Ablation of brainstem C1 neurons improves cardiac function in volume overload heart failure

David C. Andrade, Camilo Toledo, Hugo S. Diaz, Claudia Lucero, Alexis Arce-Alvarez,
Luiz M. Oliveira, Ana C. Takakura, Thiago S. Moreira, Harold D. Schultz, Noah J. Marcus, Julio Alcayaga, Rodrigo Del Rio. Clinical Science (2019).

Heart failure (HF) is a major problem among the older generations and is characterized by increased sympathetic activity. One of the most important regions in the brain which is in charge of sympathetic control is the Rostral Ventrolateral Medulla (RVLM). Recent research has shown that in cases of HF, the neurons in the RVLM are very active compared to normal. C1 neurons, catecholaminergic neurons, in the RVLM are known to control sympathetic outflow. The goal of this study was to determine the role of C1 neurons in the RVLM of HF rats.

This study used 45 adult male Sprague Dawley rats that were kept on a light dark cycle and had access to food and water. Heart failure was induced by creating an opening between the vena cava and the aorta using a needle. This causes volume overload heart failure. Sham rats were also given the same anesthesia and surgeries, but no anastomosis was created. four weeks after the heart failure surgery, rats were placed under anesthesia and given anti-dopamine-beta-hydroxylase saporin (DBH-SAP) injections bilaterally into the RVLM to destroy C1 neurons. Control rats were injected with a saline solution. Sympathetic and parasympathetic activity was tested by giving injections of Propranolol, a beta blocker, and atropine, which is used to increase heart rate. 

The injections of DBH-SAP resulted in a 1.9 fold decrease in C1 neurons in the RVLM for both the control and HF rats. When rats were given Propranolol, HF rats that were given a control injection exhibited a larger decrease in heart rate when compared to the control rats given the control injection. This suggests that the HF rats had higher sympathetic activity. HF rats that were given the DBH-SAP injection exhibited a larger decrease in heart rate compared to HF rates given a control. No significant difference was shown in the control rats given the DBH-SAP injection. Atropine injections were then given to compare parasympathetic activity. HF rats given a control injection showed significantly larger decrease in heart rate than the control rats. The DBH-SAP injection did not exhibit any significant results in the HF or control rats. HR rats also showed a significant reduction in baroreflex sensitivity (BRS). After the injection of DBH-SAP, BRS was significantly improved in HF rats. HF rats given a control injection showed a decrease in both diastolic and systolic cardiac function, when compared to the control rats. Injection of DBH-SAP was shown to significantly improve cardiac function in the HF rats. HF rats exhibited more cardiac arrhythmias when compared to the control rats, but this number was significantly reduced after the injections of DBH-SAP was given. Although arrhythmias were reduced, DBH-SAP did not exhibit a change in the tissue damage found in the HF rats.

In conclusion, targeted ablation of C1 neurons in rats with HF exhibited reduced sympathetic activity and improved baroreceptor sensitivity. Frequency of cardiac arrhythmias also decreased after the ablation of C1 neurons, but this did not lead to a change in the damaged tissue. This study shows that the progression of HF is dependent on C1 neurons in the RVLM. This past Thursday, the department hosted Dr. Osborn to discuss renal hypertension and inflammation. He discussed in detail how neuron ablation can affect sympathetic and parasympathetic responses. I have to be honest and say I did not know this was a possible treatment option. I then wondering how this would affect neurons in the in RVLM region, which brought me to this research. The researchers in this study discuss the possibility of targeted ablation becoming a possible hypertension or heart failure treatment, but stress that much more research must be done to determine if it is possible in humans. Dr. Osborn further discussed how neuromodulation may be the future treatment option due to the fact that completely ablating sets of neurons can lead to many side effects. 

-Paul M