In the NLV group, women had higher heart rate and lower right atrial pressure, mean pulmonary artery pressure, and pulmonary capillary wedge pressure. Left ventricular peak systolic pressure was higher, and LV end-diastolic pressure was lower in women. In the HF group, no sex differences were observed in any hemodynamic measurement. In both groups, no sex differences were observed in isovolumic contractility or relaxation., Conclusions: Sex differences in hemodynamics are observed in patients with NLV function but not with HF. The intrinsic or extrinsic factors responsible for sex differences observed in patients with NLV function may be eclipsed by the HF disease state or its treatment.

Objectives: This study sought to determine, in patients with heart failure (HF), whether untreated moderate to severe obstructive sleep apnea (OSA) is associated with a higher mortality rate than in patients with mild to no sleep apnea (M-NSA)., Background: Obstructive sleep apnea is common in patients with HF and exposes the heart and circulation to adverse mechanical and autonomic effects. However, its effect on mortality rates of patients with HF has not been reported., Methods: In a prospective study involving 164 HF patients with left ventricular ejection fractions (LVEFs) < or =45%, we performed polysomnography and compared death rates between those with M-NSA (apnea-hypopnea index [AHI] <15/h of sleep) and those with untreated OSA (AHI > or =15/h of sleep)., Results: During a mean (+/- SD) of 2.9 +/- 2.2 and a maximum of 7.3 years of follow-up, the death rate was significantly greater in the 37 untreated OSA patients than in the 113 M-NSA patients after controlling for confounding factors (8.7 vs. 4.2 deaths per 100 patient-years, p = 0.029). Although there were no deaths among the 14 patients whose OSA was treated by continuous positive airway pressure (CPAP), the mortality rate was not significantly different from the untreated OSA patients (p = 0.070)., Conclusions: In patients with HF, untreated OSA is associated with an increased risk of death independently of confounding factors.

Background: Adverse effects of obstructive sleep apnea (OSA), including sleep deprivation, can contribute to the progression of heart failure. The usual indication to diagnose and treat sleep apnea is subjective sleepiness. Previous studies suggest that patients with both heart failure and obstructive sleep apnea often do not complain of sleepiness, albeit their sleep time may be reduced. Therefore, we tested the hypothesis that patients with heart failure have less sleepiness and sleep less compared with subjects without heart failure for a given severity of OSA., Methods: Sleepiness assessed with the Epworth Sleepiness Scale and sleep structure measured with polysomnography were compared among 155 consecutive patients with heart failure and from a random community sample (n = 1139) according to categories of the apnea-hypopnea index (<5, no OSA; 5-14, mild OSA; and > or =15, moderate to severe OSA)., Results: Compared with the community sample, for any given severity of OSA, patients with heart failure had lower mean +/- SE Epworth Sleepiness Scale scores (7.1 +/- 0.4 vs 8.3 +/- 0.2 [P = .005]; 6.7 +/- 0.7 vs 9.2 +/- 0.3 [P < .001]; and 7.8 +/- 0.7 vs 9.8 +/- 0.4 [P = .01]), indicating less sleepiness despite sleeping less (total sleep time mean +/- SE [in minutes]: 306 +/- 7 vs 384 +/- 2, 295 +/- 19 vs 384 +/- 5, and 285 +/- 13 vs 359 +/- 7 for no, mild, and moderate to severe OSA, respectively; P < .001 for all comparisons)., Conclusions: Patients with heart failure have less subjective daytime sleepiness compared with individuals from a community sample, despite significantly reduced sleep time, whether or not they have OSA. In patients with heart failure, the absence of subjective sleepiness is not a reliable means of ruling out OSA.

The positive effect of vitamin C on left ventricular (LV) inotropic responses to dobutamine, observed in patients with preserved LV function, is lost in heart failure (HF). We tested the hypothesis that in HF, endogenous nitric oxide (NO) opposes the positive effect of vitamin C on adrenergically stimulated contractility by examining the effects of vitamin C on dobutamine responses during NO synthase inhibition. In 11 HF patients, a micromanometer-tipped catheter was inserted into the LV and an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary N(G)-monomethyl-L-arginine (l-NMMA) was infused before reinfusion of dobutamine (L-NMMA + Dob-2). Finally, intracoronary vitamin C was infused in addition to intracoronary L-NMMA and dobutamine (L-NMMA + Dob-2 + vitamin C). Intracoronary L-NMMA alone had no effect on LV +dP/dt. After a stable inotropic response to intracoronary L-NMMA and dobutamine was established, the addition of intracoronary vitamin C resulted in a modest but significant increase in LV +dP/dt. The change in LV +dP/dt in response to dobutamine alone was 25 +/- 5%, with intracoronary L-NMMA, 27 +/- 6%, and with intracoronary L-NMMA plus vitamin C, 37 +/- 5% (P < 0.05 vs. Dob-1 and L-NMMA + Dob-2). These findings demonstrate that an interaction between endogenous NO and redox environment exists and exerts some influence on stimulated contractility in HF.

Background: Multidisciplinary heart failure (HF) programs reduce hospital readmission and improve clinical outcomes. Although dietitians are often members of such teams, no randomized studies have demonstrated the independent benefit of dietitian-administered dietary counseling for patients with HF. The purpose of this study was to evaluate the effect of dietitian education on adherence to a sodium-restricted diet in ambulatory patients with stable HF., Methods: Patients with HF (left ventricular ejection fraction < 35%) were randomized into a dietitian education group (n = 23) or a usual care group (n = 24), then observed for 3 months. Both groups received a 2 g/d dietary sodium prescription. The usual care group received nutrition advice by way of self-help literature, whereas the dietitian education group returned for 2 counseling sessions with a dietitian., Results: Dietitian education resulted in a significant decrease in sodium intake at 3 months (2.80 +/- 0.30 to 2.14 +/- 0.23 g/d, P < .05). In contrast, there was no change in sodium intake in the usual care group (3.00 +/- 0.31 to 2.74 +/- 0.35 g/d, P = ns)., Conclusions: Dietitian-administered counseling was more effective than providing literature in reducing dietary sodium intake in patients with stable HF.

We have documented a pre-junctional beta-2 adrenoceptor mediated reduction in cardiac norepinephrine spillover (CNES) in heart failure patients receiving chronic beta-blockade. Our present objective was to ascertain the consequence of this decrease for vagal heart rate (HR) regulation by determining CNES, arterial baroreflex sensitivity for HR (BRS) and arterial baroreflex modulation of muscle sympathetic nerve activity (MSNA) before and upon 4 months of beta-blockade with either carvedilol or metoprolol. In 19 heart failure patients in sinus rhythm (age: 55+/-2 [mean+/-S.E.]; ejection fraction: 20+/-2%), beta-blockade increased BRS from 4.8+/-0.9 to 7.9+/-1.3 ms/mm Hg (P<0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P<0.05). Chronic beta-blockade in heart failure augments reflex vagal control of HR at an efferent site of interaction involving blockade of cardiac sympathetic pre-junctional beta-2 adrenoceptors that facilitate NE release.

It has been suggested that oxidative stress contributes to impaired left ventricular (LV) contractility in the setting of heart failure (HF). To test this hypothesis, we studied the effect of an antioxidant on contractility at rest and in response to dobutamine in 10 HF patients. We hypothesized that vitamin C would augment contractility in HF and that this effect would be of a greater magnitude in HF patients compared with patients with normal LV (NLV) function. Data from 10 patients with NLV function who participated in this study are included in this report and have been published elsewhere. A micromanometer-tipped catheter was introduced into the LV. In the experimental protocol, an infusion catheter was positioned in the left main coronary artery. The peak positive rate of change of LV pressure (LV +dP/dt) was measured in response to the intravenous infusion of dobutamine before and during the intracoronary infusion of vitamin C (96 mg/min). Vitamin C had no effect on basal LV +dP/dt in either HF or NLV groups. The infusion of vitamin C augmented the LV +dP/dt response to dobutamine by 22 +/- 4% in the NLV function group. In contrast, vitamin C had no effect on the inotropic response to dobutamine in the HF group. In the control protocol, without vitamin C, no differences were observed between responses to two sequential dobutamine infusions in either group (HF, n = 11; NLV, n = 9). Therefore, a positive effect of vitamin C on contractility was limited to patients with NLV function. The absence of this effect in HF patients may suggest that normal redox responsiveness is lost in this disease state.

Study Objectives: Obstructive sleep apnea (OSA) is an independent risk factor for hypertension in the general population. Hypertension is, in turn, an important risk factor for the development and progression of congestive heart failure (CHF). Our objective was to determine whether OSA would be associated with elevated daytime BP in medically treated patients with CHF., Design: Cross-sectional study., Setting: Tertiary care, university-affiliated sleep disorders and heart failure clinics., Patients: Three hundred one consecutive patients with CHF., Measurements and Results: We measured daytime BP and performed overnight sleep studies to assess for the presence of OSA. Among these patients, OSA was present in 121 patients (40%) and their systolic BP was significantly higher than in patients without OSA. Patients with OSA were 2.89 times (95% confidence interval, 1.25 to 6.73) more likely to have systolic hypertension (ie, BP > or = 140 mm Hg) than those without OSA after controlling for other risk factors, including obesity. The degree of systolic BP elevation was directly related to the frequency of obstructive apneas and hypopneas., Conclusions: In medically treated patients with CHF, daytime systolic BP and the prevalence of systolic hypertension are significantly increased in patients with OSA, compared to those without OSA, independent of other potentially confounding factors. OSA may therefore have contributed to the presence of systolic hypertension in some of these patients.

Objectives: We sought to determine whether patients with congestive heart failure (CHF) avoid the left lateral decubitus (LLD) position during sleep and, if so, whether this avoidance would be more pronounced in those with greater degrees of cardiomegaly., Background: Anecdotal reports suggest that, in patients with CHF, the LLD position is associated with discomfort due to the enlarged apical heart beat and greater degree of dyspnea (trepopnea) than other positions. It has also been suggested that the LLD position is associated with increased sympathetic nervous activity., Methods: A total of 75 patients with CHF and 75 control subjects underwent nocturnal polysomnography with monitoring of body position. Echocardiography was performed in all patients with CHF to determine left ventricular end-diastolic diameter (LVEDD). A total of 40 patients underwent cardiac catheterization from which pulmonary capillary wedge pressure (PCWP) and cardiac output (CO) were obtained., Results: Patients with CHF spent significantly less time in the LLD position than in the right lateral decubitus position. No such difference was observed among control subjects. Among patients with CHF, those with larger LVEDD, higher PCWP, and lower CO spent less time in the LLD position., Conclusions: Patients with CHF avoid the LLD position spontaneously during sleep. This may be a protective strategy to avoid discomfort from the enlarged apical heart beat or further hemodynamic or autonomic compromise.

Objectives: The goal of this work was to study the effects of short-term infusion of dobutamine on efferent cardiac sympathetic activity., Background: Increased efferent cardiac sympathetic activity is associated with poor outcomes in the setting of congestive heart failure (CHF). Dobutamine is commonly used in the therapy of decompensated CHF. Dobutamine, through its effects on excitatory beta-receptors, may increase cardiac sympathetic activity., Methods: Seven patients with normal left ventricular (LV) function and 13 patients with CHF were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) before and during an intravenous infusion of dobutamine titrated to increase the rate of rise in LV peak positive pressure (+dP/dt) by 40%., Results: Systemic arterial pulse pressure increased significantly in response to dobutamine in the normal LV function group (74 +/- 3 mm Hg to 85 +/- 3 mm Hg, p = 0.005) but remained unchanged in the CHF group. Dobutamine caused a significant decrease in LV end-diastolic pressure in the CHF group (14 +/- 2 mm Hg to 11 +/- 2 mm Hg, p = 0.02), an effect not observed in the normal LV group. In the normal LV function group, CANESP did not change in response to dobutamine (75 +/- 22 pmol/min vs. 72 +/- 22 pmol/min, p = NS). In contrast, dobutamine infusion was associated with a significant reduction in CANESP in patients with CHF (199 +/- 43 pmol/min to 128 +/- 30 pmol/min, p < 0.0009)., Conclusions: Dobutamine infusion caused a significant sympatholytic response in patients with CHF. This sympathetic withdrawal response is probably related to reduction of LV filling pressures and/or activation of ventricular mechanoreceptors with dobutamine infusion.