Heart biopsy the first step on a complex path

Karen Titus

May 2016—The stories are haunting: a young, seemingly healthy athlete collapses on the playing field and dies. For Joseph Maleszewski, MD, section head of cardiovascular pathology, Mayo Clinic, Rochester, Minn., these deaths also seem sadly familiar, especially given his work with the NCAA on such cases. “Every community, it seems, has a story,” says Dr. Maleszewski, who is also associate professor, laboratory medicine and pathology, and associate professor, medicine. “A child died on the basketball court, on the football field, while running track. These young athlete deaths are not uncommon at all—or even young nonathlete deaths.”

Difficult as these stories are, they don’t end there.

“A patient comes in, and they tell us, ‘I had a brother or sister die suddenly and young,’ and the pathologist who performed the autopsy suspected a cardiomyopathy or a heritable arrhythmia syndrome,” Dr. Maleszew-ski continues. “Maybe a parent has died. Or perhaps—most tragically—a parent comes in and says, ‘I’ve had a child die suddenly.’” The questions hang in the air. Will the same thing happen to me? To my other children?

“Everybody’s heard these stories,” says Dr. Maleszewski. But not everybody has answers.

“One of the nagging issues pathologists are dealing with is the nonuniformity in our approach to cardiac dissection and evaluation,” says Dr. Maleszewski. Particularly in the postmortem setting, he says, it’s less acceptable to obtain an expert’s opinion for cardiovascular disease, the way it is often done with neuropathology. One reason is cost. “And perhaps there’s not a good understanding of how important it is for these family members to understand the heritable implications in these cases.”

When it comes to cardiovascular mysteries, even the answers—if they finally come—can be surprising, says Stephen Cohle, MD, a cardiovascular pathologist with Michigan Pathology Specialists, which is affiliated with Spectrum Health, Grand Rapids, Mich. As Dr. Cohle has learned over the years, it doesn’t take a dramatic, sudden death to jolt pathologists.

Most of the endomyocardial biopsies Dr. Cohle interprets are tied to Spectrum’s heart transplant program. In addition to monitoring patients for rejection, Dr. Cohle examines explanted hearts—and sometimes encounters cases where the diagnosis that prompted the transplant was in error.

“They needed to be transplanted—it’s not like these were otherwise healthy hearts,” says Dr. Cohle, who is also chief medical examiner for Kent County, Mich. Nevertheless, in two cases, he says, the diagnosis was simply nonischemic cardiomyopathy—the equivalent, he says, of “nobody knows the cause.” When he looked at the hearts, he found noncompaction of the left ventricle. “It was satisfying to come up with the actual diagnosis.” In other cases with an initial diagnosis of nonischemic cardiomyopathy (which precludes coronary artery disease), he’s found that CAD was indeed the culprit.

In stories like these, the denouement would appear to be an endomyocardial biopsy. As Dr. Cohle puts it, “There’s no substitute for actually looking.” Endomyocardial biopsies are a bit like the lottery, as it turns out. It costs to play, and the odds of winning may seem uncomfortably slim. But if you don’t play, you can’t win. And if you don’t look, you won’t see.

There’s good reason to look, says Heinz-Peter  Schultheiss, MD, professor for internal medicine, cardiology, and intensive care, and chief of cardiology, Charité-Universitätsmedizin Berlin. Patients with cardiomyopathies, myocarditis, amyloidosis, genetic conditions, etc., don’t always get a correct diagnosis, and, by extension, may not get the right treatment.

The roots of this confusion are deep and tangled. For years, he says, physicians assumed genetic factors were likely the primary cause of many heart muscle diseases. It’s a view that dominated the literature, and in recent years, there’s been plenty of published evidence to support the notion that genetics does play a critical role. “We have more than 3,000 mutations regarding cardiomyopathies,” says Dr. Schultheiss, who is also CEO and founder, Institute of Cardiac Diagnostics and Therapy, Berlin. What do these mutations mean? Although some mutations are clearly pathological, such as lamin A/C, which is associated with dilated cardiomyopathy, they are the outliers.

But by emphasizing genetics, researchers might have overlooked other, nongenetic components when doing retrospective studies. “We were not looking for other aspects,” says Dr. Schultheiss.

Viral myocarditis further complicates matters. How do the genetic and viral components interact? Nor is it always clear if a patient has viral persistence and chronic inflammation, Dr. Schultheiss says. “For a long time, people thought we could see that by MR. But nowadays we know that is not the case—we cannot see if there is virus in the myocardium.” While MRI can reveal fulminant myocarditis, the same is not true of low-grade inflammation, in the chronic phase of the disease. By relying on MRI findings over the years, “A lot of well-known clinics didn’t make a clear-cut diagnosis because they didn’t take endomyocardial biopsies.”

This hasn’t been a call to arms, however. Physicians often fear the perceived risks of doing endomyocardial biopsies, assuming they outweigh the clinical advantages, Dr. Schultheiss says.

Even when physicians agree endomyocardial biopsy might play a larger clinical role, they don’t have many prospective randomized studies to support those views. Moreover, they’re unlikely to be done, at least right now. “Who is going to pay for that?” Dr. Schultheiss asks. The reasoning unfolds like M.C. Escher’s brain-twisting stair print: No one wants to sponsor such studies because there are no new treatments, which aren’t developed because the number of patients affected by these various diseases is somewhat unclear, perhaps due to a lack of clear-cut diagnosis, without which there’s little interest in supporting studies to explore the value of endomyocardial biopsy.

Until the first endomyocardial biopsy was performed through the internal jugular, in 1964 in Japan, heart pathology was obtained only at time of surgery or, rarely, a transthoracic needle biopsy, says Leslie Cooper, MD, chairman of the Department of Cardiology and professor of medicine, Mayo Clinic, Jacksonville, Fla.

Endomyocardial biopsy, as noted, now has widespread use in monitoring heart patients post-transplant, though some are proposing that serum or blood tests might be a less-invasive way to look for antibody-mediated rejection. Nevertheless, endomyocardial biopsy is the gold standard and will likely remain so. “I don’t see that going away anytime soon,” says Dr. Maleszewski.

From the mid-1990s on, says Dr. Cooper, the advent of MRI (and, to a lesser degree, PET scanning) has changed the role of biopsy. “We’re usually able to distinguish ischemic from nonischemic without a biopsy,” he says, and a number of diseases like hemochromatosis can be made using other laboratory tests and MRI. Likewise, the role for endomyocardial biopsy in peripartum cardiomyopathy has diminished greatly, since the prognosis tends to be quite good with guideline-directed care, he says.

In the nontransplant setting, the common clinical setting for endomyocardial biopsy is acute heart failure. Biopsy can help identify inflammation of the heart muscle and, if present, whether it’s viral or some other infectious-type myocarditis, or if it’s noninfectious. That will largely tailor therapy in the ensuing weeks. Giant cell myocarditis, for example, tends to be treated with immunosuppressive therapies, “to try to calm the waters, so to speak, so that a heart can start functioning a little bit better again,” says Dr. Maleszewski. Some patients will recover, but others will require a ventricular assist device, either as a destination therapy or as a bridge to eventual transplantation.

In other cases, patients may be taking drugs that affect the heart, such as chemotherapeutics or those targeting connective tissue diseases (most commonly lupus). When such patients present with a poorly functioning heart, an endomyocardial biopsy can be used to see if histopathologic changes are in line with a drug-mediated toxicity.

The remaining area where endomyocardial biopsies are done in the nontransplant setting is when patients present with what appears to be unexplained, possibly chronic cardiac dysfunction. It could be a cardiomyopathy or a primary disease of the heart muscle, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic cardiomyopathy. Endomyocardial biopsy’s role here is somewhat limited, according to Dr. Maleszewski, as the findings are fairly nonspecific.

Nevertheless, when there’s the possibility of a storage disease or underlying genetic disease, an endomyocardial biopsy “makes a lot of sense,” he continues, because findings on storage diseases tend to be more specific. Fabry disease can mimic hypertrophic cardiomyopathy. The two diseases are said to be phenocopies of one another, he says, looking the same from both an imaging standpoint and from cardiac function behavior. “But the endomyocardial biopsy will reveal a very different picture.”

Just as the role of endomyocardial biopsy can be divided into post-transplant and nontransplant settings, it can also be divided into U.S. and European camps.

The European Society of Cardiology’s Working Group on Myocardial and Pericardial Diseases recommends widespread use of biopsy for patients with suspected myocarditis, notes Dr. Cooper. Its current scientific statement includes a recommendation to biopsy people with nonischemic primary heart muscle disease, regardless of whether they present with chest pain, heart failure, or arrhythmia-type syndrome. This approach is based on data generated in Europe, he says.
U.S. scientific opinion, on the other hand, expressed in guidelines published in 2007 and 2013, steers physicians toward a more limited use. Two clinical scenarios, based on class 1 evidence, have emerged, says Dr. Cooper:

• heart failure of less than two weeks duration, associated with diminished heart function and requiring inotropic or mechanical circulatory support. “That’s the clinical scenario of fulminant myocarditis,” Dr. Cooper explains. A biopsy may diagnose a rare disease; in some cases, such as lymphocytic myocarditis, the prognosis is good, and patients can avoid a transplant.
• heart failure with a dilated ventricle of two weeks to three months, if it’s associated with one of three clinical scenarios that would suggest giant cell myocarditis.

Beyond that, says Dr. Cooper, indications for endomyocardial biopsy are supported by class 2A or 2B evidence. In other words, “They may be or are probably helpful, or possibly helpful.”

The literature supports an important role for endomyocardial biopsy in a number of niche situations that fail to respond to usual care, says Dr. Cooper. The real clinical standard, of course, is whether the diagnosis changes management.

In an academic cardiology practice such as his, those scenarios affect 10 to 15 percent of patients, he says. For the other roughly 85 percent who are potential biopsy patients, “Insurance in the United States may not cover the cost of a biopsy, and the out-of-pocket costs would usually be a significant impediment to getting the procedure.”

Such situations call into relief the differences between European and U.S. approaches. Guidelines in Europe “don’t account for the reality that we have vastly different payer systems,” says Dr. Cooper.

Physicians at Berlin’s Institute of Cardiac Diagnostics and Therapy (IKDT), for example, might argue that patients with inflammatory cardiomyopathy should receive interferon beta, but U.S. insurers won’t pay for its use in cases of viral cardiomyopathy. “I’ve been through this often with insurers,” Dr. Cooper says.

But in other cases, an endomyocardial biopsy can be absolutely critical, given evolving treatments. With giant cell myocarditis, use of calcineurin inhibitor-based therapy has moved the needle dramatically. “We have gone from a 90 percent rate of death for transplant to a 90 percent survival rate in the last 20 years,” Dr. Cooper reports. “There are dozens or hundreds of people alive today without a heart transplant, based on that therapy. That’s a great example of when a biopsy will make a life-changing difference.”

Data are less strong, but still solid, for cardiac sarcoid, which generally in the acute setting responds to immunosuppressive therapy in addition to guideline-directed therapy. “And you can decrease the risk of death from transplant in all likelihood in that setting,” Dr. Cooper says.

Finally, there’s chronic dilated cardiomyopathy. Patients can be put on guideline-directed therapy, but they will continue to decline, Dr. Cooper says. In that setting, the European guideline supports performing an endomyocardial biopsy for viral genome analysis and an immunoperoxidase stain to guide either immunosuppression or antiviral strategy. Dr. Cooper says there’s enough evidence to make that a valid therapy, but few in the United States are following this path right now. While he’d like to see his U.S. colleagues consider viral genome analysis, “That’s a cost that’s simply absorbed by the medical institution sending the sample”—and it’s hardly the cheapest bottle of wine, so to speak, on the menu.

At IKDT, “We only look at endomyocardial biopsies,” says Dr. Schultheiss, who estimates they see biopsies of 1,500 to 2,000 patients a year, including from the United States.

The lab he founded is funded on several fronts: Charité, industry, and groups such as the German Research Foundation. He’s quite sympathetic to institutions that may not have similar support. “At the end of the day, you must earn money,” he concedes. Both he and Dr. Cooper think it would be helpful to establish a few specialty centers in the United States, for reasons of cost and expertise. It’s possible his lab will collaborate with a U.S.-based lab, Dr. Schultheiss says. “But this is a work in progress. It’s too early to talk about that.”

What has his experience taught him about endomyocardial biopsies?

Most well-trained pathologists can perform histology on endomyocardial biopsies to determine whether there is an acute myocarditis, says Dr. Schultheiss. The problem is the next step: immune histology to determine whether the patient has a chronic inflammatory or a chronic viral disease. Distinguishing between different types of infiltrating cells appears to be important, he says. “You have to quantify all the cells, and you need 10 slices of biopsy for that.” Based on an analysis he and his colleagues performed, a low number—2.9 cells per square millimeter—of cytotoxic T cells (perforin positive) was consistent with a significantly bad prognosis. But with T-memory cells, the number needs to be much higher—> 60 cells/mm2—to indicate poor prognosis. “If we see that somebody has four or five cytotoxic T cells, it’s no question anymore that these patients have to be treated immediately by immune-suppressive agents.”

While prospective randomized studies are lacking, Dr. Schultheiss and his colleagues recently submitted for publication a study showing that in about 120 patients treated with immune suppression, 80 to 90 percent improved significantly.

Dr. Schultheiss sees a clear message in work like this: The earlier patients are treated, the better the prognosis. That, in his view, is a call to do endomyocardial biopsy the same way Chicagoans used to vote: early and often. When patients are treated when their ejection fraction is about 20 percent, he notes, they already have a considerable amount of fibrous tissue in the biopsy. But a patient whose treatment begins when their ejection fraction is, say, 50 percent, has had disease only a short time and will not have fibrous tissue.

“We think that you shouldn’t wait until we have a classical severe dilated cardiomyopathy,” he says. Instead, “We should start thinking about making a clear-cut diagnosis when especially young patients have myocarditis or suddenly have an ejection fraction which is no longer normal. We shouldn’t wait until it’s 30 or 20.” While it’s true some patients will improve spontaneously, Dr. Schultheiss says, close monitoring is essential. And if spontaneous improvement doesn’t occur within several months, chance of improvement then becomes quite small. “There is real progression in a certain percentage of patients.”

In addition to distinguishing between infiltrative cells, Dr. Schultheiss and colleagues look for different types of macrophages. “We look for adhesion molecules, which is very informative. You often see a very high expression of adhesion molecules, but you don’t see the cells.” Pathologists must then think about whether that indicates a sampling error has occurred (not a rare occurrence, says Dr. Schultheiss) and whether a second biopsy might be needed.

Amyloidosis presents its own challenges. Dr. Schultheiss notes that his lab sees many cases of apparent hypertrophic cardiomyopathy—a diagnosis many physicians will then simply assume is a classic case of the genetic form of the disease. But the picture might be more complex. “If you take an endomyocardial biopsy, you are surprised how often you see amyloidosis or Fabry disease, which you can then probably treat.” In early stages of hypertrophic cardiomyopathy, when the wall thickness is neither normal nor extremely thick, Dr. Schultheiss says, it thus makes sense to do the biopsy.

“It’s taken us a long time to learn that there’s a relatively high percentage of so-called hypertrophic cardiomyopathies that are actually something else,” he says. “People are finally recognizing this is a problem.”

Based on the work being done at IKDT, he says, it also appears that knowing the genetic profile early is important. “So now, if we get biopsies from patients with acute myocarditis, we routinely analyze the genetic profile, even if at that time we don’t know whether we see giant cells and so on in the biopsies. We start immediately with the genetic profiling.” Dr. Schultheiss says he and his colleagues can identify giant cell myocarditis with a high degree of accuracy—something histology does not do—and that there’s evidence such early detection improves patient care. “This, for me, is a real step forward regarding these acute forms of myocarditis.”

Even as physicians consider an expanded role for endomyocardial biopsy, they remain frustrated by lingering doubts about the procedure’s risks. The main problem with endomyocardial biopsies, says Dr. Schultheiss, is “finding doctors who are willing to do them. They think the technical aspect of taking biopsies is difficult.”

Endomyocardial biopsies are operator dependent, Dr. Cooper says. They’re also equipment-dependent. With the Stanford-Caves bioptome—the most common type—risk of death is one in 1,000; risk of cardiac perforation, one in 250. In the United States, overall risk of any complication is six percent for right ventricular biopsy; left ventricular carries a risk of stroke (one in 300), so these are rarely done in this country. (In Europe, Dr. Cooper notes, the bioptomes are much smaller and more flexible, and thus have lower risks for right and left ventricular biopsies.) The biopsy is performed under fluoroscopic guidance.

Says Dr. Cooper: “The short answer is, it’s less risky than a standard coronary angiogram.”

For pathologists, concerns about the procedure turn on whether they’re prepared to handle specimens.

Ideally, cardiologists would give the pathologist a heads-up before doing an endomyocardial biopsy, giving the pathologist ample time to make sure the cath lab has the appropriate media to fix the specimen, or even to reach out to a larger center with subspecialty knowledge for guidance. Says Dr. Maleszewski: “Having all those pieces in place, and knowing the plan upfront, is infinitely better than the pathologists hearing, ‘Hey, we just did this biopsy—now what do we do?’ What we’re trying to avoid is finding out the questions after everything’s been processed.”

If, for example, a drug-mediated toxicity is a possibility, pathologists will need one portion of the biopsy placed in glutaraldehyde, which will allow the pathologist to do an ultrastructural evaluation.

Another challenge is the processing time. Since some clinical situations are dire, pathologists might need to turn specimens around quickly. “To do so, we really need a good understanding of what the clinical question is upfront,” says Dr. Maleszewski, “so we can order all the ancillary studies we’ll need right at the outset.”

If the question hinges on myocarditis, “We’re going to want to make sure that we put all of that up for light microscopy,” Dr. Maleszewski says. Pathologists typically won’t do ultrastructural analysis if the question is one of myocarditis in the acute heart failure-type setting. “And we’re going to want to get a lot of levels through the tissues.” In cases where cardiomyopathy or storage disease might be the culprit, this may not be necessary, because the process itself is believed to be more diffuse and likely present in all the levels being examined.

If there’s a possibility of a disease like hemochromatosis, the pathologist will order an iron stain upfront. And if amyloidosis or another infiltrative process—if the patient presents with restrictive hemodynamics or restrictive physiology, say—is a consideration, “knowing that will allow us to order stains for amyloid upfront.”

Dr. Cooper agrees that pathologists need to be kept in the loop. He recalls a patient with lupus who was taking Plaquenil. Lupus can cause myocarditis; Plaquenil causes a noninflammatory cardiomyopathy that looks identical clinically to myocarditis. The only way to distinguish between the two is with an endomyocardial biopsy. “So I called the pathologist and the cath lab to make sure they had glutaraldehyde in the room to properly fix the specimens.”

At his institution, says Dr. Maleszewski, requisition slips reflect all the clinical questions that need to be answered, allowing clinicians to check every item in their differential diagnosis. When specimens arrive in accessioning, the accessioner contacts the on-call cardiovascular pathologist. “We listen to what the clinicians think might be the clinical scenario. It allows for efficient handling of these specimens in a way that’s clinically useful.”

Not every hospital has a team of cardiovascular pathologists at the ready. “Cardiac pathology is a small to almost nonexistent part of a community pathologist’s practice,” says Spectrum Health’s Dr. Cohle. Even in his practice, an active transplant center with 30 to 40 cardiologists, the diagnostic biopsies aren’t common. “If you don’t see many of these, it’s probably better to consult a cardiovascular pathologist,” he says.

Dr. Cooper sees two limitations in community pathology. First, the routine and special stains needed to assess tissue may be too expensive for labs to maintain if they do endomyocardial biopsies only rarely.

Secondly, he says, in rarer forms of myocarditis, such as giant cell, labs that encounter one case every decade or so might miss making the correct diagnosis. “It’s not always straightforward,” Dr. Cooper says. “There are subtle differences between cases that could lead to a different diagnosis, which could be the decision between doing a heart transplant or not.” For those reasons, Dr. Cooper strongly recommends that heart biopsies be over-read by cardiac pathologists who regularly see the rare inflammatory cardiomyopathies.

“You need enough volume to be competent,” agrees Dr. Cohle. “It’s like anything else in pathology.”

That doesn’t pull community pathologists out of the picture, however.

Most pathologists will have much of what they need to handle endomyocardial biopsies upfront, Dr. Maleszewski says. “It’s just going to be routine, like microscopy, in a lot of cases.” If the lab doesn’t have access to ancillary studies, they can send formalin-fixed, paraffin-embedded specimens to a larger academic center.

For community practitioners, says Dr. Maleszewski, “The clinical story is key, and that will largely direct whether a piece needs to be held back for endomyocardial biopsy. Apart from that, if they embed the tissue in wax, the way that they would any other case, and they’re careful about sectioning, most everything we’ll need to do can be done on that paraffin.”

All of this involves communication, regardless of where the pathologist practices. “If I’m aware of a particular concern that my clinical colleagues have about a disease or a type of rejection,” says Dr. Cohle, “then I’ll know to look for that.” If a nontransplant patient is in heart failure and has multiple myeloma, for example, there’s a strong association between that disease and amyloidosis.

But there’s also the challenge of separating amyloid from simply interstitial fibrosis, Dr. Cohle continues. Knowing whether the clinical scenario involves longstanding hypertension, multiple myeloma, or a family history of amyloidosis—“We have such a family in Grand Rapids,” Dr. Cohle says—can help pathologists look. “I would like to think I could find the amyloid without the clinical hint, but I don’t want to take a chance.”

Talking to pathologists isn’t a luxury; it’s a necessity, Dr. Cooper adds. “Are you looking for amyloid? Because if you are, and you find it, you need to go to the next step, which may be tandem mass spectrometry.”

Dr. Maleszewski couldn’t agree more. “I strongly encourage very tight working relationships between pathologists and clinical colleagues.” At Mayo, he says, “I couldn’t do my job if I wasn’t on the phone with my clinicians every day.” Dr. Maleszewski, it turns out, hates surprises even more than editors do. “I don’t want to feel like I’m going to be blindsided at any moment.”

Dr. Maleszewski knows he’s seeking this in a time of constrained resources. “But in the long run, such interactions are time saving and cost saving in their own right.” Even in the busiest of practices, he says, “some steps are reasonable and can be taken, like having a well-designed requisition that alerts the person to the relevant issues upfront. And it would pay dividends right away.”

As more testing becomes available, and as ancillary tests grow more sophisticated, Dr. Maleszewski predicts communication will become even more essential.

The newer generation of ancillary tests includes molecular genetic testing and proteomic-type testing. Dr. Maleszewski and his colleagues use the former to test for three broad categories: cardiomyopathies, collagen vascular, and heritable arrhythmias syndromes, or what are sometimes called channelopathies.

The heritable diseases, as he already noted, are difficult. When young adults die in these cases, molecular genetic testing is rarely done, which leaves families and physicians with an incomplete understanding of the cause of death. In such cases, there may be an assumption a heritable arrhythmia syndrome was involved, or a suspected cardiomyopathy, “but we don’t necessarily understand the gene that was implicated,” Dr. Maleszewski says.

With more widespread molecular genetic testing, pathologists should gain a better understanding of disease, how it’s transmitted and variably expressed within families, and how to treat it. “Because right now we’re really limited by the fact that not all the information that can be captured is being captured. Individuals aren’t evaluating the specific areas of the heart to exclude one phenotype versus another. Histology is not necessarily routinely being taken,” says Dr. Maleszewski. Some of these cardiomyopathies can affect one in 250 to one in 500. “We’re just starting to get the message out now” about the importance of understanding the molecular genetics of these cases.

Similarly, he notes, “It’s not uncommon for patients to be followed for years with a diagnosis of hypertrophic cardiomyopathy, only to have that diagnosis overturned by a pathologist who looks at the muscle under the microscope and recognizes a storage disease. That patient will need to be treated differently; the family will need to be followed differently. It has huge implications.”

Testing surviving members is quite difficult without knowing whether the deceased had the same genetic variant. Driven by that conundrum, Mayo has developed a test that will enable genetic testing on tissue obtained from an autopsy and archived. Most medical examiners and coroners tend to keep formalin-fixed, paraffin-embedded tissue for years if not decades, he notes, “and we can now go back and interrogate those.”

Dr. Schultheiss is also keenly interested in genetic profiling. Is progression associated only with mutations, or is an associated inflammatory process also the culprit? “Nobody’s looked at that yet,” Dr. Schultheiss says. “So far, the genetics people have only looked for genetics, and the people analyzing endomyocardial biopsies only look at endomyocardial biopsies,” although he reports that his lab and U.S. colleagues will soon be embarking on a 1,000-
patient study to assess how multiple factors might overlap.

Viral testing is now being done more regularly on cases of myocarditis, though it’s still not widespread, says Dr. Maleszewski. In the next five or so years, he predicts, physicians will have a far better appreciation for what types of viral settings, and perhaps what host-mediated factors, cause myocarditis.

In the past, says Dr. Schultheiss, physicians primarily looked for, and found, coxsackievirus and adenovirus in myocardial biopsies. The former accounts for five to 10 percent of patients with viral infections, while the latter is present in about five percent.

The main virus of clinical significance, he continues, is parvovirus B19. “The problem here is it’s hard to say at what point in time it’s relevant,” Dr. Schultheiss says. The virus doesn’t infect myocytes; the primary location of infection is bone marrow. Endothelial cells from the bone marrow then disturb the regeneration of endothelium in the myocardium. Perhaps, Dr. Schultheiss suggests, for patients with parvovirus B19, the first clinical symptom is atypical angina. He and his colleagues have shown that those patients exhibit rarefication of the capillary density, which can end up in the typical clinical picture of a dilated cardiomyopathy. “That is a completely different mechanism than if you have a coxsackievirus infection.”

To determine which patients might be at risk, pathologists need to determine not only viral load in the endomyocardial biopsy, but replicative activity, which can be detected by mRNA and is associated with inflammation. Dr. Schultheiss says his lab routinely looks for parvovirus B19 load, mRNA, and associated inflammation. “This is clinically important and has a consequence,” he says. “If we only find parvovirus load, without replication, without inflammation, it doesn’t play any role regarding the pathophysiology.”

In such cases, the genetic profile is normal, he continues. But in patients with replicative activity and inflammation, the genetic profile is pathological: this occurs in about five to 12 percent of patients. Not every patient, in other words, who is parvovirus positive has a pathophysiologically important process going on.

The permutations seem endless, he concedes. “If you find the parvovirus, you have to make all these analyses to decide in the end whether that is clinically relevant or not,” he says with a laugh. The endomyocardial biopsy is only the first step. “Then it gets really complicated.”

For all his excitement at the work ahead, Dr. Schultheiss remains rooted in one principle: “We have to decide as early as possible which direction the disease will go.” The reason is simple, he says: “We shouldn’t wait too long before we start treating the patients.” He takes as his model the classic cardiological example of unstable angina. “We don’t wait until the assay says myocardial infarction before we start making coronary angiography,” he says. “I think it’s the same here—if we have a patient with the beginning of a cardiomyopathy, I think we have to have the information to decide, very early, which direction to go. It makes sense to take the biopsy as early as possible. We need to help the clinician make a clear decision as early as possible. That must be the main aim for the next years.”
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Karen Titus is CAP TODAY contributing editor and co-managing editor. Dr. Cooper recommends that patients and physicians use the Myocarditis Foundation (www.myocarditisfoundation.org) for support and up-to-date information.