It seems especially strange that “untwisting” continues to be used, since the MRI, our gold standard of imaging, reveals a whole heart clockwise motion. So “untwisting” should really be replaced by “uncoiling,” “recoiling,” or “unwinding.” These correct cardiac movements must be named and recognized — since understanding the mechanics behind them is fundamental to solving why diastolic dysfunction occurs.
With the right words comes the right understanding, along with the passageway toward our long-sought answers.
The Secret of Suction
My pursuit of solutions to diastolic dysfunction is steered by my belief that nature provides us with the clues to resolve medical conditions.
We can begin by looking to the natural harmony of waves in the sea created by the balance of their “ebb and flow.” Imagine standing on a beach, watching the normality of a wave’s crescendo followed by its rapid withdrawal. Then envision a disruption of this natural balance. Interrupt either one of these functions, and their interdependence will cause the other to be dramatically altered. As said before, this ebb and flow analogy to the body’s circulation came from Galen, who described it in AD 180. Could this return of its relevance now help us uncover the cause and treatment of diastolic dysfunction?
Focusing only upon the diastolic phase (when suction occurs) has been the traditional approach to determine what goes wrong during diastolic dysfunction. But no solutions could be found from that. This is what set me wondering: could it be shortsighted to only study diastole? Could interdependence between the systolic (ejection) and diastolic (suction) phases define the root of the problem?
After all, the heart cannot prepare to fill… until it completes its twisting.
Here is what I realized: the action of the ventricle uncoiling — a motion that is essential to the suction for filling — is made up of two steps. First, there is what I have called “prepare for suction,” during which 50 to 60%122 of uncoiling occurs to make the ventricle ready for suction. Second, the remainder of uncoiling (the other 40 to 50%) then provides the suction needed for rapid filling of the ventricle.
Both of these two phases of uncoiling are needed for optimal suction… yet the cause of diastolic dysfunction really takes place during the “prepare for suction” phase.
This interval occurs between the end of contraction and extends to the beginning of suction. I could now easily see a dilemma arising if the ejection twisting period (contraction) became prolonged beyond normal. Why? Because that would then delay the start of this “prepare for suction” phase, and shorten this vital period for uncoiling. There would not be sufficient time to develop the centrifugal force needed for suction. Instead, ventricular filling would suddenly depend only upon pressure differences between atrium and ventricle.
These observations felt like clues, and this “prepare for suction” phase took top billing for my attention!
The Answer: Delay = Diastolic Dysfunction
It had become clear to me that the uncoiling during this “prepare for suction” phase, a motion that prepares the heart for suction, becomes pivotal for its success — and thus is the key element to solving diastolic dysfunction.
Fortunately, I had the tools needed to explore this new realization.
We could readily calculate the duration of the “prepare for suction” phase — by measuring the interval between when the inner helical arm contraction ends (when ejection stops) — and when outer helical arm contraction ends (suction starts)!104 I further realized this “preparation for action” phase has artistic and sports analogies. For example, rehearsals always precede a show, and warm-up before a sporting event is essential. Performing well in acting, dancing, and sports is not possible without such a preparation. Yet no one had appreciated that compromise of this “prepare for suction” phase set the stage for development of diastolic dysfunction.
This would now become our research focus.
Manuel Castella (the Spanish research fellow who helped test Paco’s model) collaborated on this study. We needed first to cause diastolic dysfunction in a test animal. This could be readily done by temporarily limiting blood flow to the heart by closing a nourishing artery for 15 minutes. Diastolic dysfunction predictably followed, providing us a perfect chance to evaluate the “prepare for suction” phase.
What we found was very specific — and very revealing.
When diastolic dysfunction developed, the contraction of the inner helix arm (twisting for ejection) lasted longer than normal. This delayed the start of uncoiling — and significantly shortened the interval between ejection and suction. It compromised the crucial “prepare the heart for suction” period needed to prepare for developing suction. This awful persistence (of the prolonged twisting phase) became the central dilemma in the process! Quite simply, the heart cannot get ready to fill — if it is still twisting (contracting).
This observation contradicted the conventional belief that “all is well, since there is a normal ejection fraction,” a concept that is simply incorrect. Instead, this longer time of twisting (or torsion) curtails the “prepare for suction period.” The warm-up period is compromised. In fact, evidence of this is apparent in patients with impaired suction, as their hearts consistently have prolonged systolic torsion (taking longer for ejection).123 This unmistakable connection has escaped detection by most of those that treat diastolic dysfunction. Consequently, contracting longer does not yield a better outcome. Said differently, torsion is important, but its prolongation promotes diastolic dysfunction.
Getting Closer
Recognizing that the systolic issue (prolonged contraction during ejection) is responsible for diastolic dysfunction, led to my asking two fundamental questions: Why does prolonged ejection happen? and How can we fix it?
I realized we could not develop a treatment until these questions were answered. This is particularly true since patients with a variety of different diseases can develop diastolic dysfunction — but each of them shares the same underlying problem of a prolonged ejection interval. These diseases include restricted coronary blood flow (just as we simulated in our experimental study), high blood pressure (hypertension), aortic stenosis (narrowing of the opening of the aortic valve), the aging or elderly population, and finally those with a stretched and failing dilated heart.
Despite this commonality, the impact of prolonged contraction (ejection) has not been addressed, except in patients with high blood pressure or in those who had aortic valve narrowing.124–126 We know that diastolic function improves after either lowering blood pressure in patients with hypertension or after correcting a narrowed aortic valve.123 Yet it wasn’t known why these treatments worked, largely due to an absence in understanding of the mechanism causing diastolic dysfunction (they happened to offset prolonged contraction, and restore normal twisting and uncoiling).123 The lack of effective treatments for diastolic dysfunction in aging patients, or in younger patients without high blood pressure — is due to this same void in understanding of why it happens.
This was the challenge facing me.
Luckily, I had knowledge of the helical heart — a starting point to search for the answer.
Calcium, the Diastolic Warlord
When I recognized that a prolonged contraction (ejection) would compromise this “prepare for suction” interval and lead to diastolic dysfunction — I recalled my own experiences with patients who’d had post-operative muscle damage after cardiac surgery, in which the heart took a longer time to eject. This brought me back to the experience at the beginning of my career, when John Kirklin told me the heart muscle became stiff when its blood supply was returned after being absent (ischemia). I suggested it might be like a charley horse, which led me to reduce calcium as I tried to prevent reperfusion injury in surgical patients.
It now dawned on me that diastolic dysfunction stemmed from this same problem: prolonged contraction of the inner helix arm was the culprit. Normally, contraction happens with high cell calcium — and relaxation happens when ca
lcium is pumped out. But if excess calcium remains — the contraction persists. This scenario would match well with possible causes for diastolic dysfunction in the older population, as their ability to pump calcium out of cells is less efficient.
Because of this, I wondered if excess calcium could be the indisputable warlord of diastolic dysfunction, causing the “awful persistence” that allows prolongation of systolic contraction (ejection) — and prevents the ventricles from filling properly. Moreover, I knew that calcium retention also stiffens the heart, which further inhibits its ability to suction.
While this theory was based upon our past experiences and made sense, testing was needed to confirm it. Once proven, our subsequent goal would be to answer these two questions: why does excess calcium occur in the cells, and how can this problem be remedied?
Fortunately, fresh and unexpected answers came to light as I followed my motto: “traveling to teach allows me to learn.”
Pharmacologist Unlocks the Mystery
I had a fascinating experience during an international conference at the University of Western Ontario in Canada, where I’d gone to give a talk. There I was taught about a chemical reaction I had never heard of. It describes a natural sequence that allows the body to avoid accumulation of acid that damages its tissues. Morris Karmazyn, a luminous physiologist and pharmacologist, educated us by explaining the sodium-hydrogen exchange mechanism.
This is a normal process that occurs in the tissues of all within the animal kingdom. A cell becomes acidotic (excess acid) if too many hydrogen ions accumulate within it. The cell tries to get rid of the acid by pumping it out, using this sodium-hydrogen exchange mechanism in which it actively exchanges hydrogen for sodium. Then, because a sick cell cannot develop the energy to get rid of the sodium in the normal way, the cell — exchanges sodium for calcium.
The problem is, if too much sodium amasses in the cell — this cell then becomes overloaded by the calcium that enters to replace the sodium — and the high intracellular calcium drama begins.
I sat there listening… absorbing. The sequence he described made sense. I now understood why people accumulate excess calcium in the cell.
What got me even more excited was that Morris reported a pharmaceutical company had worked with him to develop a unique way to inhibit this sodium-hydrogen exchange mechanism. I realized if their new drug prevented this devastating sequence, it would counteract the awful calcium persistence that may produce prolonged ejection — and may solve the basic mechanism behind diastolic dysfunction!
Could this be the answer I was searching for?
The findings Morris presented had an extraordinary impact upon me. I learned that Cariporide (Morris’ drug) successfully reversed calcium-related damage in the eye, brain, lung, gastrointestinal system, thyroid, prostate… and heart. It was remarkable, and astoundingly, a discovery few had heard of. Not cardiologists. Not surgeons. Yet here was this incredible drug that changed all these different diseases in all these varied areas. The importance of this was overwhelming, since the role of this exchange mechanism was universal and existed in all tissues. Yet this concept is not taught in medical school and its remedy is never used in patients.
I took a walk with Morris after his presentation.
“What you’re doing is unbelievable!” I told him. “I consider this to be a landmark finding, one that rivals the discovery of nitric oxide — that won the Nobel Prize for Lou Ignarro, my colleague at UCLA.”
A twinkle flashed in Morris’ eyes as he quietly admitted, “I think the benefits will exceed those of nitric oxide.”
I knew he was correct, but this reality could only be possible if someone listened, tested it, and started the ball rolling.
Getting Involved
My discussion with Morris would turn out to have a unique outcome. I soon received an invitation to participate in the drug studies for Cariporide. I had previously demonstrated that reducing calcium would limit reperfusion damage, so the drug company asked me to now evaluate if this new pharmaceutical agent would limit calcium buildup after coronary artery bypass surgery.
I also saw this as an opportunity to explore whether this drug could combat the probable excess calcium component of diastolic dysfunction.
Fortunately, an established framework to test a solution to diastolic dysfunction was already soundly in place. Our prior experience using ultrasonic crystal probes could now allow us to detect the timing of the end of the inner and outer helical arm contractions, and determine if this drug could counter any prolongation of the ejection phase (the action that shortens the preparation for suction phase and causes diastolic dysfunction).
I was eager to start.
Experiment Begins
In the first portion of our testing, the blood supply to a region of the heart was closed for 15 minutes (duplicating the condition that exists in coronary artery bypass surgery). As expected, this lengthened the period of ejection, as the inner helix muscle contraction was prolonged due to the awful calcium persistence.
Cariporide was studied during part two. It was administered just before closing off the blood supply for 15 minutes. Diastolic dysfunction again occurred immediately after new blood supply was restored — but by the end of one hour, all measurements had returned to normal. Diastolic dysfunction completely disappeared, natural twisting recovered, and uncoiling returned to normal!126 These observed findings were consistently repeated.
It was absolutely marvelous. We now not only understood the muscular reasons for diastolic dysfunction. We also had successfully tested a remarkable new drug to reverse it!
The Next Step
How exciting that a medical remedy to this dilemma now existed. This drug reflected the potential for a monumental breakthrough. Next, we’d need to confirm these expectations in a clinical trial with patients.
My involvement in the study continued as I served on the Medical Steering Committee that established the parameters for a clinical trial, which would study whether heart damage after coronary artery bypass operations is reduced by this drug. I was optimistic, though wary, since the validity of such studies depends upon the credibility of the investigation. I was still deeply troubled by the highly flawed STICH trial that tested ventricular restoration as a counter to heart failure,94, 99 and terribly saddened that their tragic failure to maintain credibility had produced results that adversely affected the lives of countless sick patients.
Recognizing this drug’s potential as a game-changer, the pharmaceutical company (instead of the NIH, in this case) sponsored a very large, very expensive, prospective randomized trial for Cariporide. The steering committee defined the dose and duration strategies for use of the drug, emphasizing that it should be used only during the period of reperfusion in the operating room, and perhaps during the immediate stay in the intensive care unit.
Each steering committee member was thrilled about the significance of potential positive trial outcomes.
However, a problem developed.
I suspect the drug company’s desire to sell great quantities of their product may have been what caused them to alter the steering committee’s recommendations. They changed our guidelines to extend drug delivery to 48 hours and added a high dose delivery — instead of using a lower drug concentration during a much shorter post-reperfusion period. They did this despite our emphasizing that these patients did not need elevated doses.
Trial findings showed clear cardiac improvement, but slightly increased neurological damage was evident as well. This adverse outcome resulted in the non-marketing and abandonment of this drug.
These mishaps caused their own major tragedy, as the potential expansion of these findings might have allowed many diastolic dysfunction patients to receive a potentially life-saving treatment. Plus, Cariporide could offer massive benefits that go beyond those with heart failure, as I previously cited its role in reversing related calcium damage in the eye, brain, lung, gastrointestinal system, thyroid, prostate, and other organ
s.
So Cariporide is not available. But this does not preclude others from viewing the collected data. This information may help future pharmaceutical research solve diastolic dysfunction by modifying how calcium is exchanged… rather than only employing approaches that aim at its symptoms.
The Future
Diastolic dysfunction is still not viewed as a muscular disease, and this glaring error underlies the gaping inadequacies of current treatments. From what we found, successful managing of this disease requires understanding the form / function relationship behind it. The mechanism relates to the prolonged inner helix contraction during ejection, which in turn shortens the “prepare for suction” phase. This basic knowledge is essential as drugs may be developed to rectify this process (we used a sodium-hydrogen exchange blocker, but other calcium mobility agents may also accomplish this goal).
Unfortunately, neither fundamental concept (the helical ventricular myocardial band or the sodium-hydrogen exchange mechanism) is taught in medical schools. This vital information remains unknown within the fields of cardiology and cardiac surgery. A lamentable problem, as we may have the means to solve diastolic dysfunction, but nobody is looking at the two basic issues that might explain and reverse it.
Fortunately, science is not like politics. The truth wins, not popularity. Understanding these essential building blocks will eventually prevail and may generate a groundswell of exploration. Hopefully sooner rather than later, since the high mortality from diastolic dysfunction has remained constant for over three decades.127 It is certainly time for a change.
The triumph of truth is the cornerstone of history.
CHAPTER 23
Art and Science: The Cardiac Dance; Spirals of Life
I received many invitations to speak after showing the Helix and Heart video. Organizations were intrigued by this new perception of the heart, which sprung from observing the simplicity of design after the heart was unwrapped. I believed this new knowledge might usher in a fresh understanding of heart structure, one that could — and should — lead to a revolution of how we treat the heart.
Solving the Mysteries of Heart Disease Page 41