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1.	Brignole, Michele, et al. (författare) Low-blood pressure phenotype underpins the tendency to reflex syncope 2021 Ingår i: Journal of Hypertension. - 1473-5598. ; 39:7, s. 1319-1325 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: We hypothesized that cardiovascular physiology differs in reflex syncope patients compared with the general population, predisposing such individuals to vasovagal reflex.METHODS: In this multicohort cross-sectional study, we compared aggregate data of resting SBP, DBP, pulse pressure (PP) and heart rate (HR), collected from six community-based cohort studies (64 968 observations) with those from six databases of reflex syncope patients (6516 observations), subdivided by age decades and sex.RESULTS: Overall, in male individuals with reflex syncope, SBP (-3.4 mmHg) and PP (-9.2 mmHg) were lower and DBP (+2.8 mmHg) and HR (+5.1 bpm) were higher than in the general population; the difference in SBP was higher at ages above 60 years. In female individuals, PP (-6.0 mmHg) was lower and DBP (+4.7 mmHg) and HR (+4.5 bpm) were higher than in the general population; differences in SBP were less pronounced, becoming evident only above 60 years. Compared with male individuals, SBP in female individuals exhibited slower increase until age 40 years, and then demonstrated steeper increase that continued throughout remaining life.CONCLUSION: The patients prone to reflex syncope demonstrate a different resting cardiovascular haemodynamic profile as compared with a general population, characterized by lower SBP and PP, reflecting reduced venous return and lower stroke volume, and a higher HR and DBP, suggesting the activation of compensatory mechanisms. Our data contribute to a better understanding why some individuals with similar demographic characteristics develop reflex syncope and others do not.VIDEO ABSTRACT: http://links.lww.com/HJH/B580.
2.	Casselbrant, Andreas, et al. (författare) Common physiologic and proteomic biomarkers in pulmonary and coronary artery disease 2022 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 17:3 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE: Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) are leading causes of global morbidity and mortality. There is a well-known comorbidity between COPD and CAD, which is only partly explained by smoking and other known common risk factors. In order to better understand the relationship between COPD and CAD, we analyzed myocardial perfusion, pulmonary function and novel cardiovascular biomarkers in patients with symptoms suggesting myocardial ischemia.METHODS: A total of 396 subjects from the Swedish Biomarkers and Genetics CardioPulmonary Physiology Study (BiG CaPPS) were included, all of whom had been referred to myocardial perfusion imaging due to suspected myocardial ischemia. Subjects performed myocardial perfusion imaging (MPI), pulmonary function tests (PFT) and analysis of 92 proteomic biomarkers, previously associated with cardiovascular disease. Linear regression was used to study the relationship between MPI and PFT results and proteomic biomarkers.RESULTS: Subjects with CAD (n = 159) had lower diffusing capacity (DLCO) than patients without CAD (6.64 versus 7.17 mmol/(minkPal); p = 0.004) in models adjusted for common covariates such as smoking, but also diabetes and brain natriuretic peptide (BNP). The association remained significant after additional adjustment for forced expiratory volume in one second (FEV1) (p = 0.009). Subjects with CAD, compared with subjects without CAD, had higher total airway resistance (0.37 vs 0.36 kPa/(l/s); p = 0.036). Among 92 protein biomarkers, nine were associated with a combined diagnosis of CAD and airflow obstruction: VSIG2, KIM1, FGF-23, REN, XCL1, GIF, ADM, TRAIL-R2 and PRSS8.SIGNIFICANCE: Diffusing capacity for carbon monoxide is decreased in patients with CAD, independently of decreased FEV1, diabetes, and elevated BNP. Several cardiovascular biomarkers are associated with co-existent CAD and airflow obstruction, but none with airflow obstruction only. The current findings indicate that the interaction between CAD and lung function is complex, including mechanisms beyond the known association between CAD and reduced ventilation.
3.	Engström, Gunnar, et al. (författare) Cardiovagal Function Measured by the Deep Breathing Test : Relationships With Coronary Atherosclerosis 2022 Ingår i: Journal of the American Heart Association. - 2047-9980. ; 11:7 Tidskriftsartikel (refereegranskat)abstract Background The cardiovagal function can be assessed by quantification of respiratory sinus arrhythmia (RSA) during a deep breathing test. However, population studies of RSA and coronary atherosclerosis are lacking. This population-based study examined the relationship between RSA during deep breathing and coronary atherosclerosis, assessed by coronary artery calcium score (CACS). Methods and Results SCAPIS (Swedish Cardiopulmonary Bioimage Study) randomly invited men and women aged 50 to 64 years from the general population. CACS was obtained from computed tomography scanning, and deep breathing tests were performed in 4654 individuals. Expiration-inspiration differences (E-Is) of heart rates were calculated, and reduced RSA was defined as E-I in the lowest decile of the population. The relationship between reduced RSA and CACS (CACS≥100 or CACS≥300) was calculated using multivariable-adjusted logistic regression. The proportion of CACS≥100 was 24% in the lowest decile of E-I and 12% in individuals with E-I above the lowest decile (P<0.001), and the proportion of CACS≥300 was 12% and 4.8%, respectively (P<0.001). The adjusted odds ratio (OR) for CACS≥100 was 1.42 (95% CI, 1.10-1.84) and the adjusted OR for CACS≥300 was 1.62 (95% CI, 1.15-2.28), when comparing the lowest E-I decile with deciles 2 to 10. Adjusted ORs per 1 SD lower E-I were 1.17 (P=0.001) for CACS≥100 and 1.28 (P=0.001) for CACS≥300. Conclusions Low RSA during deep breathing is associated with increased coronary atherosclerosis as assessed by CACS, independently of traditional cardiovascular risk factors. Cardiovagal dysfunction could be a prevalent and modifiable risk factor for coronary atherosclerosis in the general population.
4.	Engström, Gunnar, et al. (författare) Pulmonary function and atherosclerosis in the general population : causal associations and clinical implications 2024 Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 39:1, s. 35-49 Tidskriftsartikel (refereegranskat)abstract 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.
5.	Fedorowski, Artur, et al. (författare) Do we need to evaluate diastolic blood pressure in patients with suspected orthostatic hypotension? 2017 Ingår i: Clinical Autonomic Research. - : Springer Science and Business Media LLC. - 0959-9851 .- 1619-1560. ; 27:3, s. 167-173 Tidskriftsartikel (refereegranskat)abstract 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.
6.	Fedorowski, Artur, et al. (författare) Orthostatic Hypotension : Management of a Complex, But Common, Medical Problem 2022 Ingår i: Circulation: Arrhythmia and Electrophysiology. - 1941-3084. ; 15:3 Tidskriftsartikel (refereegranskat)abstract Orthostatic hypotension (OH), a common, often overlooked, disorder with many causes, is associated with debilitating symptoms, falls, syncope, cognitive impairment, and risk of death. Chronic OH, a cardinal sign of autonomic dysfunction, increases with advancing age and is commonly associated with neurodegenerative and autoimmune diseases, diabetes, hypertension, heart failure, and kidney failure. Management typically involves a multidisciplinary, patient-centered, approach to arrive at an appropriate underlying diagnosis that is causing OH, treating accompanying conditions, and providing individually tailored pharmacological and nonpharmacological treatment. We (1) propose a novel streamlined pathophysiological classification of OH; (2) review the relationship between the cardiovascular disease continuum and OH; (3) discuss OH-mediated end-organ damage; (4) provide diagnostic and therapeutic algorithms to guide clinical decision making and patient care; (5) identify current gaps in knowledge and try to define future research directions. Using a case-based learning approach, specific clinical scenarios are presented highlighting various presentations of OH to provide a practical guide to evaluate and manage patients who have OH.
7.	Fedorowski, Artur, et al. (författare) Other syndromes of orthostatic intolerance : Delayed orthostatic hypotension, postprandial hypotension, postural orthostatic tachycardia syndrome, and reflex syncope 2021 Ingår i: Orthostatic Hypotension in Older Adults. - Cham : Springer International Publishing. - 9783030624934 - 9783030624927 ; , s. 121-143 Bokkapitel (refereegranskat)abstract Apart from classical orthostatic hypotension, the gravitational force may strongly contribute to other forms of orthostatic intolerance, delayed and postprandial OH, postural orthostatic tachycardia syndrome (POTS), and reflex syncope. In delayed OH, the significant blood pressure drop occurs first after 3-min period of orthostasis, whereas in postprandial OH, the symptoms appear first approximately 15-30 min after the meal. POTS is rarely seen in older adults and presents as abnormal sinus tachycardia on standing with symptoms of orthostatic intolerance, dizziness, fatigue, and cognitive impairment. Reflex syncope may manifest as orthostatic vasovagal reflex, situational syncope, or carotid sinus hypersensitivity, which becomes a clinical syndrome when associated with history of unexplained syncope and positive provocation test, carotid sinus massage. Older patients with a history of orthostatic intolerance, unexplained syncope and fall trauma, and negative result of active standing test should be further evaluated using cardiovascular autonomic tests such as head-up tilt testing, Valsalva maneuver, and carotid sinus massage.
8.	Fedorowski, Artur, et al. (författare) Underlying hemodynamic differences are associated with responses to tilt testing 2021 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11, s. 1-6 Tidskriftsartikel (refereegranskat)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 < 0.001), DBP (76.2 ± 11.5 vs 77.7 ± 11.7 mmHg, p < 0.001) and HR (68.0 ± 11.5 vs 70.5 ± 12.5 bpm, p < 0.001). In multivariable analyses, tilt-test positivity was independently associated with younger age (Odds ratio (OR) per 10 years:1.04; 95% confidence interval (CI), 1.01–1.07, p = 0.014), SBP ≤ 128 mmHg (OR:1.27; 95%CI, 1.11–1.44, p < 0.001), HR ≤ 69 bpm (OR:1.32; 95%CI, 1.17–1.50, p < 0.001), and absence of hypertension (OR:1.58; 95%CI, 1.38–1.81, p < 0.001). In conclusion, among patients with suspected reflex syncope, younger age, lower blood pressure and lower heart rate are associated with positive tilt-test result.
9.	Firth, Karl, et al. (författare) Psychological Stress in Postural Orthostatic Tachycardia Syndrome : A Pilot Pre‑COVID Survey 2023 Ingår i: Heart and Mind. - 2468-6476. ; 7:4, s. 246-254 Tidskriftsartikel (refereegranskat)abstract 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.
10.	Hall, Juliette, et al. (författare) Detection of G Protein-Coupled Receptor Autoantibodies in Postural Orthostatic Tachycardia Syndrome Using Standard Methodology 2022 Ingår i: Circulation. - 1524-4539. ; 146:8, s. 613-622 Tidskriftsartikel (refereegranskat)abstract 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; mean age, 29 years) and 81 healthy controls (84% female; mean 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.CONCLUSION: 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.
11.	Halldén, Sara, et al. (författare) Gene variance in the nicotinic receptor cluster (CHRNA5-CHRNA3-CHRNB4) predicts death from cardiopulmonary disease and cancer in smokers. 2016 Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 279:4, s. 388-398 Tidskriftsartikel (refereegranskat)abstract Genetic variation in the cluster on chromosome 15, encoding the nicotinic acetylcholine receptor subunits (CHRNA5-CHRNA3-CHRNB4), has shown strong associations with tobacco consumption and an additional risk increase in smoking-related diseases such as chronic obstructive pulmonary disease (COPD), peripheral artery disease and lung cancer.
12.	Hamrefors, Viktor, et al. (författare) A gene score of nine LDL and HDL regulating genes is associated with fluvastatin induced cholesterol changes in women. 2010 Ingår i: Journal of Lipid Research. - 1539-7262. ; 51:3, s. 625-634 Tidskriftsartikel (refereegranskat)abstract While conventional pharmacogenetic studies have considered single gene effects, we tested if a genetic score of nine LDL- and HDL-associated SNPs, previously shown to predict cardiovascular disease, is related to fluvastatin induced lipid change. In patients with asymptomatic plaque in the right carotid artery, thus candidates for statin therapy, we related Score LDL (APOB(rs693), APOE(rs4420638), HMGCR(rs12654264), LDLR(rs1529729) and PCSK9(rs11591147) and score HDL (ABCA1(rs3890182), CETP(rs1800775), LIPC(rs1800588) and LPL(rs328) ) as well as the combined score LDL+HDL to fluvastatin induced LDL reduction (+/- metoprolol) (n=395) and HDL increase (n=187) following one year fluvastatin treatment. In women, increasing number of unfavorable alleles (i.e. alleles conferring higher LDL and lower HDL) of score LDL+HDL (P=0,037) and of score LDL (P=0,023) was associated with less pronounced fluvastatin induced LDL reduction. Furthermore, in women both score LDL+HDL (P=0,001) and score HDL (P=0,022) was directly correlated with more pronounced fluvastatin induced HDL increase, explaining 5,9-11,6 % of the variance in treatment response in women. There were no such associations in men. This suggests that a gene score based on variation in nine different LDL and HDL associated genes is of importance for the magnitude of fluvastatin HDL increase in women with asymptomatic plaque in the carotid artery.
13.	Hamrefors, Viktor, et al. (författare) A myocardial infarction genetic risk score is associated with markers of carotid atherosclerosis. 2012 Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 271, s. 271-281 Tidskriftsartikel (refereegranskat)abstract Objective: To assess whether a genetic risk score that was previously shown to be associated with myocardial infarction and coronary artery disease is also associated with markers of carotid atherosclerosis. Design: A total of 4022 middle-aged subjects from the general Swedish population were genotyped and individually assigned a genetic risk score based on 13 single-nucleotide polymorphisms (SNPs), previously associated with myocardial infarction and coronary artery disease. The genetic score (Score-MI) was then related to carotid bulb intima-media thickness (IMT), common carotid artery IMT and to the occurrence of carotid plaques in the study population. Results: Score-MI was associated with IMT of the bulb (P<0.001) and the common carotid artery (P<0.001) in unadjusted analyses, and with IMT of the bulb after adjustment for cardiovascular risk factors (P=0.003). The effect size of Score-MI on IMT of the bulb was similar to that of LDL cholesterol. After adjustment for cardiovascular risk factors, Score-MI was also associated with the occurrence of carotid plaques (odds ratio per quintile of Score-MI=1.11; 95% confidence interval 1.04-1.18; P=0.001). In addition to SNPs with known effects on LDL levels, Score-MI showed nominal associations with increasing systolic blood pressure and decreasing C-reactive protein levels. Conclusions: This genetic risk score was independently associated with carotid bulb IMT and carotid plaques, providing evidence of an association with early markers of atherosclerosis. This might imply that the genetic myocardial infarction risk conferred by the score is related to early atherosclerosis and that the risk score may identify at an early stage candidates at risk of developing intermediate phenotypes of atherosclerosis. Further studies should test whether assessing the genetic score could be valuable for early treatment decisions in these subjects.
14.	Hamrefors, Viktor (författare) Cardiovascular Risk Genes in Prevention and Treatment Response 2014 Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract GENERAL AIM: To investigate how common single-nucleotide-polymorphisms (SNPs) that associate with cardiovascular disease (CVD) could be used in prevention and treatment of CVD. SUBJECTS: Subjects from the population-based Malmö-Diet-and-Cancer-(MDC)-Study (n=30447) and hypertensives from the Nordic-Diltiazem-(NORDIL)-Study (n=10881). METHODS AND RESULTS: A nine-SNP-lipid-genetic-risk-score was related to fluvastatin treatment-response in 395 MDC subjects with asymptomatic carotid atherosclerosis. In women, a higher score (conferring unfavorable baseline-lipid-levels) correlated with HDL-increase (P=0.001), explaining 11.6-12.9% of the variance in HDL-change. A 13-SNP-myocardial-infarction-(MI)-genetic-risk-score was related to carotid atherosclerosis-markers in 4022 MDC-subjects. The MI-gene-score associated with carotid-bulb-intima-media-thickness (IMT) (beta=0.038 standard deviations of IMT per MI-gene-score-quintile; P-trend=0.005) and plaque (odds-ratio per MI-gene-score-quintile=1.11; 95% confidence interval (CI):1.04-1.18; P=0.001) in multivariable models. It was tested if eight blood-pressure-associated SNPs affected antihypertensive treatment-response in 3863 Swedish hypertensives from NORDIL. No robust associations were identified. Finally, interactions between life-style-factors and the CVD-SNP rs4977574 on chromosome 9p21 were evaluated in 24944 MDC-subjects during 15 years follow-up. There were interactions between rs4977574 and smoking on incident CAD (P=0.035) and CVD-mortality (P=0.012). The risk conferred by rs4977574 in never-smokers (n=9642; Hazard-ratio(HR) per risk-allele(CAD)=1.26; 95%CI:1.13-1.40; HR per risk-allele(CVD-mortality)=1.40; 95%CI:1.20-1.63) was attenuated in smokers (n=7000; HR per risk-allele(CAD)=1.05; 95%CI:0.95-1.16; HR per risk-allele(CVD-mortality)=1.08; 95%CI:0.94-1.23). CONCLUSIONS: CVD-genetics identifies subjects with markers of subclinical atherosclerosis, suggesting that early atherosclerosis-prevention may be targeted to such individuals. Smoking attenuates the relative influence of the thus far strongest identified polygenic CVD-risk-locus, implying potential utility of common CVD-genetics in mainly conventional lower-risk subjects. Lipid-polymorphisms may predict statin-induced HDL-increase in women, but eight blood-pressure-SNPs did not affect antihypertensive treatment-response.
15.	Hamrefors, Viktor (författare) Common genetic risk factors for coronary artery disease: new opportunities for prevention? 2015 Ingår i: Clinical Physiology and Functional Imaging. - : Wiley. - 1475-0961. Tidskriftsartikel (refereegranskat)abstract Atherosclerotic cardiovascular disease (CVD) is a leading cause of mortality and morbidity worldwide, with coronary artery disease (CAD) being the single leading cause of death. Better control of risk factors, enhanced diagnostic techniques and improved medical therapies have all substantially decreased the mortality of CAD in developed countries. However, CAD and other forms of atherosclerotic CVD are projected to remain the leading cause of death by 2030 and we face a number of challenges if the outcomes of CAD are to be further improved. The fact that a substantial fraction of high-risk subjects do not reach treatment goals for important risk factors is one of these challenges. At the same time, there is also a non-negotiable fraction of 'concealed' high-risk subjects who are not detected by current risk algorithms and diagnostic modalities. In recent years, we have started to rapidly increase our knowledge of the framework of common genetics underlying CAD and atherosclerotic CVD in the population. In conjunction with modern diagnostic and therapeutic options, this new genetic knowledge may provide a valuable tool for further improvements in prevention. This review summarizes the recent findings from the search for common genetic risk factors for CAD. Furthermore, the author discusses how such recent findings could potentially be used in a number of clinical applications within CAD prevention, including in clinical risk stratification, in prediction of drug treatment response and in the search for targets for novel preventive therapies.
16.	Hamrefors, Viktor, et al. (författare) Gut microbiota composition is altered in postural orthostatic tachycardia syndrome and post-acute COVID-19 syndrome 2024 Ingår i: Scientific Reports. - 2045-2322. ; 14:1 Tidskriftsartikel (refereegranskat)abstract 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.
17.	Hamrefors, Viktor, et al. (författare) Low Adrenomedullin and Endothelin-1 Predict Cardioinhibitory Response During Vasovagal Reflex in Adults Over 40 Years of Age 2017 Ingår i: Circulation: Arrhythmia and Electrophysiology. - 1941-3084. ; 10:10 Tidskriftsartikel (refereegranskat)
18.	Hamrefors, Viktor, et al. (författare) Orthostatic Hypotension and Elevated Resting Heart Rate Predict Low-Energy Fractures in the Population : The Malmö Preventive Project 2016 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 11:4, s. 0154249-0154249 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Autonomic disorders of the cardiovascular system, such as orthostatic hypotension and elevated resting heart rate, predict mortality and cardiovascular events in the population. Low-energy-fractures constitute a substantial clinical problem that may represent an additional risk related to such autonomic dysfunction.AIMS: To test the association between orthostatic hypotension, resting heart rate and incidence of low-energy-fractures in the general population.METHODS AND RESULTS: Using multivariable-adjusted Cox regression models we investigated the association between orthostatic blood pressure response, resting heart rate and first incident low-energy-fracture in a population-based, middle-aged cohort of 33 000 individuals over 25 years follow-up. The median follow-up time from baseline to first incident fracture among the subjects that experienced a low energy fracture was 15.0 years. A 10 mmHg orthostatic decrease in systolic blood pressure at baseline was associated with 5% increased risk of low-energy-fractures (95% confidence interval 1.01-1.10) during follow-up, whereas the resting heart rate predicted low-energy-fractures with an effect size of 8% increased risk per 10 beats-per-minute (1.05-1.12), independently of the orthostatic response. Subjects with a resting heart rate exceeding 68 beats-per-minute had 18% (1.10-1.26) increased risk of low-energy-fractures during follow-up compared with subjects with a resting heart rate below 68 beats-per-minute. When combining the orthostatic response and resting heart rate, there was a 30% risk increase (1.08-1.57) of low-energy-fractures between the extremes, i.e. between subjects in the fourth compared with the first quartiles of both resting heart rate and systolic blood pressure-decrease.CONCLUSION: Orthostatic blood pressure decline and elevated resting heart rate independently predict low-energy fractures in a middle-aged population. These two measures of subclinical cardiovascular dysautonomia may herald increased risks many years in advance, even if symptoms may not be detectable. Although the effect sizes are moderate, the easily accessible clinical parameters of orthostatic blood pressure response and resting heart rate deserve consideration as new risk predictors to yield more accurate decisions on primary prevention of low-energy fractures.
19.	Hamrefors, Viktor, et al. (författare) Pharmacogenetic implications for eight common blood pressure-associated single-nucleotide polymorphisms. 2012 Ingår i: Journal of Hypertension. - 1473-5598. ; 30:6, s. 1151-1160 Tidskriftsartikel (refereegranskat)abstract OBJECTIVE:: We aimed to test whether eight common recently identified single-nucleotide polymorphisms (SNPs), strongly associated with blood pressure (BP) in the population, also have impact on the degree of BP reduction by antihypertensive agents with different mechanisms. METHODS:: In 3863 Swedish hypertensive patients, we related number of unfavorable alleles of each SNP (i.e. alleles associated with higher baseline BP) to the magnitude of BP reduction during 6 months of monotherapy with either a beta-blocker, a thiazide diuretic or diltiazem. RESULTS:: For six SNPs (rs16998073, rs1378942, rs3184504, rs1530440, rs16948048, rs17367504) no pharmacogenetic interactions were suggested, whereas two SNPs showed nominal evidence of association with treatment response: PLCD3-rs12946454 associated with more SBP (beta = 1.53 mmHg per unfavorable allele; P = 0.010) and DBP (beta = 0.73 mmHg per unfavorable allele; P = 0.014) reduction in patients treated with diltiazem, in contrast to those treated with beta-blockers or diuretics wherein no treatment response association was found. CYP17A1-rs11191548 associated with less DBP reduction (beta = -1.26 mmHg per unfavorable allele; P = 0.018) in patients treated with beta-blockers or diuretics, whereas there was no treatment response association in diltiazem-treated patients. However, if accounting for multiple testing, the significant associations for rs12946454 and rs11191548 were attenuated. CONCLUSION:: For a majority of these, eight recently identified BP-associated SNPs, there are probably no important pharmacogenetic interactions for BP reduction with use of beta-blockers, diuretics or diltiazem. Whether the nominally significant associations for rs12946454 and rs11191548 are true signals and could be of possible clinical relevance for deciding treatment of polygenic essential hypertension should be further tested.
20.	Hamrefors, Viktor, et al. (författare) Procoagulatory changes induced by head-up tilt test in patients with syncope : Observational study 2017 Ingår i: Thrombosis Journal. - : Springer Science and Business Media LLC. - 1477-9560. ; 15:1 Tidskriftsartikel (refereegranskat)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±21years; 46% men) were analysed. Blood samples were collected during supine rest and after 3min 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 3min 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±19.6s; p<0.001, and 30.8±3.7 vs. 32.1±3.8s; 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.
21.	Hamrefors, Viktor, et al. (författare) Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21. 2014 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:1 Tidskriftsartikel (refereegranskat)abstract Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors.
22.	Hamrefors, Viktor, et al. (författare) Susceptibility to diarrhea is related to hemodynamic markers of sympathetic activation in the general population 2019 Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 1502-7708 .- 0036-5521. ; 54:12, s. 1426-1432 Tidskriftsartikel (refereegranskat)abstract 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.
23.	Hamrefors, Viktor, et al. (författare) Syndromes of orthostatic intolerance and syncope in young adults 2017 Ingår i: Open Heart. - : BMJ. - 2053-3624. ; 4:1 Tidskriftsartikel (refereegranskat)abstract Objective To explore the clinical and neuroendocrine characteristics of syndromes of orthostatic intolerance and syncope in young adults. Methods Two hundred and thirty-six patients aged 18-40 years with orthostatic intolerance and/or syncope were examined by head-up tilt test (HUT). Plasma levels of epinephrine, norepinephrine, renin, C-terminal-pro-arginine-vasopressin (CT-proAVP), C-terminal-endothelin-1 and mid-regional-fragment of pro-atrial-natriuretic-peptide (MR-proANP) were analysed. Patients' history, haemodynamic parameters and plasma biomarkers were related to main diagnoses such as vasovagal syncope (VVS), postural tachycardia syndrome (POTS), orthostatic hypotension (OH) and negative HUT. Results No self-reported symptom of orthostatic intolerance was highly specific for any diagnosis. Patients with VVS (n=103) were more likely to be men (p=0.011) and had lower resting heart rate (HR; 66±11) compared with POTS (73±11; n=72; p=0.001) and negative HUT (74±11; n=39; p=0.001). Patients with POTS demonstrated greater rise in norepinephrine (p=0.008) and CT-proAVP (p=0.033) on standing compared with negative HUT, and lower resting MR-proANP compared with VVS (p=0.04) and OH (p=0.03). Patients with OH had lower resting renin (p=0.03). Subjects with a resting HR <70 and MR-proANP >45 pm/L had an OR of 3.99 (95 % CI 1.68 to 9.52; p=0.002) for VVS compared with subjects without any of these criteria; if male sex was added the OR was 21.8 (95% CI 3.99 to 119; p<0.001). Conclusions Syndromes of orthostatic intolerance and syncope share many characteristics in younger persons. However, patients with VVS are more likely to be men, have lower HR and higher MR-proANP at rest compared with POTS, which might be taken into account at an early stage of evaluation.
24.	Hindy, George, et al. (författare) The chromosome 9p21 variant interacts with vegetable and wine intake to influence the risk of cardiovascular disease : a population based cohort study 2014 Ingår i: BMC Medical Genetics. - : Springer Science and Business Media LLC. - 1471-2350. ; 15 Tidskriftsartikel (refereegranskat)abstract BACKGROUND: Chromosome 9p21 variants are associated with cardiovascular disease (CVD) but not with any of its known risk markers. However, recent studies have suggested that the risk associated with 9p21 variation is modified by a prudent dietary pattern and smoking. We tested if the increased risk of CVD by the 9p21 single nucleotide polymorphism rs4977574 is modified by intakes of vegetables, fruits, alcohol, or wine, and if rs4977574 interacts with environmental factors on known CVD risk markers.METHODS: Multivariable Cox regression analyses were performed in 23,949 individuals from the population-based prospective Malmö Diet and Cancer Study (MDCS), of whom 3,164 developed CVD during 15 years of follow-up. The rs4977574 variant (major allele: A; minor allele: G) was genotyped using TaqMan® Assay Design probes. Dietary data were collected at baseline using a modified diet history method. Cross-sectional analyses were performed in 4,828 MDCS participants with fasting blood levels of circulating risk factors measured at baseline.RESULTS: Each rs4977574 G allele was associated with a 16% increased incidence of CVD (95% confidence interval (CI), 1.10-1.22). Higher vegetable intake (hazard ratio (HR), 0.95 [CI: 0.91-0.996]), wine intake (HR, 0.91 [CI: 0.86-0.96]), and total alcohol consumption (HR, 0.92 [CI: 0.86-0.98]) were associated with lower CVD incidence. The increased CVD incidence by the G allele was restricted to individuals with medium or high vegetable intake (Pinteraction = 0.043), and to non- and low consumers of wine (Pinteraction = 0.029). Although rs4977574 did not associate with any known risk markers, stratification by vegetable intake and smoking suggested an interaction with rs4977574 on glycated hemoglobin and high-density lipoprotein cholesterol (Pinteraction = 0.015 and 0.049, respectively).CONCLUSIONS: Our results indicate that rs4977574 interacts with vegetable and wine intake to affect the incidence of CVD, and suggest that an interaction may exist between environmental risk factors and rs4977574 on known risk markers of CVD.
25.	Härstedt, Maria, et al. (författare) Cardiovascular biomarkers and risk of low-energy fractures among middle-aged men and women—A population-based study 2018 Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 13:9 Tidskriftsartikel (refereegranskat)abstract 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-agedmen, 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 MRpro- ADM may improve prediction of bone fractures.
26.	Johansson, Madeleine, et al. (författare) Arterial stiffness is associated with impaired orthostatic diastolic blood pressure reaction and increased central blood pressure: A prospective population‑based study 2021 Ingår i: Artery Research. - : Springer Science and Business Media LLC. - 1872-9312 .- 1876-4401. ; 27, s. 5-6 Konferensbidrag (refereegranskat)abstract Background: Arterial stiffness is independently associated with orthostatic hypotension. We aimed to investigate the relationship between orthostatic blood pressure reaction and arterial stiffness as well as central hemodynamics in younger subjects from the general population.Methods: We analyzed a large prospective cohort study of 3756 individuals from the general population (mean age 41.9±14.5 years, 52.1% women) in the Malmö Offspring Study (MOS), Sweden. Assessment of arterial stiffness and central hemodynamics was made by measurement of carotid-femoral pulse wave velocity (c-f PWV) (Sphygmocor® AtCor, Australia) and pulse wave analysis (PWA) at thearteria radialis in relation to an orthostatic blood pressure reaction after 5 min standing using linear regression models.Results: We found a significant association between orthostatic diastolic blood pressure reaction and c-f PWV levels, that is, increased c-f PWV as observed in arterial stiffness, was associated with lower diastolic blood pressure increase upon standing after adjusting for age and sex (p=0.016). Moreover, we observed that increased systolic blood pressure on standing was associated with a higher central blood pressure in the ascending aorta after adjusting for age, sex, hemoglobin A1C (HbA1c) levels, and current smoking (p=0.006).Conclusions: Our preliminary findings suggest that orthostatic hypotension, which is commonly observed in older individuals, is associated with markers of arterial stiffness (vascular ageing) and hemodynamic changes also in a younger population.
27.	Johansson, Madeleine, et al. (författare) Association of incident fragility fractures in patients hospitalised due to unexplained syncope and orthostatic hypotension 2021 Ingår i: Europace. - : Oxford University Press (OUP). - 1532-2092. ; 23:Supplement 3 Konferensbidrag (refereegranskat)abstract 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.PurposeTo investigate the relationship of hospital admissions due to unexplained syncope and OH with incident fragility fractures in a middle-aged population.MethodsWe 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).ResultsThe 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 < 0.02) and OH (HR: 1.40; 95% CI 1.20–1.64; p < 0.001), respectively (Kaplan-Meier curves; Figure 1).ConclusionsPatients 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.
28.	Johansson, Madeleine, et al. (författare) BLOOD PRESSURE ADAPTATIONS AND ARTERIAL STIFFNESS IN THE GENERAL POPULATION 2022 Ingår i: Journal of Hypertension. - : Ovid Technologies (Wolters Kluwer Health). - 1473-5598 .- 0263-6352. ; , s. 107-107 Konferensbidrag (refereegranskat)abstract Objective: Arterial stiffness is independently associated with orthostatic hypotension (OH) in older individuals. The relationship between orthostatic blood pressure (BP) and arterial stiffness has not been thoroughly examined in the younger population. To investigate the relationship between orthostatic BP adaptations, central aortic hemodynamics, and arterial stiffness in the general population of young and mid-aged adults.Design and method: A cross-sectional, observational, population-based study of 4223 individuals. We assessed arterial stiffness and central hemodynamics by carotid-femoral pulse wave velocity (c-f PWV) and pulse wave analysis (PWA) at the arteria radialis in relation to an orthostatic BP adaptation after 3 min standing.Results: The mean age of the population was 41.9 ± 14.5 years and 52.1% were women. We found that higher standing BP was associated with lower arterial stiffness after full adjustment in both men (unstandardized beta coefficient () -0.09, p = 0.02) and women (-0.08, p = 0.03). An increased diastolic BP on standing was inversely correlated with PWV and central aortic hemodynamics in both younger (PWV -0.01, p = 0.02) and older individuals (-0.02, p = 0.001). The lowest arterial stiffness was observed in the lowest and highest quartiles of standing systolic BP differences (p < 0.001), while a gradual reduction in arterial stiffness was observed across increasing quartiles of standing diastolic BP difference for both PWV and measurements of central aortic hemodynamics (p < 0.001).Conclusions: The co-existence of orthostatic hypotension, increased blood pressure variability, and vascular stiffness represents a hemodynamic ageing syndrome with important prognostic implications for public health. Our findings demonstrate that impaired hemodynamic response to orthostatic challenges, traditionally observed in older individuals, are independently and inversely associated with markers of arterial stiffness (vascular ageing) and hemodynamic changes also in a younger population. Further studies are required to assess the relationship between impaired blood pressure adaptations on standing in younger subjects and risk of future incident cardiovascular events.
29.	Johansson, Madeleine, et al. (författare) Cardiovascular biomarkers predict fragility fractures in older adults 2019 Ingår i: Heart. - : BMJ. - 1355-6037 .- 1468-201X. ; 105:6, s. 449-454 Tidskriftsartikel (refereegranskat)abstract Objective To assess the role of four biomarkers of neuroendocrine activation and endothelial dysfunction in the longitudinal prediction of fragility fractures. Methods We analysed a population-based prospective cohort of 5415 community-dwelling individuals (mean age, 68.9±6.2 years) enrolled in the Malmö Preventive Project followed during 8.1±2.9 years, and investigated the longitudinal association between C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), the mid-regional fragments of pro-adrenomedullin (MR-proADM) and pro-atrial natriuretic peptide (MR-proANP), and incident vertebral, pelvic and extremity fractures. Results Overall, 1030 (19.0%) individuals suffered vertebral, pelvic or extremity fracture. They were older (70.7±5.8 vs 68.4±6.3 years), more likely women (46.9% vs 26.3%), had lower body mass index and diastolic blood pressure, were more often on antihypertensive treatment (44.1% vs 38.4%) and had more frequently history of fracture (16.3% vs 8.1%). Higher levels of MR-proADM (adjusted HR (aHR) per 1 SD: 1.51, 95% CI 1.01 to 2.28, p<0.001) and MR-proANP (aHR: 1.23, 95% CI 1.05 to 1.45, p<0.001) were independently associated with increased risk of any fracture. The fracture risk increased linearly across MR-proANP quartiles. Individuals who were in the top quartile of all four biomarkers had a significant higher risk of fracture at any site (aHR: 2.32, 95% CI 1.86 to 2.91), vertebral fracture (aHR: 3.16, 95% CI 1.97 to 5.07) and femoral fracture (aHR: 2.35, 95% CI 1.64 to 3.36). Conclusions Elevated levels of MR-proADM and MR-proANP independently predict fragility fractures in older adults. In subjects with top quartile levels of all four biomarkers there is a twofold to threefold increase in risk of vertebral and femoral fractures.
30.	Johansson, Madeleine, et al. (författare) Circulating levels of growth hormone in postural orthostatic tachycardia syndrome 2021 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11 Tidskriftsartikel (refereegranskat)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.
31.	Johansson, Madeleine, et al. (författare) Downregulation of growth hormone in postural orthostatic tachycardia syndrome: insights from the SYSTEMA cohort 2020 Ingår i: European Heart Journal, Supplement. - : Oxford University Press (OUP). - 1520-765X .- 0195-668X .- 1522-9645. ; 41:Issue Supplement_2 Konferensbidrag (refereegranskat)abstract Background Postural orthostatic tachycardia syndrome (POTS) is a variant of cardiovascular autonomic disorder occurring predominantly in young women. POTS is characterized by an excessive heart rate increase when assuming upright posture accompanied by symptoms of orthostatic intolerance. The pathophysiology of POTS has not been fully established and is believed to be multifactorial. Purpose We aimed to investigate the alterations in circulating growth hormone level in POTS. Methods We conducted an age-matched case-control study enrolling 42 patients with POTS (age 31±9 years; 36 women) verified by positive head-up tilt testing and cardiovascular autonomic tests, and 46 controls (32±9 years; 35 women) with negative active standing test and no history of syncope, orthostatic intolerance and endocrine disease. We measured plasma levels of growth hormone using a high-sensitivity chemiluminescence immunoassay in relation to presence of POTS diagnosis. All study participants completed the validated Orthostatic Hypotension Questionnaire (OHQ), consisting of two components: the symptoms assessment scale (OHSA) and daily activity scale (OHDAS) to evaluate the burden of symptoms. We applied standard statistical tests for group differences. Growth hormone values were log-transformed and standardized before the group comparison. Results POTS patients had significantly lower plasma levels of growth hormone (ng/mL) (median=0.53, IQR, 0.10–2.83 vs. median=2.33, IQR, 0.26–7.2, p=0.04) than controls. Levels of growth hormone were reversely related to OHDAS (p=0.049) among POTS patients. Supine heart rate was significantly higher in POTS patients (69.0±11.1 beats/min vs. 63.3±10.8 beats/min, p=0.02), as well as diastolic blood pressure (72.9±9.1 mmHg vs. 69.0±8.5 mmHg, p=0.04). We observed no significant difference in supine systolic blood pressure (116.6±13.3 mmHg vs. 115.2±10.0 mmHg, p=0.60). POTS patients had a significantly higher composite OHQ score than controls (60.0±18.6 vs. 4.2±7.5, p<0.001), as well as OHSA (36.2±10.0 vs. 3.6±6.4, p<0.001) and OHDAS (23.8±9.7 vs. 0.6±1.3, p<0.001). Conclusion(s) Our study shows that patients with POTS have significantly reduced plasma levels of circulating growth hormone. Lower growth hormone levels among POTS patients are associated with increased impairment of daily life activities. Further studies are necessary to confirm our findings in the independent populations and explain the mechanisms behind this alteration.
32.	Johansson, Madeleine, et al. (författare) Orthostatic blood pressure adaptations, aortic stiffness, and central hemodynamics in the general population: insights from the Malmö Offspring Study (MOS) 2023 Ingår i: Clinical Autonomic Research. - : Springer Science and Business Media LLC. - 1619-1560 .- 0959-9851. ; 33:1, s. 29-40 Tidskriftsartikel (refereegranskat)abstract PurposeArterial 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.MethodsWe 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.ResultsThe 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.ConclusionsOur 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.
33.	Johansson, Madeleine, et al. (författare) Plasma proteomic profiling in postural orthostatic tachycardia syndrome (POTS) reveals new disease pathways 2022 Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12 Tidskriftsartikel (refereegranskat)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 < 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.
34.	Jordan, Jens, et al. (författare) Orthostatic Hypertension : Critical Appraisal of an Overlooked Condition 2020 Ingår i: Hypertension. - 1524-4563. ; 75:5, s. 1151-1158 Tidskriftsartikel (refereegranskat)abstract Orthostatic hypertension, which appears to be mediated through excess neurohumoral activation while standing, is a common blood pressure trait among patients with and without arterial hypertension. However, lack of consensus regarding the definition of orthostatic hypertension makes it difficult to assess the true prevalence of this condition. Orthostatic hypertension appears to predict the risk for progression to arterial hypertension in younger and risk of cardiovascular morbidity and mortality in older persons. Yet, the risk may differ between populations. Whether orthostatic hypertension indicates a generally increased risk of death, constitutes an intermediate variable in the causal pathway of cardiovascular risk factors, a simple measure of disease severity, or an independently acting mechanism is not known. Since both orthostatic hypotension and orthostatic hypertension herald increased risk of cardiovascular disease, it appears reasonable to screen the patients for abnormal orthostatic blood pressure responses using simple orthostatic testing. However, how presence of orthostatic hypertension may affect clinical management decisions such as the choice of antihypertensive drugs is currently difficult to ascertain. Clearly, this issue deserves more attention.
35.	Jönsson, Andreas, et al. (författare) High prevalence of undiagnosed COPD among patients evaluated for suspected myocardial ischaemia 2018 Ingår i: Open Heart. - : BMJ. - 2053-3624. ; 5:2 Tidskriftsartikel (refereegranskat)abstract Objective: Chronic obstructive pulmonary disease (COPD) and coronary artery disease (CAD) are leading causes of global morbidity and mortality. Despite the well-known comorbidity between COPD and CAD, the presence of COPD may be overlooked in patients undergoing coronary evaluation. We aimed to assess the prevalence of undiagnosed COPD among outpatients evaluated due to suspected myocardial ischemia.Methods: Among 500 outpatients who were referred to myocardial perfusion imaging due to suspected stable myocardial ischaemia, 433 patients performed spirometry. Of these, a total of 400 subjects (age 66 years; 45% women) had no previous COPD diagnosis and were included in the current study. We compared the prevalence of previously undiagnosed COPD according to spirometry criteria from The Global Initiative for Chronic Obstructive Lung Disease (GOLD) or lower limit of normal (LLN) and reversible myocardial ischaemia according to symptoms and clinical factors.Results: A total of 134 (GOLD criteria; 33.5 %) or 46 patients (LLN criteria; 11.5%) had previously undiagnosed COPD, whereas 55 patients (13.8 %) had reversible myocardial ischaemia. The presenting symptoms (chest discomfort, dyspnoea) did not differ between COPD, myocardial ischaemia and normal findings. Except for smoking, no clinical factors were consistently associated with previously undiagnosed COPD.Conclusions: Among middle-aged outpatients evaluated due to suspected myocardial ischaemia, previously undiagnosed COPD is at least as common as reversible myocardial ischaemia and the presenting symptoms do not differentiate between these entities. Patients going through a coronary ischaemia evaluation should be additionally tested for COPD, especially if there is a positive history of smoking.
36.	Kharraziha, Isabella, et al. (författare) Cerebral Oximetry in Syncope and Syndromes of Orthostatic Intolerance 2019 Ingår i: Frontiers in Cardiovascular Medicine. - : Frontiers Media SA. - 2297-055X. ; 6 Forskningsöversikt (refereegranskat)abstract 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.
37.	Kharraziha, Isabella, et al. (författare) Effect of aging on cerebral tissue oxygenation in relation to reflex syncope 2021 Ingår i: Europace. - : Oxford University Press (OUP). - 1532-2092. ; 23:Supplement 3 Konferensbidrag (refereegranskat)abstract Background: There is an increased susceptibility to syncope with aging attributed to age-related physiological impairments. Cerebral oxime-try non-invasively measures cerebral tissue oxygenation (SctO2) and has been shown to be valuable in syncope evaluation. SctO2 has beenfound to decrease with aging but it is unknown whether the decrease in SctO2 is related to increased susceptibility to syncope during ortho-static provocation. By measuring SctO2 during head up tilt test (HUT) we can study age-related differences in SctO2 and their impact ondeveloping reflex syncope.Purpose: To investigate the effect of age on the cerebral tissue oxygenation threshold for syncope and presyncope among patients withvasovagal syncope.Methods: Non-invasive haemodynamic monitoring and near-infrared spectroscopy (NIRS) were applied during head-up tilt (HUT) in 139vasovagal 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, 30seconds prior to syncope ("presyncopal phase") and during syncope in different age groups (<30, 30-60 and >60 years) were comparedusing one-way ANOVA and Tukey"s multiple comparison test. Associations between age and SctO2 were studied using linear regressionmodels 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 pa-tients (B=-0.036, p = 0.114). No age-related differences in SctO2 were found after 3 and 10 minutes of HUT and during syncope. MeanSctO2 (%) during the presyncopal phase decreased over the advancing age groups (<30: 66.9 ± 6.2, 30-60: 64.5 ± 6.1, >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 (<30: 85.6 ± 21.8, 30-60:77.6 ± 19.7, >60: 77.6 ± 20.8 mmHg, p = 0.133). Age was associated with lower SctO2 during the presyncopal phase after adjusting for sexand SBP (B = 0.096, p = 0.001).Conclusion: Older VVS patients have lower cerebral tissue oxygenation in the presyncopal phase compared with younger patients inde-pendently of systolic blood pressure. These results suggest either that with imminent reflex syncope cerebral tissue oxygenation diminishesmore with advancing age or that cerebral deoxygenation is better tolerated by older reflex syncope patients.
38.	Kharraziha, Isabella, et al. (författare) Impaired cerebral oxygenation in heart failure patients at rest and during head-up tilt testing 2021 Ingår i: ESC Heart Failure. - : Wiley. - 2055-5822. ; 8:1, s. 586-594 Tidskriftsartikel (refereegranskat)abstract AIMS: Heart failure (HF) confers potentially negative effects on the brain and autonomic nervous system. The measurement cerebral tissue oxygen saturation (SctO2 ) may aid in understanding such effects. We aimed to investigate if compensated HF affects SctO2 at rest and during orthostatic challenge.METHODS AND RESULTS: Non-invasive haemodynamic monitoring and near-infrared spectroscopy were applied during head-up tilt (HUT) in 61 HF patients [mean (SD) 71 (11) years, 82% male, New York Heart Association (NYHA) class I-III] and 60 controls [60 (12) years, 42% male). Group differences in continuous variables were compared using Student's t-test. Associations between HF and SctO2 were studied using multivariable linear regression models adjusted for age, sex, diabetes, smoking, systolic blood pressure (SBP), and heart rate in supine position and after 10 min of HUT. Mean SctO2 was lower in HF patients compared with controls both in the supine position (67 vs. 71%; P < 0.001) and after 10 min of HUT (64 vs. 69%; P < 0.001). The HUT-induced SctO2 decrease was greater in HF patients compared with controls (P = 0.026). SBP did not change in neither HF patients nor controls during HUT, whereas diastolic blood pressure and heart rate increased in both groups. HF was associated with lower SctO2 in supine (B = -2.5%, P = 0.023) and after 10 min of HUT (B = -2.6%, P = 0.007) after multivariable adjustments.CONCLUSIONS: Cerebral tissue oxygenation is lower in HF patients both at rest and during orthostasis compared with subjects without HF. Future studies should test if the lower cerebral oxygenation associates with negative prognosis and with impaired cognitive function.
39.	Kharraziha, Isabella, et al. (författare) Monitoring of cerebral oximetry in patients with postural orthostatic tachycardia syndrome 2019 Ingår i: Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology. - : Oxford University Press (OUP). - 1532-2092. ; 21:10, s. 1575-1583 Tidskriftsartikel (refereegranskat)abstract 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.
40.	Kharraziha, Isabella, et al. (författare) Serum Activity Against G Protein-Coupled Receptors and Severity of Orthostatic Symptoms in Postural Orthostatic Tachycardia Syndrome 2020 Ingår i: Journal of the American Heart Association. - 2047-9980. ; 9:15 Tidskriftsartikel (refereegranskat)abstract 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<0.01 for all). The area under the curve was 0.88 (0.80-0.97, P<0.001) combining all 4 receptors. Adrenergic α1 receptor activation associated with OHQ composite score (β=0.77 OHQ points per SD of activity, P=0.009) and with reduced tolerability for prolonged standing (P=0.037) and walking for short (P=0.042) or long (P=0.001) periods. All 4 receptors were associated with vision problems (P<0.05 for all). Conclusions Our results indicate the presence of circulating proteins activating adrenergic, muscarinic, and nociceptin receptors in patients with POTS. Serum-mediated activation of these receptors has high predictive value for POTS. Activation of adrenergic α1 receptor is associated with orthostatic symptoms severity in patients with POTS.
41.	Kharraziha, Isabella, et al. (författare) The Influence of Age on Cerebral Tissue Oxygenation in Vasovagal Syncope and Orthostatic Hypotension 2022 Ingår i: Journal of Clinical Medicine. - : MDPI AG. - 2077-0383. ; 11:15, s. 1-12 Tidskriftsartikel (refereegranskat)abstract 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.
42.	Malinovschi, Andrei, 1978-, et al. (författare) Consequences of Using Post- or Prebronchodilator Reference Values in Interpreting Spirometry 2023 Ingår i: American Journal of Respiratory and Critical Care Medicine. - : American Thoracic Society. - 1073-449X .- 1535-4970. ; 208:4, s. 461-471 Tidskriftsartikel (refereegranskat)abstract RATIONALE: Post-bronchodilator (BD) spirometry is used for diagnosis of chronic obstructive pulmonary disease (COPD). However, pre-BD 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 post-BD reference values generated within the Swedish CArdioPulmonary bioImage Study (SCAPIS) when interpreting post-BD spirometry in a general population.METHODS: SCAPIS reference values for post-BD and pre-BD 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 post-BD reference values, with respiratory burden in the SCAPIS general population (28,851 individuals).MEASUREMENTS AND MAIN RESULTS: Bronchodilation resulted in higher predicted median and lower limit of normal (LLN) for FEV1/FVC ratio. The prevalence of post-BD FEV1/FVC < pre-bronchodilator LLN was 4.8% and that of post-BD FEV1/FVC < post-bronchodilator LLN was 9.9% for the general population. An additional 5.1% was identified as having an abnormal post-BD FEV1/FVC ratio and this group had more respiratory symptoms, emphysema (13.5% vs. 4.1%, p<0.001) and self-reported physician-diagnosed COPD (2.8% vs. 0.5%, p<0.001) than subjects with post-BD FEV1/FVC ratio > LLN for both pre- and post-bronchodilation).CONCLUSIONS: Pre- and post-bronchodilator spirometry reference values differ with regard to FEV1/FVC ratio. Use of post-bronchodilator reference values doubled the population prevalence of airflow obstruction; this was related to a higher respiratory burden. Using post-bronchodilator reference values when interpreting post-bronchodilator spirometry might enable identification of individuals with mild disease and be clinically relevant.
43.	Medic Spahic, Jasmina, et al. (författare) Evidence for Impaired Renin Activity in Postural Orthostatic Tachycardia Syndrome 2023 Ingår i: Journal of Clinical Medicine. - 2077-0383. ; 12:14 Tidskriftsartikel (refereegranskat)abstract 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.
44.	Medic Spahic, Jasmina, et al. (författare) Malmö POTS symptom score : Assessing symptom burden in postural orthostatic tachycardia syndrome 2022 Ingår i: European Heart Journal, Supplement. - : Oxford University Press (OUP). - 1520-765X .- 1554-2815. ; 24:Supplement K Konferensbidrag (refereegranskat)abstract BackgroundPostural 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.MethodsWe 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.ResultsPOTS patients showed significantly higher total MAPS score (78±20 vs. 14±12, pConclusionsSymptom 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.
45.	Medic Spahic, Jasmina, et al. (författare) Proconvertase furin is down regulated in postural orthostatic tachycardia syndrome 2019 Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 13 Tidskriftsartikel (refereegranskat)abstract 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.
46.	Medic Spahic, Jasmina, et al. (författare) Proteomic analysis reveals sex-specific biomarker signature in postural orthostatic tachycardia syndrome 2020 Ingår i: BMC Cardiovascular Disorders. - : Springer Science and Business Media LLC. - 1471-2261. ; 20 Tidskriftsartikel (refereegranskat)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 < 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.
47.	Memarian, Ensieh, et al. (författare) Associations between physical activity and autonomic function during deep breathing test : the Swedish CArdioPulmonary bioImage Study (SCAPIS). 2023 Ingår i: Clinical Autonomic Research. - : Springer. - 0959-9851 .- 1619-1560. ; 33:4, s. 411-420 Tidskriftsartikel (refereegranskat)abstract 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.
48.	Moberg, Louise, et al. (författare) Early menopause and weight loss are significant factors associated with risk of future fracture in middle-aged women 2022 Ingår i: BMC Musculoskeletal Disorders. - : Springer Science and Business Media LLC. - 1471-2474. ; 23:1 Tidskriftsartikel (refereegranskat)abstract 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.
49.	Nawaz, Sara, et al. (författare) Novel inflammatory biomarkers in postural orthostatic tachycardia syndrome 2023 Ingår i: Europace. - 1532-2092 .- 1099-5129. ; , s. 345-345 Konferensbidrag (refereegranskat)abstract IntroductionPostural Orthostatic Tachycardia Syndrome (POTS) is a disorder characterized by excessive orthostatic tachycardia and orthostatic intolerance. While traditional inflammatory biomarkers tend to be normal, a subclinical inflammatory process may be present in POTS.PurposeWe aimed to analyse novel inflammatory biomarkers in POTS patients: Growth Differentiation Factor 15 (GDF15), Neutrophil Gelatinase Associated Lipocalin (NGAL), Intercellular Adhesion Molecule 1 (ICAM-1), Tumour Necrosis Factor Receptor 1 (TNFR1) and Tumour Necrosis Factor Receptor 2 (TNFR2) and compared them to healthy controls. These inflammatory biomarkers have been shown to be independent predictors of major adverse cardiovascular events in other populations.MethodsAn age- and sex-matched case-control study included 65 patients verified to have POTS by positive head-up tilt-testing and cardiovascular autonomic tests, and 65 healthy controls (mean age: 31.1 vs 31.5 years, 84% females) with negative active standing tests and no history of syncope, orthostatic intolerance, or endocrine disease. High-sensitivity chemiluminescence sandwich immunoassay was used to measure plasma levels of inflammatory biomarkers in a blinded fashion. Descriptive statistics compared groups and a univariate ANOVA was employed. Biomarker values were log-transformed. A score incorporating all biomarkers was generated to see if the totality of biomarkers discriminated POTS patients from controls.ResultsBaseline characteristics are displayed in Table 1. Mean levels of GDF15 (p=0.01), NGAL (p=0.003), ICAM-1 (p=0.04) and TNFR1 (p=0.03) were significantly higher in POTS vs controls, whereas TNFR2 (p=0.04) was significantly lower in POTS (p=0.04). The product of four upregulated biomarkers divided by TNFR2 produced a receiver operator curve (ROC) with an area under the curve (AUC) of 0.703 (pConclusionPOTS patients had increased GDF15, NGAL, TNFR1 and ICAM-1 levels and reduced TNFR2 levels suggesting underlying, yet undefined, subclinical inflammatory processes involving neutrophil and endothelial activation.
50.	Ovenholm, Hanna, et al. (författare) Inhomogeneity of ventilation in smokers and mild COPD assessed by the ratio of alveolar volume to total lung capacity 2024 Ingår i: Respiratory Medicine. - : Elsevier. - 0954-6111 .- 1532-3064. ; 222 Tidskriftsartikel (refereegranskat)abstract 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.

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