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

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

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

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

Prevalence of atherosclerosis in individuals with prediabetes and diabetes compared to normoglycaemic individuals-a Swedish population-based study.

BACKGROUND: Patients with type 2 diabetes have an increased risk of death and cardiovascular events and people with diabetes or prediabetes have been found to have increased atherosclerotic burden in the coronary and carotid arteries. This study will estimate the cross-sectional prevalence of atherosclerosis in the coronary and carotid arteries in individuals with prediabetes and diabetes, compared with normoglycaemic individuals in a large population-based cohort. METHODS: The 30,154 study participants, 50-64 years, were categorized according to their fasting glycaemic status or self-reported data as normoglycaemic, prediabetes, and previously undetected or known diabetes. Prevalence of affected coronary artery segments, severity of stenosis and coronary artery calcium score (CACS) were determined by coronary computed tomography angiography. Total atherosclerotic burden was assessed in the 11 clinically most relevant segments using the Segment Involvement Score and as the presence of any coronary atherosclerosis. The presence of atherosclerotic plaque in the carotid arteries was determined by ultrasound examination. RESULTS: Study participants with prediabetes (n = 4804, 16.0%) or diabetes (n = 2282, 7.6%) had greater coronary artery plaque burden, more coronary stenosis and higher CACS than normoglycaemic participants (all, p < 0.01). Among male participants with diabetes 35.3% had CACS ≥ 100 compared to 16.1% among normoglycaemic participants. For women, the corresponding figures were 8.9% vs 6.1%. The prevalence of atherosclerosis in the coronary arteries was higher in participants with previously undetected diabetes than prediabetes, but lower than in patients with known diabetes. The prevalence of any plaque in the carotid arteries was higher in participants with prediabetes or diabetes than in normoglycaemic participants. CONCLUSIONS: In this large population-based cohort of currently asymptomatic people, the atherosclerotic burden in the coronary and carotid arteries increased with increasing degree of dysglycaemia. The finding that the atherosclerotic burden in the coronary arteries in the undetected diabetes category was midway between the prediabetes category and patients with known diabetes may have implications for screening strategies and tailored prevention interventions for people with dysglycaemia in the future.

Severe Covid-19 and acute pulmonary hypertension: 24-month follow-up regarding mortality and relationship to initial echocardiographic findings and biomarkers.

INTRODUCTION: Critically ill Covid-19 patients are likely to develop the sequence of acute pulmonary hypertension (aPH), right ventricular strain, and eventually right ventricular failure due to currently known pathophysiology (endothelial inflammation plus thrombo-embolism) that promotes increased pulmonary vascular resistance and pulmonary artery pressure. Furthermore, an in-hospital trans-thoracic echocardiography (TTE) diagnosis of aPH is associated with a substantially increased risk of early mortality. The aim of this retrospective observational follow-up study was to explore the mortality during the 1-24-month period following the TTE diagnosis of aPH in the intensive care unit (ICU). METHODS: A previously reported cohort of 67 ICU-treated Covid-19 patients underwent an electronic medical chart-based follow-up 24 months after the ICU TTE. Apart from the influence of aPH versus non-aPH on mortality, several TTE parameters were analyzed by the Kaplan-Meier survival plot technique (K-M). The influence of biomarkers for heart failure (NTproBNP) and myocardial injury (Troponin-T), taken at the time of the ICU TTE investigation, was analyzed using receiver-operator characteristics curve (ROC) analysis. RESULTS: The overall mortality at the 24-month follow-up was 61.5% and 12.8% in group aPH and group non-aPH, respectively. An increased relative mortality risk continued to be present in aPH patients (14.3%) compared to non-aPH patients (5.6%) during the 1-24-month period. The easily determined parameter of a tricuspid valve regurgitation, allowing a measurement of a systolic pulmonary artery pressure (regardless of magnitude), was associated with a similar K-M outcome as the generally accepted diagnostic criteria for aPH (systolic pulmonary artery pressure >35 mmHg). The biomarker values of NTproBNP and Troponin-T at the time of the TTE did not result in any clinically useful ROC analysis data. CONCLUSION: The mortality risk was increased up to 24 months after the initial examination in ICU-treated Covid-19 patients with a TTE diagnosis of aPH, compared to non-aPH patients. Certain individual TTE parameters were able to discriminate 24-month risk of morality.

Can transthoracic echocardiography be used to a greater extent in the diagnostics of infective endocarditis to avoid unnecessary transoesophageal examinations without jeopardising accuracy?

BACKGROUND: Infective endocarditis (IE) is a serious condition that requires prompt diagnosis and treatment. Transthoracic echocardiography (TTE) is usually the initial imaging modality, however transoesophageal echocardiography (TOE) is sometimes necessary because of its higher sensitivity for IE. Yet, TOE may imply an increased risk of complications. This project aims to evaluate whether TTE can be used to a greater extent in the diagnostics of IE to avoid unnecessary TOE examinations without jeopardizing diagnostic accuracy. METHODS: Data from all TOE examinations performed on patients hospitalized with clinical suspicion of IE between 2019-05-01 and 2020-04-30 at a university hospital in Stockholm, Sweden, were obtained and analysed. Variables included for analysis were age, sex, blood culture results, aetiology, results from TOE, number of TOEs during the inclusion period, results from positron emission tomography/computed tomography (PET/CT), new regurgitation, cardiac murmur, previous IE, prosthetic valve, predisposing factors, i.e. cardiac comorbidities, injection drug use, fever, vascular phenomena, and immunological phenomena. To assess associations between predisposing factors or aetiology of IE and TOE findings, chi square tests and logistic regression models were used. For continuous variables, linear regression was used for comparisons of means and quantile regression was used for comparisons of medians. P < 0.05 was considered significant. RESULTS: In total 195 TOE examinations (Table 1) from 160 patients were included, of which 61 (31%) were positive for IE. In total, 36 examinations had negative TTE prior to TOE of which 32 (86%) also had negative TOE. Of the 5 (14%) negative TTE prior to TOE that had positive TOE, all had cardiovascular implantable electronic device (CIED) and/or prosthetic valves. CONCLUSIONS: The existing recommendations for TOE in patients with clinical suspicion of IE are probably broad enough not to miss patients with IE, but there might be an unnecessarily large number of patients being referred for TOE with negative results. Negative TTE examination with good image quality and no CIED or prosthetic valves, may be sufficient without jeopardizing the IE diagnosis.

Pre- and postoperative left atrial and ventricular volumetric and deformation analyses in severe aortic regurgitation.

BACKGROUND: The impact of volume overload due to aortic regurgitation (AR) on systolic and diastolic left ventricular (LV) indices and left atrial remodeling is unclear. We assessed the structural and functional effects of severe AR on LV and left atrium before and after aortic valve replacement. METHODS: Patients with severe AR scheduled for aortic valve replacement (n = 65) underwent two- and three-dimensional echocardiography, including left atrial strain imaging, before and 1 year after surgery. A control group was selected, and comprised patients undergoing surgery for thoracic aortic aneurysm without aortic valve replacement (n = 20). Logistic regression analysis was used to assess predictors of impaired left ventricular functional and structural recovery, defined as a composite variable of diastolic dysfunction grade ≥ 2, EF < 50%, or left ventricular end-diastolic volume index above the gender-specific normal range. RESULTS: Diastolic dysfunction was present in 32% of patients with AR at baseline. Diastolic LV function indices and left atrial strain improved, and both left atrial and LV volumes decreased in the AR group following aortic valve replacement. Preoperative left atrial strain during the conduit phase added to left ventricular end-systolic volume index for the prediction of impaired LV functional and structural recovery after aortic valve replacement (model p < 0.001, accuracy 70%; addition of left atrial strain during the conduit phase to end-systolic volume index p = 0.006). CONCLUSIONS: One-third of patients with severe AR had signs of diastolic dysfunction. Aortic valve surgery reduced LV and left atrial volumes and improved diastolic indices. Left atrial strain during the conduit phase added to the well-established left ventricular end-diastolic dimension for the prediction of impaired left ventricular functional and structural recovery at follow-up. However, long-term follow-up studies with hard endpoints are needed to assess the value of left atrial strain as predictor of myocardial recovery in aortic regurgitation.

Assessment of Global Lung Function Initiative (GLI) reference equations for diffusing capacity in relation to respiratory burden in the Swedish CArdioPulmonary bioImage Study (SCAPIS).

The Global Lung Function Initiative (GLI) has recently published international reference values for diffusing capacity of the lung for carbon monoxide (D LCO). Lower limit of normal (LLN), i.e. the 5th percentile, usually defines impaired D LCO We examined if the GLI LLN for D LCO differs from the LLN in a Swedish population of healthy, never-smoking individuals and how any such differences affect identification of subjects with respiratory burden.Spirometry, D LCO, chest high-resolution computed tomography (HRCT) and questionnaires were obtained from the first 15 040 participants, aged 50-64 years, of the Swedish CArdioPulmonary bioImage Study (SCAPIS). Both GLI reference values and the lambda-mu-sigma (LMS) method were used to define the LLN in asymptomatic never-smokers without respiratory disease (n=4903, of which 2329 were women).Both the median and LLN for D LCO from SCAPIS were above the median and LLN from the GLI (p<0.05). The prevalence of D LCO GLI LLN but GLI LLN but GLI LLN and >SCAPIS LLN). No differences were found with regard to physician-diagnosed asthma.The GLI LLN for D LCO is lower than the estimated LLN in healthy, never-smoking, middle-aged Swedish adults. Individuals with D LCO above the GLI LLN but below the SCAPIS LLN had, to a larger extent, an increased respiratory burden. This suggests clinical implications for choosing an adequate LLN for studied populations.

Sector-wise golden-angle phase contrast with high temporal resolution for evaluation of left ventricular diastolic dysfunction.

PURPOSE: To develop a high temporal resolution phase-contrast pulse sequence for evaluation of diastolic filling patterns, and to evaluate it in comparison to transthoracic echocardiography. METHODS: A phase-contrast velocity-encoded gradient-echo pulse sequence was implemented with a sector-wise golden-angle radial ordering. Acquisitions were optimized for myocardial tissue (TE/TR: 4.4/6.8 ms, flip angle: 8º, velocity encoding: 30 cm/s) and transmitral flow (TE/TR: 4.0/6.6 ms, flip angle: 20º, velocity encoding: 150 cm/s). Shared velocity encoding was combined with a sliding-window reconstruction that enabled up to 250 frames per cardiac cycle. Transmitral and myocardial velocities were measured in 35 patients. Echocardiographic velocities were obtained with pulsed-wave Doppler using standard methods. RESULTS: Myocardial velocity showed a low difference and good correlation between MRI and Doppler (mean ± 95% limits of agreement 0.9 ± 3.7 cm/s, R2 = 0.63). Transmitral velocity was underestimated by MRI (P < .05) with a difference of -11 ± 28 cm/s (R2 = 0.45). The early-to-late ratio correlated well (R2 = 0.66) with a minimal difference (0.03 ± 0.6). Analysis of interobserver and intra-observer variability showed excellent agreement for all measurements. CONCLUSIONS: The proposed method enables the acquisition of phase-contrast images during a single breath-hold with a sufficiently high temporal resolution to match transthoracic echocardiography, which opens the possibility for many clinically relevant variables to be assessed by MRI.

Increased iron absorption in patients with chronic heart failure and iron deficiency.

BACKGROUND: Iron deficiency (ID) is common in patients with chronic heart failure (CHF), but the underlying causes are not fully understood. We investigated whether ID is associated with decreased iron absorption in patients with CHF. METHODS AND RESULTS: We performed an oral iron-absorption test in 30 patients and 12 controls. The patients had CHF with reduced (n = 15) or preserved (n = 15) ejection fraction and ID, defined as s-ferritin < 100 µg/L, or s-ferritin 100-299 µg/L and transferrin saturation < 20%. The controls had no HF or ID and were of similar age and gender. Blood samples were taken before and 2 hours after ingestion of 100 mg ferroglycin sulphate. The primary endpoint was the delta plasma iron at 2 hours. The delta plasma iron was higher in the group with HF than in the control group (median increase 83.8 [61.5;128.5] µg/dL in HF vs 47.5 [30.7;61.5] µg/dL in controls, P = 0.001), indicating increased iron absorption. There was no significant difference between the groups with preserved or reduced ejection fraction (P = 0.46). CONCLUSION: We found increased iron absorption in patients with CHF and ID compared to controls without ID and HF, indicating that reduced iron absorption is not a primary cause of the high prevalence of ID in patients with CHF. CLINICAL TRIAL REGISTRATION: EudraCT 2017-000158-21.

Metabolomic Profile in HFpEF vs HFrEF Patients.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are associated with metabolic derangements, which may have different pathophysiological implications. METHODS AND RESULTS: In new-onset HFpEF (EF of ≥50%, n = 46) and HFrEF (EF of <40%, n = 75) patients, 109 endogenous plasma metabolites including amino acids, phospholipids and acylcarnitines were assessed using targeted metabolomics. Differentially altered metabolites and associations with clinical characteristics were explored. Patients with HFpEF were older, more often female with hypertension, atrial fibrillation, and diabetes compared with patients with HFrEF. Patients with HFpEF displayed higher levels of hydroxyproline and symmetric dimethyl arginine, alanine, cystine, and kynurenine reflecting fibrosis, inflammation and oxidative stress. Serine, cGMP, cAMP, l-carnitine, lysophophatidylcholine (18:2), lactate, and arginine were lower compared with patients with HFrEF. In patients with HFpEF with diabetes, kynurenine was higher (P = .014) and arginine lower (P = .014) vs patients with no diabetes, but did not differ with diabetes status in HFrEF. Decreasing kynurenine was associated with higher eGFR only in HFpEF (Pinteraction = .020). CONCLUSIONS: Patients with new-onset HFpEF compared with patients with new-onset HFrEF display a different metabolic profile associated with comorbidities, such as diabetes and kidney dysfunction. HFpEF is associated with indices of increased inflammation and oxidative stress, impaired lipid metabolism, increased collagen synthesis, and downregulated nitric oxide signaling. Together, these findings suggest a more predominant systemic microvascular endothelial dysfunction and inflammation linked to increased fibrosis in HFpEF compared with HFrEF. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT03671122 https://clinicaltrials.gov.

Cardiac implantable electrical devices in patients with hypertrophic cardiomyopathy: single center implant data extracted from the Swedish pacemaker and ICD registry.

Objectives: To investigate cardiac implantable electrical device (CIED) first implants in patients with hypertrophic cardiomyopathy (HCM) in a Swedish tertiary university hospital. Design: Clinical and technical data on pacemaker, implantable cardioverter defibrillator (ICD), and cardiac resynchronization therapy (CRT) first implants performed in HCM patients at the Karolinska University Hospital from 2005 to 2016 were extracted from the Swedish Pacemaker and ICD Registry. Echocardiographic data were obtained by review of hospital recordings. Results: The number of first pacemaker implants in HCM patients was 70 (1.5% of total pacemaker implants). The mean age of HCM pacemaker patients was 71 ± 10 years. Pacemaker implants were almost uniformly distributed between genders. Dual-chamber pacemakers with or without CRT properties were prevalent (6 and 93%, respectively). The number of first ICD implants in HCM patients was 99 (5.1% of total ICD implants). HCM patients receiving an ICD were 53 ± 15 years and prevalently men (70%). Sixty-five (66%) patients were implanted for primary prevention. Dual-chamber ICDs with or without CRT were 21 and 65%, respectively. Obstructive HCM was present in 47% pacemaker patients and 25% ICD patients with available pre-implant echo. Conclusions: This retrospective registry-based study provides a picture of CIED first implants in HCM patients in a Swedish tertiary university hospital. ICDs were the most commonly implanted devices, covering 59% of CIED implants. HCM patients receiving a pacemaker or an ICD had different epidemiological and clinical profiles.

Aerobic exercise capacity is maintained over a 5-year period in mild-to-moderate chronic kidney disease: a longitudinal study.

BACKGROUND: Aerobic exercise capacity is reduced in non-dialysis chronic kidney disease (CKD), but the magnitude of changes in exercise capacity over time is less known. Our main hypothesis was that aerobic ExCap would decline over 5 years in individuals with mild-to-moderate CKD along with a decline in renal function. A secondary hypothesis was that such a decline in ExCap would be associated with a decline in muscle strength, cardiovascular function and physical activity. METHODS: We performed a 5-year-prospective study on individuals with mild-to-moderate CKD, who were closely monitored at a nephrology clinic. Fiftytwo individuals with CKD stage 2-3 and 54 age- and sex-matched healthy controls were included. Peak workload was assessed through a maximal cycle exercise test. Muscle strength and lean body mass, cardiac function, vascular stiffness, self-reported physical activity level, renal function and haemoglobin level were evaluated. Tests were repeated after 5 years. Statistical analysis of longitudinal data was performed using linear mixed models. RESULTS: Exercise capacity did not change significantly over time in either the CKD group or controls, although the absolute workloads were significantly lower in the CKD group. Only in a CKD subgroup reporting low physical activity at baseline, exercise capacity declined. Renal function decreased in both groups, with a larger decline in CKD (p = 0.05 between groups). Peak heart rate, haemoglobin level, handgrip strength, lean body mass and cardiovascular function did not decrease significantly over time in CKD individuals. CONCLUSIONS: On a group level, aerobic exercise capacity and peak heart rate were maintained over 5 years in patients with well-controlled mild-to-moderate CKD, despite a slight reduction in glomerular filtration rate. In line with the maintained exercise capacity, cardiovascular and muscular function were also preserved. In individuals with mild-to-moderate CKD, physical activity level at baseline seems to have a predictive value for exercise capacity at follow-up.

Pulmonary outcomes in adults with a history of Bronchopulmonary Dysplasia differ from patients with asthma.

BACKGROUND: Bronchopulmonary dysplasia (BPD) is a risk factor for respiratory disease in adulthood. Despite the differences in underlying pathology, patients with a history of BPD are often treated as asthmatics. We hypothesized that pulmonary outcomes and health-related quality of life (HRQoL) were different in adults born preterm with and without a history of BPD compared to asthmatics and healthy individuals. METHODS: We evaluated 96 young adults from the LUNAPRE cohort ( clinicaltrials.gov/ct2/show/NCT02923648 ), including 26 individuals born preterm with a history of BPD (BPD), 23 born preterm without BPD (preterm), 23 asthmatics and 24 healthy controls. Extensive lung function testing and HRQoL were assessed. RESULTS: The BPD group had more severe airway obstruction compared to the preterm-, (FEV1- 0.94 vs. 0.28 z-scores; p ≤ 0.001); asthmatic- (0.14 z-scores, p ≤ 0.01) and healthy groups (0.78 z-scores, p ≤ 0.001). Further, they had increased ventilation inhomogeneity compared to the preterm- (LCI 6.97 vs. 6.73, p ≤ 0.05), asthmatic- (6.75, p = 0.05) and healthy groups (6.50 p ≤ 0.001). Both preterm groups had lower DLCO compared to healthy controls (p ≤ 0.001 for both). HRQoL showed less physical but more psychological symptoms in the BPD group compared to asthmatics. CONCLUSIONS: Lung function impairment and HRQoL in adults with a history of BPD differed from that in asthmatics highlighting the need for objective assessment of lung health.

Aortic dimensions in relation to bicuspid and tricuspid aortic valve pathology.

BACKGROUND AND AIM OF THE STUDY: The relationship between aortic valve pathology and the aortic root and ascending aortic dimensions in cardiac surgery patients is unclear, and its clarification was the objective of this study. METHODS: The severity of valve pathology, whether aortic valve stenosis (AS) or aortic valve regurgitation (AR), and the aortic dimensions (aortic root and ascending aorta) were prospectively evaluated with echocardiography in 500 consecutive patients with tricuspid aortic valve (TAV) or bicuspid aortic valve (BAV) who had undergone surgery due to aortic valve and/or ascending aortic disease. RESULTS: The distribution of valve pathology was similar in TAV and BAV patients when the aorta was non-dilated. However, when the aorta was dilated, AS was seen predominantly in BAV patients (n = 76) compared to TAV patients (n = 2). In TAV and BAV patients with non-dilated aortas, an increased severity of valve pathology was associated with smaller dimensions of the aortic root and the ascending aorta. In TAV and BAV patients with dilated aortas, an increase in the severity of AR was associated with a decreasing dimension of the ascending aorta but an increasing dimension of the aortic root. In BAV patients with aneurysm, the severity of AS was associated with a decreased dimension of the aortic root and the ascending aorta. CONCLUSION: Patients with AS and ascending aortic dilatation almost exclusively have a BAV. An increasing severity of valve pathology was related to decreasing dimensions of the aortic root and the ascending aorta, and the pattern was strikingly similar in TAV and BAV patients. The high frequency of ascending aortic dilatations in BAV patients cannot be explained by the valve pathology.

Alcohol septal ablation for hypertrophic obstructive cardiomyopathy: do mitral valve leaflet length, septal thickness, or sex affect the outcome?

This retrospective cohort study aimed to assess whether basal septal wall thickness (BSWT), anterior (AML) and posterior (PML) mitral leaflet length, or sex were associated with remaining left ventricular outflow tract obstruction (LVOTO) in patients with hypertrophic obstructive cardiomyopathy (HOCM) undergoing alcohol septal ablation (ASA). One hundred fifty-four patients who underwent ASA at the Karolinska University Hospital in Stockholm, Sweden, between 2009 and 2021, were included retrospectively. Anatomical and hemodynamic parameters were collected from invasive catheterization before and during ASA, and from echocardiography (ECHO) examinations before, during, and at 1-year follow-up after ASA. Linear and logistic regression models were used to assess the association between sex, BSWT, AML, PML, and outcome, which was defined as the remaining LVOTO (≥ 30 mmHg) after ASA. The median follow-up was 364 days (interquartile range 334-385 days). BSWT ≥ 23 mm (n = 13, 12%) was associated with remaining LVOTO at follow-up (p = 0.004). Elongated mitral valve leaflet length (either AML or PML) was present in 125 (90%) patients. Elongated AML (> 24 mm) was present in 67 (44%) patients, although AML length was not associated with remaining LVOTO at follow-up. Elongated PML (> 14 mm) was present in 114 (74%) patients and was not associated with remaining LVOTO at follow-up. No significant sex differences were observed regarding the remaining LVOTO. ECHO measurement of BSWT can be effectively used to select patients for successful ASA and identify those patients with a risk of incomplete resolution of LVOTO after ASA.

Cardiac biopsies reveal differences in transcriptomics between left and right ventricle in patients with or without diagnostic signs of heart failure.

New or mild heart failure (HF) is mainly caused by left ventricular dysfunction. We hypothesised that gene expression differ between the left (LV) and right ventricle (RV) and secondly by type of LV dysfunction. We compared gene expression through myocardial biopsies from LV and RV of patients undergoing elective coronary bypass surgery (CABG). Patients were categorised based on LV ejection fraction (EF), diastolic function and NT-proBNP into pEF (preserved; LVEF ≥ 45%), rEF (reduced; LVEF < 45%) or normal LV function. Principal component analysis of gene expression displayed two clusters corresponding to LV and RV. Up-regulated genes in LV included natriuretic peptides NPPA and NPPB, transcription factors/coactivators STAT4 and VGLL2, ion channel related HCN2 and LRRC38 associated with cardiac muscle contraction, cytoskeleton, and cellular component movement. Patients with pEF phenotype versus normal differed in gene expression predominantly in LV, supporting that diastolic dysfunction and structural changes reflect early LV disease in pEF. DKK2 was overexpressed in LV of HFpEF phenotype, potentially leading to lower expression levels of ß-catenin, α-SMA (smooth muscle actin), and enhanced apoptosis, and could be a possible factor in the development of HFpEF. CXCL14 was down-regulated in both pEF and rEF, and may play a role to promote development of HF.

Iron deficiency in new onset heart failure: association with clinical factors and quality of life.

AIMS: The prevalence of iron deficiency (ID) in newly diagnosed heart failure (HF) and the progression of ID in patients after initiation of HF therapy are unknown. We aimed to describe the natural trajectory of ID in patients with new onset HF during the first year after HF diagnosis, assessing associations between ID, clinical factors, and quality of life (QoL). METHODS AND RESULTS: A prospective cohort of patients with new onset HF in hospitals or outpatient clinics at five major hospitals in Stockholm, Sweden, during 2015-2018 were analysed with clinical assessment, electrocardiogram, blood samples including iron levels, Minnesota living with heart failure questionnaire (MLHFQ), and echocardiogram at baseline and after 12 months. Of 547 patients with new-onset HF, 482 (88%) had complete iron data at baseline. Mean age was 70 years (interquartile range 61-77) and 311 (65%) were men; 55% of patients had ejection fraction (EF) ≤ 40%, 19% had EF 41-49%, and 26% had HF with preserved EF (HFpEF). At baseline, 163 patients (34%) had ID defined as ferritin <100 µg/L or ferritin 100-299 µg/L and transferrin saturation <20%. After 12 months of follow-up, 119 (32%) had ID of the 368 patients who had complete iron data both at baseline and after 12 months and did not receive intravenous (i.v.) iron during follow-up. During the first year after HF diagnosis, 19% had persistent ID, 13% developed ID, 11% resolved ID, and 57% never had ID, consequently 24% changed their classification. Anaemia at baseline was the strongest independent predictor of ID 1 year after diagnosis [odds ratio (OR) 3.91, 95% confidence interval (CI) 1.88-8.13, P < 0.001], followed by HF hospitalization (OR 2.21, 95% CI 1.24-3.95, P < 0.01), female sex (OR 2.04, 95% CI 1.25-3.32, P < 0.01), HFpEF (OR 1.96, 95% CI 1.13-3.39, P < 0.05), and diabetes mellitus (OR 1.92, 95% CI 1.06-3.48, P < 0.05). ID was associated with low QoL at baseline (MLHFQ score mean difference 7.4 points, 95% CI 3.1-11.7, P < 0.001), but not at follow-up. CONCLUSIONS: About one third of patients with new onset HF had ID both at the time of HF diagnosis and after 1 year, though a quarter of the patients changed their ID status. Patients with anaemia, HF hospitalization, female gender, HFpEF, or diabetes mellitus at baseline were more likely to have ID after 1 year implying that these should be carefully screened for ID to find those in need of i.v. iron treatment.

Soluble CD14 and Osteoprotegerin Associate with Ankle-Brachial Index as a Measure of Arterial Stiffness in Patients with Mild-to-Moderate Chronic Kidney Disease in a Five-Year Prospective Study.

INTRODUCTION: Vascular lesions and arterial stiffness appear at early stages of chronic kidney disease (CKD) and follow an accelerated course with disease progression, contributing to high cardiovascular mortality. There are limited prospective data on mechanisms contributing to progression of arterial stiffness in mild-to-moderate CKD (stages 2-3). METHODS: We applied an affinity proteomics approach to identify candidates of circulating biomarkers with potential impact on vascular lesions in CKD and selected soluble cluster of differentiation 14 (sCD14), angiogenin (ANG), and osteoprotegerin (OPG) for further analysis. We studied their association with ankle-brachial index (ABI) and carotid intima-media thickness, as measures of arteriosclerosis and atherosclerosis, respectively, in 48 patients with CKD stages 2-3, who were prospectively followed and intensively treated for 5 years, and 44 healthy controls. RESULTS: Concentrations of sCD14 (p < 0.001), ANG (p < 0.001), and OPG (p < 0.05) were higher in patients with CKD 2-3 at baseline, and sCD14 (p < 0.001) and ANG (p < 0.001) remained elevated in CKD patients at follow-up. There were positive correlations between ABI and sCD14 levels (r = 0.36, p = 0.01) and between ABI and OPG (r = 0.31, p = 0.03) at 5 years. The changes in sCD14 during follow-up correlated to changes in ABI from baseline to 5 years (r = 0.41, p = 0.004). CONCLUSION: Elevated levels of circulating sCD14 and OPG in patients with CKD 2-3 were significantly associated with ABI, a measure of arterial stiffness. An increase in sCD14 over time in CKD 2-3 patients was associated with a corresponding increase in ABI. Further studies are needed to examine if early intensive multifactorial medication to align with international treatment targets may influence cardiovascular outcomes.

Body weight at age 20 and in midlife is more important than weight gain for coronary atherosclerosis: Results from SCAPIS.

BACKGROUND AND AIMS: Elevated body weight in adolescence is associated with early cardiovascular disease, but whether this association is traceable to weight in early adulthood, weight in midlife or to weight gain is not known. The aim of this study is to assess the risk of midlife coronary atherosclerosis being associated with body weight at age 20, body weight in midlife and body weight change. METHODS: We used data from 25,181 participants with no previous myocardial infarction or cardiac procedure in the Swedish CArdioPulmonary bioImage Study (SCAPIS, mean age 57 years, 51% women). Data on coronary atherosclerosis, self-reported body weight at age 20 and measured midlife weight were recorded together with potential confounders and mediators. Coronary atherosclerosis was assessed using coronary computed tomography angiography (CCTA) and expressed as segment involvement score (SIS). RESULTS: The probability of having coronary atherosclerosis was markedly higher with increasing weight at age 20 and with mid-life weight (p < 0.001 for both sexes). However, weight increase from age 20 until mid-life was only modestly associated with coronary atherosclerosis. The association between weight gain and coronary atherosclerosis was mainly seen in men. However, no significant sex difference could be detected when adjusting for the 10-year delay in disease development in women. CONCLUSIONS: Similar in men and women, weight at age 20 and weight in midlife are strongly related to coronary atherosclerosis while weight increase from age 20 until midlife is only modestly related to coronary atherosclerosis.

Upregulation of the 5-lipoxygenase pathway in human aortic valves correlates with severity of stenosis and leads to leukotriene-induced effects on valvular myofibroblasts.

BACKGROUND: The development of aortic valve stenosis is not only associated with calcification and extracellular matrix remodeling, but also with inflammation. The aim of this study was to determine the role of proinflammatory signaling through the leukotriene (LT) pathway in aortic stenosis. METHODS AND RESULTS: After macroscopic dissection of surgically removed human aortic valves, RNA was extracted from 311 preparations derived from 68 patients to differentiate normal, thickened, and calcified areas from each cusp. Subsequently, quantitative polymerase chain reaction analysis was used to correlate gene expression patterns with preoperative echocardiographic parameters. The messenger RNA levels of the LT-forming enzyme 5-lipoxygenase increased 1.6- and 2.2-fold in thickened and calcified tissue, respectively, compared with normal areas of the same valves. In thickened tissues, messenger RNA levels for 5-lipoxygenase (r= -0.35; P=0.03), its activating protein (5-lipoxygenase activating protein; r= -0.39; P=0.02), and LTA(4) hydrolase (r= -0.48; P=0.01) correlated inversely with the velocity-time integral ratio. In addition, leukotriene A(4) hydrolase transcripts correlated inversely with aortic valve area, indexed for body surface area (r= -0.52; P=0.007). Immunohistochemical stainings revealed LT receptor expression on valvular myofibroblasts. In primary cultures of human myofibroblasts derived from stenotic aortic valves, Leukotriene C(4) (LTC(4)) increased intracellular calcium, enhanced reactive oxygen species production, reduced the mitochondrial membrane potential, and led to morphological cell cytoplasm changes and calcification. CONCLUSIONS: The upregulation of the LT pathway in human aortic valve stenosis and its correlation with clinical stenosis severity, taken together with the potentially detrimental LT-induced effects on valvular myofibroblasts, suggests one possible role of inflammation in the development of aortic stenosis.