Download Bionic Brain is a Potentiated Novel Therapy for Cardiovascular

Bionic Brain is a Potentiated Novel Therapy for Cardiovascular Diseases
Takuya Kishi, MD, PhD
Department of Advanced Therapeutics for Cardiovascular Diseases, Kyushu University
Graduate School of Medical Sciences
KEYWORD: sympathetic nervous system, baroreflex, bionic brain
What is the target of the therapeutics for cardiovascular diseases? Now we have many
pharmacological and non-pharmacological therapeutics for vascular and heart itself.
However, the survival of cardiovascular diseases, especially heart failure, remains to be
wrong. One of the reasons is the insufficiency in the therapy for abnormal and excessive
sympathoexcitation. Sympathetic nerve activation is determined by the negative
feedback loop system of baroreflex control. The native arterial baroreceptor senses a
change in arterial pressure (AP) and transmits the message to the vasomotor center via
afferent nerves (the aortic depressor nerves and the carotid sinus nerves). The
vasomotor center modulates the sympathetic outflow depending on the inputs from the
baroreceptors. The efferent sympathetic nerve firing facilitates the cardiovascular
actuators and induces resultant AP change. This negative feedback loop is the biological
mechanism that stabilizes AP. Previous many studies have demonstrated that
sympathoexcitation with baroreflex failure is involved in the pathogenesis of
cardiovascular diseases, such as hypertension and/or heart failure. In the aspects of the
therapies targeting baroreflex failure, several studies have already reported that
baroreflex activation therapy or renal afferent nerve denervation have the benefits on
hypertension via sympathoinhibition. However, they are not “direct” therapy for central
arch of baroreflex control (brain). We focused this baroreflex failure in heart failure.
Patients with heart failure and preserved ejection fraction (HFpEF) are
supersensitive to volume overload, and flash pulmonary edema often occurs transiently
which is rapidly resolved by intravascular volume reduction. The stressed blood volume
and systemic blood pressure are controlled by several systems. Among them, the
baroreflex system is an important and powerful regulator. Baroreflex receptors are
stretch receptors located within the arterial wall of elastic vessels such as the aortic arch
and carotid sinuses. Atherosclerosis stiffens the arterial wall, and inevitably impairs
baroreflex transduction. Major risk factors of HFpEF, such as aging, hypertension,
diabetes, and renal insufficiency, also promote atherosclerosis and thereby baroreflex
failure. Therefore, we hypothesized that atherosclerosis-induced baroreflex failure plays
a pivotal role in the pathogenesis of HFpEF independent of left ventricular (LV)
dysfunction. To test this hypothesis, we developed a baroreflex failure model in rats
with normal LV function, and assessed the left atrial pressure (LAP) responses to
volume overload. We investigated the effect of baroreflex failure on LAP and systemic
AP responses to volume loading in rats with normal LV function in which baroreflex
failure was mimicked by maintaining constant carotid sinus pressure (CSP). In
anesthetized Sprague-Dawley rats, we isolated bilateral carotid sinuses and controlled
CSP by a servo-controlled piston pump. We mimicked normal baroreflex (NORM) by
matching CSP to instantaneous AP, and baroreflex failure (FAIL) by maintaining CSP
at a constant value regardless of AP. We infused dextran stepwise (infused volume; Vi)
until LAP reached 15 mmHg and obtained the LAP-Vi relationship. We estimated the
critical Vi when LAP reached 20 mmHg. In FAIL, critical Vi decreased markedly from
19.4±1.6 mL/kg to 15.6±1.6 ml/kg (p<0.01), while AP at the critical Vi increased
(194±6 mmHg vs. 163±6 mmHg, p<0.01). These results strongly suggest that baroreflex
failure could induce volume intolerance independent of LV systolic function, and that
baroreflex failure would be the main cause of flash pulmonary edema in HFpEF.
In addition, we examined the effects of an artificial (bionic) baroreflex system we
recently developed in the absence of native baroreflex. The bionic baroreceptor consists
of an AP sensor, a neuro-stimulator and a regulator. The bionic pressure sensor senses
AP and the regulator translates AP into neuro-stimulation. Then we identified the
operating rule required for the bionic regulator to translate ∆CSP into ∆STM. The total
transfer function from CSP to AP (HCSP-AP) can be divided into two components: the
transfer function translating CSP into STM by the bionic regulator (HBionic) and the
transfer function from STM to AP (HSTM-AP). HBionic is obtained from HCSP-AP/HSTM-AP,
and HCSP-AP and HSTM-AP can be measured experimentally in individual rats. Fourier
transform algorithm to identify HCSP-AP and HSTM-AP. HBionic was calculated as the ratio of
HCSP-AP to HSTM-AP. The HBionic obtained was converted to impulse response, which is the
operating rule, by an inverse fast Fourier transform algorithm. Previously we
determined that our bionic baroreflex system restores the pressure buffering function,
and that the bionic baroreceptor would be an attractive therapy for orthostatic
hypotension caused by baroreceptor impairment in rats. In the present examination, our
bionic baroreflex system was able to fully reverse the physiological volume intolerance
in the FAIL animals (the critical Vi: 23.1±1.7 mL/kg, and systolic AP at critical Vi:
206±7 mmHg). These results suggest that the bionic baroreflex system would be an
attractive therapeutic tool in preventing flash pulmonary edema in HFpEF caused by
baroreflex failure.
In conclusion, we consider that baroreflex failure induces striking volume
intolerance in the absence of LV dysfunction and that baroreflex failure could be the
therapeutic target in HFpEF. Our bionic baroreflex system has the novel potential to be
a therapy for HFpEF. Furthermore, our concept could be extended to other
cardiovascular diseases caused by the abnormal and excessive sympathoexcitation.