Recent research has made important progress in characterizing the role of the autonomic nervous system (ANS) under physiological and pathophysiological conditions as an integrative component in the interorgan interplay.

Early diagnosis of ANS dysfunction within intensive care patients poses a challenge as the majority will go on to display features of sympatho-vagal dysregulation during the course of the disease (e.g. [1]).

Through the measurement of specific ANS parameters clinicians and researchers are enabled to improve cardiovascular and cerebrovascular risk stratification.

The following chapter briefly outlines ANS functions and interactions and summarizes the most relevant methods of its measurement through Heart Rate Variability (HRV) analysis. Prognostic evaluation of critical care patients using such a cost and time-efficient tool as a Holter-ECG in conjunction with clinical scores have been assessed in a number of clinical studies. Here, we will review the present evidence from these studies for such highly relevant pathophysiological conditions of heart failure and myocardial infarction with focus on prognosis of sudden cardiac death, and stroke with a special emphasis neurological outcome related to ANS dysfunction.

Autonomic nervous system (ANS) responses to (patho-) physiological stimuli have been characterized by a complex interaction between the different components of the ANS on the one hand, and visceral organs and (involuntary) innervated glands on the other hand. In conjunction with the sensory and motor nervous system, the autonomic nervous system (ANS) is responsible for fast, continuous and normally subconscious control of basic physiological functions, such as heart rate, blood pressure, respiratory rate, body temperature and gastrointestinal motility. Forming a functional network of peripheral and central mechanisms throughout the body the autonomic nervous system, however, has two basic divisions: the parasympathetic and the sympathetic component. The classical thinking that parasympathetic and sympathetic nervous system are usually acting in opposition holds true for many ANS functions as in cardiovascular, respiratory as well as gastrointestinal and urinary tract innervations and reactions. But in many other situations the two divisions work synergistically in response to a simultaneous sympathetic and vagus nerve stimulus.

The ANS consists of efferent neurons running in series to innervate smooth musculature of all viscerals and vessels, the heart and glands. Afferent neurons relay visceral input to different parts of the brain. The sympathetic postganglionic transmitter is norepinephrine, whereas the parasympathetic postganglionic transmitter is acetylcholine.

ANS, however, also interacts with different brain structures. The central and peripheral autonomic information is processed by the central nervous system, involving forebrain structures (frontal premotor cortex), hypothalamus, pituitary, amygdala, and the insular cortex. Included in this central network are also several brainstem structures, such as nucleus tractus solitarius (NTS), dorsal motor nucleus of the vagus (DMN), and nucleus ambiguous (NA).

To generate a homeostatic signal level three pathways are relevant: the hypothalamo-pituitary-adrenal (HPA) axis, the parasympathetic and the sympathetic nervous system [2]. Hypothalamic signal input results in the release of corticotrophin-releasing factor from the paraventricular nucleus, by which the HPA axis and the sympathetic nervous system as well as the parasympathetic system are modulated. The HPA axis activation finally leads to production of glucocorticoids, resulting in immunomodulation among other hormone related effects.

Peripherally, afferent vagus nerve fibers forward visceral (inflammatory) signals to the brain. Inhibition of inflammation by suppressing pro-inflammatory cytokine release through efferent vagus nerve signals (mediated by acetylcholine, the principle vagal neurotransmitter) has been proposed as the cholinergic anti-inflammatory pathway [3]. Synergistic with the parasympathetic nervous system, the sympathetic activation and secretion of epinephrine and norepinephrine from the adrenal medulla and release from sympathetic nerve terminals also results in beta adrenergic mediated immunological and autonomic modulation [4, 5].

These mechanisms aim to keep sympatho-vagal homeostasis. The role of the ANS, however, remains to be further elucidated as a possible key player in the bodies’ response to pathophysiological conditions in order to consolidate cardio- and cerebrovascular and immune function as well as to develop implications for early diagnosis and treatment of respective dysfunctions.

Myocardial infarction (MI) and heart failure are the leading causes of death and morbidity in industrial countries. Investigations of patients after MI revealed ANS dysfunction as a predictor for cardiac mortality in association with increased incidence of sudden cardiac death [33]. For the general clinical use HRV measures are of particular interest in cases where they add prognostic value independent of the established clinical variables or where they can substitute complicated clinical scores by easily obtainable HRV indices during monitoring.

Therefore, since more than one decade HRV analysis is established in clinical cardiology and accepted as a part of risk assessment concerning sudden cardiac death. Currently, the development of HRV based ICD (implantable cardioverter defibrillator) control parameters is one of the predominant questions.

The autonomic rhythms represented by heart rate patterns reflect certain pathophysiological aspects of several cardiac disorders, like myocardial infarction, congestive heart failure, cardiomyopathy, or ischemic heart disease. The comorbidity of cardiac diseases with for example psychiatric or mental disorders leads to even more complicated identification of the origin of a measured HRV pattern. For example, the very low frequency (VLF) band power in depressive in comparison to non-depressive patients (both groups with recent acute myocardial infarction (MI)) is reduced due to depression and MI, whereby both disorders constitute independent factors of mortality [34].

Additionally, HRV is influenced by current physical activity, sleep states, circadian rhythm, as well as on age of the patient (e.g. [35-42]).

Representative results of larger clinical prognosis studies of patients with cardiac diseases using 24 hours HRV are summarized in Table 2. A comprehensive review of HRV based predictors of mortality after myocardial infarction by Kleiger et al. [24] includes the selected key results presented here. The strongest clinical risk predictor is a reduced left ventricular ejection fraction (LVEF). A main objective of clinical studies is to evaluate whether HRV indices provide independent additional prognostic value.

Reflecting the briefly summarized results presented in Table 2 obviously the reduced overall variability (SDNN, HRV index) or slow rhythms (VLF band power) provide consistent HRV based risk predictors.

In chronic heart failure patients and those with unstable angina also reduced LF or LF/HF showed predictive value. A reduced DFA index (reduced fractal correlations) was found of superior predictive value than SDNN in a study of post-myocardial infarction patients [43].

Due to the interindividual heterogeneity and the complex contributions such as autonomic, mental, psychiatric, physical activity, circadian rhythm, etc. besides the cardiac dysfunction, and furthermore the often unclear causality and comorbidity, it is unlikely to find the “optimal” HRV index. However, selected indices may be sensitive to particular aspects of pathophysiological autonomic control and hence particular patient groups.

Maestri et al. [44] compared 20 nonlinear indices and SDNN as the best discriminating linear HRV index in a group of 200 patients with chronic heart failure (CHF). They found two nonlinear indices (one from empirical mode decomposition, one from symbolic dynamics) as significant predictors independent of the clinical parameters and SDNN. A third respective set of significant nonlinear predictors of this CHF patient group was found by autonomic information flow (AIF) characteristics [45]. These provided additional predictive value to the best clinical indices NYHA class and LVEF. The Kaplan Mayer survival curves (Fig. 4) show their discriminatory power. The result of this patient group indicates the predictive value of the complex overall autonomic adjustment as superior compared to particular rhythms, such as HF or LF, which did not significantly contribute in that study.

Fig. (4). Kaplan-Meier survival curves for total cardiac mortality, AIF index according to [45].

In a scientific statement from the American Heart Association Council on Clinical Cardiology Committee on Electrocardiography and Arrhythmias and Council on Epidemiology and Prevention noninvasive risk stratification techniques for identifying patients at risk for Sudden Cardiac Death (SCD) were reported [46]. LVEF, QRS duration, QT interval, QT dispersion, signal-averaged electrocardiogram, as well as, short-term HRV were concluded as with limited predictive value. Long-term ECG recordings provide information about both, ventricular arrhythmias and long-term HRV. Ventricular arrhythmias were found as an abundant and recommended SCD predictor in post-MI patients. Depressed HRV was confirmed to be a clear predictor of overall mortality in several studies such as also reported in Table 2. In particular in non-arrhythmic mortality long-term HRV may be a better predictor. Finally, HRT, which assesses the autonomic response modulating the heart rate, turned out as promising candidate for SCD prediction. The latter two results, namely long-term HRV and HRT, confirm the relevance of considering the autonomic control and dysfunction, respectively, as independent predictors of SCD.

In conclusion, the key results of the studies summarized in Table 2 clearly show the independent prognostic value of the autonomic nervous system related indices in extension to clinical and functional variables. Nevertheless, other influences such as age, gender, history, NYHA class, treatment (thrombolysis, beta-blocker, ACE inhibitors), major depression, etc. were partly considered as confounders of HRV indices.

The consistent prognostic value of long term variability and correlations (SDNN, SDNNindex, VLF, beta-slope) may reflect the importance of the complex adjustment of several underlying mechanisms such as vagal and sympathetic rhythms (Table 2). Those results confirm the importance of complex autonomic adjustments and thus strongly motivate applying AIF analysis in the risk assessment in CHF and MI patients [45]. Furthermore, these results support the importance of a complex systemic analysis, reflecting both the particular cardiac disorder and compensation/adaptation by autonomic and other systemic mechanisms. In conclusion, the established linear HRV analysis provides sensitive markers of the cardiovascular-systemic response to cardiac dysfunctions, which can significantly be extended by novel nonlinear methods.

In stroke as the third most important cause of death in industrial countries a variety of ANS disturbances can occur. They are attributed to the damage of the different compartments of the central autonomic network, i.e. frontoparietal cortical areas and brain stem (see above, and Fig. 5) or may result from disrupted autonomic pathways (hypothalamus-mesencephalon-pons-medulla oblongata-spinal cord). Among the ANS dysfunctions in stroke victims cardiovascular sympathetic/ parasympathetic dysbalance is most evident in the acute phase of stroke. This cardiovascular as well as infection related morbidity within the first days after stroke is very relevant for survival and neurological outcome after stroke [52].

Fig. (5). Stroke related autonomic disturbances and their clinical relevance.

Since the early 1990^th studies in ischemic brain infarction revealed frequent ANS dysfunctions in association with pathological activation of the sympathetic system. Such a sympathetic hyperactivation and autonomic imbalance in acute ischemic stroke patients resulted in increased risk and incidence of severe cardiac arrhythmias and sudden cardiac death [53-56].

Based on NN interval analysis Colivicchi et al. showed in 208 stroke patients the best predictive value for 1 year survival using SDNN, however the occurrence of ventricular tachycardia had an even higher predictive value [57]. Interestingly, stroke localization seems to play an important role in this context: HRV dysregulation (i.e. decreased LF, HF and SDNN) was more frequent in association with right hemispheric and insular stroke independent of the use of either time frame or spectral analysis. Right hemispheric brain infarction with insular involvement is associated with the highest degree of ANS dysfunction (measured as decreased HRV and increased heart rate) [55]. This ANS dysfunction was associated with higher incidence of sudden death [58].

The prognostic importance of a sympathetic activation post stroke was demonstrated in more than 100 patients studied by [59]. An elevated norepinephrine concentration was associated with insular involvement, nocturnal elevated blood pressure and prolonged QTc interval in the ECG. One year post stroke these patients showed a higher incidence of cardio- and cerebrovascular events, a lower degree of neurological restitution of stroke symptoms in conjunction with lower rate of independence [59].

Relevant studies analyzing stroke associated changes in ANS activity and of those assessing the prognostic value of HRV indices after stroke based on 24 hours ECG recordings are reviewed in Table 3.

Predictors for a lethal outcome are diminished heart rate variability (HRV), insular cortex involvement, and the occurrence of complex arrhythmias within 72 h after admission [55,57]. A decreased nocturnal vagal dominance leading to hypertension and decreased HRV during night-time resulted in a long lasting autonomic dysfunction and thus chronic risk [60]. The standard deviation of all normal to normal R-R (NN) intervals (SDNN) is a very strong prognostic predictor, together with the cardiac arrhythmia rate [55,57,60,61].

In summary, a number of experimental and clinical studies have revealed that ANS dysfunction represents a relevant pathogenetic factor and indicator for post stroke morbidity and mortality. Thus, using HRV related indices in acute and postacute stroke victims may improve prognostic evaluation and also counseling of patients, and may thus eventually lead to new preventive strategies recognizing the important relationship of ANS dysfunction and central nervous system injury.

Heart rate patterns which can easily be obtained from Holter ECG recordings reflect important characteristics of the complex autonomic control. They are not only associated with cardiac arrhythmias, but implicate sympathetic and parasympathetic modulations.

In stroke and cardiovascular disease as well as in other very relevant clinical constellations, such as in sepsis and MODS (multiple organ dysfunction syndrome; e.g. [14,25] a selective pathological disturbance leads to a complex systemic compensation and adaptation process. Consequently, final decompensation and respective risk assessment might be related rather to an overall systemic response than to a particular mechanism, unless this is fatally altered itself. Therefore, it is not surprising, that for heart failure / MI patients the comprehensive HRV measures like SDNN, VLF, beta slope, complexity, and AIF measures were found to have the best predictive value (as reviewed above). On the other hand, specific indices, such as the shifted adjustment between sympathetic and vagal activity (sympatho-vagal (im)-balance) due to stroke and cardiovascular diseases provided predictive value with more specific physiological implications.

From the clinical point of view the main question is, whether HRV indices provide additional pathophysiological and predictive value going beyond the conventional risk factors and clinical parameters which are so far not completely satisfying in particular in severely and acutely ill patients. This objective becomes even more challenging since multiple “cardiovascular” confounders, such as diabetes, age, daytime, as well as pharmacological interventions like beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and statins which modulate autonomic tone and systemic proinflammatory responses [68] have to be considered.

Besides the autonomic modulations, which are assessed following the established HRV guidelines [6], cardiac arrhythmias such as atrial fibrillation, sinoatrial dysfunction and ectopic complexes are of essential prognostic value and their patterns are subject of current research. Especially after stroke the HRV-index SDNN and the presence of non-sustained ventricular tachycardia were independent predictors of the 1-year mortality [57]. Cardiogenic arrhythmias and autonomic modulations cannot be completely separated, because of the complex autonomic-cardiovascular system, but both aspects have to be considered in a way appropriate for the respective situation, such as sinus rhythm or cardiac arrhythmia. Furthermore, stroke related immunodepression [2] has to be considered as another important player in this relationship between ANS, CNS and cardiovascular system.

Due to the multiple influences on the autonomic function and the rapid development of confounding or targeted therapies large scale clinical studies are immediately necessary to further evaluate the clinical value of the above mentioned HRV indices in cardio- and cerebrovascular risk assessment und management.