Orthostatic hypotension is associated with higher levels of circulating endostatin.

Aims: The pathophysiology of orthostatic hypotension (OH), a common clinical condition, associated with adverse outcomes, is incompletely understood. We examined the relationship between OH and circulating endostatin, an endogenous angiogenesis inhibitor with antitumour effects proposed to be involved in blood pressure (BP) regulation. Methods and results: We compared endostatin levels in 146 patients with OH and 150 controls. A commercial chemiluminescence sandwich immunoassay was used to measure circulating levels of endostatin. Linear and multivariate logistic regressions were conducted to test the association between endostatin and OH. Endostatin levels were significantly higher in OH patients (59 024 ± 2513 pg/mL) vs. controls (44 090 ± 1978pg/mL, P < 0.001). A positive linear correlation existed between endostatin and the magnitude of systolic BP decline upon standing (P < 0.001). Using multivariate analysis, endostatin was associated with OH (adjusted odds ratio per 10% increase of endostatin in the whole study population = 1.264, 95% confidence interval 1.141-1.402), regardless of age, sex, prevalent cancer, and cardiovascular disease, as well as traditional cardiovascular risk factors. Conclusion: Circulating endostatin is elevated in patients with OH and may serve as a potential clinical marker of increased cardiovascular risk in patients with OH. Our findings call for external validation. Further research is warranted to clarify the underlying pathophysiological mechanisms.

Gastrointestinal symptoms in patients with postural orthostatic tachycardia syndrome in relation to hemodynamic findings and immunological factors.

Gastrointestinal (GI) symptoms are common in postural orthostatic tachycardia syndrome (POTS). We aimed to explore the prevalence and severity of GI symptoms in POTS, and to investigate immunological factors, hemodynamic findings, and their possible association with GI symptoms in POTS. Forty-three patients (93% female, median age 30.6 (26.0-41.0) years), previously diagnosed with POTS and 74 healthy controls (78% female, median age 35.6 (28.8-41.7) years) were included. The participants completed a questionnaire including prevalence of GI symptoms, the irritable bowel syndrome severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS). All POTS patients were previously examined by tilt test (2010-2021) and the vast majority with more recent active standing test (2017-2021), which included monitoring of heart rate (HR). ΔHR was calculated as difference between supine and upright position. Continuous variables from IBS-SSS and VAS-IBS were correlated to ΔHR. A microarray containing several autoantigens commonly targeted in systemic autoimmune disorders was used to assess prevalent autoantibodies in POTS and controls. Total IgE and S-tryptase were analyzed. GI symptoms were more prevalent and severe in POTS than in controls; nausea being the most prevalent (79.1% vs 4.9%, p < 0.001) and bloating and flatulence being the most severe (median 65 (25-88) vs 0 (0-14), p < 0.001). The median total IBS-SSS was 213 (135-319) in POTS vs 13 (0-54) in controls (p < 0.001). Total IBS-SSS was associated with low psychological wellbeing (r = 0.539, p < 0.001) in POTS. ΔHRmax correlated inversely with abdominal pain (r = -0.406, p = 0.007). After adjustments for psychological wellbeing, total IBS-SSS still associated inversely with ΔHR10min (ß: 4.748; 95% CI: -9.172 to -0.324; p = 0.036). Similar results were seen with active standing test. The prevalence of autoantibodies did not differ between POTS and controls (29.4% vs 33.3%, p = 0.803). There was no association between GI symptoms and autoantibody status. Total IgE and tryptase were elevated in a few cases. This study confirms the high prevalence of GI symptoms in POTS. More pronounced tachycardia upon tilt table testing seems to be inversely correlated with severity of chronic GI symptoms in POTS. This study did not support the hypothesis that POTS is associated with immunological factors.

Gut microbiota composition is altered in postural orthostatic tachycardia syndrome and post-acute COVID-19 syndrome.

Postural Orthostatic Tachycardia Syndrome (POTS) reflects an autonomic dysfunction, which can occur as a complication to COVID-19. Our aim was to examine gastrointestinal symptoms and gut microbiota composition in patients with POTS and post-acute COVID-19 syndrome (PACS), compared with controls. POTS patients (n = 27), PACS patients (n = 32) and controls (n = 39) delivered fecal samples and completed a 4-day food diary, irritable bowel syndrome-severity scoring system (IBS-SSS), and visual analog scale for IBS (VAS-IBS). A total of 98 DNA aliquots were sequenced to an average depth of 28.3 million (M) read pairs (Illumina 2 × 150 PE) per sample. Diversity and taxonomic levels of the microbiome, as well as functional abundances were calculated for POTS and PACS groups, then compared with controls. There were several differences in taxonomic composition between POTS and controls, whereas only the abundance of Ascomycota and Firmicutes differed between PACS and controls. The clinical variables total IBS-SSS, fatigue, and bloating and flatulence significantly correlated with multiple individual taxa abundances, alpha diversity, and functional abundances. We conclude that POTS, and to a less extent PACS, are associated with differences in gut microbiota composition in diversity and at several taxonomic levels. Clinical symptoms are correlated with both alpha diversity and taxonomic and functional abundances.

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.

Inhomogeneity of ventilation in smokers and mild COPD assessed by the ratio of alveolar volume to total lung capacity.

BACKGROUND: Previous studies have shown that the ratio between alveolar volume (VA) and total lung capacity (TLC) reflects ventilation heterogeneity in subjects with chronic obstructive pulmonary disease (COPD). However, the ratio and its correlation to respiratory symptoms had to our knowledge not previously been investigated in subjects with mild chronic airflow obstruction or without airflow obstruction (normal ratio FEV1/VC). The purpose of this study was to investigate potential connection between VA/TLC and respiratory symptoms, smoking habits and lung function parameters in subjects with normal spirometry and with mild chronic airflow obstruction. METHODS: We examined 450 subjects (82 non-smokers with normal spirometry, 298 subjects who smoked or had smoked earlier but had a normal spirometry and 70 subjects with chronical airflow obstruction) with routine lung function tests and a questionnaire regarding respiratory symptoms. RESULTS: This study showed 31 out of 54 subjects with a low VA/TLC had a normal ratio FEV1/VC. Of these subjects, 58.1 % had respiratory symptoms, compared to the group with normal ratio for both VA/TLC and FEV1/VC where 35.8 % had respiratory symptoms (p-value 0.02). CONCLUSION: This study has shown that within the group of subjects with a normal ratio FEV1/VC, those with a decreased ratio VA/TLC had a higher prevalence of respiratory symptoms compared to subjects with a normal VA/TLC ratio. These findings indicate that including the ratio VA/TLC in the evaluation of a pulmonary function test assessment might increase the possibility to identify subjects with early or at risk of lung disease.

Tilt table testing, methodology and practical insights for the clinic.

Tilt table testing (TTT) has been used for decades to study short-term blood pressure (BP) and heart rate regulation during orthostatic challenges. TTT provokes vasovagal reflex in many syncope patients as a background of widespread use. Despite the availability of evidence-based practice syncope guidelines, proper application and interpretation of TTT in the day-to-day care of syncope patients remain challenging. In this review, we offer practical information on what is needed to perform TTT, how results should be interpreted including the Vasovagal Syncope International Study classification, why syncope induction on TTT is necessary in patients with unexplained syncope and on indications for TTT in syncope patient care. The minimum requirements to perform TTT are a tilt table with an appropriate tilt-down time, a continuous beat-to-beat BP monitor with at least three electrocardiogram leads and trained staff. We emphasize that TTT remains a valuable asset that adds to history building but cannot replace it, and highlight the importance of recognition when TTT is abnormal even without syncope. Acknowledgement by the patient/eyewitness of the reproducibility of the induced attack is mandatory in concluding a diagnosis. TTT may be indicated when the initial syncope evaluation does not yield a certain, highly likely, or possible diagnosis, but raises clinical suspicion of (1) reflex syncope, (2) orthostatic hypotension (OH), (3) postural orthostatic tachycardia syndrome or (4) psychogenic pseudosyncope. A therapeutic indication for TTT in the patient with a certain, highly likely or possible diagnosis of reflex syncope, may be to educate patients on prodromes. In patients with reflex syncope with OH TTT can be therapeutic to recognize hypotensive symptoms causing near-syncope to perform physical countermanoeuvres for syncope prevention (biofeedback). Detection of hypotensive susceptibility requiring therapy is of special value.

The relationships between the plasma metabolome and orthostatic blood pressure responses.

Whereas autonomic dysfunction and the metabolic syndrome are clinically associated, the relationships with the plasma metabolome is unknown. We explored the association between orthostatic blood pressure responses and 818 plasma metabolites in middle-aged subjects from the general population. We included 3803 out of 6251 subjects (mean age, 57 years; 52% women) from the Malmö sub-cohort of The Swedish CardioPulmonary bioImage Study with information on smoking habits, diabetes, antihypertensive drug treatment, anthropometrics, hemodynamic measurements and 818 plasma metabolites (mass-spectrometry). The associations between each metabolite and orthostatic systolic blood pressure responses were determined using multivariable linear regression analysis and p values were corrected using the Bonferroni method. Six amino acids, five vitamins, co-factors and carbohydrates, nine lipids and two xenobiotics were associated with orthostatic blood pressure after adjusting for age, gender and systolic blood pressure. After additional adjustments for BMI, diabetes, smoking and antihypertensive treatment, the association remained significant for six lipids, four amino acids and one xenobiotic. Twenty-two out of 818 plasma metabolites were associated with orthostatic blood pressure responses. Eleven metabolites, including lipids in the dihydrosphingomyelin and sphingosine pathways, were independently associated with orthostatic systolic blood pressure responses after additional adjustment for markers of cardio-metabolic disease.

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.

Evidence for Impaired Renin Activity in Postural Orthostatic Tachycardia Syndrome.

BACKGROUND: Postural orthostatic tachycardia syndrome (POTS) is a heterogeneous condition predominantly affecting autonomic control of the cardiovascular system. Its extensive symptom diversity implies multi-organ involvement that interacts in ways still requiring full exploration. Current understanding of POTS pathophysiology suggests alterations in the renin-angiotensin-aldosterone system as a possible contributing factor. Therefore, we investigated the relationship between the activity of the renin-angiotensin-aldosterone system and hemodynamic parameters in a cohort of POTS patients and controls recruited at a tertiary referral center. METHODS: The case-control study included 46 patients with POTS (27 ± 9 years), and 48 healthy controls (30 ± 9 years) without orthostatic intolerance. Plasma renin activity, expressed as angiotensin I generation, and plasma aldosterone were measured by enzyme-linked immunosorbent assay and were correlated with hemodynamic parameters obtained during active standing tests. RESULTS: Renin activity was significantly downregulated in POTS patients compared to healthy individuals (median, 3406 ng/mL vs. 9949 ng/mL, p < 0.001), whereas aldosterone concentration did not differ between POTS and healthy controls (median, 218 pmol/L vs. 218 pmol/L, p = 0.26). A significant inverse correlation between renin activity and supine and orthostatic blood pressure levels was observed in healthy individuals (p < 0.05 for all), but not in POTS patients. CONCLUSIONS: Renin activity, but not aldosterone concentration, is downregulated in patients with POTS. Moreover, renin activity in POTS is dissociated from supine and standing blood pressure levels in contrast to healthy individuals. These findings suggest impaired renin function in POTS, which may direct future therapeutic approaches.

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.

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.

Twenty-Four-Hour Ambulatory Blood Pressure Profile in Patients With Reflex Syncope and Matched Controls.

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 <90 to 100 mm Hg were analyzed. Variables associated with reflex syncope were investigated using multivariable logistic regression. Patients with reflex syncope displayed significantly lower 24-hour SBP (112.9±12.6 versus 119.3±11.5 mm Hg, P=0.002), higher 24-hour diastolic BP (85.2±9.6 versus 79.1±10.6 mm Hg, P<0.001), and markedly lower 24-hour PP (27.7±7.6 versus 40.3±9.0 mm Hg, P<0.001) compared with controls. Daytime SBP drops <90 mm Hg were more prevalent in patients with syncope (44% versus 17%, P<0.001). Daytime SBP drops <90 mm Hg, 24-hour PP <32 mm Hg, 24-hour SBP ≤110 mm Hg, and 24-hour diastolic BP ≥82 mm Hg were independently associated with reflex syncope, with 24-hour PP <32 mm Hg achieving the highest sensitivity (80%) and specificity (86%). Conclusions Patients with reflex syncope have lower 24-hour SBP but higher 24-hour diastolic BP and more frequent daytime SBP drops <90 mm Hg than individuals without syncope. Our results support the presence of lower SBP and PP in reflex syncope and suggest a role for ambulatory BP monitoring in the diagnostic work-up of this condition.

Subclinical atherosclerosis and risk factors in relation to autonomic indices in the general population.

OBJECTIVE: Orthostatic hypotension and resting heart rate (RHR) are associated with cardiovascular disease (CVD). However, it is unknown how these factors relate to subclinical CVD. We examined the relationship between orthostatic blood pressure (BP) response, RHR and cardiovascular risk factors, including coronary artery calcification score (CACS) and arterial stiffness, in the general population. METHODS: We included 5493 individuals (age 50-64 years; 46.6% men) from The Swedish CArdioPulmonary-bio-Image Study (SCAPIS). Anthropometric and haemodynamic data, biochemistry, CACS and carotid-femoral pulse wave velocity (PWV) were retrieved. Individuals were categorized into binary variables that manifest orthostatic hypotension and in quartiles of orthostatic BP responses and RHR, respectively. Differences across the various characteristics were tested using χ 2 for categorical variables and analysis of variance and Kruskal-Wallis test for continuous variables. RESULTS: The mean (SD) SBP and DBP decrease upon standing was -3.8 (10.2) and -9.5 (6.4) mmHg, respectively. Manifest orthostatic hypotension (1.7% of the population) associated with age ( P  = 0.021), systolic, diastolic and pulse pressure ( P  < 0.001), CACS (<0.001), PWV ( P  = 0.004), HbA1c ( P  < 0.001) and glucose levels ( P  = 0.035). Age ( P  < 0.001), CACS ( P  = 0.045) and PWV ( P  < 0.001) differed according to systolic orthostatic BP, with the highest values seen in those with highest and lowest systolic orthostatic BP-responses. RHR was associated with PWV ( P  < 0.001), SBP and DBP ( P  < 0.001) as well as anthropometric parameters ( P  < 0.001) but not CACS ( P  = 0.137). CONCLUSION: Subclinical abnormalities in cardiovascular autonomic function, such as impaired and exaggerated orthostatic BP response and increased resting heart rate, are associated with markers of increased cardiovascular risk in the general population.

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.

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.

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.

Plasma proteomic profiling in postural orthostatic tachycardia syndrome (POTS) reveals new disease pathways.

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 < 0.05. A total of 393 differential plasma proteins were identified. Label-free quantification of DIA-data identified 30 differentially expressed proteins in POTS compared with healthy controls. Pathway analysis identified the strongest network interactions particularly for proteins involved in thrombogenicity and enhanced platelet activity, but also inflammation, cardiac contractility and hypertrophy, and increased adrenergic activity. Our observations generated by the first use a label-free unbiased quantification reveal the proteomic footprint of POTS in terms of a hypercoagulable state, proinflammatory state, enhanced cardiac contractility and hypertrophy, skeletal muscle expression, and adrenergic activity. These findings support the hypothesis that POTS may be an autoimmune, inflammatory and hyperadrenergic disorder.

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.

The Influence of Age on Cerebral Tissue Oxygenation in Vasovagal Syncope and Orthostatic Hypotension.

Age-related physiological impairment increases susceptibility to syncope. We tested the hypotheses that cerebral oxygenation during orthostatic provocation, as well as the level at which syncope occurs, differs according to age. Non-invasive hemodynamic monitoring and cerebral oximetry were applied during a head-up tilt test in 139 patients with vasovagal syncope (mean (SD) 45, (17) years, 60%-female); 121 patients with orthostatic hypotension (61.4 (19.2) years, 49.6%-female); and 82 patients with a negative head-up tilt test (45 (18) years, 61%-female). Group differences in cerebral tissue oxygenation levels and systolic blood pressure were assessed in supine at 3 and 10 min of orthostatic provocation, 30 s before (i.e., presyncopal phase) and during syncope in age groups of <30, 30−60, and >60 years. During the head-up tilt test, cerebral tissue oxygenation at the presyncopal phase decreased with age, both in patients with vasovagal syncope (<30 years: 66.9 ± 6.2, 30−60: 64.5 ± 6.1, >60: 62.2 ± 5.8%; p = 0.009) and orthostatic hypotension (<30: 67.4 ± 4.4, 30−60: 61.6 ± 6.2, >60: 57.5 ± 3.9; p < 0.001). Mean systolic blood pressure at the presyncopal phase did not differ according to age. Cerebral oxygenation prior to syncope in older individuals with vasovagal syncope and orthostatic hypotension is lower compared with younger individuals independently of systolic blood pressure. This suggests that the level of cerebral oxygenation at which syncope is elected is lower in older individuals.