Autonomic nervous dysfunction in essential hypertension

Borderline hypertension, a condition in which the blood pressure oscillates between normal and high values, is a predictor of future more severe hypertension. Pathophysiologically, borderline hypertension is different from established hypertension. A large proportion of such patients have elevated cardiac output and a normal vascular resistance. In established hypertension, the output is normal and resistance is elevated. The elevation of cardiac output in borderline hypertension is neurogenic; it can be abolished by an autonomic blockade of the heart. In addition to an increased cardiac sympathetic drive, increased sympathetic tone to the kidney, arterioles, and veins has also been found. In parallel with the hypersympathetic state, patients with borderline hypertension also show decreased parasympathetic tone. The enhanced sympathetic tone leads to a decreased cardiac responsiveness, and eventually, the cardiac output returns to the normal range. High blood pressure causes vascular hypertrophy, and hypertrophic vessels are hyperresponsive to vasoconstriction. These secondary changes in the responsiveness of the heart and blood vessels are the basis of transition from a high cardiac output to high-resistance hypertension. These hemodynamic changes are associated with a downregulation of the sympathetic tone. A picture of an apparently nonneurogenic high-resistance hypertension emerges. Nevertheless, when assessed in regard to the enhanced pressor responsiveness, the sympathetic drive in such patients is still excessive. Despite the apparently normal tone, the sympathetic nervous system continues to play an important pathophysiological role in established hypertension. Borderline hypertension is associated with numerous metabolic abnormalities including obesity and insulin resistance. It is tempting to view all these abnormalities as a common expression of the increased sympathetic drive in hypertension. Explanation of the basis of the association of hypertension and metabolic abnormalities promises to bring new insights into the pathophysiology of two common diseases of civilization: hypertension and diabetes mellitus.     

Autonomic tone as a cardiovascular risk factor: the dangers of chronic fight or flight.

Chronic imbalance of the autonomic nervous system is a prevalent and potent risk factor for adverse cardiovascular events, including mortality. Although not widely recognized by clinicians, this risk factor is easily assessed by measures such as resting and peak exercise heart rate, heart rate recovery after exercise, and heart rate variability. Any factor that leads to inappropriate activation of the sympathetic nervous system can be expected to have an adverse effect on these measures and thus on patient outcomes, while any factor that augments vagal tone tends to improve outcomes. Insulin resistance, sympathomimetic medications, and negative psychosocial factors all have the potential to affect autonomic function adversely and thus cardiovascular prognosis. Congestive heart failure and hypertension also provide important lessons about the adverse effects of sympathetic predominance, as well as illustrate the benefits of beta-blockers and angiotensin-converting enzyme inhibitors, 2 classes of drugs that reduce adrenergic tone. Other interventions, such as exercise, improve cardiovascular outcomes partially by increasing vagal activity and attenuating sympathetic hyperactivity.     

Heart rate as a cardiovascular risk factor: do women differ from men?

Considerable progress has been made in our understanding of the role of high heart rate in determining cardiovascular morbidity and mortality. However, whether the association between fast heart rate and cardiovascular disease is equally strong in males and females is still a matter for debate. In most studies, the predictive value of tachycardia for all-cause mortality has been found to be weaker in women than in men, and in some studies no association between heart rate and cardiovascular mortality was observed. In particular, high heart rate appeared to be a weak predictor of death from coronary heart disease in the female gender. Multiple mechanisms by which sympathetic overactivity could cause hypertension and the metabolic syndrome of insulin resistance have been documented. Recent results obtained at the Ann Arbor laboratory from the analysis of four populations indicate that these mechanisms are operative mostly in males in whom tachycardia reflects a heightened sympathetic tone. In women, fast heart rate would merely represent the extreme of a normal distribution. However, tachycardia can also have a direct impact on the arterial wall, as demonstrated in laboratory studies, and can favour the occurrence of cardiac arrhythmias. The impact of these mechanisms may be similar in men and women and could explain why a high heart rate has been found to have a detrimental effect also in the female gender. Pharmacological reduction of high heart rate is an additional desirable goal of therapy in several clinical conditions such as hypertension, myocardial infarction and congestive heart failure. Although a greater effect is expected in men, cardiac slowing could counteract the detrimental haemodynamic effect of tachycardia also in women.     

Chronic Idiopathic Pain Syndrome

Considerable progress has been made in our understanding of the role of high heart rate in determining cardiovascular morbidity and mortality. However, whether the association between fast heart rate and cardiovascular disease is equally strong in males and females is still a matter for debate. In most studies, the predictive value of tachycardia for all-cause mortality has been found to be weaker in women than in men, and in some studies no association between heart rate and cardiovascular mortality was observed. In particular, high heart rate appeared to be a weak predictor of death from coronary heart disease in the female gender. Multiple mechanisms by which sympathetic overactivity could cause hypertension and the metabolic syndrome of insulin resistance have been documented. Recent results obtained at the Ann Arbor laboratory from the analysis of four populations indicate that these mechanisms are operative mostly in males in whom tachycardia reflects a heightened sympathetic tone. In women, fast heart rate would merely represent the extreme of a normal distribution. However, tachycardia can also have a direct impact on the arterial wall, as demonstrated in laboratory studies, and can favour the occurrence of cardiac arrhythmias. The impact of these mechanisms may be similar in men and women and could explain why a high heart rate has been found to have a detrimental effect also in the female gender. Pharmacological reduction of high heart rate is an additional desirable goal of therapy in several clinical conditions such as hypertension, myocardial infarction and congestive heart failure. Although a greater effect is expected in men, cardiac slowing could counteract the detrimental haemodynamic effect of tachycardia also in women.     

Insights Into the Pathogenesis of Sudden Cardiac Death From Analysis of Circadian Fluctuations of Potential Triggering Factors

Sudden cardiac death continues to be a poorly understood event in terms of its underlying pathophysiological mechanisms. The observation of a circadian variability in the incidence of this catastrophic event with a prominent peak in the early morning hours provides an opporfunity to study triggering factors that may play a causative role in the genesis of sudden cardiac death. As reviewed in this article, there is convincing evidence that transient disturbances in autonomic tone and the resulting consequences may predispose the heart to increased electrical vulnerability. This evidence is based for instance on circadian fluctuations of spontaneous ventricular ectopic activity and transient ischemia, which may serve as trigger factors for the genesis of sustained ventricular tachyarrhythmias. Analysis of heart rate variability provides further evidence of reduced vagal and elevated sympathetic tone during the morning hours particularly in patients with compromised left ventricuiar function. Diurnal variations in ventricular repolarization as indicated by QT interval changes in the surface ECG also support the concept of triggering factors in the genesis of sudden cardiac death. Therapeutic measures aiming at a reduction in sympathetic input to the heart have been successful in preventing ventricular fibrillation and thus indicate the importance of unbalanced sympathetic tone in patients prone to sudden cardiac death.     

Do increased catecholamines and plasma methionine enkephalin in cirrhosis promote bleeding oesophageal varices?

Increased sympathetic tone and adrenal medullary activity in hepatic cirrhosis may promote portal hypertension. We suggest that they may be imperfect homeostatic mechanisms attempting to maintain systemic arterial pressure in response to chronic vasodilatation and that small, endogenous opioid peptides may play a part in this vasodilatation. As initial investigation of this hypothesis, we measured noradrenaline (an indicator of sympathetic tone), adrenaline and methionine enkephalin in the plasma of patients with cirrhosis with oesophageal varices which had or had not bled previously, patients with cirrhosis without varices, patients with acute liver disease and controls. In patients with cirrhosis, noradrenaline, adrenaline and methionine enkephalin were all greatest in those with oesophageal varices which had previously bled. In this group, noradrenaline correlated strongly with the widely used prognostic guide, Pugh's modification of Child's classification. In patients with acute liver disease, methionine enkephalin and adrenaline were increased six- and four-fold respectively. However, noradrenaline was normal, suggesting that increased sympathetic tone in cirrhosis may develop gradually. The use of opioid antagonists may enable determination of whether elevated plasma opioid peptides in cirrhosis stimulate the increase in sympathetic tone and plasma adrenaline, and promote bleeding oesophageal varices.     

Cardiac sympathovagal balance during sleep apnea episodes

Summary. The main acute cardiovascular effects of obstructive sleep apnea syndrome (OSAS) are elevation of blood pressure and reflectory bradycardia, which are followed by an abrupt tachycardia on resumption of breathing. This haemodynamic instability is related to hypoxemia and arousal, and may lead to increased risk from cardiac arrhythmias and sudden cardiac death, as well as to the development of chronic arterial hypertension, in these patients. The aim of this study was to apply frequency domain analysis of heart rate variability (HRV) measured from continuous electrocardiogram (ECG) recordings to evaluate how cardiac autonomic function, and especially cardiac sympathovagal tone, changes during sleep apnea episodes. We identified 41 apneas leading to more than 4%-unit arterial oxygen desaturation in 12 patients (11 men, 1 women, age range 27–67 years). Frequency domain analysis of HRV was performed from ECG recordings using 4 min epochs starting 20 min before apnea began and lasting 20 min after the beginning of apnea. The mean (± SEM) fall in oxygen saturation during the apnea was 6.8±0.6%-units. While high frequency band (HF, reflects cardiac vagal activity) remained unchanged, low frequency band (LF, mainly sympathetic activity) showed a constant increase, leading to significant change in the sympathovagal balance (LF/HF ratio). In conclusion, concordantly with previous peripheral sympathetic-nerve recordings, frequency domain analysis of HRV is able to detect sympathetic activation during sleep apnea episodes, leading to marked change in the sympathovagal balance.     

Autonomic nervous system profile in fibromyalgia patients and its modulation by exercise: a mini review

This review imparts an impressionistic tone to our current understanding of autonomic nervous system abnormalities in fibromyalgia. In the wake of symptoms present in patients with fibromyalgia (FM), autonomic dysfunction seems plausible in fibromyalgia. A popular notion is that of a relentless sympathetic hyperactivity and hyporeactivity based on heart rate variability (HRV) analyses and responses to various physiological stimuli. However, some exactly opposite findings suggesting normal/hypersympathetic reactivity in patients with fibromyalgia do exist. This heterogeneous picture along with multiple comorbidities accounts for the quantitative and qualitative differences in the degree of dysautonomia present in patients with FM. We contend that HRV changes in fibromyalgia may not actually represent increased cardiac sympathetic tone. Normal muscle sympathetic nerve activity (MSNA) and normal autonomic reactivity tests in patients with fibromyalgia suggest defective vascular end organ in fibromyalgia. Previously, we proposed a model linking deconditioning with physical inactivity resulting from widespread pain in patients with fibromyalgia. Deconditioning also modulates the autonomic nervous system (high sympathetic tone and a low parasympathetic tone). A high peripheral sympathetic tone causes regional ischaemia, which in turn results in widespread pain. Thus, vascular dysregulation and hypoperfusion in patients with FM give rise to ischaemic pain leading to physical inactivity. Microvascular abnormalities are also found in patients with FM. Therapeutic interventions (e.g. exercise) that result in vasodilatation and favourable autonomic alterations have proven to be effective. In this review, we focus on the vascular end organ in patients with fibromyalgia in particular and its modulation by exercise in general.     

Vasodilator correction of hypotension in the postoperative period

This case is unusual in that hypotension, as opposed to hypertension, was a consequence of increased sympathetic tone in the postoperative period, but it illustrates the well known fact that patients in compensated congestive heart failure do poorly when faced with an elevated myocardial oxygen need from either increased rate or afterload. Vasodilator therapy was effective in immediately reducing afterload and systolic regurgitant fraction, thereby increasing oxygen supply and lowering myocardial oxygen consumption.     

Cardiac contractility,central haemodynamics and blood pressure regulation during semistarvation

Eight obese patients were studied before and after 2 weeks of treatment by a very-low-calorie diet (VLCD). Cardiac output and central blood volume (pulmonary blood volume and left atrial volume) were determined by indicator dilution (¹²⁵I-albumin) and radionuclide angiocardiography (first pass and equilibrium technique by [⁹⁹Tc^m]red blood cells). Cardiac output decreased concomitantly with the reduction in oxygen uptake as the calculated systemic arteriovenous difference of oxygen was unaltered. There were no significant decreases in left ventricular contractility indices, i.e. the ejection fraction, the peak ejection rate and changes in end-systolic volume. Also the diastolic function evaluated by the peak filling rate remained normal. Furthermore, no sign of backward failure could be demonstrated since the central blood volume was not significantly increased. Both systolic and diastolic blood pressure (BP) declined. The fall in BP was caused by the reduction in cardiac output as the total peripheral resistance was unchanged. Finally, the decline in total blood volume was not significant. These findings together with a reduction in heart rate indicated that a reduced sympathetic tone via increased capacitance of the venous bed was the main operator of a reduced venous return. Thus, the haemodynamic alterations in obese patients during short-term semistarvation may be caused by the fall in oxygen uptake and produced mainly by changes in the sympathetic tone.     

Risk factors for intraoperative hypotension in traumatic intracranial hematoma

Patients suffering from traumatic intracranial hemorrhage (TICH) may experience an episode of catastrophic intraoperative hypotension (IHT), after decompression of the brain. The aim of this study was to investigate the risk factors for IHT during emergency craniotomy A total of 67 patients, who underwent emergency craniotomy due to TICH, were divided into two groups: IHT ( n=31 ) or without IHT ( n=36 ). Data concerning (1) age; (2) gender; (3) mechanism of injury; (4) Glasgow Coma Scale (GCS) on admission; (5) abnormality of the pupils (anisocoria or mydriasis); (6) mean arterial blood pressure; (7) heart rate; (8) time elapsed before craniotomy from injury; (9) initial brain CT scans; (10) duration of craniotomy; and (11) total infusion or urine volume until craniotomy were collected prospectively as IHT risk factors. Low GCS score (<5), tachycardia (heart rate >112min(-1)) and hypertension (mean blood pressure >131mmHg) before emergency craniotomy were strongly ( P<0.05 ) associated with IHT. Delayed surgery (>173min until craniotomy) also had a significant ( P<0.005 ) effect on IHT. The risk factors for IHT were considered as a low GCS score on admission, tachycardia, hypertension before emergency craniotomy and delayed surgery. These results suggested the patients with IHT had a high sympathetic tone before emergency craniotomy A sudden reduction in sympathetic tone after surgical decompression of the brain might cause IHT. We concluded that an important factor in the occurrence of IHT was not only the injury severity, but also the balance between sympathetic and parasympathetic activity before decompression surgery.     

Sympathetic Neural Mechanisms in Human Cardiovascular Health and Disease

The sympathetic nervous system plays a key role in regulating arterial blood pressure in humans. This review provides an overview of sympathetic neural control of the circulation and discusses the changes that occur in various disease states, including hypertension, heart failure, and obstructive sleep apnea. It focuses on measurements of sympathetic neural activity (SNA) obtained by microneurography, a technique that allows direct assessment of the electrical activity of sympathetic nerves in conscious human beings. Sympathetic neural activity is tightly linked to blood pressure via the baroreflex for each individual person. However, SNA can vary greatly among individuals and that variability is not related to resting blood pressure; that is, the blood pressure of a person with high SNA can be similar to that of a person with much lower SNA. In healthy normotensive persons, this finding appears to be related to a set of factors that balance the variability in SNA, including cardiac output and vascular adrenergic responsiveness. Measurements of SNA are very reproducible in a given person over a period of several months to a few years, but SNA increases progressively with healthy aging. Cardiovascular disease can be associated with substantial increases in SNA, as seen for example in patients with hypertension, obstructive sleep apnea, or heart failure. Obesity is also associated with an increase in SNA, but the increase in SNA among patients with obstructive sleep apnea appears to be independent of obesity per se. For several disease states, successful treatment is associated with both a decrease in sympathoexcitation and an improvement in prognosis. This finding points to an important link between altered sympathetic neural mechanisms and the fundamental processes of cardiovascular disease.MI = myocardial infarction; MSNA = muscle sympathetic neural activity; OSA = obstructive sleep apnea; SA = sinoatrial; SNA = sympathetic neural activityThe sympathetic nervous system plays a vital role in the everyday lives of human beings. Sympathetic neural responses are essential to simple tasks such as changing posture. Movement from a supine or sitting position to an upright position requires complex adjustments in blood flow and blood pressure, and these adjustments are ultimately coordinated by sympathetic nerves in conjunction with parasympathetic modulation of heart rate. Without such adjustments, blood flow to the brain would fall below autoregulatory limits, and standing up would consistently cause syncope. Indeed, some persons with severe autonomic failure are unable to stand (or sometimes even to sit upright) without fainting.^1,2This article presents an overview of our current understanding of sympathetic neural mechanisms in human cardiovascular control. It focuses on measurements of sympathetic neural activity (SNA) that are obtained by microneurography, a technique that can directly measure the electrical activity of sympathetic nerves in intact, conscious human beings. During the past 3 decades, the information yielded by this technique has greatly increased our clinical and mechanistic understanding of sympathetic neural mechanisms in health and disease. Ongoing research using this technique continues to yield new insights into the pathophysiology of cardiovascular diseases, including hypertension, coronary artery disease, and heart failure, and into the cardiovascular risk associated with diseases such as obstructive sleep apnea (OSA) and obesity.     

Pathophysiology of essential hypertension: an update

ABSTRACT

Introduction: Hypertension is caused by increased cardiac output and/or increased peripheral resistance.

Areas covered: The various mechanisms affecting cardiac output/peripheral resistance involved in the development of essential hypertension are covered. These include genetics; sympathetic nervous system overactivity; renal mechanisms: excess sodium intake and pressure natriuresis; vascular mechanisms: endothelial cell dysfunction and the nitric oxide pathway; hormonal mechanisms: the renin-angiotensin-aldosterone system (RAAS); obesity, obstructive sleep apnea (OSA); insulin resistance and metabolic syndrome; uric acid; vitamin D; gender differences; racial, ethnic, and environmental factors; increased left ventricular ejection force and hypertension and its association with increased basal sympathetic activity – cortical connections.

Expert commentary: Maximum association of hypertension is found with sympathetic overactivity which is directly or indirectly involved in different mechanisms of hypertension including RAAS, OSA, obesity, etc.. It is not overt sympathetic activity but disturbed basal sympathetic tone. Basal sympathetic tone arises from hypothalamus; possibly affected by cortical influences. Therefore, hypertension is not merely a disease of circulatory system alone. Its pathogenesis involves alteration in ANS (autonomic nervous system) and likely in cortical-hypothalamic connections. Assessment of ANS and cortical-hypothalamic connections may be required for better understanding of hypertension.     

Pharmacologic reduction of sympathetic drive increases platelet alpha-2-receptor number

Several lines of evidence implicate sympathetic nervous system involvement in the pathophysiology of essential hypertension in man. Extrapolations are frequently made from in vitro measurements of plasma catecholamine levels to the physiologic role of the sympathetic system in hypertension. We assessed the utility and validity of such extrapolation from in vitro to in vivo measures of adrenergic function. Addition of guanadrel to diuretic therapy in 11 patients with essential hypertension reduced supine intra-arterial blood pressure from 135 +/- 14/76 +/- 9 to 127 +/- 13/67 +/- 5 mm Hg (P less than 0.02). Supine heart rate was also reduced, from 77 +/- 14 to 63 +/- 13 bpm (P less than 0.001). Plasma norepinephrine levels fell from 303 +/- 107 to 170 +/- 46 pg/ml (P less than 0.01). Platelet alpha 2-receptor number ([3H]yohimbine maximal binding) increased from 204 +/- 77 to 301 +/- 150 fmol/mg (P less than 0.02). The pupillary mydriatic response to phenylephrine and the forearm arterial vasoconstrictor response to intra-arterial norepinephrine did not change. Thus guanadrel reduced blood pressure by decreasing sympathetic tone. In this milieu of low sympathetic activity the platelet alpha 2-receptor number increased, but physiologic responses to exogenous alpha-agonists did not change. Caution is therefore advised when extrapolating from in vitro measurement of plasma catecholamine levels and platelet alpha 2-receptor number to the in vivo physiologic significance.     

Abnormality of blood congulation

Obstructive Sleep Apnea(OSA) is associated with an increased prevalence of cardiovascular complication such as systemic hypertension, ischemic heart disease and stroke, which may lead to unexpected or early death. Sleep in patients with OSA demonstrates a pattern of recurrent arousals, hemodynamic changes, and sympathetic neural activity that have been associated with adverse carviovascular events following awakening in the morning. Neurologic problems in patients with OSA include cognitive impairment, poor memory, and high risk for cerebral infarction. These central nervous system symptoms might be due to hypoxemia and sleep fragmentations. The vascular endothelial damage, platelet aggregation, and hemodynamic changes during sleep apnea are influenced by changes in oxygen and carbon dioxide tension inducing alterations of vascular tone. The cerebral hemodynamics in relation to apneas may not only influence daytime cerebral symptoms but may also have implications for the generation of cerebrovascular disease in OSA. These changes resulted from OSA might play an important role in pathophysiological aspects of the central nervous system. And these changes will be improved after CPAP application.     

Ramipril Enhances Autonomic Control in Essential Hypertension: A Study Employing Spectral Analysis of Heart Rate Variation

We estimated the effect of an angiotensin-converting enzyme inhibitor, ramipril, on the sympathetic and parasympathetic input to the sinoatrial node of hypertensive patients using spectral and time domain analysis of heart rate variation (HRV). The heart rate of patients with essential hypertension was recorded during spontaneous breathing at rest and during controlled deep breathing. The periodic HRV was quantified at low-frequency (0.025--0.075 Hz), mid-frequency (0.075--0.125 Hz) and high-frequency (0.15--0.40 Hz) bands. Ramipril changed the balance of autonomic nervous system assessed by spectra: the parasympathetic tone increased (p < 0.05) and the sympathetic tone decreased (p < 0.01). There was an inverse correlation between the decrease in diastolic blood pressure and increase in the mid-frequency HRV, which is connoted with resetting of the baroreceptor reflex by ramipril. Thus, ramipril treatment was associated with improved autonomic control of the circulatory system.     

Significance of primary T wave aberrations in the electrocardiogram of asymptomatic young men, III. Systolic time intervals and autonomic tone

Fifteen healthy male subjects, aged 18-19 years, with primary T wave aberrations consisting mainly of notches in the T wave without concomitant ST depression (group T) were compared to twenty-six controls of the same age with normal electrocardiograms. The T wave aberrations were eliminated by beta-adrenergic blockade in thirteen subjects in group T. Physical exercise decreased all the T wave aberrations. Group T was on average shorter and had signs of higher sympathetic tone, as shown by a higher heart rate and systolic blood pressure, than the controls and the parasympathetic tone was lower, as indicated by a higher heart rate during beta-adrenergic blockade. No significant differences in physical work capacity and heart volumes were found. Measurement of systolic time intervals suggested increased sympathetic influence on the heart and no signs of cardiac impairment. Thus the majority of subjects with aberrant T waves had changes in the autonomic tone and no signs of functional impairment of the heart.     

Renal haemodynamics before and after splanchnic block in patients with hypertension

In eighteen patients with hypertension of presumed renal origin the haemodynamics of the kidney were studied by arterial pressure recording, blood flow measurement and selective arteriography before and after a splanchnic block. The material was divided into kidneys with and kidneys without arterial stenosis. In these patients with hypertension a positive correlation was found between mean arterial pressure and renal vascular resistance both before and after the splanchnic block. In patients with renal arterial stenosis the change in relative renal vascular resistance was negatively correlated to the initial resistance, implying that in kidneys with a high initial vascular resistance the resistance decreased to a relatively greater extent than in kidneys with a low initial resistance. At high blood pressures ischaemic areas in the kidney were found. The volume of these areas is dependent upon sympathetic tone, such that a high sympathetic tone results in ischaemia of a larger volume of the kidney. This applies both to kidneys with and to those without arterial stenosis. The results of this investigation thus support the assumption that in the presence of hypertension a kidney is under the control of a sympathetic tone that may form a part of the pathogenetic process in hypertension.     

Stress, depression and cardiac arrhythmias

A relationship between behavioural factors and cardiac arrhythmogenesis in humans has been described. Three sets of conditions contribute to the occurrence of arrhythmias: myocardial electrical instability, most often due to coronary artery disease; an acute triggering event, frequently related to mental stress; and a chronic, pervasive, and intense psychological state, often including depression and hopelessness. The autonomic nervous system plays an important role in the occurrence of cardiac arrhythmias and it is well documented that mood alterations as mental stress and depression influence cardiac autonomic balance. There is an increasing body of evidence that patients with the greatest changes in cardiac neural regulation with decreased parasympathetic tone coupled with increased sympathetic activity are at the greatest risk for developing fatal ventricular arrhythmias. These patients have a reduced heart rate variability, increased QT-dispersion and a decreased baroreceptor sensitivity. The influence of stress and depression on the autonomic nervous system and the impact on the occurrence of both atrial and ventricular arrhythmias is being discussed.