The Heart

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Taking cholesterol medication before aneurysm repair improves outcomes

Patients taking statins before endovascular aortic aneurysm surgery more likely to survive.

Rupture of an abdominal aortic aneurysm is one of the most dramatic medical emergencies a person can face. It usually strikes without warning, killing approximately 50 percent of those who experience it before they reach a hospital. Of those who do get to a health facility alive, only about 50 percent survive. When diagnosed through screening, aortic aneurysms are carefully monitored for signs of enlargement, and surgical intervention often is needed to prevent rupture of the vessel. Now, University of Missouri researchers have found that patients who took cholesterol-lowering medications before endovascular surgery experienced fewer complications and better outcomes.

"Although this condition usually occurs in men older than 50 with a family history of the disease, anyone can have an abdominal aortic aneurysm," said Todd Vogel, associate professor and chief of the Division of Vascular Surgery at the MU School of Medicine, and lead author of the study. "Most patients with this disease are older and tend to have other health conditions such as high cholesterol. In an effort to prevent cardiovascular disease they take statin medications. These cholesterol-lowering medications protect blood vessels from plaque formation and stress, and in some cases can even slow the progression of aortic aneurysms. We wanted to understand the impact statin use has on surgical outcomes when repairing this type of aneurysm."

Vogel's research team reviewed nearly 20,000 cases where patients either had open surgery or an endovascular repair - a minimally invasive procedure that uses a catheter to access the aneurysm. The team then identified patients who took cholesterol-lowering medication before surgery.

"Our research showed that patients who took statins before either open or minimally invasive interventions had better outcomes compared to those who did not take statin medications," Vogel said. "The patients who took statins and had endovascular repairs had a 26 percent decrease in mortality up to one year after surgery. Patients who took statins and had traditional open procedures also did better, but the difference was not nearly as significant as with endovascular repair. The bottom line is that patients who used statins were more likely to survive during and after an elective endovascular procedure."

Additionally, the study showed that statin use also reduced post-surgical complications for patients with other health issues such as peripheral artery disease, a condition that causes arterial blockages of blood vessels in the limbs.

"This information could be beneficial to patients who are about to have elective endovascular abdominal aortic aneurysm repair," Vogel said. "However, further research is needed to assess the benefits of using statins before surgical repair of other types of aneurysms."

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Medication deintensification in older patients with low HbA1c or blood pressure

Among older patients with diabetes whose treatment has resulted in very low hemoglobin A1c (HbA1c) levels or blood pressure values, only 27 percent or fewer underwent medication deintensification, a lost opportunity to reduce overtreatment, according to an article published online by JAMA Internal Medicine.

New guidelines and the Choosing Wisely campaign recommend less aggressive treatment for older patients and those with limited life expectancy, such as a target HbA1c level of 7.5 percent or 8.0 percent. Another report recommends older patients seek to achieve a systolic blood pressure (SBP) of 150 mm Hg and no longer try to reach a level below 140 mm Hg. However, little is known about the process of medication deintensification, including how often it happens and for whom.

Jeremy B. Sussman, M.D., M.S., of the Veterans Affairs Center for Clinical Management Research, Ann Arbor, Mich., and coauthors describe the frequency of medication deintensification among older adults with diabetes using data from the U.S Veterans Health Administration. Participants included 211,667 patients older than 70 receiving active treatment in 2012. Active treatment was defined as blood pressure-lowering medications other than angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, or glucose-lowering medications other than metformin hydrochloride.

More than half of the 211,667 participants actively treated for blood pressure had moderately low (SBP of 120 to 129 mm Hg or diastolic blood pressure [DBP] less than 65 mm Hg) or very low (SBP less than 120 mm Hg or DBP less than 65 mm Hg) blood pressure levels. Treatment was deintensified in 16 percent of the 25,955 patients with moderately low blood pressure levels and in 18.8 percent of the 81,226 patients with very low blood pressure levels. Of the patients with very low blood pressure levels whose treatment was not deintensified, only 0.2 percent had a follow-up blood pressure measurement that was elevated (≥ 140/90 mm Hg), according to the results.

The actively treated HbA1c group included 179,991 individuals. Treatment was deintensified in 20.9 percent of the 23,769 patients with moderately low HbA1c (6.0 percent to 6.4 percent) levels and in 27 percent of the 12,917 patients with very low HbA1c (less than 6.0 percent). Of the patients with very low HbA1c whose treatment was not deintensified, fewer than 0.8 percent had a follow-up elevated HbA1c (≥ 7.5 percent), the results indicate.

The authors acknowledge several reasons why low blood pressure or HbA1c levels have a weak association with medication deintensification. Those reasons include requiring a shift in how treatment is understood by patients and explained by health care professionals. Also, guidelines and performance measures are more focused on preventing underuse than overuse.

"Future performance management systems should consider how to create incentives against both overuse and underuse to motivate appropriate treatment, including deintensification of treatment that is personalized to individual needs, risks and benefits. In addition, health care professionals should assess the harms of intensive therapy just as they do the benefits. These changes may require new clinical decision support tools, new performance measures and, most important, a new perspective focusing on personalized, appropriate care," the authors conclude.

Research Letter: Appropriate Prescribing for Patients with Diabetes

A research letter Tanner J. Caverly, M.D., M.P.H., of the Ann Arbor Veterans Affairs Center for Clinical Management Research, Michigan, and coauthors examined the beliefs of primary care health-care professionals (PCPs) as to how receptive they might be to recommendations for limiting medications for some older patients, including a hypothetical scenario involving a 77-year-old man with diabetes at risk for hypoglycemia. The authors surveyed Department of Veterans Affairs PCPs, including physicians, nurse practitioners and physician assistants. Of 1,222 eligible PCPs, 594 returned usable surveys. The results indicate that almost half of the PCPs reported that they would not worry about the harms of tight glycemic control for an older patient at risk for hypoglycemia. Nearly one-quarter of PCPs reported they would worry that deintensifying medication for the man in the hypothetical situation could leave them vulnerable to future malpractice claims.

Commentary: Targeting Vascular Risk Factors in Older Adults: From Polypill to Personalized Prevention

A related commentary by Enrico Mossello, M.D., Ph.D., of the University of Florence and Careggi Teaching Hospital, Florence, Italy, also is available.

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Scientists identify genes associated with peripheral artery disease

Researchers from the RIKEN Center for Integrative Medical Sciences have worked with a number of universities and hospitals in Japan to use gene maps in the Japanese population to identify three genes associated with peripheral artery disease, a common but debilitating disease that makes walking painful and that can, in serious cases, lead to limb loss. The work, published in PLOS ONE, is the first to identify specific genetic factors with the condition.

PAD, though not as well-known as heart attacks and strokes, is also a condition caused by atherosclerosis--deposits of plaque on the inner lining of blood vessels. In addition to limb pain and difficulty walking, it can lead to major cardiovascular and cerebrovascular events, and is estimated to be the third leading cause of death associated with atherosclerosis.

The researchers began by collecting genetic information on 735 people who suffered from PAD from the BioBank Japan project and compared their genomes with 3,383 people without the condition taken from the general population. They looked for simple genetic variations--called single nucleotide polymorphisms, or SNPs--that were more common in the patients than in controls. There were a large number of SNPs that were more common in patients, but the number of patients was not sufficient to allow them to identify which were really significant. They next took the 500 most likely candidate gene variations and analyzed the genes of a further 1,150 cases and 16,752 controls to look for SNPs that were significantly more common in the PAD patients. They found 13 that were statistically significant. They added a further 1,229 cases, and based on this analysis identified three gene loci that were clearly associated with the disease. "It seems," says Kouichi Ozaki of the IMS Laboratory for Cardiovascular Disease, one of the first authors of the study, "that people with these three gene polymorphisms are particularly vulnerable to this disease."

"The three gene polymorphisms were all found to be in the region flanking two different genes," continues Ozaki, "so we needed to find out which gene they were affecting and how." The first polymorphism, on chromosome 13, was found to be associated with the expression of IPO5, encoding a protein that is involved in ridding peripheral arteries of lipoprotein A--which forms part of LDL, or bad, cholesterol. A second was found to be associated with a gene that encodes a receptor of endothelin-1, a peptide that promotes the constriction of blood vessels and inflammation--two processes known to be associated with PAD. And the third was associated with a gene that encodes a protein called histone deacetylase-9, that can regulates cell growth and may be responsible for the thick blood vessel walls typical of PAD.

"What is important," says Ozaki, "is that although this study does help to identify people who might be at risk for PAD, the findings could also be used to elucidate the mechanism through which PAD arises, and hence could help to identify therapeutic targets for future treatments. It is important to remember, however, that the study was done in a Japanese population, so that there could be different patterns in other populations, and further studies should be done in other groups."

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How mechanical stretching forces impact human vascular cells

Cardiovascular diseases are globally the main cause of death and vascular tissue integrity is important for the proper functionality and homeostasis of the blood system. Therefore, a profound understanding of vascular cell physiology is beneficial in successfully treating vascular diseases and for improving strategies for regenerative medicine. Blood vessels walls are mainly composed of smooth muscle cells (SMCs) and endothelial cells (ECs). These cells are continuously subjected to a repeated mechanical stretching (cyclic tensile strain) caused by the pulsatile blood flow driven by the heart.

Dr. Ralf Kemkemer and colleagues located at the Max Plank Institute for Intelligent Systems, The Karlsruhe Institute of Technology, the University of Heidelberg and Reutlingen University in Germany assumed that SMCs and ECs might react differently to mechanical perturbation in their in vitro study providing evidence for cell-type specific dynamic mechano-responses. In a report published in the Oct. 2015 issue of Experimental Biology and Medicine they cultured SMCs and ECs separately on elastic membranes and subjected them to a range of uniaxial periodic stretching with frequencies from 0.01 to 1 Hz with constant amplitude of 8 percent. It is know that different cell types adapt their cell body upon exposure to uniaxial cyclic stretching by perpendicular alignment to the direction of stretch. SMCs and ECs show such a morphological adaption response. Dr. Kemkemer said "Due to the novel experimental method of time-lapse microscopy during the stretching experiment we were also able to quantify the kinetics of that adaptation. Strikingly, we could reveal that the dynamic reorientation response of SMCs and ECs show different levels and speed of reorientation dependent on the stretch frequency. Furthermore, a cell-type dependent minimum threshold frequency is detected below which no responses are detectable." These results were accompanied by matching data for actin cytoskeleton reorientation, cell-matrix adhesion realignment and size, GTPase activities (RhoA and Rac1), and membrane protrusion activity depending on the vascular cell type and the stretching conditions.

Overall, these promising results indicate a cell-type dependent mechano-response of ECs and SMCs and may allow cell-type specific activation of vascular cells by frequency-selective mechanical stretching. In addition, understanding in more detail the reactions of vascular cells to mechanical perturbations can be helpful in elucidating physiological and pathological aspects in vessel biology.

Dr Steven R. Goodman, Editor-in-Chief of Experimental Biology and Medicine said "Greiner et al have demonstrated different properties of ECs and SMCs in response to mechanical stretch. These studies provide improved insight into how vascular cells react to mechanical stresses in the normal and pathological cardiovascular system".

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New drug candidate is promising therapeutic option for angiogenic retinal diseases

Research models show that a small peptide provents the overgrowth of blood vessels in the eye's retina - and can be delivered in the form of eye drops

A research team led by scientists at Beth Israel Deaconess Medical Center (BIDMC) and the University of New Mexico School of Medicine has identified a small molecule that treats animal models of aged macular degeneration (AMD) and retinopathy of prematurity (ROP) by preventing the overgrowth of blood vessels that are characteristic of these two retinal diseases.

The new findings, described in the journal Science Translational Medicine, show that this molecule, named Vasotide in this paper, can be delivered in the form of eye drops, a discovery that offers a promising alternative to current therapies for these retinal diseases, which require monthly injections of large molecules directly into the eyeball.

"Angiogenesis, the abnormal overgrowth of blood vessels, underlies many severe diseases, and when angiogenesis develops in the eye's retina it causes decreased vision and can even lead to blindness," said the study's corresponding author Richard L. Sidman, MD, an investigator in the Department of Neurology at BIDMC and Bullard Professor of Neuropathology (Neuroscience), Emeritus, at Harvard Medical School. Sidman is a leader in the field of mammalian brain development whose studies have focused on disease mechanisms in mouse neuro-genetic disorders, including disorders of the retina, the light-sensitive layer of brain tissue at the inner surface of the back of the eye that transmits image information to other parts of the brain via the optic nerve.

AMD develops in approximately 14 million older individuals throughout the U.S. This overgrowth of blood vessels damages the photoreceptor cells near the center of the eye's retina, resulting in the loss of central vision so that individuals can no longer see objects directly in front of them. Retinopathy of prematurity (ROP) occurs in premature infants, who develop a similar retinal disease as a side effect of high-level oxygen treatments used until their lungs develop sufficiently to handle the much lower oxygen levels in room air.

In previous investigations, the study's co-senior authors Renata Pasqualini, PhD, and Wadih Arap, MD, PhD, of the University of New Mexico, had developed a laboratory screening technique called in vivo phage display and used it to identify an early version of this peptide. (A peptide is a short chain of linked amino acids, a small version of a protein.)

In this new study, Sidman and his coauthors tested Vasotide in three separate animal models - two forms of AMD and one form of ROP. Their results showed that Vasotide led to decreased blood vessel growth in all three models when the agent was administered by either systemic injection, or through eye drops.

"Under normal circumstances, a protein called vascular endothelial growth factor [VEGF] binds to pertinent endothelial cell receptors lining the blood vessels, causing these cells to multiply, migrate, and form new blood vessels," he noted. "Vasotide is the only external agent that uniquely blocks VEGF from binding to two different endothelial receptor molecules -- VEGF receptor-1 and neuropilin-1 -- to keep excessive blood vessels from forming."

Although a few other anti-VEGF drugs have been approved for therapy of AMD, they must be delivered directly into the eye through monthly intravitreal injections. "These treatments are costly, require highly skilled professional execution, and, in rare cases, can cause bleeding or infection in the eye," said Sidman. Furthermore, he added, not all patients respond to these agents and, for many patients, responsiveness decreases after about six months.

"In addition to future clinical trials on AMD and ROP, we think that diabetic retinopathy and certain forms of cancer may also prove to be responsive to Vasotide," said Sidman.

"This is a very exciting development in that it has the potential to allow the self-administration of a sight-saving drug to patients with AMD," said Harold F. Dvorak, MD, Mallinckrodt Distinguished Professor of Pathology at HMS and BIDMC, whose laboratory first identified the VEGF signaling protein nearly 30 years ago.

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