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Coronary Vasospasm Following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy
Accepted Manuscript Coronary Vasospasm following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy Mia Bertic, MD, Colin Dominic Chue, MBChB(Hons), PhD, Sean Virani, MD, MSc, MPH, Margot K. Davis, MD, SM, Andrew Ignaszewski, MD, Tara Sedlak, MD, MBA PII:
S0828-282X(18)31058-4
DOI:
10.1016/j.cjca.2018.08.022
Reference:
CJCA 3022
To appear in:
Canadian Journal of Cardiology
Received Date: 18 July 2018 Revised Date:
14 August 2018
Accepted Date: 14 August 2018
Please cite this article as: Bertic M, Chue CD, Virani S, Davis MK, Ignaszewski A, Sedlak T, Coronary Vasospasm following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.08.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Coronary Vasospasm following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy Mia Bertic, MD1; Colin Dominic Chue, MBChB(Hons), PhD1; Sean Virani, MD, MSc, MPH1; Margot K. Davis,
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MD,SM1; Andrew Ignaszewski, MD1; Tara Sedlak, MD, MBA1. 1. Division of Cardiology, University of British Columbia, Vancouver, BC
Corresponding Author Contact Information:
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Tara Sedlak, MD, MBA, FRCPC [email protected] University of British Columbia 9th Floor 2775 Laurel St. Vancouver, BC V5Z1M9 Phone: 604-875-5487 Fax: 604-875-5504
Brief Summary
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Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients but is rare in the post-transplanted, denervated heart. Severe CVS has been associated with accelerated cardiac allograft vasculopathy (CAV) and allograft rejection. We present a case of severe symptomatic CVS with
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Abstract
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subsequent rapid development of severe CAV.
Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients but is rare in the post-transplanted, denervated heart. Severe CVS has been associated with accelerated cardiac allograft vasculopathy (CAV) and allograft rejection. Allograft vasculopathy is the leading cause of decreased long-term survival in OHT. The prognostic significance and relationship of the presence and severity of CVS with CAV are not well understood. We present a case of severe symptomatic CVS with rapid development of severe CAV. Our case emphasizes the need for close angiographic surveillance and intracoronary imaging for early detection of CAV in the presence of vasospasm.
ACCEPTED MANUSCRIPT
Case Report A 40-year-old female with a history of non-ischemic cardiomyopathy underwent orthotopic heart
RI PT
transplantation 9 years after initial diagnosis. She did not have a history of diabetes, dyslipidemia or hypertension. Routine post-transplant surveillance cardiac biopsies showed no histological evidence of cellular or antibody-mediated rejection. Echocardiography revealed normal biventricular function with no regional wall motion abnormalities. Routine surveillance coronary angiography and intravascular
SC
ultrasound (IVUS) performed one-year post-transplant revealed eccentric intimal thickening up to 1mm with mild calcification in the left anterior descending (LAD) artery with 40% disease in the mid circumflex. Review of donor coronary angiogram suggested this was atherosclerotic disease of the
M AN U
donor heart rather than de novo cardiac allograft vasculopathy (CAV). Marked spasm of the LAD was noted during placement of the IVUS catheter, which resolved fully with intracoronary nitrate administration. Two years post OHT, the patient developed recurrent episodes of retrosternal chest discomfort unrelated to exertion, most disabling at night, with up to 20 episodes in 24 hours. She was started on topical nitrates and amlodipine which were ultimately up-titrated to maximal doses based on the patient’s symptoms. Despite these therapies, her symptoms persisted necessitating frequent use of
TE D
sublingual and oral short acting nitrates. Her other medications included mycophenolate mofetil, tacrolimus, aspirin, rosuvastatin, furosemide and pantoprazole. Given the escalation of her symptoms, repeat coronary artery catheterization was performed which revealed no new lesions or stenoses. Repeat cardiac biopsy showed no cellular or antibody-mediated
EP
rejection. Treatment with oral ranolazine 500mg twice daily on special authority from the United States was initiated given persistent symptoms. There was marked symptom improvement after 3 weeks with
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a 75% reduction in angina when assessed objectively using the Seattle Angina Questionnaire. Unfortunately, her symptoms progressed culminating in a hospital admission for non-ST elevation myocardial infarction after an episode of prolonged chest pain. Urgent coronary angiography revealed diffuse occlusive disease of the entire coronary tree with extensive collateralization. Compared to the coronary angiogram ten months prior, the mid LAD, circumflex, right coronary artery and posterior descending arteries were now occluded with severe branch disease (Figure 1). She underwent percutaneous coronary intervention of the right coronary artery followed by staged stenting to the circumflex. Given the rapid progression and severity of CAV, she underwent repeat cardiac
ACCEPTED MANUSCRIPT
transplantation. Pathology report from the explanted heart revealed extensive cardiac allograft vasculopathy with minimal acute cellular rejection. Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients, but is rare in the post-transplanted, denervated heart1. CVS has been associated with accelerated CAV or may also be
RI PT
a sign of underlying allograft rejection1,2. Cardiac allograft vasculopathy is an accelerated form of coronary artery disease characterized by diffuse, concentric intimal proliferation, and luminal
obstruction of the epicardial coronary arteries2. It is the leading cause of late graft failure, mortality and increased morbidity among OHT patients affecting up to 50% at 5 years2. The prognostic significance and
SC
relationship of CVS with CAV are not well understood. Coronary vasospasm is associated with
accelerated atherosclerosis and sudden death, but whether CVS is a cause of CAV or merely a bystander
M AN U
is unclear. Kushawa et al reported 4 cases of CVS in OHT recipients, with all four patients developing rapidly progressive CAV1. There are also reports of CVS in the OHT patient where there is no evidence of allograft rejection or angiographic evidence of CAV3. The true incidence of CVS is likely to be higher when considering techniques such as IVUS, which are more likely to induce spasm secondary to instrumentation. When evaluating the clinical relevance of catheter induced spasm, a review by Decklebaum et al4 suggests that catheter induced spasm may identify a patient population prone to
TE D
vasospastic angina and may not solely be attributed to mechanical irritation of the catheter. Intravascular imaging, however, is recommended as an adjunct to coronary angiography to increase sensitivity for detection of CAV in patients with CVS. Intravascular imaging detects CAV in 50% of patients whereas angiography detects disease in only 10–20% one-year post OHT. Intravascular
EP
ultrasound is considered the gold standard for the diagnosis of CAV and is the most sensitive tool for this purpose in OHT recipients2.
AC C
Our case emphasizes the importance of close angiographic surveillance and intracoronary imaging for early detection of CAV in the setting of CVS as coronary vasospasm may reflect an alternate presentation of high risk CAV. Optimizing the immunosuppressive regimen to include a mammalian target of rapamycin inhibitor such as sirolimus is recommended post-transplant to reduce progression of CAV once abnormalities of intimal thickness are evident on IVUS5. Whether this is of any benefit in patients with CVS is unknown and is an area that requires further evaluation. Our knowledge of the prognostic significance of CVS and its association with CAV is limited and further research in this area is required.
ACCEPTED MANUSCRIPT
Figure 1. Coronary Angiographic surveillance images two years post OHT (A-C) and repeat images 10 months later, (D-F). Right anterior oblique caudal view of the LAD and LCx, (A) and right anterior oblique cranial view, (B), of the LAD and LCx artery. Left anterior oblique cranial view of the RCA, (C). Images revealing significant occlusion of the proximal and mid LAD, LCx (D, E) RCA, and posterior descending
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arteries (F). LAD: left anterior descending. LCx: left circumflex artery. RCA: right coronary artery. Disclosures
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The authors have no conflict of interests to declare.
M AN U
References
1. Kushawaha S, Mitchell AG, Yacoub MH. Coronary artery spasm after cardiac transplantation. Am J Cardiol 1990;65:1515–8.
2. Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg 2005 Aug; 48(4): 319–327.
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3. Omondi A, Briceno D, Villablanca PA. Coronary vasospasm: a silent enemy in orthotopic heart transplant. Coron Artery Dis. 2018, 29:86–87. 4. Decklebaum LI, Isner JM, Konstam MA, Salem DN. Catheter-induced versus spontaneous spasm:
EP
Do these coronary bedfellows deserve to be estranged?. Am J Med 1985;79:1-4.
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5. Raichlin E, Bae JH, Khalpey Z, Edwards BS, Kremers WK, Clavell AL, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation 2007; 116: 2726–33.
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EP
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SC
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ACCEPTED MANUSCRIPT
S0828-282X(18)31058-4
DOI:
10.1016/j.cjca.2018.08.022
Reference:
CJCA 3022
To appear in:
Canadian Journal of Cardiology
Received Date: 18 July 2018 Revised Date:
14 August 2018
Accepted Date: 14 August 2018
Please cite this article as: Bertic M, Chue CD, Virani S, Davis MK, Ignaszewski A, Sedlak T, Coronary Vasospasm following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy, Canadian Journal of Cardiology (2018), doi: 10.1016/j.cjca.2018.08.022. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
Coronary Vasospasm following Heart Transplantation: Rapid Progression to Aggressive Cardiac Allograft Vasculopathy Mia Bertic, MD1; Colin Dominic Chue, MBChB(Hons), PhD1; Sean Virani, MD, MSc, MPH1; Margot K. Davis,
RI PT
MD,SM1; Andrew Ignaszewski, MD1; Tara Sedlak, MD, MBA1. 1. Division of Cardiology, University of British Columbia, Vancouver, BC
Corresponding Author Contact Information:
M AN U
SC
Tara Sedlak, MD, MBA, FRCPC [email protected] University of British Columbia 9th Floor 2775 Laurel St. Vancouver, BC V5Z1M9 Phone: 604-875-5487 Fax: 604-875-5504
Brief Summary
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Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients but is rare in the post-transplanted, denervated heart. Severe CVS has been associated with accelerated cardiac allograft vasculopathy (CAV) and allograft rejection. We present a case of severe symptomatic CVS with
AC C
Abstract
EP
subsequent rapid development of severe CAV.
Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients but is rare in the post-transplanted, denervated heart. Severe CVS has been associated with accelerated cardiac allograft vasculopathy (CAV) and allograft rejection. Allograft vasculopathy is the leading cause of decreased long-term survival in OHT. The prognostic significance and relationship of the presence and severity of CVS with CAV are not well understood. We present a case of severe symptomatic CVS with rapid development of severe CAV. Our case emphasizes the need for close angiographic surveillance and intracoronary imaging for early detection of CAV in the presence of vasospasm.
ACCEPTED MANUSCRIPT
Case Report A 40-year-old female with a history of non-ischemic cardiomyopathy underwent orthotopic heart
RI PT
transplantation 9 years after initial diagnosis. She did not have a history of diabetes, dyslipidemia or hypertension. Routine post-transplant surveillance cardiac biopsies showed no histological evidence of cellular or antibody-mediated rejection. Echocardiography revealed normal biventricular function with no regional wall motion abnormalities. Routine surveillance coronary angiography and intravascular
SC
ultrasound (IVUS) performed one-year post-transplant revealed eccentric intimal thickening up to 1mm with mild calcification in the left anterior descending (LAD) artery with 40% disease in the mid circumflex. Review of donor coronary angiogram suggested this was atherosclerotic disease of the
M AN U
donor heart rather than de novo cardiac allograft vasculopathy (CAV). Marked spasm of the LAD was noted during placement of the IVUS catheter, which resolved fully with intracoronary nitrate administration. Two years post OHT, the patient developed recurrent episodes of retrosternal chest discomfort unrelated to exertion, most disabling at night, with up to 20 episodes in 24 hours. She was started on topical nitrates and amlodipine which were ultimately up-titrated to maximal doses based on the patient’s symptoms. Despite these therapies, her symptoms persisted necessitating frequent use of
TE D
sublingual and oral short acting nitrates. Her other medications included mycophenolate mofetil, tacrolimus, aspirin, rosuvastatin, furosemide and pantoprazole. Given the escalation of her symptoms, repeat coronary artery catheterization was performed which revealed no new lesions or stenoses. Repeat cardiac biopsy showed no cellular or antibody-mediated
EP
rejection. Treatment with oral ranolazine 500mg twice daily on special authority from the United States was initiated given persistent symptoms. There was marked symptom improvement after 3 weeks with
AC C
a 75% reduction in angina when assessed objectively using the Seattle Angina Questionnaire. Unfortunately, her symptoms progressed culminating in a hospital admission for non-ST elevation myocardial infarction after an episode of prolonged chest pain. Urgent coronary angiography revealed diffuse occlusive disease of the entire coronary tree with extensive collateralization. Compared to the coronary angiogram ten months prior, the mid LAD, circumflex, right coronary artery and posterior descending arteries were now occluded with severe branch disease (Figure 1). She underwent percutaneous coronary intervention of the right coronary artery followed by staged stenting to the circumflex. Given the rapid progression and severity of CAV, she underwent repeat cardiac
ACCEPTED MANUSCRIPT
transplantation. Pathology report from the explanted heart revealed extensive cardiac allograft vasculopathy with minimal acute cellular rejection. Coronary artery vasospasm (CVS) has been described in heart transplant (OHT) patients, but is rare in the post-transplanted, denervated heart1. CVS has been associated with accelerated CAV or may also be
RI PT
a sign of underlying allograft rejection1,2. Cardiac allograft vasculopathy is an accelerated form of coronary artery disease characterized by diffuse, concentric intimal proliferation, and luminal
obstruction of the epicardial coronary arteries2. It is the leading cause of late graft failure, mortality and increased morbidity among OHT patients affecting up to 50% at 5 years2. The prognostic significance and
SC
relationship of CVS with CAV are not well understood. Coronary vasospasm is associated with
accelerated atherosclerosis and sudden death, but whether CVS is a cause of CAV or merely a bystander
M AN U
is unclear. Kushawa et al reported 4 cases of CVS in OHT recipients, with all four patients developing rapidly progressive CAV1. There are also reports of CVS in the OHT patient where there is no evidence of allograft rejection or angiographic evidence of CAV3. The true incidence of CVS is likely to be higher when considering techniques such as IVUS, which are more likely to induce spasm secondary to instrumentation. When evaluating the clinical relevance of catheter induced spasm, a review by Decklebaum et al4 suggests that catheter induced spasm may identify a patient population prone to
TE D
vasospastic angina and may not solely be attributed to mechanical irritation of the catheter. Intravascular imaging, however, is recommended as an adjunct to coronary angiography to increase sensitivity for detection of CAV in patients with CVS. Intravascular imaging detects CAV in 50% of patients whereas angiography detects disease in only 10–20% one-year post OHT. Intravascular
EP
ultrasound is considered the gold standard for the diagnosis of CAV and is the most sensitive tool for this purpose in OHT recipients2.
AC C
Our case emphasizes the importance of close angiographic surveillance and intracoronary imaging for early detection of CAV in the setting of CVS as coronary vasospasm may reflect an alternate presentation of high risk CAV. Optimizing the immunosuppressive regimen to include a mammalian target of rapamycin inhibitor such as sirolimus is recommended post-transplant to reduce progression of CAV once abnormalities of intimal thickness are evident on IVUS5. Whether this is of any benefit in patients with CVS is unknown and is an area that requires further evaluation. Our knowledge of the prognostic significance of CVS and its association with CAV is limited and further research in this area is required.
ACCEPTED MANUSCRIPT
Figure 1. Coronary Angiographic surveillance images two years post OHT (A-C) and repeat images 10 months later, (D-F). Right anterior oblique caudal view of the LAD and LCx, (A) and right anterior oblique cranial view, (B), of the LAD and LCx artery. Left anterior oblique cranial view of the RCA, (C). Images revealing significant occlusion of the proximal and mid LAD, LCx (D, E) RCA, and posterior descending
RI PT
arteries (F). LAD: left anterior descending. LCx: left circumflex artery. RCA: right coronary artery. Disclosures
SC
The authors have no conflict of interests to declare.
M AN U
References
1. Kushawaha S, Mitchell AG, Yacoub MH. Coronary artery spasm after cardiac transplantation. Am J Cardiol 1990;65:1515–8.
2. Ramzy D, Rao V, Brahm J, Miriuka S, Delgado D, Ross HJ. Cardiac allograft vasculopathy: a review. Can J Surg 2005 Aug; 48(4): 319–327.
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3. Omondi A, Briceno D, Villablanca PA. Coronary vasospasm: a silent enemy in orthotopic heart transplant. Coron Artery Dis. 2018, 29:86–87. 4. Decklebaum LI, Isner JM, Konstam MA, Salem DN. Catheter-induced versus spontaneous spasm:
EP
Do these coronary bedfellows deserve to be estranged?. Am J Med 1985;79:1-4.
AC C
5. Raichlin E, Bae JH, Khalpey Z, Edwards BS, Kremers WK, Clavell AL, et al. Conversion to sirolimus as primary immunosuppression attenuates the progression of allograft vasculopathy after cardiac transplantation. Circulation 2007; 116: 2726–33.
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M AN U
SC
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ACCEPTED MANUSCRIPT