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Beta blocker for patients with pulmonary arterial hypertension: A single center experience
International Journal of Cardiology 184 (2015) 528–532
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Beta blocker for patients with pulmonary arterial hypertension: A single center experience Claudio Moretti a, Walter Grosso Marra a, Fabrizio D'Ascenzo a,⁎, Pierluigi Omedè a, Margherita Cannillo a, Daniela Libertucci c, Enrico Fusaro d, Ilaria Meynet a, Francesca Giordana a, Davide Salera a, Umberto Annone a, S.L. Chen e, Sebastiano Marra b, Fiorenzo Gaita a a
Division of Cardiology, University of Turin, Città Della Salute e Della Scienza, Turin, Italy Division of Cardiology, Città Della Salute e Della Scienza, Turin, Italy c Division of Pneumology, Department of Internal Medicine, Città Della Salute e Della Scienza, Turin, Italy d Division of Rheumatology, Department of Internal Medicine, Città Della Salute e Della Scienza, Turin, Italy e Department of Cardiology, Njang, China b
a r t i c l e
i n f o
Article history: Received 31 December 2014 Accepted 21 February 2015 Available online 24 February 2015 Keywords: Pulmonary arterial hypertension PAH Beta blockers
Consequently we wanted to assess impact of BBs on PAH patients (defined as in current guidelines [11,12]) referred to our center. At each medical contact baseline features (age, comorbidity, kind of PAH), therapeutic choice (target therapies and not PAH related drugs), echocardiographic and right catheterization data were recorded. Prespecified visits were performed each 6 months, with exceptions due to clinical or instrumental variations or introduction of new therapies. All data were recorded and analyzed according to use of beta blockers, its indications, and ninety-four patients were enrolled in two years.
Table 1 Baseline features of patients.
Pulmonary arterial hypertension (PAH) leads to right ventricle (RV) failure, the most frequent cause of death [1] with an ominous impact on prognosis [2]. The most validated target therapies are based on inhibition of endothelin and thromboxane or augmentation of nitric oxide (NO) and prostacyclin [3] with an improvement of symptoms and of instrumental data, but without a defined impact on prognosis [3,4]. These drugs are focused on arterial remodeling but as a matter of fact mortality and symptoms are closely related to unfavorable remodeling of RV [5]. This negative evolution of a cardiomyopathy represents a common finding in left ventricle diseases, for which beta blockers represent a validated therapy [6]. In guidelines Beta Blockers (BBs) are described as potentially harmful, due to their negative inotropic effect [7]. This indication, however, relies on only one study of ten patients with portopulmonary PAH [8]. Bisoprolol has been shown to reduce progression to RV failure in experimental models, reducing sympathetic stimulation [9]. A report on more than 100 patients showed a neutral effect of BBs therapy on PAH patients, although without conclusive data on RV function, which may represent the most important target for BBs therapy [10]. ⁎ Corresponding author. E-mail address: [email protected] (F. D'Ascenzo). URL: http://www.cardiogroup.org (F. D'Ascenzo).
http://dx.doi.org/10.1016/j.ijcard.2015.02.033 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Female gender Age Weight PAH diagnosis – Idiopathic – Connective tissue related – HIV – Portal hypertension – Congenital heart disease – Post pulmonary embolism – Out of proportion – Mixed WHO class – I – II – III – IV Risk – Low – Intermediate – High NT-proBNP (pg/ml) Systolic arterial pressure (mm Hg) Heart rate (bpm)
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
3 (30%) 59 ± 13 60 ± 13
25 (42) 61 ± 14 68 ± 13
0.37 0.81 0.12
1 (11) 3 (30) 0 (0) 3 (30) 1 (11) 0 (0) 1 (11) 0 (0)
13 (22) 9 (15) 1 (1.7) 6 (10) 4 (7) 13 (22) 7 (12) 5 (9)
0.41 0.19 0.97 0.09 0.52 0.09 0.72 0.48
0 (0) 7 (70) 3 (30) 0 (0)
5 (8.6) 17 (30) 32 (55) 4 (6.9)
0.44 0.02 0.13 0.52
1 (11) 5 (56) 3 (30) 2940 ± 1500 139 ± 17
14 (23) 27 (46) 18 (35) 1271 ± 1300 120 ± 12
0.45 0.51 0.34 0.03 0.02
75 ± 8
74 ± 9
0.56
C. Moretti et al. / International Journal of Cardiology 184 (2015) 528–532 Table 2 Therapy of patients.
Diuretic Oral anti-coagulant therapy Digoxin Calcium channel blockers Spironolactone Ace-inhibitors Endothelin receptor antagonist Phosphodiesterase type 5 inhibitor Patients on monotherapy Patients on double therapy
529
Table 3 Beta blocker therapy. Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
9 (90) 4 (40) 1 (10) 5 (50) 6 (60) 5 (50) 5 (50) 1 (10)
45 (70) 45 (70) 4 (7) 17 (28) 40 (65) 15 (30) 31 (57) 14 (23)
0.41 0.04 0.34 0.45 0.51 0.45 0.59 0.31
4 (40) 1 (10)
33 (50) 6 (10)
0.29 0.89
Atenolol 100 mg
1 dose 1 pt 1/2 dose 1 pt 1/4 2 pts 1/2 2 pts 2 cp 1 pt 1 + 1/2 cp 1 pt 1/4 × 2 1 pt 1 cp 1 pt
Bisoprolol 5 mg
Baseline features of patients are summarized in Table 1. Endothelin receptor antagonists were the most exploited target therapies (Table 2). Ten patients assumed BBs therapies, being systemic arterial hypertension the most frequent indication (Fig. 1) and bisoprolol the most frequent choice (Table 3). Patients assuming BBs did not show significant differences in baseline features, apart from presenting with higher systolic arterial systemic pressure and proBNP values (Table 1). Baseline data at right catheterization and at echocardiography did not differ between patients assuming and non-assuming BBs (Table 4). After a median follow-up of 24 months (9–36) 3 patients died, 13 reported heart failure and 13 were hospitalized for RV failure (Table 5). BBs were well tolerated and not discontinued in any patients. It has not been recorded any difference between the patients belonging to the two groups in the target therapy (Table 6) At right catheterization (Fig. 2), a parallel and not different increase in mean pulmonary pressure was noted (10 ± 9 vs. 10 ± 8, p 0.45) without differences in cardiac output, while arteriolar resistance was significantly reduced for patients assuming BBs (− 1.5 ± 0.5 vs. − 0.5 ± 0.3, p 0.045). At echocardiographic assessment (Fig. 3), patients on BBs showed a higher improvement in TAPSE (6.50 ± 4 vs. 0.62 ± 2, p 0.021) and a reduction of RV diameter (− 4.50 ± 2.1 vs. 1.13 ± 0.67, p 0.04). Symptomatic status did not change, while proBNP decreased more significantly for BBs patients (up/l −410 ± 300 vs. −100 ± 50, p 0.42, see Figs. 1–4). Our results suggest a high tolerability of BBs in PAH patients, and a positive impact on instrumental variables. Though in other setting of patients BBs are commonly discontinued, due to the relevant side effects [13], this did not occur during the followup. The negative inotropic effect of BBs doesn't seem to translate into clinical arm for PAH patients: no differences in WHO class, hospitalization for heart failure and in syncope were reported. On the contrary, BBs positively modify RV dimension and function, with a reduction of
1.0
Propranolol 40 mg Metoprolol 100 mg Nadolol 20 mg
Table 4 Baseline right catheterization and echocardiographical data. Patients on beta blockers (10;11%) Right catheterization data Cardiac output (l/min) Wedge pressure (mm Hg) Systolic pulmonary pressure (mm Hg) Medium pulmonary pressure (mm Hg) Diastolic pulmonary pressure (mm Hg) Arteriolar pulmonary resistance (Woods unit) Echocardiographic data Ejection fraction E/e′ Systolic pulmonary pressure (mm Hg) Right atrial pressure TAPSE (mm) FAC (%) Diameter of right ventricle (mm) Area of right ventricle (mm2)
Patients not on beta blockers (84;89%)
p
4.2 ± 0.8 14 ± 6 64 ± 12
4.8 ± 1.2 12 ± 9 68 ± 22
0.23 0.34 0.69
41 ± 13
43 ± 14
0.69
26 ± 7
25 ± 9
0.61
6.6 ± 2.2
6.8 ± 3.1
0.87
58 ± 4 16 ± 9 73 ± 32
61 ± 6 13 ± 4 71 ± 22
0.71 0.06 0.45
8.7 ± 4.1 18 ± 3 32 ± 3 46 ± 8 35 ± 4
0.26 0.45 0.54 0.51 0.39
10.7 ± 6 19 ± 4 35 ± 6 43 ± 7 27 ± 2
its diameter and an improvement of TAPSE, possibly due to a reduction of RV fibrosis [14]. Meantime, probably due to a reduction of right ventricle's stress, it decreased RV inflammation, with a potential protective effect towards fibrosis, a common finding in many pro-inflammatory clinical situation [15], especially for patients with PAH associated with connective disease [16]. Since pulmonary pressure increased equally between the two arms, but TAPSE improved and RV diameter decreased in the BBs arm, we hypothesized BBs can prevent right heart remodeling. At a first glance, this result collides with the negative inotropic effect of BBs. Similarly to what happened with BBs in left-heart failure, we interpreted these paradoxical results with the neuro-ormonal theory of heart failure,
1.0
1.0
1.0
6.0
coronary artery disease
systemic arterial hypertension
heart failure
Fig. 1. Reason for assuming beta-blockers.
atrial arrythmias
cirrhosis
530
C. Moretti et al. / International Journal of Cardiology 184 (2015) 528–532
Table 5 Outcome of patients after 24 (8–39) months.
Heart failure related to right ventricle Hospitalization for heart failure related to right ventricle Syncope Death Reduction of – Systolic blood pressure (mm Hg) – Heart rate (bpm)
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
3 (30)
10 (37)
0.56
0 (0)
5 (18)
0.8
0 (0) 1 (10)
1 (4) 2 (5)
0.9 0.7
−11.3 ± 4.5
3.5 ± 10.4
0.03
−4.5 ± 0.5
−3.3 ± 0.7
0.04
We also evaluated plasma concentration of NT-proBNP which was significantly reduced in BBs branch of study, suggesting a lower parietal stress in right atrium, and indirectly a better RV systolic function. Our study suggests that BBs could be used safely in PAH patients, focusing primarily on right-heart remodeling, that actually doesn't have a dedicated therapy. According to our small cohort and study design we have found some crucial issues. Firstly, safety of BBs was insured by the absence of a significant increase in number of deaths, heart-failure, hospitalization or syncope. Secondly, BBs use doesn't turn into a hemodynamic impairment, but BBs seem to have a cardio-protective effect against myocardial functional damage lead by catecholamine stress, as supposed in left-heart failure. There are some initial experiences on patients with PAH, that showed no adverse effects [10], but led to a significant functional improvement in patients with IPH and reductions in RV dimensions [19].
according to which high plasma concentration of catecholamine may determine a significant functional impairment and mechanical remodeling of myocardium [17,18].
Variation for cardiac output (l/min)
1.80
Variation for cardiac output (l/min)
0.80
Variation for wedge pressure (mmHg)
4.00
Variation for wedge pressure (mmHg)
3.00
Variation for PAPs (mmHg)
10.00
Variation for PAPs (mmHg)
11.00
Variation for PAPd (mmHg)
5.00
Variation for PAPd (mmHg)
4.00
Variation for PAPm (mmHg)
20.00
Variation for PAPm (mmHg)
16.00
Variation for arterioral resistance (Wood units)
-1.00
Variation for arterioral resistance (Wood units) -10
-5
-0.50 0
5
10
15
20
25
30
Fig. 2. Variation of cath lab data after a median of 24 months.
Variation for ejection fraction
5.30
Variation for ejection fraction
3.24
Variation for E/e' ratio
7.00
Variation for E/e' ratio
7.11
Variation for sPAP
4.00
Variation for sPAP
3.00
Variation for right ventricle diameter
-4.50
Variation for right ventricle diameter
1.13
Variation for TAPSE
6.50
Variation for TAPSE
-10
-5
0.62
Variation for FAC
5.00
Variation for FAC
4.50
0
5
10
15
20
Fig. 3. Variation of echo data after a median of 24 months (decrease of right ventricle diameter and increase of TAPSE was significant, p 0.021 and 0.04, respectively).
C. Moretti et al. / International Journal of Cardiology 184 (2015) 528–532
Variation for WHO
-0.50
-0.20
Variation for WHO
Variation for 6MWT (m)
150.00
Variation for 6MWT (m)
156.00
Variation for proBNP
-410.00
-100.00
Variation for proBNP
-500
-400
-300
-200
-100
531
0
100
200
300
400
500
% Fig. 4. Variation of clinical data after a median of 24 months (decrease of proBNP was significant, p 0.42).
Table 6 Target therapy of the patients at follow-up.
Endothelin receptor antagonist Phosphodiesterase type 5 inhibitor Patients on monotherapy Patients on double therapy
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
6 (55)
43 (59)
0.61
4 (10)
19 (28)
0.98
4 (40) 6 (60)
33 (45) 51 (55)
0.29 0.76
Our preliminary data need to be read taking into account several limitations. First of all, the observational architecture of the study doesn't allow us to establish a causal correlation between positive findings and treatment. The small numerosity, and consequent low statistical power, probably has masked many potential positive results. Future studies are however needed to confirm on a larger scale these preliminary results, investigating deeper the correlation between clinical and hemodynamic outcomes with specific BBs at specific dosages in patients afflicted by PAH. Conflict of interest The authors report no relationships that could be construed as a conflict of interest. References [1] S.L. Archer, E.K. Weir, M.R. Wilkins, Basic science of pulmonary arterial hypertension for clinicians: new concepts and experimental therapies, Circulation 121 (18) (May 11 2010) 2045–2066. [2] T. Thenappan, S.J. Shah, S. Rich, M. Gomberg-Maitland, A USA-based registry for pulmonary arterial hypertension: 1982–2006, Eur. Respir. J. 30 (2007) 1103–1110. [3] G. Biondi-Zoccai, F. D'Ascenzo, M. Cannillo, N.J. Welton, W.G. Marra, P. Omedè, D. Libertucci, E. Fusaro, M. Capriolo, J. Perversi, F. Fedele, G. Frati, M. Mancone, J.J. Dinicolantonio, C.D. Vizza, C. Moretti, F. Gaita, Choosing the best first line oral drug agent in patients with pulmonary hypertension: evidence from a network meta-analysis, Int. J. Cardiol. 168 (4) (Oct 9 2013) 4336–4338. [4] N. Galiè, A. Manes, L. Negro, M. Palazzini, M.L. Bacchi-Reggiani, A. Branzi, A metaanalysis of randomized controlled trials in pulmonary arterial hypertension, Eur. Heart J. 30 (4) (Feb 2009) 394–403.
[5] M.L. Handoko, F.S. de Man, C.P. Allaart, W.J. Paulus, N. Westerhof, A. VonkNoordegraaf, Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart, Eur. Respir. Rev. 19 (115) (Mar 2010) 72–82. [6] S. Chatterjee, G. Biondi-Zoccai, A. Abbate, F. D'Ascenzo, D. Castagno, B. Van Tassell, D. Mukherjee, E. Lichstein, Benefits of β blockers in patients with heart failure and reduced ejection fraction: network meta-analysis, BMJ 346 (Jan 16 2013) f55. [7] N. Galiè, M.M. Hoeper, M. Humbert, A. Torbicki, J.L. Vachiery, J.A. Barbera, M. Beghetti, P. Corris, S. Gaine, J.S. Gibbs, M.A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau, ESC Committee for Practice Guidelines (CPG), Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT), Eur. Heart J. 30 (20) (Oct 2009) 2493–2537. [8] S. Provencher, P. Herve, X. Jais, D. Lebrec, M. Humbert, G. Simonneau, O. Sitbon, Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension, Gastroenterology 130 (1) (Jan 2006) 120–126. [9] F.S. de Man, M.L. Handoko, J.J. van Ballegoij, I. Schalij, S.J. Bogaards, P.E. Postmus, J. van der Velden, N. Westerhof, W.J. Paulus, A. Vonk-Noordegraaf, Bisoprolol delays progression towards right heart failure in experimental pulmonary hypertension, Circ. Heart Fail. 5 (1) (Jan 2012) 97–105. [10] P.P. So, R.A. Davies, G. Chandy, D. Stewart, R.S. Beanlands, H. Haddad, C. Pugliese, L.M. Mielniczuk, R. Bouallal, F. Godart, C. Francart, A. Richard, C. Foucher-Hossein, C. Lions, Usefulness of beta-blocker therapy and outcomes in patients with pulmonary arterial hypertension, Am. J. Cardiol. 109 (10) (May 15 2012) 1504–1509. [11] V.V. McLaughlin, S.L. Archer, D.B. Badesch, R.J. Barst, H.W. Farber, J.R. Lindner, M.A. Mathier, M.D. McGoon, M.H. Park, R.S. Rosenson, L.J. Rubin, V.F. Tapson, J. Varga, American College of Cardiology Foundation, Task Force on Expert Consensus Documents, American Heart Association, American College of Chest Physicians, American Thoracic Society, American Heart Association, American College of Chest Physicians, American Thoracic Society, Pulmonary Hypertension Association, ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians, American Thoracic Society, Inc., and the Pulmonary Hypertension Association, J. Am. Coll. Cardiol. 53 (2009) 1573–1619. [12] G. Simonneau, I.M. Robbins, M. Beghetti, R.N. Channick, M. Delcroix, C.P. Denton, C.G. Elliott, S.P. Gaine, M.T. Gladwin, Z.C. Jing, M.J. Krowka, D. Langleben, N. Nakanishi, R. Souza, Updated clinical classification of pulmonary hypertension, J. Am. Coll. Cardiol. 54 (2009) S43–S54 (3). [13] P.M. Ho, A. Lambert-Kerzner, E.P. Carey, I.E. Fahdi, C.L. Bryson, S.D. Melnyk, H.B. Bosworth, T. Radcliff, R. Davis, H. Mun, J. Weaver, C. Barnett, A. Barón, E.J. Del Giacco, Multifaceted intervention to improve medication adherence and secondary prevention measures after acute coronary syndrome hospital discharge: a randomized clinical trial, JAMA Intern. Med. 174 (2) (Feb 1 2014) 186–193. [14] H.J. Bogaard, R. Natarajan, S. Mizuno, A. Abbate, P.J. Chang, V.Q. Chau, N.N. Hoke, D. Kraskauskas, M. Kasper, F.N. Salloum, N.F. Voelkel, Adrenergic receptor blockade reverses right heart remodeling and dysfunction in pulmonary hypertensive rats, Am. J. Respir. Crit. Care Med. 182 (2010) 652–660.
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[15] E. Cerrato, F. D'Ascenzo, G. Biondi-Zoccai, A. Calcagno, S. Frea, W. Grosso Marra, D. Castagno, P. Omedè, G. Quadri, F. Sciuto, D. Presutti, G. Frati, S. Bonora, C. Moretti, F. Gaita, Cardiac dysfunction in pauci symptomatic human immunodeficiency virus patients: a meta-analysis in the highly active antiretroviral therapy era, Eur. Heart J. 34 (19) (May 2013) 1432–1436. [16] R. Hesselstrand, A. Scheja, D.M. Wuttge, H. Arheden, M. Ugander, Enlarged rightsided dimensions and fibrosis of the right ventricular insertion point on cardiovascular magnetic resonance imaging is seen early in patients with pulmonary arterial hypertension associated with connective tissue disease, Scand. J. Rheumatol. 40 (2) (Mar 2011) 133–138.
[17] G. Iaccarino, E.D. Tomhave, R.J. Lefkowitz, W.J. Koch, Reciprocal in vivo regulation of myocardial G protein-coupled receptor kinase expression by beta-adrenergic receptor stimulation and blockade, Circulation 98 (1998) 1783–1789. [18] M.J. Lohse, S. Engelhardt, T. Eschenhagen, What is the role of beta-adrenergic signaling in heart failure? Circ. Res. 93 (2003) 896–906. [19] Tao Yang, Yu Liang, Yan Zhang, Qing Gu, Guo Chen, Xin-Hai Ni, Xiu-Zhang Lv, ZhiHong Liu, Chang-Ming Xiong, Jian-Guo He, Echocardiographic parameters in patients with pulmonary arterial hypertension: correlations with right ventricular ejection fraction derived from cardiac magnetic resonance and hemodynamics, PLoS One 8 (8) (2013) e71276 (Published online 2013 August 14).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Beta blocker for patients with pulmonary arterial hypertension: A single center experience Claudio Moretti a, Walter Grosso Marra a, Fabrizio D'Ascenzo a,⁎, Pierluigi Omedè a, Margherita Cannillo a, Daniela Libertucci c, Enrico Fusaro d, Ilaria Meynet a, Francesca Giordana a, Davide Salera a, Umberto Annone a, S.L. Chen e, Sebastiano Marra b, Fiorenzo Gaita a a
Division of Cardiology, University of Turin, Città Della Salute e Della Scienza, Turin, Italy Division of Cardiology, Città Della Salute e Della Scienza, Turin, Italy c Division of Pneumology, Department of Internal Medicine, Città Della Salute e Della Scienza, Turin, Italy d Division of Rheumatology, Department of Internal Medicine, Città Della Salute e Della Scienza, Turin, Italy e Department of Cardiology, Njang, China b
a r t i c l e
i n f o
Article history: Received 31 December 2014 Accepted 21 February 2015 Available online 24 February 2015 Keywords: Pulmonary arterial hypertension PAH Beta blockers
Consequently we wanted to assess impact of BBs on PAH patients (defined as in current guidelines [11,12]) referred to our center. At each medical contact baseline features (age, comorbidity, kind of PAH), therapeutic choice (target therapies and not PAH related drugs), echocardiographic and right catheterization data were recorded. Prespecified visits were performed each 6 months, with exceptions due to clinical or instrumental variations or introduction of new therapies. All data were recorded and analyzed according to use of beta blockers, its indications, and ninety-four patients were enrolled in two years.
Table 1 Baseline features of patients.
Pulmonary arterial hypertension (PAH) leads to right ventricle (RV) failure, the most frequent cause of death [1] with an ominous impact on prognosis [2]. The most validated target therapies are based on inhibition of endothelin and thromboxane or augmentation of nitric oxide (NO) and prostacyclin [3] with an improvement of symptoms and of instrumental data, but without a defined impact on prognosis [3,4]. These drugs are focused on arterial remodeling but as a matter of fact mortality and symptoms are closely related to unfavorable remodeling of RV [5]. This negative evolution of a cardiomyopathy represents a common finding in left ventricle diseases, for which beta blockers represent a validated therapy [6]. In guidelines Beta Blockers (BBs) are described as potentially harmful, due to their negative inotropic effect [7]. This indication, however, relies on only one study of ten patients with portopulmonary PAH [8]. Bisoprolol has been shown to reduce progression to RV failure in experimental models, reducing sympathetic stimulation [9]. A report on more than 100 patients showed a neutral effect of BBs therapy on PAH patients, although without conclusive data on RV function, which may represent the most important target for BBs therapy [10]. ⁎ Corresponding author. E-mail address: [email protected] (F. D'Ascenzo). URL: http://www.cardiogroup.org (F. D'Ascenzo).
http://dx.doi.org/10.1016/j.ijcard.2015.02.033 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
Female gender Age Weight PAH diagnosis – Idiopathic – Connective tissue related – HIV – Portal hypertension – Congenital heart disease – Post pulmonary embolism – Out of proportion – Mixed WHO class – I – II – III – IV Risk – Low – Intermediate – High NT-proBNP (pg/ml) Systolic arterial pressure (mm Hg) Heart rate (bpm)
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
3 (30%) 59 ± 13 60 ± 13
25 (42) 61 ± 14 68 ± 13
0.37 0.81 0.12
1 (11) 3 (30) 0 (0) 3 (30) 1 (11) 0 (0) 1 (11) 0 (0)
13 (22) 9 (15) 1 (1.7) 6 (10) 4 (7) 13 (22) 7 (12) 5 (9)
0.41 0.19 0.97 0.09 0.52 0.09 0.72 0.48
0 (0) 7 (70) 3 (30) 0 (0)
5 (8.6) 17 (30) 32 (55) 4 (6.9)
0.44 0.02 0.13 0.52
1 (11) 5 (56) 3 (30) 2940 ± 1500 139 ± 17
14 (23) 27 (46) 18 (35) 1271 ± 1300 120 ± 12
0.45 0.51 0.34 0.03 0.02
75 ± 8
74 ± 9
0.56
C. Moretti et al. / International Journal of Cardiology 184 (2015) 528–532 Table 2 Therapy of patients.
Diuretic Oral anti-coagulant therapy Digoxin Calcium channel blockers Spironolactone Ace-inhibitors Endothelin receptor antagonist Phosphodiesterase type 5 inhibitor Patients on monotherapy Patients on double therapy
529
Table 3 Beta blocker therapy. Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
9 (90) 4 (40) 1 (10) 5 (50) 6 (60) 5 (50) 5 (50) 1 (10)
45 (70) 45 (70) 4 (7) 17 (28) 40 (65) 15 (30) 31 (57) 14 (23)
0.41 0.04 0.34 0.45 0.51 0.45 0.59 0.31
4 (40) 1 (10)
33 (50) 6 (10)
0.29 0.89
Atenolol 100 mg
1 dose 1 pt 1/2 dose 1 pt 1/4 2 pts 1/2 2 pts 2 cp 1 pt 1 + 1/2 cp 1 pt 1/4 × 2 1 pt 1 cp 1 pt
Bisoprolol 5 mg
Baseline features of patients are summarized in Table 1. Endothelin receptor antagonists were the most exploited target therapies (Table 2). Ten patients assumed BBs therapies, being systemic arterial hypertension the most frequent indication (Fig. 1) and bisoprolol the most frequent choice (Table 3). Patients assuming BBs did not show significant differences in baseline features, apart from presenting with higher systolic arterial systemic pressure and proBNP values (Table 1). Baseline data at right catheterization and at echocardiography did not differ between patients assuming and non-assuming BBs (Table 4). After a median follow-up of 24 months (9–36) 3 patients died, 13 reported heart failure and 13 were hospitalized for RV failure (Table 5). BBs were well tolerated and not discontinued in any patients. It has not been recorded any difference between the patients belonging to the two groups in the target therapy (Table 6) At right catheterization (Fig. 2), a parallel and not different increase in mean pulmonary pressure was noted (10 ± 9 vs. 10 ± 8, p 0.45) without differences in cardiac output, while arteriolar resistance was significantly reduced for patients assuming BBs (− 1.5 ± 0.5 vs. − 0.5 ± 0.3, p 0.045). At echocardiographic assessment (Fig. 3), patients on BBs showed a higher improvement in TAPSE (6.50 ± 4 vs. 0.62 ± 2, p 0.021) and a reduction of RV diameter (− 4.50 ± 2.1 vs. 1.13 ± 0.67, p 0.04). Symptomatic status did not change, while proBNP decreased more significantly for BBs patients (up/l −410 ± 300 vs. −100 ± 50, p 0.42, see Figs. 1–4). Our results suggest a high tolerability of BBs in PAH patients, and a positive impact on instrumental variables. Though in other setting of patients BBs are commonly discontinued, due to the relevant side effects [13], this did not occur during the followup. The negative inotropic effect of BBs doesn't seem to translate into clinical arm for PAH patients: no differences in WHO class, hospitalization for heart failure and in syncope were reported. On the contrary, BBs positively modify RV dimension and function, with a reduction of
1.0
Propranolol 40 mg Metoprolol 100 mg Nadolol 20 mg
Table 4 Baseline right catheterization and echocardiographical data. Patients on beta blockers (10;11%) Right catheterization data Cardiac output (l/min) Wedge pressure (mm Hg) Systolic pulmonary pressure (mm Hg) Medium pulmonary pressure (mm Hg) Diastolic pulmonary pressure (mm Hg) Arteriolar pulmonary resistance (Woods unit) Echocardiographic data Ejection fraction E/e′ Systolic pulmonary pressure (mm Hg) Right atrial pressure TAPSE (mm) FAC (%) Diameter of right ventricle (mm) Area of right ventricle (mm2)
Patients not on beta blockers (84;89%)
p
4.2 ± 0.8 14 ± 6 64 ± 12
4.8 ± 1.2 12 ± 9 68 ± 22
0.23 0.34 0.69
41 ± 13
43 ± 14
0.69
26 ± 7
25 ± 9
0.61
6.6 ± 2.2
6.8 ± 3.1
0.87
58 ± 4 16 ± 9 73 ± 32
61 ± 6 13 ± 4 71 ± 22
0.71 0.06 0.45
8.7 ± 4.1 18 ± 3 32 ± 3 46 ± 8 35 ± 4
0.26 0.45 0.54 0.51 0.39
10.7 ± 6 19 ± 4 35 ± 6 43 ± 7 27 ± 2
its diameter and an improvement of TAPSE, possibly due to a reduction of RV fibrosis [14]. Meantime, probably due to a reduction of right ventricle's stress, it decreased RV inflammation, with a potential protective effect towards fibrosis, a common finding in many pro-inflammatory clinical situation [15], especially for patients with PAH associated with connective disease [16]. Since pulmonary pressure increased equally between the two arms, but TAPSE improved and RV diameter decreased in the BBs arm, we hypothesized BBs can prevent right heart remodeling. At a first glance, this result collides with the negative inotropic effect of BBs. Similarly to what happened with BBs in left-heart failure, we interpreted these paradoxical results with the neuro-ormonal theory of heart failure,
1.0
1.0
1.0
6.0
coronary artery disease
systemic arterial hypertension
heart failure
Fig. 1. Reason for assuming beta-blockers.
atrial arrythmias
cirrhosis
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Table 5 Outcome of patients after 24 (8–39) months.
Heart failure related to right ventricle Hospitalization for heart failure related to right ventricle Syncope Death Reduction of – Systolic blood pressure (mm Hg) – Heart rate (bpm)
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
3 (30)
10 (37)
0.56
0 (0)
5 (18)
0.8
0 (0) 1 (10)
1 (4) 2 (5)
0.9 0.7
−11.3 ± 4.5
3.5 ± 10.4
0.03
−4.5 ± 0.5
−3.3 ± 0.7
0.04
We also evaluated plasma concentration of NT-proBNP which was significantly reduced in BBs branch of study, suggesting a lower parietal stress in right atrium, and indirectly a better RV systolic function. Our study suggests that BBs could be used safely in PAH patients, focusing primarily on right-heart remodeling, that actually doesn't have a dedicated therapy. According to our small cohort and study design we have found some crucial issues. Firstly, safety of BBs was insured by the absence of a significant increase in number of deaths, heart-failure, hospitalization or syncope. Secondly, BBs use doesn't turn into a hemodynamic impairment, but BBs seem to have a cardio-protective effect against myocardial functional damage lead by catecholamine stress, as supposed in left-heart failure. There are some initial experiences on patients with PAH, that showed no adverse effects [10], but led to a significant functional improvement in patients with IPH and reductions in RV dimensions [19].
according to which high plasma concentration of catecholamine may determine a significant functional impairment and mechanical remodeling of myocardium [17,18].
Variation for cardiac output (l/min)
1.80
Variation for cardiac output (l/min)
0.80
Variation for wedge pressure (mmHg)
4.00
Variation for wedge pressure (mmHg)
3.00
Variation for PAPs (mmHg)
10.00
Variation for PAPs (mmHg)
11.00
Variation for PAPd (mmHg)
5.00
Variation for PAPd (mmHg)
4.00
Variation for PAPm (mmHg)
20.00
Variation for PAPm (mmHg)
16.00
Variation for arterioral resistance (Wood units)
-1.00
Variation for arterioral resistance (Wood units) -10
-5
-0.50 0
5
10
15
20
25
30
Fig. 2. Variation of cath lab data after a median of 24 months.
Variation for ejection fraction
5.30
Variation for ejection fraction
3.24
Variation for E/e' ratio
7.00
Variation for E/e' ratio
7.11
Variation for sPAP
4.00
Variation for sPAP
3.00
Variation for right ventricle diameter
-4.50
Variation for right ventricle diameter
1.13
Variation for TAPSE
6.50
Variation for TAPSE
-10
-5
0.62
Variation for FAC
5.00
Variation for FAC
4.50
0
5
10
15
20
Fig. 3. Variation of echo data after a median of 24 months (decrease of right ventricle diameter and increase of TAPSE was significant, p 0.021 and 0.04, respectively).
C. Moretti et al. / International Journal of Cardiology 184 (2015) 528–532
Variation for WHO
-0.50
-0.20
Variation for WHO
Variation for 6MWT (m)
150.00
Variation for 6MWT (m)
156.00
Variation for proBNP
-410.00
-100.00
Variation for proBNP
-500
-400
-300
-200
-100
531
0
100
200
300
400
500
% Fig. 4. Variation of clinical data after a median of 24 months (decrease of proBNP was significant, p 0.42).
Table 6 Target therapy of the patients at follow-up.
Endothelin receptor antagonist Phosphodiesterase type 5 inhibitor Patients on monotherapy Patients on double therapy
Patients on beta blockers (10;11%)
Patients not on beta blockers (84;89%)
p
6 (55)
43 (59)
0.61
4 (10)
19 (28)
0.98
4 (40) 6 (60)
33 (45) 51 (55)
0.29 0.76
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