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.