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Background: Permanent ablation of the right greater splanchnic nerve (GSN) has previously been demonstrated to improve quality of life and functional outcomes, as well as reduce abnormally high intracardiac filling pressures, in patients with heart failure with preserved ejection fraction (HFpEF) at 1, 3 and 12 months following the procedure. We hypothesize that hemodynamic changes that ensue from surgical right GSN ablation would be apparent as early as 24 h after the medical intervention. Methods and Results: This is a prespecified analysis of a single-arm, two-center, open-label study evaluating the effects of right GSN ablation via thoracoscopic surgery in HFpEF patients with pulmonary capillary wedge pressure (PCWP) ≥15 mmHg at rest or ≥25 mmHg with supine cycle ergometry. A total of seven patients (median age 67 years, 29% female) underwent GSN removal followed by invasive right heart catheterization within 24 h. GSN ablation resulted in a significant reduction in PCWP 24 h after the procedure compared to baseline for both 20 W exercise (baseline (28.0 ± 4.3 mmHg) to 24 h (19.6 ± 6.9 mmHg); p = 0.0124) and peak exercise (baseline (25.6 ± 2.4 mmHg) to 24 h (17.4 ± 5.9 mmHg); p = 0.0025). There were no significant changes in resting or leg-up hemodynamics. Conclusions: Permanent right GSN ablation leads to a reduction in intracardiac filling pressures during exercise, apparent as early as 24 h following the procedure.

The purpose of this article is to evaluate the utility of ultrasound in identifying carotid bodies (CBs) in patients with drug-resistant arterial hypertension.We enrolled 13 patients with drug-resistant hypertension into a trial for surgical CB excision. CT angiography (CTA) and Doppler ultrasound (DUS) of the cervical arteries were performed before surgery. CBs were identified in a blind manner at both CTA and DUS. CBs were defined at CTA as ovoid avidly enhancing structures at the inferomedial aspect of the carotid bifurcation. At DUS, CBs were defined as ovoid solid structures in the inferomedial aspect of the bifurcation.CBs were identified in 12 of 13 patients (23/26 sides) using CTA and in 11 of 13 patients (18/26 sides) using DUS. Identification of CB with DUS and CTA correlated in 17 of 18 cases; in one instance, CB was identified with DUS but not CTA. There was no statistically significant difference in size and volume of CB measured by both methods.Noncarcinogenic CBs can be visualized using DUS, with good correlation of size and location compared with CTA. The findings show that DUS can be reliably used to further examine the role of CBs in cardiovascular disorders and can be used in conjunction with therapies that target CBs.

Background In HFpEF, increased sympathetic outflow to the splanchnic venous system causes chronic redistribution of blood volume into the central circulation, which leads to exercise limitations, hemodynamic deterioration, and worsening outcomes. We have previously shown that surgical right greater splanchnic nerve (GSN) ablation in HFpEF leads to a reduction of PCWP, improved quality of life and exercise capacity. Objective Demonstrate feasibility of a novel transvenous approach to right-sided GSN ablation for the treatment of HFpEF. Methods In a non-randomized, open-label trial, 11 HFpEF patients (3 male, 8 female, 70±8 years) with NYHA class II/III, LVEF ≥ 50% and high baseline PCWP at rest or with exercise, underwent right GSN ablation with the Axon Transvenous GSN Ablation System. Follow-up assessments (1 and 3 months) include the 6MWT, KCCQ, blood labs, and echocardiography. Change from baseline ablation to each follow-up were compared using paired Wilcoxon rank-sum tests. Data shown as mean ± standard deviation, unless otherwise noted. Results Two procedure related events were reported in 2 patients prior to the 1-month timepoint: bradycardia due to anesthesia and acute decrease in eGFR of >20 ml/min/1.73 m2, both of which returned to baseline without sequelae. Expected AEs related to the catheterization procedure were observed and resolved without sequalae, including access site hematoma (1), access site pain (1), right intercostal pain (1). There were no device related adverse cardiac events and no unanticipated adverse device effects. Efficacy results (Table) demonstrate marked improvements and/or favorable trends in quality of life (NYHA and KCCQ), exercise capacity (6MWT), diastolic function (E/e’ ratio) and HF severity (NTproBNP). Although the study was underpowered to show a statistically significant improvement in 6MWT from baseline, there was a clinically relevant improvement in distance compared to baseline of at least 30 m in all patients at 1 and 3 months, and at least a 45 m in 5/11 patients at 1 month and 8/11 patients at 3 months. Conclusion These results demonstrate, for the first time ever, the feasibility of treating HFpEF with endovascular right-sided GSN ablation. The encouraging safety and efficacy results provide rationale for a phase 2 randomized controlled trial.

The splanchnic vascular compartment is the major reservoir for intravascular blood volume, and dysregulation of the compartment was implicated in a series of cardiovascular conditions. We explored feasibility and effectiveness of an implantable cuff system on the greater splanchnic nerve (GSN) in healthy canines for short- and long-term neuromodulation to affect the circulation. Five mongrel hounds underwent minimally invasive right-sided unilateral GSN cuff placement. All animals underwent same day GSN stimulation and repeat stimulation at 9-30 days. Stimulation parameter optimization was conducted both acutely and chronically. Parameters ranged from 1-250 Hz, 0.25 mA-35 mA, 0.1-0.5 ms, and 30-s pulse duration. Two animals were survived for 9 days and 3 animals for 30 days. Stimulation of the right GSN increased mean arterial blood pressure by 36.9 mmHg ± 13.4 (p < 0.0001), central venous pressure by 6.9 mmHg ± 1.7 (p < 0.0001), and mean pulmonary arterial pressure by 6.3 mmHg ± 2.0 (p < 0.0001). Peak effects were observed within 30 s, and magnitude of effects was comparable between stimulation cycles (p = 0.4). Stimulation-induced changes in hemodynamics were independent of afferent nerve fibers (pain response) or the adrenal gland. Necropsy showed no evidence of nerve damage on histologic studies up to 30 days after implantation. GSN stimulation via an implanted nerve cuff provided a reproducible and rapid method to increase arterial, central venous, and pulmonary arterial pressures. The neuromodulation cuff was well tolerated and elicited a response up to 30 days after implantation. The clinical application of GSN stimulation as a tool to change central and peripheral cardiovascular hemodynamics needs to be explored.

Altered electrical behavior alongside healed myocardial infarcts (MIs) is associated with increased risk of sudden cardiac death. However, the multidimensional mechanisms are poorly understood and described. This study characterizes, for the first time, the intramural spread of electrical activation in the peri-infarct region of chronic reperfusion MIs. Four sheep were studied 13 wk after antero-apical reperfusion infarction. Extracellular potentials (ECPs) were recorded in a ~20 × 20-mm2 region adjacent to the infarct boundary (25 plunge needles NEW & NOTEWORTHY Intramural in vivo measurements of peri-infarct electrical activity were not available before this study. We use pace-mapping in a three-dimensional electrode array to show that a subset of stimuli in the peri-infarct region initiates coordinated myocardial activation some distance from the stimulus site with substantial associated time delays. This is site dependent and heterogeneous and occurs for

Aims Augmented reflex responses from peripheral chemoreceptors, which are mainly localized in the carotid bodies (CBs), characterize patients with systolic heart failure and contribute to adrenergic hyperactivation. We investigated whether surgical resection of CBs in these patients can be performed safely to decrease sympathetic tone. Methods and results We studied 10 male patients with systolic heart failure (age, 59 ± 3 years; LVEF, 27 ± 7%) who underwent unilateral right-sided CB resection (four patients) or bilateral CB resection (six patients). Primary endpoints of the study were changes in muscle sympathetic nerve activity (MSNA) and peripheral chemosensitivity measured as ventilatory response to hypoxia from baseline to 1 month post-CB resection. Safety analysis included analysis of arterial blood gas and oxygenation at night through 2 months post-procedure and adverse events assessed up to 12 months. At the 1-month visit, CB resection was associated with a significant decrease both in MSNA (86.6 ± 3.1 vs. 79.7 ± 4.2 bursts/100 beats, P = 0.03) and in peripheral chemosensitivity (1.35 ± 0.19 vs. 0.41 ± 0.17 L/min/SpO2, P = 0.005). It also resulted in improved exercise tolerance. Amongst some patients with bilateral CB resection, there was a trend towards worsening of oxygen saturation at night, which in one case required therapy with non-invasive ventilation. Conclusion We present first-in-man evidence that CB resection in patients with systolic heart failure is associated with a decrease in sympathetic activity. A bilateral procedure may carry a risk of worsening oxygenation at night. CB modulation constitutes an interesting research avenue, but careful consideration of the balance between safety and efficacy is necessary before further clinical trials.

Stimulation of peripheral chemoreceptors by acute hypoxia causes an increase in minute ventilation (VI), heart rate (HR) and arterial blood pressure (BP). However, the contribution of particular chemosensory areas - carotid (CB) vs. aortic bodies - to this response in humans remains unknown. We performed a blinded, randomized and placebo controlled study in 11 conscious patients (9 men, 2 women) undergoing common carotid artery angiography. Doses of adenosine ranging from 4 to 512 μg or placebo solution of matching volume were administered in randomized order via a diagnostic catheter located in a common carotid artery. Separately, ventilatory and hemodynamic responses to systemic hypoxia were also assessed. Direct excitation of a CB with intra-arterial adenosine increased VI, systolic BP, mean BP and decreased HR. No responses in these variables were seen after injections of placebo. The magnitude of the ventilatory and hemodynamic responses depended on both the dose of adenosine used and on the level of chemosensitivity as determined by the ventilatory response to hypoxia. Percutaneous radio-frequency ablation of the CB abolished the adenosine evoked respiratory response and partially depressed the cardiovascular response in one participant. Our study confirms the excitatory role of purines in CB physiology in humans and suggests that adenosine may be used for selective stimulation and assessment of CB activity. The trial is registered at ClinicalTrials.gov NCT01939912. This article is protected by copyright. All rights reserved

BACKGROUND: Bilateral thoracoscopic stellectomy has antiarrhythmic effects, however, the procedure is invasive with associated morbidity. Sympathetic nerves from both stellate ganglia form the deep cardiac plexus (CP) in the aortopulmonary window (APW), anterior to the trachea. OBJECTIVE: To demonstrate a novel and minimally invasive transtracheal approach to block the cardiac plexus in porcine models. METHODS: In 12 Yorkshire pigs, right (RSG) and left (LSG) stellate ganglia were electrically stimulated and sympathetic baseline response recorded (hemodynamic parameters and T wave pattern). APW was accessed transtracheally with endobronchial ultrasound (EBUS) guidance and local stimulation of CP confirmed the location. Injection of 1% lidocaine (n=10) or saline solution (n=2) was performed and RSG and LSG responses were re-evaluated and compared with baseline. RESULTS: Transtracheal lidocaine injection into the CP successfully blocked bilateral sympathetic induced changes (%) in T wave amplitude (282.8±152.2 vs 20.1±16.5%, p

New Findings What is the central question of this study? Carotid body denervation removes the ventilatory response to acute hypoxia, although haemodynamic responses to acute hypoxia after carotid body removal have not been described conclusively in humans. What is the main finding and its importance? Carotid body removal results in dissociation of heart rate and blood pressure responses to hypoxia in human subjects. While the heart rate response (tachycardia) is maintained, there is a significant attenuation of the blood pressure response (hypertension), which indicates the existence of different sensory afferent pathways in the haemodynamic response to hypoxia that has important clinical implications for this novel therapeutic modality. While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1 month after CBR [median (interquartile range): age, 58.5 (56–61) years old; and ejection fraction, 32 (25–34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (∆91%, P

The carotid body (CB) has previously been found to be enlarged and hyperactive in various disease states such as heart failure (HF), hypertension (HTN), and respiratory disease. Evaluation of CB size in these disease states using imaging has not been performed. The purpose of this case-control study was to compare CB sizes in patients with HF and HTN with those of controls using CT angiography.A retrospective review was performed on 323 consecutive patients who had neck computed tomography angiography (CTA) exams in 2011. Following extensive review, 17 HF and HTN patients and 14 controls were identified. Two radiologists blinded to the patient disease status made consensus bilateral carotid body (CB) measurements on the CTA exams using a previously described standardized protocol. CB axial cross-sectional areas were compared between HF and HTN cases and controls using a paired t test.The right CB demonstrated a mean cross-sectional area of 2.79 mm(2) in HF and HTN patients vs. 1.40 mm(2) in controls (p = 0.02). The left CB demonstrated a mean cross-sectional area of 3.13 mm(2) in HF and HTN patients vs. 1.53 mm in controls (p = 0.03).Our results provide imaging evidence that the carotid bodies are enlarged in patients with HF and HTN. Our case-control series suggests that this enlargement can be detected on neck CTA.

Aims Augmented peripheral chemoreflex response is an important mechanism in the pathophysiology of chronic heart failure (CHF). This study characterizes prevalence and clinical predictors of this phenomenon in optimally managed male CHF patients, and seeks to describe the hemodynamic consequences of chemoreceptor hypersensitivity. Methods and Results Thirty-four optimally managed CHF patients and 16 control subjects were prospectively studied. Hypoxic ventilatory response (HVR)—a measure of peripheral chemosensitivity—was calculated with the use of short nitrogen gas administrations. Systolic blood pressure (SBP) and heart rate (HR) following transient hypoxic challenges were recorded with a Nexfin monitor. Hemodynamic responses to hypoxia were expressed by the linear slopes between oxygen saturation (%) and SBP (mm Hg) or HR (beats/min). Elevated HVR was present in 15 (44%) of the CHF patients. Patients with elevated HVR exhibited higher levels of N-terminal pro–B-type natriuretic peptide, lower left ventricular ejection fraction, and higher prevalence of atrial fibrillation. CHF patients with elevated HVR had significantly greater SBP and HR responses to hypoxia than CHF patients with normal HVR. Conclusions Despite comprehensive pharmacotherapy, elevated HVR is prevalent in CHF patients, related to severity of the disease and associated with augmented hemodynamic responses to hypoxia. CHF patients with elevated HVR may be prone to unfavorable hemodynamic changes.

Hypertension, heart failure (HF), type II diabetes mellitus, and chronic kidney disease represent significant and growing global health issues.1 The rates of control of blood pressure and the therapeutic efforts to prevent progression of HF, chronic kidney disease, diabetes mellitus, and their sequelae remain unsatisfactory.2–5 Although patient nonadherence and nonpersistence with medications participate in this failure, especially in asymptomatic disorders, the inherent complexity of drug titration, drug interactions, and both the real and perceived adverse events collectively contribute to the failure of lifelong polypharmacy. Furthermore, therapy targeting the potentially unique contribution of autonomic imbalance is limited by the poorly tolerated systemic adverse effects of adrenergic blocking agents. Recent introduction of medical procedures, such as renal denervation,6,7 and devices such as deep brain stimulation,8 baroreceptor stimulation,9 and direct vagus nerve stimulation10 begin to address these gaps in selective patients. The contribution of excessive sympathetic nerve activity to the development and progression of hypertension, insulin resistance, and HF has been demonstrated in both preclinical and human experiments. Preclinical experiments in models of these diseases have successfully used sympathetic or parasympathetic modifications to alter the time course of their progression.11,12 Reduction of blood pressure after dorsal rhizotomy in rats with renal hypertension and reduced total body noradrenaline and muscle sympathetic nerve activity in humans after renal denervation confirm that the afferent signals from the kidney underlie some of the excessive sympathetic drive seen in these states.13,14 However, additional afferent signals may arise from sites elsewhere in the body and in particular the carotid body (CB). We propose targeting the CB in patients with increased chemosensitivity to address the underlying autonomic imbalance seen in hypertension, HF, insulin resistance, and chronic kidney disorders. ### The CB: A Peripheral Chemosensor The CB (Figure 1), the dominant …

In humans, excitation of peripheral chemoreceptors with systemic hypoxia causes hyperventilation, hypertension and tachycardia. However, the contribution of particular chemosensory areas (carotid vs. aortic bodies) to this response is unclear. We showed that selective stimulation of the carotid body by the injection of adenosine into the carotid artery causes a dose-dependent increase in minute ventilation and blood pressure with a concomitant decrease in heart rate in conscious humans. The ventilatory response was abolished and the haemodynamic response was diminished following carotid body ablation. We found that the magnitude of adenosine evoked responses in minute ventilation and blood pressure was analogous to the responses evoked by hypoxia. By contrast, opposing heart rate responses were evoked by adenosine (bradycardia) vs. hypoxia (tachycardia). Intra-carotid adenosine administration may provide a novel method for perioperative assessment of the effectiveness of carotid body ablation, which has been recently proposed as a treatment strategy for sympathetically-mediated diseases.Stimulation of peripheral chemoreceptors by acute hypoxia causes an increase in minute ventilation (VI), heart rate (HR) and arterial blood pressure (BP). However, the contribution of particular chemosensory areas, such as carotid (CB) vs. aortic bodies, to this response in humans remains unknown. We performed a blinded, randomized and placebo-controlled study in 11 conscious patients (nine men, two women) undergoing common carotid artery angiography. Doses of adenosine ranging from 4 to 512 μg or placebo solution of a matching volume were administered in randomized order via a diagnostic catheter located in a common carotid artery. Separately, ventilatory and haemodynamic responses to systemic hypoxia were also assessed. Direct excitation of a CB with intra-arterial adenosine increased VI, systolic BP, mean BP and decreased HR. No responses in these variables were seen after injections of placebo. The magnitude of the ventilatory and haemodynamic responses depended on both the dose of adenosine used and on the level of chemosensitivity as determined by the ventilatory response to hypoxia. Percutaneous radiofrequency ablation of the CB abolished the adenosine evoked respiratory response and partially depressed the cardiovascular response in one participant. The results of the present study confirm the excitatory role of purines in CB physiology in humans and suggest that adenosine may be used for selective stimulation and assessment of CB activity. The trial is registered at ClinicalTrials.gov NCT01939912.

The peripheral chemoreflex is known to be enhanced in individuals with hypertension. In pre-hypertensive (PH) and adult spontaneously hypertensive rats (SHRs) carotid body type I (glomus) cells exhibit hypersensitivity to chemosensory stimuli and elevated sympathoexcitatory responses to peripheral chemoreceptor stimulation. Herein, we eliminated carotid body inputs in both PH-SHRs and SHRs to test the hypothesis that heightened peripheral chemoreceptor activity contributes to both the development and maintenance of hypertension. The carotid sinus nerves were surgically denervated under general anaesthesia in 4- and 12-week-old SHRs. Control groups comprised sham-operated SHRs and aged-matched sham-operated and carotid sinus nerve denervated Wistar rats. Arterial blood pressure was recorded chronically in conscious, freely moving animals. Successful carotid sinus nerve denervation (CSD) was confirmed by testing respiratory responses to hypoxia (10% O(2)) or cardiovascular responses to i.v. injection of sodium cyanide. In the SHR, CSD reduced both the development of hypertension and its maintenance (P

While the ventilatory response to hypoxia is known to be mediated by the carotid bodies, the origin of the haemodynamic alterations evoked by hypoxia is less certain. Bilateral carotid body removal (CBR) performed to treat congestive heart failure may serve as a model to improve our understanding of haemodynamic responses to hypoxia in humans. We studied six congestive heart failure patients before and 1 month after CBR [median (interquartile range): age, 58.5 (56-61) years old; and ejection fraction, 32 (25-34)%]. Peripheral chemosensitivity (hypoxic ventilatory response) was equated to the slope relating lowest oxygen saturation to highest minute ventilation following exposures to hypoxia. Likewise, systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR) slopes were calculated as slopes relating the lowest oxygen saturations to the highest SBP, DBP and HR responses. We found that CBR reduces the hypoxic ventilatory response (91%, P 0.05), SBP (71%, P 0.05) and DBP slopes (59%, P = 0.07). In contrast, the HR slope remained unchanged. The dissociation between the blood pressure and HR responses after CBR shows involvement of a different chemoreceptive site(s) maintaining the response to acute hypoxia. We conclude that carotid bodies are responsible for ventilatory and blood pressure responses, while the HR response might be mediated by the aortic bodies. The significant reduction of the blood pressure response to hypoxia after CBR suggests a decrease in sympathetic tone, which is of particular clinical relevance in congestive heart failure.

Aim To test the hypothesis that computed tomographic angiography (CTA) can identify carotid body enlargement in patients with sympathetically mediated diseases. Materials and methods A retrospective chart review of all patients obtaining CTAs of the cervical vasculature at University of Utah Health Sciences Center over a 6-month period was performed. Widest axial measurements of both carotid bodies were performed on a picture archiving and communication system (PACS). Statistical analysis was then performed to compare the mean carotid body size between control patients and patients with diabetes mellitus, hypertension, and congestive heart failure. Results Measurements were performed on 288 patients, with 134 controls. Of the remaining 154, 72 patients had diabetes mellitus, 46 had congestive heart failure, and 130 had hypertension. The control patients had a mean carotid body diameter of 2.3 mm. There was a statistically significant ( p 0.01) 20–25% increase in mean diameter with diabetes mellitus (2.8 mm), hypertension (2.7 mm), and congestive heart failure (2.7 mm; p 0.01). Conclusions This study found a 20–25% larger mean carotid body size in patients with diabetes mellitus, hypertension, and congestive heart failure relative to controls. However, this small enlargement should not mimic other carotid body diseases, such as a paraganglionoma. Moreover, these findings further support the proposed functional relationship between the carotid body and sympathetically mediated disease states.

We thank Prof Andrea Porzionato1 for her comment and support of our review2 that raises the issue of the role of the carotid body in obesity-related sympathoactivation. In our review,2 we summarized the intriguing association of raised peripheral chemosensitivity in several disease states, including hypertension, heart failure, and sleep apnea. On the basis of our recent preclinical data,3 we emphasized that in addition to increased peripheral chemoreflex sensitivity, the carotid body develops substantial afferent tone in hypertensive (but not normotensive) rats, and that by severing its connection to the central nervous system, arterial pressure falls substantially. This was associated with a reduction in sympathetic vasomotor …

Background Augmented reflex response from peripheral chemoreceptors characterises chronic heart failure (CHF), contributes to autonomic imbalance and exercise intolerance and predicts poor outcome. Methods and results We present a case of a 56-year-old male patient with ischaemic CHF, who underwent surgical, unilateral carotid body resection to reduce peripheral chemosensitivity. At 2-month and 6-month follow-ups, we document a persistent decrease in peripheral chemosensitivity accompanied by an improvement in exercise capacity, sleep disordered breathing and quality of life. Autonomic balance was favourably affected as evidenced by improved heart rate variability and augmented cardiac baroreflex sensitivity. There were no procedure-related adverse events. Conclusions Denervation of a carotid body may offer a clinical strategy to restore autonomic balance and improve morbidity in heart failure (NCT01653821).

The peripheral chemoreflex is known to be enhanced in individuals with hypertension. In pre-hypertensive (PH) and adult spontaneously hypertensive rats (SHRs) carotid body type I (glomus) cells exhibit hypersensitivity to chemosensory stimuli and elevated sympathoexcitatory responses to peripheral chemoreceptor stimulation. Herein, we eliminated carotid body inputs in both PH-SHRs and SHRs to test the hypothesis that heightened peripheral chemoreceptor activity contributes to both the development and maintenance of hypertension. The carotid sinus nerves were surgically denervated under general anaesthesia in 4- and 12-week-old SHRs. Control groups comprised sham-operated SHRs and aged-matched sham-operated and carotid sinus nerve denervated Wistar rats. Arterial blood pressure was recorded chronically in conscious, freely moving animals. Successful carotid sinus nerve denervation (CSD) was confirmed by testing respiratory responses to hypoxia (10% O(2)) or cardiovascular responses to i.v. injection of sodium cyanide. In the SHR, CSD reduced both the development of hypertension and its maintenance (P0.05) and was associated with a reduction in sympathetic vasomotor tone (as revealed by frequency domain analysis and reduced arterial pressure responses to administration of hexamethonium; P0.05 vs. sham-operated SHR) and an improvement in baroreflex sensitivity. No effect on blood pressure was observed in sham-operated SHRs or Wistar rats. In conclusion, carotid sinus nerve inputs from the carotid body are, in part, responsible for elevated sympathetic tone and critical for the genesis of hypertension in the developing SHR and its maintenance in later life.

Background— Marked changes in ventricular APD restitution and associated alternans rhythm have been demonstrated in structural heart disease (SHD). However, whether this is due to structural heterogeneity or regional variation in cellular properties remains uncertain. In this study, we address the hypothesis that the structural heterogeneity associated with SHD is sufficient to alter dynamic restitution and increase the probability of electric instability. Methods and Results— Activation was simulated in a 14�14 mm 2 domain in the presence and absence (control) of a central region containing nonuniform discontinuities resembling patchy fibrosis. A modified LR1 cardiac activation model was used in a bidomain formulation with isotropic conductivities. Bipolar stimulation was imposed above the central region with coupling intervals decreasing progressively from 500 ms and then maintained at 105 ms. Structural discontinuities had little effect on electric activation at low stimulus rates, but activation time and APD distributions became highly nonuniform within and adjacent to the discontinuous region at high rates. Discordant APD alternans occurred in both “fibrosis” and control, but at lower stimulus rates and with markedly greater extent in the former. Tortuous conduction through the discontinuous region resulted in large fluctuations of diastolic intervals giving rise to regional electric instability, which modulates dynamic conduction velocity and APD restitution. This led to heterogeneous conduction block and reentry not observed in control. Conclusions— We show that structural discontinuities can amplify discordant alternans and provide a rate-dependent substrate for reentry. This work provides new insights into the mechanisms by which fibrosis may contribute to arrhythmogenesis.

Two-dimensional in silico models have been constructed for investigating electrical dynamics arising due to pacing rates and tissue discontinuities. Discontinuities (structures) are introduced explicitly through flux discontinuities in the intracellular space. These models use isotropic electrophysiological properties with heterogeneity arising solely from tissue structure. Both simplified and tissue-specific structures can be used together with membrane models with varying restitution properties. Stimuli are delivered at increasing pacing rates, and solution restarts enable the investigation of repeat stimulation at any of the rates. Investigations using these models are providing new insights into mechanisms leading to conduction block and arrhythmogenesis in cardiac tissue.