A simple, versatile valve model for use in lumped parameter and one-dimensional cardiovascular models.

Lumped parameter and one-dimensional models of the cardiovascular system generally employ ideal cardiac and/or venous valves that open and close instantaneously. However, under normal or pathological conditions, valves can exhibit complex motions that are mainly determined by the instantaneous difference between upstream and downstream pressures. We present a simple valve model that predicts valve motion on the basis of this pressure difference, and can be used to investigate not only valve pathology, but a wide range of cardiac and vascular factors that are likely to influence valve motion.

Haematologic determinants of left atrial spontaneous echo contrast in mitral stenosis.

OBJECTIVES: To determine if a relationship exists in mitral stenosis, in patients with either sinus rhythm or atrial fibrillation, between left atrial spontaneous echo contrast and the haematologic indices haematocrit, red cell concentration, mean corpuscular volume, platelet count and volume. METHODS: Left atrial spontaneous echo contrast severity was graded on a scale of 0-4 in 163 patients with symptomatic mitral stenosis (84 patients in sinus rhythm, 79 patients in atrial fibrillation) undergoing transesophageal echocardiography, cardiac catheterization and full blood examination as part of assessment prior to balloon mitral valvuloplasty. RESULTS: In sinus rhythm, spontaneous echo contrast grade was negatively correlated with cardiac index (r=-0.33), mitral valve area (r=-0.25) and mitral regurgitation grade (r=-0.22) and positively correlated with haematocrit (r=0.24) and red cell concentration (r=0.25). Spontaneous echo contrast grade was not correlated with left atrial diameter or mean corpuscular volume. In atrial fibrillation, spontaneous echo contrast grade was also negatively correlated with mitral valve area (r=-0.25) and mitral regurgitation (r=-0.36) but was positively correlated with left atrial diameter (r=0.34) and was not correlated with cardiac index, haematocrit or red cell concentration. There was no correlation between spontaneous echo contrast grade and platelet variables in either group. CONCLUSIONS: Natural variation in red cell concentration in patients with symptomatic mitral stenosis was an independent predictor of the severity of left atrial spontaneous echo contrast in sinus rhythm, but no relationship between red cell concentration and spontaneous echo contrast grade was evident in atrial fibrillation.

Increased systemic oxygen consumption offsets improved oxygen delivery during dobutamine infusion in newborn lambs.

OBJECTIVE: To determine: 1) if dobutamine elicited a thermogenic response during postnatal development; and 2) if this response impacted on the balance between systemic O(2) delivery (DO(2)) and O(2) consumption (VO(2)), and involved one or a combination of adrenoceptor subtypes. DESIGN: Prospective non-randomized unblinded study. SETTING: University research laboratory. SUBJECTS: Thirty-five Border-Leicester cross lambs used in a main study performed at 1-2 days (n=7), 7-10 days (n=7), and 6-8 weeks (n=8), and in a adrenoceptor blockade substudy performed at 1-2 days (n=13). INTERVENTIONS: Lambs were instrumented under anaesthesia and dobutamine was infused at incremental rates of 1-40 microg/kg per minute. In separate subgroups of 1-2 day-old lambs, dobutamine was infused after selective or combined alpha1, beta 1, and beta 2-adrenoceptor blockade. MEASUREMENTS: Cardiac output, aortic and pulmonary arterial blood gases, and body temperature were measured. DO(2) and VO(2) were calculated. MAIN RESULTS: Dobutamine increased DO(2) similarly at all three ages. Dobutamine also increased VO(2) in the absence of muscle shivering, but the average rise in 1-2 day-old lambs was sevenfold to 12-fold greater (P<0.001) than in 7-10 day-old and 6-8 week-old animals, was associated with an increase in systemic O(2) extraction, and accounted for approximately 90% of the rise in DO(2). Body temperature rose by 1.3+/-0.5 degrees C in 1-2 day-old animals (P<0.001), but was unchanged in 7-10 day-old or 6-8 week-old lambs. In 1-2 day-old lambs, rises in DO(2), VO(2), and body temperature induced by dobutamine were not affected by selective alpha1, beta1 or beta2 adrenoceptor blockade, but were markedly attenuated by combined adrenoceptor blockade. CONCLUSIONS: A substantial rise in VO(2) which accompanied a pronounced thermogenic effect of dobutamine in newborn lambs utilized most of the associated increase in DO(2) and appeared to be dependent on activation of multiple adrenoceptor subtypes.

Low-dose postoperative aprotinin reduces mediastinal drainage and blood product use in patients undergoing primary coronary artery bypass grafting who are taking aspirin: a prospective, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Although low-dose aprotinin administered after cardiopulmonary bypass has been reported to reduce mediastinal blood loss and blood product requirements in patients not taking aspirin, it is unknown whether low-dose postoperative aprotinin has any beneficial effects in patients undergoing coronary artery bypass operations who are at high risk of excessive postoperative bleeding and increased transfusion requirements because of aspirin use until just before the operation. METHODS: Fifty-five patients undergoing primary coronary artery operations with cardiopulmonary bypass who continued taking aspirin (150 mg/d) until the day before the operation were enrolled in a prospective, randomized, double-blind trial to receive a single dose of either placebo (n = 29) or 2 x 10(6) kallikrein inhibiting units of aprotinin (n = 26) at the time of sternal skin closure. RESULTS: Patients in the aprotinin group had a lower rate (28 +/- 18 vs 43 +/- 21 mL/h [mean +/- standard deviation], P <.005) and total volume of mediastinal drainage (955 +/- 615 vs 1570 +/- 955 mL, P <.007), as well as a shorter duration of mediastinal drain tube insertion (24.4 +/- 13.8 vs 31.3 +/- 16.5 hours, P <.05). In addition, a smaller proportion of patients receiving aprotinin required a blood product (31% vs 62%, P =.03), resulting in a reduction in the use of packed cells by 47% (P =.05), platelets by 77% (P =.01), fresh frozen plasma by 88% (P =.03), and total blood products by 68% (P =.01) in this group. CONCLUSIONS: These results suggest that postoperative administration of low-dose aprotinin in patients taking aspirin until just before primary coronary artery operations with cardiopulmonary bypass not only reduces the rate and total amount of postoperative mediastinal blood loss but also lowers postoperative blood product use.

Effects of combined oral hormone replacement therapy on tissue factor pathway inhibitor and factor VII.

Oral combined hormone replacement therapy (HRT) with oestradiol and norethisterone increases plasma levels of prothrombin fragment 1+2 (F1+2), indicating an increase in thrombin generation, but the mechanisms underlying this increase are uncertain. The aim of this randomized, placebo-controlled study was to determine whether an increase in factor VII, a factor that combines with tissue factor to activate the extrinsic pathway, or a decrease in tissue factor pathway inhibitor (TFPI), an inhibitor of extrinsic pathway activation, may contribute to increases in thrombin generation occurring with HRT. Healthy postmenopausal women aged 50-75 years received placebo (n=19) or oral combined HRT (n=18) and had blood collected for measurement of factor VII coagulation activity (VIIc), activated factor VII (VIIa) and TFPI at baseline and at 6 weeks. Baseline characteristics were similar in the two groups, including age, body mass index and cholesterol levels. As reported previously, HRT increased the F1+2 concentration by 20%. Placebo had no effect on VIIc, VIIa or TFPI, but 6 weeks of combined HRT decreased VIIc [from 1.11+/-0.06 (mean+/-S.E.M.) to 1.03+/-0.06 i.u./ml; P<0.03], VIIa [from 43.9; 10.8-198.3 (median; range) to 35.0; 6.3-66.8 m-units/ml; P<0.03] and TFPI [from 81.3+/-6.5 to 60.4+/-5.5 ng/ml; P<0.0001]. The decrease in TPFI with HRT was not correlated with the elevation in F1+2 levels. In conclusion, the increase in thrombin generation seen with HRT is not due to an effect on factor VII; in addition, while a contribution from the decrease in TFPI is possible, increased thrombin generation is not directly related to the decrease in TFPI.

NO supports right ventricular flow dominance and whole body O(2) utilization in midgestation fetal lambs.

It is unknown if nitric oxide (NO) modulates the relative levels of left (LV) and right (RV) ventricular output, fetal O2 consumption, or blood flow distribution between the body and placenta at midgestation. To address these questions, six fetal lambs were instrumented at 89-96 days gestation (term 147 days), and blood flows were measured with radioactive microspheres 3-4 days later at baseline and after inhibition of NO synthesis with 10 mg/kg (L-NNA10) and 25 mg/kg (L-NNA25) N(omega)-nitro-L-arginine. LV output fell by 74 +/- 15 ml. min(-1). kg(-1) at L-NNA10 (P < 0.005), whereas RV output decreased by 90 +/- 18 ml. min(-1). kg(-1) at L-NNA10 (P < 0.02) and by a further 80 +/- 22 ml. min(-1). kg(-1) at L-NNA25 (P < 0.05). As a result, RV output exceeded LV output at baseline (P = 0.03) and L-NNA10 (P < 0.02) but not at L-NNA25. Fetal body blood flow fell by 95 +/- 25 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01), but because placental blood flow decreased by 70 +/- 22 ml. min(-1). kg(-1) at L-NNA10 (P < 0.01) and a further 71 +/- 21 ml. min(-1). kg(-1) at L-NNA25 (P < 0.01), the fetal body-to-placental blood flow ratio was near unity at baseline and L-NNA10 but rose to 1.5 +/- 0.3 at L-NNA25 (P < 0.05). In association with these flow changes, fetal O2 consumption declined by 1.4 +/- 0.3 ml. min(-1). kg(-1) at L-NNA10 (P < 0.05) and by a further 1.5 +/- 0.6 ml. min(-1). kg(-1) at L-NNA25 (P < 0.02). These findings suggest that, in midgestation fetal lambs, NO supports an RV flow dominance, whole body O2 utilization, and the maintenance of a near-equal fetoplacental blood flow distribution.

Balloon mitral valvuloplasty at Monash Medical Centre: follow up of 201 procedures over an 11-year period.

Over a period of 11 years from 1988 to 1999, 201 patients underwent balloon mitral valvuloplasty (BMV) at Monash Medical Centre, Australia. Before BMV,133 patients (66%) were symptomatic with minimal activity or at rest. BMV increased mitral valve area and cardiac output, and reduced transmitral, left atrial and pulmonary pressures, with infrequent procedural complications (<8%). At the initial 3-month follow up after BMV, symptoms were absent or minimal in 178 patients (89%), with 85% remaining event free at 12 months. At long-term follow up (median: 30 months; range: 0-129 months), cumulative event-free survival was 73% after 5 years. After BMV, 37 patients (18%) underwent mitral valve surgery, while a repeat BMV was performed in three patients (1.5%). The results of this series provide additional data for the growing body of evidence which suggests that BMV is a relatively safe and effective procedure for producing long-term benefit in patients with symptomatic mitral stenosis.

Effects of balloon mitral valvuloplasty on systemic and regional left atrial levels of prothrombin fragment 1+2 in mitral stenosis.

A proportion of mitral stenosis patients with left atrial spontaneous echo contrast but without thrombus exhibit a regional hypercoagulable state, characterized by increased left atrial levels, but normal venous levels, of prothrombin fragment 1+2 (F1+2), a marker of thrombin generation. Valve dilatation by balloon mitral valvuloplasty has beneficial effects on left atrial spontaneous echo contrast, but its effect on left atrial thrombin generation is unknown. We examined the effects of balloon mitral valvuloplasty on venous and left atrial levels of F1+2 in 37 patients with mitral stenosis, divided into those with normal (group 1; n=22) and those with increased (group 2; n=15) regional left atrial thrombin generation, as described previously. The mitral valve area increased by a similar degree after the valvuloplasty procedure in the two groups. In group 1, the venous (P<0.005) and left atrial (P<0.0005) levels of F1+2 increased similarly after valvuloplasty, and as a result the left-atrial-venous F1+2 difference was unchanged. The venous F1+2 level also increased after valvuloplasty in group 2 (P<0.005); however, in contrast with group 1, the left atrial level decreased (P<0.03) and as a result the left-atrial-venous difference fell (P<0.05). These results show that balloon mitral valvuloplasty results in an immediate increase in thrombin generation, but a decrease in the left-atrial-venous F1+2 difference, in patients with increased left atrial thrombin generation. The divergent changes in venous and left atrial levels of F1+2 further highlight the limitations of assessing regional changes in coagulation activity by measuring venous levels of coagulation markers.

Influence of prenatal adrenaline infusion on arterial blood gases after caesarean delivery in the lamb.

The efficacy of pulmonary gas exchange immediately after delivery is inversely related to the volume of liquid in the lung at birth, but aspiration of as much liquid as possible from the lung before Caesarean delivery fails to improve postnatal oxygenation (Pa,O2) to the level achieved after spontaneous term delivery. We hypothesised that the differing respiratory benefit of aspiration and vaginal delivery results from the differing volume of lung liquid remaining after aspiration (17 ml (kg body weight)-1) and labour (7 ml kg-1). We addressed this hypothesis by reducing lung liquid volume to an estimated 7 ml kg-1 by infusing adrenaline to seven fetal lambs at 140 days gestation (term is 147 days) before performing Caesarean delivery and obtaining postnatal blood gases for comparison with samples from lambs delivered vaginally. Infusion of adrenaline to fetuses caused a progressive decline in arterial O2 saturation (Sa, O2), pH and base excess, but no change in arterial partial pressure of O2 (Pa,O2) or CO2 (Pa,CO2). After birth, Pa,O2 rapidly rose to the same level in adrenaline-treated and vaginal-delivery groups. A severe acidosis occurred in the adrenaline-treated group and this appeared to be related to a higher Pa,CO2 and a transiently lower Sa, O2 in this group. We conclude that adrenaline infusion can enhance postnatal Pa,O2 levels in the newborn lamb, but this beneficial effect may be outweighed by the severe acidosis that develops after prolonged prenatal adrenaline treatment.

Release of activin and follistatin during cardiovascular procedures is largely due to heparin administration.

Recent evidence has suggested that activin A complexed to its binding protein, follistatin, may be present on the surface of cells through their interaction with heparan sulfate proteoglycans. As heparin is used routinely in many cardiovascular procedures for its anticoagulation properties, it may also cause the release of heparin-binding growth factors, including activin and follistatin, from the vascular endothelium. We examined the effect of two cardiovascular procedures and the use of heparin directly on the circulating concentrations of activin A and follistatin. A rapid and robust release of activin A and follistatin occurred in the circulation of patients undergoing abdominal aortic aneurysm repair or carotid endarterectomy at the time of vessel clamping and administration of heparin (5000 IU). This release pattern was dissimilar to that of the inflammatory marker, interleukin-1beta. However, administering heparin (2500 IU) to coronary angiography patients produced a similar activin and follistatin response, whereas placebo-treated angiography patients had no response. These findings illustrate that the routine use of heparin in surgical procedures elicits a rapid and robust release of activin and follistatin. This has direct clinical relevance by potentially activating heparin-binding growth factors that are important in injury, hyperplasia, and restenosis of vessels.

Postmenopausal hormone replacement therapy increases coagulation activity and fibrinolysis.

Hormone replacement therapy (HRT) appears to be cardioprotective in postmenopausal women; however, concerns exist over its thrombogenic effects. To address the effects of combined HRT on coagulation and fibrinolysis, we have measured circulating markers of these processes in a double-blind placebo-controlled trial. Forty-two healthy postmenopausal women aged 50 to 75 years received continuous combined HRT with 2 mg estradiol+1 mg norethisterone or placebo for 6 weeks. Hormone profiles were measured at baseline, and lipid and hemostatic parameters were measured at baseline and after 6 weeks of therapy. Baseline characteristics were similar in the 2 groups. With change from baseline the main outcome measure, HRT increased the markers of coagulation (prothrombin fragments 1+2, 0.20+/-0.06 versus 0.06+/-0.04 nmol/L, P=0.0005; soluble fibrin, 2.3+/-0.4 versus 0.25+/-0.3 microgram/mL, P=0.0004), reduced plasma fibrinolytic inhibitory activity (plasminogen activator inhibitor-1, -0.67+/-0.16 versus 0.24+/-0.21 U/mL, P=0.002), and increased fibrinolysis (D-dimer, 24+/-12 versus -6+/-8 ng/mL, P=0.04) compared with placebo. Increases in soluble fibrin and D-dimer were positively correlated (r=0.59, P=0.02), but changes in plasminogen activator inhibitor-1 and D-dimer were unrelated. Although baseline hemostatic and lipid parameters were correlated, there were no associations between changes in hemostatic markers and lipids after treatment. Short-term oral combined continuous HRT (estradiol and norethisterone) increased thrombin and fibrin generation, reduced plasma fibrinolytic inhibitory activity, and increased fibrinolysis. Enhanced fibrinolysis was related to increased fibrin generation but not reduced plasma fibrinolytic inhibitory activity. Coagulation activation may partly explain the increases in venous thrombosis and cardiovascular events reported with the use of combined HRT.

Increased left atrial thrombin generation in mitral stenosis is not reflected in arterial prothrombin fragment 1+2 levels.

A proportion of patients with mitral stenosis have increased left atrial thrombin generation, with elevated left atrial but normal peripheral venous levels of prothrombin fragment 1+2 (F1+2). Whether this pattern of left atrial and venous F1+2 levels is related to limited spillover of F1+2 from the left atrium into the systemic circulation, or to washout of increased left atrial F1+2 production into the arterial circulation with subsequent systemic clearance, is unclear. We examined the relationship between arterial and venous F1+2 levels in mitral stenosis patients without left atrial thrombus. The study group comprised 36 patients with either a normal (n=29) or prolonged (n=7) international normalized ratio (INR; a measure of clotting time) who were undergoing percutaneous balloon mitral valvuloplasty. Baseline arterial and venous blood samples were collected at the beginning of the valvuloplasty procedure, and left atrial and venous samples were collected after trans-septal puncture. The left atrial F1+2 level exceeded the corresponding venous level in patients with a normal INR (P<0.03); however, baseline arterial and venous F1+2 levels were similar. Arterial and venous F1+2 levels were also similar in the subgroup of patients with evidence of a regional increase in left atrial thrombin generation, and were not different from arterial and venous F1+2 levels in patients without such an increase. Baseline arterial and venous F1+2 levels were both lower in the presence of a prolonged INR. Thus the pattern of increased left atrial but normal venous F1+2 levels in mitral stenosis is due to limited spillover from the left atrium into the systemic circulation.

Blunting of pulmonary but not systemic vasodilator responses to dobutamine in newborn lambs.

Little is known about the changes in systemic and pulmonary vascular responses to dobutamine that occur during postnatal development. To address this question, vascular pressures and cardiac output were measured in anesthetized 1- to 2-d-old (n = 6), 7- to 10-d-old (n = 7), and 6- to 8-wk-old lambs (n = 6) while dobutamine was infused incrementally in the dose range of 0.5-40 microg x kg(-1) x min(-1). Dobutamine reduced pulmonary vascular resistance in the three age groups (all p<0.005). However, although this reduction reached a plateau over the infusion range of 15-40 microg x kg(-1) x min(-1) at all ages, its magnitude was less (p<0.02) in 1- to 2-d-old lambs (24+/-2%) than in 7- to 10-d-old (41+/-7%) or 6- to 8-wk-old lambs (42+/-6%). Over the same infusion range, dobutamine produced a fall in systemic vascular resistance (all p<0.005) that was proportionally similar in 1- to 2-d-old (51+/-3%), 7- to 10-d-old (48+/-3%), and 6- to 8-wk-old lambs (42+/-6%). In separate subgroups of 1- to 2-d-old lambs, pulmonary and systemic responses to dobutamine were not affected by pretreatment with selective alpha1-, beta1-, or beta2-adrenoceptor antagonists. Taken together, these findings suggest that the pulmonary but not systemic vasodilator response to dobutamine in lambs is blunted in the initial days after birth, and that this pulmonary effect is not directly related to the adrenoceptor-stimulating properties of dobutamine.

Total body catecholamine kinetics before and after birth in spontaneously hypoxemic fetal lambs.

To study the effect of fetal hypoxemia on perinatal norepinephrine and epinephrine total body kinetics, 13 near-term fetal lambs were instrumented with vascular catheters under general anesthesia. One week later, norepinephrine and epinephrine kinetics were measured in normoxemic (n = 7) or spontaneously hypoxemic fetuses (n = 6) with isotope dilution methodology. Hypoxemic fetuses had lower body (P < 0.02) and placental (P = 0.01) weights and a threefold elevation in plasma norepinephrine (P < 0.005) and epinephrine (P < 0.025) associated with correspondingly higher total body norepinephrine (P < 0.005) and epinephrine (P < 0.05) spillovers. After birth, total body norepinephrine and epinephrine spillover increased 45% and 3.2-fold, respectively, in normoxemic animals (both P < 0.001). However, in the hypoxemic group, norepinephrine total body spillover was unchanged between fetal and 1-h lambs and then fell in 4-h lambs (P < 0.005). In addition, total body epinephrine release rose postnatally (P < 0.05) but less than in the normoxemic group (P < 0.02). No differences in norepinephrine or epinephrine total body clearance occurred between normoxemic and hypoxemic groups in either fetal or newborn lambs. These findings indicate that in hypoxemic and growth-restricted fetuses 1) elevated circulating norepinephrine and epinephrine levels are related to increased sympathoadrenal activity and 2) birth is associated with an initial maintenance and subsequent decline in global sympathetic activity but a blunting of adrenal medullary activation.

Inverse relation of haematocrit to cardiac index in mitral stenosis and atrial fibrillation.

We investigated the relationship between atrial fibrillation and the red cell parameters haematocrit, red cell concentration and mean corpuscular volume in 95 female patients with mitral stenosis (mean age 51+/-11 years, 38 patients in atrial fibrillation, 57 patients in sinus rhythm) who had undergone full blood examination and right and left heart catheterisation. Haematocrit was a positive correlate of atrial fibrillation (r=0.29, p<0.009) and a negative correlate of cardiac index (r=-0.37, p<0.003), but cardiac index was the only independent correlate of haematocrit on multivariate analysis (r2=0.14). The mean corpuscular volume was a positive correlate of age (r=0.42, p<0.0001) and atrial fibrillation (r=0.29, p<0.005) and a negative correlate of cardiac index (r=-0.22, p<0.04) and red cell concentration (r=-0.56, p<0.0001). On multivariate analysis, however, only age and red cell concentration were independent correlates of mean corpuscular volume (r2=0.43). Cardiac index was inversely correlated with both haematocrit and red cell concentration in the subgroup of patients with atrial fibrillation but not those with sinus rhythm. This study demonstrates that the major determinant of the higher haematocrit in mitral stenosis patients with atrial fibrillation is an associated reduction in cardiac index.

Mechanisms of blood pressure increase induced by dopamine in hypotensive preterm neonates.

AIMS: To compare changes in global haemodynamics as well as anterior cerebral and superior mesenteric artery perfusion after dopamine treatment. METHODS: Anterior cerebal and superior mesenteric artery perfusion was measured using Doppler ultrasonography in hypotensive preterm neonates in whom cardiac output increased (group 1, n=10) or decreased (group 2, n=40) after dopamine treatment. RESULTS: Despite a lower dopamine infusion rate, the blood pressure increase (mm Hg) in group 2 [Delta=13(1); mean(SE)] exceeded that in group 1 [Delta=8(1)], while systemic vascular resistance (mm Hg/l/min/kg) rose in group 2 [Delta=106 (37)], but was unchanged in group 1 [Delta=9 (6)]. Anterior cerebral artery blood velocity and resistance were unaffected by dopamine. However, compared with unchanged values in group 1, superior mesenteric artery blood velocity fell by 14.7(4.8) cm/s and resistance increased by 4.1(0.7) mm Hg/cm in group 2. CONCLUSIONS: These results suggest that, in a portion of hypotensive preterm neonates, the increase in blood pressure induced by dopamine is related to a predominant vasoconstrictor action and is associated with a fall in bowel perfusion.