—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 3 - Hypersensitivity Myocarditis

Bruce McManus
University of British Columbia
Vancouver, BC, Canada


Click on each slide thumbnail image for an enlarged view
Introduction
For the USCAP evening session, we describe a female patient who was admitted to hospital after several days of nausea and fever. After an initial examination, the patient was believed to have cardiac problems and an endomyocardial biopsy procedure was performed. Upon examination of the biopsy specimens, the patient was diagnosed as having hypersensitivity myocarditis, possibly caused by Chinese herbal medications. In addition to the clinical summary, in this paper we discuss the histopathology of hypersensitivity myocarditis, the causes and mechanisms of hypersensitivity, the global use of herbal medication and mechanisms of herbal bioactivation and toxicity.

Clinical Summary
A 54-year-old Chinese woman with a background history of hypothyroidism was admitted to a hospital emergency room with a three-day history of nausea, vomiting and fever. She had an asystolic arrest, but was resuscitated and went into ventricular tachycardia. She was found to be in cardiogenic shock and was taken to the catheterization laboratory where her ejection fraction was found to be 10-20%. Coronary artery contrast injections showed normal anatomy. An endomyocardial biopsy was taken and the patient was transferred to a second hospital – the regional heart centre – for consideration of heart transplantation.

Evaluation of the endomyocardial tissue revealed a prominent inflammatory cell infiltrate accompanied by readily indefinable myocyte injury and loss. The infiltrate was predominantly mononuclear in nature, although readily identifiable eosinophils were present in small numbers. Giant cells and granulomas were not identified. The inflammatory process was found to extend to, and include, the subendocardial tissues. No evidence of vasculitis or mesothelial cells was seen. A differential diagnosis of acute myocarditis was proposed. The presence of eosinophils raised, among other conditions, the possibility of hypersensitivity myocarditis. After consulting the cardiac pathologist, the attending cardiologist chose to treat the case as myocarditis of a hypersensitivity-type reaction.

The patient was treated with a range of vasoactive and anti-arrhythmic medications including dopamine, dobutamine, milrinone and Levophed. A Swan–Ganz catheter was inserted for hemodynamic monitoring. On suspicion of hypersensitivity myocarditis, boluses of Solu-Medrol 1000 mg were given three times.

Over the next 72 hours, the patient improved remarkably. The vasoactive drugs and a balloon pump were withdrawn and the patient was started on a beta blocker and transferred to the ward. At this time, she had hypotension and dizziness, despite an echocardiogram showing an ejection fraction of 65%. The patient's brain natriuretic peptide levels fell from 11,000 to 500 pg/ml: 195-230 pg/ml is the normal laboratory range for a female of this age category. The beta blocker was promptly discontinued.


Case 3 - Figure 1 -
Hematoxylin and eosin stained slide of the endomyocardial biopsy showing the general architecture of the tissue and the extent of the interstitial and endocardial inflammatory infiltrate. (X10)
Case 3 - Figure 2 -
Higher magnification of the same area as in Figure 1 showing a percolating, largely mononuclear cell infiltrate with some distortion of architecture and focal myocyte damage. (X40)
Case 3 - Figure 3 -
An image of the same biopsy piece showing how the infiltrate involves the endocardium. Focal fibrosis is noted. (X40)



Case 3 - Figure 4 -
Hematoxylin and eosin stained slide of a second biopsy piece showing an area of infiltration by mature adipocytes. Inflammation is noted nearby. (X10)
Case 3 - Figure 5 -
A second view of the second biopsy piece shows the extent of neighboring myocarditis. (X10)
Case 3 - Figure 6 -
Higher magnification of the same area shows features similar to those in the other biopsy piece, emphasizing architectural disruption, numerous macrophages, some lymphocytes and occasional eosinophils. (X40)



Case 3 - Figure 7 -
A higher power of the second piece showing similar features as in Figure 6. (X40)
Case 3 - Figure 8 -
A higher magnification of the second piece showing the infiltrate and occasional apoptotic bodies. (X40)



Case 3 - Figure 9 -
Full view of the biopsy showing the inflammatory process and fatty accumulation. (X10)
Case 3 - Figure 10 -
A fourth piece of the biopsy showing prominent endocardial inflammation including many lymphocytes. Occasional eosinophils are


Additional Clinical History
The patient was referred to a clinical allergist/immunologist for consultation. The allergist recorded a long list of Chinese herbal medications taken by the patient including a concoction of several herbs- Tong Xin Luo Jiaonang. Based upon subsequent examinations, the allergist agreed that the myocarditic episode was likely due to hypersensitivity myocarditis possibly related to an ingredient in one of the Chinese herbal medications, and the patient was asked to stop taking the medication. The patient was discharged from the heart centre 11 days after admission, having resolved any evidence of heart failure.

Diagnosis
Based on the histopathology of endomyocardial biopsy specimen, especially the inflammatory cell infiltrate predominated by mononuclear cells, a differential diagnosis includes virus-induced myocarditis, although other etiologies are associated with such an infiltrate. The readily identifiable eosinophils and absence of giant cells, narrow the spectrum of diagnoses to a condition that is of a parasitic, hypersensitive or hypereosinophilic nature. The response of this patient to prednisone indirectly narrows the final diagnosis to hypersensitivity myocarditis.

Hypersensitivity Myocarditis - Histopathology
Myocarditis associated with drug therapy was first recognized by French and Weller who reported it in association with sulfonamide administration [1]. Morphologically, hypersensitivity myocarditis (HM) is characterized by lesions of similar morphology involving the myocardium of all four cardiac chambers [2], [3]. Microscopically, there is a patchy interstitial inflammatory infiltrate typically consisting of eosinophils and mononuclear cells, particularly lymphocytes, as well as occasional plasma cells. The cellular infiltrate may be focal or diffuse and is most prominent interstitially. Myocyte necrosis is not a prominent feature of HM, but occasional degenerative myocytes may be seen at the margins of the infiltrate [4]. While giant cells and ill-formed granulomas may be present, granulation tissue and replacement fibrosis are typically absent. Lesions appear to be of the same age [3, 4] .

The time from initial drug exposure to the development of hypersensitivity myocarditis may vary from hours to months. Many drug categories are known to be associated with HM including methyldopa, sulfonamides, penicillins, streptomycin, and tetracyclines, among others [5]. More recently, there have been reports of HM following tetanus vaccination [6], use of herbal medication Ma Huang (Ephedra-based) [7], and clozapine (anti-psychotic) [8, 9] . While it is difficult to establish an incidence of HM in the general population, there is a growing literature of incidence rates of HM among heart transplant candidates. Many reports of HM in explanted hearts have put this particular incidence rate between 2.4% – 7.2% [10].

Drug Hypersensitivity – Mechanisms and Genetics
Hypersensitive drug reactions are currently explained by the hapten and pro-hapten models. Chemically reactive small compounds (haptens) bind to proteins or peptides and modify them. These are then processed and presented as hapten-modified peptides to T cells, which can react to them [11]. Due to a delayed-type hypersensitivity response, T lymphocytes are activated and liberate eosinophil-stimulating cytokines such as IL-5 [12]. Pro-haptens need to undergo an intermediate metabolic step to become chemically active haptens [13].

Recently, the p-i concept -'direct pharmacological interaction of drugs with immune receptors'- has been put forth to elaborate on the pharmacologic interaction of drugs with immune receptors [14]. The p-i concept proposes that under certain conditions: 1) a drug–T-cell interaction may lead to an immune response with the drug-T-cell combination fitting into a T-cell receptor and 2) the interaction of the T-cell receptor with an MHC molecule. In this mechanism, 1 + 2 will result in an exclusive T-cell stimulation and a hypersensitivity reaction [14].

Genetic factors are also thought to play an important role in drug hypersensitivity. Recent data has shown an association between HLA-class 1 alleles and the HIV-1 reverse-transcriptase inhibitor abacavir. The drug has shown to affect multiple organs in approximately 5% of treated patients wherein the majority carried the HLA-B57 allele. This association was strongest among Australian Caucasians [15]. Others have shown an association between carbamazepine and Stevens Johnson syndrome among Han Chinese carrying HLA-B*1502 [16], allopurinol for treatment of gout and hyperuricemia among Han Chinese carrying HLA-B*5801 [17], and nevirapine (non-nucleoside reverse transcriptase inhibitor for HIV treatment) among a predominantly Caucasian cohort carrying the HLA-DRB1*0101 allele [18].

Herbal Medications
Many cultures have used plants and herbs for healing and therapeutic purposes throughout history. Written records about medicinal plants date back at least 5000 years to the Sumerians [19]. Archaeological analysis of Bronze Age gardens in Britain point to use of plants for medicinal and ritualistic purposes - a possible pivotal function in social structure [20]. In China, traditional Chinese medicine (TCM) has been used for centuries. The first fundamental textbook on TCM was completed around 200 BC and describes the theory and philosophy of TCM and the therapeutic benefits of herbal medicines [21]. In addition to the human use of herbs and plants for therapeutic purposes, non-human primates have been observed to use specific plants with medicinal properties for the treatment and prevention of disease – termed 'zoopharmacognosy' [22]. For example, the common chimpanzee has been observed to swallow leaves of Aspilia and 18 other species of plants to expel intestinal worms [23].

In Western society, herbal medications have increased in popularity. By the late 1990's the herbal industry in North America was estimated to be a $3 billion per year enterprise [24]. During this time-period, surveys of alternative medicine use in the United States indicate widespread use of herbal medications and estimate that three out of 10 Americans use botanical remedies in a given year [25], however this statistic varies greatly among authors. The demand for dietary supplements is believed to be driven by a variety of factors including an aging population with disposable income, a growing trend to self-medicate, and an overall perception that natural is healthy and, in turn, plants and herbs as medication are also safe if not effective [25].

Despite the growing popularity of herbal medications, there is a growing body of literature on their side-effects. Herbal medications are known to cause allergic and toxic reactions [7, 26] , mutagenic effects, and drug-herb interaction [27, 28] . Herbal medications themselves are subject to adulteration, substitution, contamination, misidentification and lack of standardization [27, 29] . These latter points are at the heart of a growing debate surrounding safety, quality control, and marketing of herbal medications and supplements: while both prescription and over-the-counter drugs require stringent examination before being made available, herbal preparation are usually marketed as dietary supplements and thus avoid this scrutiny [30].

Herbal Medications – Bioactivation and Toxicity
Herbal medications are readily used to treat a wide variety of conditions. Common pharmacological effects provided by herbal medications include: activation of cell-mediated immunity, inhibition of platelet aggregation, antihypertensive activity, a decrease in blood glucose, inhibition of neurotransmitter reuptake, and sedation among other effects [30]. However, while readily used, little is known about the composition of herbal extracts [31] or the mechanisms by which these herbal medications work.

Recently, there has been an increasing application of genomic approaches to examine the responses to herbal medicines. For example, using GeneChip microarray analysis of in vivo and in vitro responses to Ginko biloba leaf (used to improve blood flow), several differentially expressed genes have been hierarchically grouped into those for transcription factors, heat shock proteins, antioxidants, mitochondrial proteins, cell cycle regulators, and transcripts for DNA repair enzymes [31, 32] . Such genomic approaches may offer a way to define and predict pharmacological activity of herbal medicines.

However, the use of herbal medicines is made more complicated by the additional synergisms that are introduced when the herbs are used in combination as practiced in TCM [25]. Recently, one study has attempted to investigate the pharmacokinetic interaction of paeoniflorin and sinomenine – two herbs believed to have synergic effects in treating arthritis in TCM [33]. In rat models, it was found that sinomenine elevates the plasma concentration of paeoniflorin, and thus improves the bioavailability of paeoniflorin.

In summary, while herbal medicines are used therapeutically, the quantity of data regarding their toxicity is extensive. Herbal/dietary constituents are believed to be metabolized by human cytochrome P450 (CYP) system to nontoxic metabolites and excreted, however the formation of toxic metabolites is also possible [27]. It has been hypothesized that resultant reactive metabolites following herbal bioactivation covalently bind to cellular proteins and DNA leading to toxicity via mechanisms such as cytotoxicity, oncogene activation and hypersensitivity reactions [27]. Herbal use has been associate with organ toxicities in the heart, liver, blood, kidneys, central nervous system, and skin [7, 28] , [27]. The current patient appears to illustrate such profound, yet reversible toxicity.

Acknowledgments
Lise Matzke MSc and Mike Allard MD provided invaluable expertise and time to the preparation of this presentation. I thank them both.

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