Mandibular advancement reduces pharyngeal collapsibility by enlarging the airway rather than affecting velopharyngeal compliance.

Mandibular advancement devices (MADs) are frequently prescribed for obstructive sleep apnea (OSA) patients, but approximately one third of patients experience no therapeutic benefit. Understanding the mechanisms by which MADs prevent pharyngeal collapse may help optimize MAD therapy. This study quantified the relative contributions of changes in airspace cross-sectional area (CSA) versus changes in velopharyngeal compliance in determining MAD efficacy. Sixteen patients with moderate to severe OSA (mean apnea-hypopnea index of 32 ± 15 events/h) underwent measurements of the velopharyngeal closing pressure (PCLOSE ) during drug induced sedated endoscopy (DISE) via stepwise reductions in nasal mask pressure and recording of the intraluminal pressure with a catheter. Airspace CSA was estimated from video endoscopy. Pharyngeal compliance was defined as the slope of the area-pressure relationship of the velopharyngeal airspace. MAD therapy reduced PCLOSE from a median of 0.5 cmH2 O pre-advancement to a median of -2.6 cmH2 O post-advancement (p = 0.0009), increased the minimal CSA at the velopharynx by approximately 20 mm2 (p = 0.0067), but did not have a statistically significant effect on velopharyngeal compliance (p = 0.23). PCLOSE had a strong correlation with CSA but did not correlate with velopharyngeal compliance. Our results suggest that MADs reduce velopharyngeal collapsibility by increasing airway size as opposed to affecting velopharyngeal compliance. This contradicts the speculation of previous literature that the effectiveness of MADs is partially due to a reduction in velopharyngeal compliance resulting from stretching of the soft palate. These findings suggest that quantification of velopharyngeal CSA pre- and post-MAD advancement has potential as a biomarker to predict the success of MAD therapy.

Targeted disruption of glycogen synthase kinase-3ß in cardiomyocytes attenuates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.

Type 1 diabetic Akita mice develop severe cardiac parasympathetic dysfunction that we have previously demonstrated is due at least in part to an abnormality in the response of the end organ to parasympathetic stimulation. Specifically, we had shown that hypoinsulinemia in the diabetic heart results in attenuation of the G-protein coupled inward rectifying K channel (GIRK) which mediates the negative chronotropic response to parasympathetic stimulation due at least in part to decreased expression of the GIRK1 and GIRK4 subunits of the channel. We further demonstrated that the expression of GIRK1 and GIRK4 is under the control of the Sterol Regulatory element Binding Protein (SREBP-1), which is also decreased in response to hypoinsulinemia. Finally, given that hyperactivity of Glycogen Synthase Kinase (GSK)3ß, had been demonstrated in the diabetic heart, we demonstrated that treatment of Akita mice with Li+, an inhibitor of GSK3ß, increased parasympathetic responsiveness and SREBP-1 levels consistent with the conclusion that GSK3ß might regulate IKACh via an effect on SREBP-1. However, inhibitor studies were complicated by lack of specificity for GSK3ß. Here we generated an Akita mouse with cardiac specific inducible knockout of GSK3ß. Using this mouse, we demonstrate that attenuation of GSK3ß expression is associated with an increase in parasympathetic responsiveness measured as an increase in the heart rate response to atropine from 17.3 ± 3.5% (n = 8) prior to 41.2 ± 5.4% (n = 8, P = 0.017), an increase in the duration of carbamylcholine mediated bradycardia from 8.43 ± 1.60 min (n = 7) to 12.71 ± 2.26 min (n = 7, P = 0.028) and an increase in HRV as measured by an increase in the high frequency fraction from 40.78 ± 3.86% to 65.04 ± 5.64 (n = 10, P = 0.005). Furthermore, patch clamp measurements demonstrated a 3-fold increase in acetylcholine stimulated peak IKACh in atrial myocytes from GSK3ß deficiency mice compared with control. Finally, western blot analysis of atrial extracts from knockout mice demonstrated increased levels of SREBP-1, GIRK1 and GIRK4 compared with control. Taken together with our prior observations, these data establish a role of increased GSK3ß activity in the pathogenesis of parasympathetic dysfunction in type 1 diabetes via the regulation of IKACh and GIRK1/4 expression.

QRS/T-wave and calcium alternans in a type I diabetic mouse model for spontaneous postmyocardial infarction ventricular tachycardia: A mechanism for the antiarrhythmic effect of statins.

BACKGROUND: The incidence of sudden arrhythmic death is markedly increased in diabetics. OBJECTIVE: The purpose of this study was to develop a mouse model for postmyocardial infarction (post-MI) ventricular tachycardia (VT) in the diabetic heart and determine the mechanism of an antiarrhythmic effect of statins. METHODS: ECG transmitters were implanted in wild-type (WT), placebo, and pravastatin-treated type I diabetic Akita mice. MIs were induced by coronary ligation, and Ca2+ transients were studied by optical mapping, and Ca2+ transients and sparks in left ventricular myocytes (VM) by the Ionoptix system and confocal microscopy. RESULTS: Burst pacing of Akita mouse hearts resulted in rate-related QRS/T-wave alternans, which was attenuated in pravastatin-treated mice. Post-MI Akita mice developed QRS/T-wave alternans and VT at 2820 ± 879 beats per mouse, which decreased to 343 ± 115 in pravastatin-treated mice (n = 13, P <.05). Optical mapping demonstrated pacing-induced VT originating in the peri-infarction zone and Ca2+ alternans, both attenuated in hearts of statin-treated mice. Akita VM displayed Ca2+ alternans, and triggered activity as well as increased Ca2+ transient decay time (Tau), Ca2+ sparks, and cytosolic Ca2+ and decreased SR Ca2+ stores all of which were in part reversed in cells from statin treated mice. Homogenates of Akita ventricles demonstrated decreased SERCA2a/PLB ratio and increased ratio of protein phosphatase (PP-1) to the PP-1 inhibitor PPI-1 which were reversed in homogenates of pravastatin-treated Akita mice. CONCLUSION: Pravastatin decreased the incidence of post-MI VT and Ca2+ alternans in Akita mouse hearts in part by revering abnormalities of Ca2+ handling via the PP-1/PPI-1 pathway.

Glycogen synthase kinase-3ß inhibition ameliorates cardiac parasympathetic dysfunction in type 1 diabetic Akita mice.

Decreased heart rate variability (HRV) is a major risk factor for sudden death and cardiovascular disease. We previously demonstrated that parasympathetic dysfunction in the heart of the Akita type 1 diabetic mouse was due to a decrease in the level of the sterol response element-binding protein (SREBP-1). Here we demonstrate that hyperactivity of glycogen synthase kinase-3ß (GSK3ß) in the atrium of the Akita mouse results in decreased SREBP-1, attenuation of parasympathetic modulation of heart rate, measured as a decrease in the high-frequency (HF) fraction of HRV in the presence of propranolol, and a decrease in expression of the G-protein coupled inward rectifying K(+) (GIRK4) subunit of the acetylcholine (ACh)-activated inward-rectifying K(+) channel (IKACh), the ion channel that mediates the heart rate response to parasympathetic stimulation. Treatment of atrial myocytes with the GSK3ß inhibitor Kenpaullone increased levels of SREBP-1 and expression of GIRK4 and IKACh, whereas a dominant-active GSK3ß mutant decreased SREBP-1 and GIRK4 expression. In Akita mice treated with GSK3ß inhibitors Li(+) and/or CHIR-99021, Li(+) increased IKACh, and Li(+) and CHIR-99021 both partially reversed the decrease in HF fraction while increasing GIRK4 and SREBP-1 expression. These data support the conclusion that increased GSK3ß activity in the type 1 diabetic heart plays a critical role in parasympathetic dysfunction through an effect on SREBP-1, supporting GSK3ß as a new therapeutic target for diabetic autonomic neuropathy.

Increased inducibility of ventricular tachycardia and decreased heart rate variability in a mouse model for type 1 diabetes: effect of pravastatin.

Although a reduction in the high-frequency (HF) component of heart rate variability (HRV) is a major complication of diabetes and a risk factor for sudden death, its relationship to ventricular tachycardia (VT) is unknown. We developed a mouse model for the study of VT and its relationship to changes in HRV in the Akita type 1 diabetic mouse. Programmed ventricular stimulation of anesthetized mice demonstrated that Akita mice were more inducible for VT compared with wild-type mice: 78.6% versus 28.6% (P = 0.007). Optical mapping of perfused hearts demonstrated multifocal breakthroughs that occasionally gave rise to short-lived rotors consistent with focal initiation and maintenance of VT. Treatment of Akita mice with pravastatin, which had been previously shown clinically to decrease ventricular ectopy and to increase HRV, decreased the inducibility of VT: 36.8% compared with 75.0% with placebo treatment (P = 0.022). The HF fraction of HRV was reduced in Akita mice (48.6 ± 5.2% vs. 70.9 ± 4.8% in wild-type mice, P = 0.005) and was increased compared with placebo treatment in pravastatin-treated mice. Pretreatment of Akita mice with the muscarinic agonist carbamylcholine or the ß-adrenergic receptor blocker propranolol decreased the inducibility of VT (P = 0.001). In conclusion, the increased inducibility of focally initiated VT and reduced HF fraction in Akita mice were partially reversed by both pravastatin treatment and pharmacologic reversal of parasympathetic dysfunction. In this new animal model for the study of the pathogenesis of VT in type 1 diabetes, pravastatin may play a role in the prevention of VT by attenuating parasympathetic dysfunction.

Preliminary observations on the vasomotor responses to electrical stimulation of the ventrolateral surface of the human medulla.

OBJECT: Pulsatile arterial compression (AC) of the ventrolateral medulla (VLM) is hypothesized to produce the hypertension in a subset of patients with essential hypertension. In animals, a network of subpial neuronal aggregates in the VLM has been shown to control cardiovascular functions. Although histochemically similar, neurons have been identified in the retro-olivary sulcus (ROS) of the human VLM, but their function is unclear. METHODS: The authors recorded cardiovascular responses to electrical stimulation at various locations along the VLM surface, including the ROS, in patients who were undergoing posterior fossa surgery for trigeminal neuralgia. This vasomotor mapping of the medullary surface was performed using a bipolar electrode, with stimulation parameters ranging from 5- to 30-second trains (20-100 Hz), constant current (1.5-5 mA), and 0.1-msec pulse durations. Heart rate (HR) and blood pressure (BP) were recorded continuously from baseline (10 seconds before the stimulus) up to 1 minute poststimulus. In 6 patients, 17 stimulation responses in BP and HR were recorded. RESULTS: The frequency threshold for any cardiovascular response was 20 Hz; the stimulation intensity threshold ranged from 1.5 to 3 mA. In the first patient, all stimulation responses were significantly different from sham recordings (which consisted of electrodes placed without stimulations). Repeated stimulations in the lower ROS produced similar responses in 3 other patients. Two additional patients had similar responses to single stimulations in the lower ROS. Olive stimulation produced no response (control). Hypotensive and/or bradycardic responses were consistently followed by a reflex hypertensive response. Slight right/left differences were noted. No patient suffered short- or long-term effects from this stimulation. CONCLUSIONS: This stimulation technique for vasomotor mapping of the human VLM was safe and reproducible. Neuronal aggregates near the surface of the human ROS may be important in cardiovascular regulation. This method of vasomotor mapping with measures of responses in sympathetic tone (microneurography) should yield additional data for understanding the neuronal network that controls cardiovascular functions in the human VLM. Further studies in which a concentric bipolar electrode is used to generate this type of vasomotor map should also increase understanding of the pathophysiological mechanisms of neurogenically mediated hypertension, and assist in the design of studies to prove the hypothesis that it is caused by pulsatile AC of the VLM.