Does a single oral administration of amiloride affect spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults?

Preclinical models indicate that amiloride (AMD) reduces baroreflex sensitivity and perturbs homeostatic blood pressure (BP) regulation. However, it remains unclear whether these findings translate to humans. This study investigated whether oral administration of AMD reduces spontaneous cardiac and sympathetic baroreflex sensitivity and perturbs BP regulation in healthy young humans. Heart rate (HR; electrocardiography), beat-to-beat BP (photoplethysmography), and muscle sympathetic activity (MSNA, microneurography) were continuously measured in 10 young subjects (4 females) during rest across two randomized experimental visits: 1) after 3 h of oral administration of placebo (PLA, 10 mg of methylcellulose within a gelatin capsule) and 2) after 3 h of oral administration of AMD (10 mg). Visits were separated for at least 48 h. We calculated the standard deviation and other indices of BP variability. Spontaneous cardiac baroreflex was assessed via the sequence technique and cardiac autonomic modulation through time- and frequency-domain HR variability. The sensitivity (gain) of the sympathetic baroreflex was determined via weighted linear regression analysis between MSNA and diastolic BP. AMD did not affect HR, BP, and MSNA compared with PLA. Indexes of cardiac autonomic modulation (time- and frequency-domain HR variability) and BP variability were also unchanged after AMD ingestion. Likewise, AMD did not modify the gain of both spontaneous cardiac and sympathetic arterial baroreflex. A single oral dose of AMD does not affect spontaneous arterial baroreflex sensitivity and BP variability in healthy young adults.NEW & NOTEWORTHY Preclinical models indicate that amiloride (AMD), a nonselective antagonist of the acid-sensing ion channels (ASICs), impairs baroreflex sensitivity and perturbs blood pressure regulation. We translated these findings into humans, investigating the impact of acute oral ingestion of AMD on blood pressure variability and spontaneous cardiac and sympathetic baroreflex sensitivity in healthy young humans. In contrast to preclinical evidence, AMD does not impair spontaneous arterial baroreflex sensitivity and blood pressure variability in healthy young adults.

Glucose metabolism and autonomic function in healthy individuals and patients with type 2 diabetes mellitus at rest and during exercise.

Autonomic dysfunction is a common complication of type 2 diabetes mellitus (T2DM). However, the character of dysfunction varies in different reports. Differences in measurement methodology and complications might have influenced the inconsistent results. We sought to evaluate comprehensively the relationship between abnormal glucose metabolism and autonomic function at rest and the response to exercise in healthy individuals and T2DM patients. We hypothesized that both sympathetic and parasympathetic indices would decrease with the progression of abnormal glucose metabolism in individuals with few complications related to high sympathetic tone. Twenty healthy individuals and 11 T2DM patients without clinically evident cardiovascular disease other than controlled hypertension were examined. Resting muscle sympathetic nerve activity (MSNA), heart rate variability, spontaneous cardiovagal baroreflex sensitivity (CBRS), sympathetic baroreflex sensitivity and the MSNA response to handgrip exercise were measured. Resting MSNA was lower in patients with T2DM than in healthy control subjects (P = 0.011). Resting MSNA was negatively correlated with haemoglobin A1c in all subjects (R = -0.45, P = 0.024). The parasympathetic components of heart rate variability and CBRS were negatively correlated with glycaemic/insulin indices in all subjects and even in the control group only (all, P < 0.05). In all subjects, the MSNA response to exercise was positively correlated with fasting blood glucose (R = 0.69, P < 0.001). Resting sympathetic activity and parasympathetic modulation of heart rate were decreased in relationship to abnormal glucose metabolism. Meanwhile, the sympathetic responses to handgrip were preserved in diabetics. The responses were correlated with glucose/insulin parameters throughout diabetic and control subjects. These results suggest the importance of a comprehensive assessment of autonomic function in T2DM.

Baroreflex responses to limb venous distension in humans.

The venous distension reflex (VDR) is a pressor response evoked by peripheral venous distension and accompanied by increased muscle sympathetic nerve activity (MSNA). The effects of venous distension on the baroreflex, an important modulator of blood pressure (BP), have not been examined. The purpose of this study was to examine the effect of the VDR on baroreflex sensitivity (BRS). We hypothesized that the VDR will increase the sympathetic BRS (SBRS). Beat-by-beat heart rate (HR), BP, and MSNA were recorded in 16 female and 19 male young healthy subjects. To induce venous distension, normal saline equivalent to 5% of the forearm volume was infused into the veins of the occluded forearm. SBRS was assessed from the relationship between diastolic BP and MSNA during spontaneous BP variations. Cardiovagal BRS (CBRS) was assessed with the sequence technique. Venous distension evoked significant increases in BP and MSNA. Compared with baseline, during the maximal VDR response period, SBRS was significantly increased (-3.1 ± 1.5 to -4.5 ± 1.6 bursts·100 heartbeats-1·mmHg-1, P < 0.01) and CBRS was significantly decreased (16.6 ± 5.4 to 13.8 ± 6.1 ms·mmHg-1, P < 0.01). No sex differences were observed in the effect of the VDR on SBRS or CBRS. These results indicate that in addition to its pressor effect, the VDR altered both SBRS and CBRS. We speculate that these changes in baroreflex function contribute to the modulation of MSNA and BP during limb venous distension.

A 10-mg dose of amiloride increases time to failure during blood-flow-restricted plantar flexion in healthy adults without influencing blood pressure.

Amiloride has been shown to inhibit acid-sensing ion channels (ASICs), which contribute to ischemia-related muscle pain during exercise. The purpose of this study was to determine if a single oral dose of amiloride would improve exercise tolerance and attenuate blood pressure during blood-flow-restricted (BFR) exercise in healthy adults. Ten subjects (4 females) performed isometric plantar flexion exercise with BFR (30% maximal voluntary contraction) after ingesting either a 10-mg dose of amiloride or a volume-matched placebo (random order). Time to failure, time-tension index (TTI), and perceived pain (visual analog scale) were compared between the amiloride and placebo trials. Mean blood pressure, heart rate, blood pressure index (BPI), and BPI normalized to TTI (BPInorm) were also compared between trials using both time-matched (TM50 and TM100) and effort-matched (T50 and T100) comparisons. Time to failure (+69.4 ± 63.2 s, P < 0.01) and TTI (+1,441 ± 633 kg·s, P = 0.02) were both significantly increased in the amiloride trial compared with placebo, despite no increase in pain (+0.4 ± 1.7 cm, P = 0.46). In contrast, amiloride had no significant influence on the mean blood pressure or heart rate responses, nor were there any significant differences in BPI or BPInorm between trials when matched for time (all P ≥ 0.13). When matched for effort, BPI was significantly greater in the amiloride trial (+5,300 ± 1,798 mmHg·s, P = 0.01), likely owing to an increase in total exercise duration. In conclusion, a 10-mg oral dose of amiloride appears to significantly improve the tolerance to BFR exercise in healthy adults without influencing blood pressure responses.

Effect of pulmonary vein isolation on the relationship between left atrial reverse remodeling and sympathetic nerve activity in patients with atrial fibrillation.

PURPOSE: Catheter ablation (CA) to isolate the pulmonary vein, which is an established treatment for atrial fibrillation (AF), is associated with left atrium reverse remodeling (LARR). The intrinsic cardiac autonomic nervous system includes the ganglion plexi adjacent to the pulmonary vein in the left atrium (LA). However, little is known about the effect of CA on the relationship between LARR and sympathetic nerve activity in patients with AF. METHODS: This study enrolled 22 AF patients with a normal left ventricular ejection fraction (LVEF) aged 64.6 ± 12.9 years who were scheduled for CA. Sympathetic nerve activity was evaluated by direct recording of muscle sympathetic nerve activity (MSNA) before and 12 weeks after CA. Blood pressure, heart rate (HR), HR variability, and echocardiography were also measured. RESULTS: The heart rate increased significantly after CA (63 ± 10.9 vs. 70.6 ± 7.7 beats/min, p < 0.01), but blood pressure did not change. A high frequency (HF) and low frequency (LF) of HR variability decreased significantly after ablation, but no significant change in LF/HF was observed. CA significantly decreased MSNA (38.9 ± 9.9 vs. 28 ± 9.1 bursts/min, p < 0.01). Moreover, regression analysis revealed a positive correlation between the percentage change in MSNA and the LA volume index (r = 0.442, p < 0.05). CONCLUSIONS: Our results show that CA for AF reduced MSNA and the decrease was associated with the LA volume index in AF patients with a normal LVEF. These findings suggest that LARR induced by CA for AF decrease sympathetic nerve activity.

Acute effects of sublingual nitroglycerin on cardiovagal and sympathetic baroreflex sensitivity.

The effects of nitroglycerin (glyceryl trinitrate, GTN) on baroreflex sensitivity (BRS) are incompletely understood. Moreover, there are no reports evaluating the acute responses in both the sympathetic BRS (SBRS) and the cardiovagal BRS (CBRS) to the administration of sublingual GTN. We hypothesized that sublingual GTN modulates both CBRS and SBRS. In 10 healthy subjects, beat-to-beat heart rate (HR), blood pressure (BP), and muscle sympathetic nerve activity (MSNA) were recorded before and for 10 min after sublingual administration of GTN 0.4 mg. SBRS was evaluated from the relationship between spontaneous variations in diastolic BP and MSNA. CBRS was assessed with the sequence technique. These variables were assessed during baseline, during 3rd-6th min (post A), and 7th-10th min (post B) after GTN administration. Two min after GTN administration, MSNA increased significantly and remained significantly elevated during recording. Compared with baseline, CBRS decreased significantly (post A: 12.9 ± 1.6 to 7.1 ± 1.0 ms/mmHg, P < 0.05), whereas SBRS increased significantly (post A: 0.8 ± 0.2 to 1.5 ± 0.2 units·beat-1·mmHg-1, P < 0.05) with an upward shift of the operating point. There were no differences in these variables between posts A and B. A clinical dose of GTN increased MSNA rapidly through effects on both CBRS and SBRS. These effects should be kept in mind when nitrates are used to clinically treat chest pain and acute coronary syndromes and used as vasodilators in experimental settings.

Takotsubo cardiomyopathy complicated by cardiac tamponade due to non-hemorrhagic pericardial effusion: a case report.

BACKGROUND: Cardiac tamponade is a rare but serious complication of Takotsubo cardiomyopathy (TC). Two cases of cardiac tamponade subsequent to TC have been reported. The pericardial effusion in these cases was hemorrhagic and caused by ventricular rupture. Cardiac tamponade induced by an inflammatory effusion complicated with TC has not been reported. This is the first case report of TC, which developed cardiac tamponade during the recovery phase with a large volume non-hemorrhagic inflammatory effusion. CASE PRESENTATION: We describe a case of an 81-year-old woman admitted to our hospital because of severe chest pain. Her symptoms began soon after her son's hospitalization. We diagnosed her with TC based on results of an electrocardiogram, echocardiogram, and emergent coronary angiography. Her symptoms and left ventricular dysfunction improved gradually. She developed newly confirmed chest pain and dyspnea on day 9 after admission. A large pericardial effusion developed, resulting in cardiac tamponade. Her symptoms and hemodynamic status improved immediately after the pericardiocentesis. The effusion was non-hemorrhagic and exudative. No specific signs of infection, collagen disease, or malignant tumors were observed, except for TC. CONCLUSIONS: We experienced a case of circulatory collapse induced by TC-related inflammatory pericardial effusion at recovery phase. This case emphasizes the importance of careful follow-up even after improved left ventricular dysfunction in a patient with TC.

Diabetes impairs the angiogenic capacity of human adipose-derived stem cells by reducing the CD271+ subpopulation in adipose tissue.

Type 2 diabetes mellitus is an important risk factor for cardiovascular diseases (CVDs). Therapeutic angiogenesis using adipose-derived stem cells (ADSCs) is attractive for CVD therapy. However, although it would be critical for ADSC application on CVD therapy, whether and how diabetes impairs human ADSC therapeutic potential is still uncertain. In this study, we aimed to investigate the impact of diabetes on the angiogenic potential of ADSCs in patients with CVDs, with special focus on stemness-related genes and cellular alteration of ADSCs. We established cultured ADSCs from diabetic (DM-ADSCs) and non-diabetic patients (nonDM-ADSCs) with CVDs. DM-ADSCs demonstrated limited proliferative capacity and reduced paracrine capacity of VEGF, with lower expression of the stemness gene SOX2. Angiogenic capacity and ADSC engraftment were assessed using xenograft experiments in a hindlimb ischemia model of athymic nude mice. Consistent with the results of in vitro assays, DM-ADSCs did not rescue limb ischemia. In contrast, nonDM-ADSCs induced neovascularization with enhanced engraftment. To elucidate the mechanism underlying these ADSC changes, we compared the surface marker profiles of freshly isolated ADSCs obtained from diabetic and non-diabetic patients by flow cytometry. Among studied subsets, the CD34+CD31-CD271+ subpopulation was reduced in the adipose tissues of diabetic patients. In addition, SOX2 expression and proliferative capacity were considerably reduced in nonDM-ADSCs derived from the stromal vascular fraction (SVF) with depletion of CD271+ cells (p < 0.01). Our observations elucidated that reduced CD271+ subpopulation is critical for the impairment of ADSCs in diabetic patients. Further investigations on the CD271+ subset of ADSCs might provide novel insights into the mechanisms and solutions for diabetes-related ADSC dysfunction in cell therapy.

Significant Association Between Coronary Artery Low-Attenuation Plaque Volume and Apnea-Hypopnea Index, But Not Muscle Sympathetic Nerve Activity, in Patients With Obstructive Sleep Apnea Syndrome.

BACKGROUND: Obstructive sleep apnea syndrome (OSAS) is associated with augmented sympathetic nerve activity and cardiovascular diseases. However, the interaction between coronary artery plaque characteristics and sympathetic nerve activity remains unclear. The purpose of this study was to clarify the relationships between coronary artery plaque characteristics, sleep parameters and single- and multi-unit muscle sympathetic nerve activity (MSNA) in OSAS patients. Methods and Results: A total of 32 OSAS patients who underwent full-polysomnography participated in this study. The coronary plaque volume was calculated with 320-slice coronary computed tomography (CT). Single- and multi-unit MSNA were obtained during the daytime within 1 week from full-polysomnography. Patients were divided into 2 groups according to their apnea-hypopnea index (AHI) score (mild-moderate group, AHI <30; and severe group, AHI ≥30). There were no group differences in risk factors for atherosclerosis; however, severe AHI patients showed significantly high single-unit MSNA, and low- and intermediate-attenuation plaque volumes. In regression analysis, the plaque volume of any CT value was not associated with single- or multi-unit MSNA; only AHI significantly correlated with low-attenuation plaque volume (R=0.52, P<0.05). CONCLUSIONS: Our findings provided the evidence that AHI is an independent predictor for low-attenuated, vulnerable plaque volume, but not daytime MSNA, in patients with OSAS.

Significant correlation between renal 123I-metaiodobenzylguanidine scintigraphy and muscle sympathetic nerve activity in patients with primary hypertension.

BACKGROUND: Iodine-123 metaiodobenzylguanidine (123I-MIBG) scintigraphy is used as a noninvasive imaging method for assessing cardiac sympathetic nerve activity. We tested the hypothesis that renal 123I-MIBG imaging is correlated with muscle sympathetic nerve activity (MSNA) in patients with primary hypertension. METHODS: Thirty-one consecutive patients with primary hypertension were included. Multiunit MSNA was recorded from the peroneal nerve to evaluate direct efferent sympathetic nerve activity. Planar renal and cardiac 123I-MIBG images were acquired. Early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rates (WR) were calculated. RESULTS: In 27 of 31 patients, blood pressure was controlled on antihypertensive medication. Mean systolic and diastolic blood pressures were 118 ± 18 and 67 ± 15 mmHg, respectively. Although early and late K/M and H/M were not significantly correlated with MSNA, both cardiac and average renal WR were significantly correlated with MSNA (r = 0.45, P = .0035 and r = 0.68, P < .001, respectively). Right and left renal WR were similarly correlated with MSNA. Renal WR was significantly higher than cardiac WR (43.2% vs 25.8%, P < .001) in these patients with hypertension. CONCLUSIONS: Renal 123I-MIBG WR was significantly associated with multiunit MSNA. Renal 123I-MIBG imaging offers a noninvasive clinical methodology for assessing renal sympathetic nerve function.

The role of peripheral venous distension reflex in regulating hemodynamics: mini review.

Significant volume is pooled in veins in humans and the amount is dramatically altered by various physiological stresses and diseases. Several animal and human studies demonstrated that limb venous distension evoked significant increases in blood pressure and sympathetic nerve activity (venous distension reflex, VDR). VDR has attracted much attention because of its potential to explain the still unknown mechanism of autonomic dysfunction in several diseases, which would lead to a new treatment approach. This mini review discusses accumulated evidence of VDR at this point and what should be investigated in the future to apply the current understanding of VDR in clinical practice.

Study Protocol for the Pleiotropic Effects of Sodium-Glucose Cotransporter 2 Inhibitor on Organ-Specific Sympathetic Nerve Activity and Insulin Sensitivity in Participants with Type 2 Diabetes.

INTRODUCTION: Hyperinsulinemia and hyperglycemia are associated with exaggerated systemic sympathetic nerve activity (SNA) in patients with type 2 diabetes. Sodium-glucose cotransporter 2 (SGLT2) inhibitors lower insulin levels, whereas sulfonylureas increase insulin levels. We will test whether these two classes of antidiabetic agents have different effects on SNA. METHODS: The present study is an ongoing, 24-week, one-center (only Kanazawa University Hospital), open-label, randomized, parallel trial (jRCTs 041200035). Participants with type 2 diabetes with multiple atherosclerosis risk factors are randomly assigned in a 1:1 manner to receive 2.5 mg luseogliflozin or 0.5 mg glimepiride once daily. The sample size was calculated to be 14 in each group, with a significance level of 0.05 and a power of 0.80. The design required 40 evaluable study participants. Our primary endpoint will be the change in muscle SNA (MSNA). The secondary endpoints included organ-specific insulin sensitivity measured by a hyperinsulinemic-euglycemic clamp study using an artificial pancreas combined with a stable isotope-labeled glucose infusion, bioelectrical impedance analysis, and organ-specific (cardiac, renal, and hepatic) 123I-meta-iodobenzylguanidine (MIBG) innervation imaging. PLANNED OUTCOMES: Study recruitment started in April 2020 and will end in June 2024, with 40 participants randomized into the two groups. The treatment follow-up of the participants is currently ongoing and is due to finish by March 2025. TRIAL REGISTRATION: The study protocol has been approved by the Certified Review Board, Kanazawa University, Ishikawa, Japan, in accordance with the guidelines stipulated in the Declaration of Helsinki (CRB4180005, 2019-001). This trial is registered with the Japan Registry of Clinical Trials, jRCTs 041200035.

Effect of Cyclooxygenase Inhibition on Peripheral Venous Distension Reflex in Healthy Humans.

BACKGROUND: Peripheral venous distension evokes a pressor reflex (venous distension reflex). Afferent group III and IV nerves innervating veins are suggested as the afferent arm of the venous distension reflex. Prostaglandins stimulate/sensitize group III/IV nerves. We hypothesized that inhibition of prostaglandin synthesis by local cyclooxygenase blockade would attenuate the muscle sympathetic nerve activity (MSNA) and blood pressure responses to venous distension. METHODS: Nineteen healthy volunteers (age, 27±5 years) participated in the study with 2 visits. To induce venous distension, a volume of solution (saline alone or 9 mg ketorolac tromethamine in saline) was infused into the vein in the antecubital fossa of an arterially occluded forearm. During the procedure, beat-by-beat heart rate, blood pressure and MSNA were recorded simultaneously. The vein size was measured with ultrasound. RESULTS: In both visits, the venous distension procedure significantly increased blood pressure, heart rate, and MSNA (all, P<0.05). The increase in mean arterial pressure and MSNA in the ketorolac visit was significantly lower than in the control visit (∆ mean arterial pressure, 7.0±6.2 versus 13.8±7.7 mm Hg; ∆MSNA, 6.0±7.1 versus 14.8±7.7 bursts/min; both, P<0.05). The increase in vein size induced by the infusion was not different between visits. CONCLUSIONS: The presented data show that cyclooxygenase blockade attenuates the responses in MSNA and blood pressure to peripheral venous distension reflex. The results suggest that cyclooxygenase products play a key role in evoking afferent activation responsible for the venous distension reflex.

Relationships between muscle sympathetic nerve activity and novel indices of arterial stiffness using single oscillometric cuff in patients with hypertension.

The arterial velocity pulse index (AVI) and arterial pressure-volume index (API) have been proposed as new arterial stiffness indices that can be measured using an oscillometric cuff. Sympathetic nerve activity (SNA) contributes to arterial stiffness via increasing vascular smooth muscle tone. However, the associations between SNA and the AVI or API are not understood. The purpose of this study was to evaluate the relationships between muscle sympathetic nerve activity (MSNA) and the AVI or API in healthy individuals and patients with hypertension (HT). Forty healthy individuals (40.1 ± 15.2 years, 8 females) (healthy group) and 40 patients with HT (60.2 ± 13.6, 18 females) (HT group) were included in this study. The AVI, API, MSNA, beat-by-beat blood pressure, and heart rate were recorded simultaneously. The AVI and API were higher in the HT group than in the healthy group (AVI, 26.1 ± 7.6 vs. 16.5 ± 4.0, p < 0.001; API, 31.2 ± 8.6 vs. 25.5 ± 7.2, p = 0.002). MSNA in the HT group was also higher than in the healthy group (p < 0.001). MSNA was correlated with the AVI, but not with the API, in both the healthy group (R = 0.52, p = 0.001) and HT group (R = 0.57, p < 0.001). MSNA was independently correlated with the AVI in multivariate analysis (ß = 0.34, p = 0.001). In conclusion, AVI, obtained by a simple and less user-dependent method, was related to the MSNA in healthy individuals and patients with HT.

Different Responses of Muscle Sympathetic Nerve Activity to Dapagliflozin Between Patients With Type 2 Diabetes With and Without Heart Failure.

Background Sodium-glucose cotransporter 2 inhibitors improve cardiovascular outcomes in patients with diabetes with and without heart failure (HF). However, their influence on sympathetic nerve activity (SNA) remains unclear. The purpose of this study was to evaluate the effect of sodium-glucose cotransporter 2 inhibitors on SNA and compare the responses of SNA to sodium-glucose cotransporter 2 inhibitors in patients with type 2 diabetes with and without HF. Methods and Results Eighteen patients with type 2 diabetes, 10 with HF (65.4±3.68 years) and 8 without HF (63.3±3.62 years), were included. Muscle SNA (MSNA), heart rate, and blood pressure were recorded before and 12 weeks after administration of dapagliflozin (5 mg/day). Sympathetic and cardiovagal baroreflex sensitivity were simultaneously calculated. Brain natriuretic peptide level increased significantly at baseline in patients with HF than those without HF, while MSNA, blood pressure, and hemoglobin A1c did not differ between the 2 groups. Fasting blood glucose and homeostatic model assessment of insulin resistance did not change in either group after administering dapagliflozin. MSNA decreased significantly in both groups. However, the reduction in MSNA was significantly higher in patients with HF than patients with non-HF (-20.2±3.46 versus -9.38±3.65 bursts/100 heartbeats; P=0.049), which was concordant with the decrease in brain natriuretic peptide. Conclusions Dapagliflozin significantly decreased MSNA in patients with type 2 diabetes regardless of its blood glucose-lowering effect. Moreover, the reduction in MSNA was more prominent in patients with HF than in patients with non-HF. These results indicate that the cardioprotective effects of sodium-glucose cotransporter 2 inhibitors may, in part, be attributed to improved SNA.

A case of pulmonary arterial hypertension with chronic hepatitis that resulted in hepatosplenomegaly after administration of prostaglandin I2.

The prognosis of pulmonary arterial hypertension (PAH) has significantly improved over the past two decades due to advances in medications, including pulmonary vasodilators. However, the side effects of these drugs remain problematic in some patients. A 51-year-old woman with chronic hepatitis C was diagnosed with PAH 7 years before presenting to our hospital. She was unable to continue her treatment with pulmonary vasodilators due to various side effects. She had a World Health Organization functional class of IV and was started on continuous infusion of prostaglandin I2 (PGI2). This therapy improved her symptoms, including dyspnea and fatigue. However, she began to complain of abdominal distension after 4 months of PGI2 therapy. Computed tomography showed significant hepatosplenomegaly. Her abdominal distension improved slightly after decreasing PGI2 treatment, but her dyspnea on exertion was exacerbated. She died 12 years after diagnosis of PAH due to uncontrollable heart failure. Here, we describe a rare case of PAH with hepatosplenomegaly after administration of PGI2. .

Renal iodine123-metaiodobenzylguanidine scintigraphy relates to muscle sympathetic nervous activity in heart failure with reduced ejection fraction.

BACKGROUND: Renal denervation is effective for modulating augmented sympathetic nerve activity (SNA) in heart failure with reduced ejection fraction (HFrEF). We have demonstrated that renal iodine123-metaiodobenzylguanidine (123I-MIBG) scintigraphy is associated with muscle sympathetic nerve activity (MSNA) in patients with hypertension. However, it is unclear whether renal 123I-MIBG scintigraphy is useful for assessment of SNA in HFrEF. METHODS: The study population consisted of 24 HFrEF patients and 11 healthy subjects as controls. Patients with HFrEF underwent 123I-MIBG scintigraphy and hemodynamics using a Swan-Ganz catheter (SGC). HFrEF was defined as echocardiography with left ventricular ejection fraction (LVEF) < 50%. MSNA was measured from the peroneal nerve for direct evaluation of SNA. Renal 123I-MIBG scintigraphy was performed simultaneously with cardiac scintigraphy. The early and delayed kidney-to-mediastinum ratio (K/M), early and delayed heart-to-mediastinum ratio (H/M), and washout rate (WR) were calculated. RESULTS: LVEFs were 35% ± 11% in patients with HFrEF and 63% ± 10% in the controls (p < 0.01). The WR of cardiac 123I-MIBG showed no relation to MSNA, but was related to stroke volume (r = 0.45, p < 0.05). In contrast, the WR of renal 123I-MIBG scintigraphy (average of both sides) showed a strong correlation with MSNA (BI, r = 0.70, p < 0.01; BF, r = 0.66, p < 0.01); however, no significant correlations were detected between renal 123I-MIBG scintigraphy and SGC results. CONCLUSIONS: The WR of renal 123I-MIBG scintigraphy may reflect MSNA. Further studies are needed to clarify the relationship between renal 123I-MIBG imaging and renal SNA.

Different prognosis between severe and very severe obstructive sleep apnea patients; Five year outcomes.

BACKGROUND: Obstructive sleep apnea (OSA) is characterized by augmented sympathetic nerve activity. In our previous study, patients with OSA and an apnea-hyperpnea index (AHI)>55events/h showed increased single-unit muscle sympathetic nerve activity compared to patients with OSA and AHI of 30-55events/h. However, the prognostic impact in these patients remains unclear. METHODS: Ninety-one OSA patients were included. All patients who had indication for continuous positive airway pressure (CPAP) were treated with CPAP. Patients were divided into three groups: mild/moderate OSA (S), AHI<30events/h (n=44); severe OSA (SS), AHI 30-55events/h (n=29); and very severe OSA (VSS), AHI>55events/h (n=18). The primary endpoint was a composite outcome composed of death, cardiovascular events, stroke, and heart failure with hospitalization. RESULTS: In the 5-year follow-up, the primary event rate in the SS group [3 events (7%)] was the same as that in the S group [3 events (10%)]. However, the VSS group showed a significantly higher primary event rate among the three groups [6 events (33%), p<0.05]. In Cox regression analysis, the VSS group had the highest hazard ratio compared to other risk factors. CONCLUSIONS: CPAP was effective for preventing cardiovascular disease in patients with severe OSA, however patients with very severe OSA still had a high event rate, indicating that CPAP treatment might be insufficient to reduce the OSA-related risk burden in patients with very severe OSA. Additional systemic medical treatment for CPAP might be needed in patients with very severe OSA.

Severity Indices for Obstructive Sleep Apnea Syndrome Reflecting Glycemic Control or Insulin Resistance.

Objective We aimed to identify obstructive sleep apnea syndrome (OSAS) severity indices reflecting the anthropometric and metabolic characteristics of patients with OSAS. Methods A total of 76 patients with OSAS underwent nasal continuous positive airway pressure (nCPAP). We also investigated the effects of nCPAP on OSAS-associated muscle sympathetic nerve activity (MSNA), risk for cardiovascular diseases, and insulin secretion and sensitivity. Results Among the OSAS severity indices, HbA1c was significantly correlated with the apnea-hypopnea index, whereas HOMA-beta, HOMA-IR, and hepatic insulin resistance were significantly correlated with % SpO2<90%, independent of age, gender, and body mass index (BMI). Burst incidence of MSNA was independently associated with only a 3% oxygen desaturation index. nCPAP therapy significantly lowered the OSAS severity indices and reduced the burst rate, burst incidence, and heart rate. Conclusion The OSAS severity indices reflecting apnea/hypopnea are associated with glycemic control, whereas those reflecting hypoxia, particularly % SpO2<90%, are associated with hepatic insulin resistance independent of obesity. Both types of OSAS severity indices, especially the 3% oxygen desaturation index (reflecting intermittent hypoxia), are independently associated with MSNA, which is dramatically lowered with the use of nCPAP therapy. These findings may aid in interpreting each OSAS severity index and understanding the pathophysiology of OSAS in clinical settings.