domoic-acid and Cardiomyopathies

Exposure to the excitotoxin domoic acid (DOM) has been shown to produce cardiac lesions in both clinical and animal studies. We have previously shown that DOM failed to directly affect cardiomyocyte viability and energetics, but the development of this cardiomyopathy has remained unexplained. The present study compared effects of high-level seizure induction obtained by intraperitoneal (2 mg/kg) or intrahippocampal (100 pmol) bolus administration of DOM on development of cardiac pathologies in a rat model. Assessment of cardiac pressure derivatives and coronary flow rates revealed a significant time-dependent decrease in combined left ventricular (LV) systolic and diastolic function at 1, 3, 7, and 14 days after intraperitoneal administration and at 7 and 14 days after intrahippocampal DOM administration. LV dysfunction was matched by a similar time-dependent decrease in mitochondrial respiratory control, associated with increased proton leakage, and in mitochondrial enzyme activities. Microscopic examination of the LV midplane revealed evidence of progressive multifocal ischemic damage within the subendocardial, septal, and papillary regions. Lesions ranged from reversible early damage (vacuolization) to hypercontracture and inflammatory necrosis progressing to fibrotic scarring. Plasma proinflammatory IL-1α, IL-1β, and TNF-α cytokine levels were also increased from 3 days after seizure induction. The observed cardiomyopathies did not differ between intraperitoneal and intrahippocampal groups, providing strong evidence that cardiac damage after DOM exposure is a consequence of a seizure-evoked autonomic response.

Topics: Animals; Behavior, Animal; Cardiomyopathies; Cytokines; Disease Models, Animal; Kainic Acid; Male; Mitochondria; Myocardial Ischemia; Neuromuscular Depolarizing Agents; Rats; Rats, Sprague-Dawley; Respiration; Seizures; Ventricular Dysfunction, Left

Domoic acid produced by marine algae has been shown to cause acute and chronic neurologic sequelae in Californian sea lions following acute or low-dose exposure. Histological findings in affected animals included a degenerative cardiomyopathy that was hypothesized to be caused by over-excitation of the glutamate receptors (GluRs) speculated to be present in the sea lion heart. Thus tissues from five sea lions without lesions associated with domoic acid toxicity and one animal with domoic acid-induced chronic neurologic sequelae and degenerative cardiomyopathy were examined for the presence of GluRs. Immunohistochemistry localized mGluR 2/3, mGluR 5, GluR 2/3 and NMDAR 1 in structures of the conducting system and blood vessels. NMDAR 1 and GluR 2/3 were the most widespread as immunoreactivity was observed within sea lion conducting system structures. PCR analysis, cloning and subsequent sequencing of the seal lion GluRs showed only 80% homology to those from rats, but more than 95% homologous to those from dogs. The cellular distribution and expression of subtypes of GluRs in the sea lion hearts suggests that exposure to domoic acid may induce cardiac damage and functional disturbances.

Topics: Animals; Base Sequence; Cardiomyopathies; Cloning, Molecular; DNA Primers; Immunohistochemistry; Kainic Acid; Marine Toxins; Molecular Sequence Data; Myocardium; Neurotoxins; Polymerase Chain Reaction; Receptors, Glutamate; Sea Lions

Domoic acid, produced by marine algae, can cause acute and chronic neurologic sequela in California sea lions (Zalophus californianus) from acute toxicity or sublethal exposure. Eight sea lions, representing acute and chronic cases, both sexes, and all age classes, were selected to demonstrate a concurrent degenerative cardiomyopathy. Critical aspects of characterizing the cardiomyopathy by lesion distribution and morphology were the development of a heart dissection and tissue-trimming protocol and the delineation of the cardiac conducting system by histomorphology and immunohistochemistry for neuron-specific protein gene product 9.5. Histopathologic features and progression of the cardiomyopathy are described, varying from acute to chronic active and mild to severe. The cardiomyopathy is distinguished from other heart lesions in pinnipeds. Based on histopathologic features, immunopositive staining for cleaved caspase-3, and comparison with known, similar-appearing cardiomyopathies, the proposed pathogenesis for the degenerative cardiomyopathy is the primary or at least initial direct interaction of domoic acid with receptors that are suspected to exist in the heart. l-Carnitine, measured in the heart and skeletal muscle, and troponin-I, measured in serum collected at the time of death from additional animals (n = 58), were not predictive of the domoic acid-associated cardiomyopathy. This degenerative cardiomyopathy in California sea lions represents another syndrome beyond central neurologic disease associated with exposure to domoic acid and may contribute to morbidity and mortality.

Topics: Animals; Cardiomyopathies; Caspase 3; Dissection; Female; Immunohistochemistry; Kainic Acid; Male; Marine Toxins; Myocardium; Neurotoxins; Sea Lions