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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 7  |  Issue : 2  |  Page : 64-68

Tadalafil and exercise capacity after fontan operation


Rajaie Cardiovascular Medical and Research Center, Iran University of Medical Sciences, Tehran, Iran

Date of Web Publication22-May-2018

Correspondence Address:
Dr. Maryam Golari
Rajaie Cardiovascular Medical and Research Center, Vali-e-Asr Ave., Niayesh Highway, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/rcm.rcm_18_17

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  Abstract 


Background: Patients with congenital heart defects that have single functional ventricle undergo Fontan surgery. After the surgery, patients will develop reduced capacity for physical activity and exercise. Phosphodiesterase inhibitor drugs have vasodilatory effects and can decrease blood flow resistance. Thereby, they can help to improve the exercise capacity of patients. The aim of this study was to assess the effect of tadalafil on exercise capacity in these patients. Materials and Methods: In this before and after interventional study, 16 patients who had undergone Fontan operation were treated with tadalafil (10 mg daily for 2 weeks and then 10 mg every 12 h for 6 months). Demographic data, heart disease morphology, pulse oximetry, blood pressure (BP), functional class, age at the time of surgery, and the surgery type were collected. Pulmonary function and exercise capacity were assessed by 6-min walk test and VO2 max (maximal oxygen consumption). Results: Mean distance based on 6-min walk test increased from 418.75 m to 439.06 m (P = 0.004). Mean maximal oxygen consumption increased from 0.84 L/min to 1.07 L/min (P < 0.001). Furthermore, preexercise test oxygen saturation increased from 89% to 90.94% (P = 0.02). No significant change was observed regarding other variables. Conclusion: Tadalafil was found to be effective in improving exercise capacity of the patients with a previous history of Fontan surgery. However, tadalafil had no significant effect on systolic or diastolic BP and heart rate.

Keywords: Exercise, Fontan surgery, single ventricle, tadalafil


How to cite this article:
Khajali Z, Peighambari MM, Lotfian S, Golari M, Galeshi B, Rouhani M, Alizadeh Z. Tadalafil and exercise capacity after fontan operation. Res Cardiovasc Med 2018;7:64-8

How to cite this URL:
Khajali Z, Peighambari MM, Lotfian S, Golari M, Galeshi B, Rouhani M, Alizadeh Z. Tadalafil and exercise capacity after fontan operation. Res Cardiovasc Med [serial online] 2018 [cited 2018 Dec 17];7:64-8. Available from: http://www.rcvmonline.com/text.asp?2018/7/2/64/232973




  Introduction Top


The Fontan operation was introduced in 1968 for tricuspid atresia.[1] This operation has been performed since its introduction for other congenital heart conditions where there is only one functional ventricle. When there is single ventricle, this ventricle has to maintain blood circulation in both systemic and pulmonary systems.[2] The problem with this circulation is that it results in arterial desaturation, intensified during exercise. In Fontan operation, a new circulation is created surgically named “Fontan circulation” where the systemic venous return is connected to pulmonary circulation with a cavopulmonary physiology.[3]

This procedure has been life-saving for many children with such congenital heart disease. After its introduction, several modifications have been made to this technique to improve its outcome. Currently, several modifications of original Fontan technique are used (e.g., atrioventricular connection, atriopulmonary connection, and total cavopulmonary connection). However, as children who underwent this surgery now have become adults, it appears that several limitations exist in this surgery. One of this limitations is exercise capacity decline over time.[4] Another is decreased peak oxygen consumption (VO2).[5] It has been shown that maximal aerobic capacity is lower in Fontan patients who are older.[6] Several factors appear to be affective in this exercise capacity decline such as the technique used and whether the patient had functional left or right ventricle, or the presence of Glenn anastomosis.[7],[8]

One of the factors that have been suggested as contributing factor in exercise performance decline in Fontan patients is pulmonary artery hypertension (PAH) and inability to increase stroke volume during exercise.[5],[9],[10] Furthermore, reduced ventricular preload was reported during stress echocardiography.[11] Based on this observation, it has been argued that medications which can decrease pulmonary vascular resistance can improve exercise performance and oxygen saturation in Fontan patients. One class of these medications is phosphodiesterase type 5 inhibitors (PDE5i). Nitric oxide is involved in PAH, and this agent causes vasodilation. The action of nitric oxide is mediated by its second messenger, cyclic guanosine monophosphate. This messenger is degraded by phosphodiesterase.[12]

Several trials have examined the effect of PDEi sildenafil in Fontan patients with promising results.[13],[14],[15],[16] All these studies have reported that sildenafil therapy had significant effect on improving exercise performance in Fontan patients with minimal or no side effects. Another PDEi studied in one trial is tadalafil.[17] The PDEi medications used have been studied on limited number of patients with various durations (from single intravenous administration [15] to 6-week period [17]) and different dosages. Hence, it seems that further studies are required for better understanding of the effect of PDEi medications in Fontan patients.

The current study was performed to determine the effect of PDEi tadalafil on exercise performance and VO2 of Fontan patients.


  Materials and Methods Top


Study population

In this before and after interventional study which was done at out university heart center, 16 Fontan patients who had undergone this operation at our center were included. The exclusion criteria were severe heart failure (New York Heart Association [NYHA] IV), liver or kidney dysfunction, hearing or visual disturbances, pregnancy, evidence of Fontan blockade (angiography or echocardiography), arrhythmia during exercise, taking tadalafil during the last 3 months, allergic reactions to tadalafil or similar compounds, systolic blood pressure (BP) <75 mmHg, coarctation of aorta, or remaining heart defect.

Study variables and design

First, the patients were contacted and invited to participate at the study. On presentation, the basic physical examination was done and the following variables were documented: Age, gender, morphology of heart defect, the type of operation, age at the time of operation, NYHA functional class, pulse rate (PR), systolic BP, diastolic BP, and pulse oximetry. Then, the patients underwent exercise tolerance test (ETT). During the test, 6-min walk test and VO2 max were measured. After the ETT, PR, oxygen saturation, and systolic and diastolic BP measurements were recorded. Then, the patients received tadalafil 10 mg daily for 2 weeks and then 10 mg every 12 h for 6 months. After tadalafil use, the patients were examined for the second time with ETT and the aforementioned variables were recorded once more.

Statistical analyses

The descriptive statistics including frequency, percentage, mean, and its standard deviation (±SD) were used to express data. The normal distribution of data before and after tadalafil was determined using the Kolmogorov–Smirnov and Shapiro–Wilk tests along with histograms. To compare the change in variables with normal distribution, the paired t-test was used. For variables with nonnormal distribution, the Wilcoxon-signed rank test was used. To compare the change in NYHA functional class, the McNemar's test was used. All analyses were done using SPSS software (ver. 20, IBM Corp., Armonk, NY, USA). The P < 0.05 was considered statistically significant.

Ethics

The study protocol was approved by the Ethics Committee of our university. The objectives of the study were explained to the participants and written consent was obtained before enrollment. The study protocol was in conformity with the Declaration of Helsinki.


  Results Top


Sixteen patients were studied. There were eight male (50%) and eight (50%) female. Mean (±SD) age at the time of the study was 24.87 (±5.70) years. Mean (±SD) age at the time of Fontan operation was 9.75 (±4.15) years. Mean (±SD) time interval from the operation to the study was 15.1 (±8.29) years. Ten patients (62.5%) were school or college students, three (18.8%) were clerks, two (12.5%) were homemakers, and one patient was unemployed. [Table 1] presents the heart defect morphology and the type of operations performed.
Table 1: Cardiac defect morphology and the procedures performed in 16 Fontan patients

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Mean (SD) 6-min walk test before tadalafil was 418.75 (58.86) m. After tadalafil, this significantly increased to 439.06 (55.08) m. [Table 2] presents 6-min walk test and VO2 max values before and after tadalafil use. As seen, changes in both 6-min walk test and maximal oxygen consumption were significant and showed improvements after tadalafil use. [Figure 1] shows boxplot diagrams of mean difference in 6-min walk test and VO2 max values.
Table 2: Comparison of mean standard deviation values of 6-min walk test and maximal oxygen consumption before and after tadalafil use in 16 Fontan patients

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Figure 1: Boxplot diagrams showing 95% confidence intervals of changes in 6-min walk test (left) and maximal oxygen consumption (right) seen after 6 months of tadalafil use in 16 Fontan patients

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[Table 3] presents mean (SD) values of oxygen saturation, heart rate, systolic BP, and diastolic BP before and after tadalafil use. As seen, except for oxygen saturation before ETT which showed significant increase after tadalafil, no other statistically significant changes were found regarding other variables.
Table 3: Comparison of changes in oxygen saturation, heart rate, and blood pressure before and after tadalafil use in 16 Fontan patients

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At baseline, seven patients had NYHA I (43.8%) and nine patients had NYHA II. After tadalafil, eleven patients (68.75%) had NYHA I. Although more patients were categorized as NYHA class I after tadalafil, this change was not statistically significant (P = 0.12).


  Discussion Top


Based on the obtained findings, tadalafil for 6 months was effective in improving exercise performance of patients who had undergone Fontan palliative operation due to having single functional ventricle. Oxygen saturation before ETT also showed significant improvement. However, regarding other measured variables, no statistically significant change was observed. Although we did not find significant improvement from the statistical point of view, the changes in these variables, especially systolic and diastolic BP measurements show reduction after tadalafil. This may be due to low sample size that was studied. It is highly likely that by recruiting larger sample sizes, these changes become significant.

The results we observed here are in conformity with previous-related studies. In a former study in Isfahan,[17] the effect of 6-week tadalafil was evaluated in 15 Fontan patients with age range of 6–30 years. Although the duration of tadalafil use was shorter than what we studied, the authors reported that tadalafil was effective in improving exercise performance, myocardial function, NYHA class, and intima-media thickness of the ventricle. Similar to our study, systolic BP before ETT decreased significantly, but other variables did not show statistically significant changes. Most studies considering PDEi medications have evaluated the efficacy of sildenafil. In another clinical trial, sildenafil was used for 6 weeks,[13] and it was shown that respiratory rate and minute ventilation at peak exercise decreased significantly. However, despite our findings, sildenafil did not improve VO2 max. In another study [18] using magnetic resonance imaging (MRI) at rest and during bicycle exercise (mild, moderate, and high intensity) on 10 Fontan patients, the effect of sildenafil on exercise hemodynamics was studied. It was reported that sildenafil increased cardiac index and stroke volume index, in particular at high-intensity exercise. Furthermore, pulmonary resistance index reduced at both rest and at exercise.

Further studies are required for better demonstration of beneficial effects of PDEi medications. As there are several studies with small number of participants and different methods to determine respiratory and exercise capacity, performing a systematic review and meta-analysis is advised. Another issue is that whether the changes observed in short-term follow-up periods reported in the studies are maintained in long-term durations. It should also be determined whether these changes actually improve general wellness of these patients in long-term. Furthermore, another issue is the effect that sildenafil or tadalafil can have on other complications of Fontan. For example, sildenafil was shown to be beneficial in the management of Fontan complications such as bronchial cast and protein-losing enteropathy.[15] These findings expand our knowledge about the complicated physiology we encounter in Fontan patients.

Limitations

The sample size was small as Fontan operation is not done frequently. With larger sample size, it is possible to perform more statistical analyses on different modifications of Fontan procedure and also on various cardiac defects. Furthermore, other diagnostic methods such as echocardiography and MRI can yield more information, but we were not able to perform these.


  Conclusion Top


Tadalafil use for 6 months was effective in improving exercise performance of Fontan patients with no adverse side effects. Further studies to determine other beneficial effects of these medications are required.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
de Leval MR, Deanfield JE. Four decades of fontan palliation. Nat Rev Cardiol 2010;7:520-7.  Back to cited text no. 1
[PUBMED]    
2.
Gewillig M. The fontan circulation. Heart 2005;91:839-46.  Back to cited text no. 2
[PUBMED]    
3.
Rychik J. Forty years of the fontan operation: A failed strategy. Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2010;13:96-100.  Back to cited text no. 3
[PUBMED]    
4.
Giardini A, Hager A, Pace Napoleone C, Picchio FM. Natural history of exercise capacity after the Fontan operation: A longitudinal study. Ann Thorac Surg 2008;85:818-21.  Back to cited text no. 4
[PUBMED]    
5.
Paridon SM, Mitchell PD, Colan SD, Williams RV, Blaufox A, Li JS, et al. A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol 2008;52:99-107.  Back to cited text no. 5
[PUBMED]    
6.
Fredriksen PM, Therrien J, Veldtman G, Warsi MA, Liu P, Siu S, et al. Lung function and aerobic capacity in adult patients following modified Fontan procedure. Heart 2001;85:295-9.  Back to cited text no. 6
[PUBMED]    
7.
Gewillig M, Brown SC, Eyskens B, Heying R, Ganame J, Budts W, et al. The Fontan circulation: Who controls cardiac output? Interact Cardiovasc Thorac Surg 2010;10:428-33.  Back to cited text no. 7
[PUBMED]    
8.
Durongpisitkul K, Driscoll DJ, Mahoney DW, Wollan PC, Mottram CD, Puga FJ, et al. Cardiorespiratory response to exercise after modified Fontan operation: Determinants of performance. J Am Coll Cardiol 1997;29:785-90.  Back to cited text no. 8
[PUBMED]    
9.
Goldberg DJ, Shaddy RE, Ravishankar C, Rychik J. The failing Fontan: Etiology, diagnosis and management. Expert Rev Cardiovasc Ther 2011;9:785-93.  Back to cited text no. 9
[PUBMED]    
10.
Hosein RB, Clarke AJ, McGuirk SP, Griselli M, Stumper O, De Giovanni JV, et al. Factors influencing early and late outcome following the Fontan procedure in the current era. The 'two commandments'? Eur J Cardiothorac Surg 2007;31:344-52.  Back to cited text no. 10
[PUBMED]    
11.
Senzaki H, Masutani S, Ishido H, Taketazu M, Kobayashi T, Sasaki N, et al. Cardiac rest and reserve function in patients with Fontan circulation. J Am Coll Cardiol 2006;47:2528-35.  Back to cited text no. 11
[PUBMED]    
12.
Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-57.  Back to cited text no. 12
    
13.
Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, et al. Impact of oral sildenafil on exercise performance in children and young adults after the Fontan operation: A randomized, double-blind, placebo-controlled, crossover trial. Circulation 2011;123:1185-93.  Back to cited text no. 13
[PUBMED]    
14.
Goldberg DJ, French B, Szwast AL, McBride MG, Marino BS, Mirarchi N, et al. Impact of sildenafil on echocardiographic indices of myocardial performance after the Fontan operation. Pediatr Cardiol 2012;33:689-96.  Back to cited text no. 14
[PUBMED]    
15.
Reinhardt Z, Uzun O, Bhole V, Ofoe V, Wilson D, Onuzo O, et al. Sildenafil in the management of the failing Fontan circulation. Cardiol Young 2010;20:522-5.  Back to cited text no. 15
[PUBMED]    
16.
Tunks RD, Barker PC, Benjamin DK Jr., Cohen-Wolkowiez M, Fleming GA, Laughon M, et al. Sildenafil exposure and hemodynamic effect after fontan surgery. Pediatr Crit Care Med 2014;15:28-34.  Back to cited text no. 16
    
17.
Sabri MR, Zolfi-Gol A, Ahmadi A, Haghjooy-Javanmard S. Effect of tadalafil on myocardial and endothelial function and exercise performance after modified fontan operation. Pediatr Cardiol 2016;37:55-61.  Back to cited text no. 17
[PUBMED]    
18.
Van De Bruaene A, La Gerche A, Claessen G, De Meester P, Devroe S, Gillijns H, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging 2014;7:265-73.  Back to cited text no. 18
[PUBMED]    


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