Airflow Limitation and Endothelial Dysfunction. Unrelated and Independent Predictors of Atherosclerosis.

RATIONALE: Lower FEV1 is associated with increased prevalence of atherosclerosis; however, causal mechanisms remain elusive. OBJECTIVES: To determine if systemic endothelial dysfunction mediates the association between reduced FEV1 and increased atherosclerosis. METHODS: Brachial artery endothelial function, pulmonary function, coronary artery calcium, and carotid plaque were assessed in 231 Pittsburgh SCCOR (Specialized Centers for Clinically Oriented Research) study participants; peripheral arterial endothelial function, pulmonary function, and coronary artery calcium were assessed in 328 HeartSCORE (Heart Strategies Concentrating on Risk Evaluation) study participants. MEASUREMENTS AND MAIN RESULTS: Lower FEV1 was independently associated with increased atherosclerosis in both cohorts (per 25% lower % predicted FEV1: odds ratio [OR], 1.76; 95% confidence interval [CI], 1.30-2.40; P < 0.001 for carotid plaque in SCCOR participants) (per 25% lower % predicted FEV1: OR, 1.35; 95% CI, 1.02-1.77; P = 0.03 for coronary artery calcium in HeartSCORE participants). Similarly, reduced endothelial function was independently associated with increased atherosclerosis in both cohorts (per SD lower endothelial function: OR, 1.30; 95% CI, 1.01-1.67; P = 0.04 for carotid plaque in SCCOR participants) (per SD lower endothelial function: OR, 1.38; 95% CI, 1.09-1.76; P = 0.008 and OR, 1.41; 95% CI, 1.07-1.86; P = 0.01 for coronary artery calcium in SCCOR and HeartSCORE participants, respectively). However, there was no association between endothelial dysfunction and FEV1, FEV1/FVC, low-attenuation area/visual emphysema, and diffusing capacity in SCCOR participants, and between endothelial dysfunction and FEV1 or FEV1/FVC in HeartSCORE participants (all P > 0.05). Adjusting the association between FEV1 and atherosclerosis for endothelial dysfunction had no impact. CONCLUSIONS: Endothelial dysfunction does not mediate the association between airflow limitation and atherosclerosis. Instead, airflow limitation and endothelial dysfunction seem to be unrelated and mutually independent predictors of atherosclerosis.

Cardiac CD47 drives left ventricular heart failure through Ca2+-CaMKII-regulated induction of HDAC3.

BACKGROUND: Left ventricular heart failure (LVHF) remains progressive and fatal and is a formidable health problem because ever-larger numbers of people are diagnosed with this disease. Therapeutics, while relieving symptoms and extending life in some cases, cannot resolve this process and transplant remains the option of last resort for many. Our team has described a widely expressed cell surface receptor (CD47) that is activated by its high-affinity secreted ligand, thrombospondin 1 (TSP1), in acute injury and chronic disease; however, a role for activated CD47 in LVHF has not previously been proposed. METHODS AND RESULTS: In experimental LVHF TSP1-CD47 signaling is increased concurrent with up-regulation of cardiac histone deacetylase 3 (HDAC3). Mice mutated to lack CD47 displayed protection from transverse aortic constriction (TAC)-driven LVHF with enhanced cardiac function, decreased cellular hypertrophy and fibrosis, decreased maladaptive autophagy, and decreased expression of HDAC3. In cell culture, treatment of cardiac myocyte CD47 with a TSP1-derived peptide, which binds and activates CD47, increased HDAC3 expression and myocyte hypertrophy in a Ca(2+)/calmodulin protein kinase II (CaMKII)-dependent manner. Conversely, antibody blocking of CD47 activation, or pharmacologic inhibition of CaMKII, suppressed HDAC3 expression, decreased myocyte hypertrophy, and mitigated established LVHF. Downstream gene suppression of HDAC3 mimicked the protective effects of CD47 blockade and decreased hypertrophy in myocytes and mitigated LVHF in animals. CONCLUSIONS: These data identify a proximate role for the TSP1-CD47 axis in promoting LVHF by CaKMII-mediated up-regulation of HDAC3 and suggest novel therapeutic opportunities.

Fulminant hepatitis following chemotherapy treatment for breast cancer.

A woman in her early 50s was admitted to the intensive care unit with nausea, altered mental status and hepatic failure. She had a history of asymptomatic chronic hepatitis B and recently received chemotherapy for breast cancer. A diagnosis of hepatitis B reactivation (HBR) was made, but unfortunately she died of liver failure. Controversies around testing for hepatitis B prior to giving immunosuppressive treatments and the use of prophylactic antiviral therapy to prevent HBR are discussed.