Faculty Bibliography

Background: Vasculature involvement of AL amyloid or amyloid fibrils has been commonly reported in tissue biopsy. However, the prognostic role of vasculature involvement has not been studied. Methods: Tissue biopsies of patients with biopsy-proven AL amyloidosis were reviewed between 2006 to 2011. Tissue and vasculature involvement were recorded from Congo red staining and/or electronic microscopic detection of amyloid fibrils in tissue and/or capillaries. Amyloid deposition in vasculature was defined as Congo red staining of small vessels and fibrils deposition in capillaries under electronic microscope. EKG and echocardiography at the time of diagnosis were reviewed. NCCN Guidelines Version 1.2012 was used for reassessing cardiac involvement for all patients. Death was censored till November 30, 2011. Results: 28 patients with biopsy data available were included for the analysis. Mean age was 64.8 +/- 9.9 years. All patients had at least one organ biopsy with tissue Congo Red staining positive. 18 patients with positive amyloid deposition in vasculature (V positive), 14 (77.8%) had cardiac involvement based on NCCN criteria; 10 patients with negative amyloid deposition (V negative), 4 (40%) had cardiac involvement (P<0.01). LV wall thickness and LV filling pressure (E/e') were significantly increased in V positive group comparing with V negative group (15 mm +/- 0.07 vs 1.1 mm +/- 0.07; 21.6 +/-1.7 vs 11 +/-1.7 respectively, both P = 0.002). 7 cases in V positive group had pericardial effusion comparing 0 case in V negative group (P = 0.03). 12 cases with low voltage from ECG in V positive group comparing with 3 cases in V negative group (P = 0.03). LV ejection fraction, left atrium size, pulmonary pressure, troponin I and NT-ProBNP levels were not significantly different between two groups. Mortality rate in V positive group (10/18, 55.6%) was significantly higher comparing with V negative group (2/10, 20%) (P = 0.04) Conclusions: The patients with positive amyloid deposition in vasculature !

Background: Obese adolescent with T2DM and /or pre diabetes demonstrate endothelial dysfunction (ED), a key early event in atherogenesis. Flow mediated dilatation (FMD) of the brachial artery is a well validated surrogate for ED. Traditional cardiovascular risk factors (BMI, LDL-cholesterol, systolic blood pressure and smoking) have a deleterious effect on the vasculature in adolescents. Objective and hypotheses: We proposed to delineate the relationship between glucose tolerance categories and ED in obese adolescents. Methods: 25 adolescents with a mean age of 15.7 +/- 1.5 years, BMI 35+/- 6 (60% female and Hispanic) underwent a 75 gram oral glucose tolerance test (OGTT). Duplex ultrasound (11MHz transducer) measured endothelium dependent vasodilatation. Reference range in our vascular lab for FMD is 5.89+/- 2.88% (95% CI: 4.53- 7.23). Results: Based on OGTT results: 16 subjects had normal glucose tolerance (NGT: fasting glucose <= 99 mg/dl and/ or 2 hour post challenge glucose <= 139 mg/dl) and 6 subjects were diagnosed with pre diabetes(fasting glucose>= 100 and/ or 2 hour post challenge glucose >= 140 mg/dl). Adolescents with T2DM (n= 3) had lower FMD (3.2+/- 2.8%) compared to adolescents with NGT (6.5+/- 5.08%) and of those with NGT; five had an impaired FMD (<= 5.8%). Adolescents with pre diabetes had FMD values (9.8+/- 3.08%) higher than NGT group, though differences between the glucose tolerance categories did not reach statistical significance (NGT vs. pre diabetes vs. T2DM, p= 0.26). FMD did not correlate with CVS risk factors in these adolescents. In adolescents with NGT, FMD was negatively correlated with 2 hour glucose (r= -0.6, p= 0.03). Conclusions: Adolescents with prediabetes compared to those with T2DM appear to have preserved endothelium dependent vasodilatation. In adolescents with NGT, lower FMD predicts impaired glucose tolerance and accelerated vascular dysfunction. CVS risk factors did not appear to affect FMD in these obese adolescents

BACKGROUND: The incidence and predictors of heart failure (HF) after myocardial infarction (MI) with modern post-MI treatment have not been well characterized. METHODS AND RESULTS: A total of 2,201 stable patients with persistent infarct-related artery occlusion >24 hours after MI with left ventricular ejection fraction <50% and/or proximal coronary artery occlusion were randomized to percutaneous intervention plus optimal medical therapy (PCI) or optimal medical therapy (MED) alone. Centrally adjudicated HF hospitalizations for New York Heart Association (NYHA) III/IV HF and mortality were determined in patients with and without baseline HF, defined as a history of HF, Killip Class >I at index MI, rales, S3 gallop, NYHA II at randomization, or NYHA >I before index MI. Long-term follow-up data were used to determine 7-year life-table estimated event rates and hazard ratios. There were 150 adjudicated HF hospitalizations during a mean follow-up of 6 years with no difference between the randomized groups (7.4% PCI vs. 7.5% MED, P = .97). Adjudicated HF hospitalization was associated with subsequent death (44.0% vs. 13.1%, HR 3.31, 99% CI 2.21-4.92, P < .001). Baseline HF (present in 32% of patients) increased the risk of adjudicated HF hospitalization (13.6% vs. 4.7%, HR 3.43, 99% CI 2.23-5.26, P < .001) and death (24.7% vs. 10.8%, HR 2.31, 99% CI 1.71-3.10, P < .001). CONCLUSIONS: In the overall Occluded Artery Trial (OAT) population, adjudicated HF hospitalizations occurred in 7.5% of subjects and were associated with increased risk of subsequent death. Baseline or prior HF was common in the OAT population and was associated with increased risk of hospitalization and death.

Interaction of estrogen with iron at the systemic level is long suspected, but direct evidence linking the two is limited. In the present study, we examined the effects of 17beta-estradiol (E2) on hepcidin, a key negative regulator of iron absorption from the liver. We found that transcription of hepcidin was suppressed by E2 treatment in human liver HuH7 and HepG2 cells, and this down-regulation was blocked by E2 antagonist ICI 182780. Chromatin immunoprecipitation, deletion, and EMSA detected a functional estrogen responsive element half-site that is located between -2474 and -2462 upstream from the start of transcription of the hepcidin gene. After cloning the human hepcidin promoter into the pGL3Luc-Reporter vector, luciferase activity was also down-regulated by E2 treatment in HepG2 cells. E2 reduced hepcidin mRNA in wild-type mice as well as in hemochromatosis Fe gene knockout mice. In summary, our data suggest that hepcidin inhibition by E2 is to increase iron uptake, a mechanism to compensate iron loss during menstruation. This mechanism may also contribute to increased iron stores in oral contraceptive users.