Avoiding the 'Cart Before the Horse': The Importance of Continued Basic and Translational Studies of Renal Denervation

Jason S. Bradfield; Kalyanam Shivkumar


Europace. 2020;22(4):513-514. 

Until recently, antiarrhythmic drugs (AADs) and radiofrequency ablation (RFA) were the only treatment options for patients with ventricular arrhythmias (VAs) in the setting of structural heart disease.[1] While a mainstay in therapy, AAD has not seen significant advancements in decades. For refractory VA, this often led to recurrent admissions for loading and reloading of medications such as amiodarone and trials of other combinations of AAD, many of which have significant acute and long-term side effects.

Autonomic modulation represents an additional strategy for managing refractory arrhythmias.[2] Renal denervation (RDN) has gained significant clinical interest for the treatment of atrial fibrillation and VA. The clinical data for RDN to treat VA has been built out of clinical necessity, for a patient population with limited options in the setting of potentially life-threatening events. Patients with cardiomyopathy and depressed left ventricular ejection fractions presenting with recurrent VA storm and/or recurrent implantable cardioverter-defibrillator (ICD) shocks have very few treatment options.

Ventricular tachycardia (VT) RFA continues to show solid clinical outcomes in patients that fail AAD or prefer not to take chronic AADs. Physicians are realizing the benefit of VT RFA and the benefit of referring earlier in the treatment course.[3,4] However, success rates for VT RFA are lower in patients with non-ischaemic cardiomyopathy and certain substrates (intra-septal and other mid-myocardial locations) can be resistant to RFA techniques using currently available technology. Therefore, many of these patients require multiple VT RFA procedures to gain clinical control and decrease the likelihood of ICD shocks.

Until recently, in cases where VT RFA is not successful, patients are left with very few options aside from orthotopic heart transplant if the patient met the strict criteria. However, the utilization of autonomic modulation for VA in structural heart disease has changed this paradigm and grown significantly in recent years. Cardiac sympathetic denervation (CSD) with bilateral stellate ganglionectomy has shown an approximately 50% freedom from VT at 1 year in a high-risk patient population that has either failed VT ablation or were not candidates for RFA.[5] Despite the modest results, this autonomic intervention was effective in treating patients that had failed all other available therapies.

Originally studied for refractory hypertension, RDN has shown promise as an adjunctive therapy for atrial fibrillation and VA. Again, out of clinical need, RDN is already utilized for patient care in high-risk patients with VA resistant to RFA and/or CSD.[6] The clinical data shows promise. However, the limited clinical options for this high-risk patient population have led to a 'cart before the horse' scenario: clinical data exists demonstrating that the technique provides clinical benefit, but without sufficient basic and translational 'legs' to fully appreciate how to optimize the procedure for patient care.

Clinically there remain many open questions: Which specific populations benefits from RDN? How can we accurately clinically monitor for effective denervation? What technology most effectively targets renal nerves? Can RDN be performed as effectively through the venous system? Do the effects persist over time? These and many more questions are best guided by dedicated basic and translational studies to guide future clinical studies and interventions.

In the current issue of EP Europace, Yamada et al.[7] present their data on the effects of RDN on rabbits with heart failure and obesity. Rabbits were divided into four groups: control, high-fat diet, high-fat diet and heart failure (pacing induced), and high-fat intake with heart failure that received RDN. They found that the heart failure/high-fat model rabbits that also received RDN had significantly decreased ventricular fibrosis and significantly lower ventricular fibrillation inducibility (10% vs. 58%) compared with those that did not receive RDN, even though the ventricular effective refractory period was not significantly affected. Sympathetic staining of the heart and stellate ganglia was significantly lower in the RDN group compared with the high fat and high fat/heart failure-only groups. Their data support the concept of structural and autonomic remodelling related to obesity and heart failure and the potential benefit of RDN to prevent these changes, though the inter-relationship between heart failure and obesity is not well-delineated given the lack of a pure heart failure group in this study.

Clinical innovation is best delivered to the patient on a strong foundation of basic and translational studies. Studies like the one by Yamada et al. are crucial to the future of clinical care. Well thought out basic/translational studies lead to improved clinical delivery of therapies and ultimately to improved patient outcomes proven with appropriately designed studies. The continued development of autonomic modulation techniques such as RDN will alter the paradigm for arrhythmia management in the upcoming decades.[8]