Subtypes of Preeclampsia: Recognition and Determining Clinical Usefulness

The concept that preeclampsia is a multisystemic syndrome is appreciated in both research and clinical care. Our understanding of pathophysiology recognizes the role of inflammation, oxidative and endoplasm reticulum stress, and angiogenic dysfunction. Yet, we have not progressed greatly toward clinically useful prediction nor had substantial success in prevention or treatment. One possibility is that the maternal syndrome may be reached through different pathophysiological pathways, that is, subtypes of preeclampsia, that in their specificity yield more clinical utility. For example, early and late onset preeclampsia are increasingly acknowledged as different pathophysiological processes leading to a common presentation. Other subtypes of preeclampsia are supported by disparate clinical outcomes, long-range prognosis, organ systems involved, and risk factors. These insights have been supplemented by discovery-driven methods, which cluster preeclampsia cases into groups indicating different pathophysiologies. In this presentation, we review likely subtypes based on current knowledge and suggest others. We present a consideration of the requirements for a clinically meaningful preeclampsia subtype. A useful subtype should (1) identify a specific pathophysiological pathway or (2) specifically indicate maternal or fetal outcome, (3) be recognizable in a clinically useful time frame, and (4) these results should be reproducible and generalizable (but at varying frequency) including in low resource settings. We recommend that the default consideration be that preeclampsia includes several subtypes rather than trying to force all cases into a single pathophysiological pathway. The recognition of subtypes and deciphering their different pathophysiologies will provide specific targets for prevention, prediction, and treatment directing personalized care.

Abstract 16607: Age-induced Endoplasmic Reticulum Stress in the Heart: Role of Increased Very Long-chain Ceramides

Introduction: Mitochondrial function is impaired in aged hearts. Increased endoplasm reticulum (ER) stress contributes to the mitochondrial dysfunction observed during aging. Ceramides (CRMD) are sphingolipid metabolites that contribute key roles in cell signaling. Increased CRMD can lead to ER stress. Ceramide synthase enzymes (CerS) generate chain length specific CRMD with the CerS isoform 2 (Cers2) forming very long chain CRMD of ≥ 20 carbon acyl chain lengths. Hypothesis: An increase in CRMD content during aging contributes to age-related ER stress. Methods: Male mice (3, 18, 24 mo.) from the NIA colony were studied. Cardiac mitochondria (MITO), mitochondrial associated membranes (MAM), and ER were isolated from mouse hearts. CRMD content was measured using LC-MS. The contents of CerS enzymes were measured by immunoblotting in myocardial homogenates. Results: ER stress increased progressively during aging with increased contents of cleaved ATF6 and CHOP, indicators of increased ER stress, evident at 18 and 24 mo. (Panel A) (all data mean±SEM; *p<0.05 vs. 3 mo., † p<0.05 vs. 18 mo.). Aging increased very long-chain CRMD (≥C20) in ER (Panel B) at 18 and 24 mo. Similar CRMD trends were observed MAM (Panel C), shared membrane domains where ER and MITO interact. The content of CerS2 was increased at 24 mo. compared to 3 mo. (Panel D, n=4 each age). In contrast, the contents of CerS isoforms 4 and 5, that generate shorter chain CRMD (<C20) were unchanged (not shown). CRMD contents in MITO were unaltered with age (not shown). Thus, increased generation of very long chain CRMD in the ER is the likely mechanism of increased ER stress in the aged heart. Conclusion: Aging increased ER CRMD content by enhancing the formation of very long chain CRMD in ER by an increase in CerS2 content, concomitant with the onset of ER stress. The increase in age-induced ER stress, in turn, leads to mitochondrial dysfunction in the aged heart.

Qualitative study on “hydropic degeneration” of The hepatocytes in viral hepatitis

“Hydropic degeneration” of the hepatocytes are often found in biopsy of the liver of some kinds of viral hepatitis. Light microscopic observation, compareted with the normal hepatocytes, they are enlarged, sometimes to a marked degree when the term “balloning” degeneration is used. Their cytoplasm rarefied, and show some clearness in the peripheral cytoplasm, so, it causes a hydropic appearance, the cytoplasm around the nuclei is granulated. Up to the present, many studies belive that main ultrastructural chenges of hydropic degeneration of the hepatocytes are results of the RER cristae dilatation with degranulation and disappearance of glycogen granules.The specimens of this study are fixed with the mixed fluid of the osmium acidpotassium of ferricyanide, Epon-812 embed. We have observed 21 cases of biopsy specimens with chronic severe hepatitis and severe chronic active hepatitis, and found that the clear fields in the cytoplasm actually are a accumulating place of massive glycogen. The granules around the nuclei are converging mitochondria, endoplasm reticulum and other organelles.