Cardiovascular Toxicity Induced by Kinase Inhibitors: Mechanisms and Preclinical Approaches.

Kinase inhibitors have transformed the treatment of many cancers and are showing the same promise for other indications including inflammatory diseases. This class of drugs is one of the most predominant in the pharmaceutical industry, but development and clinical utility is often limited by a broad spectrum of cardiovascular (CV) toxicities including QT prolongation and arrhythmia, left ventricular dysfunction, congestive heart failure, ischemia and myocardial infarction, and hypertension. In this review article, we provide a broad overview of the spectrum of CV events detected in clinical trials of kinase inhibitors and the known and proposed on- and off-target links between kinase inhibitor targets and these specific cardiotoxicities. We also examine the unique features of kinase inhibitors that have impeded complete mechanistic understanding of kinase inhibitor-associated cardiotoxicities and contributed to the disconnect between preclinical predictions and clinical findings. We then discuss various in vitro models currently in use that are amenable for high-throughput screening as well as lower throughput models that are valuable for mechanistic insight. These physiologically relevant models, together with newer "omic"-wide approaches will help to increase our understanding of the mechanisms underlying kinase inhibitor-associated cardiotoxicity and enable rational design of kinase inhibitors in the future.

Ischemic necrosis of the digits and hyperlipidemia associated with atherosclerosis in a Miniature American Shepherd.

CASE DESCRIPTION A 2.5-year-old 12-kg (26.4-lb) castrated male Miniature American Shepherd was referred because of a 3-week history of a localized crusted skin lesion on the digital pad of digit 3 of the right hind limb. CLINICAL FINDINGS Skin lesions were noted on the digital pads of the right hind limb. Serum biochemical analyses indicated severe hypercholesterolemia and hypertriglyceridemia. Ultrasonography of the terminal portion of the aorta and other major arterial vessels revealed substantial arteriosclerotic change. TREATMENT AND OUTCOME Medical treatments included administration of atorvastatin calcium, a low-fat diet, and omega-3 fatty acids to reduce serum lipids concentration; clopidogrel to prevent thrombosis; pentoxifylline to improve microcirculatory blood flow; clomipramine hydrochloride and trazodone hydrochloride to help with the behavioral problems; and gabapentin to help with pain management and behavioral problems. Surgical management included amputation of the initial digit involved, then eventually the entire initial limb involved. The response to treatment was poor, and euthanasia was elected. Postmortem findings revealed severe, widespread, and chronic intimal atherosclerosis; mild, widespread, and degenerative changes in the cerebral cortex; and edema and vascular congestion in the meninges. CLINICAL RELEVANCE To the authors' knowledge, this was the first report of skin necrosis secondary to atherosclerosis in a dog. Although the incidence of atherosclerosis has been considered very low in dogs, it should be investigated in dogs with severe hyperlipidemia. Primary hyperlipidemia has not been previously described in Miniature American Shepherd dogs but was the suspected underlying metabolic disorder.

Glomerular Lipidosis in Dogs.

Glomerular lipidosis (GL) is characterized by dilated glomerular capillary loops containing lipid-laden cells (foam cells). Previously, GL was considered to be an incidental finding because affected dogs were typically not azotemic. However, the International Renal Interest Society staging system for canine chronic kidney disease has increased the awareness of other clinical parameters (eg, proteinuria and hypertension) that should be included in the assessment of renal function. As such, the aim of this study was to determine clinical abnormalities and concurrent renal lesions in dogs with GL. GL was identified in renal biopsies from 46 dogs evaluated by the International Veterinary Renal Pathology Service. GL was the sole diagnosis in 5 of 46 cases (11%), all of which were proteinuric. All 5 dogs had at least 1 additional clinicopathologic abnormality consistent with renal disease, including hypertension (4), azotemia (3), and/or hypoalbuminemia (2). The remaining 41 dogs had GL in combination with other glomerular lesions, the most common being focal segmental glomerulosclerosis (16, 35%), lesions consistent with juvenile nephropathy (8, 17%), and glomerular amyloidosis (5, 11%). Overall, dogs with severe GL were younger than were those with mild GL ( P < .001). The percentage of glomeruli affected by GL differed by concurrent diagnoses ( P = .034), with the highest percentage of affected glomeruli in dogs with GL alone or those with concurrent juvenile nephropathy. These findings suggest that GL should be a recognized histologic phenotype of glomerular injury associated with clinical renal dysfunction and/or juvenile nephropathies.

Lack of Chronic Histologic Lesions Supportive of Sublethal Spontaneous Seizures in FVB/N Mice.

FVB/N mice with 'space cadet' syndrome are prone to audiogenic seizures and are considered excitotoxic 'sensitive' mice due to the neuronal damage that accompanies seizures. FVB/N mice found dead demonstrate acute neuronal cell death--attributed to a massive seizure episode--within the hippocampus and cerebrocortical laminae. However, the behavioral features of FVB/N mice and numerous studies using excitotoxins to induce seizure activity indicate that this strain experiences multiple sublethal seizures. To assess whether FVB/N mice develop histologically detectable lesions, we evaluated the brains of 86 aged (154-847 d) FVB/N mice without a history of seizures. The hippocampus and cerebrocortical laminae were evaluated histologically for neuronal atrophy and gliosis. Neuronal atrophy was quantified by counting neurons in the hippocampus (CA3 and dentate gyrus) and cerebral cortex. Gliosis was quantified by using immunohistochemistry for glial fibrillary acidic protein and glial counting in the cerebral cortex. In addition, ventricular area was calculated. Our study revealed no changes in brain weight with age, no neuronal loss or gliosis, no correlation between neuronal or glial cell profile densities and brain weight or age, and no differences in ventricular size between FVB/N and control mice. Neuronal densities in the cerebral cortex and granule cells of the dentate gyrus were lower in FVB/N mice than in control Swiss Webster mice. We conclude that although acute lesions of seizure activity are a previous feature of the FVB/N strain, chronic seizure activity in these mice either is negligible or does not cause morphologic or phenotypic changes.

Congenital isolated cleft mitral valve leaflet and apical muscular ventricular septal defect in a Holstein calf.

A 5-week-old Holstein heifer calf presented for emergency treatment of signs referable to gastrointestinal disease and hypovolemic shock. Fluid resuscitation uncovered clinical signs of primary cardiac disease and echocardiography revealed multiple congenital cardiac defects. Malformations included a cleft anterior mitral valve leaflet resembling an isolated cleft mitral valve and an apically-located muscular ventricular septal defect. The echocardiographic and postmortem findings associated with these defects are presented and discussed in this report.