Effect of nesiritide in patients with acute decompensated heart failure.

BACKGROUND: Nesiritide is approved in the United States for early relief of dyspnea in patients with acute heart failure. Previous meta-analyses have raised questions regarding renal toxicity and the mortality associated with this agent. METHODS: We randomly assigned 7141 patients who were hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. Coprimary end points were the change in dyspnea at 6 and 24 hours, as measured on a 7-point Likert scale, and the composite end point of rehospitalization for heart failure or death within 30 days. RESULTS: Patients randomly assigned to nesiritide, as compared with those assigned to placebo, more frequently reported markedly or moderately improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in rates of death from any cause at 30 days (3.6% with nesiritide vs. 4.0% with placebo; absolute difference, -0.4 percentage points; 95% CI, -1.3 to 0.5) or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). CONCLUSIONS: Nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. It was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure. (Funded by Scios; ClinicalTrials.gov number, NCT00475852.).

Psychologic stress and threshold for repetitive ventricular response.

A psychologically stressful environment reduced the threshold of the dog's ventricle for repetitive response. Elicitation of such a response indicates the presence of electrical instability and a predisposition to ventricular fibrillation, the mechanism of sudden death.

Changes in cyclic AMP dependent protein kinase and active stiffness in the rat volume overload model of heart hypertrophy.

OBJECTIVE: The aim was to clarify the role of cyclic AMP dependent protein kinase (PKA) and changes in mechanical heart function during development of cardiac hypertrophy induced by volume overload. METHODS: Protein and DNA contents, PKA activity, and peak systolic stress-strain relationships in hearts from animals submitted to aortocaval shunt were assessed as a function of time. Sham operated (control) rats were used as controls. RESULTS: Heart weight to body weight ratio and cardiac protein content per heart increased from d 7 (p < 0.005 and p < 0.01, respectively) reaching their highest values by d 56; the same occurred with cardiac DNA content. PKA activity.g-1 tissue in soluble extracts of hearts from rats with aortocaval shunt increased by 2.7-fold on d 2 (p < 0.005), reached a ninefold peak increase by d 7 (p < 0.0001) and declined to fourfold by d 56 with respect to control values. The end peak systolic stress-strain relation slopes were: control, 368(SEM 14) g.cm-2 (n = 16); aortocaval shunt values: 2 d, 514(28) g.cm-2 (n = 6); 7 d, 579(10) g.cm-2 (n = 7); and 56 d, 554(28) g.cm-2 (n = 7). The force generating capacity at 0% strain was also significantly higher in the shunt groups as compared to sham operated controls (p < 0.01). Early activation of PKA was also confirmed through endogenous cardiac protein phosphorylation. SDS-PAGE gel electrophoretogram and autoradiography showed more heavily phosphorylated bands in aortocaval shunt hearts than in the control group. CONCLUSIONS: PKA activity and the slope of systolic stress-strain regression line followed a similar trend throughout the study, with an early increase in both variables by d 2 in the shunt group, reaching a peak at d 7, and decreasing thereafter but remaining higher than in controls. PKA activity appears to be related to increased force generating capacity rather than to hypertrophy or increased cardiac protein content. Thus PKA activation is an early biochemical event after aortocaval shunt, followed later by cardiac hypertrophy. Changes in PKA activity showed a similar trend to mechanical heart function over time. These findings help to explain the changes in the mechanical properties of the heart preceding the development of cardiac hypertrophy in the rat model of volume overload.

Role of cyclic GMP in glutamate neurotoxicity in primary cultures of cerebellar neurons.

The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and nitric oxide neurotoxicity in primary cultures of cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and nitric oxide neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase did not increase intracellular cGMP but increased the content of cGMP in the extracellular medium and prevented glutamate neurotoxicity. Moreover, addition of cGMP to the extracellular medium also prevented glutamate neurotoxicity in cerebellar neurons in culture. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.

Altered content and modulation of soluble guanylate cyclase in the cerebellum of rats with portacaval anastomosis.

It is shown that the glutamate-NO-cGMP pathway is impaired in cerebellum of rats with portacaval anastomosis in vivo as assessed by in vivo brain microdialysis in freely moving rats. NMDA-induced increase in extracellular cGMP in the cerebellum was significantly reduced (by 27%) in rats with portacaval anastomosis. Activation of soluble guanylate cyclase by the NO-generating agent S-nitroso-N-acetyl-penicillamine and by the NO-independent activator YC-1 was also significantly reduced (by 35-40%), indicating that portacaval anastomosis leads to remarkable alterations in the modulation of guanylate cyclase in cerebellum. Moreover, the content of soluble guanylate cyclase was increased ca. two-fold in the cerebellum of rats with portacaval anastomosis. Activation of soluble guanylate cyclase by NO was higher in lymphocytes isolated from rats with portacaval anastomosis (3.3-fold) than in lymphocytes from control rats (2.1-fold). The results reported show that the content and modulation of soluble guanylate cyclase are altered in brain of rats with hepatic failure, resulting in altered function of the glutamate-NO-cGMP pathway in the rat in vivo. This may lead to alterations in cerebral processes such as intercellular communication, circadian rhythms, including the sleep-waking cycle, long-term potentiation, and some forms of learning and memory.

Effects of captopril versus milrinone therapy in modulating the adrenergic nervous system response to exercise in congestive heart failure.

The potential adverse consequences of increased adrenergic nervous system activity in patients with heart failure are now recognized. Modulation of the plasma noradrenaline response to submaximal exercise should be desirable. The long-term (9 weeks) effects of milrinone (10 mg 4 times a day) or captopril (50 mg 3 times a day) compared to placebo were evaluated in a double-blind crossover study, in 16 patients with stable, congestive heart failure receiving digoxin and furosemide. After treatment, clinical status (score range 0 to 14 points) improved significantly with both milrinone (4.4 +/- 0.5, p less than 0.01) and captopril (4.1 +/- 0.4, p less than 0.01). Plasma noradrenaline at rest was similar with both drugs and not significantly different from placebo. During submaximal exercise it increased significantly to 1,228 +/- 58 pg/ml with placebo and to 1,295 +/- 174 pg/ml with milrinone; this response was reduced significantly with captopril, to 820 +/- 100 pg/ml (p less than 0.01). Thus, long-term therapy with both captopril and milrinone improved the clinical score, but only captopril reduced the plasma noradrenaline response to submaximal exercise. These findings suggest that angiotensin-enzyme inhibition with captopril will modulate the adrenergic system response to daily activities in patients with chronic congestive heart failure and therefore could have additional salutary effects beyond vasodilatation.

Association of noninvasive markers of coronary artery reperfusion to assess microvascular obstruction in patients with acute myocardial infarction treated with primary angioplasty.

Early restoration of coronary artery patency through primary angioplasty limits infarct size and improves survival. Increasing evidence, however, suggests that microvascular obstruction is often present despite coronary artery recanalization. This may limit the benefits of reperfusion therapy. We studied the use of noninvasive markers of coronary artery reperfusion as indicators of microvascular obstruction and determinants of prognosis in 98 patients with acute myocardial infarction (AMI) who were successfully treated with primary angioplasty (Thrombolysis In Myocardial Infarction grade 3 flow and residual stenosis <30%). Plasma creatine kinase (CK) levels and 12-lead electrocardiograms were performed on admission, at 90 minutes, and at 6, 12, and 24 hours after treatment. We defined: (1) reperfusion as resolution of ST-segment elevation >50% at 90 minutes, with peak CK levels within 12 hours, and T-wave inversion within 24 hours; and (2) failed reperfusion, as the absence of these parameters. Of the 98 patients studied, 87 (88.8%) had reperfusion and 11 (11.2%) had failed reperfusion. Infarct location was anterior (versus inferior) in 9 patients in the failed reperfusion group (81.8%) compared with 41 patients in the reperfusion group (47.1%) (p <0.01). Congestive heart failure >24 hours after presentation or in-hospital death occurred in 11 patients (12.6%) in the reperfusion group versus 5 (45.5%) in the failed reperfusion group (p <0.01). One-year survival was 96.1% for the reperfusion group and 60.6% for the failed reperfusion group (p <0.0001). We conclude that the association of noninvasive markers of reperfusion better identifies patients with microvascular obstruction among those who had a "successful" primary angioplasty. Evidence of impaired microvascular reperfusion is associated with a poor in-hospital and 1-year outcome.

Effect of a calcium inhibitor, nifedipine, on exercise tolerance in patients with angina pectoris: a double-blind study.

The effect of nifedipine on exercise tolerance was studied in 30 patients with stable angina and positive graded exercise testing. Treadmill exercise testing was performed on each of five consecutive days. Placebo or nifedipine, 10 mg sublingually, was given 30 minutes before exercise on the third day. The following day the intervention was reversed in a double-blind manner. Angina was abolished by nifedipine but not by placebo in 12 patients (40 percent). The time to onset of angina in the remaining patients increased from 4.1 +/- 0.4 (SEM) to 6.7 +/- 0.6 min (p less than .001). Time to ST depression greater than or equal to 2 mm increased from 4.0 +/- 0.3 to 5.4 +/- 0.5 min, while duration of exercise increased from 6.3 +/- 0.3 to 8.2 +/- 0.4 min (p less than .001). The maximum heart rate was 145 +/- 3.3 with nifedipine and 122 +/- 3.8 min-1 with placebo (p less than .01). Resting systolic blood pressure decreased 30 min after nifedipine administration from 131 +/- 3.4 to 106 +/- 2.9 mm Hg (p less than .01). Maximal systolic blood pressure during exercise was lower with nifedipine (127 +/- 4.8 mm Hg) than with placebo (155 +/- 5.6 mm Hg, p less than .01). We conclude that nifedipine significantly improves the exercise tolerance of patients with stable angina pectoris by decreasing peripheral vascular resistance and myocardial oxygen demand.

Role of nitric oxide and cyclic GMP in glutamate-induced neuronal death.

Glutamate is the main excitatory neurotransmitter in mammals. However, excessive activation of glutamate receptors is neurotoxic, leading to neuronal degeneration and death. In many systems, including primary cultures of cerebellar neurons, glutamate neurotoxicity is mainly mediated by excessive activation of NMDA receptors, leading to increased intracellular calcium which binds to calmodulin and activates neuronal nitric oxide synthase (NOS), increasing nitric oxide (NO) which in turn activates guanylate cyclase and increases cGMP. Inhibition of NOS prevents glutamate neurotoxicity, indicating that NO mediates glutamate-induced neuronal death in this system. NO generating agents such as SNAP also induce neuronal death. Compounds that can act as "scavengers" of NO such as Croman 6 (CR-6) prevent glutamate neurotoxicity. The role of cGMP in the mediation of glutamate neurotoxicity remains controversial. Some reports indicate that cGMP mediates glutamate neurotoxicity while others indicate that cGMP is neuroprotective. We have studied the role of cGMP in the mediation of glutamate and NO neurotoxicity in cerebellar neurons. Inhibition of soluble guanylate cyclase prevents glutamate and NO neurotoxicity. There is a good correlation between inhibition of cGMP formation and neuroprotection. Moreover 8-Br-cGMP, a cell permeable analog of cGMP, induced neuronal death. These results indicate that increased intracellular cGMP is involved in the mechanism of neurotoxicity. Inhibitors of phosphodiesterase increased extracellular but not intracellular cGMP and prevented glutamate neurotoxicity. Addition of cGMP to the medium also prevented glutamate neurotoxicity. These results are compatible with a neurotoxic effect of increased intracellular cGMP and a neuroprotective effect of increased extracellular cGMP.

Aluminium impairs the glutamate-nitric oxide-cGMP pathway in cultured neurons and in rat brain in vivo: molecular mechanisms and implications for neuropathology.

Aluminium (Al) is a neurotoxicant and appears as a possible etiological factor in Alzheimer's disease and other neurological disorders. The mechanisms of Al neurotoxicity are presently unclear but evidence has emerged suggesting that Al accumulation in the brain can alter neuronal signal transduction pathways associated with glutamate receptors. In cerebellar neurons in culture, long term-exposure to Al added 'in vitro' impaired the glutamate-nitric oxide (NO)-cyclic GMP (cGMP) pathway, reducing glutamate-induced activation of NO synthase and NO-induced activation of the cGMP generating enzyme, guanylate cyclase. Prenatal exposure to Al also affected strongly the function of the glutamate-NO-cGMP pathway. In cultured neurons from rats prenatally exposed to Al, we found reduced content of NO synthase and of guanylate cyclase, and a dramatic decrease in the ability of glutamate to increase cGMP formation. Activation of the glutamate-NO-cGMP pathway was also strongly impaired in cerebellum of rats chronically treated with Al, as assessed by in vivo brain microdialysis in freely moving rats. These findings suggest that the impairment of the Glu-NO-cGMP pathway in the brain may be responsible for some of the neurological alterations induced by Al.

Phase scaling properties of perturbation-induced multistability in a driven nonlinear system.

Phase scaling relations for the onsets of both saddle-node bifurcations and boundary crises induced by resonant periodic perturbations at subharmonic frequencies are found in a period-doubled system from the results of numerical simulation. These phase dependences determine the domains of existence of induced attractors in (bifurcation parameter, perturbation phase) parameter space. The overlapping of these domains leads to the formation of zones with different numbers of coexisting attractors. The numerical evidence was obtained on the basis of single-mode rate equations of a laser with parameters corresponding to a realistic loss-modulated CO2 laser.

[Evaluation of the effect of enalapril, a converting enzyme inhibitor, on lymphocytic beta-adrenergic receptors of patients with chronic cardiac insufficiency]. / Evaluación del efecto de enalapril, inhibidor de la enzima conversiva, en los receptores betaadrenérgicos de linfocitos de pacientes con insuficiencia cardíaca crónica.

We have previously corroborated that lymphocyte beta-adrenergic receptor density is significantly reduced in patients with chronic heart failure. It is well known that angiotensin converting enzyme inhibitors normalize the function of sympathetic nervous system. We have assessed the effect of enalapril on lymphocyte beta-adrenergic receptor system from patients with chronic heart failure (n = 14) using a random, cross and double blind protocol. Our results show that the improvement in clinical score and ventricular function were not related with changes in the number and affinity of beta-adrenergic receptor nor cyclic AMP content in lymphocytes obtained from these patients.

Geographic differences in outcomes in outpatients with established atherothrombotic disease: results from the REACH Registry.

AIMS: There are major differences in the prevalence and management of patients with atherothrombotic disease including coronary artery disease (CAD), cerebrovascular disease (CVD) and peripheral artery disease (PAD) across different geographical regions. There is, however, little data allowing comparisons of management and outcomes across broad geographic regions. We aimed to describe geographical differences in baseline characteristics, management and outcomes in stable outpatients with established atherothrombotic disease. METHODS AND RESULTS: From the REACH Registry of atherothrombosis, patients with documented CAD, PAD or CVD and with 4-year follow-up were included. Baseline characteristics, treatments and 4-year outcomes were recorded. Event rates were compared between geographical regions and were adjusted for risk scores predicting ischemic and bleeding events. The analyses of baseline characteristics and medications according to geographical region showed marked differences. For the composite primary outcome (cardiovascular death, non-fatal myocardial infarction (MI) and non-fatal stroke), rates ranged from 12.1% in Japan to 18.2% in Eastern Europe. After adjustment, substantial variations remained: taking North America as a reference, patients from Western Europe and Japan had a lower risk of primary outcome event (hazard ratio (HR) 0.93; p = 0.045, and HR = 0.67; p < 0.001 respectively) whereas patients from Eastern Europe had a higher risk (HR = 1.24; p < 0.001). There were no obvious differences between patients from North America and those from Latin America, the Middle East and Asia. CONCLUSION: There are important variations in the outcomes of patients with atherothrombotic across geographic regions. These observations have important implications for public health and clinical research.

[Treatment of atrial fibrillation: a persistent dilemma]. / Tratamiento de la fibrilación auricular: un dilema permanente.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. Increased life expectancy will result in a higher prevalence of AF. Treatment of AF constitutes a persistent medical dilemma. Different multicenter trials have confirmed that oral anticoagulant therapy is the best choice for the prevention of systemic embolism. It must be recognized, however, that the incidence of systemic embolism in patients with AF varies according to the presence and type of underlying heart disease. Advanced age increases the risk of emboli in patients with AF. At the same time, older patients have a higher risk of hemorrhage when treated with oral anticoagulants. Thus, careful titrated individual oral anticoagulant therapy targeted to a safe and effective INR must be considered in patients with AF. Another dilemma in AF patients is the convenience of restoring sinus rhythm and indicating permanent antiarrhythmic therapy versus the alternative of heart rate control plus oral anticoagulants. Several multicenter trials now in progress have addressed this issue and most likely will answer these questions. Identification of patients with paroxysmal AF and risk of systemic embolism constitutes another dilemma, since only a small proportion of these patients evolve to chronic arrhythmia. Advanced age, history of hypertension and left atrial enlargement in 2D Echo are well recognized risk factors for embolism in patients with non valvular paroxysmal AF. A history of previous embolism constitutes another risk factor and supports the hypothesis that AF may activate systemic coagulation factors and left atrial thrombus formation in some patients.