Is it time to reduce the length of postgraduate training for physician-scientists in internal medicine?

Physician-scientists play a crucial role in advancing medical knowledge and patient care, yet the long periods of time required to complete training may impede expansion of this workforce. We examined the relationship between postgraduate training and time to receipt of NIH or Veterans Affairs career development awards (CDAs) for physician-scientists in internal medicine. Data from NIH RePORTER were analyzed for internal medicine residency graduates who received specific CDAs (K08, K23, K99, or IK2) in 2022. Additionally, information on degrees and training duration was collected. Internal medicine residency graduates constituted 19% of K awardees and 28% of IK2 awardees. Of MD-PhD internal medicine-trained graduates who received a K award, 92% received a K08 award; of MD-only graduates who received a K award, a majority received a K23 award. The median time from medical school graduation to CDA was 9.6 years for K awardees and 10.2 years for IK2 awardees. The time from medical school graduation to K or IK2 award was shorter for US MD-PhD graduates than US MD-only graduates. We propose that the time from medical school graduation to receipt of CDAs must be shortened to accelerate training and retention of physician-scientists.

Structural insights into the career path between pre- and postgraduate physician-scientist training programs.

The growing complexities of clinical medicine and biomedical research have clouded the career path for physician-scientists. In this perspective piece, we address one of the most opaque career stage transitions along the physician-scientist career path, the transition from medical school to research-focused internal medicine residency programs, or physician-scientist training programs (PSTPs). We present the perspectives of medical scientist training program (MSTP) and PSTP directors on critical features of PSTPs that can help trainees proactively align their clinical and scientific training for successful career development. We aim to provide both trainees and MSTP directors with a conceptual framework to better understand and navigate PSTPs. We also offer interview-specific questions to help trainees gather data and make informed decisions in choosing a residency program that best supports their career.

SARS-CoV-2: Current Tools to Fight COVID-19 ST-Elevation Myocardial Infarction.

The capacity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to wreak havoc on the inflammatory and coagulation pathways via the cytokine storm has led to over 6.3 million fatalities globally. Based on recent data, the mechanism predominately involves the formation of microvascular thrombosis when pertaining to cardiovascular disease. However, a subset of coronavirus disease-2019 (COVID-19)-positive patients present emergently with acute ST-elevation myocardial infarction (STEMI) are found to have severe epicardial thrombosis which is refractory to traditional coronary revascularization. We have noted mortality in these patients presenting to our facility to be as high as 90% and all angiographically confirmed to have thrombus which was refractory to traditional therapy. We present a case series of COVID-19-positive patients presenting with STEMI found to have epicardial thrombus who were treated with different traditional STEMI therapies but with fatal outcomes. Other possible techniques including mechanical thrombectomy, optimizing traditional and nontraditional anticoagulation therapy with the use of early hemodynamic support may prove more efficacious to destroy thrombus and potentially improve mortality.

Coronary Artery Spasm-Related Heart Failure Syndrome: Literature Review.

Although heart failure (HF) is a clinical syndrome that becomes worse over time, certain cases can be reversed with appropriate treatments. While coronary artery spasm (CAS) is still underappreciated and may be misdiagnosed, ischemia due to coronary artery disease and CAS is becoming the single most frequent cause of HF worldwide. CAS could lead to syncope, HF, arrhythmias, and myocardial ischemic syndromes such as asymptomatic ischemia, rest and/or effort angina, myocardial infarction, and sudden death. Albeit the clinical significance of asymptomatic CAS has been undervalued, affected individuals compared with those with classic Heberden's angina pectoris are at higher risk of syncope, life-threatening arrhythmias, and sudden death. As a result, a prompt diagnosis implements appropriate treatment strategies, which have significant life-changing consequences to prevent CAS-related complications, such as HF. Although an accurate diagnosis depends mainly on coronary angiography and provocative testing, clinical characteristics may help decision-making. Because the majority of CAS-related HF (CASHF) patients present with less severe phenotypes than overt HF, it underscores the importance of understanding risk factors correlated with CAS to prevent the future burden of HF. This narrative literature review summarises and discusses separately the epidemiology, clinical features, pathophysiology, and management of patients with CASHF.

Adjuvant Radiation and Survival Following Surgical Resection of Sinonasal Adenocarcinoma.

OBJECTIVES: This study aims to investigate the utility of adjuvant radiation in patients who undergo surgical resection for the management of node-negative sinonasal adenocarcinoma (SNAC). STUDY DESIGN: Retrospective database review. METHODS: The 2004-2016 National Cancer Data Base (NCDB) was used to extract patients with surgically resected node-negative SNAC. Kaplan-Meier survival analysis and Cox-Proportional Hazards Modelling were used to analyze the impact of adjuvant radiation on overall survival (OS) following surgery. RESULTS: 349 patients with SNAC underwent surgical resection. Of these patients, 154 (44.1%) received adjuvant radiotherapy (RT). Although there was no significant difference in race, age, or sex of those receiving RT, those receiving RT have more advanced diseases and are more likely to have positive margins. Kaplan Meier analysis showed no significant difference in 5-year OS in patient who received adjuvant RT in comparison to those who underwent surgical resection alone (65.7% vs. 72.6%, respectively; p = 0.378). In addition, when looking at only patients with positive margins, 5-year OS still did not have a significant difference (73.8% vs. 61.6%, respectively; p = 0.101). Only patients with clinical AJCC T4 showed a statistically significant survival benefit with adjuvant RT (56.9% vs. 29.9%, respectively; p = 0.009). CONCLUSIONS: Adjuvant RT does not appear to provide a significant survival benefit in patients with resected SNAC, with the exception of those with clinically AJCC T4 disease. LEVEL OF EVIDENCE: 4 Laryngoscope, 133:2603-2612, 2023.

Pearls of wisdom for aspiring physician-scientist residency applicants and program directors.

Postgraduate physician-scientist training programs (PSTPs) enhance the experiences of physician-scientist trainees following medical school graduation. PSTPs usually span residency and fellowship training, but this varies widely by institution. Applicant competitiveness for these programs would be enhanced, and unnecessary trainee anxiety relieved, by a clear understanding of what factors define a successful PSTP matriculant. Such information would also be invaluable to PSTP directors and would allow benchmarking of their admissions processes with peer programs. We conducted a survey of PSTP directors across the US to understand the importance they placed on components of PSTP applications. Of 41 survey respondents, most were from internal medicine and pediatrics residency programs. Of all components in the application, two elements were considered very important by a majority of PSTP directors: (a) having one or more first-author publications and (b) the thesis advisor's letter. Less weight was consistently placed on factors often considered more relevant for non-physician-scientist postgraduate applicants - such as US Medical Licensing Examination scores, awards, and leadership activities. The data presented here highlight important metrics for PSTP applicants and directors and suggest that indicators of scientific productivity and commitment to research outweigh traditional quantitative measures of medical school performance.

Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm.

OBJECTIVE: Apolipoprotein (a)/lipoprotein(a) (Lp(a)), a major carrier of oxidized phospholipids, and α7-nicotinic acetylcholine receptor (α7-nAChR) may play an important role in the development of coronary artery spasm (CAS). In CAS, the association between Lp(a) and the α7-nAChR-modulated inflammatory macrophage polarization and activation and smooth muscle cell dysfunction remains unknown. METHODS: We investigated the relevance of Lp(a)/α7-nAChR signaling in patient monocyte-derived macrophages and human coronary artery smooth muscle cells (HCASMCs) using expression profile correlation analyses, fluorescence-assisted cell sorting flow cytometry, immunoblotting, quantitative real-time polymerase chain reaction, and clinicopathological analyses. RESULTS: There are increased serum Lp(a) levels (3.98-fold, p = 0.011) and macrophage population (3.30-fold, p = 0.013) in patients with CAS compared with patients without CAS. Serum Lp(a) level was positively correlated with high-sensitivity C-reactive protein (r 2 = 0.48, p < 0.01), IL-6 (r 2 = 0.38, p = 0.03), and α7-nAChR (r 2 = 0.45, p < 0.01) in patients with CAS, but not in patients without CAS. Compared with untreated or low-density lipoprotein- (LDL-) treated macrophages, Lp(a)-treated macrophages exhibited markedly enhanced α7-nAChR mRNA expression (p < 0.01) and activity (p < 0.01), in vitro and ex vivo. Lp(a) but not LDL preferentially induced CD80+ macrophage (M1) polarization and reduced the inducible nitric oxide synthase expression and the subsequent NO production. While shRNA-mediated loss of α7-nAChR function reduced the Lp(a)-induced CD80+ macrophage pool, both shRNA and anti-IL-6 receptor tocilizumab suppressed Lp(a)-upregulated α7-nAChR, p-p38 MAPK, IL-6, and RhoA-GTP protein expression levels in cultures of patient monocyte-derived macrophages and HCASMCs. CONCLUSIONS: Elevated Lp(a) levels upregulate α7-nAChR/IL-6/p38 MAPK signaling in macrophages of CAS patients and HCASMC, suggesting that Lp(a)-triggered inflammation mediates CAS through α7-nAChR/p38 MAPK/IL-6/RhoA-GTP signaling induction, macrophage M1 polarization, and HCASMC activation.

Ptychographic sensor for large-scale lensless microbial monitoring with high spatiotemporal resolution.

Traditional microbial detection methods often rely on the overall property of microbial cultures and cannot resolve individual growth event at high spatiotemporal resolution. As a result, they require bacteria to grow to confluence and then interpret the results. Here, we demonstrate the application of an integrated ptychographic sensor for lensless cytometric analysis of microbial cultures over a large scale and with high spatiotemporal resolution. The reported device can be placed within a regular incubator or used as a standalone incubating unit for long-term microbial monitoring. For longitudinal study where massive data are acquired at sequential time points, we report a new temporal-similarity constraint to increase the temporal resolution of ptychographic reconstruction by 7-fold. With this strategy, the reported device achieves a centimeter-scale field of view, a half-pitch spatial resolution of 488 nm, and a temporal resolution of 15-s intervals. For the first time, we report the direct observation of bacterial growth in a 15-s interval by tracking the phase wraps of the recovered images, with high phase sensitivity like that in interferometric measurements. We also characterize cell growth via longitudinal dry mass measurement and perform rapid bacterial detection at low concentrations. For drug-screening application, we demonstrate proof-of-concept antibiotic susceptibility testing and perform single-cell analysis of antibiotic-induced filamentation. The combination of high phase sensitivity, high spatiotemporal resolution, and large field of view is unique among existing microscopy techniques. As a quantitative and miniaturized platform, it can improve studies with microorganisms and other biospecimens at resource-limited settings.

Optofluidic ptychography on a chip.

We report the implementation of a fully on-chip, lensless microscopy technique termed optofluidic ptychography. This imaging modality complements the miniaturization provided by microfluidics and allows the integration of ptychographic microscopy into various lab-on-a-chip devices. In our prototype, we place a microfluidic channel on the top surface of a coverslip and coat the bottom surface with a scattering layer. The channel and the coated coverslip substrate are then placed on top of an image sensor for diffraction data acquisition. Similar to the operation of a flow cytometer, the device utilizes microfluidic flow to deliver specimens across the channel. The diffracted light from the flowing objects is modulated by the scattering layer and recorded by the image sensor for ptychographic reconstruction, where high-resolution quantitative complex images are recovered from the diffraction measurements. By using an image sensor with a 1.85 µm pixel size, our device can resolve the 550 nm linewidth on the resolution target. We validate the device by imaging different types of biospecimens, including C. elegans, yeast cells, paramecium, and closterium sp. We also demonstrate a high-resolution ptychographic reconstruction at a video framerate of 30 frames per second. The reported technique can address a wide range of biomedical needs and engenders new ptychographic imaging innovations in a flow cytometer configuration.

High-throughput lensless whole slide imaging via continuous height-varying modulation of a tilted sensor.

We report a new, to the best of our knowledge, lensless microscopy configuration by integrating the concepts of transverse translational ptychography and defocus multi-height phase retrieval. In this approach, we place a tilted image sensor under the specimen for introducing linearly increasing phase modulation along one lateral direction. Similar to the operation of ptychography, we laterally translate the specimen and acquire the diffraction images for reconstruction. Since the axial distance between the specimen and the sensor varies at different lateral positions, laterally translating the specimen effectively introduces defocus multi-height measurements while eliminating axial scanning. Lateral translation further introduces sub-pixel shift for pixel super-resolution imaging and naturally expands the field of view for rapid whole slide imaging. We show that the equivalent height variation can be precisely estimated from the lateral shift of the specimen, thereby addressing the challenge of precise axial positioning in conventional multi-height phase retrieval. Using a sensor with 1.67 µm pixel size, our low-cost and field-portable prototype can resolve the 690 nm linewidth on the resolution target. We show that a whole slide image of a blood smear with a 120mm2 field of view can be acquired in 18 s. We also demonstrate accurate automatic white blood cell counting from the recovered image. The reported approach may provide a turnkey solution for addressing point-of-care and telemedicine-related challenges.

Pterostilbene Increases LDL Metabolism in HL-1 Cardiomyocytes by Modulating the PCSK9/HNF1α/SREBP2/LDLR Signaling Cascade, Upregulating Epigenetic hsa-miR-335 and hsa-miR-6825, and LDL Receptor Expression.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) can promote the degradation of low-density lipoprotein (LDL) receptor (LDLR), leading to hypercholesterolemia and myocardial dysfunction. The intracellular regulatory mechanism by which the natural polyphenol pterostilbene modulates the PCSK9/LDLR signaling pathway in cardiomyocytes has not been evaluated. We conducted Western blotting, flow cytometry, immunofluorescence staining, and mean fluorescence intensity analyses of pterostilbene-treated mouse HL-1 cardiomyocytes. Pterostilbene did not alter cardiomyocyte viability. Compared to the control group, treatment with both 2.5 and 5 µM pterostilbene significantly increased the LDLR protein expression accompanied by increased uptake of LDL. The expression of the mature PCSK9 was significantly suppressed at the protein and mRNA level by the treatment with both 2.5 and 5 µM pterostilbene, respectively, compared to the control. Furthermore, 2.5 and 5 µM pterostilbene treatment resulted in a significant reduction in the protein hepatic nuclear factor 1α (HNF1α)/histone deacetylase 2 (HDAC2) ratio and sterol regulatory element-binding protein-2 (SREBP2)/HDAC2 ratio. The expression of both hypoxia-inducible factor-1 α (HIF1α) and nuclear factor erythroid 2-related factor 2 (Nrf2) at the protein level was also suppressed. Pterostilbene as compared to short hairpin RNA against SREBP2 induced a higher protein expression of LDLR and lower nuclear accumulation of HNF1α and SREBP2. In addition, pterostilbene reduced PCSK9/SREBP2 interaction and mRNA expression by increasing the expression of hsa-miR-335 and hsa-miR-6825, which, in turn, increased LDLR mRNA expression. In cardiomyocytes, pterostilbene dose-dependently decreases and increases the protein and mRNA expression of PCSK9 and LDLR, respectively, by suppressing four transcription factors, HNF1α, SREBP2, HIF1α, and Nrf2, and enhancing the expression of hsa-miR-335 and hsa-miR-6825, which suppress PCSK9/SREBP2 interaction.

Multi-Vessel Coronary Artery Ectasia.

Coronary artery ectasia is a relatively rare entity, especially when it involves the left main coronary artery. Furthermore, it is even more uncommon for such a disease process to involve multiple coronary arteries. Here we describe a case of a 78-year-old female who did not possess any of the common risk factors or vasculitic etiologies associated with coronary artery ectasia, who was found to have multi-vessel ectatic segments, including that of the left main coronary artery. This case illuminates the difficult decision making regarding stenting of the coronary arteries with ectatic segments and the decision to anticoagulate.

Microbiome: Insulin signaling shapes gut community composition.

In a C. elegans model of host-microbiome interactions, interrogation of a genetically diverse panel of host strains with a defined, complex bacterial community reveals an important role for a conserved insulin-like signaling pathway in shaping the phylogenetic composition of the gut microbiome.

Association between Coronary Artery Spasm and the risk of incident Diabetes: A Nationwide population-based Cohort Study.

Background: Non-diabetic coronary artery spasm (CAS) without obstructive coronary artery disease increases insulin resistance. We investigated the risk of incident type 2 diabetes (diabetes) associated with CAS. Methods: Patient records were retrospectively collected from the Taiwan National Health Insurance Research Database during the period 2000-2012. The matched cohorts consisted of 12,413 patients with CAS and 94,721 patients in the control group. Results: During the entire follow-up, the incidence of newly-diagnosed diabetes was 22.2 events per 1000 person-years in the CAS group and 13.9 events per 1000 person-years in the control group. The increased risk of CAS-related incident diabetes was observed regardless of sex and length of follow-up. The median time to incident diabetes was 2.9 and 3.5 years in the CAS and the control group (P <0.001), respectively, regardless of sex. Although age did not affect the risk of CAS-related incident diabetes, the risk was less apparent in the subgroups of male, dyslipidemia, chronic obstructive pulmonary disease, stroke, gout and medicated hypertension. However, CAS patients aged <50 years compared with patients ≥50 years had a greater risk of incident diabetes in females but not in males. Older CAS patients developed diabetes in a shorter length of time than younger patients. Conclusion: CAS is a risk factor for incident diabetes regardless of sex. However, females aged <50 years have a more apparent risk for CAS-related diabetes than old females, which is not observed in males. The median time of 2.9 years to incident diabetes warrants close follow-up.

Garcinol Attenuates Lipoprotein(a)-Induced Oxidative Stress and Inflammatory Cytokine Production in Ventricular Cardiomyocyte through α7-Nicotinic Acetylcholine Receptor-Mediated Inhibition of the p38 MAPK and NF-κB Signaling Pathways.

Garcinol, a nicotinic acetylcholine receptor (nAChR) antagonist, has recently been established as an anti-inflammation agent. However, the molecular mechanism by which garcinol suppresses inflammation in the context of acute myocardial infarction (AMI) remains unclear. Hypothesis: We hypothesized that the administration of physiological doses of garcinol in mice with isoproterenol-induced AMI decreased the effect of lipoprotein(a) (Lp(a))-induced inflammation both in vivo and in vitro via the α7-nAChRs mediated p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) signaling pathway. We analyzed altered reactive oxygen species (ROS) generation, the production of superoxide by mitochondria, cytokine expression patterns, and the role of the p38 MAPK/NF-κB signaling pathway after Lp(a)-stimulated human ventricular cardiomyocyte AC16 cells were treated with increasing doses of garcinol. C-reactive protein (CRP), interleukin (IL)-1ß, IL-6, or tumor necrosis factor (TNF)-α production were detected by enzyme-linked immunosorbent assay. The Cell Counting Kit-8 assay was used to evaluate drug cytotoxicity. Western blots and confocal fluorescence microscopy were used to determine altered expression patterns of inflammatory biomarkers. We also examined whether the therapeutic effect of garcinol in AMI was mediated in part by α7-nAChR. Lp(a)-induced inflammatory cardiomyocytes had increased expression of membrane-bound α7-nAChRs in vitro and in vivo. Low-dose garcinol did not affect cardiomyocyte viability but significantly reduced mitochondrial ROS, CRP, IL-1ß, IL-6, and TNF-α production in Lp(a)-stimulated cardiomyocytes (p < 0.05). The Lp(a)-induced phosphorylation of p38 MAPKs, CamKII, and NFκB, as well as NFκB-p65 nuclear translocation, was also suppressed (p < 0.05) by garcinol, while the inhibition of p38 MAPK by the inhibitor SB203580 decreased the phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK. Garcinol protected cardiomyocytes by inhibiting apoptosis and inflammation in mice with AMI. Furthermore, garcinol also enhanced the expression of microRNA-205 that suppressed the α7-nAChR-induced p38 MAPK/NF-κB signaling pathway. Garcinol suppresses Lp(a)-induced oxidative stress and inflammatory cytokines by α7-nAChR-mediated inhibition of p38 MAPK/NF-κB signaling in cardiomyocyte AC16 cells and isoproterenol-induced AMI mice.

Low-molecular weight vs. unfractionated heparin for prevention of venous thromboembolism in general surgery: a meta-analysis.

To assess the association between low-molecular weight heparin (LMWH) and unfractionated heparin (UFH) in the prevention of venous thromboembolism (VTE) among participants undergoing general surgery. LMWH and UFH are the standard of practice in the prevention of VTE in surgery. However, in the context of general surgery, studies comparing the effectiveness of these treatments are limited. A systematic search was conducted to find studies which examined the comparative effectiveness between LMWH and UFH in the prophylaxis of VTE in the context of general surgery. The number of events of VTE in groups receiving LMWH or UFH was the primary outcome of interest, and was used to calculate odds-ratios. Amongst 33,068 participants pooled from twelve studies, the rate of VTE was 1.3% in those treated with LMWH, and 3.1% in those treated with UFH. Although there was a wide difference in rates due to clinical heterogeneity, there was no statistically significant difference between treatment effects [OR 0.77; 95% CI 0.58-1.03; p value = 0.0783; I2= 62.3%; 12 studies]. In terms of the sensitivity analysis, sources overly contributing to heterogeneity were removed. The random-effects model continued to show insignificance between LMWH and UFH in the prevention of VTE in participants undergoing general surgery [OR 0.86; 95% CI 0.69-1.08; p value = 0.2005; I2= 0%; 9 studies]. Results show an equal effectiveness in the prevention of VTE between participants undergoing general surgery in those allocated to receive LMWH to those allocated to receive UFH.

Starvation Responses Throughout the Caenorhabditiselegans Life Cycle.

Caenorhabditis elegans survives on ephemeral food sources in the wild, and the species has a variety of adaptive responses to starvation. These features of its life history make the worm a powerful model for studying developmental, behavioral, and metabolic starvation responses. Starvation resistance is fundamental to life in the wild, and it is relevant to aging and common diseases such as cancer and diabetes. Worms respond to acute starvation at different times in the life cycle by arresting development and altering gene expression and metabolism. They also anticipate starvation during early larval development, engaging an alternative developmental program resulting in dauer diapause. By arresting development, these responses postpone growth and reproduction until feeding resumes. A common set of signaling pathways mediates systemic regulation of development in each context but with important distinctions. Several aspects of behavior, including feeding, foraging, taxis, egg laying, sleep, and associative learning, are also affected by starvation. A variety of conserved signaling, gene regulatory, and metabolic mechanisms support adaptation to starvation. Early life starvation can have persistent effects on adults and their descendants. With its short generation time, C. elegans is an ideal model for studying maternal provisioning, transgenerational epigenetic inheritance, and developmental origins of adult health and disease in humans. This review provides a comprehensive overview of starvation responses throughout the C. elegans life cycle.

Modular metabolite assembly in Caenorhabditis elegans depends on carboxylesterases and formation of lysosome-related organelles.

Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms.

Myocardial Ischemic Syndromes, Heart Failure Syndromes, Electrocardiographic Abnormalities, Arrhythmic Syndromes and Angiographic Diagnosis of Coronary Artery Spasm: Literature Review.

In coronary artery spasm (CAS), an excess coronary vasoconstriction causing total or subtotal vessel occlusion could lead to syncope, heart failure syndromes, arrhythmic syndromes, and myocardial ischemic syndromes including asymptomatic myocardial ischemia, stable and unstable angina, acute myocardial infarction, and sudden cardiac death. Although the clinical significance of CAS has been underrated because of the frequent absence of symptoms, affected patients appear to be at higher risk of syncope, serious arrhythmias, and sudden death than those with classic Heberden's angina pectoris. Therefore, a prompt diagnosis has important therapeutic implications, and is needed to avoid CAS-related complications. While a definitive diagnosis is based mainly on coronary angiography and provocative testing, clinical features may help guide decision-making. We perform a literature review to assess the past and current state of knowledge regarding the clinical features, electrocardiographic abnormalities and angiographic diagnosis of CAS, while a discussion of mechanisms is beyond the scope of this review.