Assessment of baroreflex sensitivity has no prognostic value in contemporary, optimally managed patients with mild-to-moderate heart failure with reduced ejection fraction: a retrospective analysis of 5-year survival.

OBJECTIVES: We evaluated the prognostic value of cardiac baroreflex sensitivity (BRS) in contemporary, optimally treated patients with mild-to-moderate heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: Data from 97 patients with HFrEF (left ventricular ejection fraction 32 ± 6%, all receiving angiotensin-converting enzyme inhibitor/angiotensin receptor blocker and beta-blocker, 85% receiving aldosterone antagonist) were analysed retrospectively. All patients underwent standard clinical assessment, cardiopulmonary exercise testing and BRS evaluation with three methods: the phenylephrine (BRS-Phe), the sequence (BRS-Seq) and the controlled breathing (BRS-CtrBr) method. Data on 5-year all-cause mortality and appropriate and documented implantable cardioverter-defibrillator (ICD) discharges were collected. During a mean follow-up of 53 ± 15 months, the composite endpoint of all-cause death and appropriate and documented ICD discharge occurred in 31 (32%) patients. BRS measures assessed using all three methods were not related to survival in univariate Cox proportional hazards analyses (all P >0.25). There were also no differences in survival between low vs. preserved BRS groups, irrespective of the method used for BRS assessment (all P ≥0.15). BRS-Phe correlated with several clinically important variables (including left ventricular ejection fraction: rS = 0.27, and peak oxygen consumption: rS = 0.32, both P < 0.05), while clinical associations of BRS-Seq and BRS-CtrBr were sparse. CONCLUSIONS: Assessment of cardiac BRS provides no prognostic information in the contemporary mild-to-moderate HFrEF population receiving optimal management.

Dynamic Cerebrovascular and Intracranial Pressure Reactivity Assessment of Impaired Cerebrovascular Autoregulation in Intracranial Hypertension.

We previously suggested that the discrepancy between a critical cerebral perfusion pressure (CPP) of 30 mmHg, obtained by increasing intracranial pressure (ICP), and 60 mmHg, obtained by decreasing arterial pressure, was due to pathological microvascular shunting at high ICP [1], and that the determination of the critical CPP by the static cerebral blood flow (CBF) autoregulation curve is not valid with intracranial hypertension. Here, we demonstrated that induced dynamic ICP reactivity (iPRx), and cerebrovascular reactivity (CVRx) tests accurately identify the critical CPP in the hypertensive rat brain, which differs from that obtained by the static autoregulation curve. Step changes in CPP from 70 to 50 and 30 mmHg were made by increasing ICP using an artificial cerebrospinal fluid reservoir connected to the cisterna magna. At each CPP, a transient 10-mmHg increase in arterial pressure was induced by bolus intravenous dopamine. iPRx and iCVRx were calculated as ΔICP/Δ mean arterial pressure (MAP) and as ΔCBF/ΔMAP, respectively. The critical CPP at high ICP, obtained by iPRx and iCVRx, is 50 mmHg, where compromised capillary flow, transition of blood flow to nonnutritive microvascular shunts, tissue hypoxia, and brain-blood barrier leakage begin to occur, which is higher than the 30 mmHg determined by static autoregulation.

Assessment of the dynamics of atrial signals and local atrial period series during atrial fibrillation: effects of isoproterenol administration.

BACKGROUND: The autonomic nervous system (ANS) plays an important role in the genesis and maintenance of atrial fibrillation (AF), but quantification of its electrophysiologic effects is extremely complex and difficult. Aim of the study was to evaluate the capability of linear and non-linear indexes to capture the fine changing dynamics of atrial signals and local atrial period (LAP) series during adrenergic activation induced by isoproterenol (a sympathomimetic drug) infusion. METHODS: Nine patients with paroxysmal or persistent AF (aged 60 +/- 6) underwent electrophysiological study in which isoproterenol was administered to patients. Atrial electrograms were acquired during i) sinus rhythm (SR); ii) sinus rhythm during isoproterenol (SRISO) administration; iii) atrial fibrillation (AF) and iv) atrial fibrillation during isoproterenol (AFISO) administration. The level of organization between two electrograms was assessed by the synchronization index (S), whereas the degree of recurrence of a pattern in a signal was defined by the regularity index (R). In addition, the level of predictability (LP) and regularity of LAP series were computed. RESULTS: LAP series analysis shows a reduction of both LP and R index during isoproterenol infusion in SR and AF (RSR = 0.75 +/- 0.07 RSRISO = 0.69 +/- 0.10, p < 0.0001; RAF = 0.31 +/- 0.08 RAFISO = 0.26 +/- 0.09, p < 0.0001; LPSR = 99.99 +/- 0.001 LPSRISO = 99.97 +/- 0.03, p < 0.0001; LPAF = 69.46 +/- 21.55 LPAFISO = 55 +/- 24.75; p < 0.0001). Electrograms analysis shows R index reductions both in SR (RSR = 0.49 +/- 0.08 RSRISO = 0.46 +/- 0.09 p < 0.0001) and in AF (RAF = 0.29 +/- 0.09 RAFISO = 0.28 +/- 0.08 n.s.). CONCLUSIONS: The proposed parameters succeeded in discriminating the subtle changes due to isoproterenol infusion during both the rhythms especially when considering LAP series analysis. The reduced value of analyzed parameters after isoproterenol administration could reflect an important pro-arrhythmic influence of adrenergic activation on favoring maintenance of AF.

Vulnerable caregivers of Alzheimer disease patients have a deficit in beta 2-adrenergic receptor sensitivity and density.

OBJECTIVE: The chronic stress of caregiving may lead to sympathetic nervous system activation and immune suppression. beta(2)-adrenergic receptors are expressed on all immune cells and contribute to the stress-induced loss of immune-cell function. The authors examined the effects of being a spousal caregiver of a patient with Alzheimer disease (AD) on the lymphocyte beta(2)-adrenergic receptor. METHODS: One hundred and six women and men, spousal caregivers and non-caregivers, participated (mean age: 71.5 years). Caregivers were classified as either vulnerable or non-vulnerable on the basis of the amount of care required by the patient relative to the amount of respite the caregiver received during the previous 6 months. beta(2)-adrenergic receptor sensitivity (cyclic-AMP response to isoproterenol stimulation) and density (radioligand binding) were determined by use of whole lymphocytes. RESULTS: Vulnerable caregivers had reduced beta(2)-adrenergic receptor sensitivity and density when compared with their non-vulnerable counterparts or with non-caregivers. CONCLUSION: The findings indicate that for more vulnerable caregivers, the stress of caregiving leads to a loss of lymphocyte beta(2)-adrenergic receptors. This finding may be relevant to previous observations of clinically-relevant reduced immunity in highly stressed caregivers of AD patients.

Analgesic and anti-inflammatory screening of two Brazilian medicinal plants: a positive and a false-positive result

Medical plants used in Brazilian folk medicine to treat pain and inflammation constitute 20 per cent of the current publications on plants in the country. The experimental methods to screen these activities, however, are frequently influenced by previous conditions of the animals and other properties of the tested material unrelated to their putative effects. An example is herein reported on studies carried out with two plants reputed for their anti-inflammatory activities: Scoparia dulcis L. collected in Sao Luis, state of Maranhao and Piper marginatum Jacq. collected in Recife, state of Pernambuco. The aerial parts were extracted in hot water, the extracts concentrated and freeze-dried. Previous treatment of rats with either water (0.5 and 1 g/Kg, p.o), decreased the edema produced by carrageenin in the rat paw (40 per cent and 70 per cent), but only the extracts of S. dulcis inhibited the exudate and leukocyte migration induced by carrageenin in the rat pleurisy model (by 60 per cent and 70 per cent, respectively). The ethanolic extract of S. dulcis was more active than the water extract. All extracts reduced the acetic acid induced writhing in mice (by 20 to 60 per cent), the S. dulcis extract being more potent than that of P. marginatum. Both extracts, however, were ineffective in the tail flick test. Intravenous injection of either extract induced hypertension in both anesthetized and unanesthetized rats, but only P. marginatum produced hypertension after oral administration. This effect was blocked after treatment with prazosin (1 mg/Kg). In the isolated rat vas deferens the aqueous and purified extracts induced contractions parallel to those produced by noradrenaline (10(-8) - 10(-4) M) which were blocked by prazosin (10(-7) M). Contractions of electrically paced rat left atria preparations were pontentiated in the presence of either extract (by 30 to 220 per cent), the effect being blocked buy propranolol (2muM). High performance liquid chromatographic analysis of purified hypertensive fractions revealed the presence of both adrenaline and noradrenaline in both extracts. The results indicated that only the S. dulcis extracts presented analgesic/anti-inflammatory effects unrelated to vasoconstriction induced by both catecholamines. The effects obtained upon injection of P. marginatum extracts were unspecific and correlated with the general sympathomimetic effects produced by the extract.

Economy of contraction of cardiomyocytes as influenced by different positive inotropic interventions.

In the present study the effects of the novel cardiotonic agent EMD-57033 on contraction and energetic demand of isolated, electrically stimulated cardiomyocytes were investigated and compared with the effects of enhancement of extracellular calcium and of the beta-mimetic isoproterenol. In a specially designed setup [H. Rose, K.H. Strotmann, S. Pöpping, Y. Fischer, D. Kulsch, and H. Kammermeier. Am. J. Physiol. 261 (Heart Circ. Physiol. 30): H1329-H1334, 1991] parameters of contractile behavior and metabolic demand (O2 consumption) of isolated cardiac myocytes were measured. For a given enhancement of contractile performance (cell shortening) the increase in energetic demand (VO2) after application of EMD-57033 were markedly lower than on treatment with elevated extracellular Ca2+ concentration or with isoproterenol. This economization of positive inotropic effects was proposed to be due to two factors. First, stimulation-related ion cycling was only slightly enhanced with marked increase in contraction amplitude after application of EMD-57033. Second, calcium sensitization reflected in a leftward shift of the calcium concentration needed for half-maximum force development could be interpreted to be mediated by modulation of the cross-bridge dynamics of the myofilaments, where reduction of the switch-off rate of the cross bridges and prolongation of their force-generating states were presumed to be involved. Lowered pH (7.0) decreased economy of contraction. EMD-57033 restored contraction amplitude and economy of contraction at lowered pH.

Cluster headache: combined assessment with pupillometry and evaporimetry.

Twenty-nine patients with cluster headache have been examined with the pupillometer and the evaporimeter. Pupils were dilated by sympathicomimetic drugs instilled into the conjunctival sacs, and responses of the two sides were compared. Forehead sweating was stimulated by body heating and by pilocarpine injection, and sweat evaporation on the two sides was compared. Most patients demonstrated the known patterns of hyposecretion on heating, of pilocarpine supersensitivity, and of deficient pupillary dilatation on OH-amphetamine stimulation on the symptomatic side and a supersensitivity of this pupil to phenylephrine. There were deviations from the rule for all methods of testing. Sixteen patients demonstrated a typical supersensitivity response of the pupil and of the sweat glands on the symptomatic side. Six patients had no such response, and seven patients had a discrepancy between the pupillary and the sweat gland response to stimulation, supersensitivity being present in one system only. There was a high degree of concordance between the results of the various methods of examination.

Intrinsic sympathomimetic activity: physiological reality or marketing phenomenon.

Intrinsic sympathomimetic activity (ISA) describes the partial beta-adrenergic agonist responses elicited by a series of beta-adrenergic antagonists. The dual effect on the beta-adrenergic receptor appears to be related to structural specificity of the drugs allowing competitive binding to the receptor (antagonist activity) and partial interaction at the receptor's activation site (agonist activity). The clinical effects of a beta-adrenergic antagonist with ISA depend on the relative balance of the drug's inherent antagonist and agonist activity and on the degree of underlying sympathetic tone in the patient. Theoretically, the agonist activity may be beneficial in the patient in whom beta-adrenergic antagonists are indicated, but who has concomitant bradycardia and/or mild to moderate congestive heart failure or compromised pulmonary function, or in the patient being withdrawn from beta-adrenergic antagonist therapy. There is positive evidence from clinical trials that in select patient populations a few of these benefits of ISA are afforded without compromise to beta-adrenergic antagonist activity. However, predisposing factors such as acute illness and individual idiosyncrasies may interfere with the manifestations of the agonist effects. Further, maximal response to full beta-adrenergic agonists will be diminished by concurrent therapy with beta-adrenergic antagonists regardless of ISA presence. In summary, ISA does have a physiological basis and increased experience in larger patient populations will help to place it in proper clinical perspective.

Effect of sympathomimetic drugs on canine bladder: surgical model for assessment of regional differences.

A surgical procedure is described in which the canine bladder was divided into body and base. The two-chambered bladder thus formed was used to assess the effect of sympathomimetic drugs in situ. Stimulation of either alpha- or beta-receptors produced a change in pressure in both chambers. The bladder base showed a greater sensitivity to alpha-receptor stimulation than did the body of the bladder. No difference in sensitivity to beta-receptor stimulation was noted between body and base.