The use of inhaled prostacyclin in nitroprusside-resistant pulmonary artery hypertension.

Because nitroprusside NTP infusion used to differentiate between fixed and reversible pulmonary artery hypertension in heart transplant candidates can result in systemic hypotension before reducing pulmonary artery pressures, we observed the effect or inhaled prostacyclin (PGI(2)) on pulmonary artery pressures and transpulmonic gradient (TPG) in patients with NTP-resistant pulmonary artery hypertension. Six patients undergoing evaluation for orthotropic heart transplant (OHTX) with NTP-resistant pulmonary artery hypertension received inhaled PGI(2), with hemodynamic measurements made at baseline, on NTP- and PGI(2) inhaled after returning to baseline. Compared with hemodynamic results with NTP, inhaled PGI(2) caused significant decrease in pulmonary artery systotic pressure, 43.8 +/- 4.8 mm Hg vs 63.2 +/- 2.04 mm Hg (p < 0.001); Mean pulmonary artery pressure, 22.7 +/- 4.18 vs 32.3 +/- 3.39 mm Hg (p < 0.05); and TPG, 11.5 +/- 3.73 vs 17.0 +/- 4.69 mm Hg (p < 0.05), with a 40% decrease in pulmonary vascular resistance/systemic vascular resistance ratio. We conclude that inhaled PGI(2) has benefit in reversing pulmonary artery hypertension resistant to NTP, in patients undergoing OHTX evaluation which is due to its more selective pulmonary vasodilation.

Stenting unprotected left main coronary artery stenosis in heart transplant patients--the good, bad, and the ugly.

The major cause of late death following orthotopic heart transplantation is coronary artery vasculopathy. Approximately 50% of heart transplant patients have coronary artery vasculopathy 5 years post-transplantation. With advances in interventional cardiology technology, heart transplant patients with selected lesions are now undergoing intravascular stenting with acute-gain and late-loss rates similar to stenting in non-transplanted patients. We describe 3 consecutive cases of stenting unprotected left main coronary artery disease in orthotropic heart transplant patients. With follow-up to 3 years and no evidence of restenosis, these results suggest that stenting unprotected left main coronary artery lesions in heart transplant patients can be performed with excellent immediate and long-term results.

Biosynthetic activity in heart valve leaflets in response to in vitro flow environments.

The development of bioreactors for tissue engineered heart valves would be aided by a thorough understanding of how mechanical forces impact cells within valve leaflets. The hypothesis of the present study is that flow may influence the biosynthetic activity of aortic valve leaflet cells. Porcine leaflets were exposed to one of several conditions for 48 h, including steady or pulsatile flow in a tubular flow system at 10 or 20 l/min, and steady shear stress in a parallel plate flow system at 1, 6, or 22 dyne/cm2. Protein, glycosaminoglycan, and DNA synthesis increased during static incubation but remained at basal levels after exposure to flow. The modulation of synthetic activity was attributed to the presence of a shear stress on the leaflet surface, which may be transmitted to cells within the leaflet matrix through tensile forces. The alpha-smooth muscle (alpha-SM) actin distribution observed in fresh leaflets was proportionately decreased after exposure to antibiotics and not recovered by either static incubation or exposure to flow. These results indicate that exposure to flow maintains leaflet synthetic activity near normal levels, but that the inclusion of another force, such as bending or backpressure, may be necessary to preserve alpha-SM actin immunoreactive cells.

Geometric distribution of chordae tendineae: an important anatomic feature in mitral valve function.

BACKGROUND AND AIM OF THE STUDY: This study examined the geometric distribution of chordae tendineae and their importance in compensating for papillary muscle (PM) displacement. METHODS: Anatomic, chordal mechanics and hemodynamic measurements were performed with porcine mitral valves. For hemodynamic measurements, physiological pulsatile flow conditions were maintained, and PM positions varied. Leaflet coaptation was documented by 2-D echocardiography, and regurgitation measured directly. RESULTS: Anatomic measurements showed the sum of marginal leaflet and marginal chordal lengths to exceed basal chordal length (1.8+/-0.4 versus 2.8+/-0.7 cm for anterior leaflets; 1.6+/-0.3 versus 2.5+/-0.6 cm for posterior leaflets). Triangular structures existed between basal chordae and marginal chordae with the marginal leaflet as the third side. Basal chordae resisted apical PM displacement in static experiments, while marginal chordae governed leaflet closure in hemodynamic experiments. Under pulsatile flow conditions, apical PM displacement decreased leaflet coaptation length and increased regurgitation (9.4+/-2.1 versus 4.0+/-1.6 ml). When marginal chordae were fused to the basal chordae, eliminating the role of the marginal chordae, severe regurgitation resulted (28.5+/-5.0 ml with apical PM displacement). CONCLUSION: Based on triangular structures involving the basal and marginal chordae, a compensatory mechanism was described which explains how the severity of mitral regurgitation can vary following PM displacement. Basal chordae provide a constant connection between the annulus and papillary muscles, while marginal chordae maintain marginal leaflet flexibility, governing proper valve closure. This study relates chordal distribution to normal valve function, and provides a better understanding of breakdown in valve function under pathophysiological conditions.

Prospective evaluation of the Batista procedure with circulating atrial natriuretic peptides.

A proposed treatment of end-stage heart disease is partial left ventricular resection (i.e., Batista procedure). To determine if congestive heart failure objectively improves after this procedure, we prospectively evaluated partial left ventriculectomy with objective plasma markers of the severity of congestive heart failure (i.e., three N-terminal atrial natriuretic peptide prohormone radioimmunoassays and atrial natriuretic peptide radioimmunoassay) prior to and during the 12 months after partial left ventriculectomy. The four measured atrial natriuretic peptides improved in 30% of the subjects at 1 month post-surgery. Eighty percent of the subjects, however, had higher circulating atrial natriuretic peptides (P<0.01) at 3, 6, and 12 months than prior to surgery indicating that their congestive heart failure was objectively worse than prior to surgery. Likewise, at 3, 6, and 12 months post-surgery the ejection fractions were not significantly better than prior to surgery. By 6 months the subjects with the highest circulating atrial natriuretic peptides had died (60% of subjects). In conclusion, congestive heart failure improves within 1 month in some patients but then deteriorates at 3, 6, and 12 months after the Batista procedure. There was no survival benefit with 60% of the patients expiring within 6 months after the Batista procedure.

Estimation of the shear stress on the surface of an aortic valve leaflet.

The limited durability of xenograft heart valves and the limited supply of allografts have sparked interest in tissue engineered replacement valves. A bioreactor for tissue engineered valves must operate at conditions that optimize the biosynthetic abilities of seeded cells while promoting their adherence to the leaflet matrix. An important parameter is shear stress, which is known to influence cellular behavior and may thus be crucial in bioreactor optimization. Therefore, an accurate estimate of the shear stress on the leaflet surface would not only improve our understanding of the mechanical environment of aortic valve leaflets, but it would also aid in bioreactor design. To estimate the shear stress on the leaflet surface, two-component laser-Doppler velocimetry measurements have been conducted inside a transparent polyurethane valve with a trileaflet structure similar to the native aortic valve. Steady flow rates of 7.5, 15.0, and 22.5 L/min were examined to cover the complete range possible during the cardiac cycle. The laminar shear stresses were calculated by linear regression of four axial velocity measurements near the surface of the leaflet. The maximum shear stress recorded was 79 dyne/cm2, in agreement with boundary layer theory and previous experimental and computational studies. This study has provided a range of shear stresses to be explored in bioreactor design and has defined a maximum shear stress at which cells must remain adherent upon a tissue engineered construct.

Mitral valve compensation for annular dilatation: in vitro study into the mechanisms of functional mitral regurgitation with an adjustable annulus model.

BACKGROUND AND AIM OF THE STUDY: Mitral annulus dilatation has been identified as an important factor in functional mitral regurgitation (FMR). However, the pathophysiologic interaction of annular dilatation and papillary muscle (PM) displacement in FMR, which occurs clinically in left ventricular (LV) dilatation, is still not well understood. It is difficult to separate these competing factors in vivo, leading to confusion in identifying the real role of the annular dilatation in FMR and its interaction with PM displacement. METHODS: To better understand the competing factors, an in vitro model was developed with a D-shaped adjustable mitral annulus that could be changed from 5.5 cm2 to 13.0 cm2 during experiments, independent of varying PM positions. Six excised normal porcine mitral valves were mounted in a left ventricular model with the adjustable annulus device and tested in a physiologic pulsatile flow system under normal cardiac output and left ventricular pressure (5.0 l/min, 120 mmHg). Papillary muscles were placed in normal and then displaced to an apical posterolateral position, to simulate pathological conditions seen clinically. Regurgitation was measured directly by a flow probe and the mitral valve geometry and leaflet coaptation were recorded by video camera through the model's atrium window. In addition, 2D echocardiography was used to evaluate leaflet coaptation and color Doppler flow mapping to detect the regurgitant flow field. RESULTS: The results showed that in normal PM position, the mitral regurgitant was consistently at low level until the annulus was enlarged to 1.75 times the normal size, at which time it increased sharply. Papillary muscle apical posterolateral displacement, which simulates a dilated LV, caused regurgitation to occur earlier (1.5 times the normal annulus size), and had an increased regurgitant volume (p < 0.05). The leaflet gaps were first observed at the commissural areas of the valves, consistent with the location of regurgitant jets detected by color Doppler flow mapping. Asymmetric PM displacement created more regurgitation than both the symmetric PM tethering (p = 0.063) and normal PM position (p < 0.01). The regurgitant jets were observed at the same commissural side as the PM displacement, even without significant enlargement of the annulus. CONCLUSIONS: This in vitro study provides insight into the interaction between annular dilatation and PM displacement on FMR. The resulting effects and their overall similarity to clinical observation could help further understand the mechanism of FMR and provide additional information to improve future therapeutic strategies.

Endovascular stenting of an unprotected left main coronary artery stenosis in a heart transplant patient.

Endoluminal revascularizaion of left main coronary artery vessels is considered to be relatively contraindicated because of a high procedural mortality and restenosis rate. This report describes the first successful case of endovascular stenting in an unprotected left main coronary artery stenosis in a heart transplant patient.

Effect of loading conditions on myocardial relaxation velocities determined by Doppler tissue imaging in heart transplant recipients.

BACKGROUND: Cardiac allograft rejection is accompanied by cellular infiltration and tissue edema resulting in myocardial relaxation abnormalities. Doppler tissue imaging is capable of measuring myocardial relaxation velocities and is useful in the detection of heart rejection. However, the influence of ventricular loading conditions on myocardial relaxation velocities has not been studied. This study is performed to determine whether myocardial relaxation velocities are affected by left ventricular loading conditions. METHODS: Twenty heart transplant recipients without evidence of rejection by endomyocardial biopsy underwent preload and afterload reduction with nitroglycerin. The pulmonary wedge pressure was reduced from 18.2+/-0.9 to 12.0+/-0.9 mm Hg 9 (p=0.001) and the mean blood pressure from 130.0+/-5.6 to 116.1+/-7.0 mm Hg (p=0.001). Pulsed-wave Doppler tissue imaging was performed before and after administration of nitroglycerin, and the peak myocardial relaxation velocities of the inferior wall were measured. RESULTS: Myocardial relaxation velocities did not change with the administration of nitroglycerin; 0.188+/-0.009 to 0.178+/- 0.006 m/sec (p=0.4) in spite of a significant reduction in pulmonary capillary wedge pressure. Furthermore, there was no correlation between pulmonary capillary wedge pressure, mean arterial pressure, wall stress, and myocardial relaxation velocities. CONCLUSIONS: Loading conditions on the left ventricle have no influence on myocardial relaxation velocities. Therefore in heart transplant recipients changes in myocardial relaxation velocities by Doppler tissue imaging may be useful in the diagnosis of rejection, in spite of diverse loading conditions.

Noninvasive detection of allograft rejection in heart transplant recipients by use of Doppler tissue imaging.

BACKGROUND: Allograft rejection in heart transplant recipients is associated with lymphocytic extracellular infiltration and edema resulting in increased myocardial stiffness and abnormal relaxation. We hypothesize that these abnormalities will result in reduced myocardial relaxation velocities. Doppler tissue imaging is a novel noninvasive imaging modality that is capable of quantifying myocardial tissue velocities and may therefore be useful to identify allograft rejection. METHODS: In this observational study, 121 heart transplant recipients underwent pulsed-wave Doppler tissue imaging at the time of their surveillance endomyocardial biopsies. Peak relaxation and systolic velocities were measured from the inferior wall blinded to clinical biopsy. Biopsy results were classified as rejecting (3a, 3b, 4) or nonrejecting (0, 1a, 1b). RESULTS: The peak relaxation velocity in nonrejecting allograft recipients (n = 98) was 0.21 m/sec +/- 0.01. During moderate allograft rejection (n = 16), peak relaxation velocities decreased to 0.14 m/sec +/- 0.01 (p < 0.0001), and subsequently increased to 0.23 m/sec +/- 0.0 after successful treatment (p = 0.0001). Peak systolic velocities did not change during rejection, 0.08 m/sec +/- 0.02 when compared with nonrejecting recipients 0.09 +/- 0.02 (p = NS). With a cutoff value of less than 0.16 m/sec, the sensitivity of peak myocardial relaxation velocities for detection of rejection was 76%. The specificity and negative predictive values were 88% and 92%, respectively. CONCLUSION: Moderate allograft rejection results in reduced myocardial relaxation velocities, which can be detected noninvasively with pulsed-wave Doppler tissue imaging. Hence, Doppler tissue imaging is a useful noninvasive tool to exclude allograft rejection.

Establishing a protocol to quantify leaflet fibroblast responses to physiologic flow through a viable heart valve.

Mechanical stresses are thought to affect the metabolism of a variety of cell types. Little quantitative data exist regarding heart valve leaflet fibroblast activity after dynamic loading. The goal of this study was to examine leaflet fibroblast function and differentiation in response to flow through an intact valve. This requires the development of a flow system capable of reproducing the valve's native environment, as well as assay protocols to analyze cellular viability and protein and collagen synthesis. As a tool to expose viable tissue valves to physiologic flow, a sterilizable pulsatile flow system has been developed to recreate the dynamic flow environment of the aortic valve while preventing contamination from room air. Physiologic flow conditions [frequency 70 bpm, aortic pressure 129/82 mmHg (systolic/diastolic), cardiac output 2.3 L/min] were sustained for 71 hr without microbiologic contamination. Analytic tools for assessment of fibroblast function include a viability assay, which demonstrated that leaflet viability decreases after prolonged exposure to antibiotics. Proline incorporation studies revealed that 11 times more protein is retained by leaflet tissue than is released into the medium, and 27% of this protein is collagen. Polyacrylamide gel electrophoresis clearly resolved collagen Types I and III from both prepared standards as well as leaflet extracts. In ongoing work, the sterile flow loop will be used to expose fresh porcine aortic valves to defined flow conditions, and the viability and protein/collagen biosynthetic activity of leaflet fibroblasts in response to flow will be quantified. These experiments will provide a baseline by which to design and evaluate future tissue engineered substitutes.

Wall shear rate measurements in an elastic curved artery model.

Since atherosclerotic lesions tend to be localized at bends and branching points, knowledge of wall shear rate patterns in models of these geometries may help elucidate the mechanism of atherogenesis. This study uses the photochromic method of flow visualization to determine both the mean and amplitude of the wall shear rate wavefront in straight and curved elastic arterial models to demonstrate the effects of curvature, elasticity, and the phase angle between the flow and pressure waveforms (impedance phase angle). Under sinusoidal flow conditions characteristic of large arteries, the mean shear rate at the inner wall of the curved tube is reduced 40-56% from its steady flow value, depending on the phase angle. Wall shear rate amplitudes in the curved tube are significantly reduced by wall motion (36-55% of the Womersley amplitude for a straight rigid tube). The shear rate amplitude at the outer wall decreases 30% as the phase angle is reduced from -20 degrees to -66 degrees, while the shear rate amplitude at the inner wall increases 45%. As a result, the oscillatory nature of flow at the outer wall decreases with decreasing negative phase angle, but flow at the inner wall becomes much more oscillatory. At large negative phase angles, characteristic of hypertension or vasoactive agents, the shear rate at the inner wall has a small mean and cycles through positive and negative values; the shear rate at the outer wall remains positive throughout the flow cycle. Thus, the impedance phase angle could affect atherogenesis along the inner wall if temporal and directional changes in wall shear rate play a role.

An in vitro investigation of the retrograde flow fields of two bileaflet mechanical heart valves.

BACKGROUND AND AIM OF THE STUDY: Fluid stresses occurring in retrograde flow fields during valve closure may play a significant role in thrombogenesis. The squeeze flow and regurgitant jets can cause damage to formed blood elements due to high levels of turbulent shear stress. The aim of this study was to characterize in detail the spatial structure and temporal behavior of the retrograde flow fields of the St. Jude Medical and Medtronic Parallel bileaflet mechanical heart valves. METHODS: Three-component, coincident laser Doppler anemometry (LDA) velocity measurements were obtained facilitating the determination of the full Reynolds stress tensor and the principal stresses in the valve flow fields. The experiments were performed in the Georgia Tech aortic flow chamber under physiologic pulsatile flow conditions. Data were collected over several hundred cardiac cycles for subsequent phase window averaging and generation of mean velocity and turbulence statistics over 20 ms intervals. A region approximately 8 mm x 10 mm was mapped 1.0 mm upstream of one hinge of each valve with an incremental resolution of 0.13-0.25 mm. Animation of the data allowed the visualization of the flow fields and a quantitative display of mean velocity and turbulent stress values. RESULTS: In the St. Jude Medical squeeze flow, the peak turbulent shear stress was 800 dynes/cm2 and the peak reverse velocity was 0.60 m/s. In the Medtronic Parallel squeeze flow, the peak turbulent shear stress was 1,000 dynes/cm2 and the peak velocity 0.70 m/s. The leakage jet fields of the two valves were very different: in the case of the St. Jude Medical valve, turbulent shear stresses reached 1,800 dynes/cm2 and peak jet velocity was 0.80 m/s; in the case of the Medtronic Parallel valve, turbulent shear stresses reached 3,690 dynes/cm2 and the peak jet velocity was 1.9 m/s. CONCLUSIONS: The retrograde flow fields of these two bileaflet mechanical heart valves appear to be design-dependent. The elevated turbulent shear stresses generated by both valve designs may indicate a propensity for blood element damage during the reverse flow phase of the cardiac cycle, but the extent of flow disturbance was twice as high with the Medtronic Parallel than with the St. Jude Medical valve. This research should yield a better understanding of the significance of retrograde flow to the functionality and potential thrombogenicity of bileaflet mechanical heart valves and aid in the development of new designs.

Compliance and diameter mismatch affect the wall shear rate distribution near an end-to-end anastomosis.

The development of intimal hyperplasia near the anastomosis of a vascular graft to an artery may be related to changes in the wall shear rate distribution. Mismatches in compliance and diameter at the end-to-end anastomosis of a compliant artery and a rigid graft cause shear rate disturbances that may induce intimal hyperplasia and ultimately graft failure. The goal of this study is to determine how compliance mismatch, diameter mismatch, and impedance phase angle affect the wall shear rate distribution in end-to-end anastomosis models under sinusoidal flow conditions. Wall shear rates are obtained through flow visualization using a photochromic dye. In a model with a well-matched graft diameter (6% undersized), the compliance mismatch causes low mean wall shear rates near the distal anastomosis. Considering diameter mismatch, the wall shear rate distributions in 6% undersized, 16% undersized, and 13% oversized graft models are markedly different at similar phase angles. In the two undersized graft models, the minimum mean shear rate occurs near the distal anastomosis, and this minimum is lower in the model with greater diameter mismatch. The oversized graft model has a minimum mean shear rate near the proximal anastomosis. Thus in all three models, the minimum mean wall shear rate is observed at the site of the divergent geometry. The impedance phase angle, which can be altered by disease states and vasoactive drugs, has a minor effect on the wall shear rate amplitude far from the anastomosis but a more pronounced effect closer to the anastomosis. Mean wall shear rates under sinusoidal flow conditions are significantly lower than under steady flow conditions at the same mean flow rate, but they are fairly insensitive to phase angle changes. In order to avoid the divergent geometry that may cause lower wall shear rates, we recommend that compliance mismatch be minimized whenever possible and that graft diameter be chosen to match the arterial diameter at the relevant physiologic pressure, not at the reduced pressure present when the graft is implanted.

Closure of a patent foramen ovale and tricuspid valve replacement after heart transplantation.

Patent foramen ovale has been noted after cardiac transplantation. Rarely is surgical intervention warranted. In this communication we report a case of severe tricuspid regurgitation and paradoxical embolism secondary to a patent foramen ovale in a patient 19 months after heart transplantation. The patient underwent successful closure of the patent foramen ovale and tricuspid valve replacement.

Normalization of circulating atrial natriuretic peptides in cardiac transplant recipients.

To assess whether heart transplantation (Htx) alters the marked elevation of circulating atrial natriuretic peptides usually found in patients with congestive heart failure (CHF), 14 subjects (nine with compensated and five with decompensated CHF), each with an ejection fraction < or = 28%, were evaluated. Immediately before and hourly for the first 12 hours after Htx, then daily for 21 days and every 1 to 4 weeks for 6 months, the circulating concentrations of the N-terminus (pro atrial natriuretic factor [ANF] 1-98), midportion of the N-terminus (pro ANF 31-67), and C-terminus (that is, ANF) of the 126 amino acid prohormone were measured. Increased (p < 0.001) levels of these peptides were found in superior vena cava, right atrial, and peripheral venous samples 1 hour after Htx in all subjects except one. The atrial natriuretic peptide levels correlated only with right atrial pressure (p < 0.01) in the first 24 hours. Circulating concentrations of these peptides returned to those of healthy adults between 5 and 12 days after Htx in 11 out of 14 Htx recipients. Thus successful Htx can restore the elevated circulating concentrations of atrial natriuretic peptides to those of healthy adults.

Cardiac tamponade in a patient with Gaucher's disease.

Gaucher's disease, a familial inborn error of metabolism associated with hepatosplenomegaly and hypersplenism, was first described by Earnest Gaucher in 1882. By 1959, Hsia found published reports on more than 300 cases. Most reports mentioned the bleeding tendencies of patients with Gaucher's, but show that major hemorrhagic complications are rare. We report a case of hemorrhagic pericarditis with cardiac tamponade in a patient with Type I Gaucher's disease.

Angioplasty of an oversized venous bypass graft using two fixed wire systems.

Oversized saphenous vein bypass grafts may be inadequately dilated using currently available coronary angioplasty catheters. The hugging balloon technique has been previously described for lesions in large saphenous vein grafts. We report the initial use of the hugging balloon technique using two fixed wire angioplasty catheters in an oversized saphenous vein graft.

Unknown extra cardiac echo-free space: diagnosis of a left ventricular pseudoaneurysm by color flow echocardiography.

At times, visualization of a ventricular pseudoaneurysm by two-dimensional echocardiography can be difficult. This case report describes the unique diagnostic potential of color flow echocardiography in the diagnosis of an unknown extra cardiac echo-free space, a left ventricular pseudoaneurysm. Using color Doppler echocardiography flow can be seen communicating between the left ventricle and the pseudoaneurysm.