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.

Risk stratification in chronic thromboembolic pulmonary hypertension predicts survival.

OBJECTIVES: To investigate if the pulmonary arterial hypertension (PAH) risk assessment tool presented in the 2015 ESC/ERS guidelines is valid for patients with chronic thromboembolic pulmonary hypertension (CTEPH) when taking pulmonary endarterectomy (PEA) into account. Design. Incident CTEPH patients registered in the Swedish PAH Registry (SPAHR) between 2008 and 2016 were included. Risk stratification performed at baseline and follow-up classified the patients as low-, intermediate-, or high-risk using the proposed ESC/ERS risk algorithm. Results. There were 250 CTEPH patients with median age (interquartile range) 70 (14) years, and 53% were male. Thirty-two percent underwent PEA within 5 (6) months. In a multivariable model adjusting for age, sex, and pharmacological treatment, patients with intermediate-risk or high-risk profiles at baseline displayed an increased mortality risk (Hazard Ratio [95% confidence interval]: 1.64 [0.69-3.90] and 5.39 [2.13-13.59], respectively) compared to those with a low-risk profile, whereas PEA was associated with better survival (0.38 [0.18-0.82]). Similar impact of risk profile and PEA was seen at follow-up. Conclusion. The ESC/ERS risk assessment tool identifies CTEPH patients with reduced survival. Furthermore, PEA improves survival markedly independently of risk group and age. Take home message: The ESC/ERS risk stratification for PAH predicts survival also in CTEPH patients, even when taking PEA into account.

A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension.

Aims: Guidelines recommend a goal-oriented treatment approach in pulmonary arterial hypertension (PAH). The aim is to reach a low-risk profile, as determined by a risk assessment instrument. This strategy is incompletely validated. We aimed to investigate the bearing of such risk assessment and the benefit of reaching a low-risk profile. Methods and results: Five hundred and thirty PAH patients were included. Follow-up assessments performed after a median of 4 (interquartile range 3-5) months were available for 383 subjects. Patients were classified as 'Low', 'Intermediate', or 'High risk' and the benefit of reaching the 'Low risk' group was estimated. Survival differed (P < 0.001) between the risk groups at baseline and at follow-up. Survival was similar for patients who remained in or improved to the 'Low risk' group. Survival was similar for patients who remained in or worsened to the 'Intermediate risk' or 'High risk' groups. Irrespective of follow-up risk group, survival was better (P < 0.001) for patients with a higher proportion of variables at low risk. Results were unchanged after excluding patients with idiopathic PAH >65 years at diagnosis, and when patients with idiopathic or connective tissue disease-associated PAH were analysed separately. Patients in the 'Low risk' group at follow-up exhibited a reduced mortality risk (hazard ratio 0.2, 95% confidence interval 0.1-0.4 in multivariable analysis adjusted for age, sex and PAH subset), as compared to patients in the 'Intermediate risk' or 'High risk' groups. Conclusion: These findings suggest that comprehensive risk assessments and the aim of reaching a low-risk profile are valid in PAH.

Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension.

Recent reports from worldwide pulmonary hypertension registries show a new demographic picture for patients with idiopathic pulmonary arterial hypertension (IPAH), with an increasing prevalence among the elderly.We aimed to investigate the effects of age and comorbidity on risk stratification and outcome of patients with incident IPAH.The study population (n=264) was categorised into four age groups: 18-45, 46-64, 65-74 and ≥75 years. Individual risk profiles were determined according to a risk assessment instrument, based on the European Society of Cardiology and the European Respiratory Society guidelines. The change in risk group from baseline to follow-up (median 5 months) and survival were compared across age groups. In the two youngest age groups, a significant number of patients improved (18-45 years, Z= -4.613, p<0.001; 46-64 years, Z= -2.125, p=0.034), but no significant improvement was found in the older patient groups. 5-year survival was highest in patients aged 18-45 years (88%), while the survival rates were 63%, 56% and 36% for patients in the groups 46-64, 65-74 and ≥75 years, respectively (p<0.001). Ischaemic heart disease and kidney dysfunction independently predicted survival.These findings highlight the importance of age and specific comorbidities as prognostic markers of outcome in addition to established risk assessment algorithms.

Plasma L-arginine levels distinguish pulmonary arterial hypertension from left ventricular systolic dysfunction.

Pulmonary arterial hypertension (PAH) is a life-threatening condition, characterized by an imbalance of vasoactive substances and remodeling of pulmonary vasculature. Nitric oxide, formed from L-arginine, is essential for homeostasis and smooth muscle cell relaxation in PAH. Our aim was to compare plasma concentrations of L-arginine, asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) in PAH compared to left ventricular systolic dysfunction (LVSD) and healthy subjects. This was an observational, multicenter study comparing 21 patients with PAH to 14 patients with LVSD and 27 healthy subjects. Physical examinations were obtained and blood samples were collected. Plasma levels of ADMA, SDMA, L-arginine, L-ornithine, and L-citrulline were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Plasma levels of ADMA and SDMA were higher, whereas L-arginine and L-arginine/ADMA ratio were lower in PAH patients compared to healthy subjects (p < 0.001). Patients with PAH also had lower levels of L-arginine than patients with LVSD (p < 0.05). L-Arginine correlated to 6 min walking distance (6MWD) (r s = 0.58, p = 0.006) and L-arginine/ADMA correlated to WHO functional class (r s = -0.46, p = 0.043) in PAH. In conclusion, L-arginine levels were significantly lower in treatment naïve PAH patients compared to patients with LVSD. Furthermore, L-arginine correlated with 6MWD in PAH. L-arginine may provide useful information in differentiating PAH from LVSD.

Prognosis and response to first-line single and combination therapy in pulmonary arterial hypertension.

OBJECTIVES: To investigate survival, treatment escalation, effects of first-line single- and first-line combination therapy and prognostic markers in idiopathic- (IPAH), hereditary- (HPAH) and connective tissue disease-associated (CTD-PAH) pulmonary arterial hypertension (PAH). DESIGN: Retrospective analysis of medical journals from PAH patients at Skåne University Hospital 2000-2011. RESULTS: 1-, 2- and 3-year survival was 87%, 67%, and 54%, respectively, for the entire population, but worse (p = 0.003) in CTD-PAH than IPAH/HPAH. After 1, 2 and 3 years, 58%, 41% and 24% of patients starting on single therapy were alive on single therapy. 37.5% of patients on first-line single therapy received escalated treatment at first follow-up. First-line combination therapy more greatly decreased pulmonary vascular resistance index (PVRI, p = 0.017) than first-line single therapy. Only first-line combination therapy improved (p = 0.042) cardiac index (CI). Higher mean right atrial pressure (MRAP, p = 0.018), MRAP/CI (p = 0.021) and WHO functional class (p < 0.001) and lower 6-min walking distance (6MWD, p = 0.001) at baseline, and higher PVRI (p = 0.008) and lower 6MWD (p = 0.004) at follow-up were associated with worse outcome. CONCLUSIONS: We confirm improved survival with PAH-targeted therapies. Survival is still poor and early treatment escalation frequently needed. First-line combination therapy may more potently improve haemodynamics. MRAP/CI may represent a new prognostic marker in PAH.

P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate-induced pulmonary vasoconstriction in vivo in the pig.

PURPOSE: To investigate the role of P2Y1 and P2Y12 receptors in hypoxia- and adenosine diphosphate (ADP)-induced pulmonary vasoconstriction. METHODS: 19 anaesthetized, mechanically ventilated pigs (31.3 ± 0.7 kg) were evaluated in normoxia and hypoxia, without (n = 6) or with P2Y1 receptor antagonist MRS2500 (n = 7) or P2Y12 receptor antagonist cangrelor (n = 6) treatment. 12 pigs (29.3 ± 0.4 kg) were evaluated before and during ADP infusion, without and with MRS2500 (n = 6) or cangrelor (n = 6) pre-treatment. RESULTS: Hypoxia increased (p < 0.05) mean pulmonary artery pressure (MPAP) by 14.2 ± 1.1 mmHg and pulmonary vascular resistance (PVR) by 2.7 ± 0.4 WU. Without treatment MPAP and PVR remained unaltered (p = ns) for 90 min hypoxia. During hypoxia MRS2500 decreased (p < 0.013) MPAP by 4.3 ± 1.2 mmHg within 15 min. Cangrelor decreased (p < 0.036) MPAP to be 3.3 ± 0.4 and 3.6 ± 0.6 mmHg lower than hypoxia baseline after 10 and 30 min. PVR was, however, unaltered (p = ns) by MRS2500 or cangrelor during hypoxia. ADP increased (p < 0.001) MPAP and PVR to stabilize 11.1 ± 1.3 mmHg and 2.7 ± 0.3 WU higher than baseline. MRS2500 or cangrelor pre-treatment totally abolished the sustained MPAP- and PVR-increases to ADP. CONCLUSIONS: ADP elicits pulmonary vasoconstriction through P2Y1 and P2Y12 receptor activation. ADP is not a mandatory modulator, but may still contribute to pulmonary vascular tone during acute hypoxia. Further investigations into the mechanisms behind ADP-induced pulmonary vasoconstriction and the role of ADP as a modulator of pulmonary vascular tone during hypoxia are warranted.

Wall shear stress measured with 4D flow CMR correlates with biomarkers of inflammation and collagen synthesis in mild-to-moderate ascending aortic dilation and tricuspid aortic valves.

AIMS: Understanding the mechanisms underlying ascending aortic dilation is imperative for refined risk stratification of these patients, particularly among incidentally identified patients, most commonly presenting with tricuspid valves. The aim of this study was to explore associations between ascending aortic haemodynamics, assessed using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR), and circulating biomarkers in aortic dilation. METHODS AND RESULTS: Forty-seven cases with aortic dilation (diameter ≥ 40 mm) and 50 sex-and age-matched controls (diameter < 40 mm), all with tricuspid aortic valves, underwent 4D flow CMR and venous blood sampling. Associations between flow displacement, wall shear stress (WSS), and oscillatory shear index in the ascending aorta derived from 4D flow CMR, and biomarkers including interleukin-6, collagen type I α1 chain, metalloproteinases (MMPs), and inhibitors of MMPs derived from blood plasma, were investigated. Cases with dilation exhibited lower peak systolic WSS, higher flow displacement, and higher mean oscillatory shear index compared with controls without dilation. No significant differences in biomarkers were observed between the groups. Correlations between haemodynamics and biomarkers were observed, particularly between maximum time-averaged WSS and interleukin-6 (r = 0.539, P < 0.001), and maximum oscillatory shear index and collagen type I α1 chain (r = -0.575, P < 0.001 in cases). CONCLUSION: Significant associations were discovered between 4D flow CMR derived whole-cardiac cycle WSS and circulating biomarkers representing inflammation and collagen synthesis, suggesting an intricate interplay between haemodynamics and the processes of inflammation and collagen synthesis in patients with early aortic dilation and tricuspid aortic valves.

Restrictive Spirometric Pattern and Preserved Ratio Impaired Spirometry in a Population 50-64 Years.

RATIONALE: Knowledge regarding prevalence and shared and unique characteristics of Restrictive spirometric pattern (RSP) and Preserved ratio impaired spirometry (PRISm) is lacking for a general population investigated with post-bronchodilator spirometry and computed tomography of the lungs. OBJECTIVES: To investigate shared and unique features for RSP and PRISm. METHODS: In the Swedish CArdioPulmonary bioImage Study (SCAPIS), a general population sample of 28,555 people aged 50 - 64 years (including 14,558 never-smokers) was assessed. The participants answered a questionnaire and underwent computed tomography of the lungs, post-bronchodilator spirometry, and coronary artery calcification score (CACS). Odds ratios (OR) with 95% confidence intervals (CI) were calculated using adjusted logistic regression. RSP was defined as FEV1/FVC≥0.70 and FVC<80%. PRISm was defined as FEV1/FVC≥0.70 and FEV1<80%. A local reference equation was applied. MEASUREMENTS AND RESULTS: The prevalence of RSP and PRISm were 5.1% (95% CI 4.9 - 5.4) and 5.1% (95% CI 4.8 - 5.3), respectively, with similar values seen in never-smokers. For RSP and PRISm, shared features were current smoking, dyspnea, chronic bronchitis, rheumatic disease, diabetes, ischemic heart disease (IHD), bronchial wall thickening, interstitial lung abnormalities (ILA), and bronchiectasis. Emphysema was uniquely linked to PRISm (OR 1.69, 1.36-2.10) vs 1.10 (0.84-1.43) for RSP. CACS≥300 was related to PRISm, but not among among never-smokers. CONCLUSIONS: PRISm and RSP have respiratory, cardiovascular, and metabolic conditions as shared features. Emphysema is only associated with PRISm. Coronary atherosclerosis may be associated with PRISm. Our results indicate that RSP and PRISm may share more features than not. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).