Acute effect of spinal cord stimulation on autonomic nervous system function in patients with heart failure.

AIMS: To test the hypothesis that spinal cord stimulation (SCS) acutely improves heart rate variability (HRV) and baroreceptor sensitivity (BRS) in patients with heart failure (HF). METHODS: SCS (15 minutes) was delivered in four different settings: 90% of maximal tolerated stimulation amplitude (MTA) targeting the T1-T4 spinal cord segments (SCS90T1-4), 60% of MTA (SCS60T1-4), 90% of MTA with cranial (SCS90CR) and caudal (SCS90CA) electrode configuration. HRV and BRS were recorded continuously and stimulation was compared to device off. RESULTS: Fifteen HF patients were included. SCS90T1-4 did not change the standard deviation of intervals between normal beats (SDNN, p = 0.90), BRS (p = 0.55) or other HRV parameters. In patients with baseline SDNN <50 ms, SCS90T1-4 significantly increased SDNN (p = 0.004). CONCLUSIONS: Acute SCS at 60-90% of MTA targeting upper thoracic spinal cord segments does not improve autonomic balance or baroreceptor sensitivity in unselected patients with heart failure but may improve HRV in patients with low SDNN.

Effects of Spinal Cord Stimulation on Cardiac Sympathetic Nerve Activity in Patients with Heart Failure.

BACKGROUND: Spinal cord stimulation (SCS) reduces sympathetic activity in animal models of heart failure with reduced ejection fraction (HF) but limited data exist of SCS in patients with HF. The aim of the present study was to test the primary hypothesis that SCS reduces cardiac sympathetic nerve activity in HF patients. Secondary hypotheses were that SCS improves left ventricular function and dimension, exercise capacity, and clinical variables relevant to HF. METHODS: HF patients with a SCS device previously participating in the DEFEAT-HF trial were included in this crossover study with 6-week intervention periods (SCS-ON and SCS-OFF). SCS (50 Hz, 210-µs pulse duration, aiming at T2-T4 segments) was delivered for 12 hours daily. Indices of myocardial sympathetic neuronal function (heart-to-mediastinum ratio, HMR) and activity (washout rate, WR) were assessed using 123 I-metaiodobenzylguanidine (MIBG) scintigraphy. Echocardiography, exercise testing, and clinical data collection were also performed. RESULTS: We included 13 patients (65.3 ± 8.0 years, nine males) and MIBG scintigraphy data were available in 10. HMR was not different comparing SCS-ON (1.37 ± 0.16) and SCS-OFF (1.41 ± 0.21, P = 0.46). WR was also unchanged comparing SCS-ON (41.5 ± 5.3) and SCS-OFF (39.1 ± 5.8, P = 0.30). Similarly, average New York Heart Association class (2.4 ± 0.5 vs 2.3 ± 0.6, P = 0.34), quality of life score (24 ± 16 vs 24 ± 16, P = 0.94), and left ventricular dimension and function as well as exercise capacity were all unchanged comparing SCS-ON and SCS-OFF. CONCLUSION: In patients with HF, SCS (12 hours daily, targeting the T2-T4 segments of the spinal cord) does not appear to influence cardiac sympathetic neuronal activity or function as assessed by MIBG scintigraphy.

Glucagon-like peptide-1 enhances cardiac L-type Ca2+ currents via activation of the cAMP-dependent protein kinase A pathway.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) is a hormone predominately synthesized and secreted by intestinal L-cells. GLP-1 modulates multiple cellular functions and its receptor agonists are now used clinically for diabetic treatment. Interestingly, preclinical and clinical evidence suggests that GLP-1 agonists produce beneficial effects on dysfunctional hearts via acting on myocardial GLP-1 receptors. As the effects of GLP-1 on myocyte electrophysiology are largely unknown, this study was to assess if GLP-1 could affect the cardiac voltage-gated L-type Ca2+ current (I(Ca)). METHODS: The whole-cell patch clamp method was used to record I(Ca) and action potentials in enzymatically isolated cardiomyocytes from adult canine left ventricles. RESULTS: Extracellular perfusion of GLP-1 (7-36 amide) at 5 nM increased I(Ca) by 23 ± 8% (p < 0.05, n = 7). Simultaneous bath perfusion of 5 nM GLP-1 plus 100 nM Exendin (9-39), a GLP-1 receptor antagonist, was unable to block the GLP-1-induced increase in I(Ca); however, the increase in I(Ca) was abolished if Exendin (9-39) was pre-applied 5 min prior to GLP-1 administration. Intracellular dialysis with a protein kinase A inhibitor also blocked the GLP-1-enhanced I(Ca). In addition, GLP-1 at 5 nM prolonged the durations of the action potentials by 128 ± 36 ms (p < 0.01) and 199 ± 76 ms (p < 0.05) at 50% and 90% repolarization (n = 6), respectively. CONCLUSIONS: Our data demonstrate that GLP-1 enhances I(Ca) in canine cardiomyocytes. The enhancement of I(Ca) is likely via the cAMP-dependent protein kinase A mechanism and may contribute, at least partially, to the prolongation of the action potential duration.

Carotid baroreceptor stimulation blood pressure response mapped in patients undergoing carotid endarterectomy (C-Map study).

OBJECTIVE: Continuous stimulation of the carotid baroreceptors has been shown to evoke a sustained systolic blood pressure (SBP) reduction in hypertensive subjects. This study conducted a detailed mapping of the SBP and heart rate response to electrical stimulus at different locations in the carotid sinus region in patients undergoing a carotid endarterectomy (CEA). METHODS: The Carotid Sinus Autonomic Response Mapping (C-Map) Study is a multicenter, prospective, non-randomized, acute feasibility study conducted in 10 hypertensive subjects undergoing CEA. Electrode pairs were placed in multiple locations in the region of the carotid sinus for acute stimulation, and the tests were repeated after plaque removal and vessel repair. RESULTS: The configuration that elicited the largest pressure reduction in 8 of 10 patients was with the electrodes arranged longitudinally along the medial (in relation to the bifurcation) wall of the internal carotid artery (ICA) near the bifurcation (11.2±8.1mmHg, p<0.05). There was no difference in average maximum response pre vs. post plaque removal. Spontaneous baroreflex sensitivity increased from 6.0±3.2ms/mmHg pre-CEA to 8.2±5.4ms/mmHg post-CEA (p=0.040). CONCLUSIONS: Endarterectomy surgery did not affect maximal acute stimulation response but improved baroreflex sensitivity acutely. Acute extravascular baroreceptor stimulation (BRS) mapping demonstrated that blood pressure reductions are dependent on electrode location and orientation. In most subjects, the largest SBP reductions were elicited in the region of the medial wall of the ICA. This area can be targeted for future BRS lead design and implant.