Chronic treatment of heart failure patients with beta-blockers reduces mortality rates  however, doctors still do not fully understand how these drugs affect the heart and improve patient health. A new study by scientists at York University Toronto, identified a group of cardiac genes which are switched on in experimental heart failure and turned off by beta-blockers, providing comprehensive insight into the biological mechanism behind the restorative effects associated with beta-blocker treatment.

What is heart failure?

Over half a million people in the UK are living with heart failure, according to the NHS.[1] Heart failure is a chronic condition where the heart can’t pump enough blood to meet the body’s needs and is often caused by a combination of factors such as coronary artery disease or high blood pressure. Symptoms include shortness of breath, tiredness and swelling (usually in the feet or ankles).

What happens to the heart muscle during heart failure?

If the heart is damaged, for example after a heart attack, it can slowly start to weaken and eventually fail. Initially, when a portion of the heart muscle is damaged, the undamaged healthy tissue must pump harder to compensate. To pump with greater force, individual heart cells become bigger and the heart wall gets thicker but, enlargement of the heart wall is limited and after a while the wall starts to stretch and become thinner. This dilated heart wall renders the heart incapable of pumping blood effectively around the body.


Beta-blocker treatment for heart failure

The options for heart failure patients are currently limited and mainly involve symptom management, such as medication to control blood pressure.  Beta-blockers (beta-adrenoreceptor blocking agents) are drugs that decrease the activity of the heart by blocking the actions of hormones such as adrenaline. These drugs have become integral elements in the treatment strategy for heart failure as they reduce the heart rate and the force which the heart contracts, giving the organ time to fill properly. Although this partially explains how beta-blockers improve heart function, this does not provide a complete explanation for how beta-blockers are effective at halting the progression of the disease. Understanding the genetic changes that occur during heart failure and during treatment may provide avenues for future drug discovery.


New study provides insight into how beta-blockers reverse the effects of heart failure

Researchers in Toronto induced heart failure in a group of mice by surgically tightening the mouse aorta (the main artery that supplies blood to the body). This procedure forces the heart to work harder in order to pump blood around the body and consequently, the heart muscle thickens and the mouse develops heart failure. Genetic analysis of these mice revealed an increase in a molecule called MEF2 (myocyte enhancer factor 2) that is present in heart cells and acts as a switch for turning genes on and off.

The first major finding of this study was that four weeks of beta-blocker treatment caused a reversal in heart failure symptoms such as the thickening of the heart wall and restoration of the pumping capacity of the heart. Interestingly, the investigators also observed a decrease in MEF2 activity. [2]

Delving deeper into the genetic changes in these mice following beta-blocker treatment, the researchers identified 65 genes which were different between their experimental heart failure mice and mice which did not have their aorta constricted.

In general, the genes affected by heart failure were associated with two prominent features of the disease, cell death and remodelling of the heart structure.  Interestingly, treatment with beta-blockers increasing the production of muscle proteins which helps explain why beta-blocker treatment is so beneficial for heart failure patients, as the drugs reduce disease-causing genetic changes and increase the production of the basic building blocks of cardiac muscle. [2]

Changes in individual heart cells confirm the findings in mice

To confirm that the genes switched on in heart failure mice were responsible for the thickening of the heart wall and cell death, they introduced some of these genes into isolated heart cells, in the laboratory. Astonishingly, they found that the introduction caused the cells to increased in size and when they reduced the protein product which is made from these genes, they observed that fewer heart cells died! [2]

MEF2 may be the key to genetic changes

To understand how these genes were being switched on and off, Tobin and colleagues went back to look at MEF2 activity, as they believed this was a key molecule. They reduced MEF2 activity in isolated human heart cells and observed that 107 genes associated with cell death and inflammation were switched on and 68 were switched off.

Finally, the investigators from York University focused on one gene in particular, Rarres2. In isolated heart cells, switching the Rarres2 gene on caused an increase in cell size, suggesting that Rarres2 may be responsible for the enlargement of the heart wall which was observed in the heart failure mice. [2]

Although further work in mice is required, Tobin and colleagues have identified some of the key players involved in experimental heart failure such as MEF2 and Rarres2.  Crucially, they have also potentially identified the underlying mechanisms behind the beneficial effects of beta-blocker treatment.

Understanding the genetic changes in heart failure is vital to understanding how the disease is caused, how it progresses, and ultimately how it can be treated. Perhaps most importantly, the genes identified in this work provide potentially new and exciting drug targets that may provide a better alternative to the limited and in many cases futile treatment strategies currently available for heart failure.


[2] S. W. Tobin, S. Hashemi, K. Dadson, S. Turdi, K. Ebrahimian, J. Zhao, G. Sweeney, J. Grigull & J. C. McDermott. 2017. Heart Failure and MEF2 Transcriptome Dynamics in Response to β-Blockers. Scientific Reports 7,  4476.

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