Relationship of hydraulic impedance and elasticity in the pulmonary artery of maturing newborn pigs.

The current study determined the dynamic stress-strain elastic moduli (E(Y)) and characteristic impedances (Z(0(2-7Hz))) of the main pulmonary artery in open-chest, anesthetized newborn pigs at 2 days, 2 weeks, and 3 months of age. E(Y) and Z(0(2-7Hz)) were compared to those values derived from the Womersley and Moens-Korteweg equations (denoted E(W-MK) and Z(0W-MK), respectively) to test the validity of these equations in describing the elasticity of the intact newborn pulmonary artery. E(Y) was defined as the ratio of stress to strain. The current study hypothesized that: (1) E(Y) and E(W-MK) are numerically similar, and therefore the Womersley and Moens-Korteweg equations accurately describe the viscoelastic properties of the main pulmonary artery of the newborn pig, and (2) that both E(Y) and Z(0) are elevated at birth and undergo a steady decline with maturation. E(Y) was not significantly different from E(W-MK), while Z(0(2-7Hz)) was nearly identical to Z(0W-MK) in all groups. The elastic modulus peaked (P < 0.001) in 2-week-old pigs compared with both younger and older animals, while Z(0(2-7Hz)) decreased with increasing age (48 h = 1237 +/- 251 [SEM] dyn s cm(-5), 2-week = 433 +/- 95 dyn s cm(-5), 3 month = 162 +/- 17 dyn s cm(-5), P < 0.001). These experiments validate the Womersley and Moens-Korteweg equations as accurately describing the elastic properties of the intact newborn pig pulmonary artery. These data also demonstrate that a diminution in Z(0) may occur even with increased wall stiffness, as observed in our 2-week-old pigs.

Nucleoside analogues as highly potent and selective inhibitors of herpes simplex virus thymidine kinase.

A series of carboxamide derivatives of 5'-amino-2',5'-dideoxy-5-ethyluridine has been prepared as inhibitors of HSV-TK (herpes simplex virus thymidine kinase). The most potent compounds were derived from xanthene, thioxanthene and dihydroanthracene carboxylic acids. The lead compounds show subnanomolar IC(50) values against HSV TKs.

Characterization of the pulmonary arterial response to endothelin-1 and bosentan in neonatal pigs.

BACKGROUND: This study determined the pulmonary vascular responses to intravenous (IV) administration of endothelin-1 (ET-1) before and after an IV bolus of bosentan (Ro 47-0203), an endothelin receptor antagonist, in anesthetized open-chest 48-hour-old and 2-week-old Yorkshire pigs. METHODS: Eighteen 48-hour-old and 25 2-week-old pigs were randomly allocated to receive either (1) 400 ng x kg(-1) x min(-1) of ET-1 or (2) 5 mg/kg or 10 mg/kg of Ro 47-0203 followed by 400 ng x kg(-1) x min(-1) of ET-1 over a 10-minute interval. Pulmonary vascular resistance (PVR, dyne sec/cm(-5)), elastic modulus (E(Yo), dyne/cm2), and characteristic impedance (Zo) were determined (+/- SEM). RESULTS: In 48-hour-old pigs, ET-1 decreased pulmonary artery pressure (PAP, dyne/cm2; 21,317 +/- 1,833 versus 17,757 +/- 1,823; p = 0.003). In 2-week-old pigs, ET-1 elevated PAP (19,009 +/- 1,834 versus 21,935 +/- 2,104; p = 0.003) and PVR (1,624 +/- 254 versus 2,302 +/- 416; p = 0.001), whereas bosentan abolished the ET-1 induced pulmonary and systemic vasoconstriction. Neither agent altered E(Y) or Z(o). CONCLUSIONS: ET-1 caused a pulmonary depressor response in 48-hour-old pigs and a constrictor response in 2-week-old pigs, whereas bosentan inhibited the ET-1 induced pulmonary arteriolar vasoconstriction in 2-week-old pigs. The response to ET-1 changes from dilation in 48-hour-old pigs (neonates) to constriction in 2-week-old pigs (infants) suggests a maturational dependent alteration in ET receptors during the first 2 weeks of life. These data suggest that bosentan may have potential clinical application in the treatment of newborn pulmonary hypertensive episodes as it ablated ET-1 induced pulmonary vasoconstriction, while maintaining systemic pressure.

Reproducible echocardiography in juvenile sheep and its application in the evaluation of a pulmonary valve homograft implant.

Increased use of the ovine animal model in cardiovascular surgical research has created a salient need for standardized echocardiography techniques. To demonstrate a reproducible image in this species and confirm the validity of echocardiography as a diagnostic tool, we implanted 10 sheep with a pulmonary valve homograft and monitored them through weekly echocardiographic examinations until 20 weeks after implantation. We obtained good images from the left cranial and the left caudal transducer windows without needing to sedate the animals. Sedated sheep yielded adequate views from the right apical window. Echocardiographic data on the implanted homografts (including functional capacity, presence of calcification, and hemodynamic information and measurements), completely agreed with the results of the post-explantation examinations.

Veno-arterial modified ultrafiltration in children after cardiopulmonary bypass.

A method of performing veno-arterial modified ultrafiltration is described that utilizes conventional blood flow through the aortic and venous cannulae. A dual-pump blood cardioplegia console is adapted to aspirate blood from the cardiopulmonary bypass venous line. The blood is ultrafiltered, sent through the cardioplegia heat exchanger, and returned to the aorta via the cardioplegia needle. Veno-arterial modified ultrafiltration has produced no visual evidence of air entrainment in the cardiopulmonary arterial line. This method allows the immediate resumption of cardiopulmonary bypass without the need for the surgeon to recannulate or alter tubing. Thirty-five children underwent veno-arterial modified ultrafiltration; the results show significant increases in postoperative hematocrit, early extubation, and improved rheology.

Interstitial cellular and matrix restoration of cardiac valves after cryopreservation.

OBJECTIVES: We previously characterized the porcine aortic leaflet interstitial cell phenotype as having both synthetic and contractile characteristics; that is, it is a myofibroblast. In this study we hypothesized (1) that the cryopreservation of aortic valves causes a significant reduction in cell density, (2) that it simultaneously causes alterations in representative components of extracellular matrix, and (3) that both of these processes are reversible. METHODS: Seventy-two leaflets from 24 porcine aortic valves were studied. Whole valves were subjected to variable lengths of preharvest ischemia (group 1), ischemia followed by processing analogous to clinical methods (group 2), and ischemia followed processing with an organ culture type of resuscitation (group 3). Vital dye exclusion by cells enzymatically dispersed from leaflets was used to quantify viability. Electron and light microscopy, immunohistochemical assay, and a silicone rubber substratum contractility assay were used both in dispersed cell preparations and in leaflet cross sections to examine structural, ultrastructural, and functional changes across the 3 groups through a range of preharvest ischemic times. RESULTS: Results indicated that harvest ischemic periods between 2 and 24 hours after donor death were not responsible for cell number reductions. During this interval overt dissolution of chondroitin sulfate simultaneous with a relative sparing of fibronectin was evidenced by immunohistochemical staining. Although not reduced in number, ischemic interstitial cells did show significant ultrastructural evidence of injury and suppressed monoclonal binding to vimentin and alpha-smooth muscle actin. After cryopreservation, viable cell numbers were always markedly reduced at all ischemic intervals and damage to both soluble extracellular matrix components and cell ultrastructure was increased. At all time and processing points, however, some retention of matrix secretory and cellular contractile capabilities was observed among the surviving cells. After the extended periods of preharvest ischemia (2-24 hours) followed by processing, a restitution of functioning cells was accomplished by means of whole-leaflet incubation in 15% fetal bovine serum. CONCLUSIONS: After application of the described methods, new cells within restored intact leaflets as well as in single-cell preparations demonstrated normal ultrastructure and contractile and synthetic functions (normal phenotypic expression). If functioning leaflet interstitial cells can contribute to homograft durability, bioengineering methods for pretransplantation cell repopulation could be refined with these techniques and applied to clinical valve transplantation.

Ultrashort laser pulse bioeffects and safety.

Recent studies of retinal damage due to ultrashort laser pulses have shown that less energy is required for retinal damage for pulses shorter than 1 ns than that for longer pulses. It has also been shown that more energy is required for near-infrared (NIR) wavelengths than in the visible because the light focuses behind the retina, requiring more energy to produce a damaging fluence on the retina. We review the progress made in determining the trends in retinal damage from laser pulses of 1 ns to 100 fs in the visible and NIR wavelength regimes. We have determined the most likely damage mechanism(s) operative in this pulse width regime.

Allograft heart valves: the role of apoptosis-mediated cell loss.

OBJECTIVE: The purpose of this study was to determine whether apoptosis of endothelial and connective tissue cells is responsible for the loss of cellularity observed in implanted aortic allograft valves. METHODS: Fresh (n = 6) and cryopreserved (n = 4) aortic allograft valves were retrieved at 2 days to 20 weeks after implantation in an ovine model. Sections of these valves were studied with the use of histologic and electron microscopic methods, nick end-labeling and dual immunostaining for factor VIII-related antigen and proliferating cell nuclear antigen, followed by counterstaining for DNA and laser scanning confocal fluorescence microscopic observation. RESULTS: The endothelial cells and cusp connective tissue cells of implanted valvular allografts showed loss of proliferating cell nuclear antigen (indicative of cessation of mitotic activity) and evidence of apoptosis (nick end labeling). The latter was manifested by nuclear condensation and pyknosis, positive nick end labeling, and formation of intra- and extracellular apoptotic bodies derived from the fragmentation of apoptotic cells. These changes began to develop at 2 days after implantation, peaking at 10 to 14 days, and became complete by 20 weeks, at which time the valves had the typical acellular morphologic features of allografts implanted for long periods of time. CONCLUSIONS: Apoptosis occurs in endothelial cells and cuspal connective tissue cells of implanted allografts and appears to be a cause of their loss of cellularity. This apoptosis may be related to various factors, including immunologic and chemical injury, and hypoxia during valve processing and reperfusion injury at the time of implantation.

Comparative study of laser damage threshold energies in the artificial retina.

Laser damage threshold energies produced from ultrashort (i.e., ⩽1 ns) laser pulses are investigated as a function of both pulse width and spot size for an artificial retina. A piece of film acts as the absorbing layer and is positioned at the focus of a variant on the Cain artificial eye [C. Cain, G. D. Noojin, D. X. Hammer, R. J. Thomas, and B. A. Rockwell, "Artificial eye for in vitro experiments of laser light interaction with aqueous media," J. Biomed. Opt.2, 88-94 (1997)]. Experiments were performed at the focal point and at two and ten Rayleigh ranges (RR) in front of the focus with the damage end point being the presence of a bubble imaged at the film plane. Pulse energy thresholds were determined for wavelengths of 1064, 580, and 532 nm with pulse durations ranging from the nanosecond (ns) to the femtosecond (fs) regime. For the at-focus data in the visible regime, the threshold dropped from 0.25 µJ for a 532 nm, 5 ns pulse to 0.11 µJ for a 580 nm, 100 fs pulse. The near-infrared (NIR) threshold changed from 5.5 µJ for a 5 ns pulse to 0.9 µJ for a 130 fs pulse at a distance two RR in front of the focus. The experiment was repeated using the same pulse widths and wavelengths, except the water path was removed to determine the impact of nonlinear self-focusing in water. A vertical microscope imaging system was employed in order to observe the threshold event. The NIR fluence threshold of 0.5 J/cm2 remained constant within an experimental uncertainty for all pulse widths, which corresponds to values in the literature [C. P. Lin and M. W. Kelly, "Ultrafast time-resolved imaging of stress transient and cavitation from short pulsed laser irradiated melanin particles," SPIE Laser-Tissue Interactions VI, Proc. SPIE2391, 294-299 (1995)]. The visible data also demonstrated a nearly constant fluence of 0.07 J/cm2. The disparity in thresholds between the two techniques arises from nonlinear optical phenomena related to propagation differences in the ocular fluid. © 1999 Society of Photo-Optical Instrumentation Engineers.

Interleukin-6 levels in serum and lung lavage fluid of children undergoing open heart surgery correlate with postoperative morbidity.

OBJECTIVE: To evaluate the relationship of perioperative levels of interleukin 6 (IL-6) in serum and bronchoalveolar fluid with morbidity and mortality in children undergoing cardiopulmonary bypass (CPB). DESIGN: Prospective, noninterventional study. SETTING: Operating room and pediatric intensive care unit (PICU) of a university hospital. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: IL-6 levels were measured in serum and lung lavage fluid obtained before, during, and after CPB using the B9.9 bioassay. Alveolar epithelial lining fluid (AELF) volume was calculated using the urea correction method. Mean intraoperative AELF IL-6 levels increased fourfold compared to preoperative levels, and mean serum IL-6 levels increased fivefold after CPB. Mean intraoperative AELF IL-6 levels correlated with intraoperative blood transfusion (r2 = 0.18; p = 0.049) and duration of inotropic support (r2 = 0.29; p = 0.009), mechanical ventilation (r2 = 0.24; p = 0.019), and PICU stay (r2 = 0.29; p = 0.008). Mean serum IL-6 levels 2 h after CPB correlated with intraoperative blood transfusion (r2 = 0.3;p = 0.007), and with Pediatric Risk of Mortality score on postoperative day 3 (r2 = 0.24; p = 0.022), and were higher in patients with massive fluid retention (p = 0.014) and in nonsurvivors (p = 0.003). CONCLUSIONS: Serum and alveolar IL-6 levels increase after CPB, and correlate with postoperative morbidity. Serum IL-6 levels also correlate with mortality. They may be useful in assessing the severity of the systemic inflammatory response after CPB.

Sympathetic blockade blunts hypercapnic pulmonary arterial vasoconstriction in newborn piglets.

OBJECTIVE: Hypercapnia has been implicated in the pathophysiology of pulmonary hypertensive disease in newborns. However, little has been done to determine how its vasoconstrictive actions are mediated. The purpose of this study is to define the role of the sympathetic nervous system in modulating the response of the newborn pulmonary circulation to hypercapnia. Specifically, we studied the effect of sympathetic blockade on mean and pulsatile pulmonary arterial hemodynamics in 48-h-old, intact, open-chest Yorkshire piglets during hypercapnic ventilation. METHODS: All animals were anesthetized and then instrumented for high fidelity measurement of pulmonary artery pressure (PAP), flow (PAF), aortic pressure and radius of the main pulmonary artery (Rmn). Baseline data were acquired in all animals. Control animals (n = 7) were subjected to 30 s intervals of hypercapnia (inspired CO2 fraction (FiCO2) = 0.20). Experimental animals (n = 7) were pre-treated with an intravenous bolus of the adrenergic blocking agent guanethidine (20 mg/kg) before being subjected to the hypercapnic stress. Characteristic impedance (Zo) and input mean impedance (Zm) were determined through application of a Fourier analysis of the PAP and PAF waveforms. The modulus of elasticity (Ey) was calculated from Zo and Rmn. Pulmonary vascular resistance (PVR) was calculated as (PAP - LAP/PAF). RESULTS: Control animals underwent significant increases in PVR (4860 +/- 341 dyne cm s(-5) versus 8090 +/- 387 dyne cm s(-5), P < 0.01) and Zm (7215 +/- 495 dyne cm s(-5) versus 10228 +/- 993 dyne cm s(-5), P < 0.01) when exposed to hypercapnia. Pre-treatment with guanethidine attenuated this response (PVR, 5552 +/- 368 dyne cm s(-5) versus 7105 +/- 611 dyne cm s(-5), P = 0.31 and ZM, 7922 +/- 446 dyne cm s(-5) versus 9745 +/- 600 dyne cm s(-5), P = 0.31). Characteristic impedance, modulus of elasticity and the radius of the main pulmonary artery were unchanged in both groups. CONCLUSIONS: These data indicate that vasoconstriction secondary to hypercapnia in the neonatal pulmonary arterial circulation occurs at the level of the distal arteriolar bed, rather than the more proximal pulmonary arteries. In addition, this response is partially modulated by the sympathetic nervous system and may therefore respond clinically to manipulation of sympathetic input to the pulmonary arterial circulation.

Early discharge of patients with new-onset atrial fibrillation after cardiovascular surgery.

BACKGROUND: Atrial fibrillation is one of the most frequent complications after cardiovascular surgery. It may result in thromboembolic events, hemodynamic deterioration, and an increased length and cost of hospitalization. METHODS: We retrospectively studied 504 consecutive adult patients undergoing cardiovascular surgery to determine whether patients with new-onset postoperative atrial fibrillation could be safely discharged in atrial fibrillation after ventricular rate had been controlled and anticoagulation initiated. RESULTS: Postoperative atrial fibrillation occurred in 79 (16.2%) of the 487 survivors. Of these patients, 67 were discharged in sinus rhythm, whereas the remaining 12 were discharged in atrial fibrillation. Patients discharged in atrial fibrillation tended to be older, have higher Parsonnet risk scores, and have an increased incidence of valvular heart surgery. Despite this result, this cohort had a shorter length of hospital stay (7.3+/-2.0 days vs 10.9+/-9.3 days, p = 0.006), decreased hospital costs ($14,188+/-$2635 vs $23,016+/-$21,963, p = 0.002), and decreased hospital charges ($37,878+/-$7420 vs $58,289+/-$50,980, p = 0.003) compared with patients with atrial fibrillation discharged in sinus rhythm. In the 12 persons discharged home in atrial fibrillation, no repeat hospitalizations, bleeding complications, or thromboembolic events occurred. CONCLUSION: A strategy of early discharge of patients with persistent postoperative atrial fibrillation appears promising and deserves prospective testing on a larger scale.

The design, synthesis and properties of highly potent and selective inhibitors of herpes simplex virus types 1 and 2 thymidine kinase.

The rational design and synthesis of nucleotide analogues as inhibitors of herpes simplex virus (HSV) thymidine kinase is described. Starting from thymidine, product analogues which included phosphates, phosphonates, sulphonates, sulphonamides and carboxamides were prepared. The carboxamide series showed good structure-activity relationships and afforded a lead structure which inhibited the HSV-2 enzyme in the low micromolar range. Replacing the 5-methyl group in thymidine by ethyl enhanced the potency of the lead structure 10-fold. Further optimization of the carboxamide moiety afforded inhibitors active in the sub-nanomolar range and finally the introduction of a 2'-beta-fluoro substituent improved the potency a further twofold. The low water solubility of the most potent inhibitor was overcome by conversion to the 3'-valyl ester, which had good oral bioavailability and showed activity by the oral route in murine models of infection.

Maturation alters the pulmonary arterial response to hypoxia and inhaled nitric oxide in the presence of endothelial dysfunction.

Surgical intervention in ever younger patients has led to a new appreciation of the unique physiology of the neonate. Specifically, newborn patients may respond very differently to hypoxic episodes and subsequent treatment with inhaled nitric oxide than older infants. In the current study, we examined differences in the pulmonary arterial response to hypoxia and inhaled nitric oxide in 48-hour-old (n = 8) and 14-day-old (n = 8) Yorkshire pigs in a model of nitric oxide synthase inhibition, as might be seen with endothelial dysfunction. Data were acquired after treatment with the nitric oxide synthase inhibitor N omega-nitro-L-arginine during hypoxia (inspired oxygen fraction = 0.10) and during inhalation of nitric oxide (100 ppm). Input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility, were calculated. The modulus of elasticity, a measure of the "stiffness" of the proximal vessels, was also calculated. Hypoxia caused a large increase in input mean impedance in both 48-hour-old and 14-day-old pigs (4826 +/- 272 versus 8744 +/- 488 dyne.cm.sec-5 and 3129 +/- 73 versus 6000 +/- 134 dyne.cm.sec-5, respectively; p = 0.0078). Characteristic impedance was not altered in the younger animals (1171 +/- 76 dyne.cm.sec-5) but increased in the older animals (419 +/- 15 versus 797 +/- 20 dyne.cm.sec-5. p = 0.0078). Older animals also experienced an increase in the modulus elasticity (1.92E06 +/- 3.2E05 versus 1.05E07 +/- 3.9E05 dyne/cm2, p = 0.0078). These data show that inhibited nitric oxide production, as might be seen in endothelial dysfunction, potentiates the profound hypoxic vasoconstriction observed at the level of the distal pulmonary arterioles in both neonatal and infant animals. In contrast, only older animals had a stiffening of the larger, more proximal vessels with hypoxia. In both age groups, inhaled nitric oxide effectively reduced the increases in impedance.

Precipitous exit block with epicardial steroid-eluting leads.

Between January 1990 and October 1992, we implanted 16 steroid-eluting ventricular epicardial pacing leads (Medtronic 10295A and 10295B/4965) in 12 patients. There were 8 males and 4 females ranging in age from 3 months to 49 years (mean 8.7 +/- 13.2, median 6.0 years). Structural cardiac disease was present in 11 of 12 patients. Follow-up ranged from 3-73 months postimplant (mean 35.7 +/- 22.3, median 28.5 months). Lead fracture (10295A) occurred in 1 of 12 patients. Of the remaining 11 patients, 8 of 11 have very low long-term pacing thresholds. Unexpectedly, 3 patients demonstrated precipitous threshold increases from 3 months to 3.5 years postimplant. Although no deaths resulted in these exit block patients, 1 of 3 exit block patients developed marked worsening of congestive heart failure. We reviewed and analyzed the data obtained at 4 weeks postimplant for all of the 10295A and 4965 patients in the entire Medtronic clinical study database. Using the criterion of a 4 week postimplant pacing threshold > or = 0.12 ms (5 V), we found that the long-term risk of eventual exit block was 27.3% for the 10295A lead (P = 0.005) and 7.5% for the 10295B/4965 lead (P = 0.03). We, therefore, recommend that in patients implanted with the 4965 steroid-eluting epicardial lead, ventricular pacing thresholds > or = 0.12 ms (5 V) measured at 4 weeks postimplant should prompt frequent threshold testing to detect late and potentially sudden ventricular pacing threshold increases.

Aschoff bodies in an operatively excised mitral valve.

Aschoff bodies are granulomatous lesions believed to be pathognomonic of rheumatic fever. Most histologic descriptions have been limited to locations adjacent to or within the myocardium. Aschoff bodies within valves are uncommon findings. We report a case showing the typical granulomas in an excised mitral valve. We suggest that Aschoff bodies can, and do, occur in valve tissue during acute rheumatic carditis and that structural differences between valves and typical intramyocardial locations, variations in frequency and strength of individual infections, individual host responses, and time intervals between infection and histologic examination often obscure their findings in valves.

Initial postoperative serum lactate levels predict survival in children after open heart surgery.

OBJECTIVE: To evaluate the relationship between postoperative serum lactate levels and outcome in children undergoing open heart surgery. DESIGN: Prospective, noninterventional study. SETTING: Pediatric intensive care unit (PICU) of a university hospital. PATIENTS: 41 nonconsecutive children who had had cardiopulmonary bypass for repair of congenital heart disease. INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Serum lactate levels were measured on admission to the PICU immediately after open heart surgery. Lactate levels were correlated with bypass and cross clamp times, estimated intraoperative blood loss, lowest temperature on bypass, admission Pediatric Risk of Mortality score, anion gap, and measures of postoperative morbidity. Mean lactate levels on admission to the PICU were 6.86 +/- 0.79 mmol/l for nonsurvivors (n = 7) and 2.38 +/- 0.13 mmol/l for survivors (n = 34) (p < 0.0001), and 4.87 +/- 0.7 mmol/l and 2.35 +/- 0.19 mmol/l, for patients with (n = 11) and without (n = 30) multiple organ system failure, respectively (p < 0.0001). Admission lactate levels correlated with all measurements of postoperative morbidity. A serum lactate level of greater than 4.2 mmol/l had a positive predictive value of 100% and a negative predictive value of 97% for postoperative death. CONCLUSIONS: Initial postoperative serum lactate levels after pediatric open heart surgery may be predictive of outcome. Lactate levels are also higher in patients who go on to develop multiple organ system failure. Elevated postoperative lactate levels may reflect intraoperative tissue hypoperfusion, and measures aimed at increasing oxygen delivery, with normalization of lactate, may improve patient outcome.

Pulmonary arterial endothelial dysfunction potentiates hypercapnic vasoconstriction and alters the response to inhaled nitric oxide.

BACKGROUND: Pulmonary hypertensive crisis can be initiated by episodes of hypercapnic acidosis. Hypercapnic vasoconstriction in the newborn pulmonary arterial circulation may be modulated by endogenous production of nitric oxide (NO) by the endothelial cell and effectively treated with inhalation of NO. METHODS: Sixteen 48-hour-old piglets were randomized to receive a hypercapnic challenge after administration of either saline vehicle or the NO synthase inhibitor N-omega-nitro-L-arginine (L-NA). Pulmonary arterial pressure, flow, and radius measurements were taken at baseline, after infusion of vehicle or L-NA, during hypercapnia (inspired fraction of carbon dioxide, 0.15), and during inhalation of NO (100 ppm). Fourier analysis was used to calculate input mean impedance, reflecting distal arteriolar vasoconstriction, and characteristic impedance, reflecting proximal arterial geometry and distensibility. RESULTS: Input mean impedance was increased with L-NA administration. Animals pretreated with L-NA also underwent a much larger increase in input mean impedance with exposure to hypercapnia than untreated animals. Characteristic impedance increased in the treated animals, but not in the controls. CONCLUSIONS: In the newborn pulmonary arterial circulation, endogenous NO production by the endothelial cell modulates resting tone distally, but not proximally. In addition, lack of a functional endothelium markedly potentiates the distal vasoconstrictor response to hypercapnia and produces proximal vasoconstriction. Despite impaired endothelial function, inhaled NO remains an effective vasodilator in hypercapnic pulmonary vasoconstriction.

Ventricular outflow tract reconstructions with cryopreserved cardiac valve homografts. A single surgeon's 10-year experience.

OBJECTIVE: From January 1, 1985 through December 31, 1994, one surgeon implanted cryopreserved valved homografts into 149 patients--65 since December 1988. This latter series (II) was accomplished in a single hospital, facilitating patient follow-up with biannual echocardiograms. Analysis of these 65 patients is the primary focus of this report; the indications and early surgical results for the two parts of the series (I and II) are compared to assess the evolution of a single surgeon's use of homografts in a mixed pediatric and adult practice. METHODS: Fifty-one variables for each patient (series II) were entered into a computerized database and analyzed (multivariate and univariate) using SPSS 6.1 software (Statistical Products and Service Solutions, Chicago, IL). Cox proportional hazard model was used to identify the independent contribution of each variable for patient mortality and homograft failure. Cumulative survival estimates were made using Kaplan-Meier analysis. Homograft failure was defined as requirement for replacement or death. In series I, there were 41 left ventricular outflow tract (LVOT) reconstructions (31 adult) and 43 right ventricular outflow tract (RVOT) reconstructions (42 pediatric). In series II, there were 55 RVOT reconstructions (52 pediatric) and 10 LVOT reconstructions (7 adult). RESULTS: There were no technical surgical failures. Total surgical mortality rate was 6% (5/84) in series I (3 LVOT, 2 RVOT) and 15% (10/65) in series II (2 LVOT, 8 RVOT) (I vs. II NS; p = 0.11, two-tailed Fisher exact test). By the Cox analysis, only age < 2 years (p < 0.03) and cross-clamp time > 120 minutes (p < 0.05) were significant predictors for death. Age-based survival curves were compared in a sequential bivariate analyses (log rank test) and age < 2 years again was a significant predictor of decreased patient survival (p < 0.006). Actuarial freedom from patient death or reoperation for homograft failure was 82% +/- 7% at 1000 days and 77% +/- 10% at 2000 days. Three patients required re-replacement for homograft failure (5.4%); one of these patients died. The only significant predictor of homograft failure was postoperative endocarditis (p < 0.05). Homograft performance was evaluated by an extensive echocardiography protocol: in surviving patients and homografts, three valved conduits were judged to have severely impaired performance (stenosis or regurgitation), awaiting surgical replacement for a putative total homograft-related structural failures rate of 11% at 5 1/2 years. CONCLUSIONS: Comparisons of series I and II shows, in one surgeon's practice, an evolution away from use of cryopreserved homografts for LVOT reconstructions except when needed for destructive bacterial endocarditis or complex congenital anatomy. Homograft efficacy and durability were similar in RVOT and LVOT positions, with 78.5% of patients surviving at 5 1/2 years; in surviving patients, 89% of homografts have continued to function well. Homografts are not immune to prosthetic bacterial endocarditis, and its occurrence is associated with accelerated deterioration. Cryopreserved homograft valves are an imperfect but satisfactory biological material for specific ventricular outflow reconstructions.

Circulating neuropeptide Y in humans: relation to changes in catecholamine levels and changes in hemodynamics.

Neuropeptide-Y (NPY) is a sympathetic cotransmitter, which causes vasoconstriction, decreases coronary blood flow and decreases cardiac output. Circulating immunoreactive NPY (ir-NPY) levels increase with exercise, in patients admitted to the coronary care unit, and during thoracic surgery, and may play a role in postoperative hemodynamics. We studied changes in ir-NPY, epinephrine (E) and norepinephrine (NE) arterial plasma levels, and their correlation to simultaneous hemodynamic measurements at 8 perioperative time points in 13 patients undergoing open heart surgery. Changes in circulating ir-NPY negatively correlated with changes in systemic vascular resistance index (SVRI), mean arterial pressure (MAP) and mean pulmonary arterial pressure (MPAP) (P < 0.05), suggesting that the hemodynamic changes were the cause of the changes in ir-NPY levels, inducing overflow of NPY into the circulation via sympathetic activation. Changes in NE and E levels positively correlated with changes in heart rate (HR), SVRI and MPAP. Changes in E levels also positively correlated with changes in stroke volume index (SVI), central venous pressure (CVP) and cardiac index (CI). NE levels correlated well with E levels, but catecholamine levels did not correlate with ir-NPY levels. These results suggest, that the elevation in circulating NPY levels previously noted in patients with heart failure and acute myocardial infarction may reflect changes in NPY overflow and/or clearance secondary to increased sympathetic activity and to hemodynamic changes.