Pulmonary function and atherosclerosis in the general population: causal associations and clinical implications.

Reduced lung function is associated with cardiovascular mortality, but the relationships with atherosclerosis are unclear. The population-based Swedish CArdioPulmonary BioImage study measured lung function, emphysema, coronary CT angiography, coronary calcium, carotid plaques and ankle-brachial index in 29,593 men and women aged 50-64 years. The results were confirmed using 2-sample Mendelian randomization. Lower lung function and emphysema were associated with more atherosclerosis, but these relationships were attenuated after adjustment for cardiovascular risk factors. Lung function was not associated with coronary atherosclerosis in 14,524 never-smokers. No potentially causal effect of lung function on atherosclerosis, or vice versa, was found in the 2-sample Mendelian randomization analysis. Here we show that reduced lung function and atherosclerosis are correlated in the population, but probably not causally related. Assessing lung function in addition to conventional cardiovascular risk factors to gauge risk of subclinical atherosclerosis is probably not meaningful, but low lung function found by chance should alert for atherosclerosis.

Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry.

Rationale: Postbronchodilator spirometry is used for the diagnosis of chronic obstructive pulmonary disease. However, prebronchodilator reference values are used for spirometry interpretation. Objectives: To compare the resulting prevalence rates of abnormal spirometry and study the consequences of using pre- or postbronchodilator reference values generated within SCAPIS (Swedish CArdioPulmonary bioImage Study) when interpreting postbronchodilator spirometry in a general population. Methods: SCAPIS reference values for postbronchodilator and prebronchodilator spirometry were based on 10,156 and 1,498 never-smoking, healthy participants, respectively. We studied the associations of abnormal spirometry, defined by using pre- or postbronchodilator reference values, with respiratory burden in the SCAPIS general population (28,851 individuals). Measurements and Main Results: Bronchodilation resulted in higher predicted medians and lower limits of normal (LLNs) for FEV1/FVC ratios. The prevalence of postbronchodilator FEV1/FVC ratio lower than the prebronchodilator LLN was 4.8%, and that of postbronchodilator FEV1/FVC lower than the postbronchodilator LLN was 9.9%, for the general population. An additional 5.1% were identified as having an abnormal postbronchodilator FEV1/FVC ratio, and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%; P < 0.001), and self-reported physician-diagnosed chronic obstructive pulmonary disease (2.8% vs. 0.5%, P < 0.001) than subjects with a postbronchodilator FEV1/FVC ratio greater than the LLN for both pre- and postbronchodilation. Conclusions: Pre- and postbronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of postbronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using postbronchodilator reference values when interpreting postbronchodilator spirometry might enable the identification of individuals with mild disease and be clinically relevant.

Detection of G Protein-Coupled Receptor Autoantibodies in Postural Orthostatic Tachycardia Syndrome Using Standard Methodology.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a disorder of orthostatic intolerance that primarily affects women of childbearing age. The underlying pathophysiology of POTS is not fully understood, but it has been suggested that autoimmunity may play a role. The aim of this study was to compare concentrations of autoantibodies to cardiovascular G protein-coupled receptors between patients with POTS and healthy controls. METHODS: Sera were collected from 116 patients with POTS (91% female; medium age, 29 years) and 81 healthy controls (84% female; medium age, 27 years) from Calgary, Canada, and Malmö, Sweden. Samples were evaluated for autoantibodies to 11 receptors (adrenergic, muscarinic, angiotensin II, and endothelin) using a commercially available enzyme-linked immunosorbent assay. RESULTS: Autoantibody concentrations against all of the receptors tested were not significantly different between controls and patients with POTS. The majority of patients with POTS (98.3%) and all controls (100%) had α1 adrenergic receptor autoantibody concentrations above the seropositive threshold provided by the manufacturer (7 units/mL). The proportion of patients with POTS versus healthy controls who fell above the diagnostic thresholds was not different for any tested autoantibodies. Receiver operating characteristic curves showed a poor ability to discriminate between patients with POTS and controls. CONCLUSIONS: Patients with POTS and healthy controls do not differ in their enzyme-linked immunosorbent assay-derived autoantibody concentrations to cardiovascular G protein-coupled receptors. These findings suggest that these tests are not useful for establishing the role of autoimmunity in POTS.

Malmö POTS symptom score: Assessing symptom burden in postural orthostatic tachycardia syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a common cardiovascular autonomic disorder characterized by excessive heart rate (HR) increase on standing and symptoms of orthostatic intolerance, posing significant limitations on functional capacity. No objective tool exists to classify symptom burden in POTS. METHODS: We conducted a case-control study in 62 POTS patients and 50 healthy controls to compare symptom burden between groups using the newly developed, self-rating, 12-item, Malmö POTS Score (MAPS; 0-10 per item, total range 0-120) based on patients own perception of symptoms through visual analogue scale assessment. We have also explored correlations between symptom severity assessed by MAPS, basic clinical parameters and postural haemodynamic changes. RESULTS: POTS patients showed significantly higher total MAPS score (78 ± 20 vs. 14 ± 12, p < 0.001), higher baseline systolic blood pressure (BP), diastolic BP and HR (p < 0.001) compared with healthy controls. The most prominent symptoms in POTS were palpitations, fatigue and concentration difficulties. Haemodynamic parameters on standing were significantly correlated with palpitations in POTS after adjustment for age and sex (lower systolic and diastolic BP, and higher HR) (p < 0.001 for all). Orthostatic HR was significantly associated with concentration difficulties and total MAPS score. The optimal cut-point value of MAPS to differentiate POTS and healthy controls was ≥42 (sensitivity, 97%; specificity, 98%). CONCLUSIONS: Symptom severity, as assessed by MAPS score, is fivefold higher in POTS compared with healthy individuals. The new MAPS score can be useful as a semiquantitative system to assess symptom burden, monitor disease progression and evaluate pre-test likelihood of disease.

Mechanisms behind diffuse idiopathic peripheral neuropathy in humans - a systematic review.

INTRODUCTION: Diffuse peripheral neuropathy is a well-known complication of several conditions, whereas many patients have peripheral neuropathy of unknown etiology and pathophyisology. Increased knowledge of mechanisms may provide insight into enteric neuropathy with gastrointestinal dysmotility. The aim of the present systematic review was to identify mechanisms behind diffuse idiopathic peripheral neuropathies in humans. METHODS: Searches were performed in PubMed, Embase, and Web of Science. Human original and review articles, written in English, describing mechanisms behind diffuse peripheral neuropathy verified by objective examinations were intended to be studied. Articles that described animal models, well-described hereditary diseases, drug-induced neuropathy, pain syndromes, malnutrition, and local neuropathy were excluded. RESULTS: In total, 4712 articles were identified. After scrutinizing titles and abstracts, 633 remained and were studied in full text. After the removal of articles not fulfilling inclusion or exclusion criteria, 52 were finally included in this review. The most frequently described neuropathy was diabetic neuropathy, with a wide range of mechanisms involving mitochondrial dysfunction such as oxidative stress and inflammation. Microvascular changes in diabetes and vasculitis lead to ischemia and secondary oxidative stress with inflammation. Structural changes in neurons and glial cells are observed, with abnormalities in different neurotrophic factors. Neuropathy induced by autoantibodies or immunological mechanisms is described in infectious and systemic inflammatory diseases. Several ion channels may be involved in painful neuropathy. No study identified why some patients mainly develop large fiber neuropathy and others small fiber neuropathy. CONCLUSION: Metabolic and immunological factors and channelopathy may be considered in diffuse idiopathic peripheral neuropathy.

Definitive aetiology of unexplained syncope after cardiovascular autonomic tests in a tertiary syncope unit.

AIMS: Syncope is a common condition with many possible causes, ranging from benign to life-threatening aetiologies. Establishing a diagnosis can be difficult, and specialized syncope units, using cardiovascular autonomic tests (CATs), including a head-up tilt test, can increase the diagnostic yield. However, up to one-fifth of examined patients have inconclusive CAT results. The aim of the present study was to investigate the predictive value of history, and clinical findings for unexplained syncope after CAT and characterize the group with negative results. METHODS AND RESULTS: Consecutive syncope patients [n = 2663, 61% women, median age 52 (32-69) years] were evaluated and CAT explained aetiology of syncope in 79% of cases, whereas 21% remained unexplained. Predictors of negative CAT were older age at first syncope (+8% higher odds per 10-year increment, P = 0.042), higher supine heart rate (HR; +12% per 10 b.p.m.; P = 0.003), absence of prodromes (+48%; P < 0.001), hypertension (+45%; P = 0.003), diabetes (+82%; P < 0.001), heart failure (+98%; P = 0.014), and coronary artery disease (+51%; P = 0.027). Compared with vasovagal syncope, patients with negative CAT were older, reported more often the absence of prodromes, and had a higher burden of cardiovascular comorbidities. CONCLUSION: A cardiovascular autonomic test established the cause of syncope in 79% of patients evaluated in a syncope unit. Syncope without prodromes and cardiovascular comorbidities were significant predictors of failure to reveal an aetiology from assessment by CAT. These are known risk factors for cardiac syncope and patients with inconclusive CAT warrant further investigation.

Orthostatic blood pressure adaptations, aortic stiffness, and central hemodynamics in the general population: insights from the Malmö Offspring Study (MOS).

PURPOSE: Arterial stiffness is independently associated with orthostatic hypotension in older individuals. The relationship between orthostatic blood pressure adaptation and aortic stiffness has not been thoroughly examined in a younger population. We investigated the relationship between orthostatic blood pressure adaptations, central aortic hemodynamics, and aortic stiffness in a cohort of predominantly younger and middle-aged adults. METHODS: We analyzed an observational, population-based study of 5259 individuals living in Malmö, Sweden. We related aortic stiffness and central hemodynamics assessed by carotid-femoral pulse wave velocity and pulse wave analysis at the arteria radialis using Sphygmocor to orthostatic blood pressure adaptation after 3 min standing. RESULTS: The mean age of the population was 41.9 ± 14.5 years, and 52.1% were women. We observed the highest aortic stiffness and central aortic blood pressure measurements in the lowest and highest quartiles of orthostatic systolic blood pressure differences (p < 0.001). Aortic stiffness and central aortic blood pressure gradually decreased across increasing quartiles of orthostatic diastolic blood pressure difference (p < 0.001). After full adjustment, orthostatic diastolic blood pressure remained significantly associated with aortic stiffness (p = 0.001) and central aortic blood pressure (p < 0.001), whereas orthostatic systolic blood pressure was significantly associated only with central aortic systolic blood pressure (p = 0.009). No significant associations were found between subclinical orthostatic hypotension, aortic stiffness, and central hemodynamics. CONCLUSIONS: Our findings demonstrate that altered blood pressure responses to orthostatic challenges, both blood pressure reductions and blood pressure increases, are independently and inversely associated with markers of aortic stiffness (vascular aging) in a predominantly young to middle-aged population.

Associations between physical activity and autonomic function during deep breathing test: the Swedish CArdioPulmonary bioImage Study (SCAPIS).

PURPOSE: The deep breathing test (DBT) is a sensitive test of cardiovagal function. The aim of this study was to explore associations between physical activity and sedentary time, measured by accelerometer, and autonomic function, using DBT. METHODS: In the Swedish Cardio-Pulmonary bioImage Study, men and women aged 50-64 were randomly invited from the general population. A total of 4325 subjects who underwent DBT and assessment of physical activity and sedentary time by accelerometery were included. ECG files from 1-min DBT were used to calculate measures of respiratory sinus arrhythmia [RSA; expiration-inspiration (E-I) difference and E/I ratio], heart rate variability [HRV; root mean square of successive differences (RMSSD), standard deviation of heart rates and mean circular resultant]. Low RSA and HRV was defined as the lowest 10% in the population. RESULTS: For accelerometer-assessed physical activity, there were significant associations between high percentage of sedentary time and low E/I (p < 0.01), and low RMSSD (p < 0.01) in an age- and sex-adjusted model, and between percentage of sedentary time and low RMSSD (p = 0.04) in a risk factor-adjusted model. Low RMSSD was less common in those with a high percentage of moderate to vigorous physical activity (p = 0.04, after risk-factor adjustment). These associations became non-significant when further adjusting for heart rate. CONCLUSION: We report associations between degree of physical activity and indices of autonomic dysfunction in a large population. The relationships were no longer significant after adjustments for heart rate, indicating that the relationship between physical activity and cardiovagal function partly is accounted for by reduced heart rate.

Early and late-onset syncope: insight into mechanisms.

AIMS: Unexplained syncope is an important clinical challenge. The influence of age at first syncope on the final syncope diagnosis is not well studied. METHODS AND RESULTS: Consecutive head-up tilt patients (n = 1928) evaluated for unexplained syncope were stratified into age groups <30, 30-59, and ≥60 years based on age at first syncope. Clinical characteristics and final syncope diagnosis were analysed in relation to age at first syncope and age at investigation. The age at first syncope had a bimodal distribution with peaks at 15 and 70 years. Prodromes (64 vs. 26%, P < 0.001) and vasovagal syncope (VVS, 59 vs. 19%, P < 0.001) were more common in early-onset (<30 years) compared with late-onset (≥60 years) syncope. Orthostatic hypotension (OH, 3 vs. 23%, P < 0.001), carotid sinus syndrome (CSS, 0.6 vs. 9%, P < 0.001), and complex syncope (>1 concurrent diagnosis; 14 vs. 26%, P < 0.001) were more common in late-onset syncope. In patients aged ≥60 years, 12% had early-onset and 70% had late-onset syncope; older age at first syncope was associated with higher odds of OH (+31% per 10-year increase, P < 0.001) and CSS (+26%, P = 0.004). Younger age at first syncope was associated with the presence of prodromes (+23%, P < 0.001) and the diagnoses of VVS (+22%, P < 0.001) and complex syncope (+9%, P = 0.018). CONCLUSION: In patients with unexplained syncope, first-ever syncope incidence has a bimodal lifetime pattern with peaks at 15 and 70 years. The majority of older patients present only recent syncope; OH and CSS are more common in this group. In patients with early-onset syncope, prodromes, VVS, and complex syncope are more common.

Association between hypotension during 24†h ambulatory blood pressure monitoring and reflex syncope: the SynABPM 1 study.

AIMS: Diagnostic criteria for ambulatory blood pressure monitoring (ABPM) in patients with suspected reflex syncope are lacking. The study hypothesis was that patients with reflex syncope have a higher prevalence of systolic blood pressure (SBP) drops on ABPM. METHODS AND RESULTS: ABPM data from reflex syncope patients and controls, matched by average 24 h SBP, age, sex, and hypertension were compared. Patients with constitutional hypotension, orthostatic hypotension, and predominant cardioinhibition during carotid sinus massage or prolonged electrocardiogram monitoring or competing causes of syncope were excluded. Daytime and nighttime SBP drops (<110, 100, 90, 80 mmHg) were assessed. Findings were validated in an independent sample. In the derivation sample, daytime SBP drops were significantly more common in 158 syncope patients than 329 controls. One or more daytime drops <90 mmHg achieved 91% specificity and 32% sensitivity [odds ratio (OR) 4.6, P < 0.001]. Two or more daytime drops <100 mmHg achieved 84% specificity and 40% sensitivity (OR 3.5, P = 0.001). Results were confirmed in the validation sample of 164 syncope patients and 164 controls: one or more daytime SBP drops <90 mmHg achieved 94% specificity and 29% sensitivity (OR 6.2, P < 0.001), while two or more daytime SBP drops <100 mmHg achieved 83% specificity and 35% sensitivity (OR 2.6, P < 0.001). CONCLUSION: SBP drops during ABPM are more common in reflex syncope patients than in controls. Cut-off values that may be applied in clinical practice are defined. This study expands the current indications for ABPM to patients with reflex syncope.

Early menopause and weight loss are significant factors associated with risk of future fracture in middle-aged women.

BACKGROUND: To identify factors related to reproductive history and weight change associated with first incident fracture in middle-aged women. METHODS: In total, 18,326 women from the Malmö Diet and Cancer study were included in this prospective population-based cohort study. Participants were included 1991-1996 and followed to 2016. Using data from the National Patient Registry, linked with every participants' unique personal identification number, any first fracture affecting spine, thoracic cage, upper and lower extremities was identified. The association of baseline factors with incident fracture risk was analyzed using Cox regression models. RESULTS: For participating women, median age 56.0 years, the multivariable Cox regression analysis observed that early menopause (40-44 years) (hazard ratio (HR) 1.14, 95% confidence interval (CI) 1.03-1.27) but not premature menopause < 40 years (HR 1.06, 95% CI 0.91-1.24) was associated with future fracture risk. Self-reported weight loss since age 20 was also associated with future fracture risk (HR 1.39, 95% CI 1.17-1.65) whereas a daily alcohol consumption in the third quartile (5.36-11.42 g/day) compared to the lowest quartile (0-0.80 g/day) was associated with decreased future fracture risk (HR 0.88, 95% CI 0.81-0.96). The multivariable Cox regression analysis also observed that increasing age and weight at baseline, current smoking, a positive history of previous fracture and family history of fractures were associated with increased fracture risk whereas an increasing BMI was associated with a decreased fracture risk. No association to parity or period of lactation was observed nor ever-use of oral contraceptives and menopausal hormone therapy. CONCLUSION: This study shows that early menopause between 40 to 45 years and self-reported weight loss since age of 20 are relevant factors associated with increased fracture risk in middle-aged women. These factors were independent of traditional predictors of fracture risk among women and may be considered in preventive initiatives. TRIAL REGISTRATION: Clinicaltrials.gov with identifier: NCT04151732, since Nov 5th 2018.

Risk of incident fractures in individuals hospitalised due to unexplained syncope and orthostatic hypotension.

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.

Clustering of blood cell count abnormalities and future risk of death.

BACKGROUND: The identification of novel predictors of poor outcome may help stratify cardiovascular risk. Aim was to evaluate the individual contribution of blood cell count parameters, as well as their clustering, on the risk of death and cardiovascular events over the long term in the population-based Malmö Diet and Cancer Study cohort. METHODS: In 30,447 individuals (age 57 ± 8 years), we assessed the incidence of all-cause death (primary endpoint) and major adverse cardiovascular events (MACE, secondary outcome measure) according to absence or presence of one, two and three factors at baseline out of the following: anaemia, leukocytosis and thrombocytosis. Median follow-up was 16 years. RESULTS: The percentages of all-cause death were 19.5% in individuals without factors, 21.3% in those with one factor, 27.4% with two and 46.4% with three (log-rank test P < .001). The crude incidence of MACE was 28.0%, 29.2%, 35.5% and 57.1%, respectively (log-rank test P < .001). At multivariate analysis, we found a stepwise increase in overall mortality with increasing number of prevalent factors (one factor: HR 1.23, 95% CI 1.14-1.31, P < .001; two factors: 1.61, 1.37-1.89, P < .001; three factors: 2.69, 1.44-5.01, P = .002, vs no factor). Similar findings were observed for the incidence of MACE (one factor: adjusted HR 1.18, 95% CI 1.11-1.24, P < .001; two factors: 1.52, 1.33-1.76, P < .001; three factors: 2.03, 1.21-3.67, P < .001, vs no factor). CONCLUSIONS: The easily assessable clustering of anaemia, leukocytosis and thrombocytosis heralds higher incidence of death and adverse cardiovascular events.

Proteomic analysis reveals sex-specific biomarker signature in postural orthostatic tachycardia syndrome.

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 < 0.001) and had lower BMI than controls. The discovery algorithm identified growth hormone (GH) and myoglobin (MB) as the most specific biomarker fingerprint for POTS. Plasma level of GH was higher (9.37 vs 8.37 of normalised protein expression units (NPX); p = 0.002), whereas MB was lower (4.86 vs 5.14 NPX; p = 0.002) in POTS compared with controls. In multivariate regression analysis, adjusted for age and BMI, and stratified by sex, lower MB level in men and higher GH level in women remained independently associated with POTS. CONCLUSIONS: Cardiovascular proteomics analysis revealed sex-specific biomarker signature in POTS featured by higher plasma level of GH in women and lower plasma level of MB in men. These findings point to sex-specific immune-neuroendocrine dysregulation and deconditioning as potentially key pathophysiological traits underlying POTS.

The co-predictive value of a cardiovascular score for CV outcomes in diabetic patients with no atrial fibrillation.

BACKGROUND: Risk factors included in the cardiovascular (CHA2 DS2 -VASc) score, currently used for atrial fibrillation (AF), may predispose to cardiovascular events whether or not AF is present. The aim was to explore the predictive role of CHA2 DS2 -VASc score on cardiovascular outcomes in diabetic patients without AF. METHODS: We accessed individual data from 610 diabetic patients without AF at baseline included in the prospective cohort of the Malmö Diet and Cancer study. Main outcome measure was the occurrence of cardiovascular events (stroke, coronary events) and death. Mean follow-up was 14.5 ± 5 years (8845 person/years). RESULTS: The CHA2 DS2 -VASc score significantly predicted the risk of all outcome measures. There was a significant increase in stroke, coronary events, and death risk by each point of CHA2 DS2 -VASc score elevation [stroke: adjusted hazard ratio (aHR) 1.43, 95% CI 1.14-1.79, P = 0.001; coronary events: aHR 1.55, 95% CI 1.34-1.80, P < 0.0001; death: aHR 1.94, 95% CI 1.71-2.21, P < 0.0001]. A CHA2 DS2 -VASc score ≥4 was associated with higher incidence of ischemic stroke (aHR 1.47, 95% CI 1.18-1.82; P = 0.001), coronary events (aHR 1.32; 95% CI 1.11-1.58; P = 0.002), and death (aHR 1.36; 95% CI 1.20-1.54; P < 0.001). CONCLUSIONS: In this population-based study on diabetic patients without AF, the CHA2 DS2 -VASc score was an independent predictor of ischemic stroke, coronary events, and overall mortality. Regardless of the AF status, the CHA2 DS2 -VASc score might represent a rapid and user-friendly tool for clinical assessment of diabetic patients at higher cardiovascular risk.

Susceptibility to diarrhea is related to hemodynamic markers of sympathetic activation in the general population.

Objectives: Functional gastrointestinal (GI) symptoms, such as IBS (irritable bowel syndrome), have been suggested to be associated with autonomic neuropathy. We therefore examined associations between hemodynamic indices of autonomic control, functional GI symptoms and stress in a population-based cohort.Methods and materials: The study included 2094 participants of the Malmö Offspring Study (mean age 40.6 ± 13.8 years, 53.9% women). 509 (24.3%) reported having GI symptoms the last 2 weeks, without having organic GI disease, and 347 subjects (16.6%) reported IBS. Office and ambulatory 24-h systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate were measured. Associations between hemodynamic parameters and abdominal pain, diarrhea, constipation, bloating and flatulence, vomiting and nausea and psychological well-being according to the visual analog scale for IBS (VAS-IBS), and stress, were performed by Spearman's correlation test and linear regression models.Results: Subjects who reported GI symptoms had lower office supine and standing DBP and lower 24 h SBP and DBP compared with those without GI symptoms. Regarding specific symptoms, diarrhea was correlated with 24-h measurements of SBP (rs = 0.197), DBP (rs = 0.173) and heart rate (rs = 0.134). Subjects with the most severe diarrhea had higher 24-h SBP (125.2 vs. 119.0 mmHg; p = .038), DBP (74.0 vs. 69.0 mmHg; p = .033) and heart rate (74.5 vs 71.1 beats/minute; p = .048), after adjustments for confounders, compared to the other. There were no associations between other GI symptoms, IBS, stress and hemodynamic alterations.Conclusion: Functional diarrhea was associated with hemodynamic indices of sympathetic activation, supporting a possible role of the autonomic nervous system in diarrhea.

Monitoring of cerebral oximetry in patients with postural orthostatic tachycardia syndrome.

AIMS: Postural orthostatic tachycardia syndrome (POTS) is a disorder of unknown aetiology characterized by orthostatic intolerance and tachycardia with diverse other symptoms, including neurocognitive deficits. Cerebral oximetry non-invasively measures cerebral tissue saturation (SctO2) and has been shown to be informative in syncope evaluation. We aimed to assess SctO2 in POTS patients and those with normal response to orthostatic provocation, relative to haemodynamic parameters and symptoms. METHODS AND RESULTS: Thirty-four patients with POTS (29.1 ± 9.5 years; 26 females) and 34 age-/sex-matched controls with normal head-up tilt tests (HUTs) were included. SctO2 at rest and during HUT were compared between POTS and controls. The relation between SctO2, systolic blood pressure (SBP), and heart rate (HR) during HUT was linearly assessed. SctO2 values were related to dizziness or syncope during HUT. The minimum SctO2-value during HUT was lower (65.4 ± 5.6 vs. 68.2 ± 4.2%, P = 0.023) and changes in SctO2 from supine to minimum HUT value were more pronounced in POTS patients (-5.7 ± 2.9% vs. -4.3 ± 2.1%, P = 0.028). Decrease in SBP from supine to minimum HUT value (P = 0.004) and increase in HR from supine to HUT value at 3 min (P = 0.022) correlated with more pronounced SctO2 decrease in POTS but not controls. SctO2 did not predict syncope or dizziness during HUT. CONCLUSION: Postural orthostatic tachycardia syndrome patients have lower cerebral tissue saturation during orthostatic provocation compared with those subjects having normal haemodynamic response to tilt. Orthostatic decrease in cerebral saturation only weakly correlates with HR increase and does not predict vasovagal reflex in POTS. Other hitherto unknown factors may affect cerebral tissue saturation in POTS.

Markers of cardiovascular autonomic dysfunction predict COPD in middle-aged subjects.

Autonomic dysfunction is commonly observed in chronic obstructive pulmonary disease (COPD) and may relate to the known comorbidity with coronary artery disease (CAD). We hypothesised that clinical markers of cardiovascular autonomic dysfunction predict COPD in the population, independently of CAD.In a population-based cohort of 24 768 subjects (mean age 45 years) without baseline airflow obstruction, we analysed the cross-sectional relationship of one-minute orthostatic systolic (SBP) and diastolic (DBP) blood pressure changes, and resting heart rate with forced vital capacity (FVC) and forced expiratory volume (FEV1). Cox-regression-models were used to analyse the association of orthostatic SBP and DBP changes (SBP/DBP-decrease) and resting heart rate with incident COPD over 32-year follow-up.Baseline orthostatic SBP-decrease (p=0.020) and DBP-decrease (p=0.001) associated with reduced FVC, whereas resting heart rate associated with reduced FVC and FEV1 (p<0.001). After adjustment for smoking and baseline lung function, SBP-decrease predicted COPD (Hazard ratio [HR] 1.10 per 10 mmHg; 95% confidence interval [CI]:1.03-1.18). Resting heart rate predicted COPD among smokers (HR 1.11 per 10 beats-per-minute increase; 95%CI:1.05-1.18). Results were similar in subjects without CAD.Subtle signs of cardiovascular autonomic dysfunction may precede development of COPD in middle-aged subjects. This association is independent of the relationship between cardiovascular autonomic dysfunction and CAD.

Procoagulatory changes induced by head-up tilt test in patients with syncope: observational study.

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 < 0.001) and fibrinogen (2.84 ± 0.60 vs. 2.75 ± 0.60, p < 0.001) increased, whereas APTT/C+/- (75.1 ± 18.8 vs. 84.3 ± 19.6 s; p < 0.001, and 30.8 ± 3.7 vs. 32.1 ± 3.8 s; p < 0.001, respectively) and APC-resistance (2.42 ± 0.43 vs. 2.60 ± 0.41, p < 0.001) decreased compared with supine values. Significant changes in fibrinogen were restricted to women (p < 0.001) who also had lower LA1 during HUT (p = 0.007), indicating increased coagulability. Diagnosis vasovagal syncope was associated with less increase in VWF:Ag during HUT compared to other diagnoses (0.01 ± 0.16 vs. 0.09 ± 0.17; p = 0.004). CONCLUSIONS: Procoagulatory changes in haemostatic plasma components are observed early during orthostasis in patients with history of syncope, irrespective of syncope aetiology. These findings may contribute to the understanding of orthostatic hypercoagulability and chronobiology of cardiovascular disease.

Do we need to evaluate diastolic blood pressure in patients with suspected orthostatic hypotension?

PURPOSE: The contribution of diastolic blood pressure measurement to the diagnosis of classical orthostatic hypotension is not known. We aimed to explore the prevalence of isolated systolic and diastolic orthostatic hypotension components in patients with syncope and orthostatic intolerance. METHODS: A total of 1520 patients aged >15 years with suspected syncope and/or symptoms of orthostatic intolerance were investigated in a tertiary center using tilt-table testing and continuous non-invasive blood pressure monitoring. Classical orthostatic hypotension was defined as a decline in systolic blood pressure ≥20 mmHg and/or diastolic blood pressure ≥10 mmHg at 3 min of tilt test. The prevalence of upright systolic blood pressure <90 mmHg and its overlap with isolated diastolic orthostatic hypotension was also assessed. RESULTS: One hundred eighty-six patients (12.2%) met current diagnostic criteria for classical orthostatic hypotension. Of these, 176 patients (94.6%) met the systolic criterion and 102 patients (54.8%) met the diastolic criterion. Ninety-two patients (49.5%) met both systolic and diastolic criteria, whereas ten patients (5.4%) met the diastolic criterion alone. Of these, three had systolic blood pressure <90 mmHg during tilt test and were diagnosed with orthostatic hypotension on the grounds of low standing blood pressure. Based on patient history and ancillary test results, causes of orthostatic intolerance and syncope other than orthostatic hypotension were present in the remaining seven patients. CONCLUSIONS: An abnormal orthostatic fall in diastolic blood pressure without an abnormal fall in systolic blood pressure is rare among patients with syncope and orthostatic intolerance. Approximately 95% of patients with classical orthostatic hypotension can be identified by systolic criterion alone.