Featured Heart and Pulmonary Research

Wendy Luce, PhD

In the NICU at Nationwide Children’s, up to 30% of our very low birth weight (less than 1500 grams) infants will develop at least one episode of culturepositive sepsis during their hospital stay which is associated with a 25% mortality rate. Despite its common occurrence, the mechanisms of cardiac dysfunction in neonatal sepsis have not been defined and treatment options are limited.

Recent studies, especially in adults, have shown that innate immunity responses and resultant inflammation in myocardium likely plays a putative role in depressed cardiac function during sepsis. Separate reports have illustrated that these same innate immunity pathways are developmentally regulated, and that neonates have an exaggerated inflammatory response to infectious stimuli in comparison to adults. In order to develop successful therapies and improve outcomes in neonates, the cardiovascular response to inflammation in the setting of sepsis must be more clearly defined.

My research focuses on the interaction of innate immunity, inflammation and calcium handling pathways in the cardiac myocyte and the role these interactions play in the development of sepsis-associated cardiac failure.

I am particularly interested in the developmental influences on these pathways and their interactions, and in identifying therapeutic strategies that are tailored to the neonate population. Our lab has found an important cross-over between innate immunity and calcium handling pathways in the cardiac myocyte that has not previously been reported and is associated with sepsis-induced cardiac failure.
  

Figure 1. Phospho-p38 MAP kinase staining in myocardium.  MAP Kinase Phosphatase-1 (MKP-1)  is a key negative regulator of the  innate immune and inflammatory  response to sepsis. Immunohistochemistry  sections show increased  staining in the myocardium of MKP-1  null mice versus the MKP-1 +/+ mice  both at baseline (p<0.001)(C) and 24  hours after LPS injection (p<0.001)  (D).

Baseline PP-38 activation in the setting of MKP-1 deficiency is suggested  by the increased nuclear localization  of PP-38 in the myocytes of  the null mice (p<0.001)(C), which  then appears to be released into the  cytoplasm after LPS exposure  (p<0.0001)(D).   

 
To study these interactions, we have established a murine model of neonatal sepsis that can be used to evaluate the innate immune and cardiovascular responses to endotoxin (LPS). Neonatal mice have a profound decrease in cardiac function in response to low-dose LPS that is not seen in adult mice and is associated with an increase in both baseline and post-LPS levels of pro-inflammatory cytokines. In addition, the pattern of cytokine expression differs in plasma and organ tissues (i.e. heart and liver). These characteristics are similar to findings in humans, therefore the animal model will help us better understand the developmental influences on the systemic versus cardiac innate immune responses to sepsis and could lead to the development of novel therapies for sepsis in premature neonates.

In parallel to our animal experiments we are also currently developing a clinical study to investigate the innate immune, inflammatory and cardiovascular response to sepsis in very low birth weight neonates in the NICU. In this study, we will utilize a new imaging strategy to evaluate sepsis-related cardiac dysfunction in neonates. This translational research approach will provide innovative insight into the mechanisms underlying sepsis-related cardiac dysfunction in neonates and ultimately provide an opportunity for improvements in medical care for this special patient population.

		Figure 2. Cardiac cross-sections. MKP-1 deficiency in mice leads to marked left ventricular dilation (D) just 24 hours after low-dose LPS injection, which is not seen in the MKP-1 +/+ mice (p<0.05)(A & B) or the MKP-1 null mice at baseline (p<0.05)(C).

This LV dilation is associated with significantly decreased LV contractile function (LV fractional shortening) on echocardiography (p<0.05) and a 60-fold increase in myocardial phosphorylated phospholamban (key regulator of calcium handling in the cardiomyocyte) in the MKP-1 null mice 24 hours after LPS.
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Loren E. Wold, PhD

The use of myocytes allows us to assess the “functional unit” of the heart under disease states and determine how alterations in myocyte function can translate into changes in whole heart function.  I have also become interested in how the heart responds to environmental stressors, including particles within the air.

While doing a postdoctoral fellowship in Los Angeles, we performed a study showing that particles from the air, termed ultrafine particulate matter, were able to traverse the endothelial lining of a blood vessel and travel through the bloodstream.

This allowed the particles direct access to the heart, with resultant depressions in cardiac function.  We also know from the clinic that on days of high air pollution, there is a significant increase in sudden cardiac death, which is exacerbated in patients with pre-existing heart conditions (such as seen in diabetics).  Currently, we are interested in the signaling mechanisms involved in this functional change, as well as how particles directly effect isolated cardiomyocytes.
 
My work is funded by the American Heart Association, National Affiliate (Scientific Development Grant, “Ultrafine particle-induced heart dysfunction”) and we have submitted a project to the National Institute of Health examining how exposure to particulates affects the development of insulin resistance in a mouse model of infant particle exposure.

Isolated cardiomyocytes from a rat.  Note the striations and unique structure of the cells.  These cells make up the "functional unit." of the heart.

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Aymen Naguib, MD

This increased stress response has been observed in adults and babies irrespective of the type of surgery they have received. The stress response and associated inflammation have been shown to result in increased morbidity and mortality during the post-operative recovery period.

However, due to their delicate metabolic balance, neonates and infants undergoing cardiac surgery are at even greater risk of experiencing complications and poor outcomes due to surgical stress and inflammation.

It has been suggested that the surgical stress response can be modulated or reduced through the use of different doses or combinations of anesthesia and analgesia drugs. Only a few studies, however, have explored this claim. In addition to reducing stress response, we believe that using low-dose narcotic technique in addition to dexmedetomidine will also promote early extubation, which can further reduce morbidity and mortality by eliminating ventilator associated complications. A review of our experience at Nationwide Children's Hospital using low dose fentanyl (7-10 mcg/kg) with inhalational agent alone or in combination with propofol or dexmedetomidine infusion illustrated that early extubation in the OR after congenital cardiac surgery is both safe and achievable. Of 874 cases we reviewed, 614 patients were extubated in the OR, and only 9 (1.5%) required reintubation. Our data also showed that the average length of ICU stay, an indication of post-operative morbidity, for the patients who were extubated early was 3.6 days, while the average length of ICU stay for the patients who remained intubated was 13.2 days.

In this study, we want to compare these techniques (low dose fentanyl alone or in combination with dexmedetomidine) to the high dose fentanyl technique being adopted at many centers across the country. In our retrospective study, we have successfully performed early extubation on VSD, AVSD, and TOF surgical patients after using either low dose fentanyl alone or low dose fentanyl plus dexmedetomidine over the past five years. Therefore, we plan to use this patient group in a prospective, randomized blinded study to compare the relative effectiveness of the different anesthetic techniques in reducing cardiac surgical stress. Patients will be randomly assigned to one of three groups in a block randomization trial design.

Our hypothesis is that dexmedetomidine, in addition to a low narcotic anesthesia and analgesia regimen, will reduce stress hormone levels while promoting early extubation after surgery, resulting in a measurable reduction in post-operative complications. This will lead to better outcomes for our patients. In addition, this study will produce much needed data in an area that has been understudied to date.

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