Heart rate variability metrics and myocardial recovery in heart failure with reduced ejection fraction.

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.

Noninvasive low-level tragus stimulation attenuates inflammation and oxidative stress in acute heart failure.

PURPOSE: Acute decompensated heart failure (ADHF) is associated with inflammation, oxidative stress, and excess sympathetic drive. It is unknown whether neuromodulation would improve inflammation and oxidative stress in acute heart failure. We, therefore, performed this proof-of-concept study to evaluate the effects of neuromodulation using noninvasive low-level tragus stimulation on inflammation and oxidative stress in ADHF. METHODS: Nineteen patients with ejection fraction < 40% were randomized to neuromodulation 4 h twice daily (6-10 a.m. and 6-10 p.m.) (n = 8) or sham stimulation (n = 11) during hospital admission. All patients received standard-of-care treatment. Blood samples were collected at admission and discharge. Serum cytokines were assayed using standard immunosorbent techniques. Reactive oxygen species inducibility from cultured coronary endothelial cells exposed to patient sera was determined using a dihydrodichlorofluorescein probe test (expressed as fluorescein units). RESULTS: Compared to sham stimulation, neuromodulation was associated with a significant reduction of circulating serum interleukin-6 levels (-78% vs. -9%; p = 0.012). Similarly, neuromodulation led to a reduction of endothelial cell oxidative stress in the neuromodulation group (1363 units to 978 units, p = 0.003) compared to sham stimulation (1146 units to 1083 units, p = 0.094). No significant differences in heart rate, blood pressure, or renal function were noted between the two groups. CONCLUSION: In this proof-of-concept pilot study, in acute decompensated heart failure, neuromodulation was feasible and safe and was associated with a reduction in systemic inflammation and attenuation of coronary endothelial cellular oxidative stress. CLINICAL TRIAL REGISTRATION: NCT02898181.

Effects of Low-Level Tragus Stimulation on Endothelial Function in Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Autonomic dysregulation in heart failure with reduced ejection fraction plays a major role in endothelial dysfunction. Low-level tragus stimulation (LLTS) is a novel, noninvasive method of autonomic modulation. METHODS AND RESULTS: We enrolled 50 patients with heart failure with reduced ejection fraction (left ventricular ejection fraction of ≤40%) in a randomized, double-blinded, crossover study. On day 1, patients underwent 60 minutes of LLTS with a transcutaneous stimulator (20 Hz, 200 µs pulse width) or sham (ear lobule) stimulation. Macrovascular function was assessed using flow-mediated dilatation in the brachial artery and cutaneous microcirculation with laser speckle contrast imaging in the hand and nail bed. On day 2, patients were crossed over to the other study arm and underwent sham or LLTS; vascular tests were repeated before and after stimulation. Compared with the sham, LLTS improved flow-mediated dilatation by increasing the percent change in the brachial artery diameter (from 5.0 to 7.5, LLTS on day 1, P = .02; and from 4.9 to 7.1, LLTS on day 2, P = .003), compared with no significant change in the sham group (from 4.6 to 4.7, P = .84 on day 1; and from 5.6 to 5.9 on day 2, P = .65). Cutaneous microcirculation in the hand showed no improvement and perfusion of the nail bed showed a trend toward improvement. CONCLUSIONS: Our study demonstrated the beneficial effects of acute neuromodulation on macrovascular function. Larger studies to validate these findings and understand mechanistic links are warranted.

The ligament of Marshall and arrhythmias: A review.

The ligament of Marshall (LOM) is a remnant of the embryonic sinus venosus and left cardinal vein, and contains fat and fibrous tissues, blood vessels, muscle bundles, nerve fibers, and ganglia. The complexity of LOM's structure makes it as a source of triggers and drivers as well as substrates of re-entry for atrial arrhythmias, especially for atrial fibrillation (AF). LOM also serves as a portion of left atrial macro-re-entrant circuit, especially peri-mitral isthmus re-entrant circuit. Experimental studies demonstrate that the LOM acts as a sympathetic conduit between the left stellate ganglion and the ventricles, and participates in the initiation and maintenance of ventricular arrhythmias. Endocardial or epicardial catheter ablation or ethanol infusion into the vein of Marshall may serve as an important adjunct therapy to pulmonary vein isolation in patients with advanced stage of AF, and may help alleviate ventricular arrhythmias as well.

Metformin regulates adiponectin signalling in epicardial adipose tissue and reduces atrial fibrillation vulnerability.

Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF-dependent EAT remodelling and AF vulnerability in dogs. A canine AF model was developed by 6-week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP-induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa-B (NF-κB) phosphorylation; up-regulated interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and transforming growth factor-ß1 (TGF-ß1) levels in LA and EAT; decreased peroxisome proliferator-activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL-6, TNF-α and TGF-ß1 expression and decreased PPARγ/APN expression in 3T3-L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL-1 cells with LPS-stimulated 3T3-L1 conditioned medium (CM) significantly increased IL-6, TNF-α and TGF-ß1 expression and decreased SERCA2a and p-PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP-induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF-dependent EAT remodelling and AF vulnerability by MET.

Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodelling in a rat model of heart failure with preserved ejection fraction.

NEW FINDINGS: What is the central question of this study? What is the effect of chronic intermittent low-level transcutaneous vagus nerve stimulation on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of heart failure with preserved ejection fraction? What is the main finding and its importance? In salt-sensitive rats fed with high salt diet, low-level transcutaneous vagus nerve stimulation significantly attenuated blood pressure elevation, ameliorated diastolic function, and attenuated left ventricular inflammation and fibrosis compared to the sham group. Further studies to examine the efficacy of this novel treatment in humans are warranted. ABSTRACT: Inflammation and fibrosis play a central role in the development of heart failure with preserved ejection fraction (HFpEF). We previously showed that low-level, transcutaneous stimulation of the vagus nerve at the tragus (LLTS) is anti-inflammatory. We investigated the effect of chronic intermittent LLTS on cardiac inflammation, fibrosis and diastolic dysfunction in a rat model of HFpEF. Dahl salt-sensitive (DS) rats were randomized in three groups: low salt (LS, 0.3% NaCl; n = 12; control group without stimulation) and high salt (HS, 4% NaCl) with either active (n = 18) or sham (n = 18) LLTS at 7 weeks of age. After 6 weeks of diet (baseline), sham or active LLTS (20 Hz, 2 mA, 0.2 ms) was implemented for 30 min daily for 4 weeks. Echocardiography was performed at baseline and 4 weeks after treatment (endpoint). At endpoint, left ventricle (LV) histology and gene expression were examined. After 6 weeks of diets, HS rats developed hypertension and LV hypertrophy compared to LS rats. At endpoint, LLTS significantly attenuated blood pressure elevation, prevented the deterioration of diastolic function and improved LV circumferential strain, compared to the HS sham group. LV inflammatory cell infiltration and fibrosis were attenuated in the HS active compared to the HS sham group. Pro-inflammatory and pro-fibrotic genes (tumour necrosis factor, osteopontin, interleukin (IL)-11, IL-18 and IL-23A) were differentially altered in the two groups. Chronic intermittent LLTS ameliorates diastolic dysfunction, and attenuates cardiac inflammation and fibrosis in a rat model of HFpEF, suggesting that LLTS may be used clinically as a novel non-invasive neuromodulation therapy in HFpEF.

The importance of identifying conduction breakthrough sites across the mitral isthmus by elaborate mapping for mitral isthmus linear ablation.

AIMS: Mitral isthmus (MI) ablation is challenging. We hoped to close those conduction breakthrough sites (CBS) across the MI by elaborate mapping. METHODS AND RESULTS: After the initial linear ablation, elaborately mapping large areas above and below the MI line and inside the coronary sinus (CS) was sequentially performed to identify the CBS. The shortest distance from the CBS to the MI line was measured. The distant CBS (D-CBS) was identified as those CBS >5.0 mm away from the MI line. We prospectively enrolled 177 consecutive patients. Bidirectional conduction blockage across MI was obtained in 50 (28.2%) patients after the initial linear ablation and was achieved in additional 115 (65.0%) patients following elaborate mapping and reinforcement ablation. After initial linear ablation, 272 CBS (2.14 ± 0.99 CBS/person) were identified, and 226 (83.1%) of them were characterized as D-CBS, including 98 sites (36.0%) >10.0 mm and 39 sites (14.3%) >15.0 mm away. Endocardial and epicardial (CS) reinforcement ablation eliminated 119/272 (43.8%) and 58/272 (21.3%) CBS, respectively. Among the 177 eliminated CBS, 138 D-CBS (78.0%, 11.2 ± 5.6 mm) were confirmed in 95 (74.8%) patients. Moreover, CBS along the course of ligament of Marshall was closed by endocardial ablation more frequently than that along the course of great cardiac vein (52.6%% vs. 35.1%, P = 0.004). Eventually, CS ablation was required only in 64 (38.8%) patients. CONCLUSION: Distant CBS, accounted for the majorities of the residual conduction across the MI after initial ablation, could be effectively identified and accurately eliminated by elaborate mapping and ablation around the MI ablation line.

Acetylcholine-Atropine Interactions: Paradoxical Effects on Atrial Fibrillation Inducibility.

Atropine (ATr) is well known as a cholinergic antagonist, however, at low concentrations ATr could paradoxically accentuate the parasympathetic actions of acetylcholine (ACh). In 22 pentobarbital anesthetized dogs, via a left and right thoracotomy, a leak-proof barrier was attached to isolate the atrial appendages (AAs) from the rest of the atria. In group 1 (Ach+ATr+Ach), ACh, 100 mM, was placed on the AA followed by the application of ATr, 2 mg/mL. The average atrial fibrillation (AF) duration was 17 ± 7 minutes. After ATr was applied to the AA and ACh again tested, the AF duration was markedly attenuated (2 ± 2 minutes, P < 0.05). In group 2 (ATr+Ach), ATr was initially applied to the AA followed by the application of ACh, 100 mM. There was no significant difference in AF duration (16 ± 4 minutes vs. 18 ± 2 minutes, P = NS). The inhibitory effect of ATr on induced HR reduction (electrical stimulation of the anterior right ganglionated plexi and vagal nerves) was similar between groups 1 and 2. These observations suggest that when ATr is initially administered it attaches to the allosteric site of the muscarinic ACh receptor (M2) leaving the orthosteric site free to be occupied by ACh. The M3 receptor that controls HR slowing does not show the same allosteric properties.

Spectral Analysis of Electrocardiograms in Patients with Inducible Atrial Fibrillation after Catheter Ablation Predicts Sinus Rhythm Maintenance.

BACKGROUND: We aimed to develop a novel predictive marker for atrial fibrillation (AF) recurrence in patients with inducible AF after catheter ablation, based on power spectral analysis of baseline and postablation electrocardiograms. METHODS: Twenty-five patients who had undergone their first AF ablation procedure (pulmonary vein isolation and ganglionated plexi ablation) and had inducible AF after ablation were included. A 30-second interval of AF was chosen for each patient before and after ablation, and a periodogram of the atrial activity was computed. A ratio of the power in the dominant frequency to the power in the remainder of the periodogram (DFR) was calculated. RESULTS: Eight (32%) patients had recurrent AF at 1 year. The clinical and echocardiographic characteristics of patients with and without recurrence were similar (P > 0.05). After ablation, there was organization of atrial activity, evidenced by an increase in the DFR (0.28 ± 0.22 vs 0.53 ± 0.29; P = 0.001). The percent change in DFR before and after ablation (median [interquartile range]) was significantly higher in patients without AF recurrence (120% [30% to 344%] vs 3% [-27% to 66%]; P = 0.01). Receiver operating curve (ROC) analysis demonstrated that a less than 16% increase in DFR postablation was able to predict recurrence of AF (area under ROC curve = 0.82; P = 0.03) with 75% sensitivity and 94% specificity. CONCLUSION: AF ablation leads to variable organization of atrial activity. Organization of atrial activity after AF ablation is associated with lower 1-year recurrence rates and may be used intraprocedurally after as a novel end point for AF ablation. Larger prospective studies are warranted.

Spectral Analysis of Baseline Electrocardiogram During Atrial Fibrillation Predicts Response to Antiarrhythmic Drug Therapy in Patients With Persistent Atrial Fibrillation.

BACKGROUND: We evaluated the ability of spectral analysis of the baseline ECG during atrial fibrillation (AF) to predict the response of persistent AF to antiarrhythmic drug therapy. METHODS: Patients with persistent AF who were admitted for dofetilide loading were prospectively enrolled in the study. Atrial activity was extracted from the ECG using an Independent Component Analysis method and then subjected to a Modified Periodogram. The regularity index was computed as the ratio of the power in the dominant frequency and all its harmonics to the total power in the spectrum. Patients were followed at 1 month, 3 months and every 3 months thereafter. RESULTS: Of 28 patients enrolled in the study, 14 (50%) converted acutely to sinus rhythm during the 3-day hospital loading period. The clinical and echocardiographic characteristics of patients with and without acute pharmacologic conversion were similar. The regularity index was significantly higher in those who converted to sinus rhythm compared to those who did not (0.71 ± 0.20 vs. 0.38 ± 0.13, respectively; P < 0.0001). A regularity index ≥0.44 had a 79% sensitivity and 93% specificity to predict acute conversion and was associated with a nearly 5-fold increase in the acute conversion rate (odds ratio = 4.89; 95% confidence interval 1.74-13.75; P = 0.003). The regularity index was the only independent predictor of acute conversion. Neither acute conversion, nor the regularity index predicted sinus rhythm maintenance, after a median follow-up of 10 months. CONCLUSION: Increased regularity index predicts acute conversion of persistent AF during dofetilide loading, but does not predict long-term sinus rhythm maintenance.

Autonomic Remodeling: How Atrial Fibrillation Begets Atrial Fibrillation in the First 24 Hours.

BACKGROUND: The mechanism(s) of how atrial fibrillation (AF) sustains itself in the first 24 hours is not well understood. OBJECTIVE: We sought to investigate the role of autonomic remodeling in the first 24 hours of AF simulated by rapid atrial pacing (RAP). METHODS: Forty-eight rabbits were divided into 6 groups. One group (n = 8) was euthanized after baseline recordings. Another group (n = 8) did not receive RAP during the 24-hour period to serve as controls. In the other 4 groups, rabbits were euthanized after RAP for 4, 8, 12, or 24 hours (n = 8 for each). Before and after designated hours of RAP, atrial effective refractory period, heart rate variability, and left vagal and sympathetic nerve activity (VNA and SNA, respectively) were determined. The right and left atrial tissues were obtained for immunocytochemical analysis for growth-associated protein 43 (GAP43), tyrosine hydroxylase (TH), and choline acetyltransferase (ChAT). RESULTS: RAP resulted in progressively shortened atrial effective refractory period and slower heart rate. In the first 12 hours of RAP, both SNA and VNA progressively increased. Then, VNA remained stably elevated but SNA began to attenuate. The high-frequency component and low-frequency/high-frequency ratio of heart rate variability followed the trend of VNA and SNA, respectively. The density of GAP43-positive, ChAT-positive, and TH-positive neural elements in the right and left atria was progressively higher with RAP. CONCLUSIONS: AF resulted in progressive autonomic remodeling, manifesting as nerve sprouting, sympathetic and vagal hyperinnervation. Autonomic remodeling may play an important role in sustaining AF in the first 24 hours.

Electrical Stimulation of Vascular Autonomic Nerves: Effects on Heart Rate, Blood Pressure, and Arrhythmias.

BACKGROUND: Recent clinical studies have shown conflicting results of the efficacy of renal sympathetic denervation (RSD) to mitigate hypertension. In this study, we compared electrical stimulation (ES) of autonomic nerves on the surface of the left pulmonary artery (LPA) and renal arteries (RAs) on heart rate (HR), systolic blood pressure (SBP) and diastolic blood pressure (DBP), and cardiac arrhythmias. METHODS: In 16 pentobarbital anesthetized dogs, standard electrocardiography leads and blood pressure (BP) were continuously recorded. After a left thoracotomy, a circumferential multielectrode catheter was secured around the LPA. Atrial pacing was coupled to the ES applied around the LPA during the QRS complex to avoid ventricular excitation. Flank incisions allowed retroperitoneal expose of the RAs and the aortico-renal ganglia (ARG). HR and SBP/DBP were determined at baseline (BL) and during ES of LPA, RA, or ARG. RESULTS: During ES applied to the LPA, HR was unchanged compared to BL values. In four of six animals, ventricular tachyarrhythmias were induced by ES. SBP increased significantly (BL vs ES, 129 ± 17 mm Hg vs 163 ± 21 mm Hg, P ≤ 0.05). ES applied to the RAs and ARG did not affect the HR, but significantly increased SBP/DBP (baseline: 134 ± 24/96 ± 18 mm Hg; RAs stimulation: 157 ± 26/114 ± 18 mm Hg; ARG stimulation: 207 ± 44/147 ± 26 mm Hg, P < 0.05). CONCLUSION: ES of vascular autonomic nerves on LPA, RAs, and ARG significantly increased BP but without effects on HR. ES of ARG induced substantially greater hypertensive responses than ES of RAs, implying that ES of ARG may serve as a biomarker or ablation targets for RSD.

Marked suppression of pulmonary vein firing after circumferential pulmonary vein isolation in patients with paroxysmal atrial fibrillation: is pulmonary vein firing an epiphenomenon?

INTRODUCTION: Rapid firing in pulmonary veins (PVs) is a leading cause of paroxysmal atrial fibrillation. We hypothesized that PV firing (PV-F) should continue after circumferential PV isolation (CPVI) because the PV tissue responsible for PV-F remains intact. METHODS AND RESULTS: In Group-1 (n = 92), isoproterenol (ISP) and adenosine triphosphate (ATP) were co-administered to provoke PV-F before and after CPVI. The site of rapid focal discharge that initiated atrial fibrillation (AF) defined PV-F versus non-PV-F. Additional 17 patients with PV-F induced by ISP+ATP before CPVI were enrolled into Group-2 and various pacing maneuvers were used in conjunction to ISP+ATP to provoke PV-F after CPVI. In Group-1, AF was induced in 47/81 (58.0%) and 16/88 (18.2%) patients before and after CPVI, respectively (P < 0.01). Before CPVI, 43/47 (91.5%) of the rapid firing originated from PV. After successful CPVI, 88/92 patients were in sinus rhythm and non-PV-F was induced in 14/88 patients. PV-F was induced in 2/88 patients, which was eliminated by ganglionated plexus ablation outside the CPVI line. In Group-2, various pacing maneuvers with ISP+ATP only induced PV-F in 1/17 patients after CPVI. CONCLUSION: Marked suppression of PV-F after CPVI strongly suggests that the real source of PV-F is located in the atrium. PV-F may be an epiphenomenon.

Left renal nerves stimulation facilitates ischemia-induced ventricular arrhythmia by increasing nerve activity of left stellate ganglion.

INTRODUCTION: Renal sympathetic nerve (RSN) activity plays a key role in systemic sympathetic hyperactivity. Previous studies have shown that cardiac sympathetic hyperactivity, especially the left stellate ganglion (LSG), contributes to the pathogenesis of ventricular arrhythmias (VAs) after acute myocardial infarction (AMI). METHODS AND RESULTS: Twenty-eight dogs received 3 hours of continuous left-sided electrical stimulation of RSN (LRS; Group-1, n = 9), sham RSN stimulation (Group-2, n = 9), or LSG ablation plus 3 hours of LRS (Group-3, n = 10) were included. AMI was induced by ligating the proximal left anterior descending coronary artery. LRS was performed using electrical stimulation on the adventitia of left renal artery at the voltage increasing the systolic blood pressure (BP) by 10%. BP, heart rate variability (HRV), serum norepinephrine (NE) level, and LSG function were measured at baseline and the end of each hour of LRS. C-fos and nerve growth factor (NGF) protein expressed in the LSG were examined in Group-1 and Group-2. Compared with baseline, 3 hours of LRS induced a significant increase in BP, sympathetic indices of HRV, serum NE level, and LSG function. The incidence of VAs in Group-1 was significantly higher than other groups. The expression of c-fos and NGF protein in the LSG was significantly higher in Group-1 than Group-2. CONCLUSION: Three hours of LRS induces both systemic and cardiac sympathetic hyperactivity and increases the incidence of ischemia-induced VAs.

Non-invasive Neuromodulation of Arrhythmias.

The autonomic nervous system plays a central role in the pathogenesis of arrhythmias. Preclinical and clinical studies have demonstrated the therapeutic effect of neuromodulation at multiple anatomic targets across the neurocardiac axis for the treatment of arrhythmias. In this review, we discuss the rationale and clinical application of noninvasive neuromodulation techniques in treating arrhythmias and explore associated barriers and future directions, including optimization of stimulation parameters and patient selection.

Cardio-respiratory coupling and myocardial recovery in heart failure with reduced ejection fraction.

INTRODUCTION: The interaction between the cardiovascular and respiratory systems in healthy subjects is determined by the autonomic nervous system and reflected in respiratory sinus arrhythmia. Recently, another pattern of cardio-respiratory coupling (CRC) has been proposed linking synchronization of heart and respiratory system. However, CRC has not been studied precisely in heart failure (HF) with reduced ejection fraction (EF) (HFrEF) according to the myocardial recovery. METHODS: 10-min resting electrocardiography measurements were performed in persistent HFrEF patients (n=40) who had a subsequent left ventricular EF (LVEF) of ≤ 40 %, HF with recovered EF patients (HFrecEF) (n=41) who had a subsequent LVEF of > 40 % and healthy controls (n=40). Respiratory frequency, respiratory rate, CRC index, time-domain, frequency-domain and nonlinear heart rate variability indices were obtained using standardized software-Kubios™. CRC index was defined as respiratory high-frequency peak minus heart rate variability high-frequency peak. RESULTS: Respiratory rate was positively correlated with high-frequency (HF) peak (Hz) in both persistent HFrEF group (p<0.001) and HFrecEF group (p<0.001), while respiratory rate was negatively correlated with HF power (ms2) in the healthy controls (p<0.05). CRC index was lowest in the persistent HFrEF group followed by HFrecEF and was high in healthy controls (0.008 vs 0.012 vs 0.056 Hz, p=0.03). CONCLUSION: CRC index was lowest in patients with impaired myocardial recovery, which indicates that cardio-respiratory synchrony is stronger in persistent HFrEF. This may represent a higher HF peak (Hz)/lower HF power (ms2) and abnormal sympathovagal balance in persistent HFrEF group compared to healthy controls. Further work is underway to tests this hypothesis and determine the utility of CRC index in HF phenotypes and its utility as a potential biomarker of response with neuromodulation.

Neuromodulation of Cardiovascular Risks Associated With Cardiotoxic Chemotherapy: A First-in-Human Randomized Pilot Study. Neuromodulation in Cancer Study (NCAN).

OBJECTIVES: Cardiotoxic chemotherapy is used to treat malignancies such as breast cancer and lymphoma. These treatments predispose patients to cardiotoxicity that can lead to cancer treatment-related cardiac dysfunction (CTRCD). The use of high doses of anthracyclines or in combination with human epidermal growth factor receptor 2 antagonists is associated with a progressively higher risk of CTRCD. CTRCD is preceded by increased activation of the sympathetic nervous system and abnormal left ventricular mechanical deformation as measured by abnormal global longitudinal strain (GLS). Low-level tragus stimulation (LLTS) is a new, safe, noninvasive technique that offers great potential to reduce increased sympathetic activation and improve GLS. Here, we describe a study method to examine the effects of LLTS on autonomic balance and cardiac function in breast cancer or lymphoma patients treated with anthracyclines. METHODS: A first-in-human pilot, randomized, double-blind feasibility study will evaluate 104 patients (age >50 y) with breast cancer or lymphoma who receive anthracyclines with one additional CTRCD risk factor. Patients undergo 2 weeks of LLTS daily (1 h/d). Autonomic balance will be measured using heart rate variability metrics. Strain imaging using GLS will be performed pre and post-LLTS. Endothelial inflammation and oxidative stress measures will be performed using in vitro assays at baseline and after 2 weeks. CONCLUSION: We hypothesize that LLTS stabilizes sympathovagal imbalance and improves cardiac performance in anthracycline-treated patients with breast cancer or lymphoma.