1442
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
Ann Thorac Surg 2015;99:1442–4
FEATURE ARTICLES
Fig 4. (A) Incomplete expansion of the transcatheter valve prosthesis in situ and (B) its oval shape to conform to the mitral ring, after explantation. (B) Note the unchanged oval contour of the mitral ring.
less than 10 years in most previous studies [2]. This might have had an impact on the flexibility of the ring owing to potential material fatigue. Finally, the patient had a mitral homograft in addition to the ring, and a potential influence of the homograft on the suboptimal deployment of the transcatheter valve cannot be excluded. In conclusion, the feasibility of TMViRI has been described, although this procedure remains experimental. The present report shows that this treatment can fail in some patients. Both an excessive transcatheter valve oversizing and the inability of the ring to adopt a circular shape may have played a major role in the failure of the procedure. Careful evaluation of the case, including ring properties and appropriate valve sizing, are mandatory to obtain a good result. However, more data are needed to determine the best method for accurate sizing of the mitral annulus, to predict ring deformability and ultimately to identify potential factors influencing procedural success, especially in the presence of a mitral homograft.
References 1. Cheung A, Webb JG, Barbanti M, et al. 5-year experience with transcatheter transapical mitral valve-in-valve implantation for bioprosthetic valve dysfunction. J Am Coll Cardiol 2013;61: 1759–66. 2. Descoutures F, Himbert D, Maisano F, et al. Transcatheter valve-in-ring implantation after failure of surgical mitral repair. Eur J Cardiothorac Surg 2013;44:e8–15. 3. Wilbring M, Alexiou K, Tugtekin SM, et al. Pushing the limits: further evolutions of transcatheter valve procedures in the mitral position, including valve-in-valve, valve-in-ring, and valve-in-native-ring. J Thorac Cardiovasc Surg 2014;147:210–9. 4. Carpentier AF, Lessana A, Relland JY, et al. The “physioring”: an advanced concept in mitral valve annuloplasty. Ann Thorac Surg 1995;60:1177–85. 5. Tavlasoglu M, Durukan AB, Kurkluoglu M. Can valved mitral prosthesis be implanted within all kinds of the mitral annuloplasty rings? Catheter Cardiovasc Interv 2013;81:172. Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
Intraoperative Coronary Artery Dissection in Fibromuscular Dysplasia Xiaoying Lou, BS, Sumeet S. Mitter, MD, John E. Blair, MD, Keith Benzuly, MD, Ivancarmine Gambardella, MD, and S. Chris Malaisrie, MD Department of Cardiothoracic Surgery, Northwestern University, Chicago, Illinois
A 61-year-old woman with bicuspid aortic stenosis, an ascending aortic aneurysm, and a remote history of renal fibromuscular dysplasia underwent aortic root replacement complicated by extensive dissection of the left circumflex artery extending retrograde into the left anterior descending artery. This was managed by coronary artery bypass grafting, left ventricular support, and percutaneous coronary intervention for propagation of the dissection. This case highlights the prevalence, diagnosis, and management of intraoperative coronary dissection secondary to fibromuscular dysplasia. (Ann Thorac Surg 2015;99:1442–4) Ó 2015 by The Society of Thoracic Surgeons
F
ibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease that may lead to stenosis, occlusion, aneurysm, and dissection. Although the prevalence of FMD in the general Accepted for publication June 13, 2014. Address correspondence to Dr Malaisrie, Department of Cardiothoracic Surgery, Northwestern University, 675 N St. Clair, Galter 19-100, Chicago, IL 60611; e-mail: [email protected].
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.06.107
Ann Thorac Surg 2015;99:1442–4
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
1443
Fig 1. (A) Renal artery angiogram reveals fibromuscular dysplasia. (B) Flow-limiting dissection of the left anterior descending artery.
A 61-year-old woman with a bicuspid aortic valve and moderate aortic stenosis was referred for surgical repair of a rapidly enlarging ascending aorta. She had hypertension, and FMD had been diagnosed on renal angiogram 9 years prior (Fig 1A). Computed tomography demonstrated an ascending aortic aneurysm measuring 5.2 cm at the maximum diameter and extending into the proximal arch. The preoperative evaluation revealed angiographically normal coronary arteries and left ventricular function. Cardiopulmonary bypass (CPB) and direct ostial cannulation for antegrade delivery of potassium-rich cardioplegia were used during replacement of the aortic root with a bioprosthetic valve-graft conduit. The ascending aorta and proximal transverse arch were replaced with a Dacron graft (DuPont, Wilmington, DE) using a hemiarch technique, and the coronary arteries were reimplanted as buttons. Upon weaning from CPB, she required high-dose inotropes, and intraoperative transesophageal echocardiography demonstrated severe hypokinesis of the lateral wall. Full CPB was restarted. The first obtuse marginal artery was opened, found to be acutely thrombosed, and subsequently bypassed with a saphenous vein graft (SVG). Intracoronary thrombus was removed by flushing the coronaries with antegrade and retrograde cardioplegia; however, complete thrombus removal was not possible.
A second attempt at weaning from CPB resulted in similar requirements for inotropic support, and the posterolateral wall remained hypokinetic. The second obtuse marginal artery was opened, found to be nearly circumferentially dissected, and bypassed with a second SVG. A third attempt at weaning from CPB was unsuccessful, and the anterior wall of the left ventricle was noted to be hypokinetic. The left anterior descending (LAD) artery was opened, found to be nearly circumferentially dissected, and bypassed with a third SVG. The patient was successfully weaned from CPB with intraaortic balloon pump support, and transesophageal echocardiography demonstrated recovered left ventricular systolic function. During the subsequent 12 hours, she required escalation of inotropes. An electrocardiogram revealed sinus rhythm with nonspecific ST changes but no definitive evidence of myocardial injury. Echocardiography demonstrated depressed ventricular function, with an ejection fraction of 0.15. The patient was brought back to the hybrid operating room on postoperative day (POD) 1 for mediastinal reexploration. Clot was removed around her right atrium and inferior vena cava, and a temporary Impella 5.0 left ventricular assist device (Abiomed, Danvers, MA) was inserted through a 10-mm Dacron graft anastomosed to the right axillary artery across the aortic bioprosthesis into the left ventricle. An intraoperative angiogram revealed extensive spiral coronary dissection involving the left main, LAD, and circumflex arteries (Fig 1B); the SVGs were patent. The dissection appeared to have propagated distally from the proximal LAD, compromising SVG outflow. A guidewire was advanced across the anastomosis into the distal LAD, and a 2.25-mm 12-mm everolimus-eluting Xience Xpedition stent (Abbott, Abbott Park, IL) was placed at 12 atms, with good angiographic result and no distal dissection.
FEATURE ARTICLES
population is unknown, it is underdiagnosed and disproportionately affects women. FMD most commonly affects the renal (79.7%) and extracranial carotid (74.3%) arteries but can manifest in virtually every arterial bed, including the coronary arteries (3.8%) [1]. Several case series have documented acute coronary syndrome secondary to spontaneous dissection as the initial presentation of coronary artery FMD; however, no such cases have been described in the operative setting.
1444
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
The remainder of the patient’s hospital course was uncomplicated, with intraaortic balloon pump removal on POD 3, extubation on POD 4, and Impella removal on POD 6. She was discharged on POD 14. Predischarge echocardiography demonstrated an ejection fraction of 0.50, normal ventricular size and thickness, and no wall motion abnormalities or valvular lesions. Follow-up echocardiography at 1 month revealed improvement of ejection fraction to 0.54, mild ventricular dilation but normal thickness, mild mitral regurgitation, and no aortic insufficiency.
FEATURE ARTICLES
Comment Spontaneous coronary artery dissection (SCAD), a rare cause of acute coronary syndrome and sudden cardiac death, is defined as separation of the arterial wall by hemorrhage, with or without intimal tear. An association between FMD and SCAD was first demonstrated by Saw and colleagues [2]. Analysis of 50 nonatherosclerotic SCAD patients (98% female; mean age, 51 years) encountered at a single center during a 6-year period identified the LAD as the most commonly involved artery (36%), followed by branches of the circumflex (30%) and right coronary artery (28%) [2]. A separate study by Tweet and colleagues [3] of 87 SCAD patients (82% female; mean age, 42.6 years) at a single center identified iliac artery FMD in half of the femoral angiograms performed before vascular closure device placement. Underlying FMD may thus predispose to SCAD. Literature review reveals few reports of intraoperative coronary dissections. In non-FMD patients, Machado and colleagues [4] reported an acute dissection 2 days after aortic valve replacement in a 73-year-old woman with hypertension and severe aortic stenosis. Angiography demonstrated dissection extending from the left main artery to its branches, managed by SVG bypass grafting. In addition, Michalak and colleagues [5] reported a patient with right coronary dissection after ostium cannulation during a Ross procedure managed with resection and pharmacologic therapy with antiplatelets, anticoagulants, and antihypertensives. There have been virtually no reports, however, of intraoperative coronary dissections in FMD patients. Poulter and colleagues [6] described a 57-year-old woman undergoing stent implantation in a coronary FMD lesion that was complicated by perforation managed with prolonged balloon dilatation. Criteria for surgical treatment or catheter-based interventions are controversial in SCAD. Reports suggest that for patients with small dissections, spontaneous healing with medical management alone is sufficient, whereas in acute dissections complicated by hemodynamic instability, stenting or bypass
Ann Thorac Surg 2015;99:1442–4
grafting with realignment of the true lumen may be necessary. However, percutaneous intervention is associated with propagation of intramural hematoma and dissection, and although bypass grafting is effective in the short-term, it is associated with high long-term rates of graft occlusion. In general, dissection localized to 1 vessel should be managed with stenting and multivessel involvement with bypass grafting [7]. To our knowledge, no reports have been published of intraoperative coronary dissections secondary to FMD. Coronary artery abnormalities in FMD predispose vessels to dissection and perforation. In cardiac operations, rapid coronary spasm during ostia cannulation can exacerbate these risks, leading to intima damage and dissection that can progress to occlusion. We speculate that pathologic coronary involvement in our patient predisposed her to SCAD in the setting of aortic root replacement. This case highlights the insensitivity of angiography in the detection of coronary FMD, the systemic nature of FMD [8], and the fact that SCAD may occur in the absence of angiographically evident FMD. In addition, it illustrates the challenging management of SCAD. A combined heart team approach with adjunctive coronary angiography and intervention in a dedicated hybrid operating room was instrumental in the diagnosis and successful treatment of this patient.
References 1. Olin JW, Gornik HL, Bacharach M, et al. Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association. Circulation 2014;129:1048–78. 2. Saw J, Poulter R, Fung A, Wood D, Hamburger J, Buller CE. Spontaneous coronary artery dissection in patients with fibromuscular dysplasia. Circ Cardiovasc Interv 2012;5:134–7. 3. Tweet MS, Hayes SN, Pitta SR, et al. Clinical features, management and prognosis of spontaneous coronary artery dissection. Circulation 2012;126:579–88. 4. Machado FP, Sampaio RO, Mazzucato FL, Tarasoutchi F, Spina GS, Grinberg M. Acute coronary artery dissection after aortic valve replacement. Arq Bras Cardiol 2010;94: e23–5. 5. Michalak KW, Moszura T, Peruga JZ, Moll JJ. Right coronary artery dissection during intraoperative ostium cannulation. Presentation of successful treatment. Kardiol Pol 2011;69(9): 966–8; discussion 969. 6. Poulter R, Ricci D, Saw J. Perforation during stenting of a coronary artery with morphologic changes of fibromuscular dysplasia: an unrecognized risk with percutaneous intervention. Can J Cardiol 2013;29:519.e1–e3. 7. Jonjev Z, Redzek A, Farah H. Successful emergency surgery for spontaneous coronary artery dissection in a young woman. Ind J Thorac Cardiovasc Surg 2007;23: 215–7. 8. Ganesh SK, Morissette R, Xu Z, et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-b expression and connective tissue features. FASEB J 2014;28:3313–24.
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
Ann Thorac Surg 2015;99:1442–4
FEATURE ARTICLES
Fig 4. (A) Incomplete expansion of the transcatheter valve prosthesis in situ and (B) its oval shape to conform to the mitral ring, after explantation. (B) Note the unchanged oval contour of the mitral ring.
less than 10 years in most previous studies [2]. This might have had an impact on the flexibility of the ring owing to potential material fatigue. Finally, the patient had a mitral homograft in addition to the ring, and a potential influence of the homograft on the suboptimal deployment of the transcatheter valve cannot be excluded. In conclusion, the feasibility of TMViRI has been described, although this procedure remains experimental. The present report shows that this treatment can fail in some patients. Both an excessive transcatheter valve oversizing and the inability of the ring to adopt a circular shape may have played a major role in the failure of the procedure. Careful evaluation of the case, including ring properties and appropriate valve sizing, are mandatory to obtain a good result. However, more data are needed to determine the best method for accurate sizing of the mitral annulus, to predict ring deformability and ultimately to identify potential factors influencing procedural success, especially in the presence of a mitral homograft.
References 1. Cheung A, Webb JG, Barbanti M, et al. 5-year experience with transcatheter transapical mitral valve-in-valve implantation for bioprosthetic valve dysfunction. J Am Coll Cardiol 2013;61: 1759–66. 2. Descoutures F, Himbert D, Maisano F, et al. Transcatheter valve-in-ring implantation after failure of surgical mitral repair. Eur J Cardiothorac Surg 2013;44:e8–15. 3. Wilbring M, Alexiou K, Tugtekin SM, et al. Pushing the limits: further evolutions of transcatheter valve procedures in the mitral position, including valve-in-valve, valve-in-ring, and valve-in-native-ring. J Thorac Cardiovasc Surg 2014;147:210–9. 4. Carpentier AF, Lessana A, Relland JY, et al. The “physioring”: an advanced concept in mitral valve annuloplasty. Ann Thorac Surg 1995;60:1177–85. 5. Tavlasoglu M, Durukan AB, Kurkluoglu M. Can valved mitral prosthesis be implanted within all kinds of the mitral annuloplasty rings? Catheter Cardiovasc Interv 2013;81:172. Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
Intraoperative Coronary Artery Dissection in Fibromuscular Dysplasia Xiaoying Lou, BS, Sumeet S. Mitter, MD, John E. Blair, MD, Keith Benzuly, MD, Ivancarmine Gambardella, MD, and S. Chris Malaisrie, MD Department of Cardiothoracic Surgery, Northwestern University, Chicago, Illinois
A 61-year-old woman with bicuspid aortic stenosis, an ascending aortic aneurysm, and a remote history of renal fibromuscular dysplasia underwent aortic root replacement complicated by extensive dissection of the left circumflex artery extending retrograde into the left anterior descending artery. This was managed by coronary artery bypass grafting, left ventricular support, and percutaneous coronary intervention for propagation of the dissection. This case highlights the prevalence, diagnosis, and management of intraoperative coronary dissection secondary to fibromuscular dysplasia. (Ann Thorac Surg 2015;99:1442–4) Ó 2015 by The Society of Thoracic Surgeons
F
ibromuscular dysplasia (FMD) is a nonatherosclerotic, noninflammatory vascular disease that may lead to stenosis, occlusion, aneurysm, and dissection. Although the prevalence of FMD in the general Accepted for publication June 13, 2014. Address correspondence to Dr Malaisrie, Department of Cardiothoracic Surgery, Northwestern University, 675 N St. Clair, Galter 19-100, Chicago, IL 60611; e-mail: [email protected].
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2014.06.107
Ann Thorac Surg 2015;99:1442–4
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
1443
Fig 1. (A) Renal artery angiogram reveals fibromuscular dysplasia. (B) Flow-limiting dissection of the left anterior descending artery.
A 61-year-old woman with a bicuspid aortic valve and moderate aortic stenosis was referred for surgical repair of a rapidly enlarging ascending aorta. She had hypertension, and FMD had been diagnosed on renal angiogram 9 years prior (Fig 1A). Computed tomography demonstrated an ascending aortic aneurysm measuring 5.2 cm at the maximum diameter and extending into the proximal arch. The preoperative evaluation revealed angiographically normal coronary arteries and left ventricular function. Cardiopulmonary bypass (CPB) and direct ostial cannulation for antegrade delivery of potassium-rich cardioplegia were used during replacement of the aortic root with a bioprosthetic valve-graft conduit. The ascending aorta and proximal transverse arch were replaced with a Dacron graft (DuPont, Wilmington, DE) using a hemiarch technique, and the coronary arteries were reimplanted as buttons. Upon weaning from CPB, she required high-dose inotropes, and intraoperative transesophageal echocardiography demonstrated severe hypokinesis of the lateral wall. Full CPB was restarted. The first obtuse marginal artery was opened, found to be acutely thrombosed, and subsequently bypassed with a saphenous vein graft (SVG). Intracoronary thrombus was removed by flushing the coronaries with antegrade and retrograde cardioplegia; however, complete thrombus removal was not possible.
A second attempt at weaning from CPB resulted in similar requirements for inotropic support, and the posterolateral wall remained hypokinetic. The second obtuse marginal artery was opened, found to be nearly circumferentially dissected, and bypassed with a second SVG. A third attempt at weaning from CPB was unsuccessful, and the anterior wall of the left ventricle was noted to be hypokinetic. The left anterior descending (LAD) artery was opened, found to be nearly circumferentially dissected, and bypassed with a third SVG. The patient was successfully weaned from CPB with intraaortic balloon pump support, and transesophageal echocardiography demonstrated recovered left ventricular systolic function. During the subsequent 12 hours, she required escalation of inotropes. An electrocardiogram revealed sinus rhythm with nonspecific ST changes but no definitive evidence of myocardial injury. Echocardiography demonstrated depressed ventricular function, with an ejection fraction of 0.15. The patient was brought back to the hybrid operating room on postoperative day (POD) 1 for mediastinal reexploration. Clot was removed around her right atrium and inferior vena cava, and a temporary Impella 5.0 left ventricular assist device (Abiomed, Danvers, MA) was inserted through a 10-mm Dacron graft anastomosed to the right axillary artery across the aortic bioprosthesis into the left ventricle. An intraoperative angiogram revealed extensive spiral coronary dissection involving the left main, LAD, and circumflex arteries (Fig 1B); the SVGs were patent. The dissection appeared to have propagated distally from the proximal LAD, compromising SVG outflow. A guidewire was advanced across the anastomosis into the distal LAD, and a 2.25-mm 12-mm everolimus-eluting Xience Xpedition stent (Abbott, Abbott Park, IL) was placed at 12 atms, with good angiographic result and no distal dissection.
FEATURE ARTICLES
population is unknown, it is underdiagnosed and disproportionately affects women. FMD most commonly affects the renal (79.7%) and extracranial carotid (74.3%) arteries but can manifest in virtually every arterial bed, including the coronary arteries (3.8%) [1]. Several case series have documented acute coronary syndrome secondary to spontaneous dissection as the initial presentation of coronary artery FMD; however, no such cases have been described in the operative setting.
1444
CASE REPORT LOU ET AL CORONARY ARTERY DISSECTION IN FMD
The remainder of the patient’s hospital course was uncomplicated, with intraaortic balloon pump removal on POD 3, extubation on POD 4, and Impella removal on POD 6. She was discharged on POD 14. Predischarge echocardiography demonstrated an ejection fraction of 0.50, normal ventricular size and thickness, and no wall motion abnormalities or valvular lesions. Follow-up echocardiography at 1 month revealed improvement of ejection fraction to 0.54, mild ventricular dilation but normal thickness, mild mitral regurgitation, and no aortic insufficiency.
FEATURE ARTICLES
Comment Spontaneous coronary artery dissection (SCAD), a rare cause of acute coronary syndrome and sudden cardiac death, is defined as separation of the arterial wall by hemorrhage, with or without intimal tear. An association between FMD and SCAD was first demonstrated by Saw and colleagues [2]. Analysis of 50 nonatherosclerotic SCAD patients (98% female; mean age, 51 years) encountered at a single center during a 6-year period identified the LAD as the most commonly involved artery (36%), followed by branches of the circumflex (30%) and right coronary artery (28%) [2]. A separate study by Tweet and colleagues [3] of 87 SCAD patients (82% female; mean age, 42.6 years) at a single center identified iliac artery FMD in half of the femoral angiograms performed before vascular closure device placement. Underlying FMD may thus predispose to SCAD. Literature review reveals few reports of intraoperative coronary dissections. In non-FMD patients, Machado and colleagues [4] reported an acute dissection 2 days after aortic valve replacement in a 73-year-old woman with hypertension and severe aortic stenosis. Angiography demonstrated dissection extending from the left main artery to its branches, managed by SVG bypass grafting. In addition, Michalak and colleagues [5] reported a patient with right coronary dissection after ostium cannulation during a Ross procedure managed with resection and pharmacologic therapy with antiplatelets, anticoagulants, and antihypertensives. There have been virtually no reports, however, of intraoperative coronary dissections in FMD patients. Poulter and colleagues [6] described a 57-year-old woman undergoing stent implantation in a coronary FMD lesion that was complicated by perforation managed with prolonged balloon dilatation. Criteria for surgical treatment or catheter-based interventions are controversial in SCAD. Reports suggest that for patients with small dissections, spontaneous healing with medical management alone is sufficient, whereas in acute dissections complicated by hemodynamic instability, stenting or bypass
Ann Thorac Surg 2015;99:1442–4
grafting with realignment of the true lumen may be necessary. However, percutaneous intervention is associated with propagation of intramural hematoma and dissection, and although bypass grafting is effective in the short-term, it is associated with high long-term rates of graft occlusion. In general, dissection localized to 1 vessel should be managed with stenting and multivessel involvement with bypass grafting [7]. To our knowledge, no reports have been published of intraoperative coronary dissections secondary to FMD. Coronary artery abnormalities in FMD predispose vessels to dissection and perforation. In cardiac operations, rapid coronary spasm during ostia cannulation can exacerbate these risks, leading to intima damage and dissection that can progress to occlusion. We speculate that pathologic coronary involvement in our patient predisposed her to SCAD in the setting of aortic root replacement. This case highlights the insensitivity of angiography in the detection of coronary FMD, the systemic nature of FMD [8], and the fact that SCAD may occur in the absence of angiographically evident FMD. In addition, it illustrates the challenging management of SCAD. A combined heart team approach with adjunctive coronary angiography and intervention in a dedicated hybrid operating room was instrumental in the diagnosis and successful treatment of this patient.
References 1. Olin JW, Gornik HL, Bacharach M, et al. Fibromuscular dysplasia: state of the science and critical unanswered questions: a scientific statement from the American Heart Association. Circulation 2014;129:1048–78. 2. Saw J, Poulter R, Fung A, Wood D, Hamburger J, Buller CE. Spontaneous coronary artery dissection in patients with fibromuscular dysplasia. Circ Cardiovasc Interv 2012;5:134–7. 3. Tweet MS, Hayes SN, Pitta SR, et al. Clinical features, management and prognosis of spontaneous coronary artery dissection. Circulation 2012;126:579–88. 4. Machado FP, Sampaio RO, Mazzucato FL, Tarasoutchi F, Spina GS, Grinberg M. Acute coronary artery dissection after aortic valve replacement. Arq Bras Cardiol 2010;94: e23–5. 5. Michalak KW, Moszura T, Peruga JZ, Moll JJ. Right coronary artery dissection during intraoperative ostium cannulation. Presentation of successful treatment. Kardiol Pol 2011;69(9): 966–8; discussion 969. 6. Poulter R, Ricci D, Saw J. Perforation during stenting of a coronary artery with morphologic changes of fibromuscular dysplasia: an unrecognized risk with percutaneous intervention. Can J Cardiol 2013;29:519.e1–e3. 7. Jonjev Z, Redzek A, Farah H. Successful emergency surgery for spontaneous coronary artery dissection in a young woman. Ind J Thorac Cardiovasc Surg 2007;23: 215–7. 8. Ganesh SK, Morissette R, Xu Z, et al. Clinical and biochemical profiles suggest fibromuscular dysplasia is a systemic disease with altered TGF-b expression and connective tissue features. FASEB J 2014;28:3313–24.
