Autonomic Cardiac Nervous System Research Articles

ARNI effects in HFrEF. Risk reduction beyond LVEF

Abstract Background The imbalance of cardiac autonomic nervous system function plays an important role in heart failure associated mortality. ARNI has demonstrated a paramount effect in reducing risk of death and hospitalization for worsening of heart failure. However, its exact mechanism of action remains only partly understood. We sought to prospectively compare heart rate variability as a noninvasive measure of cardiac autonomic nervous system function. Methods The study design was prospective sequential observational. Patients served as their own internal control. Patients with heart failure with reduced ejection fraction (HFrEF) receiving optimal medical therapy who were scheduled for a switch to ARNI therapy underwent echocardiography and a standardized 30-minute 12-lead Holter ECG recording before starting ARNI therapy. A monitoring of the parameters was performed 3 months after the start of therapy. Physicians were instructed to increase ARNI dose to the highest tolerated or maximum dose. Besides left ventricular ejection fraction (LVEF) we assessed heart rate (HR), standard deviation of normal-to-normal intervals (SDNN) and mean square of differences between consecutive R-R intervals (RMSSD). Results We recruited 55 patients and baseline characteristics were as follows: age 65±12 years, male sex 78%, NT-proBNP 4989±809 pg/ml, LVEF 28±6%, HR 75±9 bpm, SDNN 43±2 ms, RMSSD 19±2 ms. All patients received beta-blocker therapy and the dosage was similar at baseline and follow-up. After 3 months of ARNI therapy, heart rate showed a significant reduction of 7% (74±14 bpm vs. 69±11 min, P=0.005). SDNN increased by 49% (43±2 ms vs. 64±4 ms, P<0.001) and RMSSD by 42% (19±2 ms vs. 27±3 ms, P=0.01). These results were accompanied by increased LVEF (28±6% vs. 38±10%, P<0.001) and reduced plasma NT-proBNP levels (4989±809 pg/ml vs. 2602±87 pg/ml, P<0.04). NYHA Class of affected patients changed from III to II. Conclusion After changing from ACE/AT1-I to ARNI, significant improvement of autonomic cardiac nervous system function could be observed. ARNI apparently activates the parasympathetic nervous system as suggested by decreased HR and increased SDNN and RMSSD. Therefore, part of its cardioprotective and beneficial effects may relate to the restoration of autonomic cardiac nervous system function. Potential beneficial effects regarding incidence of sudden cardiac arrest may relate to these observations. Funding Acknowledgement Type of funding sources: None.

The autonomic cardiac nervous system and arrhythmogenesis: risk stratification in the foreseeable future.

Both experimental and clinical studies have shown that the autonomic nervous system plays an important role in arrhythmogenesis. Many methods describing cardiovascular autonomic regulation have been developed and tested for use as predictors of arrhythmic and other cardiovascular events. The majority of studies have focused on patients with known cardiac disease, such as prior myocardial infarction or congestive heart failure. All-cause mortality, as well as non-sudden and sudden cardiac death have been used as main endpoints. Sudden cardiac death has often been considered to be equivalent to arrhythmic cardiac arrest. Despite promising results in this field, markers of the autonomic nervous system are still not routinely used in clinical practice, mainly due to the fact that measurement of these markers does not result in evidence-based therapeutic implications. There is still a lack of randomized trials using autonomic markers as pre-defined variables in selecting patients for the studies, which would have yielded results that an intervention reduces the arrhythmic or other endpoint in those with abnormal or impaired autonomic regulation. Hence, at present, the possible use of autonomic assessment in predicting life-threatening arrhythmias is restricted to individual cases at the borders of intervention guidelines.

Acupuncture at the auricular branch of the vagus nerve enhances heart rate variability in humans: An exploratory study.

BackgroundRecent animal and human studies have shown antiarrhythmic effects inhibiting inducibility of atrial fibrillation through low-level transcutaneous electrical stimulation at the auricular branch of the vagus nerve (ABVN).ObjectiveThe present study investigated effects of acupuncture at the ABVN on the autonomic cardiac nervous system in humans through analysis of heart rate and heart rate variability (HRV) parameters.MethodsWe enrolled 24 healthy male volunteers and compared acupuncture at the ABVN to placebo-acupuncture performed at the Ma-35 point (an acupuncture point used in traditional Chinese medicine to treat pain caused by gonarthrosis). An additional measurement without acupuncture served as control. We analyzed the following heart rate and HRV parameters: standard deviation of normal-to-normal intervals (SDNN), root mean square of successive R-R interval differences (RMSSD), high frequency (HF), low frequency (LF), LF/HF ratio.ResultsIn comparison to placebo acupuncture, acupuncture at the ABVN led to a significant reduction in heart rate (approximately 4%–6%, P < .05) and an increase in overall HRV demonstrated by SDNN (approximately 19%, P < .05). RMSSD and power spectral density parameters (HF, LF, LF/HF) showed statistical trends (P < .1) induced by auricular acupuncture in favor of vagal tone. No relevant difference was shown between control and placebo group.ConclusionAcupuncture of the region innervated by the ABVN may activate the parasympathetic nervous system, as suggested by reduction in heart rate and increase in SDNN. However, given the lack of clear significant changes in other HRV parameters, this effect seems modest and its evaluation requires further investigation.

QTc Prolongation in Patients with Dementia and Mild Cognitive Impairment: Neuropsychological and Brain Imaging Correlations.

The QTc interval is the electrocardiographic manifestation of ventricular depolarization and repolarization. This marker is often prolonged in acute and chronic neurological conditions. The cause of the cerebrogenic QT prolongation remains unclear. The aim of the study was to analyze the relation between QTc interval and the degree of cognitive impairment and structural brain imaging changes in patients with dementia and mild cognitive impairment (MCI). To this aim, 269 patients were screened, of whom 61 met one or more exclusion criteria. The remaining 208 patients (56 control subjects, 44 patients with MCI, and 108 with dementia) were recruited. Eighty-five patients using drugs causing prolongation of QT interval were further excluded. The QT interval was measured manually in all 12 leads by a single blinded observer, assuming the longest QT value adjusted for heart rate by using the Bazett's formula. All patients underwent a structural brain imaging and the following measures were obtained: the bicaudate ratio and the periventricular hyperintensity and deep white matter hyperintensity using the modified Fazekas scale. Prolonged QTc interval was prevalent in 1) patients with dementia, especially in those with moderate-severe degree; 2) subjects with impairment of praxis and attention, low functional status, and behavioral symptoms; 3) patients with global and temporal atrophy and with higher scores on the Fazekas or leukoaraiosis scales. Degenerative and vascular processes might play a main role in QTc interval prolongation because of the damage to brain areas involved in the control of the autonomic cardiac nervous system.

Non-invasive Modulation of Autonomic Cardiac Nervous System

Non-invasive Modulation of Autonomic Cardiac Nervous System

Autonomic nervous system and cardiovascular risk assessment during one year of growth hormone replacement therapy in adults with growth hormone deficiency.

This prospective study aimed to evaluate the impact of growth hormone deficiency (GHD) on cardiac autonomic tone and on cardiovascular risk and the changes after 12 months of GH replacement therapy (GHRT). GHD is associated with increased cardiovascular morbidity and mortality. This has been attributed to increased markers of cardiovascular risk and to abnormalities of both the cardiac and peripheral autonomic nervous systems. The autonomic cardiac nervous system (ACNS) can be indirectly evaluated by analysis of heart rate variability (HRV) in clinostatism and orthostatism. We compared 14 GHD patients at baseline and after 12 months of GHRT and 17 healthy controls. We analyzed a number of cardiovascular risk factors and we used analysis of HRV during the Tilt Test that identified high frequency (HF) and low frequency (LF), representing parasympathetic and sympathetic activity, respectively. Compared with the control group, in either clinostatism or in orthostatism our patients showed a significantly lower value of LF (P=0.047; P=0.004, respectively), whereas HF was significantly reduced in orthostatism (P=0.037), and indicatively in clinostatism (P=0.065). These values remained unchanged after 12 months of GHRT. No statistically significant differences were found between the LF/HF ratio in untreated and treated patients. In GHD patients, there was a significant reduction of cardiovascular risk in 12 months of replacement therapy (P=0.002). Our study highlights the absence of sympathovagal imbalance in GHD patients; GHRT does not change ACNS during the first year of GH treatment but it reduces the absolute cardiovascular risk in these patients.

Comparative Morphological Configuration of the Cardiac Nervous System in Lorises and Galagos (Infraorder Lorisiformes, Strepsirrhini, Primates) with Evolutionary Perspective

The detailed systematic morphology and comparative anatomy of the autonomic cardiac nervous system (ACNS) with its surrounding structures were examined in 14 sides of 7 Lorisiformes species (lorises and galagos) to consider its evolutionary differences and similarities to others in the primate lineage. Our detailed descriptions clarified that (1) a family-dependent morphology of the ACNS does not exist although several variations are recognized as common variation in Lorisiformes, (2) the morphology of the ACNS in Lorisiformes is almost consistent regardless of the number of presacral vertebrae and cardiac positions, and (3) the ACNS morphology in Lorisiformes is extremely different from that in New and Old World monkeys, gibbons, and human, specifically in a narrower contribution of the superior cervical ganglion to the spinal cervical nerves, the caudal position and organization of the cervicothoracic ganglion, and the narrower origins of the sympathetic cardiac nerves, although all parasympathetic vagal cardiac branches are consistently present among the primates. Based on these detailed findings, the systematic and evolutionary morphologies of the ACNS are discussed and compared with our previous works. These results suggest the primate ACNS preserves its evolutionary history without modification and specialization by its functional adaptation as seen in the somatic system.

Anatomy of the cardiac nervous system with clinical and comparative morphological implications

Unlike autonomic nervous preservation in other surgeries for improving patient quality of life, autonomic cardiac nervous system (ACNS) preservation has been neglected in cardiovascular surgery because of technical difficulties and other unsolved issues. Because such ACNS preservation in cardiovascular surgery is anticipated in the future, detailed anatomical investigation of the human ACNS is required. Therefore, we have conducted morphological studies of the ACNS from macroscopic, clinical, and evolutionary anatomical viewpoints. In this study, I review detailed anatomical studies of the human ACNS together with their clinical implications. In addition, the evolutionary comparative anatomical significance of primate ACNS is also summarized to help understand and translate the findings of functional experiments to humans. These integrated findings will be the subject of a future study unifying molecular embryological and anatomical findings to clarify cardiac functions based on functional animal experiments, clinical applications such as improving surgery techniques and individual order-made surgery in cardiac surgery, and for future evaluation in regenerative medicine.

Comparative Anatomy and Evolution of the Cardiac Innervation in New World Monkeys (Platyrrhini, E. Geoffroy, 1812)

The morphology of the autonomic cardiac nervous system (ACNS) was examined in 24 sides of 12 New World monkeys (Platyrrhini) of all four families to document the morphology systematically and to study the evolutionary changes of the ACNS in this primate lineage. We report the following: (1) Although several trivial intra- and inter-specific variations are present, a family-dependent morphology of the ACNS does not exist in New World monkeys. (2) The sympathetic ganglia in New World monkeys consist of the superior cervical, the middle cervical, and the cervicothoracic which is composed of the inferior cervical and first and second thoracic, and the thoracic ganglia starting with the third thoracic. The general cardiac nervous system is the sympathetic middle and inferior cardiac nerves and all parasympathetic vagal cardiac branches. (3) The morphology of the ACNS in the New World monkeys is almost consistent regardless of the number of vertebrae, the cardiac position and deviation (axis), and the great arterial branching pattern of the aortic arch, and it is very similar to that in the Old World monkeys, with only one difference: the superior cervical ganglion in the New World monkeys tends to be relatively smaller, higher, and provides a narrower contribution to the spinal nerves than in the Old World monkeys. The ACNS morphology exhibits significant evolutionary changes within the primate lineage from New and Old World monkeys to humans. The comparative morphology within the lineage is concordant with the phylogeny, suggesting that the primate ACNS preserves its evolutionary history in close alignment with phylogeny.

Ablation of permanent AF

Atrial fibrillation (AF) is highly prevalent and accounts for significant morbidity, mortality, and health care costs. Catheter ablation has become a therapeutic option in the management of this challenging arrhythmia. To optimize procedure safety and long-term efficacy, innovative technologies and ablation strategies have been targeting either the triggers initiating AF or the substrate responsible for its maintenance. Pulmonary vein (PV) isolation, initially limited to the PVs, has been modified to encompass the left atrial myocardium surrounding the PV ostia, namely the LA-PV antra. Our current intracardiac echo-guided approach to PV antra isolation, including the adjunct of superior vena cava isolation, has likely accounted for higher success rates by electrically isolating further AF trigger sites, modifying the substrate for AF maintenance and possibly by modulating a dysfunctional autonomic cardiac nervous system. However, the long-term outcome following ablation of permanent AF can be further improved by incorporating adjunctive ablation strategies to PV isolation, such as targeting ablation at sites exhibiting complex atrial fractionated electrograms (CFAEs)during AF or at sites exhibiting the so-called AF nests during real-time spectral mapping in sinus rhythm.

Systematic Morphology and Evolutionary Anatomy of the Autonomic Cardiac Nervous System in the Lesser Apes, Gibbons (Hylobatidae)

We examined the morphology of the autonomic cardiac nervous system (ACNS) on 20 sides of 10 gibbons (Hylobatidae) of three genera, and we have inferred the evolution of the anatomy of the primate ACNS. We report the following. (1) Several trivial intraspecific and interspecific variations are present in gibbons, but the general arrangement of the ACNS in gibbons is consistent. (2) Although the parasympathetic vagal cardiac nervous system is extremely consistent, the sympathetic cardiac nervous system, such as the composition of the sympathetic ganglia and the range of origin of the sympathetic cardiac nerves, exhibit topographical differences among primates. (3) The vertebral ganglion, seldom observed in the Old World monkeys (Cercopithecidae), was consistently present in gibbons as well as in humans. (4) There are fewer thoracic ganglia contributing to the cervicothoracic ganglion in humans than in gibbons and in gibbons than in Old World monkeys. (5) The superior cardiac nerve originating from the superior cervical ganglion, rarely observed in Old World monkeys but commonly observed in humans, was present in 13 of 20 sides (65%), mostly on the left. Accordingly, the ACNS morphology exhibits evolutionary changes within the primate lineage. These evolutionary differences between Old World monkeys, gibbons, and humans are most parsimoniously interpreted as resulting from regular changes in the lineages leading from their common ancestor to the extant species that we dissected. They include the reduction in the number of thoracic ganglia contributing to the cervicothoracic ganglion and the expansion of the range of the cardiac nervous origin.

Evolutionary and comparative anatomical investigations of the autonomic cardiac nervous system in the African cercopithecidae

The purpose of this study was to clarify the general architecture and morphological variations of the autonomic cardiac nervous system (ACNS) in the African Cercopithecidae (Old World monkeys), and to discuss the evolutionary changes between this system in African/Asian Cercopithecidae and humans. A detailed macroscopic comparative morphological investigation of the ACNS was performed by examining the left and right sides of 11 African cercopithecid specimens, including some previously unreported species (Abyssinian colobus, Angola pied colobus, Savanna monkey, and lesser white-nosed guenon). The common characteristics of the ACNS in the African Cercopithecidae are described in detail. Consequently, homologies of the ACNS between Asian (macaques) and African Cercopithecidae, and differences between the Asian/African Cercopithecidae and humans, were found. In particular, differences in the sympathetic (cardiac) systems of the Cercopithecidae and humans were recognized, despite the similar morphology of the parasympathetic vagal (cardiac) system. These differences include the composition of the cervicothoracic ganglion, the lower positions of the middle cervical and cervicothoracic ganglia, and the narrow range for the origin of the cardiac nerves in the Cercopithecidae, compared with that in humans. In conclusion, these findings are considered with regard to the morphology of the last common ancestors of the Cercopithecidae.

Topological changes of the human autonomic cardiac nervous system in individuals with a retroesophageal right subclavian artery: two case reports and a brief review

The topological changes of the human autonomic cardiac nervous system in two cadavers with a retroesophageal right subclavian artery (Rersa) were compared with the normal autonomic cardiac nervous system. The following new results were obtained in addition to the conventional deficient finding of the right recurrent laryngeal nerve. (1) Right superior cardiac nerves arising from the superior cervical ganglion were consistently observed in both cadavers, in addition to the right thoracic cardiac nerves along the Rersa. (2) A segmental accompanying tendency of the right cardiac nerves was recognized: the cardiac nerves arising from the sympathetic trunk cranial to the middle cervical ganglia ran along with the right common carotid artery, whereas the cardiac nerves arising from the sympathetic trunk caudal to the vertebral ganglion ran along the Rersa. (3) The right thoracic cardiac nerves, which have never been observed to accompany the normal right subclavian artery, ran along the proximal part of the Rersa. According to previous reports of individuals with the Rersa, a thick right thoracic cardiac nerve is commonly observed instead of a right superior cardiac nerve. However, all the cardiac nerves were recognized in both the individuals described in the present report. Therefore, we strongly disagree with the previous idea that the origin of the right cardiac nerves from the sympathetic trunk and ganglia is shifted caudally in individuals with the Rersa. The topological changes of the autonomic cardiac nervous system in two cases of Rersa also reflected spatial changes of great arteries.

Comparative anatomical study of the autonomic cardiac nervous system in macaque monkeys

The main aim of this study was to clarify the general morphology of the autonomic cardiac nervous system in macaque monkeys. A submacroscopic comparative anatomical study of the autonomic cardiac nervous system was performed by examining 22 sides of 11 bodies of four species of macaque monkeys, including some previously unreported species (pig-tailed and stump-tailed monkeys), under a surgical stereomicroscope. The following results were obtained. 1) The basic arrangement of the autonomic cardiac nervous system is constant in all examined macaques. 2) A superior cardiac nerve originating from the superior cervical ganglion was not observed, whereas the thoracic cardiac nerve originating from the sympathetic trunk/ganglia under the cervicothoracic ganglion was rarely observed in all the examined macaques. 3) The main cardiac nerve is the middle cardiac nerve originating from the middle cervical ganglion, similar to the situation in humans. 4) Although the superior, inferior, and thoracic cardiac branches of the vagus nerve were consistently observed, the left thoracic cardiac branch is rarely absent because of its lower origin to the heart. 5) The cranial autonomic nerves tend to distribute into the heart medially (arterial porta), and the caudal autonomic nerves tend to distribute into the heart laterally (venous porta). To comprehend the comparative morphological and evolutionary changes more completely, these results were compared with our previous studies and some references. Consequently, differences in the sympathetic cardiac nerves of macaques and humans are recognized, in spite of the similar morphologies of the vagal cardiac branches. These differences include the composition of the cervicothoracic ganglion, the lower positions of the middle cervical and cervicothoracic ganglia, and the narrow range for the origin of the cardiac nerves in macaques compared to that in humans.

The autonomic nervous system of the human heart with special reference to its origin, course, and peripheral distribution

A submacroscopic anatomical investigation of the entire autonomic cardiac nervous system, from origin to peripheral distribution, was performed by examining 36 sides of 18 adult human cadavers under a stereomicroscope. The following new results and points of discussion were obtained: (1) The superior cervical, the middle cervical, the vertebral, and the cervicothoracic (stellate) ganglia, composed of the inferior cervical and 1st thoracic ganglia, were mostly consistent among the specimens. (2) The superior, middle, and inferior cardiac nerves innervated the heart by simply following the descent of the great arteries. In contrast, the thoracic cardiac nerve in the posterior mediastinum followed a complex course because of the long distance to the middle mediastinum. (3) The actual course of the right thoracic cardiac nerve differed from that of the previous descriptions in that it ascended obliquely or ran transversely to the vertebrae, regardless of the intercostal vessels. Regarding the right thoracic cardiac nerve, two descending courses were observed: the descent of the right thoracic cardiac nerve via the azygos vein and right venous porta, and the descent of the recurrent right thoracic cardiac nerve via the aorta. (4) The cranial cardiac nerve and branch tended to distribute into the heart medially, and the caudal cardiac nerve and branch tended to distribute into the heart laterally. (5) The mixing positions (cardiac plexus) of the sympathetic cardiac nerve and the vagal cardiac branch, as well as the definitive morphology of brachial arteries with the recurrent laryngeal nerves, tended to differ on both sides. These new and detailed anatomical descriptions of the human autonomic cardiac nervous system may provide important clues regarding the morphogenesis of autonomic cardiac nerves in addition to contributing to the improvement of cardiac surgery.

Cardiac sympathetic denervation in early stages of amyotrophic lateral sclerosis demonstrated by 123I-MIBG-SPECT.

Involvement of the autonomic cardiac nervous system in early stages of amyotrophic lateral sclerosis (ALS) was evaluated in 40 patients. I-123-metaiodobenzylguanidine-single photon emission computed tomography (MIBG-SPECT) and heart rate variability (HRV) yielded information about sympathetic and parasympathetic innervation of the heart. MIBG-SPECT is a sensitive diagnostic method for demonstration of early cardiac sympathetic denervation. Both sympathetic and parasympathetic dysfunction was observed in 16 (40%) out of 40 patients. Mean cardiac MIBG uptake as demonstrated by the heart/mediastinum ratio was significantly reduced in all ALS patients in comparison with controls (P<0.01). The global MIBG-SPECT score was clearly abnormal in 29% and slightly abnormal in 22% of patients. HRV was diminished in 6 of 38 patients, 4 of whom having an abnormal MIBG-SPECT score as well. The presented results indicate that ALS patients with mild to moderate impairment may have evidence of postganglionic sympathetic adrenergic cardiac or cardiovagal denervation. To our knowledge, this is the first study indicating possible postganglionic sympathetic denervation in ALS. The original concept of ALS as an isolated degeneration of motor neurons seems to extend to a more widespread understanding of the disease which possibly represents different entities.