An Obesity Paradox: Increased Body Mass Index Is Associated with Decreased Aortic Atherosclerosis.

Brodsky et al. (Cardiovasc Pathol 25(6), 515-520, 2016) recently have reported that there was an unexpected and highly significant inverse correlation between body mass index (BMI) and atherosclerosis of the aortas of morbidly obese decedents (BMI >40 kg/m2). In a series of 304 decedents, 65 of whom were morbidly obese, minimal or no atherosclerosis was seen in 46 of them (70%) versus 20 (30%) who had severe atherosclerosis (P = 0.008). This obesity paradox was unexpected and raises important questions about the etiology and pathogenesis of atherosclerosis, which will be the subject of this commentary. The concept of healthy versus unhealthy adiposity may in part provide an explanation for the "obesity paradox." Another factor that will be considered is the possible role of adipokines and their genetic determinants that may significantly reduce the risk of developing aortic atherosclerosis in morbidly obese individuals. Considering the marked variability in the pattern and extent of atherosclerosis of the aorta, hemodynamic factors and endothelial cell shear stress may be the most important determinants that might explain the obesity paradox that we have observed. Finally, the possible role of gut microbiota and inflammation as factors in the etiopathogenesis of atherosclerosis will be considered, but their importance is less clear than that of hemodynamic factors. We conclude with the remarkable finding that a 5300-year-old, well-preserved mummy of the "Iceman," Ötzi had atherosclerotic disease of a number of major arteries and the interesting questions that this raises.

Mitochondria in Ischemic Heart Disease.

A core feature of ischemic heart disease is injury to cardiomyocytes (CMC). Ischemic CMC manifest the molecular mechanisms to undergo the major forms of cell injury and death, namely, oncotic necrosis, necroptosis, apoptosis and unregulated autophagy. Important modulators of ischemic injury are reperfusion and conditioning. Mitochondria have a major role in mediating the injury to CMC through membrane protein complexes referred to as death channels. Apoptosis is mediated by activation of a channel regulated by the Bcl-2 protein family leading to mitochondrial outer membrane permeabilization (MOMP). Oncotic type injury is mediated by opening of the mitochondrial permeability transition pore (mPTP). Mitochondria also have a reperfusion salvage kinase pathway (RISK). With cyclosporine A serving as a prototype, ongoing research is aimed at developing pharmacological approaches to condition and preserve mitochondrial integrity in order to promote CMC survival during episodes of myocardial ischemia.

Immune checkpoint inhibitor myocarditis: elucidating the spectrum of disease through endomyocardial biopsy.

AIMS: Although immune checkpoint inhibitor (ICI) myocarditis carries a high reported mortality, increasing reports of smoldering myocarditis suggest a clinical spectrum of disease. Endomyocardial biopsy (EMB) remains the gold standard for diagnosis of ICI myocarditis, but different pathologic diagnostic criteria exist. The objective of this study was to classify the spectrum of ICI myocarditis and myocardial inflammation by pathology findings on EMB and correlate this with clinical outcomes. METHODS AND RESULTS: All patients who had EMB at MD Anderson Cancer Center between January 2018 and August 2019 for suspected ICI myocarditis were retrospectively reviewed. A grading system (Grades 0-2) based on the degree of inflammatory infiltrate was developed by pathologists. Cardiovascular outcomes and treatment were compared between grades of pathology. We identified 28 patients who had EMB for suspected ICI myocarditis, of which 18 were positive for myocarditis/inflammation. There were four deaths (two in Grade 2 and two in Grade 1), but only one was attributable to myocarditis. Grade 2 patients had no myocarditis-associated deaths despite having the highest troponin T values (median 2063 pg/mL). Four patients with Grade 1 myocardial inflammation continued ICI without any immunomodulation, and all were alive without adverse cardiovascular events at follow-up. CONCLUSION: We defined an EMB grading system for ICI myocarditis encompassing a spectrum of histologic findings of inflammatory infiltrates. A subset of low-grade myocardial inflammation patients were able to continue ICI without immunosuppressive therapy. Further studies are needed to identify low-risk patients who can be safely treated with ICI.