PracticeUpdate Cardiology March 2019

EXPERT OPINION 19

Getting a B (as in Apolipoprotein B) Is Good Enough By Paul D. Thompson MD

C linicians and researchers have debated the role of triglycerides (TGs) in atherosclerosis and coronary heart disease (CHD) since Steven Hul- ley argued against their role in 1980. 1 Ference and colleagues have now, in my opinion, settled the issue. 2 These authors used lipid, genetic, and outcome data from 654,783 par- ticipants from multiple sources to examine the relationship among genes encoding for the LDL receptor (LDLR) and those encoding for the enzyme lipoprotein lipase (LPL). LPL is a critical enzyme in triglyceride metabolism because it removes TGs from the VLDL particle, thereby transforming these particles into LDL and enabling their clearance by the LDL receptor. The authors created an LPL and LDLR genetic score for each of the genes encoding for lower TGs or lower LDL values. As expected, the LPL genetic score was associated with lower TGs and slightly higher LDL cholesterol val- ues, whereas the LDLR genetic score was associated with lower LDL and slightly lower TGs. When both the LPL and LDLR scores were matched for the magnitude of their apolipoprotein B (ApoB) reduction, there was no dif- ference in their effect on CHD outcomes. In other words, after adjusting for these genes’ effects on ApoB, neither the LDL nor TG were related to CHD outcomes. Because each “bad” cholesterol particle, whether it’s a VLDL or LDL particle, has one ApoB, this suggests that the real culprit is the number of lipid particles. So, TGs are a risk marker for CHD because they indicate increased atherogenic ApoB-containing particles. The key clinical implications of these findings are that TGs are a risk marker for CHD and that ApoB levels are a more accurate measurement of that risk than TGs alone because ApoB indicates the number of atherogenic particles. Consequently, ApoB measurement is the key measurement of atheroscle- rotic risk. Also, because the amount of TGs associated with each ApoB is large, large reductions in TGs are required to reduce ApoB levels and to approximate the magnitude of benefit achieved by lowering LDL. This helps to explain why the relatively small reductions in TGs in prior studies failed to reduce CHD events. These results explain the role of TGs and also why there has been such a debate on the issue. Bottom line? In contrast to what your parents told you, getting a B, as in apo- lipoprotein B, is probably good enough. This commentary is based upon the article Association of Triglyceride-Lowering LPL Variants and LDL-C-Lowering LDLR Variants With Risk of Coronary Heart Disease by Ference et al. Reference 1. Hulley SB, Rosenman RH, Bawol RD, Brand RJ. Epidemiology as a guide to clinical decisions. The association between triglyceride and coronary heart disease. N Engl J Med 1980;302(25):1383-1389. 2. Ference BA, Kastelein JJP, Ray KK, et al. Association of triglyceride-lowering LPL variants and LDL-C-lowering LDLR variants with risk of coronary heart disease. JAMA 2019;321(4)364-373. www.practiceupdate.com/c/79188

Regarding MSCs, multiple studies (with different designs using both autologous and allogeneic cells) have addressed different populations, with mixed results, but again with consistent safety when administered to patients with HF. The field of cell therapy has been soiled recently by revelations of extensive scientific fraud by Piero Anversa and coworkers dating back at least 15 years, prompting numerous retractions from prestigious journals (including The New England Journal of Medicine ). Anversa had promulgated the concept, now discredited, that heart cells selected for the c-Kit antigen were true cardiac stem cells. The consequences of this scandal include the recent decision by NIH to pause the CONCERT-HF trial, which was studying c-Kit–positive heart cells (with or without concomitant MSCs) in patients with ischemic cardiomyopathy. The disgrace surrounding c-Kit– positive cells, however, should not be generalized to other cell types such as CDCs and MSCs, where evidence of efficacy is broad-based, and mechanistic insights are extensive…and point convincingly toward paracrine factors as being central. Regardless, not a single cell type has been approved by the FDA for the treatment of any form of heart disease. Key to forward momentum will be solid, reproducible, hypothesis-driven proof-of concept and preclinical studies. Additionally, it would be important when designing clinical trials (with differ- ent cell types) to have strict requirements such as homogeneity of the population, proper controls, and hard endpoints, just to name a few. The future will only tell which cell type (if any) may win this race. For now, as always in science, solid basic science foun- dations are fundamental to continue to advance this exciting field. www.practiceupdate.com/c/78596

VOL. 4 • NO. 1 • 2019