Background-Patients with congestive heart failure (CHF) often have low serum triiodothyronine (T 3 ) concentrations. In a rodent model of myocardial infarction-induced CHF and low serum T 3 , we hypothesized that replacing T 3 to euthyroid levels would improve left ventricular function without producing untoward signs of thyrotoxicosis. Methods and Results-Adult male Sprague-Dawley rats were subjected to left anterior descending coronary artery ligation (myocardial infarction). One week post-myocardial infarction, left ventricular fractional shortening was significantly reduced to 22Ϯ1% in CHF animals versus 38Ϯ1% for sham-operated controls (PϽ0.001). Serum T 3 concentration was also significantly reduced (80Ϯ3 versus 103Ϯ6 ng/dL; PϽ0.001), in CHF animals versus Shams. At 9 weeks post-myocardial infarction, systolic function (ϩdP/dt max) was significantly attenuated in CHF animals (4773Ϯ259 versus 6310Ϯ267 mm Hg/s; PϽ0.001) as well as diastolic function measured by half time to relaxation (15.9Ϯ1.2 versus 11.1Ϯ0.3 ms; PϽ0.001). ␣-myosin heavy chain expression was also significantly reduced by 77% (PϽ0.001), and ␤-myosin heavy chain expression was increased by 21%. Continuous T 3 replacement was initiated 1 week post-myocardial infarction with osmotic mini-pumps (6 g/kg/d), which returned serum T 3 concentrations to levels similar to Sham controls while resting conscious heart rate, arterial blood pressure and the incidence of arrhythmias were not different. At 9 weeks, systolic function was significantly improved by T 3 replacement (6279Ϯ347 mm Hg/s; PϽ0.05) and a trend toward improved diastolic function (12.3Ϯ0.6 ms) was noted. T 3 replacement in CHF animals also significantly increased ␣-and reduced ␤-MHC expression, (PϽ0.05). Conclusions-These data indicate that T 3 replacement to euthyroid levels improves systolic function and tends to improve diastolic function, potentially through changes in myocardial gene expression. (Circ Heart Fail. 2009;2:243-252.)

Serum triiodothyronine (T3) concentration is reduced in patients with congestive heart failure which may contribute to altered T3 dependent gene expression and cell signaling. This effect could be due to an increase in type III deiodinase (D3) activity. D3 is a fetal enzyme that inactivates thyroxine as well as T3. We hypothesized that myocardial D3 expression would increase in a rodent model of myocardial infarction (MI) and attenuate activation of serine/threonine‐specific protein kinases (Akt) and endothelial nitric oxide synthase (eNOS). Echocardiography was used to assess left ventricular (LV) structure and function in male Sprague Dawley rats before and after coronary artery ligation. One week post‐MI, D3 expression was significantly increased while serum T3 and T4 were attenuated, (90.1±5.7 vs. 74.4±2.2ng/dL) and (4.54±0.15 vs. 4.17±0.10ug/dL), respectively. Additionally, Akt and eNOS activation were reduced as early as 3‐days post‐MI. By 7wks, serum T3 and T4 concentrations were no longer significantly different; however, LV systolic and diastolic volumes progressively increased over the 9wk study. Importantly, D3 expression remained elevated at 9wks. These findings support the hypothesis that myocardial D3 expression is increased and downstream targets of T3 may be attenuated after a myocardial infarction. Funding: Ralph and Marian Falk Medical Research Trust and King Pharmaceuticals.

FRNK (FAK‐Related Non‐Kinase) expression is greatly increased in remodeled arteries, and may serve to limit neointimal formation via inhibition of smooth muscle cell (SMC) migration and proliferation. To determine the role of tyrosine phosphorylation of FRNK, rat carotid arteries were balloon‐injured and FRNK expression and phosphorylation were examined by immunoprecipitation and Western blotting with phosphospecific antibodies. FRNK expression increased 3‐4 fold in injured, but not in contralateral, control arteries, and the upregulated FRNK was phosphorylated at residues Y168 and Y232. A 5‐6 fold increase in total FAK levels was also detected. Furthermore, endogenously expressed FRNK was phosphorylated at Y168 and Y232 under basal conditions, and Y168/Y232 phosphorylation increased in response to Ang II treatment of cultured A7r5 cells. When adenovirally overexpressed in cultured A7r5 cells and rat aortic SMC, GFP‐wtFRNK was phosphorylated at residues Y168 and Y232, and GFP‐wtFRNK inhibited cell spreading. GFP‐FRNK mutated at Y168 abrogated FRNK‐mediated inhibition of cell spreading. We conclude that FRNK phosphorylation at Y168 plays an important role in inhibition of FAK‐dependent signal transduction. Supported by the Falk Medical Research Trust and an AHA Predoctoral Fellowship.