Mats Stridsberg

N-Terminal Pro–Brain Natriuretic Peptide and Other Risk Markers for the Separate Prediction of Mortality and Subsequent Myocardial Infarction in Patients With Unstable Coronary Artery Disease A Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV Substudy

Background Biochemical markers are useful for prediction of cardiac events in patients with non‐ST‐segment‐elevation acute coronary syndrome (ACS). The associations between N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) and other biochemical and clinical risk indicators, as well as their prognostic value concerning the individual end points of death and myocardial infarction (MI), were elucidated in a large cohort of ACS patients. Methods and Results NT‐proBNP, troponin T, and C‐reactive protein (CRP) were analyzed in blood samples obtained at a median of 9.5 hours from symptom onset in 6809 of 7800 ACS patients in the Global Utilization of Strategies To Open occluded arteries‐IV (GUSTO‐IV) trial. Levels of NT‐proBNP were correlated independently with age, female gender, low body weight, diabetes, renal dysfunction, history of MI, heart failure, heart rate, ongoing myocardial damage, and time since onset of ischemia. Increasing quartiles of NT‐proBNP were related to short‐ and long‐term mortality that reached 1.8%, 3.9%, 7.7%, and 19.2%, (P<0.001), respectively, at 1 year. Levels of troponin T, CRP, heart rate, and creatinine clearance, in addition to ST‐segment depression, were also correlated independently with 1‐year mortality, but NT‐proBNP was the marker with the strongest relation. In contrast, only troponin T, creatinine clearance, and ST‐segment depression were independently related to future MI. The combination of NT‐proBNP and creatinine clearance provided the best prediction, with a 1‐year mortality of 25.7% with both markers in the top quartile vs 0.3% with both markers in the bottom quartile. Conclusions The use of NT‐proBNP appears to add critical prognostic insight to the assessment of patients with ACS. (Circulation. 2003;108:275‐281.)

Carcinoid tumors: Analysis of prognostic factors and survival in 301 patients from a referral center

BACKGROUND Little is known about factors related to prognosis in patients with carcinoid disease. In this study we have tried to identify such factors. PATIENTS AND METHODS We have evaluated 301 consecutive carcinoid patients (256 midgut, 39 foregut and six hindgut) referred during 15 years for medical treatment with respect to tumor distribution, hormone production, prognostic factors and survival. RESULTS Survival was significantly shorter in midgut carcinoid patients with > or = 5 liver metastases or with high levels of urinary 5-hydroxyindoleacetic acid, plasma chromogranin A or neuropeptide K. By univariate analysis, these variables together with the presence of carcinoid syndrome were related to a higher risk of dying. In multivariate analyses, performed in the 71 patients with full information on all variables, advanced age and plasma chromogranin A > 5000 micrograms/l were independent predictors of overall survival. CONCLUSIONS Poor prognostic factors for midgut carcinoid patients were multiple liver metastases, presence of carcinoid syndrome and high levels of the tumor markers studied. In this study the only independent predictors of bad prognosis in midgut, carcinoid patients were advanced age, which however is inherently related to overall survival, and plasma chromogranin A > 5000 micrograms/l. Thus, chromogranin A may prove to be an important prognostic marker for patients with carcinoid tumors.

N-terminal pro brain natriuretic peptide on admission for early risk stratification of patients with chest pain and no ST-segment elevation☆

OBJECTIVES The study evaluated the prognostic value of single measurement of N-terminal pro brain natriuretic peptide (NT-proBNP) obtained on admission in patients with symptoms suggestive of an acute coronary syndrome and no ST-segment elevation. BACKGROUND Patients with symptoms suggestive of an acute coronary syndrome and no ST-segment elevation constitute a large and heterogeneous population. Early risk stratification has been based on clinical background factors, electrocardiography (ECG) and biochemical markers of myocardial damage. The neurohormonal activation has, so far, received less attention. METHODS The NT-proBNP was analyzed on admission in 755 patients admitted because of chest pain and no ST-segment elevation. Patients were followed concerning death for 40 months (median). RESULTS The median NT-proBNP level was 400 (111 to 1646) ng/l. Compared to the lowest quartile, patients in the second, third and fourth quartiles had a relative risk of subsequent death of 4.2 (1.6 to 11.1), 10.7 (4.2 to 26.8) and 26.6 (10.8 to 65.5), respectively. When NT-proBNP was added to a Cox regression model including clinical background factors, ECG and troponin T, the NT-proBNP levels were independently associated with prognosis. CONCLUSIONS A single measurement of NT-proBNP on admission will substantially improve the early risk stratification of patients with symptoms suggestive of an acute coronary syndrome and no ST-segment elevation. A combination of clinical background factors, ECG, troponin T and NT-proBNP obtained on admission will provide a highly discerning tool for risk stratification and further clinical decisions.

Physiological Hyperglycemia Slows Gastric Emptying in Normal Subjects and Patients With Insulin-Dependent Diabetes Mellitus

BACKGROUND & AIMS Marked hyperglycemia slows and hypoglycemia accelerates gastric emptying. The aim of this study was to determine the effect of physiological changes in blood glucose gastric emptying. METHODS In 8 healthy subjects and 9 patients with insulin-dependent diabetes mellitus (IDDM) without gastrointestinal tract symptoms or evidence of neuropathy, gastric emptying of a mixed meal was measured by scintigraphy. Using an insulin-glucose clamp, the blood glucose concentration was stabilized at 4 and 8 mmol/L on 2 separate days. RESULTS The intragastric retention of the solid meal component at 100 minutes was 55.2% +/- 4.5% at 8 mmol/L vs. 36.7% +/- 5.5% at 4 mmol/L (P = 0.004) in normal subjects and 44.2% +/- 4.2% vs. 35.7% +/- 4.2% (P = 0.004) in patients with IDDM. The time taken for 50% emptying of the liquid meal was 57.0 +/- 10.8 minutes at 8 mmol/L vs. 32.2 +/- 12.6 minutes at 4 mmol/L (P = 0.002) in normal subjects and 41.3 +/- 3.4 minutes vs. 29.1 +/- 3.5 minutes (P = 0.002) in patients with IDDM. CONCLUSIONS Changes in blood glucose within the normal postprandial range have a significant impact on gastric emptying in both normal subjects and patients with IDDM.

Tumor Markers in Neuroendocrine Tumors

Most neuroendocrine tumors produce and secrete a multitude of peptide hormones and amines. Some of these substances cause a specific clinical syndrome: carcinoid, Zollinger-Ellison, hyperglycemic, glucagonoma and WDHA syndrome. Specific markers for these syndromes are basal and/or stimulated levels of urinary 5-HIAA, serum or plasma gastrin, insulin, glucagon and vasoactive intestinal polypeptide, respectively. Some carcinoid tumors and about one third of endocrine pancreatic tumors do not present any clinical symptoms and are called ‘nonfunctioning’ tumors. Therefore, general tumor markers such as chromogranin A, pancreatic polypeptide, serum neuron-specific enolase and subunits of glycoprotein hormones have been used for screening purposes in patients without distinct clinical hormone-related symptoms. Among these general tumor markers chromogranin A, although its precise function is not yet established, has been shown to be a very sensitive and specific serum marker for various types of neuroendocrine tumors. This is because it may also be elevated in many cases of less well-differentiated tumors of neuroendocrine origin that do not secrete known hormones. At the moment, chromogranin A is considered the best general neuroendocrine serum or plasma marker available both for diagnosis and therapeutic evaluation and is increased in 50–100% of patients with various neuroendocrine tumors. Chromogranin A serum or plasma levels reflect tumor load, and it may be an independent marker of prognosis in patients with midgut carcinoids.

N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease.

OBJECTIVES We sought to examine whether measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP), in addition to cardiac troponin T (cTnT) and interleukin-6 (IL-6), improve the ability to identify high-risk patients who benefit from an early invasive strategy. BACKGROUND Biochemical indicators of cardiac performance (e.g., NT-proBNP), inflammation (e.g., IL-6), and myocardial damage (e.g., cTnT) predict mortality in unstable coronary artery disease (UCAD) (i.e., unstable angina or non-ST-segment elevation myocardial infarction [MI]). In these patients, an early invasive treatment strategy improves the outcome. METHODS Levels of NT-proBNP, cTnT, and IL-6 were measured in 2,019 patients with UCAD randomized to an invasive or non-invasive strategy in the FRagmin and fast revascularization during InStability in Coronary artery disease (FRISC-II) trial. Patients were followed up for two years to determine death and MI. RESULTS Patients in the third NT-proBNP tertile had a 4.1-fold (95% confidence interval [CI] 2.4 to 7.2) and 3.5-fold (95% CI 1.8 to 6.8) increased mortality in the non-invasive and invasive groups, respectively. An increased NT-proBNP level was independently associated with mortality. In patients with increased levels of both NT-proBNP and IL-6, an early invasive strategy reduced mortality by 7.3% (risk ratio 0.46, 95% CI 0.21 to 1.00). In patients with lower NT-proBNP or IL-6 levels, the mortality was not reduced. Only elevated cTnT was independently associated with future MI and a reduction of MI by means of an invasive strategy. CONCLUSIONS N-terminal proBNP is independently associated with mortality. The combination of NT-proBNP and IL-6 seems to be a useful tool in the identification of patients with a definite survival benefit from an early invasive strategy. Only cTnT is independently associated with future MI and a reduction of MI by an invasive strategy.

Hypocalcemia and parathyroid hormone secretion in critically ill patients.

Objective: To investigate possible causes of hypocalcemia and to assess parathyroid hormone (PTH) secretion in intensive care unit (ICU) patients. Design: Combined cross‐sectional and prospective study. Setting: ICU in a university hospital. Patients: Thirteen patients with sepsis and 13 patients who underwent major surgery. Interventions: None. Measurements and Main Results: Calcium metabolic indices were investigated during the first 24 hrs in the ICU and after 2 days. Eight of the surgical patients and five of the septic patients were subjected to a citrate/calcium infusion on day 1 in the ICU, to study the dynamics of PTH secretion. The blood ionized calcium (Ca2+) concentration was generally low in the septic patients (mean ± SD, 1.03 ± 0.08 mmol/L; reference value, 1.10‐1.30) and increased, but not normalized, after 2 days. Hypocalcemia was only occasionally seen in the surgical patients. In the septic patients, urinary excretion of calcium was low; and, in both patient groups, elevated concentrations of two markers of bone resorption, deoxypyridinoline and ICTP (serum carboxy‐terminal cross‐linked telopeptide of type I collagen), were found. In cases of sepsis, the concentrations of proinflammatory cytokines were high (394 ± 536 pg/mL for tumor necrosis factor‐α and 5676 ± 5190 pg/mL for interleukin‐6, both normally <10‐20). The Ca2+ concentration was inversely related to tumor necrosis factor‐α and interleukin‐6 (r2 = .35 − .42; p < .01), as well as to procalcitonin (r2 = .71; p < .01). Despite normocalcemia in the surgical patients, serum PTH concentrations were elevated in both patient groups (97 and 109 ng/L) (reference value, <55 ng/L), both on day 1 and day 3 in the ICU. The citrate/calcium infusion revealed an increased secretory response of PTH to lowered Ca2+ concentrations in both groups of patients (p < .05), when compared with matched healthy controls. Conclusion: Hypocalcemia was common in septic ICU patients and was not the result of an increased urinary excretion of calcium or of an attenuated bone resorption, but seemed related to the inflammatory response. An increased PTH secretion was found in both patient groups.

Catecholamine release-inhibitory peptide catestatin (chromogranin A352-372): Naturally occurring amino acid variant Gly364Ser causes profound changes in human autonomic activity and alters risk for hypertension

Background— Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release–inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. Methods and Results— Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. Conclusions— The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

Neuroendocrine differentiation in carcinomas of the prostate. Do neuroendocrine serum markers reflect immunohistochemical findings

The aim of the present study was to examine the correlation between the immunohistochemical findings and the serum markers for neuroendocrine (NE) cells in patients with carcinoma of the prostate. Preoperative serum values of chromogranin A (CgA), chromogranin B (CgB), pancreastatin (Pst), neuron‐specific enolase (NSE), and prostatic specific antigen (PSA) were determined in 22 patients. The tissue specimens were obtained by a palliative transurethral resection of the prostate (TURP) because of urinary outflow obstruction. Immunohistochemistry was performed by using antibodies against CgA, CgB, NSE, serotonin, thyroid‐stimulating hormone (TSH), and somatostatin. Tumor cells with NE differentiation were found in 91% of the cases. No patient had elevated serum values of NSE, despite the presence of NSE‐positive tumor cells in 77% of the tumors. Neither did CgB in serum correlate with the immunohistochemical findings. Elevated serum values of CgA were found in 59% of patients. A positive correlation between the number of CgA‐staining cells and the serum values of CgA was found, as seven out of eight patients with groups of CgA‐positive tumor cells had elevated serum values of CgA. We conclude that CgA, in contrast to NSE, CgB, and Pst, seems to be a useful serum marker in predicting the extent of NE differentiation in prostatic tumors. Prostate 30:1–6, 1997

Clinical symptoms, hormone profiles, treatment, and prognosis in patients with gastric carcinoids

Background—Type 1 gastric carcinoids are associated with hypergastrinaemia and chronic atrophic gastritis, type 2 occur in patients with multiple endocrine neoplasia type 1 combined with Zollinger-Ellison syndrome, and type 3 lack any relation to hypergastrinaemia. Type 1 tumours are usually benign whereas type 3 are highly malignant. Aims—To identify possible tumour markers in patients with gastric carcinoids. Patients/method—Nine patients with type 1, one with type 2, and five with type 3 were evaluated with regard to symptoms, hormone profile, and prognosis. Results—Plasma chromogranin A was increased in all patients but was higher (p<0.01) in those with type 3 than those with type 1 carcinoids. All patients with type 3 carcinoids died from metastatic disease, but none of the type 1 patients died as a result of their tumours. One type 1 patient with a solitary liver metastasis received interferon α and octreotide treatment. Nine months later, the metastasis was no longer detectable. She is still alive eight years after diagnosis, without recurrent disease. This represents the only reported case of foregut carcinoid with an unresectable liver metastasis that seems to be have been cured by biotherapy. Conclusions—Plasma chromogranin A appears to be a valuable tumour marker for all types of gastric carcinoid. Combination therapy with interferon α and octreotide may be beneficial in patients with metastasising type 1 gastric carcinoids.