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Background Postural orthostatic tachycardia syndrome (POTS) is a common cardiovascular autonomic disorder characterized by excessive heart rate 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 Conclusions Symptom severity, as assessed by MAPS score, is 5-fold higher in POTS compared with healthy individuals. The new MAPS score can be useful as a semi-quantitative system to assess symptom burden, monitor disease progression and evaluate pre-test likelihood of disease.

Background Syncope is a common clinical problem with a sharp rise in the incidence after 70 years. In older patients, syncope is often a diagnostic challenge. It is unclear whether the age at which patients experience syncope for the first time impacts the results of syncope investigation. Purpose To study the influence of early-onset vs. mature-onset syncope on clinical characteristics and final head-up tilt (HUT) diagnosis in a large sample of unexplained syncope patients. Methods Consecutive patients (n=1928) with unexplained syncope after initial evaluation examined with a standard HUT protocol in a syncope unit were stratified into age groups below and above 60 years. Clinical characteristics and the final HUT diagnosis were analysed in relation to self-reported age at first syncope and age at investigation. The distribution of age at first syncope was bimodal with peaks at 15 and 70 years (Figure 1). In the present analysis, patients aged >60 years (n=836) with early-onset (60 years) syncope were compared. Results Vasovagal syncope (VVS) was more common in early-onset syncope, 39% vs 19% (p60 years.Complex syncope etiology (findings suggesting overlap between VVS, OH and/or CSS) was more common among patients with early-onset syncope, 37% vs 26% (p=0.023). No definite HUT-derived diagnosis was more common in mature-onset syncope, 23% vs 13% (p=0.023). Heart failure, 9% vs 2% (p=0.024) and atrial fibrillation, 20% vs 9% (p=0.013) were more common in mature-onset syncope. Prodromes were less common in mature-onset syncope, 26% vs 52% (p Conclusions Mature-onset syncope was more often associated with absence of prodromes, orthostatic hypotension, inconclusive HUT findings and presence of heart failure and atrial fibrillation suggesting cardiac syncope to be the likely cause. Early-onset syncope was associated with presence of prodromes, vasovagal reflex mechanism and complex syncope diagnosis. Lifelong and mature-onset unexplained syncope may have different pathophysiological mechanisms in older patients and aetiologies other than vasovagal syncope should be carefully considered in patients with first-ever syncope in later life. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Swedish heart and lung foundationCrafoord foundation

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): The Swedish Heart and Lung Foundation, The Swedish Heart and Lung Association, ALF funds, Skåne University Hospital Funds, The Crafoord Foundation. Background There is an increased susceptibility to syncope with aging attributed to age-related physiological impairments. Cerebral oximetry non-invasively measures cerebral tissue oxygenation (SctO2) and has been shown to be valuable in syncope evaluation. SctO2 has been found to decrease with aging but it is unknown whether the decrease in SctO2 is related to increased susceptibility to syncope during orthostatic provocation. By measuring SctO2 during head up tilt test (HUT) we can study age-related differences in SctO2 and their impact on developing reflex syncope. Purpose To investigate the effect of age on the cerebral tissue oxygenation threshold for syncope and presyncope among patients with vasovagal syncope. Methods Non-invasive haemodynamic monitoring and near-infrared spectroscopy (NIRS) were applied during head-up tilt (HUT) in 139 vasovagal syncope patients (mean [SD] 45[17] years, 60% female), and 82 control patients with a normal response to HUT (45[18] years, 61% female). Group differences in SctO2 and systolic blood pressure (SBP) during HUT in supine position, after 3 and 10 min of HUT, 30 seconds prior to syncope ("presyncopal phase") and during syncope in different age groups (60 years) were compared using one-way ANOVA and Tukey"s multiple comparison test. Associations between age and SctO2 were studied using linear regression models adjusted for sex and concurrent SBP. Results Lower SctO2 in supine position was associated with increasing age among controls (B=-0.085, p = 0.010) but not among VVS patients (B=-0.036, p = 0.114). No age-related differences in SctO2 were found after 3 and 10 minutes of HUT and during syncope. Mean SctO2 (%) during the presyncopal phase decreased over the advancing age groups (60: 62.2 ± 5.8; p = 0.009 for inter-group comparison). In contrast, mean SBP during the presyncopal phase did not differ by age groups (60: 77.6 ± 20.8 mmHg, p = 0.133). Age was associated with lower SctO2 during the presyncopal phase after adjusting for sex and SBP (B = 0.096, p = 0.001). Conclusion Older VVS patients have lower cerebral tissue oxygenation in the presyncopal phase compared with younger patients independently of systolic blood pressure. These results suggest either that with imminent reflex syncope cerebral tissue oxygenation diminishes more with advancing age or that cerebral deoxygenation is better tolerated by older reflex syncope patients. Abstract Figure.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): The study was funded by The Swedish Heart-Lung Foundation, The Greta and Johan Kock Foundation, and an Agreement for Medical Education and Research (ALF) grant by Swedish Research Council funding for clinical research in medicine. Background Fragility fractures are caused by low-energy insults such as falls from standing height or less and pose a growing health challenge as their incidence rises with increasing age. Impaired orthostatic blood pressure response and a number of cardiovascular biomarkers have been previously identified as risk factors for fractures. It is likely that severe episodes of syncope and orthostatic hypotension increase the risk of subsequent fragility fractures, however this relationship has not been thoroughly examined. Purpose To investigate the relationship of hospital admissions due to unexplained syncope and OH with incident fragility fractures in a middle-aged population. Methods We analysed a large population-based prospective cohort of 30,446 middle-aged individuals (age, 57.5 ± 7.6; men, 39.8%). We included patients hospitalised due to unexplained syncope and OH. Cox regression analysis adjusted for age, sex, prevalent fractures, body mass index (BMI) were applied to assess the impact of unexplained syncope/OH hospitalisations on subsequent incident fragility fractures. Prevalent fractures occurring before syncope/OH hospitalisation were excluded (n = 39) as well as cases with no follow-up time after the event of syncope/OH (n= 8). Results The mean follow-up from baseline to first incident fracture or end of follow-up was 17.8 + 6.5 years, and 8201 (27%) suffered incident fracture. The mean age of patients with unexplained syncope (n = 493) and OH patients (n = 406) at baseline was 61.5 ± 7.1 years (50.1%, male) and 62.6 ± 6.6 years (49.8% male), respectively. The mean time between baseline and first admission for syncope and OH was 12.3 ± 4.5 years, and the mean age at first hospitalisation was 74.4 ± 7.6 years. In the multivariable-adjusted Cox regression, the risk of subsequent incident fractures was increased among patients hospitalised due to unexplained syncope (HR: 1.20; 95% CI 1.03–1.40; p Conclusions Patients hospitalised due to unexplained syncope and OH demonstrate increased risk of subsequent fragility fractures. We suggest that patients who are hospitalised for unexplained syncope and OH should be clinically assessed for true syncope aetiology, systematically treated against fall risk, and evaluated for additional risk factors for fragility fractures. Abstract Figure 1. Kaplan-Meier curves

Introduction Endothelin 1 is a potent vasoconstrictor released from mainly vascular endothelial cells and to a lesser extent adipose, muscle and renal tissues. Its involvement in cardiovascular disease is well documented, with increasing ET-1 levels correlated to cardiovascular events. Less is however, known about its role in insulin resistance and type 2 diabetes. Purpose To test if ET-1 plasma levels predict the risk of developing type 2 diabetes independently of known risk factors. Method The Malmo Preventive project is a prospective single centre population-based study which recruited 33 346 inhabitants in Malmo, Sweden between 1974–1992. A follow up study was conducted between 2002 and 2006 on willing participants of which 18 240 accepted. Cardiovascular risk factors were documented along with blood plasma samples frozen to −80°C available for further analysis among approximately 5000 subjects. Record linkage with national and regional diagnoses and drug prescription registries was performed to identify all new onset type 2 diabetes cases in this cohort during a mean follow-up period of nine years. C-terminal proendothelin-1 (proET-1), a stable precursor to ET-1, levels were analysed by a double sandwich immunoassay (ThermoFisher) among 4536 individuals with complete data and without diabetes at baseline. The subjects were divided into quartiles based on proET-1 levels and hazard ratios (HR) for new onset diabetes were calculated by Cox Proportional Hazards Model adjusting for age, gender, smoking, hypertension, body mass index (BMI) and fasting glucose. Results There was a positive relationship between increasing proET-1 quartiles and age (p Conclusion Raised proET-1 levels among non-diabetic individuals independently predict risk of new onset type 2 diabetes. The predictive value is driven by the part of the population without prediabetes, suggesting that proET-1 might identify individuals at “hidden high risk”, i.e. indivduals who do not get medical attention by having prediabetes. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Knut & Alice Wallenberg Foundation Clinical Scholars and Göran Gustafsson Foundation

Background Postural orthostatic tachycardia syndrome (POTS) is characterised by an excessive heart rate increase upon standing and orthostatic intolerance. Previous studies indicate autoimmune involvement mediated via G-protein coupled receptors (GPCRs) as a possible aetiology. Purpose To test if serum from POTS patients and controls activates selected GPCRs and if the activation associates with the severity of symptoms. Methods A total of 34 POTS patients (age 28.9 [9.9] years; 29 women) and a population-based control group of 25 healthy subjects (age 30.7 [8.6] years; 21 women) were included. The subjects performed an active standing test and completed the orthostatic hypotension questionnaire (OHQ) including ten items related to orthostatic intolerance. The OHQ composite score was calculated (range 0–10). Sera were analysed by a FRET-based reporter system (Tango GeneBLAzer, Thermo Fischer) based on a beta-arrestin-linked transcription factor driving transgenic betalactamase transcription. HEK293M-cells over-expressing one of the GPCRs, adrenergic alpha-1 (ADRA1), adrenergic beta-2 (ADRB2), muscarinic type-2 (CHRM2) and opioid-receptor-like 1 (OPRL1) receptor were plated in 96-well optical plates and allowed to re-attach during 48 hrs. The cells were treated with 10% sera diluted in RPMI for 5 hours, followed by addition of the FRET-substrate, incubation for 60 min and quantification analysis in a CLARIOStar multi-purpose plate reader. Quantification of the activation of the GPCRs was log-transformed and related to the OHQ composite and individual scores in age-adjusted linear regression models. OHQ scores were compared according to the median of sera activation, using independent samples t-test. Results Serum ADRA1 activation associated with the OHQ composite score (beta 0.77 OHQ points per SD of activity; p=0.009), whereas there were no significant associations among controls (p=0.953). The association between ADRA1 and total OHQ was significant also after adjusting for heart rate and systolic blood pressure at 3 min (p=0.024). The OHQ composite score was higher in with above median serum ADRA1 activation (Figure 1). ADRA1 activation associated with a higher score for vision problems (p The activity of ARB2, CHRM2 and OPRL1 did not associate with OHQ composite score in neither POTS patients nor controls. Figure 1. OHQ according to ADRA1 activation Conclusions Activating serum proteins for the adrenergic alpha-1 receptor are associated with the severity of orthostatic symptoms in POTS patients, partly independent of the orthostatic hemodynamic response. Serum activity against alpha1 receptors is related particularly to symptoms of disturbed vision and symptoms during walking or prolonged standing. Serum activity against the adrenergic alpha 1 receptor may be a one factor underlying the orthostatic symptoms in POTS. Acknowledgement/Funding The Swedish Heart-Lung Foundation, The Swedish Heart and Lung Association, Solidex, ALF funds, Crafoord Foundation, Ernhold Lundströms Foundation.

Background Studies evaluating the relationship between platelet indices and cardiovascular outcome yielded conflicting results. In particular, the evidence from large, population-based, prospective studies with extended follow-up duration is scarce. Purpose We investigated the incidence of major adverse events in relation to baseline values of platelet count, mean platelet volume (MPV) and platelet distribution width (PDW) in the prospective cohort of the Malmö Diet and Cancer Study. Methods A total of 30,314 middle-aged individuals (mean age 57±8 years; 40% men) were overall included and followed up for a median of 16 years (in total, 468,490 person-years). The following outcome measures were considered: all-cause death, myocardial infarction (MI) and ischemic stroke. Results There was no relationship between increase in MPV or PDW values and adverse events during follow-up. In particular, the incidence of all-cause death, MI and stroke in patients in the 4thquartile of MPV was 19.8% (vs. 20.7% in the 1stquartile; p=0.08), 8.5% (vs. 8.2%; p=0.78) and 7.9% (vs. 7.1%; p=0.09), respectively. The rates of all-cause death, MI and stroke in patients in the 4thquartile of PDW were 20.1% (vs. 20.7% in the 1stquartile; p=0.16), 8.7% (vs. 8.1%; p=0.30) and 8.1% (vs. 7.2%; p=0.09), respectively. There was a significant rise in mortality by platelet count increase (log-rank p264 x 109/L) showed a significantly higher incidence of all-cause death (HR 1.17, 95% CI 1.07–1.28; p=0.001), MI (HR 1.24, 95% CI 1.08–1.43; p=0.003) and stroke (HR 1.20, 95% CI 1.04–1.39; p=0.014) vs the 1stquartile. The higher mortality in the 4thquartile of platelet count was independent of the history of previous stroke, was significant in patients without prior MI (HR 1.18, 95% CI 1.08–1.29; p Conclusions In this population-based, prospective, cohort study there was no difference in the incidence of adverse events across various strata of baseline platelet morphology. However, patients with highest platelet count at baseline showed a significantly higher risk of all-cause death, MI and stroke. Whether or not these individuals should be targeted by more aggressive primary prophylactic measures including antiplatelet treatment, remains to be proven.

Background: Postural Orthostatic Tachycardia Syndrome (POTS) is a cardiovascular dysautonomic condition affecting predominantly young women. POTS is defined as the presence of chronic symptoms of orthostatic intolerance associated with an increased heart rate ≥30 bpm, or heart rate exceeding 120 bpm, within 10 minutes of standing or head-up tilt in the absence of orthostatic hypotension. The etiology is still unknown though autoimmunity has been hypothesized to play an important role. Purpose: To investigate whether an inflammatory biomarker signature is associated with POTS. Methods: We performed a cross-sectional study enrolling 475 patients aged between 15 and 55 years with unexplained syncope or symptoms of orthostatic intolerance. Of these 118 have been diagnosed with POTS and 357 controls demonstrated normal hemodynamic response during passive phase of HUT i.e. no orthostatic hypotension or POTS. A total of 318 patients provided supine blood plasma samples that were analyzed through the antibody-based Proximity Extension Assay technique, simultaneously measuring 53 inflammatory and cancer-related human protein biomarkers. After excluding 5 biomarkers with low call rate