Right Ventricular Hypertension Research Articles

Abstract 11700: Hemodynamic Impact of Severe Pulmonary Regurgitation in Patients With Right Ventricular Hypertension Secondary to Peripheral Pulmonary Arterial Stenosis

Introduction: Severe pulmonary regurgitation (PR) is a common sequela of surgery for dysfunctional right ventricular outflow tract (RVOT). Peripheral pulmonary arterial stenosis (PPS) is frequently associated with conotruncal anomalies like Tetralogy of Fallot. Whether severe PR, which increases the right ventricular stroke volume, worsens right ventricular hypertension (RVHTN) in patients with PPS has not been previously investigated. Hypothesis: In patients with RVH secondary to PPS, the abolishment of severe PR ameliorates the degree of RVH. Methods: Retrospective longitudinal study of patients with PPS and severe PR, who underwent transcatheter pulmonary valve replacement (TPVR) at Boston Children’s Hospital between 01/2016 and 12/2019. Patients were included if they met all 3 of the following criteria: (1) PPS, (2) RVHTN immediately before TPVR (defined as an RV to Ao systolic pressure ratio [RV/AO] of at least 0.5 after interventions on the RVOT/PPS and before TPVR), and (3) severe PR. Patients with missing data were excluded. Hemodynamic data were collected at baseline, before TPVR (following the interventions for PPS and on the RVOT), and after TPVR. Variables were analyzed using a repeated-measure non-parametric ANOVA (Friedman test). A post-hoc analysis with Dunn-Bonferroni adjustment was performed. Results: In the study period, 17 patients (median age 14.6 years, IQR 10.1-19.7) met the inclusion criteria and had available hemodynamic data. Right ventricle systolic pressure, RVOT gradient, and RV/AO changed significantly overtime (all p<0.001). While there was no significant difference in RVOT gradient before and after TPVR, re-establishment of valve competence did result in a further significant drop in RV pressure (Table 1). Conclusion: In patients with RVHTN secondary to PPS and severe PR, reestablishment of pulmonary valve competence significantly decreases the degree of RV hypertension compared to RVOT/PPS interventions alone.

Pulmonary artery sheath hematoma.

Dissection of the ascending aorta (AA) represents a life-threatening condition typically treated by emergent surgical repair. A rare, potential complication of AA dissection is pulmonary artery (PA) sheath hematoma. Due to the presence of a common adventitial layer between the proximal AA and the PA, dissection can propagate between both vessels, potentially compromising the PA lumen. The resultant acute narrowing of the PA lumen may abruptly increase right ventricular (RV) afterload. Recognition of PA sheath hematoma is important; when seen on echocardiography it is suggestive of AA dissection and has the potential to result in RV hypertension and dysfunction if significant PA compression occurs.

Management of high risk pulmonary embolism in the intensive unit care of IBN Rochd University Hospital, Casablanca

High-risk acute pulmonary embolism (PE) is associated with a mortality approaching 25% and remains defined by shock or hypotension. The high early mortality in the presence of a state of shock makes it an urgent diagnosis by favoring examinations in the patient's bed. The aim of this study was to describe the clinical features of patients admitted for acute high-risk PE, the main findings and their prognosis. This is a retrospective study conducted on 112 patients hospitalized in cardiology intensive care unit at IBN ROCHD University Hospital of Casablanca, Morocco for PE between January 2016 and October 2018, including 25 with acute PE at high risk. The average age of the patients with cardiogenic shock was 64.9 years, with a standard deviation of 17.3; with a higher frequency in the elderly > 70 years ( P = 0.06). The sex ratio (M/F) was 0.37, the risk factors for venous thromboembolism were not different from the non-shock group. The clinical presentation was a respiratory distress chart with SpO2 < 95%, arterial hypotension < 90 mmHg systolic and tachycardia > 100bpm in 88% of cases ( P = 0.003). Electrically, rhythm disorders were not more frequent than in stable patients. The echocardiography made it possible to make the diagnosis and initiate the treatment by thrombolysis without waiting for the results of the thoracic angioscanner. A thrombus was found in 24% of cases, right ventricular (RV) dysfunction in 72% of patients ( P = 0.04) with dilatation of RV, paradoxical septum and Pulmonary hypertension in more than 80% of patients. Thrombolysis was used in 88% of patients ( P < 0.001), treatment with non fractionnal heparine, dobutamine was initiated in 52% of cases ( P < 0.01). Mortality was 36% compared to 7% in the non-shock group ( P = 0.026). Despite rapid management and treatment thrombolytics and vasoactive drugs, high-risk acute PE remains a poor prognosis with significant intra-hospital mortality.

What influences right ventricle function in pulmonary hypertension due to HFpEF?

Right ventricular (RV) function and pulmonary hypertension (PH) are increasingly recognized in heart failure with preserved ejection fraction (HFpEF), with high prevalence and poor outcome. Factors leading to worse RV function in PH-HFpEF patients are unknown. We thought to determine the parameters of RV dilation in HFpEF patients with PH. We analysed clinical, echocardiographic and hemodynamic characteristics of 112 PH-HFpEF patients (71 women) enrolled prospectively in our center. PH-HFpEF was defined by a resting mean pulmonary artery pressure (mPAP) ≥ 25 mmHg and pulmonary artery wedge pressure (PAWP) > 15 mmHg. RV dysfunction was defined as tricuspid annular plane systolic excursion (TAPSE) < 16 mm at echocardiography. Mean age (± SD) was 69 ± 11 years, mPAP was 40 ± 10 mmHg, PAWP was 21 ± 5 mmHg. Forty-seven PH-HFpEF patients (40%) had RV dysfunction. In univariate analysis, RV dysfunction was related to history of hypertension ( P = 0.04, OR = 1.01), atrial fibrillation ( P < 0.01; OR = 0.21), mPAP ( P = 0.06; OR = 0.97), and right atrial pressure (RAP) ( P = 0.02, OR = 0.92). In PH-HFpEF patients, we documented a significant relationship between RV dysfunction and Hypertension, atrial fibrillation, mPAP and RAP.

Early versus late cardiac remodeling during right ventricular pressure load and impact of preventive versus rescue therapy with endothelin-1 receptor blockers

Pulmonary artery banding (PAB) causes right ventricular (RV) dysfunction, biventricular fibrosis, and apoptosis, which are attenuated by endothelin-1 receptor blockade (ERB). Little is known about the time course of remodeling and whether early versus late ERB confers improved outcome. PAB was performed in five groups of rabbits: Shams, 3-wk PAB (3W), 6-wk PAB (6W), 6-wk PAB + ERB administered from day 1 (6WERB1), and 6-wk PAB + ERB administered from day 21 (6WERB21). Biventricular development of profibrotic molecular signaling, fibrosis, apoptosis, and conductance catheter and echocardiography function were studied. Thirty-three rabbits [ n = 6-7 per group; 3.00 (0.23) kg, mean (SD)] developed half to full systemic RV pressures. Biventricular profibrotic signaling and collagen deposition [RV collagen: Shams 3.8 (0.58) vs. 3W 8.69 (2.52) vs. 6W 8.83 (4.02)%, P < 0.005] and apoptosis [RV: Shams 8.32 (3.2) vs. 3W 55.95 (47.55) vs. 6W 38.85 (17.26) apoptotic cells per microfield, P < 0.0005] increased with PAB. Early and late ERB attenuated fibrosis [RV: 6WERB1 5.55 (1.18), 6WERB21 5.63 (0.72)%] and apoptosis [RV: 6WERB1 11.1 (5.25), 6WERB21 20.24 (7.16) apoptotic cells per microfield, P < 0.0001 vs. 6W]. RV dimensions progressively increased at 3W and 6W and decreased with early ERB [end-diastolic dimensions: Shams 0.4 (0.13) vs. 3W 0.55 (0.78) vs. 6W 0.78 (0.25) vs. 6WERB1 0.71 (0.26) vs. 6WERB21 0.49 (0.23) cm, P < 0.05]. Despite increased RV contractility with PAB [RV end-systolic pressure-volume relationship: Shams 3.76 (1.76) vs. 3W 12.21 (3.44) vs. 6W 19.4 (6.88) mmHg/ml], biventricular function and cardiac output [Shams 196.1 (39.73) vs. 3W 149.9 (34.82) vs. 6W 151 (31.69) ml/min] worsened in PAB groups and improved with early and late ERB [6WERB1 202.8 (26.8), 6WERB21 194.8 (36.93) ml/min, P < 0.05 vs. PAB]. In conclusion, RV pressure overload induces early biventricular fibrosis, apoptosis, remodeling, and dysfunction that worsens with persistent RV hypertension. This remodeling is attenuated by early and late ERB. NEW & NOTEWORTHY Our results in a rabbit model of progressive right ventricular (RV) pressure loading indicate that biventricular fibrosis, apoptosis, and dysfunction are already present when RV hypertension is reached at 3 wk of progressive pulmonary artery banding. These findings worsen with persistent RV hypertension to 6 wk and are attenuated with both early and late endothelin-1 receptor blockade, with some advantages to early therapy. These findings highlight the role of endothelin-1 in driving biventricular remodeling secondary to RV hypertension and suggest that early therapy with an endothelin-1 receptor blocker may be beneficial in attenuating biventricular remodeling but that late therapy is also effective.

An opportunistic study evaluating pharmacokinetics of sildenafil for the treatment of pulmonary hypertension in infants.

ObjectiveTo assess sildenafil and N-desmethyl sildenafil (DMS) exposure in infants receiving sildenafil for the treatment of pulmonary hypertension (PH).Study designData were collected from 6 infants receiving sildenafil for the treatment of PH, and plasma samples were collected at the time of routine laboratory blood draws. The echocardiography results were assessed for improvement in right ventricular (RV) hypertension following sildenafil treatment.ResultThe median (range) sildenafil and DMS concentrations were 27.4 ng/mL (2.6-434.0) and 105.5 ng/mL (3.6-314.0), respectively. The median metabolite-to-parent ratio was higher in infants receiving co-medications that can induce cytochrome P450 (CYP) enzymes (5.2 vs. 0.7). The echocardiography results showed improvement in RV hypertension for the majority of infants (5/6).ConclusionThe concentrations of sildenafil and DMS were within the previously observed ranges. Our results suggest that caution may be warranted when CYP-related co-medications are administered during sildenafil treatment for PH.

Pulmonary hypertension is present in a rodent model of bronchopulmonary dysplasia at 21 days but not 6 months of age (715.1)

In preterm infants, mechanical ventilation with supplemental O2 can cause bronchopulmonary dysplasia (BPD), characterized by dysmorphic pulmonary vasculature and simplified alveoli. Although vascular cross‐sectional area is diminished, contributing to right ventricular hypertension (RVH), it is unknown whether this improves with age. We hypothesized that RVH would continue into adulthood in a rat model of BPD. Rats were exposed to 21% or 95% O2 from birth to postnatal day 8. At 21 days or 6 months of age, a fluid‐filled catheter was placed in the RV to measure RV pressure and inject 2x108 4μm fluorescent spheres. At the conclusion of the experiment, lungs were harvested, air dried, and imaged using laser scanning confocal microscopy to investigate capillary density. At 21 days, rats exposed to 95% O2 demonstrated RVH (31±5 mmHg), which was absent in both 21 day controls (16±2 mmHg, p=0.028) and 6 month old rats exposed to 95% O2 (20±10 mmHg, p=0.014). Interestingly, the density and distribution of spheres was not different between 6 month old rats exposed to 95% or 21%, suggesting that the normalization of right heart pressure by 6 months is the result of improved alveolar capillary density. Our findings indicate that children and infants with BPD may be at high risk for RVH, but that this resolves with age.Grant Funding Source: Supported by NIH 5R01HL115061

Doppler Echocardiography Inaccurately Estimates Right Ventricular Pressure in Children with Elevated Right Heart Pressure

Doppler echocardiography (DE) is widely used as a surrogate for right heart catheterization (RHC), the gold standard, to assess and monitor elevated right heart pressure in children. However, its accuracy has not been prospectively validated in children. The objectives of this study were to evaluate the accuracy of DE in predicting simultaneously measured right ventricular (RV) pressure by RHC in pediatric patients and to determine if the degree of RV hypertension affects the accuracy of DE in assessing right heart pressure. Eighty children (age range, 0-17.9 years; median age, 5.5 years) with two-ventricle physiology and a wide range of right heart pressures underwent simultaneous DE and RHC. The pressure gradient between the right ventricle and the right atrium was directly measured by RHC and simultaneously estimated by DE using tricuspid regurgitation. Patients were then grouped on the basis of RHC-measured RV systolic pressure (RVSP): group 1 (n= 43), with RVSP < 1/2 systemic systolic blood pressure (SBP); group 2 (n= 37), with RVSP ≥ 1/2 SBP; group 3 (n= 56), with RVSP < 2/3 SBP; and group 4 (n= 24), with RVSP ≥ 2/3 SBP. Correlation and Bland-Altman analyses were performed on all groups. Accuracy was predefined as 95% limits of agreement within ±10 mm Hg. Despite a reasonable correlation between DE and RHC in all groups, there was poor agreement between techniques as RVSP/SBP increased. DE was inaccurate in one of 43 patients in group 1 (2%) versus nine of 37 in group 2 (24%) and was inaccurate in one of 56 patients in group 3 (2%) versus eight of 24 in group 4 (33%). Overestimation and underestimation occurred equally in all groups. DE inaccurately estimates RV pressure in children with elevated right heart pressure. It should not be relied on as the sole method of assessing right heart hemodynamics in children with RV hypertension.

Indications for Pulmonary Valve Replacement in Repaired Tetralogy of Fallot

Until Blalock and Taussig developed the first palliative systemic-to-pulmonary shunt operation in 1945,1 tetralogy of Fallot (TOF) was a nearly uniformly lethal congenital cardiac anomaly. In the 5 decades since Lillehei and his colleagues at the University of Minnesota reported the first successful intracardiac repair in 1955,2 early mortality has decreased markedly from 50% to <2%.2–4 In the modern surgical era, most infants with TOF survive the initial surgical repair and reach adulthood. More recently, the excellent results in the pediatric age group have led the field to shift its attention to late sequelae of repaired TOF in the rapidly growing population of adult patients, including the increasing rates of morbidity and mortality. Article see p 1861 Despite many advances in surgical repair during the past 6 decades, the majority of TOF patients continue to experience residual hemodynamic and electrophysiological abnormalities.5,6 To effectively relieve the obstructed right ventricular outflow tract (RVOT), the surgeon must often disrupt the integrity of the pulmonary valve, which results in pulmonary regurgitation. The ensuing chronic right ventricular (RV) volume overload and akinesis or dyskinesis of the RVOT wall, along with conduction delay from the nearly universal right bundle-branch block, initiate a cascade of pathophysiological abnormalities that lead to RV dilatation and ultimately dysfunction.7 Left ventricular dysfunction, arrhythmias, exercise intolerance, heart failure symptoms, and death may follow.8 Residual intracardiac shunts, tricuspid regurgitation, RVOT or pulmonary artery stenosis, impaired diastolic properties, atrial enlargement, RV hypertension, intraventricular and interventricular dyssynchrony, and diffuse myocardial fibrosis are some of the factors that might accelerate the adverse cardiac remodeling and lead to worse clinical outcomes. Indeed, the adverse remodeling that leads to electromechanical cardiomyopathy manifests in increasing rates of morbidity and mortality beginning during the third decade of life.9 Pulmonary …

Transesophageal echocardiography and intraoperative phlebotomy during surgical repair of coarctation of aorta in a patient with atrial septal defect, moderately severe mitral regurgitation and severe pulmonary hypertension

Acute left ventricular (LV) or right ventricular (RV) dysfunction during repair of coarctation of aorta (CoA) is rare. Well-developed collateral circulation between branches of both the subclavian arteries (SCAs) and upper descending thoracic aorta decompress LV and prevents acute rise in afterload. An adult patient presented for CoA repair. On chest X-ray, rib notching was not seen. Magnetic Resonance Imaging showed about 7 mm long CoA distal to the origin of left common carotid artery. Reconstruction images of distal arch and descending thoracic aorta showed origin of both the SCAs from CoA segment. Transthoracic echocardiography showed 1.3 cm atrial septal defect (ASD), left to right shunt, moderately severe mitral regurgitation (MR), dilated RV, and severe pulmonary artery hypertension (PH). During cardiac catheterization, the peak gradient across CoA was 60 mmHg. On aortic-root angiography, both the common carotids and the distal arch opacified simultaneously, the CoA segment and the distal aorta opacified a little later. Both the SCAs were filling retrograde. A unique anatomy in which aortic-clamping proximal to CoA and both the SCAs would increase flow to spinal-cord as clamping of the SCAs will stop stealing of blood into the CoA but potentially increase LV afterload, MR, left to right shunt across ASD and RV volume and pressure load depending on the magnitude of flow across the CoA. The increases in LV afterload, MR, and RV afterload and volume overload were managed by controlled phlebotomy and fine-tuned by manipulating inhaled isoflurane concentration whereas the Transesophageal echocardiography (TEE) monitored and guided the management.

Arrhythmogenic substrate in hearts of rats with monocrotaline-induced pulmonary hypertension and right ventricular hypertrophy

Mechanisms associated with right ventricular (RV) hypertension and arrhythmias are less understood than those in the left ventricle (LV). The aim of our study was to investigate whether and by what mechanisms a proarrhythmic substrate exists in a rat model of RV hypertension and hypertrophy. Rats were injected with monocrotaline (MCT; 60 mg/kg) to induce pulmonary artery hypertension or with saline (CON). Myocardial levels of mRNA for genes expressing ion channels were measured by real-time RT-PCR. Monophasic action potential duration (MAPD) was recorded in isolated Langendorff-perfused hearts. MAPD restitution was measured, and arrhythmias were induced by burst stimulation. Twenty-two to twenty-six days after treatment, MCT animals had RV hypertension, hypertrophy, and decreased ejection fractions compared with CON. A greater proportion of MCT hearts developed sustained ventricular tachycardias/fibrillation (0.83 MCT vs. 0.14 CON). MAPD was prolonged in RV and less so in the LV of MCT hearts. There were decreased levels of mRNA for K(+) channels. Restitution curves of MCT RV were steeper than CON RV or either LV. Dispersion of MAPD was greater in MCT hearts and was dependent on stimulation frequency. Computer simulations based on ion channel gene expression closely predicted experimental changes in MAPD and restitution. We have identified a proarrhythmic substrate in the hearts of MCT-treated rats. We conclude that steeper RV electrical restitution and rate-dependant RV-LV action potential duration dispersion may be contributing mechanisms and be implicated in the generation of arrhythmias associated with in RV hypertension and hypertrophy.

Catecholamine-Induced Cardiomyopathy and Pheochromocytoma

A previously asymptomatic 37-yr-old man presented to the hospital with acute hypertension of 220/120 mm Hg and unstable ventricular tachycardia requiring cardioversion. A transthoracic echocardiogram (TTE) 1 yr earlier had shown mitral valve prolapse with moderate mitral regurgitation (MR), normal left ventricular (LV) size and function and mild right ventricular (RV) dilation. His TTE after admission revealed dilated, hypokinetic RV with mild tricuspid regurgitation and flattening of the interventricular septum (IVS) (Video Clip 1; please see video clip available at www.anesthesia-analgesia.org). The estimated LV ejection fraction (EF) was 55% with moderate MR. The rest of the TTE was unremarkable. Further workup revealed elevated urine catecholamine levels and a 5 6 cm right adrenal mass. The patient was started on phenoxybenzamine and labetalol and was scheduled for adrenalectomy. A repeat, preoperative TTE 1 wk after admission demonstrated a deteriorated LVEF of 30% and an otherwise unchanged examination. Consequently, the diagnosis of pheochromocytoma and catecholamine-induced cardiomyopathy was made. A biventricular assist device was on standby in anticipation of intraoperative cardiac deterioration. Intraoperative transesophageal echocardiography (TEE) demonstrated a massively dilated and severely hypokinetic RV distorting the normal cardiac anatomy. Systolic and diastolic IVS flattening was present (Fig. 1, Video Clip 2; please see video clip available at www.anesthesia-analgesia.org). The right atrium was enlarged and tricuspid regurgitation remained mild. The LV was also significantly dilated with an estimated EF of 25%–30% (Video 1). The mitral valve annulus was widened at 5.1 cm. Mitral valve prolapse with severe, eccentric MR (vena contracta width 1 cm) was visualized (Video Clip 3; please see video clip available at www.anesthesiaanalgesia.org). The intraoperative anesthetic management was based on the stage of surgery, hemodynamic changes and TEE findings. His measured pulmonary artery pressures were mildly elevated with episodic increases to 80/40 mm Hg. The cardiac index was 2.6 L/m and the systemic vascular resistance was 1500 dynes s cm . Sodium nitroprusside, esmolol, and phentolamine were titrated to effect for intermittent hypertension of up to 240/130 mm Hg. Severe hypotension to 60/30mm Hg (cardiac index 3.2 L/m, systemic vascular resistance 500 dynes s cm ) followed adrenalectomy requiring treatment with epinephrine, norepinephrine, arginine vasopressin, and volume expansion. His arterial blood pressure slowly improved to 90/60 mm Hg. The estimated LVEF improved to 35% and ventricular assist device placement was deemed unnecessary. The patient had an uncomplicated postoperative course. TTE 1 mo later showed normalization of LV size and function. The mitral valve annulus was less dilated (4.2 cm) and the MR was moderate (vena contracta width of 0.55 cm). RV function improved slightly with less dilation and minimal IVS flattening (Video 1). This article has supplementary material on the Web site: www.anesthesia-analgesia.org.

Moderate Pulmonary Arterial Hypertension in Male Mice Lacking the Vasoactive Intestinal Peptide Gene

Vasoactive intestinal peptide (VIP), a pulmonary vasodilator and inhibitor of vascular smooth muscle proliferation, has been reported absent in pulmonary arteries from patients with idiopathic pulmonary arterial hypertension (PAH). We have tested the hypothesis that targeted deletion of the VIP gene may lead to PAH with pulmonary vascular remodeling. We examined VIP knockout (VIP-/-) mice for evidence of PAH, right ventricular (RV) hypertrophy, and pulmonary vascular remodeling. Relative to wild-type control mice, VIP-/- mice showed moderate RV hypertension, RV hypertrophy confirmed by increased ratio of RV to left ventricle plus septum weight, and enlarged, thickened pulmonary artery and smaller branches with increased muscularization and narrowed lumen. Lung sections also showed perivascular inflammatory cell infiltrates. No systemic hypertension and no arterial hypoxemia existed to explain the PAH. The condition was associated with increased mortality. Both the vascular remodeling and RV remodeling were attenuated after a 4-week treatment with VIP. Deletion of the VIP gene leads to spontaneous expression of moderately severe PAH in mice during air breathing. Although not an exact model of idiopathic PAH, the VIP-/- mouse should be useful for studying molecular mechanisms of PAH and evaluating potential therapeutic agents. VIP replacement therapy holds promise for the treatment of PAH, and mutations of the VIP gene may be a factor in the pathogenesis of idiopathic PAH.

LONG-TERM BIVENTRICULAR SUPPORT WITH AN AXIAL FLOW PUMP IN A CALF MODEL

Purpose: The continuous-flow Jarvik FlowMaker is used clinically for treating left ventricular (LV) failure. Because simultaneous right ventricular (RV) support sometimes is also necessary, we developed a method for biventricular support and assessed its long-term feasibility in a calf model. Methods: One FlowMaker was implanted in the LV with the outflow graft anastomosed to the descending aorta. The other was implanted in the RV, via the tricuspid valve, affixed to the right atrial appendage with the outflow graft anastomosed to the pulmonary artery (PA) trunk. Hemodynamics were recorded for 30 days. On day 30, before sacrifice, both pumps were operated at varying speeds, the PA was gradually occluded distal and proximal to the anastomotic site, and dual pump efficacy was assessed at various degrees of pulmonary vascular resistance, RV hypertension, global heart failure, and ventricular fibrillation (VF). Results: Hemodynamics remained stable during the 30-day chronic study and no major adverse events occured. During all acute physiologic manipulations, before sacrifice, the cardiac output ranged from 3 to 11 L/min, LVEDP from 11 to 24 mmHg, and CVP from 9 to 25 mmHg. Necropsy was non-remarkable. Conclusion: The dual technique offered stable satisfactory biventricular assistance for 30 days and during the acute hemodynamic manipulations. Additional studies will assess the effects of pulseless perfusion on the pulmonary circulation and develop a single pump-speed controller to coordinate simultaneous dual pump operation.

Cell-based gene transfer of vascular endothelial growth factor attenuates monocrotaline-induced pulmonary hypertension.

Pulmonary arterial hypertension is characterized by increased pulmonary vascular resistance secondary to a decrease in the caliber and number of pulmonary vascular channels. We hypothesized that the targeted overexpression of an angiogenic factor within the lung would potentially minimize the development and progression of pulmonary arterial hypertension by preventing the loss of existing vessels or by inducing the development of new blood vessels within the lung. We used a cell-based method of gene transfer to the pulmonary microvasculature by delivering syngeneic smooth muscle cells overexpressing vascular endothelial growth factor (VEGF)-A to inbred Fisher 344 rats in which pulmonary hypertension was induced with the pulmonary endothelial toxin monocrotaline. Four weeks after simultaneous endothelial injury and cell-based gene transfer, right ventricular (RV) hypertension and RV and vascular hypertrophy were significantly decreased in the VEGF-treated animals. Four weeks after gene transfer, the plasmid VEGF transcript was still detectable in the pulmonary tissue of animals injected with VEGF-transfected cells, demonstrating survival of the transfected cells and persistent transgene expression. In addition, delay of cell-based gene transfer until after the development of pulmonary hypertension also resulted in a significant decrease in the progression of RV hypertension and hypertrophy. These results indicate that cell-based VEGF gene transfer is an effective method of preventing the development and progression of pulmonary hypertension in the monocrotaline model and suggest a potential therapeutic role for angiogenic factors in the therapy of this devastating disease.

Isolated Peripheral Pulmonary Artery Stenoses in the Adult

Isolated peripheral pulmonary artery stenosis (PPS) in the adult is rare and frequently unsuspected. We review in this article our experience with 12 adult patients with isolated PPS, half of whom had been previously diagnosed with chronic pulmonary thromboembolic disease. The presentation, evolution, and management of 12 adults with isolated PPS, 17 to 51 years of age (mean, 36.2 +/- 9.7 years), were evaluated. Presenting symptoms were dyspnea and fatigue. Three patients had New York Heart Association (NYHA) functional class III or greater. Lung perfusion scans revealed multiple segmental abnormalities in flow distribution in all patients. Oxygen desaturation at rest was present in 4 patients. At catheterization, right ventricular (RV) pressure was suprasystemic in 2 patients, systemic in 1, and more than half-systemic in 7. All had multiple bilateral non-uniform stenoses in segmental and subsegmental arteries. Balloon pulmonary angioplasty (BPA) to decrease RV hypertension and improve pulmonary flow distribution was performed in 11 patients. After BPA, vessel diameter increased > 50% in 10 patients, distal pulmonary artery pressure increased > or = 30% in 6, and RV pressure decreased > 30% in 5. One patient died shortly after BPA as a result of pulmonary hemorrhage. Immediate procedural success was achieved in 9 of 11 patients. At a mean follow-up period of 52 +/- 32 months, 7 patients had sustained symptomatic improvement (NYHA class I-II). We describe a severe syndrome of isolated PPS in the adult that mimics chronic pulmonary thromboembolic disease. Pulmonary hemodynamics and angiography are required for definitive diagnosis. BPA may offer these patients successful short-term reduction in RV hypertension and alleviation of symptomatology.

Effects of aortic constriction during experimental acute right ventricular pressure loading. Further insights into diastolic and systolic ventricular interaction.

Acute right ventricular (RV) hypertension may result in hemodynamic collapse. The associated reduction in left ventricular (LV) end-diastolic volume is thought to result from reduced RV output (secondary to RV ischemia) and adverse direct ventricular interaction. Aortic constriction improves cardiac function in these circumstances; this has been attributed to a reversal of the RV ischemia caused by an increased coronary perfusion pressure. We hypothesized that altered ventricular interaction, potentially via altered septal mechanics, may also contribute to the beneficial effects of aortic constriction. We instrumented nine dogs with ultrasonic dimension crystals to measure RV segment length, septum-to-RV free wall and septum-to-LV free wall diameters, and LV anterioposterior diameter. Catheter-tipped manometers were used to measure LV and RV pressures. Pericardial pressure was measured with flat, liquid-containing balloon transducers. Inflatable cuff constrictors were placed on the pulmonary artery (PA) and aorta, and a flow probe was placed on the PA. The right coronary artery (RCA) was perfused independently by a roller pump calibrated for flow. During moderate PA constriction, while RCA pressure was maintained at control level, RCA flow did not change significantly (15.8 +/- 6.2 to 16.9 +/- 11.5 mL/min) and was similar during severe PA constriction (18.6 +/- 9.8 mL/min). During severe PA constriction, RV stroke volume decreased from a control value of 10.3 +/- 4.9 to 2.3 +/- 1.4 mL/beat (P < .05). When aortic constriction was added while RCA pressure was maintained at control level, there was an increase in RV stroke volume to 4.5 +/- 2.0 mL/beat (P < .05) with no associated change in RCA flow (17.8 +/- 9.5 mL/min). However, pressure-dimension loops clearly demonstrated changes in diastolic and systolic ventricular interaction; with aortic constriction, there was a large increase in the transeptal pressure gradient associated with a rightward septal shift. During either isolated severe PA constriction or simultaneous severe PA and aortic constriction, RCA flow was increased until RCA pressure was approximately equal to that in the aorta. This produced an increase in RCA flow of 50% (P < .05); however, this increase in coronary flow was ineffective in improving any measure of RV function. In this model of acute RV hypertension, aortic constriction improves cardiac function, at least in part, by altering ventricular interaction independent of changes in RCA flow. Changes in RCA flow do not appear to have a significant impact on cardiac function in this model in which coronary artery pressure was maintained at normal or increased levels.

Maximal vascular conductance in right ventricular myocardial circulation.

With acutely increasing right ventricular (RV) hypertension, failure eventually occurs because of RV ischemia. This study examines the effects of RV hypertension on the diastolic right coronary circulation. Conscious dogs instrumented to measure right coronary artery pressure and blood flow were studied after maximal coronary vasodilation with chromonar. Diastolic coronary pressure-flow relations, described by slope (conductance) and zero-flow, pressure axis intercept (Pf = 0), were generated before and during RV hypertension. Diastolic Pf = 0 increased from 11.8 +/- 6.5 to 17.1 +/- 7.1 (means +/- SD, P < 0.01) Torr, with no change in conductance. During RV hypertension, RV diastolic pressure increased. To examine possible mechanisms for the increase in Pf = 0, pressure-flow relations were generated before and after volume loading, without systolic hypertension. Diastolic Pf = 0 increased from 15.5 +/- 3.1 to 20.8 +/- 4.1 Torr, suggesting that changes in Pf = 0 with RV hypertension were mediated by increased filling pressures. Pressure flow relations were derived from mean right coronary flow and RV driving pressure before and during RV hypertension. Under these conditions, Pf = 0 is close to zero; the use of RV driving pressure provides a method for calculating maximal right coronary conductance.

The Effect of an Increase in Systemic Arterial Pressure in the Newborn with Right Ventricular Hypertension

To evaluate the effect of an elevation in systemic arterial pressure upon pulmonary blood flow and arterial oxygenation during right ventricular hypertension (RVH), we acutely studied 13 1-d-old piglets. Catheters were positioned in the pulmonary artery, both atria, and the aorta for hemodynamic measurements. An electromagnetic probe was positioned in the main pulmonary artery for pulmonary blood flow measurement. Systemic and regional blood flow were measured with the radiolabeled microsphere technique. A balloon-mounted catheter was advanced in the aorta and maintained at the lower thoracic level. After induction of RVH (pulmonary artery banding), a significant decrease in arterial O2 pressure from 54.4 +/- 1.6 to 10.6 +/- 0.4 kPa (p less than 0.01), a 30% reduction in systemic arterial pressure, and a 44% decrease in pulmonary blood flow were observed. During RVH, partial inflation of the aortic balloon to restore the systemic arterial pressure to its initial value led to an increase in arterial O2 pressure to 23.5 +/- 3.1 kPa (p less than 0.01). Full inflation of the balloon further increased the arterial O2 pressure to 32.6 +/- 2.9 kPa (p less than 0.01). Aortic balloon inflation increased pulmonary blood flow in 11 and systemic O2 delivery in nine of the 13 animals. RVH was associated with a significant increase in cerebral and right ventricular myocardial free-wall blood flow and a decrease in renal and bowel blood flow and O2 delivery (p less than 0.01). Aortic balloon inflation during RVH did not change either the cerebral or myocardial free-wall blood flow, but further significantly decreased renal and bowel blood flow and O2 delivery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adverse effects of halothane in a canine model of acute right ventricular hypertension.

The effects of acute right ventricular (RV) hypertension (RVH) induced by pulmonary artery (PA) constriction, and of two concentrations (mean inspired 0.8 and 1.5%) of halothane (HAL) during RVH on global and regional RV performance (ultrasonic dimension technique), and on coronary hemodynamics (electromagnetic flow probes) were studied in 12 open-chest dogs anesthetized and paralyzed by continuous infusions of fentanyl and pancuronium. Following PA constriction, RV systolic pressure more than doubled, RV end-diastolic and systolic dimensions increased, and stroke volume (SV) and segment shortening fell (P all less than 0.05). There was no evidence of regional myocardial dysfunction (i.e., akinesis, systolic lengthening, postsystolic shortening), and reactive hyperemia in response to right coronary artery occlusion was present. Subsequent addition of HAL (0.8%) resulted in further increases in end-diastolic and systolic dimensions, and in marked decreases in right coronary blood flow, segment shortening, SV, and aortic pressure. During HAL 1.5% (range: 1.2-1.6%), regional myocardial dysfunction developed in three animals, reactive hyperemia was abolished in five out of six animals tested, and metabolic acidosis developed. Release of PA constriction during 1.5% HAL in seven animals resulted in improved global and regional RV performance, disappearance of regional myocardial dysfunction, and restoration of reactive hyperemia. In this canine model of acute RVH, increasing concentrations of HAL led to increasing deterioration in global and regional RV performance most likely due to inadequate coronary perfusion.