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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.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.Among HF patients, potassium-wasting and potassium-sparing medications do not influence the agreement between the two methods in the assessment of potassium intake.

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.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.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%; P0.001 and -16.2 ± 9.9% vs -3.7 ± 8.3%; P0.001, respectively). Overnight changes in SV and CO correlated inversely with total apnea-hypopnea index (r = -0.551; P0.001 and r = -0.522; P0.001, respectively). In 21 patients with OSA, CPAP reduced the total apnea-hypopnea index from 37.7 ± 21.4 to 15.0 ± 16.0 (P0.001) 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).In patients with HF, coexisting OSA causes overnight declines in SV and CO that are prevented through reversal of OSA by CPAP.

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.

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 r =−0.755, P r =−0.765, P 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.

ObjectivesThe 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).BackgroundDependent 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.MethodsSodium intake was estimated by food recordings in 54 HF patients who underwent overnight polysomnography.ResultsThirty-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.ConclusionsThese findings suggest that in patients with HF, sodium intake plays a role in the pathogenesis of SA.

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.

Periodic leg movements during sleep (PLMs) are a disorder characterized by regularly recurring movements of the legs during sleep. Although PLMs are common in patients with heart failure (HF), their clinical significance is unknown. The aim of this study was to determine whether, in patients with HF, PLMs are associated with increased mortality risk. In a prospective cohort study, 218 consecutive patients with systolic HF newly referred to an HF clinic from 1997 to 2004 who underwent overnight polysomnography, regardless of symptoms or signs of sleep disorders, were enrolled. The frequency of PLMs per hour of sleep was quantified as the PLM index (PLMI). Patients were classified as either normal (PLMI

Background: Muscle sympathetic nerve firing rate increases as chronic heart failure (CHF) progresses, yet its oscillation, particularly within the frequency range encompassing 0.13Hz, 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

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 ≤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 P =0.007) and 0.75 (95% CI, 0.53 to 1.07; P =0.12) when discharge SBPs were 140 to 159 and ≥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 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 β-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) ≤45% underwent sleep studies between 1997 and 2004 and were classified as having moderate to severe sleep apnea (apnea-hypopnea index ≥15hours 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 β-blockers and spironolactone ( P trend P trend P trend =.005). Conclusions OSA and CSA remain common in patients with HF, despite increases in β-blocker and spironolactone use.

To determine whether the influence of sleep apnoea (SA) on the risk of death differs in patients with ischaemic and in those with non-ischaemic heart failure (HF).Prospective observational study.Consecutive patients with HF with left ventricular ejection fractionor =45% newly referred to the HF clinic between 1 September 1997 and 1 December 2004.Patients underwent sleep studies and were divided into those with moderate to severe SA (apnoea-hypopnoea indexor =15/h of sleep) and those with mild to no SA (apnoea-hypopnoea index15/h of sleep). They were followed up for a mean of 32 months to determine all-cause mortality rate.Of 193 patients, 34 (18%) died. In the ischaemic group, mortality risk adjusted for confounding factors was significantly higher in those with SA than in those without it (18.9 vs 4.6 deaths/100 patient-years, hazards ratio (HR) = 3.03, 95% CI 1.04 to 8.84, p = 0.043). In contrast, in the non-ischaemic HF group, there was no difference in adjusted mortality risk between those with, and those without, SA (3.9 vs 4.0 deaths/100 patient-years, p = 0.929).In patients with HF, the presence of SA is independently associated with an increased risk of death in those with ischaemic, but not in those with non-ischaemic, aetiology. These findings suggest that patients with ischaemic cardiomyopathy are more susceptible to the adverse haemodynamic, autonomic and inflammatory consequences of SA than are those with non-ischaemic cardiomyopathy.

Background Reduced potassium excretion caused by angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) may increase the risk of hyperkalemia (serum potassium concentration >5 mmol/L) in the setting of increased potassium intake. Objective The purpose of this study was to assess the effect of increasing dietary potassium on serum potassium concentration in hypertensive individuals with normal renal function treated with an ACEi or ARB. We hypothesized that an increase in dietary potassium would not provoke hyperkalemia in this population despite treatment with either an ACEi or ARB. Design We conducted a controlled, parallel-design clinical trial in 20 hypertensive subjects with normal renal function treated with an ACEi or ARB, with random assignment to a usual diet or a high-potassium diet (HKD). Fruit and vegetable intake was used to increase potassium intake. Serum potassium concentration, 3-d food records, and 24-h urine collections were completed at baseline and 4 wk. Results In the usual-diet group there were no statistically significant differences for potassium excretion, intake, or serum levels at end of study compared with baseline. The HKD group had significant differences in urinary potassium excretion (83 ± 26 mmol/d at baseline compared with 109 ± 35 mmol/d at 4 wk, P = 0.01) and dietary potassium intake (3775 ± 1189 mg/d at baseline compared with 5212 ± 1295 mg/d at 4 wk, P = 0.02). Despite increased potassium intake in the HKD group, serum potassium concentrations did not significantly increase from baseline at midpoint or end of study (4.1 ± 0.6, 4.3 ± 0.3, and 4.2 ± 0.4 mmol/L, respectively). Conclusion This study demonstrates that an increase in dietary potassium over a 4-wk period is safe in hypertensive subjects who have normal renal function and are receiving ACEi and/or ARB therapy. This trial was registered at www.clinicaltrials.gov as NCT02759367.

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

Obstructive sleep apnea is common among patients with heart failure and exposes the left ventricle to trophic mechanical and adrenergic stimuli. We hypothesized that in heart failure patients with nonischemic dilated cardiomyopathy (a condition characterized by eccentric hypertrophy), those with obstructive sleep apnea would have a higher prevalence of left ventricular hypertrophy by wall thickness criteria (or = 12 mm), and greater septal thickness than those without obstructive sleep apnea.We performed echocardiography and polysomnography in 47 patients with nonischemic dilated cardiomyopathy. Obstructive sleep apnea was present in 45% of these patients. The prevalence of left ventricular hypertrophy was greater in those with than in those without obstructive sleep apnea (47.6 vs. 15.4%, p = 0.016). Interventricular septal thickness (p0.001) and relative wall thickness (p = 0.011) were significantly greater in those with than in those without obstructive sleep apnea. However, there was no significant difference in posterior wall thickness between the groups. The frequency of obstructive apneas and hypopneas during sleep was the only significant independent correlate of septal thickness (p = 0.001).In patients with nonischemic dilated cardiomyopathy, the presence of obstructive sleep apnea is associated with an increased prevalence of left ventricular hypertrophy. The higher relative wall thickness and interventricular septal thickness in patients with obstructive sleep apnea indicate that the left ventricle is relatively less eccentric than in patients without obstructive sleep apnea, and that such remodeling affects mainly the septum. These structural adaptations may reflect unique nocturnal mechanical and adrenergic stimuli associated with obstructive sleep apnea.

In a retrospective study of 36 patients who developed cardiogenic shock after myocardial infarction, intravenous vasopressin therapy increased mean arterial pressure from 56 to 73 mm Hg at 1 hour (p0.001) and maintained it for 24 hours without changing pulmonary capillary wedge pressure, cardiac index, urine output, or other inotropic requirements. After norepinephrine administration, mean pulmonary capillary wedge pressure increased at 1 hour from 21 to 24 mm Hg (p = 0.04); however, this increase was not sustained at 12 and 24 hours. Norepinephrine was associated with a significant increase in cardiac power index at 24 hours, whereas there was only a trend for an increase in cardiac power with vasopressin therapy. In a cohort of patients who developed refractory cardiogenic shock after myocardial infarction, vasopressin was associated with increased mean arterial pressure and no adverse effect on other hemodynamic parameters.

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 (P0.005) but had no effect on arterial baroreflex modulation of MSNA. Changes in CNES and BRS were inversely related (r=-0.52; n=16, P0.05). 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.

There is extensive experimental evidence from in vitro and animal experiments that congestive heart failure (CHF) is a state of oxidative stress. Moreover, in animal models, the development of CHF is accompanied by changes in the antioxidant defense mechanisms of the myocardium as well as evidence of oxidative myocardial injury. This has led to the hypothesis that oxidative stress may be a mechanism of disease progression in CHF. Indeed, many patients consume antioxidant supplements making the assumption that no harm will result and, possibly, that this therapy will yield some clinical benefits. The focus of this review is to examine the oxidative stress hypothesis of CHF as it pertains to humans. To date, human studies that have sought evidence for a role of oxidative stress in patients with CHF have fallen short of providing strong support for this hypothesis. Studies that have demonstrated an association between oxidant stress and CHF are small and are hindered by methodologic limitations that diminish the impact of their conclusions. Randomized trials of antioxidant supplementation for CHF are scarce, and to our knowledge no study yet convincingly demonstrates any benefit from consuming antioxidant supplements. Therefore, the available evidence is insufficient to support or negate the oxidative stress hypothesis of CHF and the use of antioxidants cannot be recommended as a specific therapy for this condition.

Background Activation of the sympathetic nervous system has important prognostic implications in chronic heart failure. Nonselective versus selective β-adrenergic receptor antagonists may have differential effects on norepinephrine release from nerve terminals mediated by prejunctional β 2 -adrenergic receptors. Methods and Results — Thirty-six patients with chronic heart failure were randomized to the nonselective β-blocker carvedilol or the selective β-blocker metoprolol (double-blind). Measurements of hemodynamics and cardiac and systemic norepinephrine spillover as well as microneurographic recordings of muscle sympathetic nerve traffic were made before and after 4 months of therapy. In the carvedilol group (n=17), there were significant reductions in both total body (−1.7±0.5 nmol/min, P P P Conclusions Therapy with carvedilol caused significant decreases in systemic and cardiac norepinephrine spillover, an indirect measure of norepinephrine release. Such changes were not observed in patients treated with metoprolol. There was no effect of either agent on sympathetic efferent neuronal discharge to skeletal muscle. These findings suggest that carvedilol, a nonselective β-blocker, caused its sympathoinhibitory effect by blocking peripheral, prejunctional β-adrenergic receptors.

Background —We studied the effect of an antioxidant, the intracoronary infusion of vitamin C, on basal and dobutamine-stimulated left ventricular (LV) contractility. Methods and Results —Nineteen patients with normal ventricular function participated in this study. A micromanometer-tipped catheter was inserted into the LV. In the experimental group (n=10), an infusion catheter was positioned in the left main coronary artery. LV peak +dP/dt (LV +dP/dt) was measured in response to the intravenous infusion of dobutamine before (Dob) and during (Dob+vit C) the intracoronary infusion of vitamin C. The intracoronary infusion of vitamin C had no effect on basal LV +dP/dt or any other hemodynamic parameter. The infusion of vitamin C augmented the LV +dP/dt response to dobutamine by 22±4% (Dob, 1680±76 mm Hg/s; Dob+vit C, 1814±97 mm Hg/s, P P =NS). Conclusions —The administration of the antioxidant vitamin C augments the inotropic response to dobutamine in humans. This suggests that redox environment contributes to the adrenergic regulation of ventricular contractility.

Background: Lipid peroxidation generates several unsaturated aldehydes, such as 4-OH-nonenal (HNE), which may interact with any modify the function of other molecules that are of biological importance. Although congestive heart failure (CHF) is a state of generalized oxidative stress, the resultant spectrum of saturated and unsaturated aldehydes has not been systematically characterized in this condition. Methods: We studied 8 CHF patients and 8 age-matched patients with normal left ventricular (LV) function. The concentrations of 22 aldehydes produced by lipid peroxidation, including saturated (n-alkanals) and unsaturated (t-2-alkenals, t-2,t-4-alkadienals, 4-OH-alkenals) aldehydes, were measured in arterial plasma by gas chromatography mass spectrometry (GC/MS). LV contractility (+dP/dt) and relaxation (Tau) were directly measured with a micromanometer-tipped catheter. Results: Compared with patients who have normal LV function, CHF patients had higher levels of total aldehydes (9,311 ± 835 ν 6,594 ± 344 nmol/L, P < .01), as well as multiple unsaturated aldehydes (t-2-alkenals and 4-OH-alkenals, including HNE). In the CHF group, a strong relationship was observed between total aldehyde concentration and both +dP/dt (correlation coefficient = −0.76, P < .05) and Tau (correlation coefficient = 0.78, P < .05). Conclusion: Unsaturated aldehyde levels were consistently elevated in the plasma of CHF patients compared with patients who have normal LV function. In CHF patients, elevated aldehyde levels were associated with impairment of LV contractility.

Summary: Previous studies have shown that atrial natriuretic peptide (ANP) has relative sympathoinhibitory effects that are of potential benefit in patients with congestive heart failure (CHF). In this study, cardiac and systemic sympathetic responses to ANP were evaluated and compared with responses to sodium nitroprusside (SNP) in patients with CHF. Right- and left-heart hemodynamics were obtained simultaneously with cardiac (CANESP) and total body (TBNESP) norepinephrine spillover; these were measured by using the radiotracer technique. Reductions in arterial blood pressure and cardiac filling pressures were similar with both drugs. ANP and SNP caused a significant and similar increase in TBNESP. Mean values for CANESP did not change in either group, but the response of individual patients was dependent on the effect on diastolic blood pressure (r = −0.71, p < 0.01). These results do not provide evidence for a sympathoinhibitory effect of ANP, but suggest that in patients with CHF, cardiac sympathoexcitatory response to arterial baroreceptor unloading may be countered by a potential sympathoinhibitory effect caused by a reduction in cardiac filling pressures. In the setting of CHF, vasodilator therapy may decrease cardiac sympathetic activity if systemic hypotension is avoided.

Background —On the basis of the presence of β 2 -receptors within the sympathetic nervous system, β 2 -stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory β 2 -receptors are present in the human left ventricle. Methods and Results —The β 2 -agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no β-blocker therapy), group 2 (n=7, β 1 -selective blockade with atenolol), and group 3 (n=6, nonselective β-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44±6% increase in +dP/dt in group 1, a 25±6% increase in group 2 ( P P Conclusions —Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by β 1 -receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac β 2 -receptors.

High concentrations of inspired oxygen have been reported to have significant hemodynamic effects that may be related to increased free radical production. If oxygen therapy increases free radical production, it may also modify hemodynamic responses to a nitric oxide donor. Twenty-nine healthy male volunteers were studied using randomized, double-blind, placebo-controlled, crossover designs to determine whether oxygen therapy is associated with hemodynamic and forearm vascular effects. We measured hemodynamic parameters and forearm vascular responses before and 1 h after exposure to 100% oxygen versus medical air. Plasma 8-iso-PGF2α and plasma vitamin C were measured to assess the biochemical effects of oxygen administration. Hemodynamic measurements were also made following the acute administration of sublingual nitroglycerin. Oxygen therapy caused no significant change in blood pressure, plasma 8-iso-PGF2α, or vitamin C. Oxygen did cause a significant reduction in heart rate and forearm blood flow, and an increase in peripheral vascular resistance. Oxygen caused no change in the hemodynamic response to nitroglycerin. Therefore, in healthy young adults, therapy with 100% oxygen does not affect blood pressure, despite causing an increase in vascular resistance, is not associated with evidence of increased free radical injury, and does not affect the hemodynamic responses to nitroglycerin.Key words: oxygen, nitroglycerin, free radicals, blood pressure, heart rate, plethysmography.

Objectives. We studied the effects of clonidine on cardiac sympathetic activity and left ventricular function in patients with congestive heart failure (CHF).Background. Sympathetic activation has major prognostic implications in patients with heart failure. Clonidine, an imidazoline and alpha2-receptor agonist, has been shown to cause a reduction in generalized sympathetic activity.Methods. Nine patients with CHF (left ventricular ejection fraction 22 ± 4% [mean ± SEM]) received a 50 μg and 100 μg bolus of clonidine intravenously. Study measurements included right and left heart hemodynamics, cardiac output, rate of rise in left ventricular peak positive pressure (LV +dP/dt) and tau, along with cardiac and total body norepinephrine spillover. The radiotracer method was used for calculation of norepinephrine spillover.Results. Right and left heart filling pressures did not change in response to either dose of clonidine. Mean arterial pressure fell after the second dose of clonidine, from 94 ± 8 to 82 ± 6 mm Hg (p < 0.05). The LV + dP/dt was reduced from 737 ± 53 to 629 ± 43 mm Hg/s (p < 0.05). Clonidine also caused a significant increase in tau, as measured by the method of Weiss (65 ± 3 vs. 74 ± 4 ms, p < 0.01) and the direct pressure half-time technique (48 ± 2 vs. 54 ± 3 ms, p < 0.01). Cardiac norepinephrine spillover fell from 121 ± 29 to 52 ± 20 pmol/min in response to 100 μg of clonidine (p < 0.01 vs. control).Conclusions. Despite a significant fall in arterial pressure, clonidine caused a marked reduction in sympathetic activity directed at the heart. The negative inotropic and lusitropic effects appear to be secondary to this reduction in sympathetic drive. Because increased cardiac and generalized sympathetic activity are strong predictors of an adverse outcome in patients with CHF, the role of centrally active sympathoinhibitory agents in the therapy of CHF deserves further exploration.

Objectives. The purpose of this study was to investigate whether therapy with nitroglycerin (GTN) would lead to abnormal coronary artery responses to the endothelium-dependent vasodilator acetylcholine. Background. Nitroglycerin therapy is associated with specific biochemical changes in the vasculature that may lead to increased vascular sensitivity to vasoconstrictors. Methods. Patients were randomized to continuous transdermal GTN, 0.6 mg/h (n = 8), or no therapy (n = 7), for 5 days prior to a diagnostic catheterization. Patients had similar risk factors for endothelial dysfunction. Quantitative angiography was performed in the morning to measure the mean luminal diameter of the left anterior descending coronary artery (LAD) in response to intracoronary acetylcholine (peak concentration, 10−4mol/liter). The transdermal preparation was removed from the GTN group, and 3 h later experimental procedures were repeated. Results. In the morning, the GTN group experienced greater coronary constriction in response to acetylcholine infusion than those not receiving GTN (−19.6 ± 4.2 vs. −3.8 ± 3.0%; p = 0.01). Three hours later, the GTN group continued to display greater constriction to acetylcholine (−24.1 ± 5.9%) as compared to the non-GTN group (−1.8 ± 4.8%). When the morning and afternoon responses to acetylcholine were compared, the increase in coronary constriction in the GTN group was greater than the change observed in the non-GTN group (p < 0.05). Conclusions. This study demonstrates that therapy with GTN causes abnormal coronary vasomotor responses to the endothelium-dependent vasodilator acetylcholine, changes that were persistent for up to 3 hours after GTN discontinuation. This nitrate-associated vasomotor dysfunction has implications with respect to the development of nitrate tolerance and the potential for adverse events during nitrate withdrawal.

Cardiac disease is the leading cause of maternal death. Non-fatal ischemic events may go unnoted during the time of delivery. The aim of this study was to assess the incidence of subclinical myocardial ischemia amongst parturients, as evidenced by a raised troponin assay in the postpartum period.We undertook a prospective observational pilot study in a tertiary obstetric hospital with over 7000 deliveries a year. Targeted sampling was used to enter subjects in pre-defined high- or low-risk groups for myocardial strain, according to their clinical history and a brief questionnaire. Troponin T levels of 140 women were assessed between 8 and 24h postpartum.Ninety-one women considered to be at high risk and 49 at low risk women for myocardial strain were enrolled. The overall mean (±SD) serum troponin T level at 24h postpartum was 8.7±19.7ng/L (normal range14ng/L). The incidence of a positive troponin result was 4.3% (95% CI 1.6, 9.1). Four patients (8.2%) of the low-risk group and two (2.2%) in the high-risk group had elevated troponin T assays.This study found that 4% of women had elevated postpartum troponin assays, within levels in the range suggestive of myocardial damage. However, we were unable to ascertain how to identify this group of women prospectively. At this time, we recommend a low threshold for investigation should be maintained.

Although experimental evidence has demonstrated that brief periods of myocardial ischemia are not associated with norepinephrine overflow from the heart, cardiac sympathetic responses to myocardial ischemia in humans remain unclear. Eleven patients undergoing angioplasty of the left anterior descending coronary artery had cardiac norepinephrine spillover measured immediately before inflation, during the final minute of a 5-min balloon inflation, and 1 min after deflation. Angioplasty caused significant S-T segment elevation and a reduction in the transcardiac lactate extraction ratio. Cardiac norepinephrine spillover was reduced from a mean value of 58 +/- 14 pmol/min at control to 41 +/- 15 pmol/min during balloon inflation and 38 +/- 14 pmol/min after deflation (P < 0.05 vs. control for both inflation and deflation values). In contrast, during balloon inflation, there were significant increases in arterial norepinephrine and epinephrine concentrations. Therefore, a brief period of myocardial ischemia caused by angioplasty of the left anterior descending coronary artery does not result in cardiac sympathetic activation, despite evidence of generalized sympathoadrenal activation.

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 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.

The objective of this study was to evaluate the effect of muscarinic receptor modulation on basal and beta-adrenergic stimulated left ventricular function in patients with heart failure. 21 heart failure patients and 14 subjects with normal ventricular function were studied. In Protocol 1 intracoronary acetylcholine resulted in a 60+/-8% inhibition of the left ventricular +dP/dt response to intracoronary dobutamine in the normal group, and a similar 70+/-13% inhibition in the heart failure group. Acetylcholine also attenuated the dobutamine-mediated acceleration of isovolumic relaxation (Tau) in both groups. Acetylcholine alone had no effect on Tau in the normal group, while it prolonged Tau in the heart failure group. In Protocol 2 intracoronary atropine resulted in a 35+/-10% augmentation of the inotropic response to dobutamine in the normal group, versus a non-significant 12+/-15% augmentation of the dobutamine response in the heart failure group. In Protocol 3, in 6 heart failure patients, both effects of acetylcholine, the slowing of ventricular relaxation and the inhibition of beta-adrenergic responses, were reversed by the addition of atropine. Therefore, in the failing human left ventricle muscarinic stimulation has an independent negative lusitropic effect and antagonizes the effects of beta-adrenergic stimulation.

Background Although there is indirect evidence of impaired baroreflex control of sympathetic outflow directed at heart muscle, the regulation of cardiac sympathetic activity in the setting of heart failure is largely unexplored. We used the norepinephrine spillover method to address the hypothesis that baroreflex control of cardiac sympathetic activity is reduced in heart failure. Methods and Results Twenty-three patients were studied, 17 in a group with heart failure and 6 in a group with normal ventricular function. In both groups, cardiac norepinephrine spillover was assessed in response to nitroprusside infused to steady-state conditions. Nitroprusside resulted in significant reductions in mean systemic arterial pressure (normal group, −15±3% [mean±SEM]; heart failure group, −13±1%) and mean pulmonary artery pressure (normal group, −25±10%; heart failure group, −29±4%). In response to nitroprusside, there was a 98±16% increase in cardiac norepinephrine spillover in the normal group (from 81±10 to 159±25 pmol/min, P P =NS), a response that was significantly smaller than that seen in the normal group. Conclusions In patients with heart failure compared with subjects with normal ventricular function, there was a significantly smaller increase in cardiac sympathetic activity in response to a steady-state infusion of nitroprusside. This result provides evidence for reduced baroreflex control of cardiac sympathetic activity in heart failure.

Background β-Blockers may reduce cardiac sympathetic activity in patients with heart failure by antagonizing β-adrenergic receptors that facilitate sympathetic outflow to the heart. To explore this possible effect of β-blockade, we measured cardiac norepinephrine spillover responses in patients with heart failure after the acute administration of either propranolol, a nonselective β-blocker, or metoprolol, a β 1 -selective agent. Methods and Results Eighteen patients were studied. Repeated intravenous doses of propranolol (0.5 mg; nine patients; left ventricular ejection fraction, 14±2%) or metoprolol (1.0 mg; nine patients; left ventricular ejection fraction, 18±2%) were administered until one of the following end points was reached: a 15% decrease in heart rate, left ventricular +dP/dt, or mean arterial blood pressure or a 5 mm Hg increase in left ventricular end-diastolic pressure. Propranolol (mean dose, 2.0 mg) and metoprolol (mean dose, 3.6 mg) caused similar reductions in heart rate, +dP/dt, and coronary sinus plasma flow. Cardiac norepinephrine spillover was reduced after propranolol (277±55 to 262±53 pmol/min, P P P Conclusions The administration of a β 1 -selective antagonist was associated with increased cardiac norepinephrine spillover. In contrast, the administration of a nonselective β-blocker until similar hemodynamic end points were reached caused a reduction in norepinephrine spillover. This suggests that in patients with heart failure, nonselective β-blockade may have favorable inhibitory effects on cardiac sympathetic activity.

This study evaluated the effect of digoxin on cardiac sympathetic activity in patients with congestive heart failure.Digoxin favorably alters autonomic tone in heart failure. Whether it reduces cardiac sympathetic drive in the setting of heart failure is unknown.Digoxin (0.25 mg intravenously) was administered to 12 patients with severe heart failure and elevated left ventricular end-diastolic pressure (14 mm Hg, Group A), 5 patients with less severe heart failure who had normal left ventricular end-diastolic pressure (14 mm Hg, Group B) and 6 patients with normal ventricular function. Seven additional patients with heart failure were studied as a time control group. Cardiac and total body norepinephrine spillover, systemic arterial pressure, left ventricular filling pressure and peak positive first derivative of left ventricular pressure were all assessed before and 30 min after administration of digoxin.In Group A there were no changes in hemodynamic variables or total body norepinephrine spillover after digoxin administration; however, there was a significant reduction in cardiac norepinephrine spillover (263 +/- 70 to 218 +/- 62 pmol/min, mean +/- SEM, p0.001). In contrast, in Group B, digoxin caused a significant increase in cardiac norepinephrine spillover that was not associated with any hemodynamic changes or a change in total body spillover. There were no hemodynamic changes or a change in total body spillover. There were no hemodynamic or spillover changes in the time control or normal ventricular function group.Digoxin, in the absence of detectable inotropic or hemodynamic effects, caused a reduction in cardiac norepinephrine spillover in patients with heart failure who had elevated filling pressures. This finding suggests a potentially beneficial primary autonomic action of digoxin in patients with severe heart failure.

Introduction Cardiac troponins are sensitive and specific biomarkers of myocardial necrosis. We evaluated troponin, CK, and ECG abnormalities in patients with septic shock and compared the effect of vasopressin (VP) versus norepinephrine (NE) on troponin, CK, and ECGs. Methods This was a prospective substudy of a randomized trial. Adults with septic shock randomly received, blinded, a low-dose infusion of VP (0.01 to 0.03 U/min) or NE (5 to 15 μg/min) in addition to open-label vasopressors, titrated to maintain a mean blood pressure of 65 to 75 mm Hg. Troponin I/T, CK, and CK-MB were measured, and 12-lead ECGs were recorded before study drug, and 6 hours, 2 days, and 4 days after study-drug initiation. Two physician readers, blinded to patient data and drug, independently interpreted ECGs. Results We enrolled 121 patients (median age, 63.9 years (interquartile range (IQR), 51.1 to 75.3), mean APACHE II 28.6 (SD 7.7)): 65 in the VP group and 56 in the NE group. At the four time points, 26%, 36%, 32%, and 21% of patients had troponin elevations, respectively. Baseline characteristics and outcomes were similar between patients with positive versus negative troponin levels. Troponin and CK levels and rates of ischemic ECG changes were similar in the VP and the NE groups. In multivariable analysis, only APACHE II was associated with 28-day mortality (OR, 1.07; 95% CI, 1.01 to 1.14; P = 0.033). Conclusions Troponin elevation is common in adults with septic shock. We observed no significant differences in troponin, CK, and ECGs in patients treated with vasopressin and norepinephrine. Troponin elevation was not an independent predictor of mortality. Trial registration Controlled-trials.com ISRCTN94845869

Background There are α-adrenergic receptors on human myocardium that exert positive inotropic effects. The effect of α-adrenergic receptor blockade on human left ventricular (LV) performance has not been fully explored. Although α-adrenergic receptor blockade might have effects on LV function that are mediated via blockade of postsynaptic myocardial α-adrenergic receptors, it is also possible that blockade of presynaptic α 2 -adrenergic receptors and subsequent increased release of norepinephrine would have effects on LV performance. In the present study, we explored the effects of nonselective α-adrenergic receptor blockade on LV performance and transcardiac norepinephrine concentrations in a group of patients with normal LV function and in a group of patients with congestive heart failure secondary to dilated cardiomyopathy. Methods and Results Using an intracoronary drug infusion technique, we administered the nonselective α-adrenergic antagonist phentolamine to 13 patients with normal LV function and 19 patients with congestive heart failure secondary to dilated cardiomyopathy. With a high-fidelity LV catheter, the systolic (+dP/dt) and diastolic (−dP/dt and Tau) LV function responses to intracoronary infusion of phentolamine (0.2 mg/min×5 minutes) were assessed. In 8 patients with normal ventricular function and 10 patients with congestive heart failure, arterial and coronary sinus blood samples were drawn to determine the effects of phentolamine on catecholamine concentrations. Phentolamine had no measurable effect on LV performance or catecholamine concentrations in the normal ventricular function group. In patients with congestive heart failure, intracoronary phentolamine caused a significant increase in +dP/dt and the rate of isovolumic LV relaxation (−dP/dt and Tau). These hemodynamic effects were accompanied by a significant increase in coronary sinus norepinephrine concentration but no change in arterial norepinephrine concentration. Conclusions Myocardial α-adrenergic receptor blockade causes significant inotropic and lusitropic effects in the failing but not the nonfailing human LV. These effects appear to be mediated by increased release of norepinephrine from cardiac nerves secondary to blockade of presynaptic α 2 -adrenergic receptors. Differences in the responses of the failing and nonfailing human LV appear to reflect the higher level of sympathetic activation that is seen in the group with congestive heart failure. This suggests that the presynaptic α 2 -adrenergic receptor exerts a tonic inhibitory effect on the release of norepinephrine from cardiac nerves in patients with congestive heart failure.

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.

Background The post-trial period is the time period after the end of study drug administration. It is unclear whether post-trial arrangements for patient surveillance are routinely included in study protocols and consents, and whether research ethics boards (REB) consider the post-trial period. Objectives The objective was to determine whether trial protocols and consent forms reviewed by the REB describe procedures for post-trial period surveillance. Methods An observational study of protocols of randomised trials of chronic therapies for cardiac conditions, approved by the REB of two academic institutions affiliated with the University of Toronto in Canada (University Health Network and Mount Sinai Hospital) from 1995 to 2007. Plans for patient surveillance in the post-trial period described in the protocol or in the consent form before and after REB approval were recorded. Results 42 studies were identified including 18 heart failure and 15 coronary artery disease trials. Only four studies planned a clinical visit after trial termination, and an additional three planned a telephone contact after trial completion. Five trials submitted consent forms to the REB with a discussion of the post-trial period. Conclusions The majority of protocols and consent forms did not discuss plans for post-trial period surveillance. The post-trial period and the REB approval process could be improved by systematic follow-up being described in the protocol and consent form. The small number of trial protocols evaluated in the study may impair the degree to which the results can be generalised.

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; p24 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

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.

Clinical outcomes for cardiovascular syndromes such as heart failure differ between men and women.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).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 fraction40% and NYHA class II-III symptoms. Within each group a matched cohort analysis, identifying two control men for each woman, was performed.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, p0.05). 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, p0.05 for both).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— 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 P co 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 ≤45%), we measured change in leg fluid volume and neck circumference before and after polysomnography, and we measured transcutaneous P co 2 during polysomnography. Patients were divided into an obstructive-dominant group (≥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 r =−0.881, P co 2 . In central-dominant patients, the overnight reduction in leg fluid volume correlated inversely with the apnea-hypopnea index ( r =−0.919, P r =−0.568, P =0.013) and directly with transcutaneous P co 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 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.

Introduction: Past studies showed that in patients with heart failure (HF), sleep apnea (SA) increases mortality risk, but these patients were not characterized on the basis of HF etiology. Hypothesis: Since patients with ischemic HF may suffer greater adverse consequences of SA-related hypoxia and hypertension than those with non-ischemic HF, SA will increase risk of death in patients with ischemic, but not in those with non-ischemic HF. Methods: From 1997 to 2004, consecutive HF patients with ejection fraction (EF) ≤ 45% had sleep studies and were divided into those with SA (apnea-hypopnea index ≥ 15/hr of sleep) and those without SA. They were followed prospectively to determine all-cause mortality rate. Results: Of 218 patients enrolled, follow up data were obtained in 95%. Of these, 87 (40%) had ischemic HF. SA was found in 53% of those with ischemic HF and in 41% of those with non-ischemic HF. 14 patients with obstructive sleep apnea on CPAP therapy were excluded from the analysis. Of the remaining 193 patients, 34 (18%) died during a mean follow up of 32 months. In the non-ischemic HF group, there was no difference in mortality between those with, and those without SA (Figure ). In contrast, in the ischemic group, mortality was significantly higher in those with SA than those without it (18.9 vs. 4.6 deaths/100 patient-years, P = 0.003). After adjusting for age, EF, New York Heart Association class, β-blocker use, and the presence of diabetes using multivariate Cox analysis, SA remained a significant independent risk for death (HR 3.02, 95%CI 1.07– 8.59, P = 0.037). Conclusions: These data show that ischemic etiology identifies those HF patients with SA at increased risk of death.

Background: The post trial period is the period after the end of study drug administration. The Declaration of Helsinki (DOH) states that “at the conclusion of the study, every patient entered into the study should be assured of access to the best proven prophylactic, diagnostic and therapeutic methods identified by the study.” It further adds that “post trial access arrangements or other care must be described in the study protocol so the ethical review committee may consider such arrangements during its review.” Therefore our objectives were: to determine whether research trial protocols systematically consider post trial period issues including planned follow-up and patient surveillance in the post trial period; and to assess if consent forms addressed end of trial issues. Methods: We searched the research ethics board (REB) databases at 2 academic institutions in Toronto from 1995 to 2006 to identify approved randomized clinical trials of chronic medical therapies for cardiac conditions. Results: Fourty-two studies were identified including 18 heart failure and 15 coronary artery disease trials. Thirty-eight of these trials were industry funded. Almost all trials (n=37) ended study drug abruptly at the last clinic visit, while only 4 studies offered a clinical visit post trial termination, and an additional 3 reported a telephone contact after trial completion. Only 5 trials submitted consent forms to the REB with a discussion of the post trial period. After REB review, no additional consent forms addressed the post trial period. When comparing the time period before and after the updated version of the DOH in 2000, there was a trend towards a decline in addressing post trial care (p=0.08). Conclusion: The majority of cardiac trials end study drug abruptly with unknown and potentially negative consequences, and most patients have no systematic post trial follow up from trial investigators. Study patients are also not made aware of the post trial period, as the majority of study consent forms do not discuss post trial care. Therefore, an important aspect of clinical trial design, the post trial period, could be improved by systematic follow-up described in the protocol, and full discussion of this aspect of trial participation in the consent form.

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.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 fraction35%, 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.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.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.

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.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; andor =15, moderate to severe OSA).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).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/d t) was measured in response to intravenous dobutamine (Dob-1). After recontrol, intracoronary NG-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/d t. 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/d t. The change in LV +dP/d t 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.