Almost six million people in the United States suffer from heart failure (HF). Often stemming from acute trauma such as myocardial infarction, HF is a chronic condition in which the contractility and resulting efficiency of the heart tissue vastly decreases, leading to poor circulation that results in systemic problems. As such, HF contributes to almost 300,000 deaths per year in the US alone. Fortunately, a number of cardiovascular drugs and devices have reduced the overall morbidity of heart failure by improving cardiac output, either by directly stimulating the myocardium to contract more vigorously (e.g. inotropy, which alters the ion composition in the cytoplasm of muscle cells) or by improving the timing and efficiency of contractions (e.g. pacemakers).
One of the most successful interventions for HF is called cardiac resynchronization therapy (CRT) and involves placing two pacemaker leads on the heart walls – one on both the right and left ventricles – to synchronize heart contractions. This improves the mechanical performance of the heart as well as its efficiency, so energy is not unduly wasted. Since it was approved by the FDA ten years ago, CRT has saved or improved tens of thousands of lives. It has remained a hot area of research because soon after approval it became apparent that its clinical benefits did not simply stem from device-based electromechanical stimulation; rather, CRT was inducing actual molecular changes in the heart tissue that augmented its benefits. Just this month a paper in Science Translational Medicine was published that elucidates some of the molecular mechanisms by which CRT improves cardiac efficiency.
Medgadget editor Shiv Gaglani had the opportunity to sit down with Dr. David Kass – an original pioneer of CRT, principal investigator of this recent study, and Weiss Professor of Cardiology at the Johns Hopkins School of Medicine – and ask him about CRT and the implications of his recent molecular research.
Shiv Gaglani, Medgadget:
Thank you for taking the time to share your thoughts with Medgadget readers, Dr. Kass. Would you please begin by discussing your original work with cardiac resynchronization therapy?
Dr. David Kass:
It’s my pleasure. Our initial work with CRT, which occurred in the mid-to-late 90s, helped set up the paradigm that it improved heart function much like tuning a car engine did, by properly timing contraction to enhance chamber-level mechanics and efficiency. We published a key paper in 2000 that established that the energetics of CRT were different than that for previously explored therapies, such as the prototype inotrope dobutamine. When you stimulate the heart with dobutamine, because of the nature of the phosphorylation cascades that are involved, you end up getting something for something – it costs you to get that contractility; for example oxygen utilization goes up. However, we discovered from our cath-lab based studies of CRT that we were essentially getting something for nothing. This observation fed the chamber concept behind improving heart contractility.
That’s interesting, can you elaborate on the differences between inotropy and the device-based interventional aspect of CRT?
Well, the dogma that had evolved by the late 90s is that you just don’t touch inotropy. Many inotropes such as phosphodiesterase inhibitors which increased the levels of cAMP improved heart function in the near term, but the cost was that they often worsened long-term outcome including increasing mortality. Hence inotropes were thought of as pro-morbid, and actually compared to whipping a dying horse: the whip just gets the horse to go a little further but then hastens how quickly it collapses.
There was tremendous interest in CRT when it first came out, but it was accompanied by a fair share of skepticism. People thought anything that would make the heart put out twice as much stroke volume was going to kill it in the end, just like the inotropic drugs that acutely improved cardiac performance had done.. When that didn’t happen with CRT, it led to the widespread adoption of the device to treat patients with heart failure, especially those who have dyssynchronous hearts. We have learned that not everyone who gets the device ends up with a benefit, and many have tried to figure out how to better find the responders and why some do not respond. But even here, the focus has been on the way it worked at the chamber level.
But as your paper in Science Translational Medicine describes, there is a molecular story behind CRT. Can you briefly describe that mechanism?
Yes, in brief what happens is that in patients with heart failure a specific G protein [proteins that are involved in transmitting hormone signals to influence heart muscle contractions] called Gi is overexpressed. Gi inhibits contraction or pumping of heart muscle tissue by preventing the action of another G protein, Gs, that stimulates heart muscle. Returning to the car engine analogy, Gs can be thought of as the accelerator pedal and Gi as the brake pedal. Heart failure results in braking at the same time you are trying to accelerate.
We found that CRT raises the level of the regulator of G-protein-signaling (RGS) proteins, which help restore the healthy balance of Gi and Gs. In essence, CRT takes the foot off of the brake pedal by inhibiting Gi so that the heart muscle is more able to respond to hormones like adrenaline. This is one of the exciting molecular mechanisms that we’ve found so far, and one that likely augments the electrical resynchronization benefits from the device itself.
How did you initially decide to transition from device-level studies to molecular studies of CRT, and what were the original findings of those latter studies?
The same year we published the seminal paper (2000) we created a large animal model (dog) for heart failure with the help of a visiting physician researcher from France, Christophe LeClercq, who had contacted me about doing a sabbatical year in my lab. That led to a series of studies over the past decade that sought to understand how CRT could lead to such improvements in the mechanical and energetic properties of the heart. In 2003 the first paper came out suggesting that there was a molecular signature for dyssynchronous heart failure. The following year we received an NIH grant to study the pathobiology of cardiac synchrony and dyssynchrony that enabled us to lay the foundation for the present discovery and establish that CRT had a number of surprising biologic effects. The beta adrenergic story, which came out of my group, was one of those effects.
Another effect was that CRT has is the interesting ability to reverse a number of ion channel dysfunctions in myocardium. We also published a paper showing that dyssynchrony creates genetic heterogeneity in the heart, meaning that the right and left sides could actually express different proteins or levels of protein; we found that CRT can ameliorate this by homogenizing transcriptome patterns. In addition, CRT is able to improve mitochondrial efficiency, so at that point we realized that we weren’t just talking about tuning the car engine anymore, we were talking about changing the pistons – really fundamentally changing the engine, the powerplants, the link between the accelerator and braking systems, etc.
It’s interesting that the device application was developed first and only after are the molecular mechanisms being discovered.
Exactly right, it’s like history backwards and I actually liken it to the case of Benjamin Button. If CRT was originally developed in an animal model and was scrutinized for a laundry list of molecular changes, my suspicion would be that it would have taken longer to approve – people would have been nervous about trying it out given the history of inotropy. However, it was sort of reverse-engineered because the simple device concept was approved first since it showed considerable improvement in patients with heart failure. It’s great though because we already know the punch line to this story, and it’s a good one.
Back to your analogy about Gi as the brake and Gs as the accelerator: at what point is it deleterious to prevent the actions of Gi, e.g. can it lead to tachycardia?
Well, that depends upon the input signal and relative role of RGS signals. In failing hearts Gi is already greatly upregulated so what we are doing is trying to recreate the balance found in normal hearts. CRT does not reverse expression of the protein, but puts a “brake on the brake” using another protein that alleviates the influence of upregulated Gi. You are right that Gi is also important in the atrium – which sets the heart rate, and the impact of increasing RGS proteins to the entire failing heart remains to tested.
Over the past few years we’ve gathered a lot of evidence that not all mechanisms for manipulating the adrenergic signaling pathway in heart tissue are detrimental. And in this particular case I’m optimistic, though we will not know for sure until we conduct the whole animal study, which we will likely test using diffuse gene therapy.
An interesting result described in your paper is that “depressed myocyte function, calcium handling, and beta adrenergic responsiveness in synchronous and dyssynchronous heart failure are much improved in hearts that were first dyssynchronous and later resychronized.”
This opened the door for your paper’s provocative conclusion that “one might purposely induce dyssynchrony by right ventricular pacing in synchronous heart failure for a limited duration (weeks to a few months) and then revert to normal sinus. Many HF patients receive implantable defibrillators to counter a high risk of sudden death, and these systems could be easily modified for this purpose.”
Would you please comment on any plans of testing this?
We’re as excited about that as anything and have already begun discussing with a manufacturer how we can leverage that finding using current pacemaker technology. If it turns out that you only need to induce dyssynchrony in the heart a few times to bring about the beneficial molecular changes, then you could imagine the pacemaker being modified to do so during the night for a few hours or every other day. This could be accomplished with a trivial software fix. In some ways the dosing is the issue right now; in our case it is more complicated than determining the optimal concentration for, say, a drug. Variables include how often the patient needs to come back to get paced and how long it will take to see the molecular changes. We currently have plans to pursue this in the dog model to see how rapidly we can see the beneficial changes.
That would be a tremendous and immediate application. You also raised the point that the CRT device itself may not be needed in the future if the molecular changes can be mimicked – a so-called “Pacemaker in a Bottle”. Please elaborate on this intriguing concept.
The “bottle” may refer to anything that is not a device. Gene therapy with RGS proteins would be the first option because it allows us to directly target the heart. There are already at least three current or pending clinical trials involving gene therapy for other cardiac proteins, such as a sarcoplasmic reticulum ATPase and beta adrenergic receptor kinase. The technology is getting to the point now where we have tools that seem to work, that is we can get the stuff into people’s hearts. We will be exploring this option in animal models in the near future.
A second option would be standard small molecule therapy, in which case the small molecule would be an RGS protein activator. This is absolutely conceivable, though you’d have to screen. I’d be shocked if none of the large pharmaceutical companies already had such a small molecule somewhere in their vast candidate drug libraries. I think this is closer to something that people could taste as a potentially translatable therapy.
There are other things that we are pursuing that also are suggestive of “CRT in a bottle.” For example we’ve found that CRT may improve the sensitivity of calcium binding to myofilaments in heart tissue and we are working hard to figure out which proteins have been modified and how. If we can confirm that that’s the target we can develop a small molecule screen and potentially find a safe inotrope.
And there may be other lessons of CRT that can be turned into drugs, for example with regard to the mitochondrial research. Mitochondrial dysfunction is a large part of heart failure – the organelles just don’t work well. A collaborating team just published a paper showing that CRT can improve the efficiency of ATP production in mitochondria. Could that ultimately turn into a mitochondrial booster without generating reactive oxygen species? Maybe. Would that be cool? Definitely. That may result in applications for cases that are not necessarily pathological.
This is all really exciting stuff. We look forward to keeping up-to-date on how your work progresses and hopefully covering some direct applications that come out of your lab, as CRT did a decade ago. Thank you very much for your time, Dr. Kass.
Abstract from Science Translational Medicine: Gαs-Biased β2-Adrenergic Receptor Signaling from Restoring Synchronous Contraction in the Failing Heart