Relationship Among Epicardial Coronary Disease, Tissue Myocardial Perfusion, and Survival in Heart Transplantation

doi:10.1016/j.healun.2004.07.017

The Journal of Heart and Lung Transplantation

Volume 24, Issue 8, August 2005, Pages 1019-1025

https://doi.org/10.1016/j.healun.2004.07.017 Get rights and content

Background

Cardiac allograft vasculopathy continues to represent the major limitation to long-term cardiac allograft survival. Routine angiography and intravascular ultrasound fall short in their ability to detect microcirculatory aberrations. Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grades (TMPG) have been used as a measure of microvascular circulation in patients treated for acute myocardial infarction. We studied the correlation of epicardial coronary anatomy with microvascular flow as determined by TMPG and correlated it with patient outcome.

Methods

We enrolled 66 consecutive cardiac transplant recipients (49 men; mean age 52 ± 13 years; range 15–70 years) undergoing surveillance coronary angiogram during a 9-month period. All angiograms were interpreted for epicardial coronary anatomy by an independent investigator. Another investigator, blinded for clinical data and angiogram interpretation, interpreted TMPGs. TMPG 0 was defined as no apparent tissue-level perfusion; TMPG 1 indicated presence of myocardial blush but no clearance from the microvasculature; TMPG 2 blush cleared slowly; and TMPG 3 indicated that blush began to clear during washout (blush is minimally persistent after 3 cardiac cycles of washout). Cardiac deaths served as the primary outcome variable.

Results

Fifty-eight of 66 patients had an abnormal TMPG. Mean TMPG in all these patients was 4.2 ± 3 (normal is 9). Forty-four patients (Group A) with no angiographic coronary narrowing had TMPG 4.81 ± 3.1, and 22 patients (Group B) with epicardial coronary narrowing 40% of lumen diameter had TMPG 3.0 ± 2.5 (p = 0.007). There was no difference in TMPG related to the coronary territory involved. At a mean follow-up of 30 ± 2.5 months, 6 (13.6%) of 44 patients in Group A had died, and 7 (31.8%) of 22 in Group B had died (p < 0.03).

Conclusions

Microcirculatory aberrations as assessed by tissue TMPG is abnormal across all coronary territories in cardiac transplant recipients and associated with poor survival, suggesting a generalized microvascular involvement even in the presence of a normal angiogram. Patients with focal epicardial coronary narrowing have significantly greater decline in tissue perfusion, independent of the coronary territory involved, and exhibit poor survival compared with patients without epicardial coronary disease.

Section snippets

Patients and Study Design

The study group consisted of 66 consecutive cardiac transplant recipients undergoing surveillance coronary angiogram during a 9-month period (August 2000 to April 2001), including 49 men and 17 women with a mean age of 52 ± 13 years (range 15 to 70 years). All patients received immunosuppressive therapy, and none had evidence of acute rejection or infection during the time of study. The gradation of epicardial CAV was based on an established classification scheme as previously described by Gao

Patient Characteristics

The total study population included 66 patients with mean age of 53 ± 14 years. No differences were found between the 2 groups with respect to the age, sex, and race, time since transplantation, hypertension, and left ventricular function. Risk factor analysis showed similar presence of diabetes mellitus, use of statin therapy, cyclosporin and tacrolimus use, first year mean biopsy score, and histocompatibility. In Group B, the reason for heart transplantation was significantly more from

Principal Findings

We used yet another approach to evaluate microvascular circulation by use of TMPGs. The results of our study indicate that the cardiac transplant milieu is associated with a widespread propensity for abnormal microcirculatory flow, as evidenced by global decreases in myocardial tissue perfusion as indicated by lower overall TMPG even in the presence of normal angiogram. More importantly, we have once again confirmed the prognostic utility of epicardial coronary artery disease on survival but

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Cited by (25)

Persistent mild lesions in coronary angiography predict poor long-term survival of heart transplant recipients
2014, Journal of Heart and Lung Transplantation
Citation Excerpt :
Although our patients with persistent mild coronary lesions were also characterized by a lower left ventricle ejection fraction, we could not determine whether this epicardial artery pathology alone was a risk factor; however, our advice would be to closely monitor patients with repetitive CAGs results, even in the absence of left ventricle functional abnormalities. Although not many reports have described the prognostic role of epicardial artery lesions, they are strongly reflected in the ISHLT position paper that describes the working formulation of CAV.1,14 Our results support this statement, with an indication to pay greater attention to CAV 1 patients.
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.
Management of the ACC/AHA Stage D Patient. Cardiac Transplantation
2014, Cardiology Clinics
Citation Excerpt :
In one study, those with angiographic disease had a 3.4-fold increased risk of major cardiac events and a 4.6-fold increase risk of death over a 3.5-year follow-up.43 In patients without apparent angiographic epicardial disease, microvascular abnormalities may be present, and are associated with adverse outcomes.44 Given the denervation of the transplanted heart, patients do not experience typical angina, and the presentation of CAV differs from that of nontransplant CAV, as outlined in Table 3.45
Biomarkers of heart transplant rejection: The good, the bad, and the ugly!
2012, Translational Research
Acute cellular rejection (ACR), antibody-mediated rejection (AMR), and cardiac allograft vasculopathy (CAV) are important limitations for the long-term survival of heart transplant recipients. Although much progress has been made in reducing ACR with modern immunosuppressive treatments and continuous biopsy surveillance, there is still a long way to go to better understand and treat AMR, to enable early detection of patients at risk of CAV, and to reduce the development and sustained progression of this irreversible disease that permanently compromises graft function. This review considers the advances made in ACR detection and treatment allowing a more prolonged survival and the risk factors leading to endothelial injury, dysfunction, inflammation, and subsequent CAV, as well as new treatment modalities for CAV. The review also evaluates the controversies around the definition, pathogenesis, and treatment of AMR. To date, much progress is still needed to significantly reduce post-transplant complications and increase graft and patient survival.
International Society for Heart and Lung Transplantation working formulation of a standardized nomenclature for cardiac allograft vasculopathy-2010
2010, Journal of Heart and Lung Transplantation
The development of cardiac allograft vasculopathy remains the Achilles heel of cardiac transplantation. Unfortunately, the definitions of cardiac allograft vasculopathy are diverse, and there are no uniform international standards for the nomenclature of this entity. This consensus document, commissioned by the International Society of Heart and Lung Transplantation Board, is based on best evidence and clinical consensus derived from critical analysis of available information pertaining to angiography, intravascular ultrasound imaging, microvascular function, cardiac allograft histology, circulating immune markers, non-invasive imaging tests, and gene-based and protein-based biomarkers. This document represents a working formulation for an international nomenclature of cardiac allograft vasculopathy, similar to the development of the system for adjudication of cardiac allograft rejection by histology.
Quantitative myocardial blush grade for the detection of cardiac allograft vasculopathy
2010, American Heart Journal
Citation Excerpt :
All these mechanisms may account for microvascular dysfunction, in the absence of critical epicardial lesions, so that the evaluation of lumen narrowing on coronary angiograms may miss early stages of the disease.2,3 In this regard, previous studies investigated the impact of TIMI frame counts and visually assessed blush grade on clinical outcomes, elegantly demonstrating that abnormal microvascular function is present even in transplant recipients with normal coronary vessels and that both indexes are associated with mortality.22,23 Further recent data from histopathologic studies support the presence of microvasculopathy in the absence of epicardial disease, and its impact on mortality.5
Cardiac allograft vasculopathy (CAV) progressively compromises microvascular perfusion and function in heart transplantation (HTx)-recipients. The aim of our study was to investigate the ability of quantitative myocardial blush grade (MBG) to detect CAV.
In consecutive HTx-recipients (n = 72) who underwent surveillance cardiac catheterization, MBG was assessed visually and quantitatively, by analyzing the time course of contrast agent intensity rise. Hereby, the parameter G_max/T_max was calculated as the plateau of grey-level intensity (G_max) divided by the time-to-peak intensity (T_max). HTx-recipients and 18 healthy volunteers underwent cardiac magnetic resonance, to assess diastolic strain rates and myocardial perfusion reserve during pharmacologic hyperemia.
Significant correlations were observed between G_max/T_max with perfusion reserve and with mean diastolic strain rates (r² = 0.68 and r² = 0.58, P < .001 for both). Visual and quantitative MBG using a cutoff value of G_max/T_max = 2.7/s yielded significantly higher accuracy than stenosis severity on coronary angiograms for the detection of impaired microvascular integrity as a surrogate marker for CAV (AUC = 0.78, SE = 0.06, 95% CI = 0.66-0.87 for lumen narrowing versus AUC = 0.91, SE = 0.03, 95%CI = 0.84-0.97 for G_max/T_max; P < .01). Furthermore, quantitative MBG provided more robust prediction of survival (χ²= 14.0, P < .001), compared to visually estimated blush (χ²= 5.4, P = .02) and to coronary lumen narrowing assessment, (χ²= 4.8, P = .04).
Quantification of MBG can be performed on coronary angiograms of HTx-recipients, and may help with the identification of early CAV in patients with impaired perfusion reserve but without angiographically evident atherosclerosis.
Early right coronary vasospasm presenting with malignant arrhythmias in a heart transplantation recipient without allograft vasculopathy
2009, International Journal of Cardiology
Citation Excerpt :
Endothelial dysfunction, documented by an abnormal response to acetylcholine, which predicts subsequent clinical end points [10–12], has already been demonstrated in heart transplant recipients. In addition, Mehra et al. [13] have already demonstrated that all cardiac transplant recipients have microcirculatory abnormalities [detected by Timi Myocardial Perfusion Grade (TMPG) score, ranging from 0, i.e. no tissue level perfusion, to 9, i.e. normal washout] irrespective of the coexistence of epicardial coronary artery stenosis. Actually, 67% of the patients had abnormal TMPG with no angiographical coronary stenosis.
In heart transplant recipients, the aetiology of coronary vasospasm is largely unknown but it has been reported to be related to coronary vasculopathy or allograft rejection. We report a case of acute, reversible coronary vasospasm which caused malignant arrhythmias in a cardiac transplant recipient one month after transplantation without evidence of coronary vasculopathy or allograft rejection. The patient had a normal post-operative course with no other complications; this case supports the hypothesis that coronary vasospasm is not necessarily related to epicardial coronary artery disease or allograft rejection, but rather may be due to an abnormal reversible vasoreactivity.

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Allograft vasculopathyRelationship Among Epicardial Coronary Disease, Tissue Myocardial Perfusion, and Survival in Heart Transplantation

Background

Methods

Results

Conclusions

Section snippets

Patients and Study Design

Patient Characteristics

Principal Findings

J Heart Lung Transplant

JAMA

Am J Cardiol

J Am Coll Card

J Heart Lung Transplant

Intracoronary ultrasound in cardiac transplant recipientsin-vivo evidence of “angiographically silent” intimal thickening

Circulation

Coronary artery imaging with intravascular ultrasound in patients following cardiac transplantation

Transplantation

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

J Heart Lung Transplant

Allograft vasculopathy
Relationship Among Epicardial Coronary Disease, Tissue Myocardial Perfusion, and Survival in Heart Transplantation