Neonatal exendin-4 leads to protection from reperfusion injury and reduced rates of oxidative phosphorylation in the adult rat heart.

PURPOSE: Glucagon like peptide-1 (7-36) amide (GLP-1) is an incretin hormone with multiple salutary cardiovascular effects. A short course of the GLP-1 analogue Exendin-4 (Ex-4) in the neonatal period prevents the development of mitochondrial dysfunction and oxidative stress in a rat prone to obesity and diabetes. We sought to evaluate whether neonatal Ex-4 can exert the same effect in the normal rat heart, as well as whether Ex-4 could affect susceptibility to cardiac reperfusion injury. METHODS: After birth, Sprague Dawley rat pups were given either Ex-4 (1 nmole/kg body weight) or vehicle (1% BSA in 0.9% saline) subcutaneously for 6 days. Animals were studied at juvenile (4-6 weeks) and adult (8-9 months) ages. Using the Langendorff isolated perfused heart, cardiovascular function was assessed at baseline and following ischemia-reperfusion. Mitochondria were isolated from fresh heart tissue, and oxidative phosphorylation and calcium sequestration were analyzed. TBARS, MnSOD activity, and non-enzymatic anti-oxidant capacity were measured to assess the degree of oxidative stress present in the two groups. RESULTS: Both at the juvenile and adult age, Ex-4 treated rats demonstrated improved recovery from an ischemic insult. Rates of oxidative phosphorylation were globally reduced in adult, but not juvenile Ex-4 treated animals. Furthermore, mitochondria isolated from adult Ex-4 treated rats sequestered less calcium before undergoing the mitochondrial permeability transition. Oxidative stress did not differ between groups at any time point. CONCLUSION: A short course of Exendin-4 in the neonatal period leads to protection from ischemic injury and a preconditioned mitochondrial phenotype in the adult rat.

Anakinra for myocarditis in juvenile idiopathic arthritis.

A 20-year-old pregnant woman with a history of juvenile idiopathic arthritis presented with flu-like symptoms, systemic inflammation with myocarditis, and severe cardiomyopathy. Six weeks earlier, her chronic-arthritis therapy had been changed from anakinra, an interleukin-1ß receptor antagonist, to etanercept. When she resumed taking anakinra, her condition improved dramatically, including a complete recovery of ventricular function. Myocarditis is a well-recognized complication of systemic vasculitides. This unusual case emphasizes the important pathophysiologic role of interleukin receptors in the successful treatment of myocarditis. We suggest that clinical cardiologists be aware of the therapeutic usefulness of biological agents such as anakinra in patients with rheumatic conditions.

Longitudinal shortening accounts for the majority of right ventricular contraction and improves after pulmonary vasodilator therapy in normal subjects and patients with pulmonary arterial hypertension.

BACKGROUND: The right ventricle has a unique contraction pattern, with a greater portion of the shortening occurring in the longitudinal plane. However, the relative contributions of longitudinal and transverse shortening to overall right ventricular (RV) function have not been quantified. We sought to quantify the proportions of longitudinal and transverse shortening to RV function in normal subjects and in patients with pulmonary arterial hypertension (PAH) at baseline and following PAH-specific therapy. METHODS: The normal cohort comprised 90 subjects with normal clinical echocardiograms, whereas the PAH cohort included 36 patients, of whom 25 had echocardiograms before and after initiation of PAH-specific therapy. Assessment of RV function included tricuspid annular plane systolic excursion, RV fractional area change (RVFAC), and relative change in RV area in longitudinal and transverse planes. RESULTS: Longitudinal fractional area change (LFAC) accounted for the majority of total RVFAC (77% ± 14%) in normal subjects. Among patients with PAH, longitudinal shortening still represented the majority of RVFAC, even though it was less than in normal subjects (63% ± 18%, P < .0001). Following PAH therapy, overall RV function improved (RVFAC, 30% ± 13% to 36% ± 9%; P = .026), solely because of an increase in longitudinal area change. As a result, the proportion of longitudinal shortening increased (LFAC, 58% ± 18% to 69% ± 17%; P = .002), whereas transverse shortening fell (transverse fractional area change, 42% ± 18% vs 31% ± 17%; P = .002). CONCLUSIONS: Longitudinal shortening accounts for the majority of RV contraction in normal subjects and patients with PAH, although less so in PAH. Improved RV function following pulmonary vasodilator therapy occurs solely from improvements in longitudinal contraction, suggesting that longitudinal shortening may represent the afterload-responsive element of RV functional recovery.

Chronic glucagon-like peptide-1 infusion sustains left ventricular systolic function and prolongs survival in the spontaneously hypertensive, heart failure-prone rat.

BACKGROUND: Glucagon-like peptide-1 (GLP-1) treatment leads to short-term improvements in myocardial function in ischemic and nonischemic cardiomyopathy. It is unknown whether GLP-1 improves survival when administered over a longer time period. Spontaneously hypertensive, heart failure-prone (SHHF) rats progress to advanced heart failure and death over a 15-month period. The authors sought to determine whether a continuous infusion of GLP-1 would reduce mortality in this model. METHODS AND RESULTS: At 9 months of age, 50 SHHF rats were randomized to receive a 3-month, continuous infusion of either GLP-1 or saline. Metabolic parameters were measured and cardiac ultrasounds performed at study initiation and completion of treatment. Surviving rats were euthanized at 12 months. Hearts were perfused in an isolated, isovolumic heart preparation, and Tunel staining of myocardial samples was performed. Baseline metabolic and cardiac functional parameters were comparable. GLP-1-treated SHHF rats had greater survival (72% versus 44%, P=0.008) at 12 months of age. In addition, GLP-1 treatment led to higher plasma insulin, lower plasma triglycerides, and preserved left ventricular (LV) function. GLP-1-treated rats demonstrated decreased myocyte apoptosis by Tunel staining as well as reduced caspase-3 activation. No increase in p-BAD expression was seen. In isolated hearts, the LV systolic pressure and LV-developed pressure were greater in the GLP-1 group. Myocardial glucose uptake was also increased in GLP-1-treated SHHF rats. CONCLUSIONS: Chronic GLP-1 treatment prolongs survival in obese SHHF rats. This is associated with preserved LV function and LV mass index, increased myocardial glucose uptake, and reduced myocyte apoptosis.