A component of the Vascular Medicine Research Program within the Cardiovascular Division and the Department of Medicine, the Mohler Lab investigates new diagnostic and therapeutic modalities for patients with vascular disease. The primary concentrations of the Mohler Lab include:
- Peripheral artery disease (PAD) — Improving diagnostic imaging and treatment of PAD, particularly the development of a novel therapy for claudication;
- Vascular Health Profile (VHP) — A powerful novel technique that provides a comprehensive assessment of vascular health;
- Vascular Imaging — Near infrared optical technology for imaging of skeletal muscle oxygenation and blood flow in the legs of patients with PAD;
- The genetic origins of varicose veins.
Research Projects at the Mohler Lab
Peripheral Artery Disease (PAD)
Previous clinical studies for treatment of claudication have included small molecule drugs, gene therapy to deliver proangiogenic compounds and cell therapy. The Mohler Lab is currently performing an IRB-approved study to evaluate how exercise improves the symptoms of claudication.
The Microcirculation in Claudication and Exercise Rehabilitation
- To determine in a group of patients with moderate PAD, the relationship between claudication limited exercise tolerance (Peak Walking Time-PWT) and microvascular blood flow.
- To determine if changes in PWT with exercise rehabilitation correlate with changes in microvascular blood flow.
- To determine if the vascular health profile, as measured with circulating Endothelial Progenitor Cells (EPCs) and endothelially-derived microparticles (MPs), biomarkers of endothelial health, improves following exercise rehabilitation and correlate with microvascular blood flow.
Design & Methods:
Subjects with moderate PAD will undergo measurement of treadmill PWT. Continuous Arterial Spin Labeling-Perfusion MRI will be used to measure skeletal muscle calf microvascular blood flow and flow cytometry will be used to characterize the endothelial vascular health profile described above. We anticipate that a supervised exercise rehabilitation program will improve PWT, microvascular blood flow, and the endothelial vascular health profile.
Public Health Relevance:
Peripheral arterial disease is a highly prevalent condition in the United States, affecting approximately 8-12 million Americans. Early disability derives from claudication or ischemic muscle pain, inhibiting ambulation. The pathophysiology of this disorder is thought to be of macrovascular origin, however the contribution of the microvasculature to this disorder is not well understood and may be important. Improved knowledge of the contribution of the microvasculature to this disorder, and improvement in our ability to monitor, via relatively noninvasive imaging and circulating cellular biomarker assays, the impact of rehabilitation or other therapeutic interventions, may assist in the treatment of this disorder.
Vascular Health Profile
Patients who appear to be similar in their vascular disease risk often demonstrate substantially different morbidity, mortality, and responses to therapy because of their differing clinical characteristics.
The Vascular Health Profile (VHP) is a powerful novel technique that provides a comprehensive assessment of vascular health. The VHP is a multicomponent clinical assay that integrates a number of cellular biomarkers of genetic and environmental risk factors, including vascular microparticles (MPs) and endothelial progenitor cells (EPCs) into a cost-effective clinically significant profile using unique computational methods. The VHP uses the power of cytomics (the study of cell systems in the body) to capture the biocomplexity of vascular disease and to deliver a simple, yet comprehensive measure of cardiovascular health. There are ongoing clinical studies evaluating the VHP is certain diseases that predispose to heart attack and stroke such as diabetes mellitus and psoriasis.
Patients with PAD have abnormal skeletal muscle oxygenation and blood flow and the legs. The information obtained from this optical device could potentially assist with diagnosis, prognosis and optimize treatment for patients with PAD.
The Mohler laboratory is investigating diffuse optical imaging (DOI) using near infrared optical technology to noninvasively measure skeletal muscle oxygenation and blood flow in the legs of patients with PAD. DOI employs photons in the near-infrared range that diffuse through tissue and can be detected millimeters to centimeters away from the source. Diffuse optical techniques provide direct assessment of oxygenation and perfusion processes at the microvasculature level and have the advantage of portability and high temporal resolution, as well as the capacity to probe deep tissues.
Diffuse optical spectroscopy (DOS)
DOS involves the interaction of light with the main chromophores in the tissue — oxy-hemoglobin (HbO2) and deoxy-hemoglobin (Hb) — to provide dynamic information about HbO2 and Hb concentrations, total hemoglobin concentration (THC), and tissue blood oxygen saturation (StO2) in deep tissues.
Diffuse Correlation Spectroscopy (DCS)
DCS is an emerging diffuse optical technique for continuous noninvasive measurement of blood flow in deep tissues. DCS quantifies the temporal fluctuations of detected light with high temporal (~100 ms) and limited spatial (mm to cm) resolutions in tissue. These fluctuations are sensitive to the motions of scatterers in tissue, such as red blood cells. Therefore, the DCS signal provides a direct measure of blood flow, and can be used to derive a parameter typically known as blood flow index.
A clinical study is ongoing evaluating the genetic cause of varicose veins. The DNA of families with varicose veins is being study to determine the genes that influence the development of varicose veins.
- Emile R. Mohler III, MD, Director
- Victor Ferrari, MD
- Jay Giri, MD
- Michael Parmacek, MD
- Muredach Reilly, MB
- Robert L. Wilensky, MD
Selected publications from the Mohler Lab at Penn Cardiovascular Institute in Philadelphia, Pennsylvania.
- Wassel CL, Lamina C, Nambi V, Coassin S, Mukamal KJ, Ganesh SK, Jacobs DR, Franceschini N, Papanicolaou GJ, Gibson Q, Yanek LR, van der Harst P, Ferguson JF, Crawford DC, Waite LL, Allison MA, Criqui MH, McDermott MM, Mehra R, Cupples LA, Hwang S-J, Redline S, Kaplan RC, Heiss G, Rotter JI, Boerwinkle E, Taylor HA, Eraso LH, Haun M, Li M, Meisinger Ca, O'Connell JR, Shuldiner AR, Tybjærg-Hansen A, Frikke-Schmidt R, Kollerits B, Rantner B, Dieplinger B, Stadler M, Mueller T, Haltmayer M, Klein-Weigel P, Summerer M, Wichmann H-E, Asselbergs FW, Navis G, Mateo LI, Brown-Gentry K, Goodloe R, Assimes TL, Becker DM, Cooke JP, Absher DM, Olin JW, Mitchell BD, Reilly MP, Mohler ER, North KE, Reiner AP, Kronenberg F, Murabito JM. Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium. Atherosclerosis. 2012;222:138-147.
- Shah B, Sha D, Xie D, Mohler ER, Berger JS. The relationship between diabetes, metabolic syndrome, and platelet activity as measured by mean platelet volume: the national health and nutrition examination survey, 1999-2004. Diabetes Care. 2012; 35:1074-1078.
- Grunwald JE, Ying G-S, Maguire M, Pistilli M, Daniel E, Alexander J, Whittock-MR, Parker C, Mohler E, Lo J C-M, Townsend R, Gadegbeku CA, Lash JP, Fink JC, Rahman M, Feldman H, Kusek JW, Xie D, Coleman M, Keane MG. Association between retinopathy and cardiovascular disease in patients with chronic kidney disease (from the Chronic Renal Insufficiency Cohort [CRIC] Study). Am J Cardiol. 2012;110: 246-253.
- Ouma GO, Jonas RA, U Usman MH, Mohler ER. Targets and delivery methods for therapeutic angiogenesis in peripheral artery disease. Vasc Med. 2012;17:174-192.
- Chen J*, Mohler ER*, Xie D, Shlipak M, Townsend RR, Appel L, Raj D, Ojo A, Schreiber M, Strauss L, Zhang X, Wang X, He J, Hamm LL, for the Chronic Renal Insufficiency Cohort (CRIC) Study Investigators. Risk factors for peripheral arterial disease among patients with chronic kidney disease. Am J Cardiol . 2012;110:136-141. *Notes: Chen and Mohler contributed equally to this article.
- Qayyum R, Snively BM, Ziv E, Nalls MA, Liu Y, Tang W, Yanek LR, Lange L, Evans MK, Ganesh S, Austin MA, Lettre G, Becker DM, Zonderman AB, Singleton AB, Harris TB, Mohler ER, Logsdon BA, Kooperberg C, Folsom AR, Wilson JG, Becker LC, Reiner AP. A meta-analysis and genome-wide association study of platelet count and mean platelet volume in African-Americans. PLoS Genet. 2012;8(3): e1002491.
- Layne AJ, Fairman RM, Jackson BM, Woo EY, Davis JT, Mohler ER, Wang GJ. Analysis of femoral artery intima-media thickness during the cardiac cycle. J Surg Res.
- Murabito JM, White CC, Kavousi M, Sun YV, Feitosa MF, Nambi V, Lamina C, Schillert A, Coassin S, Bis JC, Broer L, Crawford DC, Franceschini N, Frikke-Schmidt R, Haun M, Holewijn S, Huffman JE, Hwang S-J, Kiechl S, Kollerits B, Montasser ME, Nolte IM, Rudock ME, Senft A, Teumer A, van der Harst P, Vitart V, Waite LL, Wood AR, Wassel CL, Absher DM, Allison MA, Amin N, Arnold A, Asselbergs FW, Aulchenko Y, Bandinelli S, Barbalic M, Boban M, Brown-Gentry K, Couper DJ, Criqui MH, Dehghan A, den Heijer M, Dieplinger B, Ding J, Dörr M, Espinola-Klein C, Felix SB, Ferrucci L, Folsom AR, Fraedrich G, Gibson Q, Goodloe R, Gunjaca G, Haltmayer M, Heiss G, Hofman A, Kieback A, Kiemeney LA, Kolcic I, Kullo IJ, Kritchevsky SB, Lackner KJ, Li X, Lieb W, Lohman K, Meisinger Ca, Melzer D, Mohler ER, Mudnic I, Mueller T, Navis G, Oberhollenzer F, Olin JW, O'Connell J, O'Donnell CJ, Palmas W, Penninx BW, Petersmann A, Polasek O, Psaty BM, Rantner B, Rice K, Rivadeneira F, Rotter JI, Seldenrijk A, Stadler M, Summerer M, Tanaka T, Tybjaerg-Hansen A, Uitterlinden AG, van Gilst WH, Vermeulen SH, Wild SH, Wild PS, Willeit J, Zeller T, Zemunik T, Zgaga L, Assimes TL, Blankenberg S, Boerwinkle E, Campbell H, Cooke JP, de Graaf J, Herrington D, Kardia SLR, Mitchell BD, Murray A, Münzel T, Newman AB, Oostra BA, Rudan I, Shuldiner AR, Snieder H, van Duijn CM, Völker U, Wright AF, Wichmann H-E, Wilson JF, Witteman JCM, Liu Y, Hayward C, Borecki IB, Ziegler A, North KE, Cupples LA, Kronenberg F. Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. Circ Cardiovasc Genet. 2012;5:100-112.
- Mohler ER, Bundens Warner, Denenberg J, Medenilla E, Hiatt WR, Criqui MH. Progression of asymptomatic peripheral artery disease over 1 year. Vasc Med. 2012;17:10-16.
- Oka RK, Conte MS, Owens CD, Rapp J, Fung G, Alley HF, Giacomini JC, Myers J, Mohler ER. Efficacy of optimal long-term management of multiple cardiovascular risk factors (CVD) on walking and quality of life in patients with peripheral artery disease (PAD): protocol for randomized controlled trial. Vasc Med. 2012;17: 17-28.