Carnitine levels in skeletal muscle, blood, and urine in patients with primary carnitine deficiency during intermission of L-carnitine supplementation.

BACKGROUND: Primary carnitine deficiency (PCD) is a disorder of fatty acid oxidation with a high prevalence in the Faroe Islands. Only patients homozygous for the c.95A>G (p.N32S) mutation have displayed severe symptoms in the Faroese patient cohort. In this study, we investigated carnitine levels in skeletal muscle, plasma, and urine as well as renal elimination kinetics before and after intermission with L-carnitine in patients homozygous for c.95A>G. METHODS: Five male patients homozygous for c.95A>G were included. Regular L-carnitine supplementation was stopped and the patients were observed during five days. Blood and urine were collected throughout the study. Skeletal muscle biopsies were obtained at 0, 48, and 96 h. RESULTS: Mean skeletal muscle free carnitine before discontinuation of L-carnitine was low, 158 nmol/g (SD 47.4) or 5.4% of normal. Mean free carnitine in plasma (fC0) dropped from 38.7 (SD 20.4) to 6.3 (SD 1.7) µmol/L within 96 h (p < 0.05). Mean T 1/2 following oral supplementation was approximately 9 h. Renal reabsorption of filtered carnitine following oral supplementation was 23%. The level of mean free carnitine excreted in urine correlated (R (2) = 0.78, p < 0.01) with fC0 in plasma. CONCLUSION: Patients homozygous for the c.95A>G mutation demonstrated limited skeletal muscle carnitine stores despite long-term high-dosage L-carnitine supplementation. Exacerbated renal excretion resulted in a short T 1/2 in plasma carnitine following the last oral dose of L-carnitine. Thus a treatment strategy of minimum three daily separate doses of L-carnitine is recommended, while intermission with L-carnitine treatment might prove detrimental.

Pentraxin-3 level at admission is a strong predictor of short-term mortality in a community-based hospital setting.

BACKGROUND: The pattern recognition molecule pentraxin-3 (PTX3) is a novel potential marker of prognosis, as elevated levels are associated with both disease severity and mortality in patients with a wide range of conditions. However, the usefulness of PTX3 as a prognostic biomarker in a general hospital setting is unknown. PATIENTS AND METHODS: The study cohort consisted of 1326 unselected, consecutive patients (age >40 years) admitted to a community hospital in Copenhagen, Denmark. Patients were followed until death or for a median of 11.5 years after admission. The main outcome measure was all-cause mortality. Serum samples collected from patients at admission and from 192 healthy control subjects were quantified for PTX3 level by enzyme-linked immunosorbent assay. RESULTS: PTX3 was elevated in patients (median 3.7 ng mL(-1) , range 0.5-209.8) compared with healthy nonhospitalized subjects (median 3.5 ng mL(-1) , range 0.0-8.3; P = 0.0003). Elevated PTX3 levels, defined as above the 95th percentile of the concentration in healthy subjects, were associated with increased overall mortality during the study (P < 0.0001). This increase in mortality was greatest in the short term, with an unadjusted hazard ratio (HR) of 6.4 [95% confidence interval (CI) 3.8-11.0] at 28 days after admission, compared to 1.7 (95% CI 1.4-2.0) at the end of follow-up. These results were still significant after adjustment for age, gender and glomerular filtration rate: adjusted HR of 5.0 (95% CI 2.9-8.8) and 1.4 (95% CI 1.2-1.8), respectively. CONCLUSION: These results suggest that PTX3 could be a widely applicable marker of short-term mortality in hospitalized patients and may be useful in the initial risk stratification.

Hyponatraemia at hospital admission is a predictor of overall mortality.

BACKGROUND: Hyponatraemia is a prognostic marker of increased mortality and morbidity in selected groups of hospitalised patients. The aim of the present study was to examine the prevalence and prognostic significance of hyponatraemia at hospital admission in an unselected population with a broad spectrum of medical and surgical diagnoses. METHODS: Consecutive patients >40 years of age admitted to a general district hospital in Greater Copenhagen between 1 April 1998 and 31 March 1999. Median follow-up time was 5.16 years (range 0-4372 days). Plasma sodium measurements were available in 2960 patients, and hyponatraemia defined as P-Na(+) <137 mmol/L at hospital admission was present in 1105 (37.3 %) patients. RESULTS: One-year mortality was higher for hyponatraemic patients than for normonatraemic patients: 27.5% versus 17.7%. Moreover, hyponatraemia was an independent predictor of short and long-term all-cause mortality after 1 year and after the entire observation period respectively: hazard ratio (HR) 1.6 (95 % confidence interval (CI) 1.4-1.9, P < 0.0001) and HR 1.4 (95 % CI 1.3-1.6, P < 0.0001). Patients with hyponatraemia had longer hospitalisations than patients with normonatraemia: 7.6 (±0.38) days vs 5.6 (±0.21) days, P < 0.001. There was no interaction between hyponatraemia at admission and any admission diagnoses (P > 0.05 for all interaction analyses). CONCLUSION: Hyponatraemia is associated with increased all-cause mortality and longer admission length independently of diagnosis and clinical variables.

Cardiovascular risk in patients with sleep apnoea with or without continuous positive airway pressure therapy: follow-up of 4.5 million Danish adults.

BACKGROUND: The prognostic significance of age and continuous positive airway pressure (CPAP) therapy on cardiovascular disease in patients with sleep apnoea has not been assessed previously. METHODS: Using nationwide databases, the entire Danish population was followed from 2000 until 2011. First-time sleep apnoea diagnoses and use of CPAP therapy were determined. Incidence rate ratios (IRRs) of ischaemic stroke and myocardial infarction (MI) were analysed using Poisson regression models. RESULTS: Amongst 4.5 million individuals included in the study, 33 274 developed sleep apnoea (mean age 53, 79% men) of whom 44% received persistent CPAP therapy. Median time to initiation of CPAP therapy was 88 days (interquartile range 34-346). Patients with sleep apnoea had more comorbidities compared to the general population. Crude rates of MI and ischaemic stroke were increased for sleep apnoea patients (5.4 and 3.6 events per 1000 person-years compared to 4.0 and 3.0 in the general population, respectively). Relative to the general population, risk of MI [IRR 1.71, 95% confidence interval (CI) 1.57-1.86] and ischaemic stroke (IRR 1.50, 95% CI 1.35-1.66) was significantly increased in patients with sleep apnoea, in particular in patients younger than 50 years (IRR 2.12, 95% CI 1.64-2.74 and IRR 2.34, 95% CI 1.77-3.10, respectively). Subsequent CPAP therapy was not associated with altered prognosis. CONCLUSIONS: Sleep apnoea is associated with increased risk of ischaemic stroke and MI, particularly in patients younger than 50 years of age. CPAP therapy was not associated with a reduced rate of stroke or MI.

The inflammatory biomarker YKL-40 at admission is a strong predictor of overall mortality.

OBJECTIVES: YKL-40 is an inflammatory biomarker associated with disease activity and mortality in patients with diseases characterized by inflammation and tissue remodelling. The aim of this study was to describe the prognostic value of YKL-40 in an unselected patient population. DESIGN: In consecutive patients admitted to hospital during a 1-year period, blood was collected and information regarding final diagnosis and mortality was collected. Median follow-up time was 11.5 years. SETTING: District hospital, Copenhagen, Denmark. PATIENTS: A total of 1407 patients >40 years of age were admitted acutely. MAIN OUTCOME MEASURE: All-cause mortality. RESULTS: Median YKL-40 was increased in patients (157 µg L(-1) , range 13-7704 µg L(-1) ) compared to healthy controls (40 µg L(-1) , range 29-58 µg L(-1) ; P < 0.001). Patients with YKL-40 in the highest quartile had a hazard ratio (HR) of 7.1 [95% confidence interval (CI) 4.2-12.0] for all-cause mortality in the first year and 3.4 (95% CI 2.8-4.2) in the total study period, compared to those in the lowest quartile (HR = 1). The HR for death for all patients with YKL-40 above the normal age-corrected 95th percentile was 2.1 (95% CI 1.6-2.7) after 1 year and 1.5 (95% CI 1.3-1.7) during the total study period, compared to patients with YKL-40 below the age-corrected 95th percentile. The results of multivariable analysis showed that YKL-40 was an independent biomarker of mortality; this was most significant in the first year. YKL-40 was a marker of prognosis in all disease categories. The HR for death was increased in patients with YKL-40 above the normal age-corrected 95th percentile in healthy subjects independent of type of disease (all P < 0.001). CONCLUSION: The level of YKL-40 at admission is a strong predictor of overall mortality, independent of diagnosis and could be useful as a biomarker in the acute evaluation of all patients.

Value of BNP to estimate cardiac risk in patients on cardioactive treatment in primary care.

UNLABELLED: Cardiac dysfunction may be suspected in patients with cardiovascular disease but identifying those with the highest risk is problematic. B-type natriuretic peptide (BNP) is a strong marker of heart failure in un-treated patients. This study evaluates a combined BNP and clinical algorithm for detecting cardiac dysfunction and the risk of death, in patients receiving cardioactive medication. METHODS: 459 stable general practice patients, who were taking typical heart failure drugs for any indication, were included. Echocardiography, ECG, and assay of NT-proANP and BNP (two methods) were performed. Regression models were used to identify items in a Risk Score to detect cardiac dysfunction. RESULTS: A Risk Score based on history of myocardial infarction (1 point), abnormal ECG (2 points), atrial fibrillation (1 point) and raised BNP (1-2 points) detected cardiac dysfunction with an AUC of ROC of 0.85. A Risk Score > or = 2 had a sensitivity of 90%, specificity of 58%, and positive and negative predictive values of 37% and 96%. Risk Score and LVEF<0.36 also predicted mortality. Abnormal BNP defined as either >100 pg/ml (Shionogi), or as age and sex related values, had similar predictive value. CONCLUSION: In patients on cardioactive medication, a structured Risk Score based on raised BNP, history of MI, atrial fibrillation and abnormal ECG was useful for identifying patients for immediate further examination and those who could be evaluated later.

C-reactive protein, heart rate variability and prognosis in community subjects with no apparent heart disease.

OBJECTIVES: Increased C-reactive protein (CRP) and reduced heart rate variability (HRV) both indicate poor prognosis. An inverse association between HRV and CRP has been reported, suggesting an interaction between inflammatory and autonomic systems. However, the prognostic impact of this interaction has not been studied. We thus investigated the prognostic impact of CRP, HRV and their combinations. DESIGN: Population-based study. SUBJECTS: A total of 638 middle-aged and elderly subjects with no apparent heart disease from community. METHODS: All were studied by clinical and laboratory examinations, and 24-h Holter monitoring. Four time domain measures of HRV were studied. All were prospectively followed for up to 5 years. RESULTS: Mean age was 64 years (55-75). During the follow-up, 46 total deaths and 11 cases of definite acute myocardial infarction were observed. Both CRP and three of four HRV measures were significantly associated with increased rate of death or myocardial infarction. In a Cox model with CRP >or=2.5 microg mL(-1), standard deviation for the mean value of the time between normal complexes

Neuroendocrine testing in community patients with heart disease: plasma N-terminal proatrial natriuretic peptide predicts morbidity and mortality stronger than catecholamines and heart rate variability.

BACKGROUND: Patients with heart disease are at risk of developing congestive heart failure (CHF). Neurohormonal activation may make an important contribution. AIM: In stable heart patients from primary care, to examine neuroendocrine markers of cardiac performance for the association to cardiac dysfunction, morbidity and mortality. METHODS: Plasma N-terminal atrial natriuretic peptide (N-ANP), catecholamines, 24-h ECG and blood pressure, serum urea and creatinine, echocardiography, chest X-ray and physical examination were performed. Death was recorded during 5 to 7 years of follow-up. RESULTS: The study included 56 patients. Mean age was 71 years, 54% were men, 43% had clinical signs of CHF, 39 + 52 + 9% were in NYHA I + II + III, 34% had echocardiographic cardiac dysfunction, and 18 died during follow-up. N-ANP was related to all subtypes of cardiac dysfunction (p < 0.05). Catecholamines and premature ventricular captures (PVC) were related to valvular and systolic dysfunction, but heart rate variability and dipping blood pressure were not (p > 0.05). On multivariate analyses only, N-ANP and PVC were associated with clinical signs of CHF, echocardiographic cardiac dysfunction, and mortality (p < 0.05). CONCLUSIONS: Plasma N-ANP was stronger than catecholamines and variables of 24-h monitoring (blood pressure and electrocardiogram) in predicting morbidity and mortality, thereby supporting the use of cardiac natriuretic peptides (i.e. N-ANP, BNP, or N-BNP) as the most valuable biomarker in community patients at risk of CHF.

N-terminal proBNP and mortality in hospitalised patients with heart failure and preserved vs. reduced systolic function: data from the prospective Copenhagen Hospital Heart Failure Study (CHHF).

UNLABELLED: Preserved systolic function among heart failure patients is a common finding, a fact that has only recently been fully appreciated. The aim of the present study was to examine the value of NT-proBNP to predict mortality in relation to established risk factors among consecutively hospitalised heart failure patients and secondly to characterise patients in relation to preserved and reduced systolic function. MATERIAL: At the time of admission 2230 consecutively hospitalised patients had their cardiac status evaluated through determinations of NT-proBNP, echocardiography, clinical examination and medical history. Follow-up was performed 1 year later in all patients. RESULTS: 161 patients fulfilled strict diagnostic criteria for heart failure (HF). In this subgroup of patients 1-year mortality was approximately 30% and significantly higher as compared to the remaining non-heart failure population (approx. 16%). Using univariate analysis left ventricular ejection fraction (LVEF), New York Heart Association classification (NYHA) and plasma levels of NT-proBNP all predicted mortality independently. However, regardless of systolic function, age and NYHA class, risk-stratification was provided by measurements of NT-proBNP. Having measured plasma levels of NT-proBNP, LVEF did not provide any additional prognostic information on mortality among heart failure patients (multivariate analysis). CONCLUSION: The results show that independent of LVEF, measurements of NT-proBNP add additional prognostic information. It is concluded that NT-proBNP is a strong predictor of 1-year mortality in consecutively hospitalised patients with heart failure with preserved as well as reduced systolic function.

Cross sectional study estimating prevalence of heart failure and left ventricular systolic dysfunction in community patients at risk.

OBJECTIVE: To examine a general practice population to measure the prevalence of signs and symptoms of heart failure (SSHF) and left ventricular systolic dysfunction (LVSD). DESIGN: Cross sectional screening study in three general practices followed by echocardiography. SETTING AND PATIENTS: All patients >/= 50 years in two general practices and >/= 40 years in one general practice were screened by case record reviews and questionnaires (n = 2158), to identify subjects with some evidence of heart disease. Among these, subjects were sought who had SSHF (n = 115). Of 357 subjects with evidence of heart disease, 252 were eligible for examination, and 126 underwent further cardiological assessment, including 43 with SSHF. MAIN OUTCOME MEASURES: Prevalence of SSHF as defined by a modified Boston index, LVSD defined as an indirectly measured left ventricular ejection fraction /= 50 years of age 6.4% had SSHF, 2.9% had LVSD, and 1.9% (95% confidence interval 1.3% to 2.5%) had both. To detect one case with LVSD in primary care, 14 patients with evidence of heart disease without SSHF and 5.5 patients with SSHF had to be examined. CONCLUSION: SSHF is extremely prevalent in the community, especially in primary care, but more than two thirds do not have LVSD. The number of subjects with some evidence of heart disease needing an echocardiogram to detect one case of LVSD is 14.

Risk assessment of left ventricular systolic dysfunction in primary care: cross sectional study evaluating a range of diagnostic tests.

OBJECTIVES: To assess the probability of left ventricular systolic dysfunction without echocardiography in patients from general practice. DESIGN: Cross sectional study using multivariate regression models to examine the relation between clinical variables and left ventricular systolic dysfunction as determined by echocardiography. SETTING: Three general practices in Copenhagen. SUBJECTS: 2158 patients aged >40 years were screened by questionnaires and case record reviews; 357 patients with past or present signs or symptoms of heart disease were identified, of whom 126 were eligible for and consented to examination. MAIN OUTCOME MEASURES: Clinical variables that were significantly (P<0.05) related to ejection fraction 0.8 nmol/l? (P=0.040)? Only one of 60 patients with a normal electrocardiogram had systolic dysfunction (2%, 95% confidence interval 0% to 9%) regardless of response to the other two questions. The risk of dysfunction was appreciable in patients with a yes answer to two or three questions (50%, 27% to 73%). CONCLUSIONS: A normal electrocardiogram implies a low risk of left ventricular systolic dysfunction. Patients can be identified for echocardiography on the basis of an abnormal electrocardiogram combined with increased natriuretic peptide concentration or a heart rate greater than diastolic blood pressure, or both.

[Diagnosis of acute myocardial infarction in Denmark]. / Diagnostik af akut myokardieinfarkt i Danmark.

The introduction of new biochemical markers for myocardial damage in the recent years and different application of these methods in different centres may have an impact on the diagnostic criteria for acute myocardial infarction (AMI). By means of a questionnaire we studied the diagnostic criteria for AMI in relation to the use of different biochemical markers among 78 Danish hospitals. There were large variations with regard to the choice of cardiac markers and diagnostic values for different markers. CK-B is the cardiac marker mostly used followed by CK-MB. Troponin-T test was used by about 20% of the centres. Many centres are planning to use CK-MB and Troponin-T test. A common national and international policy for diagnosis of AMI in relation to different cardiac markers should reduce these improper differences.

Precision and accuracy of a noninvasive inert gas washin method for determination of cardiac output in men.

Stout et al. (J. Appl. Physiol. 38:913-918, 1975) suggested an open-circuit multibreath (MB) inert gas method for determining pulmonary capillary blood flow (Qc) in anesthetized dogs receiving artificial ventilation. In the present work we investigated the accuracy and reproducibility of the MB method in nine healthy human subjects at spontaneous ventilation, and we compared the MB method with the inert gas rebreathing (RB) method. Qc was calculated at rest and during exercise at 50 or 100 W, and experimental errors were evaluated in computer simulations of a two-alveoli lung model. The calculated mean Qc values of the MB method were 5.56 +/- 1.23 (SD), 10.02 +/- 0.78, and 13.2 +/- 0.84 l/min, and the mean difference (MB Qc - RB Qc) was not significantly different (P > 0.05). The variation in Qc of the MB method was found to be significantly larger than that in Qc of the RB method (P < 0.01). Random measurement errors and uneven distribution of ventilation contributed to the experimental errors. We conclude that the MB method is inferior to the RB method but that the MB method may be useful under exercise conditions.

Nonlinear curve fitting improves noise sensitivity of the single-breath method for estimation of cardiac output.

In a recent theoretical study, Srinivasan (10) presented a new nonlinear curve fitting algorithm for computing pulmonary blood flow by the single-breath method. The results obtained with the new algorithm showed a considerably lower sensitivity of the estimated pulmonary blood flow to experimental noise than with the linear curve fitting technique reported previously by Grønlund (5). In the present study, we have compared the linear and the nonlinear algorithms using computer simulations and experimental single-breath data. The results showed only a small difference between the two methods. Further, we showed that the difference between the noise sensitivities obtained by Grønlund (5) and Srinivasan (10) can be explained almost entirely by a difference between the models used to simulate experimental noise.