Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity–quality paradox

doi:10.1016/S1053-2498(02)00492-8

The Journal of Heart and Lung Transplantation

Volume 22, Issue 2, February 2003, Pages 118-123

https://doi.org/10.1016/S1053-2498(02)00492-8 Get rights and content

Abstract

Background:

Pre-angiographic detection of intimal proliferation using intravascular ultrasound in heart transplant recipients has focused investigators’ attention on the prognostic utility of such early information. Not all heart transplant recipients who exhibit a “prognostically relevant” threshold of severe (>0.5 mm) intimal thickening experience cardiac events. We sought to contrast clinical characteristics of heart transplant recipients who have prognostically relevant, severe intimal proliferation and who experience cardiac events with those who remain event free.

Methods:

We prospectively followed an inception cohort of 54 consecutive heart transplant recipients with severe intimal proliferation (intimal thickness >0.5mm) of the coronary arteries after index intravascular ultrasound examination to assess the development of cardiac events (sudden cardiac death, myocardial infarction) and/or the necessity for coronary revascularization with percutaneous techniques (angioplasty, atherectomy, stent implantation) or surgical bypass.

Results:

Based on the occurrence of adverse cardiac events during the subsequent 24 months, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). Both groups demonstrated similar intimal thickness at the index ultrasound (Group 1, 0.89 ± 0.27 mm, vs Group 2, 0.94 ± 0.36 mm; p = not significant). Those with cardiac events were more likely than those without events to have hyperlipidemia, to have greater exposure to cumulative and average daily prednisone, and to exhibit greater average biopsy rejection scores at follow-up.

Conclusions:

These observations underscore the importance of the quality and not merely the quantity of intimal proliferation in determining occurrence of morbid cardiac events and further emphasize the interaction of immunologic and non-immunologic factors in determining event vulnerability in cardiac allograft vasculopathy.

Section snippets

Patient population

The study population consisted of an inception cohort of 54 consecutive heart transplant recipients with evidence of prognostically relevant severe intimal proliferation (intimal thickness, >0.5 mm), determined by intravascular ultrasound examination of the coronary arteries between 1994 to 1995. These patients were then prospectively followed after index intravascular ultrasound examination and to assess the development of cardiac events. All study participants provided informed consent and

Clinical characteristics

The study population included 54 consecutive heart transplant recipients (50 men and 4 women) with a mean age of 53 ± 8 years (range, 22 to 68 years) who were prospectively followed for 24 months after index ultrasound examination that detected prognostically relevant intimal proliferation (>0.5mm). Based on the occurrence of adverse cardiac events, we divided the study cohort into 2 groups: Group 1 (no event, n = 33) and Group 2 (cardiac event, n = 21). All subsequent results compare clinical

Discussion

The findings of this investigation demonstrate that factors independent of survival time and magnitude of intimal thickness determine the expression of clinical events in patients with cardiac allograft vasculopathy manifested with prognostically relevant intimal proliferation detected by intravascular ultrasound.3 Thus, heart transplant recipients with significant cardiac allograft vasculopathy who were exposed to greater cumulative prednisone consumption (a surrogate marker for worse

Conclusions

The results of our study provide important support for the presence of a prognostically relevant threshold for intimal thickening but challenges the notion of cardiac allograft vasculopathy as a quantitative disease process. Furthermore, it describes putative qualitative interactions between non-immunologic and immunologic events that mediate event predilection.

References (11)

M.R. Mehra
Crossing the vasculopathy bridge from morphology to therapya single center experience
J Heart Lung Transplant
(2000)
M.R. Mehra et al.
Predictive model to assess risk for cardiac allograft vasculopathyan intravascular ultrasound study
J Am Coll Cardiol
(1995)
P. Libby
Coronary artery injury and the biology of atherosclerosisinflammation, thrombosis, and stabilization
Am J Cardiol
(2000)
M.R. Mehra et al.
Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy
J Heart Lung Transplant
(1995)
P.R. Rickenbacher et al.
Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation
Circulation
(1995)

There are more references available in the full text version of this article.

Cited by (17)

The scourge and enigmatic journey of cardiac allograft vasculopathy
2017, Journal of Heart and Lung Transplantation
Persistent mild lesions in coronary angiography predict poor long-term survival of heart transplant recipients
2014, Journal of Heart and Lung Transplantation
Even though coronary angiography (CAG) underestimates coronary allograft vasculopathy (CAV) development, especially in the distal parts of arteries, it remains a frame of reference for International Society for Heart and Lung Transplantation (ISHLT) CAV classification. A retrospective analysis was performed to assess the prognostic value of CAG findings.
Among 310 orthotopic heart transplantation (OHT) recipients with at least 2 CAGs at 2-year intervals, we identified 197 (146 men and 41 women; 55 ± 13 years) without lesions (Group 0), 27 (15 men and 12 women; 58 ± 8 years) in whom mild changes remained in consecutive CAGs (Group 1), 28 (24 men and 4 women; 58 ± 10 years) in whom mild lesions decreased in consecutive CAGs (Group 1REG), and 58 (53 men and 5 women; 56 ± 10 years) in whom the stenosis criteria of ISHLT CAV 2 or 3 were covered (Group 2). We compared survival and other clinical variables among the groups.
The average follow-up was 10 ± 4 years. Forty-one (21%) deaths occurred in Group 0, 15 (56%) in Group 1 (p = 0.002), 9(31%) in Group 1REG (p = NS), and 26 (46%) in Group 2 (p = 0.004, chi-square test). Time free from all-cause death was significantly shorter in Group 1 (T1/2 = 8 years) than in Group 0 (T1/2 = 15.5 years; p = 0.00072, log-rank test). Time free from cardiovascular death was significantly shorter in Groups 1 and 2, as was time free from CAV-related death in Groups 1, 1REG, and 2. Multivariate analysis, using a Cox proportional hazards model, revealed that Group 1 inclusion criterion of CAG findings is an independent predictor of all-cause death, cardiovascular death, and CAV-related death.
Persistent mild coronary lesions, observed in consecutive CAG, predicted shorter survival of OHT recipients.
Prevalence of donor-transmitted atherosclerosis - Clinical utility of intracoronary ultrasound early after heart transplantation. A single-center study
2013, Cor et Vasa
Citation Excerpt :
Patients with these values were shown to have significantly worse 4-year survival rates (73% vs 96%). It was just the absence of IVUS assessment immediately post-transplant and, consequently, the inability to distinguish DCA from CAV that were the main limitations of Mehra et al.'s study who had otherwise demonstrated that the presence of the same intima–media thickness at 3 years post-HTx may, but need not, result in cardiac events occurring in these patients [15]. When evaluating the effect of the rate of intimal thickening progression on a patient's fate post-HTx, Kapadia noted that rapid intimal thickening progression (>0.5 mm) over the first post-transplant year increases the risk for serious cardiac events in that patient subgroup (myocardial infarction, death, heart failure) [16].
Coronary allograft vasculopathy (CAV) is one of the main factors limiting long-term survival following orthotopic heart transplantation (HTx). Whether or not and, if so, how donor-transmitted atherosclerosis (DCA) affects the post-transplant course of the allograft recipient is still unclear. Conventional coronary angiography is a moderately accurate technique for DCA detection as it will reveal only the more gross morphological lesions. By contrast, intravascular ultrasound (IVUS) has been shown to be a much more sensitive technique for CAV and DCA detection. In our study we sought to determine the prevalence of DCA in our HTx patient population and identify main risk factors of DCA based on donor characteristics.
We performed a retrospective analysis of data of 119 patients (92 men, 27 women) undergoing transplantation in our center from August 2006 through September 2012, who had survived their first post-transplant month and had coronary angiography and IVUS.
DCA was present in 39 patients, and not documented in 80 patients. The main risk factors for DCA included donor age, cigarette smoking, and hypertension; the other parameters were not shown to be statistically significant. In-hospital mortality was low in both groups (DCA positive and DCA negative), with one patient dying in either group. One-year mortality rates post-HTx were likewise almost identical in both groups (15.4% and 15% in DCA positive and negative, respectively).
The prevalence of DCA in our patients was 32.8%, with major risk factors for DCA including donor age, cigarette smoking, and hypertension. As age seems to be the strongest predictor, coronary angiography should be a routine examination in individuals aged over 40 years; the examination should be considered in younger individuals with a cluster of several of risk factors. The 1-year survival in this selected patient population was identical in both groups, the implication being that the diagnosis of DCA had no effect on 1-year survival post-HTx.
Microvasculopathy Observed in Early or Late Endomyocardial Biopsies Is Not Related to Angiographically Confirmed Transplanted Heart Coronary Vasculopathy
2009, Transplantation Proceedings
The aim of the study was to examine the potential relation between microvasculopathy observed in endomyocardial biopsies (EMBs) and clinical coronary vasculopathy (CAV) after orthotopic heart transplantation (OHT).
We preformed a retrospective analysis involving 68 OHT patients in whom the procedure was performed before 1999. The CAV(+) group consisted of 37 subjects (35 males/2 females) of overall mean age of 45 ± 11 years. Ischemic cardiomyopathy was the diagnosis in 57% of the cohort that displayed CAV established by angioplasty, myocardial infarction, or CAV-related death. The control group contained 31 subjects (24 male/7 female) of overall mean age of 43 ± 16 years. The pretransplant diagnosis was ischemic c-pathy in 39%. These subjects displayed negative coronary angiography at 10 years after OHT. Based upon studies early after OHT 55 subjects were divided based on the myocardial blush grade (MBG) upon coronary angiography performed between 4^th and 6^th week after surgery: one cohort of six individuals showed decreased MBG (6 males) of mean age 52 ± 7 years. There was prior ischemic c-pathy in 50%. In contrast, 49 subjects showed a normal MBG (43 males/67 females) of overall mean age of 45 ± 12 years. Ischemic c-pathy had been present in 39%. Microvasculopathy was defined as the presence of prominent endothelial cells, vacuolation of the endothelium, thickening of the basal membrane and/or muscle layer, the presence of lymphocytes in the arteriolar wall, periarteriolar fibrosis, or stenotic arteriolar lumenia in the 12- and 36 month EMB (CAV groups) or the 4-week EMB (MBG groups).
Rejection grades were comparable in CAV(+) and CAV(−) groups, but decreased in normal MBG group. The only significant difference was observed in the occurrence of basal membrane thickening, which was present in 22% of subjects from the CAV(+) group and 3% of individuals from the CAV(−) group in the 12-month EMB.
Microvasculopathy observed early or late after OHT was not related to angiographically confirmed CAV.
Percutaneous coronary interventions with stents in cardiac transplant recipients
2006, Journal of Heart and Lung Transplantation
Allograft coronary vasculopathy is a major cause of death beyond the first year after cardiac transplantation. The aim of this study was to review our experience with percutaneous coronary intervention (PCI) with stents in cardiac transplant recipients.
We identified patients who were treated with PCI using stents. Patient characteristics, procedure information and clinical outcomes were assessed for these patients by review of their medical records. We also compared results for those who had bare metal stents vs those who had drug-eluting stents.
Forty patients from our program’s 865 cardiac transplant recipients received a total of 78 coronary stents. There were 35 males (87.5%) and 5 females (12.5%). The indication for PCI was progressive asymptomatic coronary vasculopathy in 18 patients (45%), angina in 5 (12.5%), acute myocardial infarction (MI) in 4 (10%) and congestive heart failure (CHF) in 6 (15%). Primary success (<50% residual stenosis) was obtained in 71 (91%) of 78 stents. During the mean follow-up of 40.8 ± 34.5 months, 6 patients died (15%) and 2 (5%) were re-transplanted. There was a lower rate of re-stenosis with drug-eluting stents (2 of 13, 15%) compared with bare metal stents (20 of 65, 31%), although this difference was not statistically significant (p = 0.27).
In cardiac transplant recipients, PCI with stents can be performed with high rates of primary success. Restenosis rates are higher compared with PCI in native coronary arteries. A trend toward less restenosis with drug-eluting stents was observed, which needs to be confirmed in larger studies.
Peritransplant ischemic injury is associated with up-regulation of stromal cell-derived factor-1
2005, Journal of the American College of Cardiology
Citation Excerpt :
The present study confirms similar poor clinical outcome in gender-mismatched hearts in response to ischemic injury. Immune and nonimmune factors have been implicated in the pathogenesis of cardiac allograft vasculopathy (39,40). We have previously shown up-regulation of αvβ3 (vitronectin receptor) and tissue factor, activation of the matrix metalloproteinase induction system, and increased myocardial fibrosis in response to peritransplant ischemic injury (14) that may contribute to the subsequent development of allograft vasculopathy.
We evaluated chimerism and stromal cell-derived factor-1 (SDF-1) expression in response to peritransplant ischemic injury following human heart transplantation.
Myocardial ischemia has been shown to trigger mobilization of stem cells to the heart in animal experiments.
Between January 1998 and April 2002, a total of 114 male recipients received hearts from female donors. Of these 114 recipients, 26 had evidence of ischemic injury on their initial heart biopsies (ischemia group). These were compared to the remaining 88 patients (control group). Heart biopsy specimens obtained initially at one week and at one year after transplant were evaluated from 20 matched patients of each group for the presence of Y chromosome-containing nuclei. The SDF-1 messenger ribonucleic acid (mRNA) and protein expression were also evaluated on initial heart biopsy specimens.
At one week, Y chromosome-containing nuclei were significantly increased in the ischemia group (0.68% vs. 0.04%; p < 0.0001) compared to the control group. These were positive for the stem cell factor receptor c-kit. A significant 3.3-fold increased mRNA expression (p = 0.001) and 2.8-fold increased protein expression (p = 0.01) of SDF-1 was noted in the ischemia group. At one year, Y chromosome was detected in 0.29% of cardiomyocyte nuclei in the ischemia group but none in the control group. The ischemia group had poorer survival and increased vasculopathy.
This is the first report to describe chimerism and up-regulation of SDF-1 in human heart transplantation in response to ischemic injury.

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Allograft vasculopathyIs all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity–quality paradox

Abstract

Background:

Methods:

Results:

Conclusions:

Section snippets

Patient population

Clinical characteristics

Discussion

Conclusions

J Heart Lung Transplant

J Am Coll Cardiol

Am J Cardiol

Presence of severe intimal thickening by intravascular ultrasonography predicts cardiac events in cardiac allograft vasculopathy

J Heart Lung Transplant

Prognostic importance of intimal thickness as measured by intracoronary ultrasound after cardiac transplantation

Circulation

Allograft vasculopathy
Is all intimal proliferation created equal in cardiac allograft vasculopathy? The quantity–quality paradox