cardioprotective

The setting is every wedding, reunion, or family gathering in the Spring of 2018, and I’m in a circle of distant relatives or friends-of-friends, clarifying the distinction between a pharmacologist and a pharmacist. If you want to be the life of the party at this summer’s neighborhood BBQ, explain to the stranger next to you in the buffet line why you’re not “that kind of doctor,” and yet your career requires over two decades of schooling.

Readers of the Early Career Voices column are a different audience – students, clinicians, and public health specialists – possessing a much better grasp of the pharmacologist’s day-to-day than my great aunt or high school classmate. Most AHA professionals even had a pharmacology course or two at some point in their training. I’m here to convince you, fellow Early Career Professionals, that regardless of what profession you put on your tax forms last month, we should all be pharmacologists.

Plug in “pharmacologist” on your favorite job-search board. You’ll find that pharmacologists influence every aspect of a drug’s journey from the lab bench to the patients. In academia and industry, pharmacologists work in multidisciplinary and collaborative teams as experts in drug absorption, distribution throughout the body, metabolism, and elimination. They understand disease states and collect, interpret, present, and explain data on a drug’s action at all levels. A “drug” can encompass everything from a small-molecule inhibitor that has been synthesized in the lab to biologics and immunotherapeutics.

In my current position as a PhD candidate in basic cardiovascular sciences, I’m routinely utilizing pharmacological tools to accomplish my research goals. If I hypothesize that a protein of interest is critical to cardioprotection, I use a drug to inhibit that protein’s function and determine whether the cardioprotective effect persists in its absence. You’ll see me present this sort of work at AHA’s Scientific Sessions, when we all come together from our various career paths to talk about cardiovascular disease.

What should you consider when standing in front of a pharmacologist’s poster at Sessions? The same sorts of questions you should ask anytime throughout the year when reading a research article, listening to a seminar, or designing experiments that involve drugs. A few suggestions from a real life-pharmacologist:

The chemical nature of the drug. What is the mechanism of action? Does it get past the blood brain barrier? How long does it last in the body?
Frequency, timing, and route of administration. How often and in what way should the drug be given based on its known kinetics?
Dose (mg/kg). What does gives you the best therapeutic or on-target effects and minimizes side effects?
Specificity and efficacy. Does the drug work in the way that you expect it to, and how well does it do so?
Safety and drug-drug interactions. Is there a risk of adverse reactions, and does the drug play nice with any other drugs in the system?

The answers to these questions are extraordinarily valuable to biomedical scientists, but can be just as helpful to professionals throughout the AHA. Pharmacology is deeply integrated into many of the core cardiovascular disciplines; by strengthening our pharmacology skillset, familiarizing ourselves with our drug toolbox, and considering how pharmacologists work, we can better understand and critique developments across the cardiovascular field.

Annie Roessler is a PhD Candidate at Loyola University in Chicago, IL. Her research focuses on the neurobiology and molecular mechanisms of electrically-induced cardioprotection. She tweets @ThePilotStudy and blogs at flaskhalffull.com

That question.

It’s always looming. It comes from the tenured professor at the back of the room during my annual progress report to the department. It comes from the clinician from another field who pauses in front of my AHA Sessions poster. Heck, it even comes from my mother as I chat about my day in the lab. It reliably resurfaces with uncanny punctuality every time I talk about my research.

“So… if you can’t predict a heart attack, why does this matter?”

My dissertation project focuses on cardioprotection. That is, the phenomenon that a nonlethal stimulus applied prior to a heart attack can protect the heart against the insult.

Cardioprotection was first investigated in the context of acute myocardial infarction (MI). In the 1980s, it was discovered that brief, nonlethal bouts of ischemia and reperfusion (I/R) to the heart prior to a subsequent ischemic challenge can reduce the size of the infarct in a canine model, termed ischemic preconditioning¹. This study was seminal because it demonstrated the existence of an endogenous cardioprotective network that might be harnessed for therapeutic benefit. In later studies, researchers found that ischemia and reperfusion at a remote vascular bed, organ, or limb can bring also protect the heart via remote preconditioning^{2, 3}. Remote preconditioning is even more clinically translational and relevant; it’s far less challenging to slip a blood pressure cuff on a patient’s bicep than, say, occlude an artery.

But still. These studies looked at interventions applied before the heart attack.

If you can’t predict a heart attack, is this important?

My answer is a well-rehearsed and resounding YES. Let me summarize and consolidate, quick and dirty, the vast amount of info I’ve learned during my PhD about the value of preconditioning and cardioprotection. Here are three reasons why preconditioning and cardioprotection are important:

1. Some of the pathways invoked by preconditioning might also be useful during or after reperfusion. Basic scientists uncovering the complex signaling and mechanism of cardioprotection have revealed a number of therapeutic targets that could lead to the development of drugs or therapeutics that activate these pathways when most needed⁴. In other words, we believe that advancements developed within the preconditioning models might also be useful for perconditioning (during reperfusion) or postconditioning (after reperfusion). This gives us hope that we can intervene during the ambulance ride, at the time of stenting, or throughout recovery and still benefit the patient.

2. Cardioprotection can be reframed outside of acute myocardial infarction. There is a need for myocardial salvage in clinical scenarios where a high risk of ischemia and reperfusion injury is expected. These situations include cardiac surgery and coronary artery bypass graft surgery, organ transplantation, where situations of I/R adversely affect the organ’s lifespan, and elective percutaneous coronary intervention (PCI). PCI alone is performed on millions of patients annually, and perioperational MI occurs in at least 10% of those patients, depending on how you measure it⁵. In such cases, strategies to preserve myocardia can reduce susceptibility to perioperative injury in situations where MI can be reliably predicted.

3. The jackpot— any evidence that cardioprotective interventions might work in man. A slew of clinical trials have suggested that cardioprotection, whether based in ischemic techniques or pharmacological strategies, can be effective in humans⁶. The caveat is that these clinical studies are inconsistent and vary widely in the exact methodology and measured outcome (such as biomarkers, imaging, or major adverse cardiovascular and cerebrovascular events). We still don’t have an approved cardioprotective therapy, but this seems encouraging!

As an early career investigator, routinely and enthusiastically defending my work has led to some challenging conversations. Those difficult, engaging discussions have given me guts as a grad student and awareness as a scientist.

Now I can focus on that next big question: “When are you going to graduate?”

Murry, C.E., R.B. Jennings, and K.A. Reimer, Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation, 1986. 74(5): p. 1124-36.
Przyklenk, K., et al., Regional ischemic ‘preconditioning’ protects remote virgin myocardium from subsequent sustained coronary occlusion. Circulation, 1993. 87(3): p. 893-9.
Kharbanda, R.K., et al., Transient limb ischemia induces remote ischemic preconditioning in vivo. Circulation, 2002. 106(23): p. 2881-3.
Hausenloy, D.J., Cardioprotection techniques: preconditioning, postconditioning and remote conditioning (basic science). Curr Pharm Des, 2013. 19(25): p. 4544-63.
Lansky, A.J. and G.W. Stone, Periprocedural myocardial infarction: prevalence, prognosis, and prevention. Circ Cardiovasc Interv, 2010. 3(6): p. 602-10.
Heusch, G., Cardioprotection: chances and challenges of its translation to the clinic. Lancet, 2013. 381(9861): p. 166-75.

We Should All Be Pharmacologists.

Why I Study Cardioprotection