Screening for peripartum cardiomyopathies using artificial intelligence in Nigeria (SPEC-AI Nigeria): Clinical trial rationale and design.

BACKGROUND: Artificial intelligence (AI), and more specifically deep learning, models have demonstrated the potential to augment physician diagnostic capabilities and improve cardiovascular health if incorporated into routine clinical practice. However, many of these tools are yet to be evaluated prospectively in the setting of a rigorous clinical trial-a critical step prior to implementing broadly in routine clinical practice. OBJECTIVES: To describe the rationale and design of a proposed clinical trial aimed at evaluating an AI-enabled electrocardiogram (AI-ECG) for cardiomyopathy detection in an obstetric population in Nigeria. DESIGN: The protocol will enroll 1,000 pregnant and postpartum women who reside in Nigeria in a prospective randomized clinical trial. Nigeria has the highest reported incidence of peripartum cardiomyopathy worldwide. Women aged 18 and older, seen for routine obstetric care at 6 sites (2 Northern and 4 Southern) in Nigeria will be included. Participants will be randomized to the study intervention or control arm in a 1:1 fashion. This study aims to enroll participants representative of the general obstetric population at each site. The primary outcome is a new diagnosis of cardiomyopathy, defined as left ventricular ejection fraction (LVEF) < 50% during pregnancy or within 12 months postpartum. Secondary outcomes will include the detection of impaired left ventricular function (at different LVEF cut-offs), and exploratory outcomes will include the effectiveness of AI-ECG tools for cardiomyopathy detection, new diagnosis of cardiovascular disease, and the development of composite adverse maternal cardiovascular outcomes. SUMMARY: This clinical trial focuses on the emerging field of cardio-obstetrics and will serve as foundational data for the use of AI-ECG tools in an obstetric population in Nigeria. This study will gather essential data regarding the utility of the AI-ECG for cardiomyopathy detection in a predominantly Black population of women and pave the way for clinical implementation of these models in routine practice. TRIAL REGISTRATION: Clinicaltrials.gov: NCT05438576.

Sex differences in left-ventricular strain in a murine model of coxsackievirus B3 myocarditis.

Myocarditis is typically caused by viral infections, but most cases are thought to be subclinical. Echocardiography is often used for initial assessment of myocarditis patients but is poor at detecting subtle changes in cardiac dysfunction. Cardiac strain, such as global longitudinal strain (GLS) and global circumferential strain (GCS), represents an increasingly used set of measurements which can detect these subtle changes. Using a murine model of coxsackievirus B3 myocarditis, we characterized functional changes in the heart using echocardiography during myocarditis and by sex. We found that 2D GLS, 4D mode, and 4D strains detected a significant reduction in ejection fraction and GLS during myocarditis compared to baseline and in males compared to females. Furthermore, worse GLS correlated to increased levels of CD45+, CD11b+, and CD3+ immune cells. Our findings closely resemble published reports of GLS in patients with myocarditis indicating the usefulness of this animal model for translational studies of myocarditis.

Characteristics, Treatment Patterns, and Clinical Outcomes After Heart Failure Hospitalizations During the COVID-19 Pandemic, March to October 2020.

OBJECTIVE: To compare clinical characteristics, treatment patterns, and 30-day all-cause readmission and mortality between patients hospitalized for heart failure (HF) before and during the coronavirus disease 2019 (COVID-19) pandemic. PATIENTS AND METHODS: The study was conducted at 16 hospitals across 3 geographically dispersed US states. The study included 6769 adults (mean age, 74 years; 56% [5033 of 8989] men) with cumulative 8989 HF hospitalizations: 2341 hospitalizations during the COVID-19 pandemic (March 1 through October 30, 2020) and 6648 in the pre-COVID-19 (October 1, 2018, through February 28, 2020) comparator group. We used Poisson regression, Kaplan-Meier estimates, multivariable logistic, and Cox regression analysis to determine whether prespecified study outcomes varied by time frames. RESULTS: The adjusted 30-day readmission rate decreased from 13.1% (872 of 6648) in the pre-COVID-19 period to 10.0% (234 of 2341) in the COVID-19 pandemic period (relative risk reduction, 23%; hazard ratio, 0.77; 95% CI, 0.66 to 0.89). Conversely, all-cause mortality increased from 9.7% (645 of 6648) in the pre-COVID-19 period to 11.3% (264 of 2341) in the COVID-19 pandemic period (relative risk increase, 16%; number of admissions needed for one additional death, 62.5; hazard ratio, 1.19; 95% CI, 1.02 to 1.39). Despite significant differences in rates of index hospitalization, readmission, and mortality across the study time frames, the disease severity, HF subtypes, and treatment patterns remained unchanged (P>0.05). CONCLUSION: The findings of this large tristate multicenter cohort study of HF hospitalizations suggest lower rates of index hospitalizations and 30-day readmissions but higher incidence of 30-day mortality with broadly similar use of HF medication, surgical interventions, and devices during the COVID-19 pandemic compared with the pre-COVID-19 time frame.

Non-invasive detection of cardiac allograft rejection among heart transplant recipients using an electrocardiogram based deep learning model.

Aims: Current non-invasive screening methods for cardiac allograft rejection have shown limited discrimination and are yet to be broadly integrated into heart transplant care. Given electrocardiogram (ECG) changes have been reported with severe cardiac allograft rejection, this study aimed to develop a deep-learning model, a form of artificial intelligence, to detect allograft rejection using the 12-lead ECG (AI-ECG). Methods and results: Heart transplant recipients were identified across three Mayo Clinic sites between 1998 and 2021. Twelve-lead digital ECG data and endomyocardial biopsy results were extracted from medical records. Allograft rejection was defined as moderate or severe acute cellular rejection (ACR) based on International Society for Heart and Lung Transplantation guidelines. The extracted data (7590 unique ECG-biopsy pairs, belonging to 1427 patients) was partitioned into training (80%), validation (10%), and test sets (10%) such that each patient was included in only one partition. Model performance metrics were based on the test set (n = 140 patients; 758 ECG-biopsy pairs). The AI-ECG detected ACR with an area under the receiver operating curve (AUC) of 0.84 [95% confidence interval (CI): 0.78-0.90] and 95% (19/20; 95% CI: 75-100%) sensitivity. A prospective proof-of-concept screening study (n = 56; 97 ECG-biopsy pairs) showed the AI-ECG detected ACR with AUC = 0.78 (95% CI: 0.61-0.96) and 100% (2/2; 95% CI: 16-100%) sensitivity. Conclusion: An AI-ECG model is effective for detection of moderate-to-severe ACR in heart transplant recipients. Our findings could improve transplant care by providing a rapid, non-invasive, and potentially remote screening option for cardiac allograft function.

Clinical Characteristics of Patients with Myocarditis following COVID-19 mRNA Vaccination: A Systematic Review and Meta-Analysis.

COVID-19 mRNA vaccinations have recently been implicated in causing myocarditis. Therefore, the primary aim of this systematic review and meta-analysis was to investigate the clinical characteristics of patients with myocarditis following mRNA vaccination. The secondary aims were to report common imaging and laboratory findings, as well as treatment regimes, in these patients. A literature search was performed from December 2019 to June 2022. Eligible studies reported patients older than 18 years vaccinated with mRNA, a diagnosis of myocarditis, and subsequent outcomes. Pooled mean or proportion were analyzed using a random-effects model. Seventy-five unique studies (patient n = 188, 89.4% male, mean age 18-67 years) were included. Eighty-six patients had Moderna vaccines while one hundred and two patients had Pfizer-BioNTech vaccines. The most common presenting symptoms were chest pain (34.5%), fever (17.1%), myalgia (12.4%), and chills (12.1%). The most common radiologic findings were ST-related changes on an electrocardiogram (58.7%) and hypokinesia on cardiac magnetic resonance imaging or echocardiography (50.7%). Laboratory findings included elevated Troponin I levels (81.7%) and elevated C-reactive protein (71.5%). Seven patients were admitted to the intensive care unit. The most common treatment modality was non-steroid anti-inflammatory drugs (36.6%) followed by colchicine (28.5%). This meta-analysis presents novel evidence to suggest possible myocarditis post mRNA vaccination in certain individuals, especially young male patients. Clinical practice must therefore take appropriate pre-cautionary measures when administrating COVID-19 mRNA vaccinations.

Upregulation of Endothelin-1 May Predict Chemotherapy-Induced Cardiotoxicity in Women with Breast Cancer.

As survival in breast cancer patients from newer therapies increases, concerns for chemotherapy-induced cardiotoxicity (CIC) have offset some of these benefits, manifesting as a decline in left ventricular ejection fraction (LVEF). Patients receiving anthracycline-based chemotherapy followed by trastuzumab are at risk for CIC. Previous research evaluating whether clinical biomarkers predict cardiotoxicity has been inconsistent. Recently, angiotensin II type 1 receptor (ATR1) and endothelin 1 (ET1) have been shown to play a role in breast tumor growth. We evaluated ATR1 and ET1 expression in breast cancer tissue and its association with CIC. A total of 33 paraffin-embedded breast tissue specimens from women with breast cancer treated with anthracycline-based chemotherapy and trastuzumab were analyzed by immunohistochemistry (IHC) and qRT-PCR. We found that ET1 expression was increased in patients with an LVEF ≤ 50% (p = 0.032) with a lower LVEF correlating with higher ET1 expression (r = 0.377, p = 0.031). In patients with a change in LVEF of greater than 10%, greater ET1 expression was noted compared to those without a change in LVEF (p = 0.017). Increased ET1 expression in breast tumor tissue is associated with reduced LVEF. Future studies need to examine whether ET1 may be a tissue biomarker that helps predict the risk of developing CIC in women with breast cancer.

Sex Differences in the Impact of Aortic Valve Calcium Score on Mortality After Transcatheter Aortic Valve Replacement.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is now an approved alternative to surgical aortic valve replacement for the treatment of severe aortic stenosis. As the clinical adoption of TAVR expands, it remains important to identify predictors of mortality after TAVR. We aimed to evaluate the impact of sex differences in aortic valve calcium score (AVCS) on long-term mortality following TAVR in a large patient sample. METHODS: We included consecutive patients who successfully underwent TAVR for treatment of severe native aortic valve stenosis from June 2010 to May 2021 across all US Mayo Clinic sites with follow-up through July 2021. AVCS values were obtained from preoperative computed tomography of the chest. Additional clinical data were abstracted from medical records. Kaplan-Meier curves and Cox-proportional hazard regression models were employed to evaluate the effect of AVCS on long-term mortality. RESULTS: A total of 2543 patients were evaluated in the final analysis. Forty-one percent were women, median age was 82 years (Q1: 76, Q3: 86), 18.4% received a permanent pacemaker following TAVR, and 88.5% received a balloon expandable valve. We demonstrate an increase in mortality risk with higher AVCS after multivariable adjustment (P<0.001). When stratified by sex, every 500-unit increase in AVCS was associated with a 7% increase in mortality risk among women (adjusted hazard ratio, 1.07 [95% CI, 1.02-1.12]) but not in men. CONCLUSIONS: We demonstrate a notable sex difference in the association between AVCS and long-term mortality in a large TAVR patient sample. This study highlights the potential value of AVCS in preprocedural risk stratification, specifically among women undergoing TAVR. Additional studies are needed to validate this finding.

Detecting cardiomyopathies in pregnancy and the postpartum period with an electrocardiogram-based deep learning model.

AIMS: Cardiovascular disease is a major threat to maternal health, with cardiomyopathy being among the most common acquired cardiovascular diseases during pregnancy and the postpartum period. The aim of our study was to evaluate the effectiveness of an electrocardiogram (ECG)-based deep learning model in identifying cardiomyopathy during pregnancy and the postpartum period. METHODS AND RESULTS: We used an ECG-based deep learning model to detect cardiomyopathy in a cohort of women who were pregnant or in the postpartum period seen at Mayo Clinic. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, and specificity. We compared the diagnostic probabilities of the deep learning model with natriuretic peptides and a multivariable model consisting of demographic and clinical parameters. The study cohort included 1807 women; 7%, 10%, and 13% had left ventricular ejection fraction (LVEF) of 35% or less, <45%, and <50%, respectively. The ECG-based deep learning model identified cardiomyopathy with AUCs of 0.92 (LVEF ≤ 35%), 0.89 (LVEF < 45%), and 0.87 (LVEF < 50%). For LVEF of 35% or less, AUC was higher in Black (0.95) and Hispanic (0.98) women compared to White (0.91). Natriuretic peptides and the multivariable model had AUCs of 0.85 to 0.86 and 0.72, respectively. CONCLUSIONS: An ECG-based deep learning model effectively identifies cardiomyopathy during pregnancy and the postpartum period and outperforms natriuretic peptides and traditional clinical parameters with the potential to become a powerful initial screening tool for cardiomyopathy in the obstetric care setting.

Preoperative risk factors for mortality after biventricular assist device implantation.

BACKGROUND: A right ventricular assist device is a treatment option for patients with severe right ventricular failure after left ventricular assist device (LVAD) implantation. Recognition of risk factors for mortality after biventricular assist device (BiVAD) implantation is important for patient selection and optimal outcomes. METHODS: We reviewed our experiences between 1991 and 2005 in 44 patients who were supported by both an LVAD and a right ventricular assist device. RESULTS: Thirteen patients (30%) survived until heart transplantation, and 31 patients (70%) died while on support. The multivariate analysis shows that post-LVAD extracorporeal membrane oxygenation and worsening renal function are associated with the highest postoperative mortality. The univariate analysis also included previous thoracic surgery and ischemic cardiomyopathy as potential preoperative indicators for poor outcome after BiVAD implants. No differences were observed in the rates for the need of preoperative support with a ventilator, an intra-aortic balloon pump, or extracorporeal membrane oxygenation, or in the rates of postoperative complications between survivors and nonsurvivors. CONCLUSIONS: BiVAD implantation remains one of the challenges in treating severe heart failure. Previous cardiac surgery, elevated creatinine, and post-LVAD extracorporeal membrane oxygenation were risk factors for mortality after BiVAD implantation. Dialated Cardiomyopathy on the other hand was associated with a more favorable outcome.

Thymoglobulin induction and steroid avoidance in cardiac transplantation: results of a prospective, randomized, controlled study.

BACKGROUND: Chronic use of corticosteroids (CS) following transplantation is associated with significant long-term morbidities. Minimizing exposure to CS to improve long-term outcomes, without compromising allograft function, remains an important goal in transplantation. OBJECTIVES: This single-center, prospective, randomized, open-label study was designed to evaluate the efficacy of Thymoglobulin as part of a CS-sparing regimen in cardiac transplantation. METHODS: Thirty-two low-risk cardiac transplant patients were randomized in a 1:1 ratio to receive either a Thymoglobulin-based CS-avoidance regimen (CS-avoidance group; n = 16) or a long-term CS-based regimen with no antibody induction (control group; n = 16). Pulse CS therapy was used for the treatment of acute cellular rejection in both groups. RESULTS: Baseline characteristics were similar between groups. At one yr, there was no significant difference in the mean incidence of acute cellular rejection (>or=3A) episodes between the CS-avoidance and control groups, 0.81+/-1.05 and 1.07+/-1.03, respectively. Importantly, the CS-avoidance patients had significant improvement in muscle strength and less bone loss compared with the control patients during the first six months post-transplant. CONCLUSIONS: CS-avoidance regimen with Thymoglobulin induction appeared to be safe and effective in cardiac transplantation. Further studies are required to demonstrate the long-term safety and benefits of such a regimen.

Myocardial degradation and left bundle branch block predict conversion to low ejection fraction in heart failure with preserved systolic function.

The authors prospectively investigated whether left bundle branch block (LBBB) and myocardial degradation as indicated by elevated troponin T (tnT) predict the phenomenon of systolic conversion to low ejection fraction (EF 40%). Thirty consecutive patients with HFPSF were included and followed over a 4-year interval. A follow-up EF assessment was performed in 25 patients. Six of 15 patients with tnT >or=0.01 ng/mL demonstrated systolic conversion to low EF on follow-up, while none of the 10 patients with tnT <0.01 ng/mL experienced this phenomenon (P=.03). Five of the 6 converters presented with LBBB, while only 1 of the 19 nonconverters had this abnormality (P=.0007). Four of the 6 converters had an initial EF >50%. Myocardial degradation and LBBB predicted systolic conversion in HFPSF patients with nonsignificant coronary disease.

Hypogammaglobulinemia and infection risk in solid organ transplant recipients.

PURPOSE OF REVIEW: Hypogammaglobulinemia may develop as a result of a number of immune deficiency syndromes that can be devastating. This review article explores the risk of infection associated with hypogammaglobulinemia in solid organ transplantation and discusses therapeutic strategies to alleviate such a risk. RECENT FINDINGS: Hypogammaglobulinemia is associated with increased risk of opportunistic infections, particularly during the 6-month posttransplant period when viral infections are most prevalent. The preemptive use of immunoglobulin replacement results in a significant reduction of opportunistic infections in patients with moderate and severe hypogammaglobulinemia. SUMMARY: Monitoring immunoglobulin G levels may aid in clinical management of solid organ transplant recipients. The preemptive use of immunoglobulin replacement may serve as a new strategy for managing solid organ transplant recipients with hypogammaglobulinemia.

Heart transplantation: a magnified model of heart-brain interactions.

The human heart transplant model unmasks the heart-brain link as an active process that is clinically demonstrated and confirmed at the tissue level. Further studies are needed to elucidate the relative contribution of each of these isolated observations to the pathogenesis of coronary allograft vasculopathy, which remains enigmatic. Recent studies have suggested that mTOR inhibitors may have the ability to attenuate this lethal process that limits the long-term survival of cardiac transplant recipients. The observations we have discussed here suggest that other targeted therapies, including glycoprotein IIb/IIIa inhibitors, tissue metalloproteinase inhibitors, and angiotensin receptor blockers, may facilitate the attenuation of cardiac transplant vasculopathy, but clinical trials are difficult to conduct in this relatively small population of patients. These observations may shed insight, however, into the pathophysiology of hypertension and its impact on the vascular system, as cardiac transplantation provides a setting in which heart-brain interactions are magnified and the pathophysiology occurs over years rather than decades.

Is digoxin a drug of the past?

Digoxin has been the cornerstone of the treatment of heart failure for more than 2 centuries. Now that newer therapies have been introduced that reduce the mortality rate in heart failure and recent trials have failed to prove the same for digoxin, its use has significantly decreased. But a careful review of the multiple pharmacologic actions of digoxin and closer analysis of the results of recent trials suggest that digoxin may in fact continue to be an effective treatment for heart failure.

Myocardial ischemic injury after heart transplantation is associated with upregulation of vitronectin receptor (alpha(v)beta3), activation of the matrix metalloproteinase induction system, and subsequent development of coronary vasculopathy.

BACKGROUND: Myocardial ischemic injury after heart transplantation is associated with subsequent development of graft vasculopathy. Both vitronectin receptor (integrin alpha(v)beta3) and tissue factor play key roles in vascular endothelial cell injury. Matrix metalloproteinases (MMPs) are activated in ischemic injury models. METHODS AND RESULTS: Thirteen patients developed myocardial ischemic injury within 2 weeks of cardiac transplantation (ischemia group). These were compared with 10 transplantation patients who had no evidence of ischemia (control group). Endomyocardial biopsies were evaluated within 2 weeks of transplantation for alpha(v)beta3, tissue factor, and extracellular MMP inducer (EMMPRIN). At 1 year, MMPs were evaluated, and interstitial myocardial fibrosis was quantified. All patients underwent intravascular ultrasound at 1 month and 1 year after transplantation. Compared with control, the ischemia group demonstrated evidence of significant increased expression of alpha(v)beta3 (3.2-fold, P<0.001), tissue factor (2.5-fold, P<0.001), and EMMPRIN (1.9-fold, P=0.01). At 1 year, the ischemia group had a significant increase in myocardial fibrosis (24+/-1.8% versus 14+/-1.1%, P<0.001) and zymographic activity of MMP-2 (1.4-fold, P<0.001), MMP-3 (1.2-fold, P<0.001), and MMP-9 (1.3-fold, P=0.01). Coronary vasculopathy progression was also more advanced in the ischemia group (change in coronary maximal intimal thickness over 1 year 0.54+/-0.1 versus 0.26+/-0.06 mm; P=0.031). CONCLUSIONS: Myocardial ischemic injury after cardiac transplantation is associated with upregulation of alpha(v)beta3, tissue factor, and activation of the MMP induction system, which may contribute to the subsequent development of allograft remodeling and vasculopathy.

Donor spontaneous intracerebral hemorrhage is associated with systemic activation of matrix metalloproteinase-2 and matrix metalloproteinase-9 and subsequent development of coronary vasculopathy in the heart transplant recipient.

BACKGROUND: Matrix metalloproteinase (MMP)-2 and MMP-9 have been shown to play a role in the progression of hemorrhagic stroke. We hypothesized that donor intracerebral hemorrhage (ICH) is associated with activation of the metalloproteinases before transplantation that play a key role in the subsequent development of transplant vasculopathy. METHODS AND RESULTS: We evaluated mRNA expressions of MMP-2 and MMP-9 in donor spleen lymphocytes (before transplantation) and in heart biopsies at 1 week after transplantation in 20 recipients from ICH donors and 20 recipients from trauma donors. Patients underwent serial coronary intravascular ultrasound, and interstitial myocardial fibrosis was quantified at 1 year. The baseline characteristics were similar except for increased donor age in the ICH group. Heart biopsies from the ICH group showed significant increased expression of MMP-2 (17-fold, P<0.0001) and MMP-9 (20-fold, P<0.0001) compared with the trauma group. Furthermore, the ICH group showed 1.8-fold (P=0.016) increased mRNA expression of MMP-2 and 1.7-fold (P=0.015) increased mRNA expression of MMP-9 in the donor spleen lymphocytes, suggesting the presence of systemic activation of metalloproteinases before transplantation. At 1 year, the ICH group showed increased myocardial fibrosis and accelerated coronary vasculopathy. Using multivariate regression analysis, MMP-9 was found to be associated with increased risk for vasculopathy independent of donor age (OR, 2.41; P=0.01; 95% CI, 1.24 to 4.69). CONCLUSIONS: This is the first report to describe systemic activation of MMP-2 and MMP-9 in donors with intracerebral hemorrhage and subsequent development of allograft vasculopathy.

Patterns of myocardial endothelin-1 expression and outcome after cardiac transplantation.

BACKGROUND: Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy. METHODS AND RESULTS: Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (P=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P=0.002), lower mean episodes of acute rejection (> or = grade 2) during the first 3 months of transplant (1.09+/-0.66 versus 1.86+/-1.6, P=0.048), and more common vasculopathy at 2 years (50% versus 15%, P=0.02), and they tended to have worse survival (83.2% versus 100%, P=0.058). CONCLUSIONS: Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.

Angiotensin II receptors from peritransplantation through first-year post-transplantation and the risk of transplant coronary artery disease.

OBJECTIVES: We evaluated whether the angiotensin II (Ang II) receptors from perioperation through one-year post-transplantation predict the transplant coronary artery disease (TCAD) progression. BACKGROUND: The role of Ang II receptors (type 1: AT(1)R; type 2: AT(2)R) in TCAD is uncertain. METHODS: We investigated 28 heart donors and the corresponding recipients. The levels of AT(1)R and AT(2)R messenger ribonucleic acid (mRNA) were examined in lymphocytes from the donor spleen and in the donor heart at one-week and one-year posttransplantation to determine their association with the progression of TCAD, measured as changes in maximal intimal thickness (CMIT) and plaque volume (CPV) by intravascular ultrasound (IVUS) examinations. RESULTS: The AT(1)R mRNA in lymphocytes from the donor spleen (CMIT: r = 0.73, p < 0.0001; CPV: r = 0.69, p < 0.0001) and in the donor hearts at one-week (CMIT: r = 0.52, p = 0.005; CPV: r = 0.56, p = 0.002) and at one-year (CMIT: r = 0.63, p < 0.0001; CPV: r = 0.43, p = 0.004) post-transplantation along with AT(2)R mRNA in the donor hearts at one-year post-transplantation (CMIT: r = 0.3, p < 0.0001; CPV: r = 0.53, p = 0.009) were univariate predictors, whereas AT(1)R mRNA in lymphocytes and in the donor hearts at one-year post-transplantation proved to be multivariate predictors of the progression of TCAD. CONCLUSIONS: These data suggest a role for Ang II receptors in the pathogenesis of TCAD and support a novel concept that TCAD may have its origin in the donor per se and may be modulated by the recipient's inherent biological factors.

The role of vitronectin receptor (alphavbeta3) and tissue factor in the pathogenesis of transplant coronary vasculopathy.

OBJECTIVES: This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin alphavbeta3. BACKGROUND: The vitronectin receptor (integrin alphavbeta3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury. METHODS: A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n = 35) or with acute rejection (grade >1A, n = 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and alphavbeta3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis. RESULTS: Patients with CV (n = 24) had increased expression of alphavbeta3 (2.7-fold, p = 0.003) and TF (7.9-fold, p = 0.04) compared with patients without evidence of vasculopathy (n = 8). In the absence of myocardial fibrosis, alphavbeta3 expression correlated significantly with the cellular rejection score (r = 0.58, p = 0.02). CONCLUSIONS: Transplant vasculopathy is associated with increased expression of both TF and alphavbeta3. The significant correlation of alphavbeta3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy.