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I am a physician-scientist and the overall theme my research has been the genetic basis of cardiovascular disease across the continuum from Discovery to the development of Model Systems to the Translation of these findings to the clinic and most recently to the Public Health aspect of genetics. I completed his MD-PhD at UNC with Prof. Nobuyo Maeda and Nobel Laureate Oliver Smithies. I did Internal Medicine residency and Cardiology fellowship training at Stanford working with Dr. Tom Quertermous. Currently my Discovery and basic translational efforts center on understanding the genetic basis of insulin resistance using GWAS studies coupled with exploration in model systems including iPSCs and CRISPR screens. My clinical translational focus is on Familial Hypercholesterolemia (FH) and I am the volunteer Chief Medical Advisor of the FH Foundation (FHF) which is a patient-led organization dedicated to increasing awareness of FH, identifying and treating patients with FH and screening family members to prevent deleterious outcomes. I helped lead the FHF efforts to establish a national patient registry (CASCADE FH), apply for an ICD10 code for FH and am now using cutting-edge “big-data” approaches to identify previously undiagnosed FH patients in electronic medical records (FIND FH). I have published over 90 papers with research projects currently funded by the National Institutes of Health, the American Diabetes Association, the American Heart Association and the Doris Duke Charitable Foundation.
The FH Foundation
The overall theme of my work is to understand the genetic basis of complex cardiovascular diseases such as coronary disease and insulin resistance. Currently, I am involved in genome wide association (GWA) studies of coronary disease through the NIH-funded ADVANCE study and of insulin resistance through the international GENESIS project. After using the GWA approach to discover and validate interesting candidate genes, I hope to explore the biology underlying these genes and pathways using cell culture and in vivo model systems. I am also using iPSC technology (induced pluripotent stem cells) to develop model systems for the study of insulin resistance through the NIH-funded GENESiPS project. <br/><br/>I also have a strong interest in developing tools to help translate newly emerging genetic data into clinical practice and am currently the PI of a randomized trial where we are examining whether we can improve patient coronary disease risk factor profiles by giving them information about their inherited risk of coronary disease. <br/><br/>Clinically, I am interested in the care of patients with inherited cardiovascular conditions. In particular I am focused on individuals with Familial Hypercholesterolemia. I also have an interest in treating Hypertrophic Cardiomyopathy. I take care of these patients in the Stanford Center for Inherited Cardiovascular Disease.
Relationship Between Insulin Resistance and Statin Induced Type 2 Diabetes, and Integrative Personal Omics Profiling
There is general agreement that statin-treatment of patients to lower plasma cholesterol
levels can increase the incidence of type 2 diabetes mellitus (T2D) in some individuals1-5.
The physiologic mechanism for the increased risk for T2D from statin treatment is unknown but
could result from effects on insulin sensitivity or insulin secretion. This study will
evaluate how the medication atorvastatin (trade name Lipitor) works in non-diabetic
individuals in regards to its effect on insulin sensitivity and insulin secretion to help
further understand the possible cause of the increased occurrence of T2D in people who are at
risk for T2D. This research study will also examine what metabolic characteristics and
variables (for example insulin resistance, high triglycerides, or both) will identify those
people at highest risk of statin-induced T2D.
The goals of this study are to:
1. determine the effect of high-intensity atorvastatin (40 mg/day) for ~ 10 weeks on
insulin sensitivity and insulin secretion (defined with gold standard methods) (PRIMARY
OUTCOMES) as well as other glycemic traits (SECONDARY OUTCOMES);
2. compare a number of cardio-metabolic characteristics (e.g. weight, lipids) before,
during, and after administration of atorvastatin;
3. determine if significant deterioration of insulin action and/or secretion following
statin treatment will be confined to those with baseline insulin resistance
(PRE-SPECIFIED SUBGROUP ANALYSES);
4. perform Personal Omics Profiling (iPOP) 6,7 before and after taking atorvastatin to
examine treatment-associated changes in all baseline variables and to analyze not only
previously-known drug efficacy but also untargeted drug efficacy (EXPLORATORY ANALYSES).
This will be an open-label study to evaluate the diabetogenic effect of atorvastatin (40
mg/day for 10 weeks) on both insulin action and insulin secretion in nondiabetic individuals.
To ensure we recruit individuals across a broad range of insulin sensitivity, we will target
recruitment to enrich for those with combined increases in LDL-C and TG concentrations (see
SIGNIFICANCE and RATIONALE). The experimental population will consist of ~75 apparently
healthy, non-diabetic volunteers eligible for statin therapy but without pre-existing
atherosclerotic cardiovascular disease. Following baseline assessments of co-primary outcome
measures: insulin sensitivity (by insulin suppression test, IST) and insulin secretion (by
graded glucose infusion test, GGIT), participants will be placed on a weight maintenance diet
and treated with 40 mg/day of atorvastatin. All baseline measurements will be repeated ~10
weeks later with iPOP8 measurements done at baseline, at weeks 2, 4, and 10 on atorvastatin,
and at weeks 4 and 8 off atorvastatin.
Stanford is currently not accepting patients for this trial.
For more information, please contact Cindy Lamendola, MSN, NP, 650-723-3141.
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Personal Genomics for Preventive Cardiology
The purpose of this study is to see if providing information to a person on their inherited
(genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their
diet, lifestyle or medication regimen to alter their risk.
Stanford is currently not accepting patients for this trial.
For more information, please contact Josh Knowles, 650-804-2526.