Proximal Proximal Pulmonary Artery Research Articles

Abstract 14407: Right Ventricular Myocardial Stiffening is Associated With Pulmonary Arterial Stiffening in Pulmonary Hypertension

Introduction: Pulmonary hypertension (PH) increases vascular resistance in the lung leading to remodeling of the proximal pulmonary artery (PA). PH also leads to the right ventricular (RV) remodeling following increased RV afterload. Studies of tissue remodeling in PH have focused on either the RV or PA, leaving the understanding of the RV-PA remodeling relationship elusive. We hypothesize that PA proximal tissue stiffening is associated with RV free wall (RVFW) stiffening. Methods: The mild model of PH was developed by placing SD rats (n=6) in a hypoxia chamber (10% O2) for 3 weeks, followed by one week of normoxia. The severe model of PH was developed by injecting one dose of SU5416 (20 mg/kg sc) into CDF rats (n=6) followed by the hypoxia protocol. Control rats (n=6 each for SD and CDF) were kept in normoxia at all times. Each group was half male and half female. RVFW and main PA tissues were harvested and characterized through mechanical tests. Tissue stiffness was calculated as the slope of the ensemble stress-strain curve (sum of circumferential and longitudinal stress) at a large strain (>30%) for the RVFW and PA specimens. Results: RVSP increased, and PAT decreased in both models. These changes were significant only in the severe model (Figs. 1A, B). Similarly, RVFW and PA stiffnesses increased significantly only in the severe model (Figs. 1C, D). A significant positive correlation between RVFW and PA stiffness was observed (R2 = 0.59, p=0.0001, Fig. 1E). Conclusions. Our results demonstrate, for the first time, a significant correlation between RVFW and PA stiffening in PH. Proximal PA stiffening changes the pulsatile component of the RV afterload, contributing to the RVFW stiffening, which is known to be a key precursor of RV failure. Our results suggest that the proximal PA stiffening may worsen RV stiffening independent of increases in PA distal resistance. Further studies are needed to determine the role of resistive vs. pulsatile RV afterload in the outcome of RV remodeling.

Prenatal features of ductus arteriosus-related branch pulmonary stenosis in fetal pulmonary atresia.

Ductus arteriosus (DA)-related branch pulmonary stenosis (PS), due to ductal tissue migration into the proximal pulmonary artery (PA) ipsilateral to the DA, is common in newborns with pulmonary atresia (PAtr) and contributes significantly to their mortality and morbidity. We sought to define fetal echocardiographic predictors of DA-PS in PAtr. This was a study of all neonates diagnosed prenatally with PAtr and a DA-dependent pulmonary circulation, with a DA that joined the underbelly of the arch, who had undergone surgical or catheter intervention in our hospital between 2009 and 2018. The postnatal echocardiograms and clinical records were reviewed to confirm the presence or absence of DA-PS based on the need for angioplasty at initial intervention and/or development of proximal PA stenosis post intervention. Fetal echocardiograms were examined for the features of DA-PS. Of 53 fetuses with PAtr, 34 (64%) had analyzable images, including 20/34 (59%) with and 14/34 (41%) without DA-PS. An inability to visualize the branch PAs in the same plane, largely associated with abnormal DA insertion into the ipsilateral PA (85% of cases), had sensitivity, specificity and positive (PPV) and negative (NPV) predictive values of 75%, 100%, 100% and 74%, respectively, for the prediction of postnatal DA-PS. The mean branch PA posterior bifurcation angle was more obtuse in cases with DA-PS compared to cases without DA-PS (117° ± 17° vs 79° ± 17°, P < 0.001), and an angle of > 100°, the preoperative cut-off observed previously in affected newborns, had a sensitivity, specificity, PPV and NPV of 88%, 79%, 82% and 85%, respectively. The receiver-operating-characteristics curve revealed an angle of ≥ 105° to have a sensitivity and specificity of 88% and 93%, respectively, for prenatal prediction of DA-PS. The presence of one or both features (inability to image in the same plane and the posterior bifurcation angle of ≥ 105°) had a sensitivity, specificity, PPV and NPV of 100%, 93%, 95% and 100%, respectively. An inability to visualize the branch PAs in the same plane, associated with abnormal insertion of the DA in most cases, and/or the presence of a posterior PA bifurcation angle of ≥ 105° are predictive features of postnatal DA-PS in fetuses with PAtr. © 2020 International Society of Ultrasound in Obstetrics and Gynecology.

The autonomic neural mechanism of right ventricular outflow tract tachycardia.

Ventricular tachycardia (VT) and ventricular premature complexes (VPCs) originating from the right ventricular outflow tract (RVOT) are generally considered as benign arrhythmias, with ECG morphology showing LBBB pattern and inferior axis. Pathogenic mechanisms in the genesis of RVOT VT/VPC remain largely unknown. We aimed to investigate the neural mechanism in RVOT ventricular arrhythmias in canine model. Twelve mongrel dogs (13.7 ± 1.3 kg, 5 male dogs) were studied through midline thoracotomies. High-frequency stimulation (HFS) was applied to the proximal pulmonary artery (PA) to induce RVOT VT/VPC. An EnSite Array and a mapping catheter were used for electroanatomical mapping. The RVOT and PA were surgically excised for immunohistochemistry studies, including tyrosine hydroxylase (TH) stain for sympathetic nerves and choline acetyltransferase (ChAT) stain for parasympathetic nerves. In nine (75%) out of twelve dogs, HFS of the proximal PA induced RVOT VT/VPC. The density of TH-positive nerves was significantly higher than that of ChAT-positive nerves (6803 ± 700 vs. 670 ± 252 μm2/mm2, p < 0.001). Furthermore, the density of TH-positive nerves was also significantly higher in the VT/VPC origin sites than that in the non-origin sites (18,044 ± 2866 vs. 5554 ± 565 μm2/mm2, p = 0.002). Catheter ablation of the proximal PA eliminated the inducibility of RVOT VT/VPC successfully. HFS of the proximal PA could induce RVOT VT/VPC. The sympathetic nerves were densely innervated to the origin of RVOT VT/VPC, indicating the critical role of sympathetic hyperactivity in the initiation and perpetuation of RVOT VT/VPC.

Proximal Pulmonary Artery Evaluation in Infants With Shunt-Dependent Pulmonary Blood Flow: Computed Tomographic Angiography Versus Transthoracic Echocardiography

Background: Infants with shunt-dependent pulmonary blood flow are at risk for developing proximal pulmonary artery (PA) stenosis, which may result in morbidity and mortality. Transthoracic echocardiography (TTE) is the primary means of surveillance for PA narrowing but has significant limitations and has not been compared to computed tomographic angiography (CTA)–derived measurements of the proximal PA anatomy in this population. Methods: A retrospective chart review identified infants with shunt-dependent pulmonary blood flow who had both TTE and CTA performed &lt;14 days apart during a five-year period. Proximal right pulmonary artery (RPA) and left pulmonary artery (LPA) diameters were measured by TTE and CTA. Pulmonary artery z-score, linear and intraclass correlation (ICC) coefficients, and Bland-Altman plots were computed. Results: Seventeen pairs of studies were analyzed. The TTE and CTA proximal PA diameters had moderate linear correlation and agreement ( R = 0.67, P ≤ .0001, ICC = 0.65); the RPA showed stronger correlation and agreement ( R = 0.76, P = .0004, ICC = 0.72) than the LPA (R = 0.59, P = .01, ICC = 0.59). Computed tomographic angiography detected missed PA stenosis ( Z score &lt; −2) in five (14.7%) cases, four of which were on the LPA. Conclusion: In this study of infants with shunt-dependent pulmonary blood flow, TTE and CTA proximal PA diameters had only moderate correlation and agreement overall, which was worse when comparing LPA measurements. This resulted in missed PA stenosis by TTE. Computed tomographic angiography may be warranted in patients with poorly visualized PAs by TTE or suspicion for deficient pulmonary blood flow.

The Role of Autonomic Nervous System on Right Ventricular Outflow Tract Tachycardia

Background: Right ventricular outflow tract ventricular tachycardia (VT) and ventricular premature complexes (VPCs) are characterized as benign in entity with ECG morphology showing LBBB pattern and inferior axis. Pathogenic mechanisms in the genesis of RVOT VT/VPC remain largely unknown. We aimed to investigate the neural mechanism in RVOT VT/VPC in canine model. Methods: Twelve mongrel dogs (13.7 ± 1.3 Kg, 5 male dogs) were studied through midline thoracotomies. High-frequency stimulation (HFS) was applied to the proximal pulmonary artery (PA) to induce RVOT VT/VPC. An EnSite Array and a mapping catheter were used for electroanatomical mapping. The RVOT and PA were surgically excised for immunohistochemistry studies, including tyrosine hydroxylase (TH) stain for sympathetic nerves and choline acetyltransferase (ChAT) stain for parasympathetic nerves. Results: In nine (75%) out of twelve dogs, HFS of the proximal PA induced RVOT-VT/VPC. The density of THpositive nerves was significantly higher than that of ChAT-positive nerves (6803 ± 700 vs. 670 ± 252 μm2/mm2, p<0.001). Moreover, the density of TH-positive nerves was also significantly higher in the VT/VPC origin sites than that in the non-origin sites (18044 ± 2866 vs. 5554 ± 565 μm2/mm2, p=0.002). Catheter ablation of the proximal PA eliminated the inducibility of RVOT VT/VPC successfully. Conclusion: HFS of the proximal PA could induce RVOT VT/VPC. The sympathetic nerves were densely innervated to the origin of RVOT VT/VPC, indicating the critical role of sympathetic hyperactivity in the initiation and perpetuation of RVOT VT/VPC.

Effects of Proximal Pulmonary Artery Occlusion on Pulsatile Right Ventricular Afterload in Rats.

In patients with proximal pulmonary artery (PA) thromboembolism, an increased PA resistance contributes to abnormal right ventricular (RV) afterload. However, the effects of proximal thromboembolism on the dynamic properties of RV afterload, which is determined by PA impedance, have not been analyzed quantitatively. The present study aimed to identify changes in PA impedance after the pulmonary perfusion volume was greatly reduced by unilateral proximal PA occlusion. Ten male Sprague-Dawley rats were used. PA flow and pressure waveforms were recorded during irregular pacing, before and 10 min after left PA occlusion. PA impedance was parameterized by using a three-element Windkessel model consisting of peripheral resistance (RP), arterial compliance (CP) and characteristic impedance (ZC). After proximal PA occlusion, PA impedance modulus increased over a frequency range of interest.ZCincreased significantly (after PA occlusion vs. baseline: 0.128±0.016 vs. 0.074±0.010 mmHg·min/ml, P<0.001), whereasCPandRPdid not change significantly. Proximal PA occlusion increasedZCwith the attenuation ofRPincrease andCPdecrease predicted from the decreased pulmonary perfusion volume. The insignificant changes inRPandCPindicate that a recruitment phenomenon may result in this attenuation. The existence of compensation by a recruitment mechanism suggests the relative importance of increasedZCin defining abnormal RV afterload in patients with proximal PA thromboembolism. (Circ J 2016; 80: 2010-2018).

Intrauterine endotoxin-induced impairs pulmonary vascular function and right ventricular performance in infant rats and improvement with early vitamin D therapy.

High pulmonary vascular resistance (PVR), proximal pulmonary artery (PA) impedance, and right ventricular (RV) afterload due to remodeling contribute to the pathogenesis and severity of pulmonary hypertension (PH). Intra-amniotic exposure to endotoxin (ETX) causes sustained PH and high mortality in rat pups at birth, which are associated with impaired vascular growth and RV hypertrophy in survivors. Treatment of ETX-exposed pups with antenatal vitamin D (vit D) improves survival and lung growth, but the effects of ETX exposure on RV-PA coupling in the neonatal lung are unknown. We hypothesized that intrauterine ETX impairs RV-PA coupling through sustained abnormalities of PA stiffening and RV performance that are attenuated with vit D therapy. Fetal rats were exposed to intra-amniotic injections of ETX, ETX+vit D, or saline at 20 days gestation (term = 22 days). At postnatal day 14, pups had pressure-volume measurements of the RV and isolated proximal PA, respectively. Lung homogenates were assayed for extracellular matrix (ECM) composition by Western blot. We found that ETX lungs contain decreased α-elastin, lysyl oxidase, collagen I, and collagen III proteins (P < 0.05) compared control and ETX+vit D lungs. ETX-exposed animals have increased RV mechanical stroke work (P < 0.05 vs. control and ETX+vit D) and elastic potential energy (P < 0.05 vs. control and ETX+vit D). Mechanical stiffness and ECM remodeling are increased in the PA (P < 0.05 vs. control and ETX+vit D). We conclude that intrauterine exposure of fetal rats to ETX during late gestation causes persistent impairment of RV-PA coupling throughout infancy that can be prevented with early vit D treatment.

Pulmonary artery relative area change is inversely related to ex vivo measured arterial elastic modulus in the canine model of acute pulmonary embolization

A low relative area change (RAC) of the proximal pulmonary artery (PA) over the cardiac cycle is a good predictor of mortality from right ventricular failure in patients with pulmonary hypertension (PH). The relationship between RAC and local mechanical properties of arteries, which are known to stiffen in acute and chronic PH, is not clear, however. In this study, we estimated elastic moduli of three PAs (MPA, LPA and RPA: main, left and right PAs) at the physiological state using mechanical testing data and correlated these estimated elastic moduli to RAC measured in vivo with both phase-contrast magnetic resonance imaging (PC-MRI) and M-mode echocardiography (on RPA only). We did so using data from a canine model of acute PH due to embolization to assess the sensitivity of RAC to changes in elastic modulus in the absence of chronic PH-induced arterial remodeling. We found that elastic modulus increased with embolization-induced PH, presumably a consequence of increased collagen engagement, which corresponds well to decreased RAC. Furthermore, RAC was inversely related to elastic modulus. Finally, we found MRI and echocardiography yielded comparable estimates of RAC. We conclude that RAC of proximal PAs can be obtained from either MRI or echocardiography and a change in RAC indicates a change in elastic modulus of proximal PAs detectable even in the absence of chronic PH-induced arterial remodeling. The correlation between RAC and elastic modulus of proximal PAs may be useful for prognoses and to monitor the effects of therapeutic interventions in patients with PH.

Human Model Simulating Right Ventricular Outflow Tract Tachycardia by High‐Frequency Stimulation in the Left Pulmonary Artery: Autonomics and Idiopathic Ventricular Arrhythmias

Frequent monomorphic premature ventricular contractions (PVC) and/or ventricular tachycardia (VT) in patients with structurally normal heart usually arise from the right ventricular outflow tract (RVOT). An animal model simulating RVOT tachycardia by high-frequency stimulation (HFS) of the sympathetic input to the proximal pulmonary artery (PA) has been previously described. The aim of this study was to similarly induce RVOT tachycardia in humans. In 9 patients with no history of ventricular arrhythmias, a circumferential catheter was placed in the left, main, and proximal PA to contact the endovascular circumference of the PA. A 50-ms train of HFS (200 Hz/0.3 ms pulse duration), coupled to atrial pacing, was applied at each bipolar pair of the circumferential catheter. The coupling interval was adjusted so that the 50-ms train occurred during the ventricular refractory period. In 6 out of 9 patients, HFS in the left PA during dobutamine infusion induced monomorphic PVCs and/or VT with left bundle branch block (LBBB) morphology and inferior axis at an average stimulation level of 12.5 +/- 2.7 V. HFS in the main PA and in the proximal PA did not induce any ventricular arrhythmias with the highest energy of 15 V in baseline state and during dobutamine infusion. HFS in the left PA was associated with hiccough in all patients. Stimulation of the sympathetic input to the left PA during dobutamine infusion induces PVCs and/or VT exhibiting LBBB-morphology and inferior axis, closely simulating clinical RVOT tachycardia in humans.

Experimental Model Simulating Right Ventricular Outflow Tract Tachycardia: A Novel Technique to Initiate RVOT‐VT

The mechanism(s) whereby a discrete area of myocardium in the RVOT becomes arrhythmogenic remains unknown. In 13 dogs, a circular catheter was placed in the proximal pulmonary artery (PA) to contact the endovascular circumference of the PA. A 50-msec train of high-frequency stimulation (HFS, 200 Hz), coupled to atrial pacing, was applied at each bipolar pair of the circular catheter. The coupling interval was adjusted so that the 50-msec train occurred during the ventricular refractory period, that is, the QRS complex, in order to prevent stimulation of the myocardial sleeve within the proximal PA. In all dogs, HFS induced ventricular premature depolarizations and VTs with a left bundle branch block (LBBB) morphology and inferior axis (average 6.8 +/- 1.6 V). Earliest activation was consistently recorded from the proximal PA. Esmolol, a short-acting beta-blocker (1 mg/kg), was administered intravenously in 11 dogs. The inducible ventricular ectopy was abolished in 10 dogs (>12 V, P < 0.05) and the response to HFS was blunted in one dog (10-11 V). After 30 minutes, the response to HFS returned to pre-esmolol levels. Stimulation of the sympathetic input to the proximal PA induces ventricular ectopy and VTs exhibiting a left bundle branch block morphology and inferior axis, closely simulating clinical RVOT-VT. Beta-blockade either abolishes or blunts this response, corroborating the sympathetic etiology in this model and in some clinical cases of RVOT tachycardias.

PULMONARY REPLACEMENT WITH A TOTAL ARTIFICIAL LUNG

Purpose: An oxygenator with low resistance may be perfused by the native cardiac output (CO) and serve as a Total Artificial Lung (TAL). However, the absence of compliance may increase pump load in a pulsatile system. Impedance is the resistance to pulsatile flow, and is expressed as a function of harmonic. While the zero harmonic impedance (Z9) represents the resistance to steady flow, the first harmonic (Z1) dominates the load to pulsatile flow. The tension-time index (TTI) is a correlate of myocardial oxygen consumption. We sought to characterize right ventricular (RV) load and adaptation in the setting of pulmonary replacement with a TAL. Methods: Five adult male sheep were instumented with micromanometers in the RV, proximal pulmonary artery (PA), and left atrium (LA), and an ultrasonic flow probe was placed around the proximal PA. Conduits were anastamosed to the PA and LA, and connected to a TAL. Data were obtained under two conditions: 1) conduits clamped, allowing native pulmonary circulation, and 2) distal PA occluded, diverting the total RV output through the TAL. Epicardial and intracardiac echocardiographs were obtained. The pulsatility index (PI) was calculated by dividing the amplitude of flow in the first harmonic by the CO. Results: Although CO, mean PA pressure (mPAP) and resistance were unchanged (CO: 6.2 ± 1.5 vs 5.6 ± 0.9 L/min, p=NS; mPAP: 18.5 ± 3.6 vs 18.1 ± 3.2 mmHg, p=NS; Z0: 3.1 ± 0.6 vs 3.3 ± 0.5 Woods Units, p=NS), there was a substantial increase in Z1 (0.4 ± 0.1 vs 5.8 ± 1.4 Woods Units, p<0.01). This elevated impedance was associated with an increase in the TTI from 843.5 ± 113.3 to 1032.1 ± 224.3 mmHg-s/min, p=0.04. Blood flow ejected from the right ventricle became less pulsatile, reflected by a reduction in the PI from 0.64 ± 0.12 to 0.23 ± 0.09, p<0.01. Echocardiographs suggested incomplete closure of the pulmonic valve with forward diastolic flow. In the setting of pulmonary replacement with a TAL, high impedance with unchanged resistance alters cardiac function, and may have long-term effects upon the RV. Addition of a compliance chamber can reduce Z1, and may restore normal ventricular function.

Prospective echocardiographic analysis of progressive obstruction of the proximal pulmonary artery in congenital heart disease and obstructed pulmonary flow

Background It is uncertain whether proximal pulmonary artery (PA) obstruction exists soon after birth and whether its progress relates directly to postnatal ductal constriction in congenital heart disease and obstructed pulmonary flow. Methods Serial morphometric analyses of the PA branches by echocardiogram were performed in 28 patients (mean age at initial study 2.5 days) until severe constriction of the ductus occurred (mean age 47 days). These patients were divided into 2 groups by subsequent angiographic or postmortem confirmation; 10 with proximal PA obstruction (group 1) and 18 without obstruction (group 2). Results At the time of initial examination, the mean indexed diameter of the proximal PA on the side of the ductus arteriosus in group 1 was significantly smaller than that on the contralateral side (5.2 ± 0.7 versus 9.0 ± 0.7 mm/BSA 0.5 , P < .001) or that in group 2 (8.0 ± 0.4 mm/BSA 0.5 , P < .001). In group 1, 8 patients had a proximal PA index on the ductal side ≤ 5.5 mm/BSA 0-5 , which was less than those of any group 2 patients. After severe constriction of the ductus, the proximal PA index on the ductal side further decreased only in group 1 ( P < .01). Conclusions These data indicate that unilateral obstructive lesion of branch PA is present shortly after birth and its progression relates directly to ductal constriction. Neonates with branch PA obstruction can be identified on their initial echocardiogram as having a proximal PA index on the ductal side ≤ 5.5 mm/BSA 0.5 . (Am Heart J 1998;136:837-43.)