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Comparison of Resveratrol Supplementation and Energy Restriction Effects on Sympathetic Nervous System Activity and Vascular Reactivity: A Randomized Clinical Trial.
Gonçalinho, GHF, Roggerio, A, Goes, MFDS, Avakian, SD, Leal, DP, Strunz, CMC, Mansur, AP
Molecules (Basel, Switzerland). 2021;(11)
Abstract
Background: Chronic sympathetic nervous system activation is associated with endothelial dysfunction and cardiometabolic disease, which may be modulated by resveratrol (RSV) and energy restriction (ER). This study aimed to examine the effects of RSV and ER on plasma noradrenaline (NA), flow-mediated vasodilation (ed-FMD), and endothelium-independent nitrate-mediated vasodilation (ei-NMD). Methods: The study included 48 healthy adults randomized to 30-days intervention of RSV or ER. Results: Waist circumference, total cholesterol, HDL-c, LDL-c, apoA-I, and plasma NA decreased in the ER group, whilst RSV increased apoB and total cholesterol, without changing plasma NA. No effects on vascular reactivity were observed in both groups. Plasma NA change was positively correlated with total cholesterol (r = 0.443; p = 0.002), triglycerides (r = 0.438; p = 0.002), apoA-I (r = 0.467; p = 0.001), apoB (r = 0.318; p = 0.032) changes, and ei-NMD (OR = 1.294; 95%CI: 1.021-1.640). Conclusions: RSV does not improve cardiometabolic risk factors, sympathetic activity, and endothelial function. ER decreases plasma NA and waist circumference as well as improves blood lipids, but does not modify endothelial function. Finally, plasma NA was associated with ei-NMD, which could be attributed to a higher response to nitrate in patients with greater resting sympathetic vasoconstriction.
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Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial.
Shimizu, W, Kubota, Y, Hoshika, Y, Mozawa, K, Tara, S, Tokita, Y, Yodogawa, K, Iwasaki, YK, Yamamoto, T, Takano, H, et al
Cardiovascular diabetology. 2020;(1):148
Abstract
BACKGROUND Protection from lethal ventricular arrhythmias leading to sudden cardiac death (SCD) is a crucial challenge after acute myocardial infarction (AMI). Cardiac sympathetic and parasympathetic activity can be noninvasively assessed using heart rate variability (HRV) and heart rate turbulence (HRT). The EMBODY trial was designed to determine whether the Sodium-glucose cotransporter 2 (SGLT2) inhibitor improves cardiac nerve activity. METHODS This prospective, multicenter, randomized, double-blind, placebo-controlled trial included patients with AMI and type 2 diabetes mellitus (T2DM) in Japan; 105 patients were randomized (1:1) to receive once-daily 10-mg empagliflozin or placebo. The primary endpoints were changes in HRV, e.g., the standard deviation of all 5-min mean normal RR intervals (SDANN) and the low-frequency-to-high-frequency (LF/HF) ratio from baseline to 24 weeks. Secondary endpoints were changes in other sudden cardiac death (SCD) surrogate markers such as HRT. RESULTS Overall, 96 patients were included (46, empagliflozin group; 50, placebo group). The changes in SDANN were + 11.6 and + 9.1 ms in the empagliflozin (P = 0.02) and placebo groups (P = 0.06), respectively. Change in LF/HF ratio was - 0.57 and - 0.17 in the empagliflozin (P = 0.01) and placebo groups (P = 0.43), respectively. Significant improvement was noted in HRT only in the empagliflozin group (P = 0.01). Whereas intergroup comparison on HRV and HRT showed no significant difference between the empagliflozin and placebo groups. Compared with the placebo group, the empagliflozin group showed significant decreases in body weight, systolic blood pressure, and uric acid. In the empagliflozin group, no adverse events were observed. CONCLUSIONS This is the first randomized clinical data to evaluate the effect of empagliflozin on cardiac sympathetic and parasympathetic activity in patients with T2DM and AMI. Early SGLT2 inhibitor administration in AMI patients with T2DM might be effective in improving cardiac nerve activity without any adverse events. TRIAL REGISTRATION The EMBODY trial was registered by the UMIN in November 2017 (ID: 000030158). UMIN000030158; https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000034442 .
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Reducing Dietary Sodium to 1000 mg per Day Reduces Neurovascular Transduction Without Stimulating Sympathetic Outflow.
Babcock, MC, Robinson, AT, Migdal, KU, Watso, JC, Wenner, MM, Stocker, SD, Farquhar, WB
Hypertension (Dallas, Tex. : 1979). 2019;(3):587-593
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Abstract
The American Heart Association recommends no more than 1500 mg of sodium/day as ideal. Some cohort studies suggest low-sodium intake is associated with increased cardiovascular mortality. Extremely low-sodium diets (≤500 mg/d) elicit activation of the renin-angiotensin-aldosterone system and stimulate sympathetic outflow. The effects of an American Heart Association-recommended diet on sympathetic regulation of the vasculature are unclear. Therefore, we assessed whether a 1000 mg/d diet alters sympathetic outflow and sympathetic vascular transduction compared with the more commonly recommended 2300 mg/d. We hypothesized that sodium reduction from 2300 to 1000 mg/d would not affect resting sympathetic outflow but would reduce sympathetic transduction in healthy young adults. Seventeen participants (age: 26±2 years, 9F/8M) completed 10-day 2300 and 1000 mg/d sodium diets in this randomized controlled feeding study (crossover). We measured resting renin activity, angiotensin II, aldosterone, blood pressure, muscle sympathetic nerve activity, and norepinephrine. We quantified beat-by-beat changes in mean arterial pressure and leg vascular conductance (femoral artery ultrasound) following spontaneous sympathetic bursts to assess sympathetic vascular transduction. Reducing sodium to 1000 mg/d increased renin activity, angiotensin II, and aldosterone ( P<0.01 for all) but did not alter mean arterial pressure (78±2 versus 77±2 mm Hg, P=0.56), muscle sympathetic nerve activity (13.9±1.3 versus 13.9±0.8 bursts/min, P=0.98), or plasma/urine norepinephrine. Sympathetic vascular transduction decreased ( P<0.01). These data suggest that reducing sodium from 2300 to 1000 mg/d stimulates the renin-angiotensin-aldosterone system, does not increase resting basal sympathetic outflow, and reduces sympathetic vascular transduction in normotensive adults.
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Docosahexaenoic acid reduces resting blood pressure but increases muscle sympathetic outflow compared with eicosapentaenoic acid in healthy men and women.
Lee, JB, Notay, K, Klingel, SL, Chabowski, A, Mutch, DM, Millar, PJ
American journal of physiology. Heart and circulatory physiology. 2019;(4):H873-H881
Abstract
Supplementation with monounsaturated or ω-3 polyunsaturated fatty acids ( n-3 PUFA) can lower resting blood pressure (BP) and reduce the risk of cardiovascular events. The independent contributions of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on BP, and the mechanisms responsible, are unclear. We tested whether EPA, DHA, and olive oil (OO), a source of monounsaturated fat, differentially affect resting hemodynamics and muscle sympathetic nerve activity (MSNA). Eighty-six healthy young men and women were recruited to participate in a 12-wk, randomized, double-blind trial examining the effects of orally supplementing ~3 g/day of EPA ( n = 28), DHA ( n = 28), or OO ( n = 30) on resting hemodynamics; MSNA was examined in a subset of participants ( n = 31). Both EPA and DHA supplements increased the ω-3 index ( P < 0.01). Reductions in systolic BP were greater [adjusted intergroup mean difference (95% confidence interval)] after DHA [-3.4 mmHg (-0.9, -5.9), P = 0.008] and OO [-3.0 mmHg (-0.5, -5.4), P = 0.01] compared with EPA, with no difference between DHA and OO ( P = 0.74). Reductions in diastolic BP were greater following DHA [-3.4 mmHg (-1.3,-5.6), P = 0.002] and OO [-2.2 mmHg (0.08,-4.3), P = 0.04] compared with EPA. EPA increased heart rate compared with DHA [4.2 beats/min (-0.009, 8.4), P = 0.05] and OO [4.2 beats/min, (0.08, 8.3), P = 0.04]. MSNA burst frequency was higher after DHA [4 bursts/min (0.5, 8.3), P = 0.02] but not OO [-3 bursts/min (-6, 0.6), P = 0.2] compared with EPA. Overall, DHA and OO evoked similar responses in resting BP; however, DHA, but not OO, increased peripheral vasoconstrictor outflow. These findings may have implications for fatty acid supplementation in clinical populations characterized by chronic high BP and sympathetic overactivation. NEW & NOTEWORTHY We studied the effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and olive oil supplementation on blood pressure (BP) and muscle sympathetic nerve activity (MSNA). After 12 wk of 3 g/day supplementation, DHA and olive oil were associated with lower resting systolic and diastolic BPs than EPA. However, DHA increased MSNA compared with EPA. The reductions in BP with DHA likely occur via a vascular mechanism and evoke a baroreflex-mediated increase in sympathetic activity.
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Effects of a combined dietary, exercise and behavioral intervention and sympathetic system on body weight maintenance after intended weight loss: Results of a randomized controlled trial.
Mai, K, Brachs, M, Leupelt, V, Jumpertz-von Schwartzenberg, R, Maurer, L, Grüters-Kieslich, A, Ernert, A, Bobbert, T, Krude, H, Spranger, J
Metabolism: clinical and experimental. 2018;:60-67
Abstract
BACKGROUND Lifestyle based weight loss interventions are hampered by long-term inefficacy. Prediction of individuals successfully reducing body weight would be highly desirable. Although sympathetic activity is known to contribute to energy homeostasis, its predictive role in body weight maintenance has not yet been addressed. OBJECTIVES We investigated, whether weight regain could be modified by a weight maintenance intervention and analyzed the predictive role of weight loss-induced changes of the sympathetic system on long-term weight regain. DESIGN 156 subjects (age > 18; BMI ≥ 27 kg/m2) participated in a 12-week weight reduction program. After weight loss (T0), 143 subjects (weight loss > 8%) were randomized to a 12-month lifestyle intervention or a control group. After 12 months (T12) no further intervention was performed until month 18 (T18). Weight regain at T18 (regainBMI) was the primary outcome. Evaluation of systemic and tissue specific estimates of sympathetic system was a pre-defined secondary outcome. RESULTS BMI was reduced by 4.67 ± 1.47 kg/m2 during the initial weight loss period. BMI maintained low in subjects of the intervention group until T12 (+0.07 ± 2.98 kg/m2; p = 0.58 compared to T0), while control subjects regained +0.98 ± 1.93 kg/m2 (p < 0.001 compared to T0). The intervention group regained more weight than controls after ceasing the intervention (1.17 ± 1.34 vs. 0.57 ± 0.93 kg/m2) until T18. Consequently, BMI was not different at T18 (33.49 (32.64; 34.33) vs. 34.18 (33.61; 34.75) kg/m2; p=0.17). Weight loss-induced modification of urinary metanephrine excretion independently predicted regainBMI (R2 = 0.138; p < 0.05). The lifestyle intervention did not modify the course of urinary metanephrines after initial weight loss. CONCLUSIONS Our lifestyle intervention successfully maintained body weight during the intervention period. However, no long-term effect could be observed beyond the intervention period. Predictive sympathetic activity was not persistently modified by the intervention, which may partially explain the lack of long-term success of such interventions.
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Impact of an exercise training program on cardiac neuronal function in heart failure patients on optimal medical therapy : A randomized Iodine-123 metaiodobenzylguanidine scintigraphy study.
Valborgland, T, Isaksen, K, Munk, PS, Grabowski, ZP, Larsen, AI
Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology. 2018;(4):1164-1171
Abstract
BACKGROUND The syndrome of heart failure (HF) is characterized by left ventricular dysfunction and a compensatory chronic over activation of the sympathetic nervous system. We wanted to investigate if the beneficial effects of exercise training (ET) in HF patients on optimal medical therapy (OMT) are associated with alterations in cardiac sympathetic activity. METHODS Cardiac sympathetic activity was evaluated at baseline and after 12 weeks using metaiodobenzylguanidine scintigraphy in 23 patients with stable HF participating in the SmartEx trial. Patients with HF in New York Heart Association class II or III and left ventricular ejection fraction <35 % were randomized to three different ET groups. RESULTS We found no statistically significant changes in cardiac sympathetic activity after 12 weeks of ET. Heart to mediastinum (H/M) ratio at 15 minutes (0.00174 ± 0.0841, P = 0.922), H/M ratio at 4 hours (-0.00565 ± 0.1163, P = 0.818) and washout ratio (WR) (-1.2666 ± 16.5412, P = 0.717). A further group-wise analysis of the three ET groups did not show any difference between the groups. CONCLUSION A 12-week ET program did not alter the abnormal cardiac sympathetic activity in stable HF patients on modern OMT.
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Ischemic preconditioning does not alter muscle sympathetic responses to static handgrip and metaboreflex activation in young healthy men.
Incognito, AV, Doherty, CJ, Lee, JB, Burns, MJ, Millar, PJ
Physiological reports. 2017;(14)
Abstract
Ischemic preconditioning (IPC) has been hypothesized to elicit ergogenic effects by reducing feedback from metabolically sensitive group III/IV muscle afferents during exercise. If so, reflex efferent neural outflow should be attenuated. We investigated the effects of IPC on muscle sympathetic nerve activity (MSNA) during static handgrip (SHG) and used post-exercise circulatory occlusion (PECO) to isolate for the muscle metaboreflex. Thirty-seven healthy men (age: 24 ± 5 years [mean ± SD]) were randomized to receive sham (n = 16) or IPC (n = 21) interventions. Blood pressure, heart rate, and MSNA (microneurography; sham n = 11 and IPC n = 18) were collected at rest and during 2 min of SHG (30% maximal voluntary contraction) and 3 min of PECO before (PRE) and after (POST) sham or IPC treatment (3 × 5 min 20 mmHg or 200 mmHg unilateral upper arm cuff inflation). Resting mean arterial pressure was higher following sham (79 ± 7 vs. 83 ± 6 mmHg, P < 0.01) but not IPC (81 ± 6 vs. 82 ± 6 mmHg, P > 0.05), while resting MSNA burst frequency was unchanged (P > 0.05) with sham (18 ± 7 vs. 19 ± 9 bursts/min) or IPC (17 ± 7 vs. 19 ± 7 bursts/min). Mean arterial pressure, heart rate, stroke volume, cardiac output, and total vascular conductance responses during SHG and PECO were comparable PRE and POST following sham and IPC (All P > 0.05). Similarly, MSNA burst frequency, burst incidence, and total MSNA responses during SHG and PECO were comparable PRE and POST with sham and IPC (All P > 0.05). These findings demonstrate that IPC does not reduce hemodynamic responses or central sympathetic outflow directed toward the skeletal muscle during activation of the muscle metaboreflex using static exercise or subsequent PECO.
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Exercise training improves neurovascular control and calcium cycling gene expression in patients with heart failure with cardiac resynchronization therapy.
Nobre, TS, Antunes-Correa, LM, Groehs, RV, Alves, MJ, Sarmento, AO, Bacurau, AV, Urias, U, Alves, GB, Rondon, MU, Brum, PC, et al
American journal of physiology. Heart and circulatory physiology. 2016;(5):H1180-H1188
Abstract
Heart failure (HF) is characterized by decreased exercise capacity, attributable to neurocirculatory and skeletal muscle factors. Cardiac resynchronization therapy (CRT) and exercise training have each been shown to decrease muscle sympathetic nerve activity (MSNA) and increase exercise capacity in patients with HF. We hypothesized that exercise training in the setting of CRT would further reduce MSNA and vasoconstriction and would increase Ca2+-handling gene expression in skeletal muscle in patients with chronic systolic HF. Thirty patients with HF, ejection fraction <35% and CRT for 1 mo, were randomized into two groups: exercise-trained (ET, n = 14) and untrained (NoET, n = 16) groups. The following parameters were compared at baseline and after 4 mo in each group: V̇o2 peak, MSNA (microneurography), forearm blood flow, and Ca2+-handling gene expression in vastus lateralis muscle. After 4 mo, exercise duration and V̇o2 peak were significantly increased in the ET group (P = 0.04 and P = 0.01, respectively), but not in the NoET group. MSNA was significantly reduced in the ET (P = 0.001), but not in NoET, group. Similarly, forearm vascular conductance significantly increased in the ET (P = 0.0004), but not in the NoET, group. The expression of the Na+/Ca2+ exchanger (P = 0.01) was increased, and ryanodine receptor expression was preserved in ET compared with NoET. In conclusion, the exercise training in the setting of CRT improves exercise tolerance and neurovascular control and alters Ca2+-handling gene expression in the skeletal muscle of patients with systolic HF. These findings highlight the importance of including exercise training in the treatment of patients with HF even following CRT.
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Effects of α-lipoic acid therapy on sympathetic heart innervation in patients with previous experience of transient takotsubo cardiomyopathy.
Marfella, R, Barbieri, M, Sardu, C, Rizzo, MR, Siniscalchi, M, Paolisso, P, Ambrosino, M, Fava, I, Materazzi, C, Cinquegrana, G, et al
Journal of cardiology. 2016;(2):153-61
Abstract
BACKGROUND Takotsubo syndrome is a stress cardiomyopathy, characterized by reversible left ventricle (LV) apical ballooning in the absence of significant angiographic coronary artery stenosis. The frequent association with emotional stress suggests in this disease an autonomic nervous system involvement. We could think that a therapeutic treatment targeting heart sympathetic dysfunction could be of crucial importance. METHODS From January 2010 to June 2012, 886 patients were consecutively evaluated at Cardarelli Hospital, Naples, Italy. Among these, 48 patients met takotsubo cardiomyopathy (TCM) criteria. Each patient was assessed with history and physical examination, 12-lead electrocardiogram, serum troponin, coronary arteriography, and left ventricular angiogram, perfusion myocardial scintigraphy with technetium 99m, with echocardiography and 123I-metaiodobenzylguanidine (MIBG) myocardial scintigraphy. At discharge, the surviving patients were randomly assigned to α-lipoic acid (ALA) treatment (600mg once daily) or placebo. Following discharge, after the initial TCM event, patients returned to our outpatient clinic at Internal Medicine of the Second University Naples for the follow-up evaluation quarterly until 12 months. Routine analysis, myocardial damage serum markers, oxidative stress serum markers, pro-inflammatory cytokines, and sympathetic tone activity were evaluated in all patients. RESULTS ALA administration improved MIBG defect size at 12 months compared to placebo. CONCLUSIONS Adrenergic cardiac innervation dysfunction in TCM patients persists after previous experience of transient stress-induced cardiac dysfunction. ALA treatment improves the adrenergic cardiac innervation. This study evaluates whether sympatho-vagal alterations are TCM event-related.
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Effects of adding intravenous nicorandil to standard therapy on cardiac sympathetic nerve activity and myocyte dysfunction in patients with acute decompensated heart failure.
Kasama, S, Toyama, T, Funada, R, Takama, N, Koitabashi, N, Ichikawa, S, Suzuki, Y, Matsumoto, N, Sato, Y, Kurabayashi, M
European journal of nuclear medicine and molecular imaging. 2015;(5):761-70
Abstract
PURPOSE Nicorandil, an adenosine triphosphate-sensitive potassium channel opener, improves cardiac sympathetic nerve activity (CSNA) in ischemic heart disease or chronic heart failure. However, its effects on CSNA and myocyte dysfunction in acute heart failure (AHF) remain unclear. We investigated the effects of adding intravenous nicorandil to standard therapy on CSNA and myocyte dysfunction in AHF. METHODS We selected 70 patients with mild to moderate nonischemic AHF who were treated with standard conventional therapy soon after admission. Thirty-five patients were assigned to additionally receive intravenous nicorandil (4-12 mg/h; group A), whereas the remaining patients continued their current drug regimen (group B). Delayed total defect score (TDS), delayed heart to mediastinum count (H/M) ratio, and washout rate (WR) were determined by (123)I-metaiodobenzylguanidine (MIBG) scintigraphy within 3 days of admission and 4 weeks later. High sensitivity troponin T (hs-TnT) level was also measured at the same time points. RESULTS After treatment, MIBG scintigraphic parameters significantly improved in both groups. However, the extent of the changes in these parameters in group A significantly exceeded the extent of the changes in group B [TDS -11.3 ± 4.3 in group A vs -4.0 ± 6.0 in group B (p < 0.01); H/M ratio 0.31 ± 0.16 vs 0.14 ± 0.16 (p < 0.01); WR -13.8 ± 7.8 % vs -6.1 ± 8.9 % (p < 0.01)]. The hs-TnT level decreased significantly from 0.052 ± 0.043 to 0.041 ± 0.033 ng/ml (p < 0.05) in group A, but showed no significant change in group B. Moreover, in both groups, no relationships between the extent of changes in MIBG parameters and hs-TnT level were observed. CONCLUSION Adding intravenous nicorandil to standard therapy provides additional benefits for CSNA and myocyte dysfunction over conventional therapy alone in AHF patients. Furthermore, the mechanisms of improvement in CSNA and myocyte dysfunction after nicorandil treatment in AHF patients were distinct.