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Objective: To assess the efficacy of inhaled ciclesonide in reducing the duration of oxygen therapy (an indicator of time to clinical improvement) among adults hospitalised with COVID-19. Design: Multicentre, randomised, controlled, open-label trial .Setting: 9 hospitals (3 academic hospitals and 6 non-academic hospitals) in Sweden between 1 June 2020 and 17 May 2021. Participants: Adults hospitalised with COVID-19 and receiving oxygen therapy. Intervention: Inhaled ciclesonide 320 mu g two times a day for 14 days versus standard care. Main outcome measures: Primary outcome was duration of oxygen therapy, an indicator of time to clinical improvement. Key secondary outcome was a composite of invasive mechanical ventilation/death. Results: Data from 98 participants were analysed (48 receiving ciclesonide and 50 receiving standard care; median (IQR) age, 59.5 (49-67) years; 67 (68%) men). Median (IQR) duration of oxygen therapy was 5.5 (3-9) days in the ciclesonide group and 4 (2-7) days in the standard care group (HR for termination of oxygen therapy 0.73 (95% CI 0.47 to 1.11), with the upper 95% CI being compatible with a 10% relative reduction in oxygen therapy duration, corresponding to a < 1 day absolute reduction in a post-hoc calculation). Three participants in each group died/received invasive mechanical ventilation (HR 0.90 (95% CI 0.15 to 5.32)). The trial was discontinued early due to slow enrolment. Conclusions: In patients hospitalised with COVID-19 receiving oxygen therapy, this trial ruled out, with 0.95 confidence, a treatment effect of ciclesonide corresponding to more than a 1 day reduction in duration of oxygen therapy. Ciclesonide is unlikely to improve this outcome meaningfully.

Objectives: Aortic stenosis (AS) is the most prevalent valvular heart disease among adults. The adipocyte-derived hormones, leptin and adiponectin, have profound metabolic actions. We examined whether these adipokines are independently associated with future aortic valve replacement (AVR). Design: In this longitudinal case-control study, we identified 336 cases who had undergone AVR due to AS, and who had previously participated in population-based health surveys. Two referents were matched to each case and leptin and adiponectin concentrations were analysed from stored baseline survey samples. Uni- and multivariable logistic regression analyses were used to estimate the risk of future AVR. An additional cohort was identified for validation including 106 cases with AVR and 212 matched referents. Results: Median age (interquartile range (IQR)) in years at survey was 59.9 (10.4) and at surgery 68.3 (12.7), and 48% were women. An elevated concentration of leptin was not associated with future AVR (odds ratio [95% confidence interval]) (1.10 [0.92–1.32]), although leptin was associated with a higher risk in patients with coronary artery disease (CAD) having more than 5 years between survey and AVR (1.41 [1.08–1.84]). Adiponectin was not associated with higher risk for future AVR (0.95 [0.82–1.11]), although after stratification for age, higher levels were associated with reduced risk for AVR in persons aged ≥60 years at surgery (0.79 [0.64–0.98]). In the validation study, leptin was associated with future AVR whereas adiponectin was not. None of the associations remained significant after adjustment for body mass index (BMI). Conclusions: The adipokine leptin may promote the development of AS.

OBJECTIVES: Surgery of ascending aortic aneurysms is performed prophylactically or acute. The expected survival after surgery is uncertain. The goal of this study was to compare mortality in people with aortic surgery with matched controls. METHODS: All patients undergoing ascending aortic surgery at Umeå University Hospital from 1988 to 2012, who previously participated in 1 of 3 population-based health surveys, were matched to 2 randomly selected controls from the same health survey and followed until death or until censoring on 24 August 2017, whichever came first. Mortality was calculated using the Kaplan-Meier method and the log-rank test. Cox regression analyses were made for all-cause mortality, adjusted for traditional cardiovascular risk factors. Deaths during the first 90 days after surgery and at >90 days postoperatively were studied separately. RESULTS: The median follow-up time was 9.2 years. A total of 61 of 189 patients and 51 of 370 controls died [hazard ratio (HR) 2.77, 95% confidence interval (CI) 1.91-4.01]. Mortality was increased during the first 90 days post-surgery (HR 43.4, 95% CI 5.83-323), as well as after the first 90 days (HR 1.90, 95% CI 1.25-2.88) and after acute surgery (HR 6.05, 95% CI 2.92-12.56) as well as after elective surgery (HR 2.10, 95% CI 1.35-3.27). Among 57 surgical patients with information about cause of death, 23 (40%) died of aortic disease. CONCLUSIONS: During follow-up, more patients died than matched controls. Findings were consistent when adjusting for traditional cardiovascular risk factors and across subgroups. Both short-term and long-term postoperative deaths were increased as well.

BACKGROUND: Early detection of coronary atherosclerosis using coronary computed tomography angiography (CCTA), in addition to coronary artery calcification (CAC) scoring, may help inform prevention strategies. We used CCTA to determine the prevalence, severity, and characteristics of coronary atherosclerosis and its association with CAC scores in a general population. METHODS: We recruited 30 154 randomly invited individuals age 50 to 64 years to SCAPIS (the Swedish Cardiopulmonary Bioimage Study). The study includes individuals without known coronary heart disease (ie, no previous myocardial infarctions or cardiac procedures) and with high-quality results from CCTA and CAC imaging performed using dedicated dual-source CT scanners. Noncontrast images were scored for CAC. CCTA images were visually read and scored for coronary atherosclerosis per segment (defined as no atherosclerosis, 1% to 49% stenosis, or ≥50% stenosis). External validity of prevalence estimates was evaluated using inverse probability for participation weighting and Swedish register data. RESULTS: In total, 25 182 individuals without known coronary heart disease were included (50.6% women). Any CCTA-detected atherosclerosis was found in 42.1%; any significant stenosis (≥50%) in 5.2%; left main, proximal left anterior descending artery, or 3-vessel disease in 1.9%; and any noncalcified plaques in 8.3% of this population. Onset of atherosclerosis was delayed on average by 10 years in women. Atherosclerosis was more prevalent in older individuals and predominantly found in the proximal left anterior descending artery. Prevalence of CCTA-detected atherosclerosis increased with increasing CAC scores. Among those with a CAC score >400, all had atherosclerosis and 45.7% had significant stenosis. In those with 0 CAC, 5.5% had atherosclerosis and 0.4% had significant stenosis. In participants with 0 CAC and intermediate 10-year risk of atherosclerotic cardiovascular disease according to the pooled cohort

Importance: Aortic stenosis (AS) has no approved medical treatment. Identifying etiological pathways for AS could identify pharmacological targets. Objective: To identify novel genetic loci and pathways associated with AS. Design, Setting, and Participants: This genome-wide association study used a case-control design to evaluate 44 703 participants (3469 cases of AS) of self-reported European ancestry from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort (from January 1, 1996, to December 31, 2015). Replication was performed in 7 other cohorts totaling 256 926 participants (5926 cases of AS), with additional analyses performed in 6942 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Follow-up biomarker analyses with aortic valve calcium (AVC) were also performed. Data were analyzed from May 1, 2017, to December 5, 2019. Exposures: Genetic variants (615 643 variants) and polyunsaturated fatty acids (ω-6 and ω-3) measured in blood samples. Main Outcomes and Measures: Aortic stenosis and aortic valve replacement defined by electronic health records, surgical records, or echocardiography and the presence of AVC measured by computed tomography. Results: The mean (SD) age of the 44 703 GERA participants was 69.7 (8.4) years, and 22 019 (49.3%) were men. The rs174547 variant at the FADS1/2 locus was associated with AS (odds ratio [OR] per C allele, 0.88; 95% CI, 0.83-0.93; P = 3.0 × 10-6), with genome-wide significance after meta-analysis with 7 replication cohorts totaling 312 118 individuals (9395 cases of AS) (OR, 0.91; 95% CI, 0.88-0.94; P = 2.5 × 10-8). A consistent association with AVC was also observed (OR, 0.91; 95% CI, 0.83-0.99; P = .03). A higher ratio of arachidonic acid to linoleic acid was associated with AVC (OR per SD of the natural logarithm, 1.19; 95% CI, 1.09-1.30; P = 6.6 × 10-5). In mendelian randomization, increased FADS1 liver expression and arachidonic acid were associa

Aims: High-sensitivity troponin T (hs-TnT) and high-sensitivity C reactive protein (hs-CRP) may convey prognostic information in patients with aortic stenosis (AS). This study evaluated if hs-TnT and hs-CRP associate with myocardial mass, and risk of future surgery for AS. Methods: In total, 336 patients (48% women) with surgery for AS with previous participation in large population surveys were identified. Preoperatively, myocardial mass and the presence of coronary artery disease (CAD) were assessed. Two matched referents were allocated for each case, and hs-TnT and hs-CRP were determined in stored plasma from the baseline survey. Conditional logistic regression analysis was used to estimate the risk (OR (95% CI)) related to one (natural logarithm) SD increase in hs-TnT and hs-CRP. Kaplan-Mayer and Cox regression analyses were used to evaluate time to surgery. Results: Median age (IQR) was 59.8 (10.3) years at survey, and median time between survey and surgery was 10.9 (9.3) years. Hs-TnT was independently associated with surgery for AS (1.24 (1.06–1.44)) irrespective of CAD, whereas Hs-CRP was not (1.05 (0.90–1.22)). Elevated hs-TnT levels at survey associated with shorter time to surgery (p<0.001), and with increased myocardial mass (p=0.002). Hs-CRP did not associate with time to surgery or with myocardial mass. Conclusions: Hs-TnT—but not hs-CRP—was associated with increased risk of—and shorter time to—future surgery for AS. Hs-TnT associated with myocardial mass at surgery which indicates that hs-TnT could be a potential biomarker for determining intervention., Previously included in thesis in manuscript form

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Recently, a new approach was proposed to detect mild impairment in renal function: a reduced ratio between estimated glomerular filtration rate (eGFR) calculated by cystatin C and eGFR calculated by creatinine. We aimed to evaluate if this ratio is associated with aortic stenosis (AS) requiring surgery. We identified 336 patients that first participated in population surveys and later underwent surgery for AS (median age [interquartile range] 59.8 [10.3] years at survey and 68.3 [12.7] at surgery, 48% females). For each patient, two matched referents were allocated. Cystatin C and creatinine were determined in stored plasma. eGFR(cystatin C) and eGFR(creatinine) and their ratio were estimated. Conditional logistic regression analyses were used to estimate the risk (odds ratio (OR) with [95% confidence interval (CI)]) related to one (ln) standard deviation increase in the ratio between eGFR(cystatin C) and eGFR(creatinine). A high ratio was associated with lower risk for AS requiring surgery (OR [95% CI]) (OR 0.84 [0.73-0.97]), especially in women (0.74 [0.60-0.92] vs. 0.93 [0.76-1.13] in men). After further stratification for coronary artery disease (CAD), the association remained in women with CAD but not in women without CAD (0.60 [0.44-0.83] and 0.89 [0.65-1.23], respectively). In conclusion, a high ratio between eGFR(cystatin C) and eGFR(creatinine) was associated with lower risk for surgery for AS, especially in women. Mild impairment of renal function is thus associated with future risk for AS requiring surgery.

OBJECTIVES: Due to age-related differences in aortic valve structure, it is likely that the pathophysiology of aortic stenosis (AS) and associated risk factors differ between age groups. Here we prospectively studied the influence of traditional cardiovascular risk factors on AS development requiring surgery among patients without concomitant coronary artery disease (CAD) and stratified for age. DESIGN: This study included 322 patients, who had prior to surgery for AS participated in population-based surveys, and 131 of them had no visible CAD upon preoperative coronary angiogram. For each case, we selected four referents matched for age, gender, and geographic area. To identify predictors for surgery, we used multivariable conditional logistic regression with a model including arterial hypertension (or measured blood pressure and antihypertensive medication), cholesterol levels, diabetes, body mass index (BMI), and smoking. RESULTS: In patients without CAD, future surgery for AS was associated with arterial hypertension and elevated levels of diastolic blood pressure in patients younger than 60 years at surgery (odds ratio [95% confidence interval]), (3.40 [1.45-7.93] and 1.60 [1.09-2.37], respectively), and with only impaired fasting glucose tolerance in patients 60 years or older at surgery (3.22 [1.19-8.76]). CONCLUSION: Arterial hypertension and elevated diastolic blood pressure are associated with a risk for AS requiring surgery in subjects below 60 years of age. Strict blood pressure control in this group is strongly advocated to avoid other cardiovascular diseases correlated to hypertension. If hypertension and elevated diastolic blood pressure are risk factors for developing AS requiring surgery need further investigations. Notably, elevated fasting glucose levels were related to AS requiring surgery in older adults without concomitant CAD.

Introduction: Aortic stenosis (AS) is the most common hemodynamic significant valvular heart disease and affects about 2% of the population. The incidence increases with age. When symptoms of the stenotic aortic valve disease eventually occur the 2-year mortality exceeds 50%. Aortic valve replacement (AVR) by surgery or by catheter intervention is the only known treatment. The causes of AS are only partly known, despite that the disease has been known since the beginning of 17th century. In younger individuals, a bicuspid valve is present in about 80% of the cases. The traditional cardiovascular risk-factors for ischemic heart disease have been linked to AS, and the histology of the stenotic aortic valve and the atherosclerotic plaques shares several features such as inflammation, lipid deposition and calcification. High levels of the lipoprotein Lp(a) has been linked to both atherosclerosis and AS, and a causal relation with AS is supported by Mandelian randomisation. End-stage renal disease is associated with increased risk of AS but if early impairment increases the risk is not known. Material and methods: We identified 799 patients with surgery for valvular heart disease and/or disease of the ascending aorta with a prior participation in one of three large population based health surveys in northern Sweden (Västerbotten Intervention Program [VIP], MONItoring Of trends and Determinants in CArdivascular Disease survey [MONICA], and the Mammary Screening Project [MSP]). For each case, four referents matched by age, gender, type and date of survey, and geographical area were randomly selected. From the health surveys, data on cardiovascular risk-factors and health history as well as measurements of anthropometry, blood pressure, glucose and cholesterol levels were retrieved. Each case was carefully validated and data from pre- and perioperative assessments were collected. The presence of coronary artery disease (CAD) was determined from the preoperative coronary ang

BACKGROUND: Aortic stenosis (AS) has different clinical phenotypes, including AS with or without concomitant coronary artery disease (CAD). It is unknown whether these phenotypes share the same risk factors. In particular, lipoprotein(a) [Lp(a)] and apolipoproteins (Apo) are associated with AS, but it is unknown whether these associations differ among phenotypes. In this prospective analysis we examined the impact of Lp(a) and Apo in subgroups of patients with AS. METHODS AND RESULTS: We identified 336 patients (mean age at survey 56.7 years, 48% female) who underwent surgery for AS after a median 10.9 years (interquartile range 9.3 years), participants in 1 of 3 large population surveys. For each patient, 2 matched referents were allocated. Lp(a) and Apo were analyzed in the baseline samples. Uni- and multivariable logistic regression analyses were used to estimate risks related to a 1 (ln) standard deviation increase in Lp(a) and the ratio of Apo B to Apo A1 (Apo B/A1 ratio). High levels of Lp(a) predicted surgery for AS in 203 patients with concomitant CAD (odds ratio [95% confidence intervals]) (1.29 [1.07-1.55]), but not in 132 patients without CAD (1.04 [0.83-1.29]) in the fully adjusted model. Similarly, a high Apo B/A1 ratio predicted surgery in patients with concomitant CAD (1.43 [1.16-1.76]) but not in those without CAD (0.87 [0.69-1.10]). CONCLUSIONS: High levels of Lp(a) and a high Apo B/A1 ratio were associated with surgery for AS in patients with concomitant CAD but not in those with isolated AS. This finding may lead to a new avenue of research for targeted risk factor interventions in this population.

Background: Risk factors for developing heart valve and ascending aortic disease are based mainly on retrospective data. To elucidate these factors in a prospective manner, we have performed a nested case-referent study using data from large, population-based surveys. Methods and Results: A total of 777 patients operated for heart valve disease or disease of the ascending aorta had previously participated in population-based health surveys in Northern Sweden. Median time (interquartile range) from survey to surgery was 10.5 (9.0) years. Primary indications for surgery were aortic stenosis (41%), aortic regurgitation (12%), mitral regurgitation (23%), and dilatation/dissection of the ascending aorta (17%). For each case, referents were allocated, matched for age, sex, and geographical area. In multivariable models, surgery for aortic stenosis was predicted by hypertension, high cholesterol levels, diabetes mellitus, and active smoking. Surgery for aortic regurgitation was associated with a low cholesterol level, whereas a high cholesterol level predicted surgery for mitral regurgitation. Hypertension, blood pressure, and previous smoking predicted surgery for disease of the ascending aorta whereas diabetes mellitus was associated with reduced risk. After exclusion of cases with coronary atherosclerosis, only the inverse associations between cholesterol and aortic regurgitation and between diabetes mellitus and disease of the ascending aorta remained. Conclusions: This is the first truly prospective study of traditional cardiovascular risk factors and their association with valvular heart disease and disease of the ascending aorta. We confirm the strong association between traditional risk factors and aortic stenosis, but only in patients with concomitant coronary artery disease. In isolated valvular heart disease, the impact of traditional risk factors is varying.

Supplement: 1Meeting Abstract: 4054