Predictors Of Cardiac Allograft Vasculopathy Research Articles

Non-immune risk predictors of cardiac allograft vasculopathy: Results from the U.S. organ procurement and transplantation network

BackgroundCardiac allograft vasculopathy (CAV) remains a major long-term complication in heart transplant (HT) recipients related to increased mortality. We aimed to identify non-immune recipient- and donor-related risk factors for the development of CAV in HT patients. Methods40,647 recipients, prospectively enrolled from April 1995 to January 2019 in the Organ Procurement and Transplantation Network (OPTN), were analyzed after exclusion of pediatric patients, those with missing information on CAV, and re-transplantation. Multivariable-adjusted Cox regression analyses were performed to identify recipient- and donor-related risk factors for CAV. 5-year population attributable risk for classical cardiovascular risk factors was calculated to estimate the recipients' CAV risk. Analyses were based on OPTN data (June 30, 2019). ResultsOf 40,647 post-transplant patients, 14,698 (36.2%) developed CAV with a higher incidence in males (37.3%) than in females (32.6%) (p < 0.001). The mean follow-up time was 68.2 months. In recipients, male sex, African American and Asian ethnicity, ischemic cardiomyopathy, body mass index and smoking were associated with CAV occurrence. In donors, older age, male sex, smoking, diabetes and arterial hypertension were related to CAV. Results remained fairly stable after analysis of different time periods. 5-year attributable CAV risk for classical cardiovascular risk factors was 9.1%. ConclusionsIn this large registry with known limitations concerning data completeness, CAV incidence was higher in males than in females. Next to male sex and donor age, the classical cardiovascular risk factors were related to incident CAV. Classical cardiovascular risk factors played only a minor role for the 5-year attributable CAV risk.

P6310Risk predictors of cardiac allograft vasculopathy after heart transplantation: results from the United States Organ Procurement and Transplantation Network

Abstract Background Cardiac allograft vasculopathy (CAV) is a major long-term complication after heart transplantation leading to chronic graft failure and increased mortality. Purpose The aim of this study was to determine recipient- and donor-related risk factors for the development of CAV in patients after heart transplantation. Methods Overall, data from 34,994 heart transplant recipients prospectively enrolled from July 2004 to March 2015 in the Organ Procurement and Transplantation Network (OPTN) were analyzed. Patients aged &lt;18 years and those without information about CAV and re-transplantation were excluded. Multivariable-adjusted analyses were performed to identify recipient- and donor-related risk factors for new-onset CAV. The mean follow-up time was 66.8 months. Analyses are based on OPTN data as of March 6, 2017. Results Of 34,994 patients after heart transplantation, 12,668 (36.2%) patients developed CAV. Mean age was 52±12 years for the recipients (76.1% men) and 31±12 years for the donors (71.0% men), respectively. In recipients, male sex (hazard ratio [HR] 1.14, 95% confidence interval [CI] 1.09–1.19, p&lt;0.001), African American ethnicity (HR 1.11, 95% CI 1.06–1.17, p&lt;0.001), body mass index (BMI) (HR per 5 kg/m2 increase 1.08, 95% CI 1.06–1.11, p&lt;0.001) and smoking (HR 1.07, 95% CI 1.01–1.13, p=0.03) were associated with incident CAV. Moreover, recipients with ischemic (HR 1.30, 95% CI 1.09–1.55, p=0.003) and hypertrophic cardiomyopathy (HR 1.26, 95% CI 1.02–1.57, p=0.03) had a higher risk for new-onset CAV than patients with other cardiomyopathies. In donors, age (HR 1.11, 95% CI 1.10–1.11, p&lt;0.001), male sex (HR 1.28 95% CI 1.22–1.34, p&lt;0.001), BMI (HR per 5 kg/m2 increase 1.04, 95% CI 1.02–1.05, p&lt;0.001), smoking (HR 1.09, 95% CI 1.04–1.13, p&lt;0.001), diabetes (HR 1.21 95% CI 1.09–1.36, p&lt;0.001) and arterial hypertension (HR 1.13, 95% CI 1.07–1.20, p&lt;0.001) were associated with new-onset CAV. Contrarily, African American (HR 0.93, 95% CI 0.88–0.98, p=0.007) and Hispanic ethnicity (HR 0.94, 95% CI 0.89–0.99, p=0.03) seemed to be protective. Conclusion Both recipient and donor male sex as well as the classical cardiovascular risk factors BMI and smoking were associated with incident CAV. On the donor side, additionally, diabetes and arterial hypertension were related to new-onset CAV. Diverse ethnicities were differentially related to new-onset CAV. Further studies are needed to clarify whether modification of cardiovascular risk factors as well as improved donor selection will reduce CAV burden.

Cardiac Allograft Vasculopathy is Linked to Impaired Generation of Regulatory M2 Macrophages

Purpose There is mounting evidence for the role of innate immunity in acute cardiac allograft rejection, but this does not necessarily extend to cardiac allograft vasculopathy (CAV) and predictors of CAV remain elusive. We hypothesized that circulating monocytes and their derived macrophage subtypes correlate with CAV. Methods 49 consecutive heart transplant recipients ≥ 2 years post-transplant were enrolled. CAV was assessed on angiogram with IVUS by ISHLT and Stanford classification grading. Peripheral blood mononuclear cells were isolated by density gradient centrifugation, with monocytes stained and measured by flow cytometry for classical (CD14++/CD16−), intermediate (CD14++/CD16+), and nonclassical (CD14lo/CD16++) subtypes. Monocytes were cultured into macrophages, driven by M-CSF, and assayed for polarization markers CD86 and CD206. Results were also compared to 22 non-transplant patients with atherosclerotic coronary artery disease (CAD) and healthy controls (no CAD). Results 22 patients had no significant CAV (Stanford class I-II) while 27 had significant CAV (class III-IV). Other than time since transplant (no CAV 77±13 vs CAV 135±12 months), there were no significant differences, including immunosuppression, between the two groups. There were no differences between monocyte subgroups in isolation, but when combined with derived macrophage polarization, patients with CAV had significantly lower M2 (CD206+) macrophage production (0.19±0.04%) than those without CAV (0.45±0.13%), p Conclusion CAV patients are characterized by reduced ability to generate regulatory M2 macrophages. The circulating monocyte and macrophage subtypes differ from those of native CAD and these cell-based markers could be useful to differentiate high vs. low CAV risk phenotypes.

Uric acid is an independent predictor of cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy (CAV) is a major complication after heart transplantation (HT). Uric acid (UA) may play a role in CAV due to its role in stimulating T-cell-mediated immunity. Sirolimus is associated with CAV attenuation through a number of mechanisms, including immune-mediated effects. We aimed to determine whether UA is an independent predictor of CAV and whether conversion to sirolimus as primary immunosuppression modulates UA levels. We retrospectively analyzed a cohort of 224 patients who underwent HT between 2004 and 2015 and had serial coronary intravascular ultrasound (IVUS) studies. Serum UA levels were measured at baseline and last follow-up IVUS in all participants. CAV progression was assessed by measuring the change in plaque volume (ΔPV) and plaque index (ratio of plaque volume to vessel volume [ΔPI]) between last follow-up and baseline IVUS after correction for time of follow-up. Patients with high (≥7 mg/dl) compared with low (<7 mg/dl) UA had increased median ΔPV (0.33 [interquartile range 0.08 to 0.93] vs 0.07 [-0.17 to 0.38] mm3/mm/year; p < 0.001) and ΔPI (2.0% [0.31% to 3.9%] vs 0.33% [-1.2% to 2.0%]; p < 0.001). Elevated UA levels were associated with a significantly increased risk of developing significant CAV progression (ΔPV >0.50 mm3/mm) (hazard ratio 2.2, 95% confidence interval 1.1 to 4.6; p = 0.037). Sirolimus resulted in decreased UA levels (5.8 ± 1.4 vs 5.2 ± 1.5; p = 0.002) and patients converted to sirolimus and had low UA levels had the least CAV progression (p < 0.001). After adjustment for potential confounders, change in UA level was also an independent predictor of CAV progression. UA is an independent predictor of CAV after HT. Sirolimus is associated with decreased UA levels and may explain one of the mechanisms by which sirolimus attenuates CAV progression.

Cardiogenic shock and coronary endothelial dysfunction predict cardiac allograft vasculopathy after heart transplantation.

Cardiac allograft vasculopathy remains one of the major causes of death post-heart transplantation. Its etiology is multifactorial and prevention is challenging. The aim of this study was to prospectively determine factors related to cardiac allograft vasculopathy after heart transplantation. This research was planned on 179 patients submitted to heart transplant. Performance of an early coronary angiography with endothelial function evaluation was scheduled at three-month post-transplant. Patients underwent a second coronary angiography after five-yr follow-up. At the 5- ± 2-yr follow-up, 43% of the patients had developed cardiac allograft vasculopathy (severe in 26% of them). Three independent predictors of cardiac allograft vasculopathy were identified: cardiogenic shock at the time of the transplant operation (OR: 6.49; 95% CI: 1.86-22.7, p = 0.003); early coronary endothelial dysfunction (OR: 3.9; 95% CI: 1.49-10.2, p = 0.006), and older donor age (OR: 1.05; 95% CI: 1.00-1.10, p = 0.044). Besides early endothelial coronary dysfunction and older donor age, a new predictor for development of cardiac allograft vasculopathy was identified: cardiogenic shock at the time of transplantation. In these high-risk patient subgroups, preventive measures (treatment of cardiovascular risk factors, use of novel immunosuppressive agents such as mTOR inhibitors) should be earlier and much more aggressive.

Abstract 2886: Angiotesin-Converting Enzyme Inhibitors Attenuate Age-related Progression of Cardiac Allograft Vasculopathy - A Serial Volumetric Intravascular Ultrasound Study

Background : The development of cardiac allograft vasculopathy (CAV) portends an adverse clinical outcome in heart transplant recipients. Previous studies of clinical predictors of CAV have investigated small cohorts and have not evaluated the volumetric extent of disease. This study determined predictors of progression of the volumetric severity of vasculopathy in a large cohort of heart transplant recipients. Methods : Serial intravascular ultrasound examinations were performed in 119 heart transplant recipients at 1 month and 1 year following transplantation. Clinical predictors of serial changes in atheroma volume were determined. In particular, the impact of donor and recipient age stratified according to the median was investigated. Results : Patients ( donor age 33.3 ± 14.2 years, recipient age 54.5 ± 12.6 years, 71.9 % male) demonstrated an increase in atheroma volume (64.2 ± 41.7 mm 3 at 1 month vs. 78.1 ± 53.4 mm 3 at 1 year, p &lt; 0.001) and a decrease in lumen volume (334.2 ± 197.3 mm 3 at 1 month vs. 321.6 ± 187.8 mm 3 at 1 year, p = 0.001). Greater increases in atheroma volume were observed in the setting of older donor age (r = 0.24, p = 0.008), older recipient age (r = 0.23, p = 0.01) and recipients not treated with an angiotensin-converting enzyme (ACE) inhibitor (without ACE inhibitor, 21.1 ± 33.3 mm 3 vs. with ACE inhibitor, 9.1 ± 27.6 mm 3 , p = 0.03). In multivariate analysis, donor age ( p = 0.01) and the lack of treatment with an ACE inhibitor ( p = 0.02) remained independent predictors of increases in atheroma volume. Increased disease progression with age was attenuated with the use of ACE inhibitors (table ). Conclusion : Donor age and ACE inhibitor treatment are major determinants of CAV progression. This analysis suggests that treatment with ACE inhibitors would attenuate age-related progression of CAV. Large randomized clinical trials are warranted to ascertain such a beneficial effect.

Probrain Natriuretic Peptide and C-Reactive Protein as Markers of Acute Rejection, Allograft Vasculopathy, and Mortality in Heart Transplantation

N-terminal probrain natriuretic peptide (NT-proBNP) and C-reactive protein (CRP) are useful in risk stratification of patients with congestive heart failure. They could also be markers of distinctly altered hormonal and immunological milieus, but the combined prognostic value of these biomarkers in heart transplant (HTx) recipients has not been assessed previously. We sought to assess the individual and combined value of NT-proBNP and CRP as markers of acute rejection, cardiac allograft vasculopathy (CAV) and all-cause mortality in HTx recipients. We evaluated 101 patients for acute rejection and 210 patients for CAV and all-cause mortality. Patients evaluated for rejection had serial endomyocardial biopsies and plasma sampling performed during the first year postHTx. All other patients had plasma samples taken upon inclusion at an annual visit. Median follow-up for CAV and all-cause mortality was 2.2 years and 5.4 years, respectively. Altogether, 1131 biopsy procedures were performed, and increased NT-proBNP and CRP levels were not useful markers of acute cellular rejection. In total, 78 (37%) patients developed CAV, and 39 (19%) patients died. Neither biomarker was a predictor of CAV, but both were independent predictors of mortality. When combining both biomarkers, elevated levels of both NT-proBNP and CRP identified patients at highest risk for CAV (HR 2.10, P=0.01) and all-cause mortality (HR 3.14, P=0.01). In HTx recipients, NT-proBNP and CRP are not useful as markers of acute cellular rejection during the first year postHTx, but combined analysis adds significantly to their predictive value for development of CAV and all-cause mortality.

955 Coronary flow velocity pattern by contrast-enhanced transthoracic echocardiography: a new noninvasive predictor of cardiac allograft vasculopathy

Cardiac allografl vasculopalhy (CAV) represents a major cause el morbidity and mortality in heart transplantation (HT). Several noninvasive tests have proven unsatisfactory as diagnostic tools. We studied the potential role el coronary flow velocity pattern by contrast-enhanced translhoracic echocardiography (CE-T]E) in CAV detection. Diastolic peak velocity (DPV) and deceleration lime of diastolic flow velocity (DDT) were measured in the lelt anterior descending coronary artery (LAD) by CE-TTE in 78 HT recipients (65 male, aged 50412 years at HT, at 8.1 4-4.3 years alter HT). Coronary flow velocity pattern was measured blindly lrom coronary angiography results and within 24 hours from catheterization. CAV was defined as any angiographic lesion and significant CAV as stenosis _> 50%. CAV was diagnosed in 32 out of 78 patients (pls) (41%) (group A) while 46 pls had normal coronary angiograms (group B). DPV and DDT were 274-9 cm/s and 9124-909 ms in all pls, respectively. DPV was higher in group A vs group B (314-11 vs 254-6 cm/s, p= 0.01 ) and DDT was reduced in group A vs group B (8224-930 vs 9754-170 ms, p= 0.001). A DDT outpoint of _ 2.8 cm/s and DDT _< 922 ms (RR 3.1,95% CI 1.1-9, p= 0.03 and RR 36, 95% CI 1.2-10.7, p= 0.02, respectively). Noninvasive assessment by CE-TTE reveals that a shorter DDT is associated with angiographically delectable CAV. A DDT culolf _< 922 ms proved accurate to rule out the presence of CAV and is an independent predictor ,31 CAV. Thus, DDT evaluation by CE-TTE in HT recipients may reduce the need lor routine coronary angiography.

Impaired coronary flow reserve by contrast-enhanced transthoracic echocardiography predicts cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) represents a major cause of morbidity and mortality in heart transplantation (HT). The evaluation of coronary flow reserve (CFR) provides valuable information on the status of coronary vessels. Invasive studies have suggested progressive CFR impairment in HT, although its correlation with CAV is controversial. We assessed the potential role of noninvasive CFR evaluation as predictor of CAV.

Cardiac allograft vasculopathy.

As the survival rates for cardiac transplant patients improve, the long-term complications of the procedure are becoming apparent. One such complication is a rapidly progressing form of coronary artery disease known as cardiac allograft vasculopathy (CAV). CAV is a major limiting factor in long-term graft survival. It is thought to develop immediately after transplantation, although initially it may be unrecognized because of a lack of sensitive screening techniques. It is estimated that 12% of cardiac transplant recipients will develop CAV each year after transplantation. Most researchers agree that CAV is primarily an immune-related response to transplantation. However, other factors such as hyperlipidemia and obesity have also been implicated as predictors of CAV. This article explores the pathophysiology, risk factors, detection, and treatment of CAV in the cardiac transplant population.