- Email: [email protected]
Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation
PPC-00973; No of Pages 5 Progress in Pediatric Cardiology xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation Katie E. Cohen a, Matthew Buelow a, Jennifer Dixon a, Ruta Brazauskas b, Scott Cohen c, Michael G. Earing a,c, Salil Ginde a,⁎ a b c
Division of Pediatric Cardiology, Department of Pediatrics, Medical College of Wisconsin, 9000 W. Wisconsin Avenue, MS 713, Milwaukee, WI 53226, USA Division of Biostatistics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA Division of Adult Cardiovascular Medicine, Department of Internal Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Suite 5100, Milwaukee, WI 53226, USA
1. Introduction Due to advances in cardiology and cardiac surgery, the 15-year survival after the Fontan operation for palliation of single-ventricle congenital heart disease (CHD) is now over 90% [1,2]. However, survivors with Fontan circulation are at risk for developing long-term complications that include exercise intolerance, congestive heart failure, protein losing enteropathy, plastic bronchitis, arrhythmias, stroke, and cirrhosis, all of which contribute to the risk for hospitalization and death in long-term follow-up [2–6]. Recent data also demonstrate a high prevalence of abnormal lung function in patients after the Fontan operation, with up to 45 to 60% having reduced forced vital capacity (FVC) measured by spirometry [7, 8]. Furthermore, reduced FVC is a clinically important determinant of exercise intolerance in patients after the Fontan operation [9,10]. The contribution of abnormal lung function on the risk for hospitalization and death in the adult Fontan population is not well known. In adults with normal 2-ventricular circulation and acquired cardiovascular disease, abnormal lung function independently predicts the risk for mortality [11–13]. At least 1 single-center study demonstrated a similar relationship between low FVC and mortality in a heterogeneous population of adults with CHD [14]. Given that the Fontan circulation relies on passive pulmonary blood flow in the absence of a subpulmonary ventricle, it is conceivable that abnormal lung function can have a significant impact on Fontan hemodynamics and subsequent risk for adverse outcomes and death. We sought to determine the impact of abnormal pulmonary function on clinical outcomes in a cohort of adult Fontan patients by assessing the relationship between FVC and the risk for hospitalization and death in this population. 2. Patients and Methods 2.1. Population Adult patients (age ≥ 18 y/o) with history of the Fontan procedure, who underwent pulmonary function measurements with spirometry ⁎ Corresponding author. E-mail address: [email protected] (S. Ginde).
at the time of cardiopulmonary exercise testing (CPET) between 1/1/ 2000 and 3/31/2014 at Children's Hospital of Wisconsin were included in the study. There were no exclusion criteria. CPET was performed either as part of clinical follow-up protocol or for the assessment of symptoms. Our institution's Fontan clinical follow-up protocol recommends CPET every 2 years in asymptomatic patients. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Children's Hospital of Wisconsin institutional review board. 2.2. Assessment of Lung Function Spirometry was performed according to reviewed standards, with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) obtained [15]. Values for FVC and FEV1 were expressed as a percent predicted for age, sex, and height according to reference values [16]. Lung function was classified categorically based on FVC % predicted as normal (FVC N70% predicted), mildly reduced (FVC = 60–70% predicted), and moderate-to-severely reduced (FVC b 60% predicted). An FEV1/FVC ratio b 0.70 was considered obstructive lung physiology. 2.3. Data Collection and Assessment of Risk Factors Demographics and clinical data were obtained by retrospective chart review. Variables included primary congenital heart diagnosis, age at Fontan, type of Fontan connection (modified atriopulmonary, lateral tunnel, extracardiac conduit), number of previous surgeries/ sternotomies/thoracotomies, history of surgical aorto-pulmonary shunt during infancy, baseline hypoxia at time of spirometry testing (defined as oxygen saturation measured with pulse oximetry b 90%), New York Heart Association (NYHA) functional class, and smoking history. Obesity at time of spirometry was defined as body mass index (kilograms/meters2) ≥ 30. Results from CPET performed immediately following spirometry were collected. CPET was performed using a standard Bruce protocol on a treadmill ergometer with incremental increases in speed and grade to voluntary exhaustion. Peak oxygen consumption (VO2) measured electronically on a breath-by-breath basis (CareFusion Corp., Yorba Linda, CA, USA) was expressed as a percentage predicted for stature, body mass, and age based on previously
http://dx.doi.org/10.1016/j.ppedcard.2017.01.007 1058-9813/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
2
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx
published normative values [17]. Ventilatory efficiency was calculated as the slope of the regression line between minute ventilation (VE) and carbon dioxide produced (VCO2) acquired throughout the entire period of exercise. Heart rate reserve was defined as difference between peak heart rate during exercise and resting heart rate. Chronotropic index was defined by the equation (peak heart rate − resting heart rate) / (220 − age − resting heart rate). Single ventricle systolic function was assessed semi-quantitatively by an experienced blinded reviewer based on an echocardiogram performed within 6 months of spirometry as normal, mildly decreased, moderately decreased, and severely decreased systolic function. Persistent Fontan fenestration was also identified based on echocardiographic imaging. 2.4. Follow-up and Outcomes Assessment of the combined clinical outcome of death and/or nonelective hospitalization for primary cardiac or respiratory indication during the time period following the spirometry was obtained by retrospective chart review. “Fontan-associated complications” were included as cardiac indications for hospitalization. Indications for non-elective hospitalization included congestive heart failure, arrhythmia, thromboembolic complication, protein-losing enteropathy, plastic bronchitis, pneumonia, and/or respiratory failure of any etiology. Elective catheterizations or surgeries were not included as part of the outcome data. Follow-up was complete for all patients included in the study during the study period. 2.5. Statistical Analysis Descriptive statistics such as means with standard deviations for continuous variables and counts with percentages for categorical variables were used to summarize sample characteristics. Cox proportional hazards model was used to identify variables associated with the primary outcome of non-elective hospitalization or death. Kaplan-Meier curve was used to summarize the time to hospitalization or death among patients with normal and mildly reduced lung function versus those who had moderately-to-severely reduced lung function. Logrank test was employed to compare the two groups of patients. Logistic regression model was used for identifying the risk factors of having moderately-to-severely reduced lung function. All p-values are twosided and alpha of 0.05 was used throughout. Analyses were carried out using SAS 9.4 statistical software (SAS Institute, Inc. Cary, NC). 3. Results A total of 47 patients were included in the study. Table 1 summarizes the baseline characteristics of the study population. The mean age at the time of spirometry was 27.3 ± 7.9 years. The majority of patients, 37 (78.7%) had a morphologic single left ventricle, 15 (31.9%) had an atriopulmonary Fontan connection, 25 (53.2%) had a lateral tunnel connection, and 7 (14.9%) had an extracardiac conduit connection. Based on FVC percent predicted measured with spirometry, lung function was classified as normal in 33 (70.2%) patients, mildly reduced in 7 (14.9%), and moderate-to-severely reduced in 7 (14.9%). Only 1 patient had an FEV1/FVC ratio b0.70 suggesting a primary obstructive lung physiology. Exercise capacity was reduced for the cohort with a mean peak VO2 percent predicted of 59.6 ± 16.5. The mean follow-up for the cohort after spirometry testing was 4.24 ± 2.63 (median = 3.54) years. During the follow-up period, a total of 17 patients reached the combined end-point of non-elective hospitalization for a primary cardiac or respiratory indication (n = 12) or death (n = 5). Indications for hospitalizations included atrial arrhythmia in 7 patients, congestive heart failure in 4 patients, and hemoptysis in 1 patient. Two patients died from complications related to progressive heart failure with multi-organ dysfunction, 1 underwent
Table 1 Selected baseline characteristics.
Characteristics Age at spirometry (years) Lung function Normal Mildly reduced Moderate/severely reduced Forced vital capacity % predicted Female Diagnosis DILV Tricuspid atresia Unbalanced AVSD Pulmonary atresia/IVS HLHS Other Ventricular morphology Left ventricle Right ventricle Age at Fontan operation (years) Fontan duration (years) Type of Fontan connection Atrio-pulmonary Lateral tunnel Extracardiac conduit Persistent Fontan fenestration (n = 43) # previous cardiac surgeries 1–2 N2 # previous thoracotomies 0 1 N2 History of aortopulmonary shunt (prior to Fontan operation) Scoliosis Diaphragm paralysis Obese Baseline hypoxia (n = 46) Tobacco smoking status Never Former smoker Current smoker NYHA Functional Class I II III IV CPET results Peak VO2% predicted (n = 43) VE/VCO2 slope (n = 39) Heart rate reserve Chronotropic index Systemic ventricular systolic function Normal Mildly reduced Moderately reduced Severely reduced
Number (%) or mean ± SD (n = 47) 27.3 ± 7.9 33 (70.2%) 7 (14.9%) 7 (14.9%) 73.3 ± 12.8 (range = 42– 107) 17 (36.2%) 19 (40.4%) 15 (31.9%) 3 (6.4%) 2 (4.3%) 2 (4.3%) 6 (12.8%) 37 (78.7%) 10 (21.3%) 8.4 ± 5.9 (range = 1.7–27) 19.1 ± 5.4 (range = 8.8– 31.9) 15 (31.9%) 25 (53.2%) 7 (14.9%) 18 (41.9%) 19 (40.4%) 28 (59.6%) 17 (36.2%) 22 (46.8%) 8 (17.0%) 28 (59.6%) 2 (4.3%) 1 (2.1%) 8 (17.0%) 7 (15.2%) 38 (80.9%) 4 (8.5%) 5 (10.6%) 36 (76.6%) 7 (14.9%) 4 (8.5%) 0 59.6 ± 108) 31.9 ± 53.2) 73.2 ± 0.61 ±
16.5 (range = 31– 7.3 (range = 20– 27.4 0.21
37 (78.7%) 9 (19.2%) 1 (2.1%) 0
AVSD, atrioventricular septal defect; CPET, cardiopulmonary exercise test; DILV, doubleinlet left ventricle; HLHS, hypoplastic left heart syndrome; IVS, intact ventricular septum; NYHA, New York Heart Association.
orthotopic heart transplant for protein-losing enteropathy and died prior to discharge, and 2 deaths were of unclear etiology. Table 2 summarizes the univariate analysis for predictors of the combined clinical outcome of hospitalization or death during the follow-up period. No multivariable model was significant in predicting the outcome. Having an FVC b60% predicted was a significant risk factor for the combined clinical outcome (Relative risk, RR = 3.22; 95%
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx Table 2 Risk factors for combined clinical outcome of non-elective hospitalization or death (single predictor models).
Characteristics
Relative risk (95% confidence interval)
p-Value
FVC b 60% predicted NYHA functional class
3.22 (1.18–8.73)
I II III Reduced systemic ventricular systolic function (vs. normal systolic function) Peak VO2% predicted VE/VCO2 slope Body mass index
Referent 3.65 (1.22–10.95) 2.29 (0.49–10.76) 2.04 (0.70–5.89)
0.0207 0.2929 0.1892
1.01 (0.97–1.04) 0.99 (0.92–1.06) 0.94 (0.84–1.05)
0.6389 0.8406 0.2863
0.0217 0.0616 (2df)
df, degrees of freedom; FVC, forced vital capacity; NYHA, New York Heart Association.
Confidence Interval, CI, 1.18–8.73, p = 0.022) (Table 3). Patients with a NYHA functional class II were also at a significantly higher risk for hospitalization or death as compared to those with a NYHA functional class I (RR = 3.65, 95% CI 1.22–10.95, p = 0.021). Chronotropic index, peak VO2, VE/VCO2 slope, and BMI were not statistically significant risk factors for the clinical outcome. When assessing individual risk factors for abnormal lung function, older age at Fontan was the only factor associated with moderate-to-severely reduced FVC (OR = 1.25/year, 95% CI
Table 3 Risk factors for having moderate-to-severely reduced lung function (single predictor models).
Characteristic Age at spirometry # prev surgeries (N2 vs 1–2)
Odds ratio (95%CI) 1.05 (0.95–1.16) 1.85 (0.32–10.69)
# prev thoracotomies 0 1 N2 Scoliosis (yes vs no)
Current smoker BMI (for every 1 kg/m2 increase in BMI) Peak VO2% predicted (for every 1 mL/min/m2 increase) Resting cyanosis (yes vs. no) O2 sat at rest (for every one unit increase) O2 sat at peak exercise (for every one unit increase) VE/VCO2 slope (for every one unit increase) Systemic left ventricle (yes vs no) Age at Fontan operation (for every one year increase in age) Fontan duration (for every one year increase) Type of Fontan Atrio-pulmonary Lateral tunnel Extracardiac conduit Fenestration (yes vs no) Shunt dependent pulmonary blood flow as neonate (yes vs no) BMI, body mass index.
0.2848 0.4930 0.5330 (2df)
Referent 0.47 (0.07–3.17) 1.56 (0.20–11.83) 6.07 (0.33–109.97)
Smoking Status Never Former smoker
p-Value
0.4354 0.6695 0.2220 0.8359 (2df)
Referent 0.56 (0.02–16.26) 1.67 (0.18–14.99) 1.08 (0.94–1.23) 0.96 (0.90–1.01)
0.2768 0.1288
0.92 (0.09–9.04) 0.94 (0.79–1.11) 0.96 (0.89–1.02)
0.9406 0.4809 0.2089
0.97 (0.86–1.10) 0.57 (0.06–5.41) 1.25 (1.05–1.47)
0.6589 0.6278 0.0094
0.97 (0.81–1.16)
0.7301 0.3530 (2df)
Referent 0.35 (0.05–2.37) 1.60 (0.20–12.69) 1.47 (0.26–8.27) 4.91 (0.54–44.60)
0.7329 0.6484
0.2812 0.6565 0.6643 0.1576
3
1.05–1.47, p = 0.009) (Table 3). Number of previous cardiac surgeries, number of thoracotomies, history of scoliosis, or history of aorto-pulmonary shunt during infancy were not significantly associated with moderate-to-severely reduced FVC. Fig. 1 demonstrates the probability of being alive and having no hospitalization in patients with normal or mildly reduced lung function (FVC ≥ 60%) vs. moderately-to-severely reduced lung function (FVC b 60%). The freedom from death or hospitalization was significantly lower for patients with worse lung function (log rank p = 0.0153).
4. Discussion This study demonstrates a significant relationship between abnormal lung function and higher risk for morbidity and mortality in a cohort of adult Fontan patients. Fontan patients with an FVC b 60% predicted had a three-times greater risk of experiencing the combined outcome of non-elective hospitalization and/or death. The exact mechanism for the relationship between low FVC and adverse outcomes in Fontan patients is not clear. A likely explanation is that low FVC reflects underlying lung disease that may contribute to elevations in pulmonary vascular resistance. Given that the Fontan circulation relies on passive pulmonary blood flow, any additional factor that increases pulmonary vascular resistance may further impair cardiac output, elevated central venous pressures, and increase risk for complications long-term. This relationship between abnormal lung function and cardiac output in Fontan patients may also explain the relationship between low FVC and reduced peak VO2 and exercise capacity measured in Fontan patients during cardiopulmonary exercise testing [9,10]. The exact etiology behind low FVC in patients with Fontan circulation remains unclear. Restrictive lung disease physiology may be secondary to extrinsic abnormalities of the thoracic rib cage that results from a history of multiple sternotomies and thoracotomies during early childhood [9,14]. Scoliosis is common in patients after the Fontan operation, and the risk increases over time [18]. A history of diaphragmatic palsy or respiratory muscle weakness may also contribute to restrictive lung disease physiology in this population [7]. In our study, we did not find history of thoracotomies, scoliosis, or diaphragm paralysis to be risk factors for low FVC, suggesting another mechanism for abnormal lung function may be present in Fontan patients. Patients with Fontan circulation may have abnormalities in pulmonary vasculature and parenchyma that can also contribute to abnormal lung function. The growth of pulmonary vasculature and parenchyma starts in utero and continues for several years after birth [19,20]. Abnormal, and in particular decreased, pulmonary blood flow during the prenatal and post-natal period in the setting of CHD is associated with hypoplasia of the lung parenchyma and vasculature [21–24]. Patients with single ventricle CHD are at risk for abnormal pulmonary blood flow both before and after Fontan operation. Prior to the Fontan operation, patients with single ventricle CHD typically undergo staged surgical palliation that may limit pulmonary blood flow and affect pulmonary development. Interestingly, we found that older age at Fontan, suggesting a longer duration of pre-Fontan single-ventricle physiology, was significantly associated with abnormal lung function. After the Fontan operation, non-pulsatile pulmonary blood flow can also lead to reduced lung growth and abnormal vascular development [25–27]. A better understanding of the etiology behind abnormal lung function in Fontan patients can help with design of future trials with targeted interventions that can improve lung function, and in turn, potentially reduce risk for adverse events over time. Currently, our clinical practice is to actively identify patients with reduced FVC on spirometry during CPET and refer for formal pulmonary function testing with body plethysmography. Based on these results, patients are then referred to pulmonology for consideration of pulmonary medications or pulmonary rehabilitation when appropriate.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
4
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx
Fig. 1. Probability of being alive and having no hospitalization in Fontan patients based on lung function (normal/mildly reduced FVC vs. moderate-to-severely reduced FVC).
4.1. Limitations This is a retrospective study at a tertiary referral center, which may result in selection bias. Patients may have been referred for cardiopulmonary exercise testing with spirometry to assess symptoms, thus skewing the study cohort towards a more high-risk group of patients. Lung function was assessed in this study using spirometry. Spirometry may only be suggestive of restrictive lung disease physiology. Pulmonary function testing with body plethysmography is needed to confirm the diagnosis of restrictive lung disease by showing a reduction in total lung capacity. Advantages of spirometry, however, are that it is low cost and typically performed during routine cardiopulmonary exercise testing, therefore making it a useful screening test in this population. 5. Conclusion Abnormal pulmonary function characterized by reduced FVC is common in adult patients with Fontan physiology. FVC provides prognostic information in adult Fontan patients, and is associated with a higher rate of hospitalization and/or death compared to those with normal or mildly reduced pulmonary function. References [1] Giannico S, Hammad F, Amodeo A, et al. Clinical outcome of 193 extracardiac Fontan patients: the first 15 years. J Am Coll Cardiol 2006;47(10):2065–73. [2] d'Udekem Y, Iyengar AJ, Galati JC, et al. Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 2014;130(11 Suppl 1):S32–8. [3] Khairy P, Fernandes SM, Mayer JEJ, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008;117(1): 85–92. [4] Diller G, Giardini A, Dimopoulos K, et al. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010;31(24):3073–83. [5] Assenza GE, Graham DA, Landzberg MJ, et al. MELD-XI score and cardiac mortality or transplantation in patients after Fontan surgery. Heart 2013;99(7):491–6.
[6] Tabtabai S, DeFaria Yeh D, Stefanescu A, Kennedy K, Yeh RW, Bhatt AB. National trends in hospitalizations for patients with single-ventricle anatomy. Am J Cardiol 2015;116(5):773–8. [7] Fredriksen PM, Therrien J, Veldtman G, et al. Lung function and aerobic capacity in adult patients following modified Fontan procedure. Heart 2001;85(3):295–9. [8] Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg MJ, Rhodes J. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr Cardiol 2010;31(2):175–80. [9] Ginde S, Bartz PJ, Hill GD, et al. Restrictive lung disease is an independent predictor of exercise intolerance in the adult with congenital heart disease. Congenit Heart Dis 2013;8(3):246–54. [10] Opotowsky AR, Landzberg MJ, Earing MG, et al. Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity. Am J Physiol Heart Circ Physiol 2014;307(1):H110–7. [11] Iversen KK, Kjaergaard J, Akkan D, et al. The prognostic importance of lung function in patients admitted with heart failure. Eur J Heart Fail 2010;12(7):685–91. [12] Lee HM, Le H, Lee BT, Lopez VA, Wong ND. Forced vital capacity paired with Framingham Risk Score for prediction of all-cause mortality. Eur Respir J 2010;36(5): 1002–6. [13] Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127(6):1952–9. [14] Alonso-Gonzalez R, Borgia F, Diller G, et al. Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival. Circulation 2013;127(8):882–90 (26). [15] Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;26(2):319–38. [16] American Thoracic Society, editor. Lung function testing: selection of reference values and interpretative strategiesAm Rev Respir Dis 1991;144(5):1202–18. [17] Wasserman K, Hansen J, Sue DY, et al. Normal values. Principles of Exercise Testing and Interpretation. 5th ed. PA: Lippincott Williams & Wilkins; 2012. p. 154–80. [18] Kadhim M, Pizarro C, Holmes LJ, Rogers KJ, Kallur A, Mackenzie WG. Prevalence of scoliosis in patients with Fontan circulation. Arch Dis Child 2013;98(3):170–5. [19] Reid L. 1976 Edward B.D. Neuhauser lecture: the lung: growth and remodeling in health and disease. AJR Am J Roentgenol 1977;129(5):777–88. [20] Shaheen S, Barker DJ. Early lung growth and chronic airflow obstruction. Thorax 1994;49(6):533–6. [21] De Troyer A, Yernault JC, Englert M. Lung hypoplasia in congenital pulmonary valve stenosis. Circulation 1977;56:647–51. [22] Haworth SG, Reid L. Quantitative structural study of pulmonary circulation in the newborn with pulmonary atresia. Thorax 1977;32(2):129–33. [23] Johnson RJ, Sauer U, Buhlmeyer K, Haworth SG. Hypoplasia of the intrapulmonary arteries in children with right ventricular outflow tract obstruction, ventricular septal defect, and major aortopulmonary collateral arteries. Pediatr Cardiol 1985;6(3): 137–43.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx [24] Zhang X, Liu Y, Ruan Y, Yu C. Relationship between the quantitative structural study of lung and the right ventricle outflow tract reconstruction in infants with tetralogy of Fallot. Chung-Kuo i Hsueh Ko Hsueh Yuan Hsueh Pao Acta Acad Med Sin 2006; 28(3):402–5. [25] Adachi I, Ueno T, Hori Y, Sawa Y. Alterations in the medial layer of the main pulmonary artery in a patient with longstanding Fontan circulation. Interact Cardiovasc Thorac Surg 2010;11(5):682–3.
5
[26] Zongtao Y, Huishan W, Zengwei W, et al. Experimental study of nonpulsatile flow perfusion and structural remodeling of pulmonary microcirculation vessels. Thorac Cardiovasc Surg 2010;58(8):468–72. [27] Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation 2003;107(25):3204–8.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
Contents lists available at ScienceDirect
Progress in Pediatric Cardiology journal homepage: www.elsevier.com/locate/ppedcard
Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation Katie E. Cohen a, Matthew Buelow a, Jennifer Dixon a, Ruta Brazauskas b, Scott Cohen c, Michael G. Earing a,c, Salil Ginde a,⁎ a b c
Division of Pediatric Cardiology, Department of Pediatrics, Medical College of Wisconsin, 9000 W. Wisconsin Avenue, MS 713, Milwaukee, WI 53226, USA Division of Biostatistics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226, USA Division of Adult Cardiovascular Medicine, Department of Internal Medicine, Medical College of Wisconsin, 9200 W. Wisconsin Ave., Suite 5100, Milwaukee, WI 53226, USA
1. Introduction Due to advances in cardiology and cardiac surgery, the 15-year survival after the Fontan operation for palliation of single-ventricle congenital heart disease (CHD) is now over 90% [1,2]. However, survivors with Fontan circulation are at risk for developing long-term complications that include exercise intolerance, congestive heart failure, protein losing enteropathy, plastic bronchitis, arrhythmias, stroke, and cirrhosis, all of which contribute to the risk for hospitalization and death in long-term follow-up [2–6]. Recent data also demonstrate a high prevalence of abnormal lung function in patients after the Fontan operation, with up to 45 to 60% having reduced forced vital capacity (FVC) measured by spirometry [7, 8]. Furthermore, reduced FVC is a clinically important determinant of exercise intolerance in patients after the Fontan operation [9,10]. The contribution of abnormal lung function on the risk for hospitalization and death in the adult Fontan population is not well known. In adults with normal 2-ventricular circulation and acquired cardiovascular disease, abnormal lung function independently predicts the risk for mortality [11–13]. At least 1 single-center study demonstrated a similar relationship between low FVC and mortality in a heterogeneous population of adults with CHD [14]. Given that the Fontan circulation relies on passive pulmonary blood flow in the absence of a subpulmonary ventricle, it is conceivable that abnormal lung function can have a significant impact on Fontan hemodynamics and subsequent risk for adverse outcomes and death. We sought to determine the impact of abnormal pulmonary function on clinical outcomes in a cohort of adult Fontan patients by assessing the relationship between FVC and the risk for hospitalization and death in this population. 2. Patients and Methods 2.1. Population Adult patients (age ≥ 18 y/o) with history of the Fontan procedure, who underwent pulmonary function measurements with spirometry ⁎ Corresponding author. E-mail address: [email protected] (S. Ginde).
at the time of cardiopulmonary exercise testing (CPET) between 1/1/ 2000 and 3/31/2014 at Children's Hospital of Wisconsin were included in the study. There were no exclusion criteria. CPET was performed either as part of clinical follow-up protocol or for the assessment of symptoms. Our institution's Fontan clinical follow-up protocol recommends CPET every 2 years in asymptomatic patients. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by the Children's Hospital of Wisconsin institutional review board. 2.2. Assessment of Lung Function Spirometry was performed according to reviewed standards, with forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) obtained [15]. Values for FVC and FEV1 were expressed as a percent predicted for age, sex, and height according to reference values [16]. Lung function was classified categorically based on FVC % predicted as normal (FVC N70% predicted), mildly reduced (FVC = 60–70% predicted), and moderate-to-severely reduced (FVC b 60% predicted). An FEV1/FVC ratio b 0.70 was considered obstructive lung physiology. 2.3. Data Collection and Assessment of Risk Factors Demographics and clinical data were obtained by retrospective chart review. Variables included primary congenital heart diagnosis, age at Fontan, type of Fontan connection (modified atriopulmonary, lateral tunnel, extracardiac conduit), number of previous surgeries/ sternotomies/thoracotomies, history of surgical aorto-pulmonary shunt during infancy, baseline hypoxia at time of spirometry testing (defined as oxygen saturation measured with pulse oximetry b 90%), New York Heart Association (NYHA) functional class, and smoking history. Obesity at time of spirometry was defined as body mass index (kilograms/meters2) ≥ 30. Results from CPET performed immediately following spirometry were collected. CPET was performed using a standard Bruce protocol on a treadmill ergometer with incremental increases in speed and grade to voluntary exhaustion. Peak oxygen consumption (VO2) measured electronically on a breath-by-breath basis (CareFusion Corp., Yorba Linda, CA, USA) was expressed as a percentage predicted for stature, body mass, and age based on previously
http://dx.doi.org/10.1016/j.ppedcard.2017.01.007 1058-9813/© 2017 Elsevier B.V. All rights reserved.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
2
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx
published normative values [17]. Ventilatory efficiency was calculated as the slope of the regression line between minute ventilation (VE) and carbon dioxide produced (VCO2) acquired throughout the entire period of exercise. Heart rate reserve was defined as difference between peak heart rate during exercise and resting heart rate. Chronotropic index was defined by the equation (peak heart rate − resting heart rate) / (220 − age − resting heart rate). Single ventricle systolic function was assessed semi-quantitatively by an experienced blinded reviewer based on an echocardiogram performed within 6 months of spirometry as normal, mildly decreased, moderately decreased, and severely decreased systolic function. Persistent Fontan fenestration was also identified based on echocardiographic imaging. 2.4. Follow-up and Outcomes Assessment of the combined clinical outcome of death and/or nonelective hospitalization for primary cardiac or respiratory indication during the time period following the spirometry was obtained by retrospective chart review. “Fontan-associated complications” were included as cardiac indications for hospitalization. Indications for non-elective hospitalization included congestive heart failure, arrhythmia, thromboembolic complication, protein-losing enteropathy, plastic bronchitis, pneumonia, and/or respiratory failure of any etiology. Elective catheterizations or surgeries were not included as part of the outcome data. Follow-up was complete for all patients included in the study during the study period. 2.5. Statistical Analysis Descriptive statistics such as means with standard deviations for continuous variables and counts with percentages for categorical variables were used to summarize sample characteristics. Cox proportional hazards model was used to identify variables associated with the primary outcome of non-elective hospitalization or death. Kaplan-Meier curve was used to summarize the time to hospitalization or death among patients with normal and mildly reduced lung function versus those who had moderately-to-severely reduced lung function. Logrank test was employed to compare the two groups of patients. Logistic regression model was used for identifying the risk factors of having moderately-to-severely reduced lung function. All p-values are twosided and alpha of 0.05 was used throughout. Analyses were carried out using SAS 9.4 statistical software (SAS Institute, Inc. Cary, NC). 3. Results A total of 47 patients were included in the study. Table 1 summarizes the baseline characteristics of the study population. The mean age at the time of spirometry was 27.3 ± 7.9 years. The majority of patients, 37 (78.7%) had a morphologic single left ventricle, 15 (31.9%) had an atriopulmonary Fontan connection, 25 (53.2%) had a lateral tunnel connection, and 7 (14.9%) had an extracardiac conduit connection. Based on FVC percent predicted measured with spirometry, lung function was classified as normal in 33 (70.2%) patients, mildly reduced in 7 (14.9%), and moderate-to-severely reduced in 7 (14.9%). Only 1 patient had an FEV1/FVC ratio b0.70 suggesting a primary obstructive lung physiology. Exercise capacity was reduced for the cohort with a mean peak VO2 percent predicted of 59.6 ± 16.5. The mean follow-up for the cohort after spirometry testing was 4.24 ± 2.63 (median = 3.54) years. During the follow-up period, a total of 17 patients reached the combined end-point of non-elective hospitalization for a primary cardiac or respiratory indication (n = 12) or death (n = 5). Indications for hospitalizations included atrial arrhythmia in 7 patients, congestive heart failure in 4 patients, and hemoptysis in 1 patient. Two patients died from complications related to progressive heart failure with multi-organ dysfunction, 1 underwent
Table 1 Selected baseline characteristics.
Characteristics Age at spirometry (years) Lung function Normal Mildly reduced Moderate/severely reduced Forced vital capacity % predicted Female Diagnosis DILV Tricuspid atresia Unbalanced AVSD Pulmonary atresia/IVS HLHS Other Ventricular morphology Left ventricle Right ventricle Age at Fontan operation (years) Fontan duration (years) Type of Fontan connection Atrio-pulmonary Lateral tunnel Extracardiac conduit Persistent Fontan fenestration (n = 43) # previous cardiac surgeries 1–2 N2 # previous thoracotomies 0 1 N2 History of aortopulmonary shunt (prior to Fontan operation) Scoliosis Diaphragm paralysis Obese Baseline hypoxia (n = 46) Tobacco smoking status Never Former smoker Current smoker NYHA Functional Class I II III IV CPET results Peak VO2% predicted (n = 43) VE/VCO2 slope (n = 39) Heart rate reserve Chronotropic index Systemic ventricular systolic function Normal Mildly reduced Moderately reduced Severely reduced
Number (%) or mean ± SD (n = 47) 27.3 ± 7.9 33 (70.2%) 7 (14.9%) 7 (14.9%) 73.3 ± 12.8 (range = 42– 107) 17 (36.2%) 19 (40.4%) 15 (31.9%) 3 (6.4%) 2 (4.3%) 2 (4.3%) 6 (12.8%) 37 (78.7%) 10 (21.3%) 8.4 ± 5.9 (range = 1.7–27) 19.1 ± 5.4 (range = 8.8– 31.9) 15 (31.9%) 25 (53.2%) 7 (14.9%) 18 (41.9%) 19 (40.4%) 28 (59.6%) 17 (36.2%) 22 (46.8%) 8 (17.0%) 28 (59.6%) 2 (4.3%) 1 (2.1%) 8 (17.0%) 7 (15.2%) 38 (80.9%) 4 (8.5%) 5 (10.6%) 36 (76.6%) 7 (14.9%) 4 (8.5%) 0 59.6 ± 108) 31.9 ± 53.2) 73.2 ± 0.61 ±
16.5 (range = 31– 7.3 (range = 20– 27.4 0.21
37 (78.7%) 9 (19.2%) 1 (2.1%) 0
AVSD, atrioventricular septal defect; CPET, cardiopulmonary exercise test; DILV, doubleinlet left ventricle; HLHS, hypoplastic left heart syndrome; IVS, intact ventricular septum; NYHA, New York Heart Association.
orthotopic heart transplant for protein-losing enteropathy and died prior to discharge, and 2 deaths were of unclear etiology. Table 2 summarizes the univariate analysis for predictors of the combined clinical outcome of hospitalization or death during the follow-up period. No multivariable model was significant in predicting the outcome. Having an FVC b60% predicted was a significant risk factor for the combined clinical outcome (Relative risk, RR = 3.22; 95%
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx Table 2 Risk factors for combined clinical outcome of non-elective hospitalization or death (single predictor models).
Characteristics
Relative risk (95% confidence interval)
p-Value
FVC b 60% predicted NYHA functional class
3.22 (1.18–8.73)
I II III Reduced systemic ventricular systolic function (vs. normal systolic function) Peak VO2% predicted VE/VCO2 slope Body mass index
Referent 3.65 (1.22–10.95) 2.29 (0.49–10.76) 2.04 (0.70–5.89)
0.0207 0.2929 0.1892
1.01 (0.97–1.04) 0.99 (0.92–1.06) 0.94 (0.84–1.05)
0.6389 0.8406 0.2863
0.0217 0.0616 (2df)
df, degrees of freedom; FVC, forced vital capacity; NYHA, New York Heart Association.
Confidence Interval, CI, 1.18–8.73, p = 0.022) (Table 3). Patients with a NYHA functional class II were also at a significantly higher risk for hospitalization or death as compared to those with a NYHA functional class I (RR = 3.65, 95% CI 1.22–10.95, p = 0.021). Chronotropic index, peak VO2, VE/VCO2 slope, and BMI were not statistically significant risk factors for the clinical outcome. When assessing individual risk factors for abnormal lung function, older age at Fontan was the only factor associated with moderate-to-severely reduced FVC (OR = 1.25/year, 95% CI
Table 3 Risk factors for having moderate-to-severely reduced lung function (single predictor models).
Characteristic Age at spirometry # prev surgeries (N2 vs 1–2)
Odds ratio (95%CI) 1.05 (0.95–1.16) 1.85 (0.32–10.69)
# prev thoracotomies 0 1 N2 Scoliosis (yes vs no)
Current smoker BMI (for every 1 kg/m2 increase in BMI) Peak VO2% predicted (for every 1 mL/min/m2 increase) Resting cyanosis (yes vs. no) O2 sat at rest (for every one unit increase) O2 sat at peak exercise (for every one unit increase) VE/VCO2 slope (for every one unit increase) Systemic left ventricle (yes vs no) Age at Fontan operation (for every one year increase in age) Fontan duration (for every one year increase) Type of Fontan Atrio-pulmonary Lateral tunnel Extracardiac conduit Fenestration (yes vs no) Shunt dependent pulmonary blood flow as neonate (yes vs no) BMI, body mass index.
0.2848 0.4930 0.5330 (2df)
Referent 0.47 (0.07–3.17) 1.56 (0.20–11.83) 6.07 (0.33–109.97)
Smoking Status Never Former smoker
p-Value
0.4354 0.6695 0.2220 0.8359 (2df)
Referent 0.56 (0.02–16.26) 1.67 (0.18–14.99) 1.08 (0.94–1.23) 0.96 (0.90–1.01)
0.2768 0.1288
0.92 (0.09–9.04) 0.94 (0.79–1.11) 0.96 (0.89–1.02)
0.9406 0.4809 0.2089
0.97 (0.86–1.10) 0.57 (0.06–5.41) 1.25 (1.05–1.47)
0.6589 0.6278 0.0094
0.97 (0.81–1.16)
0.7301 0.3530 (2df)
Referent 0.35 (0.05–2.37) 1.60 (0.20–12.69) 1.47 (0.26–8.27) 4.91 (0.54–44.60)
0.7329 0.6484
0.2812 0.6565 0.6643 0.1576
3
1.05–1.47, p = 0.009) (Table 3). Number of previous cardiac surgeries, number of thoracotomies, history of scoliosis, or history of aorto-pulmonary shunt during infancy were not significantly associated with moderate-to-severely reduced FVC. Fig. 1 demonstrates the probability of being alive and having no hospitalization in patients with normal or mildly reduced lung function (FVC ≥ 60%) vs. moderately-to-severely reduced lung function (FVC b 60%). The freedom from death or hospitalization was significantly lower for patients with worse lung function (log rank p = 0.0153).
4. Discussion This study demonstrates a significant relationship between abnormal lung function and higher risk for morbidity and mortality in a cohort of adult Fontan patients. Fontan patients with an FVC b 60% predicted had a three-times greater risk of experiencing the combined outcome of non-elective hospitalization and/or death. The exact mechanism for the relationship between low FVC and adverse outcomes in Fontan patients is not clear. A likely explanation is that low FVC reflects underlying lung disease that may contribute to elevations in pulmonary vascular resistance. Given that the Fontan circulation relies on passive pulmonary blood flow, any additional factor that increases pulmonary vascular resistance may further impair cardiac output, elevated central venous pressures, and increase risk for complications long-term. This relationship between abnormal lung function and cardiac output in Fontan patients may also explain the relationship between low FVC and reduced peak VO2 and exercise capacity measured in Fontan patients during cardiopulmonary exercise testing [9,10]. The exact etiology behind low FVC in patients with Fontan circulation remains unclear. Restrictive lung disease physiology may be secondary to extrinsic abnormalities of the thoracic rib cage that results from a history of multiple sternotomies and thoracotomies during early childhood [9,14]. Scoliosis is common in patients after the Fontan operation, and the risk increases over time [18]. A history of diaphragmatic palsy or respiratory muscle weakness may also contribute to restrictive lung disease physiology in this population [7]. In our study, we did not find history of thoracotomies, scoliosis, or diaphragm paralysis to be risk factors for low FVC, suggesting another mechanism for abnormal lung function may be present in Fontan patients. Patients with Fontan circulation may have abnormalities in pulmonary vasculature and parenchyma that can also contribute to abnormal lung function. The growth of pulmonary vasculature and parenchyma starts in utero and continues for several years after birth [19,20]. Abnormal, and in particular decreased, pulmonary blood flow during the prenatal and post-natal period in the setting of CHD is associated with hypoplasia of the lung parenchyma and vasculature [21–24]. Patients with single ventricle CHD are at risk for abnormal pulmonary blood flow both before and after Fontan operation. Prior to the Fontan operation, patients with single ventricle CHD typically undergo staged surgical palliation that may limit pulmonary blood flow and affect pulmonary development. Interestingly, we found that older age at Fontan, suggesting a longer duration of pre-Fontan single-ventricle physiology, was significantly associated with abnormal lung function. After the Fontan operation, non-pulsatile pulmonary blood flow can also lead to reduced lung growth and abnormal vascular development [25–27]. A better understanding of the etiology behind abnormal lung function in Fontan patients can help with design of future trials with targeted interventions that can improve lung function, and in turn, potentially reduce risk for adverse events over time. Currently, our clinical practice is to actively identify patients with reduced FVC on spirometry during CPET and refer for formal pulmonary function testing with body plethysmography. Based on these results, patients are then referred to pulmonology for consideration of pulmonary medications or pulmonary rehabilitation when appropriate.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
4
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx
Fig. 1. Probability of being alive and having no hospitalization in Fontan patients based on lung function (normal/mildly reduced FVC vs. moderate-to-severely reduced FVC).
4.1. Limitations This is a retrospective study at a tertiary referral center, which may result in selection bias. Patients may have been referred for cardiopulmonary exercise testing with spirometry to assess symptoms, thus skewing the study cohort towards a more high-risk group of patients. Lung function was assessed in this study using spirometry. Spirometry may only be suggestive of restrictive lung disease physiology. Pulmonary function testing with body plethysmography is needed to confirm the diagnosis of restrictive lung disease by showing a reduction in total lung capacity. Advantages of spirometry, however, are that it is low cost and typically performed during routine cardiopulmonary exercise testing, therefore making it a useful screening test in this population. 5. Conclusion Abnormal pulmonary function characterized by reduced FVC is common in adult patients with Fontan physiology. FVC provides prognostic information in adult Fontan patients, and is associated with a higher rate of hospitalization and/or death compared to those with normal or mildly reduced pulmonary function. References [1] Giannico S, Hammad F, Amodeo A, et al. Clinical outcome of 193 extracardiac Fontan patients: the first 15 years. J Am Coll Cardiol 2006;47(10):2065–73. [2] d'Udekem Y, Iyengar AJ, Galati JC, et al. Redefining expectations of long-term survival after the Fontan procedure: twenty-five years of follow-up from the entire population of Australia and New Zealand. Circulation 2014;130(11 Suppl 1):S32–8. [3] Khairy P, Fernandes SM, Mayer JEJ, et al. Long-term survival, modes of death, and predictors of mortality in patients with Fontan surgery. Circulation 2008;117(1): 85–92. [4] Diller G, Giardini A, Dimopoulos K, et al. Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010;31(24):3073–83. [5] Assenza GE, Graham DA, Landzberg MJ, et al. MELD-XI score and cardiac mortality or transplantation in patients after Fontan surgery. Heart 2013;99(7):491–6.
[6] Tabtabai S, DeFaria Yeh D, Stefanescu A, Kennedy K, Yeh RW, Bhatt AB. National trends in hospitalizations for patients with single-ventricle anatomy. Am J Cardiol 2015;116(5):773–8. [7] Fredriksen PM, Therrien J, Veldtman G, et al. Lung function and aerobic capacity in adult patients following modified Fontan procedure. Heart 2001;85(3):295–9. [8] Fernandes SM, McElhinney DB, Khairy P, Graham DA, Landzberg MJ, Rhodes J. Serial cardiopulmonary exercise testing in patients with previous Fontan surgery. Pediatr Cardiol 2010;31(2):175–80. [9] Ginde S, Bartz PJ, Hill GD, et al. Restrictive lung disease is an independent predictor of exercise intolerance in the adult with congenital heart disease. Congenit Heart Dis 2013;8(3):246–54. [10] Opotowsky AR, Landzberg MJ, Earing MG, et al. Abnormal spirometry after the Fontan procedure is common and associated with impaired aerobic capacity. Am J Physiol Heart Circ Physiol 2014;307(1):H110–7. [11] Iversen KK, Kjaergaard J, Akkan D, et al. The prognostic importance of lung function in patients admitted with heart failure. Eur J Heart Fail 2010;12(7):685–91. [12] Lee HM, Le H, Lee BT, Lopez VA, Wong ND. Forced vital capacity paired with Framingham Risk Score for prediction of all-cause mortality. Eur Respir J 2010;36(5): 1002–6. [13] Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127(6):1952–9. [14] Alonso-Gonzalez R, Borgia F, Diller G, et al. Abnormal lung function in adults with congenital heart disease: prevalence, relation to cardiac anatomy, and association with survival. Circulation 2013;127(8):882–90 (26). [15] Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005;26(2):319–38. [16] American Thoracic Society, editor. Lung function testing: selection of reference values and interpretative strategiesAm Rev Respir Dis 1991;144(5):1202–18. [17] Wasserman K, Hansen J, Sue DY, et al. Normal values. Principles of Exercise Testing and Interpretation. 5th ed. PA: Lippincott Williams & Wilkins; 2012. p. 154–80. [18] Kadhim M, Pizarro C, Holmes LJ, Rogers KJ, Kallur A, Mackenzie WG. Prevalence of scoliosis in patients with Fontan circulation. Arch Dis Child 2013;98(3):170–5. [19] Reid L. 1976 Edward B.D. Neuhauser lecture: the lung: growth and remodeling in health and disease. AJR Am J Roentgenol 1977;129(5):777–88. [20] Shaheen S, Barker DJ. Early lung growth and chronic airflow obstruction. Thorax 1994;49(6):533–6. [21] De Troyer A, Yernault JC, Englert M. Lung hypoplasia in congenital pulmonary valve stenosis. Circulation 1977;56:647–51. [22] Haworth SG, Reid L. Quantitative structural study of pulmonary circulation in the newborn with pulmonary atresia. Thorax 1977;32(2):129–33. [23] Johnson RJ, Sauer U, Buhlmeyer K, Haworth SG. Hypoplasia of the intrapulmonary arteries in children with right ventricular outflow tract obstruction, ventricular septal defect, and major aortopulmonary collateral arteries. Pediatr Cardiol 1985;6(3): 137–43.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007
K.E. Cohen et al. / Progress in Pediatric Cardiology xxx (2017) xxx–xxx [24] Zhang X, Liu Y, Ruan Y, Yu C. Relationship between the quantitative structural study of lung and the right ventricle outflow tract reconstruction in infants with tetralogy of Fallot. Chung-Kuo i Hsueh Ko Hsueh Yuan Hsueh Pao Acta Acad Med Sin 2006; 28(3):402–5. [25] Adachi I, Ueno T, Hori Y, Sawa Y. Alterations in the medial layer of the main pulmonary artery in a patient with longstanding Fontan circulation. Interact Cardiovasc Thorac Surg 2010;11(5):682–3.
5
[26] Zongtao Y, Huishan W, Zengwei W, et al. Experimental study of nonpulsatile flow perfusion and structural remodeling of pulmonary microcirculation vessels. Thorac Cardiovasc Surg 2010;58(8):468–72. [27] Khambadkone S, Li J, de Leval MR, Cullen S, Deanfield JE, Redington AN. Basal pulmonary vascular resistance and nitric oxide responsiveness late after Fontan-type operation. Circulation 2003;107(25):3204–8.
Please cite this article as: Cohen KE, et al, Forced vital capacity predicts morbidity and mortality in adult patients with Fontan circulation, Prog Pediatr Cardiol (2017), http://dx.doi.org/10.1016/j.ppedcard.2017.01.007