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1.  Factors influencing the echocardiographic estimate of right ventricular systolic pressure in normal patients and clinically relevant ranges according to age 
Previous studies have shown that in the absence of underlying cardiac pathology, the echocardiographic estimate of right ventricular systolic pressure (RVSP) increases progressively and normally with age. There are limited data in patients older than 60 years of age.
To define the ranges of RVSP according to age and to include more elderly patients than have previously been reported.
All patients undergoing echocardiography since May 26, 1999, at the Kingston Heart Clinic (Kingston, Ontario) have had their data entered into a locally designed cardiology database (CARDIOfile; Registered trademark, Kingston Heart Clinic). RVSP was calculated from the peak tricuspid regurgitant jet velocity (V) using the modified Bernoulli equation (RVSP = 4V2 + RAP), with the mean right atrial pressure (RAP) estimated to be 10 mmHg. Of the 22,628 patients who had undergone echocardiography, 10,905 had RVSP measured. All abnormal echocardiograms were excluded, leaving 1559 echocardiograms for analysis.
Patient age ranged from 15 to 93 years. The mean age was 49 years. RVSP increased significantly only after the age of 50 years. The mean (± SD) RVSP for those younger than 50 years, 50 to 75 years, and older than 75 years of age was 27.3±5.7 mmHg, 30.2±7.6 mmHg and 34.8±8.7 mmHg, respectively (P<0.0001 among all age groups). The normal range (95% CI) of RVSP in those younger than 50 years, 50 to 75 years, and older than 75 years of age was 16 mmHg to 39 mmHg, 15 mmHg to 45 mmHg, and 17 mmHg to 52 mmHg, respectively. Multivariate analysis indicated that age, mitral diastolic early-to-late filling velocity ratio, ejection fraction, aortic size and early mitral filling velocity/early diastolic mitral annular velocity were the only significant independent variables. There were significant changes in diastolic function with increasing age, which may have been responsible for the changes in RVSP.
RVSP remains stable in both men and women until the age of 50 years. Thereafter, RVSP increases progressively in a linear manner with age and is significantly higher in patients older than 75 years of age. The changes may relate to changes in diastolic function. These ranges should be taken into account when using echocardiogram-derived RVSP for the diagnosis of pulmonary hypertension in the absence of cardiovascular disease.
PMCID: PMC2851398  PMID: 20151056
Echocardiography; Pulmonary hypertension
2.  Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD) 
Pulmonary hypertension (PH) is a complication of chronic obstructive pulmonary disease (COPD). This study examined genetic variations in mediators of vascular remodelling and their association with PH in patients with COPD. In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.
In patients with COPD, we genotyped 7 SNPs in 6 candidate PH genes (NOS3, ACE, EDN1, PTGIS, SLC6A4, VEGFA). We tested for association with right ventricular systolic pressure (RVSP), spirometry and gas transfer, and hypoxemia.
580 COPD patients were recruited, 341 patients had a transthoracic echocardiogram, with RVSP measurable in 278 patients (mean age 69 years, mean FEV1 50% predicted, mean RVSP 44 mmHg, median history of 50 pack-years). Of the 7 tested SNPs, the NOS3-VNTR polymorphism was significantly associated with RVSP in a dose-dependent fashion for the risk allele: mean RVSP for a/a and a/b genotypes were 52.0 and 46.6 mmHg respectively, compared to 43.2 mmHg for b/b genotypes (P = 0.032). No associations were found between RVSP and other polymorphisms. ACE II or ID genotypes were associated with a lower FEV1% predicted than the ACE DD genotype (P = 0.028). The NOS3-298 TT genotype was associated with lower KCO % predicted than the NOS3-298 GG or GT genotype (P = 0.031).
The NOS3-VNTR polymorphism was associated with RVSP in patients with COPD, supporting its involvement in the pathogenesis of PH in COPD. ACE and NOS3 genotypes were associated with COPD disease severity, but not with the presence of PH. Further study of these genes could lead to the development of prognostic and screening tools for PH in COPD.
PMCID: PMC3431274  PMID: 22695028
COPD; Pulmonary hypertension; Genetic polymorphism
3.  Reactivity of pulmonary circulation and right ventricle function to inhaled nitric oxide in systemic sclerosis patients 
Clinical Rheumatology  2011;31(1):99-104.
Systemic sclerosis (SSc) is complicated by pulmonary hypertension and right ventricle (RV) failure in approximately 10% of the patients. Factors influencing the reactivity of pulmonary circulation to vasodilators are not established, while the examination of vasoreactivity is important in determining the treatment, because systemic administration of oral vasodilators can induce severe adverse events in nonresponders. The mechanism of RV failure in SSc is unclear and may result either from increased RV afterload or intrinsic myocardial disease. The aim of the study was to assess the reactivity of pulmonary circulation to inhaled nitric oxide (iNO) and to evaluate its influence on RV function in SSc patients with elevated right ventricle systolic pressure (RVSP). In 60 SSc patients aged 24–73 (58 females, two males; 33 patients with limited SSc and 27 with diffuse SSc), echocardiographic examination with tissue Doppler echocardiography (TDE) was performed. RV function was measured by systolic (S) and early diastolic (E) velocity of tricuspid annulus by TDE. In patients with RVSP >45 mmHg, the reactivity of pulmonary circulation was assessed by iNO test. High-resolution computerized tomography (HRCT) was performed to assess the extent of pulmonary fibrosis. Of 14 SSc subjects with elevated RVSP (13 females, one male; RVSP 47–62 mmHg), positive reaction to iNO was observed in five (RVSP decreased from 51.6 ± 3.7 to 32.24 ± 2.3 mmHg); nine patients were not reactive (RVSP 53.5 ± 5.7 mmHg before iNO vs. 49.6 ± 6.7 mmHg). RV systolic function was decreased in patients with elevated RVSP as compared to the patients with normal pulmonary pressure (S velocity 13.2 ± 1.3 vs. 14.4 ± 1.6 cm/s, respectively, p < 0.05). Significant increase of RV systolic function during iNO test was found in reactive patients only (S velocity before iNO 12.8 ± 1.2 cm/s, during iNO 14.5 ± 1.5 cm/s, p < 0.01). RVSP decrease strongly correlated with S velocity increase (r = 0.95, p < 0.0001). Response to iNO was found only in limited form of SSc; diffuse SSc patients showed no response. Pulmonary fibrosis on HRCT was more frequent in subjects nonreactive to iNO (67% of patients) than in the reactive group (40% of patients). The reactivity of pulmonary circulation to iNO in SSc patients with elevated RVSP was found predominantly in limited form of the disease. Pulmonary fibrosis typical for diffuse SSc was more frequent in nonreactive subjects. Elevated pulmonary pressure plays an important role in RV systolic dysfunction. Pulmonary pressure decrease during iNO test leads to the improvement of RV systolic function. Therapy for right-heart failure in reactive SSc patients should be directed, if possible, at the decrease in pulmonary resistance.
PMCID: PMC3249214  PMID: 21670950
Heart failure; Pulmonary circulation; Right ventricle; Systemic sclerosis
4.  Latent pulmonary hypertension in atrial septal defect: Dynamic stress echocardiography reveals unapparent pulmonary hypertension and confirms rapid normalisation after ASD closure 
Netherlands Heart Journal  2013;21(7-8):333-343.
Closure of atrial septal defects (ASD) prevents pulmonary hypertension, right heart failure and thromboembolic stroke. The exact timing for ASD closure is controversial.
In a prospective study to address the question whether unapparent pulmonary hypertension can be revealed prior to right ventricular (RV) remodelling, patients were investigated before and 6, 12, and 24 months after ASD closure using exercise stress echocardiography (ESE) and ergospirometry (n = 24).
At rest, RV systolic pressure (RVSP) was normal in 58.8 %, slightly elevated in 26.5 %, and moderately elevated in 11.8 %. One patient showed severe pulmonary hypertension. During ESE, all patients with normal RVSP at rest exhibited an increase (25.7 ± 1.2 mmHg vs. 45.3 ± 2.3 mmHg, p < 0.001). After closure the RVSP was lower, both at rest and ESE. RV diameters decreased too. Tricuspid annulus plane systolic excursion (TAPSE) at rest remained lower after closure (24.0 ± 0.9 vs. 22.0 ± 0.9 mm, p < 0.05). TAPSE in ESE was elevated, and stayed stable after closure (30.1 ± 1.8 mm vs. 29.3 ± 1.6 mm). Before closure, RV systolic tissue velocities (sa) at rest were normal and decreased after closure (14.0 ± 1.0 cm/s vs. 11.5 ± 0.7 (6 month) vs. 10.6 ± 0.5 cm/s (12 month), p < 0.05). During ESE, sa velocity was similar before and after closure (23.0 ± 1.3 cm/s vs. 23.3 ± 1.9 cm/s). Maximal oxygen uptake (VO2/kg) did not differ between baseline and follow-ups.
Latent pulmonary hypertension may become apparent in ESE. ASD closure leads to a significant reduction in this stress-induced pulmonary hypertension and to a decrease in the right heart diameters indicating reverse RV remodelling. RV functional parameters at rest did not improve. The VO2/kg did not change after ASD closure.
PMCID: PMC3722387  PMID: 23640576
Pulmonary hypertension; ASD closure; Exercise stress echocardiography; Ergospirometry
5.  Changes in Estimated Right Ventricular Systolic Pressure Predict Mortality and Pulmonary Hypertension in a Cohort of Scleroderma Patients 
Annals of the rheumatic diseases  2012;72(7):10.1136/annrheumdis-2012-201861.
Annual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. Accordingly, we evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients.
The study population consisted of scleroderma patients who had at least 3 echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality, and change in RVSP/year, adjusted for relevant covariates.
613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05,1.11) and 1.12 (95% CI 1.08,1.15) per 1mmHg increase in RVSP/year, respectively. Compared to patients with a stable RVSP, the relative hazards for development of PAH was 1.90 (95% CI 0.91,3.96), 5.09 (95% CI 2.53,10.26) and 6.15 (95% CI 3.58,10.56) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+mmHg/year. Compared to the same reference group, the relative hazards for death was 0.92 (95% CI 0.48,1.73), 2.16 (95% CI 1.16,4.01), and 5.05 (95% CI 3.47,7.34) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99, and 3+mmHg/year.
In a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.
PMCID: PMC3839570  PMID: 22887850
Systemic Sclerosis; Pulmonary Hypertension; Echocardiography
6.  Electrocardiography Patterns and the Role of the Electrocardiography Score for Risk Stratification in Acute Pulmonary Embolism 
Korean Circulation Journal  2010;40(10):499-506.
Background and Objectives
Data on the usefulness of a combination of different electrocardiography (ECG) abnormalities in risk stratification of patients with acute pulmonary embolism (PE) are limited. We thus investigated 12-lead ECG patterns in acute PE to evaluate the role of the ECG score in risk stratification of patients with acute PE.
Subjects and Methods
One hundred twenty-five consecutive patients (63±14 years, 56 men) with acute PE who were admitted to Kyungpook National University Hospital between November 2001 and January 2008 were included. We analyzed ECG patterns and calculated the ECG score in all patients. We evaluated right ventricular systolic pressure (RVSP) (n=75) and RV hypokinesia (n=80) using echocardiography for risk stratification of acute PE patients.
Among several ECG findings, sinus tachycardia and inverted T waves in V1-4 (39%) were observed most frequently. The mean ECG score and RVSP were 7.36±6.32 and 49±21 mmHg, respectively. The ECG score correlated with RVSP (r=0.277, p=0.016). The patients were divided into two groups {high ECG-score group (n=38): ECG score >12 and low ECG-score group (n=87): ECG score ≤12} based on the ECG score, with the maximum area under the curve. RV hypokinesia was observed more frequently in the high ECG-score group than in the low ECG-score group (p=0.006). Multivariate analysis revealed that a high ECG score was an independent predictor of high RVSP and RV hypokinesia.
Sinus tachycardia and inverted T waves in V1-4 were commonly observed in acute PE. Moreover, the ECG score is a useful tool in risk stratification of patients with acute PE.
PMCID: PMC2978292  PMID: 21088753
Pulmonary embolism; Electrocardiography; Right ventricle; Systolic pressure
7.  Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in idiopathic pulmonary fibrosis 
Respiratory medicine  2008;102(9):1305-1310.
Pulmonary hypertension (PH) commonly complicates the course of patients with idiopathic pulmonary fibrosis (IPF). It has a significant impact on outcomes and is, therefore, important to detect.
We sought to characterize the accuracy and performance characteristics of the right ventricular systolic pressure (RVSP) as estimated by echocardiography (ECHO) alone and in conjunction with physiologic indices in predicting the presence of PH in IPF patients.
Cross-sectional study of IPF patients from two large tertiary centers in whom both ECHO and right-heart catheterization (RHC) were available.
Measurements and main results
There were 110 patients with available ECHOs and RHCs. Estimates of RVSP were reported in 60 of these patients (54.5%) of whom 22 (36.6%) had PH, while 16 of the 50 patients without RVSP estimate (32%) had PH. Twenty-four of 60 (40%) ECHOs accurately reflected the pulmonary arterial systolic pressure as measured by RHC. An optimal RVSP threshold for the screening of PH could not be detected. When assessed in combination with various thresholds of PFT and 6-minute walk test (6MWT) parameters, the performance characteristics of the RVSP were slightly improved.
The RVSP is not an accurate test for the assessment of PH in IPF patients. Awareness of the various combinations of threshold values for RVSP with and without PFT and 6MWT might nonetheless assist clinicians in risk stratifying IPF patients for the presence of PH.
PMCID: PMC2649722  PMID: 18619825
Hypertension; Pulmonary; Oximetry; Pulmonary fibrosis; Pulmonary function tests; Pressure; Pulmonary artery
8.  Non-invasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension 
Genetically-modified mice offer the unique opportunity to gain insights into the pathophysiology of pulmonary arterial hypertension (PAH). In mice, right heart catheterization is the only available technique to measure right ventricular systolic pressure (RVSP). However, it is a terminal procedure and does not allow for serial measurements. Our objective was to validate a non-invasive technique to assess RVSP in mice.
Methods and Results
Right ventricle catheterization and echocardiography (30-MHz transducer) were simultaneously performed in mice with pulmonary hypertension induced acutely by infusion of a thromboxane analogue, U-46619, or chronically by lung-specific over-expression of interleukin 6 (IL-6). Pulmonary acceleration time (PAT) and ejection time (ET) were measured in the parasternal short axis view by pulsed-wave Doppler of pulmonary artery flow. Infusion of U-46619 acutely increased RVSP, shortened PAT, and decreased PAT/ET. The pulmonary flow pattern changed from symmetric at baseline to asymmetric at higher RVSPs. In wild-type and IL-6-over-expressing mice, the PAT correlated linearly with RVSP (r2=−0.67; p<0.0001), as did PAT/ET (r2=−0.76; p<0.0001). Sensitivity and specificity for detecting high RVSP (>32 mmHg) were 100% (7/7) and 86% (6/7), respectively, for both indices (cutoff values: PAT <21 ms and PAT/ET <39%). Intra-observer and inter-observer variability of PAT and PAT/ET were less than 6%.
Right ventricular systolic pressure can be estimated non-invasively in mice. Echocardiography is able to detect acute and chronic increases in RVSP with high sensitivity and specificity, as well as to assess the effects of treatment on RVSP. This non-invasive technique may permit the characterization of the evolution of PAH in genetically-modified mice.
PMCID: PMC3075498  PMID: 20044514
Echocardiography; right ventricular systolic pressure; mice
9.  Immediate- and medium-term effects of balloon pulmonary valvuloplasty in infants with critical pulmonary stenoses during the first year of life: A prospective single center study☆ 
Balloon pulmonary valvuloplasty (BPV) represents the standard of management for all patients with severe pulmonary stenosis (PS) irrespective of their age. Nevertheless neonates and infants with critical PS represent a high-risk group that needs to be studied.
The study population included 72 infants with severe congenital valvular PS and four infants with imperforate pulmonary valve (PV) who were subjected to detailed history taking, full clinical examination, resting 12-lead ECG, Chest roentgenogram and transthoracic echocardiography. BPV was attempted in all infants with a peak-to-peak gradient across the PV of 50 mmHg or greater at catheterization-laboratory. Full echocardiographic evaluation was done 24 hours after the procedure as well as 3 and 6 months later.
Seventy-six infants with severe PS or imperforate PV with a mean age of 5.63 ± 2.99 months were subjected to BPV with or without wire perforation. Immediately after the procedure patients had a significant reduction of the right ventricular systolic pressure (RVSP) (104.69 ± 24.98 mm Hg Vs 43.6 ± 13 mm Hg, p < 0.001) and RV-PA systolic pressure gradient (PG) (82.5 ± 23.76 mm Hg Vs 17.35 ± 8.96 mm Hg, p < 0.001). The immediate success rate defined as the drop in the RVSP to less than or equal to 50% of the baseline measurement was achieved in 85% of the cases. There was a progressive drop in the PG across the PV by Doppler echocardiogram throughout a follow-up period of six months from a mean of 93.3 ± 28.2 mm Hg to a mean of 17.4 ± 10.42 mm Hg (p < 0.001). There was a significant increase of the mean PV annulus diameter after balloon dilatation (p < 0.001). There was also a highly significant inverse correlation between the growth of the pulmonary annulus and the annular size at the baseline before dilatation (r = −0.74, p value <0.001). The incidence of PR significantly increased immediately after BPV to 64% followed by a progressive decline over a 6 months period of follow-up to 20%. There was a significant decrease in the incidence of tricuspid regurgitation (TR) over the same period of follow-up (from 55.6% at baseline to less than 20% at follow-up).
BPV is safe and effective to relieve critical PS in infants during the first year of life. The balloon promotes advantageous changes in both, pulmonary annulus and PG across the RVOT. In addition, the Doppler gradient observations during the follow-up support the expectation that BPV is a “curative” therapy.
PMCID: PMC3727503  PMID: 23960620
Balloon pulmonary valvuloplasty; Infants; Critical pulmonary stenosis; ASD, atrial septal defect; BPV, balloon pulmonary valvuloplasty; BSA, body surface area; ECG, electrocardiogram; PADP, pulmonary artery diastolic pressure; PASP, pulmonary artery systolic pressure; PDA, patent ductus arteriosus; PFO, patent foramen ovale; PG, pressure gradient; PR, pulmonary regurgitation; PS, pulmonary stenosis; PV, pulmonary valve; RV, right ventricle; RVDP, right ventricular diastolic pressure; RVOT, right ventricular outflow tract; RVSP, right ventricular systolic pressure; TR, tricuspid regurgitation; TTE, transthoracic echocardiography; VSD, ventricualr septal defect
10.  Iron deposition and increased alveolar septal capillary density in nonfibrotic lung tissue are associated with pulmonary hypertension in idiopathic pulmonary fibrosis 
Respiratory Research  2010;11(1):37.
Early diagnosis of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) has potential prognostic and therapeutic implications but can be difficult due to the lack of specific clinical manifestations or accurate non-invasive tests. Histopathologic parameters correlating with PH in IPF are also not known. Remodeling of postcapillary pulmonary vessels has been reported in the nonfibrotic areas of explanted lungs from IPF patients. We hypothesized that iron deposition and increased alveolar capillaries, the findings often seen in postcapillary PH, might predict the presence of clinical PH, independent of the severity of fibrosis or ventilatory dysfunction in IPF patients. To test this hypothesis, we examined the association between these histologic parameters and the degree of PH, with consideration of the severity of disease in IPF.
Iron deposition and alveolar septal capillary density (ASCD) were evaluated on histologic sections with hematoxylin-eosin, iron, elastin and CD34 stainings. Percentage of predicted forced vital capacity (FVC%) was used for grading pulmonary function status. Fibrosis score assessed on high resolution computed tomography (HRCT) was used for evaluating overall degree of fibrosis in whole lungs. Right ventricular systolic pressure (RVSP) by transthoracic echocardiography was used for the estimation of PH. Univariate and multivariate regression analyses were performed.
A cohort of 154 patients was studied who had the clinicopathological diagnosis of IPF with surgical lung biopsies or explants during the period of 1997 to 2006 at Mayo Clinic Rochester. In univariate analysis, RVSP in our IPF cases was associated with both iron deposition and ASCD (p < 0.001). In multivariate analysis with FVC% and HRCT fibrosis score included, iron deposition (p = 0.02), but not ASCD (p = 0.076), maintained statistically significant association with RVSP. FVC% was associated with RVSP on univariate analysis but not on multivariate analysis, while fibrosis score lacked any association with RVSP by either univariate or multivariate analyses.
Iron deposition and ASCD in non fibrotic lung tissue showed an association with RVSP, suggesting that these features are possible morphologic predictors of PH in IPF.
PMCID: PMC2867975  PMID: 20398288
11.  Combination of Echocardiographic and Pulmonary Function Test Parameters Improves Sensitivity for the Diagnosis of Systemic Sclerosis-Associated Pulmonary Arterial Hypertension- Analysis of Two Cohorts 
The Journal of rheumatology  2013;40(10):1706-1711.
To evaluate routinely collected non-invasive tests from two systemic sclerosis (SSc) cohorts to determine their predictive value alone and in combination vs. right heart catheterization (RHC)- confirmed pulmonary arterial hypertension (PAH).
We evaluated two cohorts of patients who were at risk or with incident PAH: (1) The Pulmonary Hypertension Assessment and Recognition Outcomes in Scleroderma (PHAROS) cohort and (2) an inception SSc cohort at Cochin Hospital. Estimated right ventricular systolic pressure (eRVSP) on echocardiogram (TTE) and and pulmonary function tests (PFT) parameters were evaluated and their predictive values determined. We then evaluated patients with PAH missed on TTE cutoffs that were subsequently identified by a PFT parameter.
In the PHAROS cohort (N=206), 59 (29%) had RHC-defined PAH. An eRVSP threshold of 35–50mmHg failed to diagnose PAH in 7–31% of patients, 50–70% of which (N=2–13) were captured by PFT parameters. In the Cochin cohort (N=141), 10 (7%) patients had RHC confirmed PAH. An eRVSP threshold of 35–50mmHg missed 0–70% (N = 0–7) patients, of which 0–68% (N = 0–6) were captured by PFT parameters. The combination of TTE and PFT improved the negative predictive value for diagnosing PAH.
In 2 large SSc cohorts, screening with TTE and PFT captured majority of patients with PAH. TTE and PFT complement each other for the diagnosis of PAH.
PMCID: PMC3798032  PMID: 23950183
Echocardiogram; Pulmonary Function Tests; Screening; Diagnosis; Systemic Sclerosis; Pulmonary Hypertension; Pulmonary Arterial Hypertension
12.  Genetic ablation of the Bmpr2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension 
Circulation  2008;118(7):722-730.
Pulmonary arterial hypertension (PAH) is a rare but fatal lung disease of diverse etiologies. PAH is now further subclassified as idiopathic (IPAH), familial (FPAH) and associated (APAH) varieties. Heterozygous mutations in BMPR2 can be detected in 50-70% of patients with FPAH and 10-40% of patients with IPAH. Although endothelial cells have been suspected as the cellular origin of PAH pathogenesis, no direct in vivo evidence has been clearly presented. The present study was designed to investigate whether endothelial Bmpr2 deletion can predispose to PAH.
Methods and Results
The Bmpr2 gene was deleted in pulmonary endothelial cells (pECs) using Bmpr2 conditional knockout mice and a novel endothelial Cre transgenic mouse line. Wide ranges of right ventricular systolic pressure (RVSP) were observed in mice with heterozygous (21.7 - 44.1 mmHg, median: 23.7 mmHg) and homozygous (20.7- 56.3 mmHg, median: 27 mmHg) conditional deletion of Bmpr2 in pECs in comparison with control mice (19.9 - 26.7 mmHg, median: 23 mmHg) at two to seven months of age. A subset of mice with RVSP greater than 30 mmHg exhibited right ventricular hypertrophy and an increase in the number and wall thickness of muscularized distal pulmonary arteries. In the lungs of these high RVSP mice, expression of proteins involved in the pathogenesis of PAH, such as serotonin transporter and tenacin-C, were elevated in distal arteries, and had a high incidence of perivascular leukocyte infiltration and in situ thrombosis.
Conditional hetero or homozygous Bmpr2 deletion in pECs predisposes mice to develop PAH.
PMCID: PMC3920834  PMID: 18663089
endothelium; genetics; hypertension; pulmonary; BMP receptor; animal model
13.  Increased Susceptibility to Pulmonary Hypertension in Heterozygous BMPR2-Mutant Mice 
Circulation  2005;112(4):553-562.
Bone morphogenetic protein (BMP) receptor-II (BMPR2) heterozygous mutant (BMPR2+/−) mice have a similar genetic trait as certain patients with idiopathic pulmonary arterial hypertension (IPAH). To understand the role of the BMPR2 in the development of IPAH, we examined the phenotype of BMPR2+/− mice and its response to inflammatory stress.
BMPR2+/− mice were found to have the same life span, right ventricular systolic pressure (RVSP), and lung histology as those of wildtype mice under unstressed conditions. However, when treated with recombinant adenovirus expressing 5-lipoxygenase (Ad5LO), BMPR2+/− mice exhibited significantly higher RVSP than wildtype mice. The increase of RVSP occurred in the first two weeks after Ad5LO delivery. Modest but significant muscularization of distal pulmonary arterioles appeared in BMPR2+/− mice four weeks after Ad5LO treatment. Measurement of urinary metabolites of vasoactive molecules showed that cysteinyl leukotrienes, prostacyclin metabolites, and prostaglandin E2 were all increased to a similar degree in both BMPR2+/− and wildtype mice during 5LO transgene expression, while urinary endothelin-1 remained undetectable. Urinary thromboxane A2 metabolites, in contrast, were significantly higher in BMPR2+/− than wildtype mice and paralleled the increase in RVSP. Platelet activation markers, serotonin, and sP-selectin showed a trend toward higher concentrations in BMPR2+/− than wildtype mice. Cell culture studies found that BMP treatment reduced IL-1β-stimulated thromboxane A2 production in the pulmonary epithelial cell line A549.
BMPR2+/− mice do not develop pulmonary hypertension spontaneously; however, under inflammatory stress, they are more susceptible to an increase in RVSP, thromboxane A2 production, and vascular remodeling than wildtype mice.
PMCID: PMC1472405  PMID: 16027259
BMPR2; pulmonary hypertension; thromboxane
14.  Prevention of Pulmonary Hypertension by Angiotensin Converting Enzyme 2 Gene Transfer 
Hypertension  2009;54(2):365-371.
In spite of recent advancements in the treatment of pulmonary hypertension (PH), successful control is yet to be accomplished. Abundant presence of ACE2 in the lungs, and its impressive effect in the prevention of acute lung injury, led us to test the hypothesis that pulmonary overexpression of this enzyme could produce beneficial outcomes against PH. Monocrotaline (MCT) treatment of mice for eight weeks resulted in significant increases in right ventricular systolic pressure (RVSP), right ventricle/left ventricle + septal (RV/LV+S) weight ratio and muscularization of pulmonary vessels. Administration of a lentiviral vector containing ACE2 (lenti-ACE2) seven days prior to MCT treatment prevented the increases in RVSP (Control: 25 ± 1 mmHg; MCT: 44 ± 5 mmHg; MCT+ACE2: 26 ± 1 mmHg, n=6, p<0.05) and RV/LV +S weight ratio (Control: 0.25 ± 0.01 mg/mg; MCT: 0.31 ± 0.01 mg/mg; MCT+ACE2: 0.26 ± 0.01mg/mg, n=8, p<0.05). A significant attenuation in muscularization of pulmonary vessels induced by MCT was also observed in animals overexpressing ACE2. These beneficial effects were associated with an increase in the AT2 receptor/AT1 receptor mRNA ratio. Also, PH-induced increases in pro-inflammatory cytokines were significantly attenuated by lenti-ACE2 treatment. Furthermore, ACE2 gene transfer in mice following six weeks of MCT treatment resulted in significant reversal of RVSP. These observations demonstrate that ACE2 overexpression prevents and reverses RVSP and associated pathophysiology in MCT-induced PH by a mechanism involving a shift from the vasoconstrictive, proliferative and fibrotic axis to the vasoprotective axis of the renin-angiotensin system and inhibition of pro-inflammatory cytokines.
PMCID: PMC2732127  PMID: 19564552
Cardiovascular diseases; Gene therapy; Hypertension; pulmonary; Lung; Remodeling
15.  PK10453, a nonselective platelet-derived growth factor receptor inhibitor, prevents the progression of pulmonary arterial hypertension 
Pulmonary Circulation  2014;4(1):82-102.
The platelet-derived growth factor (PDGF) signaling pathway has been found to be activated in human pulmonary arterial hypertension (PAH) and in animal models of the disease. Our study tested the hypothesis that a novel, nonselective inhaled PDGF receptor inhibitor, PK10453, would decrease pulmonary hypertension both in the rat monocrotaline (MCT) model and the rat MCT plus pneumonectomy (MCT+PN) model of PAH. PK10453, delivered by inhalation for 4 (D4)- and 8 (D8)-minute exposures 3 times a day for 2 weeks, decreased right ventricular systolic pressure (RVSP) in both the rat MCT and rat MCT+PN models: RVSP was 80.4 ± 2.6 mmHg in the vehicle MCT group (n = 6), 44.4 ± 5.8 mmHg in the D4 MCT group (n = 6), and 37.1 ± 4.5 mmHg in the D8 MCT group (n = 5; P < 0.001 vs. vehicle); RVSP was 75.7 ± 7.1 mmHg in the vehicle MCT+PN group (n = 9), 40.4 ± 2.7 mmHg in the D4 MCT+PN group (n = 10), and 43.0 ± 3.0 mmHg in the D8 MCT+PN group (n = 8; P < 0.001). In the rat MCT+PN model, continuous telemetry monitoring of pulmonary artery pressures also demonstrated that PK10453 prevented the progression of PAH. Imatinib given by inhalation was equally effective in the MCT model but was not effective in the MCT+PN model. Immunohistochemistry demonstrated increased activation of the PDGFβ receptor compared to the PDGFα receptor in neointimal and perivascular lesions found in the MCT+PN model. We show that imatinib is selective for the PDGFα receptor, whereas PK10453 has a lower half-maximal inhibitor concentration (IC50) for inhibition of kinase activity of both the PDGFα and PDGFβ receptors compared to imatinib. In conclusion, PK10453, when delivered by inhalation, significantly decreased the progression of PAH in the rat MCT and MCT+PN models. Nonselective inhibition of both the PDGFα and PDGFβ receptors may have a therapeutic advantage over selective PDGFα receptor inhibition in PAH.
PMCID: PMC4070754  PMID: 25006424
pulmonary arterial hypertension; kinase inhibitors; platelet-derived growth factor (PDGF)
16.  Hypoxia Induced Changes in Lung Fluid Balance in Humans is Associated with Beta-2 Adrenergic Receptor Density on Lymphocytes 
Previous studies have demonstrated an important role for beta-2 adrenergic receptors (β2AR) in lung fluid clearance. The purpose of this investigation was to examine the relationship between β2AR density on lymphocytes and indices of lung water in healthy humans exposed to ~17hr of hypoxia (FIO2 12.5% in a hypoxia tent).
Thirteen adults (mean±SEM; age=31±3yr, BMI=24±1 kg/m2, VO2Peak=40±2 ml/kg/min) participated. Pulmonary function, CT derived lung tissue volume (Vtis-tissue, blood & water), lung diffusing capacity for carbon monoxide (DCO) and nitric oxide (DNO), alveolar-capillary conductance (DM), pulmonary capillary blood volume (Vc) and lung water (CT Vtis − Vc) were assessed before and after ~17hr normobaric hypoxia (FIO2 12.5%). β2AR density on lymphocytes was measured via radioligand binding. Arterial oxygen saturation (SaO2), cardiac output (Q), right ventricular systolic pressure (RVSP) and blood pressure (BP) were also assessed.
After 17hr hypoxia, SaO2 decreased from 97±1 (normoxia) to 82±4% and RVSP increased from 15±9 (normoxia) to 28±4mmHg (p<0.05) with little change in Q or BP. Vc and DM both increased with hypoxia with a small increase in DM/Vc ratio (p>0.05). CT Vtis decreased and lung water was estimated to decline 7±13%, respectively. β2AR density averaged 1497±187 receptors/lymphocyte and increased 21±34% with hypoxia (range −31 to +86%). The post-hypoxia increase in β2AR density was significantly related to the reduction in lung water (r=−0.64, p<0.05), with the subjects with the greatest increase in density demonstrating the largest decline in lung water.
Lung water decreases with 17hr normobaric hypoxia are associated with changes in beta adrenergic receptor density on lymphocytes in healthy adults.
PMCID: PMC3423090  PMID: 22772314
Lung water; edema; altitude physiology; pulmonary congestion
17.  Bosentan Attenuates Right Ventricular Hypertrophy and Fibrosis in Normobaric Hypoxia Model of Pulmonary Hypertension 
Maladaptive right ventricular (RV) hypertrophic responses lead to RV dysfunction and failure in patients with pulmonary arterial hypertension, but the mechanisms responsible for these changes are not well understood. The objective of this study was to evaluate the effect of treatment with bosentan on RV hypertrophy (RVH), fibrosis and expression of protein kinase C (PKC) isoforms in the RV of rats exposed to chronic hypoxia.
Adult Sprague Dawley rats were housed in normoxia or hypoxia (FiO2: 10%) and administered vehicle or 100mg/kg/day of bosentan. After 3 weeks, echocardiographic, hemodynamic assessment was performed. PKC, procollagen-1, and collagen expression was assessed using immunoblot or colorimetric assay.
RV systolic pressure (RVSP) and RVH were higher in hypoxic compared to normoxic animals (RVSP: 72 ± 4 vs. 25 ± 2 mmHg, p<0.05; RVH: 1.2 ± 0.06 vs. 0.5 ± 0.03 mg/g body wt., p<0.05). Bosentan had no effect on RVSP or mass in normoxic animals, but did attenuate RVH in hypoxic animals (Hypoxic/vehicle: 1.2 ± 0.06; Hypoxic/bosentan: 1.0 ± 0.05 mg/g body wt., p<0.05). Hypoxia increased RV procollagen-I, and total collagen expression, effects that were attenuated by bosentan treatment. Hypoxia increased RV total and cytosolic PKC-δ protein expression, but had no effect on PKC-α or -ε isoforms. Administration of bosentan did not affect total PKC-δ protein expression. However, animals treated with bosentan had an increase in membranous PKC-δ when exposed to hypoxia.
Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia possibly via alteration of PKCδ activity.
PMCID: PMC3536478  PMID: 21550822
Endothelin; Endothelin Receptor blocker; Chronic Hypoxia; Pulmonary Hypertension; Right Ventricle; Protein Kinase C
18.  Percutaneous mitral valve repair using the edge-to-edge technique in a high-risk population 
Netherlands Heart Journal  2010;18(9):437-443.
Background. Percutaneous mitral valve (MV) repair using the edge-to-edge clip technique might be an alternative for patients with significant mitral regurgitation (MR) and an unacceptably high risk for operative repair or replacement. We report the short-term safety and efficacy of this new technique in a high-risk population.
Methods. All consecutive high-risk patients who underwent percutaneous MV repair with the Mitraclip® between January and August 2009 were included. All complications related to the procedure were reported. Transthoracic echocardiography for MR grading and right ventricular systolic pressure (RVSP) measurement were performed before, and at three and 30 days after the procedure. Differences in NYHA functional class and quality of life (QoL) index were reported.
Results. Nine patients were enrolled (78% male, age 75.9±9.0 years, logistic EuroSCORE 33.8±9.0%). One patient developed inguinal bleeding. In one patient partial clip detachment occurred, a second clip was placed successfully. The MR grade before repair was ≥3 in 100%, one month after repair a reduction in MR grade to ≤2 was present in 78% (p=0.001). RVSP decreased from 43.9±12.1 to 31.6±11.7 mmHg (p=0.009), NYHA functional class improved from median 3 (range 3 to 4) to 2 (range 1 to 4) (p=0.04), and QoL index improved from 62.9±16.3 to 49.9±30.7 (p=0.12).
Conclusion. In high-risk patients, transcatheter MV repair seems to be safe and a reduction in MR can be achieved in most patients, resulting in a short-term improvement of functional capacity and QoL. (Neth Heart J 2010;18:437–43.)
PMCID: PMC2941130  PMID: 20862239
Mitral Valve Repair; Mitral Valve Regurgitation; High Risk; Percutaneous
19.  The usefulness of contrast during exercise echocardiography for the assessment of systolic pulmonary pressure 
The systolic pulmonary artery pressure (PAPs) can be accurately estimated, non-invasively, using continuous-wave Doppler (CWD) ultrasound measurement of the peak velocity of a tricuspid regurgitant (TR) jet.
However, it is often difficult to obtain adequate tricuspid regurgitation signals for measurement of PAPs, what could lead to its underestimation. Therefore, utilization of air-blood-saline contrast has been implemented for the improvement of Doppler signal in several clinical contexts.
It is now recommended in the evaluation of patients with pulmonary hypertension. Physical activity is severely restricted in patients with PAH, being exertional dypnea the most typical symptom. Exercise stress echo-Doppler imaging allows assessment of the response to exercise. It is an excellent screening test for patients with suspected PAH. Our purpose was to evaluate the value and accuracy of agitated saline with blood contrast echocardiography, in the improvement of the Doppler signal, to quantify PAPs during treadmill exercise-echocardiography.
To evaluate the value of contrast echocardiography, using agitated saline with blood, in the improvement of the Doppler signal used to quantify the pulmonary artery systolic pressure during exercise.
From a total of 41 patients (pts), we studied 38 pts (93%), 35 women, aged 54 ± 12 years-old. 27 with the diagnosis of systemic sclerosis, 10 with history of pulmonary embolism and one patient with a suspected idiopathic PAH, who were referred to the Unity of Heart Failure and Pulmonary Hypertension for screening of PAH. According to the Unity protocol, a transthoracic echocardiogram was made, in left decubitus (LD), with evaluation of right ventricle-right atria gradient (RV/RAg). A peripheral venous access was obtained, with a 3-way stopcock and the patients were placed in orthostatism (O), with a new evaluation of RV/RAg. Exercise echocardiography (EE) was begun, with evaluation of RV/RAg at peak exercise (P) and afterwards agitated saline (8 cc with 1 cc of air and 1 cc of blood) was injected, followed by a new evaluation of RV/RAg (PC) and then the interruption of the EE. Pulmonary Hypertension was diagnosed when RV/RAg at the end of the exercise was superior to 40 mmHg.
The quality of Doppler signal was deteriorated in 5 pts, maintained in 6 pts and improved in 26 pts, with the use of contrast. In one patient, an interventricular septal defect was diagnosed. In 6 pts, a Doppler signal was only obtained with the use of contrast. In 15 pts, a RV/RAg superior to 40 mmHg was only obtained with the use of contrast. Of these, 9 have already been submitted to right heart cathetherism, that confirmed the diagnosis of pulmonary hypertension in 5 of them (56%). RV/RAg (P) was 44 ± 11 mmHg and RV/RAg (PC) was 54 ± 11 mmHg, p < 0,001.
1. The method is applicable in a large number of patients. 2. RV/RA gradients obtained at peak exercise are higher with the use of contrast, and the clinical meaning of this difference should be evaluated in a larger number of pts submitted to right heart cathetherism. The high number of false positives should lead to a higher diagnostic threshold. 3. This method seems to have relevant clinical value in the diagnosis of pulmonary arterial hypertension.
PMCID: PMC2570360  PMID: 18851729
20.  Effect of preoperative oral sildenafil on severe pulmonary artery hypertension in patients undergoing mitral valve replacement 
Indian Journal of Pharmacology  2014;46(3):281-285.
Long standing mitral valve disease is usually associated with severe pulmonary hypertension. Perioperative pulmonary hypertension is a risk factor for right ventricular (RV) failure and a cause for morbidity and mortality in patients undergoing mitral valve replacement. Phosphodiesterase 5 inhibitor-sildenafil citrate is widely used to treat primary pulmonary hypertension. There is a lack of evidence of effects of oral sildenafil on secondary pulmonary hypertension due to mitral valve disease. The study aims to assess the effectiveness of preoperative oral sildenafil on severe pulmonary hypertension and incidence of RV failure in patients undergoing mitral valve replacement surgery.
Materials and Methods:
A total of 40 patients scheduled for mitral valve replacement with severe pulmonary hypertension (RV systolic pressure (RVSP) ≥60 mmHg) on preoperative transthoracic echo were randomly treated with oral sildenafil 25 mg (N = 20) or placebo (N = 20) eight hourly for 24 h before surgery. Hemodynamic variables were measured 20 min after insertion of pulmonary artery catheter (PAC) under anesthesia (T1), 20 min at weaning from cardiopulmonary bypass (CPB) (T2) and after 1,2, and 6 h (T3, T4, T5, respectively) during the postoperative period.
Systolic and mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance index (PVRI) were significantly lower (P < 0.0001) in sildenafil group at all times. Ventilation time and postoperative recovery room stay were significantly lower (P < 0.001) in sildenafil group.
Sildenafil produces significant pulmonary vasodilatory effect as compared with placebo in mitral valve replacement patients with severe pulmonary hypertension. It also reduces ventilation time and intensive care unit (ICU) stay time as compared with placebo. It is concluded that sildenafil is effective in reducing pulmonary hypertension when administered preoperatively in patients with severe pulmonary hypertension undergoing mitral valve replacement surgery.
PMCID: PMC4071704  PMID: 24987174
Mitral valve disease; oral sildenafil; phosphodiesterase 5; phosphodiesterase 5 inhibitor; pulmonary hypertension; right ventricular failureEctua vigna Sim terurs
21.  Exercise Hemodynamic Findings in Patients with Exertional Dyspnea 
Texas Heart Institute Journal  2000;27(2):100-105.
To determine whether upright bicycle exercise could provide useful information about disabling exertional dyspnea in the absence of severe abnormalities (as shown by traditional testing methods), we evaluated 13 such patients. There were 3 men and 10 women with a mean age of 49 ± 15 (SD) years. We used pulmonary artery catheterization at rest and during upright bicycle exercise to evaluate these patients. All patients had normal left ventricular function except for 1, who had an ejection fraction of 45%. The mean duration to peak exercise was 9 ± 6 minutes.
Normal systolic pulmonary artery pressure was defined as 25 ± 5 mmHg. Four patients had normal systolic pulmonary pressure, and 9 exhibited pulmonary hypertension with exercise. In those 9, the mean mixed pulmonary venous oxygen saturation at rest was 61% ± 9% and fell to 32% ± 9% at peak exercise. Six of the 9 patients also had some degree of resting pulmonary hypertension that worsened with exercise: their mean pulmonary artery systolic pressure at rest was 47 ± 14 mmHg and rose to 75 ± 25 mmHg at peak exertion (P = 0.01). The other 3 patients showed no pulmonary hypertension at rest; their mean pulmonary artery systolic pressure was 27 ± 6 mmHg. However, this level rose to 53 ± 4 mmHg at peak exertion (P = 0.04).
In this pilot study of patients with dyspnea, 9 of 13 (69%) displayed marked pulmonary hypertension with exercise. The resting hemodynamic levels were normal in 3 (33%) of those with exercise pulmonary hypertension. We conclude that hemodynamic data from bicycle exercise tests can provide additional information regarding the mechanisms of exertional dyspnea.
PMCID: PMC101041  PMID: 10928494
Catheterization; dyspnea; exercise test; hemodynamics; hypertension, pulmonary/diagnosis
22.  Telangiectases in Scleroderma: A Potential Clinical Marker of Pulmonary Arterial Hypertension 
The Journal of rheumatology  2009;37(1):98-104.
Clinical markers are needed to identify scleroderma patients at risk for pulmonary arterial hypertension (PAH) since early therapy may improve survival. We investigated whether increased numbers of telangiectases in scleroderma associate with measures of pulmonary vascular disease.
One hundred forty-seven consecutive adult patients with scleroderma were enrolled in this cross-sectional study and scored for the presence of matted telangiectases on 11 body areas. Per body area, telangiectases were scored as 0 if none were present, 1 if there were fewer than 10 telangiectases, and 2 if 10 or more telangiectases were counted. Linear regression analysis was performed to assess the association between right ventricular systolic pressure (RVSP) and telangiectasia score, adjusted for age, race, smoking status, scleroderma subtype, disease duration, and autoantibody status. Logistic regression analysis was performed with PAH by right-heart catheterization (RHC) as the dependent variable.
The mean telangiectasia score was 6.0 (SD 4.5, range 0–20). RVSP and telangiectasia score were positively correlated (r = 0.271, p = 0.001). The mean RVSP increased by 10.9 mm Hg for every 10-point increase in telangiectasia score (95% CI 3.6–18.3 mm Hg, p = 0.004), adjusted for potential confounders. The adjusted relative odds of PAH by RHC were 12.4 for patients with a 10-point increase in telangiectasia score (95% CI 1.78–85.9, p = 0.01).
Increased numbers of telangiectases strongly associate with the presence of pulmonary vascular disease. Telangiectases may be a clinical marker of more widespread aberrant microvascular disease in scleroderma.
PMCID: PMC3419384  PMID: 19955048
23.  Pulmonary Hypertension Associated with Lung Transplantation Obliterative Bronchiolitis and Vascular Remodeling of the Allograft 
Pathologic obliterative bronchiolitis (OB)/Bronchiolitis obliterans syndrome (pathologic OB/BOS) is the major obstacle to long-term survival post-lung transplantation (LT). Our group has demonstrated that pulmonary hypertension (PH) complicates the course of chronic inflammatory lung diseases that have similarities to pathologic OB/BOS and that vascular remodeling of the bronchial circulation occurs during BOS. Consequently, we hypothesized that PH is associated with pathologic OB/BOS and may result from a vasculopathy of the allograft pulmonary circulation.
We conducted a single-center, retrospective study and examined the presence of PH and vasculopathy in patients with pathologic OB/BOS. Fifty-two pathologic specimens post-LT were recovered from January 10, 1997 to January 5, 2007 and divided into two groups, those with and without pathologic OB/BOS. PH was defined as a mean pulmonary artery pressure (mPAP) > 25 mmHg by right heart catheterization (RHC) or right ventricular systolic pressure (RVSP) ≥45 mmHg by transthoracic echocardiogram (TTE).
PH was more prevalent in those LT recipients with pathologic OB/BOS (72% vs. 0%, p = 0.003). Furthermore, pulmonary arteriopathy and venopathy were more prevalent in patients with pathologic OB/BOS (84% vs. 4%, p < 0.0001, and 77% vs. 35%, p = 0.004, respectively).
PH is common in LT recipients with pathologic OB/BOS and is associated with a vasculopathy of the allograft pulmonary circulation.
PMCID: PMC4207285  PMID: 18671677
Arteriopathy; bronchiolitis obliterans; chronic rejection; lung transplantation; pulmonary hypertension; vasculopathy; venopathy
24.  Acute effects of sildenafil and dobutamine in the hypertrophic and failing right heart in vivo 
Pulmonary Circulation  2013;3(3):599-610.
The purpose of this study was to investigate whether acute intravenous administration of the phosphodiesterase type 5 (PDE-5) inhibitor sildenafil in a single clinically relevant dose improves the in vivo function of the hypertrophic and failing right ventricle (RV). Wistar rats () were subjected to pulmonary trunk banding (PTB) causing RV hypertrophy and failure. Four weeks after surgery, they were randomized to receive an intravenous bolus dose of sildenafil (1 mg/kg; ), vehicle (), or dobutamine (10 μg/kg; ). Invasive RV pressures were recorded continuously, and transthoracic echocardiography was performed 1, 5, 15, 25, 35, 50, 70, and 90 minutes after injecting the bolus. Cardiac function was compared to baseline measurements to evaluate the in vivo effects of each specific treatment. The PTB procedure caused significant hypertrophy, cardiac fibrosis, and reduction in RV function evaluated by echocardiography (TAPSE) and invasive pressure measurements. Sildenafil did not improve the function of the hypertrophic failing right heart in vivo, measured by TAPSE, RV systolic pressure (RVsP), and dp/dtmax. Dobutamine improved RV function 1 minute after injection measured by TAPSE ( vs. cm; ), RVsP ( vs. mmHg; ), and dp/dtmax ( vs. mmHg/s; ). Acute administration of the PDE-5 inhibitor sildenafil in a single clinically relevant dose did not modulate the in vivo function of the hypertrophic failing right heart of the rat measured by echocardiography and invasive hemodynamics. In the same model, dobutamine acutely improved RV function.
PMCID: PMC4070794  PMID: 24618544
right heart failure; pulmonary circulation and disease; sildenafil; cardiovascular pharmacology; animal models of human disease
25.  Reducing TRPC1 Expression through Liposome-Mediated siRNA Delivery Markedly Attenuates Hypoxia-Induced Pulmonary Arterial Hypertension in a Murine Model 
Stem Cells International  2014;2014:316214.
We tested the hypothesis that Lipofectamine siRNA delivery to deplete transient receptor potential cation channel (TRPC) 1 protein expression can suppress hypoxia-induced pulmonary arterial hypertension (PAH) in mice. Adult male C57BL/6 mice were equally divided into group 1 (normal controls), group 2 (hypoxia), and group 3 (hypoxia + siRNA TRPC1). By day 28, right ventricular systolic pressure (RVSP), number of muscularized arteries, right ventricle (RV), and lung weights were increased in group 2 than in group 1 and reduced in group 3 compared with group 2. Pulmonary crowded score showed similar pattern, whereas number of alveolar sacs exhibited an opposite pattern compared to that of RVSP in all groups. Protein expressions of TRPCs, HIF-1α, Ku-70, apoptosis, and fibrosis and pulmonary mRNA expressions of inflammatory markers were similar pattern, whereas protein expressions of antifibrosis and VEGF were opposite to the pattern of RVSP. Cellular markers of pulmonary DNA damage, repair, and smooth muscle proliferation exhibited a pattern similar to that of RVSP. The mRNA expressions of proapoptotic and hypertrophy biomarkers displayed a similar pattern, whereas sarcomere length showed an opposite pattern compared to that of RVSP in all groups. Lipofectamine siRNA delivery effectively reduced TRPC1 expression, thereby attenuating PAH-associated RV and pulmonary arteriolar remodeling.
PMCID: PMC4281407  PMID: 25587286

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