Circulating sensory peptide levels within 24 h of human bone fracture.

We designed this study to examine the circulatory levels of wound modulatory peptides [substance P (SP), calcitonin gene related peptide (CGRP] in patients with muscle injuries with bone fractures and within 24 h of the injury. The peripheral plasma levels of these sensory nerve peptides were measured on hospital admission (OA) and 24 h post-injury (PI), using ELISA technique. Mean (s.d) ng/liter of CGRP was higher in patients OA (270 +/- 199), and PI (205 +/- 176); than the controls (3 +/- 81) P < 0.05. Substance P also increased in the patients OA: 101 +/- 50; PI: 46 +/- 3 than controls [8 +/- 9] P < 0.001. Elastase (predictor of posttraumatic complication) was examined and there was no significant differences between patients and control samples (P = NS). This study shows that sensory nerve peptides are increased in bone fracture related injuries up to 24 h after injury. An intact nociceptor system of primary afferent sensory nerves is important for the initiation of the inflammatory process and successful tissue repair as dysfunction of this system could be a contributing factor for a delayed wound healing.

Levels of myosin heavy chain fragment in patients with tissue damage.

BACKGROUND: Myosin heavy chain fragments (MHC) levels are observed to be higher in myoskeletal injuries after surgery. MHC could be a helpful supplementary tool in the study of myoskeletal injuries. METHODS: Serum levels of myosin heavy chain fragments (MHC) were assessed in orthopedic patients before operation (OBO) and after operative (OAO) repairs and in the early phase of soft tissue injury (STI) using a radioimmunoassay involving monoclonal antibodies to the human beta-type MHC. RESULTS: Mean (SD) microU/L of MHC in comparison with the control subjects (75.3 +/- 47.1) was higher in OAO (305.8 +/- 38.1) p <0.0001, and no significant changes in MHC were found in STI (67 +/- 77.5). Myoglobin was notably higher in OBO (81.9 +/- 95.0) compared to STI (43.9 +/- 55.9) or controls p <0.05, but there was no further change in the protein after surgery. The mean proportional raised level of myoglobin in OBO was >twofold, and MHC increased by 27%. Neither myoglobin nor MHC increased in the plasma of the STI within 24 h of injury. CONCLUSIONS: These data suggest that the release of MHC could be a helpful supplementary tool in the study of tissue damage in humans.

Skeletal troponin-I release in orthopedic and soft tissue injuries.

The skeletal isoform of troponin-I (sTnI) is a myofibrillar protein highly specific for myoskeletal injury. We used an indirect immunoenzymometric assay method with high analytical sensitivity to measure sTnI in patients with soft-tissue injury and in orthopedic patients. We assessed 20 soft-tissue injury patients and 16 orthopedic patients for sTnI, cardiac troponin-I (cTnI), creatine kinase (CK), myoglobin, and elastase within 24h of injury, in comparison with 17 control subjects. The mean (SD) ng/ml value for sTnI was higher in orthopedic patients (15.25 +/- 2.4) and in soft-tissue injury patients (10.41 +/- 1.8) than that in controls (2.5 +/- 0.9) P < 0.001, P < 0.05 respectively. Cardiac TnI was not detectable in any subjects (below the assay detectable limit of 0.3ng/ml). CK was significantly higher in orthopedic patients than in controls (P < 0.005) and myoglobin and elastase were not significantly changed in patients samples. The assay appeared to be suitable as a supplementary tool of reliability and relevance, for the study, identification, and diagnosis of skeletal muscle specific injuries in humans.

Levels of vasodilators (SP, CGRP) and vasoconstrictor (NPY) peptides in early human burns.

An intact nociceptor system of primary afferent sensory nerves is important for the initiation of the inflammatory process and successful tissue repair. Dysfunction of this system could be a contributing factor for delayed wound healing in humans. We examined the levels of vasodilators [substance P (SP), calcitonin gene-related peptide (CGRP)] and a vasoconstrictor peptide [neuropeptide Y (NPY)] in the peripheral blood samples of patients with burns covering from 20 to 75% of body surface area. Thirteen patient samples were obtained immediately on admission (OA), which was within 12 h of the thermal injury, and 24 h post-admission (PA). Enzyme immunoassay techniques were used for the measurement of the neuropeptides. In addition, an inflammatory marker, tumour necrosis factor-alpha (TNF-alpha), and a myofibrillar protein, creatine kinase (CK), were examined and compared with levels in 13 control subjects. CGRP was high OA and the levels were maintained PA (P < 0.05). SP was also significantly high at both sampling times (P < 0.05). Although TNF-alpha and NPY were somewhat higher in the patients' samples than in the control samples, these levels were not statistically significant (P = NS). CK was higher OA (P < 0.01) than PA (P < 0.04), compared to controls. Plasma levels of SP and CGRP increased significantly in patients with thermal injuries. These peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in burns.

Plasma levels of N-terminal peptide of pro-atrial natriuretic peptides in myoskeletal injuries.

To determine whether concentrations of the N-terminal peptide of pro-atrial natriuretic peptide (proANP) and of alpha atrial natriuretic peptide 1-28 (aANP) releases are affected by myoskeletal injuries, samples from 24 patients with muscle injuries were therefore collected within 48 h of injury. The mean age of patients was 65; range: 17-90 years. These were compared with 18 non-injured subjects with a mean age of 40; range: 17-80 years. A specific enzyme immunoassay (EIA) method suitable for the determination of proANP and aANP was used. aANP required plasma extraction and no extraction was needed for proANP determination.ProANP level was significantly higher in patients on admission and this level was maintained 24 h after admission (p < 0.05) compared to controls. However, aANP 1-28 level remained statistically unchanged in the patients samples. The level of proANP was over 10 times greater than the levels obtained with aANP. N-terminal peptide of proANP may be a supplementary tool in the study of early phase of myoskeletal injuries in human.

Endothelin-1 levels in severe burn injuries.

HYPOTHESIS: Most investigators have reported high levels of endothelin (ET)-1 in patients with thermal injury. We attempted to examine the hypothesis that ET-1 levels increase in patients with severe burn injury. PATIENTS AND METHODS: Plasma from 28 adult subjects, 14 of whom had thermal injuries with a median (range) percentage of total burn surface area of 22% (20%-76%), was assessed for ET-1 and tumor necrosis factor (TNF) alpha. Samples from closely age-matched patients were obtained on admission (day 1) and 24 hours postinjury (day 2). Samples were obtained before blood transfusion or surgical treatment occurred. Enzyme immunoassay techniques suitable for the measurements of the cytokines were used. RESULTS: Median (range) of TNF-alpha was higher in patients (day 1, 10.0 ng/L [1.2-35.0 ng/L]; day 2, 12.0 ng/L [0.4-39.0 ng/L]) than controls (0. 8 ng/L [0.3-3.2 ng/L]) (P<.005) while ET-1 levels remained significantly unchanged in patients (mean [SD], day 1, 183.0 [42.2] ng/L; day 2, 204.7 [41.7] ng/L) compared with controls (170.0 [59.8] ng/L) (P>.05). CONCLUSIONS: We observed no significantly raised levels of ET-1 in patients with thermal injury within 24 hours after burn injury. We found no significant correlation between the plasma levels of TNF-alpha and ET-1. Endothelin-1 levels did not seem to reflect severity of illness. The actual evaluation of ET-1 release in patients with thermal injury could enhance the pathophysiological study of human thermal injury.

Elevation of plasma CGRP and SP levels in orthopedic patients with fracture neck of femur.

Calcitonin gene-related peptides (CGRP) is a 37 amino acids peptide that has a proliferative effect on human endothelial cells, and is therefore important for the formation of new vessels and wound healing. As indicated by in vitro and animal studies, CGRP is also a potent vasodilator for cutaneous, cerebral, coronary vessels, a bronchoconstrictor and endocrine regulator. Systemic CGRP increase in patients with soft tissue injuries, chronic illness and sepsis, indicates that CGRP may yet be an important peptides in chronic illness. Although CGRP is a potent vasodilator, systemic vascular resistance does not increase in some patients with high CGRP levels. We questioned whether any changes occur in systemic CGRP levels in patients with one of the most common types of bone fractures especially in the elderly. In order to evaluate further the role of this peptide in these patients, a vasoconstictor (Endothelin-1 [ET]) and another sensory neuropeptide (Substance P [SP]) were measured within 24 h of injury. A sample was obtained on admission (day 1) and within 24 h post admission (day 2) in patients with fracture neck of femur (mean age 77.6, +/- 10 years, n = 20) and compared with healthy controls (51, +/- 26.8 years, n = 20). Peptides and hormones were measured by ELISA techniques. Mean (ng/l) CGRP was elevated in patients (day 1 [314 +/- 195] and day2 [209.2 +/- 150]); compared to controls (68.2 +/-31) P<0.005. Endothelin was non-significantly higher in day-2 (day 1 [28.5 +/-31], day2 [37.4 +/-38], controls [24.2 +/-21]) P = NS. SP maintained higher levels within 24 h after injury (day 1 [85.7 +/- 94], and day2 [80.9 +/- 91.8]) compared to controls, P< 0.05. Furthermore, Elastase (a decisive marker for inflammation and infectious complications) was found to be higher in patients being pronounced in day 2 than in day 1 (day 1 [200 +/-136], day2 [139 +/-118]). Creatine kinase and myoglobin were measured and found to be notably higher in patients. These peptides may be yet another group of cytokines playing significant role in immunologic, inflammatory complications or wound healing in this group of patients.

Neuropeptide variability in man.

BACKGROUND: Previous studies have established short-term variability in the circulating plasma levels of cardiac peptides such as atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). Our aim was to investigate whether such variable patterns could be observed in other vasoactive peptides. METHODS: We measured the immunoreactivity of vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), endothelin-1 (ET-1) and calcitonin gene-related peptide (CGRP) in peripheral venous plasma collected at 2-min intervals over a 20-min period from patients with chronic cardiac failure (CCF) and from control subjects. In a second study, blood samples were obtained at 2-min intervals from the pulmonary artery, femoral artery and antecubital vein from patients with normal cardiac function while right atrial pressure and heart rate were constant. RESULTS: Peripheral blood VIP, NPY and ET-1 had peaks and troughs (levels > 2SD from the mean) in both patients and controls, with approximate intervals of 10 min. Levels of CGRP showed little variation. The overall levels [median (range); pmol L-1] of VIP [patients 27 (2.1-85.5); controls 9.8 (0-34)] and NPY [patients 20 (0-110); controls 12 (5-19)] were higher in patients (P < 0.05). Circulating plasma levels of ET-1 and CGRP were about the same in both groups [ET-1: patients 18 (2-84); controls 18 (0-48); CGRP: patients 4 (1-18.5), controls 5.5 (1-15); P = NS]. Levels of CGRP, VIP and ET-1 were similar in the pulmonary and femoral arteries, whereas systemic arterial levels of NPY were higher than in the pulmonary artery. CONCLUSIONS: The data demonstrate marked variability in circulating levels of the neuropeptides studied. In addition, peaks and troughs were observed every 10-15 min from all three vascular beds. If these peptides are secreted in a pulsatile pattern, then interpretations of single measurements should be guarded. Furthermore, this study raises interesting questions about the physiology of hormone secretion in man.

Plasma-circulating levels of natriuretic peptides in patients with bone and soft tissue injuries.

To evaluate the release and possible role of N-terminal end of atrial natriuretic factor (ANF) prohormone (proANF-1-30) and C-terminal end of ANF prohormone (aANP-1-28) in patients with soft tissue and bone injuries, 20 patients with soft tissue injuries, 18 bone-fractured patients, and 21 healthy controls were examined. Samples were collected from patients within 24 h after injury. Plasma level of proANF-1-30 and aANP-1-28 were higher in orthopedic patients than the soft tissue injury patients compared to controls (P < 0.005, P<0.05, respectively). proANF-1-30 was over 15-fold greater than aANP-1-28 in the healthy control samples. These data hypothesized that the concentration of proANF-1-30 may be related to tissue damages in man.

Plasma levels of atrial natriuretic peptide in severe burn injury.

Atrial natriuretic peptide (ANP) plays a part in the regulation of volume homeostasis and possibly, in the pathophysiology of water and electrolyte disorder. Patients with serious burn injuries risk huge body fluids losses, which are compensated for by perfusion. Blood volume and the renin and aldosterone system are also disturbed. This study measured plasma ANP and vasoactive intestinal polypeptide (VIP) in patients with >20% total burned surface area (TBSA), at admission and 24 h post-admission.Eleven patients (mean age 46.5 years, 8 males) with a mean TBSA of 34.5% were sampled. Standard treatment was given. Eleven closely age-matched volunteers were used as controls. A specific ELISA method suitable for the measurement of ANP and VIP was used.ANP was higher (p<0.0001), while VIP was lower (p=NS) in patients' samples compared to controls. While the level of VIP was higher at 24 h post-admission, mean ANP level remained about the same. The increased levels of plasma ANP may result from volaemic disturbances during resuscitation, low VIP levels, the increase in pulmonary resistance or post-burn stress.

Effects of bone fracture and surgery on plasma myosin heavy chain fragments of skeletal muscle.

OBJECTIVE: Myosin heavy chain (MHC) fragment is part of a structural or force-bearing protein expressed in the thick filament of muscle fibres. Since MHC fragment is a contractile protein, an increase in plasma MHC concentrations after muscle injury indicates degradation of the contractile apparatus. This study was conducted to determine whether MHC concentrations could be a tool in the assessment of tissue damage in patients with myoskeletal injuries. DESIGN: Prospective, controlled study. SETTING: A UK University National Health Service Centre. PATIENTS: Thirty-eight orthopedic patients, of whom 14 received surgical treatments within the 2-day study period. Patients were compared with 16 nonorthopedic control subjects. OUTCOME MEASURES: Serum levels of MHC, creatine kinase, cardiac troponin I (cTnI), and myoglobin were measured at the time of admission and 24 hours later. Data from patients undergoing surgical repairs were obtained 24 hours after surgery. A competitive radio-immunoassay for beta-type MHC was used. RESULTS: Plasma MHC concentration was higher in the patients than in the controls. The peak levels were observed 24 hours after injury or surgery (p < 0.05). cTnI concentrations were consistently below the assay detection limit of 0.3 microgram/L, thus excluding protein release from the heart muscle (cardiac beta-type MHC). Creatine kinase and myoglobin concentrations were significantly higher on admission in the non-surgical patients than in the surgically treated cases. CONCLUSIONS: Serum MHC levels could be a useful supplementary retrospective, prognostic or diagnostic tool in the study of myoskeletal disturbances involving muscle injury or bone fractures that result in membrane leakage of myoskeletal cells.

Calcitonin gene-related peptide, neuropeptide Y and atrial natriuretic peptide distribution in guinea pig heart from paraffin wax-embedded and formalin-cryoprotected tissues.

In this study, the distributions of calcitonin gene-related peptide, neuropeptide Y, and alpha-atrial natriuretic peptide 1-28 immunoreactivity, were investigated within different regions of the guinea pig heart by utilising two different methods of tissue fixation for the immunocytochemistry. The results were compared with data obtained through radioimmunoassays. We observed similar concentrations and distributions of alpha-atrial natriuretic peptide in the right atrium, with results of radioimmunoassay and immunocytochemistry, but there were no myocytes containing alpha-atrial natriuretic peptide in the left atrium or ventricles with immunocytochemistry as opposed to radioimmunoassay. The immunoreaction obtained for neuropeptide Y was more intense in the right ventricle than left. Calcitonin gene-related peptide nerve fibres were about twice as abundant in the left atrium than in the right.

Calcitonin gene-related peptide and other neuropeptides in the plasma of patients with soft tissue injury.

Calcitonin gene-related peptide [CGRP]--a powerful vasodilator, is a 37 amino acid peptide that is find primarily in the central and peripheral nervous system. It affects the regulation of local blood flow, smooth muscle tone and glandular secretion. It is an endocrine regulator and in the lungs it also exerts a bronchoconstricting effect. CGRP has a proliferative effect on human endothelial cells. Therefore, it is important for the formation of new vessels, example, in ischemia, inflammations, and in the healing of wounds. Plasma levels of CGRP are increase in patients with chronic cardiac failure and sepsis, indicating that CGRP may be another important peptide in chronic illness. We have therefore measured the release of this peptide and another sensory peptide [Substance P (SP)]; a vasoconstrictor peptide [Endothelin (ET)]; and a perivascular peptide [Neuropeptide Y (NPY)], within 24 hours of injury, in the plasma of patients with soft tissue injury. Neuropeptides were measure by enzyme immunoassay technique. Median: (lower quartile-upper quartile) in pmol/L CGRP level was elevated in patients [50.37: (12.4-110.9)] compared to controls [13.9: (10.9-36.96)] p<0.05; Endothelin and NPY did not vary much between groups p=NS; ET: patients [8.7: (1.7-87.1), controls 8.8: (1.7-32.9)]; NPY: Patients [11.7: (10.5-14.99), controls 11: (10.3-12.8)]. SP was increase in patients [302.3: (79.9-707.3)], than controls [5.6: (3.2-36.6)] p<0.05. Furthermore, Elastase (a decisive marker for inflammation and infectious complications), was measure (ng/L), and found to be slightly higher in patients (102: 25.5-223), than controls (91.8: 45.9-127). In summary, plasma levels of sensory peptides increased significantly, in patients with soft tissue injury, in contrast to vasocostrictor peptides that remained unchanged. These sensory peptides may yet be another group of neuromodulators playing a significant role in immune, pain, inflammatory and wound healing in soft tissue injury patients.

Distributions of VIP, substance P, neurokinin A and neurotensin in rat heart: an immunocytochemical study.

Vasoactive intestinal peptide (VIP) is a peptide amide containing 28 amino acids which was first isolated from the intestine and is distributed over the entire body but primarily in the nervous system. It is released in response to the electrical stimulation of nerve fibres, stimulation of the vagus, prostaglandin E1, oxytocin, operation stress, corticosterone. In the cardiovascular system, VIP has a vasodilation, hypotension, positive chronotropic and inotropic effects.

Regulatory peptides in the heart and major vessels of man and mammals.

Studies on the distribution of peptides in human tissues have been made either by measuring responses to localized stimuli or by subjecting extracts of different regions to radioimmunoassay (RIA). Attempts at isolating regulatory peptides from the mammalian tissues have resulted in the isolation of many bioactive fragments. Later, modification of initial isolation methods led to the identification of the native molecules in various tissues and body fluids. The present study examined atrial natriuretic peptide (ANP) and several other peptides in cardiac tissues of several species of laboratory mammal and human beings; using a sensitive and highly specific radioimmunoassays. In all the species studied, ANP-like immunoreactivity appeared to be highest in the heart tissue of rat. The peptide was highest in the right atrium (RA) of rat and lowest in the RA of guinea pig (P< 0.002). Neuropeptide Y (NPY) another abundant cardiac peptide was present in the cardiac tissues of all species but was more in the left atrium (LA) than the RA of all species (P<0.05). Calcitonin gene-related peptide (CGRP) was present throughout the cardiovascular system of the rat and guinea pig. Small but detectable amount of Neurotensin (NT) immunoreactivity was found in the rat but was consistently negative in the guinea pig cardiac tissues (P< 0.05). Substance P (SP) immunoreactivity was detected in the rat and higher quantities being in the Aorta but no trace of the peptide was detected in the left ventricle, aorta nor the pulmonary vein of post mortem human. Though the structure of most of the species studied has been elucidated, the primary structure of guinea pig ANP has not been fully generated. Thus the data obtained may suggest that in keeping with these mammalian peptides, the primary structures may be variant. With most of the peptides studied (e.g. ANP, Neuropepdide Y), immunoreactivity occurs predominantly in the atrial tissues, but is also present in vessels outside the heart, a finding which may be of functional significance.

Extraction of human alpha atrial natriuretic peptide and its physiological validation.

A very sensitive and specific radioimmunoassay for human alpha atrial natriuretic peptide (hANP) and a novel extraction method for hANP, have been developed. Antiserum to hANP showed no cross-reactivity with related analogues (e.g., brain natriuretic peptide). The radioimmunoassay can detect 1.2 fmol ANP/assay tube. Using a commercially available tracer, the antiserum binds 0.7 fmol of radioligand at a final dilution of 1:96,000. Production of ANP tracer, using 125I, Iodogen and reversed-phase HPLC separation, produces two products. The first has identical properties to the commercial reagent resulting in an identical antibody titre. The second, however, is more reactive with the antiserum which can be employed at a final dilution of 1:192K. These products represent oxidised and reduced peptides, respectively, inferring that the commercial tracer is oxidised. The recovery of synthetic hANP from plasma over the range of 0-1000 ng/l through Sep-Pak C18 cartridges, using an extraction method of acetic acid-acetonitrile (4:96) was 89%. Inter- and intra-assay coefficients of variation were 9.5% and 8.2%, respectively. The radioimmunoassay was validated in man by measuring plasma ANP (ng/l) following change of posture and exercise in normal man. Plasma ANP rose from 13.2 (1.0; S.D.) to 20.1 (1.6) from supine to sitting position. Plasma ANP increased to 20.1 (1.6) at rest (sitting) to 34 (2.7) ng/l at peak of exercise, but decreased from 31.2 (2.5) to 21.4 (0.1) ng/l at 3 and 6 min after exercise, respectively. These results confirm that the assay is capable of differentiating changes of concentrations within the physiological range.

Neuropeptide secretion in exercise.

Plasma concentrations of atrial natriuretic peptide immunoreactivity (irANP) and brain natriuretic peptide immunoreactivity (irBNP) in elderly normal subjects (mean age 71.1, range 66-81 years, n = 10) were examined before (rest), during (peak of exercise) and after (3 min, 6 min) a treadmill exercise test (modified Bruce protocol). An attempt was also made to determine the effect of steady state exercise (30% and 50%) and posture (supine, sitting) on circulating levels of atrial natriuretic peptide and calcitonin gene-related peptide (CGRP) in man. The results suggest that exercise gives rise to increased levels of irANP and irCGRP, but not human BNP. The study also demonstrated a >40% rise in irCGRP and irANP levels at 50% steady state exercise compared with 30% steady state exercise. irCGRP was shown to decline in the upright position compared with the supine position, and irCGRP did not rise with exercise. Although ANP is normally stored in large concentration in the atria with much less in the ventricles and BNP is derived to a much greater extent from the ventricles, the differential release rate of these peptides may make BNP concentration a more sensitive indicator of left ventricular dysfunction than ANP. The observations obtained here also raise the possibility that the ANP system may not only help to eliminate intermittent overhydration, but also participate in the postural regulation of diuresis and natriuresis and perhaps even support the maintenance of excretory kidney function in the ageing subjects.

Neuroendocrine changes in chronic cardiac failure.

Numerous hormonal and neuroendocrine changes have been described in patients with chronic cardiac failure. These affect the balance of vasodilator and vasoconstrictor factors in favour of the latter, to the detriment of the circulation. Whether this is a reaction to central cardiac (haemodynamic) abnormalities, or is an integral part of the syndrome of heart failure, remains to be determined. Catecholamine levels are increased, especially in severe heart failure, and contribute to the vasoconstriction and probably also to lethal ventricular arrhythmias. The renin-angiotensin-aldosterone system (RAAS) is also activated, causing fluid retention and further vasoconstriction. In the earlier stages, some of this increase may be iatrogenic due to the use of loop diuretics or inhibitors of angiotensin converting enzyme, but there is evidence for independent RAAS activation in more severe grades of heart failure. The role of vasoconstrictor peptides such as neuropeptide Y and endothelin is briefly considered. Counterbalancing these are vasodilator peptides, in particular atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP). The possibility of therapeutic interventions to increase circulating natriuretic hormone levels is discussed.

Variable patterns of atrial natriuretic peptide secretion in man.

Peripheral circulating levels of atrial natriuretic peptide may exhibit short-term variation compatible with a pulsatile pattern of secretion. We obtained samples every 2 min for 90 min from the antecubital vein of 16 patients with chronic cardiac failure and 13 controls. Overall levels were higher in the patients (median and quartiles 230 (125,325) vs. 26 (16,48) ng l-1; P < 0.001). In both groups there was considerable variability, with 10 (2-12) peaks, 9 (7-15) troughs (both defined as > 2 SD from the mean) and 16 (13-18) pulses (defined by computer) during the sampling period in controls, and a similar number in patients. We then carried out simultaneous sampling in the pulmonary artery, femoral artery and peripheral vein in eight subjects with normal cardiac function and six patients with impaired function due to valvular heart disease. The pattern of variability was preserved in all three sites in both groups, suggesting intermittent secretion rather than variable breakdown of the peptide in the lung. No changes in right atrial pressure or heart rate were observed to coincide with the variations, but levels of the peptide in the pulmonary artery correlated with right atrial pressure in patients (r = 0.87; P < 0.05). The mechanism of such periodicity and its pathophysiological importance remain unknown.