Researchers at the University of Maryland School of Medicine have identified a common gene variant that appears to influence people’s risk of developing high blood pressure, according to the results of a study being published online Dec. 29, 2008 in the Proceedings of the National Academy of Sciences (PNAS).

The STK39 gene is the first hypertension susceptibility gene to be uncovered through a new technique called a genome-wide association study and confirmed by data from several independent studies.  Located on chromosome 2, the gene produces a protein that helps to regulate how the kidneys process salt, which plays a key role in determining blood pressure.

“This discovery has great potential for enhancing our ability to tailor treatments to the individual – what we call personalized medicine – and to more effectively manage patients with hypertension.  We hope that it will lead to new therapies to combat this serious public health problem worldwide,” says the senior author, Yen-Pei Christy Chang, Ph.D., an assistant professor of medicine and of epidemiology and preventive medicine at the University of Maryland School of Medicine.

But, Dr. Chang says, more research is needed.  “Hypertension is a very complex condition, with numerous other genetic, environmental and lifestyle factors involved.  The STK39 gene is only one important piece of the puzzle,” she says.  “We want to determine how people with different variations of this gene respond to diuretics and other medications, or to lifestyle changes, such as reducing the amount of salt in their diet.  This information might help us discover the most effective way to control an individual patient’s blood pressure.”

One in four Americans has elevated blood pressure, or hypertension, which can lead to death or result in complications, such as cardiovascular disease, stroke and end-stage kidney disease.  Doctors consider the ideal systolic and diastolic blood pressure to be less than 120/80.  (The numbers reflect the pressure of the blood against the arteries when the heart beats and is at rest.)  When blood pressure is elevated, doctors recommend lifestyle changes or prescribe medications, such as diuretics, which force the kidneys to remove water from the body, in order to treat the condition.

However, patients respond differently to treatments and finding the best treatment among all the possible ones for specific patients is still a “try and see” process, according to Dr. Chang.

Scientists believe multiple genes are involved in the most common form of high blood pressure called essential hypertension.  But, because so many factors affect blood pressure, including diet, exercise and stress levels, it has been difficult to pinpoint a specific gene or group of genes, says the lead author, Ying Wang, Ph.D., a researcher at the University of Maryland School of Medicine.

The University of Maryland researchers identified the link between the STK39 gene and blood pressure by analyzing the DNA of 542 members of the Old Order Amish community in Lancaster County, Pa., scanning approximately 100,000 genetic markers across the entire genome for variants known as single nucleotide polymorphisms, or SNPs, associated with systolic and diastolic blood pressure.  The researchers found strong association “signals” with common variants of the serine/threonine kinase gene, or STK39, and confirmed their findings in another group of Amish people and in four other groups of Caucasians in the United States and Europe.

People with one particular variant showed slight increases in blood pressure compared to those with a more common form of the gene and were more likely to develop hypertension, researchers found.  The researchers estimate that about 20 percent of Caucasians in the general population have this variant of the STK39 gene.

“With this new ’scanning’ approach – the genome-wide association study – we are able to uncover genes that have previously eluded us.  The field of complex disease genetics has undergone a revolution in terms of discovering new genes and understanding the genetic basis of common adult-onset diseases,” says co-author Alan R. Shuldiner, M.D., professor of medicine; head of the Division of Endocrinology, Diabetes and Nutrition; and director of the Program in Genetics and Genomic Medicine at the University of Maryland School of Medicine.

The study being published online in PNAS is titled, “Whole-genome association study identifies STK39 as a novel hypertension susceptibility gene.”  It will appear in the print edition of PNAS early next month.

The Amish are ideal for such studies because they are a genetically homogeneous people whose forefathers came to Pennsylvania from Europe in the mid-1700s and share a similar diet and rural lifestyle.  Because many in the Amish community don’t have regular medical check-ups, they often don’t know they have high blood pressure or take medications for it, according to Dr. Chang.  The Amish appear to have as much hypertension as other Caucasians.  As a result of the study, some of the participants learned that they had hypertension and were able to start treatment.

The research, which was funded by the National Institutes of Health, is a spin-off project of another University of Maryland study – the Amish Family Diabetes study – looking for genes that may cause type 2 diabetes.  Researchers at the School of Medicine already have identified a number of genes that may play a role in the development of this type of diabetes.

Women who experience severe gestational hypertension may give birth to boys at lower risk for testicular cancer, although the exact reasons why are still unclear, according to a paper published in the November 1, 2008, issue of Cancer Research, a journal of the American Association for Cancer Research.

Andreas Pettersson, M.D., a doctoral student at Karolinska Institute in Sweden, said the protective effect of gestational hypertension may be due to the hormones that are released when a placenta malfunctions.

“Ironically, a malfunctioning placenta may lower the risk,” said Pettersson.  “One possible reason is that estrogens are lower in pregnancies that develop severe gestational hypertension or preeclampsia, and this lack of estrogens may lower the risk of testicular cancer.”

Pettersson and colleagues observed 293 cases of germ-cell testicular cancer in the Swedish Cancer Register and 861 controls in the Swedish Medical Birth Register.  They extracted data on maternal and pregnancy characteristics such as gestational hypertension, proteinuria, anemia and glucoseuria.

If women experienced severe gestational hypertension, their male offspring were 71 percent less likely to develop testicular cancer than those women who experienced no hypertension.  If the gestational hypertension was mild, there was a 62 percent increased risk of testicular cancer.

Beyond decreased estrogen, severe gestational hypertension and preeclampsia increases the level of human Chorionic Gonadotropin, another pregnancy-related hormone, which may also have a protective effect against testicular cancer.

Pettersson said that these findings add knowledge to the mechanisms behind testicular cancer, but he cautioned against reverse thinking.

“This study does not suggest that a woman who does not have gestational hypertension is going to give birth to a boy who is at increased risk for testicular cancer,” said Pettersson.

Published reports have shown that Asian-Indians have a higher rate of coronary heart disease than other ethnic groups, and their small arteries may be to blame. Researchers from Jamaica Hospital Medical Center in New York explored the differences in the sizes of coronary arteries between Asian-Indians, Caucasians, and African-Americans (n=273). Results showed that ethnic group significantly predicted the diameter of all arteries. Even after controlling for other risk factors, the left anterior descending and left circumflex arteries were significantly smaller in Asian-Indians than other ethnic groups.

Despite increased awareness of pulmonary arterial hypertension (PAH), the disease is being diagnosed later and in women who are reaching middle age, according to research from Baylor College of Medicine in Texas. The researchers looked at data from the current REVEAL registry compared with the original National Institutes of Health registry, the French Registry, and a large, single-center US registry. The REVEAL registry confirms that in the 21st century, the US population of patients with PAH is older (mean age of 48), with a higher female preponderance of PAH (4:1) than reported previously. In addition, despite increased awareness of PAH, the time from symptoms to diagnosis has increased by 10 months.

The use of MP3 players may be an effective way for physicians to improve their recognition of the different types of heart murmurs. In a new study by researchers at Temple University School of Medicine, 255 general internists took a pretest consisting of five heart murmurs played in random order. They then listened to audio files of five basic murmurs on an MP3 player, while viewing posters with phonocardiograms of each sound. The audio files consisted of 200 repetitions of each of the five murmurs played during a single 30-minute session. All participants took a posttest consisting of the same murmurs played in a random order. The murmurs used in the training session were simulated heart sounds, while the murmurs used for both the pretest and posttest were human heart sounds. Participants’ correct answers improved from 53.2 on the pretest to 78.9 on the posttest.

Female hospital staff members have more difficulty performing adequate chest compressions (CC) than male hospital staff. Researchers from Albert Einstein College of Medicine in New York compared the CC technique of 28 male and 30 female medical housestaff using a patient simulator, before and after CC training. Subjects also went through a posttraining endurance test where they attempted to perform adequate CC for 120 seconds or until fatigue prevented further effort. Prior to training, 50 percent of the male group performed adequate CC, while none of the female group performed adequate CC. Post-training, 89 percent of the male group performed adequate CC and 37 percent of the female group performed adequate CC. There was no correlation between body mass index and adequate CC in either group, however taller females performed better CC than shorter females. Regardless of gender, only 14 percent of subjects were able to maintain adequate CC for 120 seconds, the recommended guideline for one cycle of compressions.

Hospitalized patients who undergo repeated in-hospital CPR have a high mortality rate. Researchers from Western Pennsylvania Hospital in Pittsburgh reviewed the charts of 151 patients, aged 25 to 99 years, who underwent CPR as a consequence of cardiopulmonary arrest. Out of these patients, only 16 (eight men and eight women) required repeated CPR after the first successful attempt. None of these patients survived to the time of hospital discharge. Researchers suggest that patients who are seriously ill, as well as their families, should be well informed regarding the expected outcome of multiple in-hospital resuscitation events.

Difficulty falling asleep may be associated with a lower risk of hypertension than researchers once believed. Researchers from the University of Kentucky proposed the hypothesis that insomnia would predict hypertension, particularly among African-Americans. Data were analyzed from 1,419 older individuals with a mean age of 73.4 years who were not hypertensive at baseline. Researchers found that difficulty falling asleep, alone or in combination with other sleep complaints, predicted a significantly reduced risk of incident hypertension for men who were not African-American over a 6-year period of follow up. Furthermore, insomnia complaints did not predict hypertension in women or in African-Americans, although there may not have been enough power to show a significant association for African-Americans.

New research shows that the erectile dysfunction drug, tadalafil, may be an effective adjunct therapy for patients with pulmonary arterial hypertension (PAH). Italian researchers randomized 405 patients with PAH, of whom 53 percent were taking concomitant bosentan, to two study arms. The groups received either tadalafil or placebo orally once daily as monotherapy or as add-on therapy to bosentan. Compared with placebo, tadalafil, 40 mg, increased 6-minute walk distance, delayed the time to clinical worsening, and improved six of the eight short form (SF)-36 domains. In addition, tadalafil, 40 mg, increased cardiac output and reduced pulmonary artery pressures and pulmonary vascular resistance compared with baseline. Discontinuation due to adverse events was low (11 percent for tadalafil vs. 16 percent for placebo). Researchers conclude that tadalafil may provide an effective oral, once-daily therapy that can be combined with bosentan therapy for patients with PAH.

Patients receiving donated lungs may develop arrhythmias, including atrial fibrillation. Researchers from Baylor College of Medicine in Texas reviewed the charts of all lung transplant recipients in 2006 and 2007. Of the 75 patients who underwent lung transplant, 38 percent developed arrhythmias within 30 days of transplantation. The most common arrhythmia was atrial fibrillation, followed by atrial flutter. Researchers speculate that the donor-derived tissue (atrial cuff or pulmonary vein) is a likely source of the arrhythmias passed to lung recipients.

About 5 million people in the United States suffer from heart failure (HF). While some reports indicate that changes to diet can reduce HF risk, few large, prospective studies have been conducted. In a new study researchers observed over 14,000 participants for more than 13 years and found that whole grain consumption lowered HF risk, while egg and high-fat dairy consumption raised risk. Other food groups did not directly affect HF risk. The results are published in the November 2008 issue of the Journal of the American Dietetic Association.Diet is among the prominent lifestyle factors that influence major HF risk factors: coronary artery disease, obesity, diabetes and insulin resistance and hypertension. Using data from the Atherosclerosis Risk in Communities (ARIC) study, researchers from the Division of Epidemiology and Community Health, University of Minnesota and the Department of Epidemiology and Cardiovascular Diseases Program, University of North Carolina, analyzed the results of baseline exams of more than 14,000 White and African American adults conducted in 1987-89, with follow-up exams completed during 1990-92, 1993-95, and 1996-98. Four field centers participated in the study: Forsyth County, NC; Jackson, MS; northwest Minneapolis suburbs, MN; and Washington County, MD. The study also collected demographic characteristics and lifestyle factors, as well as other medical conditions such as cardiovascular disease, diabetes and hypertension.

Writing in the article, Jennifer A. Nettleton, Ph.D., states, “Although risk estimates were modest (7% lower risk per 1-serving increase in whole grain intake; 8% greater risk per 1-serving increase in high-fat dairy intake; 23% greater risk per 1-serving increase in egg intake), the totality of literature in this area suggests it would be prudent to recommend that those at high risk of HF increase their intake of whole grains and reduce intake of high-fat dairy and eggs, along with following other healthful dietary practices consistent with those recommended by the American Heart Association.”

Scientists at the Gladstone Institute of Cardiovascular Disease (GICD) and the University of California San Francisco (UCSF) have identified a genetic factor critical to the formation of chambers in the developing heart. The discovery of the role of a microRNA called miR-138, could offer strategies for the treatment of congenital heart defects.The heart is one of the first and most important organs to develop. In fact, embryos cannot survive long with a functioning heart. In vertebrates (animals with backbones), special cells form a heart tube; that tube loops back on itself to form the atrium and ventricle and the canal and valve that separates them. This requires a complicated sequence of genes turning on and off. MicroRNAs are very small RNAs of 20 to 25 nucleotides that regulate numerous gene functions. Approximately 650 human miRNAs are known, but only a few have yet been studied to determine what they actually do in a cell.

Researchers, led by Sarah Morton, an MD/PhD student at UCSF and GICD Director Deepak Srivastava MD, examined zebrafish, which are an ideal model system for understanding genetic functions. Zebrafish are small, reproduce fast, and are essentially transparent so that that events of heart formation can be studied while they are still alive. Yet many of their systems are quite similar to those of humans. For example, miR-138 is exactly the same in zebrafish and humans.

“What’s interesting is that a single microRNA is responsible for setting up the distinct patterning of a developing heart into separate chambers,” said Dr. Srivastava, senior author of the study. “Since many congenital heart defects involve abnormalities in the formation of the chambers, this is important information in finding ways of treating or avoiding those defects.”

The GICD scientists reported in today’s issue of the Proceedings of the National Academy of Sciences USA, that miR-138 is present in the zebrafish heart at specific times and in specific places in the developing heart. Furthermore, they showed that it is required to insure that the cardiac chambers develop properly. When the scientists used genetic engineering techniques to eliminate miR-138, cardiac function was disrupted, and the ventricles did not develop correctly, with the muscle precursor cells failing to mature properly.

“The miR-138 function was required during a discrete developmental window that occurred 24-34 hours after fertilization,” said Sarah Morton. The team also showed that the miRNA controlled development by regulating numerous factors that function jointly to define the chambers, including a key enzyme that makes retinoic acid.

Researchers have new insight into the mechanisms that underlie a pathological increase in the size of the heart.  The research, published by Cell Press in the October 24th issue of the journal Molecular Cell, may lead to the development of new strategies for managing this extremely common cardiac ailment that often leads to heart failure.

High blood pressure, heart valve disease and heart attacks can lead to a abnormal thickening of the heart muscle, called myocardial hypertrophy.  At the molecular level, signals driving myocardial hypertrophy, such as elevated levels of catecholamine hormones (i.e. adrenaline), activate the Myocyte Enhancer Factor (MEF) proteins.  This alters gene expression in heart muscle cells and induces an adverse developmental paradigm known to cardiologists as the “fetal gene response”.

“Previous research has shown that the signaling pathways leading to MEF2 are altered during pathological cardiac hypertrophy,” says senior study author Dr. John D. Scott, a Howard Hughes Medical Institute Investigator from the Department of Pharmacology at the University of Washington.  “Although we know that enzymes called histone deacetylases (HDACs) control MEF2 activity, it was not clear that HDACs and MEF2 were integrated into a larger signaling unit.”

To further identify the molecular mechanisms associated with cardiac hypertrophy, Dr. Scott and colleagues studied cardiac A-Kinase Anchoring Proteins (AKAPs), which are known to play a critical role in organizing signaling complexes in response to catecholamine hormones and transmitted signals within cells.

The researchers found that AKAP-Lbc functions as a scaffolding protein that selectively directs catecholamine signals to the transcriptional machinery to potentiate the hypertrophic response.  “Our study supports a model where AKAP-Lbc facilitates activation of protein kinase D, which in turn phosphorylates the histone deacetylase HDAC5 to promote its export from the nucleus.  The reduction in nuclear HDAC5 favored MEF2 transcription and the onset of cardiac hypertrophy.”

These studies reveal a role for AKAP-Lbc in which increased expression of the anchoring protein selectively amplifies a signaling pathway that drives cardiac muscle cells to a pathophysiological outcome.  “It will be important to explore the role of the AKAP-Lbc/PKD/HDAC5 signaling pathway in whole animal models to establish whether AKAP-Lbc is a valid biomarker for hypertrophic cardiomyopathy and to determine which genes are initiated upon up-regulation of the anchoring protein,” offers Dr. Scott.

New research continues to link tart cherries, one of today’s hottest “Super Fruits,” to lowering risk factors for heart disease. In addition to lowering cholesterol and reducing inflammation, the study being presented by University of Michigan researchers at next week’s American Dietetic Association annual meeting, found that a cherry-enriched diet lowered body weight and fat – major risk factors for heart disease.In the study, at-risk, obese rats that were fed a cherry-enriched diet saw significant decreases in body weight and fat (especially the important “belly” fat with known risk for heart disease) while maintaining lean muscle mass. After twelve weeks, the cherry-fed rats had 14 percent lower body fat compared to the other rats who did not consume cherries (cherry-fed rats were approximately 54% body fat; rats eating the Western diet alone were 63% body fat). The researchers suggested cherry consumption could have an effect on important fat genes and genetic expression. According to the American Heart Association, being overweight or obese, in particular when the weight is concentrated in the middle, is a major risk factor for heart disease . Nearly two out of three Americans are overweight.

The animals were fed a “Western diet,” characterized by high fat and moderate carbohydrate – in line with the typical American diet – with or without added whole tart cherry powder, as 1 percent of the diet. The study was funded by the Cherry Marketing Institute, which provided an unrestricted grant to the University of Michigan to conduct the research and was not directly involved in the design, conduct or analysis of the project.

“Heart disease is the number one killer of Americans today, so it’s important we continue researching ways people can improve their diet to help reduce key risk factors,” said study co-author Dr. Steven F. Bolling, a cardiac surgeon at the University of Michigan Cardiovascular Center who also heads the U-M Cardioprotection Research Laboratory, where the study was performed. “We know excess body fat increases the risk for heart disease. This research gives us one more support point suggesting that diet changes, such as including cherries, could potentially lower heart disease risk.”

Cherry-enriched diets in the study also reduced total cholesterol levels by about 11 percent and two known markers of inflammation – commonly produced by abdominal fat and linked to increased risk for heart disease. Inflammation marker TNF-alpha was reduced by 40 percent and interleukin 6 (IL-6) was lowered by 31 percent. In their genetic analysis, the researchers found that the cherry-enriched diets reduced the genes for these two inflammation compounds, suggesting a direct anti-inflammation effect. While inflammation is a normal process the body uses to fight off infection or injury, according to recent science, a chronic state of inflammation could increase the risk for diseases and may be especially common for those who are overweight or obese, at least in part because of excess weight around the middle. Researchers say the animal study is encouraging and will lead to further clinical studies in humans to explore the link between diet, weight, inflammation and lowering heart disease risk.

The Power of Eating Red

Tart cherries, frequently sold as dried, frozen or juice, contain powerful antioxidants known as anthocyanins, which provide the bright, rich red color. Studies suggest these colorful plant compounds may be responsible for cherries’ anti-inflammatory properties and other health benefits.

This new research is the latest linking this red hot “Super Fruit” to protection against heart disease and inflammation. In fact, research suggests the red compounds in cherries that deliver the anti-inflammatory benefits may also help ease the pain of arthritis and gout.

Randomized, controlled trials have shown that nurse-led disease management for patients with heart failure can reduce hospitalizations. However, there is less evidence about the cost-effectiveness of these programs. Researchers looked at cost data from a randomized trial of 203 usual care patients versus 203 nurse-managed patients with heart failure. The study consisted mainly of black and Hispanic patients with lower socioeconomic status. Patients in the nurse-managed group maintained better physical functioning throughout the 12-month intervention than did usual care patients. In addition, nurse-led case management was cost-effective (it cost $20,000 per additional year of survival in good health). Researchers concluded that nurse-led disease management was a reasonably cost-effective way to reduce the burden of heart failure in an ethnically diverse urban setting. The results might not apply to patients in other communities.