Inflammatory Burden of Cardiac Allograft Coronary Atherosclerotic Plaque Is Associated With Early Recurrent Cellular Rejection and Predicts a Higher Risk of Vasculopathy Progression

ObjectivesThis study was designed to investigate tissue characterization of the coronary allograft atherosclerotic plaque with virtual histology intravascular ultrasound (VH-IVUS) imaging to assess the presence and predictors of vessel wall inflammation and its significance in cardiac allograft vasculopathy (CAV) progression.BackgroundA unique form of accelerated atherosclerosis, CAV remains the leading cause of late morbidity and mortality in heart transplant patients. The pathogenesis of CAV is not fully elucidated.MethodsA total of 86 patients with coronary allograft vasculopathy underwent VH-IVUS examination of the left anterior descending coronary artery 3.61 ± 3.04 years following cardiac transplantation. Based on the VH-IVUS plaque characteristics, coronary allograft plaque was divided on virtual histology intravascular ultrasound-derived “inflammatory” (VHD-IP) (necrotic core and dense calcium ≥30%) and “noninflammatory” plaque (VHD-NIP) (necrotic core and dense calcium <30%). Total rejection scores were calculated based on the 2004 International Society of Heart and Lung Transplantation rejection grading system.ResultsIn the whole study population, the mean percentage of fibrous, fibrofatty, dense calcified, and necrotic core plaques in a mean length of 62.3 ± 17.4 mm of the left anterior descending coronary artery were 50 ± 17%, 16 ± 11%, 15 ± 11%, and 18 ± 9%, respectively. Patients with a 6-month total rejection score >0.3 had significantly higher incidence of VHD-IP than those with a 6-month total rejection score ≤0.3 (69% vs. 33%, p = 0.011). The presence of VHD-IP at baseline was associated with a significant increase in plaque volume (2.42 ± 1.78 mm3/mm vs. –0.11 ± 1.65 mm3/mm, p = 0.010), plaque index (7 ± 9% vs. 0 ± 8%, p = 0.04), and remodeling index (1.24 ± 0.44 vs. 1.09 ± 0.36, p = 0.030) during 12 months of follow-up when compared with the presence of VHD-NIP at baseline and during follow-up.ConclusionsThe presence of VHD-IP as assessed by VH-IVUS is associated with early recurrent rejection and with higher subsequent progression of CAV. A VH-IVUS assessment may add important information in the evaluation of transplant recipients

Damaging Cardiac and Cancer Genetic Variants in the LVAD Population

Background: Next generation sequencing technology, coupled with population genetic databases, have made broad genetic evaluation relatively inexpensive and widely available. Our objective was to assess the prevalence of potentially damaging cancer and cardiac gene variants in advanced non-ischemic cardiomyopathy patients. Methods: Explanted human heart tissue procured at LVAD placement was obtained from the University of Nebraska Medical Center Heart Tissue Bank. Genomic DNA was isolated from tissues and amplified by PCR using targeted ampliseq primer pools from an inherited disease panel. Individual libraries were amplified by emulsion PCR on Ion Sphere particles and sequencing was performed on a PGM sequencer (Ion torrent) using the Ion 316 chip. The Ion Torrent browser suite was used to map the reads and call the variants. The identified single nucleotide polymorphisms, insertions, and deletions were then annotated and characterized with ANNOVAR. Non-synonymous mutations with a population frequency of less than or equal to 1% were identified and analyzed utilizing an open source integrative genomics viewer. Amino acid substitution effects on protein function were determined by a bioinformatics algorithm. Myocardial recovery was defined as an improvement in EF to greater than 45% at three months post implant. Results: Our sample population included 12 males and 2 females with an average age of 49 and an average EF at presentation of 17%. Damaging cardiac gene variants were present in 11/14 patients. Only 1 of the 11 patients with damaging cardiac gene variants improved their ejection fraction to greater than 45% post LVAD. Two of the 2 patients without mutations improved their ejection fraction to greater than 45%, p-value=.04. Nine of the 14 patients in this population had damaging oncogene mutations. Conclusions: Damaging variants in cancer and cardiac genes are common in end-stage non-ischemic cardiomyopathy patients undergoing LVAD placement. Genetic variation likely contributes to disease progression and cancer risk

Fever of Unknown Origin in Patient after Left Ventricular Assist Device Implantation

Mechanical circulatory support (MCS) is a lifesaving procedure in patients with refractory cardiogenic shock. Despite improvement in surgical techniques, ICU care and restored hemodynamics, some patients on MCS remain severely debilitated due to multiple medical problems, including infections, respiratory failure, de-conditioning and nutritional deficits. Here we present a case of a patient with persistent high degree fever, devastating muscle weakness, and elevated lactate dehydrogenase (LDH) level, who dramatically responded to treatment with vitamin B 12

Lipoprotein-Associated Phospholipase a2 Predicts Progression of Cardiac Allograft Vasculopathy and Increased Risk of Cardiovascular Events in Heart Transplant Patients

BACKGROUND. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for coronary artery disease (CAD) in nontransplant patients. We evaluated the association between Lp-PLA2, cardiac allograft vasculopathy (CAV) assessed by 3D intravascular ultrasound, and incidence of cardiac adverse events in heart transplant recipients. MATERIALS AND METHODS. Fasting blood samples were obtained and stored from a cross-section of 112 cardiac transplant recipients attending the Mayo cardiac transplant clinic in 2000 to 2001, mean of 4.7 years after transplant. Lp-PLA2 was measured in plasma aliquots using an enzyme-linked immunoassay. Fifty-six of these patients subsequently underwent two 3D intravascular ultrasound studies in 2004 to 2006 12 months apart. Cardiovascular (CV) events included percutaneous coronary intervention, coronary artery bypass grafting (CABG), reduction in left ventricular ejection fraction (LVEF) ≤45% secondary to CAV and CV death. RESULTS. High Lp-PLA2 level was associated with increase in plaque volume (r=0.43, P=0.0026) and percent plaque volume (r=0.45, P=0.0004). The association remained significant after adjusting for clinical and lipid variables. During follow-up of 5.1±1.6 years, 24 CV adverse events occurred in 15 of 112 (13%) heart transplant patients. Lp-PLA2 level\u3e236 ng/mL (higher tertile) identified a subgroup of patients having a 2.4-fold increase of relative risk for combined endpoint of CV events (percutaneous coronary intervention, CABG, LVEF\u3c45%, and CV death; 95% CI 1.16-5.19, P=0.012) compared with patients with Lp-PLA2≤236 ng/mL. CONCLUSIONS. Lp-PLA2 is independently associated with progression of CAV and predicts a higher incidence of CV events and CV death in transplant patients. This finding supports the concept that systemic inflammation is an important mediator of CAV. Lp-PLA2 may be a useful marker for risk of CAV and a therapeutic target in posttransplant patients