Impact of COVID-19 pandemic on ST-elevation myocardial infarction in a non-COVID-19 epicenter.

OBJECTIVES: We sought to study the impact of COVID-19 pandemic on the presentation delay, severity, patterns of care, and reasons for delay among patients with ST-elevation myocardial infarction (STEMI) in a non-hot-spot region. BACKGROUND: COVID-19 pandemic has significantly reduced the activations for STEMI in epicenters like Spain. METHODS: From January 1, 2020, to April 15, 2020, 143 STEMIs were identified across our integrated 18-hospital system. Pre- and post-COVID-19 cohorts were based on March 23rd, 2020, whenstay-at-home orders were initiated in Ohio. We used presenting heart rate, blood pressure, troponin, new Q-wave, and left ventricle ejection fraction (LVEF) to assess severity. Duration of intensive care unit stay, total length of stay, door-to-balloon (D2B) time, and radial versus femoral access were used to assess patterns of care. RESULTS: Post-COVID-19 presentation was associated with a lower admission LVEF (45 vs. 50%, p = .015), new Q-wave, and higher initial troponin; however, these did not reach statistical significance. Among post-COVID-19 patients, those with >12-hr delay in presentation 31(%) had a longer average D2B time (88 vs. 53 min, p = .033) and higher peak troponin (58 vs. 8.5 ng/ml, p = .03). Of these, 27% avoided the hospital due to fear of COVID-19, 18% believed symptoms were COVID-19 related, and 9% did not want to burden the hospital during the pandemic. CONCLUSIONS: COVID-19 has remarkably affected STEMI presentation and care. Patients' fear and confusion about symptoms are integral parts of this emerging public health crisis.

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 γ coactivator-1α (PGC-1α) 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-1α in senescence pathogenesis. APPROACH AND RESULTS: We generated a PGC-1α(+/-)/apolipoprotein E(-/-) mouse model and showed that PGC-1α deficiency promotes a vascular senescence phenotype that is associated with increased oxidative stress, mitochondrial abnormalities, and reduced telomerase activity. PGC-1α 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-1α and releases the PGC-1α-FoxO1 complex from the SIRT1 promoter, thus reducing SIRT1 expression. The phosphorylation-defective mutant PGC-1α S570A is not acetylated, is constitutively active for forkhead box O1-dependent SIRT1 transcription, and prevents angiotensin II-induced senescence. Acetylation of PGC-1α by angiotensin II interrupts the PGC-1α-forkhead box O1-SIRT1 feed-forward signaling circuit leading to SIRT1 and catalase downregulation and vascular senescence. CONCLUSIONS: PGC-1α is a primary negative regulator of vascular senescence. Moreover, the central role of posttranslational modification of PGC-1α in regulating angiotensin II-induced vascular senescence may inform development of novel therapeutic strategies for mitigating age-associated diseases, such as atherosclerosis.

Cardiovascular Disease in the Older Adult: Where Are We 4 Decades Later?

The 1986 Bethesda Conference on Cardiovascular Disease (CVD) in the Elderly, co-chaired by Drs. Nanette Wenger, Frank Marcus, and Robert O'Rourke, delineated the anticipated social, political, ethical, economic and technological impact of an aging population on the incidence, prevalence, and management of CVD in the US and worldwide. In the ensuing 4 decades, older patients have come to comprise an increasingly large proportion of the CVD population, and there has been an explosion of research in all aspects of CVD affecting older adults. Correspondingly, Geriatric Cardiology is now an established field within cardiovascular medicine. In this communication, we provide a focused update on intersections between CVD and geriatrics from basic science to clinical practice, a review of major advances in diagnosis and treatment of older adults with CVD, and a preview of future research directions in the still evolving field of geriatric cardiology.

Impact of coronary collaterals on the outcomes of chronic total occlusion percutaneous coronary intervention.

This study aims to evaluate the impact that the presence of interventional collaterals has on the outcomes of CTO PCI. We examined the clinical and angiographic characteristics and procedural outcomes of 11 205 patients who underwent 11 444 CTO PCIs at 45 US and non-US centers between 2012 and 2023.

Procedural and In-Hospital Outcomes of Chronic Total Occlusion Percutaneous Coronary Interventions in Patients With Acute Myocardial Infarction: Insights From a Prospective Multicenter International Registry.

BACKGROUND: We sought to examine the procedural and clinical outcomes of patients who underwent chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in the setting of acute myocardial infarction (AMI). METHODS: We assessed the clinical and procedural characteristics, technical success, procedural success, and in-hospital outcomes of 2314 patients who underwent CTO-PCI at 20 experienced centers between 2012 and 2017, classified according to whether or not they presented with AMI. RESULTS: Mean patient age was 65 ± 10 years, 85% were men, and 154 (6.7%) presented with AMI (5.5% with non-ST segment elevation myocardial infarction, 1.1% with ST-segment elevation myocardial infarction). Compared with non-AMI patients who underwent CTO-PCI, AMI patients had higher prevalence of diabetes (56% vs 42%; P<.01) and lower median left ventricular ejection fraction (48% vs 54%; P<.001). The CTO angiographic characteristics were similar between the 2 groups. Compared with non-AMI patients undergoing CTO-PCI, AMI patients had more frequent use of antegrade wire escalation (86.0% vs 78.9%; P=.03) and more frequent use of hemodynamic support devices (16.2% vs 3.4%; P<.01), and were more likely to have a non-CTO lesion treated (34.0% vs 26.6%; P=.03). AMI and non-AMI patients had similar technical success (90% vs 87%; P=.26), procedural success (88% vs 85%; P=.38), and incidence of in-hospital MACE (2.6% vs 2.5%; P=.94). CONCLUSION: CTO-PCI is performed infrequently in AMI patients and is associated with similar technical and procedural success rates and in-hospital major adverse cardiovascular event rates when compared with CTO-PCI performed in non-AMI patients.

High expression of IMPACT protein promotes resistance to indoleamine 2,3-dioxygenase-induced cell death.

Indoleamine 2,3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. IDO expression in fibroblasts selectively induces apoptosis in immune cells but not in primary skin cells. However, the mechanism(s) of this selective effect of IDO-induced low tryptophan environment is not elucidated. The aim of present study was to investigate whether the activity of general control non-derepressible-2(GCN2) kinase stress-responsive pathway and its known inhibitor, protein IMPACT homolog, in immune and skin cells are differentially regulated in response to IDO-induced low tryptophan environment. IDO-expressing human fibroblasts were co-cultured with Jurkat cells, human T cells, fibroblasts, or keratinocytes. Activation of GCN2 pathway was significantly higher in immune cells exposed to IDO-expressing environment relative to that of skin cells. In contrast, IMPACT was highly and constitutively expressed in skin cells while its expression was very low in stimulated T cells and undetectable in Jurkat cells. A significant IDO-induced suppressive as well as apoptotic effect was demonstrated in IMPACT knocked down fibroblasts co-cultured with IDO-expressing fibroblasts. Proliferation of Jurkat cells, stably transduced with IMPACT-expressing vector, was rescued significantly in tryptophan-deficient but not IDO-expressing environment. This may be due to the ability of IMPACT to recover the effects of IDO-mediated tryptophan depletion (GCN2 dependent) but not the effects of IDO-generated cytotoxic metabolites. These findings collectively suggest for the first time that high expression of protein IMPACT homolog in non-immune cells such as skin cells acts as a protective mechanism against IDO-induced GCN2 activation, therefore, makes them resistant to the amino acid-deprived environment caused by IDO.

Mouse pancreatic islets are resistant to indoleamine 2,3 dioxygenase-induced general control nonderepressible-2 kinase stress pathway and maintain normal viability and function.

Islet transplantation is a promising treatment for diabetes. However, it faces several challenges including requirement of systemic immunosuppression. Indoleamine 2,3-dioxygenase (IDO), a tryptophan degrading enzyme, is a potent immunomodulatory factor. Local expression of IDO in bystander fibroblasts suppresses islet allogeneic immune response in vitro. The aim of the present study was to investigate the impact of IDO on viability and function of mouse islets embedded within IDO-expressing fibroblast-populated collagen scaffold. Mouse islets were embedded within collagen matrix populated with IDO adenovector-transduced or control fibroblasts. Proliferation, insulin content, glucose responsiveness, and activation of general control nonderepressible-2 kinase stress-responsive pathway were then measured in IDO-exposed islets. In vivo viabilities of composite islet grafts were also tested in a syngeneic diabetic animal model. No reduction in islet cells proliferation was detected in both IDO-expressing and control composites compared to the baseline rates. Islet functional studies showed normal insulin content and secretion in both preparations. In contrast to lymphocytes, general control nonderepressible-2 kinase pathway was not activated in islets cocultured with IDO-expressing fibroblasts. When transplanted to diabetic mice, syngeneic IDO-expressing composite islet grafts were functional up to 100 days tested. These findings collectively confirm normal viability and functionality of islets cocultured with IDO-expressing cells and indicate the feasibility of development of a functional nonrejectable islet graft.

Local expression of indoleamine 2,3-dioxygenase suppresses T-cell-mediated rejection of an engineered bilayer skin substitute.

Engineered skin substitutes (ESSs) comprising both keratinocytes and fibroblasts can afford many advantages over the use of autologous keratinocyte grafts for the treatment of full-thickness and partial-thickness burns. In this study, we investigated the efficacy of a novel ESS containing both genetically altered fibroblasts that express the immunosuppressive factor indoleamine 2,3-dioxygenase (IDO) and primary keratinocytes from a nonautologous source to confer immune protection of xenogeneic cells cultured in a bilayer ESS. The results show that engraftment of IDO expressing skin substitutes on the back of rats significantly improves healing progression over 7 days compared with both nontreated and non-IDO-expressing skin substitutes (p<0.001). Immuno-staining of CD3 and CD31 suggests that IDO-expressing skin substitutes significantly suppress T cell infiltration (p<0.001) and improve neovascularization by four-fold (12.6±1.2 vs. 3.0±1.0 vessel-like structure/high power field), respectively. In conclusion, we found that IDO expression can improve the efficacy of nonautologous ESS for the purpose of wound healing by mitigating T-cell infiltration as well as promoting vascularization of the graft.

SQSTM1/p62 and PPARGC1A/PGC-1alpha at the interface of autophagy and vascular senescence.

Defective macroautophagy/autophagy and mitochondrial dysfunction are known to stimulate senescence. The mitochondrial regulator PPARGC1A (peroxisome proliferator activated receptor gamma, coactivator 1 alpha) regulates mitochondrial biogenesis, reducing senescence of vascular smooth muscle cells (VSMCs); however, it is unknown whether autophagy mediates PPARGC1A-protective effects on senescence. Using ppargc1a-/- VSMCs, we identified the autophagy receptor SQSTM1/p62 (sequestosome 1) as a major regulator of autophagy and senescence of VSMCs. Abnormal autophagosomes were observed in VSMCs in aortas of ppargc1a-/- mice. ppargc1a-/- VSMCs in culture presented reductions in LC3-II levels; in autophagosome number; and in the expression of SQSTM1 (protein and mRNA), LAMP2 (lysosomal-associated membrane protein 2), CTSD (cathepsin D), and TFRC (transferrin receptor). Reduced SQSTM1 protein expression was also observed in aortas of ppargc1a-/- mice and was upregulated by PPARGC1A overexpression, suggesting that SQSTM1 is a direct target of PPARGC1A. Inhibition of autophagy by 3-MA (3 methyladenine), spautin-1 or Atg5 (autophagy related 5) siRNA stimulated senescence. Rapamycin rescued the effect of Atg5 siRNA in Ppargc1a+/+ , but not in ppargc1a-/- VSMCs, suggesting that other targets of MTOR (mechanistic target of rapamycin kinase), in addition to autophagy, also contribute to senescence. Sqstm1 siRNA increased senescence basally and in response to AGT II (angiotensin II) and zinc overload, two known inducers of senescence. Furthermore, Sqstm1 gene deficiency mimicked the phenotype of Ppargc1a depletion by presenting reduced autophagy and increased senescence in vitro and in vivo. Thus, PPARGC1A upregulates autophagy reducing senescence by a SQSTM1-dependent mechanism. We propose SQSTM1 as a novel target in therapeutic interventions reducing senescence. ABBREVIATIONS: 3-MA: 3 methyladenine; ACTA2/SM-actin: actin, alpha 2, smooth muscle, aorta; ACTB/ß-actin: actin beta; AGT II: angiotensin II; ATG5: autophagy related 5; BECN1: beclin 1; CAT: catalase; CDKN1A: cyclin-dependent kinase inhibitor 1A (P21); Chl: chloroquine; CTSD: cathepsin D; CYCS: cytochrome C, somatic; DHE: dihydroethidium; DPBS: Dulbecco's phosphate-buffered saline; EL: elastic lamina; EM: extracellular matrix; FDG: fluorescein-di-ß-D-galactopyranoside; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; γH2AFX: phosphorylated H2A histone family, member X, H2DCFDA: 2',7'-dichlorodihydrofluorescein diacetate; LAMP2: lysosomal-associated membrane protein 2; MASMs: mouse vascular smooth muscle cells; MEF: mouse embryonic fibroblast; NBR1: NBR1, autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; MTOR: mechanistic target of rapamycin kinase; NFE2L2: nuclear factor, erythroid derived 2, like 2; NOX1: NADPH oxidase 1; OPTN: optineurin; PFA: paraformaldehyde; PFU: plaque-forming units; PPARGC1A/PGC-1α: peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; Ptdln3K: phosphatidylinositol 3-kinase; RASMs: rat vascular smooth muscle cells; ROS: reactive oxygen species; SA-GLB1/ß-gal: senescence-associated galactosidase, beta 1; SASP: senescence-associated secretory phenotype; SIRT1: sirtuin 1; Spautin 1: specific and potent autophagy inhibitor 1; SQSTM1/p62: sequestosome 1; SOD: superoxide dismutase; TEM: transmission electron microscopy; TFEB: transcription factor EB; TFRC: transferrin receptor; TRP53/p53: transformation related protein 53; TUBG1: tubulin gamma 1; VSMCs: vascular smooth muscle cells; WT: wild type.

The Left Internal Mammary Artery Graft: Durable and Self-Reparative.

After an unsuccessful left internal mammary artery (LIMA) to left anterior descending percutaneous coronary intervention (PCI) in an outside hospital, a patient presented with ST-segment elevation myocardial infarction. The patient was found to have LIMA occlusion and underwent a second PCI. However, there was a residual disruption of LIMA, subsequently, the patient was found to have complete LIMA recanalization, which emphasized the self-reparative nature of LIMA. (Level of Difficulty: Intermediate.).

Skin cells, but not T cells, are resistant to indoleamine 2, 3-dioxygenase (IDO) expressed by allogeneic fibroblasts.

We have previously demonstrated that indoleamine 2, 3-dioxygenase (IDO) expressed by dermal fibroblasts generated a tryptophan deficient environment in which immune cells, but not skin cells, undergo apoptosis. However, the mechanism by which primary skin cells such as fibroblasts and keratinocytes are resistant to this culture environment is not elucidated. Here, we asked the question of whether the activity of the general control nondepressing-2 (GCN2) kinase pathway in primary immune and skin cells is differently regulated in response to IDO-induced tryptophan deficient environment. Before addressing this question, the expression of IDO in IDO-adenoviral infected fibroblasts, as a source of IDO expression, was validated. We then demonstrated a significant immunosuppressive effect of IDO expression in primary human T cells co-cultured with IDO expressing fibroblasts in the presence of allogeneic pieces of either epidermis or full thickness skin. Evaluating the mechanism by which skin cells, but not T cells, are resistant to IDO induced low tryptophan environment, we then co-cultured IDO-expressing fibroblasts with bystander human T cells, the fibroblasts, or keratinocytes for 3 days. The results showed a significant activation of apoptotic pathway as analyzed by caspase-3 induction as well as the expression of CHOP, a downstream effector of GCN2 kinase pathway in T cells, but not in skin cells.

Coronary Artery Straightening Causing Acute Severe Mitral Regurgitation.

A 79-year-old woman had an atretic LIMA to LAD but without significant LAD stenosis, patent SVG to OM1, patent SVG to RCA, and severe tandem lesions in a very tortuous LCX for which she underwent PCI. Placement of a BMW coronary guidewire into the LCX resulted in the straightening of the vessel.

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.

Catheter-Induced Coronary Spasm: Serious But Preventable.

While catheter-induced spasm is considered to be rare, it needs to be ruled out (especially in cases of left main stenosis) to avoid unnecessary revascularization. We present a patient where the underlying tendency for coronary spasm was so high, the severe spasm was possibly the underlying cause of a prior cardiac arrest episode.

Young Athlete With Complex Aneurysmal Coronary Stenosis.

Kawasaki disease is an acute vasculitis that occurs predominantly in infants and children younger than 5 years old. If undiagnosed and untreated, the risk of developing coronary artery aneurysms increases to about 20%. In patients who present with angina and are found to have coronary artery aneurysm on imaging and angiography, Kawasaki disease should be considered as one of the leading diagnoses.

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.