• Heart transplantation
• allograft rejection
• cardiac allograft vasculopathy
• myocardial flow reserve
• positron emission tomography
• statin

• Humans
• Heart Transplantation/adverse effects
• Male
• Female
• Middle Aged
• Retrospective Studies
• Positron-Emission Tomography/methods
• Fractional Flow Reserve, Myocardial/physiology
• Allografts
• Predictive Value of Tests
• Longitudinal Studies
• Adult
• Follow-Up Studies
• Coronary Artery Disease/diagnostic imaging
• Aged
• Myocardial Perfusion Imaging/methods

• acute allograft rejection
• cardiac allograft vasculopathy
• coronary flow reserve
• fractional flow reserve
• index of microcirculatory resistance

• Allograft vasculopathy
• In vivo immunomodulation
• Nanomedicine
• Ti3C2Tx MXene
• Tissue regeneration

• SNP
• genetic risk score
• heart transplantation
• rejection
• telomere

The median survival of patients with heart transplants is relatively limited, implying one of the most relevant questions in the field—how to expand the lifespan of a heart allograft? Despite optimal transplantation conditions, we do not anticipate a rise in long-term patient survival in near future. In order to develop novel strategies for patient monitoring and specific therapies, it is critical to understand the underlying pathological mechanisms at cellular and molecular levels. These events are driven by innate immune response and allorecognition driven inflammation, which controls both tissue damage and repair in a spatiotemporal context. In addition to immune cells, also structural cells of the heart participate in this process. Novel single cell methods have opened new avenues for understanding the dynamics driving the events leading to allograft failure. Here, we review current knowledge on the cellular composition of a normal heart, and cellular mechanisms of ischemia-reperfusion injury (IRI), acute rejection and cardiac allograft vasculopathy (CAV) in the transplanted hearts. We highlight gaps in current knowledge and suggest future directions, in order to improve cellular and molecular understanding of failing heart allografts.

• acute rejection
• cardiac allograft vasculopathy
• cellular disease mechanism
• heart transplantation
• ischemia reperfusion injury

• Ta 4C 3Tx MXene quantum dots
• allograft vasculopathy
• bioactive material
• hydrofluoric acid‐free synthesis
• in vivo immunomodulation

Cardiac allograft vasculopathy (CAV) is the major cause of increased morbidity and mortality after heart transplantation. Peripheral endothelial dysfunction (PED) is associated with early atherosclerosis and future risk of major adverse cardiovascular events (MACE) in non‐heart transplant population. We aimed to investigate the association of PED with future MACE, and plaque progression assessed by intravascular ultrasound (IVUS) after heart transplantation.

We included 66 transplant patients who underwent serial IVUS surveillance for CAV and baseline assessment of peripheral endothelial function using reactive hyperaemia peripheral arterial tonometry. PED was defined as reactive hyperaemia index < 2. The primary endpoint of the study was to investigate the association of PED with CAV progression assessed by intravascular ultrasound (IVUS). CAV progression was assessed as the change (Δ) in plaque volume divided by segment length, and Δ plaque index (plaque volume/vessel volume), adjusted for the time between IVUS measurements (median 3.0 [2.2, 3.1] years). The secondary endpoint was to investigate the association between PED and future MACE, which was defined as any incident of revascularization, heart failure hospitalization, stroke, myocardial infarction, re‐transplantation, and death. Patients with PED (n = 27) had more yearly plaque progression (0.50 ± 0.66 vs. 0.15 ± 0.50 mm³/mm/year, P = 0.02) and a higher Δ plaque index (2.41 ± 2.53% vs. 0.69 ± 2.22%, P = 0.01). Patients with PED were more likely to experience MACE during a median follow‐up of 8.2 years (interquartile range [7.6, 8.4]), after adjustment for potential cofounders such as age, high‐density lipoprotein cholesterol levels, total rejection score, baseline International Society for Heart & Lung Transplantation CAV grade, and indication of transplantation. (hazard ratio 2.15, 95% confidence interval [1.09, 4.23], P = 0.03).

Peripheral endothelial dysfunction is associated with increased plaque progression and adverse long‐term cardiovascular outcomes in transplant patients. PED assessment might be a useful clinical tool for risk stratification after heart transplantation.

• Cardiac allograft vasculopathy
• Heart transplantation
• Intravascular ultrasound
• Peripheral endothelial function
• Reactive hyperaemia peripheral arterial tonometry

Cardiac allograft vasculopathy (CAV) remains the Achilles' heel of long-term survival after heart transplantation (HTx). The severity and extent of CAV is graded with conventional coronary angiography (COR) which has several limitations. Recently, vessel fractional flow reserve (vFFR) derived from COR has emerged as a diagnostic computational tool to quantify the functional severity of coronary artery disease.

The present study assessed the usefulness of vFFR to detect CAV in HTx recipients.

In HTx patients referred for annual check-up, undergoing surveillance COR, the extent of CAV was graded according to the criteria proposed by the international society of heart and lung transplantation (ISHLT). In addition, three-dimensional coronary geometries were constructed from COR to calculate pressure losses using vFFR.

In 65 HTx patients with a mean age of 53.7 ± 10.1 years, 8.5 years (IQR 1.90, 15.2) years after HTx, a total number of 173 vessels (59 LAD, 61 LCX, and 53 RCA) were analyzed. The mean vFFR was 0.84 ± 0.15 and median was 0.88 (IQR 0.79, 0.94). A vFFR ≤ 0.80 was present in 24 patients (48 vessels). HTx patients with a history of ischemic cardiomyopathy (ICMP) had numerically lower vFFR as compared to those with non-ICMP (0.70 ± 0.22 vs. 0.79 ± 0.13, p = 0.06). The use of vFFR reclassified 31.9% of patients compared to the anatomical ISHLT criteria. Despite a CAV score of 0, a pathological vFFR ≤ 0.80 was detected in 8 patients (34.8%).

The impairment in epicardial conductance assessed by vFFR in a subgroup of patients without CAV according to standard ISHLT criteria suggests the presence of a diffuse vasculopathy undetectable by conventional angiography. Therefore, we speculate that vFFR may be useful in risk stratification after HTx.

• Cardiac allograft vasculopathy
• HMG CoA reductase inhibitors
• Heart transplantation
• Statins

• Cardiac allograft vasculopathy
• Diabetes mellitus
• Heart transplantation
• SGLT-2 inhibitors

• Allografts
• Endothelial Cells
• Graft Rejection
• Heart Transplantation
• Humans
• Sodium-Glucose Transporter 2 Inhibitors
• Transplantation, Homologous

• aspirin
• cardiac allograft vasculopathy
• coronary artery disease
• heart transplantation
• treatment

• animal models: murine
• basic (laboratory) research/science
• organ transplantation in general
• rejection

• Adult
• Allografts
• Atherosclerosis/complications
• Atherosclerosis/diagnostic imaging
• Coronary Angiography
• Coronary Artery Disease/diagnostic imaging
• Coronary Artery Disease/etiology
• Disease Progression
• Female
• Health Status
• Heart Transplantation/adverse effects
• Humans
• Imaging, Three-Dimensional
• Male
• Middle Aged
• Plaque, Atherosclerotic
• Predictive Value of Tests
• Retrospective Studies
• Risk Assessment
• Risk Factors
• Time Factors
• Tissue Donors
• Treatment Outcome
• Ultrasonography, Interventional
• Young Adult

Heart transplantation has evolved as the criterion standard therapy for end-stage heart failure, but its efficacy is limited by the development of cardiac allograft vasculopathy (CAV), a unique and rapidly progressive form of atherosclerosis in heart transplant recipients. Here, we briefly review the key processes in the development of CAV during heart transplantation and highlight the roles of transient receptor potential (TRP) channels in these processes during heart transplantation. Understanding the roles of TRP channels in contributing to the key procedures for the development of CAV during heart transplantation could provide basic scientific knowledge for the development of new preventive and therapeutic approaches to manage patients with CAV after heart transplantation.

• cardiovascular disease
• endothelial dysfunction
• nitric oxide
• oxidative stress

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Aminoquinolines/pharmacology
• Chronic Disease
• Endothelium, Vascular/drug effects
• Endothelium, Vascular/metabolism
• Endothelium, Vascular/physiopathology
• Female
• Humans
• Immunoblotting
• Male
• Middle Aged
• NADP/metabolism
• Nitric Oxide Synthase Type III/metabolism
• Oxidative Stress/drug effects
• Pyrimidines/pharmacology
• Reactive Oxygen Species/metabolism
• Saphenous Vein/drug effects
• Saphenous Vein/metabolism
• Saphenous Vein/physiopathology
• Vasodilation/drug effects
• Venous Insufficiency/metabolism
• Venous Insufficiency/physiopathology
• Young Adult
• rac1 GTP-Binding Protein/antagonists & inhibitors
• rac1 GTP-Binding Protein/biosynthesis

Cytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx.

A retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed.

Survival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0–7.4) compared with CMV disease (4.2 years; CI, 3.2–5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3–6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant.

CAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

• cardiac allograft vasculopathy
• heart transplantation
• vasa vasorum

Cardiac allograft vasculopathy (CAV) is one of the main causes of late-stage heart failure after heart transplantation. CAV is characterized by concentric luminal narrowing of the coronary arteries, but the exact pathogenesis of CAV is still not unraveled. Many researchers show evidence of an allogeneic immune response of the recipient, whereas others show contrasting results in which donor-derived cells induce an immune response against the graft. In addition, fibrosis of the neo-intima can be induced by recipient-derived circulating cells or donor-derived cells. In this review, both donor and recipient sides of the story are described to obtain better insight in the pathogenesis of CAV. Dual outcomes were found regarding the contribution of donor and recipient cells in the initiation of the immune response and the development of fibrosis during CAV. Future research could focus more on the potential synergistic interaction of donor and recipient cells leading to CAV.

Coronary allograft vasculopathy remains one of the leading causes of death beyond the first year post transplant. As a result of denervation following transplantation, patients lack ischaemic symptoms and presentation is often late when the graft is already compromised. Current diagnostic tools are rather invasive, or in case of angiography, significantly lack sensitivity. Therefore a non-invasive tool that could allow early diagnosis would be invaluable.This paper review the disease form its different diagnosis techniques,including new and less invasive diagnostic tools to its pharmacological management and possible treatments.

• Cardiac transplantation
• Allograft vasculopathy
• Paediatrics
• Diagnosis
• Management which reflect the content of the study

• T-lymphocytes
• transplantation