Gary E. Newton

Influence of obstructive sleep apnea on mortality in patients with heart failure.

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.

Nocturnal Rostral Fluid Shift A Unifying Concept for the Pathogenesis of Obstructive and Central Sleep Apnea in Men With Heart Failure

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 Pco2, 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 Pco2 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<0.001) and the apnea-hypopnea index (r=−0.881, P<0.001) but not transcutaneous Pco2. 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 Pco2 (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.

Prevalence and Physiological Predictors of Sleep Apnea in Patients With Heart Failure and Systolic Dysfunction

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=45% underwent sleep studies between 1997 and 2004 and were classified as having moderate to severe sleep apnea (apnea-hypopnea index >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.

Acute Effects of β1-Selective and Nonselective β-Adrenergic Receptor Blockade on Cardiac Sympathetic Activity in Congestive 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 β1-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 coro...

Prediction of Heart Failure Mortality in Emergent Care: A Cohort Study

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.

Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine

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(-4) mol/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.

A high-sodium diet is associated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study

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.

Reducing Cardiac Filling Pressure Lowers Norepinephrine Spillover in Patients With Chronic Heart Failure

BACKGROUND We studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF). METHODS AND RESULTS Eight patients with normal LV function (age 57+/-5 years, ejection fraction 58+/-2%) and 8 patients with CHF (age 60+/-2 years; ejection fraction 19+/-2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167+/-53 to 125+/-37 pmol/min, P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73+/-13 vs 122+/-27 pmol/min, P<0.05) but no significant change in those with CHF. CONCLUSIONS We conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.

Relationship between sleep apnoea and mortality in patients with ischaemic heart failure

Objective: 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). Design: Prospective observational study. Patients: Consecutive patients with HF with left ventricular ejection fraction ⩽45% newly referred to the HF clinic between 1 September 1997 and 1 December 2004. Main outcome measures: Patients underwent sleep studies and were divided into those with moderate to severe SA (apnoea–hypopnoea index ⩾15/h of sleep) and those with mild to no SA (apnoea–hypopnoea index <15/h of sleep). They were followed up for a mean of 32 months to determine all-cause mortality rate. Results: 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). Conclusions: 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.

Inotropic and Sympathetic Responses to the Intracoronary Infusion of a β2-Receptor Agonist A Human In Vivo Study

BACKGROUND On the basis of the presence of beta2-receptors within the sympathetic nervous system, beta2-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory beta2-receptors are present in the human left ventricle. METHODS AND RESULTS The beta2-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no beta-blocker therapy), group 2 (n=7, beta1-selective blockade with atenolol), and group 3 (n=6, nonselective beta-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<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124+/-37% increase in cardiac norepinephrine spillover in group 1 (P<0.05). 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 beta1-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 beta2-receptors.