Imagine a twenty-first century in which the deadliest scourge of humankind, heart disease—which in 2019 alone killed an American every thirty-eight seconds and cost the health-care system more than $555 billion—has been conquered. The disease would still exist but would have been tamed, just like tuberculosis was at beginning of the twentieth century, polio by the mid-twentieth century, and HIV/AIDS at the beginning of the twenty-first century. In this case, it wouldn’t be a vaccine or serum that eliminated heart disease as the leading killer of adults but rather a collection of clinical hardware, artificial intelligence (AI) software and Big Data, biological innovations, digital therapeutics, gene mapping, miniature implants, continuous-monitoring wearable devices, and bioprinted artificial heart tissue.
In this new world with greatly diminished deaths from heart disease, you would receive medications tailored to your own genetic profile to prevent the symptoms. A chatbot (think Siri) would remind you when to take your medications and also provide the latest findings of research relevant to your specific heart condition. But you really wouldn’t have to worry as much about a heart condition anymore because if you were prone to one—through familial or environmental factors—you already would have been prescreened with biomarker testing, genetic polygenic risk assessments, advanced computer imaging systems, and algorithmic identifiers to give optimal management and treatment strategies. For example, if your condition involved an irregular heartbeat (arrhythmia), you might have had a microscopic, wireless implant inserted next to your heart to provide the appropriate electric signal, which then could be monitored continuously by your own or your physician’s smartphone. If your heart was already damaged, a new valve or artery would be imprinted using engineered organic materials or harvested from off-the-shelf, allogenic stem cells. Cholesterol levels too high? You would be injected with nanoparticles that would whisk away the bad cholesterol and deliver it to the liver, where it could be broken down naturally. And your overall risk factors for chronic diseases, including heart disease and diabetes (a leading risk factor of heart disease), would be mitigated with drugs that target and block inflammation (if that is the main problem).
In short, this next era of heart disease treatment will not only slow the course of heart disease but be able to reverse any damage already done. In this chapter, we’ll take a glimpse of the future—that is, the near future, because everything about to be discussed is already in some stage of research or development.
Technology for the detection of heart disease is of exponentially increasing value. One of the most promising areas combines traditional diagnostics with cutting-edge artificial intelligence. Futurists say we’re at the dawn of the fourth “industrial revolution,” or breakthrough in technology. If steam power and electricity were at the center of the first two industrial revolutions, then we’re currently in the third, dominated by electronics and digital technology. But it’s the fourth revolution—the seamless synthesis of technologies, blurring the lines between technology, biology, and information—that holds the great potential for taking medicine to the next level. Artificial intelligence is key to the promise of the fourth revolution for heart disease detection and treatment.
What is artificial intelligence? It’s defined as the ability of computer systems to perform human tasks. Essentially, programmable machines learn for themselves. Robotics are part of the AI revolution but are more important in manufacturing. For medicine, the most important aspects are algorithms (mathematical rules and models) and how they integrate into computer systems. In short, AI allows us mortal humans to perform herculean informational tasks and calculations not previously possible.
Verily is an example of an artificial intelligence algorithm. Designed by researchers from Google and its health-tech subsidiary, it promises to predict heart disease just by taking one glance at a patient’s eyes. To build this technology, scientists scanned a database of nearly three hundred thousand patients for patterns. The “eye scans” evaluate the networks of blood vessels in the interior wall of the eye, revealing telltale signs of heart disease, such as high blood pressure. Although still in the testing stage, it’s believed the eye scan will be able to predict with 70 percent accuracy whether a patient will suffer a heart issue in the next five years.
Wearable devices are another area of new diagnostic technology. You might say that the first “wearable” in cardiovascular medicine dates back to the 1800s, when a watch with a second hand was used to measure heart rate. Today, however, wearables can monitor everything from heart rate and rhythm to blood pressure, sleep quality and duration, and physical activity. In 2018 Apple introduced its Apple Watch series featuring an electrocardiogram (EKG) function that measures heartbeat and detects irregular rhythms. Wearers are alerted with a notification if they are experiencing atrial fibrillation (an abnormal heart rhythm).
Two apps now available that I think are especially useful are Instant Heart Rate, which turns your phone’s camera lens into a heart rate monitor, recording your beats per minute, and Smart Blood Pressure, which allows you to take blood pressure readings wherever and whenever. (No more needing to visit the doctor’s office or pharmacy for a pressure cuff.)
Another smartphone app, which has been developed by researchers at the Indian Institute of Technology Bombay, will be able to detect heart attacks up to six months beforehand by measuring a cardiac biomarker. Specifically, it measures myoglobin, an iron-containing protein released into the bloodstream soon after myocardial infarction, or the sudden blockage of blood flow to the heart that leads to a heart attack.
There’s another diagnostic heart tool that’s among the most promising, however, as the headline in a recent article in the Johns Hopkins newsletter article declared, coronary artery calcium score is “The Heart Test You Might Need—but Likely Haven’t Heard of.” Why is this important, potentially life-saving diagnostic tool under the radar? One answer is that many insurance companies still won’t pay for it. Like tests for cholesterol, blood pressure, and blood sugar, coronary artery calcium (CAC) testing helps reveal your risk of heart disease but often before other diagnostic tests. The test is painless and quick. A CT scan takes images of your heart and coronary arteries that may show specks of calcium called calcifications—early signs of coronary artery disease.
Using data from almost seven thousand subjects, Johns Hopkins researchers compared two approaches to calculating heart risk. One way used only the traditional risk factors, like smoking, cholesterol, blood pressure, and diabetes. The other included the coronary calcium scan score. Results reported in the European Heart Journal showed that by looking at the coronary calcium scan, doctors could much better estimate heart disease risk, especially for those thought to be at low risk or high risk. Fifteen percent of those thought to be at very low risk using traditional risk factors actually had high coronary artery calcium scores. And 35 percent of those thought to be at high risk showed no coronary artery calcium and therefore had a lower risk of heart events. These finds echoed those from a previous study by Emory University of 9,715 participants who showed no symptoms of coronary artery disease at the time of the scans. Fifteen years later, researchers found the CAC scores accurately predicted heart disease in the patients.
Another side of the fourth revolution in medicine is the advent of Big Data. Analytics software combined with artificial intelligence is allowing medical professionals to identify high-risk patients before they become sick. Using data from large clinical trials conducted by studies previously funded by the National Institutes of Health, University of Texas Southwestern Medical Center researchers developed a way to predict which patients would benefit most from proactive treatment of high blood pressure. The algorithm they formulated combined three measurements routinely collected during clinical visits and was able to successfully identify a subgroup of patients who were at the highest risk for early major adverse cardiovascular events, including heart attack, stroke, and death (from a heart event). In effect, Big Data offers the opportunity to conduct so-called retrospective clinical studies in which new life is breathed into old research.
On the horizon in diagnostic and therapeutic tools is what’s been called “personalized prescribing.” Already there are testing panels available that analyze your genes to determine your probable response to medications commonly prescribed for attention deficit hyperactivity disorder and certain mental health disorders. Watch for this technology to be refined so that it guides not only drug selection but individualized dosing. At the moment, virtually all drugs are dispensed with dosages based on averages (and as discussed earlier in the book, usually with a bias toward males). Imagine soon selecting a cardiac medication that you know in advance will produce no or minimal side effects for your physiology and whose dosage is precisely customized for your individual genome.
In 2018 a novel imaging biomarker that can predict the risk of cardiac mortality was announced by a group of researchers led by Dr. Milind Desai from the Cleveland Clinic. Using Big Data collected from previous studies conducted between 2005 and 2009, the research showed conclusively that patients with significant coronary inflammation were associated with significantly higher rates of death from cardiac causes. The imaging biomarker, called the perivascular fat attenuation index, or FAI, revealed coronary inflammation by mapping the changes in perivascular fat. The diagnostic biomarker might prove transformative someday for prevention, because it’s based on a routine test that is already used in everyday clinical practice but for the first time captures a cardiac risk factor currently missed by all other risk scores and noninvasive tests. Knowing who is at risk for a heart attack allows for earlier intervention.
Now, what if an individual’s DNA sequence, or genome, could predict heart disease in people who have not yet had a heart attack or who might be at risk for silent heart disease? In a study whose findings were published in the American Heart Journal in 2019, researchers used polygenic risk scores (PRSs), which are based on an individual’s entire genome sequence, to predict the risk of developing coronary artery disease. The study’s finding confirmed earlier research that showed PRSs are an effective predictive tool in identifying people with a high risk for heart attack. The next step is to test the genetic scoring to determine if managing and treating people based on PRSs improves their heart health. The American Heart Association named the use of PRSs as one of the biggest advances in heart disease research in 2018.
The rapid pace of pharmacology continues unabated in cardiovascular medicine. In 2018 a record forty-six new drugs were approved by the Food and Drug Administration (FDA). Although statins remain the mainstay of lipid-lowering medications, the arsenal of pharmacotherapy for treatment of blood cholesterol has expanded to include PCSK9 inhibitors, the class of drugs that consumes the most attention among cardiologists. The enthusiasm for these biologic drugs within the medical community revolves around their capacity to reduce cardiac events in patients with known heart disease. PCSK9 inhibitors are proteins made in a laboratory. They target other proteins in your body, specifically your liver, which has cell receptors that sweep away excess cholesterol. But the PCSK9 protein actually destroys the cell receptors. That’s where the “inhibitors” part come in. They latch onto PCSK9 proteins and block them from acting. The result: more receptors are able to do their job. This lowers the amount of low-density lipoprotein (LDL) cholesterol in your blood. In fact, one review of studies found that PCSK9 inhibitors slash LDL levels by an average of 47 percent, and the PCSK9 drugs were shown to reduce the risk of heart attacks by 27 percent.
It’s estimated that 10 million Americans with high cholesterol could benefit from PCSK9 inhibitors. However, this promising new class of drugs faces two hurdles—cost and delivery. The PCSK9 drugs can cost as much as fifty times more than statins for a year’s supply. Also, they’re only available in an injectable form at the moment, which will discourage many patients from using them.
A drug is typically manufactured through chemical synthesis, which means that it is made by combining specific chemical ingredients in an ordered process. PCSK9 is a biologic drug, which is manufactured in a living system such as a microorganism or plant or animal cells. Many biologics are produced using recombinant DNA technology. Currently, available cardiovascular drugs with anti-inflammatory effects, such as aspirin and statins, predominantly exert therapeutic benefits by means other than inflammation suppression. While no definitive evidence has documented that reducing inflammation of the blood vessels will reduce cardiac events, this is a major focus of ongoing research. The research is part of a larger theory that inflammation could be the underlying cause of most chronic diseases—from diabetes to dementia, including coronary heart disease. Studies have indicated, for example, that a good deal of the benefit from exercise to cardiovascular health is attributable to its effect in lowering inflammation in the body.
A 2017 clinical trial called CANTOS involved another biologic drug, canakinumab, which blocks a specific pro-inflammatory pathway called IL-1beta. The findings were startling. This was the first scientifically gathered evidence that drugs that block inflammation could be the next chapter in cardiac medications. The trial, which involved more than ten thousand patients in thirty-nine countries, was primarily designed to determine whether an anti-inflammatory drug, by itself, could lower rates of cardiovascular disease in a large population, without simultaneously lowering levels of cholesterol, as statin drugs do. The answer was a definitive yes, and therefore the pharmaceutical industry is now deeply interested in finding ways to stop cardiac inflammation with medicines.
As we learned earlier, age is a primary risk factor in heart disease. So, what if you could turn back the clock with a medication that, in effect, slows down the heart’s aging process? Researchers have discovered that relaxin, a reproductive hormone, can suppress cardiovascular disease symptoms. “A common problem in age-associated cardiovascular disease is altered electrical signaling required for proper heart contraction,” explained Brian Martin, the lead researcher in a study on the therapeutic benefits of relaxin, in an article published in Science Daily. “When ions in the heart and their associated channels to enter or exit the heart are disrupted, complications occur.” A relaxin medication might one day soon be given to patients of a certain age with a high-risk cardiac profile as part of regular cardiac therapy.
Of course, the goal of any cardiologist is to avoid having a patient undergo surgery. A wise man once said that a good physician is one who successfully treats his patient; a great physician is one who prevents the patient from needing treatment in the first place. But in some cases the best solution to a heart problem is a surgical procedure. New surgical innovations are embracing minimally invasive procedures and new technologies, including robotics.
Harvard University and Boston Children’s Hospital researchers came up with a soft robot that fits around the heart and helps it beat. The device holds much promise for individuals whose heart has been weakened by a heart attack and who are at risk of heart failure. The robot syncs with the heart through a thin silicone sleeve with soft pneumatic actuators that mimic the heart’s outer muscle layers. It does so without any direct contact with the blood, as is the case with most currently available devices. This removes the need for potentially dangerous blood thinner medications.
Transcatheter aortic valve replacement (TAVR) is the replacement of the aortic valve of the heart through the blood vessels (as opposed to valve replacement by open-heart surgery). The replacement valve is delivered via one of several access points in the body (i.e., upper leg, collar bone, belly button). Until recently, surgical aortic valve replacement was the standard of care in adults with severe symptomatic aortic stenosis. However, since the risks associated with open-heart surgery are increased in elderly patients (and especially those who already have cardiovascular disease, chronic kidney disease, or chronic respiratory dysfunction), eliminating or reducing the risks of such surgery through new and minimally invasive procedures is certainly warranted. (The FDA recently approved TAVR.)
Stem cell and gene therapies and bioprinted tissue (using a 3-D printer) offer the prospect of creating new organic tissue to replace irreparably damaged heart tissue—the stuff of science fiction only a generation ago. Imagine replacing a damaged artery or valve or—wait for it!—the entire heart organ using one or both of these rapidly evolving procedures. This is the brave new world in the treatment of silent heart disease and the prevention of sudden death—a little scary because of possible unintended consequences but also irresistible for the potential to effectively treat heart conditions with a minimum of trauma.
BioCardia is one of a number of companies exploring biotechnology/regenerative medicine for the treatment of heart failure. Among its treatment modalities, personalized screenings help determine which patients are most likely to benefit from intramyocardial injection of therapeutic agents. BioCardia’s current efforts in cardiac regenerative medicine include therapies that focus on heart failure resulting from heart attacks. The company was cofounded by Dr. Simon Stertzer, who performed the first coronary balloon angioplasty in the United States in 1978.
Can heart attack damage be reversed? Dr. Eduardo Marban of Cedars-Sinai Medical Center in Los Angeles is betting that it can. He recently launched a study using cells taken from the hearts of organ donors, avoiding altogether the need for a patient biopsy. Officially known as the Allogeneic Heart Stem Cells to Achieve Myocardial Regeneration (ALLSTAR) trial, the study aims to involve more than three hundred patients with moderate or severe heart damage. This is an ongoing study, but early results indicate that the amount of living heart muscle increased significantly, by 23 percent on average, in the test subjects.
Stem cell therapy is still new and finding its footing. The mechanism of how stem cells work and why they work as miraculous treatments for some but not for others is still unknown. In a recent article titled “Mending a Broken Heart: Stems Cells and Cardiac Repair,” the National Institutes of Health noted that despite the relative infancy of this field, initial results from the application of stem cells to restore cardiac function have been promising.
Rather than growing replacement tissue for a damaged heart exclusively with stem cells, what if you could print it? Biolife4D, a Chicago-based biotech start-up, recently announced that it can “bioprint” a human cardiac muscle patch, using a patient’s stem cells, which can be sutured over an area of dead heart muscle to speed up recovery from acute heart failure. In 2019, a group of Israeli researchers announced they had developed a 3-D-printed heart complete with a blood vessel system. The tissue was printed using fat tissue from a donor, as well as cells from the tissue that were cultured and reprogrammed into heart cells. The procedure marks the first time anyone anywhere has successfully engineered and printed an entire heart replete with cells, blood vessels, ventricles, and chambers. The technology could one day provide printed hearts for transplants that minimize rejection by a patient’s immune system by using the patient’s own cells.
The problem with diagnostics that try to monitor a patient’s heart condition is that they don’t exist in the real world. What a patient’s heart might reveal in a clinical setting when checked for a few minutes might differ entirely from what would be learned if it were monitored, say, around the clock for an entire week of the patient’s everyday life. Until now, we’ve had to live with this issue—diagnostics machines were simply too big and bulky to be incorporated into the patients’ real-world experience. Yes, wearable devices can provide the kind of data that only exists in the real world, but their downside is that they depend to a large degree on patient initiative. Even when patients follow instructions perfectly, there are times when the devices either can’t be used (such as during bathing) or malfunction because of outside environmental factors (“Honey, the dog ate my wearable!”).
All of that is about to change. Implantable devices offer the prospect of a shift from episodic testing to continuous monitoring without having to depend on patient compliance. Supported by artificial intelligence and software, these devices will allow for a minimizing of risk and optimization of intervention when treatment is necessary.
Similarly, bionanotechnology increasingly is being used in the diagnosis and treatment of cardiac diseases. Nanotechnology is a field of research and innovation concerned with building devices on the scale of atoms and molecules. (A nanometer is one-billionth of a meter, ten times the diameter of a hydrogen atom.) The medical application of this is known as bionanotechnology.
Nanoparticles have demonstrated potential in both detection and removal of atherosclerotic plaques, which causes the narrowing of coronary arteries. Nanoparticles can deliver therapeutic biomolecules to the site of coronary atherosclerosis and shrink plaques by reducing inflammation (for example, by activating pro-resolving pathways) and removing lipids and cholesterol crystals. And because nanoparticles can mimic or alter biological processes, they might someday soon be used to deliver medications over a prescribed period following an initial injection. Finally, nanoparticles could be an effective way to deliver stem cells and bioengineered tissue to repair cardiac damage.