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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 
BACKGOUND:
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.
OBJECTIVE:
To define the ranges of RVSP according to age and to include more elderly patients than have previously been reported.
METHODS:
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.
RESULTS:
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.
CONCLUSIONS:
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.  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.
Objective
Closure of atrial septal defects (ASD) prevents pulmonary hypertension, right heart failure and thromboembolic stroke. The exact timing for ASD closure is controversial.
Methods
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).
Results
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.
Conclusion
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.
doi:10.1007/s12471-013-0425-8
PMCID: PMC3722387  PMID: 23640576
Pulmonary hypertension; ASD closure; Exercise stress echocardiography; Ergospirometry
3.  Right ventricular systolic pressure by echocardiography as a predictor of pulmonary hypertension in idiopathic pulmonary fibrosis 
Respiratory medicine  2008;102(9):1305-1310.
Summary
Rationale
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.
Objectives
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.
Methods
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.
Conclusion
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.
doi:10.1016/j.rmed.2008.03.022
PMCID: PMC2649722  PMID: 18619825
Hypertension; Pulmonary; Oximetry; Pulmonary fibrosis; Pulmonary function tests; Pressure; Pulmonary artery
4.  Non-invasive assessment of murine pulmonary arterial pressure: validation and application to models of pulmonary hypertension 
Background
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%.
Conclusion
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.
doi:10.1161/CIRCIMAGING.109.887109
PMCID: PMC3075498  PMID: 20044514
Echocardiography; right ventricular systolic pressure; mice
5.  Increased Susceptibility to Pulmonary Hypertension in Heterozygous BMPR2-Mutant Mice 
Circulation  2005;112(4):553-562.
BACKGROUND
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.
METHODS AND RESULTS
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.
CONCLUSIONS
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.
doi:10.1161/CIRCULATIONAHA.104.492488
PMCID: PMC1472405  PMID: 16027259
BMPR2; pulmonary hypertension; thromboxane
6.  Primary pulmonary hypertension during pregnancy: A case report 
We describe a case of a 25-year-old pregnant woman who presented with severe primary pulmonary hypertension (PPH). Her echocardiogram showed severe right ventricular hypertrophy with dilatation and Moderate right ventricular systolic dysfunction. Right ventricle systolic pressure (RVSP) was estimated to be 125 mmHg. She had an elective caesarean section under general anaesthesia at 32 weeks of gestation. Pulmonary artery pressures measured by a pulmonary artery catheter before anaesthesia were 102 mmHg and pulmonary vascular resistance was 429. Intraoperative nitric oxide was used to reduce pulmonary artery systolic pressure (PASP). After the delivery of a healthy infant, PASP was controlled with nebulized iloprost and silandifil. Five days later she was transferred from intensive care unit after she was started on silandifil 50 mg three times daily and a small dose of warfarin.
doi:10.1016/j.jsha.2012.12.001
PMCID: PMC3809475  PMID: 24174863
Primary pulmonary hypertension; Pregnancy; General anaesthesia; Pulmonary vasodilators
7.  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.
Methods
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.
Results
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.
Conclusion
Bosentan inhibits RVH and RV collagen expression in rats exposed to chronic hypoxia possibly via alteration of PKCδ activity.
doi:10.1016/j.healun.2011.03.010
PMCID: PMC3536478  PMID: 21550822
Endothelin; Endothelin Receptor blocker; Chronic Hypoxia; Pulmonary Hypertension; Right Ventricle; Protein Kinase C
8.  The usefulness of contrast during exercise echocardiography for the assessment of systolic pulmonary pressure 
Background
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.
Purpose
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/1476-7120-6-51
PMCID: PMC2570360  PMID: 18851729
9.  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.
doi:10.1161/HYPERTENSIONAHA.108.125468
PMCID: PMC2732127  PMID: 19564552
Cardiovascular diseases; Gene therapy; Hypertension; pulmonary; Lung; Remodeling
10.  End-Systolic Elastance and Ventricular-Arterial Coupling Reserve Predict Cardiac Events in Patients with Negative Stress Echocardiography 
BioMed Research International  2013;2013:235194.
Background. A maximal negative stress echo identifies a low-risk subset for coronary events. However, the potentially prognostically relevant information on cardiovascular hemodynamics for heart-failure-related events is unsettled. Aim of this study was to assess the prognostic value of stress-induced variation in cardiovascular hemodynamics in patients with negative stress echocardiography. Methods. We enrolled 891 patients (593 males mean age 63 ± 12, ejection fraction 48 ± 17%), with negative (exercise 172, dipyridamole 482, and dobutamine 237) stress echocardiography result. During stress we assessed left ventricular end-systolic elastance index (ELVI), ventricular arterial coupling (VAC) indexed by the ratio of the ELVI to arterial elastance index (EaI), systemic vascular resistance (SVR), and pressure-volume area (PVA). Changes from rest to peak stress (reserve) were tested as predictors of main outcome measures: combined death and heart failure hospitalization. Results. During a median followup of 19 months (interquartile range 8–36), 50 deaths and 84 hospitalization occurred. Receiver-operating-characteristic curves identified as best predictors ELVI reserve for exercise (AUC = 0.871) and dobutamine (AUC = 0.848) and VAC reserve (AUC = 0.696) for dipyridamole. Conclusions. Patients with negative stress echocardiography may experience an adverse outcome, which can be identified by assessment of ELVI reserve and VAC reserve during stress echo.
doi:10.1155/2013/235194
PMCID: PMC3760182  PMID: 24024185
11.  Exaggerated increase of exercise-induced pulmonary artery pressure in systemic sclerosis patients predominantly results from left ventricular diastolic dysfunction 
Objective
High prevalence of exaggerated pulmonary artery pressure response to exercise (EPAPR) was reported in patients with systemic sclerosis (SSc). However, pathophysiology of this phenomenon has not been well defined. Therefore, we evaluated the frequency and potential aetiology of EPAPR in SSc patients.
Methods
We included 85 patients (79 female, 6 male, mean age 54.3 ± 13.9 years) with SSc. Transthoracic echocardiography followed by exercise Doppler echocardiography (EDE) were performed. A positive EDE was defined when at least 20 mmHg increase of tricuspid regurgitation peak gradient (TRPG) was recorded. Right heart catheterization (RHC) with exercise was performed in positive EDE patients and in subjects with resting TRPG >31 mmHg.
Results
Resting TRPG >31 mmHg and/or positive EDE was found in 30 patients and they were referred to RHC. Finally, RHC was performed in 20 patients (16 pts resting TRPG >31 mmHg and 4 others normal resting TRPG and positive EDE). In 12 (60 %) of them an EPAPR with elevated pulmonary capillary wedge pressure (PCWP) was observed. Interestingly, mean left atrium (LA) diameter was greater in an EPAPR with elevated PCWP patients than in subjects with normal exercise response (39.36 ± 5.6 vs. 35.53 ± 3.48, p = 0.03). In EPAPR with elevated PCWP group greater mean value of E/E′ of mitral lateral annulus was observed (7.98 ± 3.35 vs. 6.27 ± 1.94, p = 0.03). In the univariate logistic regression analysis increased LA diameter was significant predictor of EPAPR with elevated PCWP (OR 1.199, 95 % CI 1.029–1.396, p = 0.019).
Conclusions
Despite very well-known risk of PAH in systemic sclerosis patients, the excessive increase of PAP during exercise is more commonly caused by left ventricular diastolic dysfunction than pulmonary arterial vasculopathy.
doi:10.1007/s00392-013-0594-x
PMCID: PMC3825133  PMID: 23824244
Scleroderma; Echocardiography; Pulmonary hypertension; Diastolic dysfunction
12.  Divergent Cardiopulmonary Actions of Heme Oxygenase Enzymatic Products in Chronic Hypoxia 
PLoS ONE  2009;4(6):e5978.
Background
Hypoxia and pressure-overload induce heme oxygenase-1 (HO-1) in cardiomyocytes and vascular smooth muscle cells (VSMCs). HO-1−/− mice exposed to chronic hypoxia develop pulmonary arterial hypertension (PAH) with exaggerated right ventricular (RV) injury consisting of dilation, fibrosis, and mural thrombi. Our objective was to indentify the HO-1 product(s) mediating RV protection from hypoxic injury in HO-1−/− mice.
Methodology/Principal Findings
HO-1−/− mice were exposed to seven weeks of hypoxia and treated with inhaled CO or biliverdin injections. CO reduced right ventricular systolic pressure (RVSP) and prevented hypoxic pulmonary arteriolar remodeling in both HO-1−/− and control mice. Biliverdin had no significant effect on arteriolar remodeling or RVSP in either genotype. Despite this, biliverdin prevented RV failure in the hypoxic HO-1−/− mice (0/14 manifested RV wall fibrosis or thrombus), while CO-treated HO-1−/− mice developed RV insults similar to untreated controls. In vitro, CO inhibited hypoxic VSMC proliferation and migration but did not prevent cardiomyocyte death from anoxia-reoxygenation (A-R). In contrast, bilirubin limited A-R-induced cardiomyocyte death but did not inhibit VSMC proliferation and migration.
Conclusions/Significance
CO and bilirubin have distinct protective actions in the heart and pulmonary vasculature during chronic hypoxia. Moreover, reducing pulmonary vascular resistance may not prevent RV injury in hypoxia-induced PAH; supporting RV adaptation to hypoxia and preventing RV failure must be a therapeutic goal.
doi:10.1371/journal.pone.0005978
PMCID: PMC2694354  PMID: 19543386
13.  Nicorandil Prevents Right Ventricular Remodeling by Inhibiting Apoptosis and Lowering Pressure Overload in Rats with Pulmonary Arterial Hypertension 
PLoS ONE  2012;7(9):e44485.
Background
Most of the deaths among patients with severe pulmonary arterial hypertension (PAH) are caused by progressive right ventricular (RV) pathological remodeling, dysfunction, and failure. Nicorandil can inhibit the development of PAH by reducing pulmonary artery pressure and RV hypertrophy. However, whether nicorandil can inhibit apoptosis in RV cardiomyocytes and prevent RV remodeling has been unclear.
Methodology/Principal Findings
RV remodeling was induced in rats by intraperitoneal injection of monocrotaline (MCT). RV systolic pressure (RVSP) was measured at the end of each week after MCT injection. Blood samples were drawn for brain natriuretic peptide (BNP) ELISA analysis. The hearts were excised for histopathological, ultrastructural, immunohistochemical, and Western blotting analyses. The MCT-injected rats exhibited greater mortality and less weight gain and showed significantly increased RVSP and RV hypertrophy during the second week. These worsened during the third week. MCT injection for three weeks caused pathological RV remodeling, characterized by hypertrophy, fibrosis, dysfunction, and RV mitochondrial impairment, as indicated by increased levels of apoptosis. Nicorandil improved survival, weight gain, and RV function, ameliorated RV pressure overload, and prevented maladaptive RV remodeling in PAH rats. Nicorandil also reduced the number of apoptotic cardiomyocytes, with a concomitant increase in Bcl-2/Bax ratio. 5-hydroxydecanoate (5-HD) reversed these beneficial effects of nicorandil in MCT-injected rats.
Conclusions/Significance
Nicorandil inhibits PAH-induced RV remodeling in rats not only by reducing RV pressure overload but also by inhibiting apoptosis in cardiomyocytes through the activation of mitochondrial ATP-sensitive K+ (mitoKATP) channels. The use of a mitoKATP channel opener such as nicorandil for PAH-associated RV remodeling and dysfunction may represent a new therapeutic strategy for the amelioration of RV remodeling during the early stages of PAH.
doi:10.1371/journal.pone.0044485
PMCID: PMC3436887  PMID: 22970229
14.  Genetic influences on right ventricular systolic pressure (RVSP) in chronic obstructive pulmonary disease (COPD) 
Background
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.1186/1471-2466-12-25
PMCID: PMC3431274  PMID: 22695028
COPD; Pulmonary hypertension; Genetic polymorphism
15.  Incidence of pulmonary hypertension in patients with chronic myeloproliferative disorders. 
STUDY OBJECTIVE: To assess the incidence of pulmonary hypertension (PH) in patients with chronic myeloproliferative disorders (CMPD). METHOD: Twenty-seven patients with a diagnosis of CMPD were included in the study. Patients were excluded if they had a secondary cause of PH. Diagnosis of PH was established if right ventricular systolic pressure (RVSP) by transthoracic echocardiography (TTE) was >35 mmHg. RESULTS: Diagnosis of PH was established in 14 out of 27 patients. Two patients were excluded from analysis because of poor ejection fraction on TTE, resulting in a final diagnosis of PH in 12 of 25 (48%) patients. Of these 25 patients, seven of nine with essential thrombocytosis (ET), five of 14 with polycythemia vera (PV), and 0 out of two with chronic myeloid leukemia (CML) had PH. All patients were asymptomatic at the time of their most recent visit. There was no relationship between PH and age at diagnosis, duration of disease, platelet count and hematocrit at diagnosis or during follow-up, both for the entire cohort or for specific diagnosis of ET or PV. CONCLUSION: Pulmonary hypertension appears to be common in patients with CMPD. Further studies are needed to evaluate the impact of treatment on PH and long-term survival in these patients.
PMCID: PMC2569799  PMID: 17128687
16.  Gene expression in lungs of mice lacking the 5-hydroxytryptamine transporter gene 
Background
While modulation of the serotonin transporter (5HTT) has shown to be a risk factor for pulmonary arterial hypertension for almost 40 years, there is a lack of in vivo data about the broad molecular effects of pulmonary inhibition of 5HTT. Previous studies have suggested effects on inflammation, proliferation, and vasoconstriction. The goal of this study was to determine which of these were supported by alterations in gene expression in serotonin transporter knockout mice.
Methods
Eight week old normoxic mice with a 5-HTT knock-out (5HTT-/-) and their heterozygote(5HTT+/-) or wild-type(5HTT+/+) littermates had right ventricular systolic pressure(RVSP) assessed, lungs collected for RNA, pooled, and used in duplicate in Affymetrix array analysis. Representative genes were confirmed by quantitative RT-PCR and western blot.
Results
RVSP was normal in all groups. Only 124 genes were reliably changed between 5HTT-/- and 5HTT+/+ mice. More than half of these were either involved in inflammatory response or muscle function and organization; in addition, some matrix, heme oxygenase, developmental, and energy metabolism genes showed altered expression. Quantitative RT-PCR for examples from each major group confirmed changes seen by array, with an intermediate level in 5HTT +/- mice.
Conclusion
These results for the first time show the in vivo effects of 5HTT knockout in lungs, and show that many of the downstream mechanisms suggested by cell culture and ex vivo experiments are also operational in vivo. This suggests that the effect of 5HTT on pulmonary vascular function arises from its impact on several systems, including vasoreactivity, proliferation, and immune function.
doi:10.1186/1471-2466-9-19
PMCID: PMC2688484  PMID: 19426553
17.  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
18.  Pacing stress echocardiography 
Background
High-rate pacing is a valid stress test to be used in conjunction with echocardiography; it is independent of physical exercise and does not require drug administration. There are two main applications of pacing stress in the echo lab: the noninvasive detection of coronary artery disease through induction of a regional transient dysfunction; and the assessment of contractile reserve through peak systolic pressure/ end-systolic volume relationship at increasing heart rates to assess global left ventricular contractility.
Methods
The pathophysiologic rationale of pacing stress for noninvasive detection of coronary artery disease is obvious, with the stress determined by a controlled increase in heart rate, which is a major determinant of myocardial oxygen demand, and thereby tachycardia may exceed a fixed coronary flow reserve in the presence of hemodynamically significant coronary artery disease. The use of pacing stress echo to assess left ventricular contractile reserve is less established, but promising. Positive inotropic interventions are mirrored by smaller end-systolic volumes and higher end-systolic pressures. An increased heart rate progressively increases the force of ventricular contraction (Bowditch treppe or staircase phenomenon). To build the force-frequency relationship, the force is determined at different heart rate steps as the ratio of the systolic pressure (cuff sphygmomanometer)/end-systolic volume index (biplane Simpson rule). The heart rate is determined from ECG.
Conclusion
Two-dimensional echocardiography during pacing is a useful tool in the detection of coronary artery disease. Because of its safety and ease of repeatability noninvasive pacing stress echo can be the first-line stress test in patients with permanent pacemaker.
The force-frequency can be defined as up- sloping (normal) when the peak stress pacing systolic pressure/end-systolic volume index is higher than baseline and intermediate stress values, biphasic with an initial up- sloping followed by a later down-sloping trend, or flat or negative when peak stress pacing systolic pressure/end-systolic volume index is equal or lower than baseline stress values. This approach is certainly highly feasible and allows a conceptually immaculate definition of contractility with prognostic usefulness, but its therapeutic implications remains to be established. Bowditch treppe, assessed with pacing stress, can be used to assess the optimal stimulation frequency and to optimise the patient's chronotropic response in programming rate-adaptive pacemakers.
doi:10.1186/1476-7120-3-36
PMCID: PMC1334217  PMID: 16336679
19.  Pre- and post-operative cardiac evaluation of dogs undergoing lobectomy and pneumonectomy 
Journal of Veterinary Science  2010;11(3):257-264.
This study aimed to assess the influence of lobectomy and pneumonectomy on cardiac rhythm and on the dimensions and function of the right-side of the heart. Twelve dogs undergoing lobectomy and eight dogs undergoing pneumonectomy were evaluated preoperatively and one month postoperatively with electrocardiography and Doppler echocardiography at rest. Pulmonary artery systolic pressure (PASP) was estimated by the tricuspid regurgitation jet (TRJ) via the pulse wave Doppler velocity method. Systemic inflammatory response syndrome criteria (SIRS) were also evaluated based on the clinical and hematological findings in response to lobectomy and pneumonectomy. Following lobectomy and pneumonectomy, we predominantly detected atrial fibrillation and varying degrees of atrioventricular block (AVB). Dogs that died within seven days of the lobectomy (n = 2) or pneumonectomy (n = 1) had complete AVB. Preoperative right atrial, right ventricular, and pulmonary artery dimensions increased gradually during the 30 days (p<0.05) following pneumonectomy, but did not undergo significant changes during that same period after lobectomy. Mean PASP was 56.0 ± 4.5 mmHg in dogs having significant TRJ after pneumonectomy. Pneumonectomy, but not lobectomy, could lead to increases (p<0.01) in the SIRS score within the first day post-surgery. In brief, it is important to conduct pre- and postoperative cardiac evaluation of dogs undergoing lung resections because cardiac problems are a common postoperative complication after such surgeries. In particular, complete AVB should be considered a life-threatening complication after pneumonectomy and lobectomy. In addition, pneumonectomy appears to increase the likelihood of pulmonary hypertension development in dogs.
doi:10.4142/jvs.2010.11.3.257
PMCID: PMC2924488  PMID: 20706034
dog; heart function; lobectomy; pneumonectomy; pulmonary hypertension
20.  What Is Really a Nonobstructive Hypertrophic Cardiomyopathy? The Importance of Orthostatic Factor in Exercise Echocardiography 
ISRN Cardiology  2011;2011:346797.
The authors report the case of a 23-year-old girl with nonobstructive hypertrophic cardiomyopathy evaluated by resting echocardiography. The patient complained of syncope after playing basketball. The patient was submitted to treadmill exercise echocardiogram, and she exercised for 9 minutes in standard Bruce protocol. The left ventricular outflow gradient did not occur at peak workload; however she developed intraventricular gradient greater than 100 mmHg after exercise in orthostatic position. There was fall in arterial pressure, and the patient was then put in supine position. The authors suggest the possible role of exercise stress echo in symptomatic patients with no significant gradient at baseline, as well as maintenance in orthostatic position after exercise, as an important stress factor. This can disclose the occurrence of left ventricular outflow tract obstruction that should not be detected in other way and has potential relevance in the patient's symptoms understanding.
doi:10.5402/2011/346797
PMCID: PMC3262522  PMID: 22347638
21.  A Novel Expression of Exercise Induced Pulmonary Hypertension in Human Immunodeficiency Virus Patients: A Pilot Study 
Background:
Patients with the human immunodeficiency virus (HIV) are at risk for multiple pulmonary complications including pulmonary hypertension. Exercise induced pulmonary hypertension (EIPH) has been previously described in patients with scleroderma, sickle cell disease and chronic obstructive pulmonary disease, yet has not been associated with the HIV population.
Methods:
A prospective case-control study design was implemented. Four HIV patients with unexplained dyspnea and four healthy controls underwent symptom-limited stationary bicycle exercise. Transthoracic Doppler Echocardiography was used to measure tricuspid regurgitation velocity which was used to calculate the right ventricular to right atrial pressure (RV-RA) gradient at rest and at peak exercise using the simplified Bernoulli’s equation. Change in RV-RA gradient between rest and peak exercise was calculated and considered to represent change in pulmonary arterial systolic pressure.
Results:
The mean age was 41.25 years (±8.7) for patients and 33.5 years (±6.0) for controls. The mean CD4 count of patients was 191.5 cells/μL (±136.2). Patients had a significantly higher increase in RV-RA gradient as compared to controls (180.2% vs. 27.5%, p = 0.03).
Discussion:
This pilot study suggests that it is feasible to use recumbent bicycle and transthoracic Doppler echocardiography for the evaluation of EIPH among HIV patients with dyspnea of unknown etiology. The study is too small to draw any broad conclusion. Further evaluation of this concept with a larger study is warranted.
doi:10.2174/1874192401206010044
PMCID: PMC3339433  PMID: 22550549
Human immunodeficiency virus (HIV); pulmonary hypertension; exercises induced pulmonary hypertension.
22.  Increased pulmonary arterial pressure in children with nephrotic syndrome 
Du, Z | Cao, L | Liang, L | Chen, D | Li, Z
Archives of Disease in Childhood  2004;89(9):866-870.
Aims: To evaluate the pulmonary arterial pressure in children with nephrotic syndrome (NS).
Methods: Doppler echocardiography was performed in 40 children with NS (aged 1.5–13 years) at NS onset (n = 28) or relapse (n = 12), and 40 normal controls. Pulmonary pressure was estimated by: (1) measuring the systolic transtricuspid gradient from tricuspid regurgitation; and (2) measuring the time to peak velocity of pulmonary flow.
Results: Thirty five of the 40 patients with NS had measurable tricuspid regurgitation with a pulmonary systolic pressure ranging from 21 to 48 mm Hg. Pulmonary systolic pressure was >40 mm Hg in seven patients. The pulmonary time to peak velocity was shortened and the ratio of time to peak velocity and right ventricular ejection time decreased compared with controls. The patients with increased pulmonary pressure had a longer time since onset of NS. One patient developed thrombus in the inferior vena cava during hospitalisation.
Conclusion: Pulmonary arterial pressure was increased in children with NS. Further work is needed to evaluate the aetiology and clinical implications of this abnormality.
doi:10.1136/adc.2003.039289
PMCID: PMC1763209  PMID: 15321868
23.  Abnormal shortened diastolic time length at increasing heart rates in patients with abnormal exercise-induced increase in pulmonary artery pressure 
Background
The degree of pulmonary hypertension is not independently related to the severity of left ventricular systolic dysfunction but is frequently associated with diastolic filling abnormalities. The aim of this study was to assess diastolic times at increasing heart rates in normal and in patients with and without abnormal exercise-induced increase in pulmonary artery pressure (PASP). Methods. We enrolled 109 patients (78 males, age 62 ± 13 years) referred for exercise stress echocardiography and 16 controls. The PASP was derived from the tricuspid Doppler tracing. A cut-off value of PASP ≥ 50 mmHg at peak stress was considered as indicative of abnormal increase in PASP. Diastolic times and the diastolic/systolic time ratio were recorded by a precordial cutaneous force sensor based on a linear accelerometer.
Results
At baseline, PASP was 30 ± 5 mmHg in patients and 25 ± 4 in controls. At peak stress the PASP was normal in 95 patients (Group 1); 14 patients (Group 2) showed an abnormal increase in PASP (from 35 ± 4 to 62 ± 12 mmHg; P < 0.01). At 100 bpm, an abnormal (< 1) diastolic/systolic time ratio was found in 0/16 (0%) controls, in 12/93 (13%) Group 1 and 7/14 (50%) Group 2 patients (p < 0.05 between groups).
Conclusion
The first and second heart sound vibrations non-invasively monitored by a force sensor are useful for continuously assessing diastolic time during exercise. Exercise-induced abnormal PASP was associated with reduced diastolic time at heart rates beyond 100 beats per minute.
doi:10.1186/1476-7120-9-36
PMCID: PMC3268730  PMID: 22104611
Diastolic time; Pulmonary hypertension; Cutaneous heart sensor
24.  The Effect of Amlodipine and Sildenafil on the NT-ProBNP Level of Patients with COPD-Induced Pulmonary Hypertension  
Pulmonary hypertension (PH) is an important cause of heart failure in chronic obstructive pulmonary disease (COPD). The pro brain natriuretic peptide N-terminal (NT-proBNP) has been suggested as a noninvasive marker to evaluate ventricular function. However, there is no evidence to support the use of NT-proBNP in monitoring the benefits of vasodilators in COPD induced PH. Thus, we used NT-proBNP as a biomarker to evaluate the effect of oral vasodilators on cardiac function in COPD-induced PH.
Forty clinically-stable PH patients were enrolled with history of COPD, normal left ventricular ejection-fraction (LVEF), right ventricular systolic pressure (RVSP) > 45 mmHg and baseline blood NT-proBNP levels >100 pg/mL. Patients were randomized into two groups, one group received sildenafil and second group were given amlodipine for two weeks. NT-proBNP and systolic pulmonary arterial pressure (systolic PA-pressure) were measured at the beginning and the end of study.
Mean NT-proBNP level in the first group was 1297 ± 912 pg/mL before therapy and 554 ± 5 pg/mL after two weeks drug therapy, respectively. Similarly, in second group NT-proBNP level was 1657 ± 989 pg/mL and 646 ± 5 pg/mL before and after treatment. Amlodipine or sildenafil significantly reduced NT-proBNP levels in COPD-induced PH patients (p < 0.05).
Our study shows that amlodipine and sildenafil have a similar effect on NT-proBNP levels. In both groups NT- proBNP levels were significantly reduced after treatment. Therefore, our findings support the potential benefits of treatment with vasodilators in COPD induced PH.
Pulmonary hypertension, Chronic obstructive pulmonary disease, NT-proBNP, Amlodipine, Sildenafil
PMCID: PMC3977066
25.  C-type natriuretic peptide does not attenuate the development of pulmonary hypertension caused by hypoxia and VEGF receptor blockade 
Life sciences  2011;89(13-14):460-466.
AIMS
C-type natriuretic peptide (CNP) is a local regulator of vascular tone and remodeling in many vascular beds. However, the role of CNP in modulating pulmonary arterial hypertensive and vascular remodeling responses is unclear. The purpose of this study was to determine if CNP is capable of preventing the development of pulmonary hypertension (PH).
MAIN METHODS
We used animal models of PH caused by chronic hypoxia alone or in combination with the VEGF receptor blocker SU5416. We measured pulmonary hemodynamics, right ventricular hypertrophy and vascular remodeling effects in response to a continuous infusion of low dose or high dose CNP or vehicle placebo.
KEY FINDINGS
Right ventricular hypertrophy and a marked elevation in right ventricular systolic pressure (RVSP) were seen in both models of PH. Rats treated with the combination of SU5416 and chronic hypoxia also developed pulmonary endothelial hyperproliferative lesions. Continuous intravenous infusion of CNP at either dose did not attenuate the development of PH, right ventricular hypertrophy or vascular remodeling in either of the models of PH despite a three-fold increase in serum CNP levels.
SIGNIFICANCE
CNP does not prevent the development of PH in the chronic hypoxia or SU5416 plus hypoxia models of pulmonary hypertension suggesting that CNP may not play an important modulatory role in human PH.
doi:10.1016/j.lfs.2011.07.009
PMCID: PMC3533228  PMID: 21820448
C-type Natriuretic Peptide; VEGF Receptor Blockade; Chronic Hypoxia; Pulmonary Hypertension; SU5416

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