Long-term mortality in older patients discharged after acute decompensated heart failure: a prospective cohort study.

BACKGROUND: Data are available on short- and intermediate-term mortality rates after discharge for acutely decompensated heart failure (ADHF). However, few studies specifically addressed ADHF outcomes in patients aged 75 years or over, who contribute more than half of all ADHF admissions. Our objectives here were to estimate the long-term mortality of patients aged 75 years or over who were discharged after admission for ADHF and to identify factors, especially geriatric findings, independently associated with 2-year mortality. METHODS: This prospective cohort study in five French hospitals included consecutive patients aged 75 years or older and discharged after emergency-department admission for ADHF meeting Framingham criteria (N = 478; median age, 85 years; 68% female). Kaplan-Meier 1-year and 2-year survival curves were plotted. Admission characteristics independently associated with overall 2-year mortality were identified using multivariable Cox proportional-hazards regression. RESULTS: Mortality was 41.7% (95% confidence interval [95% CI], 37.2%-53.5%) after 1 year and 56.0% (95% CI, 51.5%-60.7%) after 2 years. By multivariable analysis, independent predictors of 2-year mortality were male sex (hazard ratio [HR], 1.36; 95% CI, 1.00-1.82), age >85 years (HR, 1.57; 95% CI, 1.19-2.07), higher number of impaired activities of daily living (HR, 1.11 per impaired item; 95% CI, 1.05-1.17), recent weight loss (HR, 1.61; 95% CI, 1.14-2.28), and lower systolic blood pressure (HR, 0.86 per standard deviation increase; 95% CI, 0.74-0.99). Creatinine clearance ≤30 mL/min showed a trend toward an association with 2-year mortality (HR, 1.36; 95% CI, 0.97-2.00). CONCLUSION: Functional impairment before admission is associated with higher long-term mortality in patients ≥75 years admitted for ADHF. This study focused on geriatric markers not traditionally collected in heart-failure patients but did not analyse all cardiologic parameters associated with outcomes in other studies. Nevertheless, our findings may contribute to identify those patients admitted for ADHF who have the worst prognosis.

Functional status and co-morbidities are associated with in-hospital mortality among older patients with acute decompensated heart failure: a multicentre prospective cohort study.

BACKGROUND: Among patients admitted for acute decompensated heart failure (ADHF), half are aged 75 years or over. The high prevalence of co-morbidities and functional impairments in this age group may affect patient outcomes. OBJECTIVE: To assess the association between co-morbidities, functional status and in-hospital mortality in patients with ADHF aged ≥75 years. DESIGN: A prospective, multicentre cohort study. SETTING: Five French hospitals. SUBJECTS: Five hundred and fifty-five patients aged ≥75 years admitted to the emergency department with ADHF. METHODS: Baseline clinical data and co-morbidities were recorded at admission. Functional status and cognition were assessed using the Katz index and Mini-Mental Status Examination score, respectively. The primary outcome was in-hospital mortality. RESULTS: We found high prevalences of co-morbidities and functional impairments including hypertension (74.0%), atrial fibrillation (40.2%), prior acute coronary syndrome (32.3%) and diabetes (18.2%). The average creatinine clearance was 56.3 ml/min/1.73 m(2) (interquartile range, 39.2-77.0). In-hospital mortality was 67/555 (12.1%; 95% confidence interval, 9.4-14.8). In multivariate analysis, in-hospital mortality showed a statistically positive association with prior loss of self-sufficiency (Odds ratio [OR]: 5.85 [2.25-12.19]), hyperglycaemia (OR: 1.80 [1.26-2.54] per 1 SD increase), prior cerebral ischaemic event (OR: 3.56 [1.51-8.44]) and troponin I elevation above upper limit of normal (OR: 2.81 [1.37-5.77]). In addition, systolic blood pressure (OR: 0.98 [0.97-0.99] per 1 mmHg increase) and creatinine clearance (OR: 0.72 [0.51-1.00] per 1 SD increase) were negatively associated with in-hospital mortality. CONCLUSION: Co-morbidities and functional impairments are associated with a worse short-term prognosis in patients aged ≥75 years admitted for ADHF. Assessing these parameters at admission may improve patient management.

Long-term effects of an educational seminar on antibiotic prescribing by GPs: a randomised controlled trial.

BACKGROUND: High levels of outpatient antibiotic use remain observed in many European countries. Several studies have shown a strong relationship between antibiotic use and bacterial resistance. AIM: To assess the long-term effect of a standardised educational seminar on antibiotic prescriptions by GPs. DESIGN AND SETTING: Randomised controlled trial of 171 GPs (of 203 initially randomised) in France. METHOD: GPs in the control group (n = 99) received no antibiotic prescription recommendation. Intervention group GPs (n = 72) attended an interactive seminar presenting evidence-based guidelines on antibiotic prescription for respiratory infections. The proportion of prescriptions containing an antibiotic in each group and related costs were compared to the baseline up to 30 months following the intervention. Data were obtained from the National Health Insurance System database. RESULTS: In the intervention group, 4-6 months after the intervention, there was a significant decrease in the proportion of prescriptions containing an antibiotic from 15.2 ± 5.4% to 12.3 ± 5.8% (-2.8% [95% CI = -3.8 to -1.9], P<0.001). By contrast, an increase was observed in controls from 15.3 ± 6.0 to 16.4 ± 6.7% (+1.1% [95% CI = +0.4 to +1.8], P<0.01), resulting in a between-group difference of 3.93% ([95% CI = 2.75 to 5.11], P<0.001). The between-group difference was maintained 30 months after intervention (1.99% [95% CI = 0.56 to 3.42], P<0.01). Persistence of the intervention effect over the entire study period was confirmed in a hierarchical multivariate analysis. CONCLUSION: This randomised trial shows that a standardised and interactive educational seminar results in a long-term reduction in antibiotic prescribing and could justify a large-scale implementation of this intervention.

Ambulatory transradial percutaneous coronary intervention: a safe, effective, and cost-saving strategy.

OBJECTIVES: The aim of this prospective, multicenter study was to assess the safety, feasibility, acceptance, and cost of ambulatory transradial percutaneous coronary intervention (PCI) under the conditions of everyday practice. BACKGROUND: Major advances in PCI techniques have considerably reduced the incidence of post-procedure complications. However, overnight admission still constitutes the standard of care in most interventional cardiology centers. METHODS: Eligibility for ambulatory management was assessed in 370 patients with stable angina referred to three high-volume angioplasty centers. On the basis of pre-specified clinical and PCI-linked criteria, 220 patients were selected for ambulatory PCI. RESULTS: The study population included a substantial proportion of patients with complex procedures: 115 (52.3%) patients with multivessel coronary artery disease, 50 (22.7%) patients with multilesion procedures, and 60 (21.5%) bifurcation lesions. After 4-6 hr observation period, 213 of the 220 patients (96.8%) were cleared for discharge. The remaining seven (3.2%) patients were kept overnight for unstable angina (n = 1), atypical chest discomfort (n = 2), puncture site hematoma (n = 1), or non-cardiovascular reasons (n = 3). Within 24 hr after discharge, no patients experienced readmission, stent occlusion, recurrent ischemia, or local complications. Furthermore, 99% of patients were satisfied with ambulatory management and 85% reported no anxiety. The average non-procedural cost was lower for ambulatory PCI than conventional PCI (1,230 ± 98 Euros vs. 2,304 ± 1814 Euros, P < 10(-6)). CONCLUSIONS: Ambulatory PCI in patients with stable coronary artery disease is safe, effective, and well accepted by the patients. It may both significantly reduce costs and optimize hospital resource utilization.

CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation.

Donor T cells play a pivotal role in the graft-versus-tumor effect after allogeneic hematopoietic stem cell transplantation. Regulatory T cells (T(reg)s) may reduce alloreactivity, the major component of the graft-versus-tumor effect. In the setting of donor lymphocyte infusion after hematopoietic stem cell transplantation, we postulated that T(reg) depletion could improve alloreactivity and likewise the graft-versus-tumor effect of donor T cells. The safety and efficacy of T(reg)-depleted donor lymphocyte infusion was studied in 17 adult patients with malignancy relapse after hematopoietic stem cell transplantation. All but one had previously failed to respond to at least one standard donor lymphocyte infusion, and none had experienced graft-versus-host disease. Two of the 17 patients developed graft-versus-host disease after their first T(reg)-depleted donor lymphocyte infusion and experienced a long-term remission of their malignancy. Four of the 15 patients who did not respond after a first T(reg)-depleted donor lymphocyte infusion received a second T(reg)-depleted donor lymphocyte infusion combined with lymphodepleting chemotherapy aimed to also eliminate recipient T(reg)s. All four developed acute-like graft-versus-host disease that was associated with a partial or complete and durable remission. In the whole cohort, graft-versus-host disease induction through T(reg) depletion was associated with improved survival. These results suggest that T(reg)-depleted donor lymphocyte infusion is a safe, feasible approach that induces graft-versus-host or graft-versus-tumor effects in alloreactivity-resistant patients. In patients not responding to this approach, the combination of chemotherapy-induced lymphodepletion of the recipient synergizes with the effect of T(reg)-depleted donor lymphocyte infusion. These findings offer a rational therapeutic approach for cancer cellular immunotherapy.

Medical information and surrogate designation: results of a prospective study in elderly hospitalised patients.

OBJECTIVES: To determine the preferences of French elderly inpatients concerning medical information and surrogate designation in life-threatening situations. METHODS: Intention-to-act questionnaire was completed by two geriatricians during a patient interview in the week following admission in three geriatric units in France. The participants were elderly patients (> or =70 years) with adequate cognitive performance for decision making as assessed by the Mini Mental State Examination. The impact of socio-demographic factors, level of confidence in medical care, cognitive or physical disability on surrogate designation and amount of medical information expected were measured. MEASUREMENTS: Impact of socio-demographic factors, level of confidence in medical care, cognitive or physical disability on surrogate designation and amount of medical information expected. RESULTS: 426 consecutive elderly patients were recruited. 32.6% wanted to receive complete information about their care and 77% declared they would want to be informed if they were in a life-threatening situation. 4.5% reported they would not want any medical information. A family member was designated as surrogate by 73% of the patients. In 28%, a second surrogate was also designated, usually the family physician (22%) or a member of the hospital medical staff (10%). Polytomous logistic regression analysis was used to assess determinants of the amount of information expected and social and medical parameters. MMSE score, the presence of physical disability, a low level of confidence in medicine and the presence of children were identified as independent determinants of a high level of information expectation. CONCLUSION: Elderly hospitalised patients expressed a strong desire to receive extensive information and were willing to designate a surrogate in a life-threatening situation. The surrogate was usually a family member alone or with another person, usually a practitioner.

Cardiac effects of growth hormone treatment in chronic heart failure: A meta-analysis.

CONTEXT: Experimental studies suggest that GH treatment may improve cardiovascular parameters in chronic heart failure (CHF). However, clinical trials involved small numbers of patients and did not allow a conclusion to be drawn on the effect of this treatment in humans. OBJECTIVE: We systematically reviewed and analyzed all randomized controlled trials and open studies of sustained GH treatment in CHF. STUDY SELECTION: Twelve trials were identified in three databases. We conducted a combined analysis of GH effects on cardiovascular parameters using the overall effect size to evaluate significance and computing the weighted mean differences with and without treatment to assess effect size. DATA SYNTHESIS: GH treatment significantly modified morphological cardiovascular parameters [interventricular septum thickness, +0.55 (sd, 0.43) mm (P < 0.001); posterior wall thickness, +1.01 (0.44) mm (P < 0.01); left ventricle (LV) end-diastolic diameter, -2.02 (1.22) mm (P < 0.01); and LV end-systolic diameter, -5.30 (2.33) mm (P < 0.05)]; LV and systemic hemodynamics [LV end-systolic wall stress, -38.9 (13.3) dynes/cm(2) (P < 0.001); LV ejection fraction, +5.10 (1.74)% (P < 0.05); and systemic vascular resistance, +195.0 (204.5) dyn x sec(-1) x cm(-5) (P < 0.01)]; and functional parameters [New York Heart Association class, -0.97 (0.23) (P < 0.01); exercise duration, +103.7 (37.6) sec (P < 0.001); and maximal oxygen uptake, +2.48 (1.76) ml/kg x min (P < 0.01)]. Subgroup analysis and meta-regression showed significant relationships between the IGF-I response and GH treatment effects. CONCLUSION: Our meta-analysis suggests that GH treatment improves several relevant cardiovascular parameters in patients with CHF. However, these results must be confirmed by a large randomized placebo-controlled trial on hemodynamic, morphological, and functional parameters during long-term high-dose GH treatment of patients with CHF.

Coronary vasomotor response to phenylephrine in heart transplant patients.

BACKGROUND: Coronary vasomotor responses to sympathetic stimulation vary with endothelial-layer integrity or presence of atherosclerosis. Our study objective was to assess the effects of phenylephrine-induced alpha-adrenergic stimulation on coronary vasomotion in heart transplant recipients with and without graft atherosclerosis. METHODS: Intracoronary phenylephrine (alpha(1)-selective agonist) was injected in 6 control subjects, 9 recipients with angiographically normal coronary arteries and 8 recipients with mild or moderate atherosclerosis. Coronary flow velocity was measured using a Doppler guide-wire. The diameters of 3 epicardial segments of the left coronary artery and coronary blood flow and resistance were assessed at baseline, after infusion of increasing acetylcholine doses (10(-7) and 10(-6) mol/liter) and after phenylephrine (150- to 200-microg bolus). Systemic and coronary hemodynamic parameters were measured immediately after acetylcholine and 1, 3, 5, 7, 10 and 15 minutes after phenylephrine. RESULTS: Phenylephrine induced similar significant increases in rate pressure product in the 3 groups. Acetylcholine induced epicardial vasodilation in controls and vasoconstriction in transplant recipients. Phenylephrine induced epicardial vasodilation in controls and in angiographically normal recipients; subsequent vasoconstriction occurred in this last group. In the recipients with angiographic abnormalities, sustained vasoconstriction occurred. At peak phenylephrine effect, coronary blood flow (CBF) increased significantly (p < 0.001 vs baseline) in all 3 groups. Coronary resistance decreased in the 3 groups but the decrease was smaller in the recipients with angiographic abnormalities (p < 0.05 vs controls). CONCLUSIONS: In heart transplant patients, graft atherosclerosis unmasks the direct coronary vasoconstricting effects of pharmacologic alpha-adrenergic stimulation.

Coronary vasomotor response to the selective B1-kinin-receptor agonist Des-Arg9-bradykinin in humans.

OBJECTIVES: The aim of the present study was to assess the effects of selective B1-receptor stimulation with des-Arg9-bradykinin on coronary vasomotion in transplanted and non-transplanted patients. BACKGROUND: Bradykinin B1-receptors have been identified on endothelial and smooth muscle cells in human coronary arteries in vitro; however, their physiologic role in the coronary circulation is unknown. METHODS: Twelve heart transplant patients were compared with 10 control subjects at 3.2 +/- 2.2 months after surgery. Coronary flow velocity was measured using guide-wire Doppler. The diameter of 3 epicardial segments of the left coronary artery and coronary blood flow were assessed at baseline, immediately after infusions of increasing doses of des-arginine(Arg9)-bradykinin at estimated coronary blood concentrations of 5.4 x 10(-9), 5.4 x 10(-8), 5.4 x 10(-7) and 1.6 x 10(-6) mol/liter, and of acetylcholine at 10(-8), 10(-7) and 10(-6) mol/liter). RESULTS: Des-Arg9-bradykinin induced a similar decrease in all measured epicardial diameters in both groups and no change in coronary blood flow. Vasoconstriction was significant only at the 2 highest concentrations: -6 +/- 9% (p < 0.01) and -7 +/- 11% (p < 0.01) in control subjects, and -8 +/- 8% (p < 0.001) and -9 +/- 11% (p < 0.001) in heart transplant patients. Acetylcholine induced significant epicardial vasodilation in control subjects and vasoconstriction in transplant patients. The presence of allograft rejection did not modify the responses to des-Arg9-bradykinin with regard to both conductance and resistance vessels. CONCLUSIONS: Kinin B1-receptors exist and can be stimulated in humans. The vasoconstrictive action on epicardial coronary arteries of des-Arg(9)-bradykinin in humans argues for a predominant action of B1-receptor stimulation at the level of smooth muscle cells.

Impaired alpha1-adrenergic responses in aged rat hearts.

To determine age-related changes in the cardiac effect of alpha1-adrenergic stimulation, both cardiomyocyte Ca2+-transient and cardiac protein kinase C (PKC) activity were measured in 3-month- (3MO) and 24-month- (24MO) old Wistar rats. Ca2+ transients obtained under 1 Hz pacing by microfluorimetry of cardiomyocyte loaded with indo-1 (405/480 nm fluorescence ratio) were compared in control conditions (Kreb's solution alone) and after alpha1-adrenergic stimulation (phenylephrine or cirazoline, an alpha1-specific agonist). PKC activity and PKC translocation index (particulate/total activity) were also assayed before and after alpha1-adrenergic stimulation. In 3MO, cirazoline induced a significant increase in Ca2+ transient for a 10(-9) M concentration which returned to control values for larger concentrations. In contrast, in 24MO, we observed a constant negative effect of cirazoline on the Ca2+ transient with a significant decrease at 10(-6) M compared with both baseline and Kreb's solution. Preliminary experiments showed that, in a dose-response curve to phenylephrine, the response of Ca2+ transient was maximal at 10(-7) M. This concentration induced a significant increase in Ca2+ transient in 3MO and a significant decrease in 24MO. The same concentration was chosen to perform PKC activity measurements under alpha1-adrenergic stimulation. In the basal state, PKC particulate activity was higher in 24MO than that in 3MO but was not different in cytosolic fractions; so that the translocation index was higher in 24MO (P < 0.01). After phenylephrine, a translocation of PKC toward the particulate fraction was observed in 3MO but not in 24MO. In conclusion, cardiac alpha1-adrenoceptor response was found to be impaired in aged hearts. The negative effect of alpha1-adrenergic stimulation on Ca2+ transient in cardiomyocytes obtained from old rats can be related to an absence of alpha1-adrenergic-induced PKC translocation.

Uptake-1 carrier downregulates in parallel with the beta-adrenergic receptor desensitization in rat hearts chronically exposed to high levels of circulating norepinephrine: implications for cardiac neuroimaging in human cardiomyopathies.

UNLABELLED: Imaging techniques have demonstrated in various cardiomyopathies that an altered uptake of radiolabeled norepinephrine (NE) analogs may coexist with beta-adrenergic receptor downregulation, but the relationships between these 2 alterations and their mechanisms remain unclear. The aim of this study was to evaluate the hypothesis of a chronic elevation of circulating NE levels as a mechanism of decreased uptake of radiolabeled NE analogs and reduced beta-adrenergic receptor sites in the heart. METHODS: Osmotic minipumps containing either NE or NaCl were implanted intravenously in rats for 5 d. The uptake-1 function was assessed in vitro by measuring in excised hearts (3)H-NE and (123)I-metaiodobenzylguanidine ((123)I-MIBG) uptakes and uptake-1 carrier density using (3)H-mazindol binding assay. The myocardial beta-adrenergic receptor pathway was assessed in vitro by (3)H-CGP 12177 binding and measurement of adenylyl cyclase activity at baseline and under stimulation. RESULTS: A 34% decrease in (3)H-NE uptake and a 35% decrease in (123)I-MIBG uptake were found in the hearts of rats infused with the NE pump compared with that of rats infused with saline solution (P < 0.05 for both). Moreover, the uptake-1 carrier protein density was decreased by 29% (P < 0.05) and 33% (P < 0.05) in right and left ventricles, respectively, of rats infused with NE compared with those infused with saline solution. Myocardial beta-adrenergic receptor desensitization was associated with a 36% reduction in receptor density in the right ventricle (P < 0.05) and a 31% reduction in the left ventricle (P < 0.05) of rats infused with NE compared with those infused with saline solution. CONCLUSION: The decrease in myocardial beta-adrenergic receptors and radiolabeled NE analog uptake found in different cardiomyopathies using neuroimaging techniques may be related to a functional mechanism of NE-induced downregulation of both beta-adrenergic receptor and uptake-1 carrier sites.

The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy.

Mitogen-activated protein kinase kinase kinase (MEKK1) mediates activation of c-Jun NH(2)-terminal kinase (JNK). Although previous studies using cultured cardiac myocytes have suggested that the MEKK1-JNK pathway plays a key role in hypertrophy and apoptosis, its effects in cardiac hypertrophy and apoptosis are not fully understood in adult animals in vivo. We examined the role of the MEKK1-JNK pathway in pressure-overloaded hearts by using mice deficient in MEKK1. We found that transverse aortic banding significantly increased JNK activity in Mekk1(+/+) but not Mekk1(-/-) mice, indicating that MEKK1 mediates JNK activation by pressure overload. Nevertheless, pressure overload caused significant levels of cardiac hypertrophy and expression of atrial natriuretic factor in Mekk1(-/-) animals, which showed higher mortality and lung/body weight ratio than were seen in controls. Fourteen days after banding, Mekk1(-/-) hearts were dilated, and their left ventricular ejection fraction was low. Pressure overload caused elevated levels of apoptosis and inflammatory lesions in these mice and produced a smaller increase in TGF-beta and TNF-alpha expression than occurred in wild-type controls. Thus, MEKK1 appears to be required for pressure overload-induced JNK activation and cytokine upregulation but to be dispensable for pressure overload-induced cardiac hypertrophy. MEKK1 also prevents apoptosis and inflammation, thereby protecting against heart failure and sudden death following cardiac pressure overload.

Accelerated cardiomyopathy in mice with overexpression of cardiac G(s)alpha and a missense mutation in the alpha-myosin heavy chain.

BACKGROUND: To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln missense mutation in the alpha-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G(s)alpha (G(s)alpha x403). METHODS AND RESULTS: Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14 bpm) and G(s)alpha x403 mice (718+/- 19 bpm) compared with littermate wild-type mice (WT; 623+/- 18 bpm) and 403 mice (594+/- 16 bpm). Left ventricular ejection fraction (LVEF), as determined by echocardiography, was enhanced in G(s)alpha x403 mice (88+/- 1%, P<0.001) compared with WT (69+/- 1%), 403 (75+/- 1%), and G(s)alpha (69 +/- 2%) mice. Isolated cardiomyocytes from G(s)alpha x403 mice also exhibited higher (P<0.001) baseline percent contraction (11.9+/- 0.5%) than WT (7.0+/- 0.5%), 403 (5.5+/- 0.5%), and G(s)alpha (7.8+/- 0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in G(s)alpha and normalized in G(s)alpha x403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 microgram . kg(-1) . min(-1)) increased LVEF to maximal levels in G(s)alpha x403 and G(s)alpha, whereas in 403, the response was attenuated compared with WT. At 10 months of age, G(s)alpha x403 had significantly depressed LVEF (57 +/- 4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young G(s)alpha x403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of G(s)alpha x403 was 0% compared with 100% for WT, 71% for G(s)alpha, and 100% for 403 mice (P<0.05). CONCLUSIONS: These results show that the cardiomyopathy developed by G(s)alpha x403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.