Targeting cardiac fibrosis with engineered T cells.

Fibrosis is observed in nearly every form of myocardial disease1. Upon injury, cardiac fibroblasts in the heart begin to remodel the myocardium by depositing excess extracellular matrix, resulting in increased stiffness and reduced compliance of the tissue. Excessive cardiac fibrosis is an important factor in the progression of various forms of cardiac disease and heart failure2. However, clinical interventions and therapies that target fibrosis remain limited3. Here we demonstrate the efficacy of redirected T cell immunotherapy to specifically target pathological cardiac fibrosis in mice. We find that cardiac fibroblasts that express a xenogeneic antigen can be effectively targeted and ablated by adoptive transfer of antigen-specific CD8+ T cells. Through expression analysis of the gene signatures of cardiac fibroblasts obtained from healthy and diseased human hearts, we identify an endogenous target of cardiac fibroblasts-fibroblast activation protein. Adoptive transfer of T cells that express a chimeric antigen receptor against fibroblast activation protein results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice. These results provide proof-of-principle for the development of immunotherapeutic drugs for the treatment of cardiac disease.

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review.

Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

Innate Immunity Effector Cells as Inflammatory Drivers of Cardiac Fibrosis.

Despite relevant advances made in therapies for cardiovascular diseases (CVDs), they still represent the first cause of death worldwide. Cardiac fibrosis and excessive extracellular matrix (ECM) remodeling are common end-organ features in diseased hearts, leading to tissue stiffness, impaired myocardial functional, and progression to heart failure. Although fibrosis has been largely recognized to accompany and complicate various CVDs, events and mechanisms driving and governing fibrosis are still not entirely elucidated, and clinical interventions targeting cardiac fibrosis are not yet available. Immune cell types, both from innate and adaptive immunity, are involved not just in the classical response to pathogens, but they take an active part in "sterile" inflammation, in response to ischemia and other forms of injury. In this context, different cell types infiltrate the injured heart and release distinct pro-inflammatory cytokines that initiate the fibrotic response by triggering myofibroblast activation. The complex interplay between immune cells, fibroblasts, and other non-immune/host-derived cells is now considered as the major driving force of cardiac fibrosis. Here, we review and discuss the contribution of inflammatory cells of innate immunity, including neutrophils, macrophages, natural killer cells, eosinophils and mast cells, in modulating the myocardial microenvironment, by orchestrating the fibrogenic process in response to tissue injury. A better understanding of the time frame, sequences of events during immune cells infiltration, and their action in the injured inflammatory heart environment, may provide a rationale to design new and more efficacious therapeutic interventions to reduce cardiac fibrosis.

Temporal Frame of Immune Cell Infiltration during Heart Failure Establishment: Lessons from Animal Models.

Heart failure (HF) is a cardiovascular syndrome characterized by maladaptive changes with an underlying inflammatory mediated pathogenesis. Nevertheless, current therapy is aimed at the heart workload and neurohormonal axis; thus, prognosis remains poor. To continue improving treatment, we rely on murine models for a better understanding of HF pathophysiology. Among them, pressure overload HF (PO-HF) animal models are a common strategy. Development of PO-HF is characterized by monocyte infiltration, which orchestrates a cascade of events leading to sustained inflammation and maladaptive changes. Here, we divide the PO-HF model progression into four phases and describe the inflammatory, structural, and gene expression profiles. This division is relevant due to its similarities with clinical hypertensive heart disease progression to HF. Evidence shows improvement in hemodynamic and other local parameters by altering the inflammatory response in a specific immune response at a specific point of time. Thus, it is relevant to focus on the time-dependent immune response interaction in order to provide more effective therapy. This review summarizes the pathogenesis of PO-HF murine models, highlighting the inflammatory events in a time frame view. By this approach, we expect to provide researchers with a better understanding of the intertwining time-dependent events that occur in PO-HF.

Deferiprone attenuates inflammation and myocardial fibrosis in diabetic cardiomyopathy rats.

We attempted to investigate the therapeutic effects of deferiprone on DC rats and explore the underlying mechanism. Total 24 6-week-old male Wistar rats (weighing from 180 g to 220 g) were subjected to DC model construction and then randomly divided to three groups (8 rats per group): DC group, DC + 50 mg, and DC + 100 mg deferiprone treatment group. The 8 normal rats were considered as controls. After deferiprone treatment for 20 weeks, the blood samples were collected for the biochemical parameters test, including fasting glucose, HOMA-IR (homeostasis model assessment of the insulin resistance), serum iron, ferritin and transferrin saturation (TS). The oxidative stress was assessed by detecting the level of malondialdehyde (MDA) and superoxide dismutase (SOD). Histopathologic changes were determined by Masson's trichrome staining and electron microscopy imaging. The expression levels of NF-κB (nuclear factor kappa B), COX2 (cytochrome c oxidase), tenascin C, collagen IV were measured by RT-PCR and western blotting. The expression of nitrotyrosine and MCP-1 (monocyte chemotactic protein 1) were determined by immunohistochemistry. Deferiprone treatment reduced iron deposition and IR in DC rats except for blood glucose. After deferiprone treatment, MDA level was significantly decreased and SOD level was increased significantly. The level of NF-κB, cyclooxygenase-2, tenascin C, collagen IV MCP-1 and nitrotyrosine were significantly reduced. There was no significant difference in the effect of deferiprone at 50 and 100 mg doses. Deferiprone showed therapeutic effects on DC by regulating the pro-inflammatory and pro-fibrotic factors.

[Intervention effect of quercetin on inflammatory secretion of cardiac fibroblasts].

To establish neonatal rat cardiac fibroblast inflammatory secretion model by using LPS 100 microg x L(-1) combined with ATP 5 mmol x L(-1), in order to study the inhibitory effect of quercetin on the secretion of inflammatory factors TNF-alpha, IL-1beta and IL-6 of cardiac fibroblasts, further investigate the effect of quercetin on the protein expression of p-NF-kappaB p65 (S276) and p-Akt (S473) by western blot, and discuss the inhibitory effect of quercetin on the inflammatory secretion of cardiac fibroblasts. According to the findings, quercetin with the concentrations between 51.74 micromol x L(-1) and 827.81 micromol x L(-1) had no significant effect on the activity of cardiac fibroblasts. Quercetin with the concentrations of 82.78, 41.39, 20.70 micromol x L(-1) could notably inhibit the increase of TNF-alpha and IL-1beta induced by LPS 100 microg x L(-1) for 3 h and then ATP 5 mmol x L(-1) for 36 h (P < 0.01 or P < 0.05). Quercetin with the concentrations of 82.78, 41.39 micromol x L(-1) could notably inhibit the increase of IL-6 induced LPS 100 microg x L(-1) for 3 h and then ATP 5 mmol x L(-1) for 36 h (P < 0.05), without any notable effect of quercetin with the concentration of 20.70 micromol x L(-1). Quercetin with the concentrations of 82.78, 41.39, 20. 70 micromol x L(-1) could notably inhibit the NF-kappaB p65 (S276) activation induced by LPS 100 microg x L(-1) for 3 h and then ATP 5 mmol x L(-1) for 15 min, with the most significant effect in 20.70 micromol x L(-1). Quercetin with the concentrations of 82.78, 41.39, 20.70 micromol x L(-1) could notably inhibit the increase of p-Akt(473) expression induced by LPS 100 microg x L(-1) for 3 h and then ATP 5 mmol x L(-1) for 240 min (P < 0.05). Therefore, this study believes that quercetin could attenuate the secretion of inflammatory factors TNF-alpha, IL-1beta and IL-6 of cardiac fibroblasts by inhibiting the activation of NF-kappaB p65 (S276) and Akt (473).

Cyclophilin A affects inflammation, virus elimination and myocardial fibrosis in coxsackievirus B3-induced myocarditis.

Extracellular cyclophilin A (CyPA) and its receptor Extracellular Matrix Metalloproteinase Inducer (EMMPRIN, CD147) modulate inflammatory processes beyond metalloproteinase (MMP) activity. Recently, we have shown that CyPA and CD147 are upregulated in patients with inflammatory cardiomyopathy. Here we investigate the role of CyPA and CD147 in murine coxsackievirus B3 (CVB3)-induced myocarditis. CVB3-infected CyPA(-/-) mice (129S6/SvEv) revealed a significantly reduced T-cell and macrophage recruitment at 8 days p.i. compared to wild-type mice. In A.BY/SnJ mice, treatment with the cyclophilin-inhibitor NIM811 was associated with a reduction of inflammatory lesions and MMP-9 expression but with enhanced virus replication 8 days p.i. At 28 days p.i. the extent of lesion areas was not affected bei NIM811, whereas the collagen content was reduced. Initiation of NIM811-treatment on day 12 (after an effective virus defense) resulted in an even more pronounced reduction of myocardial fibrosis. In conclusion, in CVB3-induced myocarditis CyPA is important for macrophage and T cell recruitment and effective virus defense and may represent a pharmacological target to modulate myocardial remodeling in myocarditis.

The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions.

BACKGROUND: Transgenic mice with cardiac-restricted overexpression of tumor necrosis factor (MHCsTNF mice) develop progressive myocardial fibrosis, diastolic dysfunction, and adverse cardiac remodeling. Insofar as tumor necrosis factor (TNF) does not directly stimulate fibroblast collagen synthesis, we asked whether TNF-induced fibrosis was mediated indirectly through interactions between mast cells and cardiac fibroblasts. METHODS AND RESULTS: Cardiac mast cell number increased 2 to 3 fold (P<0.001) in MHCsTNF mice compared with littermate controls. Outcrossing MHCsTNF mice with mast cell-deficient (c-kit(-/-)) mice showed that the 11-fold increase (P<0.001) in collagen volume fraction in MHCsTNF/c-kit(+/-) mice was abrogated in MHCsTNF/c-kit(-/-) mice, and that the leftward shifted left ventricular pressure-volume curve in the MHCsTNF/c-kit(+/-) mice was normalized in the MHCsTNF/c-kit(-/-) hearts. Furthermore, the increase in transforming growth factor ß1 and type I transforming growth factor ß receptor messenger RNA levels was significantly (P=0.03, P=0.01, respectively) attenuated in MHCsTNF/c-kit(-/-) when compared with MHCsTNF/c-kit(+/-) mice. Coculture of fibroblasts with mast cells resulted in enhanced α-smooth muscle actin expression, increased proliferation and collagen messenger RNA expression, and increased contraction of 3-dimensional collagen gels in MHCsTNF fibroblasts compared with littermate fibroblasts. The effects of mast cells were abrogated by type I transforming growth factor ß receptor antagonist NP-40208. CONCLUSIONS: These results suggest that increased mast cell density with resultant mast cell-cardiac fibroblast cross-talk is required for the development of myocardial fibrosis in inflammatory cardiomyopathy. Cardiac fibroblasts exposed to sustained inflammatory signaling exhibit an increased repertoire of profibrotic phenotypic responses in response to mast cell mediators.

In situ expression of regulatory cytokines by heart inflammatory cells in Chagas' disease patients with heart failure.

Chagas' disease is caused by the protozoan parasite Trypanosoma cruzi. The immune system plays an important role in the reduction of parasite load, but may also contribute to the development of lesions observed during the chronic phase of the disease. We analyzed cytokines produced by inflammatory heart cells in 21 autopsy samples obtained from patients with Chagas' disease divided according to the presence or absence of heart failure (HF). Left ventricular sections were analyzed by immunohistochemistry using antibodies against human IL-4, IFN-γ, TGF-ß, TNF-α, and NOS2. In situ mRNA expression was quantified by a Low Density Array. The number of IFN-γ-positive cells was significantly higher than IL-4 positive cells. TNF-α, TGF-ß and NOS2 were detected in 65%, 62% and 94% of samples respectively. There was an association between TNF-α-producing cells and the presence of HF. Subjects with HF presented higher levels of STAT4 mRNA, whereas FoxP3 and STAT6 levels were similar in the two groups. A Th1 cytokine pattern predominated in the cardiac inflammatory cell infiltrate of Chagas' disease patients associated with HF. High degree of fibrosis was associated with low NOS2 expression. These results support the idea that Th1 immune responses are involved in heart lesions of Chagas' disease patients.

CD69 limits the severity of cardiomyopathy after autoimmune myocarditis.

BACKGROUND: Experimental autoimmune myocarditis (EAM), a mouse model of post-infectious cardiomyopathy, reflects mechanisms of inflammatory cardiomyopathy in humans. EAM is characterized by an infiltration of inflammatory cells into the myocardium that can be followed by myocyte fibrosis, edema, and necrosis, leading to ventricular wall dysfunction and heart failure. Different data indicate that CD69 exerts an important immunoregulatory effect in vivo. However, the possible role of CD69 in autoimmune myocarditis has not been studied. METHODS AND RESULTS: We have explored the role of the leukocyte regulatory molecule CD69 in the inflammation that leads to cardiac dysfunction after myocardial injury in EAM. We have found that after induction of EAM, the draining lymph nodes from CD69-deficient mice developed an exacerbated Th17 inflammatory response, resulting in increases in the numbers of infiltrating leukocytes in the myocardium. In the chronic phase of EAM, transthoracic echocardiography revealed a significantly reduced left ventricular fractional shortening and a decreased ejection fraction in CD69-deficient mice, indicative of an impaired cardiac contractility. This condition was accompanied by a greater extent of myocardial fibrosis, an elevated number of sinus pauses on ECG, and an enhanced ratio of heart weight to body weight in CD69-/- mice. Moreover, both bone marrow transplantation and adoptive transfer of Th17 cells isolated from immunized CD69-/- mice with EAM into naive wild-type recipients reproduced the severity of the disease, demonstrating that CD69 exerts its function within the lymphocyte compartment. CONCLUSION: Our findings indicate that CD69 negatively regulates heart-specific Th17 responses, cardiac inflammation, and heart failure progression in EAM.

Atrial fibrillation and atrial fibrosis.

Atrial fibrillation (AF) is the most common arrhythmia in humans. It affects 5% of the population older than age 65 years and is projected to rise as the population ages. Experimental data from animal models of AF show that AF is associated with progressive structural and electrical remodeling of the atria. Atrial fibrosis alters atrial electrical conduction and excitability and provides a substrate for AF maintenance. However, whether fibrosis is causally related to AF or an epiphenomenon and the precise mechanisms underlying atrial fibrosis remain unclear. A variety of signaling systems involving angiotensin II and related mediators are centrally involved in atrial fibrosis. This article reviews the role that atrial fibrosis plays in AF, the mechanisms of atrial fibrosis, and emerging therapeutic approaches to AF aimed at attenuating atrial fibrosis.

T-cell regulation of fibroblasts and cardiac fibrosis.

Inflammation contributes to the development of heart failure (HF) through multiple mechanisms including regulating extracellular matrix (ECM) degradation and deposition. Interactions between cells in the myocardium orchestrates the magnitude and duration of inflammatory cell recruitment and ECM remodeling events associated with HF. More recently, studies have shown T-cells have signficant roles in post-MI wound healing. T-cell biology in HF illustrates the complexity of cross-talk between inflammatory cell types and resident fibroblasts. This review will focus on T-cell recruitment to the myocardium and T-cell specific factors that might influence cardiac wound healing and fibrosis in the heart with consideration of age and sex as important factors in T-cell activity.

Immunophenotypical pleomorphism expression in sudden cardiac death.

This study was undertaken to assess several histopathological and immunohistochemical markers regarding some lesional aspects of ischemically and hypoxically damaged myocardium in sudden cardiac death. Tissue samples of myocardium from 17 middle age and young patients with sudden cardiac death, following acute or chronic cardio(myo)pathies, were analyzed using standard HE stain and indirect tristadial ABC peroxidase immunohistochemical method, for a panel of 12 antibodies grouped in three categories: antibodies involved in programmed cell death (bcl-2, p53, Fas/CD95, Fas-L, bax, caspase 9), muscular markers (Myo-D1, myogenin, desmin, actin) and growth factor receptors (b-FGF, VEGF, NGF). Myogenin was more sensitive in identifying the ischemic perilesional myocardic fibers than Myo-D1, but less specific, while desmin had a greater sensitivity than myogenin and Myo-D1 taken separately, but with no specificity for myocardic fibers. Fas-L, caspase 9 and bax were expressed in more than 75% of cases in perilesional residual cardiomyocytes, correlating to each other (r = 0.45, respectively r = 0.6, p<0.05). b-FGF, VEGF and NGF had a focally variable expression in subendocardial and subepicardial cardiomyocytes and were statistically independent. Even if there was a polymorphic expression of antibodies in the studied batch, our findings indicate that some parameters (Fas-L, b-FGF, Myo-D1) might be independent markers for predicting sudden cardiac death in patients with previously damaged myocardium.

Proliferation in cardiac fibroblasts induced by ß1-adrenoceptor autoantibody and the underlying mechanisms.

Chronic sustained stimulation of ß-adrenoceptor is closely related to cardiac fibrosis which is bad for cardiac function. Growing evidence showed that the high prevalence of ß1-adrenoceptor autoantibody (ß1-AA) in the sera of patients with various types of cardiovascular diseases decreased cardiac function. In the current study, we demonstrated that ß1-AA impaired the cardiac function evaluated by echocardiography and that ß1-AA triggered cardiac fibrosis in terms of increased expression of α-smooth muscle actin as the marker of myofibroblast and collagen deposition in a passive ß1-AA immunized mice model during 16 weeks. Further, we showed that ß1-AA activated ß1-AR/cAMP/PKA pathway and promoted proliferation in primary cardiac fibroblasts through specific binding to ß1-AR but not to ß2-AR. Moreover, ß1-AA was also likely to promote proliferation in cardiac fibroblasts through activating p38MAPK and ERK1/2 as p38MAPK inhibitor SB203580 and ERK1/2 inhibitor PD98059 partially reversed the proliferative effect. The persistent activating signalling of PKA and P38MAPK in 1 h induced by ß1-AA was associated with lacking agonist-induced desensitization phenomena. The conditioned medium from ß1-AA-stimulated cardiac fibroblasts induced cardiomyocyte apoptosis, which indicated that ß1-AA changed the secretion of cardiac fibroblasts contributing to cardiac injury. These findings will contribute to our understanding of the pathological mechanisms of ß1-AA.

Cardiac fibrosis and inflammation: interaction with hemodynamic and hormonal factors.

It is generally admitted that the pathogenesis of perivascular and interstitial cardiac fibrosis involves the response to two types of stimuli: a hormonal one, mainly involving the renin-angiotensin-aldosterone system and the more recently described endothelin system, and a hemodynamic stimulus, particularly high blood pressure. We propose in the present review a third step which, although not exclusive, interacts with the hormonal and hemodynamic ones, and involves inflammatory mechanisms. Indeed, hypertension is invariably associated with inflammatory cell infiltration either in the intimal part of large vessels or in the adventitial region of arterioles. This has led us to hypothesize that arterial wall cells may trigger the initial communications attracting inflammatory cells to the perivascular region. In this paper, we review the proinflammatory intercellular communications as well as the intracellular signaling which confer an inflammatory phenotype to arteries. In this context, the profibrogenic and proinflammatory effects of hemodynamic overload and peptidergic systems such as angiotensin II and endothelin are considered. The study of the inflammatory process is not without interest, especially in view of the strong modulating effect of the inflammatory mediators both on the inflammatory process itself and on the fibrotic process. The principal and the most potent mediators are reviewed. Finally, the hypothesis that the inflammatory process could be in reality an immune specific process is suggested.

Serum immunoglobulins in children with cardiomyopathies.

Serum immunoglobulins G, A, M and E were determined in four groups of children, including 14 patients with dilated cardiomyopathy (DCM), 17 with endomyocardial fibrosis (EMF), 18 with rheumatic heart disease (RHD) and 35 age-matched controls, in an attempt to assess the role of infections in the aetiology of childhood cardiomyopathies. Mean IgA and IgM concentrations in all four groups were not significantly different. However, mean IgG concentrations were higher in patients with EMF (1729 mg/100 ml), DCM (1745 mg/100 ml) and RHD (1978 mg/100 ml) than in controls (1429 mg/100 ml), and in about 30% of these cardiac patients the levels were higher than the 97th percentile for controls. In addition, mean serum IgE was higher in EMF (3577 iu/ml) than in RHD (2814 iu/ml), DCH (1000 iu/ml) or controls (1666 iu/ml), and in 29% of the EMF patients serum IgE exceeded 6834 iu/ml, the 89th percentile for controls. Intestinal helminths and moderate eosinophilia (mean count, 10%) were detected in most of the EMF patients. These results suggest that some cases of EMF and DCM are, like RHD, complications of infections, and that intense helminth-induced anaphylaxis is a probable cause of cardiac damage in such cases of EMF.

Endomyocardial disease and eosinophilia.

The authors discuss the hypereosinophilic syndrome:incidence, terminology, cytotoxicity, clinical presentation and diagnosis, prognosis, and treatment, and they provide a literature review.

Degranulated eosinophils, eosinophil granule basic proteins and humoral factors in Nigerians with endomyocardial fibrosis.

The frequency of eosinophilia, degranulated eosinophils, and raised serum levels of eosinophil granule basic proteins was determined in ten Nigerians with EMF and fifteen normal controls matched for age and sex, and from the same environment and social background as the patients. Sera from the patients and control subjects were also examined for auto-antibodies, immune complexes, filaria antibodies and immunoglobulins. A mild eosinophilia was observed in four of the patients. The mean direct eosinophil count in the patients (0.407 +/- 0.14 X 10(9)/l) was, however, not significantly different from that of the control subjects (0.399 +/- 0.07 x 10(9)/l). Degranulated eosinophils were absent in the blood and bone marrow aspirates of the patients, and peripheral blood of the controls. It was also found that the mean concentration of eosinophil granule basic proteins (ECP/EPX) in the patients (0.278 +/- 0.1 micrograms/ml) was not significantly different from the mean value for the control subjects (0.371 +/- 0.1 micrograms/ml, P greater than 0.5). Serological studies using Brugia pahangi antigens failed to demonstrate filaria antibodies in the patients and the control subjects. Microfilaria were also absent in their peripheral blood films. Using the indirect immunofluorescent technique, anti-heart antibodies were not demonstrated in the sera of the EMF patients and control subjects. Five (50%) of the patients and four (30.7%) of the normal controls had immune complexes levels far in excess of the upper limit of normal. However, the mean concentration of immune complexes in the patients (16.35%) was not significantly different from the value for control subjects (12.13%, P greater than 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Helminthiasis, the hypereosinophilic syndrome and endomyocardial fibrosis: some observations and an hypothesis.

It has been shown that chronic African endomyocardial fibrosis (E.m.f.) is most likely the burnt-out phase of parasite-induced hypereosinophilia. It has also been shown that African E.m.f. and Loffler's heart disease are pathologically identical. The mechanism by which these parasites and/or eosinophilia are associated with endomyocardial damage remains, however, unknown. The parasites which have been associated with induction of eosinophilia in E.m.f. include filariasis; trichinosis; ascariasis and hookworm and schistosomiasis. These parasites are known to produce neurologic, cardiac, pneumonic, hepatic and dermal damage during the migration of their larvae; at which time eosinophilia is usually most severe. The tissue damage induced by larval migration of these parasites appears comparable to findings seen in the hypereosinophilic syndrome. The evidence from our observations and this review suggests that the cardiac damage induced by larval migration, like the neurologic, pneumonic and dermal damage, is allergic in nature. Endomyocardial fibrosis has previously been shown to be an allergic heart disease. It appears reasonable to regard African endomyocardial fibrosis as representing the most intense, non-specific cardiac allergic reaction to helminthic larvae.