Farshad Forouzandeh

Metformin Beyond Diabetes: Pleiotropic Benefits of Metformin in Attenuation of Atherosclerosis

Background Clinical studies show that metformin attenuates all‐cause mortality and myocardial infarction compared with other medications for type 2 diabetes, even at similar glycemic levels. However, there is paucity of data in the euglycemic state on the vasculoprotective effects of metformin. The objectives of this study are to evaluate the effects of metformin on ameliorating atherosclerosis. Methods and Results Using ApoE−/− C57BL/6J mice, we found that metformin attenuates atherosclerosis and vascular senescence in mice fed a high‐fat diet and prevents the upregulation of angiotensin II type 1 receptor by a high‐fat diet in the aortas of mice. Thus, considering the known deleterious effects of angiotensin II mediated by angiotensin II type 1 receptor, the vascular benefits of metformin may be mediated, at least in part, by angiotensin II type 1 receptor downregulation. Moreover, we found that metformin can cause weight loss without hypoglycemia. We also found that metformin increases the antioxidant superoxide dismutase‐1. Conclusion Pleiotropic effects of metformin ameliorate atherosclerosis and vascular senescence.

Peroxisome Proliferator-Activated Receptor γ Coactivator-1α Is a Central Negative Regulator of Vascular Senescence

Objective—Cellular senescence influences organismal aging and increases predisposition to age-related diseases, in particular cardiovascular disease, a leading cause of death and disability worldwide. Peroxisome proliferator-activated receptor &ggr; coactivator-1&agr; (PGC-1&agr;) is a master regulator of mitochondrial biogenesis and function, oxidative stress, and insulin resistance. Senescence is associated with telomere and mitochondrial dysfunction and oxidative stress, implying a potential causal role of PGC-1&agr; in senescence pathogenesis. Approach and Results—We generated a PGC-1&agr;+/–/apolipoprotein E–/– mouse model and showed that PGC-1&agr; deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1&agr; disruption results in reduced expression of the longevity-related deacetylase sirtuin 1 (SIRT1) and the antioxidant catalase, and increased expression of the senescence marker p53 in aortas. Further, angiotensin II, a major hormonal inducer of vascular senescence, induces prolonged lysine acetylation of PGC-1&agr; and releases the PGC-1&agr;–FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1&agr; S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II–induced senescence. Acetylation of PGC-1&agr; by angiotensin II interrupts the PGC-1&agr;–forkhead box O1–SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence. Conclusions—PGC-1&agr; is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1&agr; in regulating angiotensin II–induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis.

PGC-1α Modulates Telomere Function and DNA Damage in Protecting against Aging-Related Chronic Diseases

Cellular senescence and organismal aging predispose age-related chronic diseases, such as neurodegenerative, metabolic, and cardiovascular disorders. These diseases emerge coincidently from elevated oxidative/electrophilic stress, inflammation, mitochondrial dysfunction, DNA damage, and telomere dysfunction and shortening. Mechanistic linkages are incompletely understood. Here, we show that ablation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) accelerates vascular aging and atherosclerosis, coinciding with telomere dysfunction and shortening and DNA damage. PGC-1α deletion reduces expression and activity of telomerase reverse transcriptase (TERT) and increases p53 levels. Ectopic expression of PGC-1α coactivates TERT transcription and reverses telomere malfunction and DNA damage. Furthermore, alpha lipoic acid (ALA), a non-dispensable mitochondrial cofactor, upregulates PGC-1α-dependent TERT and the cytoprotective Nrf-2-mediated antioxidant/electrophile-responsive element (ARE/ERE) signaling cascades, and counteracts high-fat-diet-induced, age-dependent arteriopathy. These results illustrate the pivotal importance of PGC-1α in ameliorating senescence, aging, and associated chronic diseases, and may inform novel therapeutic approaches involving electrophilic specificity.

Performance of J-CTO and PROGRESS CTO Scores in Predicting Angiographic Success and Long-term Outcomes of Percutaneous Coronary Interventions for Chronic Total Occlusions

Patient selection for and predicting clinical outcomes of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) remain challenging. We hypothesized that both J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores will predict not only angiographic success but also long-term clinical outcomes of the patients who underwent PCI of CTO. Of 325 CTO PCIs performed at 2 Emory University hospitals from January 2012 to August 2015, 249 patients with complete baseline clinical, angiographic and follow-up data, were included in this analysis. Major adverse cardiovascular events (MACEs) consisted of a composite of death, myocardial infarction, and target vessel revascularization. Mean age was 63 ± 11 years old and mean follow-up was 19.8 ± 13.1 months. Angiographic success rates increased from 74.5% in 2012 to 85.7% in 2015. Greater J-CTO and PROGRESS CTO scores were not only associated with lower likelihood of angiographic success but also higher rates of long-term MACE. Compared with the scores of 0 to 2, J-CTO and PROGRESS CTO scores of ≥3 were associated with higher MACE. Multivariable analysis demonstrated that PROGRESS CTO scores of ≥3, male sex, and peripheral vascular disease were independent predictors of MACE. In conclusion, J-CTO and PROGRESS CTO scores are useful in predicting procedural success. In addition, the PROGRESS CTO score, and to a lesser degree J-CTO score, have predictive value for long-term outcomes in patients who underwent CTO PCI.

Percutaneous Coronary Intervention Versus Robotic-Assisted Coronary Artery Bypass for Left Anterior Descending Artery Chronic Total Occlusion

Revascularization for left anterior descending artery (LAD) chronic total occlusion (CTO) lesions usually requires coronary artery bypass grafting (CABG) via sternotomy. Recent advances in CTO percutaneous coronary intervention (PCI) techniques, including a rapid escalation of the hybrid algorithm

SPONTANEOUS CORONARY ARTERY DISSECTION: HEART TEAM APPROACH IN MANAGING AN UNCOMMON BUT SERIOUS CAUSE OF MYOCARDIAL INFARCTION

Spontaneous Coronary Artery Dissection (SCAD) is a rarely encountered but serious cause of acute coronary syndrome that occurs mostly in young women. A 31-year-old female presented to an outside hospital (OSH) with cardiac arrest 9 days postpartum. The patient was breast feeding her baby when she