The Heart Healers (48 page)

Raj would replace Leon’s diseased aortic valve using a technique invented by another former fellow, Dr. Alain Cribier, from the days when I was director of our research program. I have long since handed the reins to others, but I take pride in knowing that over four decades, my mentors and I taught so many creative young cardiologists who advanced our specialty. In 1985, now returned to Rouen, Cribier became deeply frustrated by seeing elderly patients with severe aortic stenosis condemned to death because they were deemed inoperable based on age. So he attempted to open the stenosed valve by passing a deflated balloon into the narrowed valve orifice and then inflating it with great force. His initial results were dramatic: the patients were immediately relieved of symptoms. But just as with coronary angioplasty, the aortic valves also restenosed within a year or so.

Cribier had an intuition: what if restenosis in aortic valves was the same process as restenosis in coronary arteries? If so, after it was opened, could aortic valve restenosis also be prevented by a stent? He tested his idea in autopsied hearts with aortic stenosis. He got himself a synthetic aortic valve used by the surgeons, mounted it within a cylindrical stent, and put a balloon catheter inside the synthetic valve. When he inflated the balloon, it forced open the stenosed valve, which was flattened against the aortic wall, leaving his synthetic valve as its replacement. Most important, he also discovered that the stent was stuck there … he could not remove it, even with forceful tugging. That was the easy part: how in the world could he transport his valve-in-stent into its position between the ventricle and aorta without opening the chest?

Cribier decided he needed engineering help. He approached medical device companies to design and mount a valve within the stent, and place the entire assembly on a catheter-tipped balloon. His experience with manufacturers recalled Andreas Gruentzig and balloon angioplasty two decades earlier. Cribier could interest absolutely no one. So with a couple of engineers and interventional cardiologist Martin Leon in the United States, they formed their own company.

Cribier initially faced (need I say, the usual) withering criticism from members of the cardiology establishment, who were easily able to identify ridiculous ideas. First they said that such a valve could not be created. But if it was, it would be impossible to deliver the valve into the aorta. And even if a valve could be maneuvered into the aorta, it most assuredly would obstruct the coronary arteries, killing the patient in the process. Cribier, like so many risk-takers in our Golden Era, ignored the experts. He began implanting his new valve in patients who had no surgical option. When he had irrefutably proven his point by treatment of forty patients he finally was able to attract a medical device company. Edwards Laboratories, which four decades earlier had triggered the valve surgery revolution with the Starr-Edwards valve, acquired his little company. With the Edwards Laboratories’ expertise in valve manufacturing, clinical trial design and execution, and sponsorship of educational programs, a new era was born. For me personally, the story comes full circle as our fellow from the 1970s Alain Cribier teaches his technique to our fellow of the 1990s Raj Makkar, and Raj in turn teaches the next generation. Cardiology gives meaning to my life when it reminds me, like my own mentors, a teacher never knows where his influence ends; he affects eternity.

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I WILL BE
your eyes as Raj replaces Leon Saliba’s severely diseased aortic valve. Prior to the procedure, Leon has a multislice computerized angiogram of the chest, abdomen, and pelvis (CAT scan), which Raj uses to determine the best size of the replacement valve. In the catheterization laboratory, we see the past merge with the present and the future. Team members insert a balloon catheter (the one I helped develop forty years earlier) in Leon’s pulmonary artery for continuous monitoring of cardiac function. A pacemaker wire (recall Paul Zoll’s pacemaker) is passed into the right ventricle. Using the wire exchange technique (recall Mason Sones’s angiogram), a catheter is placed just above the aortic valve for injecting X-ray dye. Raj makes an incision above the leg artery and passes a catheter with a deflated two-inch long balloon near its tip (recall Andreas Gruentzig’s angioplasty). As his assistant injects X-ray dye to visualize Leon’s aortic valve, Raj slides the deflated balloon across the stenosed aortic valve. He inflates and deflates the balloon several times, making the valve opening large enough for his next maneuver, which will be to insert his new valve.

Raj now exchanges catheters. The new catheter carries a synthetic aortic valve mounted within a stent (recall Albert Starr’s valve). The valve-in-stent over a balloon has been carefully crimped so that the diameter of the whole catheter assembly apparatus is about a quarter of an inch in diameter (recall Ulrich Sigwart’s stent crimped on a balloon). That makes it less than a quarter of the original valve diameter. Now its diameter is small enough that Raj can slide it into an artery in Leon’s leg. When fully reexpanded the valve will be more than an inch in diameter.

Raj passes the valve-in-stent across Leon’s aortic valve. Satisfied that he has properly positioned it, Raj orders the pacemaker to be briefly turned on at a rate of 180 to 200 beats per minute. At a heart rate of 200, the quivering heart delivers very little blood flow across the valve. It’s a critical step, because without it, the force of blood flow exiting the ventricle can make the valve flutter like a sheet in a wind tunnel while the balloon is being expanded. Raj stares intently at the pressure monitor, to be sure that Leon’s blood pressure falls precipitously, indicating pacing is having the desired effect. After several seconds, Raj inflates the balloon, causing his new valve-in-stent to instantly plaster the diseased valve flat against the aortic wall. He keeps the balloon inflated for a few seconds, then deflates it. Leon has a new aortic valve. The whole miraculous replacement, pacing-inflation-deflation, has occurred in a period of about ten seconds, maybe less. Satisfied with the new valve’s position, Raj calls for an echocardiographic recording to document that the new valve is opening and closing properly, performs a final injection of contrast material confirming that Leon’s coronary arteries remain open. Raj removes his catheter. An assistant sews up the incision. The entire procedure including anesthesia, “skin-to-skin” in medical slang, has taken about an hour. As Raj pulls off his mask and gloves, Leon awakes. Raj wants the patient to be awake and talking before he leaves the laboratory.

For me, among all the amazing developments that I have seen in my fifty years of medicine, this ranks as the most visually astounding. Raj has replaced Leon’s valve without cracking open his chest, without using a heart-lung machine and without stopping and restarting the heart.

The next day Leon is sitting in a chair, and on day three he is ready for discharge. Had Leon been treated by open heart surgery, he would face several months of significant discomfort as his chest wall, separated during surgery, knit itself back together. Instead, his principal aggravation would be a week or two of lesser discomfort from the sites of the catheter insertions.

The first devices were approved in Europe in 2007. By 2009, 4,500 aortic valve procedures were performed. In the next year the number of procedures doubled. By 2011, the annual number had quadrupled over just two years. The first reports of mitral valve replacement are now appearing. Raj has done a few. Replacement of valves without surgery, the latest in a series of unimaginable breakthroughs, will be the next great advance in Cardiology’s Golden Era.

Today is Leon’s two-year follow-up. He is now 103. He comes with two of his children. His son Tom proudly tells me that Leon, independent as always, likes to sit on his patio and wave at the golfers as they pass in their carts. The regulars, of course, all know Leon and beam as they wave back. Tom says that Leon brightens each person’s day. He certainly brightens mine.

Leon smiles as Raj and I congratulate him on his good health. As I shake his hand, he thanks me. Embarrassed, I say, “Don’t thank me, Leon, thank Raj. I had nothing to do with this.” And Raj puts his arm around my shoulder and says, “Yes you did, Papa Jim, yes you did.”

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ONGENITAL HEART DISEASE: TINY HEARTS WITH TINY DEFECTS

HEART SURGERY IN
infants with congenital heart defects is made exceptionally challenging by two factors not encountered in adults: the heart is tiny, and no two congenital heart abnormalities are identical. If only, on the day before the operation, a surgeon could hold each child’s heart in his hands, examine its every nook and cranny, and then thoroughly plan the surgical procedure with associates. This year that impossible dream became reality.

At the University of Louisville’s engineering school scientists fed thousands of digital cross X-ray images of little fourteen-month-old Roland C’s heart into a 3-D printer. The printer built a precise replica of his heart by laying down thin layers of a flexible plastic polymer similar in consistency to heart muscle, about 250 layers per inch.

As Louisville cardiac surgeon Dr. Erle Austin planned surgery on Roland’s tiny heart, he asked that Roland’s heart model be reconstructed two times its actual size in three separate sections so that he could touch every part of its interior, view it from every angle, eliminate uncertainty, and plan his incisions with great precision.

As Surgeon Austin explained to the Louisville
Courier-Journal
: “Some people think when you do heart surgery, you go in and can see everything. Well, to see everything, you have to slice through vital structures. Sometimes the surgeon has to guess at what’s the best operation.” The model of little Roland’s heart made it clear that Austin could tunnel between the aortic valve and a ventricle, avoiding multiple exploratory incisions. “Once I had a model, I knew exactly what I needed to do and how I could do it. It was a tremendous benefit.” Unanticipated anatomic disasters will soon be a distant memory for tomorrow’s cardiac surgeons.

In the past year, we witnessed a futuristic application of 3-D printing in living hearts. Collaborators at the University of Illinois at Urbana-Champaign and Washington University in St. Louis programmed a 3-D printer to replicate a high resolution digital image of an individual rabbit heart. From this model, they created a thin elastic “sock” that perfectly encloses the heart. The elasticity of the membrane allows it to move synchronously with each heartbeat, just like the heart’s own pericardium, but with a twist. Within this man-made pericardium the engineers place a network of electrodes that monitor both the heart’s electrical and mechanical function. When it detects a disordered heart rhythm, the sock can deliver an electric shock to terminate arrhythmias like ventricular fibrillation.

But now let’s let our imagination wander even further. What if we could replace the plastic in our 3-D printer with human cells? Reminiscent of the apparent problem of oxygenation faced by creators of the heart-lung machine, many cells are too delicate to survive the current printing process technique. But some tissue is easier than others. Human ears have been bioprinted; human skin for burn victims is in testing. A human liver is on the drawing board. Can hearts be far behind? It only seems a matter of time until bioprinting enters the mainstream of medicine, creating a future that seems almost beyond our imagination.

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ORONARY HEART DISEASE: THE NEXT WONDER DRUGS ARE…
?

CAD AS YOU
now know is due to excess cholesterol trapped in the blood vessel wall, some of which elicits an inflammatory reaction. For years we have been bedeviled by what to do for patients whose blood cholesterol remains high despite potent cholesterol-lowering therapy. Cardiology’s newest potential “wonder drugs,” the ones that treat the previously untreatable, have just appeared on the far horizon. Their discovery illuminates another wonderful twist in pursuit of science.

The principal mechanism by which statins lower cholesterol is by decreasing its synthesis. But like many drugs, statins have what we call a negative feedback loop, the yin-yang of pharmacology. Statins also increase the expression of a substance called PCSK9 that destroys LDL receptors that pull cholesterol out of the circulating blood. So PCSK9 limits the effectiveness of statins in lowering blood cholesterol.

One way to stop PCSK9 from destroying the LDL receptor is with an antibody. Last year in the
Journal of the American College of Cardiology,
we had a stunning report of a small randomized trial of patients already treated with the potent drug atorvastatin (Lipitor) who were given the antibody. LDL was further reduced by 40% to 70% in these patients. The PCSK9 freed up the statin to have its full effect on LDL lowering. So the drug is additive to the effect of statins. Today I can envision what I never even imagined: a future in which virtually all our patients can live with a blood cholesterol level in the desirable range.

PCSK9 inhibition is a classic example of a magical thing simply waiting for our intuition to grow sharper. At this early stage, PCSK9 seems like the ideal adjunct to statin therapy. As yet there is no prohibitive short-term toxicity with the drug.

Since there are several potential methods for inhibiting PCSK9, I am now watching a mad scramble among pharmaceutical research teams to find the ideal formulation. Yet cardiologists are already imagining the meaning of the capacity to lower LDL to an ideal level in every one of their patients. As lipidologist Dr. Robert Vogel speculated in an editorial accompanying this publication of the early PCSK9 antibody results, “Brown and Goldstein won a Nobel Prize for their identification of the LDL receptor in 1985 … the therapeutic triumph of statins logically follows their pioneering efforts. So may PCSK9 inhibition.”

On the horizon is a potential miracle treatment for people with high LDL cholesterol (LDL-C). In their animal laboratories, scientists at Harvard and the University of Pennsylvania claim to have reduced LDL-C permanently with a single injection. Here’s how it’s done: you permanently disrupt the function of the PCSK9 gene. Harvard cardiologist Dr. Kiran Musunuru reports his technique reduces LDL-C by 35 to 40%, an effect comparable to statin drugs: “The kicker is we were able to do that with a single injection, permanently changing the genome [the structure of the individual gene]. Once that changes, it’s there forever … it’s not too much of a leap to think that if it works in mice, it will work as well in humans.” The two-step method of reengineering gene structure has promise for many inherited diseases. The first step is to create a break in the DNA sequence of the target gene. The reengineered gene is then attached to a virus that carries the new modified gene to the liver, where it takes up permanent residence. In effect, with one shot, a patient would be transformed into an individual like those who naturally have the good loss-of-function mutation in their PCSK9 gene. Before this approach can be used in humans, however, proof of effectiveness and safety in humans will be required, a process that may require five to ten years.