theHeart.org feature CWRUmedicine research on shared molecular pathway identified for cardiac and vascular disease

theHeart.org | US researchers have pinpointed a genetic factor that affects diseases of both the heart and blood vessels and identified a molecular pathway shared between the two. They propose that a subset of human heart and vascular disease may be due to deficiency of this genetic factor, known as Krüppel-like factor 15 (Klf15), and that amending the pathway in some way could help ameliorate both diseases.

Dr Saptarsi M Haldar (Case Western Reserve University, Cleveland, OH) and colleagues report their findings online April 7, 2010 in Science Translational Medicine.

“Often, people think of cardiac disease and vascular disease as separate entities, but they often run together—for example, in Marfan’s syndrome or in aging, when there are degenerative changes to both the heart and blood vessels,” senior author Dr Mukesh K Jain (Case Western Reserve University) explained to heartwire.

Some years ago, his research team identified the genetic factor Klf15 and showed that it was expressed in both the heart and aorta; they also demonstrated that in human tissue from patients with heart failure or aortic aneurysmal disease, the expression of Klf15 was markedly reduced. The new research is an attempt to identify a common molecular pathway for these effects that could represent a potential therapeutic target.

Both heart and blood vessels affected by Klf15 deficiency

“We hypothesized that maybe the absence of Klf15 or its relative deficiency might be unhealthy, so we generated mice to mimic this,” Jain explains. The mice, which were completely deficient in Klf15, were then stressed using angiotensin 2, and they developed heart failure and, “quite unusually,” aneurysms at the same time, he notes, “so we showed that both the heart and blood vessels of the mice were affected by deficiency of Klf15.

“We then wondered whether there was a common molecular mechanism that might explain this shared pathology,” he continued.

They went on to show that enhancement of the activity of p53—a protein most often associated with protection against cancer—appeared to be causing the adverse effects in the setting of Klf15 deficiency.

Furthermore, they showed that Klf15 functions as a “molecular brake” on p53 function by inhibiting p53 acetylation, which is a critical “on” switch for this protein.

These molecular effects were operative both in the Klf15-deficient mice and in human tissues from heart-failure patients, which were also found to be Klf15 deficient.

Boosting Klf15 production or blocking p53 acetylation may be of benefit

“This now lends us the opportunity to try to identify a chemical compound that might either boost the activity of Klf15 or somehow block the acetylation of p53, which might help ameliorate diseases affecting both the heart and blood vessels,” Jain noted. As well as aging and Marfan’s syndrome, this includes peripartum cardiomyopathy and in particular a subset of women who develop aortic dilatation as well as heart failure in the setting of pregnancy, he explained.

The discovery of new molecular pathways that are amenable to therapeutic manipulation is of immense clinical value,” he says, adding that research into compounds targeting Klf15 or p53 is already under way. Researchers have already demonstrated that a compound called curcumin, the active constituent of the spice turmeric that is often used in Asian cooking, is able to block the acetylation of p53, and they are actively trying to identify other compounds that could enhance the expression of Klf15.

Read the abstract on CWRUmedicine.org

CWRUmedicine and UH develops New Drugs to improve oxygen delivery to tissues

Case Western Reserve University and University Hospitals are pleased to announce the awarding of a $4.7 million contract from the Defense Advanced Research Projects Agency (DARPA) to Dr. Jonathan Stamler, Director of the Institute for Transformative Molecular Medicine (ITMM).

The grant will fund development of a new class of drugs that selectively vasodilate under hypoxia and thereby enhance performance at high altitude (e.g. soldiers on mountains in Afganistan).

It is also anticipated that the grant will generate new physiologic information on high-altitude adaptation and new therapeutic interventions to treat patients suffering from conditions where oxygen delivery is impaired, including heart failure, ischemic heart disease, stroke, sickle cell disease and diabetes.

Studies will involve a transdisciplinary approach, including the Department of Anesthesia (James Reynolds) the division of Pulmonary Medicine (Kingman Stroh), and the Harrington-McLaughlin Cardiovascular Institute (Sahil Parikh).

Learn more at CWRUmedicine.org

Armand Krikorian, MD publishes “Comparisons of Different Insulin Infusion Protocols”

“Comparisons of different insulin infusion protocols: a review of recent literature”

Curr Opin Clin Nutr Metab Care. 2010 March
Krikorian A, Ismail-Beigi F, Moghissi ES.

Division of Clinical & Molecular Endocrinology
Case Western Reserve University
University Hospitals, Cleveland

Read the abstract at CWRUmedicine.org

Journal of Lipid Research publish Dr Charles Hoppels recent work on the inner mitochondrial membrane

“Separation and characterization of cardiolipin molecular species by reverse-phase ion pair high-performance liquid chromatography-mass spectrometry”

J Lipid Res. 2010 Apr
Minkler PE, Hoppel CL.

Center for Mitochondrial Diseases, Division of Pharmacology, Department of Medicine, Case Medical Center, University Hospitals, Cleveland

Read the full abstract on CWRUmedicine.org

Message from Richard A. Walsh, MD

We have over 250 full time faculty, 120 medical housestaff, 80 fellows and 400 support staff working at the CWRU School of Medicine, University Hospitals Case Medical Center and the Cleveland VA Medical Center Wade Park Campus.

We are proud of our premier, extramurally funded research programs, our delivery of high-quality, cost-effective patient care at University Hospitals (ranked as a Top Ten Health Care System by Thompson Reuters) and our VA Hospital (ranked first in the entire VA system for Health Care Delivery Measures).

We are also deeply committed to medical student, graduate student and post graduate training.

Our faculty, trainees and staff are committed to the highest standard of excellence in all of our activities in a collegial, integrated and interactive work environment.

We invite you to navigate our website to learn more about who we are and what we do. Visit us at CWRUmedicine.org
If we can be of help, please contact us.

Richard A. Walsh, MD

Chair, Department of Medicine

Which social tool do you use?

It doesn’t take much effort to see the impact social media is having on almost every avenue of our lives, both professionally and personally. Tools such as LinkedIn, Twitter and Facebook, just to name a few, are changing the way and frequency in which we communicate. It should be no surprise, then, that even Healthcare would find itself impacted by the influence and immediacy that social media provides.

We value your opinion and want to know what tools you use to stay up with the latest news and information. Give us your thoughts. Take our poll on social media in healthcare, and let us know what tool(s) you use.

Take the Poll and see results at CWRUmedicine.org

New Research Published on Antibiotic resistance determinants in Acinetobacter spp

We explored the association of antibiotic-resistant phenotypes and genotypes in Acinetobacter spp with clinical outcomes and characteristics in 75 patients from a major military treatment facility. Amikacin resistance was associated with nosocomial acquisition of A baumannii, and carbapenem resistance and bla(OXA-23) were associated with the need for mechanical ventilation. The presence of bla(OXA-23) also correlated with longer hospital and ICU stay. Associations between bla(OXA-23) and complexity, duration, and changes made to antibiotic regimens also existed. Copyright 2010.

Learn more at CWRUmedicine.org

Read why Cushing’s syndrome: Why is diagnosis so difficult?

Practicing and perfecting the art of medicine demands recognition that uncertainty permeates all clinical decisions. When delivering clinical care, clinicians face a multiplicity of potential diagnoses, limitations in diagnostic capacity, and “sub-clinical” disease identified by tests rather than by clinical manifestations. In addition, clinicians must recognize the rapid changes in scientific knowledge needed to guide decisions. Cushing’s syndrome is one of several disorders in which there may be considerable difficulty and delay in diagnosis. This article describes a current model of clinical reasoning, some of its challenges, and the application of the principles of clinical epidemiology to meet some of those challenges.

Learn more at CWRUmedicine.org

Learn about the Clinical Role of Exercise Training in Management of Patients With Chronic Heart Failure

J Cardiopulm Rehabil Prev. 2010 Mar

Prior exercise research and the recently completed HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training) trial indicate that regular exercise represents an effective therapy in the management of patients with stable chronic heart failure (HF) due to left ventricular systolic dysfunction. This review summarizes the results from these studies and provides a guide for prescribing exercise. Regular aerobic-type exercise training improves exercise capacity; does not worsen and may, in fact, mildly improve cardiac function; and partially improves other physiological abnormalities that develop because of chronic HF (eg, autonomic and skeletal muscle function). Regular exercise is safe, improves health status, and modestly reduces ( approximately 15%) combined risk for cardiovascular death or HF-related hospitalization. Even greater physiological and clinical benefits appear likely in patients with HF who adhere to a higher volume of exercise (eg, 6 MET-hr per week). The exercise regimen should include an aerobic-type activity performed at least 30 minutes, 5 or more days per week, and at an intensity approximating 55% to 80% of heart rate reserve. Resistance training should be considered for patients who first demonstrate they are able to tolerate aerobic exercise training. Common to other interventions that also rely on human behavior, long-term adherence to exercise in patients with HF remains a challenge and requires additional research to determine strategies aimed at improving compliance. Areas of needed research include identifying which patient subgroup(s) benefits the most and determination of the optimal intensity, duration, and frequency of exercise needed to maximize clinical benefits and attenuate fatigue.

Read the full article on CWRUmedicine.org

New Research on Older Patients with Acute Myeloid Leukemia in their first complete remission

“Effect of Age on Outcome of Reduced-Intensity Hematopoietic Cell Transplantation for Older Patients With Acute Myeloid Leukemia in First Complete Remission or With Myelodysplastic Syndrome”

McClune BL, Weisdorf DJ, Pedersen TL, da Silva GT, Tallman MS, Sierra J, Dipersio J, Keating A, Gale RP, George B, Gupta V, Hahn T, Isola L, Jagasia M, Lazarus H, Marks D, Maziarz R, Waller EK, Bredeson C, Giralt S.
J Clin Oncol. 2010 Mar 8

PURPOSE:
Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) primarily afflict older individuals. Hematopoietic cell transplantation (HCT) is generally not offered because of concerns of excess morbidity and mortality. Reduced-intensity conditioning (RIC) regimens allow increased use of allogeneic HCT for older patients. To define prognostic factors impacting long-term outcomes of RIC regimens in patients older than age 40 years with AML in first complete remission or MDS and to determine the impact of age, we analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

PATIENTS AND METHODS:
We reviewed data reported to the CIBMTR (1995 to 2005) on 1,080 patients undergoing RIC HCT. Outcomes analyzed included neutrophil recovery, incidence of acute or chronic graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, disease-free survival (DFS), and overall survival (OS).

RESULTS:
Univariate analyses demonstrated no age group differences in NRM, grade 2 to 4 acute GVHD, chronic GVHD, or relapse. Patients age 40 to 54, 55 to 59, 60 to 64, and >/= 65 years had 2-year survival rates as follows: 44% (95% CI, 37% to 52%), 50% (95% CI, 41% to 59%), 34% (95% CI, 25% to 43%), and 36% (95% CI, 24% to 49%), respectively, for patients with AML (P = .06); and 42% (95% CI, 35% to 49%), 35% (95% CI, 27% to 43%), 45% (95% CI, 36% to 54%), and 38% (95% CI, 25% to 51%), respectively, for patients with MDS (P = .37). Multivariate analysis revealed no significant impact of age on NRM, relapse, DFS, or OS (all P > .3). Greater HLA disparity adversely affected 2-year NRM, DFS, and OS. Unfavorable cytogenetics adversely impacted relapse, DFS, and OS. Better pre-HCT performance status predicted improved 2-year OS. CONCLUSION: With these similar outcomes observed in older patients, we conclude that older age alone should not be considered a contraindication to HCT.