Response to Inhaled Nitric Oxide, but Neither Sodium Nitroprusside Nor Sildenafil, Predicts Survival in Patients With

Home , Sodium nitroprusside

Jachec et al., J Clin Exp Cardiolog 2015, 6:6 Clinical & Experimental Cardiology http://dx.doi.org/10.4172/2155-9880.1000376

Research Article Open Access Response to Inhaled Nitric Oxide, But neither Sodium Nitroprusside nor Sildenafil, Predicts Survival in Patients with Dilated Cardiomyopathy Complicated with Pulmonary Hypertension Wojciech Jacheć1*, Celina Wojciechowska2, Andrzej Tomasik2, Damian Kawecki2, Ewa Nowalany-Kozielska2 and Jan Wodniecki2 1II Katedra i Oddział Kliniczny Kardiologii w Zabrzu Śląskiego Uniwersytetu Medycznego w Katowicach, ul. Skłodowskiej 10, 41-800 Zabrze, Polska 2Department of Cardiology in Zabrze, Medical University of Silesia in Katowice, Poland *Corresponding author: Wojciech Jacheć, II Katedra i Oddział Kliniczny Kardiologii w Zabrzu Śląskiego Uniwersytetu Medycznego w Katowicach, ul. Skłodowskiej 10, 41-800 Zabrze, Polska, Tel: +48 32 373 23 72; Fax: +48 32 271 10 10; E-mail: [email protected] Received date: May 26, 2015, Accepted date: Jun 25, 2015, Published date: Jun 29, 2015 Copyright: ©2015 Jacheć W. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Pulmonary hypertension in patients with dilated cardiomyopathy is associated with higher mortality.

Objectives: The aim of the study was to assess the predictive value of the vasodilator response to three different drugs, sodium nitroprusside, inhaled nitric oxide, and oral sildenafil, in patients with dilated cardiomyopathy complicated with pulmonary hypertension.

Patients and methods: Twenty-nine patients with dilated cardiomyopathy complicated with postcapillary pulmonary hypertension (left ventricle ejection fraction (LVEF) 20.6 ± 8.2%, mean pulmonary artery pressure (mPAP) 42.49 ± 7.27 mmHg, transpulmonary gradient (TPG)>12 mmHg or pulmonary vascular resistance index (PVRI)>5 WU/m2) underwent single-session vaso reactivity testing with sodium nitroprusside, inhaled nitric oxide (120 ppm), oral sildenafil (50 mg), and a combination of sildenafil and inhaled nitric oxide. The vasodilator responders were defined as those participants who achieved a reduction of PVRI<5 WU/m2 and TPG<12 mmHg.

The primary study endpoint was death in the 30-month-long follow-up. Kaplan-Meier analysis and Cox proportional hazard modelling were used to identify the predictors of survival.

Results: In the follow-up, eight patients died (six patients with irreversible pulmonary hypertension). Six patients underwent successful heart transplantation. Multivariate Cox proportional hazard analysis disclosed a response to nitric oxide as the only predictor of longer survival (HR=11.77, 95% CI=1.12-123.9 at P=0.04).

Conclusions: Vasodilator response to inhaled nitric oxide predicts longer survival in patients with dilated cardiomyopathy complicated with pulmonary hypertension.

Keywords: Dilated cardiomyopathy; Pulmonary hypertension; (cGMP) in vascular smooth muscle cells, resulting in pulmonary Nitric oxide; Vasodilator response; Survival arteries vasorelaxation [8]. INO administered to patients with heart failure, in contrast to intravenous sodium nitroprusside, reduces Introduction selectively pulmonary vascular resistance without influence on systemic arterial pressure or systemic resistance [9]. Pulmonary hypertension is frequently observed in patients with dilated cardiomyopathy and heart failure. This results from passive Sildenafil citrate, a phosphodiesterase-5 inhibitor, leads to transmission of elevated left ventricle end-diastolic pressure, and accumulation of cGMP, and it has been proven to be selective for eventually reactive pulmonary vasoconstriction occurs [1]. It is pulmonary circulation [10]. A single oral dose of sildenafil has also considered a relative contraindication to cardiac transplantation been proven to be as effective pulmonary vasodilator as iNO, and their listing, if irreversible [2], and is associated with higher mortality and combination synergistically increases cGMP level [11]. morbidity in heart transplant candidates, recipients [3], and other Several papers have concerned the use of various drugs for testing patients [4,5]. of pulmonary hypertension reversibility in a pre-transplant evaluation According to Costard-Jackle et al. [6], and Drakos et al. [7] [12-14]. The results of these studies were inconsistent. Some favored vasoreactivity testing with intravenous sodium nitroprusside in heart either prostaglandin or prostacyclin, and others favored iNO. It is of transplant candidates, identifies a subgroup of patients with excellent note that the major limitation of these studies was the small number of post-transplant prognosis. enrolled patients. Moreover, the issue of the predictive value of vasodilator response in patients with dilated cardiomyopathy Inhaled nitric oxide (iNO), more specific pulmonary vasodilator, complicated with pulmonary hypertension remains unanswered. increases the concentration of cyclic guanosine monophosphate

J Clin Exp Cardiolog Volume 6 • Issue 6 • 1000376 ISSN:2155-9880 JCEC, an open access journal Citation: Jachec W, Wojciechowska C, Tomasik A, Kawecki D, Nowalany-Kozielska E et al. (2015) Response to Inhaled Nitric Oxide, But neither Sodium Nitroprusside nor Sildenafil, Predicts Survival in Patients with Dilated Cardiomyopathy Complicated with Pulmonary Hypertension. J Clin Exp Cardiolog 6: 376. doi:10.4172/2155-9880.1000376

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Therefore, we designed and conducted this prospective cohort predicting long-term survival in patients with dilated cardiomyopathy study to examine the utility of vasodilator response to three different and pulmonary hypertension. agents and a combination thereof (oral sildenafil and iNO) in

All patients (n=29) Survivors (n=21) Deaths (n=8) P

Women n (%) 6 (20.7) 5 (23.8) 1 (12.5) NSa

Age, years 45.5 ± 8.9 45.58 ± 8.9 45.8 ± 9.6 NSb

Duration of disease, years 5.8 ± 3.8 6.34 ± 3.94 4.52 ± 3.19 NSb

Diabetes n (%) 3 (10.3) 1 (4.8) 2 (25) NSa

Systemic hypertension n (%) 3 (10.3) 3 (14.3) 0 (0) NSa

NTproBNP, pg/mL 1599.4 ± 847.3 1507.3 ± 928.4 1758.7 ± 662.9 NSb

I–1; II-10; I-1; II-9; II-1; III-6; NYHA class (n) NSa III–15; IV-3 III-9; IV-2 IV-1

Serum sodium, mmol/L 137.2 ± 5.80 137.3 ± 5.67 137.0 ± 6.58 NSb

Serum creatinine, mmol/L 82.88 ± 17.73 80.32 ± 18.81 89.56 ± 13.28 NSb

LVEDD, mm 71.24 ± 8.0 70.05 ± 8.50 74.75 ± 5.73 NSb

LVEDV, ml 230.5 ± 68.5 220.2 ± 73.18 260.63 ± 48.33 NSb

LVEF, % 20.6 ± 8.2 22.86 ± 8.83 15.13 ± 3.80 P<0.05b

6-MWT, m 454.1 ± 73.1 449.5 ± 70.42 486.4 ± 66.77 NSb

mABP, mmHg 92.26 ± 13.8 93.91 ± 15.08 88.05 ± 9.01 NSb

mPAP, mmHg 42.49 ± 7.27 42.07 ± 7.91 43.46 ± 5.64 NSb

TPG, mmHg 15.14 ± 4.32 14.37 ± 4.06 17.31 ± 4.44 NSb

PAWP, mmHg 27.24 ± 6.31 27.57 ± 7.35 26.14 ± 6.02 NSb

PVRI, WU/m2 8.1 ± 3.31 7.53 ± 3.32 9.69 ± 2.71 NSb

SVRI, WU/m2 41.6 ± 10.83 41.09 ± 10.50 43.42 ± 11.59 NSb

Vasodilator responder n (%):

NTP 20/29 (69.0) 16/21 (76.2) 4/8 (50.0) NSa

NO 19/29 (65.5) 17/21 (81.0) 2/8 (25.0) P<0.05a

SIL 18/29 (62.1) 15/21 (71.4) 3/8 (37.5) NSa

SIL/NO 19/29 (65.5) 17/21 (81.0) 2/8 (25.0) P<0.05a

Data presented are mean ± standard deviation or absolute numbers with percentage for categorical data. aχ2 test, bMann-Whitney U test LVEDD: Left Ventricle End-Diastolic Diameter; LVEDV: Left Ventricle End-Diastolic Volume; LVEF: Left Ventricle Ejection Fraction; mABP: Mean Arterial Blood Pressure; 6-MWT: 6 Minute Walking Test; NO: Nitric Oxide; NTP: Sodium Nitroprusside; PAWP: Pulmonary Capillary Wedge Pressure; PVRI: Pulmonary Vascular Resistance Index; SIL: Sildenafil, SIL/NO: Combination of Oral Sildenafil and Inhaled Nitric Oxide; SVRI: Systemic Vascular Resistance Index; TPG: Transpulmonary Gradient

Table 1: Demographic, echocardiographic and baseline hemodynamic (B-L) characteristics of patients stratified by vital status at completion of follow-up.

Patients and Methods between May 2005 and February 2009. We identified 79 patients with pulmonary postcapillary hypertension defined as mPAP>25 mmHg Of 150 consecutive patients with dilated cardiomyopathy and PWP>15 mmHg. Of these patients, we selected 29 patients (6 (idiopathic or post inflammatory) referred for management of heart women) with TPG>12 mm Hg (24 patients) and/or PVRI>5 WU/m2 failure, 111 patients were subject to routine procedure of periodical (5 patients) for enrollment into the study (Table I) [15]. All of the hemodynamic assessment as a part of heart transplantation evaluation

Page 3 of 8 patients underwent right heart catheterization and a single session of as cardiac index (CI). Systolic (sABP) and diastolic (dBAP) systemic pulmonary artery vasoreactivity testing with sodium nitroprusside, arterial pressure were measured non-invasively. For each examined iNO (120 ppm), and oral sildenafil (50 mg) and repeat inhalation of drug PWP was measured two times, before and after CO nitric oxide. measurements and systemic arterial pressure was measured three times: before, during third and after fifth CO measurements. Other Inclusion criteria were dilated cardiomyopathy (history of heart hemodynamic parameters were acquired five times during each CI failure longer than six months), left ventricle ejection fraction measurement-mean values were used for final evaluation. Acquired LVEF<35%, mPAP at least 25 mmHg supine at rest and no data enabled calculation of mean pulmonary artery pressure (mPAP) angiographic evidence of coronary artery disease. All patients were and mean systemic arterial pressure (mABP), transpulmonary examined for significant valvular/congenital heart disease, requiring gradient (TPG), pulmonary vascular resistance index (PVRI) and surgical repair - none of the enrolled patients had the systemic vascular resistance index (SVRI): echocardiographic evidence of significant valvular pathology. All patients were on optimal pharmacological treatment for heart failure • mPAP (mm Hg) equals the sum of dPAP and one third of a (Table 2), and the treatment was not modified within a month before subtraction of sPAP and dPAP in pulmonary artery (mPAP=dPAP enrollment into the study. The exclusion criteria were: previous use of +[sPAP-dPAP]/3) sildenafil, recent heart failure worsening, and diseases leading to • TPG (mm Hg) equals difference of mPAP and PWP pulmonary hypertension such as severe obstructive lung disease, sleep (TPG=mPAP-PWP) apnea syndrome, or pulmonary embolism. In the follow-up, patients • PVRI (WU/m2) equals quotient of TPG and CI (PVRI=TPG / CI) were evaluated every three to six months on an ambulatory basis for 30 • mABP (mm Hg) equals the sum of diastolic arterial blood pressure months. The study endpoint was death in the follow-up. The patients (dABP) and one third of a subtraction of sABP and Dabp who underwent cardiac transplantation during follow-up were (mABP=dABP+[sABP-dABP]/3) withdrawn as alive cases from further observation (censored • SVRI (WU/m2) equals quotient of subtraction of mABP, RAP and observation). CI ([mABP-RAP]/CI). All patients Survivors Deaths P Blood pressure parameters were expressed in millimeters of (n=29) (n=21) (n=8) mercury (mm Hg), CI as liters per minute per square meter (l/min/ β blockers n (%) 28 (96.5) 20 (95.2) 8 (100) NSa m2), heart rate as number of heart beats per minute. Measured parameters of resistance (PVRI, SVRI) were expressed in WU/m2. ACE-I n (%) 27 (93.1) 20 (95.2) 7 (87.5) NSa The ratio of pulmonary vascular resistance index to systemic ARB n (%) 14 (48.3) 11 (52.4) 3 (37.5) NSa vascular resistance index (PVRI/SVRI) served as a measure of Digitalis n (%) 21 (72.4) 15 (71.4) 6 (75.0) NSa pulmonary selectivity of examined drugs. In brief, drug leading to reduction of the ratio was assumed to be selective for pulmonary Spironolactone n (%) 26 (89.6) 19 (90.5) 7 (87.5) NSa circulation.

Loop diuretics n (%) 21 (79.6) 14 (66.7) 7 (87.5) NSa Protocol of vasoreactivity testing Statins n (%) 13 (44.8) 10 (47.6) 3 (37.5) NSa The hemodynamic measurements were made at baseline (NTP B- Data presented are absolute numbers and percentages L), and then, via the jugular sheath, an intravenous infusion of aχ2 test maximum tolerated dose of sodium nitroprusside (1-4 μg/kg/min) was ACE-I: Angiotensin Converting Enzyme Inhibitors ARB: Angiotensin Receptor Blockers started. NTP solution was prepared immediately before administration and we used infusion pumps with light resistant amber syringes, and IV lines to prevent NTP breakdown. The infusion of NTP was Table 2: Baseline medical treatment stratified by vital status at interrupted when TPG decreased below 12 mmHg or systemic systolic completion of follow-up. arterial blood pressure dropped below 85 mm Hg, or when reaching a maximum dose of 4 μg/kg/min. Hemodynamic data were monitored The protocol was approved by the Ethics Committee of the Medical continuously, and the data at the peak nitroprusside activity (NTP) University of Silesia. Written, informed consent was obtained from all were recorded for further analysis. The duration of nitroprusside enrolled patients before screening. infusion did not exceed 10 min throughout the study. Ten minutes were allowed for washout of sodium nitroprusside, and repeat Right heart catheterization hemodynamic measurements were taken (NO B-L). Subsequently, Patients underwent right heart catheterization via right jugular patients were administered iNO 120 parts per million (ppm). iNO access under local anesthesia in a supine position at rest. A 7F (INOmax 400 ppm mol/mol, INO Therapeutics AB, Lidingö, Sweden) introducer (Balton, Warsaw, Poland) was inserted and then flow- was administered via a face mask from a source tank equipped with a directed Swan-Ganz catheter (Edwards Lifesciences, Irvine, USA) was microflow gauge (Linde France SA, Malmaison, France). Ten minutes advanced to right heart and pulmonary artery under fluoroscopy. of iNO inhalation were allowed before consecutive hemodynamic After 10 minutes of stabilization of circulation parameters pulmonary recordings were performed (NO). After measurements, iNO wedge pressure (PWP), systolic pulmonary artery pressure (sPAP), inhalation was terminated, and 10 min were allowed for NO washout. diastolic pulmonary artery pressure (dPAP) and right atrium pressure Its half-life is approximately 3 min [11]. Afterward, third baseline (RA) were measured. Cardiac output (CO) was measured by measurements (and fifth consecutive) were recorded (SIL B-L), and 50 thermodilution using rapid bolus injection of 10 cc of cold saline. mg of sildenafil citrate (Viagra-Pfizer) was administered orally. Fifty Then cardiac output was indexed by body surface area and expressed minutes were allowed for sildenafil to start its activity, and consecutive

Page 4 of 8 hemodynamic measurements were recorded (SIL). Afterward, the final Results NO inhalation at 120 ppm was administered for 10 min with a final (seventh consecutive) hemodynamic measurement (SIL/NO) Table 1 presents the clinical, echocardiographic and baseline recording [16,17]. All measurements were performed during end hemodynamic data stratified according to participants’ vital status at expiration. At each measuring point, five results were averaged, and an the completion of follow-up. There were eight deaths (27.6%) in the arithmetic mean was recorded. It was assumed that pulmonary follow-up: one out of a group of five patients with TPG<12, seven in hypertension was reversible with a successful reduction of PVRI<5 group of patients with TPG ≥ 12 mm Hg (difference is not significant 2 WU/m2 and TPG<12 mmHg. Such an order of vasodilator drug P=0.8944, χ with Yates correction). The all cohort of decedents had a testing enabled us, in our opinion, to avoid unintentional drug significantly lower left ventricle ejection fraction, and there were interaction. The entire right heart catheterization and vasoreactivity significantly fewer responders to inhaled nitric oxide and a testing took no longer than 2 h. The feasibility and safety of such a combination of oral sildenafil and inhaled nitric oxide in this cohort. protocol was assessed in a pilot study and reported previously [18]. Four patients had chronic atrial fibrillation: three out of survivors (14.3%) and one out of decedents (12.5%, the difference is not 2 Statistical analysis significant P=0.6328, χ with Yates correction). There were five patients with implanted ICD, 1 patient with implanted CRTP and 1 Continuous variables are presented as the mean ± standard patient with implanted CRTD in the cohort of survivors. There were 3 deviation and were compared with Mann-Whitney U test. Categorical patients with implanted CRTP in the decedent’s cohort. In this regard data are presented as absolute numbers and percentages and were the cohorts did not differ. compared using χ2 tests. Survival analysis of all death and censored Both cohorts of survivors and decedents were treated similarly at cases, based on Kaplan-Meier curves and log-rank tests were used to baseline (Table 2), and none of the patients received sildenafil citrate assess the event-free survival between responders and non-responders. in the follow-up. Cox proportional hazards regression analysis was applied to identify the variables associated with long-term outcome in these patients. All Table 3 presents hemodynamic measurements obtained during demographic, clinical, echocardiographic, and hemodynamic variables right heart catheterization and vasoreactivity testing with studied and whether the patient was a vasodilator responder were included in drugs. Sodium nitroprusside was administered intravenously at a a univariate Cox analysis, but only variables with a value of P ≤ 0.1 at mean dose of 1.83 ± 0.8 μg/kg/min. Eight patients had an initial mABP univariate analysis were included in the multivariate model. Post-hoc below 85 mmHg, and nitroprusside infusion led to a decrease of power calculations for the primary endpoint were computed either. A mABP below 85 mmHg in another 18 patients. Twenty patients two-tailed P value<0.05 was considered significant. Statistical analysis (69.0%) met the reversibility criteria. was performed with Statistica 8.0 software (Statsoft Inc., Tulsa, USA).

NTP B-L NTP iNO B-L iNO SIL B-L SIL SIL/NO

mPAP, mmHg 42.49 ± 7.27 23.79 ± 8.30a 41.22 ± 7.05 40.53 ± 7.25 43.76 ± 7.49 36 ± 9.43b 35.33 ± 9.34c

mABP, mmHg 92.26 ± 13.81 72.5 ± 10.45a 89.49 ± 13.40 92.16 ± 16.31 95.02 ± 14.23 88.23 ± 14.30 88.22 ± 13.40

PAWP, mmHg 27.24 ± 6.94 13.81 ± 6.52a 26.42 ± 6.73 32.07 ± 7.23d 28.06 ± 7.15 25.24 ± 8.24 26.91 ± 8.70

TPG, mmHg 15.15 ± 4.33 9.99 ± 3.69a 14.69 ± 4.20 8.57 ± 4.66e 15.6 ± 4.46 10.76 ± 3.98c 8.43 ± 3.90cf

CI, l/min/m2 1.96 ± 0.39 2.78 ± 0.71a 1.9 ± 0.38 1.87 ± 0.42 2.02 ± 040 2.24 ± 0.40g 2.12 ± 0.47

PVRI, WU/m2 8.09 ± 3.31 3.59 ± 1.05a 7.84 ± 3.21 4.85 ± 3.39e 8.33 ± 3.40 5.06 ± 2.38c 4.24 ± 2.28c

SVRI, WU/m2 41.6 ± 10.82 24.85 ± 7.80a 40.35 ± 10.50 44.94 ± 13.44 42.85 ± 11.15 36.68 ± 9.91g 38.04 ± 9.65

PVRI/SVRI Ratio 0.195 ± 0.057 0.154 ± 0.06h 0.195 ± 0.056 0.104 ± 0.055e 0.195 ± 0.056 0.136 ± 0.048c 0.107 ± 0.047c

Data presented are mean ± standard deviation. Statistical analysis was performed using Mann-Whitney U test. aP<0.001 between NTP and NTP B-L, bP<0.01 between SIL and SIL B-L, cP<0.001 between SIL and SIL B-L, dP<0.05 between iNO and iNO B-L, eP<0.001 between iNO and iNO B-L, fP<0.05 between SIL/NO and SIL, gP<0.05 between SIL and SIL B-L, hP<0.05 between NTP and NTP B-L. B-L: Baseline (equilibrium) measurements

Table 3: Hemodynamic measurements obtained during right heart catheterization and vasoreactivity testing with studied drugs.

During inhalation of nitric oxide nineteen patients (65.5%) were with vasoreactivity challenge was well tolerated, and none of the classified as responders. Oral sildenafil disclosed eighteen responders patients developed any adverse effects. (62.1%). The combination of oral sildenafil and iNO proved to have a Stratification of patients’ baseline hemodynamic measurements mixed effect on hemodynamic measurements. INO abolished the CI according to vasodilator response (Table 4) revealed that the cohort of increase and SVRI reduction caused by sildenafil and led to a massive responders to each of the studied drug had a significantly lower TPG consecutive reduction of TPG and PVRI/SVRI ratio to values and PVRI. Responders to studied drugs had similar clinical and comparable to iNO alone (Table 3, columns NO and SIL/NO). echocardiographic characteristics (data not shown). Nineteen patients (65.5%) were classified as responders to the combination of sildenafil and iNO. The right heart catheterization

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NTP iNO SIL SIL/NO All patients Nonresp Nonresp Nonresp Nonresp Resp (n=20) Resp (n=19) Resp (n=18) Resp (n=19) (n=9) (n=10) (n=11) (n=10)

mABP, mmHg 92.26 ± 13.8 91.98 ± 13.34 92.97 ± 15.57 91.69 ± 12.56 93.44 ± 16.55 92.00 ± 13.99 92.73 ± 14.12 94.06 ± 14.66 88.93 ± 11.96

mPAP, mmHg 42.49 ± 7.27 41.58 ± 8.30 44.40 ± 4.01 41.20 ± 8.02 44.84 ± 5.18 40.82 ± 8.38 45.13 ± 4.07 40.68 ± 7.83 45.82 ± 4.83

TPG, mmHg 15.14 ± 4.32 13.55 ± 2.74 18.79 ± 5.05a 13.15 ± 2.50 19.04 ± 4.44a 13.43 ± 2.81 18.04 ± 4.88a 13.34 ± 2.78 18.67 ± 4.61b

CI l/min/m2 1.87 ± 0.37 1.93 ± 0.32 1.77 ± 0.473 1.98 ± 0.30 1.76 ± 0.458 1.96 ± 0.33 1.77 ± 0.42 2.00 ± 0.29 1.72 ± 0.46

PAWP, mmHg 27.24 ± 6.31 27.88 ± 7.88 25.61 ± 4.12 27.90 ± 7.69 25.80 ± 5.31 27.22 ± 7.97 27.09 ± 5.15 27.19 ± 7.69 27.15 ± 5.59

PVRI, WU/m2 8.1 ± 3.31 7.03 ± 1.76 10.56 ± 4.51a 6.63 ± 1.52 10.97 ± 3.85b 6.86 ± 1.86 10.20 ± 4.05b 6.68 ± 1.58 10.88 ± 3.91b

SVRI, WU/m2 41.6 ± 10.83 40.88 ± 9.39 43.68 ± 13.47 39.53 ± 8.81 45.91 ± 12.98 40.42 ± 10.11 44.02 ± 10.01 40.42 ± 9.21 44.24 ± 13.15

Data presented are mean ± standard deviation. Statistical analysis was performed Mann-Whitney U test. aP<0.05, bP<0.01 (non-responder vs. responder for respective study drug or combination thereof)

Table 4: Baseline hemodynamic measurements stratified by vasodilator response to studied.

There were eight deaths observed in the follow-up (the mean SIL/NO non-responder) was included in the univariate proportional follow-up was 1.61 ± 0.99 years). Kaplan-Meier event-free survival hazards model (Table 5). In the final multivariate model, left ventricle curves of responders versus non-responders to studied drugs are ejection fraction, creatinine level, NYHA class, being non-responder to shown in Figure 1. Survival analysis demonstrates improved survival inhaled nitric oxide and being a non-responder to a combination of for responders to iNO and a combination of oral sildenafil and iNO oral sildenafil and iNO were included. Being a responder to iNO is the (Figure 1, panels B and D). The following clinical, echocardiographic, only variable that predicted improved survival according to the hemodynamic variables: patients’ sex, age, duration of the disease, multivariate Cox proportional hazard analysis. Contrary to this, non- LVEDD, LVEDV, LVEF, NTproBNP, creatinine, 6-MWT, NYHA responders to iNO have a death hazard ratio of 11.77 with a 95% CI classification, mABP, mPAP, TPG, PAWP, PVRI, and SVRI were used 1.117-123.9 (P=0.04). The post-hoc power computations yielded the in the univariate Cox proportional hazard analysis. Moreover, the power of 0.56 for the smaller group of iNO nor-responders (n=10) and information on whether the patient was a responder to a study drug power of 0.83 for the larger group of responders to iNO (n=19). (NTP non-responder, iNO non-responder, SIL non-responder,

Univariate Cox regression Multivariate Cox regression

n=29 HR 95% CI P HR 95% CI P

LVEF (1% increment) 0.875 0.782-0.979 0.02 0.847 0.699-1.026 0.089

Creatinine (1 μmol/L increment) 1.104 0.998-1.050 0.056 1.022 0.953-1.096 0.547

NYHA classification (1 class decrement) 2.981 0.918-9.675 0.069 0.748 0.184-3.040 0.684

iNO response (non-responder) 8.646 1.712-43.67 0.009 11.77 1.117-123.9 0.04

SIL/NO response (non-responder) 8.646 1.712-43.67 0.009 1.605 0.154-16.70 0.692

CI: Confidence Interval; HR: Hazard Ratio; LVEF: Left Ventricle Ejection Fraction; NYHA: New York Heart Association

Table 5: Univariate and multivariate Cox proportional hazard analysis. Data with P ≤ 0,1 at univariate analysis were included into multivariate model.

Patients with implanted electrotherapy devices (ICD, CRTP, patient, non-responder to all of the studied drugs, who underwent CRTD) did not show improved survival in our study. In the follow-up, heart transplantation. The results of her vasoreactivity testing were as six patients underwent successful cardiac transplantation, and as per follows: baseline TPG 12.61 mmHg, PVRI 7.11WU/m2; after protocol, they were considered alive and they were withdrawn from nitroprusside TPG 13.41 mmHg, PVRI 4,38 WU/m2; after iNO TPG further observation. 10.03 mmHg, PVRI 7.02 WU/m2; after SIL TPG 14.41 mmHg, PVRI 5.57 WU/m2, and after SIL/NO TPG 11.87 mmHg, PVRI 6.3 WU/m2. Figure 2 shows detailed scheme of vasoreactivity testing along with As seen above, none of the studied drugs proved to be effective in study follow-up. It summarizes that different studied drugs allowed identifying different patient populations. Of note is a case of female

Page 6 of 8 simultaneous reduction of both parameters to the level defined as hemodynamic properties. Two recent reports on the ability of iNO to reversible pulmonary hypertension. predict improved prognosis in adult patients with chronic thromboembolic pulmonary hypertension [19] and in a large cohort of Dana Point class 1, 3, 4, and 5 pulmonary hypertension patients [20] are available. Therefore, the results of our study are mutually supplementary with their observations and support the evidence that acute response to iNO predicts improved survival in pulmonary hypertension patients, independently of its etiology. The common denominator shared by our study and the observations of Krasuski et al. [20], acute vasodilator response to inhaled nitric oxide, requires further explanation. The first issue is the reversibility of pulmonary hypertension, and the second issue is iNO by itself. Chronically increased left ventricle end-diastolic and left atrial pressures are the driving force for a vicious cycle of continuous remodelling and functional derangements, which eventually leads to increases in pulmonary resistance and reduced pulmonary arterial compliance [21]. The significantly increased baseline TPG and PVRI in a cohort of Figure 1: Panel A: Kaplan-Meier death free survival in 30-months non-responders to studied drugs in our experiment (Table 4) support long follow-up depending on pulmonary hypertension reversibility the evidence of the progressive nature of pulmonary hypertension in tested with nitroprusside. Panel B: Kaplan-Meier death free survival left heart disease and indicate that preserved reversibility of in 30-months long follow-up depending on pulmonary hypertension is of paramount importance in improved survival. hypertension reversibility tested with nitric oxide. Panel C: Kaplan- Moreover, Krasuski et al. [20] reported a similar distribution of Meier death free survival in 30-months long follow-up depending baseline PVR values after stratification of the entire study population on pulmonary hypertension reversibility tested with sildenafil. to responders, non-responders, survivors and decedents. This Panel D: Kaplan-Meier death free survival in 30-months long observation might suggest some other factors, beyond preserved follow-up depending on pulmonary hypertension reversibility reversibility, contribute to an increased risk of mortality in patients tested with sildenafil and repeat inhalation of nitric oxide. with pulmonary hypertension and that we have not controlled for these factors in our experiment. Literature data provide evidence on right ventricle function [22], plasma big endothelin-1 level and natriuretic peptides [23-25] as other prognostic factors that might be suitable for precise risk stratification in patients with heart failure and pulmonary hypertension. Although, Wierzbicki et al. [25] reported significant correlations between pulmonary artery pressures and blood levels of NTproBNP in a cohort of patients scheduled for heart transplantation, and Fonarow et al. [24] indicated, that BNP level on admission is positively and linearly associated with in-hospital mortality, we failed to prove the prognostic ability of NTproBNP to predict mortality in our cohort. Szymik et al. [26] have reported on prognostic ability of left ventricle ejection fraction, NTproBNP, plasma glucose and bilirubin levels to predict three year survival. The discrepancies reported in the above mentioned publications and in our study may be explained by different patient populations studied. Recently a report on prognostic value of soluble ST2 protein in predicting composite endpoint of cardiovascular death, heart failure hospitalization, increase in NYHA class and increase in diuretics use Figure 2: Detailed scheme of vasoreactivity to different drugs along was published [27]. with outcomes that occurred in the follow-up. Ghio et al. [28] have reported that right ventricle function has prognostic significance in patients with chronic heart failure. Thus we might speculate that the vasodilative properties of iNO to increase Discussion PWP and secondary decrease of TPG and PVRI are the major In our prospective cohort study of patients with dilated predictors of reversible reactive component of pulmonary cardiomyopathy and mixed pulmonary hypertension, we proved that hypertension. The advantage of iNO over other tested drugs may acute responders to vasodilator challenge with iNO have improved result from redistribution of blood from precapillary to postcapillary survival. The administration of neither intravenous sodium pulmonary capacitance vessels with a consequent increase in left nitroprusside nor oral sildenafil was predictive of survival in our ventricle end-diastolic volume and filling pressure. This would have cohort of patients. All of the drugs used in our study have caused an increase in left ventricle stroke volume in normal but not in demonstrated similar efficacy in pulmonary hypertension reversibility, severily depressed left ventricle function and iNO might be considered although each of the drugs tested has unique vascular activity and

Page 7 of 8 as a drug inducing inotropic negative effect on failing left ventricle established prognostic significance in post transplantation period and [29]. nitric oxide for its predictive value in pre-transplantation period. Inhaled nitric oxide is the only drug, out of the three drugs tested in our experiment, found to be predictive of improved survival in Contribution statement patients with dilated cardiomyopathy and pulmonary hypertension. All of the authors contributed equally to the design of the study, D’Alto et al. [30] reported on the reversibility testing with collection and analysis of data, edition and preparation of final version epoprostenol infusion in patients with Eisenmenger syndrome. They of manuscript. accepted clinical worsening as a study end point, and they did not prove epoprostenol per se was predictive of improved patient prognosis. The authors concluded that the only independent predictor Acknowledgments of clinical worsening in a group of their patients was change in PVRI This research was supported by Medical University of Silesia grants (ΔPVRI). KNW-085-08 and NN-1-063/07, granted to WJ. We have not performed any further analyses that could explain this unique property of inhaled nitric oxide, but it is apparent that inhaled References nitric oxide at 120 ppm has the highest pulmonary specificity in 1. Ghio S (2005) Pulmonary hypertension in advanced heart failure. Herz comparison with sodium nitroprusside and oral sildenafil. Its 30: 311-317. pulmonary specificity might result from its extreme short half-life time 2. Mehra MR, Kobashigawa J, Starling R, Russell S, Uber PA et al. (2006) and the fact that it is degraded after passing pulmonary circulation. It Listing criteria for heart transplantation: International Society for Heart is also of note that the dose of 120 ppm used in our experiment is the and Lung Transplantation guidelines for the care of cardiac transplant highest of those reported previously [31]. Such a hemodynamic candidates-2006. The Journal of heart and lung transplantation: the vasodilator response is in contrast with that reported by Lepore et al. official publication of the International Society for Heart Transplantation [32] for 80 ppm iNO. 25: 1024-1042. 3. Butler J, Stankewicz MA, Wu J, Chomsky DB, Howser RL et al. (2005) Our results indicate the equal acute efficacy of sildenafil to reverse Pre-transplant reversible pulmonary hypertension predicts higher risk the pulmonary hypertension in comparison with infused sodium for mortality after cardiac transplantation. The Journal of heart and lung nitroprusside and inhaled nitric oxide but fail to indicate sildenafil transplantation: the official publication of the International Society for prognostic ability. This lack of prognostic properties in our Heart Transplantation 24: 170-177. experiment may be explained by alternative mechanism of sildenafil 4. Abramson SV, Burke JF, Kelly JJ Jr, Kitchen JG 3rd, Dougherty MJ, et al. action. It keeps the high level of cGMP, but earlier the natural stimuli (1992) Pulmonary hypertension predicts mortality and morbidity in have to activate its production. Nevertheless, sildenafil is of great hope patients with dilated cardiomyopathy. Ann Intern Med 116: 888-895. for the management of chronic heart failure. The drug has been 5. Cappola TP, Felker GM, Kao WH, Hare JM, Baughman KL, et al. (2002) proven to have beneficial effects on hemodynamics, clinical status, Pulmonary hypertension and risk of death in cardiomyopathy: patients with myocarditis are at higher risk. Circulation 105: 1663-1668. cardiac cachexia, and on improved peri-transplant survival in chronic 6. Costard-Jackle A, Fowler MB (1992) Influence of preoperative treatment of patients with advanced heart failure and severe pulmonary artery pressure on mortality after heart transplantation: pulmonary hypertension [33,34]. testing of potential reversibility of pulmonary hypertension with Our study has demonstrated that vasoreactivity testing with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 19: 48-54. multiple drugs is feasible and safe, but from a prognostic perspective, there is no benefit of continuing the examination beyond intravenous 7. Drakos SG, Kfoury AG, Gilbert EM, Horne BD, Long JW, et al. (2007) Effect of reversible pulmonary hypertension on outcomes after heart infusion of sodium nitroprusside and inhaled nitric oxide. transplantation. J Heart Lung Transplant 26: 319-323. Administration of oral sildenafil prolongs the examination and yields 8. Steudel W, Hurford WE, Zapol WM (1999) Inhaled nitric oxide: basic no additional predictive value. biology and clinical applications. Anesthesiology 91: 1090-1121. 9. Loh E, Stamler JS, Hare JM, Loscalzo J, Colucci WS (1994) Limitations of the study Cardiovascular effects of inhaled nitric oxide in patients with left ventricular dysfunction. Circulation 90: 2780-2785. We are aware of some limitations of our study. We have reported 10. Weimann J, Ullrich R, Hromi J, Fujino Y, Clark MW, et al. (2000) the results of a single center study, and thus, we had a relatively small Sildenafil is a pulmonary vasodilator in awake lambs with acute number of patients. Moreover, the small amount of patients is the pulmonary hypertension. Anesthesiology 92: 1702-1712. result of selection of patients with idiopathic or postinflammatory 11. Michelakis E, Tymchak W, Lien D, Webster L, Hashimoto K, et al. (2002) dilated cardiomyopathy complicated with venous pulmonary Oral sildenafil is an effective and specific pulmonary vasodilator in hypertension only. This pre selection allowed us to avoid bias resulting patients with pulmonary arterial hypertension: comparison with inhaled from the influence of myocardial ischaemia and/or congenital or nitric oxide. Circulation 105: 2398-2403. acquired valvular disease on the prognosis. 12. Radovancevic B, Vrtovec B, Thomas CD, Croitoru M, Myers TJ et al. (2005) Nitric oxide versus prostaglandin E1 for reduction of pulmonary hypertension in heart transplant candidates. The Journal of heart and Conclusion lung transplantation: the official publication of the International Society for Heart Transplantation 24: 690-695. Vasodilator response to inhaled nitric oxide predicts longer survival Sablotzki A, Hentschel T, Gruenig E, Schubert S, Friedrich I et al. in patients with dilated cardiomyopathy complicated with pulmonary 13. Hemodynamic effects of inhaled aerosolized iloprost and inhaled nitric hypertension. We postulate that nitroprusside and inhaled nitric oxide oxide in heart transplant candidates with elevated pulmonary vascular should be routinely used in vasoreactivity testing: nitroprusside for its resistance. Eur J Cardiothorac Surg 22: 746-752.

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