Post-cardiac Transplant Patient Research Articles

Interventional Radiological Treatment of Orthotopic Heart Transplant Complications

Orthoptic heart transplantation (OHT) is a life-saving procedure that has substantially improved the lives of countless patients since its inception. However, there are several procedure-related complications that require prompt management. Interventional radiology, with its ever-expanding toolkit, is a cornerstone of the multidisciplinary team following post-cardiac transplant patients. Percutaneous, endovascular therapy provides minimally invasive, safe, and effective treatments for immediate and delayed cardiac transplant complications and this paper serves to highlight the various management options interventional radiology can provide for orthoptic heart transplantation complications.

Electroconvulsive Therapy in Heart Transplant Patients: To Avoid or Embrace?

Patients with heart disease are at an increased risk of depression. Electroconvulsive therapy (ECT) is a highly effective treatment for severe depressive episodes. However, ECT may increase the risk for adverse outcomes in certain patients because of changes in blood pressure and heart rate secondary to an initial parasympathetic surge followed by a sympathetic surge and peripheral catecholamine release. In post-cardiac transplant patients, these acute hemodynamic changes on a denervated heart may bring clinical challenges. The available data on ECT in heart transplant patients are limited. The authors of this article present a summary of the available literature relating to ECT in heart transplant patients.The authors performed a literature search of 6 online databases yielding 6 English-language case reports of ECT in cardiac transplant patients. All patients experienced changes in hemodynamic variables during and immediately after ECT, ranging from moderate decrease in blood pressure to extreme hypertension. The cases did not report any serious cardiac complications during the course of ECT. In the 5 patients whose psychiatric responses to treatment were detailed, all had improvement in their depressive symptoms. Electroconvulsive therapy may be considered for severe cases of depression in patients with a history of cardiac transplant, but the potential benefit of ECT needs to be weighed against risks. In the limited number of cases reported in the literature, ECT seems to have been relatively safe and effective.

The long term prognostic value of peak left atrial strain in cardiac transplant patients

Abstract Funding Acknowledgements Type of funding sources: None. Background Left atrial (LA) dysfunction is associated with poorer outcomes in many disease processes. Left atrial strain (LAS) is a novel two-dimensional (2D) quantitative analysis of LA function. Cardiac transplantation directly involves the LA during implantation of the donor heart. Traditional echocardiographic indices after transplantation have demonstrated value in correlating with acute cellular rejection (ACR), morbidity and mortality over short- and long-term follow-up. The prognostic value of LA strain has not been previously investigated in this cohort. Purpose We hypothesized that incrementally impaired LA strain in post cardiac transplant patients with varying degrees of ACR may be prognostic of poorer outcomes on long term follow-up. Methods 87 Heart transplant patients, assessed between 2009 and 2015, underwent transthoracic echocardiography and endomyocardial biopsy. 2D strain analysis on the LV and LA were performed along with traditional echocardiographic parameters. Patients were grouped according to peak LAS (PALS) tertiles and rejection burden history was assessed and grouped according to ACR burden at a median of 12 (±5.4) months post transplantation. The primary endpoint was all-cause mortality at follow-up. Results 12 patients met the primary endpoint over a median follow-up of 66 ± 51 months. The mean LA PALS was significantly different across the tertiles (lowest tertile 12.29 ± 2.5% vs middle tertile 17.89 ± 1.1% vs highest tertile 24.54 ± 4.2%; p <0.0001). LA strain dispersion was also significantly different between the tertiles (61.03 ± 25.8ms vs 41.8 ± 15.8ms vs 44.8 ± 18.8ms; p <0.001). All other clinical and echocardiographic parameters were non-significant between the tertiles however, there was a trend towards a lower PALS in the higher rejection burden group. Kaplan Meier curves demonstrated that survival over follow-up was significantly worse in the lower tertile LA PALS group compared to the highest tertiles LA PALS group (Log-rank test = p < 0.0001). The lowest LA PALS tertile had a significantly higher risk of reaching the primary endpoint compared with patients in the highest LA PALS tertile (hazard ratio [HR] 9.802; 95% CI 1.832-52.45; p <0.008). Higher LA PALS and LV GLS (LA PALS HR 0.610 95% CI 0.401-0.926; p 0.02; LV GLS HR 0.638 95% CI 0.418-0.972; p 0.037) were significantly associated with a reduction in reaching the primary endpoint in a multi-variate regression model including clinically relevant traditional and strain-based echocardiographic parameters. Conclusions Lower LA PALS is significantly associated with poorer long-term outcomes in cardiac transplant patients with ACR. Non-invasive LA PALS may be a useful predictor of long-term outcome in patients post cardiac transplantation. Abstract Figure. Survival curves for LA PALS tertiles

Risk Prediction Model for Skin Cancers in Cardiac Transplant Patients: A UNOS Database Analysis

<h3>Purpose</h3> Post-transplant patients are at increased risk for cancers of the skin. This study attempts to generate a risk prediction model using the UNOS database population. <h3>Methods</h3> Of the 24,735 adults (age 18 years and above) heart transplant recipients between 2000 and 2015 in the UNOS database 2,625 recipients developed skin cancer. Uni- and multi-variate Cox regression analysis were performed to assess the association of different risk factors with post-transplant skin cancer, and p-values, hazard ratios and their confidence intervals derived. . Variables in the univariate analysis were selected as inputs to the multivariate analysis. Stepwise forward selection was conducted to select the final multivariate model. The multivariate model was used to predict the probability of developing skin cancer in 5, 8, and 10 years after heart transplantation. The model accuracy was assessed using Receiver Operating Characteristics (ROC) curves and Area Under Curves (AUCs). All the analysis was performed using MATLAB software from the MathWorks, Inc. <h3>Results</h3> Multivariate analysis showed that whites had an OR of 35.5 as compared to blacks (p=0.001). Males had an OR of 2.79 (p=0.001). Malignancy at listing showed an OR of 1.73 (p=0.001) while malignancy at transplant showed an OR of 2.42 (p=0.001). OKT3 had an OR of 1.54 (p=0.001) as compared to other induction agents The ROC curves generated using these risk factors showed AUC at 5, 8 and 10 years post-transplant of 0.78, 0.78, 0.77 respectively in the training set and 0.77, 0.76, 0.75 respectively in the validation set (figure 1). <h3>Conclusion</h3> Male sex, white race, malignancy at the time of listing or at transplantation and OKT3 induction are major risk factors for skin cancers post transplantation. The risk prediction model generated for the first time for skin cancers in the post-cardiac transplant patients has a c-statistic of 0.75.

Pregnancy in a post-cardiac transplant patient

Pregnancy in a post-cardiac transplant patient

Utilization of PCSK-9 Inhibitors in Statin Intolerant Cardiac Transplant Patients

Background HMG CoA Reductase Inhibitors, commonly referred to as statins, are widely used in heart transplant patients as dyslipidemia is common after cardiac transplantation and increases the risk of cardiovascular adverse events including cardiac allograft vasculopathy (CAV). However, not all patients can tolerate statins or see an adequate lowering of the low density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors have been shown to be effective at lowering LDL with great tolerance and excellent safety profiles in the general population. Yet, there is limited data regarding effect of PCSK9 inhibitors in heart transplant patients. Objective To study the effect of PSCK-9 inhibitors in post-cardiac transplant patients. Method We reviewed post heart transplant patients who received PCSK9 inhibitors at our University Medical Center from 2017 to March 2020. We found four patients who were eligible. Results The mean age of the four patients was 65.75± 4.7 years (3 Females). Indication for PCSK9 inhibitors in three patients was statin intolerance due to myopathy; the fourth patient had familial hypercholesterolemia that required more aggressive therapy. Average time for initiation of the medication since heart transplant was 10.25 years. The average duration of treatment was 18.25 months. Two patients were on Evolocumab 140mg subcutaneously once every 2 weeks, and the other two were on Alirocumab 75mg every 2 weeks. All four patients continued the medicine with no side effects. Mean LDL-C prior to initiation of the drug was 125.75± 24.42 mg/dL. At 8-12 week follow up there was significant reduction in the LDL 35.75 ±13.74mg/dL (p=0.006).There was no significant dose changes to the immunosuppressive medications. None of the four patients experienced rejection of the transplanted heart. Only one patient with familial hypercholesterolemia had mild CAV on heart catheterization prior to initiation of the drug and there was no progression of the CAV at one year follow up. Conclusion PCSK9-inhibitors were effective in reducing low-density lipoprotein levels in post-cardiac transplant patients and were well tolerated without any rejection or modifications to the transplant medications in this small cohort of patients. The study findings are promising and highlight the need for larger, prospective, multicenter studies.

Arrhythmias and sudden cardiac death in post-cardiac transplant patients.

Orthotopic heart transplantation (OHT) significantly improves morbidity and mortality in patients with end-stage heart disease. Despite advances in surgical technique, immunosuppressive therapies, and patient monitoring, long-term risk of arrhythmias and sudden cardiac death (SCD) in the denervated heart remains unchanged. SCD is responsible for approximately 10% of all posttransplant deaths with a pooled incidence rate of 1.30 per 100 person years and is strongly associated with cardiac allograft vasculopathy (CAV). Risk factors for SCD and CAV include higher donor age, younger recipient age, and reduced left ventricular ejection fraction. Little is known about the time course between CAV and SCD. Although some registry data establish ventricular fibrillation as a documented terminal rhythm, the arrhythmia may not be the mechanism of SCD. In this review, we identify risk factors and general independent predictors of arrhythmia and SCD and discuss the utility of implantable cardiac defibrillators in post-cardiac transplant patients.

Risk Prediction Model for Cutaneous SCC in Cardiac Allograft Recipients

Post-transplant patients are at increased risk for squamous cell carcinoma (SCC) of the skin, secondary to long-term immunosuppression. This study was undertaken to identify risk factors using the UNOS database population. The study population of 1766 patients derived from the UNOS database (2000-2015) was divided into two equal groups. One group was used for testing and the other for validation. Descriptive statistics were used to characterize the study cohort. Cox's proportional hazards regression was used to investigate the effect of different risk factors for SCC post-heart transplantation. Multivariate analysis was used to test the correlation between SCC and potential risk factors. Hazard ratio (OR) and the 95% confidence interval (CI) were calculated for each risk factor. Statistical significance was set at p< 0.05. Forward sequential feature selection was done to select significant risk factors for multivariate modeling. The multivariate model was used to predict the risk of SCC at 5, 8 and 10 years post-transplant. Analyses were performed using MATLAB software from The Math Works, Inc. Receiver Operating Curves (ROCs) were generated to derive Area Under the Curve (AUC) to assess the quality of the prediction model. Multivariate analysis showed that Black, Hispanic and other races as compared to whites had an OR of 0.07,0.35, 0.17 (p=0.0000). Recipient PRAs had an OR of 0.97 (p=<0.0001). Age >60 years had an OR of 2.5 (p=0.0000). Males had an OR of 2.05 (p=0.000). The ROC curves generated showed AUC at 5, 8 and 10 years post-transplant of 0.76, 0.76, 0.76 respectively in the testing set and 0.79, 0.77, 0.78 respectively in the validation set (figure 1). Male sex, white race, age >60 years higher PRAs are major risk factors for SCC. The risk prediction model generated for the first time for SCC in post-cardiac transplant patients has a robust c-statistic of >0.75. This is important for risk stratification as SCC is the most common skin cancer seen in the post-cardiac transplant population.

Intravascular Imaging for Assessment of Cardiac Allograft Vasculopathy Following Heart Transplantation

Cardiac allograft vasculopathy (CAV) is a significant cause of morbidity and mortality in the post-cardiac transplant patient population. Current guidelines recommend annual angiographic surveillance for CAV; however, angiography alone has several limitations and can lead to systematic underestimation of disease burden and the inability to sensitively track disease progression. We provide an overview of intravascular imaging in the initial and longitudinal evaluation of CAV, with a focus on the use of intravascular ultrasound (IVUS). Multiple studies have demonstrated that progression of maximal intimal thickness (MIT) on serial IVUS evaluation, particularly ≥ 0.5 mm over the first year, post-transplant, is predictive of both future development of angiographically significant CAV as well as major adverse cardiac events, including graft loss and mortality. There are also emerging data that in vivo plaque characterization, as assessed by the attenuated-signal plaque score or by virtual histology intravascular ultrasound (VH-IVUS), may provide prognostic value in this population. OCT-derived intimal measurements have been noted to correlate well with IVUS findings and may also aid in early identification of CAV. In addition to early identification and prognostication, several studies have used intravascular imaging to assess therapeutic impact of various immunosuppressive regimens on progression of established CAV. Intravascular ultrasound, and more recently, optical coherence tomography (OCT) have emerged as valuable adjuncts to angiography in the evaluation of CAV, particularly with regard to early detection, objective prognostication, and differentiation of CAV from donor-derived coronary artery disease (CAD). Furthermore, intravascular imaging may guide changes to the immunosuppressive regimen and/or percutaneous coronary intervention, when necessary.

Successful Pregnancy and Delivery Following Two Heart Transplantations

The number of post cardiac transplant patients desiring and achieving pregnancy continues to grow as more of these patients reach reproductive age.

The Safety of Neuromuscular Blockade Reversal in Patients With Cardiac Transplantation.

Neuromuscular blockade (NMB) reversal with neostigmine and glycopyrrolate has been reported to cause cardiac arrest in patients with a history of cardiac transplantation. The purpose of this study was to examine the safety of NMB reversal with acetylcholinesterase inhibitors and muscarinic anticholinergics in these patients. We queried the medical records of a large tertiary referral center for patients with a history of prior heart transplantation who underwent anesthesia including receipt of NMB reversal. Patient records were reviewed to investigate maximal decrease in heart rate (HR) after NMB reversal and incidence of death and cardiac arrest. Seventy-seven heart transplant patients underwent 118 subsequent anesthetics during which they received neostigmine and glycopyrrolate for NMB reversal. No patients had active pacemakers at the time of their anesthetics. Mean time from heart transplantation to NMB reversal was 2.9 ± 3.2 (median, 1.9; range, 0.01- 12.5) years. After NMB reversal, no patients received atropine or epinephrine, suffered cardiac arrest, or died within 30 days. Mean HR decrease, defined as the difference between the HR immediately before NMB reversal and the lowest HR within 5 minutes thereafter, after NMB reversal was 0.5 ± 3.2 with median 0 (range, -8 to 17) beats per minute. Mean HR decrease was not associated with transplantation type (biatrial versus bicaval, P = 0.2029) or with increasing duration of time from cardiac transplantation (P = 0.0874). Although rare cases of cardiac arrest after NMB reversal have been reported, our experience would support the safety of neostigmine and glycopyrrolate in cardiac transplantation patients.

Impact of Statin Use After Heart Transplantation: A Meta-Analysis.

Although various studies revealed the beneficial effects of statins in post-cardiac transplant patients, these were relatively small and low-powered studies. We performed a meta-analysis of published studies to evaluate the role of statins in post-cardiac transplant patients, specifically examining the effects on hemodynamically significant/fatal graft rejection, coronary vasculopathy, terminal cancer, and overall survival. We searched PubMed, Cochran CENTRAL, and Web of Science databases using the search terms "cardiac transplant" or "heart transplant," and "statin" for a literature search. A random-effects model with Mantel-Haenszel method was used to pool the data. We identified 10 studies, 4 randomized controlled trials, and 6 nonrandomized studies, which compared outcomes in heart transplant recipients undergoing statin therapy to statin-naive patients. A pooled analysis of 9 studies reporting mortality revealed that the use of statins was associated with significant reduction in all-cause mortality (odds ratio, 0.26; 95% confidence interval, 0.20-0.35; P<0.0001). Statins also decreased the odds of hemodynamically significant/fatal rejection (odds ratio, 0.37; 95% confidence interval, 0.21-0.65; P=0.0005), incidence of coronary vasculopathy (odds ratio, 0.33; 95% confidence interval, 0.16-0.68; P=0.003), and terminal cancer (odds ratio, 0.30; 95% confidence interval, 0.15-0.63; P=0.002). The evidence from a pooled analysis suggests that statins improve survival in heart transplant recipients. Statins may prevent fatal rejection episodes, decrease terminal cancer risk, and reduce the incidence of coronary vasculopathy. Additional prospective studies are needed to further investigate and explain this association.

In Post-Cardiac Transplant Patients, Weight Loss with a Plant-Based Diet Compares Favorably to Weight Loss with Usual Care and is Safe: A Pilot Study

In Post-Cardiac Transplant Patients, Weight Loss with a Plant-Based Diet Compares Favorably to Weight Loss with Usual Care and is Safe: A Pilot Study Objective: Weight gain after cardiac transplantation is common. A whole-food plant-based (WFPB) diet may result in weight loss in post-cardiac transplant patients. Methods: Four patients at least six months post-cardiac transplantation were encouraged to adopt a WFPB diet. Twentynine consecutive post-cardiac transplant patients undergoing standard care were the comparator group. The primary endpoint was the percentage of patients who lost ten or more pounds in each group. Results: Three of the 4 (75%) patients who at least partially adopted (>50%) the WFPB diet lost ten or more pounds compared with 7 of 29 (24%) usual care patients (p=0.07). Among patients losing any weight, the median percent weight loss was 9.0% for the WFPB group (n=3) vs. 5.3% for the usual care group (n=13), (p=0.16). No complications due to diet occurred. Conclusion and Implications: A WFPB diet was safe and may facilitate weight loss for patients at least six months post cardiactransplantation. Further study is suggested.

Constrictive Pericarditis in a Post Cardiac Transplant Patient

Constrictive pericarditis (CP) is a rare but significant complication in the post cardiac transplant patient and clinically presents as progressive heart failure. CP is defined as an inflammatory condition in which the heart is encased in a rigid non-pliable pericardium resulting in restricted diastolic filling. Generally, the risk factors associated with developing this include pericardial effusion post transplant, infections and acute rejection. Here we describe a case of CP in a post cardiac transplant patient without obvious risk factors.

Management of pregnancy in the post-cardiac transplant patient

Over the past 10 years, heart transplantation survival has increased among transplant recipients. Because of improved outcomes in both congenital and adult transplant recipients, the number of male and female patients of childbearing age who desire pregnancy has also increased within this population. While there have been many successful pregnancies in post-cardiac transplant patients reported in the literature, long-term outcome data is limited. Decisions regarding the optimal timing and management of pregnancy in male and female post-cardiac transplant patients are challenging and should be coordinated by a multidisciplinary team of healthcare providers. Pregnant patients will need to be counseled and monitored carefully for complications including rejection, graft dysfunction, and infection. This review focuses on preconception counseling for both male and female cardiac transplant recipients. The maternal and fetal risks during pregnancy and the postpartum period, including risks to the fetus fathered by a male cardiac transplant recipient will be reviewed. It also provides a brief summary of our own transplant experience and recommendations for overall management of pregnancy in the post-cardiac transplant recipient.

Abstract 18729: Serum Heat Shock Protein-70 is Associated With Decreased Frequency and Severity of Cellular Rejection in Cardiac Transplant Patients

Background: Heat Shock Protein-70 (HSP70) is a highly conserved intracellular protein that is up-regulated in cells undergoing stressful stimuli. A recent study demonstrated an inverse relationship between HSP70 expression and cellular rejection grade in endomyocardial biopsies (EBx)from cardiac transplant patients. Peripheral blood based HSP70 levels have not been studied in such individuals. We hypothesized that serum HSP70 levels will be associated with severity of cellular rejection in cardiac transplant patients. Methods: 177 cardiac transplant patients (56 ± 13 years; 8.5 ± 5 years mean time from transplant) were recruited from the Emory Cardiovascular Biobank from 2004-2012. Cellular rejection was defined based on revised International Society of Heart and Lung Transplant (ISHLT) grade of 1R or higher seen on EBx. Frequency of rejection was collected from time of transplant to enrollment date. Serum HSP70 was measured using ELISA and analyzed as detectable vs non-detectable. Nonparametric correlations and ANOVA were used to study univariate relationships while linear and ordinal logistic regression (adjusted for age, gender, race, length of time since transplant, and immunosuppressant medications) were performed to analyze the relationship between HSP70 levels and frequency and severity of cellular rejection respectively. Results: HSP70 was detectable in 35% of patients with grade 0R ISHLT class, 33% for grade 1R, 16% for Grade 2R, 0% for Grade 3R (p for group=0.005). There was an inverse correlation between HSP70 and frequency of rejection (r= -0.2, p= 0.03) with 34% of those with detectable HSP70 in the lowest quintile based on frequency of rejection whereas 9% was detected in the highest quintile (p=0.019). In adjusted regression models, HSP70 remained a significant independent predictor of a) ISHLT class with an OR of 0.43 (p=0.02) and b) frequency of rejection (β=-1.5, p=0.05). Conclusion: Detectable serum HSP70 is associated with decreased frequency and severity of cellular rejection in post cardiac transplant patients. The utility of HSP70 as a marker of graft function needs further study.

Exercise, Vascular Health, and Abdominal Aortic Aneurysms

Exercise, Vascular Health, and Abdominal Aortic Aneurysms

Donor transmitted left atrial myxoma 13 years after heart transplantation

Left atrial cardiac myxomas are among the most common cardiac masses. However, occurrence of left atrial myxomas in post-transplant patients is very rare and often misdiagnosed as left atrial thrombus formation. We report the case of a 67-year old female, who was referred due to suspected left atrial thrombus but was found to have a pediculated mass at the suture line of the left atrium on cardiac MRI. After resection, the diagnosis myxoma was confirmed histologically and the donor origin of the myxoma was proven by tissue typing. Despite a rare entity, atrial myxomas may occur in post cardiac transplant patients and may therefore support the role of advanced imaging techniques in patients with suspected left atrial masses.

XDx, Inc.

XDx, Inc. is a molecular diagnostics company focused on the discovery, development and commercialization of noninvasive gene expression-based tests for the monitoring of transplant rejection and autoimmune diseases. The company has developed a proprietary new method for noninvasively monitoring immune system activity by measuring gene expression in a patient's peripheral blood. This work is the basis for AlloMap® molecular expression testing, which provides transplant physicians with a new tool to aid in the identification of the probability of acute cellular rejection for postcardiac transplant patient management. Some of the AlloMap molecular expression technology developed and implemented by XDx in heart transplant patient management may be applicable to other diseases that involve transplant rejection and the immune system.

Modified RV Short Axis Series—A New Method for Cardiac MRI Measurement of Right Ventricular Volumes

The current standard image orientation employed in the MRI assessment of right ventricular volumes uses a series of short axis cine acquisitions located with respect to a horizontal long axis view with the first slice placed across the atrio-ventricular valve plane at end diastole. Inherent inaccuracies are encountered with the use of this image orientation due to difficulty in defining the tricuspid valve and the border between atrium and ventricle on the resultant images. Our experience indicates that because the tricuspid valve is usually not in-plane in the slice the atrio-ventricular margin is difficult to distinguish. This leads to inaccuracies in measurements at the base of the RV and miscalculation of the RV volume. The purpose of this study was to assess an alternative method of image orientation aimed at increasing the accuracy of RV volume measurements using current commercially available CMRI sequences. This technique, the modified RV short axis series, is oriented to the outflow tract of the right ventricle. We undertook a prospective study of 50 post cardiac transplant patients. A series of LV short axis multi-slice cine acquisition FIESTA images was acquired using the current standard technique. From this data set, LV and RV stroke volumes were derived on an Advantage Windows workstation using planimetry of the endocardial and epicardial borders in end systole and end diastole. Our new technique involved obtaining a set of multi-slice cine acquisition FIESTA images in a plane perpendicular to a line from the centre of the pulmonary valve to the apex of the RV. Planimetry of the RV was then performed and a stroke volume calculated using the same method of analysis. RV stroke volumes obtained from both techniques were compared with LV stroke volumes. Three operators independently derived RV data sets. On the images acquired with the new technique, the tricuspid valve was easier to define leading to more accurate and reproducible planimetry of ventricular borders. RV stroke volumes calculated from the new method showed better agreement with LV stroke volumes than with the current method. These results were consistent across the three operators. This new method improves visualisation of the tricuspid valve and makes analysis easier and less prone to operator error than the current standard technique for MRI assessment of RV volumes.