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Cancer-cardiac connection illuminates promising new drug for heart failure

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A team of researchers at the Gladstone Institutes uncovered a new strategy to treat heart failure, a leading contributor to mortality and healthcare costs in the United States. Despite widespread use of currently-approved drugs, approximately 40% of patients with heart failure die within 5 years of their initial diagnosis.

“The current standard of care is clearly not sufficient, which highlights the urgent need for new therapeutic approaches,” said Saptarsi Haldar, MD, an associate investigator at Gladstone and senior author of a new study featured on the cover of the scientific journal Science Translational Medicine. “In our previous work, we found that a drug-like small molecule called JQ1 can prevent the development of heart failure in mouse models when administered at the very onset of the disease. However, as the majority of patients requiring treatment already have longstanding cardiac dysfunction, we needed to determine if our strategy could also treat established heart failure.”

As part of an emerging treatment strategy, drugs derived from JQ1 are currently under study in early-phase human cancer trials. These drugs act by inhibiting a protein called BRD4, a member of a family of proteins called BET bromodomains, which directly influences heart failure. With this study, the scientists found that JQ1 can effectively treat severe, pre-established heart failure in both small animal and human cell models by blocking inflammation and fibrosis (scarring of the heart tissue).

“It has long been known that inflammation and fibrosis are key conspirators in the development of heart failure, but targeting these processes with drugs has remained a significant challenge,” added Haldar, who is also a practicing cardiologist and an associate professor in the Department of Medicine at the University of California, San Francisco. “By inhibiting the function of the protein BRD4, an approach that simultaneously blocks both of these processes, we are using a new and different strategy altogether to tackle the problem.”

Currently available drugs used for heart failure work at the surface of heart cells. In contrast, Haldar’s approach goes to the root of the problem and blocks destructive processes in the cell’s command center, or nucleus.

“We treated mouse models of heart failure with JQ1, similarly to how patients would be treated in a clinic,” said Qiming Duan, MD, PhD, postdoctoral scholar in Haldar’s lab and co-first author of the study. “We showed that this approach effectively treats pre-established heart failure that occurs both after a massive heart attack or in response to persistent high blood pressure (mechanical overload), suggesting it could be used to treat a wide array of patients.”

Using Gladstone’s unique expertise, the scientists then used induced pluripotent stem cells (iPSCs), generated from adult human skin cells, to create a type of beating heart cell known as cardiomyocytes.

“After testing the drug in mice, we wanted to check whether JQ1 would have the same effect in humans,” explained co-first author Sarah McMahon, a UCSF graduate student in Haldar’s lab. “We tested the drug on human cardiomyocytes, as they are cells that not only beat, but can also trigger the processes of inflammation and fibrosis, which in turn make heart failure progressively worse. Similar to our animal studies, we found that JQ1 was also effective in human heart cells, reaffirming the clinical relevance of our results.”

The study also showed that, in contrast to several cancer drugs that have been documented to cause cardiac toxicity, BRD4 inhibitors may be a class of anti-cancer therapeutics that has protective effects in the human heart.

“Our study demonstrates a new therapeutic approach to successfully target inflammation and fibrosis, representing a major advance in the field,” concluded Haldar. “We also believe our current work has important near-term translational impact in human heart failure. Given that drugs derived from JQ1 are already being tested in cancer clinical trials, their safety and efficacy in humans are already being defined. This key information could accelerate the development of a new heart failure drug and make it available to patients more quickly.”

Story Source:Materials provided by Gladstone Institutes.

URL: https://www.sciencedaily.com/releases/2017/05/170517143623.htm

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‘23% of heart failure patients die within a year of diagnosis’

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In India, 23 per cent of heart failure patients die within one year of diagnosis, a study revealed on Tuesday, adding that the country is next to Africa where the rate stands at 34 per cent.
Of the total deaths, 46 per cent were due to cardiac issues, while non-cardiac causes led to 16 per cent deaths in patients, at one year, according to the first comprehensive study on heart failures conducted across six geographies globally.

The International Congestive Heart Failure (INTER-CHF) study said that death rate of patients due to heart failures in Southeast Asia is 15 per cent, seven per cent in China, nine per cent both in South America and West Asia, significantly lower than in Indian patients.

“In India, heart-related diseases occur a decade early than the people of west. Lack of awareness, out of pocket expenditure and lack of infrastructure are corroborating to the heart-related diseases,” said Sundeep Mishra, Professor of Cardiology at All India Institute of Medical Sciences (AIIMS).
Stating that with increasing life expectancy of the population, incidence of heart failure is increasing in an epidemic proportion, the cardiology expert said that the marked variation in mortality in low-income countries like India can be attributed also to the quality and access to primary healthcare facilities.
The study was aimed at measuring mortality at one year in patients, due to heart failure in India, Africa, China, the Middle East, South East Asia and South America.
During the study, 5,823 patients across 108 centres in six geographies were enrolled. Patients were followed up at six months and one year from enrolment. The mean age of patients was 59 years, with a male to female ratio of 60:40.The primary outcome of the study was to record all cause mortality within one year.

A previous study by AIIMS, published in the journal of Practice of Cardiovascular Sciences, highlighted that late diagnosis results in one third of patients dying during hospital admission and one-fourth dying within three months of diagnosis.
Calling for a community based approach to resolve the issue, Mishra said a lot of Indians also do not understand the difference between heart failure and heart attack because of which they do not consult doctors.

“Heart failure refers to the condition where the blood pumping capacity of the heart is reduced. Whereas heart attack is secondary to blocked coronary circulation, where the blood supply to muscles of heart is cut or drastically reduced. Heart failure is a serious health hazard and can be life threatening if ignored,” Mishra told IANS, while speaking about the rising heart failure cases.
According to the World Health Organisation, heart failure impacts more than 60 million people worldwide.

The risk of death of heart failure patients is comparable to that of patients with advanced cancer. It currently costs the world economy $108 billion every year.
Although, heart failure may strike at any age, it is more common in people over the age of 65. It includes high blood pressure, prior heart attack, enlarged heart and diabetes.
Mishra said the major reason for low awareness of heart failure among people is the fact that patients mistake it for signs of getting older.
“Although there is no cure for heart failure, patients who are diagnosed early need to follow their treatment and make lifestyle changes to live longer, feel better and be more active. It is, therefore, vital that patients and care givers are aware of the symptoms of heart failure, leading to better recognition and earlier diagnosis,” said Mishra.

Source: http://timesofindia.indiatimes.com/life-style/health-fitness/health-news/23-of-heart-failure-patients-die-within-a-year-of-diagnosis/articleshow/59769273.cms

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A newly discovered cardiovascular repair process could reverse heart failure

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Scientists may have discovered a way of reversing heart failure by getting heart muscle to regenerate itself.They found that silencing a signaling pathway in mice that had developed heart failure following a heart attack activated a previously unrecognized self-healing process.

In a paper recently published in the journal Nature, the researchers, led by a team from Baylor College of Medicine in Houston, TX, report their findings about the signaling pathway, which is known as Hippo.

Heart failure is a serious condition that affects around 5.7 million adults in the United States. It develops when the heart cannot pump enough blood to meet the body’s needs.

Heart failure does not mean that the heart has stopped pumping, but it does mean that vital organs do not get the oxygen and nutrients they need to function properly. Around half of patients with heart failure do not live more than 5 years after diagnosis.

“Heart failure remains the leading cause of mortality from heart disease,” explains corresponding author James F. Martin, a professor who specializes in regenerative medicine at Baylor College of Medicine and who is also director of the Cardiomyocyte Renewal Lab at the Texas Heart Institute, also in Houston.

Injured hearts favor scarring to regeneration

At present, the best treatment for heart failure is a heart transplant. However, the number of heart failure patients far exceeds the number of hearts available for transplant. Having a ventricular assist device implanted is also an option, but it is a much less favorable one.

One of the curious things about heart muscle is that it does not regenerate when it dies after being starved of oxygen, such as after a heart attack.

Instead of generating new beating muscle cells, or cardiomyocytes, the heart replaces the dead tissue with scar tissue made from fibroblast cells.
Unlike cardiomyocytes, fibroblasts have no pumping ability, so the heart gradually gets weaker and weaker, with the result that the majority of severe heart attack patients develop heart failure.
Prof. Martin says that he and his laboratory team are studying biological pathways that are active during heart development and regeneration in order to find ways to heal heart muscle.

Biological pathways are series of molecular events inside cells that lead to changes in the cell or result in particular products. For example, they can turn genes on and off and they can trigger cells to make fats, proteins, hormones, and other molecules. They can also carry signals and cause cells to move.

Silencing the Hippo pathway

“In this study, we investigated the Hippo pathway, which is known from my lab’s previous studies to prevent adult heart muscle cell proliferation and regeneration,” Prof. Martin notes.

In their study paper, he and his colleagues explain that the Hippo pathway – “a kinase cascade that prevents adult cardiomyocyte proliferation and regeneration” – is more active in patients with heart failure.

“This,” says first author John Leach, a graduate student of molecular physiology and biophysics in Prof. Martin’s group, “led us to think that if we could turn Hippo off, then we might be able to induce improvement in heart function.”

So, the team silenced the Hippo pathway in a mouse model that mimics the type of advanced heart failure that occurs in humans after a heart attack. They compared the results with those of a group of healthy mice (the controls).

“After 6 weeks we observed that the injured hearts had recovered their pumping function to the level of the control, healthy hearts,” says Leach.

The researchers believe that silencing Hippo not only renews heart muscle cells – as investigated extensively in their study – but it also changes the process of fibrosis, or scarring. They call for further studies to investigate the effects on fibrosis.

“Our findings indicate that the failing heart has a previously unrecognized reparative capacity involving more than cardiomyocyte renewal.”

Source: https://www.medicalnewstoday.com/articles/319649.php

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