01 March 2023: Articles
Accelerated Cardiac Allograft Vasculopathy in an Orthotopic Heart Transplant Recipient with Prior COVID-19
Educational Purpose (only if useful for a systematic review or synthesis), Rare coexistence of disease or pathologyNeil U. Parikh1ABCDEF, Neal M. Dixit 2ABCDEFG, Austin B. Churchill3ABEF, Andrea Oliveira-Kowaleski4BCDE, Ryan P. Lau4BCDE, Gregory A. Fishbein 4BCDE, Jeffrey J. Hsu56ADEFG*
Am J Case Rep 2023; 24:e937955
BACKGROUND: Cardiac allograft vasculopathy (CAV) is a post-orthotopic heart transplant (OHT) complication driven by intimal smooth muscle proliferation and immune hyperactivity to donor heart tissue. Accelerated CAV leads to allograft failure within 1 year after receiving a normal angiogram result. Viruses can contribute to CAV development, but CAV after SARS-CoV-2 infection has not been reported to date.
CASE REPORT: A 48-year-old man, 5 years after OHT for non-ischemic cardiomyopathy, was admitted to the Cardiac Care Unit with 3 days of abdominal pain, dyspnea, and palpitations. His medical history included hyperlipidemia and insulin-dependent diabetes. He was compliant with all medications. Two months prior, he had a mild COVID-19 case. An echocardiogram and coronary angiogram 6 and 9 months prior, respectively, were unremarkable. Right and left heart catheterization demonstrated increased filling pressures, a cardiac index of 1.7 L/ml/m², and diffuse vasculopathy most severe in the LAD artery. Flow could not be restored despite repeated ballooning and intra-catheter adenosine. Empiric ionotropic support, daily high-dose methylprednisolone, and plasmapheresis were started. A few days later, the patient had cardiac arrest requiring venoarterial extracorporeal membranous oxygenation. Given CAV’s irreversibility, re-transplantation was considered, but the patient had an episode of large-volume hemoptysis and remained clinically unstable for transplant. The patient died while on palliative care.
CONCLUSIONS: Our patient developed accelerated CAV 2 months after having COVID-19. While CAV has known associations with certain viruses, its incidence after SARS-CoV-2 infection is unknown. Further research is needed to determine if prior SARS-CoV-2 infection is a risk factor for development of CAV in OHT recipients.
Keywords: Autoimmunity, COVID-19, Graft Rejection, Heart Transplantation, Transplantation Tolerance
Cardiac allograft vasculopathy (CAV) is a serious complication for orthotopic heart transplant (OHT) recipients. The patho-physiology of CAV is thought to be due to the recipient’s immune system reacting to the donor’s foreign heart tissue, leading to concentric fibromuscular hyperplasia of the intima of the coronary vasculature of the transplanted heart . CAV can be devastating for many OHT recipients as its onset can be early, presenting within years of the transplant, and is pervasive and angiographically detectable in approximately one-third of OHT patients within 5 years and in almost half within 10 years . CAV is difficult to manage, with no strongly effective treatment, often leading to aggressive percutaneous coronary intervention or redo heart transplantation. Accelerated CAV is characterized by an even worse prognosis, leading to allograft failure within 1 year . The risk of CAV is increased by traditional, non-immunogenic risk factors (eg, age, obesity, male sex, diabetes, and hyperlipidemia), immunologic risk factors, and donor-specific risk factors . Notably, viruses such as cytomegalovirus (CMV) and hepatitis C virus (HCV) have also been implicated in CAV. Acute COVID-19, due to infection by severe acute respiratory syndrome coronavirus-2 (SARSCoV-2), has been associated with increased risk of mortality for OHT recipients [4,5], but to date, no association has been demonstrated between SARS-CoV-2 infection and CAV. We report, to the best of our knowledge, the first case of accelerated CAV in an OHT recipient after COVID-19 .
A 48-year-old man with a history of non-ischemic cardiomyopathy status-post OHT 5 years prior presented to the Emergency Department with a 3-day history of palpitations, shortness of breath, and chest and epigastric pain . His past medical history was notable for an OHT (donor and recipient were CMV-and HCV-negative), insulin-dependent diabetes, and hyperlipidemia. His post-transplant course was notable for only 1 episode of resolved acute cellular rejection early after transplantation and mild COVID-19 illness, defined as COVID-19 not requiring anti-viral medication or hospitalization, 2 months prior to presentation. He was adherent to his immune suppression regimen, which included tacrolimus and mycophenolate. He also took aspirin, glimepiride, metformin, rosuvastatin, and fluconazole. He was unvaccinated against COVID-19. He reported no use of tobacco, alcohol, or recreational drugs. Echocardiograms and coronary angiograms were obtained annually for monitoring of the transplanted graft. The echocardiogram obtained 6 months prior, and all previous echocardiograms, were normal except for mild mitral regurgitation and mild concentric left ventricular hypertrophy. All prior coronary angiograms including the latest, from 9 months prior, obtained for annual screening of the transplanted graft, showed no significant epicardial coronary artery disease. His vital signs were notable for an increased heart rate of 130 beats per minute, a blood pressure of 124/96 mmHg, a respiratory rate of 26, and an oxygen saturation of 94% on room air. His physical exam was notable for distended neck veins and right upper quadrant and epi-gastric pain. He was fully alert and oriented. Initial laboratory studies revealed a normal complete blood count and normal renal function. Non-anion gap metabolic acidosis and elevations in transaminases were present. Serum troponin I was elevated to 10.6 ng/ml (normal <0.04 ng/ml). Tacrolimus level was within his therapeutic goal. Electrocardiogram showed junctional tachycardia.
The patient was given 1 liter of intravenous (IV) fluids, aspirin 325 mg, acetaminophen 1 gm, and morphine 4 mg IV. He then underwent an expedited right and left heart catheterization. Mean pulmonary artery pressure was 37 mmHg, and cardiac index was calculated at 1.7 L/min/m2 and 1.6 L/min/m2 by thermodilution and Fick methods, respectively. Angiographic evaluation of the coronary arteries was notable for diffuse vasculopathy with severe disease in the first obtuse marginal branch, first diagonal artery, and the apical left anterior descending (LAD) artery (Figure 1). The right coronary artery (RCA) also showed signs of vasculopathy and had 20% stenosis. Flow was unable to be restored to the LAD artery despite attempts at ballooning and administration of intra-coronary adenosine.
Methylprednisolone 500 mg daily and a milrinone 0.2 mcg/kg/ min infusion were started. The next day, an endomyocardial biopsy was obtained, which revealed pAMR1 antibody-mediated rejection without evidence of acute cellular rejection. Plasma exchange was then initiated for a planned 5-day course. Methylprednisolone was transitioned to a prednisone taper. The patient appeared to improve and milrinone had begun to be weaned when he had a cardiac arrest with pulseless electrical activity initially then ventricular fibrillation. Advance cardiovascular life support was performed for 30 minutes until venoarterial extracorporeal membrane oxygenation (ECMO) could be initiated. Following ECMO, the patient’s course was complicated by large-volume hemoptysis, multiple episodes of ventricular arrhythmia, and severely elevated pulmonary pressures.
Over the next several days the patient’s mental status improved, and he was extubated. However, he then experienced recurrent large-volume hemoptysis. A bronchoscopy revealed diffuse alveolar hemorrhage presumed to be secondary to elevated pulmonary pressures in the setting of continued acute heart failure. Unfortunately, his hemoptysis was not able to be controlled and he was considered too unstable for cardiac transplantation. The patient died on hospital day 29 after transitioning to palliative care. Figure 2 summarizes the time-line of events.
The family requested an autopsy study, which revealed severe cardiac allograft vasculopathy and acute myocardial infarction. All epicardial coronary arteries and their branches showed involvement of CAV, with maximally up to 90% stenosis of the distal LAD artery, left circumflex artery, and RCA. Microscopic examination showed concentric intimal proliferation of the LAD artery with sparing of the elastic lamina, and an intramyocar-dial artery with intimal proliferation and sparse mural chronic inflammation (Figure 3). The myocardium showed near-circumferential, subendocardial-sparing coagulative necrosis of the left ventricle, with hypereosinophilic cytoplasm, loss of nuclei, edema, hemorrhage, and focal inflammation, consistent with acute myocardial infarct from global ischemia (Figure 4).
There was no evidence of acute cellular rejection or antibody-mediated rejection. The lungs showed patchy organizing pneumonia with evidence of acute hemorrhage.
POTENTIAL MECHANISMS FOR COVID-19-INDUCED ACCELERATED CAV:
After heart transplantation, patients are placed on an immunosuppressive pharmacologic regimen to prevent the development of CAV mediated by an immune response to the donor’s foreign heart tissue. This regimen usually includes a calcineurin inhibitor (eg, tacrolimus), mycophenolate, and occasionally a proliferation signal inhibitor (eg, sirolimus or everolimus) . Unfortunately, this intentional suppression of the immune system can predispose OHT recipients to contract COVID-19 via a reduced ability to combat the infection.
When SARS-CoV-2 infects the susceptible host, evidence suggests that the virus enters endothelial cells via binding of its spike protein to the ACE2 receptor in tissues with high ACE2 expression, such as the heart [20,21]. Endothelial cells normally participate in inflammatory reactions and procoagulant responses, but ACE2-mediated entry of SARS-CoV-2 into endothelial cells can cause endothelial overactivation and dys-function .
Specifically, COVID-19-induced endothelial dysfunction can lead to increased autoimmunity via overactivation of proinflammatory cytokines such as IL-1, IL-2, IL-6, and TNF-α . This cytokine storm results in an inflamed endothelium, increased vessel permeability, a hypercoagulable state, and excessive leukocyte chemotaxis .
In fact, studies have shown that increasing levels of circulating endothelial cells in COVID-19 patients are directly correlated with increased proinflammatory cytokines from acute infection through the recovery phase, suggesting that endothelial dysfunction not only leads to production of cytokines but is also propagated by cytokines .
Although these changes may be reversible initially, in the setting of persistent endothelial dysfunction the increased immune response to donor tissue can lead to development of intimal proliferation, increased intimal thickness, and luminal occlusion characteristic of CAV.
Importantly, the mechanism outlined above can be induced by both mild and severe cases of COVID-19. Serologic testing of patients with mild and severe COVID-19 have yielded significantly higher levels of proinflammatory cytokines such as IL-6, CRP, and TNF-α compared to healthy controls more than 50% of the time [18,19]. It is unknown at this time whether vaccination against COVID-19 can protect patients from possible COVID-19-induced CAV, but vaccination has been shown to decrease infection severity in both immune-competent and immune-compromised populations .
Taken together, these potential mechanisms may explain why our patient, given his immune-suppressed state after transplant along with pre-existing risk factors for CAV (eg, insulin-dependent diabetes and hyperlipidemia), may have developed an accelerated case of CAV incited by his recent SARS-CoV-2 infection.
We acknowledge the above-average rate of infection with SARSCoV-2 in heart transplant recipients given their immunosup-pressed state; however, we report the first known case of accelerated CAV development after SARS-CoV-2 infection in an OHT recipient. We can only speculate as to why this phenomenon is not more common. It is possible that many OHT recipients who contract SARS-CoV-2 die from COVID-19-related complications prior to the development of CAV. It is also possible that the temporal relationship between COVID-19 and CAV has gone unrecognized or been under-detected. Or it could simply be that, despite the increased probability of COVID-19 in OHT recipients, infection with SARS-CoV-2 inciting the development of CAV is rare. This demonstrates a need for further investigation into the relationship between COVID-19 and CAV, especially given the established link between other viral illnesses and the consequent development of CAV.
MECHANISM FOR OTHER VIRUSES AND CAV:
Other viral agents have also been implicated in the development of accelerated CAV, including herpes-simplex virus-1 (HSV-1), herpes-simplex virus-2 (HSV-2), Epstein-Barr virus (EBV), and CMV. These viruses, and even bacteria such as Chlamydia pneumoniae and Helicobacter pylori, are associated with increased cardiovascular risk and levels of CRP, and an increasing total pathogen load is an effective predictor of severity of risk [12,24]. Acute CMV infection specifically can induce inflammation within the subendothelial wall of the allograft, leading to enhanced allograft dysfunction and rejection . After this phenomenon was observed clinically, researchers were able to replicate an acute infection with CMV in rats, demonstrating that an early inflammatory response in the adventitia and intima of the aorta and cardiac allograft resulted in increased intimal thickness and increased luminal occlusion. These changes are driven by increased leukocytes and cytokines, accelerating acute allograft rejection . Additionally, there is also evidence that hearts from HCV-positive donors have an increased rate of CAV at 1 year after transplant .
DETECTION AND MANAGEMENT OF CAV:
The symptomatology of CAV is wide-ranging, and most patients do not present acutely. Rather, patients may be largely asymptomatic, with CAV often found incidentally. Therefore, diagnosis must be based on more than just clinical criteria . Coronary angiography with or without intravascular ultrasound (IVUS) imaging remains the initial test for diagnosis of CAV, with a positive finding defined as a maximal intimal thickness of greater than or equal to 0.5 mm . Optical coherence tomography also can play an important role in determining the progression of CAV .
Non-invasive modalities include dobutamine stress echocardiography (DSE), radionuclide myocardial perfusion imaging utilizing either positron emission tomography or single-photon emission computed tomography (CT), coronary CT angiography, and cardiac magnetic resonance imaging . While these modalities are all gaining popularity, they demonstrate only a modest sensitivity and specificity in a handful of studies and further research is necessary to adequately judge their utility in CAV diagnosis.
Prevention of CAV begins with immunosuppression immediately after transplant, typically with a calcineurin inhibitor and mycophenolate mofetil . Control of hypertension and diabetes is also crucial . Notably, statin therapy has become a mainstay for CAV prevention by reducing the incidence of allograft rejection and progression of CAV through anti-inflammatory, immunomodulatory, and cholesterol-lowering effects [32,33]. When accompanied with acute antibody or cellular rejection, management of CAV may include additional treatment with high-dose steroids, intravenous immunoglobulin, thymoglobulin, and plasmapheresis . Percutaneous coronary intervention may provide temporary benefit by revascularizing stenotic focal lesions, but CAV generally results in diffuse and progressive disease . Redo OHT is most often the only definitive treatment . Many of these strategies were attempted in our patient, but unfortunately were insufficient to prevent cardiac failure from stenosed coronary arteries. Additionally, clinical instability precluded redo OHT in this case.
CAV remains a major cause of morbidity and mortality in the years following successful OHT. We describe, to the best of our knowledge, the first reported case of possible COVID-19-induced accelerated CAV in an OHT patient with pre-existing risk factors for CAV and review the pathophysiology, detection, and management of this disease. Further research into the early diagnosis and prevention of CAV is necessary to ensure that OHT recipients are correctly managed in the era of COVID-19 and in the face of many other viral infections, which demonstrate a clear and present danger to this immunosup-pressed population.
FiguresFigure 1.. Coronary angiography comparison. (A) Coronary angiogram from 9 months prior to presentation, showing mild cardiac allograft vasculopathy without any significant stenosis. (B) Coronary angiogram from the current presentation, showing diffuse cardiac allograft vasculopathy that has progressed significantly from the prior angiogram. The apical portion of the left anterior descending artery is completely occluded. Multiple attempts at balloon angioplasty were unsuccessful. Figure 2.. Detailed timeline of events. Figure 3.. Severe cardiac allograft vasculopathy. (A) Proximal left anterior descending artery; concentric proliferation of the intima (*) that spares the elastic lamina (**) (Hematoxylin and eosin staining [H&E], 40× magnification). (B) Intramyocardial artery with intimal proliferation and sparse mural chronic inflammation (arrow) (H&E, 200× magnification). Figure 4.. Acute myocardial infarction. (A) Myocardium with coagulative necrosis and hemorrhage (arrow), with subendocardial sparing (H&E, 40× magnification). (B) High-power view of the myocytes displaying contraction band necrosis, hypereosinophilia and loss of nuclei (double arrow) (H&E, 200× magnification).
1.. Felker GM, Mann D: Heart failure: A companion to Braunwald’s heart disease, 2020; 631-48, Philadelphia (PA), Elsevier
2.. Schmauss D, Weis M, Cardiac allograft vasculopathy: Recent developments: Circulation, 2008; 117; 2131-41
3.. Ortega-Legaspi JM, Bravo PE, Diagnosis and management of cardiac allograft vasculopathy: Heart, 2021; 108; 586-92
4.. Latif F, Farr MA, Clerkin KJ, Characteristics and outcomes of recipients of heart transplant with coronavirus disease 2019: JAMA Cardiol, 2020; 5; 1165-69
5.. Bottio T, Bagozzi L, Fiocco A, COVID-19 in heart transplant recipients: A multicenter analysis of the Northern Italian outbreak: JACC Heart Fail, 2021; 9; 52-61
6.. Dixit N, Parikh N, Churchill A, Hsu JJ, Accelerated cardiac allograft vasculopathy in an orthotopic heart transplant recipient with prior COVID-19: J Am Coll Cardiol, 2022; 79(9 Suppl.); 2389
7.. Singhvi A, Barghash M, Lala A, Challenges in heart transplantation during COVID-19: A single-center experience: J Heart Lung Transplant, 2020; 39; 894-903
8.. Işık ME, Günay D, Aksüt M, COVID-19 presenting with diarrhea in a heart transplant patient: Turk Gogus Kalp Damar Cerrahisi Derg, 2021; 29; 119-21
9.. Miller DV, Revelo M, Hammond E, Accelerated cardiac allograft vasculopathy: A clinical and pathologic correlation study: J Heart Lung Transplant, 2019; 38; S58
10.. Valantine HA, Cardiac allograft vasculopathy: Central role of endothelial injury leading to transplant “atheroma”: Transplantation, 2003; 76; 891-99
11.. Weis M, Von Scheidt W, Cardiac allograft vasculopathy: Circulation, 1997; 96; 2069-77
12.. Aggarwal A, Pyle J, Hamilton J, Bhat G, Early cardiac allograft vasculopathy: Are the viruses to blame?: Case Rep Med, 2012; 2012; 734074
13.. Singh G, Mathur U, Acute graft rejection in a COVID-19 patient: Co-incidence or causal association?: Indian J Ophthalmol, 2021; 69; 985-86
14.. Abuzeineh M, Tariq A, Rosenberg A, Brennan DC, Chronic active antibody-mediated rejection following COVID-19 infection in a kidney transplant recipient: A case report: Transplant Proc, 2021; 53; 1202-6
15.. Anandh U, Gowrishankar S, Sharma A, Kidney transplant dysfunction in a patient with COVID-19 infection: Role of concurrent Sars-Cov 2 nephropathy, chronic rejection and vitamin C-mediated hyperoxalosis: Case report: BMC Nephrol, 2021; 22; 91
16.. Aversa M, Benvenuto L, Anderson M, COVID-19 in lung transplant recipients: A single center case series from New York City: Am J Transplant, 2020; 20; 3072-80
17.. Saez-Giménez B, Berastegui C, Barrecheguren M, COVID-19 in lung transplant recipients: A multicenter study: Am J Transplant, 2021; 21; 1816-24
18.. Liu F, Li L, Xu M, Prognostic value of interleukin-6, C-reactive protein, and procalcitonin in patients with COVID-19: J Clin Virol, 2020; 127; 104370
19.. Song JW, Zhang C, Fan X, Immunological and inflammatory profiles in mild and severe cases of COVID-19: Nat Commun, 2020; 11; 3410
20.. Zheng YY, Ma YT, Zhang JY, Xie X, COVID-19 and the cardiovascular system: Nat Rev Cardiol, 2020; 17; 259-60
21.. Jin Y, Ji W, Yang H, Endothelial activation and dysfunction in COVID-19: From basic mechanisms to potential therapeutic approaches: Sig Transduct Target Ther, 2020; 5; 293
22.. Chioh FW, Fong SW, Young BE, Convalescent COVID-19 patients are susceptible to endothelial dysfunction due to persistent immune activation: Elife, 2021; 10; e64909
23.. Peters LL, Raymer DS, Pal JD, Ambardekar AV, Association of COVID-19 vaccination with risk of COVID-19 infection, hospitalization, and death in heart transplant recipients: JAMA Cardiol, 2022; 7; 651-54
24.. Rupprecht HJ, Blankenberg S, Bickel C, Impact of viral and bacterial infectious burden on long-term prognosis in patients with coronary artery disease: Circulation, 2001; 104; 25-31
25.. Koskinen P, Lemström K, Bruggeman C, Acute cytomegalovirus infection induces a subendothelial inflammation (endothelialitis) in the allograft vascular wall. A possible linkage with enhanced allograft arteriosclerosis: Am J Pathol, 1994; 144; 41-50
26.. Koskinen P, Kallio E, Tikkanen J, Cytomegalovirus infection and cardiac allograft vasculopathy: Transpl Infect Dis, 1999; 1; 115-26
27.. Schlendorf KH, Zalawadiya S, Shah AS, Expanding heart transplant in the era of direct-acting antiviral therapy for hepatitis C: JAMA Cardiol, 2020; 5; 167-74
28.. Lee MS, Tadwalkar RV, Fearon WF, Cardiac allograft vasculopathy: A review: Catheter Cardiovasc Interv, 2018; 92; E527-36
29.. Acharya D, Loyaga-Rendon RY, Chatterjee A, Optical coherence tomography in cardiac allograft vasculopathy: State-of-the-art review: Circ Heart Fail, 2021; 14; e008416
30.. Olymbios M, Kwiecinski J, Berman DS, Kobashigawa JA, Imaging in heart transplant patients: JACC Cardiovasc Imaging, 2018; 11; 1514-30
31.. Lund LH, Edwards LB, Kucheryavaya AY, The Registry of the International Society for Heart and Lung Transplantation: Thirty-second official adult heart transplantation report – 2015; Focus theme: Early graft failure: J Heart Lung Transplant, 2015; 34; 1244-54
32.. Kobashigawa JA, Katzenelson S, Laks H, Effect of pravastatin on outcomes after cardiac transplantation: N Engl J Med, 1995; 333; 621-27
33.. Sieg A, Weeks P, Krustchinsky L, Rajapreyar I, Statin therapy in cardiac allograft vasculopathy progression in heart transplant patients: Does potency matter?: Transplant Rev (Orlando), 2016; 30; 178-86
34.. Colvin MM, Cook JL, Chang P, Antibody-mediated rejection in cardiac transplantation: Emerging knowledge in diagnosis and management: Circulation, 2015; 13; 1608-39
21 March 2023 : Case reportKidney Transplantation from a Deceased Donor with COVID-19 Ad26.COV2-S Vaccine-Induced Thrombotic Thrombocy...
Am J Case Rep In Press; DOI: 10.12659/AJCR.938730
21 March 2023 : Case reportClassical Presentation of Disseminated Blastomycosis in a 44-Year-Old Healthy Man 3 Months After Diagnosis ...
Am J Case Rep In Press; DOI: 10.12659/AJCR.938659
22 February 2023 : Case reportA 30-Year-Old Woman with an 8-Week History of Anxiety, Depression, Insomnia, and Mild Cognitive Impairment ...
Am J Case Rep In Press; DOI: 10.12659/AJCR.938732
22 February 2023 : Case reportMultidrug-Resistant Kocuria rosea and Methicillin-Resistant Staphylococcus aureus Co-Infection in a Nigeria...
Am J Case Rep In Press; DOI: 10.12659/AJCR.938761
27 Mar 2023 : Case reportChest Tightness with Cycling Turned Out To Be Pneumomediastinum
Am J Case Rep In Press; DOI: 10.12659/AJCR.939170
27 Mar 2023 : Case reportAtypical Hemolytic Uremic Syndrome in a Pregnant Patient with a Thrombomodulin Gene Variant Treated with Pl...
Am J Case Rep In Press; DOI: 10.12659/AJCR.938896
27 Mar 2023 : Case reportBartonella Neuroretinitis: There Is More to Cat Scratch Disease than Meets the Eye
Am J Case Rep In Press; DOI: 10.12659/AJCR.938380
24 Mar 2023 : Case reportSplinter Cataract in Patients with Keratoconus and Frequent Eye Rubbing: A Novel Finding
Am J Case Rep In Press; DOI: 10.12659/AJCR.939082
Most Viewed Current Articles
13 Jul 2022 : Case reportWhistling Scrotum: An Unusual Presentation of Pneumomediastinum in the Setting of an Open Scrotal Wound
Am J Case Rep 2022; 23:e936441
06 Dec 2021 : Case reportLipedema Can Be Treated Non-Surgically: A Report of 5 Cases
Am J Case Rep 2021; 22:e934406
23 Feb 2022 : Case reportPenile Necrosis Associated with Local Intravenous Injection of Cocaine
Am J Case Rep 2022; 23:e935250
07 Dec 2021 : Case reportEdwardsiella tarda: A Classic Presentation of a Rare Fatal Infection, with Possible New Background Risk Fac...
Am J Case Rep 2021; 22:e934347