 |
| Author | Post |
|---|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sat Sep 24th, 2005 17:44 |
|
Atherosclerois (coronary artery disease)
There is an emerging school of thought in mainstream cardiology that atherosclerosis is caused by microbes; IMO the same microbes which we have found to be behind the Th1 diseases.
One of the Th1 chemokines is called CAM (Cellular Adhesion Molecule) and it is a key component both of how the plaque macrophages adhere to the arterial wall in atherosclerosis and protect themselves from the immune system. More papers are coming out on both these things every month, but mainstream medicine has still to tie CAM to occult Th1 inflammation. It will take a decade for that to happen, IMO.
In atherosclerosis it is known that hemodynamic forces (pushing and shoving) of the monocytes which eventually form plaque are what cause the plaque to build up at junctions in the arteries. This may be due to mechanical disruption of the protective L-form cytoskeletons.
"I doubt that "breaking old habits" and "improving your lifestyle" will do anything much to slow the decline of your heart health. Still, I wish you the best, and you know where to find us when you come to realize that the answers in cardiology are just about as elusive as they are in immunology, if not more so.
You may be interested in a Letter to the Editor of the BMJ I wrote a few days ago about atherosclerosis
http://bmj.bmjjournals.com/cgi/eletters/331/7513/361
An article, from the medical news section of the Saint Lewis Washington University publication, talks about how inflammatory processes are associated with disease.
"Many years ago, atherosclerosis was thought to be related to lipids and to the excessive deposit of cholesterol in the arteries," Fontana says. "Nowadays, it's clear that atherosclerosis is an inflammatory disease. There also is evidence that inflammation plays a role in cancer, and there is even evidence that it plays a role in aging. Someday we may learn that visceral fat is involved in those things, too."
The above quote is by Luigi Fontana, M.D., Ph.D., assistant professor of medicine at Washington University in St. Louis and an investigator at the Istituto Superiore di Sanita, Rome, Italy
Dr. Trevor Marshall, PhD
The following scientific studies verify the efficacy of ARBs in treating CAD:
Angiotensin receptor blockers don't seem to increase risk of MI
Severity of Hyperlipidemia Does Not Affect Antiatherosclerotic Effect of an Angiotensin II Receptor Antagonist in Apolipoprotein E-deficient Mice.
The following articles discuss the relationship of atherosclerosis and inflammation:
MEDICAL BIOLOGY: INFLAMMATION AND CORONARY ARTERY DISEASE
Inflammation and CAD
Inflammation markers signal rapidly advancing coronary disease
The Role of Infection in the Pathogenesis of Cardiovascular Disease
Is CAD caused by atherosclerosis, inflammation or both?
Healing from cardiovascular disease: bacteria, fat, cholesterol, and more
Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK
Last edited on Mon Mar 10th, 2008 00:18 by Foundation Staff
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Sep 25th, 2005 00:13 |
|
(filelink)
Elevated CRP
First Link Found Between Obesity, Inflammation and Vascular Disease
Key points:
Researchers at The University of Texas M.D. Anderson Cancer Center and The University of Texas Health Science Center at Houston have found that human fat cells produce a protein that is linked to both inflammation and an increased risk of heart disease and stroke.
They say the discovery, reported in Journal of the American College of Cardiology, goes a long way to explain why people who are overweight generally have higher levels of the molecule, known as C-reactive protein (CRP), which is now used diagnostically to predict future cardiovascular events.
Even as the CRP picture becomes clearer, there is still much that is not known, the researchers say, including the reason why fat tissue produces an inflammatory response, and just precisely how CRP participates in that process.
Dr. Marshall's comment:
They are so near and yet so far. CRP is part of the body's reaction to bacterial infection.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Wed Oct 12th, 2005 02:57 |
|
(filelink)
Bacterial etiology
New Science.com (Article Preview)
http://www.newscientist.com/article.ns?id=mg15020334.100
Can you catch a heart attack?
08 June 1996 Phyllida Brown Magazine issue 2033
Ten years ago, most people scoffed at the idea that a bacterium caused stomach ulcers. But linking chlamydia to coronary heart disease is seen as an even bigger heresy, says Phyllida Brown
IT'S spread by coughs and sneezes. And by the time you're 20, there's a fifty-fifty chance that you're carrying the infection. But could Chlamydia pneumoniae really trigger coronary heart disease, that narrowing of the arteries which suffocates the heart muscle and kills more adults worldwide than any other disease. The theory is fuelling one of the fiercest controversies ever seen in the multimillion-dollar industry of cardiovascular research.
The bacterium—often called TWAR after the original laboratory strain—is the prime suspect because its fingerprints keep appearing at the scene of the crime. People with coronary heart disease are likely to have high levels of antibodies to TWAR, suggesting that they have been persistently or repeatedly infected with it. TWAR's DNA and proteins keep showing up in atheroma, the fatty, diseased tissue that blocks the coronary arteries. And now, in as yet unpublished research, the bacterium itself has turned up alive and kicking, ...
............................................
Isn't it scary that it is 10 years since this publication (almost) and yet they still haven't solved the problem?
Koch's dogma (the determination to find one single species at the root of one specific disease) is the primary reason for this failure, IMO.
..Trevor..
See also 'More Evidence That Infections Cause Heart Disease' and 'A Host with Infectious Ideas'
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Fri Oct 14th, 2005 03:51 |
|
(filelink)
Heart failure
Angiotensin II in the failing heart. Explains how elevated levels of Angiotensin II are related to clinical signs of heart failure. Angiotensin receptor blockers block production of Angiotensin II and can improve mortality rates in heart failure patients.
Do all angiotensin II type 1 receptor blockers have the same beneficial effects? Notes that ARBs have been used to block various bad effects of Angiotensin II, including heart failure and discusses how ARBs have differing molecular characteristics.
See Congestive Heart Failure
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Oct 30th, 2005 05:38 |
|
Cardiac Herxheimer may mimic myocardial infarction
(filelink)
If the cytokines are released into muscle tissue, for example cardiac muscle, they can weaken that muscle. This causes something mimicking MI, and it is common, although not frequently documented. Here is one citation:
"Hypercalcemia due to vitamin D intoxication with clinical features mimicking acute myocardial infarction."
http://tinyurl.com/6hb59
and another:
http://tinyurl.com/3nawc
We have not seem such a case mimicking MI yet, as the release of cytokines on the MP is controlled, and the level set by the patient.
What is a cardiac Herx? When should I be concerned?
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Tue Dec 27th, 2005 07:37 |
|
Myocarditis
(filelink)
Beneficial effects of olmesartan, a novel angiotensin II receptor type 1 antagonist, upon acute autoimmune myocarditis.
1: Mol Cell Biochem. 2004 Apr;259(1-2):217-22. Beneficial effects of olmesartan, a novel angiotensin II receptor type 1 antagonist, upon acute autoimmune myocarditis.
Nimata M, Kishimoto C, Yuan Z, Shioji K.
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Excess amount of cytokine produced by inflammatory stimuli contributes to the progression of myocardial damage in myocarditis. Some angiotensin II receptor type 1 antagonists are reported to inhibit proinflammatory cytokine production in vitro and in vivo. We tested the hypothesis that olmesartan, a novel angiotensin II receptor type 1 antagonist, ameliorated experimental autoimmune myocarditis (EAM) in rats attributing to the suppression of inflammatory cytokines in the heart. We orally administered olmesartan 1, 3, and 10 mg/kg/day to rats with EAM for 3 weeks. The results showed that olmesartan decreased blood pressure significantly compared with the untreated group, but markedly reduced the severity of myocarditis by comparing the heart weight/body weight ratio, pericardial effusion scores, macroscopic scores and microscopic scores. Myocardial interleukin (IL)-
1beta expression by western blotting and IL-1beta-positive staining cells by immunohistochemistry were significantly lower in rats with EAM given olmesartan treatment compared with those of rats given vehicle. We conclude that Olmesartan ameliorates acute EAM in rats. The cardioprotection of olmesartan may be due to suppression of inflammatory cytokines dependent of the hemodynamic modifications.
PMID: 15124927 [PubMed - indexed for MEDLINE]
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Aug 13th, 2006 00:04 |
|
Tachycardia
(tachyfilelink)
There are several types of tachycardias or tachyarrhythmias (rapid heart rate). Most types are relatively benign in nature though they can produce significant symptoms.
In patients with underlying heart disease, the dangerous (malignant) forms of tachycardia - ventricular tachycardia and ventricular fibrillation - can occur.
However, a rapid heart rate is usually not a cause for alarm. There are no absolute numbers to use as a guide because other clinical signs also need to be taken into account.
A tachycardia is said to be 'reactive' if it is caused by other disorders such as severe anemia, fever, thyroid disease, or other medical conditions.
The most common reason for the heart to beat too rapidly is excess stimulation, such as a thyroid problem. Please see THYROID DISEASE and Th1 Inflammation
Significance: The benign forms of tachycardia can produce significant symptoms and functional disability if it occurs often enough. The malignant forms of tachycardia - again, seen almost exclusively in patients with underlying heart disease - are an extremely common cause of sudden death. Symptoms of significant palpitations, and especially symptoms of sudden lightheadedness or syncope (fainting), need to be carefully evaluated by a physician.
The Marshall Protocol has been designed to reduce the chance of tachycardia. Taking a cardiac medication (like a beta blocker which slows the heart), as a preventative, isn't usually necessary. Following the MP guidelines carefully should prevent any serious cardiac rhythm disturbances.
The few patients on the Marshall Protocol who experienced a disturbance in their cardiac rhythm, got relief with cessation of the antibiotic/s and increase of Benicar to 40mg every four hours.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Tue Oct 10th, 2006 04:45 |
|
Statins are overprescribed
(filelink)
Reported October 9, 2006
Sorting Out Statins
ORLANDO, Fla. -- About 11 million Americans take cholesterol-lowering drugs known as statins. They're the most widely-sold drugs in this country. Some doctors say they're over-prescribed while others say they're not prescribed enough.
Elaine Overton's cholesterol was 260, so her doctor put her on Lipitor. "My cholesterol dropped about 100 points in about six weeks' time," she says. "It was really remarkable."
Statins can lower cholesterol by 40 percent and prevent heart attacks. The newest research shows they also reduce the risk of a second stroke by 16 percent.
"If anything, they're under-prescribed," neurologist K. Michael Welch, M.D., Ph.D., of Rosalind Franklin University of Medicine and Science in Chicago, tells Ivanhoe. "They certainly have been under-prescribed for stroke."
Current guidelines say you should be on a statin if your cholesterol is higher than 190 or if you have other risk factors like heart disease. If you have diabetes, you should be on one even if your cholesterol is normal.
But Beatrice Golomb, M.D., Ph.D., an internist at University of California, San Diego, says statins are over-prescribed. She says they're only proven to help white, middle-aged men who have or are at risk for heart disease.
"There's not really evidence that the benefits exceed the harms for women, for the elderly, or for men who aren't at high risk," she says. The drugs can also cause side effects like muscle weakness, nerve damage and even memory loss.
Jane Brunzie's memory became so bad after taking Lipitor, her family thought she had Alzheimer's. "My daughter told me she didn't think that she could safely leave my granddaughter with me anymore," she says.
Doctors agree you have to decide for yourself whether a statin is the right treatment option for you. Some studies show the drugs may also prevent other diseases like Alzheimer's disease or osteoporosis, but all the doctors we interviewed agreed that the evidence isn't strong enough to prescribe the drugs to these patients yet.
Brunzie decided to go off the drug. Overton is still on hers. Both want to live long and happy lives ... One with ... And one without a statin.
===============================================
My cholesterol and/or triglycerides are very high. Will the MP help?
|
Aussie Barb
Research Team
| Joined: | Sun Sep 10th, 2006 |
| Location: | |
| Posts: | 387 |
| Status: |
Offline
|
|
Posted: Mon Oct 23rd, 2006 20:52 |
|
(filelink)
Treating heart disease with the Marshall Protocol
See When should I be concerned about cardiac symptoms?
Members' experiences
Mitral Valve Prolapse
-When I was diagnosed with MVP, I was told I might also have dysautonomia, an imbalance of the central nervous system. This is part of something called MVP Syndrome, and the imbalance can cause jittery anxiety, irritable bowel syndrome, headaches, physical sensations that mimic low blood sugar, etc. So I decided that I must have this syndrome, because I had all these symptoms. Now I realize it probably all goes back to the sarcoidosis.
If you look at the symptoms list, you'll be amazed at how many of them are Th1 inflammation disease symptoms. There's also a link to anxiety/depression. When I found this site 10 years ago I was relieved to find that I wasn't the only MVP person suffering with odd things--at different times I've suffered from about 90% of the MVP Syndrome symptoms listed--but then I found the MP site and it all began to click. ~Jen Hicks
-I hope what I have shared will give you some confidence to go forth. My heart inflammation over the past year has diminished considerably and so I no longer have the pain levels that I once suffered. That to me verifies that I am improving and I am on the right track. I still get heart herxes but they are controllable and the pressure and arrythmias although are very irritating no longer cause me such concern. I have been through the cycles enough times to have a good feel for what is going on and I can regulate them without too much distress. ~CelticLadee
-Cardiac symptoms greatly reduced with the MP. Without treating the infection/TH1 disease, my cardiac issues became more severe, the angina worsened, the EKG's more abnormal, with an increase in arythmia, and less blood perfusion to areas of the heart. Why? because treatment was aimed at the cardiac symptoms only, and the disease/infections were receiving no treatment, were progressing and affecting my heart more and more.
I am happy to report that on the MP-- My cardiac sxes have been reduced at this point to almost nil. Why? Because the Benicar is protecting that organ, and with the adjustment of Benicar dosing encouraged and manipulation of abx dosing, I can keep cardiac herxing at bay. (No more ambulance rides, ER visits, and cardiac care units.)
Even with a good size dose of Verapamil daily and nitroglycerine, pre-MP, I was experiencing cardiac sxes and events. Once I started the Benicar---they stopped.  I havent had to pop subling. nitroglycerine tabs---since starting! (Prior to starting the Benicar, I was taking 3 nitro tabs during an event, and then sometimes that wasn't enough).
Benicar puts up a wonderful blockade. But here's the point, if you have cardiac infections and are symptomatic, and are not treating, they WILL worsen. If you treat them, you will fix the problem. So the treatment is designed to prevent the inevitable progression---which is harmful---not the protocol. ~Hrts
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Thu Jan 11th, 2007 05:00 |
|
(filelink)
Hypertension, inflammation and atherosclerosis
Is Vascular Endothelial Growth Factor a Missing Link Between Hypertension and Inflammation?
Inflammation may be a bridge connecting hypertension and atherosclerosis
Inflammation and hypertension: the search for a link
Elevated high-sensitive C-reactive protein, large arterial stiffness and atherosclerosis: a relationship between inflammation and hypertension?
==================================
Inflammation in hypertension.
Savoia C, Schiffrin EL. Curr Opin Nephrol Hypertens. 2006 Mar; 15,(2):152-8
Clinical Research Institute of Montreal, University of Montreal, Montreal, Quebec, Canada.
PURPOSE OF REVIEW: In this review we summarize the recent evidence that highlights the involvement of low-grade inflammation in the development and pathophysiology of hypertension. RECENT FINDINGS: Essential hypertension is characterized by increased peripheral vascular resistance to blood flow, due in large part to vascular remodeling. Vascular changes in hypertension are associated with mechanical and humoral factors that modulate signaling events, resulting in abnormal function, media growth, extracellular matrix deposition and inflammation. Recent evidence suggests that inflammation is present in the vasculature in animal models of hypertension. Inflammatory markers, such as C-reactive protein, are associated with vascular lesions in humans, and are predictive of cardiovascular outcome. In animal and human studies, pro-inflammatory components of the renin-angiotensin-aldosterone system have been demonstrated in large conduit and small arteries in the kidney and heart. Peroxisome proliferator-activated receptor activators are drugs with metabolic properties that have been demonstrated to exert anti-inflammatory effects on the vasculature, and there is now evidence that these actions may be protective for blood vessels. SUMMARY: Inflammatory processes are important participants in the pathophysiology of hypertension and cardiovascular disease. The identification of the mechanisms leading to the activation of inflammation should contribute to the development of specific therapeutic approaches to apply in hypertension and its complications.
PMID: 16481882 [PubMed - indexed for MEDLINE]
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sat Mar 3rd, 2007 04:18 |
|
(filelink)
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sat Mar 10th, 2007 13:46 |
|
(filelink)
Pulmonary hypertension
Pulomonary hypertension may develop as a result of sarcoidosis.
Pulmonary hypertension associated with sarcoidosis:
mechanisms, hemodynamics and prognosis.
Thorax. 2005 Oct 14; [Epub ahead of print]
PMID: 16227329 [PubMed - as supplied by publisher]
Sudden death with clinically undiagnosed pulmonary
hypertension.
J Clin Forensic Med. 2005 Oct;12(5):264-7. Epub 2005
Mar 28.
PMID: 16198969 [PubMed - in process]
Pulmonary hypertension in advanced sarcoidosis:
epidemiology and clinical characteristics.
Eur Respir J. 2005 May;25(5):783-8.
PMID: 15863633 [PubMed - indexed for MEDLINE]
CT findings in severe thoracic sarcoidosis.
Eur Radiol. 2005 Jan;15(1):23-30. Epub 2004 Sep 24.
Review.
PMID: 15449010 [PubMed - indexed for MEDLINE]
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Tue Mar 13th, 2007 14:46 |
|
[filelink]
Pacemakers
Anti-theft devices might cause implanted heart devices to malfunction
"Dr. J. Rod Gimbel of East Tennessee Heart Consultants and Dr. James Cox of the University of Tennessee Medical Center in Knoxville described two cases in which anti-theft devices apparently caused implanted heart devices to malfunction.
One of the patients had a pacemaker and she collapsed after pausing in a store doorway. Another had an implantable cardiac defibrillator that shocked him after he stood near an anti-theft unit.
The devices are called electronic article surveillance or EAS systems and use an electromagnetic field.
More than 1 million EAS systems are installed worldwide," Gimbel and Cox wrote.
Store employees need to know of the danger, they cautioned.
Simply moving the person away from the anti-theft device may save their life," Gimbel said in a statement."
TENS units used for pain control may also interfere with a pacemaker.....check with your doctor before using one.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Thu Apr 19th, 2007 03:21 |
|
[filelink]
How ARBs may help atrial fibrillation
Targeting the renin–angiotensin–aldosterone system in atrial fibrillation: from pathophysiology to clinical trials
J Hum Hypertens. 2005 Nov;19(11):855-9.
PMID: 16094406 [PubMed - indexed for MEDLINE]
Old and new antiarrhythmic drugs for converting and maintaining sinus rhythm in atrial fibrillation: comparative efficacy and results of trials.
Am J Cardiol. 2003 Mar 20;91(6A):15D-26D. Review.
PMID: 12670638 [PubMed - indexed for MEDLINE]
"Some data exist suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers can prevent AF [atrial fibrillation] either by preventing atrial dilation and stretch-induced arrhythmias or by blocking the renin-angiotensin system."
Belinda
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Aug 19th, 2007 05:37 |
|
(filelink)
Angiotensin II Receptor Blockade Expert Column
Angiotensin Receptor Blockers: Benefits Beyond Blood Pressure Lowering?
Michael A. Weber, MD
Medscape Cardiology. 2007; ©2007 Medscape
Posted 06/26/2007
Editor's Note
Michael A. Weber, MD, is Professor of Medicine in the Cardiology Division at the State University of New York (SUNY) Downstate Medical College of Medicine (Brooklyn, New York). Dr. Weber's main areas of interest are hypertension and preventive cardiology, and he has been involved in numerous clinical trials in patients with hypertension and those at high risk for cardiovascular events or recurrent strokes. He is also an active participant in trials involving patients with diabetic and nondiabetic nephropathy. Dr Weber currently serves on the steering committees of several national and international clinical outcomes trials. He has published numerous research articles and has authored/edited 16 books. He was one of the founders of the American Society of Hypertension (ASH) and has served as President of the Society. He has also served on the Cardiovascular and Renal Drugs Advisory Committee of the US Food and Drug Administration.
ARBs vs ACE Inhibitors
Medscape: What do we currently know about the effects of angiotensin receptor blockers (ARBs) beyond blood pressure lowering? Do we know that they differ from angiotensin-converting enzyme (ACE) inhibitors, or are ARBs just ACE inhibitors without the side effects of cough, etc?
Dr. Weber: To date it has been difficult to fully separate ARBs from ACE inhibitors. ACE inhibitors have been around almost 15-20 years longer than ARBs, so they have built up a strong list of credentials in terms of cardiovascular and metabolic effects. For example, we know that ACE inhibitors, beyond their ability to lower blood pressure, improve outcomes and survival in patients with heart failure, people with prior myocardial infarction (MI), and patients with type 1 diabetes and kidney disease. With ARBs we expect that there might be similar but potentially also different results when we analyze outcomes, because of their different mechanism of action. They act very specifically by blocking the renin-angiotensin system, and particularly by preventing angiotensin II from having its effects at the so-called AT1 receptor. ACE inhibitors, on the other hand, have a mechanism of action that is not as precise. In fact, they may only partly prevent formation of angiotensin II and so not completely block the renin-angiotensin system. On the other hand, ACE inhibitors reduce breakdown of bradykinin, which may have beneficial effects. So from a pharmacologic point of view, it is very reasonable to assume that the 2 drug classes -- ACE inhibitors and ARBs -- may produce different outcomes.
Having said all that, we now know that ARBs have very comparable beneficial effects to ACE inhibitors in patients with heart failure,[1-5] and almost identical benefits in patients who have had an MI with residual left ventricular dysfunction.[6] We also have very strong data with ARBs in patients with diabetic nephropathy, where we see, quite independent of their blood pressure effects, significant protection for those patients in preventing progression to end-stage renal disease.[7-10] That is a subtle but potentially interesting difference between ACE inhibitors and ARBs: The data with ACE inhibitors were obtained in patients with type 1 diabetes and kidney disease, and now for the first time we have compelling data in patients with type 2 diabetes and kidney disease, but only in studies with ARBs.
Medscape: The studies that demonstrate the non-blood-pressure-lowering effects of ARBs have usually only been carried out with 1 or 2 drugs. Would the results of these studies hold for the entire ARB drug class?
Dr. Weber: We always assume the possibility that what is true for one ARB will be true for others. For instance, in heart failure we have definitive data with valsartan and candesartan. Valsartan was used in the Valsartan Heart Failure Trial (Val-HeFT)[1] and candesartan in the Candesartan in Heart Failure -- Assessment of Mortality and morbidity (CHARM) trial.[2-5] In both studies, the ARB showed significant benefits and both of these ARBs are now indicated for the treatment of heart failure. Valsartan was also shown in the Valsartan in Acute Myocardial Infarction Trial (VALIANT)[6] to be at least as good as the ACE inhibitor captopril in patients with left ventricular dysfunction following an MI. That was really a major study; and at this point valsartan is the only ARB able to claim that kind of benefit in those patients. Other ARBs might have the same effect, but we do not have any data as of yet. So it is tempting always to talk about class effects, but at the same time one ought to be cautious.
Slowing the Progression of New-Onset Diabetes
Medscape: One effect of antihypertensive drugs that always gives rise to a lot of debate is the one on new-onset diabetes mellitus. Do ARBs really have a better protective effect than other drug classes, as suggested in a recent meta-analysis?[11] Do we know anything about the mechanism of this effect?
Dr. Weber: I would say that at this time, both ACE inhibitors and ARBs can be said to be useful in preventing or delaying progression of nondiabetic patients into type 2 diabetes. So far, neither drug class, nor any single drug, has stood out. Most of the studies in which an ACE inhibitor or an ARB has appeared beneficial have been in comparison with drugs known to have potentially deleterious effects on progression to diabetes such as diuretics and beta-blockers. However, in a substudy of the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial,[12] valsartan was shown to be superior to the calcium channel blocker (CCB) amlodipine at preventing new-onset diabetes. This is interesting, because amlodipine itself is somewhat beneficial in terms of improving glucose metabolism, so for valsartan to be superior to amlodipine is quite noteworthy. Whether other ARBs could do the same remains to be examined.
It is important, though, that when we talk about preventing new-onset diabetes, we face the rather sad truth that these drugs are not completely preventing new-onset diabetes. It is more accurate to think of them as slowing down the rate of progression to true diabetes. So in the end, most patients destined to become diabetic will still become diabetic, but if they are taking valsartan they will do so at a later time, which, of course, is very useful, clinically and economically. The longer we can delay diabetes, the better off are our patients, and ARBs are very effective in that way.
Medscape: What will the ongoing Nateglinide And Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial tell us about ARBs and incident diabetes?
Dr. Weber: NAVIGATOR is using the oral antidiabetic agent nateglinide and the ARB valsartan in high-risk patients with impaired glucose tolerance. The primary endpoint of the trial is the occurrence of a major cardiovascular outcome, and I think we are all hoping to be pleased by what we might see. But a key secondary endpoint of NAVIGATOR is new-onset diabetes, and that will allow us to learn whether valsartan performs the way we predict. We expect to hear the first results of NAVIGATOR in 2008.
The Importance of Long-term Follow-up
Medscape: In the recently reported Diabetes Reduction Approaches With Ramipril and Rosiglitazone Medications (DREAM) study,[13] the use of ramipril for 3 years did not significantly reduce the incidence of diabetes in patients with impaired fasting glucose or impaired glucose tolerance over 3 years. Does this result have any implications for ARBs?
Dr. Weber: Every clinical trial inevitably seems to create its own cluster of controversies, and in the case of DREAM some people at first sight felt that the ramipril arm was something of a disappointment. There was actually a significant improvement in the patients brought into the study with so-called prediabetes (impaired glucose tolerance) back into normoglycemia; so quite a few people who appeared to have been on the brink of diabetes were rescued and returned to normal status. As far as preventing new-onset diabetes was concerned, although there was no significant benefit associated with ramipril, there was a trend in that direction. It was unfortunate that for the first year or two of the study, ramipril had no effect whatsoever in preventing new-onset diabetes; but as the study continued, the effect appeared and was getting stronger and wider with each passing month. When the study was finally stopped, the effect of the drug was not yet statistically significant, but the investigators running the study are now being criticized for stopping it too early. So there is always a story and there is always a controversy with trials; but having seen the data, I remain confident that ramipril is a useful antidiabetes drug. It may not be the best, however; there may be others, perhaps some of the ARBs, that are more effective.
Medscape: How long would a clinical trial with an ARB, or another drug, need to run to show when the effects on new-onset diabetes, diabetic nephropathy, etc, would start translating into a reduction of events?
Dr. Weber: That is such a difficult question. There was an Italian study of new-onset diabetes, not the most robust or authoritative of studies, but it indicated that the effect of new-onset diabetes on clinical events did not emerge for at least 5 years.[14] It was only because these patients were followed for 15 years that the investigators were able to get some sense of the importance of drug-induced diabetes in hypertension in leading to events.
So I believe there is a benefit in terms of event reduction if you can prevent new-onset diabetes, but it will not be apparent within 3-5 years; it may take a long time. This is a very long-term investment and I do not think that many clinical trialists could get the support or, frankly, would have the patience to follow patients for 12-15 years to see whether preventing new-onset diabetes really does prevent events. Most of us accept that preventing diabetes will have long-term benefits, but we are not likely to see authoritative proof.
Animal Studies
Medscape: What do animal studies tell us about how ACE inhibitors or ARBs prevent diabetes? For instance, there have been studies in mice suggesting that blockade of the renin-angiotensin system affects pancreatic beta cells, etc.
Dr. Weber: That is fascinating. The renin-angiotensin system seems to mediate a number of adverse events in the islets of the pancreas, and there are at least 2 ways in which angiotensin could predispose to diabetes. First, angiotensin stimulates growth factors in the islets, such as transforming growth factor beta-1 (TGF- beta 1), that increase fibrosis in the islets, which in time has the effect of damaging and engulfing the beta cells that actually produce the insulin. Second, there seems to be a direct effect of angiotensin within the islets on the beta cells themselves, and this effect seems to hasten so-called apoptosis, the permanent death of those cells. So there are several reasons to assume that effective blockade of the renin-angiotensin system would directly support the function of the pancreas, and it has been demonstrated in animal models. It would be more difficult, obviously, to show it in humans.
Medscape: A recent animal study has suggested that another benefit of ARBs might be to prevent diabetes-associated sexual dysfunction.[15]
Dr. Weber: That is something that needs to be explored. There have been some superficial clinical studies, including one in which valsartan was compared with atenolol. The people on valsartan reported better sexual activity, with atenolol having a negative effect.[16]
Protecting Against Myocardial Infarction
Medscape: There has recently been a lot of discussion, some of it contentious, about the effect of ARBs and MI.
Dr. Weber: The discussion has been about whether blockers of the renin-angiotensin system are as good at preventing MIs as we would have predicted based on our knowledge of the renin-angiotensin system and our belief that it is a major contributor to coronary events. The most recently published meta-analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC)[17] concluded that ACE inhibitors are truly efficacious at preventing MIs and perhaps superior to other drug classes in doing so. Usually there are so many variables in this sort of statement, because blood pressure reductions and many other factors that could affect the likelihood of MIs must be accounted for. In the hands of this very experienced group, however, there seemed to be evidence that the ACE inhibitors are truly beneficial and perhaps more so than other classes.
So where does this leave the ARBs? There has been some concern, perhaps driven by poorly understood data from a few of the major trials, that ARBs may be less efficacious than other drug classes in preventing heart attacks.[18-21] This has now been firmly refuted, and in their latest review the BPLTTC says quite categorically that there is no evidence whatsoever to justify any concern about ARBs, but rather that they are just as effective as any other classes of antihypertensive drugs in protecting against MIs. The group even adds that there are not yet enough data to take the analysis further and examine whether ARBs could even be superior to certain other drug classes used for treating hypertension. It is again important to recognize that the data are not yet strong enough and the experience not yet broad enough for any conclusion along those lines to be properly examined; but even so, it is promising, and ongoing studies may reveal more about this.
Important additional information in this discussion will come from the results of a very large trial, scheduled to finish at the end of 2007, which will probably be announced in March 2008. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET)[22] is a perfect study to answer the questions that we are considering here. It is a head-to-head comparison of a well-established ACE inhibitor, ramipril, which was very effective in providing survival and endpoint benefits in high-risk cardiovascular patients in the Heart Outcomes Prevention Evaluation (HOPE) trial,[23] vs telmisartan, which is a powerful, long-acting ARB. ONTARGET is basically a repeat of the HOPE study in high-risk cardiovascular patients, but now comparing an ARB and an ACE inhibitor. That will give us fascinating information and should resolve many of these issues once and for all. ONTARGET is also examining the combination of the ACE inhibitor and the ARB, and that may turn out to be most effective at improving survival and reducing major endpoints. If so, then this sort of combination treatment may become a standard approach for people with high-risk cardiovascular status.
Medscape: With respect to the HOPE trial, there was some discussion as to whether the risk reduction seen for stroke and cardiovascular endpoints in the HOPE study were really greater than could be accounted for by the small reduction in measured blood pressure.[24-27]
Dr. Weber: That is a very relevant point, because many people did believe and still do believe that some of the benefit of ramipril in the HOPE study was because it had a blood pressure-lowering effect, and even the authors of the study themselves have acknowledged that as much as 50% of the supposed benefit of the ACE inhibitor could be attributed to its blood pressure- lowering effects.[28-30] Of course, there are many people who say that they do not care whether there was a blood pressure effect or not. The point is, the trial asked whether -- on top of all the other treatments that patients with high cardiovascular risk were supposed to be taking -- would adding an ACE inhibitor provide a benefit compared with adding placebo? The answer was, yes, it provided a very strong benefit. Perhaps blood pressure lowering was a part of that, but there was nothing to stop people in the placebo arm from getting whatever antihypertensive drugs they needed to help reduce their blood pressure. So if you take the point of view that this was a true intent to treat, a full exposure of patients to the best available therapies, then however ramipril worked, and however it achieved its results, it did so. The same question will come up with the ONTARGET trial, because telmisartan is probably a better blood pressure-lowering drug than ramipril. All the ONTARGET investigators have been told to ensure that they treat any hypertension effectively, so hopefully there will not be a blood pressure story to confound the results. If there is, however, I would take the view that it is largely irrelevant if there is a blood pressure inequality, because investigators were told to do everything they could to prevent this inequality. Frankly, at this point, we have to put blood pressure behind us and see what the real results are.
Expanding Indications
Medscape: What is the Telmisartan Randomized Assessment Study in ACE-Intolerant Subjects With Cardiovascular Disease (TRANSCEND) trial?
Dr. Weber: TRANSCEND is a trial being done in parallel with ONTARGET, and it is an important study. It is a comparative study of an ARB, again telmisartan, vs placebo in patients who are intolerant of ACE inhibitors. So this is a situation where it was perfectly ethical in high-risk cardiovascular patients to compare an ARB with placebo. That study is also well advanced, and I believe the results will be announced later in 2008.
Medscape: What is your opinion about the effect of ARBs on diastolic dysfunction? The results of the Valsartan In Diastolic Dysfunction (VALIDD) trial,[31,32] announced at the recent American College of Cardiology meeting, did not show any benefit for an ARB-based regimen over aggressive blood pressure lowering with a regimen of non-renin-angiotensin system-inhibiting drugs in prehypertensive adults with diastolic dysfunction, as measured by tissue Doppler imaging.
Dr. Weber: Diastolic dysfunction in difficult to study. A long-term study is needed if it is going to be events-driven, rather than just depending on studies of function. There was an intriguing finding in the CHARM-Preserved study of a borderline benefit in preventing hospitalizations for heart failure compared with placebo on top of all other treatments, although there was no mortality benefit.[5] The currently ongoing Irbesartan in Heart Failure With Preserved Systolic Function (I-PRESERVE)[33] trial, a true large-scale, robust, well-designed comparison of irbesartan with all other drugs that are not renin-angiotensin system blockers in patients with diastolic dysfunction, will be the definitive study in this area. However, the fact that diastolic dysfunction has not responded particularly well to ACE inhibitors or to ARBs up to this point leads me to suspect that the etiology of the dysfunction, which is obviously related to the abnormal tissue properties of the left ventricle, is not being driven primarily by the renin-angiotensin system. I think we are going to have to wait for some rather innovative pharmacologies to truly address what is happening in those left ventricles.
Medscape: ARBs have also been reported to have a benefit in preventing stroke.
Dr. Weber: There have been several studies on ARBs and stroke, including the Morbidity and Mortality After Stroke, Eprosartan Compared With Nitrendipine for Secondary Prevention (MOSES)[34] trial, the Study on Cognition and Prognosis in the Elderly (SCOPE)[35] trial, and the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE)[36,37] study. In all of these trials, an ARB was better than other drugs at preventing strokes. In the LIFE study, the ARB was compared with the beta-blocker atenolol; but even if one is skeptical about a beta-blocker as a comparator, the MOSES study, which was a small but well-conducted, relatively rigorous trial, compared an ARB with a CCB, nitrendipine, which is widely used in Europe, and which has powerful antistroke credentials of its own. Nitrendipine was the drug used, for example, in the Systolic Hypertension in Europe (Syst-Eur)[38] trial, in which it showed dramatic benefits in stroke prevention.[38] In MOSES, nitrendipine and the ARB eprosartan achieved identical blood pressure effects in patients who had had previous ischemia; but by the time the study was over, eprosartan was associated with a 25% relative reduction in new strokes. That raises an issue as to whether there is something special about ARBs.
Pharmacologists have hypothesized that the ARBs do not just block the renin-angiotensin system, but they do it in such a selective way that they actually enhance the effect of angiotensin on the AT2 receptor, which may have a protective effect on nerve tissue. This has been shown in animals, but whether that is a mechanism for why these drugs may have a stroke benefit in humans is another question that has yet to be explored. Of course, the ONTARGET study will address that question as well. It will be fascinating to see whether the ARB and the ACE inhibitor combination have the same stroke effects or whether one is better than the other.
Medscape: ARBs have also been associated with a reduced risk of developing new-onset atrial fibrillation.
Dr. Weber: We are tantalized at the moment by the atrial fibrillation story. We know, particularly from meta-analyses,[39-41] that ACE inhibitors can be shown to prevent new-onset atrial fibrillation, and the same is true for ARBs.[42-45] There were some very nice data from the LIFE study,[42] and even though people are a little critical now of that study -- because atenolol is not regarded as an optimal comparator -- you would nonetheless assume that a beta-blocker should be effective at protecting against atrial fibrillation. Yet in that particular study, the patients who received losartan had about a one-third reduction in the incidence of new-onset atrial fibrillation. To me that was compelling information, and there are now some exciting mechanistic studies being done by electrophysiologists that seem to show that there are angiotensin receptors that activate -- or at least in some ways regulate -- the flow of cardiac electrical impulses. Such findings lead one to believe that drugs that block the renin-angiotensin system, perhaps particularly ARBs, could potentially be good anti-atrial fibrillation drugs. We are a long way off from making such a strong assertion, but it is a beguiling thought.
Dosing and Future Outlook
Medscape: If patients were to benefit from all these non-blood-pressure-lowering effects of ARBs, would the highest approved dose be sufficient, or do you think that they would need an even higher dose?
Dr. Weber: This is a difficult issue. With all these drugs, not only the ARBs, but also the ACE inhibitors, the CCBs, etc, we tend to achieve some sort of a belief in doses based on the first major indication for which these drugs are tested, which is often hypertension. So we learn what the best doses for ACE inhibitors and ARBs are for treating high blood pressure, and we assume that when we have reached a dose of drug beyond which you get no further reduction in blood pressure, that we have maximized the dose range. That is correct, but only for high blood pressure. There may be a totally different dose range needed to protect the kidney or to protect the myocardium. For instance, as far as the kidney is concerned, if we use the so-called maximum dose of an ARB and measure its effect on proteinuria, we will typically see about a one-third reduction in proteinuria. With so-called super doses, however, such as valsartan 640 mg instead of 160 mg or 320 mg, even though there is no further reduction in blood pressure, there is a significant further reduction in proteinuria. Likewise with irbesartan: Instead of stopping at 300 mg, if we go to 600 mg and 900 mg we see better and better proteinuria effects. So this is teaching us that just because we have reached the maximum dose for blood pressure, it does not mean that we have reached the maximum dose for what these drugs might do at other tissues, regulating other cardiovascular outcomes of interest.
Medscape: How will physicians prescribing for blood pressure control feel about these additional benefits? Maybe they do not have enough time to worry about them because they just want to get the blood pressure down to targets with the approved doses?
Dr. Weber: Your statement is absolutely accurate at the moment. The doctor treating high blood pressure will be satisfied when the blood pressure is brought under control. If there is some reason to suspect that other things are going on, such as kidney involvement or heart failure, then there might be a reason to think about alternatives. No one has done definitive studies with "super dosing" of the ARBs or the ACE inhibitors. It is a pity, because these drugs are well tolerated and it would probably be possible to go up to 2, 4, 8, or even 12 times what is now regarded as the top dose without producing major adverse effects. However, we do not have that information as yet, and so it is not possible to advise administering any dose in excess of what is currently the maximum recommended dose.
Medscape: When do you think we will have answers about these benefits beyond blood pressure lowering with ARBs?
Dr. Weber: It is an exciting time at the moment and a good time to raise these questions. I predict that by the end of 2008 we will know a lot more about these effects of ARBs.
Supported by an independent educational grant from Novartis
References
- Cohn JN, Tognoni G; Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med. 2001;345:1667-1675. Abstract
- Pfeffer MA, Swedberg K, Granger CB, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759-766. Abstract
- McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767-771. Abstract
- Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772-776. Abstract
- Yusuf S, Pfeffer MA, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781. Abstract
- Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan in Acute Myocardial Infarction Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349:1893-1906. Abstract
- Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851-860. Abstract
- Brenner BM, Cooper ME, De Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345:861-869. Abstract
- Parving H-H, Lehnert H, Bröchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870-878. Abstract
- Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672-678. Abstract
- Elliott WJ, Meyer PM. Incidence diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007;369:201-207. Abstract
- Kjeldsen SE, Julius S, Mancia G, et al; VALUE Trial Investigators. Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: the VALUE trial. J Hypertens. 2006;24:1405-1412. Abstract
- The DREAM Trial Investigators. Effect of ramipril on the incidence of diabetes. N Engl J Med. 2006;355:1551-1562. Abstract
- Verdecchia P, Reboldi G, Angeli F, et al. Adverse prognostic significance of new diabetes in treated hypertensive subjects. Hypertension. 2004;43:963-969. Abstract
- Nomura M, Nishii H, Ozaki Y, et al. An angiotensin II receptor blocker increases sexual behavior in type 2 diabetic mice. Physiol Behav. 2007;91:223-228. Abstract
- Fogari R, Preti P, Derosa G, Marasi G, et al. Effect of antihypertensive treatment with valsartan or atenolol on sexual activity and plasma testosterone in hypertensive men. Eur J Clin Pharmacol. 2002;58:177-180. Abstract
- Blood Pressure Lowering Treatment Trialists' Collaboration; Turnbull F, Neal B, Pfeffer M, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25:951-958. Abstract
- Strauss MH, Verma S. Inhibition of the reninangiotensin system in cardiovascular protection: is it important to watch your C'ARB' intake? Can J Cardiol. 2005;21:577-580.
- Verma S, Strauss M. Angiotensin receptor blockers and myocardial infarction. BMJ. 2004;329:1248-1249. Abstract
- Staessen JA, Thijs L, Birkenhager WH. VALUE: analysis of results. Lancet. 2004;364:931.
- Verdecchia P, Angeli F, Gattobigio R, Reboldi G. Do angiotensin II receptor blockers increase the risk of myocardial infarction. Eur Heart J 2005;26:2381-2386.
- Teo K, Yusuf S, Sleight P, et al; ONTARGET/TRANSCEND Investigators. Rationale, design, and baseline characteristics of 2 large, simple, randomized trials evaluating telmisartan, ramipril, and their combination in high-risk patients: the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND) trials. Am Heart J. 2004;148:52-61. Abstract
- Yusuf S, Sleight P, Pogue J, et al; The Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145-53. Abstract
- Muhlhauser I. Blood pressure and cardiovascular risk in the HOPE study. Lancet. 2002;359:2118. [Letter] Abstract
- Taylor R. Blood pressure and cardiovascular risk in the HOPE study. Lancet. 2002;359:2117-2118. [Letter]
- Sleight P, Pogue J, Yusef S. Blood pressure and cardiovascular risk in the HOPE study. Author's reply. Lancet. 2002;359:2118.
- Conundrum of the HOPE study: Time of taking ramipril may account for lack of relation between blood pressure and outcome. BMJ. 2003;327:681-682.
- Svensson P, de Faire U, Sleight P, et al. Comparative effects of ramipril on ambulatory and office blood pressures: A HOPE substudy. Hypertension. 2001;38;28-32.
- Sleight P, Yusuf S, Pogue J, et al. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet. 2001;358: 2130-2131. Abstract
- Bosch J, Yusuf S, Pogue J, et al. Effect of ramipril in preventing stroke: double blind randomised trial. BMJ. 2002;324:699-702. Abstract
- Janardhanan R, Daley WL, Naqvi TZ, et al. Rationale and design: The VALsartan In Diastolic Dysfunction (VALIDD) Trial: Evolving the management of diastolic dysfunction in hypertension. Am Heart J. 2006;152:246-252. Abstract
- Solomon SD, Janardhanan R, Verma R, et al. The influence of angiotensin receptor blockers and blood pressure lowering on diastolic function in patients with hypertension and diastolic dysfunction. Program and abstracts of ACC.07: 56th Scientific Session of the American College of Cardiology. Late-Breaking Clinical Trials I. Abstract 402-11.
- Schrader J, Luders S, Kulschewski A, et al; MOSES Study Group. Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: principal results of a prospective randomized controlled study (MOSES). Stroke. 2005;36:1218-1226. Abstract
- Lithell H, Hansson L, Skoog I, et al; SCOPE Study Group. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886. Abstract
- Dahlof B, Devereux RB, Kjeldsen SE, et al; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995-1003. Abstract
- Kizer JR, Dahlöf B, Kjeldsen SE, et al. Stroke reduction in hypertensive adults with cardiac hypertrophy randomized to losartan versus atenolol: the Losartan Intervention For Endpoint reduction in hypertension study. Hypertension. 2005;45:46-52. Abstract
- Staessen JA, Fagard R, Thijs L, et al; The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757-764. Abstract
- Carson P, Massie BM, McKelvie R, et al; for the I-PRESERVE Investigators. The irbesartan in heart failure with preserved systolic function (I-PRESERVE) trial: rationale and design. J Card Fail. 2005;11:576-585. Abstract
- Madrid AH, Peng J, Javier Zamora J, et al. The role of angiotensin receptor blockers and/or angiotensin converting enzyme inhibitors in the prevention of atrial fibrillation in patients with cardiovascular diseases. Pacing Clin Electrophysiol. 2004;27:1405-1410. Abstract
- Healey JS, Baranchuk A, Crystal E, Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45:1832-1839. Abstract
- Anand K, Mooss AN, Hee TT, Mohiuddin SM. Meta-analysis: inhibition of renin-angiotensin system prevents new-onset atrial fibrillation. Am Heart J. 2006;152:217-222. Abstract
- Wachtell K, Hornestam B, Lehto M, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: The Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:712-719. Abstract
- Maggioni AP, Latini R, Carson PE, et al. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: Results from the Valsartan Heart Failure Trial (Val-HeFT). Am Heart J. 2005;149:548-557. Abstract
- Ducharme A, Swedberg K, Pfeffer MA, et al; CHARM Investigators. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Am Heart J. 2006;152:86-92. Abstract
- Fogari R, Mugellini A, Destro M, et al. Losartan and prevention of atrial fibrillation recurrence in hypertensive patients. J Cardiovasc Pharmacol. 2006;47:46-50. Abstract
Michael A. Weber, MD, Professor of Medicine, Cardiology Division, State University of New York (SUNY) Downstate Medical College of Medicine, Brooklyn, New York
Disclosure: Michael Weber, MD, has disclosed that he has served as a consultant for Boehringer Ingelheim, Daiichi-Sankyo, Forest, Gilead, Merck & Co., Inc., Novartis, and Takeda. Dr. Weber has also disclosed that he was a speaker for Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Forest, GlaxoSmithKline, Merck & Co., Inc., Novartis, Pfizer, and sanofi-aventis.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sat Oct 6th, 2007 04:26 |
|
[filelink]
Antibiotic Shows Promise as Stroke Treatment
HealthDay
Monday, October 1, 2007
MONDAY, Oct. 1 (HealthDay News) -- An antibiotic used to treat severe acne and urinary tract infections also appears to be a potent weapon against acute ischemic stroke, a new report from Israeli researchers suggests.
Perhaps the best news about this discovery is that it widens the window of treatment for stroke from a few hours to 24 hours, experts say.
Though it is too early to change patient care, should the results be confirmed in larger, placebo-controlled, double-blinded clinical trials, "it will be probably one of the most used and effective treatments of ischemic stroke that we have," said Dr. Argye Hillis, a professor of neurology at the Johns Hopkins University School of Medicine in Baltimore.
The drug in question is minocycline, a tetracycline derivative that has been used for years to fight bacterial infections. Over the past decade, the drug has also been shown to be effective in animal models of several neurological conditions, including Parkinson's, Huntington's and Lou Gehrig's diseases.
Dr. Yair Lampl, of Tel Aviv University, and his colleagues randomized 152 patients with acute ischemic stroke into two groups, one of which received 200 milligrams of minocycline a day for five days, while the other was given a placebo. Treatment was initiated between six and 24 hours after stroke onset.
At one week, one month and three months following stroke, patient recovery was significantly improved in the antibiotic group relative to the control group on each of three tests that collectively assess neurological damage due to stroke and the patient's ability to perform daily tasks such as grooming, dressing and going to the bathroom.
"Statistically, there's a pretty marked difference between the groups," said Dr. Eric Smith, associate director of Acute Stroke Services at Massachusetts General Hospital in Boston. "Clinically, it is the difference between someone who looks almost normal compared to someone with more mild-to-moderate impairment due to stroke."
The findings were published in the Oct. 2 issue of Neurology.
This study focused specifically on ischemic stroke, the kind that is induced by clots that cut off blood flow to parts of the brain. According to Smith, minocycline appears to act as a neuroprotectant -- that is, as a compound that protects the brain from the resulting lack of oxygen and glucose, thereby allowing more brain tissue to survive.
Yet it is not at all clear just how minocycline does this, though several possible mechanisms have been proposed. Lampl suggested the effect "is at least partially dependent" on minocycline's ability to limit inflammation and apoptosis, or cell suicide.
Hillis said she found the results "potentially very exciting," both because of the magnitude of the effect, and because it was observed with a treatment that could be administered as much as a day after a stroke attack.
"They included patients who were eight to 24 hours after onset of stroke, on average 12 hours," she noted. "That's exciting, because that's about when most patients come to the hospital."
Most stroke treatments are now only effective within a few hours of stroke onset, Hillis explained. It's a therapeutic window that is too short to be effective for many patients.
Yet Hillis said she was not yet prepared to change the way she treats her own patients.
"I think this is very promising, very exciting, as a pilot study, but it's not enough to start treating people with minocycline," she said.
Smith concurred, saying, "I think this looks like a promising treatment with pretty big differences in outcome between the minocycline-treated and control groups. However, it is an early-phase study, and the results have to be considered preliminary. The field needs a larger, double-blinded study to confirm these findings."
In a double-blinded study, neither the treating physician nor the patient would be aware which treatment the patient was receiving.
According to Lampl, a larger study is being planned to address this concern.
Copyright (c) 2007 ScoutNews, LLC. All rights reserved.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Thu Nov 22nd, 2007 18:29 |
|
[filelink]
Rogue Bacteria Involved In Both Heart Disease And Infertility
ScienceDaily (Nov. 22, 2007) — Outside the laboratory, Anthony Azenabor is outgoing and talkative, an extrovert who laughs heartily at his own jokes.
But engrossed in his research, Azenabor is a shrewd and serious investigator who coaxes rogue bacteria to give up deadly secrets of how they cause several human illnesses.
Educated in Nigeria and Great Britain, Azenabor landed a fellowship sponsored by the World Health Organization soon after completing his doctorate on the bacteria Chlamydia. He was one of only two chosen worldwide.
Now an associate professor of health sciences at UW-Milwaukee, he has identified how two different kinds of Chlamydia can cause both coronary artery disease and miscarriages.
Solving one mystery gave him clues that he needed to figure out the other.
By focusing on the immune system mechanisms in Chlamydia infections, Azenabor has identified an important link in seemingly unrelated health problems.
The result could be new treatments and prevention strategies for both heart disease and infertility.
The first mystery
Chlamydia pneumoniae is a microbe that normally causes pneumonia and bronchitis, but it has long been associated with atherosclerosis, a cardiovascular disease also called "hardening of the arteries."
"It was a frightening prospect," says Azenabor, "that atherosclerosis could come from a bacterial infection." He decided to look for an explanation.
Chlamydiae are unusual, says the Nigerian-born scientist, because, unlike most other bacteria, they use the same form of cholesterol for metabolism that human cells use. Chlamydiae also are intracellular pathogens, meaning that they can only grow and reproduce inside of another cell.
But these bacteria have another peculiar ability.
Normally, when a pathogen invades human tissue, the immune response unleashes "killer cells" called macrophages, which stretch to engulf the attacker and destroy it with toxin-producing enzymes.
Chlamydiae fight back, says Azenabor, His work shows that, as they are ingested, these two species of Chlamydia can manipulate the functions of protective cells like macrophages in creative ways.
Cholesterol connection
One of the keys lies in the macrophages' cell walls, which store cholesterol and usually tightly control it.
But when it's infected with C. pneumoniae, the microbe traffics cholesterol from the macrophage cell membrane to its own, causing a change in the macrophage that makes it rigid and unable to move.
The bacterium also disturbs the macrophage's production of toxins in a process that transforms them into "signaling molecules," which support functions that keep the bacterium alive.
"C. pneumoniae really wants to hijack the cell functions for its own use, like a parasite would," he says. "The macrophage, though, wants to kill Chlamydia, but its killing ability has been converted to signaling."
This is the reason the infection becomes chronic, Azenabor says. "Because of signaling, everything else in the human cell is still fine except for the altered toxins, so the bacteria can reproduce in a short time."
As the macrophages become immobile, they accumulate in the blood vessel walls, setting the stage for atherosclerosis.
Infection and pregnancy
Armed with new information about how C. pneumoniae sabotages the immune response, Azenabor, who had also been studying the effects of estrogen on macrophages, turned his attention to another Chlamydia-related puzzle.
How is Chlamydia trachomatis, the species that causes a sexually transmitted disease, involved in the occurrence of spontaneous abortions or miscarriages?
He was immediately drawn to the protective cells in the placenta during early pregnancy -- the trophoblasts.
"It's not for nothing that trophoblasts are the early cells," says Azenabor. "They prevent any kind of infection that could threaten the fertilized egg. They produce toxic chemicals similar to those of macrophages."
Trophoblasts act like macrophages in many ways, and their functions are mediated by the hormones estrogen and progesterone. And cholesterol is the molecule used to produce those hormones.
Azenabor's research shows that, like its cousin, C. trachomatis does take cholesterol from the trophoblast, and it also reproduces once inside the cell.
"It's the same old story," says Azenabor. "Only this time the attacked cell is a trophoblast instead of a macrophage, and the depleted cholesterol hinders production of estrogen and progesterone instead of altering toxin production."
Azenabor's lab members are continuing their inquiry, and they then will need to test the theories with live animals.
But the scientist is optimistic. Already he has a patented process for blocking the effects of calcium signaling for C. pneumoniae.
"If we can prevent C. trachomatis from becoming chronic, we could apply this remedy to pregnancy," he says.
While conducting postdoctoral work at McMaster University in Ontario, he won the Canadian Distinguished Scientist Award in 1998, and moved to the University of Waterloo.
Azenabor joined the UWM faculty in 2001, after working as a scientist in a Chlamydia lab at UW--Madison. He jumped at the chance to start his own lab at UWM. Since arriving here he has won several honors, including the Shaw Distinguished Scientist Award from the James D. and Dorothy Shaw Fund in the Greater Milwaukee Foundation.
Although he didn't plan on working with Chlamydia for this long, he is now a leading researcher in the field. One attraction, he says, is the work is unpredictable.
"When you begin," he says, "you never know where you are going to go."
Adapted from materials provided by University of Wisconsin - Milwaukee
|
Foundation Staff.
.
| Joined: | Sun Jul 11th, 2004 |
| Location: | |
| Posts: | 1178 |
| Status: |
Offline
|
|
Posted: Sun Dec 2nd, 2007 18:56 |
|
Cardiac sarcoidosis underlies idiopathic dilated cardiomyopathy.Circ J. 2007 Dec;71(12):1937-41. PMID: 18037750 [PubMed - in process]
Background Cardiac sarcoidosis is frequently overlooked or misdiagnosed as idiopathic dilated cardiomyopathy (DCM), primarily because of difficulties in its diagnosis.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Mar 9th, 2008 01:05 |
|
filelink
Olmetec(R) Is First Angiotensin Receptor Blocker (ARB) To Suggest Atherosclerosis Regression (In Hypertensives With Cardiovascular Risk), UK
11 Dec 2007 - 1:00 PST
Olmetec(R) (olmesartan medoxomil), licensed in the UK for essential hypertension, is the first ARB to suggest a regression of atherosclerosis (plaque volume (PV)) , a major risk factor for cardiovascular disease (CVD)1, according to a new study published in the inaugural issue of Therapeutic Advances in Cardiovascular Disease.
Regression of PV is a compelling clinical goal, with potential to prevent cardiovascular and cerebrovascular events. In the Multicentre Olmesartan Atherosclerosis Regression Evaluation (MORE)2 study the primary end point, common carotid - intima media thickness (CC-IMT), a surrogate risk factor for CVD, decreased after 2 years treatment with olmesartan.
A post hoc analysis in patients with larger plaques demonstrated a significant reduction in PV compared to atenolol the active comparator, although change in PV for the whole study population only showed trend towards significance for olmesartan. This is a promising finding which provides a focus for further evaluation in future clinical studies.
In the MORE study, olmesartan did not significantly reduce plaque volume (PV) compared with the beta-blocker atenolol in the overall population. However a post hoc analysis of patients with above average plaques (≥33µl) at baseline (those at greater risk of cardiovascular events) olmesartan showed a significant reduction in PV by -8.9%, compared with a 2.4% increase with atenolol.
In very large plaques the beneficial effect of olmesartan was even greater - PV declined by -12.8% and increased by 2.1% respectively in the olmesartan and atenolol groups. Both olmesartan and atenolol patients showed a similar reduction in blood pressure2. The observed decrease in plaque volume may thus occur independently of blood pressure lowering and offers a further potential benefit of olmesartan.
The MORE findings add to Olmesartan's growing portfolio of vascular protective studies.3-8 "The MORE study is a landmark because it is the first study to show an anti-atherosclerotic effect using an ARB.
This suggests that in patients with hypertension, in addition to effective blood pressure lowering, olmesartan may potentially protect against cardiovascular and organ damage, benefits that should be considered seriously when prescribing an anti-hypertensive agent in patients who already have atherosclerotic disease" said Dr Lina Izzat, Associate Specialist in Cardiology, Prince Phillip Hospital, Llanelli.
|
Foundation Staff
.
| Joined: | Sat Jul 10th, 2004 |
| Location: | |
| Posts: | 17283 |
| Status: |
Offline
|
|
Posted: Sun Oct 19th, 2008 05:49 |
|
[filelink]
Obesity 'lifts inflammation risk'
Obesity and lack of fitness raise the risk of illness by impacting negatively on the body's internal chemistry, research suggests.
A US team found levels of white blood cells were highest in men who were unfit and overweight.
White blood cells are key to fighting infection, but high levels can be a sign of inflammation, which is linked to coronary heart disease.
The study appears in the British Journal of Sports Medicine.
There is nothing worse than a risk factor that an individual cannot modify, but here are two risk factors - obesity and fitness - which they can do something about
Professor Tim Church
Pennington Biomedical Research Center
A team from the Pennington Biomedical Research Center carried out tests on 452 healthy men who were taking part in a long-term study of fitness.
Blood tests were taken, and analysed for their content of various types of white blood cell.
After taking account of age, the researchers found that all groups of white blood cell were lowest in the men who were most physically fit.
The greater proportion of body fat a man had, the higher his white blood cell count was.
Total white cell count was highest in men who had a combination of higher body fat and lower levels of physical fitness.
Levels were also high among men with lower body weight but lower levels of fitness.
However, a high degree of physical fitness negated the effect of extra body fat.
Key role
White cell counts tend to rise after a bout of vigorous exercise, but the researchers said regular exercise might condition the body to respond more efficiently to the physical demands made of it.
Lead researcher Professor Tim Church said it was clear that inflammation played a key role in heart disease and other illnesses, but the factors which drove it were still relatively unclear.
He said: "There is nothing worse than a risk factor that an individual cannot modify, but here are two risk factors - obesity and fitness - which they can do something about."
June Davison, cardiac nurse at the British Heart Foundation, said: "These findings add to evidence that regular physical activity and keeping close to a healthy weight have huge benefits for your heart health."
And John Brewer, performance director at the Lucozade Sport Science Academy in Slough, stressed that an unhealthy lifestyle posed "real dangers" to health.
He said: "Whilst studies like this one, and initiatives from the government and health-promotion agencies, can raise awareness of the risks, ultimately it is down to individuals to chose a lifestyle and habits that give them the best chance of leading a healthy, active life."
Story from BBC NEWS:
http://news.bbc.co.uk/go/pr/fr/-/2/hi/health/7669966.stm
Published: 2008/10/17 23:06:54 GMT
© BBC MMVIII
|
Current time is 23:20 | |
|
|
|
|
