Heart attack: Use of amino acid supplement

Use of amino acid supplement following a heart attack provides no benefit, may be harmful

Use of the amino acid supplement L-arginine following a heart attack does not improve certain cardiac functions and measurements and may be associated with an increased risk of death, according to a study in the January 4 issue of JAMA.

L-arginine is a widely available dietary supplement and is publicized as having benefits for patients with hypertension, angina, heart failure and sexual dysfunction, according to background information in the article. Prior studies suggest that L-arginine has the potential to reduce vascular (blood vessel) stiffness.

Steven P. Schulman, M.D., of Johns Hopkins Medical Institutions, Baltimore, and colleagues conducted the Vascular Interaction with Age in Myocardial Infarction (VINTAGE MI) clinical trial to test whether administering L-arginine to patients following a first ST-segment elevation myocardial infarction (STEMI; a certain pattern on an electrocardiogram following a heart attack) over a 6-month period would decrease vascular stiffness and improve ejection fraction (a measure of how much blood the left ventricle of the heart pumps out with each contraction).

The randomized, double-blind, placebo-controlled trial included 153 STEMI patients; 77 were 60 years or older. Participants were enrolled from February 2002 to June 2004. Patients were randomly assigned to receive L-arginine (goal dose of 3 g three times a day) or matching placebo for six months.

The researchers found: "The VINTAGE MI study demonstrated that 6 months of L-arginine added to standard postinfarct medications did not reduce noninvasive measures of vascular stiffness, improve ejection fraction, or improve clinical outcomes. To the contrary, we noted a possible increased risk of death in older patients after infarction while taking L-arginine compared with those taking a placebo, leading to the early termination of the study. These findings have broad public health implications given the increasing availability and use of L-arginine in patients with and without established cardiovascular diseases."

Death occurred in 6 patients (8.6 percent) in the L-arginine group died during the 6-month study period vs. none in the placebo group.

"In conclusion, L-arginine therapy should not be given to patients following a myocardial infarction. It neither alters noninvasive measures of vascular stiffness nor improves left ventricular function. L-arginine therapy in older patients with diffuse atherosclerosis may worsen clinical outcomes," the authors write.

JAMA and Archives Journals

Repairing hearts: In laboratory experiments

Researchers discover 'sticky' proteins fuse adult stem cells to cardiac muscle, repairing hearts

HOUSTON-Cardiologists are increasingly using adult stem cells in clinical trials to repair hearts following heart attacks, but no one has understood how the therapy actually works. Now, in animal experiments, researchers at The University of Texas M.D. Anderson Cancer Center have deconstructed the process, describing how the stem cells fuse with heart muscle cells to create new cells that repopulate the ailing organ.

In a paper posted Feb 15 at Online First of the journal Circulation Research, investigators found that this fusion is only possible if two cell adhesion proteins that stick to each other like Velcro are available to attach a stem cell to a heart muscle cell. They show in cell and mice studies that if either protein is blocked, the two cells don't blend.

The investigators also discovered that these new cells, once fused, divide again in an attempt to produce enough cells to help the heart contract.

"The accepted dogma is that heart cells cannot divide, but we show that fusing stem cells onto muscle cells bestows these cells with a new and wonderful ability to divide again to repair the heart," says the study's lead author Edward T. H. Yeh, M.D., professor and chair of the Department of Cardiology at M. D. Anderson Cancer Center.

"It is marvelous that adult stem cells can help heal a heart, and by understanding the mechanisms involved, we may be able to refine and optimize the process," he says.

But there are not enough natural stem cells available in a body to mount an effective repair response to a heart attack, Yeh says, which is why researchers and clinicians are focused on boosting that response. And in the future, given what the researchers also have discovered about how stem cells can build new cells to line blood vessels, it may be possible to "choose to ether augment rebuilding of heart muscle or restoration of blood vessels, depending on what is therapeutically best for the patient."

This study is the latest undertaken in a focused research program conducted by Yeh and a team of researchers at M. D. Anderson, the Texas Heart Institute at St. Luke's Episcopal Hospital and The University of Texas Health Science Center at Houston to investigate stem cell repair of heart and vascular tissue. In an effort to understand and treat cardiotoxicity related to cancer treatment, M. D. Anderson has one of the largest cardiology programs at any cancer center.

In 2003, the researchers demonstrated that adult stem cells circulating in blood can be used to repair hearts, and that it is not necessary to take the stem cells from bone marrow. In 2004, they found stem cells use different methods to morph into the two kinds of cells needed to restore heart function. In animal studies, they showed that to make new heart muscle cells, the human stem cells fuse onto cardiac cells to produce new muscle (myocyte) cells. But to form new blood vessel cells, the stem cells "differentiate" or mature by themselves to provide new endothelial cells that patch vessel damage.

In this study, they looked into the mechanism by which stem cells fuse to cardiac myocytes. In laboratory experiments, they added adult human stem cells (those that express the CD34+ protein known to be associated with stem cells) to cardiac muscle cells from mice. After 24 hours, some fusion occurred spontaneously-cells were created that had both human and murine protein signatures-but this occurred at a very low rate. They then created conditions that reflect an ongoing heart attack, such as exposing the cells to low oxygen, and saw production of two cytokine molecules, IL-6 and TNF-a, that are part of an inflammatory reaction and which are known to be released when a heart attack occurs. Next, the researchers exposed the cells to all three conditions simultaneously (hypoxia, and extra IL-6 and TNF-a) and found that cell fusion increased 10-fold. "It went from .2 percent of cells becoming fused to 2 percent," Yeh says.

The researchers noted that as a consequence of the experimental "heart attack," expression of two cell surface adhesion molecules was increased. Expression of the protein a4ß1 was induced in the mouse cardiac cells and VCAM-1 was expressed by human stem cells. "The two molecules act like a pair, and stick to each other," Yeh says. "This is the first step to the fusion process."

To double-check that production of a4ß1 and VCAM-1 were critical to cell fusion, the research team added antibodies to each protein into the cell culture, and found fusion couldn't occur.

They then tested the fusion process in mice that don't have an immune system, so they cannot reject the human stem cells. They induced a heart attack in the animals, injected stem cells and saw production of fused cells with signatures donated by each species. However, fusion was markedly reduced in mice given antibodies to a4ß1 and VCAM-1, Yeh says.

The researchers tested whether the adhesion molecules interrupted production of new blood vessel endothelial cells, and found that because fusion is not involved, formation of these cells was not affected. Then they blocked vascular endothelial growth factor (VEGF), a protein known to spur the formation of new blood vessels, and found that if VEGF isn't available, stem cells will not differentiate into new endothelial cells.

Finally, Yeh tested the newly fused heart muscle cells to see what they did after they formed. Heart muscle cells do not divide, so the researchers did not know whether the new fused cells were an endpoint in themselves, designed to replace dying cardiac muscle, or whether they could give rise to other new cells. They discovered that fused cells took on some "stemness"-they divided, and continued to do so as long as new tissue is needed, but not long enough to produce a tumor. "In mice, we have found this process can continue for months," Yeh says.

"We show in these animal experiments that human adult stem cells can form new blood vessels and heart muscle cells, and knowing how these two different processes can be blocked could be very useful in determining the relative contribution of each toward heart repair," he said.

University of Texas M. D. Anderson Cancer Center
http://www.brightsurf.com/news

Carvedilol - Antioxidant activity

Antioxidant activity of carvedilol in cardiovascular disease

Dandona, Paresh; Ghanim, Husam; Brooks, David P

Oxidative and inflammatory stresses are cardinal in the pathogenesis of hypertension and atherosclerosis. Oxidative stress also leads to the induction of inflammation through the activation of proinflammatory transcription factors.
Understanding the mechanisms leading to oxidative stress and the means of suppressing it are important in controlling complications related to atherogenesis, since oxidative and inflammatory stress are important in the pathogenesis of atherosclerosis.
The failure of chemical antioxidants [which scavenge reactive oxygen species (ROS)], such as vitamins E and C, has led to further exploration of the ROS-suppressive effects of drugs used in the treatment of cardiovascular disease.
Carvedilol has been shown to possess both ROS-scavenging and ROS-suppressive effects, and its use is associated with a reduction in oxidative stress. Furthermore, anti-inflammatory effects of carvedilol have now been described.
Although further clinical investigations are required, these properties may contribute to the improvement in clinical outcomes observed with carvedilol.

Journal of Hypertension. 25(4):731-741, April 2007.

Diabetes and hypertension: losartan with atenolol

Effect of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension

Flammer, Andreas J; Hermann, Frank; Wiesli, Peter; Schwegler, Beat

Objective: It has been shown that angiotensin-converting enzyme inhibition or angiotensin receptor blockade may improve endothelial dysfunction, an early manifestation of atherosclerosis, in patients with diabetes. Whether this protective effect is mediated through blood pressure-lowering effects or other specific mechanisms such as a reduction in oxidative stress is not clear. We investigated the influence of losartan, compared with atenolol, on endothelial function and oxidative stress in patients with type 2 diabetes and hypertension.

Methods: Thirteen patients were included in this randomized, double-blind, crossover study; they received losartan 50 mg twice daily for 4 weeks followed by atenolol 50 mg twice daily or vice versa. Concomitant medication with renin-angiotensin blocking agents or beta-blockers was withdrawn, whereas other medication remained unchanged. At baseline and after each treatment period, flow-mediated dilation of the brachial artery and oxidative stress were measured in serum samples.

Results: Flow-mediated dilation was increased significantly after 4 weeks' treatment with losartan (3.4 +/- 0.44%) compared with atenolol (2.58 +/- 0.42%; P = 0.01). 8-Isoprostanes, a marker of oxidative stress, were significantly reduced in the losartan group compared with baseline (0.039 +/- 0.007 versus 0.067 +/- 0.006 ng/ml; P = 0.01), but did not differ from baseline with atenolol. Glucose, hemoglobin A1c, highly sensitive C-reactive protein, lipids and systolic blood pressure remained unaltered, whereas diastolic blood pressure tended to be lower in the atenolol group.

Conclusions: This study demonstrates that losartan significantly improved endothelial function in type 2 diabetes patients with hypertension compared with atenolol. This must be independent of the blood pressure-lowering effect of losartan and is probably caused by an antioxidative effect of the angiotensin receptor blocker.

Journal of Hypertension. 25(4):785-791, April 2007.

Triple antiplatelet therapy

Effects of aspirin, clopidogrel and dipyridamole administered singly and in combination on platelet and leucocyte function in normal volunteers and patients with prior ischaemic stroke

Zhao L, Fletcher S, Weaver C, Leonardi-Bee J, May J, Fox S, Willmot M, Heptinstal S, Bath P.
Division of Stroke Medicine, South Block, D Floor, Queen's Medical Centre, Nottingham NG7 2UH UK

The aim of this study was to assess whether triple antiplatelet therapy is superior to dual and mono therapy in attenuating platelet and leucocyte function.
Aspirin (A), clopidogrel (C), and dipyridamole (D) were administered singly and in various combinations (A, C, D,AC,AD, CD,ACD), each for two weeks (without washout) to 11 healthy subjects and to 11 patients with previous ischaemic stroke in two randomised multiway crossover trials. At the end of each two-week period platelet aggregation, platelet-leucocyte conjugate formation and leucocyte activation were measured ex vivo blinded to treatment. Platelets were stimulated with collagen; additional measurements were made with adenosine diphosphate (ADP), platelet activating factor (PAF), adrenaline and the combination of, ADP, PAF and adrenaline.
Results show that in the presence of collagen, ACD was superior to all antagonists or combinations, except AC, in reducing aggregation, platelet-leucocyte conjugate formation, and monocyte activation (all p<0.05). ACD was also more potent than other treatments, except AC, in inhibiting the aggregation and platelet-monocyte conjugate formation induced by the combination of ADP, PAF and adrenaline. The effects were similar in both volunteers and stroke patients. No serious adverse events or major bleeding events occurred.
Triple antiplatelet therapy did not appear to be more effective than combined aspirin and clopidogrel in moderating platelet and leucocyte function. Any additional clinical benefit provided by dipyridamole may be through other mechanisms of action.

Thromb Haemost. 2005 Mar;93(3):527-34.

Ventricular septal defect

What is a ventricular septal defect?
A ventricular septal defect (VSD) is an abnormal opening in the wall (septum) that divides the two lower chambers of the heart (ventricles). This opening allows blood from either side of the heart to cross into the opposite ventricle.

Usually, because the left side of the heart is at a higher pressure than the right side, the blood from the left ventricle flows to the right ventricle and, subsequently, back to the lungs. This abnormal shunting of oxygen-rich blood back to the oxygen-poor right side of the heart is referred to as a left-to-right shunt.
Normally, this will not cause cyanosis (bluish coloration of the skin caused by oxygen-poor blood reaching the general circulation). However, because the right side of the heart and the blood vessels in the lungs are not built to withstand increased volumes and pressures, left-to-right shunting eventually may result in heart failure and pulmonary hypertension (elevated blood pressure in the pulmonary blood vessels).

What are the signs and symptoms of a ventricular septal defect?

Signs and symptoms depend on the VSD’s size and how much blood abnormally flows across the defect. Symptoms may include:
• Breathing difficulties
• Enlarged heart
• Irregular heart rhythm (dysrhythmias), especially atrial dysrhythmias
• Heart failure

What are surgical treatments for VSD?
The surgical option for a VSD is ventricular septal defect closure.
How is the surgery performed?
Ventricular septal defect closure is considered open-heart surgery, meaning the heart will have to be opened and the patient’s blood flow will have to be diverted to a heart-lung bypass machine during the repair.
The chest is opened via a sternotomy incision, and the patient is connected to the heart-lung bypass machine. Depending on the location of the defect, an incision will be made in the right atrium, the pulmonary artery or the outflow tract of the right ventricle (infundibulum). A patch is created by the surgeon from either the patient’s pericardial tissue or a synthetic material such as Dacron. The patch then is sutured into place to close the defect. The atrial, pulmonary artery or infundibular incision is closed with sutures, and the remainder of the operation is completed.
If the patient has no other cardiac defects, this operation usually is considered a cure and no further surgeries should be needed.

Synthetic Pacemaker Channel

Gene Transfer of a Synthetic Pacemaker Channel Into the Heart
A Novel Strategy for Biological Pacing

Yuji Kashiwakura, MD, PhD; Hee Cheol Cho, PhD; Andreas S. Barth, MD; Ezana Azene, PhD; Eduardo Marbán, MD, PhD
From the Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Md.

Background— One key element of natural pacemakers is the pacemaker current encoded by the hyperpolarization-activated nucleotide-gated channel (HCN) gene family. Although HCN gene transfer has been used to engineer biological pacemakers, this strategy may be confounded by unpredictable consequences of heteromultimerization with endogenous HCN family members and limited flexibility with regard to frequency tuning of the engineered pacemaker.

Methods and Results— To circumvent these limitations, we converted a depolarization-activated potassium-selective channel, Kv1.4, into a hyperpolarization-activated nonselective channel by site-directed mutagenesis (R447N, L448A, and R453I in S4 and G528S in the pore). Gene transfer into ventricular myocardium demonstrated the ability of this construct to induce pacemaker activity with spontaneous action potential oscillations in adult ventricular myocytes and idioventricular rhythms by in vivo electrocardiography.
Conclusions— Given the sparse expression of Kv1 family channels in the human ventricle, gene transfer of a synthetic pacemaker channel based on the Kv1 family has novel therapeutic potential as a biological alternative to electronic pacemakers.

Circulation. 2006;114:1682-1686.
© 2006 American Heart Association, Inc.