The sustained increase in sympathetic outflow in HF along with the ensuing vasoconstriction has long been thought to precipitate a positive feedback mechanism that leads to worsening of HF evidence by progressive deterioration of left ventricular (LV) function, progressive LV remodeling, end-organ damage and ultimately death (1
). Therapies that target a reduction of sympathetic overdrive and enhance parasympathetic drive, are desirable in the management of chronic HF. Results of this study indicate that long-term therapy with CSB improves global LV systolic and diastolic function in dogs with advanced HF. The improvement of LV function was accompanied by improvement in global LV remodeling evidence by reduced LV size and partial restoration of LV shape to one that is more ellipsoidal rather than spherical.
In the present study, chronic carotid sinus electrical stimulation or CSB therapy in dogs with chronic HF resulted in partial normalization of components of the cardiac beta-adrenergic signal transduction specifically, up-regulation of β1-adrenergic receptors and adenylyl cyclase and down-regulation of β-adrenergic receptor kinase. This was accompanied by a significant reduction of circulating plasma norepinephrine. Chronic CSB therapy also resulted in down regulation of angiotensinogen and, hence, a possible partial de-activation of the vasoconstrictive influence of the tissue renin-angiotensin-adosterone system. Interestingly, CSB therapy also normalized nitric oxide signaling evidenced by normalization of both eNOS and iNOS. Normalization of the nitric oxide pathway can have important benefits on the progression of HF through vascular effects related to afterload reduction and reduced myocardial oxygen consumption. In the present study, normalization of signal transduction pathways was associated with improved systolic and diastolic global LV function and partial reversal of LV global and cellular remodeling. The latter also evidenced by a reduction of VFRF, VFIF, ODD and MCSA and an increase of capillary density. CSB therapy also tended to decrease HR in conscious HF dogs, providing some supportive evidence for CSB as modulator of parasympathetic activity (33
The present study cannot provide a definitive mechanism for the observed improvement of LV systolic and diastolic function from chronic CSB therapy. A paramount observation of this study was a reduction in sympathetic activity and normalization of the cardiac β-adrenergic receptor signal transduction pathway. Cardiac sympathetic dysfunction is a prime therapeutic target in HF and successful use of β-adrenergic blockers in HF is a testament to that (10
). Another possible mechanism is attenuation of the enhanced activity of the peripheral renin-angiotensin-aldosterone-system. In a study in dogs with pacing-induced HF, Zucker and colleagues suggested that the improvement in survival seen in their study may also be due, in part, to enhanced endothelial function mediated by chronic CSB therapy (10
). They postulated that this benefit may have resulted from reduced levels of circulating plasma norepinephrine and angiotensin-II seen also in their study. In the present study, we observed a normalization in the expression of cardiac endothelial and inducible nitric oxide synthases, enzymes that catalyze the production of nitric oxide from L-arginine. Nitric oxide plays a vital role in several biologic processes that include modulation of the immune system and vasodilation of blood vessels. Finally, another possible contributor to the improvement of LV function with chronic CSB therapy is the observed reduction of heart rate in treated dogs. Even though this reduction of heart rate did not reach statistical significance, the magnitude of the reduction is in-line with reduction seen following chronic therapy with β-blockers in patients with HF.
There are limitations to the study that warrant discussion. Whereas the absence of background therapy with angiotensin converting enzyme inhibitors, beta adrenergic receptor blockers and/or aldosterone antagonists focus attention on the direct effects of CSB therapy, it does limit extrapolation of the results to patients who would surely be receiving established HF therapy. The present study is also limited by the absence of data on the effects of CSB on exercise tolerance, a measure often used to assess the efficacy of therapy in patients with HF.
In conclusion, the results of this study indicate that long-term therapy with CSB improves global LV systolic and diastolic function in dogs with advanced HF. The improvement of LV function was accompanied by improvement in global LV remodeling evidence by reduced LV size and partial restoration of LV shape to one that is more ellipsoidal rather than spherical. Global LV remodeling was also accompanied by structural remodeling at the cellular level as well as by correction, albeit in part, of molecular abnormalities characteristic of the HF state as evidenced by normalized expression of cardiac β1-adrenergic receptor and nitric oxide signal transduction pathways along with and reduced interstitial fibrosis and cardiomyocyte hypertrophy. These experimental results support the initiation of clinical trials in patients with systolic HF. At present, the CSB Rheos® System used in this study is being tested in a clinical trial in patient with refractory hypertension titled “Device-based Therapy for Hypertension (DEBuT-HT) and in a trial in patients with heart failure and preserved LV ejection fraction title “Rheos Health Outcomes Prospective Evaluation for Heart Failure with EF≥40% (HOPE4HF).
Despite major advances in the development of new drugs for the treatment of chronic heart failure, the mortality and morbidity from this disease syndrome remains unacceptably high. In some patients the use of life saving standard pharmacologic therapy such as angiotensin-converting enzyme inhibitors, beta-adrenergic receptor blockers and aldosterone antagonists is suboptimal because of poor tolerability. Even in patients with heart failure who have over the years tolerated and benefited from these pharmacologic therapies, a time is reached when their effectiveness wanes and symptomatology from the disease increases and are in need to new therapeutic interventions. In the present study we tested a novel device-based therapy that can potentially be used in the treatment of such patients. The approach, termed chronic activation of the carotid sinus baroreflex (CSB) that acts via electrical stimulation of the carotid sinus nerve, was tested as monotherapy in dogs with experimental heart failure. Compared to no therapy at all, chronic CSB treatment resulted in improved left ventricular (LV) systolic and diastolic function and attenuation of LV remodeling. The improvement in ventricular function was associated with reduced LV filling pressure, reduced LV size and lowering of heart rate along with normalization of components of the renin-angiotensin-aldosterone system, the sympathetic nervous system and the nitric oxide signalling pathway. All of these benefits argue in favour of CSB therapy that is likely to provide benefit to patients with advanced chronic heart failure. Translation of the results of this study to clinical setting, however, must be used with care given that the experimentation was conducted in the absence of standard background medical therapy as would certainly be the case in patients.