The results of the landmark ONTARGET(TM) trial have demonstrated that MICARDIS(R) (telmisartan), a second-generation angiotensin II receptor blocker (ARB), is equally effective as the current standard, ramipril, in reducing the risk of cardiovascular death, myocardial infarction, stroke and hospitalization for congestive heart failure in a broad cross-section of high-risk cardiovascular patients with normal blood pressure or controlled high blood pressure, and resulted in fewer discontinuations.(1) These cardiovascular events occurred in 1,423 patients (16.7 percent) receiving telmisartan versus 1,412 patients (16.5 percent) receiving ramipril.(1) The relative risk (ratio of the probability of the event occurring in the telmisartan group versus the ramipril group) was 1.01, with a 95 percent CI of 0.94 - 1.09.

Telmisartan is now the only ARB to have demonstrated cardio and vascular risk reduction benefits beyond lowering blood pressure in this high-risk population;(1) these benefits may be attributed to the specific pharmacological properties and mode of action of the drug. Previously, in 2000, the HOPE trial showed that the cardiovascular risk for patients treated with the angiotensin-converting enzyme (ACE) inhibitor ramipril was reduced by approximately 20 percent compared with placebo.(2) This meant that every fifth serious cardiovascular event in a high risk group of patients was prevented.(2)

“The ONTARGET trial shows that telmisartan is a well-tolerated treatment in high-risk cardiovascular patients that is as effective as ramipril in preventing heart attacks, stroke and hospitalizations for heart failure and deaths,” said Professor Salim Yusuf, lead investigator of the ONTARGET Trial Program and Director of the Population Health Research Institute at McMaster University, Hamilton, Canada. “The ONTARGET results have important implications for the management of patients with cardiovascular diseases.”

In this trial, which was based on the HOPE study design, the benefits of telmisartan were demonstrated in a large group (8,542) of high-risk patients who were already receiving standard care such as statins to lower cholesterol, antiplatelet therapy, beta blockers and other antihypertensives.(3) Telmisartan treatment led to fewer discontinuations than treatment with ramipril, a widely used ACE inhibitor.(1) Although patients with an ACE inhibitor intolerance had been excluded from the trial, 360 (4.2 percent) patients in the ramipril treatment arm stopped their treatment because they experienced cough, a common ACE inhibitor side effect, versus only 93 (1.1 percent) patients in the telmisartan arm. Twenty-five patients stopped their treatment in the ramipril arm because of angioedema, versus only 10 in the telmisartan arm.(1) The incidence of hypotension was higher in the telmisartan arm (229 patients, 2.7 percent) versus the ramipril (149 patients, 1.7 percent) arm.(1)

“Boehringer Ingelheim is proud to have supported ONTARGET(TM), the largest cardiovascular outcomes trial of its kind and the first of a series of landmark clinical studies sponsored by our company. ONTARGET is just one example of Boehringer Ingelheim’s leadership in trying to address the needs of people with cardiovascular disease,” commented J. Martin Carroll, president and chief executive officer of Boehringer Ingelheim Pharmaceuticals, Inc. “We are committed to pursuing further research that evaluates ways to reduce the risk of damaging events in the heart, brain and other organs due to cardiovascular disease and to uncover new treatment strategies that may improve patient outcomes and care.”

ONTARGET also studied the value of combining telmisartan with ramipril, to evaluate whether combining an ACE inhibitor and an ARB, i.e. the dual renin-angiotensin system (RAS) blockade, could offer even better risk reduction compared to single blockade, a key question for the clinical community. The results announced today indicate that there was no additional risk reduction benefit achieved and a higher discontinuation rate if telmisartan and ramipril are combined.(1)

About the ONTARGET(TM) Trial Program

The ONTARGET Trial Program is the largest clinical trial ever undertaken with an ARB, involving more than 31,000 high-risk cardiovascular patients with either normal or controlled blood pressure. The ONTARGET Trial Program encompasses two randomized, double-blind, multi-center international outcome trials: ONTARGET, the main trial with results reported today, and TRANSCEND(TM) (Telmisartan Randomized Assessment Study in ACE-intolerant subjects with cardiovascular disease), the parallel trial with results planned to be reported later in 2008.

ONTARGET evaluated more than 25,600 high-risk cardiovascular patients with normal blood pressure or controlled high blood pressure and a history of a broad range of cardiovascular diseases. The study compared the effectiveness of the ARB telmisartan to the ACE inhibitor ramipril in reducing the combined risk of cardiovascular death, myocardial infarction, stroke and hospitalization for congestive heart failure (CHF) in patients at risk. The study also compared the efficacy of the combination of the ARB telmisartan and the ACE inhibitor ramipril compared to ramipril alone in achieving the same combined endpoint.

The combined primary endpoint in the ONTARGET trial included cardiovascular death, non-fatal myocardial infarction, non-fatal stroke and hospitalization for congestive heart failure. In addition, a broad variety of secondary and tertiary endpoints were studied, including: newly diagnosed diabetes, cognitive decline/dementia, nephropathy, atrial fibrillation and left ventricular hypertrophy.

Treatment arms for the ONTARGET(TM) trial were telmisartan 80 mg, ramipril 10 mg and a combination therapy with telmisartan 80 mg and ramipril 10 mg. All treatments were applied in addition to standard care for high-risk cardiovascular patients.

More than 700 sites throughout Asia, Australia, New Zealand, Europe, North/South America and South Africa participated in the ONTARGET Trial Program. The ONTARGET Steering Committee consists of scientists from McMaster University in Ontario, Canada; Oxford University in Oxford, England; the University of Auckland in Auckland, New Zealand; and Boehringer Ingelheim.

The ONTARGET trial was investigational and was conducted to expand scientific knowledge of telmisartan. Note that the trial included treatment for conditions outside the approved indication for telmisartan.

About Cardiovascular Disease

Cardiovascular disease (CVD) is the number one cause of death and disability globally(4) and is responsible for one of every three deaths worldwide — an estimated 17 million people per year.(5) CVD causes more deaths than cancer, chronic respiratory disease and diabetes combined.(6) By 2020, it is predicted that CVD will surpass infectious diseases to become the largest cause of death and disability worldwide.(7) It is also contributes significantly to the escalating costs of health care. In 2007, the cost of CVD in the U.S. was estimated at $403.1 billion.(8)

Boehringer Ingelheim and Cardiovascular Medicine

Boehringer Ingelheim continues its century-long history of innovation and commitment to continuing research to further understand cardiovascular disease — the number one cause of death worldwide. Boehringer Ingelheim has introduced novel agents in the management of hypertension and treatment of secondary stroke and continues to invest in a comprehensive cardiovascular pipeline. The Company’s cardiovascular medicine clinical trial program includes ONTARGET, PRoFESS, TRANSCEND and other studies involving more than 75,000 patients in more than 40 countries. These studies were designed to evaluate ways to reduce the risk of damaging events in the heart, brain and other organs due to cardiovascular disease and to uncover new treatment strategies that improve patient outcomes and care.

About Boehringer Ingelheim Pharmaceuticals, Inc.

Boehringer Ingelheim Pharmaceuticals, Inc., based in Ridgefield, CT, is the largest U.S. subsidiary of Boehringer Ingelheim Corporation (Ridgefield, CT) and a member of the Boehringer Ingelheim group of companies.

The Boehringer Ingelheim group is one of the world’s 20 leading pharmaceutical companies. Headquartered in Ingelheim, Germany, it operates globally with 137 affiliates in 47 countries and approximately 38,400 employees. Since it was founded in 1885, the family-owned company has been committed to researching, developing, manufacturing and marketing novel products of high therapeutic value for human and veterinary medicine.

In 2007, Boehringer Ingelheim posted net sales of US $13.3 billion (10.6 billion euro) while spending approximately one-fifth of net sales in its largest business segment, Prescription Medicines, on research and development.

For more information, please visit http://us.boehringer-ingelheim.com.

About Micardis(R) (telmisartan)

Telmisartan is marketed in the United States by Boehringer Ingelheim as MICARDIS(R) tablets. MICARDIS is indicated for the treatment of hypertension.

USE IN PREGNANCY

When used in pregnancy during the second and third trimesters, drugs that act directly on the renin-angiotensin system can cause injury and even death to the developing fetus. When pregnancy is detected, MICARDIS tablets should be discontinued as soon as possible (see WARNINGS, Fetal/Neonatal Morbidity and Mortality).

Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.

MICARDIS is contraindicated in patients who are hypersensitive to any of their components.

In patients with an activated renin-angiotensin system, such as volume- and/or salt-depleted patients (e.g., those receiving high doses of diuretics), symptomatic hypotension may occur after initiation of MICARDIS therapy. This condition should be corrected prior to administration of MICARDIS tablets, and treatment should start under close medical supervision.

The most common adverse events occurring with MICARDIS tablets monotherapy at a rate of 1% and greater than placebo, respectively, were: upper respiratory tract infection (URTI) (7%, 6%), back pain (3%, 1%), sinusitis (3%, 2%), diarrhea (3%, 2%), and pharyngitis (1%, 0%).

Please visit http://www.micardis.com for full Prescribing Information for MICARDIS.

References:

1 The ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008; 358:1547-59.

2 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

3 The 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

4 Facts and Figures: World Health Report 2003. World Health Organization

5 The Atlas of Heart Disease and Stroke 2004 World Health Organization http://www.who.int/cardiovascular_diseases/resources/atlas/en/index.html

6 World Health Organization, Cardiovascular Disease http://www.who.int/cardiovascular_diseases/en/

7 Levenson J. et al. Reducing the global burden of cardiovascular disease: the role of risk factors. Preventative Cardiology, 2002; 5: 188-189.

8 Thom T et al. Heart disease and stroke statistics - 2007 update. Circulation. 2007; 113:e85-e151.

Boehringer Ingelheim Pharmaceuticals, Inc.
http://us.boehringer-ingelheim.com

Interim results from the ACCOMPLISH (Avoiding Cardiovascular Events through COMbination Therapy in Patients LIving with Systolic Hypertension) trial demonstrate that high-risk, high blood pressure patients treated with Lotrel(R) (amlodipine besylate and benazepril HCl) had 20% fewer cardiovascular events than those taking a benazepril and hydrochlorothiazide (HCTZ) combination. This is the first cardiovascular outcomes trial in a hypertensive population where all patients were randomized to receive a single-pill combination treatment at the onset of the trial as opposed to a step care regimen.

“These results suggest that the combination of the angiotensin-converting enzyme inhibitor (ACEI) and calcium channel blocker in Lotrel yielded better patient outcomes in high-risk hypertensive patients than the ACEI and HCTZ combination,” explained Kenneth Jamerson, MD, professor of internal medicine at the University of Michigan Medical Center in Ann Arbor and lead investigator of the trial. “Further, a strategy of starting patients in the trial on a single-pill combination proved to be very efficient in significantly increasing blood pressure control rates.”

Lotrel is approved for the treatment of high blood pressure. It should not be used before other medications have been tried first.

Treatment with combination therapy resulted in exceptional blood pressure control at 30 months. Before entering the study, almost all patients were treated with multiple high blood pressure medicines. At study entry, only 37% of the study population had a blood pressure of
“Evidence from trials like ACCOMPLISH provides physicians with additional information to better inform their treatment decisions in high-risk hypertensive patients,” said Marjorie Gatlin, MD, Vice President and Head of Cardiovascular and Metabolism Medical Franchise US Medical and Drug Regulatory Affairs at Novartis Pharmaceuticals Corporation. “Novartis is an innovator of unique medications for the treatment of high blood pressure, including single- pill combinations, and is committed to further develop this approach for effective patient care.”

The results were presented today in a late-breaking session at the American College of Cardiology 57th Annual Scientific Session in Chicago.

ACCOMPLISH is the first large clinical outcomes trial to directly compare two single-pill combinations of commonly used high blood pressure medicines in the reduction of a composite endpoint including heart attacks, strokes, hospitalizations for unstable angina and cardiovascular deaths in high blood pressure patients at high cardiovascular risk. In October 2007, the study was stopped early because the pre-defined efficacy outcome had been achieved.

The study was a multi-national, double-blind trial and included more than 11,000 patients at 550 study sites in the US and Scandinavia. One day after stopping their current high blood pressure medication, patients received a single-pill combination of either Lotrel or a combination of benazepril and HCTZ. In the first two months of the study, doses of study medications were increased. Patients in the Lotrel arm started on 5/20 mg. The dose was increased to Lotrel 5/40 mg and, for patients not at goal blood pressure, then to 10/40 mg. Patients taking benazepril and HCTZ started at 20/12.5 mg and were increased to 40/12.5 mg and, for patients not at goal blood pressure, to 40/25 mg. The combination doses of benazepril and HCTZ 40/12.5 mg and 40/25 mg used in this study were investigational. In both arms, patients were given additional blood pressure medication if goal blood pressure was not attained on the maximum dose of study medications.

The primary study endpoint was a composite of cardiovascular disease, non- fatal heart attack, non-fatal stroke, and hospitalization for unstable angina (chest pain that occurs when the heart muscle does not get enough blood) or revascularization (a procedure that re-establishes blood flow to previously restricted regions of the heart), and cardiovascular death. The full data will be available later this year and further analyses will examine the effects on specific patient populations.

Important safety information

LOTREL and the fixed dose combination of benazepril and HCTZ are prescription medications for the treatment of high blood pressure. They should not be used before other high blood pressure medications have been tried first.

LOTREL and the fixed dose combination of benazepril and HCTZ can harm an unborn baby and even cause death. If you get pregnant, stop taking LOTREL or the benazepril and HCTZ combination. Call your doctor right away. Talk to your doctor about other ways to lower your blood pressure if you plan to become pregnant.

Don’t take LOTREL or the benazepril and HCTZ combination if you are allergic to any of the ingredients, or to any ACE inhibitor or for patients taking LOTREL, amlodipine. Do not take the benazepril and HCTZ combination if you have a history of reduced urine output, or have allergic reactions to certain drugs known as sulfonamides and tell your doctor if you have liver problems, lupus or if you take lithium. Your doctor or pharmacist can give you a complete list of the ingredients in LOTREL or the benazepril and HCTZ combination.

In rare cases with LOTREL or the benazepril and HCTZ combination, a potentially life-threatening allergic reaction (swelling of the mouth and throat) can occur. This potentially dangerous swelling of the mouth and throat has been reported more often in African American patients receiving ACE inhibitors than in non-African American patients.

The most serious side effect with LOTREL and the benazepril and HCTZ combination is low blood pressure.

The most common side effects in patients taking LOTREL and the benazepril and HCTZ combination include cough, dizziness, and headache, additionally with the benazepril and HCTZ combination fatigue and additionally with LOTREL, edema (swelling of the feet, ankles, legs, or hands).

40/12.5 mg and 40/25 mg used in this study were investigational and do not have approved prescribing information available.

About high blood pressure and treatment

High blood pressure increases a person’s risk of experiencing a cardiovascular event. For example, it has been reported that the risk of heart attack and stroke doubles with every 20/10 mmHg increase in blood pressure, starting at 115/75 mmHg. Blood pressure treatment guidelines sponsored by the National Heart, Lung and Blood Institute recommend initial combination therapy of two medications that work differently for patients who have a systolic blood pressure of 20 mmHg and a diastolic blood pressure of 10 mmHg over target goal. Systolic blood pressure is the pressure of blood flow as the heart beats and pushes blood throughout the body. Diastolic blood pressure is between heart beats, as your heart rests and refills with blood.

Approximately 73 million adults (nearly one in three) in the US have high blood pressure. It has been estimated that most adults with high blood pressure also have additional health problems that increase their risk for cardiovascular events.

Novartis: strength in cardiovascular and metabolic diseases

Novartis is focused on improving the lives of the hundreds of millions of people with diseases of the cardiovascular and metabolic systems. As a global leader and innovator in cardiovascular and metabolic health, Novartis provides novel therapies and support programs to treat high blood pressure and major public health issues. The strength of Novartis lies in its broad range of renin-angiotensin system (RAS) based therapies for the treatment of high blood pressure, which include the most prescribed angiotensin-receptor-blocker, the first approved oral direct renin inhibitor and a single agent combining two of the most prescribed antihypertensive medicines. Novartis has an extensive clinical research program in hypertension involving more than 100,000 patients. Novartis is dedicated to helping physicians and patients address cardiovascular and metabolic health through effective medicines and an ongoing commitment to education, support and research.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as “will”, “suggest”, “committed”, or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Lotrel or regarding potential future revenues from Lotrel. Such forward-looking statements reflect the current views of the Company regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Lotrel to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Lotrel will be submitted or approved for any additional indications or labeling. Nor can there be any guarantee that Lotrel will achieve any particular levels of revenue in the future. In particular, management’s expectations regarding Lotrel could be affected by, among other things, the company’s ability to obtain or maintain patent or other proprietary intellectual property protection, including for the Lotrel 5/40 mg and 10/40 mg capsules; unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; competition in general; government, industry and general public pricing pressures, and other risks and factors referred to in Novartis AG’s current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

About Novartis

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, gastrointestinal and respiratory areas. The company’s mission is to improve people’s lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS), a world leader in providing healthcare solutions that address the evolving needs of patients and societies. Focused solely on growth areas in healthcare, Novartis offers a diversified portfolio to best meet these needs: innovative medicines, cost-saving generic pharmaceuticals, preventive vaccines and diagnostic tools, and consumer health products. Novartis is the only company with leading positions in these areas. In 2007, the Group’s continuing operations (excluding divestments in 2007) achieved net sales of USD 38.1 billion and net income of USD 6.5 billion. Approximately USD 6.4 billion was invested in R&D activities throughout the Group. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 98,200 full-time associates and operate in over 140 countries around the world. For more information, please visit http://www.novartis.com.

Novartis Pharmaceuticals Corporation
http://www.pharma.us.novartis.com

Adding the relaxation response, a stress-management approach, to other lifestyle interventions may significantly improve treatment of the type of hypertension most common in the elderly. Among participants in a study conducted at the Massachusetts General Hospital (MGH) Hypertension Program and the Benson-Henry Institute for Mind-Body Medicine at MGH, those who received relaxation response training in addition to advice on reducing lifestyle risk factors were more than twice as likely to successfully eliminate at least one blood pressure medication than were those receiving lifestyle counseling only. The study appears in the Journal of Alternative and Complementary Medicine.

Relaxation training may improve control of hard-to-treat systolic hypertension
Adding the relaxation response, a stress-management approach, to other lifestyle interventions may significantly improve treatment of the type of hypertension most common in the elderly. Among participants in a study conducted at the Massachusetts General Hospital (MGH) Hypertension Program and the Benson-Henry Institute for Mind-Body Medicine at MGH, those who received relaxation response training in addition to advice on reducing lifestyle risk factors were more than twice as likely to successfully eliminate at least one blood pressure medication than were those receiving lifestyle counseling only. The study appears in the Journal of Alternative and Complementary Medicine.

“Nearly 80 million Americans are classified as having hypertension, and although we have many medications to lower blood pressure, only about a third of patients achieve adequate control of their pressures,” says Randall Zusman, MD, co-senior author of the report who leads the Hypertension Program at the MGH Heart Center. “If a practice that takes only 15 to 20 minutes a day can help decrease patients’ dependence on antihypertensive medications - reducing often-unpleasant side effects and the considerable costs of these drugs - we could not only improve their quality of life but lower direct and indirect health costs by billions of dollars.”

Among the elderly patients in whom it is most common, isolated systolic hypertension - an increase in only the peak arterial pressure - is more closely correlated with adverse events like heart attack, stroke or renal failure than is elevated diastolic pressure. Treating systolic hypertension is particularly challenging since older patients who take many medications are at greater risk for drug interactions and may be more vulnerable to other side effects.

The relaxation response is a physiologic state of deep rest - involving both physical and emotional responses to stress - that can be elicited by practices such as meditation, deep breathing and prayer. Herbert Benson, MD, director emeritus of the Benson-Henry Institute and co-senior author of the current report, first described the relaxation response almost 35 years ago, and he and his colleagues have pioneered its use in mind/body medicine. While several studies have shown that the relaxation response can help alleviate hypertension involving elevated systolic and diastolic pressures, its usefulness in treating isolated systolic hypertension has not been investigated.

The present study enrolled more than 100 patients, aged 55 and older, whose systolic pressure remained elevated despite their taking two or more antihypertensive drugs. Participants were randomly assigned to two groups. The control group received weekly counseling sessions on cardiac risk factors, the impact of stress on hypertension, and recommendations on dietary and fitness goals. The treatment group attended sessions that also included instruction and practice eliciting the relaxation response. Both groups also received audiotapes to listen to daily - the control group with general lifestyle recommendations and the treatment group a guided relaxation response session.

Participants’ blood pressure was checked after eight weeks, and those whose pressures had dropped into the normal range - less than 140 systolic and 90 diastolic - were eligible to start reducing the dose of one of their medications. If blood pressures remained normal during subsequent weeks, dosage could be further reduced or eliminated; but participants whose hypertension returned resumed their previous dosage level. The physician conducting weekly evaluations did not know to which group participants belonged, and participants were told only that the study was evaluating different “stress management” programs.

By the end of the 20-week study period, participants in both groups had experienced a significant drop in systolic blood pressure, allowing two thirds of all participants to attempt medication reduction. Among relaxation response group participants, 32 percent maintained reduced systolic pressure after eliminating one or more medications, an accomplishment achieved by only 14 percent of those in the lifestyle-counseling group.

“The other nonpharmacological interventions that we know can reduce systolic blood pressure - reducing dietary sodium, weight loss, smoking cessation and increasing physical activity - can be very difficult for patients to achieve,” says Jeffrey Dusek, PhD, the study’s lead author. “Our control group received an intensive amount of good-health information and reported making fairly dramatic lifestyle changes, but only the relaxation response group was able to significantly reduce their use of antihypertensive medications.” Formerly with the Benson-Henry Institute, Dusek is now with the Institute for Health and Healing at Abbott Northwestern Hospital in Minneapolis.

Zusman adds, “We are now going to look at the very large patient population currently termed pre-hypertensives - those whose blood pressure is elevated but does not yet meet the criteria for drug therapy. If we can train those patients to elicit the relaxation response, we may be able to delay or even avoid the onset of hypertension, improving their cardiovascular health, reducing dependence on medications and potentially reducing overall health care costs.” Zusman is an associate professor of Medicine, and Benson is the Mind/Body Medical Institute Associate Professor of Medicine at Harvard Medical School.

Additional co-authors of the report are Patricia Hibberd, MD, PhD, Bei-Hung Chang, ScD, Kathryn Dusek, Jennifer Johnston, MD, and Ann Wohlhueter of the Benson-Henry Institute, and Beverly Buczynski, RN, MGH Cardiology. The study was supported by grants from the Centers for Disease Control and Prevention and the National Institutes of Health. The Benson-Henry Institute has benefited from the interest and support of John Henry, principal owner of the Boston Red Sox.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $500 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, systems biology, transplantation biology and photomedicine.

Massachusetts General Hospital

The American Physiological Society has awarded Michigan State University Professor Stephanie W. Watts the 2008 Henry Pickering Bowditch Memorial Award for early-career achievement. The award goes to a scientist younger than 42 years whose accomplishments are both original and outstanding. It is the Society’s second-highest award

Dr. Watts, a professor of pharmacology and toxicology, has focused her research on whether serotonin (5-HT) plays a role in hypertension. The story of her research is interesting not only because it is important to find a treatment for this serious illness, but because her research resembles a mystery novel, in which the detective has her eye set on a likely suspect, only to find out that the bad guy may be the good guy.

Dr. Watts will present the Bowditch lecture “The love of a lifetime: 5-HT in the cardiovascular system,” on Sunday, April 6, at the APS session of Experimental Biology in San Diego. An audio of the interview may be found at http://www.lifelines.tv.

A silent killer

One-quarter of American adults suffer from hypertension, also known as high blood pressure. In hypertension, the blood vessels constrict, but because the body must transport the same amount of blood, it causes the blood to flow under much greater pressure.

This places greater strain on the heart and the blood vessels and can also damage the organs and tissues that receive the blood, including the brain, heart and kidneys. The disease is known as the silent killer because many people do not know they have the disease until it causes serious health problems.

Most of the body’s serotonin, about 90%, is made in the gastrointestinal tract, where it plays a role in digestion by helping the smooth muscle of the intestines move. The remaining 10% of the body’s serotonin is produced in the brain, where it plays a role in elevating mood, signaling food satiety and regulating sleep cycles.

The body needs tryptophan, obtained through the diet, to make serotonin. Tryptophan is found in a variety of foods, including poultry.

Still a hypothesis

Years of research have yielded this about serotonin’s effect on blood vessels:

-the blood vessels of hypertensive individuals are very sensitive to serotonin
-hypertensive individuals have higher levels of serotonin in their blood

Molecules, known as transporters, carry serotonin to receptors in various parts of the body. Different receptors cause serotonin to do different things. There are at least 17 such receptors in the human body, making it difficult to unravel exactly how serotonin works.

Dr. Watts hypothesized that since it takes less serotonin to make hypertensive blood vessels contract, that hypertensive individuals may have a higher number of receptors. This could explain why the blood vessels of hypertensive individuals react more strongly to serotonin. She experimented with one receptor and found that blocking it reduced blood pressure.

In 2007, Dr. Watts gave serotonin to both hypertensive and normal rats, reasoning that serotonin would raise blood pressure in the non-hypertensive rats and that the rats with hypertension would experience an even greater rise in blood pressure. Instead, the serotonin reduced blood pressure by 15-20% in the non-hypertensive rats and by 33% in the hypertensive animals. Dr. Watts’ lab has repeated the experiment with the same results.

The serotonin puzzle

So what to make of this latest clue, that serotonin lowers blood pressure when it’s given to both hypertensive and non-hypertensive rats? These results have Dr. Watts wondering if serotonin levels rise because serotonin is trying to reduce blood pressure.

“I’m wondering if hypertensive people have higher level of 5-HT because that’s a good thing,” Dr. Watts said. “Now we’re trying to figure out the multiple ways 5-HT can play with the cardiovascular system to cause these results.”

One possibility is that once an individual suffers hypertension, it changes how the blood vessel works, toughening vessels to handle the higher pressure and changing how it reacts in the presence of serotonin. “It’s really hard to tell which is the cause and which is the effect,” Dr. Watts said.

When Dr. Watts presents her lecture, she hopes to get ideas from other physiologists who can help her resolve this puzzle. The lecture will take place at 5:45 p.m., Sunday, April 6, at the APS session of Experimental Biology 2008 in San Diego.

Note

The APS annual meeting is part of the Experimental Biology 2008 conference that will be held April 5-9 at the San Diego Convention Center. The press is invited to attend or to make an appointment to interview Dr. Watts. Please contact Christine Guilfoy at (301)634-7253 or at cguilfoy@the-aps.org.

Physiology is the study of how molecules, cells, tissues and organs function to create health or disease. The American Physiological Society has been an integral part of this discovery process since it was established in 1887.

American Physiological Society

Individuals who have one or two parents with hypertension appear to have a significantly increased risk of developing elevated blood pressure throughout their adult lives, according to a report in the March 24 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

Hypertension, or high blood pressure, often clusters in families, according to background information in the article. Researchers estimate that between 35 percent and 65 percent of high blood pressure is heritable.

Nae-Yuh Wang, Ph.D., and colleagues at the Johns Hopkins University, Baltimore, assessed hypertension in 1,160 men who first filled out study questionnaires in 1947, when they were medical students. At that time, the participants underwent medical examinations and reported their medical history, health habits and dietary habits. Each year for 54 years of follow-up, they completed annual questionnaires regarding their blood pressure and the diagnosis and treatment of hypertension in themselves and their parents.

At the beginning of the study, 264 (23 percent) of the medical students reported at least one parent with hypertension, including 20 with both parents who had hypertension. During follow-up, 583 new cases of parental hypertension occurred, so that 701 (60 percent) of the group had at least one parent with high blood pressure and 166 (14 percent) had two. Men with one or two parents with hypertension had higher average systolic (top number) and diastolic (bottom number) blood pressure at the beginning of the study and were also more likely to develop hypertension at some point during adulthood than those whose parents never developed hypertension.

“Men with both parents with hypertension or men with one parent who was hypertensive before the age of 55 years had a much higher risk of developing hypertension, especially at a younger age,” the authors write. Early-onset hypertension in both parents was associated with a 6.2-fold higher risk of hypertension at any point in adulthood and a 20-fold higher risk of developing hypertension by age 35.

“Our findings emphasize the importance of asking patients about parental hypertension to identify those who are at high risk of developing hypertension, especially at a young age, for both population-based and individual-level interventions,” the authors conclude. “They also underscore the importance of primary prevention and blood-pressure monitoring early in life in men with parental hypertension, especially those who have a parent with early-onset hypertension.”

Arch Intern Med. 2008;168[6]:643-648.
http://archinte.ama-assn.org

This work was supported in part by grants from the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Archives of Internal Medicine

Adults with hypertension may be able to lower their weight and their blood pressure by following a weight-loss diet or using the medication orlistat, according to a meta-analysis of previously published studies reported in the March 24 issue of Archives of Internal Medicine, one of the JAMA/Archives journals.

High blood pressure (hypertension) is a major risk factor for cardiovascular disease and is responsible for approximately 7 million deaths worldwide each year, according to background information in the article. Lowering blood pressure levels in those with hypertension has been shown to reduce cardiovascular risk, with corresponding decreases in illness and death. “Weight reduction is recommended in major guidelines as an initial intervention in the treatment of hypertensive patients,” the authors write. “Among the possible means of reducing body weight are lifestyle modifications and pharmacologic and invasive interventions.”

Karl Horvath, M.D., of the Medical University of Graz, Australia, and colleagues performed a meta-analysis of 48 articles that were published before March 2007 and analyzed weight-loss interventions for patients with hypertension. Of those studies, 38 assessed diet and 10 focused on medications for weight loss, including five evaluating orlistat and five assessing sibutramine. No relevant articles were located regarding the weight loss drug rimonabant or evaluating surgical weight reduction.

“Patients assigned to weight loss diets, orlistat or sibutramine reduced their body weight more effectively than did patients in the usual care/placebo groups,” the authors write. “Reduction of blood pressure was higher in patients treated with weight loss diets or orlistat.” Sibutramine treatment, however, did not lower overall blood pressure and appeared to increase systolic (top number) blood pressure.

“A reduction in body weight of approximately 4 kilograms [8.8 pounds] was necessary to achieve a reduction of approximately 6 milligrams of mercury in systolic blood pressure with dietary treatment and of approximately 2.5 milligrams of mercury with orlistat,” the authors write. “None of the studies provided data to answer the question whether risk of mortality [death] or other patient-relevant end points can be lowered by weight reduction.”

Arch Intern Med. 2008;168[6]:571-580.
http://archinte.ama-assn.org

Blacks with a “suspicious, hostile personality” have higher blood pressure than whites with the same tendencies, according to a report presented on Friday at the American Psychosomatic Society meeting in Baltimore, USA Today reports.

Significant variations in blood pressure, as well as a person’s tendency toward suspicious and hostile behavior, have been linked to cardiovascular disease, Duke University psychologist and study co-author James Lane said.

For the study, Lane and Redford Williams measured the blood pressure of 152 healthy black and white adults over a 24-hour period to determine whether participants with the most hostile or suspicious behavior had more variability in their blood pressure levels. Blacks with the most hostility had roughly 25% more variability in blood pressure readings than less hostile blacks and whites. Researchers also found that the most hostile white participants had no more variability in their readings than other whites or blacks.

Lane said, “Hostility may be a more important heart disease risk factor for blacks than whites.” He added that hostile blacks “may interpret innocuous events as threatening” and perceive more threats than others, “and then you get the fight-or-flight response, which raises their blood pressure.”

Vickie Mays, a psychologist and director of a UCLA center on minority health disparities, said that “things are not as innocuous as they seem if you’ve had bad experiences before,” adding, “A white person could walk down the street and see a policeman and think he’s just directing traffic, but an African-American may feel less safe because of what’s happened to him in the past.”

She suggested that blacks try to “reframe” incidents. “You need to think, ‘If I let myself go there, it’s bad for my health, it’s not bad for their health,’” Mays said (Elias, USA Today, 3/17).

Reprinted with kind permission from http://www.kaisernetwork.org. You can view the entire Kaiser Daily Health Policy Report, search the archives, or sign up for email delivery at http://www.kaisernetwork.org/dailyreports/healthpolicy. The Kaiser Daily Health Policy Report is published for kaisernetwork.org, a free service of The Henry J. Kaiser Family Foundation© 2007 Advisory Board Company and Kaiser Family Foundation. All rights reserved.

Smoking and high blood pressure are a deadly combination that dramatically increase the risk of a blood vessel bursting inside the brain, Australian research shows.

High blood pressure and smoking are known to increase the risk of heart diseases, but Sydney researchers have shown that the two have a stronger “synergistic effect” when both are present.

A study by the George Institute for International Health in Sydney found that smokers with high blood pressure are significantly more likely to suffer from a hemorrhagic stroke, a type of “bleeding” stroke where a blood vessel bursts and bleeds in the brain, than non-smokers with blood pressure problems.

Lead researcher Professor Koshi Nakamura said the revelation should encourage smokers to quit and deal with their blood pressure as well. “Since we found that these two risk factors have a synergistic effect, quitting smoking and lowering blood pressure will contribute more to preventing stroke than if this previously unreported interaction is ignored,” Prof Nakamura said.

A hemorrhagic stroke is especially debilitating as about half of sufferers die as a result of it, while many survivors are left with paralysis or other crippling effects.

It was the only type of cardiovascular problem where researchers found this heightened risk. Smoking did not appear to exacerbate the impact of blood pressure on the risk of coronary heart disease or ischemic stroke, which was caused by a blood clot.

The researchers believe smoking may damage blood vessels in the brain that are already weakened by high blood pressure. Weakened blood vessels are prone to rupture and bleeding and are therefore particularly susceptible to hemorrhagic stroke, Prof Nakamura said.

The research, published by the American Heart Association, involved 563,144 people of mostly Asian descent.

About 40% of all deaths in Australia each year are caused be heart, stroke and vascular diseases, which is more than any other disease group.

http://www.ash.org.uk

Dr Isabel Lee, Research Liaison Officer at The Stroke Association said:

“The research in this weeks Lancet is very promising and there is certainly potential for an immunisation to control blood pressure particularly in young people as they are more likely to respond.

“One hundred and fifty thousand people in the UK have a stroke each year and high blood pressure is the single biggest risk factor for stroke - around 50,000 strokes could be prevented each year through its control. There are already very good prescribed medications available for hypertension and it is vital that everyone should have blood pressure checked no matter what their age.”

Notes

1. The Stroke Association is the only UK charity solely concerned with combating stroke in people of all ages. The charity funds research into prevention, treatement, better methods of rehabilitation and helps stroke patients and their families directly through its community services which include communications support, family and carer support, information services, welfare grants, publications and leaflets. The Stroke Association also campaigns, educates and informs to increase knowledge of stroke at all levels of society acting as a voice for everyone affected by stroke.

2. A stroke is a brain attack which causes brain damage. A stroke can be diagnosed by using FAST - Facial weakness, Arm weakness, Speech problems, Test all three. If any of these symptoms are present call an ambulance straight away.

The Stroke Association

The development of a new vaccine that can treat high blood pressure has received widespread media coverage. The Guardian reports that the vaccine works by targeting and “mopping up” the hormone, angiotensin 2, which causes blood vessels to tighten and so raise blood pressure.

The Daily Mail writes that the jab could save the lives of thousands of patients by dropping blood pressure in the early morning, “a time when the levels of angiotensin are high and the peak time for heart attacks and strokes”. They say that current medication fails to combat this danger period mainly because people tend to take their pills later in the day with their breakfast. Other newspapers report that the current tablets can have unpleasant side effects, or that as high blood pressure has no visible symptoms, people do not keep to their treatment regimes.

BBC News reports that tests have shown the jab to work in humans without side effects, and that trials had indicated the jab would be enough to give a patient four-month resistance.

This story is based on a study in 72 adults that mainly aimed to assess the safety of the new vaccine by comparing two different doses with a “dummy” injection (placebo). The initial safety results look promising, and the researchers found that a higher dose of the vaccine reduced daytime systolic blood pressure at 14 weeks compared with the dummy injection.

However, these preliminary results were obtained in a small number of people who had mild to moderate high blood pressure, and who were otherwise healthy. Larger, longer-term studies are needed in a broader group of people to assess long-term safety and to confirm the reduction in blood pressure. It will also need to be compared to current blood pressure tablets (in particular those that target the same hormone), and be assessed for how much it can reduce outcomes such as heart attacks.

Where did the story come from?

Dr Alain Tissot and colleagues from Cytos Biotechnology AG, and universities and research centres in Switzerland and Germany carried out the research. The study was funded by Cytos Biotechnology AG who make the vaccine that was tested. The study was published in the peer-reviewed medical journal: The Lancet.

What kind of scientific study was this?

This was a double blind randomised controlled trial in people with high blood pressure (hypertension). This phase IIa trial tested the safety and efficacy of a vaccine (CYT006-AngQb) that targeted a protein called angiotensin II, which is involved in regulating blood pressure.

The researchers enrolled 72 adults with mild to moderate high blood pressure (according to World Health Organization criteria - systolic blood pressure 140-179 mmHg; diastolic blood pressure 90 to 109 mmHg). Other than having hypertension, the participants were healthy. The researchers included men and women who were postmenopausal or who had been surgically sterilised. The participants had to be newly diagnosed with hypertension, or diagnosed previously but were not receiving treatment, or on treatment that could be stopped without causing adverse effects.

The participants were randomly assigned to receiving either a lower dose (100 microgrammes) of the vaccine, a higher dose (300 microgrammes), or a placebo. To reduce the risk of adverse events, the researchers at first only gave the participants either the lower dose vaccine or the placebo, and when no severe adverse events had been observed, people were randomly allocated to receiving the higher dose.

The treatments were given by injection at the start of the study and again at four and 12 weeks. The participants were monitored for any adverse effects during regular clinic visits and by telephone. Before the trial began, and 14 weeks into the trial, the researchers monitored the participants’ blood pressure for 24 hours by attaching a blood pressure monitor that the participants wore while they went about their normal activities. Blood pressure was also measured in the doctor’s office. The researchers then compared blood pressure before and after the trial between the three groups.

What were the results of the study?

Most people receiving the vaccines experienced mild local reactions at the site of the injection (including swelling and hardening) which went away without treatment. People receiving the higher dose of the vaccine had significantly more headaches than people in the lower dose and placebo groups. Three people in the lower dose group and seven people in the higher dose group experienced mild flu-like symptoms, and these symptoms were not seen in the placebo group. There were five serious adverse events during the trial, two in each of the vaccine groups and one in the placebo group (the nature of these events is not reported by the study). However, none of these events were judged to be related to the treatment received.

Five people dropped out of the study, two in the lower dose group and three in the higher dose group. The reasons for dropping out included one case each of withdrawal of consent, adverse event (fainting) after first vaccine injection, development or vertigo and two cases that were unspecified.

From the start of the study, the researchers found that the higher dose of the vaccine (but not the lower dose) reduced average daytime systolic blood pressure significantly more than placebo. The higher dose also reduced the surge in blood pressure that is normally seen in the early morning compared with placebo. Neither dose of the vaccine resulted in significant changes in nighttime blood pressure, nor was there any difference between the groups in blood pressure measured in the doctor’s office.

What interpretations did the researchers draw from these results?

The researchers concluded that the anti-angiotensin vaccine was not associated with serious side effects, and that the higher dose of the vaccine reduced daytime blood pressure in people with mild to moderate hypertension.

What does the NHS Knowledge Service make of this study?

This was a well-designed study that indicates that vaccines may have a role to play in treating high blood pressure in the future.

However, this study mainly aimed to establish the safety of the vaccine in the short term, and larger, and longer-term studies will be needed to further investigate the safety and efficacy of this vaccine. These studies will also need to investigate the effects of the vaccine in people with more severe high blood pressure, and in people who not only have hypertension, but also other health problems. The injections may not be suitable for some of the groups of people that were excluded by this study, for example they would have to be used cautiously in people with kidney problems.

It will also need to be seen how this treatment compares to current blood pressure tablets that target the same hormone (i.e. ACE inhibitors and angiotensin II receptor blockers), and to look at whether it results in a reduction in outcomes such as heart attacks.

Links to the headlines

Hope over high blood pressure jab. BBC News, March 07 2008
Blood pressure jab ‘could save thousands’. The Daily Telegraph, March 07 2008
Jab to beat high blood pressure. The Sun, March 07 2008

Links to the science

Effect of immunisation against angiotensin II with CYT006-AngQb on ambulatory blood pressure: a double-blind, randomised, placebo-controlled phase IIa study.
Tissot AC, Maurer P, Nussberger J, et al.
The Lancet 2008; 371: 821-827

This news comes from NHS Choices