The Grinch got big for us with no physical consequences. But how do we prevent aneurysms from rupturing in real life?

They say that the Grinch’s heart grew three sizes in one day. In the land of fantasy, this makes him a happier person and a friendlier neighbor to the Whos. In real life, rapid cardiovascular expansion is a silent but deadly disease.
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An aortic aneurysm can produce approximately the same effect as the Grinch’s exaggerated transformation. In due time, the walls of a blood vessel can bulge outward and balloon to twice or nearly three times the initial size. This inexorable growth can occur over the course of years, slowly weakening aortic walls until the aneurysm eventually ruptures. A rupture event is rarely predictable and usually fatal.

The problem is that we don’t have a great understanding of why aneurysms develop or grow. In the Grinch, the rapid onset of cardiac dilatation occurred because he was touched by the Whos’ unconditional love and empathy for one another.  For humans, the transition to aneurysmal disease is neither so predictable nor straightforward. Most aneurysms are found incidentally in patients undergoing medical imaging for an entirely unrelated issue.

This lack of understanding makes it hard for physicians to monitor or treat aneurysm progression. Grinch’s thrice bigger heart is a one-time deal, but doctors need to regularly track the size of an aneurysm by imaging its location every 1 to 5 years depending on how fasts it grew previously and whether the patient has any associated diseases. Over this ‘wait and see’ period, an aneurysm can burst open fatally.

Without knowing why or how aneurysms develop, tracking the size of an aneurysm over time is the only way to estimate whether it’s close to the typical failure size observed in prior patients. If the average size or rate threshold is breached, physicians will intervene surgically, as the risk of operating on the patient is now outweighed by the risk of aneurysm rupture.

Surgical repair of an aneurysm involves reinforcing the dilated location with a graft. This remains the gold standard of treatment.  Our lack of understanding as to why aneurysms grow, makes pharmacological treatment a hit or miss solution for the individual patient; often, lifestyle management (such as quitting smoking or changing diet) will be more effective than medication.

Thankfully, Dr. Seuss’s story teaches all of us to persist in the face of adversity. The Grinch might’ve stolen Christmas, but the triumphant spirit of the Whoville residents convinced him to give it all back. Empathy and endurance embiggened the Grinch’s heart. It inspired us to prevent the same from happening to people at risk of developing aneurysms.

In a sense, the start our story is perhaps as silly as a fairytale. We set out four years ago to write a good exam problem for a college class. Challenge the students a little bit. But the more we stared as this problem, the more we realized there was something more here than met the eye.

At face value, we were analyzing when flow becomes unstable in an elastic tube. That is, when does smooth, stable flow transition to a regime where the interaction between the encompassed liquid and the containing vessel becomes susceptible to perturbations?

To appease intuition, consider a ball trapped inside a valley vs one situated at the top of a hill. If you push the ball slightly in any direction, the valley-ball just returns back to its original spot. But if you push the hill ball just slightly in any down-hill direction, it rolls away and doesn’t come back, unless someone goes to retrieve it.

Similarly, we wanted to answer the question, what flow condition permits a tiny push from random noise in the system to create time varying shape fluctuations in the tube, akin to the flutter of a banner in the wind? At what point is this ball (the liquid-tube system) nestled in a “valley” vs “perched on a hill”?

We found this transition point using a math technique, explicating the physics behind the liquid and elastic vessel interacting with each other. Depending on the pressure gradient applied, the viscosity of the fluid, the strength of the vessel, etc. we got a stable (“valley”) solution that transitioned to marginally stable (“a flat plane”; critical point) to unstable (“a hill”).

Now imagine that the fluid is blood and the elastic vessel is an artery. Then to model blood flow through blood vessels, we just need to replace a constant pressure differential with a time-varying one to mimic the beating of a heart, right?

Well sure. But it needed much more work. After a lot of mathematical analysis and problem-solving we found when the blood flow through a human aorta configuration would transition to a flutter instability.

When instabilities occur, they tend to impress significant stresses and strains on the local area. This transition to unstable flow, we conjectured, was the base mechanism that either caused or signaled aneurysm development.

Our analysis provided a measurable, dimensionless number that captured the physics of the problem, including the applied pressure gradient, heartbeat frequency, fluid (kinematic) viscosity, aortic wall elasticity, etc. Crunching through the math gave us this number's critical threshold, which pinpoints the transition from stable flow to aortic instability. We defined the difference between the dimensionless number and its critical threshold to be the flutter instability parameter (FIP). So FIP > 0 denotes an unstable regime (“hill”) and FIP < 0 refers to a stable state (“valley”).

We therefore hypothesize that measuring the FIP from 4D flow MRI should tell us what will eventually happen to a patient's aneurysm. That is, FIP > 0 means the aneurysm will grow abnormally, whereas FIP < 0 predicts that the aorta will remain stable in size. We don't use any population statistics or machine learning guesstimates- the FIP captures the fundamental physics leading to the unstable 'fluttering' of the aorta.

We performed a full retrospective study of patients with aortic aneurysms who had agreed to let their imaging data be used for research into managing cardiovascular disease. We analyzed the data and extracted our FIP metric from the initial MRI taken from each patient. Then we compared this patient-specific FIP value with how the their aortic size changed at follow-up at least one year after the first MRI.

As it turns out, FIP > 0 forecasted significantly larger, aneurysmal growth (> 0.24 cm/year in aortic diameter) with over 90% accuracy, specificity and sensitivity. That is, our theory accurately predicts which aneurysms will expand abnormally and which ones will not. This informs physicians in advance, so clinical decisions regarding preventative treatment and intervention for a patient can happen before the aorta grows three sizes and ruptures fatally.

More importantly, the FIP gives us clues about aneurysm development. So as always, the scientific journey continues. Even as the year draws to a close, we are conducting further studies to see whether the FIP can tell us which medication will prevent or halt aneurysm progression in each patient. We are looking to see how other modalities like wearable device can also measure the FIP. We are checking whether this aortic instability can be observed in a patient directly.

The Grinch plundered Whoville because he feared what he didn't understand. Similarly, aneurysms are scary because we don't know how to prevent them or how to keep them under control. But just like how the Grinch eventually came to understand Christmas, we are doing everything we can to make aneurysms understandable, predictable, and treatable.

Happy Holidays everybody.

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Biomedical Engineering and Bioengineering
Technology and Engineering > Biological and Physical Engineering > Biomedical Engineering and Bioengineering
Aneurysm
Life Sciences > Health Sciences > Clinical Medicine > Diseases > Cardiovascular Diseases > Vascular Diseases > Aneurysm
Multistability
Life Sciences > Biological Sciences > Biological Techniques > Biological Models > Systems Biology > Multistability