Results from a British Heart Foundation-funded study in the U.K. have demonstrated how a drug that is used to treat erectile dysfunction may also help to hold back the progression of heart failure (HF). Research carried out in sheep by a team at the University of Manchester found that tadalafil (marketed as Cialis), which is in the same class of molecules as Viagra, helped to reverse some of the adverse biological and molecular effects of heart failure, and prevented the development of HF symptoms in treated animals. “It’s entirely possible that some patients taking it for erectile dysfunction have also unwittingly enjoyed a protective effect on their heart,” commented Andrew Trafford, PhD, professor of cardiac pathophysiology, University of Manchester and is lead author of the team’s paper, which is published today in Scientific Reports (“Phosphodiesterase 5 inhibition improves contractile function and restores transverse tubules and catecholamine responsiveness in heart failure.”) “This discovery is an important advance in a devastating condition which causes misery for thousands of people across the U.K. and beyond,” Trafford noted.

Heart failure affects almost a million people in the U.K., and occurs when the heart is too weak to pump enough blood around the body. The condition also causes a build-up of fluid that backs up into the lungs, which results in breathlessness, while fluid retention also results in swelling in different parts of the body. Unfortunately, current treatments for HF are largely ineffective, such that “survival rates for HF are worse than many common cancers and have not improved over time,” the authors explained.

Heart failure is accompanied by changes to enzyme activity and molecular signaling pathways that ultimately inhibit the heart’s responsiveness to key catecholamine hormones, such as adrenaline. Heart failure is also associated with cellular structural remodeling, including loss of the transverse tubule (TT) network that plays a critical role in calcium ion transport and the control of heart cell contractility.

Tadalafil blocks the enzyme phosphodiesterase 5 (PDE5), which regulates tissue responses to adrenaline but, somewhat surprisingly, the authors pointed out, an emerging body of evidence suggests that PDE5 inhibition can also protect the heart in patients with HF. Experimental work in animal models has supported this protective effect, but in most animal studies PDE5 inhibitor therapy has been started either before or alongside the development of HF. What is less clear is whether PDE5 inhibition has benefits when HF has already progressed to symptomatic disease, and whether treatment can improve survival. Nevertheless, Trafford commented, “we do have limited evidence from human trials and epidemiological studies that show tadalafil can be effective in treating heart failure.”

To test the hypothesis that PDE5 inhibition could be beneficial in cases of HF with reduced ejection fraction (systolic HF), the University of Manchester team carried out a series of tests in sheep, which have hearts that are physiologically similar to human hearts. The animals were fitted with pacemakers to induce heart failure, and treated using tadalafil when the heart failure had progressed enough to need therapy. The results showed that treatment with a human-equivalent dose of tadalafil halted heart failure progression within a few weeks, and some of the detrimental biochemical and signaling effects were reversed. Critically, transverse tubule network density and the heart’s ability to respond to adrenaline were both restored. And whereas most of the control animals developed subjective symptoms of HF, all of the tadalafil-treated animals remained free from signs of HF for the duration of the study. The findings also provided insights into possible mechanisms by which PDE5 inhibition can protect against worsening HF.

“Importantly, in this study we demonstrate that PDE5 inhibition reverses rather than prevents the HF-dependent changes in cellular structure and catecholamine responsiveness as both the reduction in TT density and loss of catecholamine responsiveness are already present before PDE5 inhibition is commenced,” the researchers stated. “Thus, this study adds to a growing weight of evidence on the effectiveness of PDE5 inhibition in treating systolic HF and demonstrates reversal of key elements of the disease process that are evident when cardiac dysfunction is at an advanced stage prior to initiation of PDE5 inhibition.”

The authors acknowledged that there were some limitations to their studies. And while tadalafil is “a widely used and very safe drug with minimal side effects,” Trafford stated, it’s not known whether the treatment may have off-target effects in heart failure. The benefits also only relate to cases of systolic heart failure. “Tadalafil is only suitable as a treatment for systolic heart failure, when the drug is not able to pump properly, and there may be interactions with other drugs patients are taking,” he noted. “… we would not advise the public to treat themselves with the drug and should always speak to their doctor if they have any concerns or questions.”

The potential protective effects of tadalafil and other PDE5 inhibitor-type drugs against heart failure may not be too unexpected, commented Metin Avkiran, MD, associate medical director at the British Heart Foundation. “Viagra-type drugs were initially developed as potential treatments for heart disease before they were found to have unexpected benefits in the treatment of erectile dysfunction. We seem to have gone full-circle, with findings from recent studies suggesting that they may be effective in the treatment of some forms of heart disease—in this case, heart failure … The evidence from this study—that a Viagra-like drug could reverse heart failure—should encourage further research in humans to determine if such drugs may help to save and improve lives.”

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