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Background: Whether and to what extent the reported blood pressure (BP) lowering effects of renal denervation (RDN) are associated with a central sympathoinhibition is controversial. We examined this issue by performing a meta-analysis of the microneurographic studies evaluating the BP and muscle sympathetic nerve activity (MSNA) responses to RDN in drug-resistant or uncontrolled hypertension (RHT). Methods: This analysis comprised 11 studies including a total of >400 RHT patients undergoing RDN and were followed up for 6 months. Evaluation was extended to the relationships of MSNA with clinic heart rate and BP changes associated with RDN. Results: MSNA showed a significant reduction after RDN (−4.78 bursts/100 heart beats; P P P =0.0001) BP decrease. No significant quantitative relationship was found between MSNA and systolic (r=−0.96, P =0.19) or diastolic BP (r=−0.97, P =0.23) responses to RDN. This was also the case for clinic heart rate (r=0.53, P =0.78, respectively), whose post RDN values were not significant different from the pre-RDN ones. More than 10 renal nerves ablations were found to be needed for obtaining a significant sympathoinhibition. Conclusions: This meta-analysis, the first ever done on the MSNA responses to RDN, shows that in a consistent number of RHT patients RDN is associated with a significant, although modest, central sympathoinhibition, which appears to be unrelated to the BP lowering effects of the procedure. Thus factors other than the central sympathetic outflow inhibition may concur at the BP lowering effects of RDN.

Purpose The effect of systemic hemostatic agents initiated during pre-hospital care of severely injured patients with ongoing bleeding or traumatic brain injury (TBI) remains controversial. A systematic review and meta-analysis was therefore conducted to assess the effectiveness and safety of systemic hemostatic agents as an adjunctive therapy in people with major trauma and hemorrhage or TBI in the context of developing the Italian National Institute of Health guidelines on major trauma integrated management. Methods PubMed, Embase, and Cochrane Library databases were searched up to October 2021 for studies that investigated pre-hospital initiated treatment with systemic hemostatic agents. The certainty of evidence was evaluated with the Grading of Recommendations Assessment, Development, and Evaluation approach, and the quality of each study was determined with the Cochrane risk-of-bias tool. The primary outcome was overall mortality, and secondary outcomes included cause-specific mortality, health-related quality of life, any adverse effects and blood product use, hemorrhage expansion, and patient-reported outcomes. Results Five trials of tranexamic acid (TXA) met the inclusion criteria for this meta-analysis. With a high certainty of evidence, when compared to placebo TXA reduced mortality at 24 h (relative risk = 0.83, 95% confidence interval = 0.73–0.94) and at 1 month among trauma patients (0.91, 0.85–0.97). These results depend on the subgroup of patients with significant hemorrhage because in the subgroup of TBI there are no difference between TXA and placebo. TXA also reduced bleeding death and multiple organ failure whereas no difference in health-related quality of life. Conclusion Balancing benefits and harms, TXA initiated in the pre-hospital setting can be used for patients experiencing major trauma with significant hemorrhage since it reduces the risk of mortality at 24 h and one month with no difference in terms of adverse effects when compared to placebo. Considering the subgroup of severe TBI, no difference in mortality rate was found at 24 h and one month. These results highlight the need to conduct future studies to investigate the role of other systemic hemostatic agents in the pre-hospital settings.

BACKGROUND Microneurographic recordings of muscle sympathetic nerve activity (MSNA) have shown that sympathetic activation may characterize diabetes mellitus. However, it is recognized that comorbidities and metabolic abnormalities frequently associated with both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) diabetes affect MSNA, generating potential confounding effects and making the association between sympathetic activation and diabetes mellitus still a controversial matter. METHODS The present meta-analysis evaluated 11 microneurographic studies enrolling 314 diabetes mellitus patients and healthy controls, and MSNA was chosen as the main variable of interest. Collection of the data included indirect adrenergic markers such as heart rate and venous plasma noradrenaline, together with hemodynamic, anthropometric and metabolic variables. RESULTS A total of 11 microneurographic studies were evaluated including 314 diabetes mellitus patients and controls. Diabetes mellitus displayed MSNA significantly greater than controls (mean difference amounting to 8.1, 95% confidence interval 1.21-15.08, P

Background Pregnant women who suffer from depressive disorders are likely to be treated with antidepressant (AD) medications. Recent meta-analyses underlined the possible relation between AD use and several neonatal outcomes, although the underlying mechanisms remains unclear. Methods To summarise and evaluate the associations between AD use in pregnancy and neonatal outcomes, we conducted an umbrella review of meta-analyses of observational studies published up to December 2019 in PubMed and Embase. Summary risk estimates for the associations between use of AD as a whole, or specific AD classes and drugs, and the risk of neonatal outcomes were reported. Results Our review included 22 meta-analyses investigating 69 associations. However, none were supported by convincing evidence. Highly suggestive evidence regarded the associations between (i) any time AD exposure and the risk of preterm birth (relative risk, 1.68; 95% confidence interval 1.52, 1.86), (ii) any time exposure to selective serotonin reuptake inhibitors (SSRIs) and the risk of preterm birth (1.43; 1.22, 1.37) and (iii) respiratory distress (1.33; 1.14, 1.55), and (iv) SSRI exposure during the first trimester of pregnancy and the risk of cardiovascular malformations (1.25; 1.13, 1.39). Suggestive evidence was obtained for any time AD exposure on 1-min low Apgar score (absolute average difference, −0.34; −0.53, −0.14). Conclusions Overall, the effects of AD exposure during pregnancy on neonatal outcomes have been extensively studied, but few of the associations are graded as high quality evidence. More prospective studies and large collaborations with comprehensive standardised reporting of analyses are needed.

Purpose The purpose of this study was to assess the possible relation between use of antidepressant (AD) drugs, that is, tricyclic ADs, selective serotonin reuptake inhibitors (SSRIs), and atypical ADs (AAs), and the risk of hospitalization for cardiovascular (CV) events among older patients with previous CV diseases. Methods A nested case-control study was carried out among patients aged 65 years and older from 5 Italian health care territorial units who were discharged for CV disease during 2008 to 2010. The cohort was composed by 344,747 individuals, and of these, 97,739 (28%) experienced hospital admission for CV events (myocardial infarction, arrhythmia, stroke, heart failure) during follow-up (until 2014) and were included as cases. Up to 5 controls were randomly selected and matched to each. A conditional logistic regression was fitted to estimate the risk of CV events associated with ADs past or current use. A within-patient comparison was performed by the case-crossover design to account the effect of depression. Findings Current users of SSRIs and AAs were at increased risk of CV events with odds ratios of 1.25 (95% confidence interval, 1.21-1.29) and 1.31 (1.25-1.37), respectively. An increased risk of arrhythmia and stroke was associated with current use of SSRIs and AAs, whereas an increased risk of heart failure was detected with current use of any ADs. The results were confirmed by the case-crossover approach. Implications Evidence that AD use is associated with an increased risk of CV events in accordance with specific mechanisms of action among older people with CV disease was added by this study.

Objective: Whether and to what extent the reported BP lowering effects of renal denervation (RD) are mediated by a sympathetic deactivation induced by the procedure is still largely undefined. We examined this issue by performing a meta-analysis of the microneurographic studies published so far based on the evaluation of the blood pressure (BP) and muscle sympathetic nerve traffic (MSNA) responses to RD. Design and method: The meta-analysis was based on 12 studies including a total of 394 patients with resistant hypertension underwent RD and followed up to 12 months. Evaluation was extended to the relationships of MSNA with heart rate (HR) and clinic or ambulatory blood pressure (BP) values (expressed such as mean and 95% confidence interval). Results: Baseline MSNA values amounted to 48.25 (43.86-52.64) bursts/minute, clinic HR to 66.35 (65.02-67.67) beats/minute and systo/diastolic clinic BP to 167.3 (157.6-177.01) and 90.54 (84.81-96.27) mmHg. RD caused a significant BP reduction at 3/6/12 months following the procedure amounting to 12.6 mmHg for systolic (range 20.9 to 4.39 mmhg, p = 0.003) and to 6.4 mmHg for diastolic BP (range -11.9 t0 0.9 mmHg, p = 0.02) respectively. No significant change in MSNA (-2.65, range -6.7 to 1.4 bursts/minute, P = NS) and HR (-0.58, range -3.98 to 2.81 b/min, P = NS) were concomitantly observed. No relationship was found between the number of renal ablations and the magnitude of the blood pressure or MSNA changes, this being the case also for HR. Conclusions: This meta-analysis, the first ever done on the MSNA responses to RD, shows that in a consistent number of patients underwent RD, the BP lowering effects of the procedure are not accompanied by any significant change in 2 adrenergic markers, i.e. MSNA and HR, and thus appear not to be mediated by any sympathetic deactivation.

BACKGROUND Neuroadrenegic overdrive occurs in obstructive sleep apnoea syndrome (OSAS). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities, represented major weaknesses not allowing to precisely define the main features of the phenomenon, particularly in nonobese patients. OBJECTIVE This meta-analysis detected 14 microneurographic studies based on muscle sympathetic nerve activity (MSNA) quantification in uncomplicated OSAS of different clinical severity. METHODS The evaluation was extended to the relationships of MSNA with heart rate, anthropometric and blood pressure values, metabolic variables, apnoea-hypopnea index and oxygen saturation. RESULTS MSNA is activated markedly and almost homogeneously between studies, showing a progressive increase from the healthy state to mild, moderate and severe OSAS (46.03, 48.32, 71.84, 69.27 bursts/100 heart beats). Of special interest are the findings that MSNA is significantly related to the apnoea-hypopnea index, a marker of OSAS severity (r = 0.55, P = 0.04) but not to BMI, as it occurs in OSAS associated with obesity, and heart rate is significantly and directly related to MSNA and apnoea-hypopnea index (r = 0.68 and r = 0.60, respectively P = 0.03 and P = 0.02), thus representing a surrogate marker of the sympathetic overdrive. CONCLUSION OSAS, even when uncomplicated by other cardiometabolic disease, displays a marked sympathetic activation, reflected by the MSNA and heart rate behaviour, becoming a target of therapeutic interventions aimed at exerting sympathomoderating effects, such as continuous positive airway pressure.

Nerve traffic recordings (muscle sympathetic nerve traffic [MSNA]) have shown that sympathetic activation may occur in obesity. However, the small sample size of the available studies, presence of comorbidities, heterogeneity of the subjects examined represented major weaknesses not allowing to draw definite conclusions. This is the case for the overweight state. The present meta-analysis evaluated 1438 obese or overweight subjects recruited in 45 microneurographic studies. The analysis was primarily based on MSNA quantification in obesity and overweight, excluding as concomitant conditions hypertension, metabolic syndrome, and other comorbidities. Assessment was extended to the relationships of MSNA with other neuroadrenergic markers, such as plasma norepinephrine and heart rate, anthropometric variables, as body mass index, waist-to-hip ratio, presence/absence of obstructive sleep apnea, and metabolic profile. Compared with normoweights MSNA was significantly greater in overweight and more in obese individuals (37.0±4.1 versus 43.2±3.5 and 50.4±5.0 burts/100 heartbeats, P r =0.41 and r =0.64, P r =0.68, P r =0.91, r =0.94, and r =0.80, respectively, P

BACKGROUND: Neuroadrenergic overdrive occurs in obstructive sleep apnea syndrome (OSAS). However, the small sample size of the microneurographic studies, heterogeneity of the patients examined, presence of comorbidities, represented major weaknesses not allowing to precisely define the main features of the phenomenon, particularly in nonobese patients. OBJECTIVE: This meta-analysis evaluated 850 participants recruited in 26 microneurographic studies, based on muscle sympathetic nerve activity (MSNA) quantification in uncomplicated OSAS of different clinical severity. METHODS: The evaluation was extended to the relationships of MSNA with heart rate (HR), anthropometric and blood pressure (BP) values, metabolic variables, apnea-hypopnea index (AHI) and oxygen saturation. RESULTS: MSNA is activated markedly and almost homogeneously between studies, showing a progressive increase from the healthy state to mild, moderate and severe OSAS (41.6, 48.3, 65.5 and 70.7 bursts/100 heart beats, respectively, P

BACKGROUND: Studies based on microneurographic sympathetic nerve activity (MSNA) recordings have shown that the sympathetic system is overactivated in chronic kidney disease (CKD) patients but the relationship between MSNA and renal function and other risk factors has not been systematically reviewed in this population.DESIGN AND MEASUREMENTS: This meta-analysis compares MSNA in cardiovascular complications-free CKD patients (n = 638) and healthy individuals (n = 372) and assesses the relationship of MSNA with the eGFR, age, BMI and hemodynamic variables.RESULTS: In a global analysis, MSNA was higher in CKD patients than in healthy control individuals (P

Objectives Because observational studies often use imperfect measurements, results are prone to misclassification errors. We used as a motivating example the possible teratogenic risks of antiemetic agents in pregnancy since a large observational study recently showed that first-trimester exposure to doxylamine-pyridoxine was associated with significantly increased risk of congenital malformations as a whole, as well as central nervous system defects, and previous observational studies did not show such associations. A meta-analysis on this issue was carried out with the aim to illustrate how differential exposure and outcome misclassifications may lead to uncertain conclusions. Methods Medline, searched to October 2019 for full text papers in English. Summary Odds Ratios (ORs) with confidence intervals (CIs) were calculated using random-effect models. Probabilistic sensitivity analyses were performed for evaluating the extension of differential misclassification required to account for the exposure-outcome association. Results Summary ORs were 1.02 (95 % CI, 0.92–1.15), 0.99 (0.82–1.19) and 1.25 (1.08–1.44) for overall congenital, cardiocirculatory, and central nervous system malformations respectively. By assuming exposure and outcome bias factor respectively of 0.95 (i.e., newborns with congenital defects had exposure specificity 5% lower than healthy newborns) and 1.12 (i.e., exposed newborns had outcome sensitivity 12 % higher than unexposed newborns), summary OR of central nervous system defects became 1.13 (95 % CI, 0.99–1.29) and 1.17 (95 % CI, 0.99–1.38). Conclusion Observational investigations and meta-analyses of observational studies need cautious interpretations. Their susceptibility to several, often sneaky, sources of bias should be carefully evaluated.

ObjectivesPoor worldwide rate of blood pressure control is largely due to poor adherence to antihypertensive (AHT) drug treatment. The question of whether sex affects adherence has long been debated but conflicting findings have been reported on this issue. Our objective was to evaluate sex differences in the adherence to AHT therapy.Research design and methodsStudies were identified through a systematic search of PubMed, CINAHL, PsycINFO, Web of Science and Google Scholar (through January 2020) and manual handsearching of relevant articles. Observational studies reporting adherence to AHT drugs measured by self-report or pharmacy refill prescription-based methods among men and women were included. Summarised estimates of ORs with 95% CIs were calculated using random-effects model and meta-regression models.ResultsFrom 12 849 potentially relevant publications, 82 studies (15 517 457 men and 18 537 599 women) were included. No significant between-sex differences in adherence to AHT were observed, whether all study-specific estimates were summarised (ORs 1.04, 95% CI 1.00 to 1.09, p=0.07), nor estimates were pooled according to the method for measuring adherence. Among patients aged 65 years or older, lower self-reported adherence was observed in women (ORs 0.84, 95% CI 0.72 to 0.97, p=0.02), while the main result remained unchanged according to other subgroup analyses.ConclusionsDefinitive evidence of sex differences in adherence to AHT therapy cannot be drawn. Our little knowledge about factors affecting adherence, in particular of sex effect among elderly, urgently requires high-quality studies investigating these issues.

OBJECTIVE: The microneurographic technique has shown that sympathetic overactivity may characterize patients with the metabolic syndrome. However, technical and methodological limitations of the studies prevented to draw definite conclusions. The present meta-analysis evaluated 16 microneurographic studies including 650 individuals, 444 metabolic syndrome patients and 206 healthy controls, respectively. The analysis was primarily based on muscle sympathetic nerve traffic (MSNA) quantified by microneurography in metabolic syndrome. METHODS: Assessment was extended to the relationships of MSNA with an indirect neuroadrenergic marker, such as heart rate (HR), anthropometric variables, as BMI, waist-hip ratio and metabolic profile. RESULTS: Metabolic syndrome individuals displayed MSNA values (means ± SEM) significantly greater than controls (58.6 ± 4.8 versus 41.6 ± 4.1 bursts/100 heart beats, P

Purpose: This study aims to systematically review studies quantifying the associations between antidepressants (ADs) use and the risk of cardiovascular (CV) outcomes. Methods: Medline was searched to October 2015 for full text articles in English. Prospective cohort and case-control studies were admitted if they investigated the relationship between current use of ADs as a whole, tricyclic antidepressants (TCAs) or selective serotonin reuptake inhibitors (SSRIs), and the onset CV events. Summary relative risks (RRs) with confidence intervals (CIs) were calculated using random-effects or fixed-effects models. Results: A total of 99,367 incident cases of CV outcomes who met inclusion criteria were identified from 22 observational studies. Compared with no users of ADs, use of SSRIs was associated with an increased risk of cerebrovascular disease (RRs, 1.24; 95% CI, 1.15 to 1.34), while the use of TCA was associated with an increased risk of acute heart disease (RRs, 1.29; 95% CI, 1.09 to 1.54). Conclusions: The results of this meta-analysis have to be taken with caution because even though an increased risk of cerebrovascular and acute heart disease was observed respectively in SSRIs and TCA users, the estimates are characterized by a high between study heterogeneity. Moreover, it was not possible to distinguish between the effects of ADs and depression itself. Further well-designed studies are required to confirm this association

Nerve traffic recordings (muscle sympathetic nerve traffic [MSNA]) have shown that sympathetic activation may occur in obesity. However, the small sample size of the available studies, presence of comorbidities, heterogeneity of the subjects examined represented major weaknesses not allowing to draw definite conclusions. This is the case for the overweight state. The present meta-analysis evaluated 1438 obese or overweight subjects recruited in 45 microneurographic studies. The analysis was primarily based on MSNA quantification in obesity and overweight, excluding as concomitant conditions hypertension, metabolic syndrome, and other comorbidities. Assessment was extended to the relationships of MSNA with other neuroadrenergic markers, such as plasma norepinephrine and heart rate, anthropometric variables, as body mass index, waist-to-hip ratio, presence/absence of obstructive sleep apnea, and metabolic profile. Compared with normoweights MSNA was significantly greater in overweight and more in obese individuals (37.0±4.1 versus 43.2±3.5 and 50.4±5.0 burts/100 heartbeats, P0.01). This was the case even in the absence of obstructive sleep apnea. MSNA was significantly directly related to body mass index and waist-to-hip ratio ( r=0.41 and r=0.64, P0.04 and0.01, respectively), clinic blood pressure ( r=0.68, P0.01), total cholesterol, LDL (low-density lipoprotein) cholesterol, and triglycerides ( r=0.91, r=0.94, and r=0.80, respectively, P0.01) but unrelated to plasma insulin, glucose, and homeostatic model assessment for insulin resistance. No significant correlation was found between MSNA, heart rate, and norepinephrine. Thus, obesity and overweight are characterized by sympathetic overactivity which mirrors the severity of the clinical condition and reflects metabolic alterations, with the exclusion of glucose/insulin profile. Neither heart rate nor norepinephrine appear to represent faithful markers of the muscle sympathetic overdrive.

Key Points Question What are the clinical implications of statin discontinuation in older patients receiving polypharmacy? Findings In this population-based cohort study of 29 047 patients, there was evidence that discontinuing therapy with statins was associated with a significantly increased risk of hospital admission for heart failure and any cardiovascular outcome, death from any cause, and emergency admission for any cause. Meaning The findings of this study suggest that discontinuing statins while maintaining other drug therapies may increase the long-term risk of fatal and nonfatal cardiovascular outcomes., This population-based cohort study assesses the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy., Importance Polypharmacy is a major health concern among older adults. While deprescribing may reduce inappropriate medicine use, its effect on clinical end points remains uncertain. Objective To assess the clinical implications of discontinuing the use of statins while maintaining other drugs in a cohort of older patients receiving polypharmacy. Design, Setting, and Participants This retrospective, population-based cohort study included the 29 047 residents in the Italian Lombardy region aged 65 years or older who were receiving uninterrupted treatment with statins, blood pressure–lowering, antidiabetic, and antiplatelet agents from October 1, 2013, until January 31, 2015, with follow-up through June 30, 2018. Data were collected using the health care utilization database of Lombardy region in Italy. Data analysis was conducted from March to November 2020. Exposures Cohort members were followed up to identify those who discontinued statins. Among this group, those who maintained other therapies during the first 6 months after statin discontinuation were 1:1 propensity score matched with patients who discontinued neither statins nor other drugs. Main Outcome and Measures The pairs of patients discontinuing and maintaining statins were followed up from the initial discontinuation until June 30, 2018, to estimate the hazard ratios (HRs) and 95% CIs for fatal and nonfatal outcomes associated with statin discontinuation. Results The full cohort inclued 29 047 patients exposed to polypharmacy (mean [SD] age, 76.5 [6.5] years; 18 257 [62.9%] men). Of them, 5819 (20.0%) discontinued statins while maintaining other medications, and 4010 (68.9%) of them were matched with a comparator. In the discontinuing group, the mean (SD) age was 76.5 (6.4) years, 2405 (60.0%) were men, and 506 (12.6%) had Multisource Comorbidity Scores of 4 or 5. In the maintaining group, the mean (SD) age was 76.1 (6.3) years, 2474 (61.7%) were men, and 482 (12.0%) had multisource comorbidity scores of 4 or 5. Compared with the maintaining group, patients in the discontinuing group had increased risk of hospital admissions for heart failure (HR, 1.24; 95% CI, 1.07-1.43) and any cardiovascular outcome (HR, 1.14; 95% CI, 1.03-1.26), deaths from any cause (HR, 1.15; 95% CI, 1.02-1.30), and emergency admissions for any cause (HR, 1.12; 95% CI, 1.05-1.19). Conclusions and Relevance In this study of patients receiving polypharmacy, discontinuing statins while maintaining other drug therapies was associated with an increase in the long-term risk of fatal and nonfatal cardiovascular outcomes.

Purpose: The study aimed to fill existing knowledge gaps on the safety of antidepressant drugs (ADs) by estimating the risk of hospitalization for arrhythmia associated with use of selective serotonin reuptake inhibitors (SSRIs) and newer atypical ADs (NAAs) among elderly with previous cardiovascular (CV) events. Methods: The cohort was composed by 199,569 individuals aged ≥ 65 years from five Italian healthcare territorial units who were discharged for cardiovascular outcomes in the years 2008–2010. The 17,277 patients who experienced hospital admission for arrhythmia during follow-up were included as cases. Odds of current ADs use among cases (i.e., 14 days before hospital admission) was compared with (i) odds of current use of 1:5 matched controls (between-patients case-control) and with (ii) odds of previous use during 1:5 matched control periods (within-patient case-crossover). The risk of arrhythmia associated with ADs current use was modelled fitting a conditional logistic regression. A set of sensitivity analyses was performed to account for sources of systematic uncertainty. Results: Current users of SSRIs and NAAs were at increased risk of arrhythmia with case-control odds ratios (OR) of 1.37 (95% confidence interval, CI 1.18 to 1.58) and 1.41 (1.16 to 1.71) and case-crossover OR of 1.48 (1.20 to 1.81) and 1.72 (1.31 to 2.27). An increased risk of arrhythmia was associated with current use of trazodone (NAA) consistently in case-control and case-crossover designs. Conclusions: Evidence that current use of SSRIs and NAAs is associated to an increased risk of arrhythmia among elderly with CV disease was consistently supplied by two observational approaches.

Objective:Nerve traffic recordings (MSNA) have shown that sympathetic activation may occur in obese individuals (O). However, the small sample size of the available studies, presence of comorbidities, including sleep apnea, heterogeneity of the patients examined as well as presence of confounders re

Objective:The microneurographic technique has shown that sympathetic overactivity may characterize individuals with metabolic syndrome (MS). However, technical and methodological limitations of the published studies (small sample size, presence of comorbidities including sleep apnea, presence of mul