Development Of CAV Research Articles

Short communications: Endothelin-1 in cardiac allograft vasculopathy

IntroductionCardiac allograft vasculopathy (CAV) is a leading cause of death following heart transplant. Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide derived from the vascular endothelium with multiple biological actions known to be relevant for CAV. We assessed the trans-myocardial gradient (TMG: coronary sinus minus coronary artery concentration: negative = extraction, positive = secretion) of ET-1 in heart transplant patients to determine correlations with angiographic, Intravascular Ultrasound (IVUS) and Optical Coherence Tomography (OCT) features of CAV. ResultsVessels with more severe CAV demonstrated significantly higher (more positive) ET-1 TMG (IVUS Stanford Grade IV: −0.05 [−0.21, 0.13] pg/ml versus Stanford Grade I-III: −0.31 [−0.64, −0.11] pg/ml, p = 0.01). ET-1 TMG was positively correlated with mean intimal thickness on both IVUS and OCT (IVUS: Kendall's tau-b = 0.254, p = 0.02 and OCT: Kendall's tau-b = 0.344, p < 0.0001). Patients who died had net ET-1 release compared with surviving patients (died: 0.21 [0.19–0.24] versus surviving: −0.28 [−0.52, −0.17], p = 0.01). ConclusionIn heart transplant patients, coronary arteries with more intimal thickening are associated with a higher (more positive) trans-myocardial gradient of ET-1, suggesting that up-regulated ET-1 release in the coronary circulation may be permissive for the development of CAV.

Cytomegalovirus infection is associated with impaired myocardial flow reserve after heart transplantation

BackgroundCardiac allograft vasculopathy (CAV) limits long-term survival after heart transplantation (HT). This study evaluates the relationship between clinically significant CMV infection (CS-CMVi) and CAV using cardiac positron emission tomography (PET). MethodsWe retrospectively evaluated HT patients from 2005-2019 who underwent cardiac PET for CAV evaluation. Multivariable linear and logistic regression models were used to evaluate the association between CS-CMVi and myocardial flow reserve (MFR). Kaplan-Meier and Cox regression analyses were used to assess the relationship between CS-CMV, MFR, and clinical outcomes. ResultsThirty-two (31.1%) of 103 HT patients developed CS-CMVi at a median 9 months after HT. Patients with CS-CMVi had a significantly lower MFR at Year 1 and 3, driven by reduction in stress myocardial blood flow. Patients with CS-CMVi had a faster rate of decline in MFR compared to those without infection (-0.10 vs -0.06 per year, P <0.001). CS-CMVi was an independent predictor of abnormal MFR (<2.0) (OR: 3.8, 95% CI: 1.4-10.7, P = 0.001) and a lower MFR (β = -0.39, 95% CI: -0.63 to -0.16, P = 0.001) at Year 3. In adjusted survival analyses, both abnormal MFR (log-rank P <0.001; HR: 5.7, 95% CI: 4.2-7.2) and CS-CMVi (log-rank P = 0.028; HR: 3.3, 95% CI: 1.8-4.8) were significant predictors of the primary outcome of all-cause mortality, retransplantation, heart failure hospitalization, and acute coronary syndrome. ConclusionCS-CMVi is an independent predictor of reduced MFR following HT. These findings suggest that CMV infection is an important risk factor in the development and progression of CAV.

Does the Degree of Diastolic Dysfunction in the First Year After Heart Transplant Affect Subsequent Outcomes?

<h3>Purpose</h3> Diastolic dysfunction in the first year post-heart transplantation (HTx) is not uncommon. This can be due to hypertension, rejection, or calcineurin inhibitor therapy treatments. It has not been well established whether this first-year diastolic dysfunction affects outcome post-HTx. <h3>Methods</h3> Between 2010 and 2016, we assessed HTx patients who developed diastolic dysfunction by echocardiography in the first year post-HTx. Patients with diastolic dysfunction were further divided into groups with mild, moderate, and severe diastolic dysfunction as determined by echo parameters. These patients were compared to patients who survived the first year who had no evidence of diastolic dysfunction. Subsequent 5-year survival, cardiac function (echocardiogram ejection fraction), cardiac allograft vasculopathy (CAV: stenosis ≥30% by angiography), and non-fatal major adverse cardiac events (NF-MACE: myocardial infarction, new congestive heart failure, percutaneous coronary intervention, implantable cardioverter defibrillator/pacemaker implant, stroke) were assessed for the patient groups. <h3>Results</h3> Patients with diastolic dysfunction had significantly lower 5-year survival and freedom from NF-MACE compared to the control group. The development of CAV at 5 years post-HTx was not significantly different among the study groups. There was not a linear correlation of worsening diastolic dysfunction to poorer outcomes. (See table.) <h3>Conclusion</h3> Any diastolic dysfunction appears to be a risk factor for poor outcomes post-HTx and should be addressed in terms of comorbid problems.

Hepatitis C Donors Are Not Associated with Higher Rates of Rejection After Cardiac Transplantation

<h3>Purpose</h3> Utilization of Hepatitis C (HCV) donors has led to a rapid expansion of the heart donor pool. Short term safety as measured by one year mortality has been published, however data on morbidity is lacking. We leveraged the multi-center SHORE registry to compare surrogate markers for outcomes in recipients of HCV+ vs HCV- donors. <h3>Methods</h3> The SHORE registry was queried for all heart transplant recipients with known donor status of HCV. Baseline characteristics were compared between recipients of HCV+ and HCV- donors. Since the registry does not differentiate between HCV viremic and non-viremic, the HCV+ donor group was inclusive of both. Outcomes of interest were rejection defined as ISHLT ≥ 2R and/or AMR ≥ 1 and average AlloSure levels during the first year. We also compared a composite outcome of de novo DSA, rejection, decline in LVEF, and/or development of CAV at one year. <h3>Results</h3> There were 1372 recipients of HCV- and 140 HCV+ donors. Baseline characteristics including age, sex, race and pre-transplant PRA were well matched. Over the first year, incidence of rejection was similar between groups 6.9% vs 4.3% (p=0.32). AlloSure levels over the first year were similar in the HCV- group and HCV+ groups (0.05 (0.0,8.36) vs 0.05 (0.0, 6.4)). Finally, the cumulative incidence of the composite outcome was not different between groups (Fig 1). <h3>Conclusion</h3> In this large analysis of recipients of HCV+ donor hearts, we did not find differences in the rates of rejection or clinically significant differences in levels of AlloSure in the first year. Similarly, the incidence of a composite outcome at one year was not different. These findings should reassure the community on short term safety of HCV+ donors.

Allograft Vasculopathy in Transplanted Hearts and the Role of FGF 23-Klotho Axis

Background: There are increasing evidences in the role of the involvement of the fibroblast growth factor 23 (FGF 23) - clotho axis in the pathogenesis of endothelial disfunction and cardiovascular disease. This study intended to explore the role of FGF 23 - clotho axis in the development of allograft vasculopathy. Methods: A total of 38 biatrial heart transplant patients who were operated were included in the study (20 males, 11 females; mean age: 44 ± 7 years). CFR was measured in all patients and the patients were divided into two groups according to respective CFR values. CFR &gt; 2 patients constituted CAV (-) group, CFR &lt; 2 patients were enrolled into CAV (+) group. FGF 23 and clotho levels were analyzed and compared in both groups. Results: FGF 23 levels were significantly higher in CAV (+) group (264.0±114.4 vs. 183.5±56.0 p=0.04). There was a good but inverse correlation between CFR and FGF 23 levels in CAV (+) group (r= - 0.71 p=0.03). Clotho levels were significantly lower in patients who have CAV (2.76±1.6 vs. 4.77±0.87 p=0.01). There was a moderate correlation between CFR and clotho levels in CAV (+) group (r=0.62 p=0.04). There was an inverse correlation between clotho and FGF 23 levels in both CAV (+) and CAV (-) groups. Conclusion: In transplanted patients, there was a good but negative correlation between CFR and FGF 23 levels. Conversely, there was a good correlation between CFR and clotho levels. These results gave rise to the thought clotho-FGF 23 axis has a role in the development of CAV.

Cardiac allograft vasculopathy: A review

Heart transplantation has become the standard of care for pediatric patients with end-stage heart disease, and outcomes have consistently improved over the last few decades. CAV, however, remains a leading cause of morbidity and mortality in heart transplantation and is the leading cause of death beyond 3years post-transplantation. We sought out to provide an in-depth overview of CAV in the pediatric heart transplant population. Database searches were conducted in both Medline and Embase on the topic of cardiac vasculopathy in pediatric heart transplant recipients. The search used five broad concept terms: heart transplant; pediatric; CAV; diagnosis, prognosis, and risk factors; and guidelines and reviews. References were captured if there was at least one term in each of the concepts. The search was limited to articles in the English language. A total of 148 articles were identified via the literature search with further articles identified via review of references. Pediatric data regarding the etiology and development of CAV remain limited although knowledge about the immune and non-immune factors playing a role are increasing. CAV continues to be difficult to detect with many invasive and non-invasive methods available, yet their effectiveness in the detection of CAV remains suboptimal. There remains no proven medical intervention to treat or reverse established CAV disease, and CAV is associated with high rates of graft loss once detected. However, several medications are used in hopes of preventing, slowing progression, or modifying the outcomes. This review provides a comprehensive overview of CAV, discusses its clinical presentation, risk factors, diagnostic tools used to identify CAV in the pediatric population, and highlights the current therapeutic options and the need for ongoing research.

Development of the L-type CaV / BK Complex Simulator (I): electrophysiological interaction

Complexes formed by voltage-activated calcium channels (CaV) and high-conductance potassium channels activated by Ca2+ (BK) have been studied in smooth muscle, secretory cells and in synaptic terminals, where they regulate muscle contraction, secretory activity, and neurotransmission. However, the complex formed by L- type CaV channels and BK in the soma has been poorly treated. Based on immunostaining studies showing the coexistence of these channels in the neuron soma, their possible interaction was theoretically studied. Two simulators based on the Hodgkin and Huxley formalism were developed to perform virtual experiments on current and voltage clamp. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate that the BK channels were activated with internal Ca2+ at mM concentrations. The BK channels follow the kinetics of L-type CaVs. The interaction of L-type CaV – BK complex in the soma produced a decrease in neuronal excitability.

Development of the L-type CaV / BK Complex Simulator (II): estimation of the distance between the channels

The presence, in the cell membrane, of high-conductance K+ channels and voltage-gated Ca2+ channels (CaV) forming complexes has been reported. These complexes have important functions in excitable cells. The [Ca2+]i at the mouth of the CaV channel decreases with distance and with the concentration of chelators. For the BK channel to be activated with internal Ca2, a concentration of the order of M is necessary and this implies a closeness between the BK-CaV channels. A simulator of the decay of Ca2+ in the presence of BAPTA to estimate the distance between the channels was developed. The mathematical models were implemented in Visual Basic® 6.0 and were solved numerically. The results indicate the coexistence of L-type CaV channel and BK grouped in nanodomains with a distance between channels of ~30 nm.

The Clinical Impact of ACEI/ARBs in Heart Transplantation: Perhaps Not All Good

<h3>Purpose</h3> Hypertension after heart transplantation (HTx) is noted in a majority of HTx patients due to the side effects of calcineurin inhibitors (CNI). The use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) are effective anti-hypertensive agents and may have longer term clinical benefits. We assessed our patients on ACEI/ARBs versus others in the first year post-HTx and followed them for 5-year outcomes. <h3>Methods</h3> Between 2010 and 2015, we assessed 101 HTx patients who were on ACEI/ARBs only in the first year for more than 6 months. Those patients were then followed for 5 years. Likewise, a group of patients who were placed on non-ACEI/ARBs blood pressure medications, such as calcium channel-blockers, beta blockers, and diuretics, in the first year for more than 6 months were the control group. Outcomes included 5-year survival, 5-year freedom from non-fatal major adverse cardiac event (NF-MACE: MI, new CHF, PCI, ICD implant, stroke), freedom from cardiac allograft vasculopathy (CAV: angiographic stenosis >30%), freedom from left ventricular dysfunction (left ventricular ejection fraction ≤40%) and freedom from left ventricular hypertrophy (LVH), defined as intraventricular septum or posterior wall ≥1.3cm. <h3>Results</h3> The patients treated with ACEI/ARBs in the first year post-HTx compared to those without had significantly lower 5-year survival but a trend for greater 5-year freedom from CAV. There was no significant difference between the two study groups in 5-year freedom from NF-MACE, left ventricular dysfunction and LVH (see table). Baseline demographics between groups were similar for recipient age, % female, pre-transplant diabetes and renal dysfunction (creatinine >1.5mg/dl) (data not shown). <h3>Conclusion</h3> The use of ACEI/ARBs in the first year post-HTx is associated with lower survival but other factors may be involved. A possible lower development of CAV from ACEI/ARBs may be a benefit to be explored.

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.

Prediction of the development of epiphytotics Pyricularia Orizae Cav. in rice growing areas of the Krasnodar Territory

Prediction of the development of epiphytotics Pyricularia Orizae Cav. in rice growing areas of the Krasnodar Territory

Clinical outcomes of percutaneous coronary intervention in coronary allograft vasculopathy from single center experience

Abstract Background/Introduction Cardiac allograft vasculopathy (CAV) is a leading cause of morbidity and mortality of heart transplant recipients. Percutaneous coronary intervention (PCI) is an alternative to medical treatment, however long-term data from large multicenter studies are scarce. Purpose To review clinical characteristics and outcomes of CAV undergoing PCI in our heart transplant series. Methods We analysed retrospectively 52 heart transplant recipients with CAV who underwent PCI from 2004 to 2020. Surveillance angiography was performed in 90% of stents. Stent restenosis (SR), stent thrombosis (ST), target lesion revascularization (TLR) and patient survival are reported. Results During study period, 124 lesions were treated. Primary success was obtained in 99% of lesions. Mean angiographic follow up was 37±47 months. A total of 31 (25%) stents presented events during follow-up: 24 SR, 7 ST. There were no differences between bare-metal stent (BMS) and drug-eluting stent (DES). We performed 16 (12.9%) TLR. There was no association between clinical and lesion-related features and TLR. Post-PCI survival was 75.3% at 5 and 55.7% at 10 years.. Cytomegalovirus (CMV) infection before development of CAV decreased survival in univariable analysis (p&amp;lt;0.016). Conclusions PCI with stent in CAV can be performed with high rates of primary success and low rate of complications, similar to non-transplant patients. Our series suggest that CMV infection can have negative impact in post-PCI survival, but further studies are needed. Funding Acknowledgement Type of funding source: None

Rates of CAV are Not Elevated in Recipients of HCV Non-Viremic Organs

Recent data from single centers and registry analysis have demonstrated comparable one year survival after cardiac transplantation with HCV non-viremic donors. On the other hand, long-term outcomes remain unknown which is particularly relevant given the concern for accelerated CAV from HCV donors in the pre-DAART era. Therefore, in the current analysis we report our one year rates of CAV in recipients of HCV non-viremic organs. A retrospective chart review was conducted of all transplants at Montefiore Medical Center between January 2017 and April 2019. Recipients were divided into 2 cohorts based on donor HCV status: non-HCV or HCV non-viremic (Ab+/NAT-). Donor and recipient characteristics as well as presence of CAV at one year assessment were collected. CAV was defined as intimal thickness >0.5mm by IVUS or OCT of the LAD when available or in cases without IVUS/OCT as Grade 1 or greater per the 2010 ISHLT CAV recommendations. Patients who received a HCV viremic organ, died before one year or did not have one year CAV assessment were excluded. During the study period, 97 transplants were performed. Breakdown by HCV status was: 70 non-HCV, 21 non-viremic, and 6 viremic transplants. 48 subjects in the non-HCV and 14 in HCV non-viremic categories reached one year and underwent CAV assessment. Characteristics associated with the development of CAV including recipient age, donor age, pre-transplant PRA, and rejection in the first year were not statistically different between groups. Rates of CAV were not different between recipients of non-HCV and HCV viremic organs at one year: 27% vs 14% (p=.32). At the time of presentation we anticipate data on presence of CAV on all 97 patients. In this preliminary analysis, rates of CAV in recipients of HCV non-viremic organs were comparable to non-HCV donors. This finding provides further reassurance for the use of such donors in standard risk recipients.

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.

Metformin therapy in patients with diabetes mellitus is associated with a reduced risk of vasculopathy and cardiovascular mortality after heart transplantation

BackgroundCardiac allograft vasculopathy (CAV) is a major cause of morbidity and mortality following heart transplantation (HT). Reduced cardiovascular mortality and morbidity have been reported in non-HT patients treated with metformin. Given the high prevalence of type 2 diabetes mellitus (T2DM) in HT patients, we investigated the association between metformin therapy and cardiovascular outcomes after HT.MethodsThe study population comprised 103 DM patients who had undergone HT between 1994 and 2018 and were prospectively followed-up. We excluded from the study patients with type 1 diabetes mellitus. Fifty-five HT patients (53%) in the cohort were treated with metformin. Clinical data were recorded on prospectively designed forms. The primary outcomes included CAV, survival, and the combined end-point of CAV or cardiovascular mortality.ResultsKaplan–Meier survival analysis showed that the CAV rate at 20 years of follow-up was lower in DM patients treated with metformin than in those who were not (30 vs. 65%; log-rank p = 0.044). Similarly, the combined risk of CAV or cardiovascular mortality was lower in the metformin-treated patients than in those not receiving metformin (32 vs. 68%; log rank p = 0.01). Consistently, multivariate analysis adjusted for age and comorbidities showed that metformin therapy was independently associated with a significant 90% reduction (95% confidence interval 0.02–0.46, p = 0.003) in the risk for the development of CAV, and a 91% reduction (95% confidence interval 0.02–0.42; p = 0.003) in the risk for CAV or cardiovascular mortality.ConclusionsIn diabetic HT patients, metformin therapy is independently associated with a significant reduction in the long-term risk for CAV and the combined end-point of CAV or cardiovascular mortality after HT.

Late-Breaking Clinical Trial: 10-Year Follow-Up of the Everolimus versus Azathioprine Multi-National Study

Purpose This study is the 10-year follow-up of a randomized double-blind prospective trial that compared everolimus (1.5 mg or 3 mg) to azathioprine. In the original study of 634 heart transplant patients, there were significantly fewer patients on everolimus who reached the 6 month composite endpoint of death, graft loss or re-transplantation, loss to followup, biopsy-proven acute rejection, or rejection with hemodynamic compromise (36.4% and 27.0%, compared to 46.0%, p Methods This 10-year follow-up study included 364 patients (57% of the original patients) with 116 and 124 patients assigned to everolimus 1.5 mg and 3 mg respectively, and 124 patients assigned to azathioprine. The first analysis includes intent-to-treat by study drug with 10-year endpoint of freedom from a composite endpoint of death, re-transplant, experiencing a coronary stent, myocardial infarction, or development of angiographic CAV. In addition, on-treatment by study drug at 10-years is analyzed for the composite endpoint, individual components of the composite endpoint, left ventricular dysfunction and non-fatal major adverse cardiac events. There were 138 patients with paired IVUS studies (at baseline and 1-year) with 54 patients having first-year change in maximal intimal thickness (MIT) >0.5mm and 84 patients without. Study endpoints for the 2 IVUS groups were the same as above. Further IVUS analysis is performed by study drug assignment and the presence of baseline donor disease. Results 10-year survival, freedom from angiographic CAV or NF-MACE by the intent-to-treat and on-treatment analyses by study drugs (everolimus vs azathioprine) will be revealed. Whether the change in first-year IVUS parameters (specifically change in MIT>0.5mm) can predict 10-year outcome (survival, angiographic CAV or NF-MACE) will also be revealed. Conclusion Findings with conclusions will be discussed at the late-breaking session.

Sinus Tachycardia During The First Year after Heart Transplantation is Associated with Worse Long-Term Outcomes

Background Elevated heart rate (HR) is an important risk factor for adverse outcomes in healthy people and across the entire spectrum of cardiovascular diseases. The effect of an elevated heart rate on patients post heart transplantation (HTx) though has not been well established. Objective The aim of this study was to assess the predictors and prognostic significance of elevated HR after HTx. Methods A total cohort of 394 patients who underwent HTx at two academic medical centers between 2005-2016 were divided into two groups based on HR at 1 year after HTx: 1) HR≥95 beats/min (bpm; n=162 [41%]) and 2) HR Results HR≥95 bpm at 1-year post-HTx was associated with younger donor age (OR 1.1; CI 1.0-2.3, P =0.05), whereas HR P =.04) and African-American recipients race (OR 0.40; 95% CI 0.19-0.85; P =0.02). Left ventricular diastolic dimension (4.3±0.5cm vs. 4.5±0.5cm, p Figure 1A ] and increased post-HTx mortality [ Figure 1B ] and was independent predicter of CAV (HR 2.7, 95% CI 1.4–5.5, p=0.005) and mortality (HR 3.9, 95% CI 1.4-7.7, p=0.02) after Cox proportional hazard analysis. Conclusion HR≥95 is associated with long term decrease in LV mass and systolic function, development of CAV and reduced survival. Studies investigating the effect of medical HR reduction on post-HTx outcomes are warranted.

Effects of different serotonin receptor subtype antagonists on the development of cardiac allograft vasculopathy in murine aortic allografts

BackgroundCardiac allograft vasculopathy (CAV) is the main obstacle for long-term survival after heart transplantation. Alloimmune mediated chronic vascular rejection results in several mechanisms like platelet activation, immigration of inflammatory cells through the endothelial layer and proliferation and migration of smooth muscle cells (SMCs). Serotonin (5-HT) promotes these processes via activation of 5-HT2 receptors. We hypothesized that inhibiting 5-HT2 receptors ameliorates the development of CAV. MethodsCBA/JRj mice recieved aortic grafts from C57BL/6 mice. After transplantation until recovery of organs, recipients were treated with serotonin receptor antagonists: sarpogrelate (5-HT2A), SB 204741 (5-HT2B) or terguride (5-HT2A+B). Mice were sacrificed after 14 days for qRT-PCR analysis or after 30 days for histological evaluation. Serum serotonin ELISA was done at both time points. ResultsElevated serum serotonin levels were significantly reduced after 5-HT2A antagonist treatment as was 5-HT2A receptor expression. This went along with reduced inflammation characterized by significantly fewer infiltrating macrophages and pro-inflammatory intragraft cytokines and with reduced tissue remodeling evident as significantly less neointima formation. ConclusionInhibition of the 5HT/5-HT2A receptor axis leads to significantly reduced neointima proliferation after aortic transplantation associated with reduced transendothelial migration of macrophages and decreased expression of inflammatory cytokines. These findings have translational implications as inhibitors of 5HT2A like sarpogrelate are already approved for clinical use.

The Effect of Everolimus Initiation and Early Calcineurin Inhibitor Withdrawal on Allograft Vasculopathy in De-Novo Heart Transplant Recipients: Results of the Schedule Trial after 6 Years

The SCHEDULE (Scandinavian heart transplant everolimus de-novo study with early calcineurin inhibitors avoidance) trial has sought to evaluate whether initiation of the proliferation signal inhibitor everolimus and total early cyclosporine elimination can significantly reduce the development of CAV in de-novo HTx recipients. We have previously reported that patients treated with everolimus demonstrated significantly reduced CAV progression when compared to cyclosporine therapy at both 12 and 36 months (12-month IVUS examination revealed ∆Maximal Intimal Thickness (MIT) 0.02±0.05 versus 0.08±0.12 mm (p<0.01), ∆Percent Atheroma Volume (PAV) 1.2±2.0 versus 3.7±4.1% (p<0.01), ∆Total Atheroma Volume (TAV) -0.13±20.5 mm3 versus 11.1±27.6 mm3 (p=0.08) and 36-month examination showed ∆MlT 0.09±0.05 versus 0.15±0.16 mm (p=0.01), ∆PAV 5.4±3.1 versus 7.6±5.9% (p=0.02), ∆TAV 33.9±71.2 mm3 versus 54.2±96.0 mm3 (p=0.26), respectively). Treatment according to study arm has been further extended to a total treatment period of 6 years and the IVUS results of this follow-up period will be presented. In addition, Virtual Histology (VH) data will be included to assess the morphological changes associated with everolimus treatment.

Angiotensin-Converting Enzyme Inhibition Early After Heart Transplantation

BackgroundCardiac allograft vasculopathy (CAV) remains a leading cause of mortality after heart transplantation (HT). Angiotensin-converting enzyme inhibitors (ACEIs) may retard the development of CAV but have not been well studied after HT. ObjectivesThis study tested the safety and efficacy of the ACEI ramipril on the development of CAV early after HT. MethodsIn this prospective, multicenter, randomized, double-blind, placebo-controlled trial, 96 HT recipients were randomized to undergo ramipril or placebo therapy. They underwent coronary angiography, endothelial function testing; measurements of fractional flow reserve (FFR) and coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR); and intravascular ultrasonography (IVUS) of the left anterior descending coronary artery, within 8 weeks of HT. At 1 year, the invasive assessment was repeated. Circulating endothelial progenitor cells (EPCs) were quantified at baseline and 1 year. ResultsPlaque volumes at 1 year were similar between the ramipril and placebo groups (162.1 ± 70.5 mm3 vs. 177.3 ± 94.3 mm3, respectively; p = 0.73). Patients receiving ramipril had improvement in microvascular function as shown by a significant decrease in IMR (21.4 ± 14.7 to 14.4 ± 6.3; p = 0.001) and increase in CFR (3.8 ± 1.7 to 4.8 ± 1.5; p = 0.017), from baseline to 1 year. This did not occur with IMR (17.4 ± 8.4 to 21.5 ± 20.0; p = 0.72) or CFR (4.1 ± 1.8 to 4.1 ± 2.2; p = 0.60) in the placebo-treated patients. EPCs decreased significantly at 1 year in the placebo group but not in the ramipril group. ConclusionsRamipril does not slow development of epicardial plaque volume but does stabilize levels of endothelial progenitor cells and improve microvascular function, which have been associated with improved long-term survival after HT. (Angiotensin Converting Enzyme [ACE] Inhibition and Cardiac Allograft Vasculopathy; NCT01078363)