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A novel concept is described concerning the possible effect of right ventricular pacing stimulation being detected by the cardiac autonomic nervous system and through its afferent neuronal connection to the central autonomic nervous system (spinal cord) causing reversal or attenuation of the vasovagal reflex. This could be a direct effect of electrical stimulation or may occur by the known adverse consequences on ventricular synchrony induced by stimulation which could be right ventricular site and timing in the evolution of the vasovagal reflex dependent.

Abstract Aims This study aims to determine the familial incidence of dilated (DCM) and hypertrophic cardiomyopathy (HCM) in first‐degree, second‐degree, and third‐degree relatives of affected individuals. Methods and results In this population‐based multigenerational cohort study, full‐siblings, half‐siblings, and cousin pairs born to Swedish parents between 1932 and 2015 were included, and register‐based DCM and HCM diagnoses among relatives were ascertained. Adjusted odds ratios (ORs) for DCM and HCM were calculated for relatives of individuals with DCM and HCM compared with relatives of individuals without DCM and HCM for reference. Total study population included 6 334 979 subjects and consisted of 5 577 449 full‐siblings, 1 321 414 half‐siblings, and 3 952 137 cousins. Overall, 10 272 (0.16%) unique individuals were diagnosed with DCM and 3769 (0.06%) with HCM. Of these, 7716 (75.12%) and 2375 (63.01%) were males, respectively. Familial risk ORs for DCM were 5.35 [95% confidence intervals (CI): 4.85–5.90] for full‐siblings, 2.68 (95% CI:1.86–3.87) for half‐siblings, and 1.72 (95% CI:1.12–2.64) for cousins of affected individuals. The ORs for HCM were 42.44 (95% CI:37.66–47.82) for full‐siblings, 32.70 (95% CI:21.32–50.15) for half‐siblings, and 36.96 (95% CI:29.50–46.31) for cousins of affected individuals. In sex‐stratified analysis, relatives of affected females were found more likely to be affected than were relatives of affected males, with stronger aggregation observed for HCM. Conclusions Familial risk of HCM and DCM is high and associated with genetic resemblance, with strongest aggregations observed in relatives of affected females with HCM, whereas this association was distinctly attenuated for DCM. The finding of a Carter effect, more pronounced in HCM, suggests a multifactorial threshold model of inheritance.

Background/Aims: Postural orthostatic tachycardia syndrome (POTS) is a chronic condition in which patients show a marked increase in heart rate on standing, but also suffer from a range of additional symptoms, which may include fatigue and difficulty in concentration. This study's aim was to investigate the role of psychological stress, resilience, and lifestyle as possible contributing factors in POTS onset and symptomatology. Methods: Sixty patients diagnosed with POTS at a tertiary investigation center were contacted by mail. A 64-item, online survey was developed in five sections to explore stressful events at symptom onset, present lifestyle factors, and perceptions of stress and resilience. A link was provided for the online survey to those who accepted study participation. Results: Twenty-four POTS patients completed the survey. The average age at onset of symptoms was 20 years and 4 months, with patients waiting an average of 9 years and 5 months for a POTS diagnosis. Respondents reported 54 stressful events in the 12 months leading up to the onset of their symptoms, an average of 2.48 (standard deviation [SD] = 3.24) events per person. However, the modal response was zero events. Patients with POTS had a statistically significant higher score for perceived stress (M = 19.38, SD = 8.88, P < 0.01) than the general population of Sweden (M = 13.96, SD = 5.63). However, there was no correlation between perceptions of stress and symptom severity measured by the orthostatic hypotension questionnaire. Conclusions: Swedish POTS patients have higher levels of perceived stress, similar to other disease states like chronic pain. However, no correlation between perceptions of stress and symptom severity was found. While some respondents reported many stressful events in the lead up to symptom onset, their role is unclear. Further study is required.

Abstract Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder characterized by excessive heart rate increase on standing, leading to debilitating symptoms with limited therapeutic possibilities. Proteomics is a large-scale study of proteins that enables a systematic unbiased view on disease and health, allowing stratification of patients based on their protein background. The aim of the present study was to determine plasma protein biomarkers of POTS and to reveal proteomic pathways differentially regulated in POTS. We performed an age- and sex-matched, case–control study in 130 individuals (case–control ratio 1:1) including POTS and healthy controls. Mean age in POTS was 30 ± 9.8 years (84.6% women) versus controls 31 ± 9.8 years (80.0% women). We analyzed plasma proteins using data-independent acquisition (DIA) mass spectrometry. Pathway analysis of significantly differently expressed proteins was executed using a cutoff log2 fold change set to 1.2 and false discovery rate (p-value) of

Objectives Vasospastic angina (VSA) is a complex coronary vasomotor disorder associated with an increased risk of myocardial infarction and sudden death. Despite considerable advances in understanding VSA pathophysiology, the interplay between genetic and environmental factors remains elusive. Accordingly, we aimed to determine the familial VSA risk among first-degree relatives of affected individuals.Methods A population-based multigenerational cohort study was conducted, including full-sibling pairs born to Swedish parents between 1932 and 2018. Register-based diagnoses were ascertained through linkage to the Swedish Multigeneration Register and National Patient Register. Incidence rate ratios (IRRs) and adjusted HRs were calculated for relatives of individuals with VSA compared with relatives of individuals without VSA.Results The total study population included 5 764 770 individuals. Overall, 3461 (0.06%) individuals (median age at disease onset 59 years, IQR: 63–76) were diagnosed with VSA. Of these, 2236 (64.61%) were women. The incidence rate of VSA for individuals with an affected sibling was 0.31 (95% CI: 0.24 to 0.42) per 1000 person-years compared with 0.04 (95% CI: 0.04 to 0.04) per 1000 person-years for those without an affected sibling, yielding an IRR of 7.58 (95% CI: 5.71 to 10.07). The risk of VSA for siblings with an affected sibling was significantly increased in the fully adjusted model (HR: 2.56; 95% CI: 1.73 to 3.79). No increased risk of VSA was observed in spouses of affected individuals (HR: 0.63; 95% CI: 0.19 to 2.09).Conclusions In this nationwide family study, we identified high familial risk for VSA independent of shared environmental risk factors. Our findings indicate that VSA tends to cluster in families, emphasising the need to explore genetic and non-genetic factors that may contribute.

Abstract Background The durability of immune responses to COVID-19 vaccines among older people living with HIV (PWH) is clinically important. Methods We aimed to assess vaccine-induced humoral immunity and durability in older PWH (≥ 55 years, n = 26) over 6 months (post-initial BNT162b2 series). A secondary and exploratory objective was to assess T-cell response and BNT162b2 booster reactogenicity, respectively. Our Visit 1 (3 weeks post-initial BNT162b2 dose) SARS-CoV-2 humoral immunity results are previously reported; these subjects were recruited for Visit 2 [2 weeks (+ 1 week window) post-second vaccination] and Visit 3 [6 months (± 2 week window) post-initial vaccination] in a single-center longitudinal observational study. Twelve participants had paired Visit 2/3 SARS-CoV-2 Anti-Spike IgG data. At Visit 3, SARS-CoV-2 Anti-Spike IgG testing occurred, and 5 subjects underwent T-cell immune response evaluation. Thereafter, subjects were offered BNT162b2 booster (concurrent day outside our study) per US FDA/CDC guidance; reactogenicity was assessed. The primary study outcome was presence of detectable Visit 3 SARS-CoV-2 Anti-Spike-1-RBD IgG levels. Secondary and exploratory outcomes were T-cell immune response and BNT162b2 booster reactogenicity, respectively. Wilcoxon signed-rank tests analyzed median SARS-CoV-2 Anti-Spike IgG 6-month trends. Results At Visit 3, 26 subjects underwent primary analysis with demographics noted: Median age 61 years; male n = 16 (62%), female n = 10 (38%); Black n = 13 (50%), White n = 13 (50%). Most subjects (n = 20, 77%) had suppressed HIV viremia on antiretroviral therapy, majority (n = 24, 92%) with CD4 > 200 cells/µL. At Visit 3, 26/26 (100%) had detectable Anti-Spike-1-RBD (≥ 0.8 U/mL). Among 12 subjects presenting to Visit 2/3, median SARS-CoV-2 Anti-Spike 1-RBD was 2087 U/mL at Visit 2, falling to 581.5 U/mL at Visit 3 (p = 0.0923), with a median 3.305-fold decrease over 6 months. Among subjects (n = 5) with 6-month T-cell responses measured, all had detectable cytokine-secreting anti-spike CD4 responses; 3 had detectable CD4 + Activation induced marker (AIM) + cells. Two had detectable cytokine-secreting CD8 responses, but all had positive CD8 + AIM + cells. Conclusions Among older PWH, SARS-CoV-2 Anti-Spike IgG and virus-specific T-cell responses are present 6 months post-primary BNT162b2 vaccination, and although waning, suggest retention of some degree of long-term protective immunity.

Objective:Axillary ultrasound (US) is often part of the routine assessment of the clinically negative axilla in primary breast cancer, which determines the extent of axillary surgery to be performed. This study aims to ascertain the burden of disease in the axilla of patients with a normal clinical examination (cN0) but with US detected metastatic axillary lymph nodes.Materials and Methods:We retrospectively identified 345 female patients who underwent axillary lymph node dissection, following a positive lymph node biopsy, between January 2015 and August 2019.Eighty-nine of those had a positive biopsy prior to surgery. They were divided into two groups: Those with clinically palpable axillary disease preoperatively, cN1 (n = 41), and those with a normal clinical axillary examination, cN0 (n = 48). We assessed the number of positive axillary lymph nodes dissected in the two groups.Results:In the cN0 group the mean value of excised disease-positive axillary lymph nodes was 3.6, while in the cN1 group it was 8.0 (p

Despite effective vaccines against SARS-CoV-2, therapeutic options such as anti-virals and neutralizing antibodies are critical in treating disease, especially given the breakthrough infections of emerging VOCs. Here, Peng et al. generate two potent monoclonal antibodies and a bispecific antibody with two antigenrecognition variable regions targeting SARS-CoV-2 spike, provide CryoEM structures and show in vitro and in vivo efficacy of a humanized antibody against wildtype virus and delta variant.

Background Ambulatory blood pressure (BP) monitoring has long been used to monitor BP in hypertension and lately emerged as a useful tool to detect hypotensive susceptibility in reflex syncope. However, hemodynamic characteristics in reflex syncope have not been sufficiently explored. The present study investigated the differences between ambulatory BP monitoring profiles associated with reflex syncope and normal population. Methods and Results This is an observational study comparing ambulatory BP monitoring data from 50 patients with reflex syncope and 100 controls without syncope, age‐ and sex‐matched 1:2. Mean 24‐hour systolic (SBP) and diastolic BP, pulse pressure (24‐hour PP), dipping status, and number of daytime SBP drops

Abstract Aim of this study was to explore whether differences in resting hemodynamic parameters may be associated with tilt test results in unexplained syncope. We analyzed age, gender, systolic (SBP), diastolic blood pressure (DBP) and heart rate (HR) by merging three large databases of patients considered likely to be of vasovagal reflex etiology, comparing patients who had tilt-induced reflex response with those who did not. Tilt-induced reflex response was defined as spontaneous symptom reproduction with characteristic hypotension and bradycardia. Relationship of demographics and baseline supine BP to tilt-test were assessed using logistic regression models. Individual records of 5236 patients (45% males; mean age: 60 ± 22 years; 32% prescribed antihypertensive therapy) were analyzed. Tilt-positive (n = 3129, 60%) vs tilt-negative patients had lower SBP (127.2 ± 17.9 vs 129.7 ± 18.0 mmHg, p

Abstract Background Impaired orthostatic blood pressure response and syncope confer a high risk of falls and trauma. The relationship between a history of unexplained syncope and orthostatic hypotension (OH) with subsequent fractures, however, has not been thoroughly examined. In this study, we aimed to investigate the relationship between previous hospital admissions due to unexplained syncope and OH and incident fractures in a middle-aged population. Methods We analysed a large population-based prospective cohort of 30,399 middle-aged individuals (age, 57.5 ± 7.6; women, 60.2%). We included individuals hospitalised due to unexplained syncope or OH as the main diagnosis. Multivariable-adjusted Cox regression analysis was applied to assess the impact of unexplained syncope and OH hospitalisations on subsequent incident fractures. Results During a follow-up period of 17.8 + 6.5 years, 8201 (27%) subjects suffered incident fractures. The mean time from baseline and first admission for syncope (n = 493) or OH (n = 406) was 12.6 ± 4.2 years, and the mean age of the first hospitalisation was 74.6 ± 7.4 years. Individuals with incident fractures were older, more likely to be women, and had lower BMI, higher prevalence of prevalent fractures, and family history of fractures. Multivariable-adjusted Cox regression showed an increased risk of incident fractures following hospitalisations due to unexplained syncope (HR 1.20; 95% CI 1.02–1.40; p = 0.025) and OH (HR 1.42; 95% CI 1.21–1.66; p < 0.001) compared with unaffected individuals. Conclusions Individuals hospitalised due to unexplained syncope and orthostatic hypotension have an increased risk of subsequent fractures. Our findings suggest that such individuals should be clinically assessed for their syncope aetiology, with preventative measures aimed at fall and fracture risk assessment and management.

Abstract Background Practice guidelines provide clinicians direction for the selection of ambulatory ECG (AECG) monitors in the evaluation of syncope/collapse. However, whether patients’ understand differences among AECG systems is unknown. Methods and Results A survey was conducted of USA (n = 99), United Kingdom (UK)/Germany (D) (n = 75) and Japan (n = 40) syncope/collapse patients who underwent diagnostic AECG monitoring. Responses were quantitated using a Likert‐like 7‐point scale (mean ± SD) or percent of patients indicating a Top 2 box (T2B) for a particular AECG attribute. Patient ages and diagnosed etiologies of syncope/collapse were similar across geographies. Patients were queried on AECG attributes including the ability to detect arrhythmic/cardiac causes of collapse, instructions received, ease of use, and cost. Patient perception of the diagnostic capabilities and ease of use did not differ significantly among the AECG technologies; however, USA patients had a more favorable overall view of ICM/ILRs (T2B: 42.4%) than did UK/D (T2B: 28%) or Japan (T2B: 17.5%) patients. Similarly, US patient rankings for education received regarding device choice and operation tended to be higher than UK/D or Japan patients; nevertheless, at their best, the Likert scores were low (approximately 4.7‐6.0) suggesting need for education improvement. Finally, both US and UK/D patients were similarly concerned with ICM costs (T2B, 31% vs 20% for Japan). Conclusions Patients across several geographies have a similar but imperfect understanding of AECG technologies. Given more detailed education the patient is likely to be a more effective partner with the clinician in establishing a potential symptom‐arrhythmia correlation.

Abstract Postural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder with poorly understood etiology and underlying pathophysiology. Since cardiovascular morbidity has been linked to growth hormone (GH), we studied GH levels in patients with POTS. We conducted an age-sex-matched case–control study in patients with POTS (age 31 ± 9 years; n = 42) and healthy controls (32 ± 9 years; n = 46). Plasma GH levels were measured using high-sensitivity chemiluminescence sandwich immunoassay. The burden of orthostatic intolerance symptoms was assessed by the Orthostatic Hypotension Questionnaire (OHQ), consisting of a symptom assessment scale (OHSA) and a daily activity scale (OHDAS). POTS patients had significantly higher composite OHQ score than controls, more symptoms and less activity. Supine heart rate and diastolic blood pressure (BP), but not systolic BP, were significantly higher in POTS. Median plasma GH levels were significantly lower in POTS (0.53 ng/mL) than controls (2.33 ng/mL, p = 0.04). GH levels were inversely related to OHDAS in POTS and supine systolic BP in POTS and controls, but not heart rate neither group. POTS is associated with lower GH levels. Impairment of daily life activities is inversely related with GH in POTS. A higher supine diastolic BP is inversely associated with GH levels in POTS and healthy individuals.

Swallow (deglutition) syncope is a rare form of neurally mediated cardioinhibitory reflex syncope occurring during swallowing. Patients may present to clinicians across multiple disciplines, so high awareness and careful evaluation are essential. We report 3 such individuals, describing our strategies in diagnosis, investigation and treatment, particularly focusing on conservative management. (Level of Difficulty: Intermediate.)

Abstract Background Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular (CV) autonomic disorder of unknown etiology characterized by an excessive heart rate increase on standing and orthostatic intolerance. In this study we sought to identify novel CV biomarkers potentially implicated in POTS pathophysiology. Methods We conducted a nested case-control study within the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort including 396 patients (age range, 15–50 years) with either POTS (n = 113) or normal hemodynamic response during passive head-up-tilt test (n = 283). We used a targeted approach to explore changes in cardiovascular proteomics associated with POTS through a sequential two-stage process including supervised principal component analysis and univariate ANOVA with Bonferroni correction. Results POTS patients were younger (26 vs. 31 years; p

Foi feito o estudo simultâneo das dimensões do ventrículo esquerdo por cineangiocardiografia e ecocardiografia em 15 doentes sem cardiopatia isquémica, durante o exame hemodinâmico de rotina. O feixe de ultrassons interceptou o eixo menor ventricular segundo ângulos variáveis (de -11° a +18°) na diástole e na sístole, e o eixo longitudinal de 28% a 64% do seu comprimento na diástole e de 15 % a 64 % na sístole. As dimensões ventriculares foram maiores quando medidas a partir dos angiogramas no mesmo plano do feixe de ultrassons, embora exista uma boa correlação entre as dimensões ecocardiográficas e angiocardiográficas. Também a fracção de ejecção determinada a partir dos volumes ventriculares obtidos angiograficamente, se correlaciona bem com a fracção de encurtamento obtida ecocardiograficamente. São discutidos os erros práticos envolvidos nas medições ecocardiográficas e conclui-se que a extrapolação dessas dimensões, para a determinação de volumes ventriculares, deve ser executada cautelosamente.

Human mobility datasets collected from personal mobile device locations are integral to understanding how states, counties, and cities have collectively adapted to pervasive social disruption stemming from the COVID-19 pandemic. However, while indigenous tribal communities in the United States have been disproportionately devastated by the pandemic, the relatively sparse populations and data available in these hard-hit tribal areas often exclude them from mobility studies. We explore the effects of sparse mobility data in untangling the often inter-correlated relationship between human mobility, distancing orders, and case growth throughout 2020 in tribal and rural areas of California. Our findings account for data sparsity imprecision to show: 1) Mobility through legal tribal boundaries was unusually low but still correlated highly with case growth; 2) Case growth correlated less strongly with mobility later in the the year in all areas; and 3) State-mandated distancing orders later in the year did not necessarily precede lower mobility medians, especially in tribal areas. It is our hope that with more timely feedback offered by mobile device datasets even in sparse areas, health policy makers can better plan health emergency responses that still keep the economy vibrant across all sectors.

The Task Force for the diagnosis and management of syncope of the European Society of Cardiology (ESC)Developed with the special contribution of the European Heart Rhythm Association (EHRA)Endorsed by: European Academy of Neurology (EAN), European Federation of Autonomic Societies (EFAS), European Federation of Internal Medicine (EFIM), European Union Geriatric Medicine Society (EUGMS), European Society of Emergency Medicine (EuSEM)(text is available in electronic version doi:10.15829/1560-4071-2019-7-130-194)

BackgroundElectrocardiographic (ECG) characteristics of patients with isolated hypomagnesemia are not well defined. We aimed to investigate these ECG characteristics in order to define clearly the features of isolated hypomagnesemia.HypothesisLower serum magnesium could affect ECG parameters after excluding potential confounders.MethodsThis retrospective study was of patients with low serum magnesium

Background Postural orthostatic tachycardia syndrome (POTS) is characterized by excessive heart rate increase on standing and orthostatic intolerance. Previous data indicate autoimmune involvement. We studied serum activity against G protein–coupled receptors in relation to symptoms in patients with POTS and controls using a commercial cell‐based assay. Methods and Results Forty‐eight patients with POTS (aged 28.6±10.5 years; 44 women) and 25 healthy individuals (aged 30.7±8.6 years; 21 women) were included. The 10‐item Orthostatic Hypotension Questionnaire (OHQ) was completed by 33 patients with POTS and all controls. Human embryonic kidney 293 cells overexpressing one G protein–coupled receptor: adrenergic α1 receptor, adrenergic β2 receptor, cholinergic muscarinic type 2 receptor, and opioid receptor‐like 1 were treated with sera from all patients. Receptor response was analyzed using a β‐arrestin–linked transcription factor driving transgenic β‐lactamase transcription by fluorescence resonance energy transfer method. Receiver operating characteristic curves were constructed. G protein–coupled receptor activation was related to OHQ indices in linear regression models. Sera from patients with POTS activated all 4 receptors to a higher degree compared with controls (P

Aim: Head injury is the most common trauma occurring in syncope. We aimed to assess whether syncope as cause of head-trauma affects short-and long-term prognosis.Methods: From a database retrospective analysis of 97,014 individuals attending Emergency Department (ED), we selected data of patients with traumatic head injury including age, gender, injury mechanism, brain imaging, multiple traumas, bone fracture, intracranial bleeding, and mortality. Mean follow-up was 6.4 ± 1.8 years. Outcome data were obtained from a digital national population register. The study population included 3,470 ED head injury patients: 117 of them (50.0 ± 23.6 years, 42.7% men) reported syncope as cause of head trauma and 3,315 (32.2 ± 21.1 years, 68.5% men) without syncope preceding head trauma.Results: Thirty-day mortality was low and similar in traumatic head injury with or without syncope. One year and long-term all-cause mortality were both significantly higher in syncopal vs. non-syncopal traumatic head injury (11.1 vs. 2.8% and 32 vs. 10.2%, respectively; both p < 0.001). In adjusted logistic regression analysis, death between 121st-day and 1 year in patients with head-trauma was associated with male gender [odds ratio (OR): 6.48; 95% CI: 2.59–16.25], advancing age (per year) (OR 1.09; 95% CI 1.07–1.11), Glasgow Coma Scale < 13 (OR: 6.18; 95% CI:1.68–22.8), bone fracture (OR 4.72; 95% CI 2.13–10.5), and syncope (OR 3.70; 95% CI: 1;48–9.31). In multivariable Cox regression analysis, syncope was one of the strongest independent predictors of long-term all-cause death (hazard ratio: 1.95; 95% CI 1.37–2.78).Conclusion: In patients with head trauma, history of syncope preceding injury does not increase 30-day all-cause mortality but portends increased 1 year and long-term mortality.

Reflex atrioventricular block is well-recorded although it is considered rare. Recent data suggests that it is less rare than has been supposed. It has been shown to occur in both vasovagal and carotid sinus reflexes. It has to be distinguished from paroxysmal atrioventricular block due to ventricular conduction tissue disease. Low chronic adenosine levels combined with adenosine release may mimic reflex atrioventricular block. Explanations of the mechanism of these phenomena have been lacking until the recent past. The relevance of reflex atrioventricular block to clinical decision-making is as a possible indication for pacing the heart with consideration given to the vasodepressor component of the reflex.

Background: Orthostatic hypotension (OH) is a major sign of cardiovascular autonomic failure leading to orthostatic intolerance and syncope. Orthostatic hypotension is traditionally divided into classical OH (cOH) and delayed OH (dOH), but the differences between the two variants are not well-studied. We performed a systematic clinical and neuroendocrine characterization of OH patients in a tertiary syncope unit.Methods: Among 2,167 consecutive patients (1,316 women, 60.7%; age, 52.6 ± 21.0 years) evaluated for unexplained syncope and severe orthostatic intolerance with standardized cardiovascular autonomic tests including head-up tilt (HUT), we identified those with a definitive diagnosis of cOH and dOH. We analyzed patients' history, clinical characteristics, hemodynamic variables, and plasma levels of epinephrine, norepinephrine, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1, mid-regional-fragment of pro-atrial-natriuretic-peptide and pro-adrenomedullin in the supine position and at 3-min HUT.Results: We identified 248 cOH and 336 dOH patients (27% of the entire cohort); 111 cOH and 152 dOH had blood samples collected in the supine position and at 3-min HUT. Compared with dOH, cOH patients were older (68 vs. 60 years, p < 0.001), more often male (56.9 vs. 39.6%, p < 0.001), had higher systolic blood pressure (141 vs. 137 mmHg, p = 0.05), had lower estimated glomerular filtration rate (73 vs. 80 ml/min/1.73 m2, p = 0.003), more often pathologic Valsalva maneuver (86 vs. 49 patients, p < 0.001), pacemaker-treated arrhythmia (5 vs. 2%, p = 0.04), Parkinson's disease (5 vs. 1%, p = 0.008) and reported less palpitations before syncope (16 vs. 29%, p = 0.001). Supine and standing levels of CT-proAVP were higher in cOH (p = 0.022 and p < 0.001, respectively), whereas standing norepinephrine was higher in dOH (p = 0.001). After 3-min HUT, increases in epinephrine (p < 0.001) and CT-proAVP (p = 0.001) were greater in cOH, whereas norepinephrine increased more in dOH (p = 0.045).Conclusions: One-quarter of patients with unexplained syncope and severe orthostatic intolerance present orthostatic hypotension. Classical OH patients are older, more often have supine hypertension, pathologic Valsalva maneuver, Parkinson's disease, pacemaker-treated arrhythmia, and lower glomerular filtration rate. Classical OH is associated with increased vasopressin and epinephrine during HUT, but blunted increase in norepinephrine.

For the diagnosis of reflex syncope, diligent history-building with the patient and a witness is required. In the Emergency Department (ED), the assessment of syncope is a challenge which may be addressed by an ED Observation Unit or by a referral to a Syncope Unit. Hospital admission is necessary for those with life-threatening cardiac conditions although risk stratification remains an unsolved problem. Other patients may be investigated with less urgency by carotid sinus massage (>40 years), tilt testing, and electrocardiogram loop recorder insertion resulting in a clear cause for syncope. Management includes, in general terms, patient education, avoidance of circumstances in which syncope is likely, increase in fluid and salt consumption, and physical counter-pressure maneuvers. In older patients, those that will benefit from cardiac pacing are now well defined. In all patients, the benefit of drug therapy is often disappointing and there remains no ideal drug. A role for catheter ablation may emerge for the highly symptomatic reflex syncope patient. Keywords: Cardiac pacing, Catheter ablation, Diagnosis, Drugs, Management, Reflex syncope

Abstract Background Orthostatic hypercoagulability is proposed as a mechanism promoting cardiovascular and thromboembolic events after awakening and during prolonged orthostasis. We evaluated early changes in coagulation biomarkers induced by tilt testing among patients investigated for suspected syncope, aiming to test the hypothesis that orthostatic challenge evokes procoagulatory changes to a different degree according to diagnosis. Methods One-hundred-and-seventy-eight consecutive patients (age, 51 ± 21 years; 46% men) were analysed. Blood samples were collected during supine rest and after 3 min of 70° head-up tilt test (HUT) for determination of fibrinogen, von Willebrand factor antigen (VWF:Ag) and activity (VWF:GP1bA), factor VIII (FVIII:C), lupus anticoagulant (LA1), functional APC-resistance, and activated prothrombin time (APTT) with and without activated protein C (C+/−). Analyses were stratified according to age, sex and diagnosis. Results After 3 min in the upright position, VWF:Ag (1.28 ± 0.55 vs. 1.22 ± 0.54; p

Cerebral autoregulation is crucial for maintaining cerebral blood flow and perfusion. In recent years, the importance of cerebral oxygenation in syncope and orthostatic intolerance (OI) has received increased attention. Cerebral tissue oxygenation can be measured by using near-infrared spectroscopy (NIRS), which determines the ratio of oxygenated hemoglobin to total hemoglobin in cerebral tissue. NIRS is non-invasive technology using near-infrared light, which displays real-time cerebral tissue oxygenation. Normal values of cerebral tissue oxygenation in healthy subjects are 60 to 80%. Head-up tilt test (HUT) offers the opportunity to observe the haemodynamic changes precipitating syncope and is, today, the standard method for the evaluation of syncope and orthostatic intolerance syndromes. In previous studies where NIRS was applied during HUT, a significant decrease in cerebral tissue oxygenation both prior to and during loss-of-consciousness in vasovagal syncope (VVS) has been observed. Interestingly, cerebral tissue oxygenation appears to decrease even before haemodynamic changes can be observed. Apart from VVS, cerebral tissue oxygenation decreases during orthostatic provocation in patients with orthostatic hypotension (OH) and postural orthostatic tachycardia syndrome (POTS), in the latter even in the absence of hypotension. Importantly, decline of cerebral tissue oxygenation in VVS and POTS during HUT may not correlate with hemodynamic changes. In this mini review, we summarize the current knowledge of the application of cerebral oximetry in syncope and orthostatic intolerance syndromes, discuss its likely value as a clinical diagnostic tool and also emphasize its potential in the understanding of the relevant pathophysiology.

Introduction: Syncope and orthostatic intolerance in paced patients constitute a common clinical dilemma. We, thus, aimed to determine the etiology of syncope and/or symptoms of orthostatic intolerance in paced patients.Methods: Among 1,705 patients with unexplained syncope and/or orthostatic intolerance that were investigated by cardiovascular autonomic tests, including Valsalva maneuver, active standing, carotid sinus massage, and tilt-testing, 39 patients (2.3%; age 65.6 years; 39% women) had a cardiac implantable electronic device (CIED). We explored past medical history, diagnoses found during cardiovascular autonomic tests, and the further clinical workup, in case of negative initial evaluation.Results: An etiology was identified during cardiovascular autonomic tests in 36 of the 39 patients. Orthostatic hypotension (n = 16; 41%) and vasovagal syncope (n = 12; 31%) were the most common diagnoses. There were no cases of pacemaker dysfunction. The original pacing indications followed guidelines (sick-sinus-syndrome in 16, atrioventricular block in 16, atrial fibrillation with bradycardia in five). Twenty-two of the 39 patients (56%) had experienced syncope prior to the original CIED implantation. Orthostatic hypotension was diagnosed in seven (32%) and vasovagal syncope in nine (41%) of these patients. Of the 17 patients that had not experienced syncope prior to the original CIED implantation, nine patients (53%) were diagnosed with orthostatic hypotension and vasovagal syncope was diagnosed in three (18%). Of the 39 patients, two had implantable cardioverter-defibrillators to treat malignant ventricular arrhythmias diagnosed after syncopal episodes.Conclusion: Cardiovascular autonomic tests reveal the etiology of syncope and/or orthostatic intolerance in the majority of paced patients. The most common diagnosis was orthostatic hypotension (40%) followed by vasovagal syncope (30%), whereas there were no cases of pacemaker dysfunction. Our results emphasize the importance of a complete diagnostic work-up, including cardiovascular autonomic tests, in paced patients that present with syncope and/or orthostatic intolerance.

Background Vasovagal reflex is the most common form of syncope, but the pathophysiological mechanisms that initiate the reflex are not well understood. We aimed to study supine and early orthostatic levels of the neurohormones involved in control of circulatory homeostasis in relation to the onset of tilt‐induced vasovagal syncope (VVS). Methods and Results A total of 827 patients who were investigated for unexplained syncope with head‐up tilt test (HUT) and optional nitroglycerin provocation (Italian protocol) had blood samples collected while supine and after 3‐minutes of HUT. Of these, 173 (20.9%) patients developed VVS during drug‐free HUT, 161 of whom (males 44.7%; age 45±21 years) had complete data. We analyzed levels of epinephrine, norepinephrine, C‐terminal pro–arginine vasopressin, C‐terminal endothelin‐1, and midregional fragments of pro–atrial natriuretic peptide and pro‐adrenomedullin in relation to time from tilt‐up to onset of VVS. We applied a linear regression model adjusted for age and sex. The mean time to syncope was 11±7 minutes. Older age (β=0.13; SE=0.03, P

Objective Pacemaker (PM) therapy is effective when syncope is associated with bradycardia, but syncope recurrences and fall injuries after PM implantation may occur. We aimed to survey indications and outcomes of PM implantation, following evaluation of unexplained syncope.Methods Among 1666 consecutive unpaced patients investigated in a tertiary syncope unit by carotid-sinus massage (CSM), head-up tilt test (HUT) and ECG monitoring, 106 (6.4%; age, 65 ± 17 years) received a PM. We assessed bradycardia detection methods, PM implantation indications, and explored incidence of recurrent syncope, fall-related fractures and mortality.Results Indications for PM therapy were met in 32/106 patients (30%) by CSM, in 41/106 (39%) by HUT, in 14/106 patients (13%) by implantable loop-recorder (ILR) and in 19/106 (18%) by standard ECG. Sinus arrest with asystole was the predominant PM indication during CSM/HUT and external ECG monitoring, whereas ILR detected proportionally the same numbers o f asystole due to sinus arrest and atrioventricular block. During follow-up (median, 4.3 years), 15 patients (14%) had syncope recurrence, 15 suffered fall-related fractures and 9 died. Neither syncope recurrence nor fall-related fractures were dependent on initial PM indication. The composite endpoint of recurrent syncope/fall-related fracture was associated with treated hypertension (OR 2.45; 95% CI 1.00 to 6.0), reduced glomerular filtration rate (OR 1.63 per 10 mL/min↓; 95% CI 1.22 to 2.19) and atrial fibrillation (OR 3.98; 95% CI 1.11 to 14.3). Recurrent syncope predicted increased mortality (OR 9.20; 95% CI 1.89 to 44.8).Conclusions Cardiovascular autonomic testing and ECG monitoring effectively identify pacing indications in patients with unexplained syncope. After PM implantation, treated hypertension, renal failure and atrial fibrillation predict syncope recurrence and fall-related injury. Recurrent syncope predicts increased mortality.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular autonomic disorder characterized by orthostatic intolerance and high prevalence among young women. The etiology of POTS is uncertain, though autoimmunity and inflammation may play an important role. We aimed to identify novel inflammatory biomarkers associated with POTS.Methods and Results: In the Syncope Study of Unselected Population in Malmö (SYSTEMA) cohort, we identified 396 patients (age range, 15–50 years) with either POTS (n = 113) or normal haemodynamic response during passive head-up-tilt test (n = 283). Blood samples were analyzed using antibody-based Proximity Extension Assay technique simultaneously measuring 57 inflammatory protein biomarkers. The discovery algorithm was a sequential two-step process of biomarker signature identification by supervised, multivariate, principal component analysis and verification by univariate ANOVA with Bonferroni correction. POTS patients were younger (26 vs. 31 years; p < 0.001) and there was no significant difference in sex distribution (74% vs. 67% females, p = 0.24). PCA and Bonferroni-adjusted ANOVA identified proconvertase furin as the most robust biomarker signature for POTS. Plasma level of proconvertase furin was lower (6.38 vs. 6.58 of normalized protein expression units (NPX); p < 0.001 in POTS, compared with the reference group. Proconvertase furin met Bonferroni-adjusted significance criteria in both uni- and multivariable regression analyses.Conclusion: Patients with POTS have lower plasma level of proconvertase furin compared with individuals with normal postural hemodynamic response. This finding suggests the presence of a specific autoimmune trait with disruption of immune peripheral tolerance in this hitherto unexplained condition. Further studies are needed for external validation of our results.

Guidelines for the diagnosis and management of syncope (2009).

BACKGROUND:Low-energy fractures are a growing health challenge as their incidence increases with advancing age. As cardiovascular instability may be associated with higher likelihood of traumatic falls, we aimed to investigate the associations between four cardiovascular biomarkers and the risk of low-energy fractures in a middle-aged population. METHODS:A total of 5291 individuals from the prospective Malmö Diet and Cancer (MDC) study (mean age, 57 years; 59% women) with data on baseline levels of four cardiovascular biomarkers: mid-regional-fragment of pro-adrenomedullin-peptide (MR-pro-ADM), mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP), N-terminal pro-brain natriuretic peptide (NT-pro-BNP) and C-terminal-pro-arginine-vasopressin (CT-pro-AVP/Copeptin) were included. The associations between biomarker levels and first incident low-energy fracture were tested in Cox proportional-hazard models, taking potential interactions and traditional risk factors into account. RESULTS:Participants were followed for a median time of 21.0 years, during which 1002 subjects (19%) experienced at least one low-energy fracture. Subjects with incident fracture were older, more likely to be women, had lower BMI and higher prevalence of previous fractures. Among biomarkers, there was a significant interaction between gender and MR-pro-ADM on the risk of fracture (p = 0.002). MR-pro-ADM predicted fractures in men only (hazard ratio, 1.23; 95% CI 1.09-1.40; p = 0.001), whereas there was no association among women. Levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP did not predict fractures. CONCLUSIONS:Higher circulating levels of MR-pro-ADM predict low-energy fractures among middle-aged-men, whereas levels of MR-pro-ANP, NT-pro-BNP and CT-pro-AVP are not associated with increased fracture risk. Further controlled studies should test the hypothesis whether MR-pro-ADM may improve prediction of bone fractures.