Bioactive adrenomedullin a prognostic biomarker in patients with mild to moderate dyspnea at the emergency department: an observational study.

Acute dyspnea with underlying congestion is a leading cause of emergency department (ED) visits with high rates of hospitalization. Adrenomedullin is a vasoactive neuropeptide hormone secreted by the endothelium that mediates vasodilation and maintains vascular integrity. Plasma levels of biologically active adrenomedullin (bio-ADM) predict septic shock and vasopressor need in critically ill patients and are associated with congestion in patients with acute heart failure (HF) but the prognostic value in unselected dyspneic patients at the ED is unknown. The purpose of this study is to test if bio-ADM predicts adverse outcomes when sampled in patients with acute dyspnea at presentation to the ED. In this single-center prospective observational study, we included 1402 patients from the ADYS (Acute DYSpnea at the Emergency Department) cohort in Malmö, Sweden. We fitted logistic regression models adjusted for sex, age, N-terminal pro-B-type natriuretic peptide (NT-proBNP), creatinine, and C-reactive protein (CRP) to associate bio-ADM plasma levels to mortality, hospitalization, intravenous (IV) diuretic treatment and HF diagnosis. Using receiver operating characteristic (ROC) curve analysis we evaluated bio-ADM discrimination for these outcomes compared to a reference model (sex, age, NT-proBNP, creatinine, and CRP). Model performance was compared by performing a likelihood ratio test on the deviances of the models. Bio-ADM (per interquartile range from median) predicts both 90-day mortality [odds ratio (OR): 1.5, 95% confidence interval (CI) 1.2-2.0, p < 0.002] and hospitalization (OR: 1.5, 95% CI 1.2-1.8, p < 0.001) independently of sex, age, NT-proBNP, creatinine, and CRP. Bio-ADM statistically significantly improves the reference model in predicting mortality (added χ2 9.8, p = 0.002) and hospitalization (added χ2 14.1, p = 0.0002), and is associated with IV diuretic treatment and HF diagnosis at discharge. Plasma levels of bio-ADM sampled at ED presentation in acutely dyspneic patients are independently associated with 90-day mortality, hospitalization and indicate the need for decongestive therapy.

Amino acids predict prognosis in patients with acute dyspnea.

BACKGROUND: To identify amino acids that can predict risk of 90-day mortality in patients with acute dyspnea. METHOD: Plasma levels of nine amino acids were analyzed 663 adult patients admitted to the Emergency Department (ED) with acute dyspnea. Cox proportional hazards models were used to examine the relation between amino acid levels and the risk of 90-day mortality. RESULT: Eighty patients (12.1%) died within 90 days of admission. An "Amino Acid Mortality Risk Score" (AMRS), summing absolute plasma levels of glycine, phenylalanine and valine, demonstrated that among the patients belonging to quartile 1 (Q1) of the AMRS, only 4 patients died, compared to 44 patients in quartile 4. Using Q1 of the AMRS as reference, each increment of 1 SD in the AMRS was associated with a hazard ratio (HR) of 2.15 for 90-day mortality, and the HR was > 9 times higher in Q4. CONCLUSION: Glycine, phenylalanine and valine are associated with a risk of 90-day mortality in patients admitted to the ED for acute dyspnea, suggesting that these amino acids may be useful in risk assessments.

The association of body mass index, weight gain and central obesity with activity-related breathlessness: the Swedish Cardiopulmonary Bioimage Study.

INTRODUCTION: Breathlessness is common in the population, especially in women and associated with adverse health outcomes. Obesity (body mass index (BMI) >30 kg/m2) is rapidly increasing globally and its impact on breathlessness is unclear. METHODS: This population-based study aimed primarily to evaluate the association of current BMI and self-reported change in BMI since age 20 with breathlessness (modified Research Council score ≥1) in the middle-aged population. Secondary aims were to evaluate factors that contribute to breathlessness in obesity, including the interaction with spirometric lung volume and sex. RESULTS: We included 13 437 individuals; mean age 57.5 years; 52.5% women; mean BMI 26.8 (SD 4.3); mean BMI increase since age 20 was 5.0 kg/m2; and 1283 (9.6%) reported breathlessness. Obesity was strongly associated with increased breathlessness, OR 3.54 (95% CI, 3.03 to 4.13) independent of age, sex, smoking, airflow obstruction, exercise level and the presence of comorbidities. The association between BMI and breathlessness was modified by lung volume; the increase in breathlessness prevalence with higher BMI was steeper for individuals with lower forced vital capacity (FVC). The higher breathlessness prevalence in obese women than men (27.4% vs 12.5%; p<0.001) was related to their lower FVC. Irrespective of current BMI and confounders, individuals who had increased in BMI since age 20 had more breathlessness. CONCLUSION: Breathlessness is independently associated with obesity and with weight gain in adult life, and the association is stronger for individuals with lower lung volumes.

Increased mortality among acute respiratory distress patients from immigrant dense urban districts.

PURPOSE: This study investigated whether living in immigrant dense urban districts (IDUDs) and low-income areas in the city of Malmö predicted 5-year mortality among patients admitted to the emergency department (ED) because of acute respiratory distress. PATIENTS AND METHODS: We randomly selected 184 patients with acute respiratory distress during 2007, visiting the ED at Skåne University Hospital, Malmö. In 2007, Malmö had 36% first- and second-generation immigrants. The main exposure was defined as being resident in any of the five IDUDs of Malmö compared to being resident in the five districts of Malmö with the highest proportion of Sweden-born inhabitants (SDUDs). We recorded vital parameters; medical triage priority according to Adaptive Process Triage (ADAPT), ICD-10 diagnoses, and the mean annual income for the patient's urban district. We examined 5-year mortality risk using Cox proportional hazards model. RESULTS: After adjustment for age and gender, patients from IDUDs (n=100, 54%) had an HR (95% CI) of 1.65 (1.087-2.494; P=0.019) regarding mortality at 5-year follow-up. Patients in the lowest vs highest income quartile had an HR of 2.00 (1.06-3.79; P=0.032) regarding mortality at 5-year follow-up. Age, male gender, presence of cardiopulmonary disease, and ADAPT priority also independently predicted the 5-year mortality. The excess risk of 5-year mortality associated with living in IDUDs remained significant after adjustment for age, gender, ADAPT priority, presence of cardiopulmonary disease, and income with an HR of 1.79 (1.15-2.78; P=0.010). CONCLUSION: Living in an IDUD is a strong independent risk factor for 5-year mortality in patients with acute respiratory distress. The cause is unknown. Our study suggests a need for better structured follow-up of cardiopulmonary disease in such patients.

Cardiometabolic biomarkers are predictors of readmission and death in patients hospitalized for acute dyspnea.

BACKGROUND: Acute dyspnea affects a large heterogeneous patient group with high mortality and readmission rates. PURPOSE: To investigate if cardiometabolic biomarkers and clinical characteristics predict readmission and death in patients hospitalized for acute dyspnea. METHODS: 65 dyspnea patients at a general internal medicine ward were followed for six months. The combined endpoint was readmission or death. MEASUREMENTS AND RESULTS: Cardiometabolic biomarkers at admission were related to the endpoint in Cox proportional hazard models (adjusted for sex, age, oxygen saturation, respiratory rate and C-reactive protein (CRP)). The biomarkers tissue-type plasminogen activator (tPA), prolactin (PRL), tumor necrosis factor receptor superfamily member 6 (FAS) and C-C motif chemokine 3 (CCL3) were independently and significantly related to the endpoint and combined into a biomarker risk score (BRS). Each SD increment of the BRS conferred a hazard ratio (HR) of 2.13 (1.39-3.27) P=0.001. The top vs bottom tertile of the BRS conferred a HR of 4.75 (1.93-11.68) P=0.001. Dyspnea severity was also associated with worse outcome, HR=3.43 (1.28-9.20) P=0.014. However, when mutually adjusted the BRS remained significant (P=0.004) whereas dyspnea severity was not. The BRS was related to the endpoint among patients with mild to moderate dyspnea (P=0.016) but not among those with severe dyspnea. CONCLUSION: A score of tPA, PRL, FAS and CCL3 predicts 6-month death and readmission in patients hospitalized for acute dyspnea and may prove useful to optimize length of stay and follow-up. Although the BRS outweighs dyspnea severity in prediction of the endpoint, its prognostic role is strongest in mild-moderate dyspnea.

The shrunken pore syndrome is associated with declined right ventricular systolic function in a heart failure population - the HARVEST study.

The close relationship between heart and kidney diseases was studied with respect to the 'Shrunken pore syndrome' that is characterized by a difference in renal filtration between cystatin C and creatinine. Patients were retrieved from the HeARt and brain failure inVESTigation trail (HARVEST) which is an ongoing study undertaken in individuals hospitalized for the diagnosis of heart failure. Ninety-five of 116 patients who underwent transthoracic echocardiograms (TTE) were eligible for this study. We used four different formulas for estimated glomerular filtration rate (eGFR); CKD-EPIcreatinine, CKD-EPIcystatin C, LMrev and CAPA. Presence of the syndrome was defined as eGFR cystatin C ≤ 60% of eGFR creatinine and absence of the syndrome as eGFR cystatin C >90% and <110% of eGFR creatinine. In a linear regression model, adjusted for age and sex, and the 'Shrunken pore syndrome' defined by the equation pair CAPA and LMrev and the equation pair CKD-EPIcystatin C and CKD-EPIcreatinine, echocardiographic parameters were studied. The 'Shrunken pore syndrome' showed statistically significant associations with measurements of right ventricular (RV) systolic function; (TAPSE and RV S') (according to the equation pair CKD-EPIcystatin C and CKD-EPIcreatinine). In conclusion, heart failure patients with the 'Shrunken pore syndrome' are at increased risk of having RV systolic dysfunction whilst heart failure patients without 'Shrunken pore syndrome' seem protected. These findings may indicate common pathophysiological events in the kidneys and the heart explaining the observed increased risk of mortality in subjects with the 'Shrunken pore syndrome'.

Risk factor exposure in individuals free from cardiovascular disease differs according to age at first myocardial infarction.

BACKGROUND: The pathophysiology of myocardial infarction (MI) may differ depending on whether it occurs early or late in life. We tested the hypothesis that risk factor pattern differs according to the age at MI. METHODS: We performed a matched case-control study in the population-based Malmö Preventive Project (n = 33 346), where 3687 individuals developed MI during 22 ± 7 years of follow-up (=cases). The cases were divided into quartiles (Q1-Q4) according to age at event and were assigned two matched controls free from MI during follow-up. We used conditional logistic regression to assess relationship between risk factors at baseline and case status within quartiles of age at incident MI. RESULTS: The median (range) age (years) at incident MI in Q1 was 52.9 (37.0-57.1), Q2 60.8 (57.1-63.6), Q3 66.6 (63.6-69.7), and Q4 73.5 (69.7-84.0). The odds ratio (95% CI) for incident MI associated with 1 SD increase of baseline cholesterol decreased with age of MI and was 1.68 (1.50-1.87) for Q1, 1.43 (1.28-1.61) for Q2, 1.27 (1.14-1.42) for Q3, and 1.08 (0.98-1.19) for Q4. Similarly, family history of MI had a stronger relationship with MI in Q1 than with MI in Q4 of MI age, whereas smoking displayed a U-shaped relationship. Exposure to the remaining risk factors did not differentially affect MI occurring at different age spans. CONCLUSION: Exposure to cholesterol and family history of MI more strongly predicts onset of MI at younger ages, suggesting that MI in younger subjects is preceded by a different risk factor pattern than MI presenting in older subjects.

Inflammatory biomarkers predicting prognosis in patients with acute dyspnea.

OBJECTIVE/PURPOSE: The objective was to identify inflammatory biomarkers that predict risk of 90-day mortality in patients with acute dyspnea. METHOD: We analyzed 25 inflammatory biomarkers, in plasma, in 407 adult patients admitted to the emergency department (ED) with acute dyspnea and related them to risk of 90-day mortality using Cox proportional hazard models adjusted for age, sex, oxygen saturation, respiratory rate, C-reactive protein, and Medical Emergency Triage and Treatment System-Adult score. RESULTS: Fifty patients (12%) died within 90 day from admission. Two strong and independent biomarker signals were detected: The hazard ratio (95% confidence interval) for 90-day mortality per 1-SD increment of interleukin-8 (IL-8) was 2.20 (1.67-2.90) (P = 2.5 × 10(-8)) and for growth differentiation factor-15 (GDF-15) was 3.45 (2.18-5.45) (P = 1.3 × 10(-7)) A Biomarker Mortality Risk Score (BMRS) summing standardized and weighted values of IL-8 and GDF-15 revealed that of patients belonging to quartile 1 (Q1) of the BMRS, only 1 patient died, whereas 32 patients died among those belonging to quartile 4. Each 1-SD increment of the BMRS was associated with a hazard ratio of 3.79 (2.50-5.73) (P = 2 × 10(-10)) for 90-day mortality, and the point estimate was 13 times higher in Q4 as compared with Q1 of the BMRS (P(trend) over quartiles = 2 × 10(-6)). CONCLUSION: Interleukin-8 and GDF-15 are strongly and independently related to risk of 90-day mortality in unselected patients admitted to the ED because of acute dyspnea, suggesting that they may guide first-line physicians at the ED in risk assessment which in turn could lead to more accurate level of care and treatment intensity.

High total carbon dioxide predicts 1-year readmission and death in patients with acute dyspnea.

RATIONALE: Patients with acute dyspnea are a large heterogeneous patient group where initial management is important for outcome. OBJECTIVES: The objective of the study is to investigate if venous blood gas parameters predict 1-year risk of readmission or death in patients admitted to the emergency department due to acute dyspnea. METHODS: We studied 283 patients with acute dyspnea and followed them up for 1 year regarding incidence of readmission or death. MEASUREMENTS AND MAIN RESULTS: In venous blood obtained immediately upon admission levels of total carbon dioxide (TCO2), base excess (BE), potential hydrogen (pH), and partial pressure of carbon dioxide (pCO2) were measured. In Cox proportional hazards models, patients belonging to top and bottom quartiles of TCO2, BE, pH, and pCO2 were compared to patients belonging to the 2 central quartiles and assessed for end point. After adjustment, top (hazard ratio [HR], 1.48; 95% confidence interval [CI], 1.08-2.04; P=.016) and bottom (HR, 1.54; 95% CI, 1.08-2.18; P=.017) quartiles of BE were associated with increased risk of readmission or death. The strongest predictor was top quartile of TCO2 (HR, 1.68; 95% CI, 1.21-2.35; P=.002). In the combined analysis, top quartile of TCO2 remained significantly related to the end point (HR, 1.59; 95% CI, 1.03-2.45; P=.035), whereas BE became nonsignificant. Comorbidities, for example, prevalent chronic obstructive pulmonary disease, did not explain the association. Neither pCO2 nor pH predicted the end point. CONCLUSIONS: A high value of TCO2 appears to be an easily accessible marker for 1-year readmission or death in patients with acute dyspnea and may thus add clinically important information for risk stratification and follow-up strategies.

Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21.

AIMS: Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors. METHODS AND RESULTS: A total of 24,944 middle-aged subjects (62% females) from the population-based Malmö-Diet-and-Cancer-Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95-1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574. CONCLUSION: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk-factor that it may eliminate the associated genetic effect, requires further investigation.

Cardiovascular and cancer mortality in very elderly post-myocardial infarction patients receiving statin treatment.

OBJECTIVES: The purpose of this study was to determine whether statin treatment is effective and safe in very elderly (80 years and older) acute myocardial infarction (AMI) patients. BACKGROUND: Elderly individuals constitute an increasing percentage of patients admitted to hospitals for AMI. Despite that these patients have a higher mortality risk, the application of evidence-based medicine remains much lower than for younger patients. METHODS: We included all patients 80 years and older who were admitted with the diagnosis of AMI in the Register of Information and Knowledge About Swedish Heart Intensive Care Admissions between 1999 and 2003 (n = 21,410). Of these, complete covariate and follow-up data were available for 14,907 patients (study population A). To limit the bias related comorbidity on statin therapy, we also performed analyses excluding patients who died within 14 days of the acute event (study population B) and all patients who died within 365 days (study population C). A propensity score was used to adjust for initial differences between treatment groups. RESULTS: All-cause mortality was significantly lower in patients receiving statin treatment at discharge in study population A (relative risk: 0.55, 95% confidence interval: 0.51 to 0.59), in study population B (relative risk: 0.65; 95% confidence interval: 0.60 to 0.71), and in study population C (relative risk: 0.66; 95% confidence interval: 0.59 to 0.76). Similar observations were made for cardiovascular mortality as well as for AMI mortality. There was no increase in cancer mortality in statin-treated patients. CONCLUSIONS: Statin treatment is associated with lower cardiovascular mortality in very elderly post-infarction patients without increasing the risk of the development of cancer.

Heart failure exacerbation leading to hospital admission: a cross-sectional study.

OBJECTIVES: The aim of this pilot study was to investigate cause(s) of heart failure (HF). SETTING: The emergency department and medical wards at Malmö University Hospital. METHOD: A cross sectional pilot study. MAIN OUTCOME MEASURES: Comparison of compliance, comprehension and optimal treatment on a population basis between men and women, younger (< or =75 years) and elderly (>75 years) patients, and patients in different New York Heart Association (NYHA) classes, in order to assess if exacerbation could have been caused by any of these factors. RESULTS: Of the 47 patients included, 60% reported high compliance, with significant differences between women and men, and between patients in NYHA class IV and patients in NYHA class III. Comprehension on self-care was poor. Only 30% weighed themselves regularly and 45% did not limit the amount of fluids. No more than 28% reported they would contact a health professional in the case of experiencing more symptoms. Suboptimal treatment was also found to be a great concern. The majority were treated with recommended agents, but had not achieved target dose as recommended in the guidelines. CONCLUSION: This pilot study indicates suboptimal HF management of patients with HF prior to hospital admission due to HF exacerbation. A larger study is needed to assess the extent of the problem, and establish the need and nature of management improvement in different patient subgroups.