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 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.

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.

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.

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.

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.

Differential effects of lipophilic and hydrophilic statins on muscle sympathetic nerve activity in heart failure with preserved left ventricular ejection fraction.

Augmented sympathetic nerve activity is associated with heart failure with preserved left ventricular ejection fraction (HFpEF). Lipophilic statins reduce sympathetic nerve activity in patients with heart failure with reduced left ventricular ejection fraction. However, little is known about whether all types of statins, regardless of solubility, reduce sympathetic nerve activity in HFpEF. We evaluated the effect of atorvastatin, a lipophilic statin, and rosuvastatin, a hydrophilic statin, on muscle sympathetic nerve activity (MSNA) in HFpEF patients. This study was conducted as a prospective, randomized, open-label, crossover trial. Ten HFpEF patients with untreated hyperlipidemia participated in this study. Subjects were assigned to either the atorvastatin (lipophilic) or the rosuvastatin (hydrophilic) group with each drug administered for 8 weeks. Atorvastatin and rosuvastatin treatment resulted in a similar reduction in low-density lipoprotein cholesterol (LDL-C) levels. There was no difference in the effect of either treatment on blood pressure, heart rate, or left ventricular function. Atorvastatin significantly decreased MSNA frequency compared with baseline (31.5 ±â€¯6.3 vs. 47.5 ±â€¯10.7 bursts/min, p < 0.01), but rosuvastatin had no effect on MSNA (40.9 ±â€¯7.3 bursts/min). MSNA was significantly lower in the atorvastatin group than rosuvastatin group (p < 0.05). However, the reduction in MSNA seen in either group did not correlate with the reduction in LDL-C. No significant differences were observed in either the baroreflex control of heart rate or MSNA between the two groups. These results suggest that lipophilic statins have a favorable effect on sympathetic nerve activity beyond lowering LDL-C in HFpEF, but hydrophilic statins do not.

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.

Effectiveness of Pharmacists' Comprehensive Assessment of Medication Profiles in Dementia Patients.

In Japan the prevalence of dementia has increased considerably, and pharmacists are involved in addressing these patients' medication-related problems. Here, we determined whether pharmacists' comprehensive assessment of medication profiles could reduce the burden of dementia patients' medication-related problems. In this historical cohort study 120 community pharmacies were randomly selected, and participating pharmacists completed questionnaires concerning comprehensive assessment of patient medication profiles, using a "start" questionnaire for patients prescribed medication prior to or during the study period and a "follow-up" questionnaire for patients who subsequently visited pharmacies for prescriptions. Numbers and details of problems and solutions implemented by pharmacists and identified in the start and follow-up questionnaires were compared. Changes in start and follow-up scores were also compared between patients whose problems were identified by pharmacists (identified group) and those whose problems were not (non-identified group). Data were collected for 349 patients issued medication by 60 pharmacies. The most common medication-related problems identified in the start survey were key person's understanding of donepezil (60 cases) and other dementia treatments (60 cases), and adherence to treatment (53 cases). Solutions implemented by pharmacists included gathering information regarding drug administration and dementia awareness from the key person and providing pharmaceutical counseling and instruction. Subsequently, problems related to understanding of dementia treatment, understanding donepezil, and adherence were resolved by 70.0%, 65.0%, and 58.5%, respectively. Pharmacists' comprehensive assessment of medication profiles could effectively solve dementia patients' medication-related problems.

[Pilot study of dementia medication compliance conducted among pharmacists providing home visits which evaluates the degree of drug compliance, as defined by numerous attributes, between patients at home and patients in a medical facility].

A survey was conducted among pharmacists providing "home-visit guidance on drug management" to patients taking medication for dementia. Factors related to medication adherence among patients and pharmacists' acquisition of patient information were then verified. The survey items were: (1) patient attributes (degree of care received, bed-ridden, family composition, and living environment); (2) the person controlling medications; (3) drug storage method and location; (4) dispensing method; (5) patient management of visiting nurses; (6) patient management of visiting physician; (7) details of pharmacist's home-visit guidance; (8) medication adherence; (9) five items related to cognitive function (short-term memory, autonomous judgment, fluctuations in level of consciousness, excitation and loss of orientation, understanding); and (10) ten items related of ADL (mobility in bed, transferring, mobility within the home or outdoors, dressing upper/lower body, eating, toilet use, individual hygiene, bathing). The t test was used to verify the number of items of patient information concerning cognitive function and physical function that pharmacists could acquire at a visit. It was suggested that pharmacists were able to acquire more patient information (①cognitive function and ②ADL) when they visited patients cared for at home, compared to facility residents (①p=0.008, ② p=0.006). Thus, it was suggested that there is a latent risk concerning the pharmacist's ability to discover problems with administration of medications among facility residents. These findings demonstrate that it is essential for pharmacists to be more proactive about providing home-visit guidance.

[Research survey on the information gathering methods, attitudes, and requests from care managers about the pharmaceutical service by pharmacists in home care].

Care Managers (CMs) were surveyed to clarify the issues involving the promotion of cooperation between care managers and pharmacists in long-term-care and explore solutions. The length of work experience, occupational background, experience of pharmaceutical service; pharmacist visit patients' home for providing medicine and pharmaceutical care into a care plan, degree of understanding on pharmaceutical service, and awareness of work involved in pharmaceutical service were studied to see whether there made differences in the requests from CMs for information on pharmacists and for information gathering methods. The χ(2) test was used to this end. The opinions and requests described by the CMs were validated through text mining. More CMs tended to obtain information and knowledge through training sessions and professional magazines than those who did so through cooperation with pharmacists on a practical level. However, the survey strongly indicated that CMs with high level of understanding and awareness of pharmaceutical service wished to obtain information on pharmacists through cooperation with them on a practical level, and CMs with low level of understanding and awareness of pharmaceutical service wished to obtain such information through training sessions and professional magazines. Results of text mining showed that CMs wished pharmacists to strengthen the cooperation with physicians and provide information on pharmaceutical service. These findings have led to the conclusion that the issues surrounding the promotion of cooperation between CMs and pharmacists centered around "work cooperation on a practical level" and "provision of information to CMs about the roles of pharmacies and pharmacists and their work."

[Study on incorporation of "management and guidance of home-visiting by a pharmacist" into a care plan -observation based on a survey of care managers-].

A survey of care managers ("CMs") was conducted to identify top priority issues in promoting the management and guidance of home-visiting by a pharmacist ("management and guidance") by focusing on the experience in incorporating the management and guidance into a care plan and its relevant factors. Major survey items included (1) number of years working as a CM, (2) basic occupation, (3) experience in incorporating the management and guidance into care plans, (4) understanding the management and guidance content, and (5) an awareness of the need for pharmacists' involvement in care plans. A χ² test was conducted to determine if the experience in incorporating the management and guidance into care plans caused a difference in the distribution of the number of years as a CM, the basic occupation, understanding of the management and guidance content, and an awareness of the need for pharmacists' involvement in care plans. A regression analysis was conducted to determine the degree of association between the incorporation experience and each item. The numbers of years working as a CM, the basic occupation, understanding of the management and guidance content, and an awareness of the need for pharmacists' involvement in care plans, were found to be associated with the experience in incorporating the management and guidance into care plans. Understanding of the management and guidance content was most closely associated. To promote pharmacists' management and guidance for home-based care, CMs need to deepen their understanding of this service.