Weekly doxorubicin increases coronary arteriolar wall and adventitial thickness.

BACKGROUND: Doxorubicin (DOX) is associated with premature cardiovascular events including myocardial infarction. This study was performed to determine if the weekly administration of DOX influenced coronary arteriolar medial and/or adventitial wall thickening. METHODS: Thirty-two male Sprague-Dawley rats aged 25.1± 2.4 weeks were randomly divided into three groups and received weekly intraperitoneal injections of normal saline (saline, n = 7), or low (1.5 mg/kg to 1.75 mg/kg, n = 14) or high (2.5 mg/kg, n = 11) doses of DOX. The animals were treated for 2-12 weeks, and euthanized at pre-specified intervals (2, 4, 7, or 10+ weeks) to obtain histopathologic assessments of coronary arteriolar lumen diameter, medial wall thickness, adventitial wall thickness, and total wall thickness (medial thickness + adventitial thickness). RESULTS: Lumen diameter was similar across all groups (saline: 315±34 µm, low DOX: 286±24 µm, high DOX: 242±27 µm; p = 0.22). In comparison to animals receiving weekly saline, animals receiving weekly injections of 2.5 mg/kg of DOX experienced an increase in medial (23±2 µm vs. 13±3 µm; p = 0.005), and total wall thickness (51±4 µm vs. 36±5 µm; p = 0.022), respectively. These increases, as well as adventitial thickening became more prominent after normalizing for lumen diameter (p<0.05 to p<0.001) and after adjusting for age, weight, and total cumulative DOX dose (p = 0.02 to p = 0.01). Animals receiving low dose DOX trended toward increases in adventitial and total wall thickness after normalization to lumen diameter and accounting for age, weight, and total cumulative DOX dose (p = 0.06 and 0.09, respectively). CONCLUSION: In conclusion, these data demonstrate that weekly treatment of rats with higher doses of DOX increases coronary arteriolar medial, adventitial, and total wall thickness. Future studies are warranted to determine if DOX related coronary arteriolar effects are reversible or preventable, exacerbate the known cardiomyopathic effects of DOX, influence altered resting or stress-induced myocardial perfusion, or contribute to the occurrence of myocardial infarction.

Aortic stiffness increases upon receipt of anthracycline chemotherapy.

PURPOSE Cancer survivors exposed to anthracyclines experience an increased risk of cardiovascular (CV) events. We hypothesized that anthracycline use may increase aortic stiffness, a known predictor of CV events. PATIENTS AND METHODS We performed a prospective, case-control study involving 53 patients: 40 individuals who received an anthracycline for the treatment of breast cancer, lymphoma, or leukemia (cases), and 13 age- and sex-matched controls. Each participant underwent phase-contrast cardiovascular magnetic resonance measures of pulse wave velocity (PWV) and aortic distensibility (AoD) in the thoracic aorta at baseline, and 4 months after initiation of chemotherapy. Four one-way analyses of covariance models were fit in which factors known to influence thoracic aortic stiffness were included as covariates in the models. Results At the 4-month follow-up visit, aortic stiffness remained similar to baseline in the control participants. However, in the participants receiving anthracyclines, aortic stiffness increased markedly (relative to baseline), as evidenced by a decrease in AoD (P < .0001) and an increase in PWV (P < .0001). These changes in aortic stiffness persisted after accounting for age, sex, cardiac output, administered cardioactive medications, and underlying clinical conditions known to influence aortic stiffness, such as hypertension or diabetes (P < .0001). CONCLUSION A significant increase in aortic stiffness occurs within 4 months of exposure to an anthracycline which was not seen in an untreated control group. These results indicate that previously regarded cardiotoxic cancer therapy adversely increases thoracic aortic stiffness, a known independent predictor of adverse cardiovascular events.

Left ventricular spherical remodeling and apical myocardial relaxation: cardiovascular MR imaging measurement of myocardial segments.

PURPOSE: To prospectively evaluate left ventricular (LV) shape and regional relaxation to determine if rapid, early relaxation of the LV is lost with spherical remodeling of the LV. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board. All participants gave written informed consent. Cardiovascular magnetic resonance (MR) imaging and transthoracic echocardiography (TTE) were performed in 18 individuals. Each participant was classified into one of three groups according to LV shape and TTE-derived mitral filling parameters. Pairwise comparisons of cardiovascular MR imaging measurements of LV relaxation were made between healthy individuals and those with spherically shaped LVs. RESULTS: The LV regional relaxation rates were determined in a total of 108 basal, middle, and apical myocardial segments in 18 participants (13 women, five men; age range, 35-76 years). Participants with a spherically shaped LV (sphericity index, <1.5) and a mitral inflow velocity E wave/A wave ratio of less than 1.0 exhibited apical thinning velocities that were lower than those of healthy individuals (sphericity index, > or =1.5) (P < .01). The ratio of LV relaxation velocities in the apical versus middle LV segments correlated significantly with sphericity index (R(2) = 0.53; P = .0005). CONCLUSION: LV apical relaxation velocities in participants with LV spherical remodeling (sphericity index, <1.5) were reduced compared with those of healthy individuals (sphericity index, > or =1.5).

The United States pediatric vaccine stockpile program.

The initial goal of the national vaccine stockpile program was to establish a 6-month supply of all recommended childhood vaccines, to meet national demands if a manufacturing process was interrupted. When the first vaccine stockpiles were created in 1983, the childhood immunization schedule was much less complicated than it is today, and the first stockpiles included only measles-mumps-rubella, poliovirus, and pertussis vaccines, as well as diphtheria and tetanus toxoids. However, today's vaccine needs are much greater, and current stockpiles do not include all recommended childhood vaccines, partially because inclusion of vaccines that are universally recommended, fully implemented, and produced by a single manufacturer has been made a priority. Future planning must also consider substantially higher vaccine costs, the development of new combination vaccines, a wide range of production times, and changes in immunization recommendations. Expansion and strengthening of the national vaccine stockpile program are critical to protect against future disruptions in vaccine supply.