Cardiovascular Reflexes Research Articles

Simultaneous Pancreas Kidney Transplantation Improves Cardiovascular Autonomic Neuropathy with Improved Valsalva Ratio as the Most Precocious Test.

Background Simultaneous pancreas-kidney (SPK) transplantation is a proven option of treatment for patients with type 1 diabetes mellitus (T1DM) and related end-stage renal disease. There is discrepancy between the results of different studies about the impact of prolonged normalization of glucose metabolism achieved by SPK on the course of diabetic complications including severe forms of diabetic neuropathy. The objective of the study was to evaluate the prevalence of cardiovascular autonomic neuropathy (CAN) in patients undergoing SPK transplantation and its evolution 10 years after transplantation. Methods Prospective study of 81 patients transplanted in a single center from year 2002 to 2015. Autonomic function was assessed using cardiovascular autonomic reflex tests (CARTs). CARTs were made before SPK transplantation and during the follow-up. Evolution of tests after SPK transplantation was evaluated by contrasting hypotheses (paired tests). Multiple testing was adjusted with the Benjamini-Hochberg procedure with a false discovery rate of 10%. Results 48 males and 33 females, mean age 37.4 ± 5.7 years, mean BMI 24.0 ± 3.4 kg/m2, and mean duration of diabetes 25.5 ± 6.5 years, received SPK transplantation. Ten years after SPK transplantation, 56 patients re tained the pancreatic graft (42 of them with normofunctioning pancreas and 14 with low doses of insulin therapy). These 42 patients were selected for the autonomic study. Before transplant procedure, all CART results were abnormal. After SPK transplantation, paired test analysis showed an improvement of systolic blood pressure (SBP) response to orthostasis at the 5th year after SPK (p = 0.03), as well as improvement of the Valsalva ratio at the 3rd (p < 0.001) and 5th (p = 0.001) year after SPK. After correcting for the false discovery rate, all the variables of autonomic study reached significance at different time points. Conclusions Prevalence of CAN in patients who are candidates for SPK transplantation is high and is generally advanced. SPK transplantation improves CAN with improved Valsalva ratio as the most precocious test.

Stimulation of Auricular Vagal Nerves Attenuates Pressor Cardiovascular Responses through Influence on Medullary nuclei

Stimulation of the auricular branch of the vagus nerve (ABVN) is used to manage cardiovascular disorders, including elevated blood pressure. However, precise mechanisms underlying its effects remain unclear. One previous study showed that ABVN stimulation with acupuncture at the center of the inferior concha (the “heart acupoint,” CO15) activates neurons in the nucleus tractus solitarii (NTS) through vagal inputs. Still, its actions on NTS processing and downstream influence on the nucleus regulating cardiovascular function have not been studied. Thus, the present study evaluated the effect of ABVN stimulation on pressor cardiovascular responses and the underlying neural mechanisms associated with medullary nuclei. We hypothesized that ABVN stimulation with acupuncture activates the NTS and ultimately inhibits rostral ventrolateral medulla (rVLM), a critical region controlling cardiovascular function, through opioid and GABA mechanisms. In Sprague‐Dawley rats, repeated pressor cardiovascular reflexes were induced by repetitive gastric distension (GD) under anesthesia. ABVN stimulation with manual acupuncture was performed at the CO15 acupoint with gentle rotation of the acupuncture needle at a frequency of □2 Hz for four min every 10 min during a 30 min period, 2 min in each side of the ear. During sham‐ABVN stimulation, the acupuncture needle was inserted into the same site without subsequent rotation of the needle. Unilateral microinjection of the chemical (50 nl) was conducted in the NTS and rVLM. We found that GD‐induced pressor cardiovascular reflexes significantly attenuated by ABVN stimulation (n=8; P&lt;0.05), but neither by sham‐ABVN stimulation nor mechanical stimulation with the acupuncture needle applied at the HX9 acupoint, which is located at the ear tip overlying lesser occipital nerve, the auricular somatic nerve. The modulation of pressor reflexes by ABVN stimulation was significantly (P&lt;0.05) reversed by microinjection of kynurenic acid (25 mM; n=7) into the NTS as well as naloxone (1 mM; a non‐selective opioid receptor antagonist; n=8) or gabazine (27 mM; a GABAA receptor antagonist; n=8) into the rVLM, but not by their vehicles, 0.9% normal saline. Furthermore, in rats subjected to no GD intervention, we noted that ABVN stimulation induced markedly increase in c‐Fos expression in both NTS and rVLM, compared to sham‐ABVN stimulation. Our data suggest that ABVN stimulation with manual acupuncture excites the NTS through a glutamatergic mechanism, which, in turn, attenuate excitatory cardiovascular reflexes evoked by visceral stimulation through GABA and opioids in the rVLM.Support or Funding InformationThe National Center for Complementary &amp; Integrative Health, R01 grant AT009347 and diversity supplement award to this grant.

Spinal trigeminal subnucleus pars muralis: An interface for apneic reflex

Noxious stimulation of the nasal cavity elicits protective reflexes for the upper respiratory tract, including sneezing, mucus secretion, apnea and cardiovascular reflexes. Yet, no studies have shown the full circuit responsible for the apneic response upon noxious stimulation of the nasal mucosa. Here, we show that injection of cholera toxin beta subunit into the nasal mucosa leads to terminal labeling in the transition zone between the interpolaris and caudalis subnuclei of the trigeminal sensory complex, i.e. subnucleus muralis (SpVm). We also provide physiological evidence that ammonia vapor delivered into the nasal cavity induces an apneic reaction and activates some SpVm cells. Subnucleus muralis cells also respond to mechanical stimulation of the narial pad and the nasal mucosa. Yet, none of the muralis cells responded to vibrissa deflection. Electrolytic lesion of SpVm or unilateral transection of the anterior ethmoidal nerve prevent apnea induced by ammonia delivery to the nasal epithelium, demonstrating their crucial role in the apneic reflex. We also found direct projections from SpVm to the respiratory centers, particularly the preBötzinger complex (preBötC). Inhibition of inspiratory preBötC cells and increased firing of expiratory preBötC cells are associated with ammonia‐induced apnea.Anatomical and physiological data presented here support the hypothesis that nasal induced apnea may be mediated by direct projections from nasal innervated Subnucleus muralis neurons to the PreBötC complex.

Cardiovascular Responses During Graded Lower‐Body Negative Pressure in Heart Failure with Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF) represents approximately half of the known cases of heart failure in the United States, with equally poor outcomes and rising prevalence compared to heart failure with reduced ejection fraction (HFrEF). While changes in autonomic nervous system function is a well‐known feature of HFrEF pathophysiology, whether patients with HFpEF experience a similar decrement remains unknown. Therefore, we sought to evaluate the reflex cardiovascular responses to baroreflex unloading achieved via graded levels of lower‐body negative pressure (LBNP) in patients with HFpEF compared to healthy, age‐matched controls (CON). In six participants (three HFpEF (1 male, 70±3 yrs) and three CON (2 male, 74±2 yrs)), we assessed forearm blood flow (FBF; Doppler ultrasound), mean arterial blood pressure (MAP; Finapres), heart rate (HR; electrocardiogram) and forearm vascular conductance (FVC) at rest and throughout graded levels of LBNP (−10, −20, −30 and −40 mmHg). At rest, there were no significant differences between HFpEF and CON in FBF (109±32 vs. 85±29 ml/min), MAP (90±4 vs. 96±3 mmHg), HR (60±5 vs. 61±5 bpm), or FVC (1.19±0.33 vs. 0.89±0.28 ml/min/mmHg). The reflex tachycardic response to baroreflex unloading induced by LBNP was similar between patients with HFpEF and CON. Vasoconstriction in response to LBNP decreased FBF to a similar level in both HFpEF and CON (−10: 102±31 vs. 88±28 ml/min; −20: 95±30 vs. 76±25 ml/min; −30: 91±30 vs. 78±28 ml/min; −40: 91±33 vs. 71±21 ml/min, HFpEF vs. CON), with similar changes in FVC. Together, these preliminary data suggest that baroreflex‐mediated cardiac and vascular responses are not altered in patients with HFpEF, suggesting an absence of overt autonomic dysfunction is this patient group.Support or Funding InformationThis project is funded in part by the National Institutes of Health (HL118313, R56AG057584, T32HL139451) and the U.S. Department of Veterans Affairs (I01RX001311, I01RX001697, I01RX002323, I01RX000182).

White Mountain Expedition 2019: The Impact of Sustained Hypoxia on Cerebral Blood Flow Responses and Tolerance to Simulated Hemorrhage

IntroductionTrauma‐induced hemorrhage can occur at high altitude from a variety of causes, including battlefield injuries, motor vehicle accidents, air accidents, and major falls. The hypoxic environment of high altitude can limit the ability of the cardiovascular system to compensate for blood loss injuries, due, in part, to the reduced arterial oxygen content. In humans, the effect of sustained hypoxia on tolerance to hemorrhage and the cardiovascular and cerebrovascular responses to this stress are unknown. Based on the known compensatory increases in cerebral blood flow that occur with exposure to hypoxia, we hypothesized that tolerance to simulated hemorrhage (via application of lower body negative pressure, LBNP) at high altitude would be similar compared to low altitude due to increased cerebral blood flow and oxygen delivery, and the subsequent preservation of cerebral tissue oxygenation.MethodsHealthy human subjects (N=8; 4F, 4M) participated in LBNP protocols to presyncope at low altitude (1045 m, Calgary, Canada) and at high altitude (3800 m, White Mountain, California) following 4–5 days of acclimatization. LBNP chamber pressure was initially reduced to −60 mmHg for 10‐min followed by decreases every 5‐min to −70, −80, −90 and −100 mmHg, until the onset of presyncopal symptoms. Arterial pressure, heart rate, internal carotid artery blood flow, and cerebral oxygen saturation were measured continuously. Stroke volume was derived from the arterial pressure waveform, and systemic vascular resistance was calculated from cardiac output and mean arterial pressure. Time to presyncope and cardiovascular responses were compared between the low and high altitude conditions.ResultsTime to presyncope was similar between conditions (low altitude: 1276 ± 108 s vs. high altitude: 1208± 108 s; P=0.58). Similar responses to LBNP were observed between low and high altitudes in mean arterial pressure (low altitude: −16±2 % vs. high altitude: −16±2 %; P=0.85), stroke volume (low altitude: −57±5 % vs. high altitude: −60±5 %; P=0.39), systemic vascular resistance (low altitude: +23±9 % vs. high altitude: +38±12 %; P=0.21), and heart rate (low altitude: +69±12 % vs. high altitude: +65±8 %; P=0.71). Internal carotid artery blood flow was higher at high altitude vs. low altitude (condition effect, P=0.01), and decreased with LBNP under both conditions (P≤0.005). There was no effect of high altitude on cerebral oxygen saturation at baseline and presyncope (altitude Effect, P=0.73).ConclusionThese findings suggest that the hypoxia induced by ascent to high altitude (3800 m) does not affect tolerance to simulated hemorrhage in young healthy adults, which may be due to 1) similar cardiovascular reflex responses to central hypovolemia, and/or 2) the compensatory increase in cerebral blood flow and subsequent maintenance of oxygen delivery to the tissues, resulting in the preservation of cerebral oxygen saturation.Support or Funding InformationAHA 17GRNT33671110

Mechanisms underlining excitatory synaptic plasticity in the Nucleus Tractus Solitarii following Cardiovascular Deconditioning

The nucleus tractus solitarii (nTS) is a critical central region for autonomic control and integration of cardiovascular reflexes. Neuroplasticity in nTS contributes to several cardiovascular dysfunctions. Our previous data showed that Hindlimb‐unloading (HU), a well‐established model of cardiovascular deconditioning in rats, increases glutamatergic neurotransmission yet reduces the excitability of nTS neurons. In this study we aimed to investigate the mechanisms underlining these alterations. For this purpose, stainless wire rings were placed in the tail of male Sprague‐Dawley rats (3 weeks). After one week of recovery the rings was connected to a suspension apparatus and rats were suspended at an angle of 30–35° for two weeks with free access to food and water. Control animals were maintained in normal postural conditions. After the HU protocol, coronal brainstem slices were generated and the whole‐cell patch clamp technique was performed to evaluate the synaptic neurotransmission and electrophysiological properties of nTS neurons. Compared to control rats, HU increased the amplitude of excitatory postsynaptic currents evoked by afferent tractus solitarii stimulus (TS‐EPSC). The addition of a NMDA receptor antagonist (AP5, 10 μM) significantly reduced TS‐EPSC amplitude in HU but not controls. Despite the increase in glutamatergic inputs, the neurons of HU vs control rats are hyperpolarized and have decreased excitability. The block of both NMDA and non‐NMDA (NBQX, 10 μM) glutamatergic receptors did not affect these parameters. However, in the presence of a GABAA receptor antagonist (Gabazine, 25 μM) the resting membrane potential depolarized and excitability of HU neurons were comparable to neurons from control rats. The results indicate that HU increases TS‐EPSC amplitude via a NMDA receptor component. Furthermore, the decreased excitability and hyperpolarized membrane is associated with enhanced GABAergic modulation to these neurons. This functional neuroplasticity in the nTS may contribute to the cardiovascular deconditioning induced by HU.Support or Funding InformationHL132836 AAS lundbeck fellowship

Effect of knock out of ASIC3 on cardiovascular reflexes arising from hindlimb muscle in ligated rats

The exercise pressor reflex (EPR) arises from contracting the skeletal muscle and is manifested by increases in arterial pressure, heart rate and blood flow to working muscles. Group III and IV afferents comprise the sensory arm of the exercise pressor reflex. The exercise pressor reflex is exaggerated in patients with peripheral artery disease, which is an atherosclerotic process that occludes blood flow to working muscles. The exaggeration of the exercise pressor reflex is believed to be caused by a metabolite whose concentration is increased when the working muscles are inadequately perfused. Previous work has shown that pharmacological blockade of acid‐sensing ion channel 3, which is found on the endings of group III and IV afferents, prevents the exaggeration of the exercise pressor reflex in rats with simulated peripheral artery disease. In the present experiments, we compared the magnitude of the exercise pressor reflex in decerebrated rats with a functional knockout of the ASIC3 (KO) with the magnitude of the reflex in their decerebrated wild type counterparts (WT). We found that the exercise pressor reflex in ASIC3 KO rats was significantly smaller than the exercise pressor reflex in their WT counterparts (p&lt;0.05). In addition, ASIC 3 KO rats demonstrated significantly smaller pressor responses to injection of diprotonated phosphate (86mM; pH 6.0), lactic acid (12mM; pH 2.85), and capsaicin (0.2μg; pH 7.2) into the arterial supply of the hindlimb (p&lt; 0.05). In contrast, both ligated WT and ASIC3 KO rats displayed similar pressor responses to calcaneal tendon stretch (p&gt;0.05). We conclude that ASIC3 plays an important role in evoking the exaggerated exercise pressor reflex seen in rats with peripheral artery disease.Support or Funding InformationNIH Grants R01‐AR‐059397 and P01‐HL‐134609

Clinical Tools for Peripheral Neuropathy to Exclude Cardiovascular Autonomic Neuropathy in Type 2 Diabetes Mellitus.

IntroductionAssessment for cardiovascular autonomic neuropathy (CAN) remains difficult in everyday clinical practice. We sought to examine the diagnostic utility of various simple tools for diabetic peripheral neuropathy (DPN) in the detection of CAN in type 2 diabetes mellitus.MethodsWe examined 153 type 2 diabetes mellitus subjects by various DPN tools (vibration perception threshold, 10 g Semmes-Weinstein monofilament, Ipswich touch test, NC-stat®/DPNCheck, neuropathy disability score) for the detection of CAN. CAN was diagnosed by the standardised cardiovascular autonomic reflex function tests.ResultsFor the diagnosis of CAN, assessment of small nerve fibre function (pinprick sensation, temperature perception) yielded a very high negative predictive value (97%), with high sensitivity (89%) and moderate specificity (73%). The vibration perception threshold was second in diagnostic utility (91% negative predictive value, 62% sensitivity and 75% specificity).ConclusionsBased on their high negative predictive value, simple tools for DPN may prove useful to exclude CAN in type 2 diabetes mellitus. These encouraging results merit further evaluation to enable wider screening for CAN.

The relationship between glycaemic variability and cardiovascular autonomic dysfunction in patients with type 1 diabetes: A systematic review.

Rigorous glycaemic control-reflected by low HbA1c goals-is of the utmost importance in the prevention and management of complications in patients with type 1 diabetes mellitus (T1DM). However, previous studies suggested that short-term glycaemic variability (GV) is also important to consider as excessive glucose fluctuations may have an additional impact on the development of diabetic complications. The potential relationship between GV and the risk of cardiovascular autonomic neuropathy (CAN), a clinical expression of cardiovascular autonomic dysfunction, is of increasing interest. This systematic review aimed to summarize existing evidence concerning the relationship between GV and cardiovascular autonomic dysfunction in T1DM. An electronic database search of Medline (PubMed), Web of Science and Embase was performed up to October 2019. There were no limits concerning year of publication. Methodological quality was evaluated using the Newcastle Ottawa Scale for observational studies. Six studies (four cross-sectional and two prospective cohorts) were included. Methodological quality of the studies varied from level C to A2. Two studies examined the association between GV and heart rate variability (HRV), and both found significant negative correlations. Regarding cardiovascular autonomic reflex tests (CARTs), two studies did not, while two other studies did find significant associations between GV parameters and CART scores. However, associations were attenuated after adjusting for covariates such as HbA1c, age and disease duration. In conclusion, this systematic review found some preliminary evidence supporting an association between GV and cardiovascular autonomic dysfunction in T1DM. Hence, uncertainty remains whether high GV can independently contribute to the onset or progression of CAN. The heterogeneity in the methodological approach made it difficult to compare different studies. Future studies should therefore use uniformly evaluated continuous glucose monitoring-derived parameters of GV, while standardized assessment of HRV, CARTs and other potential cardiac autonomic function parameters is needed for an unambiguous definition of CAN.

Prevalence and Correlates of Cardiovascular Autonomic Neuropathy Among Patients with Diabetes in Uganda: A Hospital-Based Cross-sectional Study.

Background:Cardiovascular autonomic neuropathy (CAN) is a common complication in individuals with diabetes mellitus (DM) but often overlooked in clinical practice. The burden and correlates of CAN have not been extensively studied in low-income countries, particularly in sub-Saharan Africa.Objectives:To determine the prevalence and correlates of CAN among adults in ambulatory diabetes care in southwestern Uganda.Method:We conducted a cross-sectional study among adults with diabetes from November 2018 to April 2019. CAN was assessed using the five autonomic function tests: deep breathing, Valsalva maneuver, postural index on standing, change in blood pressure during standing and diastolic blood pressure response to isometric exercise. We estimated the prevalence of CAN and fit regression models to identify its demographic and clinical correlates.Results:We enrolled 299 individuals. The mean age was 50.1 years (SD ± 9.8), mean HbA1c was 9.7 (SD ± 2.6) and 69.6% were female. CAN was detected in 156/299 (52.2%) of the participants on the basis of one or more abnormal cardiovascular autonomic reflex tests. Out of 299 participants, 88 (29.4%) were classified as early CAN while 61/299 (20.4%) and 7/299 (2.3%) were classified as definite and severe (advanced) CAN respectively. In multivariable regression models, age over 50 years (aOR 3.48, 95%CI 1.35 –8.99, p = 0.010), duration of diabetes over 10 years (aOR 4.09, 95%CI 1.78 –9.38, p = 0.001), and presence of diabetic retinopathy (aOR 2.25, 95%CI 1.16 –4.34, p = 0.016) were correlated with CAN.Conclusions:Our findings reveal a high prevalence of CAN among individuals in routine outpatient care for diabetes mellitus in Uganda. Older age, longer duration of diabetes and coexistence of retinopathy are associated with CAN. Future work should explore the clinical significance and long term outcomes associated with CAN in this region.

The diagnostic usefulness of the combined COMPASS 31 questionnaire and electrochemical skin conductance for diabetic cardiovascular autonomic neuropathy and diabetic polyneuropathy.

The study investigated the diagnostic performance for diabetic cardiovascular autonomic neuropathy (CAN) and diabetic polyneuropathy (DPN) of the combined use of composite autonomic symptom score (COMPASS) 31, validated questionnaire for autonomic symptoms of CAN, and electrochemical skin conductance (ESC), proposed for detecting DPN and CAN. One-hundred and two participants with diabetes (age 57 ± 14 years, duration 17 ± 13 years) completed the COMPASS 31 before assessing cardiovascular reflex tests (CARTs), neuropathic symptoms, signs, vibratory perception threshold (VPT), thermal thresholds (TT), and ESC using Sudoscan. Two patterns were evaluated: (a) the combined abnormalities in both tests (COMPASS 31+ESC), and (b) the abnormality in COMPASS 31 and/or ESC (COMPASS 31 and/or ESC). CAN (≥1 abnormal CART) and confirmed CAN (≥2 abnormal CARTs) were present in 28.1% and 12.5%, DPN (two abnormalities among symptoms, signs, VPT, and TT) in 52%, abnormal COMPASS 31 (total weighted score >16.44) in 48% and abnormal ESC (hands ESC <50 μS and/or feet ESC <70 μS) in 47.4%. Both the patterns-COMPASS 31+ESC and COMPASS 31 and/or ESC-were associated with CAN and DPN (P < .01). COMPASS 31 and ESC reached a sensitivity of 75% and 83% for confirmed CAN, and a specificity of 65% and 67% for DPN. When combining the tests, the sensitivity for CAN rose by up to 100% for CAN and the specificity up to 89% for DPN. The combination of the tests can allow a stepwise screening strategy for CAN, by suggesting CAN absence with combined normality, and prompting to CARTs with combined abnormality.

Risk Factors for Diabetic Peripheral Neuropathy and Cardiovascular Autonomic Neuropathy in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study.

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study demonstrated that intensive glucose control reduced the risk of developing diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN). We evaluated multiple risk factors and phenotypes associated with DPN and CAN in this large, well-characterized cohort of participants with type 1 diabetes, followed for >23 years. DPN was defined by symptoms, signs, and nerve conduction study abnormalities in ≥2 nerves; CAN was assessed using standardized cardiovascular reflex tests. Generalized estimating equation models assessed the association of DPN and CAN with individual risk factors measured repeatedly. During DCCT/EDIC, 33% of participants developed DPN and 44% CAN. Higher mean HbA1c was the most significant risk factor for DPN, followed by older age, longer duration, greater height, macroalbuminuria, higher mean pulse rate, β-blocker use, and sustained albuminuria. The most significant risk factor for CAN was older age, followed by higher mean HbA1c, sustained albuminuria, longer duration of type 1 diabetes, higher mean pulse rate, higher mean systolic blood pressure, β-blocker use, estimated glomerular filtration rate <60 mL/min/1.73 m2, higher most recent pulse rate, and cigarette smoking. These findings identify risk factors and phenotypes of participants with diabetic neuropathy that can be used in the design of new interventional trials and for personalized approaches to neuropathy prevention.

Geometry of the Poincaré plot can segregate the two arms of autonomic nervous system – A hypothesis

Autonomic Nervous System (ANS) operates to achieve the optimum physiological functioning and maintains homeostasis in a tonic and continuous manner. Evaluation of ANS profile is crucial in assessing autonomic dysfunction. Conventional ANS evaluation procedures fail to capture minute dynamic alterations of ANS activities.The ANS output pattern is appropriately reflected in the fine alteration of the resting heart rate (HR). HR is a non-stationary variable, results from the dynamic interplay between the multiple physiologic mechanisms. The control of cardiac rate or the chronotropic regulation of heart is considered as a coupled network of oscillators, each representing a specific facet of the cardiovascular reflex. The slower vasomotor oscillation via sympathetic system is combined with rapid respiratory oscillation by parasympathetic system to modulate the intrinsic oscillation pattern of the SA Node.Heart Rate Variability (HRV) is used to understand the autonomic influence on cardiovascular system in health and disease. Fourier decomposition of HRV offers us mainly two different frequency components. High frequency (HF) variation indicates parasympathetic variability due to respiration and Low frequency (LF) mainly implicates tonic sympathetic influence, due to slower vasomotor modulation of heart rate. However, different studies show conflicting results and direct recording of sympathetic nerve activity also failed to correlate with LF power in either healthy subjects or in patients with increased cardiac sympathetic drive.A scatter-plot where each R-R interval is plotted against the preceding R-R interval forms a distributed elliptic point cloud in two dimensional plane. The phase space realization of this plot with dimension two and delay one is referred to as Poincaré plot analysis, an emerging quantitative-visual technique where the shape of the plot is categorized into different functional classes. The plot provides summary as well as detailed beat-to-beat information of the heart. This plot can be extended to three dimensions and with multi-lag, offering more insight and information.A mathematical expression was developed by an interventional study by Toichi et al., using pharmacological blockers during different physiological variables that calculated the lengths of transverse and longitudinal axes of the Poincaré plot to derive two quantitative expressions of sympathetic and vagal influence on HRV: ‘cardiac sympathetic index’ (CSI)) and ‘cardiac vagal index’ (CVI).In the present study, we emulate Poincaré plot patterns seen in normal range of sympatho-vagal balances and also in Diabetes Mellitus (DM), known to cause autonomic dysfunction. The emerging pattern of R-R interval time series would provide valuable insight into the altered temporal dynamics and also extract crucial features embedded within. DM is a major public health crisis globally and particularly in Indian population.We hypothesize that, CSI and CVI will effectively segregate the two arms of ANS and can be utilized as an effective evaluation tool to explore the disease status in patients of Diabetes Mellitus.We also propose that, the dynamics of fluctuations in physiological rhythms that exhibit long-term correlation and memory, can also be explored and expressed quantitatively by incorporating various degrees of ‘lag’ in these recurrence plots.

Is gastroparesis that is often detected in patients with alcoholic chronic liver disease a manifestation of an autonomic dysfunction syndrome? A preliminary study.

the autonomic dysfunction defines the neuropathy of the autonomic nervous system. The prevalence of the gastric dysmotility and its relationship with the autonomic dysfunction in patients with alcohol chronic liver disease is not well known. thirty-six patients with alcohol chronic liver disease and 25 healthy controls were evaluated, in order to detect an autonomic dysfunction through different cardiovascular reflexes and gastric emptying tests. ninety-four per cent of the patients showed an impaired R index (variations in heart rate during six deep inspirations-expirations per minute) and/or S/S-HR (variations in heart rate when standing from a supine position). Seventy-five per cent of the patients showed gastroparesis (T1/2: gastric half-emptying time was delayed). There was a correlation between the R index and T1/2 (r = -0.49; p < 0.01). we suggest that gastroparesis detected in alcoholic chronic liver disease is another clinical manifestation of the autonomic parasympathetic dysfunction.

66 Simple bedside cardiovascular autonomic examinations for predicting chronotropic incompetence

Abstract Background Simple bedside cardiovascular autonomic reflex test (CARTs) are usually used to determine cardiovascular autonomic neuropathy (CAN). CAN may contribute to chronotropic incompetence (CI) which is the inability of the heart rate (HR) to rise in proportion to an increase in metabolic demand. Determination of CI is widely based on measurement of maximum HR during exercise testing. This study aimed to evaluate the role of CARTs to determine CI. Methods We included in 105 patients using a derivation and validation sampling ratio of 2:1. CARTs were performed for analyzing heart rate variation during three parasymphathetic standard tests (deep breathing, lying to standing, Valsava maneuver) and two sympathetic standard tests (systolic blood pressure from lying to standing and diastolic blood pressure during handgrip maneuver). Variables independently associated with CI in multivariable analysis in the derivation set were assigned points based on their respective odds ratios. Results CI group showed significantly lower values of among three parasympathetic standard tests (p &amp;lt; 0.05) but not significantly among two sympathetic standars tests. Valsava maneuver (OR 0.1, p &amp;lt; 0.001, 95%CI 0.001-0.004), deep breathing (OR 0.91, p = 0.025, 95% CI 0.836-0.988), and handgrip maneuver (OR 0.85, p = 0.01, 95% CI 0.744-0.961) were found to be an independent risk factor for CI from multivariate regression analysis. The accuracy of different CART parameters in the prediction of CI was described by the receiver operating curve (ROC) analysis. Regarding logistic regression model, we constructed formula of 15 - ([12 x Valsava maneuver] + [0.1 x deep breathing] + [0.2 x handgrip maneuver]) which will show negative and positive results indicating CI and non-CI, respectively. The resulting score showed good calibration and discriminatory capacity in the derivation (Hosmer-Lemeshow x² 10.051, p = 0.186, AUC = 0.878). The difference between AUCs in the derivation and validation sets was Δ = 0.122 (p = 0.174). Conclusion The decrease in heart rate variations during Valsava maneuver and deep breathing and in diastolic blood pressure during handgrip maneuver seems to be related to development of CI. Formula of CARTs score is a useful tool for predicting CI. Final score sheet based on formula Total score CI probability &amp;lt;-0.1 High probaility 0.2-0.6 Intermediate probability &amp;gt;0.6 Low probability

Autonomic dysregulation and phenobarbital in patients with masked primary hypertension

IntroductionPrimary hypertension can be masked and be responsible of a severe impact on the target bodies. The purpose of this study was to see if Phenobarbital at low dose is able to decrease the sympathetic hyperactivity assessed by cardiovascular autonomic reflexes in patients with masked hypertension. Materials and methodsThis prospective study was conducted on a total of 91 patients with masked hypertension (average age 52.1 ± 10.3 years old). The cardiovascular autonomic tests performed in this group, before and after 3 months of daily oral administration of Phenobarbital, included deep breathing, hand-grip, mental stress and orthostatic tests. Statistical analysis was done using the Student's t-test, Univariate and Multivariate logistic regression analysis; p is significant if < 0.05. ResultsCardiovascular autonomic reflexes responses before and after 3 months of Phenobarbital oral administration were as follows: Vagal response (XDB) obtained on deep breathing test was of 32.6 ± 5.4% VS 30.4 ± 6.1%, (p = 0.08), alpha peripheral sympathetic response (alpha SP) obtained on hand grip test was of 35.6 ± 8.7% VS 12.0 ± 2.5%, (p < 0.001), alpha central sympathetic response (alpha SC), beta central sympathetic response (beta SC) obtained during mental stress were of respectively 29.3 ± 9.2% VS 11.8 ± 2.4%, (p < 0.001) and 11.0 ± 5.3% VS 10.4 ± 6.1%, (p = 0.2), alpha peripheral adrenergic sympathetic (alpha PAS) obtained during orthostatic test was of 25.3 ± 6.0% VS 13.0 ± 3.4%, (p < 0.001). ConclusionThese results demonstrated that Phenobarbital at low dose may have an anti-sympathetic effect in patients with masked hypertension.

Role of Heart Rate Response to Standing and Valsalva Manoeuvre Measurement in Diagnosing Cardiovascular Autonomic Neuropathy in Patients With Diabetes Mellitus.

Diabetes is an iceberg disease with many complications like cardiovascular disease &diabetic neuropathy. One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy (CAN), Autonomic nervous system dysfunction is one of the significant complications of diabetes mellitus and this is generally associated with a poor prognosis. Standard cardiovascular reflex tests are used to assess cardiovascular autonomic function. These include changes in heart rate during standing up and, Valsalva manoeuvre to assess cardiac parasympathetic activity. Aim: To analyse the role of heart rate during standing up and , Valsalva manoeuvre in diagnosing Cardiac Autonomic Neuropathy.

Cardiac autonomic neuropathy in adult epilepsy patients in a tertiary hospital in South-Western Nigeria.

Cardiac autonomic neuropathy (CAN) resulting from seizures has been implicated in sudden unexpected death in epilepsy in persons with epilepsy (PWE), however, there are no previous studies of CAN in PWE from Nigeria. This study sought to determine the frequency and pattern of CAN in adult PWE in a tertiary hospital in South-western Nigeria and to determine the relationship between seizure variables and CAN. A cross-sectional study of 80 adult PWE and 80 matched controls aged between 18 and 60 years was carried out between March 2012 and June 2013 at the Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, Nigeria. Demographic and clinical data were obtained from all the study participants. Anxiety was excluded using the Hamilton Anxiety Scale. Those with conditions that could affect autonomic function, such as chronic renal failure, heart failure, Parkinson's disease, diabetes mellitus, anxiety, and psychiatric disorders and pregnant women were excluded. Five bedside cardiovascular reflex tests were performed on each subject after baseline heart rate and blood pressure (BP) had been recorded. The mean age of onset of epilepsy was 19 ± 10 years, whereas the mean duration of epilepsy was 10 ± 8 years. The mean seizure frequency was 14 ± 30 per month (median three seizures per month). Of the 80 patients evaluated, 42 (52.5%) had CAN, whereas none of the controls had CAN. Majority (69%) of the PWE with CAN had purely parasympathetic dysfunction, whereas 3% had purely sympathetic dysfunction and 10% had combined autonomic dysfunction. The PWE in this study had significantly lower tilt ratios and diastolic BP change with Isometric Hand grip as well as significantly higher systolic BP change on standing than the controls. Patients who had more than four seizures per month had higher odds of CAN than those with less frequent seizures (odds ratio 0.275, P value 0.023). Also, patients who had received treatment for less than 10 years were found to have greater odds of CAN than those who had received treatment for a longer period (odds ratio 11.676, P value 0.046). CAN is common in adult PWE in South-Western Nigeria and the major predictors are short duration of treatment and frequent seizure episodes. Routine screening of these patients may help with early detection of autonomic dysfunction and provide an opportunity for intervention.

Assessment of Physical Fitness and Its Association with Sympathetic Activation Among the Students of Pokhara University, Nepal

A 3-minute step test provides a feasible, low cost procedure with minimal risk to the participant for assessing physical fitness compared to maximal exercise testing. Test assessing the autonomic function (sympathetic wing) evaluates the cardiovascular reflex like increased blood pressure triggered by performing specific stimulating maneuvers such as Isometric Hand Grip Test (IHGT). We assessed & categorized the fitness level using a 3 min step test and its association with sympathetic activation during IHGT in university level students with sound health. There is increasing evidence of an association between Physical Fitness and academic performance. Two hundred consenting healthy students studying at Pokhara University (largest in western region of Nepal) aged 17-25 years underwent sub-maximal exercise as per the protocol of 3 min-step test given by Young Man’s Christian Associations (YMCA) to categorize as good & poor being based on recovery heart rate. Each groups undertook IHGT & changes in Diastolic Blood Pressure (DBP) were noted. About two third of the study participants were female and 70% of total students were of poor fitness level. Fitness level and sex was significantly associated (P=0.041, OR=1.92, CI=1.024- 3.606). More of the male participants had good fitness in comparison to that of the female participants (38.9% vs 24.8%). Differences in Diastolic Blood Pressure during IHGT and at rest (assess sympathetic activation during stress) was significantly associated with fitness level (P<0.001, OR=1.32, CI=1.201-1.446). Majority of university level students had poor fitness with high proportion in female. Students with good fitness level had good sympathetic activation to physical stress as compared to those with poor fitness level. Physical fitness (Cardiorespiratory fitness) is proven to induce angiogenesis in the motor cortex and increases blood flow, improving brain vascularization which could affect cognitive performance. So measuring physical fitness of university students at the time of admission or during the study period could help to predict their academic achievements through their reasoning function and ability of coping various stresses that they might encounter during academic journey. Those with poor physical fitness would be advised to improve the fitness by promoting physical activity.

Assessment of Conventional Autonomic Function Tests in Patients with Acute Intermittent Porphyria

Background and Aim: To assess the autonomic nerve functions in latent and manifest patients of acute intermittent porphyria. The aim of the present study was to study cardiovascular responses to autonomic nerve functions in patients of acute intermittent porphyria, we also tried to find out the relative sensitivity of the various tests employed to study cardiac dysautonomia in these cases. Methods: The study was carried out on thirty cases of acute intermittent porphyria to assess the cardiovascular reflexes. Twenty five healthy subjects closely matched for age and sex served as control. The cases were diagnosed by modified Watson Schwartz test, the cases of acute intermittent porphyria were divided into three groups. Results: The values of different autonomic nerve function tests were compared with control group and among the different groups of patients. The results were complied, compared and a conclusion was drawn. Immediate heart rate response to standing is more sensitive test than the Valsalva maneuver. Immediate heart rate response to standing is more sensitive and quite reliable which can easily be performed at bed side or even in outpatient departments, the test is simple and non–invasive. In our opinion, the test, beat to beat variation of heart rate to single deep breath is though easy to perform and more understandable, but lacks the sensitivity of other two tests. Conclusion: Significant cardiac dysautonomia is present in asymptomatic group, it is more marked in acute attack group. Immediate heart rate response to standing could be a more sensitive and reliable test in this dysfunction.