Evaluation of serum markers in the LRF CLL4 trial: ß2-microglobulin but not serum free light chains, is an independent marker of overall survival.

Chronic lymphocytic leukemia (CLL) is characterized by heterogeneous clinical behavior and there is a need for improved biomarkers. The current study evaluated the prognostic significance of serum free light chains (sFLC, kappa, and lambda) and other serum markers (bar, serum thymidine kinase (sTK), soluble CD23, and LDH) together with established biomarkers in 289 patients enrolled into the LRF CLL4 trial. In a multivariable analysis of serum markers alone, higher big and kappa light chains were statistically significant in predicting disease progression and higher blg, and sTK in predicting mortality. In multivariable analysis for overall survival the following were independently significant: ß2M levels, immunoglobulin gene (IGHV) mutational status (>98% homology), age, 17p13 deletions (>10%), and CD38 expression. ß2M is the only serum marker that retained clear independent value as a biomarker in the LRF CLL4 trial and remains powerfully prognostic requiring evaluation in any future method of risk stratifying patients.

Proton pump inhibitor associated hypomagnasaemia - a cause for concern?

AIMS: In recent years, there have been a number of case reports of severe hypomagnesaemia associated with proton pump inhibitor (PPI) use, such that both the FDA and MHRA have issued drug safety warnings. They have recommended periodic serum magnesium testing in patients prescribed PPIs but provide no guidance on timing of these measurements. METHODS: To our knowledge, we are the first to perform a prospective study to explore specifically proton pump inhibitor associated hypomagnesaemia (PPIAH). We followed 56 patients new to PPIs prospectively as well as a further 100 patients on long term PPIs cross-sectionally to identify what factors may be influencing the development of significant hypomagnesaemia. RESULTS: For the prospective arm of the study, we measured serum magnesium levels prior to starting a PPI and again at regular intervals for the next 8 months. For the cross-sectional arm of the study we measured serum magnesium levels on patients on PPI therapy ranging from less than 1 year to over 5 years. CONCLUSION: We found that, although there was a significant downward trend in serum magnesium levels in patients new to PPI therapy with time, clinically relevant hypomagnesaemia was not readily identifiable on regular blood testing. We did however identify patients on concurrent diuretic therapy as being at higher risk and so would recommend regular serum magnesium testing alongside their regular renal function monitoring on a more frequent basis such as annually.

Cardiac biomarkers at high altitude.

BACKGROUND: Classically, biomarkers such as the natriuretic peptides (NPs) BNP/NT-proBNP are associated with the diagnosis of heart failure and hs-cTnT with acute coronary syndromes. NPs are also elevated in pulmonary hypertension. High pulmonary artery systolic pressure (PASP) is a key feature of high altitude pulmonary edema (HAPE), which may be difficult to diagnose in the field. We have previously demonstrated that NPs are associated with high PASP and the presence of acute mountain sickness (AMS) in a small cohort at HA. We aimed to investigate the utility of several common cardiac biomarkers in diagnosing high PASP and AMS. METHODS: 48 participants were assessed post-trekking and at rest at three altitudes: 3833 m, 4450 m, and 5129 m. NPs, hs-cTnT and hsCRP, were quantified using immunoassays, PASP was measured by echocardiography, and AMS scores were recorded. RESULTS: Significant changes occurred with ascent in NPs, hs-cTnT, hsCRP (all p<0.001) and PASP (p=0.006). A high PASP (≥40 mm Hg) was associated with higher NPs, NT-proBNP: 137±195 vs. 71.8±68 (p=0.001); BNP 15.3±18.1 vs. 8.7±6.6 (p=0.001). NPs were significantly higher in those with AMS or severe AMS vs. those without (severe AMS: NT-proBNP: 161.2±264 vs. 76.4±82.5 (p=0.008)). The NPs correlated with hsCRP. cTnT increased with exercise at HA and was also higher in those with a high PASP (13.8±21 vs. 7.8±6.5, p=0.018). CONCLUSION: The NPs and hs-cTnT are associated with high PASP at HA and the NPs with AMS.

The effects of exercise at high altitude on high-sensitivity cardiac troponin release and associated biventricular cardiac function.

BACKGROUND: It has been consistently shown that heavy exercise leads to cardiac troponin (cTn) release and variable changes in post exercise cardiac function. This relationship has not been explored at increasing or significant high altitude (HA). This study assessed the effects of exercise at progressively increasing HA on high-sensitivity (hs)-cTnT levels and their relationship to biventricular cardiac function and severity of acute mountain sickness (AMS). METHODS: Transthoracic echocardiograms, hs-cTnT levels and AMS scores were measured at rest at 1,300 m then repeated post exercise and 12 h later after progressive trekking to 3,440, 4,270 m and at 5,150 m (after trekking to 5,643 m) on 19 healthy subjects (age 35.4 ± years, 52.6 % males). RESULTS: There was a detectable increase (>5 ng/L) in post exercise hs-cTnT with exercise at HA which became significant at 5,150 m (5.84 % at 3,440 m, 5.2 % at 4,270 m and 56.3 % at 5,150 m; p = 0.0005). Compared with baseline, HA to 5,150 m led to a significant rise in post exercise Lake Louis AMS scores (p < 0.001) pulmonary artery systolic pressure (PASP) (23.7 ± 3.8 vs 37.9 ± 11.7 mmHg: p < 0.001), cardiac output (5.2 ± 1.2 vs 7.5 ± 1.3 l/min; p < 0.001) and a fall in SpO2 (96.1 ± vs 77.4 ± 12.0 %; p < 0.001). There was no change in stroke volume (p = 0.10) or estimated filling pressures (E/E') of the left (p = 0.50) and right ventricles (p = 0.4). On multivariate analysis increasing cardiac output (p = 0.02) and PASP (p = 0.04) and decreasing SpO2 (p = 0.01) were the only independent predictors of increasing cTnT levels (overall R (2) = 0.23, p < 0.0001). CONCLUSIONS: Moderate intensity exercise at significant HA influences the post exercise increase in hs-cTnT without overt deleterious effects on cardiac function.

Neutrophil gelatinase-associated lipocalin: its response to hypoxia and association with acute mountain sickness.

Acute Mountain Sickness (AMS) is a common clinical challenge at high altitude (HA). A point-of-care biochemical marker for AMS could have widespread utility. Neutrophil gelatinase-associated lipocalin (NGAL) rises in response to renal injury, inflammation and oxidative stress. We investigated whether NGAL rises with HA and if this rise was related to AMS, hypoxia or exercise. NGAL was assayed in a cohort (n = 22) undertaking 6 hours exercise at near sea-level (SL); a cohort (n = 14) during 3 hours of normobaric hypoxia (FiO2 11.6%) and on two trekking expeditions (n = 52) to over 5000 m. NGAL did not change with exercise at SL or following normobaric hypoxia. During the trekking expeditions NGAL levels (ng/ml, mean ± sd, range) rose significantly (P < 0.001) from 68 ± 14 (60-102) at 1300 m to 183 ± 107 (65-519); 143 ± 66 (60-315) and 150 ± 71 (60-357) at 3400 m, 4270 m and 5150 m respectively. At 5150 m there was a significant difference in NGAL between those with severe AMS (n = 7), mild AMS (n = 16) or no AMS (n = 23): 201 ± 34 versus 171 ± 19 versus 124 ± 12 respectively (P = 0.009 for severe versus no AMS; P = 0.026 for mild versus no AMS). In summary, NGAL rises in response to prolonged hypobaric hypoxia and demonstrates a relationship to the presence and severity of AMS.

Acute hypoglycemia decreases myocardial blood flow reserve in patients with type 1 diabetes mellitus and in healthy humans.

BACKGROUND: Hypoglycemia is associated with increased cardiovascular mortality, but the reason for this association is poorly understood. We tested the hypothesis that the myocardial blood flow reserve (MBFR) is decreased during hypoglycemia using myocardial contrast echocardiography in patients with type 1 diabetes mellitus (DM) and in healthy control subjects. METHODS AND RESULTS: Twenty-eight volunteers with DM and 19 control subjects underwent hyperinsulinemic clamps with maintained sequential hyperinsulinemic euglycemia (plasma glucose, 90 mg/dL [5.0 mmol/L]) followed by hyperinsulinemic hypoglycemia (plasma glucose, 50 mg/dL [2.8 mmol/L]) for 60 minutes each. Low-power real-time myocardial contrast echocardiography was performed with flash impulse imaging using low-dose dipyridamole stress at baseline and during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia. In control subjects, MBFR increased during hyperinsulinemic euglycemia by 0.57 U (22%) above baseline (B coefficient, 0.57; 95% confidence interval, 0.38 to 0.75; P<0.0001) and decreased during hyperinsulinemic hypoglycemia by 0.36 U (14%) below baseline values (B coefficient, -0.36; 95% confidence interval, -0.50 to -0.23; P<0.0001). Although MBFR was lower in patients with DM at baseline by 0.37 U (14%; B coefficient, -0.37; 95% confidence interval, -0.55 to -0.19; P=0.0002) compared with control subjects at baseline, the subsequent changes in MBFR during hyperinsulinemic euglycemia and hyperinsulinemic hypoglycemia in DM patients were similar to that observed in control subjects. Finally, the presence of microvascular complications in the patients with DM was associated with a reduction in MBFR of 0.52 U (24%; B coefficient, -0.52; 95% confidence interval, -0.70 to -0.34; P<0.0001). CONCLUSIONS: Hypoglycemia decreases MBFR in both healthy humans and patients with DM. This finding may explain the association between hypoglycemia and increased cardiovascular mortality in susceptible individuals.

Laboratory-based non-clinical comparison of occlusion rates using three rapid-acting insulin analogs in continuous subcutaneous insulin infusion catheters using low flow rates.

BACKGROUND: Rapid-acting analog insulin is used increasingly for continuous subcutaneous insulin infusion therapy (CSII). As the choice of insulin may be a determinant of catheter occlusion, we compared rates of early and late occlusion of a standard CSII catheter with three insulin analogs in a laboratory-based setting. METHODS: Twenty-four pumps were used for the study. Each insulin analog (glulisine, lispro, and aspart) was assigned to eight pumps in a randomized order for each of nine runs of 5-day duration. Pumps were primed to receive a basal dose of 0.1 IU/h with a bolus dose of 2 IU given three times each day. Pumps were placed in an incubator to maintain temperature in the range of 32 to 36 degrees C. RESULTS: Over the entire study period, there were 48 occlusions. Early occlusions (within 72 hours) occurred during five of the nine runs with no evidence of any difference between insulins (p = .27); there were no occlusions before 48 hours. Over the whole of the 5-day infusion period, the probabilities of overall occlusion for each insulin were 40.9% [28 to 55%, 95% confidence interval (CI)] for glulisine, 9.2% (4 to 19.5%, 95% CI) for aspart, and 15.7% (8.1 to 28.1%, 95% CI) for lispro. All occlusions, except for three, occurred during a bolus infusion. CONCLUSIONS: During CSII under laboratory conditions, early catheter occlusions (within 72 hours) are rare and independent of the choice of insulin analog. For patients using insulin pump therapy, the importance of catheter change within 72 hours should be emphasized irrespective of the insulin used. Beyond 72 hours, the risk of occlusion differs between insulins, being more common with glulisine.