Electrical vagus nerve stimulation for the treatment of chronic heart failure

VNS in combination with beta-blockade

The effects of VNS in combination with beta-blockade were examined in dogs with HF. Dogs with LV ejection fraction of approximately 35% were randomized to 3 months of therapy with a beta-blocker alone (metoprolol succinate, 100 mg once daily, n = 6) or to metoprolol (100 mg once daily) combined with active VNS with CardioFit (n = 6). As with the monotherapy study, the CardioFit VNS system was operated in the feedback on-demand heart rate responsive mode. Dogs were started on oral metoprolol therapy 2 weeks prior to randomization to VNS therapy. After randomization, all dogs continued to receive metoprolol succinate once daily for the duration of the study.¹⁸

In HF dogs receiving background therapy with metoprolol, the addition of VNS increased LV ejection fraction and decreased LV end-systolic volume compared with dogs treated with metoprolol alone (Table 2).¹⁸ These findings suggest that the addition of VNS improves LV systolic function beyond that seen with beta-blockade alone. Adding VNS therapy to metoprolol also elicited improvements in indices of LV diastolic function. Combination therapy resulted in greater lowering of LV end-diastolic pressure and LV end-diastolic wall stress and greater increase in deceleration time of rapid mitral inflow velocity compared with metoprolol alone.

The improvements in LV systolic and diastolic function with combination therapy were associated with important changes in heart rate. Twenty-four–hour ambulatory ECG Holter monitoring studies showed no differences in minimum and average heart rate between dogs treated with metoprolol and those treated with combination therapy with VNS. Maximum heart rate, however, was significantly lower in dogs treated with the combination therapy (114 ± 12 vs 149 ± 8 beats/min, P < .05). These observations suggest that preventing heart rate escape at the high end may further improve LV systolic function compared with beta-blockade alone. This added benefit of the combination of VNS and beta-blockade was likely the result of reducing the adverse impact of increased cardiac workload and increased myocardial oxygen consumption elicited by the heart rate increase.

VNS and left ventricular remodeling

In addition to improving LV systolic and diastolic function, long-term VNS in dogs with coronary microembolization-induced HF led to important changes in cellular and structural markers of LV remodeling.¹⁹ Compared with untreated HF dogs, dogs treated with VNS as monotherapy showed a significant decrease in volume fraction of replacement and interstitial fibrosis; a decrease in oxygen diffusion distance, measured as half the distance between two adjoining capillaries; a decrease in myocyte cross-sectional area, a measure of cardiomyocyte hypertrophy; and an increase in capillary density (Figure 2). These histomorphometric measures are often, if not always, adversely affected by the HF state. Their amelioration by VNS suggests that this form of therapy can help preserve myocardial structural integrity through direct or indirect action on the failing myocardium.

VNS and proinflammatory cytokines, nitric oxide, and gap junction proteins

Elevation of proinflammatory cytokines occurs in HF and is associated with increased morbidity and mortality. Electrical VNS has been shown to decrease the release of various cytokines, including tumor necrosis factor (TNF)-alpha and interleukin (IL)-6.²⁰ In dogs with microembolization-induced HF, LV tissue levels of TNF-alpha and IL-6 are elevated compared with LV tissue from normal dogs (Table 3). Long-term monotherapy with VNS normalizes protein expression of both TNF-alpha and IL-6 in LV myocardium.²¹

Nitric oxide (NO) is formed by a family of NO synthases (NOS). The three isoforms of NOS identified to date are endothelin NOS (eNOS), inducible NOS (iNOS), and neuronal NOS (nNOS). The three isoforms have differing characteristics and roles:

eNOS. NO produced by eNOS plays an important role in the regulation of cell growth and apoptosis²² and can enhance myocardial relaxation and regulate contractility.^22,23

iNOS. Overexpression of iNOS in cardiomyocytes in mice results in peroxynitrite generation associated with fibrosis, LV hypertrophy, chamber dilation, cardiomyopathic phenotype, heart block, and sudden cardiac death.²⁴

nNOS. nNOS has been shown to be upregulated in the human failing heart and in rats following myocardial infarction.²⁵ In rats with HF, inhibition of nNOS leads to increased sensitivity of the myocardium to beta-adrenergic stimulation,²⁶ suggesting a role for nNOS in the autocrine regulation of myocardial contractility.²⁶

In dogs with coronary microembolization-induced HF, mRNA and protein expression of eNOS in LV myocardium is significantly downregulated compared with normal dogs; therapy with VNS significantly improves the expression of eNOS (Table 3).²⁷ Both iNOS and nNOS are significantly upregulated, and their expression tends to be normalized by long-term VNS therapy.²⁷

Gap junction proteins or connexins are reduced or redistributed from intercalated disks to lateral cell borders in a variety of cardiac diseases, including HF.²⁸ This so-called “gap junction remodeling” is considered highly arrhythmogenic. In mammals, gap junctions exclusively contain connexin-43 (Cx43). Reduced expression of Cx43 occurs in the failing human heart and has been shown to result in slowed transmural conduction and dispersion of action potential duration with increased susceptibility to arrhythmia and sudden cardiac death.^29,30 In dogs with coronary microembolization-induced HF, mRNA and protein expression of Cx43 in LV myocardium was shown to be markedly downregulated compared with normal dogs, and long-term therapy with VNS was associated with a significant increase in the expression of Cx43 in LV myocardium (Table 3).³¹