Serial blood volume measurements in patients with compensated chronic heart failure: How do volume profiles change over time?

Among patients with chronic heart failure (HF) intravascular volume profiles vary significantly despite similar clinical compensation. However, little is known regarding changes in blood volume (BV) profiles over time. The objective of this analysis was to identify the extent and character of changes in volume profiles over time. A prospective analysis was undertaken in patients who were hospitalized and treated for fluid overload. Quantitative BV analyses were obtained in a compensated state at hospital discharge (baseline) and follow-up at 1, 3, and 6 mo. Data were available on 10 patients who remained stable without rehospitalization or medication change over a 6-mo period. Baseline BV profiles were highly variable at hospital discharge with an average deviation of +28% above normal in 6 patients and normal BV in 4 patients. Over the follow-up period, the median change in BV was -201 mL [-3% (-6, +3%)] from baseline with profiles remaining in the same volume category in 9 out of 10 patients. Crossover from normal BV to mild contraction (-13% of normal) occurred in one patient. Red blood cell mass demonstrated the largest change over 6 mo [median -275 (-410, +175) mL] with a deviation from normal of -14 (-20, +8) % (reflecting mild anemia). These findings suggest that BV profiles in clinically compensated patients with HF do not change substantially over a 6-mo period regardless of baseline expanded or normal BV. This lack of change in volume profiles particularly from an expanded BV has implications for long-term volume management, clinical outcomes, and also our understanding of volume homeostasis in HF.NEW & NOTEWORTHY The novel findings of this study demonstrate that blood volume profiles while highly variable in clinically compensated patients with HF on stable medical therapy do not change substantially over a 6-mo period regardless of baseline expanded or normal blood volumes. This lack of change in volume profiles particularly from an expanded blood volume has implications for long-term volume management and also for how we understand the pathophysiology of volume homeostasis in chronic HF.

The Stockholm-Gotland perinatal cohort-A population-based cohort including longitudinal data throughout pregnancy and the postpartum period.

BACKGROUND: Register-based reproductive and perinatal databases rarely contain detailed information from medical records or repeated measurements throughout pregnancy and delivery. This lack of enriched pregnancy and birth data led to the initiation of the Swedish Stockholm-Gotland Perinatal Cohort (SGPC). OBJECTIVES: To describe the strengths of the SGPC, as well as the unique research questions that can be addressed using this cohort. POPULATION: The SGPC is a prospectively collected, population-based cohort that includes all births (from 22 completed gestational weeks onwards) between 1 January 2008 and 15 June 2020 in the Stockholm and Gotland regions of Sweden (335,153 singleton and 11,025 multiple pregnancies). DESIGN: Descriptive study. METHODS: The SGPC is based on the electronic medical records of women and their infants. The medical record system is used for all antenatal clinic visits and admissions, delivery and neonatal admissions, as well as postpartum clinical visits. SGPC has been further enriched with data linkages to 10 Swedish National Health Care and Quality Registers. PRELIMINARY RESULTS: In contrast to other reproductive and perinatal databases available in Sweden, including the Medical Birth Register and the Pregnancy Register, SGPC contains highly detailed medical record data, including time-varying serial measurements for physiological parameters throughout pregnancy, delivery, and postpartum, for both mother and infant. These strengths have enabled studies that were previously inconceivable; the effects of serial measurements of pregnancy weight gain, changes in haemoglobin counts and blood pressure during pregnancy, fetal weight estimations by ultrasound, duration of stages and phases of labour, cervical dilatation and oxytocin use during delivery, and constructing reference curves for umbilical cord pH. CONCLUSIONS: The SGPC-with its rich content, repeated measurements and linkages to numerous health care and quality registers-is a unique cohort that enables high-quality perinatal studies that would otherwise not be possible.

Serial measurement of circulating calprotectin as a prognostic biomarker in COVID-19 patients in intensive care setting.

OBJECTIVES: Circulating calprotectin (cCLP) has been shown to be a promising prognostic marker for COVID-19 severity. We aimed to investigate the prognostic value of serial measurements of cCLP in COVID-19 patients admitted to an intensive care unit (ICU). METHODS: From November 2020 to May 2021, patients with COVID-19, admitted at the ICU of the OLV Hospital, Aalst, Belgium, were prospectively included. For sixty-six (66) patients, blood samples were collected at admission and subsequently every 48 h during ICU stay. On every sample (total n=301), a cCLP (EliA™ Calprotectin 2, Phadia 200, Thermo Fisher Scientific; serum/plasma protocol (for Research Use Only, -RUO-) and C-reactive protein (CRP; cobas c501/c503, Roche Diagnostics) analysis were performed. Linear mixed models were used to associate biomarkers levels with mortality, need for mechanical ventilation, length of stay at ICU (LOS-ICU) and medication use (antibiotics, corticosteroids, antiviral and immune suppressant/modulatory drugs). RESULTS: Longitudinally higher levels of all biomarkers were associated with LOS-ICU and with the need for mechanical ventilation. Medication use and LOS-ICU were not associated with variations in cCLP and CRP levels. cCLP levels increased significantly during ICU hospitalization in the deceased group (n=21/66) but decreased in the non-deceased group (n=45/66). In contrast, CRP levels decreased non-significantly in both patient groups, although significantly longitudinally higher CRP levels were obtained in the deceased subgroup. CONCLUSIONS: Serial measurements of cCLP provides prognostic information which can be useful to guide clinical management of COVID-19 patients in ICU setting.

Mechanocardiography-Based Measurement System Indicating Changes in Heart Failure Patients during Hospital Admission and Discharge.

Heart failure (HF) is a disease related to impaired performance of the heart and is a significant cause of mortality and treatment costs in the world. During its progression, HF causes worsening (decompensation) periods which generally require hospital care. In order to reduce the suffering of the patients and the treatment cost, avoiding unnecessary hospital visits is essential, as hospitalization can be prevented by medication. We have developed a data-collection device that includes a high-quality 3-axis accelerometer and 3-axis gyroscope and a single-lead ECG. This allows gathering ECG synchronized data utilizing seismo- and gyrocardiography (SCG, GCG, jointly mechanocardiography, MCG) and comparing the signals of HF patients in acute decompensation state (hospital admission) and compensated condition (hospital discharge). In the MECHANO-HF study, we gathered data from 20 patients, who each had admission and discharge measurements. In order to avoid overfitting, we used only features developed beforehand and selected features that were not outliers. As a result, we found three important signs indicating the worsening of the disease: an increase in signal RMS (root-mean-square) strength (across SCG and GCG), an increase in the strength of the third heart sound (S3), and a decrease in signal stability around the first heart sound (S1). The best individual feature (S3) alone was able to separate the recordings, giving 85.0% accuracy and 90.9% accuracy regarding all signals and signals with sinus rhythm only, respectively. These observations pave the way to implement solutions for patient self-screening of the HF using serial measurements.

Point of care with serial NT-proBNP measurement in patients with acute decompensated heart failure as a therapy-monitoring during hospitalization (POC-HF): Study protocol of a prospective, unblinded, randomized, controlled pilot trial.

Despite important advances in diagnosis and medical therapy of heart failure (HF), disease monitoring and therapy guidance remains to be based on clinical signs and symptoms. NT-proBNP was repeatedly demonstrated to be a strong and independent predictor of morbidity and mortality in patients with HF. Only few - and conflicting - data are available on the efficacy of serial measurement of NT-proBNP as a tool for treatment monitoring in HF. These data are limited to the outpatient setting. Currently, no data are available on the effects of this approach in patients hospitalized for acute decompensated HF. The goal of this study is to explore whether the availability of serial NT-proBNP measurements may influence treatment decisions in patients with acute decompensated HF, and whether this leads to more rapid dose adjustments of prognostically beneficial medical therapies and earlier hospital discharge. In the intervention group, serial measurements of NT-proBNP every second business day are performed and made available to the treating physician, while no serial measurements are available in control group. HF therapy is left at the discretion of the treating physician. The primary endpoints are defined as the effects of monitoring NT-proBNP on medical HF therapy decisions, including type and dosing of medical therapies and the rapidity of adjustments, length of hospital stay, and evaluation of the changes in NT-proBNP values. Additional secondary endpoints include incidence of electrolyte imbalances and renal failure, changes in NYHA functional class, vital signs, body weight, quality of life, incidence of adverse events, transfer to Intensive Care Units, and mortality.

NT-proBNP Concentration and Early Cardiac Dysfunction in Patients Receiving Dialysis: A Prospective Cohort Study.

INTRODUCTION: The significance of N-terminal pro-B type natriuretic peptide (NT-proBNP) to detect heart failure in patients with end-stage kidney diseases on dialysis is controversial. OBJECTIVE: To assess whether serial measurements of NT-proBNP can predict worsening cardiac function in dialysis patients. METHODS: In this prospective, longitudinal, observational cohort study, the relationship between changes in monthly plasma NT-proBNP concentrations and changes in echocardiographic indices (left ventricular global longitudinal strain [GLS] and ejection fraction [LVEF]) were analyzed in dialysis patients without symptoms of heart failure over 24 months using multilevel mixed effects models. RESULTS: The study included 40 dialysis patients who were followed for a median period of 24 months. Logarithmically transformed baseline plasma NT-proBNP levels were correlated positively with GLS (r = 0.48, p = 0.002) and negatively with LVEF (r = -0.44, p = 0.005). Time-averaged and maximum NT-proBNP values during the echocardiogram intervals were significantly correlated with GLS and LVEF over time. Every 1-unit increase in average NT-proBNP level during the echocardiogram interval was associated with a 0.99 (95% confidence interval, 0.41-1.56) higher GLS (%) and 2.90 (1.22-4.57) lower LVEF (%). Every 1-unit increase in maximum NT-proBNP level was associated with a 0.90 (0.35-1.45) higher GLS (%) and 2.67 (1.03-4.30) lower LVEF (%). This increase in GLS indicates a reduction in systolic performance. CONCLUSIONS: Our cohort study demonstrated that serial plasma NT-proBNP concentrations may be useful for early identification of individuals with worsening cardiac function over time.

Serial Measurements of N-Terminal Pro-B-Type Natriuretic Peptide Serum Level for Monitoring Pulmonary Arterial Hypertension in Children.

OBJECTIVE: To assess the association between serially measured N-terminal pro-B-type natriuretic peptide (NT-proBNP) serum levels and disease severity in children with pulmonary arterial hypertension (PAH), and to assess its predictive value for death or (heart-)lung transplantation. STUDY DESIGN: This was a longitudinal cohort study of the Dutch National Network for Pediatric Pulmonary Hypertension conducted between 2003 and 2017. Data on NT-proBNP and disease severity markers (World Health Organization Functional Class [WHO-FC], 6-minute walking distance [6MWD], and tricuspid annular plane systolic excursion [TAPSE]) were collected every 3 to 6 months from 82 children with PAH. The outcome measure was death or (heart-)lung transplantation. Also, NT-proBNP levels over time were compared between survivors and nonsurvivors. RESULTS: The median patient age was 8.8 years (IQR, 4.6-13.5 years), and 61% were female. The median duration of follow-up was 4.8 years (IQR, 1.9-10.0 years). At all times during the course of disease, higher NT-proBNP levels were associated with higher WHO-FC (ß = 0.526; 95% CI, 0.451-0.600), lower 6MWD z-score (ß = -0.587; 95% CI, -0.828 to -0.346), lower TAPSE z-score (ß = -0.783; 95% CI, -1.016 to -0.549), and elevated risk of death or (heart-)lung transplantation (hazard ratio 16.61; 95% CI, 7.81-35.33). Compared with survivors, nonsurvivors had NT-proBNP levels that were higher at first measurement and increased exponentially over time (P = .005). Changes in NT-proBNP serum level over time were predictive of outcome. CONCLUSIONS: Throughout the disease course of pediatric PAH, serial measurements of NT-proBNP are associated with disease severity and transplant-free survival. Monitoring NT-proBNP levels over time provides important prognostic information that can support clinical decision making in combination with other established prognostic markers.

Detecting patients with PMI post-CABG based on cardiac troponin-T profiles: A latent class mixed modeling approach.

BACKGROUND: Diagnosis of perioperative myocardial infarction (PMI) after coronary artery bypass grafting (CABG) is fraught with complexity since it is primarily based on a single cut-off value for cardiac troponin (cTn) that is exceeded in over 90% of CABG patients, including non-PMI patients. In this study we applied an unsupervised statistical modeling approach to uncover clinically relevant cTn release profiles post-CABG, including PMI, and used this to improve diagnostic accuracy of PMI. METHODS: In 624 patients that underwent CABG, cTnT concentration was serially measured up to 24 h post aortic cross clamping. 2857 cTnT measurements were available to fit latent class linear mixed models (LCMMs). RESULTS: Four classes were found, described by: normal, high, low and rising cTnT release profiles. With the clinical diagnosis of PMI as golden standard, the rising profile had a diagnostic accuracy of 97%, compared to 83% for an optimally chosen cut-off and 21% for the guideline recommended cut-off value. CONCLUSION: Clinically relevant subgroups, including patients with PMI, can be uncovered using serially measured cTnT and a LCMM. The LCMM showed superior diagnostic accuracy of PMI. A rising cTnT profile is potentially a better criterion than a single cut-off value in diagnosing PMI post-CABG.

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

RATIONALE & OBJECTIVE: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD. STUDY DESIGN: Retrospective analysis nested in a cohort study. SETTING & PARTICIPANTS: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847). EXPOSURE: Years before ESKD. OUTCOMES: Serial FGF-23, PTH, serum phosphate, and serum calcium levels. ANALYTICAL APPROACH: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD. RESULTS: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased. LIMITATIONS: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied. CONCLUSIONS: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.

Trajectory of right ventricular indices is an early predictor of outcomes in hypoplastic left heart syndrome.

BACKGROUND: Children with hypoplastic left heart syndrome (HLHS) have risk for mortality and/or transplantation. Previous studies have associated right ventricular (RV) indices in a single echocardiogram with survival, but none have related serial measurements to outcomes. This study sought to determine whether the trajectory of RV indices in the first year of life was associated with transplant-free survival to stage 3 palliation (S3P). METHODS: HLHS patients at a single center who underwent stage 1 palliation (S1P) between 2000 and 2015 were reviewed. Echocardiographic indices of RV size and function were obtained before and following S1P and stage 2 palliation (S2P). The association between these indices and transplant-free survival to S3P was examined. RESULTS: There were 61 patients enrolled in the study with 51 undergoing S2P, 20 S3P, and 18 awaiting S3P. In the stage 1 perioperative period, indexed RV end-systolic area increased in patients who died or needed transplant following S2P, and changed little in those surviving to S3P (3.37 vs -0.04 cm2 /m2 , P = .017). Increased indexed RV end-systolic area was associated with worse transplant-free survival. (OR = 0.815, P = .042). In the interstage period, indexed RV end-diastolic area increased less in those surviving to S3P (3.6 vs 9.2, P = .03). CONCLUSION: Change in indexed RV end-systolic area through the stage 1 perioperative period was associated with transplant-free survival to S3P. Neither the prestage nor poststage 1 indexed RV end-systolic area was associated with transplant-free survival to S3P. Patients with death or transplant before S3P had a greater increase in indexed RV end-diastolic area during the interstage period. This suggests earlier serial changes in RV size which may provide prognostic information beyond RV indices in a single study.

Serial fractional exhaled nitric oxide measurements off and at work in the diagnosis of occupational asthma.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) before and after specific inhalation challenge has been postulated as an additional tool in the diagnosis of occupational asthma (OA), but little is known about serial FeNO measurements at home and at work. The aim of the present study was to assess the contribution of serial measurements of FeNO off and at work toward the diagnosis of OA. METHODS: Forty-one subjects with suspected (n = 35) or diagnosed (n = 6) OA performed FeNO measurements once daily during a 2-week holiday and a subsequent 2-week work period. A work-related increase in FeNO by 20 ppb (parts per billion) or more was considered positive. Subjects with negative or doubtful specific inhalation challenge but a FeNO increase of 20 ppb or more were evaluated individually by an overall expert rating taking into account all available information. RESULTS: Seven of 35 subjects (20%) with suspected and three of six subjects (50%) with diagnosed OA showed a work-related FeNO increase of 20 ppb or more. Six of the seven with suspected OA were reclassified as having an OA diagnosis by the overall expert rating which also considered these FeNO changes. CONCLUSIONS: Serial FeNO measurements off and at work provide complementary information in the diagnosis in about one-fifth of cases with suspected OA, especially if specific inhalation challenges are negative or cannot be performed.

The Role of Serial NT-ProBNP Level in Prognosis and Follow-Up Treatment of Acute Heart Failure after Coronary Artery Bypass Graft Surgery.

BACKGROUND: After coronary artery bypass graft (CABG) surgery, heart failure is still major problem. The valuable marker for it is needed. AIM: Evaluating the role of serial NT-proBNP level in prognosis and follow-up treatment of acute heart failure after CABG surgery. METHODS: The prospective, analytic study evaluated 107 patients undergoing CABG surgery at Ho Chi Minh Heart Institute from October 2012 to June 2014. Collecting data was done at pre- and post-operative days with measuring NT-proBNP levels on the day before operation, 2 hours after surgery, every next 24 h until the 5th day, and in case of acute heart failure occurred after surgery. RESULTS: On the first postoperative day (POD1), the NT-proBNP level demonstrated significant value for AHF with the cut-off point = 817.8 pg/mL and AUC = 0.806. On the second and third postoperative day, the AUC value of NT- was 0.753 and 0.751. It was statistically significant in acute heart failure group almost at POD 1 and POD 2 when analyzed by the doses of dobutamine, noradrenaline, and adrenaline (both low doses and normal doses). CONCLUSION: Serial measurement of NT-proBNP level provides useful prognostic and follow-up treatment information in acute heart failure after CABG surgery.

Prognostic Value of Serial N-Terminal Pro-B-Type Natriuretic Peptide Measurements in Adults With Congenital Heart Disease.

BACKGROUND: A single NT-proBNP (N-terminal pro-B-type natriuretic peptide) measurement is a strong prognostic factor in adult congenital heart disease. This study investigates NT-proBNP profiles within patients with adult congenital heart disease and relates these to cardiovascular events. METHODS AND RESULTS: In this prospective cohort, 602 patients with adult congenital heart disease were enrolled at the outpatient clinic (years 2011-2013). NT-proBNP was measured at study inclusion in 595 patients (median age 33 [IQR 25-41] years, 58% male, 90% NYHA I) and at subsequent annual visits. The primary end point was defined as death, heart failure, hospitalization, arrhythmia, thromboembolic event, or cardiac intervention; the secondary end point as death or heart failure. Repeated measurements were analyzed using linear mixed models and joint models. During a median follow-up of 4.4 [IQR 3.8-4.8] years, a total of 2424 repeated measurements were collected. Average NT-proBNP increase was 2.9 pmol/L the year before the primary end point (n=199, 34%) and 18.2 pmol/L before the secondary end point (n=58, 10%), compared with 0.3 pmol/L in patients who remained end point-free (P-value for difference in slope 0.006 and <0.001, respectively). In patients with elevated baseline NT-proBNP (>14 pmol/L, n=315, 53%), repeated measurements were associated with the primary end point (HR per 2-fold higher value 2.08; 95% CI 1.31-3.87; P<0.001) and secondary end point (HR 2.47; 95% CI 1.13-5.70; P=0.017), when adjusted for the baseline measurement. CONCLUSIONS: NT-proBNP increased before the occurrence of events, especially in patients who died or developed heart failure. Serial NT-proBNP measurements could be of additional prognostic value in the annual follow-up of patients with adult congenitive heart disease with an elevated NT-proBNP.

"30-minute-delta" of high-sensitivity troponin I improves diagnostic performance in acute myocardial infarction.

BACKGROUND: Rapid and accurate diagnosis of acute myocardial infarction (AMI) are critical for the initiation of effective medical treatment. Recently, a high-sensitivity cardiac troponin I (hs-cTnI) assay was developed as a biochemical marker for the early diagnosis of AMI. Current guidelines recommend that serial measurements of cardiac troponin should be performed in patients who present symptoms suggestive of acute coronary syndrome. The aim of this study was to evaluate the diagnostic performance of 30-minute serial measurements of hs-cTnI for the detection of AMI. METHODS: We prospectively enrolled patients presenting with suspected AMI within 12h from symptom onset. We measured hs-cTnI levels at presentation and 30min later to calculate the "30-minute-delta". The diagnostic performance was determined by the area under the receiver operating characteristic curve (AUC). RESULTS: Among the 71 patients enrolled in this study, 55 (77%) were diagnosed with AMI. The hs-cTnI level at presentation was significantly greater in the patients with AMI than in those without AMI [306.2 (77.3-1809.9)pg/mL versus 22.5 (7.2-115.5)pg/mL, p<0.01]. The "30-minute-delta" was also significantly greater in patients with AMI [54.6 (13.5-288.0)pg/mL versus 1.9 (0.6-6.3)pg/mL, p<0.01]. The AUC of the "30-minute-delta" was significantly greater than that of a single measurement at presentation (0.911 versus 0.829, p<0.05). CONCLUSIONS: The "30-minute-delta" of hs-cTnI presents improved diagnostic performance for AMI compared with a single measurement.

Serially measured circulating microRNAs and adverse clinical outcomes in patients with acute heart failure.

AIMS: Previous studies have identified candidate circulating microRNAs (circmiRs) as biomarkers for heart failure (HF) using relatively insensitive arrays, validated in small cohorts. The present study used RNA sequencing to identify novel candidate circmiRs and compared these with previously identified circmiRs in a large, prospective cohort of patients with acute HF (AHF). METHODS AND RESULTS: RNA sequencing of plasma from instrumented pigs was used to identify circmiRs produced by myocardium. Production of known myomiRs and microRNA (miR)-1306-5p was identified. The prognostic values of this and 11 other circmiRs were tested in a prospective cohort of 496 AHF patients, from whom blood samples were collected at up to seven time-points during the study's 1-year follow-up. The primary endpoint was the composite of all-cause mortality and HF rehospitalization. In the prospective AHF cohort, 188 patients reached the primary endpoint, and higher values of repeatedly measured miR-1306-5p were positively associated with risk for reaching the primary endpoint at the same time-point [hazard ratio (HR) 4.69, 95% confidence interval (CI) 2.18-10.06], independent of clinical characteristics and NT-proBNP. Baseline miR-1306-5p did not improve model discrimination/reclassification significantly compared with NT-proBNP. For miR-320a, miR-378a-3p, miR-423-5p and miR-1254, associations with the primary endpoint were present after adjustment for age and sex (HR 1.38, 95% CI 1.12-1.70; HR 1.35, 95% CI 1.04-1.74; HR 1.45, 95% CI 1.10-1.92; HR 1.22, 95% CI 1.00-1.50, respectively). Rates of detection of myomiRs miR-208a-3p and miR-499a-5p were very low. CONCLUSIONS: Repeatedly measured miR-1306-5p was positively associated with adverse clinical outcome in AHF, even after multivariable adjustment including NT-proBNP. However, baseline miR-1306-5p did not add significant discriminatory value to NT-proBNP. Low-abundance, heart-enriched myomiRs are often undetectable, which mandates the development of more sensitive assays.

Nerve Conduction Studies as a Measure of Disease Progression: Objectivity or Illusion?

BACKGROUND: Clinical nerve conduction studies (NCS) are often used as a secondary outcome measure in therapeutic trials, but show a high degree of inter-trial variability even when technical factors known to affect the recorded responses are minimised. This raises the intriguing possibility that some of the observed variability may reflect true changes in nerve activity. OBJECTIVES: Our aim was determine how much variability these factors might produce, and how this might affect the results of commonly used neuropathy rating scales. METHODS: A standardised protocol was repeated over forty consecutive trials by the same operators in two healthy subjects. The protocol included recordings that shared either a stimulating or a recording electrode position, such that changes due to electrode position could be excluded, and hand temperature was closely controlled. RESULTS: Despite controlling for inter-operator differences, electrode position, and hand temperature, the variability in sensory nerve action potential (SNAP) amplitude was extremely high (Range 23 µV, CoV = 10.7-18.8). This variability was greater than the change in amplitude needed to move a subject from point 0 to point 4 on the CMT neuropathy rating scale. Neither temperature or electrode position accounted for all of this variability, suggesting that additional as yet unidentified factors are responsible. CONCLUSION: Even under closely controlled conditions and sophisticated laboratory methods, test-to-test variability can be significant. The factors responsible for this variability may be difficult to control, limiting the utility of single nerve recordings as a trial outcome measure.

Do Serially Recorded Prognostic Scores Predict Outcome Better Than One-Time Recorded Score on Admission? A Prospective Study in Adult Intensive Care Patients.

OBJECTIVES: The prognosticating ability of one-time recorded Acute Physiology and Chronic Health Evaluation (APACHE) IV score was compared with serially recorded Mortality Prediction Model (MPM) II scores. DESIGN AND METHODS: A prospective observational study was conducted for a period of 6 months. Acute Physiology and Chronic Health Evaluation IV score was recorded during the first day on intensive care unit (ICU) admission. Mortality Prediction Model II was recorded on admission, 24, 48, and 72 hours. Predicted mortality was compared with observed mortality. The systems were calibrated and tested for discriminant functions. RESULTS: One hundred and fifty patients were studied. The observed mortality was 21.3%. The mean predicted hospital mortality by APACHE IV was 20.6%. The mean predicted hospital mortality rate by serial MPM II measurements was 27.7%, 24.3%, 25.5%, and 25.8%. The area under the receiver-operating characteristic curve was 0.87 for APACHE IV and 0.82, 0.84, 0.85, and 0.89 for MPM II series. Both systems calibrated well with similar degree of goodness of fit. CONCLUSION: Acute Physiology and Chronic Health Evaluation IV on admission predicted hospital mortality better than serially recorded MPM, which overestimated mortality. Also, APACHE IV had a slightly better discrimination compared to MPM II on admission. One-time recording of APACHE IV on admission may be sufficient for prognostication of ICU patients rather than serial MPM scores.

Relationships between childhood growth parameters and adult blood pressure: the Fels Longitudinal Study.

Previous research has shown that childhood body size is associated with blood pressure in adulthood, and that early and rapid growth rates are correlated with adverse cardiovascular outcomes. Our objectives are to estimate associations between childhood body size growth parameters and adult blood pressure, and to examine the effect of early attainment of critical growth milestones on adult blood pressure, relative to normal or late attainment. Lifetime height and body mass index (BMI) measurements in childhood, and systolic blood pressure (SBP) and diastolic blood pressure (DBP) measurements in adulthood are taken from participants in the Fels Longitudinal Study. Childhood growth curves are estimated separately for stature and BMI using the Preece-Baines and third-degree polynomial models, respectively. Associations between the resulting parameter estimates and adult blood pressure are then examined using linear mixed models. Our findings show that the ages of achievement of the stature-based growth onset and peak velocity, as well as the age of achievement of the BMI-based adiposity rebound, are negatively associated with adult blood pressure, implying that early height or BMI growth can lead to increased blood pressure in adulthood. There were subtle differences in these relationships based on age and gender, and also between SBP and DBP. These results expand on the existing literature, showing that not only childhood body size, but also the timing of childhood growth can have a deleterious effect on adult cardiovascular health.

Determinants of temporal changes in galectin-3 level in the general population: Data of PREVEND.

BACKGROUND: High baseline galectin-3 levels are associated with increased risk for adverse cardiovascular outcomes in the general population, but determinants of changes in galectin-3 levels over time have not been established. Therefore, we aimed to identify determinants of (temporal) change in galectin-3 levels. METHODS: Galectin-3 plasma levels were measured in a large community based cohort (PREVEND study) at 3 different time points: at baseline, after ~4 and ~9years. The association of baseline clinical and biochemical factors and (temporal) changes in galectin-3 level was assessed using multivariable mixed-effects regression modeling. RESULTS: In 4355 subjects, galectin-3 plasma levels were available at all time points (mean age: 48±12years; 50% female). Median galectin-3 level at baseline was 10.7 [8.9-12.7] ng/mL which gradually increased to 11.5 [9.4-14.3] ng/mL after ~9years. Using mixed-effects regression modeling, we first validated as independent determinants of baseline circulating galectin-3: eGFR (chi square (χ(2)):210.27, p<0.0001), gender (χ(2):43.85; p<0.0001), BMI (χ(2):19.68, p=0.0001), NT-proBNP (χ(2):18.76, p=0.0001) and serum (total) cholesterol (χ(2):8.63, p=0.01). Furthermore, we identified urinary albumin excretion (χ(2):34.03, p-value: <0.0001) and systolic blood pressure (χ(2):16.81, p=0.002) as independent determinants of temporal changes of galectin-3. CONCLUSIONS: In the general population, urinary albumin excretion >30mg/24h and systolic blood pressure >170mmHg were identified as significant determinants of dynamic increases in galectin-3 levels over time. These results implicate that treatment of high blood pressure might be effective to prevent increasing galectin-3 levels and its associated conditions.