Physiological and pathophysiological sympathetic nerve hyperactivity. Nerve firing patterns and relation to blood pressure

Abstract

The sympathetic nervous system plays a crucial role in the development of cardiovascular disease. Sympathetic nerve hyperactivity constitutes an important risk factor for cardiovascular morbidity/mortality. It is therefore of general diagnostic value to be able to identify sympathetic nerve hyperactivity and of major prognostic value to be able to identify early stages of sympatho-excitation.Normal aging and adult hypopituitarism with untreated growth hormone (GH) deficiency are conditions associated with increased cardiovascular morbidity/ mortality. The two conditions share many features, and the physiological somatopaus has been suggested to constitute an age-related GH deficient state. While aging is associated with an increase in sympathetic activity (underlying causes largely unknown) the degree of sympathetic discharge has not been studied in adult GH-deficiency. The microneurographic technique has invaluable advantages over other methods in assessing sympathetic cardiovascular control as it allows direct dynamic intra-neural recordings of postganglionic sympathetic nerve traffic to the muscle vascular bed (MSA). The traditional quantification of MSA is however crude as it only allows evaluation of burst count (frequency (BF) and incidence (BI)) and not absolute burst size (area or amplitude) for individual comparisons. Both measures demonstrate large interindividual variability in healthy humans, which does not constitute a problem in situations of large changes in sympathetic nerve activity which are easily recognised, but is a draw back when it comes to identifying moderate changes in MSA between groups in cross-sectional studies. Hence, the microneurographic technique has, in agreement with norepinephrine kinetic studies, revealed sympathetic nerve hyperactivity in severe forms of hypertension and congestive heart failure. However, whether milder forms of heart failure and hypertension are conditions associated with sympathetic activation remains a matter of controversy.In the present studies we evaluated the sympathetic nervous systems relationship to changes in the GH/IGF-I axis as well as the role of MSA in the control of blood pressure level. We also evaluated whether the distribution of burst amplitudes would provide a more sensitive indicator of altered MSA by comparing known and assumed sympatho-excited conditions of different genesis. Resting MSA was recorded and analysed in patients with 1) varying degrees of cardiac failure, prior to and following cardiac transplantation (HTx), 2) hypopituitarism and untreated growth hormone (GH) deficiency and 3) in several groups of healthy controls including a large group of healthy men with a wide age range.MSA BF, BI and proportion of large amplitude bursts increased with the degree of cardiac failure and were normalised following HTx. Furthermore the amplitude distribution was able to identify altered MSA in mild cardiac failure where traditional burst counts failed. MSA BF and BI were also markedly augmented in GH deficient patients and with increasing age whereas in these conditions the burst amplitude distribution was unaffected. MSA was found to be inversely correlated to serum IGF-I concentrations and positively related to diastolic blood pressure levels both in the GH deficient patient group and aging healthy group. MSA was also shown to be an independent predictor of blood pressure level though its influence was much less than that of body mass index.We conclude that the decline in the GH/IGF-I axis seen in GH deficiency and with increasing age is coupled to the increase in MSA which contributes to the blood pressure rise and cardiovascular risk factors associated with the two conditions and that the distribution of burst amplitudes provides a more sensitive indicator of altered MSA in mild CHF, capable of discriminating between sympatho-excitation of different genesis