Molecular ‘glitch’ can lead to heart failure
Molecular glitch’ can lead to heart failure
Disorder costs $10 billion per year in medical care
A recent study by scientists at Johns Hopkins University in Baltimore and Queen’s Uni-versity in Kingston, Ontario, indicates that an abnormal form of the protein troponin I (TnI), part of a three-prong, regulatory "switch" that activates heart muscle contraction, is responsible for causing myocardial stunning, a common but potentially fatal form of acquired heart failure that affects almost all patients who have undergone open-heart surgery.
A function of the blood supply to the heart being shut down and then restored, stunning effects patients, especially children, who have had to be placed on heart/lung machines. Also highly susceptible are adult heart attack victims whose blood supply has been restored through drugs or angioplasty.
To make the heart of patients with stunning contract more forcefully, clinicians generally place them on an inotrope drug such as epinephrine for a day or two, until their heart begins to contract more forcefully.
Distinguished by a general weakness in the heart muscle, stunning is a frequent complicator of coronary artery disease. Present in up to 10% of heart patients, it can continue anywhere from hours to days. Though usually a temporary condition, some patients experience complications and die. Consequently, victims require careful monitoring, and must be hospitalized following surgery in intensive care for 24 hours. It’s hardly surprising that the disorder costs the United States an estimated $10 billion per year in postoperative medical care.
The study, which involved injecting mice with faulty TnI, marks the first time it has been shown that a problem or "glitch" at a molecular level can lead to any type of acquired heart failure. If researchers’ findings are borne out in humans, clinicians not only could gain valuable insight regarding treatment of the disorder, but could be well on their way to eliminating myocardial stunning altogether.
"Congestive heart failure is the leading cause of hospitalization in America in people over 65 years of age. Although many of those hospitalizations are associated with heart attacks, a large number also are related to cardiomyopathies such as myocardial stunning," says Charles Inman Wilmer, MD, director of angioplasty, cardiac disease specialist, and director of data management at the Fuqua Heart Center of Piedmont Hospital in Atlanta.
"A study such as [this] may well link what causes the heart to become hypocontractile, dysfunctional, and dilate, leading to heart failure and atrial fibrillation," he says. "If we can find out how to make patients less susceptible to this condition or discover ways to better treat those who do have it, then we can decrease the need for hospitalization for heart failure and cardiac transplants."
Part of a closely interacting complex of troponins that plays a vital role in heart contraction, TnI could be likened to a light switch, in that it is the protein which is responsible for switching the heart muscle from a relaxed position to a contracted one. "If the switch is down, the muscle is relaxed; if it’s up, it is contracted. If part of that switch is broken, it’s not going to work as well," says Jennifer Van Eyk, MD, one of the research participants and an assistant professor at Queen’s University’s department of physiology.
Data for the study was gathered over a period of 14 years. From earlier experiments, the researchers already were aware that animal models of stunning have damaged TnI, which, in addition to being shorter than usual, also contains fewer amino acids than usual. To determine whether TnI was, in fact, the actual cause of stunning, the team set out to mimic the change that occurs in abnormal human TnI, by creating a transgenic mouse model.
Cloning genes from the defective human protein, they injected the substitute gene into the mice. "Being able to work with lab animals into which we actually were able to incorporate the defect, gave us an advantage over past studies on acquired disorders, where researchers had to attempt by trial and error to reproduce the physiology within the animal," says Anne Murphy, MD, cardiologist at Hopkins Children’s Center, who lead the research team.
As the major proteolytic product of TnI in stunning is missing the 17 COOH-terminal residues, they created three independent lines of transgenic mice expressing TnI in the heart driven by the murine a-myosin heavy chain promoter.
The resultant findings, published in the Jan. 21, 2000 issue of the journal Science, corresponded almost to the letter with what the research team had expected: Heart cells deprived of oxygen experience a sudden increase in calcium. That high calcium level, in turn, trips the production of enzymes that are responsible for cleaving proteins.
Some 20% of the TnI in the mice studied turned out to be the shortened form. Transgenic mice also exhibited cardiac enlargement and echocardiography. In addition, in a classic response to weakened muscle, they developed ventricular dilation, as well as diminished contractility and reduced myofilament calcium responsiveness. "The force their heart muscles exerted also was far below normal," says Murphy.
"The mice resembled humans with myocardial stunning in any way that we could measure. The study not only demonstrates proof of hypothesis — that the partial breakdown in troponin actually has a causal role in bringing about cardiac dysfunction — it also provides a model in which clinicians can test a variety of new therapies," she says.
Along with revealing that as the change in TnI occurs acutely, "there’s a good chance" stunning can be cured, another, highly significant implication of the study is TnI is present in a number of diseases, including, in all probability, angina, Van Eyk says.
The study also includes data dealing with human heart patients who allowed blood specimens and very small samples of heart muscle to be extracted from them, both prior to bypass surgery and 15 minutes after the heart was restarted. Blood samples also were taken one and three days following surgery.
In addition to supporting the researchers’ hypothesis that patients experienced "some" breakdown of TnI, "What was [different] is that some sort of injury to their heart tissue had occurred prior to surgery," Murphy says.
Glorianne Ropchan, MD, a cardiac surgeon at Queen’s University, who also was a member of the research team, sees the study as being especially timely. "Before this, no one had looked at the role of troponin in heart surgery at all. At a time when we’re treating older and older people with sicker and sicker hearts, we are hoping we’ll be able to use this technique, not only to evaluate how well we protect the heart, but also to make improvements in how we do protect the heart.
"We are banking on the findings being useful, not only in helping investigate modality in order to diagnose problems, but also in helping monitor patients and tailor their therapies to their own particular needs."
John Odell, MD, head of surgery at Mayo Medical School’s section of thoracic and cardiovascular surgery in Rochester, MN, concurs that the findings, if correct, are exciting. "Like a lot of disease processes, myocardial stunning is one that we really haven’t understood. It’s interesting that they have found a molecular change in troponin that occurs in the heart’s contraction. Whether we ever will be able to form a drug that actually prevents myocardial stunning, I’m not sure. But, once you’ve located a problem, there’s no question that it’s that much easier to focus on the best ways of dealing with it."
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