The Panvascular Interplay in Pathophysiology and Prognosis of Cardiac Allograft Vasculopathy

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Even as the miraculous success of heart transplantation was heralded, a vexing problem of accelerated coronary atherosclerosis was recognized, threatening the long-term viability of this therapy. The entity of cardiac allograft vasculopathy (CAV) was initially recognized within the epicardial coronary arteries as fibro-intimal thickening in conjunction with atherosclerotic plaque, suggesting an intricate coalescence between immunological and nonimmunological factors in play. Early pathological studies of failed cardiac allografts pointed to important microvascular events that appeared in concert with epicardial coronary alterations, which included endothelial cell dysfunction, vascular inflammation, microthrombosis, and capillary rarefaction. The panvascular nature of CAV was further demonstrated in studies showing its extension to the donor portion of the aorta (as well into venules), arguing against calling it simply a “coronary” vasculopathy. Until recently, diagnostic tools enabling assessment of the microvasculature were lacking, and therefore, initial efforts to detect CAV were centered on the epicardial coronaries using coronary angiography, followed by intravascular ultrasound (IVUS), and more recently by optical coherent tomography (OCT). The relationship between the early microvascular events and the later manifestation of macrovascular coronary disease was demonstrated in pathological studies of post-transplant surveillance endomyocardial biopsy samples, which suggested that detection of endothelial cell activation immunological markers, loss of tissue plasminogen activator within the endothelium, and presence of fibrin predicted future development of angiographic epicardial coronary disease and influenced late outcomes. The central role of inflammation and cellular injury became manifest by investigations that identified C-reactive protein and troponin elevation as biomarkers for CAV development and determinants of its prognosis. Other studies suggested that the groundwork for CAV began well before engraftment and was even influenced by the priming effects of brain death upon the allograft. These observations set the stage for a comprehensive understanding of CAV as a panvascular entity initiated by pre-engraftment factors (such as brain death and ischemia-reperfusion injury), propagated by diffuse endothelial cell damage (because of inflammation and injury) and established by the intricate relationship between immunological, infectious, and cardiometabolic disruptions (Figure 1). Thus, one cannot extricate the sentinel and early role of microvascular disease in determining later manifestation of epicardial disease, which together affect the prognostic influence of CAV in heart transplantation. In an effort to reflect microvascular changes in disease severity classification, the standardized classification of CAV proposed by the International Society for Heart and Lung Transplantation in 2010 included a more specific modifier of restrictive physiology as determined by echocardiography or invasive hemodynamics. More recent studies have indicated that restrictive physiology of the allograft is a consequence of microvascular remodeling and microcapillary rarefaction rather than a reflection of interstitial fibrosis, once again supporting the importance of microvascular phenomenon in driving cardiac allograft dysfunction. 


The Genesis and Evolution of Cardiac Allograft Vasculopathy

We describe the factors responsible for development of CAV, manifestations at a macrovascular and microvascular level, the role of diagnostic testing, and evaluation of risk of major cardiac allograft-related events. CMV = cytomegalovirus; CTA = computed tomography angiography; CV = cardiovascular; HHF = hospitalizations for heart failure; IVUS = intravascular ultrasound; MBF = myocardial blood flow; MFR = myocardial flow reserve; MRI = cardiac magnetic resonance; OCT = optical coherence tomography; PET = positron emission tomography.


The advances of sophisticated imaging techniques, such as cardiac magnetic resonance imaging (which can assess fibrosis, physiological parameters of strain, and myocardial perfusion reserve) and positron emission tomography (PET), provide an opportunity to better assess the role of the microvasculature along with macrovascular manifestations. Indeed, PET imaging can detect regional perfusion deficits and may be a noninvasive gold standard for quantification of myocardial blood flow (MBF) and myocardial flow reserve (MFR), allowing for comprehensive assessment of the effects of both epicardial and microvascular alterations in CAV. In this issue of the Journal of the American College of Cardiology, Clerkin et al attempt to build upon an evolving trail of investigations seeking to establish the role of PET imaging as a comprehensive technique for the diagnosis and prognosis assessment in CAV. Their retrospective study correlated a pre-established threshold of PET-derived MFR of 2.0 as an arbiter of clinical outcome, including death, retransplantation, or cardiovascular hospitalizations. The strengths of their analysis lie in the larger number of patients and longer median follow-up duration (4.7 years) compared with previous PET studies, as well as their comprehensive correlations with post-transplant time of diagnosis, relationship to epicardial coronary disease, insights into modification of prognosis with drug therapy, and quantification of net lifetime loss caused by disease. As an example, they determine that those with longer post-transplant survival at the time of their diagnosis had the most lifetime to lose than the more recent post-transplant cohort. They also demonstrated that epicardial disease in tandem with microvascular disease confers the worst risk, followed by microvascular disease alone, and then epicardial disease alone. This is interesting and concordant with our current understanding of the disease in which microvascular involvement reflects early events that can progress to combined microvascular and macrovascular involvement. However, isolated epicardial disease may represent a dominant effect of nonimmunological factors or those that restrict involvement to the epicardial coronary arterial tree. Similar findings were reported by Bravo et al, who demonstrated that a global peak MBF <1.70 was a better discriminant than MFR for detection of moderate to severe CAV. Importantly, this study showed that a multiparametric score derived using regional myocardial perfusion, left ventricular ejection fraction, and peak MBF provided the most meaningful clinical stratification of outcome and concordance with the International Society for Heart and Lung Transplantation CAV grading scale. In another PET study, Chih et al demonstrated a high sensitivity and specificity for abnormality in >1 parameter integrating peak MBF, MFR, and coronary vascular resistance for noninvasive detection of CAV. The same group linked prognosis with these PET-derived parameters and suggested that early post-transplant and longitudinal PET evaluation could identify higher-risk patients for cardiac allograft events. 


Moving forward, well-designed randomized controlled trials are required to establish the utility and define the roles of multiparametric imaging in conjunction with current tools such as IVUS and OCT. As a start, clinical trials of drug therapy to prevent, stabilize, or reverse CAV could use these techniques as an endpoint to evaluate efficacy. We are entering an era of sophistication in our understanding of CAV that can only help us tackle this devastating complication that continues to limit the long-term viability of cardiac allografts. These early advances remind us of what Albert Einstein said, “look deep into nature, and then you will understand everything better.” 






This article is reproduced from JACC journals.




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