Researchers from Yale School of Medicine and Celera Diagnostics have confirmed and extended the significance of a genetic variant that substantially increases the risk of a frequently fatal thoracic aortic dissection or full rupture.
Thoracic aortic aneurysms, or bulges in the artery wall, can develop without pain or other symptoms. If they lead to a tear — dissection — or full rupture, the patient will often die without immediate treatment. Therefore, better identification of patients at risk for aortic aneurysm and dissection is considered essential.
The research team, following up on a previous genome-wide association study by researchers at Baylor College of Medicine, investigated genetic variations in a protein called FBN-1, which is essential for a strong arterial wall. After studying hundreds of patients at Yale, they confirmed what was found in the Baylor study: that one variation, known as rs2118181, put patients at significantly increased risk of aortic tear and rupture. In addition, the Yale team was able to show that this increased risk of tear was powerful enough to be significant even independently of aortic size.
‘Although surgical therapy is remarkable and effective, it is incumbent on us to move to a higher genetic level of understanding of these diseases,’ said senior author Dr. John Elefteriades, the William W. L. Glenn Professor of Surgery (Section of Cardiac Surgery) at Yale School of Medicine, and director of the Aortic Institute at Yale-New Haven Hospital. ‘Such studies represent important steps along that path.’
The researchers hope their confirmation of the earlier study may help lead to better clinical care of patients who may be at high risk of this fatal condition. ‘Patients with this mutation may merit earlier surgical therapy, before aortic dissection has a chance to occur,’ Elefteriades says. Yale cardiothoracic surgeons will now begin assessing this gene in clinical patients with aneurysm disease. Yale University

Large sections of the genome that were once referred to as ‘junk’ DNA have been linked to human heart failure, according to research from Washington University School of Medicine in St. Louis.
Molecules now associated with these sections of the genome are called non-coding RNAs. They come in a variety of forms, some more widely studied than others. Of these, about 90 percent are called long non-coding RNAs, and exploration of their roles in health and disease is just beginning.
Washington University investigators report results from the first comprehensive analysis of all RNA molecules expressed in the human heart. The researchers studied non-failing hearts and failing hearts before and after patients received pump support from left ventricular assist devices (LVAD). The LVADs increased each heart’s pumping capacity while patients waited for heart transplants.
‘We took an unbiased approach to investigating which types of RNA might be linked to heart failure,’ said senior author Jeanne M. Nerbonne, PhD, the Alumni Endowed Professor of Molecular Biology and Pharmacology. ‘We were surprised to find that long non-coding RNAs stood out. In fact, the field is evolving so rapidly that when we did a slightly earlier, similar investigation in mice, we didn’t even think to include long non-coding RNAs in the analysis.’
Heart failure refers to a gradual loss of heart function. The left ventricle, the heart’s main pumping chamber, becomes less efficient. Blood flow diminishes, and the body no longer receives the oxygen needed to go about daily tasks. Sometimes the condition develops after an obvious trigger such as a heart attack or infection, but other times the causes are less clear.
In the new study, the investigators found that unlike other RNA molecules, expression patterns of long non-coding RNAs could distinguish between two major types of heart failure and between failing hearts before and after they received LVAD support.
‘We don’t know whether these changes in long non-coding RNAs are a cause or an effect of heart failure,’ Nerbonne said. ‘But it seems likely they play some role in co-ordinating the regulation of multiple genes involved in heart function.’
Nerbonne pointed out that all types of RNA molecules they examined could make the obvious distinction: telling the difference between failing and non-failing hearts. But only expression of the long non-coding RNAs was measurably different between heart failure associated with a heart attack (ischemic) and heart failure without the obvious trigger of blocked arteries (non-ischemic). Similarly, only long non-coding RNAs significantly changed expression patterns after implantation of left ventricular assist devices.
Because of the difficulty in obtaining human heart tissue, the study’s sample size was relatively small, Nerbonne said. Her team analysed eight non-failing hearts, eight hearts in ischemic heart failure and eight hearts in non-ischemic heart failure. Though small, the study is unique because each of the 16 failing hearts was sampled twice, once before and once after LVAD support.
According to Nerbonne, this before-and-after sampling of heart tissue is an unusual feature of this study and one of its strengths. Cardiac surgeons first removed a sample of heart tissue while implanting the LVAD. Then, months later, transplant surgeons sampled the same failing hearts when each patient received a new donor organ. Previous studies comparing heart function before and after implanting a pump used samples taken from different patients.
This double sampling of the same organ is important for understanding what is happening on a molecular level to failing heart tissue when a pump literally takes some of the load off.
‘It’s clear that some patients experience a change in the structure and physiology of the heart tissue following pump support, and in some patients that change results in improved heart function,’ Nerbonne said. ‘One interesting question is whether these long non-coding RNAs could be a measure of whether the failing heart is getting better with an LVAD.’
Indeed, using the non-failing heart samples for comparison, about 10 percent of the long non-coding RNA expression that was disturbed in the failing hearts improved or returned to normal following LVAD support. While 10 percent may seem modest, only about 3 percent, at best, of other types of RNA expression returned to normal after pump support.
Nerbonne also is interested in exploring whether measures of long non-coding RNAs could be an early predictor of the disease, ideally before symptoms of heart failure even develop. Washington University School of Medicine in St. Louis

A new study from researchers at the University of Ottawa Heart Institute (UOHI), sheds light on a mysterious gene that likely influences cardiovascular health. After five years, UOHI researchers now know how one genetic variant works and suspect that it contributes to the development of heart disease through processes that promote chronic inflammation and cell division.
Researchers at the Ruddy Canadian Cardiovascular Genetics Centre had initially identified a variant in a gene called SPG7 as a potential contributor to coronary artery disease several years ago, but its role in multiple health processes made it difficult to tease out how it affects heart disease.
The gene holds instructions for producing a protein called SPG7. This protein resides in mitochondria—the small power plants of cells that produce the energy cells need to function. SPG7’s role is to help break down and recycle other damaged proteins within the mitochondria.
Normally, SPG7 requires a partner protein to activate itself and start this breakdown process. But, in people who carry the genetic variant in question, SPG7 can activate itself in certain circumstances, leading to increased production of free radicals and more rapid cell division. These factors contribute to inflammation and atherosclerosis.
‘We think this variant would definitely heighten the state of inflammation, and we know that inflammation affects diabetes and heart disease,’ said Dr. Stewart, Principal Investigator in the Ruddy Canadian Cardiovascular Genetics Centre and senior author of the study. ‘Interestingly, the variant also makes people more resistant to the toxic side effects of some chemotherapy drugs.’
From an evolutionary perspective, this resistance could help such a genetic variant gain a stable place in the human genome. Between 13 and 15 per cent of people of European descent possess this variant.
‘The idea of mitochondria contributing to inflammation isn’t new,’ concluded Dr. Stewart. ‘But what is new is that we’ve found one of the switches that regulate this process. We’re excited, because once you know where the switches are, you can start looking for ways to turn them on and off.’ EurekAlert

A research team lead by Academy Professor Kari Rissanen at the University of Jyväskylä has discovered a new water-soluble fluorescent detection system that is extremely sensitive to pyrophosphate (PPi).
Pyrophosphate has a key role in energy transduction, DNA replication and other metabolic processes that are dysregulated in cancer cells. The discovery might lead to the development of a method for early detection of cancer cells.

The team developed a simple metal complex which shows an intense orange fluorescent colour in the presence of very low concentration of pyrophosphate (PPi) in water. The complex, also called a probe, had almost 1000 times higher level of response than earlier methods and an unprecedented sensitivity to detect PPi at a sub-nanomolar level. The discovery represents the first water-soluble fluorescent sensor that is capable of detecting pyrophosphate at this sensitivity level under physiological conditions.

The highly sensitive probes or sensors that are able to report the PPi level could lead to improved cancer diagnostics, since PPi plays a key role in energy transduction, DNA replication and other metabolic processes that are seriously misbehaving in cancer cells. All earlier PPi-selective sensor molecules or complexes have suffered from poor water solubility and low sensitivity in water. They can reach only micromolar levels and, thus, researchers have had to rely on protein-based probes that have their own limitations.

The researchers were able to show that the probe can image the pyrophosphate in the nuclei of living (HeLa) cells, making it an excellent probe for live cell pyrophosphahe imaging. The HeLa cells, originally from Henrietta Lack’s cervix carcinoma, are the most long-lived human cancer cell line and are often used as a cancer cell model. In addition to their applicability in water, they can easily be formulated into a hydrogel and coated onto paper strips for low-cost pyrophosphate detection. University of Jyväskylä

Case Western Reserve researchers have discovered that a protein previously implicated in disease plays such a positive role in learning and memory that it may someday contribute to cures of cognitive impairments. The findings regarding the potential virtues of fatty acid binding protein 5 (FABP5) — usually associated with cancer and psoriasis.

‘Overall, our data show that FABP5 enhances cognitive function and that FABP5 deficiency impairs learning and memory functions in the brain hippocampus region,’ said senior author Noa Noy, PhD, a professor of pharmacology at the School of Medicine. ‘We believe if we could find a way to upregulate the expression of FABP5 in the brain, we might have a therapeutic handle on cognitive dysfunction or memory impairment in some human diseases.’

FABP5 resides in many tissues and is especially highly expressed in the brain. Noy and her Case Western Reserve School of Medicine and National Institute on Alcohol Abuse and Alcoholism colleagues particularly wanted to understand how this protein functioned in neurons. They performed imaging studies comparing the activation of a key transcription factor in the brain tissue of normal mice and in FABP5-deficient mice. (Transcription factor is a protein the controls the flow of genetic information). The investigations revealed that FABP5 performs two different functions in neurons. First, it facilitates the degradation of endocannabinoids, which are neurological modulators controlling appetite, pain sensation, mood and memory. Second, FABP5 regulates gene expression, a process that essentially gives cells their marching orders on structure, appearance and function.

‘FABP5 improves learning and memory both because it delivers endocannabinoids to cellular machinery that breaks them down and because it shuttles compounds to a transcription factor that increases the expression of cognition-associated genes,’ Noy said.

Even though endocannabinoids affect essential physiological processes from appetite to memory, the ‘cannabinoid’ part of the word signifies that these natural biological compounds act similarly to drugs such as marijuana and hashish. Too much endocannabinoid can lead to impaired learning and memory.

In simple terms, FABP5 transports endocannabinoids for processing. FABP5 functions like a bus and carries the brain’s endocannabinoids and their biological products to two stations within the neuron cell. FABP5 captures endocannabinoids entering the neuron and delivers them to an enzyme that degrades them (station 1). Then, that degraded product is picked up by the same protein (FABP5) and shuttled to the cell nucleus — specifically, to a transcription factor within it (station 2). Binding of the degraded product activates the transcription factor and allows it to induce expression of multiple genes. The genes that are induced in this case tell the cells to take steps that promote learning and memory.

Noy and associates also compared memory and learning in FABP5-deficient mice and in normal ones. In one test, both sets of mice repeatedly swam in mazes that had a platform in one established location where they could climb out of the water. During subsequent swims, the wild-type mice reached the platform quickly because they had learned — and remembered — its location. Their FABP5-deficient counterparts took much longer, typically finding the platform’s location by chance.

‘In addition to regulating cell growth as in skin and in cancer cells, for example, FABP5 also plays a key role in neurons of the brain,’ Noy said. ‘FABP5 controls the biological actions of small compounds that affect memory and learning and that activate a transcription factor, which regulates neuronal function.’ Case Western Reserve University School of Medicine