On a cold, bright January morning I walked south across Westminster Bridge to St Thomas’ Hospital, an institution with a proud tradition of innovation: I was there to observe a procedure generally regarded as the greatest advance in cardiac surgery since the turn of the millennium – and one that can be performed without a surgeon.

The patient was a man in his 80s with aortic stenosis, a narrowed valve which was restricting outflow from the left ventricle into the aorta. His heart struggled to pump sufficient blood through the reduced aperture, and the muscle of the affected ventricle had thickened as the organ tried to compensate. If left unchecked, this would eventually lead to heart failure. For a healthier patient the solution would be simple: an operation to remove the diseased valve and replace it with a prosthesis. But the man’s age and a long list of other medical conditions made open-heart surgery out of the question. Happily, for the last few years, another option has been available for such high-risk patients: transcatheter aortic valve implantation, known as TAVI for short.

This is a non-invasive procedure, and takes place not in an operating theatre but in the catheterisation laboratory, known as the “cath lab”. When I got there, wearing a heavy lead gown to protect me from X-rays, the patient was already lying on the table. He would remain awake throughout the procedure, receiving only a sedative and a powerful analgesic. I was shown the valve to be implanted, three leaflets fashioned from bovine pericardium (a tough membrane from around the heart of a cow), fixed inside a collapsible metal stent. After being soaked in saline it was crimped on to a balloon catheter and squeezed, from the size and shape of a lipstick, into a long, thin object like a pencil.

The consultant cardiologist, Bernard Prendergast, had already threaded a guidewire through an incision in the patient’s groin, entering the femoral artery and then the aorta, until the tip of the wire had arrived at the diseased aortic valve. The catheter, with its precious cargo, was then placed over the guidewire and pushed gently up the aorta. When it reached the upper part of the vessel we could track its progress on one of the large X-ray screens above the table. We watched intently as the metal stent described a slow curve around the aortic arch before coming to rest just above the heart.

There was a pause as the team checked everything was ready, while on the screen the silhouette of the furled valve oscillated gently as it was buffeted by pulses of high-pressure arterial blood. When Prendergast was satisfied that the catheter was precisely aligned with the aortic valve, he pressed a button to inflate the tiny balloon. As it expanded it forced the metal stent outwards and back to its normal diameter, and on the X-ray monitor it suddenly snapped into position, firmly anchored at the top of the ventricle. For a second or two the patient became agitated as the balloon obstructed the aorta and stopped the flow of blood to his brain; but as soon as it was deflated he became calm again.

Prendergast and his colleagues peered at the monitors to check the positioning of the device. In a conventional operation the diseased valve would be excised before the prosthesis was sewn in; during a TAVI procedure the old valve is left untouched and the new one simply placed inside it. This makes correct placement vital, since unless the device fits snugly there may be a leak around its edge. The X-ray picture showed that the new valve was securely anchored and moving in unison with the heart. Satisfied that everything had gone according to plan, Prendergast removed the catheter and announced the good news in a voice that was probably audible on the other side of the river. Just minutes after being given a new heart valve, the patient raised an arm from under the drapes and shook the cardiologist’s hand warmly. The entire procedure had taken less than an hour.

* * *

According to many experts, this is what the future will look like. Though available for little more than a decade, TAVI is already having a dramatic impact on surgical practice: in Germany the majority of aortic valve replacements, more than 10,000 a year, are now performed using the catheter rather than the scalpel.

In the UK, the figure is much lower, since the procedure is still significantly more expensive than surgery – this is largely down to the cost of the valve itself, which can be as much as £20,000 for a single device. But as the manufacturers recoup their initial outlay on research and development, it is likely to become more affordable – and its advantages are numerous. Early results suggest that it is every bit as effective as open-heart surgery, without many of surgery’s undesirable aspects: the large chest incision, the heart-lung machine, the long period of post-operative recovery.

The essential idea of TAVI was first suggested more than half a century ago. In 1965, Hywel Davies, a cardiologist at Guy’s Hospital in London, was mulling over the problem of aortic regurgitation, in which blood flows backwards from the aorta into the heart. He was looking for a short-term therapy for patients too sick for immediate surgery – something that would allow them to recover for a few days or weeks, until they were strong enough to undergo an operation. He hit upon the idea of a temporary device that could be inserted through a blood vessel, and designed a simple artificial valve resembling a conical parachute. Because it was made from fabric, it could be collapsed and mounted on to a catheter. It was inserted with the top of the “parachute” uppermost, so that any backwards flow would be caught by its inside surface like air hitting the underside of a real parachute canopy. As the fabric filled with blood it would balloon outwards, sealing the vessel and stopping most of the anomalous blood flow.

This was a truly imaginative suggestion, made at a time when catheter therapies had barely been conceived of, let alone tested. But, in tests on dogs, Davies found that his prototype tended to provoke blood clots and he was never able to use it on a patient.

Doctors perform minimally invasive heart surgery on a patient. Photograph: Steve Russell/Toronto Star via Getty Images

Another two decades passed before anybody considered anything similar. That moment came in 1988, when a trainee cardiologist from Denmark, Henning Rud Andersen, was at a conference in Arizona, attending a lecture about coronary artery stenting. It was the first he had heard of the technique, which at the time had been used in only a few dozen patients, and as he sat in the auditorium he had a thought, which at first he dismissed as ridiculous: why not make a bigger stent, put a valve in the middle of it, and implant it into the heart via a catheter? On reflection, he realised that this was not such an absurd idea, and when he returned home to Denmark he visited a local butcher to buy a supply of pig hearts. Working in a pokey room in the basement of his hospital with basic tools obtained from a local DIY warehouse, Andersen constructed his first experimental prototypes. He began by cutting out the aortic valves from the pig hearts, mounted each inside a home-made metal lattice then compressed the whole contraption around a balloon.

Within a few months Andersen was ready to test the device in animals, and on 1 May 1989 he implanted the first in a pig. It thrived with its prosthesis, and Andersen assumed that his colleagues would be excited by his work’s obvious clinical potential. But nobody was prepared to take the concept seriously – folding up a valve and then unfurling it inside the heart seemed wilfully eccentric – and it took him several years to find a journal willing to publish his research.

When his paper was finally published in 1992, none of the major biotechnology firms showed any interest in developing the device. Andersen’s “crazy” idea worked, but still it sank without trace.

* * *

Andersen sold his patent and moved on to other things. But at the turn of the century there was a sudden explosion of interest in the idea of valve implantation via catheter. In 2000, a heart specialist in London, Philipp Bonhoeffer, replaced the diseased pulmonary valve of a 12-year-old boy, using a valve taken from a cow’s jugular vein, which had been mounted in a stent and put in position using a balloon catheter.

In France, another cardiologist was already working on doing the same for the aortic valve. Alain Cribier had been developing novel catheter therapies for years; it was his company that bought Andersen’s patent in 1995, and Cribier had persisted with the idea – even after one potential investor told him that TAVI was “the most stupid project ever heard of”.

Eventually, Cribier managed to raise the necessary funds for development and long-term testing, and by 2000 had a working prototype. Rather than use an entire valve cut from a dead heart, as Andersen had, Cribier built one from bovine pericardium, mounted in a collapsible stainless-steel stent. Prototypes were implanted in sheep to test their durability: after two-and-a-half years, during which they opened and closed more than 100m times, the valves still worked perfectly.

Cribier was ready to test the device in humans, but his first patient could not be eligible for conventional surgical valve replacement, which is safe and highly effective: to test an unproven new procedure on such a patient would be to expose them to unnecessary risk.

In early 2002, he was introduced to a 57-year-old man who was, in surgical terms, a hopeless case. He had catastrophic aortic stenosis which had so weakened his heart that with each stroke it could pump less than a quarter of the normal volume of blood; in addition, the blood vessels of his extremities were ravaged by atherosclerosis, and he had chronic pancreatitis and lung cancer. Several surgeons had declined to operate on him, and his referral to Cribier’s clinic in Rouen was a final roll of the dice. An initial attempt to open the stenotic valve using a simple balloon catheter failed, and a week after this treatment Cribier recorded in his notes that his patient was near death, with his heart barely functioning. The man’s family agreed that an experimental treatment was preferable to none at all, and on 16 April he became the first person to receive a new aortic valve without open-heart surgery.

Over the next couple of days the patient’s condition improved dramatically: he was able to get out of bed, and the signs of heart failure began to retreat. But shortly afterwards complications arose, most seriously a deterioration in the condition of the blood vessels in his right leg, which had to be amputated 10 weeks later. Infection set in, and four months after the operation, he died.

He had not lived long – nobody expected him to – but the episode had proved the feasibility of the approach, with clear short-term benefit to the patient. When Cribier presented a video of the operation to colleagues they sat in stupefied silence, realising that they were watching something that would change the nature of heart surgery.

When surgeons and cardiologists overcame their initial scepticism about TAVI they quickly realised that it opened up a vista of exciting new surgical possibilities. As well as replacing diseased valves it is now also possible to repair them, using clever imitations of the techniques used by surgeons. The technology is still in its infancy, but many experts believe that this will eventually become the default option for valvular disease, making surgery increasingly rare.

* * *

While TAVI is impressive, there is one even more spectacular example of the capabilities of the catheter. Paediatric cardiologists at a few specialist centres have recently started using it to break the last taboo of heart surgery – operating on an unborn child. Nowhere is the progress of cardiac surgery more stunning than in the field of congenital heart disease. Malformations of the heart are the most common form of birth defect, with as many as 5% of all babies born with some sort of cardiac anomaly – though most of these will cause no serious, lasting problems. The heart is especially prone to abnormal development in the womb, with a myriad of possible ways in which its structures can be distorted or transposed. Over several decades, specialists have managed to find ways of taming most; but one that remains a significant challenge to even the best surgeon is hypoplastic left heart syndrome (HLHS), in which the entire left side of the heart fails to develop properly. The ventricle and aorta are much smaller than they should be, and the mitral valve is either absent or undersized. Until the early 1980s this was a defect that killed babies within days of birth, but a sequence of complex palliative operations now makes it possible for many to live into adulthood.

Because their left ventricle is incapable of propelling oxygenated blood into the body, babies born with HLHS can only survive if there is some communication between the pulmonary and systemic circulations, allowing the right ventricle to pump blood both to the lungs and to the rest of the body. Some children with HLHS also have an atrial septal defect (ASD), a persistent hole in the tissue between the atria of the heart which improves their chances of survival by increasing the amount of oxygenated blood that reaches the sole functioning pumping chamber. When surgeons realised that this defect conferred a survival benefit in babies with HLHS, they began to create one artificially in those with an intact septum, usually a few hours after birth. But it was already too late: elevated blood pressure was causing permanent damage to the delicate vessels of the lungs while these babies still in the womb.

A prototype of a fully implantable artificial heart, as presented by the French heart specialist Alain Carpentier. Photograph: Jacques Brinon/AP

The logical – albeit risky – response was to intervene even earlier. In 2000, a team at Boston Children’s Hospital adopted a new procedure to create an ASD during the final trimester of pregnancy: they would deliberately create one heart defect in order to treat another. A needle was passed through the wall of the uterus and into the baby’s heart, and a balloon catheter used to create a hole between the left and right atria. This reduced the pressures in the pulmonary circulation and hence limited the damage to the lungs; but the tissues of a growing foetus have a remarkable ability to repair themselves, and the artificially created hole would often heal within a few weeks. Cardiologists needed to find a way of keeping it open until birth, when surgeons would be able to perform a more comprehensive repair.

In September 2005 a couple from Virginia, Angela and Jay VanDerwerken, visited their local hospital for a routine antenatal scan. They were devastated to learn that their unborn child had HLHS, and the prognosis was poor. The ultrasound pictures revealed an intact septum, making it likely that even before birth her lungs would be damaged beyond repair. They were told that they could either terminate the pregnancy or accept that their daughter would have to undergo open-heart surgery within hours of her birth, with only a 20% chance that she would survive.

Devastated, the VanDerwerkens returned home, where Angela researched the condition online. Although few hospitals offered any treatment for HLHS, she found several references to the Boston foetal cardiac intervention programme, the team of doctors that had pioneered the use of the balloon catheter during pregnancy.

They arranged an appointment with Wayne Tworetzky, the director of foetal cardiology at Boston Children’s Hospital, who performed a scan and confirmed that their unborn child’s condition was treatable. A greying, softly spoken South African, Tworetzky explained that his team had recently developed a new procedure, but that it had never been tested on a patient. It would mean not just making a hole in the septum, but also inserting a device to prevent it from closing. The VanDerwerkens had few qualms about accepting the opportunity: the alternatives gave their daughter a negligible chance of life.

The procedure took place at Brigham and Women’s Hospital in Boston on 7 November 2005, 30 weeks into the pregnancy, in a crowded operating theatre. Sixteen doctors, with a range of specialisms, took part: cardiologists, surgeons, and four anaesthetists – two to look after the mother, two for her unborn child. Mother and child needed to be completely immobilised during a delicate procedure lasting several hours, so both were given a general anaesthetic. The team watched on the screen of an ultrasound scanner as a thin needle was guided through the wall of the uterus, then the foetus’s chest and finally into her heart – an object the size of a grape.

A guidewire was placed in the cardiac chambers, then a tiny balloon catheter was inserted and used to create an opening in the atrial septum. This had all been done before; but now the cardiologists added a refinement. The balloon was withdrawn, then returned to the heart, this time loaded with a 2.5 millimetre stent that was set in the opening between the left and right atria. There was a charged silence as the balloon was inflated to expand the stent; then, as the team saw on the monitor that blood was flowing freely through the aperture, the room erupted in cheers.

Grace VanDerwerken was born in early January after a normal labour, and shortly afterwards underwent open-heart surgery. After a fortnight she was allowed home, her healthy pink complexion proving that the interventions had succeeded in producing a functional circulation.

But just when she seemed to be out of danger, Grace died suddenly at the age of 36 days – not as a consequence of the surgery, but from a rare arrhythmia, a complication of HLHS that occurs in just 5%. This was the cruellest luck, when she had seemingly overcome the grim odds against her. Her death was a tragic loss, but her parents’ courage had brought about a new era in foetal surgery.

* * *

Much of the most exciting contemporary research focuses on the greatest, most fundamental cardiac question of all: what can the surgeon do about the failing heart? Half a century after Christiaan Barnard performed the first human heart transplant, transplantation remains the gold standard of care for patients in irreversible heart failure once drugs have ceased to be effective. It is an excellent operation, too, with patients surviving an average of 15 years. But it will never be the panacea that many predicted, because there just aren’t enough donor hearts to go round.

With too few organs available, surgeons have had to think laterally. As a result, a new generation of artificial hearts is now in development. Several companies are now working on artificial hearts with tiny rotary electrical motors. In addition to being much smaller and more efficient than pneumatic pumps, these devices are far more durable, since the rotors that impel the blood are suspended magnetically and are not subject to the wear and tear caused by friction. Animal trials have shown promising results, but, as yet, none of these have been implanted in a patient.

Another type of “total artificial heart”, as such devices are known, has, however, recently been tested in humans. Alain Carpentier, an eminent French surgeon still active in his ninth decade, has collaborated with engineers from the French aeronautical firm Airbus to design a pulsatile, hydraulically powered device whose unique feature is the use of bioprosthetic materials – both organic and synthetic matter. Unlike earlier artificial hearts, its design mimics the shape of the natural organ; the internal surfaces are lined with preserved bovine pericardial tissue, a biological surface far kinder to the red blood cells than the polymers previously used. Carpentier’s artificial heart was first implanted in December 2013. Although the first four patients have since died – two following component failures – the results were encouraging, and a larger clinical trial is now under way.

Christiaan Barnard having dinner in Monte Carlo with Princess Grace of Monaco. Photograph: AP

One drawback to the artificial heart still leads many surgeons to dismiss the entire concept out of hand: the price tag. These high-precision devices cost in excess of £100,000 each, and no healthcare service in the world, publicly or privately funded, could afford to provide them to everybody in need of one. And there is one still more tantalising notion: that we will one day be able to engineer spare parts for the heart, or even an entire organ, in the laboratory.

In the 1980s, surgeons began to fabricate artificial skin for burns patients, seeding sheets of collagen or polymer with specialised cells in the hope that they would multiply and form a skin-like protective layer. But researchers had loftier ambitions, and a new field – tissue engineering – began to emerge.

High on the list of priorities for tissue engineers was the creation of artificial blood vessels, which would have applications across the full range of surgical specialisms. In 1999 surgeons in Tokyo performed a remarkable operation in which they gave a four-year-old girl a new artery grown from cells taken from elsewhere in her body. She had been born with a rare congenital defect which had completely obliterated the right branch of her pulmonary artery, the vessel conveying blood to the right lung. A short section of vein was excised from her leg, and cells from its inside wall were removed in the laboratory. They were then left to multiply in a bioreactor, a vessel that bathed them in a warm nutrient broth, simulating conditions inside the body.

After eight weeks, they had increased in number to more than 12m, and were used to seed the inside of a polymer tube which functioned as a scaffold for the new vessel. The tissue was allowed to continue growing for 10 days, and then the graft was transplanted. Two months later the polymer scaffold around the tissue, designed to break down inside the body, had completely dissolved, leaving only new tissue that would – it was hoped – grow with the patient.

At the turn of the millennium, a new world of possibility opened up when researchers gained a powerful new tool: stem cell technology. Stem cells are not specialised to one function but have the potential to develop into many different tissue types. One type of stem cell is found in growing embryos, and another in parts of the adult body, including the bone marrow (where they generate the cells of the blood and immune system) and skin. In 1998 James Thomson, a biologist at the University of Wisconsin, succeeded in isolating stem cells from human embryos and growing them in the laboratory.

But an arguably even more important breakthrough came nine years later, when Shinya Yamanaka, a researcher at Kyoto University, showed that it was possible to genetically “reprogram” skin cells and convert them into stem cells. The implications were enormous. In theory, it would now be possible to harvest mature, specialised cells from a patient, reprogram them as stem cells, then choose which type of tissue they would become.

Sanjay Sinha, a cardiologist at the University of Cambridge, is attempting to grow a “patch” of artificial myocardium (heart muscle tissue) in the laboratory for later implantation in the operating theatre. His technique starts with undifferentiated stem cells, which are then encouraged to develop into several types of specialised cell. These are then seeded on to a scaffold made from collagen, a tough protein found in connective tissue. The presence of several different cell types means that when they have had time to proliferate, the new tissue will develop its own blood supply.

Clinical trials are still some years away, but Sinha hopes that one day it will be possible to repair a damaged heart by sewing one of these patches over areas of muscle scarred by a heart attack.

Using advanced tissue-engineering techniques, researchers have already succeeded in creating replacement valves from the patient’s own tissue. This can be done by harvesting cells from elsewhere in the body (usually the blood vessels) and breeding them in a bioreactor, before seeding them on to a biodegradable polymer scaffold designed in the shape of a valve. Once the cells are in place they are allowed to proliferate before implantation, after which the scaffold melts away, leaving nothing but new tissue. The one major disadvantage of this approach is that each valve has to be tailor-made for a specific patient, a process that takes weeks. In the last couple of years, a group in Berlin has refined the process by tissue-engineering a valve and then stripping it of cellular material, leaving behind just the extracellular matrix – the structure that holds the cells in position.

The end result is therefore not quite a valve, but a skeleton on which the body lays down new tissue. Valves manufactured in this way can be implanted, via catheter, in anybody; moreover, unlike conventional prosthetic devices, if the recipient is a child the new valve should grow with them.

If it is possible to tissue-engineer a valve, then why not an entire heart? For many researchers this has come to be the ultimate prize, and the idea is not necessarily as fanciful as it first appears.

In 2008, a team led by Doris Taylor, a scientist at the University of Minnesota, announced the creation of the world’s first bioartificial heart – composed of both living and manufactured parts. They began by pumping detergents through hearts excised from rats. This removed all the cellular tissue from them, leaving a ghostly heart-shaped skeleton of extracellular matrix and connective fibre, which was used as a scaffold onto which cardiac or blood-vessel cells were seeded. The organ was then cultured in a bioreactor to encourage cell multiplication, with blood constantly perfused through the coronary arteries. After four days, it was possible to see the new tissue contracting, and after a week the heart was even capable of pumping blood – though only 2% of its normal volume.

This was a brilliant achievement, but scaling the procedure up to generate a human-sized heart is made far more difficult by the much greater number of cells required. Surgeons in Heidelberg have since applied similar techniques to generate a human-sized cardiac scaffold covered in living tissue. The original heart came from a pig, and after it had been decellularised it was populated with human vascular cells and cardiac cells harvested from a newborn rat. After 10 days the walls of the organ had become lined with new myocardium which even showed signs of electrical activity. As a proof of concept, the experiment was a success, though after three weeks of culture the organ could neither contract nor pump blood.

A surgeon using a catheter during an operation. Photograph: Kent Nishimura/Denver Post via Getty Images

Growing tissues and organs in a bioreactor is a laborious business, but recent improvements in 3D printing offer the tantalising possibility of manufacturing a new heart rapidly and to order. 3D printers work by breaking down a three-dimensional object into a series of thin, two-dimensional “slices”, which are laid down one on top of another. The technology has already been employed to manufacture complex engineering components out of metal or plastic, but it is now being used to generate tissues in the laboratory. To make an aortic valve, researchers at Cornell University took a pig’s valve and X-rayed it in a high-resolution CT scanner. This gave them a precise map of its internal structure which could be used as a template. Using the data from the scan, the printer extruded thin jets of a hydrogel, a water-absorbent polymer that mimics natural tissue, gradually building up a duplicate of the pig valve layer by layer. This scaffold could then be seeded with living cells and incubated in the normal way.

Pushing the technology further, Adam Feinberg, a materials scientist at Carnegie Mellon University in Pittsburgh, recently succeeded in fabricating the first anatomically accurate 3D-printed heart. This facsimile was made of hydrogel and contained no tissue, but it did show a remarkable fidelity to the original organ. Since then, Feinberg has used natural proteins such as fibrin and collagen to 3D-print hearts. For many researchers in this field, a fully tissue-engineered heart is the ultimate prize.

We are left with several competing visions of the future. Within a few decades it is possible that we will be breeding transgenic pigs in vast sterile farms and harvesting their hearts to implant in sick patients. Or that new organs will be 3D-printed to order in factories, before being dispatched in drones to wherever they are needed. Or maybe an unexpected breakthrough in energy technology will make it possible to develop a fully implantable, permanent mechanical heart.

Whatever the future holds, it is worth reflecting on how much has been achieved in so little time. Speaking in 1902, six years after Ludwig Rehn became the first person to perform cardiac surgery, Harry Sherman remarked that “the road to the heart is only two or three centimetres in a direct line, but it has taken surgery nearly 2,400 years to travel it”. Overcoming centuries of cultural and medical prejudice required a degree of courage and vision still difficult to appreciate today. Even after that first step had been taken, another 50 years elapsed before surgeons began to make any real progress. Then, in a dizzying period of three decades, they learned how to open the heart, repair and even replace it. In most fields, an era of such fundamental discoveries happens only once – if at all – and it is unlikely that cardiac surgeons will ever again captivate the world as Christiaan Barnard and his colleagues did in 1967. But the history of heart surgery is littered with breakthroughs nobody saw coming, and as long as there are surgeons of talent and imagination, and a determination to do better for their patients, there is every chance that they will continue to surprise us.

Main photograph: Getty Images



This is an adapted extract from The Matter of the Heart by Thomas Morris, published by the Bodley Head

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