Adrenomedullin and endothelin-1 are hormones with opposing effects on the cardiovascular system. Adrenomedullin acts as a vasodilator and seems to be important for the initiation and continuation of the hyperdynamic circulatory response in sepsis. Endothelin-1 is a vasoconstrictor and has been linked to decreased cardiac performance. Few studies have studied the relationship between adrenomedullin and endothelin-1, and morbidity and mortality in septic shock patients. High-sensitivity troponin T (hsTNT) is normally used to diagnose acute cardiac injury but is also prognostic for outcome in intensive care. We investigated the relationship between mid-regional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and myocardial injury, measured using transthoracic echocardiography and hsTNT in septic shock patients. We were also interested in the development of different biomarkers throughout the ICU stay, and how early measurements were related to mortality. Further, we assessed if a positive biomarker panel, consisting of MR-proADM, CT-proET-1, and hsTNT changed the odds for mortality.
A cohort of 53 consecutive patients with septic shock had their levels of MR-proADM, CT-proET-1, hsTNT, and left ventricular systolic functions prospectively measured over 7 days. The relationship between day 1 levels of MR-proADM/CT-proET-1 and myocardial injury was studied. We also investigated the relationship between biomarkers and early (7-day) and later (28-day) mortality. Likelihood ratios, and pretest and posttest odds for mortality were calculated.
Levels of MR-proADM and CT-proET-1 were significantly higher among patients with myocardial injury and were correlated with left ventricular systolic dysfunction. MR-proADM and hsTNT were significantly higher among 7-day and 28-day non-survivors. CT-proET-1 was also significantly higher among 28-day but not 7-day non-survivors. A positive biomarker panel consisting of the three biomarkers increased the odds for mortality 13-fold to 20-fold.
MR-proADM and CT-proET-1 are associated with myocardial injury. A biomarker panel combining MR-proADM, CT-proET-1, and hsTNT increases the odds ratio for death, and may improve currently available scoring systems in critical care.
Glucometabolic disturbances are associated with myocardial dysfunction. Brain natriuretic peptides (BNP) are used for detecting myocardial dysfunction in clinical practice. However, studies on elderly subjects and gender-specific analyses are sparse.
We examined cross-sectional associations between Nt-proBNP and 1) fasting plasma glucose (FPG), and 2) categories of glucometabolic disturbances, in middle-aged and older subjects (1266 men, 526 women), applying multivariate linear regression analysis.
FPG was positively correlated with Nt-proBNP among middle-aged men (p = 0.04) and negatively albeit non-significantly (p = 0.1) among middle-aged women. Weaker non-significant correlations were seen among older subjects. Middle-aged men with new-onset and prevalent diabetes had higher Nt-proBNP than the reference group (FPG =5.0 mmol/L): 9.53 (p = 0.002) and 8.23 (p = 0.02) vs. 5.71 pmol/L. No differences in Nt-proBNP between categories of glucometabolic disturbance were observed among older men or women.
The results indicate an age- and gender difference in the ability of Nt-proBNP to identify myocardial dysfunction in relation to glucometabolic disturbances. Therefore, Nt-proBNP should be used with caution as a general surrogate marker for myocardial dysfunction in this setting.
the purpose of this study was to assess the predictive accuracy of conventional cardiovascular risk factors for incident heart failure and atrial fibrillation, and the added benefit of multiple biomarkers reflecting diverse pathophysiological pathways.
heart failure and atrial fibrillation are interrelated cardiac diseases associated with substantial morbidity and mortality and increasing incidence. Data on prediction and prevention of these diseases in healthy individuals are limited.
in 5,187 individuals from the community-based MDCS (Malmö Diet and Cancer Study), we studied the performance of conventional risk factors and 6 biomarkers including midregional pro-atrial natriuretic peptide (MR-proANP), N-terminal pro-B-type natriuretic peptide (NT-proBNP), midregional pro-adrenomedullin, cystatin C, C-reactive protein (CRP), and copeptin.
during a mean follow-up of 14 years, 112 individuals were diagnosed with heart failure and 284 individuals with atrial fibrillation. NT-proBNP (hazard ratio [HR]: 1.63 per SD, 95% confidence interval [CI]: 1.29 to 2.06, p
Cites: JAMA. 2009 Jul 1;302(1):49-5719567439
Cites: Circulation. 2009 May 5;119(17):2408-1619364974
The validity of atrial fibrillation (AF) diagnoses in national registers for use as endpoints in prospective studies has not been evaluated. We studied the validity of AF diagnoses in Swedish national hospital discharge and cause of death registers and the occurrence of and risk factors for AF in a middle-aged Swedish population using these registers. Our study included the 30,447 individuals(age 44-73) who attended baseline visits in 1991-1996 of the Malmö Diet and Cancer study. Individuals with a first AF diagnosis were identified by record linkage with national registers. A subset of cases was randomly selected for validation by examination of electrocardiograms and patient records. Electrocardiograms were available in 98%of the validation sample (95% definitive AF, 3% no AF).The 2% with ECGs unavailable had probable AF. Baseline AF prevalence was 1.3%, higher in men and increased with age. During 11.2 years of follow-up 1430 first AF diagnoses occurred. Risk factors were age, hypertension, BMI,diabetes, history of heart failure, history of myocardial infarction and, in men but not women, current smoking.The strongest risk factors were history of heart failure(hazard ratio men 4.5, women 8.7) and myocardial infarction(hazard ratio men 2.0, women 1.8). The largest population-attributable risks were observed for hypertension (men 38%, women 34%) and obesity (men 11%, women 10%).In conclusion, case misclassification of AF in national registers is small, indicating feasibility of use in prospective studies. Hypertension and obesity account for large portions of population risk in middle-aged individuals with low prevalence of manifest cardiac disease.
We have recently shown that low plasma levels of mid-regional atrial natriuretic peptide (MR-ANP) predict development of diabetes and glucose progression over time, independently of known risk factors for diabetes development. However, since MR-ANP levels might be influenced by unknown factors causing diabetes, we cannot rule out that such relationship might be confounded. Previous studies have shown an association of a single nucleotide polymorphism rs5068 on the natriuretic peptide precursor A (NPPA) locus gene with higher levels of circulating ANP. Since gene variants are inherited randomly and not subject to confounding, we aimed to investigate whether the variant rs5068 within the NPPA locus is associated with incident type 2 diabetes.
We genotyped the variant rs5068 within the NPPA locus in 27,307 individuals without known diabetes from the Malmö Diet Cancer Study. Incident diabetes was retrieved through national and regional registers (median follow-up time of 14 years, 2,823 incident diabetes cases).
In Cox regression analysis adjusted for age, sex and BMI, we found that the carriers of at least one copy of the G allele of rs5068 had lower likelihood of incident diabetes within 14 years (HR?=?0.88, 95% CI 0.78-0.99, p?=?0.037).
Our results indicate a role of the ANP system in the etiology of type 2 diabetes and might help provide insight in the metabolic actions of natriuretic peptides and the pathophysiology of type 2 diabetes.
It is unclear whether there are causal associations between blood lipids, statin use and cancer risks. Under certain assumptions, Mendelian randomization analysis of a genetic marker for an exposure eliminates reverse causation and confounding.
We applied Mendelian randomization analysis to genetic scores, comprising 26-41 single-nucleotide polymorphisms (SNPs), as instrumental variables (IVs) for triglycerides and low- and high-density lipoprotein cholesterol (LDLC, HDLC), using a prospective cohort of 26?904 individuals in which there were 6607 incident cancers. We also investigated cancer risk for a SNP (rs12916) in the gene encoding hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the targeted enzyme in statin treatment. We used logistic regression and SNP pleiotropy-adjusted analyses to estimate the odds ratio per standard deviation (OR).
The OR for the triglyceride IV as a predictor of any cancer was 0.91 [95% confidence interval (CI): 0.80-1.03] unadjusted, and 0.87 (95% CI: 0.78-0.95) from the pleiotropy-adjusted analysis. For the HMGCR rs12916 per LDLC-lowering T-allele, the OR was 1.09 (95% CI: 1.01-1.18) for prostate cancer and 0.89 (95% CI: 0.82-0.96) for breast cancer. The LDLC IV was not associated with prostate cancer or breast cancer. There were no associations between IVs and cancers of the lung, colon or bladder.
Under the assumptions of Mendelian randomization, there is a causal and negative association between serum triglycerides and risk of any cancer. Further, the HMGCR genetic variant might be associated with risks of prostate and breast cancers but the biological mechanisms behind these findings are unclear, as the LDLC IV was not associated with these cancers.
The aim of this study was to examine potential risk factors for GCA in a nested case-control study based on two prospective health surveys.
We used two population-based health surveys, the Malmö Preventive Medicine Program (MPMP) and the Malmö Diet Cancer Study (MDCS). Individuals who developed GCA after inclusion were identified by linking the MPMP and MDCS databases to several patient administrative registers. A structured review of the medical records of all identified cases was performed. Four controls for every confirmed case, matched for sex, year of birth and year of screening, were selected from the corresponding databases. Potential predictors of GCA were examined in conditional logistic regression models.
Eighty-three patients (70% women, 64% biopsy positive, mean age at diagnosis 71 years) had a confirmed diagnosis of GCA after inclusion in the MPMP or MDCS. A higher BMI was associated with a significantly reduced risk of subsequent development of GCA [odds ratio (OR) 0.91/kg/m(2) (95% CI 0.84, 0.98)]. Smoking was not a risk factor for GCA overall [OR 1.36 (95% CI 0.77, 2.57)], although there was a trend towards an increased risk in female smokers [OR 2.14 (95% CI 0.97, 4.68)]. In multivariate analysis, adjusted for smoking and level of formal education, the inverse association between BMI and GCA remained significant (P = 0.027).
In this study, GCA was predicted by a lower BMI at baseline. Potential explanations include an effect of reduced adipose tissue on hormonal pathways regulating inflammation.
Acute dyspnea affects a large heterogeneous patient group with high mortality and readmission rates.
To investigate if cardiometabolic biomarkers and clinical characteristics predict readmission and death in patients hospitalized for acute dyspnea.
65 dyspnea patients at a general internal medicine ward were followed for six months. The combined endpoint was readmission or death.
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.
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.
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.
To assess the role of four biomarkers of neuroendocrine activation and endothelial dysfunction in the longitudinal prediction of fragility fractures.
We analysed a population-based prospective cohort of 5415 community-dwelling individuals (mean age, 68.9±6.2 years) enrolled in the Malmö Preventive Project followed during 8.1±2.9 years, and investigated the longitudinal association between C-terminal pro-arginine vasopressin (CT-proAVP), C-terminal endothelin-1 precursor fragment (CT-proET-1), the mid-regional fragments of pro-adrenomedullin (MR-proADM) and pro-atrial natriuretic peptide (MR-proANP), and incident vertebral, pelvic and extremity fractures.
Overall, 1030 (19.0%) individuals suffered vertebral, pelvic or extremity fracture. They were older (70.7±5.8 vs 68.4±6.3 years), more likely women (46.9% vs 26.3%), had lower body mass index and diastolic blood pressure, were more often on antihypertensive treatment (44.1% vs 38.4%) and had more frequently history of fracture (16.3% vs 8.1%). Higher levels of MR-proADM (adjusted HR (aHR) per 1 SD: 1.51, 95% CI 1.01 to 2.28, p