Extended period of ventilation before delayed cord clamping augments left-to-right shunting and decreases systemic perfusion at birth in preterm lambs.

Previous studies have suggested that an extended period of ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. However, it is unknown whether this greater rise in PA flow is accompanied by increases in left ventricular (LV) output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale (FO), with decreased systemic arterial perfusion. Using an established preterm lamb birth transition model, this study compared the effect of a short (∼40 s, n = 11), moderate (∼2 min, n = 11) or extended (∼5 min, n = 12) period of initial mechanical lung ventilation before DCC on flow probe-derived perinatal changes in PA flow, LV output, total systemic arterial blood flow, ductal shunting and FO shunting. The LV output was relatively stable during initial ventilation but increased after DCC, with similar responses in all groups. Systemic arterial flow patterns displayed only minor differences during brief and moderate periods of initial ventilation and were similar after DCC. However, an increase in PA flow was augmented with an extended initial ventilation (P < 0.001), owing to an earlier onset of left-to-right ductal and FO shunting (P < 0.001), and was accompanied by a pronounced reduction in total systemic arterial flow (P = 0.005) that persisted for 4 min after DCC (P ≤ 0.039). These findings suggest that, owing to increased left-to-right shunting and a greater reduction in systemic arterial perfusion, an extended period of ventilation before DCC does not result in greater perinatal circulatory benefits than shorter periods of initial ventilation in the birth transition. KEY POINTS: Previous studies suggest that an extended period of initial ventilation before delayed cord clamping (DCC) augments birth-related rises in pulmonary arterial (PA) blood flow. It is unknown whether this greater rise in PA flow is accompanied by an increased left ventricular output and systemic arterial perfusion or whether it reflects enhanced left-to-right shunting across the ductus arteriosus and/or foramen ovale, with decreased systemic arterial perfusion. Anaesthetized preterm fetal lambs instrumented with central arterial flow probes underwent a brief (∼40 s), moderate (∼2 min) or extended (∼5 min) period of ventilation before DCC. Perinatal changes in left ventricular output were similar in all groups, but extended initial ventilation augmented both perinatal increases in PA flow, owing to earlier onset and greater left-to-right ductal and foramen ovale shunting, and perinatal reductions in total systemic arterial perfusion. Extended ventilation before DCC does not confer a greater perinatal circulatory benefit than shorter periods of initial ventilation.

Divergent effects of initial ventilation with delayed cord clamping on systemic and pulmonary arterial flows in the birth transition of preterm lambs.

A current view that delayed cord clamping (DCC) results in greater haemodynamic stability at birth than immediate cord clamping (ICC) is based on comparison of DCC vs. ICC followed by an asphyxial (∼2 min) cord clamp-to-ventilation (CC-V) interval. More recent data suggest that relatively minor perinatal differences in heart rate and blood pressure fluctuations exist between DCC and ICC with a non-asphyxial (<45 s) CC-V interval, but it is unknown how ventricular output and central arterial blood flow effects of DCC compare with those of non-asphyxial ICC. Anaesthetized preterm fetal lambs instrumented with flow probes on major central arteries were ventilated for 97 (7) s (mean (SD)) before DCC at birth (n = 10), or underwent ICC 40 (6) s before ventilation (n = 10). Compared to ICC, initial ventilation and DCC was accompanied by (1) redistribution of a similar level of ascending aortic flow away from cephalic arteries and towards the aortic isthmus after ventilation; (2) a lower right ventricular output after cord clamping that was redistributed towards the lungs, thereby maintaining the absolute contribution of this output to a similar increase in pulmonary arterial flow after birth; and (3) a lower descending thoracic aortic flow after birth, related to a more rapid decline in phasic right-to-left ductal flow only partially offset by increased aortic isthmus flow. However, systemic arterial flows were similar between DCC and non-asphyxial ICC within 5 min after birth. These findings suggest that compared to non-asphyxial ICC, initial ventilation with DCC transiently redistributed central arterial flows, resulting in lower perinatal systemic arterial, but not pulmonary arterial, flows. KEY POINTS: A current view that delayed cord clamping (DCC) results in greater haemodynamic stability at birth than immediate cord clamping (ICC) is based on comparison of DCC vs. ICC with an asphyxial (∼2 min) cord clamp-to-ventilation (CC-V) interval. Recent data suggest that relatively minor perinatal differences in heart rate and blood pressure fluctuations exist between DCC and ICC with a non-asphyxial (<45 s) CC-V interval, but how central arterial blood flow effects of DCC compare with those of non-asphyxial ICC is unknown. Anaesthetized preterm fetal lambs instrumented with central arterial flow probes underwent initial ventilation for ∼90 s before DCC at birth, or ICC for ∼40 s before ventilation. Compared to non-asphyxial ICC, initial ventilation with DCC redistributed central blood flows, resulting in lower systemic, but not pulmonary, arterial flows during this period of transition. This flow redistribution was transitory, however, with systemic arterial flows similar between DCC and non-asphyxial ICC within minutes after birth.

Optimized design of an arterial network model reproduces characteristic central and peripheral haemodynamic waveform features of young adults.

The arterial network in healthy young adults is thought to be structured to optimize wave reflection in the arterial system, producing an ascending aortic pressure waveform with three key features: early systolic peak, negative systolic augmentation and diastolic hump. One-dimensional computer models have provided significant insights into arterial haemodynamics, but no previous models of the young adult have exhibited these three features. Given that this issue was likely to be related to unrepresentative or non-optimized impedance properties of the model arterial networks, we developed a new 'YoungAdult' model that incorporated the following features: (i) a new and more accurate empirical equation for approximating wave speeds, based on area and relative distance to elastic-muscular arterial transition points; (ii) optimally matched arterial junctions; and (iii) an improved arterial network geometry that eliminated 'within-segment' taper (which causes wave reflection in conduit arteries) whilst establishing 'impedance-preserving' taper. These properties of the model led to wave reflection occurring predominantly at distal vascular beds, rather than in conduit arteries. The model predicted all three typical characteristics of an ascending aortic pressure waveform observed in young adults. When compared with non-invasively acquired pressure and velocity measurements (obtained via tonometry and Doppler ultrasound in seven young adults), the model was also shown to reproduce the typical waveform morphology observed in the radial, brachial, carotid, temporal, femoral and tibial arteries. The YoungAdult model provides support for the concept that the arterial tree impedance in healthy young adults is exquisitely optimized, and it provides an important baseline model for investigating cardiovascular changes in ageing and disease states. KEY POINTS: The origin of wave reflection in the arterial system is controversial, but reflection properties are likely to give rise to characteristic haemodynamic features in healthy young adults, including an early systolic peak, negative systolic augmentation and diastolic hump in the ascending aortic pressure waveform, and triphasic velocity profiles in peripheral arteries. Although computational modelling provides insights into arterial haemodynamics, no previous models have predicted all these features. An established arterial network model was optimized by incorporating the following features: (i) a more accurate representation of arterial wave speeds; (ii) precisely matched junctions; and (iii) impedance-preserving tapering, thereby minimizing wave reflection in conduit arteries in the forward direction. Comparison with in vivo data (n = 7 subjects) indicated that the characteristic waveform features in young adults were predicted accurately. Our findings strongly imply that a healthy young arterial system is structured to optimize wave reflection in the main conduit arteries and that reflection of forward waves occurs primarily in the vicinity of vascular beds.

Characteristics and physiological basis of falls in ventricular outputs after immediate cord clamping at delivery in preterm fetal lambs.

KEY POINTS: Controversy exists about the physiological mechanism(s) underlying decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, the four major determinants of ventricular output (afterload, preload, heart rate and contractility) were measured concurrently in fetal lambs at 15 s intervals over a 2 min period after cord clamping and before ventilation following delivery. After cord clamping, right (but not left) ventricular output fell by 20% in the initial 30 s, due to increased afterload associated with higher arterial blood pressures, but both outputs then halved over 45 s, due to a falling heart rate and deteriorating ventricular contractility accompanying rapid declines in arterial oxygenation to asphyxial levels. Ventricular outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in ventricular contractility accompanying asphyxia-induced surges in circulating catecholamines. These findings provide a physiological basis for the clinical recommendation that effective ventilation should occur within 60 s after immediate cord clamping. ABSTRACT: Controversy exists about the physiological mechanism(s) underlying large decreases in cardiac output after immediate clamping of the umbilical cord at birth. To define these mechanisms, anaesthetized preterm fetal lambs (127(1)d, n = 12) were instrumented with flow probes and catheters in major central arteries, and a left ventricular (LV) micromanometer-conductance catheter. Following immediate cord clamping at delivery, haemodynamics, LV and right ventricular (RV) outputs, and LV contractility were measured at 15 s intervals during a 2 min non-ventilatory period, with aortic blood gases and circulating catecholamine (noradrenaline and adrenaline) concentrations measured at 30 s intervals. After cord clamping, (1) RV (but not LV) output fell by 20% in the initial 30 s, due to a reduced stroke volume associated with increased arterial blood pressures, (2) both outputs then halved over the next 45 s, associated with falls in heart rate, arterial blood pressures and ventricular contractility accompanying a rapid decline in arterial oxygenation to asphyxial levels, (3) reduced outputs subsequently plateaued from 75 to 120 s, associated with rebound rises in blood pressures and ventricular contractility accompanying exponential surges in circulating catecholamines. These findings are consistent with a time-dependent decline of ventricular outputs after immediate cord clamping, which comprised (1) an initial, minor fall in RV output related to altered loading conditions, (2) ensuing large decreases in both LV and RV outputs related to the combination of bradycardia and ventricular dysfunction during emergence of an asphyxial state, and (3) subsequent stabilization of reduced LV and RV outputs during ongoing asphyxia, supported by cardiovascular stimulatory effects of marked sympathoadrenal activation.

Antenatal betamethasone redistributes central blood flows and preferentially augments right ventricular output and pump function in preterm fetal lambs.

The glucocorticosteroid betamethasone, which is routinely administered prior to anticipated preterm birth to enhance maturation of the lungs and the cardiovascular system, has diverse fetal regional blood flow effects ranging from increased pulmonary flow to decreased cerebral flow. The aim of this study was to test the hypothesis that these diverse effects reflect alterations in major central flow patterns that are associated with complementary shifts in left ventricular (LV) and right ventricular (RV) pumping performance. Studies were performed in anesthetized preterm fetal lambs (gestation = 127 ± 1 days, term = 147 days) with (n = 14) or without (n = 12) preceding betamethasone treatment via maternal intramuscular injection. High-fidelity central arterial blood pressure and flow signals were obtained to calculate LV and RV outputs and total hydraulic power. Betamethasone therapy was accompanied by 1) increased RV, but not LV, output; 2) a greater RV than LV increase in total power; 3) a redistribution of LV output away from the fetal upper body region and toward the lower body and placenta; 4) a greater proportion of RV output passing to the lungs, and a lesser proportion to the lower body and placenta; and 5) a change in the relative contribution of venous streams to ventricular filling, with the LV having increased pulmonary venous and decreased foramen ovale components, and the RV having lesser superior vena caval and greater inferior vena caval portions. Taken together, these findings suggest that antenatal betamethasone produces a widespread redistribution of central arterial and venous flows in the fetus, accompanied by a preferential rise in RV pumping performance.

Reducing lung liquid volume in fetal lambs decreases ventricular constraint.

BACKGROUND: This study evaluated whether an increased left ventricular (LV) pump function accompanying reduction of lung liquid volume in fetal lambs was related to increased LV preload, augmented LV contractility, or both. METHODS: Eleven anesthetized preterm fetal lambs (gestation 128 ± 2 days) were instrumented with (1) an LV micromanometer-conductance catheter to obtain LV end-diastolic volume (EDV) and end-diastolic pressure (EDP), the maximal rate of rise of LV pressure (dP/dtmax), LV output, LV stroke work, and LV end-systolic elastance (Ees), a relatively load-independent measure of contractility; (2) an endotracheal tube to measure mean tracheal pressure and to reduce lung liquid volume. LV transmural pressure was calculated as LV EDP minus tracheal pressure. RESULTS: Reducing lung liquid volume by 16 ± 4 ml kg-1 (1) augmented LV output (by 16%, P = 0.001) and stroke work (29%, P < 0.001), (2) increased LV EDV (12%, P < 0.001), (3) increased LV transmural pressure (2.2 mmHg, P < 0.001), (4) did not change LV dP/dtmax normalized for EDV (P > 0.7), and (5) decreased LV Ees (20%, P < 0.01). CONCLUSION: These findings suggest a rise in LV pump function evident after reduction of lung liquid volume in fetal lambs was related to increased LV preload secondary to lessening of external LV constraint, without any associated rise in LV contractility. IMPACT: This study has shown that reducing the volume of liquid filling the fetal lungs lessens the degree of external constraint on the heart. This lesser constraint permits a rise in left ventricular dimensions and thus greater cardiac filling that leads to increased left ventricular pumping performance. This study has defined a mechanism whereby a reduction in lung liquid volume results in enhanced pumping performance of the fetal heart. These findings suggest that a reduction in lung liquid volume which occurs during the birth transition contributes to increases in left ventricular dimensions and pumping performance known to occur with birth.

Arterial Stiffness in Congenital Heart Disease.

Transposition of the great arteries (TGA), coarctation of the aorta (CoA), single ventricle (SV) and tetralogy of Fallot (ToF) are forms of congenital heart disease (CHD). Despite advances in treatment, cardiovascular and cerebrovascular complications in patients with repaired CHD occur earlier in life compared to healthy subjects. A factor that may contribute to this increased risk is elevated arterial stiffness. This systematic review provides a critical assessment of current evidence on central arterial stiffness in patients with CHD compared to healthy controls. In July 2020, Medline OVID, EMBASE and Scopus were searched using keywords and MeSH terms. Articles were included if they reported indices of aortic or carotid artery stiffness in patients with TGA, CoA, SV or ToF, and compared these to controls. Additional studies were screened from the reference lists of included articles. Of 1,033 studies identified, 43 were included in the final review. Most studies identified at least one index of central arterial stiffness, commonly in the aortic root or ascending aorta, that was higher in patients with CHD compared to controls. The commonly reported surrogate markers of stiffness were pulse wave velocity, aortic distensibility and the ß stiffness index. There was a relatively small number of original studies, and synthesis of data was limited by methodological heterogeneity, highlighting the need for further studies with standardised methods. However, there was consistent evidence of early and/or accelerated arterial stiffening in CHD patients, which may contribute to the increased risk of adverse cardiovascular and cerebrovascular events in this population.

Conduit arterial wave reflection promotes pressure transmission but impedes hydraulic energy transmission to the microvasculature.

Current thinking suggests that wave reflection in arteries limits pulse pressure and hydraulic energy (HE) transmission to the microvasculature and that this protective effect reduces with advancing age. However, according to transmission line theory, pressure transmission (Tp) and reflection (R) coefficients are proportional (Tp = 1 + R), implying that wave reflection would promote rather than limit pressure transmission. We hypothesized that increasing distal pulse pressure (PPd) with age is instead related to increased proximal pulse pressure (PPp) and its forward component and that these are modulated by arterial compliance. A one-dimensional model of a fractal arterial tree containing 21 generations was constructed. Wave speed in each vessel was prescribed to achieve a uniform R at every junction, with changes in R achieved by progressively stiffening proximal or distal vessels. For both stiffening scenarios, decreasing reflection led to a decrease or no change in PPd when forward pressure or compliance were held constant, respectively, suggesting that wave reflection per se does not limit pressure transmission. Proximal pulse pressure, its forward component, and PPd increased with decreasing compliance; furthermore, proximal and distal pulse pressures were approximately proportional. With fixed compliance but decreasing reflection, HE transmission increased, whereas pressure transmission decreased, consistent with transmission line theory. In conclusion, wave reflection does not protect the microvasculature from high PPd; rather, PPp and PPd are modulated by arterial compliance, which reduces with age. Wave reflection has opposing effects on pressure and HE transmission; hence, the relative importance of pressure versus HE in contributing to microvascular damage warrants investigation.NEW & NOTEWORTHY With aging, a reduction in the stiffness gradient between elastic and muscular arteries is thought to reduce wave reflection in conduit arteries, leading to increased pulsatile pressure transmission into the microvasculature. This assumes that wave reflection limits pressure transmission in arteries. However, using a computational model, we showed that wave reflection promotes pulsatile pressure transmission, although it does limit hydraulic energy transmission. Increased microvascular pulse pressure with aging is instead related to decreasing arterial compliance.

Milrinone Acts as a Vasodilator But Not an Inotrope in Children After Cardiac Surgery-Insights From Wave Intensity Analysis.

OBJECTIVES: Milrinone is an inodilator widely used in the postoperative management of children undergoing cardiac surgery. The literature supporting its inotropic effect is sparse. We sought to study the effect of milrinone on the vasculature and its effects on the ventricular function using wave intensity analysis. We also intended to evaluate the feasibility of using wave intensity analysis by the bedside. DESIGN: prospective single-center observational study. SETTING: PICU of a tertiary children's hospital. PATIENTS: Children (< 18 yr) admitted to PICU following cardiac surgery who required to be commenced on a milrinone infusion. INTERVENTIONS: Echocardiography and Doppler ultrasound assessments for wave intensity analysis were performed prior to commencing milrinone and 4-6 hours after milrinone infusion. MEASUREMENTS AND MAIN RESULTS: Wave intensity analysis was successfully performed and analyzed in 15 of 16 patients (94%). We identified three waves-a forward compression wave, backward compression wave, and forward decompression wave. The waves were described with their cumulative intensity and wave-related pressure change. There was a 26% reduction in backward compression wave cumulative intensity following the introduction of milrinone. Other variables (backward compression wave cumulative intensity/forward compression wave cumulative intensity ratio, backward compression wave wave-related pressure change, backward compression wave wave-related pressure change/forward compression wave wave-related pressure change ratio) consistent with vasodilation also decreased after milrinone. It also decreased the vascular wavespeed by 7.1% and increased the distensibility of the vessels by 14.6%. However, it did not increase forward compression wave cumulative intensity, a variable indicating the systolic force generated by the ventricle. Forward decompression wave cumulative intensity indicating ventricular early diastolic relaxation also did not change. CONCLUSIONS: In a cohort of children recovering in PICU after having undergone cardiac surgery, we found that milrinone acted as a vasodilator but did not demonstrate an improvement in the contractility or an improved relaxation of the left ventricle as assessed by wave intensity analysis. We were able to demonstrate the feasibility and utility of wave intensity analysis to further understand ventriculo-vascular interactions in an intensive care setting.

Reducing lung liquid volume increases biventricular outputs and systemic arterial blood flows despite decreased cardiac filling pressures in fetal lambs.

As prior work has shown that reducing lung liquid volume 1) increases pulmonary arterial (PA) blood flow, 2) augments right ventricular (RV) output/power, and 3) decreases left atrial (LA) pressure, we tested the hypothesis that this perturbation has global cardiovascular effects. Ten anesthetized, open-chest fetal lambs (128 ± 2 days gestation, full term = 147 days) were acutely instrumented with 1) LA and right atrial (RA) catheters, 2) aortic and pulmonary trunk catheters, 3) brachiocephalic trunk, aortic isthmus, ductal, and left PA flow probes to obtain left ventricular (LV) and RV outputs and hydraulic power and flow in the descending thoracic aorta, and 4) an endotracheal tube to remove lung liquid. A 17 ± 7 ml/kg reduction of lung liquid volume 1) decreased LA and RA pressures similarly (1.5-1.6 mmHg, P < 0.001), 2) augmented LV and RV outputs (21-24%, P < 0.001) and total power (27-28%, P < 0.005), 3) increased systolic flows in the brachiocephalic trunk (18%, P < 0.001), aortic isthmus (29%, P < 0.005), ductus (12%, P < 0.005), and descending thoracic aorta (16%, P < 0.001), 4) increased mean PA flow via a higher systolic inflow (37%, P < 0.001) and lower diastolic backflow (-16%, P < 0.05), and 5) did not change systemic vascular conductance or arterial compliance but increased both pulmonary vascular conductance and arterial compliance (1.8-fold, P < 0.001). These data suggest that hemodynamic effects of lung liquid volume reduction are not confined to the lungs but extend to all cardiac chambers via rises in LV and RV outputs and power, despite falls in cardiac filling pressures, as well as the systemic circulation, via downstream increases in systolic flows of major central arteries.

Antenatal betamethasone augments early rise in pulmonary perfusion at birth in preterm lambs: role of ductal shunting and right ventricular outflow distribution.

The glucocorticosteroid betamethasone is routinely administered via maternal intramuscular injection to enhance fetal lung maturation before anticipated preterm birth. Although antenatal betamethasone increases fetal pulmonary arterial (PA) blood flow, whether this agent alters the contribution of 1) right ventricular (RV) output or 2) left-to-right shunting across the ductus arteriosus to rises in PA blood flow after preterm birth is unknown. To address this question, anesthetized control (n = 7) and betamethasone-treated (n = 7) preterm fetal lambs (gestation 127 ± 1 days, means ± SD) were instrumented with aortic, pulmonary, and left atrial catheters as well as ductus arteriosus and left PA flow probes to calculate RV output, with hemodynamics measured for 30 min after cord clamping and mechanical ventilation. Mean PA blood flow was higher in betamethasone-treated than in control lambs over the initial 10 min after birth (P < 0.05). This higher PA flow was accompanied by 1) a greater pulmonary vascular conductance (P ≤ 0.025), 2) a larger proportion of RV output passing to lungs (P ≤ 0.01), despite a fall in this output, and 3) earlier reversal and a greater magnitude (P ≤ 0.025) of net ductal shunting, due to the combination of higher left-to-right (P ≤ 0.025) and lesser right-to-left phasic shunting (P ≤ 0.025). These results suggest that antenatal betamethasone augments the initial rise in PA blood flow after birth in preterm lambs, with this augmented rise supported by the combination of 1) a greater redistribution of RV output toward the lungs and 2) a faster and larger reversal in net ductal shunting underpinned not only by greater left-to-right, but also by lesser right-to-left phasic shunting.

Blunted sympathoadrenal activation accompanies hemodynamic stability after early ventilation and delayed cord clamping at birth in preterm lambs.

BACKGROUND: As surges in circulating norepinephrine and epinephrine have chronotropic, pressor, and inotropic effects, we tested the hypothesis that blunted rises in these catecholamines during preterm birth accompanied hemodynamic stability observed after early ventilation and delayed cord clamping (DCC), with findings compared to immediate cord clamping (ICC) and a non-asphyxial cord clamp-to-ventilation interval. METHODS: Anesthetized preterm fetal lambs were instrumented with arterial micromanometers to obtain pressure and the maximal rate of pressure rise (dP/dtmax) as a surrogate of ventricular contractility and an aortic catheter to obtain blood samples for catecholamine assay. Fetuses were delivered and mechanically ventilated before cord clamping ∼1.5 min later (DCC, n = 9) or subjected to ICC with ventilation started ∼40 s later (n = 8). RESULTS: Perinatal hemodynamics were stable after DCC, with greater fluctuations evident following birth after ICC (P ≤ 0.05). With DCC, circulating norepinephrine and epinephrine were unchanged after early ventilation but rose following cord clamping (P ≤ 0.01), with concentrations below the threshold for hemodynamic effects. Norepinephrine was higher in the ICC group after cord clamping and immediately after ventilation (P < 0.025), but catecholamine levels were otherwise similar between groups. CONCLUSION: Hemodynamic stability at birth after DCC is accompanied by sub-threshold rises in circulating norepinephrine and epinephrine and thus blunted sympathoadrenal activation.

Assessment of single beat end-systolic elastance methods for quantifying ventricular contractility.

Multi-beat end-systolic elastance (EMB) is considered a gold-standard index of ventricular contractility. However, it is difficult to measure clinically due to the need for transient manipulation of ventricular preload or afterload. We compared the performance of 5 'single-beat' methods that do not require loading interventions, for estimating the equivalent of EMB. In 7 sheep instrumented with a micromanometer/conductance catheter, single-beat methods were compared with EMB, obtained after transiently decreasing preload or increasing afterload under a broad range of heart rates and inotropic conditions. The single-beat elastance (ESB) method described by Shishido et al. (Circulation 102(16):1983-1989, 2000) had the highest correlation (R = 0.69, y = 0.52x + 0.43) with EMB, although the absolute accuracy was poor. Interestingly, for all methods tested, a higher correlation was observed when EMB was obtained with an afterload increase (R = 0.47 - 0.78) rather than a preload reduction (R = 0.07-0.57). Within-animal regression coefficients were higher than those obtained from pooled data, with excellent within-animal correlation observed for Shishido et al. method (0.73 ≤ R ≤ 0.96) when using afterload increase as the loading intervention. We conclude that (1) current methods perform better when using an afterload increase to obtain reference EMB, (2) intra-individual ESB comparisons may be more reliable than inter-individual comparisons and (3) Shishido et al.'s method demonstrated the strongest correlation with EMB. Current ESB methods have limited and variable accuracy, but may hold promise for tracking relative changes in ventricular contractility in individuals.

Major influence of a 'smoke and mirrors' effect caused by wave reflection on early diastolic coronary arterial wave intensity.

KEY POINTS: Coronary wave intensity analysis (WIA) is an emerging technique for assessing upstream and downstream influences on myocardial perfusion. It is thought that a dominant backward decompression wave (BDWdia ) is generated by a distal suction effect, while early-diastolic forward decompression (FDWdia ) and compression (FCWdia ) waves originate in the aorta. We show that wave reflection also makes a substantial contribution to FDWdia , FCWdia and BDWdia , as quantified by a novel method. In 18 sheep, wave reflection accounted for ∼70% of BDWdia , whereas distal suction dominated in a computer model representing a hypertensive human. Non-linear addition/subtraction of mechanistically distinct waves (e.g. wave reflection and distal suction) obfuscates the true contribution of upstream and downstream forces on measured waves (the 'smoke and mirrors' effect). The mechanisms underlying coronary WIA are more complex than previously thought and the impact of wave reflection should be considered when interpreting clinical and experimental data. ABSTRACT: Coronary arterial wave intensity analysis (WIA) is thought to provide clear insight into upstream and downstream forces on coronary flow, with a large early-diastolic surge in coronary flow accompanied by a prominent backward decompression wave (BDWdia ), as well as a forward decompression wave (FDWdia ) and forward compression wave (FCWdia ). The BDWdia is believed to arise from distal suction due to release of extravascular compression by relaxing myocardium, while FDWdia and FCWdia are thought to be transmitted from the aorta into the coronary arteries. Based on an established multi-scale computational model and high-fidelity measurements from the proximal circumflex artery (Cx) of 18 anaesthetized sheep, we present evidence that wave reflection has a major impact on each of these three waves, with a non-linear addition/subtraction of reflected waves obscuring the true influence of upstream and downstream forces through concealment and exaggeration, i.e. a 'smoke and mirrors' effect. We also describe methods, requiring additional measurement of aortic WIA, for unravelling the separate influences of wave reflection versus active upstream/downstream forces on coronary waves. Distal wave reflection accounted for ∼70% of the BDWdia in sheep, but had a lesser influence (∼25%) in the computer model representing a hypertensive human. Negative reflection of the BDWdia at the coronary-aortic junction attenuated the Cx FDWdia (by ∼40% in sheep) and augmented Cx FCWdia (∼5-fold), relative to the corresponding aortic waves. We conclude that wave reflection has a major influence on early-diastolic WIA, and thus needs to be considered when interpreting coronary WIA profiles.

Increased right ventricular power and ductal characteristic impedance underpin higher pulmonary arterial blood flow after betamethasone therapy in fetal lambs.

BACKGROUND: The glucocorticosteroid betamethasone is routinely administered prior to anticipated preterm birth to enhance lung maturation. While betamethasone also increases fetal pulmonary blood flow and reduces pulmonary vascular resistance (PVR), we investigated whether alterations in right ventricular (RV) function and ductal characteristic impedance (Zc) additionally contributed to rises in pulmonary flow. METHODS: Anesthetized preterm fetal lambs with (n = 10) or without (n = 8) betamethasone pretreatment were instrumented with a pulmonary trunk micromanometer and ductus arteriosus and left pulmonary artery (PA) flow probes to calculate Zc, and obtain RV output and hydraulic power. RESULTS: Betamethasone (1) increased systolic and pulse arterial pressures (P ≤ 0.04), heart rate (P = 0.02), and lowered PVR (P = 0.04), (2) increased mean (P = 0.008) and systolic (P = 0.004), but not diastolic PA flow or PA Zc, (3) increased ductal Zc (P < 0.05), but not ductal flow, (4) increased RV output (P = 0.03) and the proportion of PT flow distributed to the lungs (P = 0.02), and (5) increased RV power (P ≤ 0.002). CONCLUSION: An increased fetal PA blood flow after betamethasone therapy was confined to the systole and underpinned not only by decreased PVR, but also greater RV power and preferential distribution of an augmented RV systolic outflow to the lungs due to higher ductal Zc.

Greater sympathoadrenal activation with longer preventilation intervals after immediate cord clamping increases hemodynamic lability at birth in preterm lambs.

This study tested the hypothesis that varying degrees of hemodynamic fluctuations seen after birth following immediate cord clamping were related to development of asphyxia with longer cord clamp-to-ventilation intervals, resulting in higher perinatal circulating levels of the catecholamines norepinephrine (NE) and epinephrine (Epi), and thus increased heart rate, blood pressures, and cardiac contractility after birth. Anesthetized preterm fetal lambs were instrumented with 1) aortic (AoT) and pulmonary trunk (PT) micromanometers to obtain pressures and the maximal rate of pressure rise (dP/dtmax) as a surrogate measure of ventricular contractility, and 2) an AoT catheter to obtain samples for blood gas and catecholamine analyses. After delivery, immediate cord clamping was followed by ventilation ∼40 s (n = 7), ∼60 s (n = 8), ∼90 s (n = 9), or ∼120 s later (n = 8), with frequent blood sampling performed before and after ventilation. AoT O2 content fell rapidly after immediate cord clamping (P < 0.001), with an asphyxial state evident at ≥60 s. Plasma NE and Epi levels increased progressively with longer cord clamp-to-ventilation intervals, with an exponential relation between falling AoT O2 content and rising catecholamines (R2 = 0.64-0.67). Elevated circulating catecholamines persisted for some minutes after ventilation onset, with postbirth surges in heart rate, AoT and PT pressures, and AoT and PT dP/dtmax linearly related to loge of catecholamine levels (R2 = 0.41-0.54, all P < 0.001). These findings suggest that 1) a greater degree of asphyxia-induced sympathoadrenal activation (reflected in elevated circulating catecholamine levels) occurs with longer intervals between immediate cord clamping and subsequent ventilation, and 2) this activation is a major determinant of hemodynamic fluctuations evident with birth.

Influence of anatomical dominance and hypertension on coronary conduit arterial and microcirculatory flow patterns: a multiscale modeling study.

Coronary hemodynamics are known to be affected by intravascular and extravascular factors that vary regionally and transmurally between the perfusion territories of left and right coronary arteries. However, despite clinical evidence that left coronary arterial dominance portends greater cardiovascular risk, relatively little is known about the effects of left or right dominance on regional conduit arterial and microcirculatory blood flow patterns, particularly in the presence of systemic or pulmonary hypertension. We addressed this issue using a multiscale numerical model of the human coronary circulation situated in a closed-loop cardiovascular model. The coronary model represented left or right dominant anatomies and accounted for transmural and regional differences in vascular properties and extravascular compression. Regional coronary flow dynamics of the two anatomical variants were compared under normotensive conditions, raised systemic or pulmonary pressures with maintained flow demand, and after accounting for adaptations known to occur in acute and chronic hypertensive states. Key findings were that 1) right coronary arterial flow patterns were strongly influenced by dominance and systemic/pulmonary hypertension; 2) dominance had minor effects on left coronary arterial and all microvascular flow patterns (aside from mean circumflex flow); 3) although systemic hypertension favorably increased perfusion pressure, this benefit varied regionally and transmurally and was offset by increased left ventricular and septal flow demands; and 4) pulmonary hypertension had a substantial negative effect on right ventricular and septal flows, which was exacerbated by greater metabolic demands. These findings highlight the importance of interactions between coronary arterial dominance and hypertension in modulating coronary hemodynamics.

Novel wave power analysis linking pressure-flow waves, wave potential, and the forward and backward components of hydraulic power.

Wave intensity analysis provides detailed insights into factors influencing hemodynamics. However, wave intensity is not a conserved quantity, so it is sensitive to diameter variations and is not distributed among branches of a junction. Moreover, the fundamental relation between waves and hydraulic power is unclear. We, therefore, propose an alternative to wave intensity called "wave power," calculated via incremental changes in pressure and flow (dPdQ) and a novel time-domain separation of hydraulic pressure power and kinetic power into forward and backward wave-related components (ΠP±and ΠQ±). Wave power has several useful properties:1) it is obtained directly from flow measurements, without requiring further calculation of velocity;2) it is a quasi-conserved quantity that may be used to study the relative distribution of waves at junctions; and3) it has the units of power (Watts). We also uncover a simple relationship between wave power and changes in ΠP±and show that wave reflection reduces transmitted power. Absolute values of ΠP±represent wave potential, a recently introduced concept that unifies steady and pulsatile aspects of hemodynamics. We show that wave potential represents the hydraulic energy potential stored in a compliant pressurized vessel, with spatial gradients producing waves that transfer this energy. These techniques and principles are verified numerically and also experimentally with pressure/flow measurements in all branches of a central bifurcation in sheep, under a wide range of hemodynamic conditions. The proposed "wave power analysis," encompassing wave power, wave potential, and wave separation of hydraulic power provides a potent time-domain approach for analyzing hemodynamics.