Research interests for Patients:
My research interests are focused on:
a. Pulmonary hypertension:
Pulmonary arterial hypertension (PAH) is an incurable, progressive disease that affects both adults and children. While there are some similarities between adult and pediatric pathophysiology, the number of life years lost in children is much greater given limited long-term survival. Pediatric pulmonary hypertension differs from adult disease also in terms of vascular function and structure, natural history, genetics, and possibly response to PAH therapies. In pediatric PAH, the vascular insult occurs at a critical time in development between birth and adulthood, during which time expansion of the alveolar and capillary surface area may increase by 20-folds via intussusceptive angiogenesis. Disruption of normal development results in the development of chronic pulmonary vascular disease later in life.
Despite significant unique factors in pediatric PAH, research in pediatric PAH, compared to adults, has been stalled, forcing clinicians to use adult guidelines (including right heart cardiac catheterization (RHC) for diagnosis and serial monitoring) and therapies approved for adults in children. Due to the risks of catheterization in the young, catheterization is not an option as a research tool in pediatric PAH. Recently, the FDA excluded catheterization as an end-point in clinical trials in children with PAH, making outcome studies even more difficult. Over the past decade, there have been 5 medications approved for adult pulmonary hypertension by the U.S. Food and Drug Administration. None have been approved for pediatric use. This means that there are no safe dosages established in children and inadequate evidence that children responds similarly to drugs approved for adults.
My overall goal in the next few years is to show the early vascular changes during childhood in PAH patients, which make them particularly susceptible to insults later in life and is what distinguishes these patients from adult patients. I also want to show that MRI is able to yield hemodynamic data previously obtained via catheterization. Success in replacing catheterization with MRI has the potential of shifting the paradigm of pediatric PH care towards a safer, noninvasive monitoring modality and significantly improve quality of life in children with PH. Furthermore, it will add a powerful tool to push pediatric research efforts ahead, particularly in clinical trials.
I have described abnormal pulmonary artery dilation, both by ultrasound and by MRI, in association to severely abnormal wall shear stress (WSS). WSS is the primary component of mechanotransduction forces that is significantly decreased in proximal pulmonary conduit in adults with PH. Studies investigating the changes in the endothelial function and morphology revealed flow and WSS association with altered cellular signaling, gene expression, and endothelial cell geometry The characterization of the stiffness and mechanotransduction events in the proximal pulmonary conduit vessels is then of great importance in order to assess the possibly ongoing pathophysiologic phenomena in children and young adolescents with PH.
I also looked at the ventricular vascular coupling ratio (VVCR), which describes the interaction between the vascular afterload and the ventricular contractility. Conventionally, VVCR is laboriously determined in the cardiac catheterization laboratory with the establishment of the pressure-volume loop under varying loading conditions and clamping of the inferior vena cava. This is virtually impossible in children due to the size of catheter needed and the cost. We showed exciting preliminary data that this value could be estimated by only MRI data.
The most state-of-the-art MRI sequence is 4D flow, in which we can describe the properties of flow in the ventricle and the major arteries with one single sequence. Preliminary data support significant correlation between 4D flow parameters and pressure data derived by catheterization. In the year coming, we will explore the use of this in pediatric PAH.
b. Diabetes: I have been working with Dr. Kristen Nadeau from Endocrinology looking at the early cardiovascular risks in adolescents with type I diabetes mellitus (T1D). We have alarming findings showing that there is already arterial stiffness in youths with T1D compared to those without diabetes. We are further exploring the cardiovascular effects of therapeutic medications.