Zoar J. Engelman

The Carotid Body as a Therapeutic Target for the Treatment of Sympathetically Mediated Diseases

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 …

Hypertension is critically dependent on the carotid body input in the spontaneously hypertensive rat

Peripheral chemoreflex sensitivity is enhanced in hypertension yet the role of these receptors in the development and maintenance of high blood pressure remains unknown. Carotid chemoreceptors were denervated in both young and adult spontaneously hypertensive rats (SHRs) by sectioning the carotid sinus nerves bilaterally while recording arterial blood pressure chronically using radio telemetry. Carotid sinus denervation (CSD) in the young animals prevented arterial pressure from reaching the hypertensive levels observed in sham‐operated animals whereas in adult SHRs arterial pressure fell by ∼20 mmHg. After CSD there was a decrease in sympathetic activity, measured indirectly using power spectral analysis and hexamethonium, and an improvement in baroreceptor reflex gain. Carotid bodies are active in the SHR and contribute to both the development and maintenance of hypertension; whether carotid body ablation is a useful anti‐hypertensive intervention in drug‐resistant hypertensive patients remains to be resolved.

Carotid body removal for treatment of chronic systolic heart failure

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).

Structural Heterogeneity Alone is a Sufficient Substrate for Dynamic Instability and Altered Restitution

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 mm2 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.

Unilateral Carotid Body Resection in Resistant Hypertension A Safety and Feasibility Trial

Summary Animal and human data indicate pathological afferent signaling emanating from the carotid body that drives sympathetically mediated elevations in blood pressure in conditions of hypertension. This first-in-man, proof-of-principle study tested the safety and feasibility of unilateral carotid body resection in 15 patients with drug-resistant hypertension. The procedure proved to be safe and feasible. Overall, no change in blood pressure was found. However, 8 patients showed significant reductions in ambulatory blood pressure coinciding with decreases in sympathetic activity. The carotid body may be a novel target for treating an identifiable subpopulation of humans with hypertension.

Dissociation between blood pressure and heart rate response to hypoxia after bilateral carotid body removal in men with systolic heart failure

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.

Carotid body resection for sympathetic modulation in systolic heart failure: results from first-in-man study.

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.

Carotid body size on CTA: Correlation with comorbidities

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.

Effects of selective carotid body stimulation with adenosine in conscious humans

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.

Response to Role of the Carotid Body in Obesity-Related Sympathoactivation

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 …