Ruzieh M, Bai C, Kimmel SE
… +7 more, Goldberger ZD, Dasa O, Petersen JW, Smoot M, Edwards ES, Kamisetty SR, Mardini MT
Clin Auton Res
· 2025 Apr · PMID 39560861
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INTRODUCTION: Syncope is common, with bimodal distribution through life, peaking in adolescence and in the elderly, and overall increases in incidence with age among both men and women. In this context, syncope-related v...INTRODUCTION: Syncope is common, with bimodal distribution through life, peaking in adolescence and in the elderly, and overall increases in incidence with age among both men and women. In this context, syncope-related visits to emergency departments (ED), hospitalizations, and testing are a significant healthcare cost burden. Ultimately, understanding the volume of testing types and settings of syncope encounters may aid in more effective healthcare utilization and high value care for this patient population. METHODS: Data for this study were collected from the Truven Health Analytics MarketScan Database from 2006 to 2019. This database contains both commercially insured patients and those with Medicare coverage. Patients with the diagnosis of syncope were identified using International Classification of Diseases (ICD)-9 and -10 codes. We assessed the incidence of various tests for syncope evaluation and ED disposition for the study period. RESULTS: The incidence of syncope among the study cohort rose from nine per 1000 patients to 13 per 1000 patients during the study period. The incidence of testing for syncope among multiple domains (neurologic, cardiac, blood testing) decreased in some categories, but routine testing remained prevalent. Women had a significantly lower incidence of testing in most testing domains. Discharge rate from the ED for patients presenting with syncope remained stable during the study period. However, admission rate to the hospital for those aged > 65 years increased during the study time. CONCLUSION: Testing and admissions for syncope remain prevalent and are drivers of healthcare-associated costs. There is a clear need for further work in developing a focused approach in the evaluation of syncope patients in order to mitigate healthcare costs and improve outcomes.
Clin Auton Res
· 2025 Apr · PMID 39546154
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PURPOSE: The prevailing hypothesis posits that Takotsubo syndrome (TTS) is caused by massive sympathetic activation, yet supporting evidence remains inconsistent. The objectives of the present study were to determine whe...PURPOSE: The prevailing hypothesis posits that Takotsubo syndrome (TTS) is caused by massive sympathetic activation, yet supporting evidence remains inconsistent. The objectives of the present study were to determine whether sympathetic activity and reactivity are enhanced in the recovery phase of TTS, and to evaluate the effect of selective β1-receptor blockade on sympathetic reactivity. METHODS: We conducted a case-control study that included 18 female patients with TTS and 13 age- and sex-matched controls. Muscle sympathetic nerve activity was measured through microneurography of the peroneal nerve at rest and during the cold pressor test. In the TTS group, recordings were repeated after randomisation to intravenous metoprolol or placebo. In 10 TTS patients, cardiac sympathetic activity was assessed using iodine 123-metaiodobenzylguanidine scintigraphy. Blood samples were collected during hospitalisation. RESULTS: Microneurography was performed a median of 27.5 days after patient admission. There were no significant differences in burst incidence, burst frequency, burst height or burst area between the TTS patients and the controls at rest, during stress or after administration of intravenous metoprolol. Iodine 123-metaiodobenzylguanidine scintigraphy was performed a median of 12.5 days after admission, revealing decreased early 1.54 ± 0.13 and late 1.40 ± 0.13 heart-to-mediastinum ratios, and an increased washout rate of 41.8 ± 12.1%. Catecholamine metabolites were comparable between the study groups. CONCLUSION: General sympathetic hyperactivity or hyperreactivity unlikely contributes to TTS, as catecholamine levels and muscle sympathetic nerve activity at rest and during stress were similar between the TTS patients and the controls. As scintigraphy showed increased cardiac sympathetic activity, a pathological cardiac adrenergic response and vulnerability to sympathetic activation may be crucial for the development of the syndrome.
Kissell CE, Young BE, Kaur J
… +4 more, Taherzadeh Z, Mohan PC, Vianna LC, Fadel PJ
Clin Auton Res
· 2025 Apr · PMID 39542982
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PURPOSE: Patients with chronic kidney disease (CKD) are more than twice as likely to die from a cardiovascular event than those with normal kidney function. Although CKD may increase resting sympathetic activity, quantif...PURPOSE: Patients with chronic kidney disease (CKD) are more than twice as likely to die from a cardiovascular event than those with normal kidney function. Although CKD may increase resting sympathetic activity, quantification of resting sympathetic outflow alone does not account for the ensuing vasoconstriction, and blood pressure (BP) change (i.e., sympathetic transduction). Patients with CKD have been reported to exhibit elevated α-adrenergic receptor sensitivity, which may predispose this population to greater sympathetic transduction. We tested the hypothesis that patients with CKD have augmented sympathetic transduction to BP. METHODS: In 16 patients with CKD, 17 bodyweight-matched (BWM) controls, and 11 lean controls of a similar age muscle sympathetic nerve activity (MSNA) and beat-to-beat BP were continuously recorded during quiet supine rest. Signal averaging was used to quantify changes in mean arterial pressure (MAP) and total vascular conductance (TVC) following spontaneous bursts of MSNA. RESULTS: Peak increases in MAP following MSNA bursts were not different among patients with CKD and the control groups (CKD: 2.3 ± 1.1 mmHg; BWM controls: 2.1 ± 1.0 mmHg; lean controls: 1.7 ± 0.9 mmHg; P = 0.28). Likewise, nadir reductions in TVC following all bursts of MSNA were not different among patients with CKD and either control group (P = 0.69). Both patients with CKD and controls had graded increases in MAP and decreases in TVC with increasing burst size, which were not different among groups (all P > 0.05). CONCLUSION: In summary, these data indicate that patients with CKD do not have augmented sympathetic transduction to BP.
Tajima Y, Komiyama M, Mimura N
… +6 more, Yamamoto M, Fukuie M, Suzuki R, Matsushima S, Hirasawa A, Shibata S
Clin Auton Res
· 2025 Apr · PMID 39476217
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INTRODUCTION: Water intake is known to be effective in preventing orthostatic hypotension (OH). However, it is unknown whether water intake would be effective in acutely preventing exercise-induced OH. METHODS: Fourteen...INTRODUCTION: Water intake is known to be effective in preventing orthostatic hypotension (OH). However, it is unknown whether water intake would be effective in acutely preventing exercise-induced OH. METHODS: Fourteen adults (men/women: 7/7, age: 20 ± 8 years) were recruited. Each subject underwent two protocols with and without 500 ml water intake using a randomized crossover design (Water vs. Control). Participants underwent 30 min of cycle ergometry at the 60-70% predicted VO max. OH and hemodynamics were assessed before and after exercise, and immediately (Water 1) and 20 min (Water 2) after the water intake. OH was evaluated with a 1-min standing test as the criteria for systolic blood pressure (SBP) < 90 mmHg. A cross-spectral analysis for RR and SBP variability was used to evaluate the cardiac autonomic activity and baroreflex sensitivity. RESULTS: In both protocols, the incidence of OH increased after the exercise. The incidence of OH was lower in Water than in Control at Water 1 (OR: 0.093, 95% CI: 0.015-0.591). Heart rate was lower and SBP was higher in Water than in Control at Water 1 and 2 (P < 0.05). High-frequency power of RR variability and transfer function gains in Water were normalized and higher than in Control at Water 1 and 2 (P < 0.05). The ratio of low- to high-frequency power of RR variability in Water was normalized and lower in Water than in Control at Water 1 (P < 0.05). CONCLUSION: Our findings indicate that water intake may prevent acute exercise-induced OH, accompanied by normalized cardiac autonomic activity and baroreflex sensitivity.
Jardine DL, Pointon R, Frampton C
… +3 more, Wright I, Buckenham T, Stewart J
Clin Auton Res
· 2025 Feb · PMID 39417948
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PURPOSE: Vasovagal syncope is thought to be mediated by a progressive fall in cardiac output secondary to venous pooling of blood in the splanchnic circulation. How and when this occurs before syncope has not been determ...PURPOSE: Vasovagal syncope is thought to be mediated by a progressive fall in cardiac output secondary to venous pooling of blood in the splanchnic circulation. How and when this occurs before syncope has not been determined. METHODS: A total of 20 patients who became hypotensive during head-up tilt (age 40.9 ± 3.4 years; 10 females) were divided into two groups-the glyceryl trinitrate (GTN) group (n = 12) and the vasovagal syncope (VVS) group (n = 8) - on the basis of whether or not nitroglycerine provocation was required. They were compared with a control group (age 38.6 ± 3.3; 8 females; n = 13). Hemodynamics, including superior mesenteric artery blood flow (SMABF) and muscle sympathetic nerve activity (MSNA) were recorded continuously during early tilt, presyncope and recovery. We used pixel-weighting to calculate average velocity from the pulsed Doppler velocity envelope. RESULTS: During baseline and early tilt, resistance to mesenteric blood flow was lower in the VVS group: 0.30 ± 0.02 to 0.30 ± 0.02 mmHg/ml/min versus controls 0.30 ± 0.03 to 0.38 ± 0.04 mmHg/ml/min (p = 0.05). During presyncope, as blood pressure and stroke volume gradually fell, SMABF was higher in the VVS group, falling from 370 ± 46 to 248 ± 35 ml/min, versus controls, falling from 342 ± 51 to 233 ± 19 (p = 0.03). At this time, MSNA was lower in the VVS group than controls: 39 ± 4 to 34 ± 3 bursts/min versus 45 ± 2 to 48 ± 3 (p = 0.001). CONCLUSION: During presyncope, increased splanchnic blood flow may pool more blood in capacitance vessels resulting in decreased venous return and cardiac output. This may be secondary to decreased vasoconstrictor sympathetic activity.
Reyes Del Paso GA, Montoro CI, Davydov DM
… +1 more, Duschek S
Clin Auton Res
· 2025 Feb · PMID 39417947
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PURPOSE: Alterations of autonomic cardiovascular control are implicated in the origin of chronic low blood pressure (BP) (hypotension), but comprehensive analysis of baroreflex function is still lacking. This study explo...PURPOSE: Alterations of autonomic cardiovascular control are implicated in the origin of chronic low blood pressure (BP) (hypotension), but comprehensive analysis of baroreflex function is still lacking. This study explored baroreflex function in its cardiac, vascular and myocardial branches METHODS: Continuous BP was recorded at rest and during a mental arithmetic task in 40 hypotensive and 40 normotensive participants. Assessed cardiovascular variables included stroke volume (SV) (calculated by the Modelflow method), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR) and heart rate variability (HRV). Baroreflex sensitivity (BRS) was calculated using the spontaneous sequence method. RESULTS: Hypotensive participants exhibited greater BRS in the three baroreflex branches, in addition to lower SV, HR and CO and higher HRV and TPR. Reactivity for BP, HRV and CO during the stress task was reduced in hypotensive individuals. The greater cardiac BRS can explain the lower HR and higher HRV observed in hypotension, suggestive of increased vagal cardiac influences. The higher vasomotor BRS may contribute to the greater TPR observed in the hypotensive participants. Abnormal associations between myocardial BRS and SV arose, suggesting aberrant autonomic control of myocardial contractility in hypotension. CONCLUSION: The results indicate that hemodynamic deficits in hypotension are related to preload factors, probably triggered by hypovolemia and reduced unstressed blood reserves, resulting in lower venous return, ventricular preload and SV. In contrast, afterload mechanisms seem to work appropriately.
Clin Auton Res
· 2025 Feb · PMID 39417946
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PURPOSE: Cardiovascular autonomic neuropathy (CAN) is a common diabetic complication associated with excess morbidity and mortality. CAN is also seen in conditions such as Parkinson's disease. Normative reference data fo...PURPOSE: Cardiovascular autonomic neuropathy (CAN) is a common diabetic complication associated with excess morbidity and mortality. CAN is also seen in conditions such as Parkinson's disease. Normative reference data for cardiovascular autonomic function are used to stratify individuals into those with and without CAN. However, reference thresholds for both cardiovascular autonomic reflex tests (CARTs) and heart rate variability (HRV) are scarce and based on small sample sizes. The aim of the study was to establish contemporary normative reference thresholds based on a large non-diabetic population free of cardiovascular disease (CVD). METHODS: Cardiovascular autonomic function, CARTs and 5-min HRV indices were assessed in individuals without diabetes and CVD from the Lolland-Falster Health Study (2018-2020) by applying the point-of-care device Vagus™. Age-specific normative reference thresholds were estimated by using log-transformed quantile regression models at the 5th and 10th percentile, with adjustments made for sex. Models assessing the association between age and HRV indices were further adjusted for heart rate. RESULTS: We present age-specific normative reference thresholds for cardiovascular autonomic function, including CARTs and HRV, for 875 individuals (48% females) aged 15-85 years. The reference thresholds are presented for both the 5th and 10th lower percentile. Higher age was inversely associated with all outcomes. Females tended to have a higher parasympathetic drive compared to males. Pre-test conditions did not affect CARTs significantly. CONCLUSIONS: The presented age-related normative reference thresholds for both CARTs and HRV indices based on a large Danish cohort may facilitate improved quality of research and treatment.
Gentile F, Giannoni A, Navari A
… +3 more, Degl'Innocenti E, Emdin M, Passino C
Clin Auton Res
· 2025 Feb · PMID 39402309
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PURPOSE: The aim of this paper is to investigate the acute effects of short-term transcutaneous vagus nerve stimulation (tVNS) on cardio-vagal baroreflex gain and heart rate variability in patients with chronic heart fai...PURPOSE: The aim of this paper is to investigate the acute effects of short-term transcutaneous vagus nerve stimulation (tVNS) on cardio-vagal baroreflex gain and heart rate variability in patients with chronic heart failure (CHF). METHODS: A total of 16 adults with CHF and left ventricular ejection fraction (LVEF) < 50% in sinus rhythm were enrolled (65 ± 8 years, 63% men, LVEF 40 ± 5%, 88% on beta-blockers, 50% on quadruple CHF therapy). Over a single experimental session, after a 10-min baseline recording, each patient underwent two trials of 10-min tVNS (Parasym Device, 200 µs, 30 Hz, 1 mA below discomfort threshold) at either the right or left tragus in a randomized order, separated by a 10-min recovery. RESULTS: Compared with baseline, tVNS did not affect heart rate, blood pressure, and respiratory rate (p > 0.05), and no patients complained of discomfort or any adverse effect. Right-sided tVNS was associated with a significant increase in cardio-vagal baroreflex gain (from 5.6 ± 3.1 to 7.5 ± 3.8 ms/mmHg, ∆ 1.9 ± 1.6 ms/mmHg, p < 0.001), while no change was observed with left-sided tVNS (∆ 0.5 ± 2.0 ms/mmHg, p = 0.914). These findings were independent of stimulation-side order (excluding any carry-over effect) and consistent across sex, LVEF category, and HF etiology subgroups (p-value for interaction > 0.05). CONCLUSIONS: Acute right-sided tVNS increases cardio-vagal baroreflex gain in patients with CHF and LVEF < 50%, with no tolerability concerns.
Hilz MJ, Canavese F, de Rojas-Leal C
… +3 more, Lee DH, Linker RA, Wang R
Clin Auton Res
· 2025 Feb · PMID 39382757
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PURPOSE: Vagomimetic fingolimod effects cause heart rate (HR) slowing upon treatment initiation but wear off with sphingosine-1-phosphate receptor downregulation. Yet, prolonged HR slowing may persist after months of fin...PURPOSE: Vagomimetic fingolimod effects cause heart rate (HR) slowing upon treatment initiation but wear off with sphingosine-1-phosphate receptor downregulation. Yet, prolonged HR slowing may persist after months of fingolimod treatment. We evaluated whether cardiovascular autonomic modulation differs before and 6 months after fingolimod initiation between patients with RRMS with and without initially prolonged HR slowing upon fingolimod initiation. METHODS: In 34 patients with RRMS, we monitored RR intervals (RRI) and blood pressure (BP), at rest and upon standing up before fingolimod initiation. Six hours and 6 months after fingolimod initiation, we repeated recordings at rest. At the three time points, we calculated autonomic parameters, including RRI standard deviation (RRI-SD), RRI-total-powers, RMSSD, RRI high-frequency [HF] powers, RRI and BP low-frequency (LF) powers, and baroreflex sensitivity (BRS). Between and among patients with and without prolonged HR slowing upon fingolimod initiation, we compared all parameters assessed at the three time points (analysis of variance [ANOVA] with post hoc testing; significance: p < 0.05). RESULTS: Six hours after fingolimod initiation, all patients had decreased HRs but increased RRIs, RRI-SDs, RMSSDs, RRI-HF-powers, RRI-total-powers, and BRS; 11 patients had prolonged HR slowing. Before fingolimod initiation, these 11 patients did not decrease parasympathetic RMSSDs and RRI-HF-powers upon standing up. After 6 months, all parameters had reapproached pretreatment values but the 11 patients with prolonged HR slowing had lower HRs while the other 23 patients had lower parasympathetic RMSSDs and RRI-HF-powers, and BRS than before fingolimod initiation. CONCLUSION: Our patients with prolonged HR slowing upon fingolimod initiation could not downregulate cardiovagal modulation upon standing up even before fingolimod initiation, and 6 months after fingolimod initiation still had more parasympathetic effect on HR while cardiovagal modulation and BRS were attenuated in the other 23 patients. Pre-existing parasympathetic predominance may cause prolonged HR slowing upon fingolimod initiation.
Clin Auton Res
· 2024 Dec · PMID 39363044
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PURPOSE: Vagus nerve stimulation (VNS) is emerging as a unique and potent intervention, particularly within neurology and psychiatry. The clinical value of VNS continues to grow, while the development of noninvasive opti...PURPOSE: Vagus nerve stimulation (VNS) is emerging as a unique and potent intervention, particularly within neurology and psychiatry. The clinical value of VNS continues to grow, while the development of noninvasive options promises to change a landscape that is already quickly evolving. In this review, we highlight recent progress in the field and offer readers a glimpse of the future for this bright and promising modality. METHODS: We compiled a narrative review of VNS literature using PubMed and organized the discussion by disease states with approved indications (epilepsy, depression, obesity, post-stroke motor rehabilitation, headache), followed by a section highlighting novel, exploratory areas of VNS research. In each section, we summarized the current role, recent advancements, and future directions of VNS in the treatment of each disease. RESULTS: The field continues to gain appreciation for the clinical potential of this modality. VNS was initially developed for treatment-resistant epilepsy, with the first depression studies following shortly thereafter. Overall, VNS has gained approval or clearance in the treatment of medication-refractory epilepsy, treatment-resistant depression, obesity, migraine/cluster headache, and post-stroke motor rehabilitation. CONCLUSION: Noninvasive VNS represents an opportunity to bridge the translational gap between preclinical and clinical paradigms and may offer the same therapeutic potential as invasive VNS. Further investigation into how VNS parameters modulate behavior and biology, as well as how to translate noninvasive options into the clinical arena, are crucial next steps for researchers and clinicians studying VNS.
Imbalzano G, Ledda C, Tangari MM
… +6 more, Artusi CA, Montanaro E, Rizzone MG, Zibetti M, Lopiano L, Romagnolo A
Clin Auton Res
· 2024 Dec · PMID 39358584
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PURPOSE: Neurogenic orthostatic hypotension (nOH) and gait impairment are frequent sources of disability in Parkinson's disease (PD). However, the impact of nOH on balance and gait features remains unclear. This cross-se...PURPOSE: Neurogenic orthostatic hypotension (nOH) and gait impairment are frequent sources of disability in Parkinson's disease (PD). However, the impact of nOH on balance and gait features remains unclear. This cross-sectional study aimed to assess the influence of nOH on postural and gait parameters in a cohort of patients with PD by means of wearable inertial sensors. METHODS: Gait and balance were assessed using Opal inertial sensors. nOH was defined as sustained systolic blood pressure (BP) drop ≥ 20 mmHg or diastolic BP drop ≥ 10 mmHg within 3 min of standing, with a ΔHR/ΔSBP ratio ≤ 0.5 bpm/mmHg. Analysis of covariance was performed to evaluate differences in gait/balance features between patients with and without nOH, adjusting for age, cognitive status, and motor disability. Moreover, we performed the same analysis considering the presence of hemodynamically relevant nOH (orthostatic mean BP ≤ 75 mmHg). RESULTS: A total of 82 patients were enrolled, 26 with nOH (31.7%), of which 13 presented with hemodynamically relevant nOH. After correcting for confounders, nOH was independently associated with lower gait speed (p = 0.027), shorter stride length (p = 0.033), longer time for postural transitions (p = 0.004), and increased postural sway (p = 0.019). These differences were even more pronounced in patients with hemodynamically relevant nOH. Higher postural sway was associated with a 7.9-fold higher odds of falls (p = 0.040). CONCLUSIONS: Our study presents an objective demonstration of the independent negative impact of nOH on gait and balance in PD, emphasizing the need for careful detection and management of nOH to mitigate gait and balance disturbances in PD.
Clin Auton Res
· 2024 Dec · PMID 39316247
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PURPOSE: Evidence from animal and human studies demonstrates that cortical regions play a key role in autonomic modulation with a differential role for some brain regions located in the left and right brain hemispheres....PURPOSE: Evidence from animal and human studies demonstrates that cortical regions play a key role in autonomic modulation with a differential role for some brain regions located in the left and right brain hemispheres. Known as autonomic asymmetry, this phenomenon has been demonstrated by clinical observations, by experimental models, and currently by combined neuroimaging and direct recordings of sympathetic nerve activity. Previous studies report peculiar autonomic-mediated cardiovascular alterations following unilateral damage to the left or right insula, a multifunctional key cortical region involved in emotional processing linked to autonomic cardiovascular control and featuring asymmetric characteristics. METHODS: Based on clinical studies reporting specific damage to the insular cortex, this review aims to provide an overview of the prognostic significance of unilateral (left or right hemisphere) post-insular stroke cardiac alterations. In addition, we review experimental data aiming to unravel the central mechanisms involved in post-insular stroke cardiovascular complications. RESULTS AND CONCLUSION: Current clinical and experimental data suggest that stroke of the right insula can present a worse cardiovascular prognosis.
Dasari TW, Nagai M, Ewbank H
… +2 more, Chakraborty P, Po SS
Clin Auton Res
· 2025 Feb · PMID 39312106
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PURPOSE: Autonomic dysregulation is observed in heart failure (HF) with reduced ejection fraction (HFrEF). Abnormal heart rate variability (HRV), a measure of such dysregulation, is associated with poor prognosis in HFrE...PURPOSE: Autonomic dysregulation is observed in heart failure (HF) with reduced ejection fraction (HFrEF). Abnormal heart rate variability (HRV), a measure of such dysregulation, is associated with poor prognosis in HFrEF. It is unknown if novel HRV metrics normalize in the patients with recovered ejection fraction (HFrecEF) compared to persistent HFrEF. The aim of this study was to investigate novel HRV indexes in persistent HFrEF in comparison to HFrecEF METHODS: A standard 10-min electrocardiography measurement was performed in patients categorized in four groups: persistent HFrEF (n = 40), HFrecEF (n = 41), stage A HF (n = 73) and healthy controls (n = 40). RESULTS: All HRV indexes were significantly different between the four groups. Specifically, novel metrics, such as higher parasympathetic nervous system (PNS) index and lower sympathetic nervous system (SNS) index, were observed in the HFrecEF group compared to the persistent HFrEF group. In multiple logistic regression analysis, higher PNS index (odds ratio [OR] 2.02, 95% confidence interval [CI] 1.17-3.49; p = 0.01) and lower SNS index (OR 0.68, 95% CI 0.52-0.87; p = 0.002) were associated with HFrecEF. Receiver operating characteristic analysis showed that the SNS index had the highest area under the curve (AUC), followed by the PNS index and mean heart rate for the HF phenotype regarding EF recovery (AUC = 0.71, 0.69 and 0.69, respectively). CONCLUSION: Myocardial functional recovery in HFrEF is associated with improved parasympathetic activity and reduced sympathetic activity, as reflected in the PNS and SNS indexes. These novel metrics can be potentially used to aid in identifying recovered versus non-recovered phenotypes in patients with HFrEF.