High-density lipoprotein and endothelial function in patients with myocardial infarction: Pieces in a puzzle

Like the colorful lights of the aurora borealis, high-density li-poproteins (HDLs) are full of character and inspire wonder. Theirextremely heterogeneous polymolecular complexity and multidi-mensional functionality demands careful scrutiny, or else theirwondrous nuances could go unappreciated [1e3]. Indeed, whileepidemiological observations have suggested an important role ofHDLinprotectionfromcardiovasculardisease(CVD),recentclinicaltrialshavetemperedenthusiasmoversimplyraisingthequantityofcholesterol within HDL [4e7]. The lack of positive clinical trials inthis space has only increased motivation for a deeper under-standing of how pieces of the puzzle ﬁt together in the HDL-CVDrelationship.Over the life course of an HDL particle, there is continualremodeling of the lipidome and proteome, and these dynamicstructural changes appear to dictate functionality. Reverse choles-terol transport is the classic function, but not necessarily the mostimportant one. Other described HDL functions include plateletreactivity, heme metabolism, vitamin binding, insulin secretion,immunity,andasaddressedinthisissuebyCarvalhoetal.[7]eanti-oxidative/anti-inﬂammatory activity and regulation of endothelialfunction.Translational mechanistic studies like Carvalho et al.'s areimportant to bridging the space between basic science andoutcomes research. In a prospective cohort design, the BrazilianHeart Study investigators examined 180 consecutive patients withST-elevation myocardial infarction (STEMI). Embracing the dy-namic nature of HDL, assessments were performed at admissionand again at day 5 and day30. The analysis showed that thosewithhigher admission HDL cholesterol levels (third tertile >42 mg/dL)had a ~50% lower acute increase in plasma nitric oxide levelscompared to those with HDL cholesterol levels <33 mg/dL andrelativelylessfavorableendothelialfunction(~40%lower)atday30by ﬂow-mediated dilatation (FMD). The study team performed aparallel anti-oxidative/anti-inﬂammatory protocol involving asubset of 9 non-diabetic STEMI patients and 9 age- and sex-matched healthy volunteers. Within 24 h of STEMI admission,HDL showed similar capacity for preventing LDL oxidation relativeto healthy subjects, but STEMI patients then demonstrated signif-icant impairment at day 5. It appeared that the acute inﬂammatoryresponse with STEMI brought dynamic structural changes in HDL(reduction in apoA-I content) associated with impaired anti-oxidant/anti-inﬂammatory activity, which may underlie theobserved relationship between HDL-C and FMD.Guidelines view FMD as a research tool for non-invasiveassessment of vascular endothelial function [8]. After release ofarterial compression, blood ﬂow stimulates nitric oxide release inhealthy endothelium, inducing vasodilation that can be quantiﬁedby ultrasound. Generally considered a technically-challengingtechnique, FMD is best performed by experienced research teamslike the Brazilian Heart Study investigators. When measured inexpert laboratories, brachial artery FMD has been linked withinvasive coronary endothelial function testing and long-term car-diovascular risk. However, standardizing FMD measurement acrossindividual patients and research labs poses a challenge given theoperator-dependency of the technique and possible variations inmeasurement at different times of day or temperatures, forinstance. While FMD as a surrogate end-point is important andinteresting, hard outcome data are critical, a lesson that has beenlearned the hard way in the HDL therapy world [2,6].Regarding hard clinical outcomes, the authors noted the recentreportof a null predictive value for HDL-C in secondary prevention.We [9] along with two other groups [10,11] have reachedcompatible ﬁndings. In addition, it is worth noting that two Men-delian randomization studies were not able to establish a causal