Raising the Bar When Assessing Cardiovascular Disease Outcome When Studies with Patients with Type 2 Diabetes Mellitus are Constructed: Revisiting ASCEND

    

    

    Figure 1: Morbidity of Heart Disease with T2DM in the United States between 1993 and 2015.
    

If the road between vascular biology deficits and MACE is set by T2DM, then Reactive Oxygen Species (ROS) is the cement that makes such a road traversable. Hyperglycemia from T2DM promotes the formation of ROS via the mitochondria through an array of mechanisms [9]. One method is through the status of insulin resistance, which causes increased serum glucose, leading to the propensity to undergo non-enzymatic condensation reactions between glucose and amine residues of proteins and some other macronutrients, such as lipids and nucleic acids. Such constituents are dubbed Advanced Glycation End Products (AGEs). In one study by Morita et al. it was shown that AGEs activates nuclear factor-κB (NF-κB) in human aortic endothelial cells through the modulation of signaling pathways [10]. NF-κB is a transcription factor which has the propensity to modulate multiple genes. Namely, NF-κB has been demonstrated to be paramount in the proliferation of Smooth Muscle Cells (SMCs) that is crucial in the process of arteriosclerosis within the vascular injury process as well as lesion acquisition resulting in increased thrombosis risk, pathways central to MACE incidents [11,12]. For example, NF-κB is regulates Vascular Cell Adhesion Molecule (VCAM)-1, which plays a role among other proteins in the promotion of cytokine and inflammatory adhesion of leukocyte mediated adhesion to vessels, which has the propensity to degranulate cytotoxic elements on damaged vasculature [13]. The damaged intima is especially susceptible to the accumulation of Low-Density Lipoprotein (LDL) in the subendotheolial space, where circulating ROS promotes pathologic plaque formation [14]. There is a tendency for these lesions to promote induction of inflammatory cytokines and chemokines, which has systemic influence as well as local formation of atherogenic structures that may embolize leading to MI, or en route to such process, promote stenotic phenotypes [15]. Moreover, hyperglycemia that has not undergone the glycosylation process has the propensity to induce ROS in mitochondria by increasing expression of ROS ligands, making the ROS accumulated throughout T2DM more viable in their downstream effects [16]. Non-glycosylated hyperglycemia also induces vascular damage through the production of TNF-a, a cytokine employed by the immune system with vast clout in the domain of human cell signaling pathway induction, and within the interest of this review, vascular tone.

In vitro studies have shown that the immunoreceptor motif CD33, which has been shown to downregulating TNF-a production, statistically significantly increases TNF-a when cultured in higher glucose concentrations via motif downregulation, with the theory that hyperglycemia overloads the electron transport chain of the mitochondria, causing the production of radicals that induce oxidative stress, stimulate cytokine production, and promote CD33 downregulation [17,18]. This process is critical as TNF-a promotes arginase activity, an enzyme that has competitive actions against Endothelial Nitric Oxide Synthase (eNOS) [19]. As the name implies, eNOS produces Nitric Oxide (NO), which leads to the W of vascular tone through vasodilation by cGMP mediated smooth muscle cell relaxation. By indirectly decreasing vascular tone homeostasis, hyperglycemia mediated TNF-a reduces endothelial cell NO and promoting endothelial cell dysfunction with a net contractile phenotype [20]. Studies of the vascular endothelium note that their neuronal innervation are dense in mitochondria, implying a reliance on oxidative phosphorylation for metabolic homeostasis [21-24]. Unfortunately, the same oxidative constituents that promote deleterious tissue metabolism in oxidative stress also lead to autonomic dysfunction in these sensitive neuronal innervation networks [25,26]. The ramifications of oxidative stress and damage of endothelium mediated vascular tone is a constriction that decreases the flow rate of oxygen, causing a vicious cycle of hypoxia and endothelial cell dysfunction [4,27,28]. The resultant hypoxia has the propensity to result in cardiomyocytes death, with the concomitant abnormalities in the myocardium hampers the coupling process of electromechanical physiology with consequences in arrhythmias, thrombus and emboli advancement, and the development of processes central to MACE [29-33].

The following dialogue raises an inquiry as to the viability of prophylactic pharmacotherapeutic protection of the vascular architecture in patients with T2DM, given their tendency to be prolific producers of ROS, have higher risks of MACE at baseline, and generally carry comorbidities that are problematic for the maintenance of long-term adequate cardiovascular history [34,35]. Such a solution would have severe ramifications in mitigating hospitalizations and deaths in patients with T2DM for MACE, of which such burden at least in the United States can be visualized in Figure 1. While there is a slight downtrend in the magnitude of the patient flux in admissions according to the National Inpatient Sample, the degree of morbidity remains high [36]. In reference to the proposition raised at the beginning of this paragraph, such a relationship and the viability of such an option has been pursued, and we will appraise the design and lessons learned from such trials. Moreover, these trials have relative distinctions in their constructs and mainstream adoption of their results. Revisiting such distinctions, especially when discussed in tandem with the severity of vascular complications in patients with T2DM as described above, will culminate in recommendations for the communications of proceedings regarding therapeutic approaches for the clinical cardiovascular sequalae of T2DM. We hope such a commentary will not only expand our knowledge of T2DM, vascular biology, and the translational biology of cardiovascular health, but will help push for contextual annotations of prospective works of literature discussing cardiology in patients with T2DM. In this commentary, we will discuss the ramifications of the results of the ASCEND t trial and the consequences it has in reporting results in T2DM and MACE concordance.

ASCEND Trial

The ASCEND (Effects of aspirin for primary prevention in persons with diabetes mellitus) trial was a trial conducted in 2018 that sought to answer the question, “In patients with T2DM without atherosclerotic disease, can low dose aspirin be used as a prophylactic compound to mitigate vascular events relative to placebo?”. The interest in this research was spurred considering that T2DM conveys a 2-4 times increase of vascular incidents according to some studies [37] through the array of mechanisms as discussed previously and can be found succinctly in Figure 2.

    

    

    Figure 2: 2: A Review of the Ramifications of Hyperglycemia on Vascular Dynamics Hyperglycemic Patient with Implications for Vascular prophylaxis. Adapted from
Servier Medical Art by Servier, which is licensed under a Creative Commons Attribution 3.0 Unported License.