Tag Archives: Heart failure

Research Roundup: Snail venom and cancer, reversal of advanced heart failure and more!

Welcome to this week’s Research Roundup. These Friday posts aim to inform our readers about the many stories that relate to animal research each week. Do you have an animal research story we should include in next week’s Research Roundup? You can send it to us via our Facebook page or through the contact form on the website.

  • Secrets found in snail venom may help treat cancer. Cone snails are marine mollusks that are found worldwide in warm climates. Usually reclusive, cone snails will produce a venomous sting when threatened using a single, harpoon-like tooth. They also use this venom to immobilize their prey, which are often much bigger and faster than the snails themselves. By examining the molecular makeup of cone snail venom, researchers are learning how a single toxin, which typically only affects the central nervous system, can also impact the immune system. This information may help develop therapies for cancers that involve uncontrolled overproduction of certain cells, such as gastric, breast, and lung cancers. Published in Scientific Reports.

In the wild, cone snails harpoon their prey as it swims by. In the lab, the cone snail has learned to exchange venom for dinner. Here, a snail extends its proboscis and discharges a shot of venom into a latex-topped tube.
Credit: Alex Holt/NIST

  • Scientists reverse advanced heart failure. Heart failure is one the most common reasons for hospital admittance in individuals 65 years or older. It occurs when the heart is unable to pump blood sufficiently to maintain the body’s needs. This week, researchers were able to reverse severe heart failure in a mouse model, by silencing the Hippo pathway. The Hippo pathway is associated with cell death, which occurs, for example, when heart tissue is starved of oxygen. Dr. James Martin, the corresponding author on this study states “Heart failure remains the leading cause of mortality from heart disease. The best current treatment for this condition is implantation of a ventricular assist device or a heart transplant, but the number of hearts available for transplant is limited”. This mouse model, which mimics the human condition of advanced heart failure, is therefore an exciting new avenue for further investigation into measures which limit the debilitating consequences of heart failure. This study appears in the journal Nature.
  • Zebrafish recover faster from stressful situations when housed together. Zebrafish are a small, schooling minnow-like species increasingly used in many aspects of biomedical research. A new study shows that when zebrafish are housed together after a stressful procedure, they recover faster, resume normal behaviours and even have lower levels of stress hormone than fish housed alone. The study also demonstrated that stress hormone levels can be measured non-invasively by sampling the water directly from fish tanks. Refining how we work with zebrafish, and discovering better ways to provide for their welfare needs are important aspects of doing valuable life-saving research with these animals. This research was published in the journal Animal Behavior.

Zebrafish: Wellcome Trust Sanger Institute

  • The link between caesarean sections, the microbiome, and obesity. Caesarean section, a.k.a. C-section, is a life-saving practice for delivering 10-15% of human newborns. However, C-section is also overused in the developed world with some regions delivering 43% of newborns by C-section. Although this practice is quite common, scientists and medical doctors understand little about the long-term effects of C-section. This week, scientists have uncovered evidence that being delivered by C-section is linked to an increased risk of obesity in mice. This link between C-section and obesity deals with the gut microbiome. When humans, or laboratory mice, are delivered normally they travel through the vaginal canal and get exposed to vaginal microbiota. C-section circumvents the vaginal canal and thus the newborns do not get exposed to this vaginal microbiota. Research published this week in Science Advances indicates that mouse pups born by C-section weigh significantly more than those born normally. They also have a different gut microbiomes. This research does not necessarily mean humans born by C-sections are at higher risk for obesity, because human newborns often get antibiotics immediately after delivery and mice are fostered to new mothers after being delivered by C-section. Nonetheless, this is a great step towards further understanding the consequences of C-section deliveries.
  • The validity of studies on the transplantation of tumours to mice questioned. This week ,a study published in the journal Nature Genetics, described changes in the genome of tumor tissue implanted into immunodeficient mice that may affect interpretation of research results. Human tumors can be studied in cell culture medium or by implanting cultured cells into immunodeficient rodent models. However, the process of ‘immortalization’ of cells grown in artificial culture medium alters the cells in ways that limit their usefulness as a model in tumor biology.  As an alternative, tumors collected from patients can be implanted directly into rodents (PDX or patient-derived xenograft avatars) to study their activity and response to therapeutic drugs.  This approach has been thought to better replicate the behavior of tumors in human patients with improved predictability of the model as a desired outcome. However, the study in Nature Genetics by Uri Ben-David and colleagues found that the unstable genome in many tumors continues to change after implantation into the mouse, and can accumulate mutations that differ in behavior and response to chemotherapeutics from the original patient tumor. These findings do not negate the value of the PDX avatar model, but do highlight the need for further investigation to determine how the genomic changes that occur affect the interpretation of results derived using this type of model.

Trial of gene therapy in heart failure launches following success in rats and pigs.

Heart failure is a deadly condition that affects about two out of every hundred adults in the USA, and occurs when the heart is unable to provide sufficient pump action to maintain blood flow to meet the needs of the body. Among the more common causes are heart attacks and hypertension, but less frequently it can also be caused by viral infections or autoimmune diseases.

While the therapies available for heart failure have improved a lot in recent years thanks to the development of drugs such as Ivabradine, heart failure is still a major cause of death and disability, particularly among the over 65’s. As you might expect scientists around the world are developing several innovative approaches to treating heart failure – the British Heart Foundation’s “Mending Broken Hearts” appeal is an excellent example of the concerted effort now underway – and we have highlighted on this blog and our Facebook page  techniques ranging from electrical stimulation of the vagus nerve to collagen patches that stimulate tissue repair.

To those animal research has added another: Gene Therapy!

Image courtesy of Imperial College London

Image courtesy of Imperial College London

Yesterday the BBC reported the recent launch in the UK of a Clinical trial of gene therapy for heart failure, and Professor Peter Weissberg of the British Heart Foundation, who funded much of the basic and applied research leading up to this trial, noted the promise that this approach holds:

Whilst drugs can offer some relief, there is currently no way of restoring function to the heart for those suffering with heart failure. This early clinical study is the culmination of years of BHF funded laboratory research and offers real promise.

“Gene therapy is one of the new frontiers in heart science and is a great example of the cutting edge technologies that the BHF is using to fight heart failure. Gene therapy aims to improve the function of weak heart muscle cells, whereas our Mending Broken Hearts Appeal is aimed at finding ways to replace dead heart muscle cells after a heart attack. Both approaches are novel and both offer great potential for the future.””

This trial, which is being run by researchers at Imperial College London and the Royal Brompton Hospital, is part of a multinational multicentre trial of 200 patients – CUPID-2b – which seeks to assess whether injection into heart tissue of a adeno-associated virus 1-based gene therapy vector driving expression of the enzyme SERCA2a can repair damaged heart tissue and improve cardiac function. The reasoning behind this is that as a calcium transport protein SERCA2a plays a key role in maintaining the correct balance of calcium ions in heart muscle cells, and studies in both human heart failure patients and animal models of heart failure the amount of SERCA2a is lower than normal. A combination of studies in human heart muscle tissue and animal models of heart failure over several years demonstrated that this decrease is associated with calcium overload, an abnormal heart rhythm and tissue damage, suggesting that increasing the amount of SERCA2a in the injured heart tissue may reverse the damage.

In 2010 paper was published reporting on the first clinical trial of this therapy1 (available to read for free), whose primary goal was to assess the safety of the technique, and it noted that studies in animal models of heart failure provided vital evidence underpinning the decision to move it into clinical trials.

In preclinical HF models in rodents,(20) pigs,(18) and sheep,(21) increasing the level of SERCA2a using recombinant AAV vectors was well tolerated and restoration of SERCA2a levels resulted in significant improvement in cardiac function and energetics, even when the underlying pathophysiology or insult (eg, mitral valve rupture or pacing induced heart failure) was not corrected. Based on these findings, this first-in-human Phase 1/2 Calcium Upregulation by Percutaneous Administration of Gene Therapy in Cardiac Disease (CUPID) trial(4) aims to restore levels of this key enzyme in HF patients via gene transfer of the SERCA2a cDNA by delivering a recombinant AAV (AAV1/SERCA2a) via percutaneous intra-coronary infusion.”

These studies, first in short- term studies in rats published in 2007 and subsequently longer duration studies in pigs and sheep published in 2008, indicated that this therapy was safe, could restore SERCA2a to normal levels, promoted heart muscle repair and improved heart function.

It’s just one more example of how animal research is contribution to the exciting field of gene therapy, and to advances in treating heart failure.

Paul Browne

1)      Jaski BE, Jessup ML, Mancini DM, Cappola TP, Pauly DF, Greenberg B, Borow K, Dittrich H, Zsebo KM, Hajjar RJ; Calcium Up-Regulation by Percutaneous Administration of Gene Therapy In Cardiac Disease (CUPID) Trial Investigators. “Calcium upregulation by percutaneous administration of gene therapy in cardiac disease (CUPID Trial), a first-in-human phase 1/2 clinical trial.” J Card Fail. 2009 Apr;15(3):171-81. doi: 10.1016/j.cardfail.2009.01.013. PMCID: PMC2752875

Dogs in Medical Research

A video clip from Understanding Animal Research, a UK organisation which tries to tackle some of the misunderstandings about animal research. This kind of open advocacy which allows people to see the conditions of animals in labs is an important step in winning and keeping public support for lifesaving medical research.

Notice the use of clicker training to get the animals to do simple tasks such as jump on the weighing scales – this reduces any stress that might be caused by trying to force the beagle to do this unwillingly. This is just one of the many enrichment techniques used to improve animal welfare in laboratories around the world.

An excellent example of the value of dogs in biomedical research is provided by a BBC report “‘Heart shrinking’ trial to combat heart failure to begin” on the launch of a multi-centre trial (see clinicaltrials.gov for details) to evaluate whether electrical stimulation of the vagus nerve can reduce cardiac hypertrophy and arrhythmia, and improve heart function in patients with heart failure. The BBC report acknowledges that “The technique is being trialled in humans after it was shown to keep rats and dogs alive for longer” and links to a 2003 paper which found that electrical stimulation of the vagus nerve increases survival in a rat model of cardiac hypertrophy.

This  technique is based on a discovery made in 1984 (1), when scientists showed that an imbalance in the autonomic nervous system – part of the nervous system that acts as a control system functioning and is comprised of parasympathetic nervous system (PSNS) and sympathetic nervous system (SNS) – has a critical role in the induction of lethal ventricular arrhythmias in dogs following heart attack, with an increase in SNS activity leading to abnormal heart rate, heart tissue growth, and heart failure. Over the past decades several drugs have been developed to treat heart failure by reducing heart tissue growth – the ‘heart shrinking’ referred to in the BBC report – and heart rate, for example Ivabradine whose development we discussed recently, but more recently another approach has received attention, modulating the PSNS through stimulation of the vagus nerve in order to rebalance the autonomic nervous system inputs into the heart.

Following a series of studies which demonstrated that stimulation of the vagus nerve could prevent death and improve heart function in a variety rat and dog models of cardiac dysfunction and heart failure (including the study mentioned by the BBC above), scientists demonstrated in that the beneficial effect of vagus nerve stimulation was additive when combined with drugs to treat heart failure in dogs. An open access review of these studies published in 2010 (2) by Professor Peter J Schwartz of the University of Pavia notes that:

An impressive aspect of these experimental studies is that they provide an unusually uniform picture of significant positive effects produced by chronic vagal stimulation in the failing heart. Furthermore, they also provide evidence for the important concept that the mechanism(s) underlying the protective effect of vagal stimulation involve something at least in part independent of the heart rate slowing.”

This result supported a decision to launch the first small phase I clinical trial of this technique in patients with heart failure, led by Professor Schwartz (3), which demonstrated the safety of the technique, and provided early hints of its effectiveness in 8 human patients. The much larger study whose launch was by the BBC uses a device manufactured by Boston Scientific rather than the BioControl Medical device used in the earlier study led by Prof. Schwartz, but is development was equally dependent on the same careful research in dog models of cardiac disease and heart failure.

It’s just one of many examples of why lab such as the one  in the Understanding Animal Research video are so valued by the medical research community.

Regards

Tom Holder

1)      Schwartz PJ, Billman GE, Stone HL. “Autonomic mechanisms in ventricular fibrillation induced by myocardial ischemia during exercise in dogs with healed myocardial infarction. An experimental preparation for sudden cardiac death.” Circulation. 1984 Apr;69(4):790-800.PubMed: 6697463

2)      Schwartz PJ.”Vagal stimulation for heart diseases: from animals to men. – An example of translational cardiology.-.” Circ J. 2011;75(1):20-7. PubMed: 21127379.

3)      Schwartz PJ, De Ferrari GM, Sanzo A, Landolina M, Rordorf R, Raineri C, Campana C, Revera M, Ajmone-Marsan N, Tavazzi L, Odero A. “Long term vagal stimulation in patients with advanced heart failure: first experience in man.” Eur J Heart Fail. 2008 Sep;10(9):884-91. PubMed 18760668

Schwartz, P. (2011). Vagal Stimulation for Heart Diseases: From Animals to Men Circulation Journal, 75 (1), 20-27 DOI: 10.1253/circj.CJ-10-1019

 

Heart failure breakthrough: animal research paved the way!

Heart failure, where the heart is unable to maintain a sufficient blood flow to supply the body’s needs, is a leading cause of death, especially among the over 65’s. Half of all chronic heart failure patients die within four years of diagnosis. It can have a number of causes, for example damage to heart tissue after a heart attack, and leads to a variety of problems in patients. Fatigue and muscle weakness are common as the muscles receive insufficient oxygen, and because waste products cannot be removed from tissues quickly enough fluid can build up in the lungs and other parts of the body, often the legs and abdomen. The extra strain placed on the heart as it tries to maintain adequate blood pressure can lead to further damage to the heart and ultimately cardiac arrest.

Ivabradine can lower the heart rate while maintaining a normal blood pressure - good news for heart failure patients. Image courtesy of the CDC Public Health Image Library.

In heart failure the rate at which the heart beats is often increased, and group of scientists led by Karl Svedberg and Michael Komajda set up the SHIfT study, to evaluate whether a drug called Ivabradine, which lowers the heart rate, could reduce risk of death or hospitalization in a group of patients who had heart failure accompanied by an elevated resting heart rate.  Significantly fewer patients taking Ivabradine in addition to their existing treatments required hospital admission during the course of the study, compared to a control group who were given a placebo in addition to their existing treatment. The most striking outcome was that Ivabradine cut the risk of death by 26%.

So what is Ivabradine, and where does it come from?

Ivabradine slows the heart rate by inhibiting an electrical current known as the If current* which is a major regulator of the activity of the sinoatrial node – better known as the pacemaker. Inhibiting the If current slows the generation of the electrical impulses by the sinoatrial node that trigger heart contraction, and therefore slows the heart rate itself. Ivabradine, then known as S16257, was first developed in the early 1990’s when it was found to be able to block the If current in-vitro in sinoatrial node tissue from rabbits and guinea pigs, and slowed the generation of electrical impulses in a manner that was safer than other bradycardic drugs (1). Ivabradine was then evaluated in live rats and dogs, where it safely reduced the heart rate, and moreover did so without reducing the blood pressure (2,3). While beta-blockers such as Propranolol can reduce the heart rate they also lower the blood pressure – indeed they are used to treat hypertension – and hence are not suitable for many patients, so the development of a drug that could reduce heart rate without affecting blood pressure was very welcome.

Following the successful animal studies Ivabradine entered human clinical trials and in 2005 was approved for the treatment of angina pectoris. In angina pectoris the heart muscle receives too little oxygen, a problem exacerbated by a fast heart beat that increases the need for oxygen, so lowering of the heart rate by Ivabradine reduced oxygen demand and prevents angina attacks. The success of Ivabradine in the treatment of angina pectoris in turn led to its evaluation in heart failure.

The successful outcome of SHIfT study is a major boost to the development of better treatment regimes for heart failure, and if it is confirmed by further clinical trials will improve and prolong the lives of many heart failure patients.

* Hence the name of the SHIfT study – Systolic Heart failure treatment with the If inhibitor ivabradine Trial

Paul Browne

1) Thollon C. et al. “Electrophysiological effects of S 16257, a novel sino-atrial node modulator, on rabbit and guinea-pig cardiac preparations: comparison with UL-FS 49.” Br J Pharmacol. Volume 112(1), Pages 37-42 (1994) PubMedCentral:PMC1910295

2) Gardiner S.M. et al. “Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats.”  Br J Pharmacol. Volume 115(4):579-586 (1995) PubMedCentral:PMC1908496

3) Simon L. et al. “Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs.”  J Pharmacol Exp Ther. Volume 275(2), Pages 659-666 (1995) PubMed:7473152