IJCA-18032; No of Pages 5 International Journal of Cardiology xxx (2014) xxx–xxx

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Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: Role of J receptors Ashima Anand a, Niraj Srivastava a, Parag Barwad b, Sivasubramanian Ramakrishnan b,⁎, Ambuj Roy b, Balram Bhargava b a b

Exertional Breathlessness Studies Laboratory, Vallabhbhai Patel Chest Institute, Delhi University, Delhi 110007, India Department of Cardiology, Cardio-Thoracic Sciences Centre, All India Institute of Medical Sciences, New Delhi 110016, India

a r t i c l e

i n f o

Article history: Received 17 September 2013 Received in revised form 20 January 2014 Accepted 12 April 2014 Available online xxxx Keywords: Eisenmenger syndrome PDE inhibitors Juxta-pulmonary capillary receptors Dyspnea

a b s t r a c t Background: In Eisenmenger syndrome (ES), oral phosphodiesterase type-5 inhibitors, which are preferential pulmonary vasodilators, reduce the elevated pulmonary artery pressure and pulmonary vascular resistance index by increasing cyclic guanosine monophosphate (cGMP). However, no information is available as to how pulmonary vasodilatation alleviates the accompanying dyspnoea and improves patient's exercising ability. Objectives: As the natural stimulus of juxtapulmonary capillary (J) receptors is an increase in interstitial pressure, the aim was to estimate their threshold level stimulation chemically by intravenous lobeline, before and after 6 weeks of sildenafil therapy in treatment-naive ES patients. Methods: Nine Eisenmenger syndrome patients [mean age = 26 (SD = 1.6) years] underwent 6MWT and an exercise test before and 6 weeks after oral sildenafil (20 mg 3× D). Their respiratory responses to threshold doses of intravenous lobeline were determined at both these stages. Results: After 6 weeks of sildenafil therapy, the 6MWD [from 453.3 (SD = 50.9) m to 516.6 (SD = 48.9) m; P = 0.001] and the duration of exercise with the modified Bruce protocol from 7 min 53 s (SD = 0.04) to 10 min 44 s (SD = 0.88) (P = 0.001) improved significantly. However, the improvement in oxygen saturation was not noteworthy. The lobeline dose required to produce threshold level of respiratory effects was higher in ES patients [37.5 (SD = 3.4) μg/kg] and with sildenafil therapy it fell significantly [20.6 (SD = 1.8) μg/kg; P = 0.001]. Conclusions: J receptor threshold doses were elevated in ES patients and fell significantly with sildenafil therapy that was associated with improved exercise tolerance, implying thereby a role of J receptors in producing dyspnea in ES patients. © 2014 Elsevier Ireland Ltd. ALL rights reserved.

1. Introduction Eisenmenger syndrome (ES) is a form of pulmonary arterial hypertension (PAH) characterized by right to left shunt as a result of untreated congenital heart defect. The patients are cyanotic and dypsneic and are easily fatigued on exertion [1,2]. Among the various mechanisms that have been postulated for the dyspnea of ES patients are systemic hypoxemia due to an increase in right to left shunting, impairment of endothelium-dependent pulmonary arteriolar relaxation resulting from decreased production of nitric oxide (NO), which leads to pulmonary vasoconstriction and an inability to increase cardiac output with exercise [2,3]. A single dose of an oral phosphodiesterase type-5 inhibitor (Tadalafil), which is known to increase cyclic guanosine monophosphate (cGMP) leading to vascular relaxation, when administered to ES patients ⁎ Corresponding author at: Department of Cardiology, All India Institute of Medical Sciences, New Delhi 110 029, India. Tel.: +91 11 26594420; fax: +91 11 26588663, +91 11 26588641. E-mail address: [email protected] (S. Ramakrishnan).

produced an acute fall in pulmonary artery pressure and pulmonary vascular resistance index [3]. Other selective pulmonary vasodilators including sildenafil and endothelin antagonists like bosentan and ambrisentan also alleviate these symptoms of ES patients and have been considered to prolong their survival [4–6]. These effects of phosphodiestrase type-5 inhibitors and endothelin receptor antagonists are also well documented in patients with idiopathic pulmonary hypertension (PAH) [7,8]. Although pulmonary bed vasodilator effects of sildenafil are well known, there is no information available as to how this or hemodynamic changes alleviate dyspnea and increase exercising ability or 6 min walk distance of these patients by nearly 12–20%. Juxta pulmonary-capillary (J) receptors, a group of sensory receptors lying in the pulmonary interstitium and accessible only via the pulmonary circulation are stimulated naturally by a rise in the interstitial pressure [9,10] (even transient) and accelerate breathing and inhibit exercise reflexly in animals, healthy individuals as well in cardiac disease patients [11–18]. Their stimulation and reflexes can also be evoked chemically—by phenyl diguanide in animals [10,11] and by lobeline in human subjects, and in the latter, these are accompanied by characteristic sensations in the upper chest that are akin to dyspnea [13].

http://dx.doi.org/10.1016/j.ijcard.2014.04.131 0167-5273/© 2014 Elsevier Ireland Ltd. ALL rights reserved.

Please cite this article as: Anand A, et al, Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: Role of J receptors, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.131

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A. Anand et al. / International Journal of Cardiology xxx (2014) xxx–xxx

Despite this well-established knowledge, no study has so far been undertaken to elucidate the level of stimulation of these receptors in any PAH situation or to investigate their possible role in giving rise to the patient's symptoms. In view of the receptor's characteristics, it can be assumed that in ES patients the underlying increased pulmonary vascular resistance would increase the sensory receptors' level of stimulation and which would increase further with a rise in pulmonary artery pressure with exercise and augment the level of their reflexes. With this in view, we hypothesized that the hemodynamic changes seen with sildenafil could reduce the level of J receptor afferent activity and thus their contribution to alleviating the respiratory distress that is seen with physical activity. We examined this by comparing the effect of 6 weeks of sildenafil treatment on the dose of i.v. lobeline that gave rise to the receptors threshold effects and on the 6 min walk test distance (6MWT) and duration of exercise with the modified Bruce protocol. 2. Methods 2.1. Patients Nine newly diagnosed patients with unequivocal diagnosis of Eisenmenger syndrome, aged 26 (SD = 1.6) years (7 male and 2 female), were included after an informed consent. The study conformed to the Helsinki Declaration and was approved by the ethics committee of All India Institute of Medical Sciences. Patients with haemoglobin b14 g%, abnormal kidney or liver function, resting arterial oxygen saturation (SaO2) less than 75%, atrial fibrillation, evidence of congestive heart failure, WHO functional class I or IV or sensitivity to sildenafil were excluded. None of the patients had received pulmonary vasodilators prior to this study. The diagnosis of Eisenmenger syndrome was established by comprehensive examination including chest radiography, electrocardiogram, a detailed transthoracic echocardiography and cardiac catheterization if needed. The patients were on stable doses of diuretics for at least 4 weeks before the study and these were continued unaltered during the study period. None of the patients were given beta-blockers or iron therapy. The ventricular septal defect (VSD) consisted of either a single aperture or multiple small ones; the total diameter ranged from 10 to 18 mm. 2.2. Design, protocols and measurements All patients underwent all tests at the same time of day, i.e., early afternoon with indoor temperature maintained at 26 °C. The investigation consisted of (i) 6MWT in a long corridor, i.e., in an area where they were not slowed down by sudden turns, (ii) exercising on a treadmill using the modified Bruce protocol [18]. A period of rest (2 hours) after which (iii) their response to intravenously injected lobeline was determined. All of these were repeated after 6 weeks of sildenafil medication (20 mg thrice daily). 2.3. Exercise study For 6MWT, the patients were instructed to stop as soon as they felt any kind of discomfort, and the distance covered in meters was noted down along with the sensations they reported. A continuous measurement of the patients systemic oxygen saturation (SaO2), heart rate (HR) and blood pressure (mmHg) was obtained at rest and during exercise testing (ET) on a treadmill using a modified Bruce protocol. [19] Exercise was terminated if the patient desired to stop due to fatigue or dyspnea, or when SaO2 fell by 20% below baseline or if the systolic blood pressure fell by 20 mm Hg.

2.4.2. Data acquisition and statistical analysis Pulmonary artery systolic pressure (PAsP) was estimated using the tricuspid regurgitation gradient and applying the modified Bernoulli equation to convert this value into pressure values. The respiratory frequency (FR) at rest was determined as the number of breaths per minute (bpm), and the response to intravenous lobeline was calculated as the % increase over this control value. A Student's paired t-test was used for finding the significance of change of the lobeline dose (for threshold sensations), before and after the medication period as well as for the estimated pulmonary artery pressure, distance walked in metres and duration of exercise by the modified Bruce protocol. The mean of each was expressed as ± SEM, and a P value of b0.05 was considered as statistically significant.

3. Results Five of the patients were cyanotic at rest and the WHO class of the group ranged from 2 to 3 (Table. 1). Their mean resting SaO2, heart rate, blood pressure (systolic) and FR were 89.7 (SD = 1.4) mmHg, 90.8 (SD = 4.2) bpm, 121.3 (SD = 5.1) mmHg and 24 bpm, respectively (Table 2). The right ventricular function as calculated from echocardiographic findings of all patients, with the exception of one was normal. This patient was the only one of the group who had experienced episodes of syncope. 3.1. Influence on clinical status After 6 weeks of oral sildenafil, the mean pulmonary artery systolic pressure fell from 108.5 to 89.2 mmHg (P = 0.01), whereas the prevailing SaO2 remained unchanged at 89% (P = 0.8). There was a significant improvement in 6MWT distance from 453.3 (SD = 50.9) to 516.6 (SD = 48.9) m (P = 0.001), and the duration of exercise undertaken according to the modified Bruce protocol increased from 7 min 53 s (SD = 0.04) to 10 min 44 s (SD = 0.88) (P = 0.001); the estimated METs likewise increased from 4.7 (SD = 0.53) to 6.7 (SD = 0.84) (P = 0.002). The respiratory sensations reported at the termination of exercise ranged from breathlessness, dryness in throat and mouth, pain in midsternal area. These were reported to be less intense after medication, i.e., the dyspnea WHO status improved to a range of 1–2 (Table 2). 3.2. Influence on responses to lobeline i.v. The mean dose of lobeline i.v. that initially produced an acceleration in breathing was 37.5 (SD = 3.4) μg/kg (range 20–45 μg/kg), and after 6 weeks of sildenafil medication, it could be produced by doses as small 20.6 (SD = 1.8) μg/kg (range 15–30) (P = 0.001). Resting FR did not change with sildenafil medication, but in response to threshold doses of lobeline i.v., it increased to 30% over resting values as compared to a 23% increase that was seen before medication. The accompanying sensations when reported were dryness in mouth or throat, slightly cold air /burning sensation /tickle in chest/ pressure in chest, heaviness in head and need to take in more air.

2.4. Lobeline study

3.3. Relationship of PAsP to lobeline threshold dose Lobeline-HCl (Sigma, USA) solution was prepared in normal saline (2 mg/ml) and injected through the right ante-cubital vein as a bolus [13]. The injections were accompanied by a continuous record of thoraco-abdominal movements by means of a pneumograph connected to a Statham P23 Gb, on a Polyrite 4 recorder (Medicare Systems, India). Respiratory frequency (FR) was calculated from it as breaths per minute (bpm). 2.4.1. Nature of respiratory sensations / symptoms evoked by lobeline i.v. The minimal dose of lobeline that produced a distinct respiratory effect was referred to as the threshold dose; determining this was possible only after repeated injections of the dose that first elicited a respiratory response. Normal saline (0.5 ml) injected into the same site served as the control or placebo. Subjects were instructed to signal when any of the following sensations were felt: (1) need to take in more air; (2) awareness of breathing rapidly; (3) awareness of tightness in throat/chest with an inability to breathe due to it; (4) suffocation/choking; (5) dryness, irritation, heat in mouth or throat; (6) pressure in nose, throat or chest of air/cold air/smoke; (7) pain or burning in midsternal or epigastric area; (8) need to cough or a cough; (9) palpitations; and (10) any other. Reticence was expected to be overcome by repeatedly drawing their attention to this list.

A significant observation was the direct relationship of PAsP to the lobeline-sensation threshold dose (Fig. 1). Fig. 1. further illustrates that these were inversely related to the distance walked with 6MWT and duration of exercise with the modified Bruce protocol. 4. Discussion After as early as 6 weeks of sildenafil medication, there was a noteworthy improvement in the clinical status of all ES patients in this group. This was evinced from a significant increase in both the distance walked with 6MWT and of the duration of treadmill exercise, which was concluded with a diminished intensity of respiratory distress. These results conformed with those of earlier studies of long term treatment

Please cite this article as: Anand A, et al, Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: Role of J receptors, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.131

A. Anand et al. / International Journal of Cardiology xxx (2014) xxx–xxx

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Table 1 Data of patients with echocardiographic findings that confirmed the diagnosis of Eisenmenger syndrome. Features such as elevated levels of haemoglobin due to erythrocytosis and urea are also typical of the syndrome. The other characteristic clinical findings of cyanosis seen in 55% of the patients (before sildenafil treatment) was seen in 33% (after treatment). Patient no.

1 2 3 4 5 6 7 8 9

Age (years) and sex

23 M 23 M 23 M 33 M 24 M 30 M 19 F 28 F 35 M

Hb (g%)

Urea (mg/dl)

15 18 22 15 17 16.5 18 15 13

22 37 29 22 32 26 20 26 46

of Eisenmenger syndrome patients with sildenafil [4,5]. However, the novel findings from this study are (i) a marked attenuation of J receptor activity as seen from their response to a fall in lobeline dose (their chemical stimulant) while being associated with alleviation of their symptoms, and (ii) no notable improvement in resting levels of SaO2 within the therapy duration. 4.1. Lobeline threshold dose; its fall and its significance A series of previous studies had established that the dose of lobeline required to produce threshold level of respiratory effects in healthy individuals was between 12 and 18 μg/kg (mean dose = 15 μg/kg) [13, 17,18]. In untreated ES patients, the mean lobeline-threshold dose of 37.5 ± 3.4 μg/kg and was significantly higher than that seen in normals (see above). After 6 weeks of sildenafil medication, the dose that produced threshold levels of respiratory stimulation and sensations fell significantly to 20.6 ± 1.8 μg/kg. In an earlier experimental study, it had been established that that with a fall in pulmonary artery pressure, the threshold dose of the chemical stimulant of J receptors, that was required to produce the same level of their neural activity as that under unchanged hemodynamics, was reduced [20]. In the context of the present observations, i.e., at higher PAsP of untreated ES patients, the lobeline dose required to produce threshold levels of respiratory sensations was in fact higher, and decreased when PAsP fell after sildenafil medication. Thus, the high lobeline threshold doses in these patients were a consequence of raised PAsP and to which they are directly related (Fig. 1). This observation is consistent with the recorded afferent activity of J receptors in the animal study [20]. As the pulmonary hemodynamic status of patients with idiopathic pulmonary hypertension or Eisenmenger syndrome does change with treatment with PDE5 inhibitors, the neural output from J receptors

Cyanosis

Syncope

WHO class

Before

After

Before

After

Before

After

0 1 1 1 0 0 1 0 1

0 1 1 1 0 0 0 0 0

0 0 0 0 0 0 0 0 1

0 0 0 0 0 1 0 0 0

2 3 3 2 2 3 2 2 3

2 2 2 2 1 2 2 1 2

would also be expected to be reduced and thus also the level of their reflexes, which in earlier studies has been established to be an increase respiratory rate accompanied by distressful respiratory sensations (dyspnea) and inhibition of exercise [14,15]. 4.1.1. Absence of respiratory sensations and responses to some injections of lobeline In view of the fact that all patients had a ventricular septal defect, not all injections of lobeline delivered intravenously arrived into the pulmonary circulation and at least some were diverted into the systemic circulation, thus bypassing the location and stimulation of J receptors. This resulted in the absence of their respiratory effects being seen with several injections of lobeline with the threshold dose being determined only after repeated injections of the lowest to higher doses in range. The frequent absence of reporting of respiratory sensations that usually accompanied respiratory stimulation could be explained by the patients not being able to differentiate them from what they normally felt. This was a noteworthy difference from patients with left heart disease who were able to describe them clearly, possibly because disease in the latter occurred in adulthood [15,6]. 4.1.2. Contribution of other pathways It has been pointed out in a recent study that in patients with congenital heart disease, an impairment of lung function occurs over a period of time [21] and it may be considered that the lung function improved with sildenafil treatment so as to alleviate symptoms. However, in ES patients, alveolar ventilation is nearly uniform with only a mild impairment of ventilatory function due to raised residual values [22,23]. It is highly unlikely that any underlying lung-function abnormalities that may have been present in these patients were reversed in the short duration of medication that was given. It may also be relevant to

Table 2 Haemodynamic estimates and clinical findings of patients with ES before after 6 weeks of medication with sildenafil 20 mg (×3DS). 6MWD increased significantly from 453 ± 50.9 s (7 min 55 s) to 516 ± 48.5 s (9 min). Exercise duration with the modified Bruce protocol increased from 522 ± 57 s (9 min 10 s) to 704 ± 51 s (12 min 13 s). After medication all patients were able to reach the next higher stage of the exercise protocol and their dyspnea index, likewise, fell to 1–2 levels below. PAsP Patient no.

1 2 3 4 5 6 7 8 9 Mean SEM P value

SaO2

(mm Hg)

Heart rate

(mm Hg)

BP (Systolic)

(bpm)

(mmHg)

6MWT

Exercise duration

(m)

Max stage reached

(s)

Before

After

Before

After

Before

After

Before

After

Before

After

Before

After

Before

After

78 103 88 117 127 104 110 104 101 103.5 4.8 0.01

82 87 78 105 100 92 86 86 87 89.2 2.8

92 92 84 90 89 98 91 88 84 89.7 1.44 0.8

91 92 88 89 90 84 92 86 92 89.3 0.95

77 85 93 96 101 83 77 90 116 90.8 4.16 0.9

55 83 81 98 105 92 104 102 100 91.1 5.37

106 122 102 127 100 124 134 142 135 121.3 5.1 0.19

85 110 93 125 112 139 102 149 98 112.5 7.1

400 360 540 720 580 480 380 440 180 453.3 50.9 0.0001

440 440 600 750 620 560 440 560 240 516.6 48.5

596 180 486 520 750 603 620 620 330 522 57 0.0001

722 480 750 689 850 850 759 815 426 704 51

3 2 3 3 4 4 3 4 2

4 3 5 4 5 5 5 5 5

Please cite this article as: Anand A, et al, Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: Role of J receptors, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.131

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A. Anand et al. / International Journal of Cardiology xxx (2014) xxx–xxx

exercise testing may have added value to such a study, but this is not available at our Centre. The patients were on stable dose of diuretics for at least 4 weeks. Other therapies including anti-arrhythmics, beta-blockers, etc., which could have affected dyspnoea and exercise capacity [28], were withheld during the study period. Majority of the patients did not have ideal haemoglobin levels for arterial saturation. Anemia is relatively more common in our country but we excluded patients with severe anemia (b14 g%). The mean haemoglobin concentration was similar to that of ES patients in other studies from our centre [28,29]. The iron status of the patients was not determined and none were treated with iron therapy during this time which has been shown to improve exercise capacity [30]. 6. Conclusions A reduction in J receptor output appears to be a definitive pathway in the “relief” of ES patients from exertional breathlessness with sildenafil medication which is indicated by a decrease in the lobeline threshold dose required for producing their respiratory effects chemically. This finding also suggests that the initial dyspneic distress and limitation of physical activity was contributed to, by an increased J receptor afferent output at the existing pulmonary hemodynamic levels. Acknowledgements

Fig. 1. Distance walked (6MWT) and duration of exercise by Eisenmenger patients were inversely related to the prevailing pulmonary artery systolic pressure or PAsP; the dose of lobeline required for eliciting threshold levels of respiratory responses was related to the latter directly (open symbols). None of these relationships changed after 6 weeks of 20 mg TDS sildenafil (filled circles). It further illustrates that within this interval, the prevailing arterial oxygen values (SaO2) remained unchanged, and from this, it may be concluded that the latter had no role in increasing the duration of exercise.

point out that in mitral stenosis patients, lung function (air flow) abnormalities still persist up to a year after percutaneous balloon valvulotomy, even though the patients become dyspnoea-free [24]. It has been reported that in patients treated with sildenafil, there is some indication of a decrease in the respiratory drive during incremental exercise which is seen as a reduction in the slope of VE/VCO2, but inexplicably in this study, there was no noteworthy improvement in 6MWT values [25]. In chronic heart failure patients, an improvement in alveolar-capillary membrane gas exchange that occurs in response to some other PDE5 inhibitors [26] could possibly be another pathway that renders “relief” to ES patients, but it is not known if and how soon after medication this changes in them. The resting SaO2 level, which did not improve within the present short duration of medication, suggests that it was not a key factor in the improvement of the clinical status of the patients, at least, within this duration. The improvement in dyspnoea following sildenafil could also be a reflection of an increase in cardiac output and/or anaerobic threshold. Hemodynamic studies in Eisenmenger syndrome carried out after treatment with Tadalafil (also an oral phoshodiestrase type-5 inhibitor) have suggested that the increase in cardiac output is marginal [4]. Furthermore, earlier studies have been unable to document a significant increase in anaerobic threshold following sildenafil in normal individuals [27,28] and in patients of ES [25]. 5. Limitations of the study Right heart catheterization study pre and postintervention would have been ideal to assess changes in hemodynamics. However, this was not acceptable to the ethics committee. Detailed cardio-pulmonary

The study was supported by Department of Science and Technology (India).Conflict of interestNo conflict of interest exists for the following authors Ashima Anand, Niraj Srivastava, Parag Barwad, Sivasubramanian Ramakrishnan, Ambuj Roy and Balram Bhargava. Authors contributionsDr. Anand had contributed to study conception, design, data analysis and interpretation and writing the manuscript and served as first author and takes full responsibility for the accuracy of data analysis. Dr. Srivastava contributed to the conduct of the lobeline study and to its data analysis and presentation. Dr. Barwad contributed to the clinical and echocardiographic evaluation of patients, acquiring their data and its analysis. Dr. S. Ramakrishnan had initiated the idea and contributed to design and interpretation and added critical content to the manuscript and served as corresponding author. Dr. Roy and Dr. Bhargava have contributed to the design of the study and have revised it critically for important intellectual content. All the authors provided final approval of the version to be published. We thank Dr. Hans Raj for his invaluable comments and discussions. References [1] Woods P. The Eisenmenger syndrome or pulmonary hypertension with reversed central shunt. Br Med J 1958;2:701–9. [2] Vongpatanasin W, Brickner ME, Hillis LD, et al. The Eisenmenger syndrome in adults. Ann Intern Med 1998;128:745–55. [3] Celermajer DS, Cullen S, Deanfield JE. Impairment of endothelium-dependent pulmonary artery relaxation in children with congenital heart disease and abnormal pulmonary hemodynamics. Circulation 1993;87(2):440–6. [4] Mukhopadhyay S, Sharma M, Ramakrishnan S, et al. Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study. Circulation 2006;114:1807–10. [5] Chau EM, Fan KY, Chow WH. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension. Int J Cardiol 2007;120:301–5. [6] Tay EL, Papaphylactou M, Diller GP, et al. Quality of life and functional capacity can be improved in patients with Eisenmenger syndrome with oral sildenafil therapy. Int J Cardiol 2011;149:372–6. [7] Michelakis E, Tymchak W, Lien D, et al. Oral sildenafil is an effective and specific pulmonary vasodilator in patients with pulmonary arterial hypertension: comparison with inhaled nitric oxide. Circulation 2002;105:2398–403. [8] Singh TP, Rohit M, Grover A, Malhotra S, Vijayvergiya R. A randomized, placebocontrolled, double-blind, crossover study to evaluate the efficacy of oral sildenafil therapy in severe pulmonary artery hypertension. Am Heart J 2006;151:851–5.

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Please cite this article as: Anand A, et al, Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: Role of J receptors, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.04.131

Dyspnea in Eisenmenger syndrome and its amelioration by sildenafil: role of J receptors.

In Eisenmenger syndrome (ES), oral phosphodiesterase type-5 inhibitors, which are preferential pulmonary vasodilators, reduce the elevated pulmonary a...
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