Orthotopic Heart Transplant Recipient with Enteric-coated Mycophenolate Sodium (Myfortic) Induced Colitis.

BACKGROUND Mycophenolic acid is an immunosuppressive drug commonly used in solid organ transplantation to prevent acute and chronic allograft rejection. There are 2 common preparations of mycophenolic acid including mycophenolate mofetil (Cellcept), and enteric-coated mycophenolate sodium (Myfortic) which was developed to reduce the high rate of gastrointestinal side effects seen with Cellcept. Cases of mycophenolate mofetil induced colitis have been described in solid organ transplant patients and rarely in heart transplant patients, but enteric-coated mycophenolate sodium induced colitis is very rare and has not been reported in heart transplant patients. CASE REPORT A 66-year old male with an orthotopic heart transplant was admitted with diarrhea. The patient was on an immunosuppression regimen including mycophenolate mofetil for 10 weeks post-transplantation until complaining of soft stools and bloating. At this time, he was switched to enteric-coated mycophenolate sodium. At week 11 post-transplantation, the patient was admitted to the hospital with worsening diarrhea. Extensive workup was unrevealing. Colonoscopy with biopsy showed features of mycophenolic acid induced colitis. Enteric coated mycophenolate sodium was discontinued, and the patient's diarrhea markedly improved over the next 48 hours. The patient had no signs of colitis or solid organ rejection at 7-month follow up appointment. CONCLUSIONS Although a diagnosis of exclusion, enteric-coated mycophenolate sodium induced colitis should be considered in the differential of an orthotopic heart transplant patient with diarrhea as discontinuing the medication can improve symptoms and avoid costly workups, however, patients should be monitored closely for signs of rebound rejection.

Increased Cardiac Arrhythmogenesis Associated With Gap Junction Remodeling With Upregulation of RNA-Binding Protein FXR1.

BACKGROUND: Gap junction remodeling is well established as a consistent feature of human heart disease involving spontaneous ventricular arrhythmia. The mechanisms responsible for gap junction remodeling that include alterations in the distribution of, and protein expression within, gap junctions are still debated. Studies reveal that multiple transcriptional and posttranscriptional regulatory pathways are triggered in response to cardiac disease, such as those involving RNA-binding proteins. The expression levels of FXR1 (fragile X mental retardation autosomal homolog 1), an RNA-binding protein, are critical to maintain proper cardiac muscle function; however, the connection between FXR1 and disease is not clear. METHODS: To identify the mechanisms regulating gap junction remodeling in cardiac disease, we sought to identify the functional properties of FXR1 expression, direct targets of FXR1 in human left ventricle dilated cardiomyopathy (DCM) biopsy samples and mouse models of DCM through BioID proximity assay and RNA immunoprecipitation, how FXR1 regulates its targets through RNA stability and luciferase assays, and functional consequences of altering the levels of this important RNA-binding protein through the analysis of cardiac-specific FXR1 knockout mice and mice injected with 3xMyc-FXR1 adeno-associated virus. RESULTS: FXR1 expression is significantly increased in tissue samples from human and mouse models of DCM via Western blot analysis. FXR1 associates with intercalated discs, and integral gap junction proteins Cx43 (connexin 43), Cx45 (connexin 45), and ZO-1 (zonula occludens-1) were identified as novel mRNA targets of FXR1 by using a BioID proximity assay and RNA immunoprecipitation. Our findings show that FXR1 is a multifunctional protein involved in translational regulation and stabilization of its mRNA targets in heart muscle. In addition, introduction of 3xMyc-FXR1 via adeno-associated virus into mice leads to the redistribution of gap junctions and promotes ventricular tachycardia, showing the functional significance of FXR1 upregulation observed in DCM. CONCLUSIONS: In DCM, increased FXR1 expression appears to play an important role in disease progression by regulating gap junction remodeling. Together this study provides a novel function of FXR1, namely, that it directly regulates major gap junction components, contributing to proper cell-cell communication in the heart.

Changes in Sonographically Measured Inferior Vena Caval Diameter in Response to Fluid Loading in Term Pregnancy.

OBJECTIVES: The purpose of this study was to determine whether the inferior vena caval (IVC) diameter is influenced by intravascular volume changes in pregnancy. METHODS: A prospective observational study was done on 2 groups of normal term gravidas. In 24 patients, we measured the IVC diameter, blood pressure, and heart rate (HR) before and after a 1-L fluid infusion in preparation for regional anesthesia, after initiation of an epidural block, and within 24 hours postpartum. In a second group of 15 women, we measured the IVC diameter sequentially during a 1-L crystalloid infusion. RESULTS: In the first group, the mean baseline IVC diameter ± SD at end-inspiration was 1.45 ± 0.32 cm, which was 19% smaller than at end-expiration (1.73 ± 0.31 cm; P= .003). This respiratory cycle variation remained significant at each measurement epoch. The mean caval diameter at end-inspiration increased by 23% after the fluid bolus (P = .012). Hydration was not, however, accompanied by any significant change in the HR, mean arterial pressure, or collapsibility index of the inferior vena cava. With epidural anesthesia, the mean arterial pressure decreased from 88 ± 9 to 80 ± 7 mm Hg (P= .018), but the HR and collapsibility index remained unchanged. Postpartum values were not significantly different from their baseline measurements, except for the mean arterial pressure, which was lower by about 6 mm Hg (P = .042). In the second group, the IVC diameter at end-inspiration increased by 31% after the 1-L infusion, and there was a positive correlation between the volume infused and the IVC diameter (r= 0.67; P< .0001). CONCLUSIONS: Measurable variations in the IVC diameter occur in response to volume changes in normal term pregnancy and postpartum.

The effects of poloxamer-188 on left ventricular function in chronic heart failure after myocardial infarction.

BACKGROUND: Poloxamer-188 (P-188) is a biological membrane sealant that prevents the unregulated entry of Ca into cardiomyocytes and has been shown to have the ability to act as a membrane-repair agent in isolated cardiac myocytes. The purpose of this study was to determine if treatment with P-188 would improve left ventricular (LV) function in a rat chronic heart failure (CHF) model. METHODS: We ligated the left coronary artery of adult male Sprague-Dawley rats to induce a myocardial infarction (MI). The rats were allowed to recover for 8 weeks until stable CHF was present and treated with a range of P-188 doses [1.5 mg/kg (N = 6), 4.6 mg/kg (N = 11), 15.3 mg/kg (N = 11), and 460 mg/kg (N = 6)] delivered via 30 minutes of intravenous infusion. The rats were randomized to study groups: control, 2 hours, 24 hours, 48 hours, 1 week, and 2 weeks posttreatment (N = 8 in each group). RESULTS: Two weeks after high dose (460 mg/kg) administration, P-188 improved (P < 0.05) left ventricular ejection fraction from 34% to 51%, which persisted over 38 hours and decreased (P < 0.05) LV end systolic diameter from 0.9 ± 0.07 to 0.6 ± 0.08 cm, in the rats with CHF. There was no statistical change in hemodynamics. Additionally, P-188 reduced (P < 0.05) circulating troponin levels 2 weeks after treatment. CONCLUSIONS: Treatment with P-188 improves the LV function and partially reverses maladaptive LV remodeling in rats with moderate CHF after MI. These data introduce the idea of using a biological membrane sealant as a new approach to treating CHF after MI.

Shocks from pacemaker cardioverter defibrillators increase with amiodarone in patients at high risk for sudden cardiac death.

The efficacy of amiodarone used in combination with a pacemaker cardioverter defibrillator (PCD) to decrease episodes of ventricular tachycardia and subsequent PCD shocks is not clear. We examined a retrospective registry of 82 patients with PCD implantation to define the efficacy of amiodarone treatment. We compared patients treated with amiodarone (for 24 consecutive months without interruption) versus no amiodarone. In patients treated with amiodarone there was a 3-fold increase (p = 0.02) in PCD shocks; in patients not on beta-blockers, amiodarone resulted in a 6-fold increase (p < 0.05) in PCD shocks. Patients with a left ventricular ejection fraction >30% on amiodarone and patients <72 years old had increases (p < 0.05) in PCD shocks. In conclusion, patients treated with amiodarone had more PCD shocks than those not treated. These findings are unexpected and merit a prospective study.