At one time, the failing heart was thought to be sympathetically denervated. Longterm administration of inotropic adrenergic agonists, to provide the cardiac catecholamine stimulation thought to be lacking, increased mortality. Noradrenaline isotope dilution methodology subsequently demonstrated that the sympathetic outflow to the heart was preferentially activated, cardiac noradrenaline spillover being increased as much as 50-fold. The level of stimulation of the cardiac sympathetic nerves was the most powerful predictor of death. These observations provide the theoretical foundation for the very successful introduction of beta-adrenergic blockers for treatment of heart failure.
Abstract-Maintenance of cardiac performance is tightly controlled by the autonomic nervous system. In congestive heart failure (CHF), although the adverse pathophysiological effects of cardiac sympathetic overactivity are increasingly recognized, the paradoxical finding of reduced sympathetic innervation density in the failing heart remains unexplained.Given these observations, we tested the hypothesis that a reduction in the myocardial production of nerve growth factor (NGF), which is important for the maintenance of sympathetic neuronal survival, could explain the conflicting neurochemical and neuroanatomical profile of CHF. In healthy humans (nϭ11), there was a significantly greater transcardiac venoarterial plasma NGF gradient than in CHF patients (nϭ11, PϽ0.05). In a rat model of CHF, a 40% reduction (PϽ0.05) NGF mRNA expression was apparent in association with a 24% reduction in tissue NGF content (PϽ0.05). In conjunction, evidence of reduced sympathetic innervation in the failing heart was apparent, as measured histologically by catecholamine fluorescence and by expression of the neuronal NGF receptor trkA. Norepinephrine (10 mol/L) exposure reduced both NGF mRNA and protein expression in isolated cardiomyocytes, suggesting that myocardial NGF downregulation may represent an adaptive response to sympathetic overactivity. These data indicate that NGF expression in the heart is dynamic and may be altered in cardiovascular disease states. In CHF, reduced NGF expression may account for alterations in sympathetic neuronal function and neuroanatomy. Key Words: heart failure Ⅲ nerve growth factor Ⅲ sympathetic nervous system T he clinical features and adverse prognosis associated with congestive heart failure (CHF) represent the result of a complex interplay between impaired cardiac performance and neurohormonal activation. Sympathetic nervous system excitation has been well documented to exist in CHF, based on measurements of plasma catecholamines, 1 radiotracer isotope dilution determination of norepinephrine (NE) spillover rates to plasma, 2 and measurement of multiunit postganglionic muscle sympathetic nerve discharge rates. 3 Coupled with these data, recent observational and clinical trial data highlight the adverse effect of prolonged sympathetic overactivity in CHF patients. 4 -7 In addition to the documentation of a systemic increase in sympathetic tone in CHF, neurochemical studies of the rate of regional NE spillover indicate considerable regional heterogeneity in the pattern of sympathetic activation, this typically occurring earliest and being most elevated in the myocardium. 2,8 Although the rate of NE spillover from cardiac sympathetic neurons to plasma is dependent on the nerve firing rate, 9 other factors including the neuronal reuptake rate and innervation anatomy are of importance. Within this context, the paradoxical observation of reduced sympathetic nervous innervation density in the failing heart despite increased catecholamine overflow remains unexplained. 10
The Postural Orthostatic Tachycardia Syndrome (POTS) is a condition in which heart rate increases abnormally when the individual assumes an upright position. In addition to the marked tachycardia, presyncope, and syncope, patients with POTS often complain of light-headedness, fatigue, and difficulty in concentrating. The present study assessed individuals with POTS for psychiatric comorbidity, anxiety sensitivity and health related quality of life and examined general cognitive ability. Data was obtained from patients with POTS (n = 15, 12 female, aged 30 ± 3 years) and age matched healthy subjects (n = 30, 21 female, aged 32 ± 2 years). Patients with POTS commonly presented with symptoms of depression, elevated anxiety and increased anxiety sensitivity, particularly with regards to cardiac symptoms, and had a poorer health related quality of life in both the physical and mental health domains. While patients with POTS performed worse in tests of current intellectual functioning (verbal and non-verbal IQ) and in measures of focused attention (digits forward) and short term memory (digits back), test results were influenced largely by years of education and the underlying level of depression and anxiety. Acute changes in cognitive performance in response to head up tilt were evident in the POTS patients. From results obtained, it was concluded that participants with POTS have an increased prevalence of depression and higher levels of anxiety. These underlying symptoms impact on cognition in patients with POTS, particularly in the cognitive domains of attention and short-term memory. Our results indicate that psychological interventions may aid in recovery and facilitate uptake and adherence of other treatment modalities in patients with POTS.
Our data challenge the established view that the final trigger for human orthostatic vasovagal reactions is sympathetic nervous system inhibition. Efferent sympathetic nerve traffic to the skeletal muscle vasculature was nearly always maintained through the faint. This finding supports an alternative viewpoint, that vasodilator mechanisms underlie the blood pressure fall in VVS.
Background-Clinical observations in patients with postural tachycardia syndrome (POTS) suggest abnormal sympathetic nervous system activity and a dysfunction of the norepinephrine (NE) transporter (NET). Methods and Results-We examined sympathetic nervous system responses to head-up tilt by combining NE plasma kinetics measurements and muscle sympathetic nerve activity recordings and by quantifying NET protein content in peripheral sympathetic nerves in patients with POTS compared with that in controls. POTS patients had an elevated heart rate during supine rest (81Ϯ2 bpm versus 66Ϯ2 bpm in healthy subjects [HS], PϽ0.01). Head-up tilt to 40°i nduced a greater rise in heart rate in patients with POTS (ϩ24Ϯ4 bpm versus ϩ13Ϯ2 bpm in HS, PϽ0.001). During rest in the supine position, muscle sympathetic nerve activity, arterial NE concentration, and whole-body NE spillover to plasma were similar in both groups. Muscle sympathetic nerve activity response to head-up tilt was greater in the POTS group (ϩ29Ϯ3 bursts/min in patients with POTS and ϩ13Ϯ2 bursts/min in HS, PϽ0.001), but the NE spillover rise was similar in both groups (51% in the POTS subjects and 50% in the HS). Western blot analysis of NET protein extracted from forearm vein biopsies in patients with POTS and HS demonstrated a decrease in the expression of NET protein in patients with POTS. Conclusion-Patients
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