This review article delves into the intricate and evolving relationship between coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM), two intriguing cardiovascular conditions increasingly recognised for their potential interplay. We examine their characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies. Emerging evidence suggests a link between microvascular dysfunction and the development of TCM, leading to a deeper exploration of their connection. Accurate diagnosis of both conditions becomes essential, as microvascular dysfunction may modify TCM outcomes. We underscore the significance of understanding this connection for improved patient care, emphasising the need for tailored interventions when CMD and TCM coexist. Collaborative research and heightened clinical awareness are advocated to advance our comprehension of this relationship. Through interdisciplinary efforts, we aim to refine diagnostic precision, develop targeted therapies, and enhance patient outcomes in cardiovascular medicine. Medical interest has surged toward two distinct yet captivating cardiovascular conditions: coronary microvascular dysfunction (CMD) and takotsubo cardiomyopathy (TCM). While initially perceived as separate entities, recent research hints at a potentially intricate link between these conditions. This article delves into this complex interplay between CMD and TCM, probing their shared pathophysiological mechanisms, clinical presentations, diagnostic challenges, and treatment implications -3.Coronary microvascular dysfunction encompasses a spectrum of disorders characterised by anomalies in the microvasculature's structure and function within the coronary circulation. Unlike traditional coronary artery disease, which affects large epicardial vessels, CMD involves dysfunction in the smaller arterioles and capillaries that regulate myocardial blood flow. Despite the absence of significant obstructive coronary artery disease, CMD leads to angina-like symptoms, myocardial ischemia, and abnormal stress test results. The elusive nature of CMD and its limited diagnostic tools pose challenges in diagnosis, rendering understanding its underlying mechanisms and clinical significance increasingly pivotal ,5.In contrast, TCM, or "broken heart syndrome," manifests as transient left ventricular dysfunction mimicking acute myocardial infarction. Chest pain, electrocardiographic changes, and elevated cardiac biomarkers typify this condition. Often arising from emotional or physical stressors, TCM's hallmark is the unique apical ballooning pattern evident in cardiac imaging. While initially viewed as reversible with a favourable prognosis, recent research illuminates potential severe complications and enduring consequences ,7.The realisation of a possible connection between CMD and TCM carries profound ramifications for both clinical practice and research. Evidence suggests that patients with TCM often exhibit microvascular dysfunction, hinting at an underlying link between these conditions. Understanding this association could offer insights into the triggers and pathogenesis of TCM. Furthermore, discerning the relationship between CMD and TCM stands to shape therapeutic strategies and enhance patient outcomes ,9.This review comprehensively explores the evolving relationship between CMD and TCM. We offer a holistic perspective on their shared pathophysiological mechanisms, clinical manifestations, diagnostic hurdles, and therapeutic implications by delving into the crossroads of these two distinct yet potentially intertwined conditions. Through a critical analysis of existing research, clinical observations, and theoretical models, our synthesis aims to provide healthcare professionals, researchers, and clinicians with an exhaustive resource. This resource illuminates conceivable connections between CMD and TCM, emphasising the importance of recognising and addressing this association in clinical practice. Our in-depth examination of CMD and TCM's complexities strives to advance medical understanding, enhance patient care, and formulate precise strategies for managing these captivating cardiovascular conditions.Coronary microvascular dysfunction (CMD)Definition and Pathophysiology of CMDCoronary microvascular dysfunction encompasses a spectrum of disorders characterised by intricate abnormalities within the smaller coronary vessels, including arterioles and capillaries. In contrast to traditional coronary artery disease, which primarily affects the larger epicardial vessels, CMD homes in on the delicate microcirculation. To comprehensively understand CMD's pathophysiology, it's crucial to explore the underlying mechanisms that have been identified. Endothelial dysfunction stands at the forefront of CMD's pathophysiology, playing a pivotal role in impairing the functionality of the microvasculature. This dysfunction is intricately linked to the imbalance of vasoactive factors and nitric oxide availability, ultimately affecting the vascular tone and endothelium-dependent vasodilation . MoreoveClinical Presentation and Diagnostic ChallengesThe clinical presentation of CMD closely mirrors that of obstructive coronary artery disease, making it challenging to distinguish between the two based solely on symptoms. Patients with CMD often report chest pain, dyspnea (shortness of breath), and exercise intolerance, commonly associated with traditional coronary artery disease. This similarity in symptoms can lead to confusion in diagnosis, mainly when relying solely on clinical presentation .One of the critical diagnostic challenges in CMD lies in the limitations of conventional diagnostic tests, such as angiography. Unlike obstructive coronary artery disease, CMD does not involve significant narrowing or stenosis of the larger coronary arteries, typically visualised through angiography. This absence of visually apparent coronary stenosis can lead to underdiagnosis or misdiagnosis, as these tests may not capture the microvascular abnormalities characteristic of CMD .Furthermore, the need for well-defined diagnostic criteria and standardised assessments for CMD exacerbates the difficulty in identifying the condition accurately. The absence of universally accepted guidelines to diagnose CMD makes it challenging for healthcare practitioners to consistently recognise and differentiate it from other cardiac conditions. This lack of standardised criteria also hampers research efforts and makes it difficult to compare findings across studies .The confluence of overlapping symptoms, along with the limited sensitivity of existing diagnostic tests, contributes to a significant underrecognition and underdiagnosis of CMD. This diagnostic shortfall is consequential, potentially resulting in treatment delays and impacting patient outcomes. An appreciable aspect to consider is the percentage of undetected cases due to these challenges. Additionally, it is pertinent to discuss the sensitivity and specificity of the employed diagnostic tests and the symptoms associated with CMD. As the landscape of CMD research evolves, the need becomes apparent to establish standardised diagnostic criteria and innovative diagnostic techniques. By addressing this pressing need, the accurate identification and effective management of this intricate condition can be significantly improved .Underlying Causes and Risk FactorsCoronary microvascular dysfunction is a complex condition influenced by various underlying causes and risk factors extending beyond traditional cardiovascular risk factors. While hypertension, diabetes, and dyslipidemia are recognised as conventional contributors to CMD, a growing body of evidence highlights the significance of non-traditional risk factors in its development .Psychosocial stress emerges as a potent contributor to CMD. Chronic stress triggers the release of stress hormones, leading to endothelial dysfunction and impaired vasomotor responses in the coronary microvasculature. This can result in reduced myocardial blood flow regulation and contribute to the manifestation of CMD symptoms .Hormonal imbalances play a role in CMD pathogenesis, particularly in women. Oestrogen, for instance, exerts protective effects on endothelial function, and its decline during menopause might contribute to microvascular dysfunction. Hormonal fluctuations during the menstrual cycle also influence vasomotor responses, potentially impacting coronary microcirculation .Systemic inflammation is increasingly recognised as a critical player in CMD. Chronic inflammation contributes to endothelial dysfunction, oxidative stress, and impaired nitric oxide bioavailability. Inflammatory cytokines can directly affect coronary microvascular function, altering vasodilation responses and contributing to CMD .Endothelial dysfunction, a hallmark feature of CMD, is a common link between these risk factors. It disrupts the delicate balance between vasodilation and vasoconstriction, impairing coronary blood flow regulation. Endothelial dysfunction contributes to the microvascular abnormalities observed in CMD and lays the groundwork for developing ischemic symptoms ,20.Available Diagnostic Techniques for CMDCoronary flow reserve measurements using Doppler ultrasound: Doppler ultrasound measures blood flow velocities within the coronary arteries during rest and stress. The coronary flow reserve is assessed by calculating the ratio of flow velocities before and after vasodilation. Reduced coronary flow reserve indicates microvascular dysfunction and impaired vasodilatory capacity, which can contribute to myocardial ischemia ,22.Positron emission tomography (PET): Positron emission tomography imaging quantitatively assesses myocardial blood flow at rest and during stress, usually induced by pharmacological agents or exercise. The comparison of these flow measurements provides insights into the functionality of the microvasculature. Positron emission tomography can help identify regions of reduced perfusion and abnormalities in microvascular function, contributing to the diagnosis of CMD ,24.Cardiac MRI: Cardiac MRI offers non-invasive visualisation of the myocardium and surrounding structures. Techniques like myocardial perfusion imaging provide information about blood flow distribution, aiding in identifying microvascular dysfunction. Cardiac MRI can help evaluate myocardial oxygen supply-demand balance and detect ischemic regions without obstructive coronary artery disease ,26.Invasive coronary reactivity testing: Invasive procedures involving the administration of vasoactive agents within the coronary arteries allow for direct assessment of microvascular function. Endothelial-dependent and independent vasodilatory responses are measured, providing insights into microvascular dysfunction. However, the invasiveness of this approach limits its routine clinical use ,28.Despite the availability of these diagnostic techniques, challenges persist in interpreting results and establishing definitive diagnostic criteria. The lack of standardised protocols and reference values makes establishing universally accepted thresholds for diagnosing CMD difficult. Variability in patient populations, equipment, and procedural protocols further complicates result interpretation. Overcoming these challenges requires collaborative efforts among researchers and clinicians to establish consensus guidelines and refine the diagnostic approach for CMD, ultimately enhancing its recognition and management .Current Treatment Strategies for CMDLifestyle modifications: Lifestyle interventions stand as the cornerstone of CMD management. Encouraging patients to adopt a heart-healthy lifestyle is paramount. This includes regular physical exercise tailored to individual capabilities, as exercise has been shown to enhance endothelial function and improve microvascular health. Furthermore, weight management plays a pivotal role, as excess body weight can contribute to metabolic disturbances and exacerbate microvascular dysfunction. Smoking cessation is of utmost importance, given that smoking damages endothelial cells and worsens microvascular health. Additionally, addressing psychosocial stressors through stress reduction techniques, mindfulness, and psychological counselling can contribute to overall well-being and potentially mitigate the impact of stress on microvascular function ,31.Pharmacological interventions: Pharmacotherapy for CMD aims to alleviate symptoms, enhance microvascular function, and target underlying risk factors. Endothelial function-enhancing agents, such as angiotensin-converting enzyme (ACE) inhibitors and statins, promise to improve endothelial health and promote vasodilation. Vasodilators, such as calcium channel blockers and nitric oxide donors, can help alleviate microvascular constriction and enhance coronary blood flow. Additionally, anti-inflammatory agents are being explored due to their potential role in reducing vascular inflammation and improving microvascular function ,33.Patient education and psychosocial support: Patient education is integral to holistic CMD management. Empowering patients with knowledge about their condition, its underlying mechanisms, and the significance of lifestyle modifications fosters active participation in their care. Moreover, addressing psychosocial stressors, including anxiety and depression, is essential, as these factors can exacerbate microvascular dysfunction. Psychological support and counselling can help patients cope with CMD’s emotional and psychological impact, promoting a holistic approach to well-being ,35.Takotsubo cardiomyopathy (TCM)Definition and Characteristic Features of TCMTakotsubo cardiomyopathy, often called "broken heart syndrome," is a unique and transient condition characterised by acute left ventricular dysfunction, typically presenting with symptoms resembling acute myocardial infarction. The hallmark feature of TCM is the distinctive ventricular ballooning observed during cardiac imaging, which resembles a Japanese octopus trap known as "takotsubo." Left ventricular dysfunction typically involves the apex but can also affect other heart segments .Proposed Mechanisms for TCM DevelopmentThe precise mechanisms driving the development of TCM remain a subject of continuous investigation and exploration. Multiple hypotheses have emerged, each offering insights into the intricate cascade of events that culminate in this unique cardiac phenomenon. These mechanisms include but are not limited to, surge-induced myocardial stunning, microvascular dysfunction, coronary artery vasospasm, and neurogenic influences .Catecholamine surge-induced myocardial stunning: One of the prominent theories centres around the significant role of the autonomic nervous system's response to stress. A sudden and excessive release of stress hormones, particularly catecholamines such as adrenaline, is thought to trigger a surge-induced myocardial stunning. This stunning effect results in transient myocardial dysfunction, marked by impaired contractility and ventricular ballooning .Microvascular dysfunction: Another hypothesis emphasises the role of microvascular dysfunction in TCM development. Under the influence of stress hormones, there is potential for the small coronary vessels, including arterioles and capillaries, to undergo dysregulation. Microvascular dysfunction disrupts normal blood flow regulation, leading to inadequate myocardial oxygen supply. This compromised perfusion contributes to myocardial stunning and the characteristic ventricular ballooning observed in TCM cases .Coronary artery vasospasm: The involvement of coronary artery vasospasm is also proposed as a mechanism for TCM initiation. Stress-induced alterations in vasomotor tone could trigger transient spasms in the coronary arteries, leading to reduced blood flow to the heart muscle. This diminished blood supply can result in myocardial dysfunction, with the apical region particularly susceptible due to its anatomical characteristics .Neurogenic influences: Neurogenic factors, including the brain-heart connection, have gained attention as potential contributors to TCM development. Emotional stressors can stimulate the autonomic nervous system, leading to altered heart rate variability, sympathetic nervous system activation, and hormonal fluctuations. This complex interplay between the brain and the heart might contribute to the intricate pathophysiology of TCM .Clinical Presentation and Diagnostic Criteria for TCMTakotsubo cardiomyopathy is characterised by a distinctive clinical presentation and diagnostic criteria that differentiate it from other cardiovascular conditions. The hallmark symptom is the sudden onset of chest pain, often accompanied by dyspnea, palpitations, and a feeling of impending doom. This presentation can closely mimic acute coronary syndrome, particularly ST-segment elevation myocardial infarction (STEMI), leading to initial diagnostic challenges .Diagnostic criteria for TCM have evolved to aid in accurate differentiation from other cardiac pathologies. Transient left ventricular dysfunction is a central feature of TCM, with echocardiography and cardiac MRI serving as crucial tools for its visualisation. Coronary angiography reveals the absence of significant coronary artery stenosis or plaque rupture, further supporting the diagnosis. This differentiation is paramount, as TCM is managed differently from acute coronary syndromes .Also, diagnostic criteria exclude other conditions that might mimic TCM's presentation. Pheochromocytoma, a rare tumour causing excess catecholamine release, and myocarditis, inflammation of the heart muscle, should be ruled out due to their potential to induce similar stress-related myocardial dysfunction .Cardiac imaging, particularly echocardiography and cardiac MRI is indispensable in confirming the diagnosis. Echocardiography unveils the hallmark feature of TCM, the unique apical ballooning pattern, which distinguishes it from other cardiac pathologies. Cardiac MRI further enhances diagnostic accuracy by providing detailed insights into myocardial tissue characteristics and perfusion patterns, facilitating the differentiation of TCM from other conditions presenting with similar symptoms .Differentiating TCM from Acute Coronary SyndromeDistinguishing TCM from acute coronary syndrome (ACS) is paramount due to their shared clinical presentations, which often include chest pain, dyspnea, and electrocardiographic changes. One crucial distinction is the absence of culprit coronary lesions on angiography in TCM cases. Unlike ACS, where obstructive coronary artery disease is typically evident, TCM patients display normal or near-normal coronary arteries. This disparity emphasises the need for comprehensive angiographic evaluation to exclude coronary artery obstruction and confirm the absence of significant stenosis .Furthermore, TCM patients tend to exhibit less pronounced elevations in cardiac biomarkers, such as troponin levels, when compared to the more typical ACS cases. While troponin elevation is a hallmark of myocardial injury, the extent of elevation in TCM is often milder than observed in ACS, further aiding differentiation. However, it is essential to note that a certain degree of troponin elevation can still be present in TCM cases, underscoring the importance of integrating multiple diagnostic criteria .Cardiac imaging is an invaluable tool in the differentiation process, particularly echocardiography and cardiac MRI. The characteristic apical ballooning pattern observed during imaging is a hallmark of TCM. This distinctive morphology, resembling the shape of a Japanese octopus trap (takotsubo), is a strong differentiator from ACS. Imaging findings directly visualise ventricular dysfunction and shape abnormalities, providing critical insights into the diagnosis .Management and Prognosis of TCMTakotsubo cardiomyopathy management encompasses a multi-faceted approach focused on supportive care to stabilise hemodynamics, address complications, and alleviate symptoms. Given the acute nature of TCM, patients often require vigilant monitoring in a specialised cardiac care setting. Stabilising hemodynamics involves carefully managing fluid balance, blood pressure, and heart rate to ensure optimal cardiac function. Efforts to maintain adequate perfusion and oxygenation are crucial, and interventions like supplemental oxygen and intravenous medications might be employed as necessary .Furthermore, addressing potential complications is of paramount importance in the management of TCM. Patients with TCM are at risk of developing heart failure due to transient left ventricular dysfunction. Standard heart failure therapies, including diuretics and beta-blockers, may be considered to manage volume overload and control heart rate. Arrhythmias, such as atrial fibrillation or ventricular tachycardia, might occur in the acute phase and necessitate appropriate treatment to restore a stable cardiac rhythm. Additionally, systemic embolism, particularly involving the left ventricular clot or thrombus formation, is a potential complication that requires attention to prevent embolic events .Most TCM cases exhibit a favourable prognosis with the spontaneous recovery of left ventricular function within weeks to months. Serial cardiac imaging, such as echocardiography or cardiac MRI, is valuable for monitoring the improvement in ventricular function over time. The heart's remarkable ability to heal and return to normal functioning underscores the transient nature of TCM. However, vigilance remains essential, as some cases might experience a protracted recovery period or recurrent episodes .Lifestyle modifications and addressing psychosocial factors play a crucial role in the long-term prognosis of TCM patients. Encouraging patients to adopt heart-healthy habits, including maintaining a balanced diet, engaging in regular physical activity, and avoiding tobacco and excessive alcohol consumption, contributes to overall cardiovascular well-being. Addressing underlying stressors and providing psychological support is equally important, as emotional triggers often precede TCM episodes. Comprehensive care extends beyond the acute phase to mitigate the potential triggers for recurrent episodes and optimise long-term cardiac health .The interplay between CMD and TCMReview of Studies Suggesting a Connection between CMD and TCMRecent years have witnessed a burgeoning body of research that unveils the captivating prospect of a multifaceted interplay between CMD and TCM. This intriguing association has emerged through meticulously scrutinising diverse studies, including case reports and retrospective analyses. These inquiries have illuminated instances where TCM manifested in individuals previously displaying indications of underlying microvascular dysfunction. These preliminary observations have ignited curiosity within the medical community, suggesting a compelling nexus between CMD and TCM's pathogenesis .Numerous case reports have documented instances in which individuals diagnosed with CMD, an ailment marked by coronary microvasculature irregularities, subsequently encountered episodes of TCM. These cases potentially offer insights into a shared physiological connection that warrants closer investigation. Likewise, retrospective patient data analyses have unveiled a suggestive pattern that a subset of TCM cases might be heralded by documented or suspected CMD, implying a temporal relationship deserving thorough exploration .While these revelations prompt inquiries into potential mechanisms and implications, they also underline the need to consider additional research methodologies. Could microvascular dysfunction contribute to or even initiate TCM's development? Could CMD influence the trajectory or prognosis of TCM episodes? Rooted in these clinically observed correlations, these queries beckon a deeper understanding of the shared pathophysiological underpinnings that might underscore this intriguing association .The studies discussed undoubtedly build a compelling case for the connection between CMD and TCM. Nevertheless, they simultaneously serve as a launchpad for broader research endeavours. The implications of such an interrelationship could resonate profoundly, impacting diagnostic precision, risk evaluation, and therapeutic strategies. Hence, the clarion call for further investigation into these intricate dynamics transcends academic curiosity. It promises to advance comprehension of these enigmatic cardiovascular conditions and, by extension, elevate patient care in a substantive and impactful manner -57.Shared Pathophysiological MechanismsEndothelial dysfunction: A central component in both CMD and TCM, endothelial dysfunction refers to the impaired function of the endothelium, the inner lining of blood vessels. In CMD, compromised endothelial function reduces vasodilation and impairs blood flow regulation within the coronary microvasculature. Similarly, endothelial dysfunction could hinder normal coronary blood flow responses in TCM, potentially contributing to the transient myocardial dysfunction observed during TCM episodes .Oxidative stress: Elevated oxidative stress, characterised by an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defences, is a common denominator in CMD and TCM. In CMD, oxidative stress can lead to endothelial dysfunction and structural alterations in the microvasculature, further impairing blood flow regulation. Takotsubo cardiomyopathy episodes, often triggered by stress, can trigger a surge in oxidative stress, which may contribute to myocardial injury and contractile dysfunction .Neurohormonal pathways: Dysregulation of neurohormonal pathways, particularly the autonomic nervous system's response to stress, plays a pivotal role in both conditions. Excessive release of stress hormones, such as adrenaline, can lead to vasoconstriction, increased heart rate, and myocardial oxygen demand. In individuals with pre-existing CMD, this heightened neurohormonal response could trigger the myocardium towards the transient dysfunction observed in TCM .Abnormal microvascular function and autonomic responses: Aberrant microvascular function, a hallmark of CMD, contributes to impaired myocardial perfusion and ischemia. In the context of TCM, microvascular dysfunction could exacerbate the myocardial stunning observed during TCM episodes. Furthermore, abnormal autonomic nervous system responses, including sympathetic overactivity, could influence both conditions, affecting coronary blood flow and myocardial contractility .Potential Role of Microvascular Dysfunction in Triggering TCMMicrovascular dysfunction is a compelling candidate for triggering TCM in specific vulnerable individuals. Coronary microvascular dysfunction, marked by compromised vasodilation and impaired myocardial perfusion in the microcirculation, could set the stage for a cascade of events contributing to the initiation of TCM. The intricate link between these conditions is grounded in the notion that microvascular dysfunction might make the myocardium susceptible to the profound physiological responses of stress-induced catecholamine release .In individuals with CMD, the altered microvascular tone and reduced perfusion capacity might weaken the myocardium's resilience against the surge of stress hormones, particularly adrenaline. Stress-induced catecholamines have been implicated in TCM as potential triggers, initiating a sequence of cardiac events that lead to the distinctive features of this condition. The heightened vulnerability created by microvascular dysfunction could predispose the myocardium to stress-induced myocardial stunning, whereby the heart's contractility becomes impaired and its ability to pump blood effectively diminishes. This state of myocardial dysfunction, combined with the surge of catecholamines, could culminate in the hallmark ventricular ballooning pattern observed in TCM, particularly affecting the apex of the heart .Unravelling the intricate connection between microvascular dysfunction and TCM could provide valuable insights into the complex mechanisms governing the onset of TCM. By understanding how microvascular dysfunction amplifies the effects of stress hormones on the heart, researchers and clinicians can develop a more nuanced understanding of the factors contributing to TCM development. This comprehension, in turn, could inform targeted therapeutic approaches that address microvascular dysfunction and stress hormone responses, potentially mitigating the risk of TCM episodes in susceptible individuals .Impact of CMD on the Prognosis and Outcomes of TCMEmerging evidence underscores the potential significance of CMD in shaping the clinical course of TCM. Research suggests that pre-existing CMD in individuals experiencing TCM could influence disease severity and subsequent clinical outcomes. This interaction between CMD and TCM holds implications for risk stratification and the development of tailored management strategies .In the context of TCM episodes, individuals with underlying CMD may exhibit more pronounced left ventricular dysfunction. The compromised microvascular function observed in CMD might render the myocardium vulnerable to the stress-induced catecholamine surge that characterises TCM. Consequently, the acute myocardial stunning and contractile impairment associated with TCM might manifest more severely in those with microvascular dysfunction. This could contribute to a heightened likelihood of complications, including heart failure and arrhythmias, impacting the overall prognosis .Recognising CMD as a potential modifier of TCM outcomes is crucial for risk assessment and management decisions. Risk stratification becomes more nuanced when CMD coexists with TCM, as these individuals might warrant closer monitoring and intensive interventions to mitigate the heightened risk of adverse events. Tailored management strategies could involve a more proactive approach to managing cardiac function, optimising fluid balance, and instituting preventative measures against potential complications. Such individualised management aligns with the complex interplay between CMD and TCM, addressing the unique vulnerabilities presented by their coexistence .Incorporating the potential impact of CMD into the risk assessment and management of TCM provides a broader perspective on the factors influencing disease progression and outcomes. As understanding this interaction evolves, healthcare practitioners can better tailor their approach to patient care, ensuring that individuals with CMD and TCM receive a comprehensive evaluation and strategic interventions that optimise their clinical trajectory .Theoretical Models Explaining the Relationship between CMD and TCMExploring the intricate relationship between CMD and TCM has given rise to several theoretical models to unravel the underlying mechanisms that potentially connect these conditions. These models provide valuable insights into the complex interplay between CMD and TCM, shedding light on possible pathways that link these distinct cardiovascular entities .The "two-hit hypothesis": This model postulates that CMD is the first "hit," rendering the myocardium more vulnerable to subsequent stressors, such as catecholamine release triggered by emotional or physical stress. In this scenario, microvascular dysfunction could act as a priming factor, altering myocardial responsiveness and making it more susceptible to the detrimental effects of stress hormones. This susceptibility could lead to myocardial stunning and the unique contractile abnormalities observed in TCM. The "two-hit hypothesis" suggests that CMD sets the stage for the development of TCM by modifying the myocardium's response to stressors .The "common substrate hypothesis": According to this model, CMD and TCM share underlying mechanisms that make them mutually predisposing conditions. These shared mechanisms could include abnormalities in neurohormonal signalling, endothelial dysfunction, and impaired autonomic regulation. Factors that contribute to CMD, such as chronic stress or metabolic disturbances, could also create an environment conducive to the development of TCM under the right circumstances. The common substrate hypothesis underscores the potential interconnectedness of CMD and TCM, proposing that they arise from an everyday pathophysiological basis . ExploriClinical assessment and diagnostic challengesChallenges in Diagnosing CMD and TCM IndividuallyDiagnosing CMD and TCM as distinct cardiovascular conditions presents significant diagnostic challenges due to their unique complexities .Coronary microvascular dysfunction's subtle presentation and diagnostic complexity: Coronary microvascular dysfunction's inconspicuous and often asymptomatic nature adds to the difficulty of its identification. Unlike typical angina associated with traditional coronary artery disease, CMD often displays vague symptoms or remains entirely asymptomatic. Recognizing CMD becomes particularly challenging as patients may lack characteristic chest pain, leading to delayed diagnosis or overlooking the condition. Moreover, the absence of well-defined diagnostic criteria for CMD further compounds accurate detection .Diverse diagnostic criteria complicate CMD identification: The absence of universally agreed-upon diagnostic criteria for CMD contributes significantly to the diagnostic predicament. Varied definitions and diagnostic approaches across different medical contexts hinder establishing a consistent identification method. This lack of standardized criteria can lead to underdiagnosis or misclassification, impeding the implementation of appropriate management strategies .Takotsubo cardiomyopathy's resemblance to ACS and diagnostic confusion: Takotsubo cardiomyopathy's clinical presentation resembles ACS with symptoms like chest pain, electrocardiographic changes similar to STEMI, and elevated cardiac biomarkers, which can cause diagnostic confusion. The overlap between TCM and ACS can result in healthcare providers selecting ACS treatment strategies without considering the possibility of TCM. Consequently, TCM patients might receive interventions like invasive coronary procedures or antithrombotic therapy that might not suit their condition .Implications of misdiagnosis: Misdiagnosing CMD and TCM can lead to inappropriate treatment plans and interventions. Mistakenly categorizing CMD patients as having non-cardiac causes for their symptoms could delay proper management, potentially exacerbating underlying microvascular dysfunction. Similarly, misidentifying TCM as ACS might expose patients to unnecessary invasive procedures and therapies, subjecting them to undue risks and potential complications .Overlapping Clinical Features and Diagnostic DilemmasThe convergence of clinical features between CMD and TCM challenges their accurate diagnosis. Patients with both CMD and TCM may present with overlapping symptoms, including angina-like chest pain, breathlessness, and abnormal results in stress tests. The shared clinical presentation of these conditions accentuates the complexity of discerning one from the other. The diagnostic dilemma arises because these symptoms are common in various cardiac disorders, making it arduous to attribute them to CMD or TCM solely based on clinical presentation .In times of diagnostic uncertainty, the importance of employing precise diagnostic tools becomes evident. These tools must go beyond identifying symptoms and delve into each condition's underlying mechanisms and structural abnormalities. While symptoms might be the initial presentation, accurate differentiation necessitates comprehensive imaging techniques and functional assessments that illuminate the distinct pathophysiological underpinnings of CMD and TCM. This not only aids in pinpointing the correct diagnosis but also forms the foundation for developing targeted management strategies .Appropriate management hinges on accurate diagnosis, especially given the potential impact of shared symptoms on patient outcomes. The pursuit of enhanced diagnostic precision has driven the exploration of advanced imaging modalities such as cardiac MRI, which can delineate the myocardial microstructure and function, aiding in differentiating CMD from TCM. Moreover, non-invasive functional assessments like coronary flow reserve measurements using Doppler ultrasound offer insights into microvascular function and help discern between these conditions. The development and validation of these diagnostic tools are pivotal in overcoming the challenges posed by overlapping clinical features and ensuring optimal patient care .Novel Imaging and Diagnostic Techniques to Assess CMD and TCMThe continuous evolution of imaging and diagnostic technologies has paved the way for innovative methods of assessing CMD and TCM. These advancements offer promising avenues to enhance our understanding and diagnostic capabilities for these conditions .Cardiac MRI with contrast-enhanced perfusion imaging: Cardiac MRI has emerged as a powerful tool for evaluating microvascular dysfunction in CMD. Utilising contrast-enhanced perfusion imaging, cardiac MRI allows for a non-invasive assessment of myocardial blood flow and perfusion patterns. This technique helps identify regions of impaired microvascular function and provides valuable insights into the subtler aspects of CMD. Moreover, cardiac MRI's ability to visualise the unique apical ballooning pattern associated with TCM aids in distinguishing it from other conditions with similar clinical presentations .Invasive techniques for microvascular assessment: Invasive techniques, such as coronary reactivity testing and Doppler ultrasound, are increasingly recognised for their potential in assessing microvascular function. Coronary reactivity testing involves administering pharmacological agents to induce controlled vasodilation and measuring the coronary blood flow response. This approach allows for the direct evaluation of microvascular reactivity and provides valuable information about the functional state of the microvasculature. Similarly, Doppler ultrasound offers insights into blood flow velocities within the microcirculation, aiding in identifying abnormalities in blood flow regulation .These novel techniques promise to improve the accuracy and specificity of diagnosing CMD and TCM. By enabling the direct assessment of microvascular function and subtle myocardial changes, these imaging and diagnostic methods enhance our ability to differentiate between these conditions and guide targeted treatment strategies. As these technologies continue to evolve, they are likely to play an increasingly significant role in the clinical management of CMD and TCM, facilitating earlier diagnosis and more personalised patient care .Importance of Accurate Diagnosis for Appropriate ManagementAccurate diagnosis is a cornerstone for effectively managing CMD and TCM. The ramifications of misdiagnosis reverberate across patient outcomes, potentially causing profound harm. A misdiagnosed CMD might lead to inappropriate therapeutic interventions that neglect its unique pathophysiology, thereby failing to mitigate underlying microvascular dysfunction. This mismanagement could perpetuate the progression of microvascular impairment, contributing to a cascade of adverse cardiovascular events. Similarly, inaccurately managed TCM could translate into inadequate care for a condition that requires distinct attention. This misalignment in management could impede the natural recovery process and exacerbate the associated symptoms and complications .A comprehensive diagnostic approach is thus paramount to tailoring treatment strategies precisely to the specific condition at hand. Recognising CMD and TCM individually and understanding their potential coexistence inform appropriate therapeutic decisions. Accurate diagnosis empowers healthcare professionals to provide targeted interventions that address the intricate mechanisms driving each condition. Such precision ensures that interventions are aligned with the underlying pathophysiology, optimising the chances of positive patient outcomes. Through an accurate and holistic diagnostic approach, clinicians can circumvent the pitfalls of misdiagnosis, avoid unnecessary interventions, and significantly enhance patient well-being by offering the most fitting and efficacious treatments .Management strategiesConventional Treatment Approaches for CMDManaging CMD entails a comprehensive and multifaceted strategy that focuses on addressing the underlying risk factors contributing to microvascular dysfunction and improving the health and function of the microvasculature itself. This approach aims to alleviate symptoms, improve myocardial perfusion, and enhance cardiovascular health .Lifestyle modifications: A cornerstone of CMD management is empowering patients to adopt healthy lifestyle practices. Encouraging individuals to embrace a heart-healthy diet is crucial, emphasising the consumption of nutrient-rich foods such as fruits, vegetables, whole grains, lean proteins, and healthy fats while minimising processed foods, sugary drinks, and excessive sodium intake. This dietary approach supports blood pressure control, lipid management, and weight maintenance, ultimately promoting better microvascular health .Regular exercise: Physical activity improves endothelial function, enhances microvascular dilation, and increases cardiac fitness. Tailored exercise programmes that combine aerobic activities, strength training, and flexibility exercises can improve blood flow regulation and oxygen delivery to the myocardium. Regular exercise also positively impacts systemic factors such as blood pressure, lipid levels, and glucose metabolism, which are crucial in mitigating microvascular dysfunction .Stress reduction: Stress reduction techniques are pivotal in CMD management. Chronic stress can contribute to endothelial dysfunction and exacerbate microvascular abnormalities. Incorporating relaxation techniques such as deep breathing, meditation, and yoga can help mitigate the effects of stress on the cardiovascular system. Stress reduction also involves addressing psychosocial factors and adopting strategies to manage daily stressors effectively .Smoking cessation: Smoking significantly contributes to endothelial dysfunction and microvascular damage. Encouraging individuals to quit smoking is paramount to improving microvascular health and reducing the risk of cardiovascular events. Smoking cessation interventions, including counselling and pharmacotherapy, can significantly enhance endothelial function .Pharmacological interventions: Pharmacotherapy often addresses associated risk factors and enhances microvascular function. Angiotensin-converting enzyme (ACE) inhibitors manage hypertension and improve endothelial function by reducing vascular resistance. Statins are beneficial for managing dyslipidemia and mitigating inflammation, which can contribute to microvascular dysfunction. Antiplatelet agents, such as aspirin, may be prescribed to reduce the risk of thrombotic events and improve microvascular flow .Current Management Strategies for TCMMonitoring and assessment: Continuous monitoring of hemodynamics, fluid balance, and cardiac biomarkers is paramount to evaluating the extent of ventricular dysfunction, assessing fluid status, and tracking improvements. Regular blood pressure, heart rate, and oxygen saturation assessments help gauge the patient's cardiovascular stability and guide adjustments in medical management .Fluid management: Optimal fluid management is crucial to maintaining an appropriate balance while preventing fluid overload or depletion. Careful monitoring of urine output and central venous pressure aids in tailoring fluid administration, especially in the acute phase. Diuretics may be used judiciously to manage fluid retention and oedema .Complication prevention: Preventing complications is a cornerstone of TCM management. Standard heart failure therapies, including angiotensin-converting enzyme inhibitors, beta-blockers, and diuretics, might be considered in patients with significant ventricular dysfunction. These medications aim to alleviate symptoms, stabilise hemodynamics, and enhance cardiac function .Spontaneous recovery: One of the remarkable aspects of TCM is its tendency towards spontaneous recovery. Most TCM cases exhibit gradual improvement in left ventricular function over time. This recovery is a testament to the transient nature of the condition, although the timeline varies between individuals. Regular echocardiographic assessments are essential to monitor improvements and guide the adjustment of medical therapy .Long-term follow-up and psychological support: Although TCM cases typically show favourable outcomes, long-term follow-up is recommended to ensure sustained recovery and identify any potential recurrence. Psychological support is an integral component of TCM management, as the emotional stress that triggers TCM can leave a lasting impact on patients. Addressing the psychosocial aspects through counselling and support groups can aid emotional healing .Special Considerations When CMD and TCM CoexistWhen confronted with cases where both CMD and TCM coexist within an individual, an intricate treatment approach is imperative. The convergence of these conditions necessitates a holistic strategy that navigates the complexities of both CMD and TCM, acknowledging their potential interrelation. Central to this approach is recognising the profound impact that microvascular dysfunction, a hallmark of CMD, can exert on the outcomes of TCM .A critical step in managing such cases is meticulously evaluating individual patient characteristics. This evaluation extends beyond the confines of CMD and TCM, encompassing the patient's broader medical history, comorbidities, and risk factors. These factors play a pivotal role in shaping the optimal treatment path. Comprehensive risk assessment guides the selection of therapies, ensuring that interventions are tailored to address the unique nuances of both conditions while considering potential interactions and complications .The personalised approach in this context acknowledges the intricate interplay between CMD and TCM. Rather than viewing these conditions in isolation, healthcare practitioners should perceive them as interconnected components of the patient's cardiovascular landscape. Tailoring interventions to this interplay enhances patient care, yielding a more effective treatment regimen. This personalised strategy may encompass lifestyle modifications, pharmacological interventions, and psychological support, all seamlessly integrated to address both CMD and TCM harmoniously .By adopting this holistic and personalised treatment paradigm, healthcare professionals optimise patient management in cases where CMD and TCM coexist. This approach reflects a nuanced understanding of their potential relationship, emphasising the need to acknowledge the complex interplay between these conditions for the most effective and comprehensive patient care .Potential Future Therapies Targeting Both CMD and TCMImproving microvascular function: Emerging research suggests that interventions designed to enhance microvascular function could hold significant promise for both CMD and TCM. Therapies focused on endothelial health and vasodilation might alleviate the microvascular dysfunction common to both conditions, potentially preventing the cascade of events that lead to TCM. By improving coronary blood flow regulation, these interventions could mitigate the susceptibility of CMD patients to TCM episodes triggered by stressors .Mitigating the effects of stress hormones: Given the role of stress hormones, particularly adrenaline, in triggering TCM, future therapies could aim to modulate the effects of these hormones on the cardiovascular system. Developing agents that buffer the impact of stress-induced catecholamines might prevent or attenuate the myocardial stunning characteristic of TCM. These interventions could safeguard individuals with CMD, who might be at higher risk of developing TCM due to underlying microvascular dysfunction .Modulating neurohormonal pathways: Neurohormonal imbalances are implicated in both CMD and TCM, suggesting that therapies targeting these pathways could benefit both conditions. Agents that influence autonomic nervous system responses, regulate sympathetic activation, and modulate the release of stress hormones could provide a comprehensive approach to managing the intricate relationship between CMD and TCM. By restoring balance to these pathways, such interventions improve microvascular function and reduce susceptibility to TCM .Collaborative efforts between cardiology subfields: The convergence of CMD and TCM highlights the importance of collaboration among various cardiology subfields. Cardiologists specialising in microvascular disorders and those focused on TCM could work synergistically to develop targeted interventions. A collaborative approach could involve integrating expertise in vascular health, heart failure management, and neurohormonal regulation, resulting in therapies that effectively address the shared pathophysiological mechanisms underlying CMD and TCM .Future directions and research implicationsAreas for Further Research into the CMD-TCM RelationshipThe intricate connection between CMD and TCM remains an area for further exploration. Research should delve deeper into understanding the underlying mechanisms that link these conditions, such as the role of shared neurohormonal pathways and their impact on microvascular function. Prospective studies could investigate whether CMD predisposes individuals to TCM and how CMD might modify TCM outcomes. Longitudinal studies assessing the prevalence of TCM in patients with documented CMD could help elucidate the temporal relationship between the two conditions.Novel Treatment Avenues Based on Understanding the LinkThe evolving understanding of the potential interplay between CMD and TCM could lead to novel treatment approaches that simultaneously target both conditions. Strategies focusing on improving microvascular function, addressing endothelial dysfunction, and modulating the impact of stress hormones hold promise in preventing or mitigating TCM episodes in susceptible individuals. Exploring the potential synergies between therapies used for CMD and TCM could yield innovative interventions that improve patient outcomes.Importance of Collaborative Research Between Cardiology DisciplinesGiven the potential overlap between CMD and TCM, collaborative research efforts among various cardiology disciplines are paramount. Cardiologists specialising in microvascular disorders and those focused on TCM should work together to uncover shared mechanisms, define diagnostic criteria, and develop comprehensive management strategies. A multidisciplinary approach integrating expertise from diverse fields, including cardiology, endocrinology, and psychology, can offer a more comprehensive understanding of the complex relationship between these conditions.In conclusion, this comprehensive review has illuminated the intricate relationship between CMD and TCM, shedding light on their potential interconnection. Through thoroughly exploring their distinct characteristics, shared pathophysiological mechanisms, diagnostic challenges, and management strategies, we have unveiled the intriguing possibility that microvascular dysfunction may contribute to the development and outcomes of TCM. This understanding has significant implications for patient care, underscoring the importance of accurate diagnosis and tailored interventions, particularly in cases where CMD and TCM coexist. As we navigate the evolving landscape of cardiovascular medicine, we advocate for ongoing collaborative research efforts and heightened clinical awareness to unravel the complexities of this relationship. By doing so, we strive to enhance diagnostic precision, refine therapeutic approaches, and ultimately improve the well-being and outcomes of individuals affected by these fascinating cardiovascular conditions.


Accurate assessment of gender identity and biological sex in dermatology research is crucial since their conflation or poor demarcation undermines patient respect and study accuracy. Clearer guidance is needed for health care researchers, particularly in light of the notable disparities in skin disease rates, skincare practices, literature representation, and the persistent underrepresentation of transgender and nonbinary patients. Although gender identity is a social determinant of health, its assessment in health care research is inadequate. We highlight the intricacy of gender and biological sex in dermatology research, revealing the need for more robust protocols for their assessment. We begin by evaluating the current protocols used to make such assessments, demonstrating lack of consensus. Next, we evaluate the relationships between biological sex and gender identity and how these impact skin health. We then examine the inadequate representation of gender minorities—including those who identify as transgender or gender nonbinary—in academic literature and how this disparity compromises the applicability of evidence-based medicine to all. Finally, we consider the importance of physician communication about gender identity.The articles analyzed in this study emphasize the importance of transparency when delineating differences between biological sex and gender identity. In addition, researchers should be coached on techniques to extinguish investigators’ biases. The models and tools for discerning gender identity and biological sex are shown in Note that the results obtained from the above methods were analyzed in conjunction with other questionnaires to assess correlations between the factors affecting overall population health ,2,4. GenQuestionnairesStanford Gender-Related Variables for Health Research (GVHR) Bem Sex-Role Inventory (BSRI) ,2BSRI: short form ,2GENESIS-PRAXY (Gender and Sex Determinants of Cardiovascular Disease: From Bench to Beyond-Premature Acute Coronary Syndrome) Guidelines and recommendationsSex and Gender Equity in Research (SAGER) guidelines Sex-gender variable: methodological recommendations for increasing scientific value of clinical studies Cisgender (gender identity corresponds to sex assigned at birth) males and females exhibit different rates of various skin diseases . IncreasGender-affirming therapies may induce drastic skin changes. Hormone therapies increase the risk of acne vulgaris, androgenetic alopecia, excessive sebum production, melasma, and hirsutism . DermatoResearchers believe numerous factors contribute to skin differences between gender identities . TransmaGender minority populations also face health care barriers from noninclusive treatment eligibility models. For instance, despite the increased prevalence of acne vulgaris in transgender populations, iPledge medication guidelines for isotretinoin use sex assigned at birth and require contraception to remain eligible .Although increasing female participation in clinical trials is widely supported, data on gender minority participation is nonexistent. Additionally, the risks of some conditions fluctuate depending on the stage of gender-affirming therapies. Although existing data sets may not use inclusive models of gender identity assessment, there is value in their implementation given the prospect of large-scale observational studies and meta-analyses in which these variables could be better assessed. As gender minority populations grow, these inclusive models will help physicians support all patients while ensuring that salient trends and health impacts are captured by research analyses.About 28% of transgender individuals delay seeking preventative care because of mistreatment by health care workers; thus, inclusive language is important to build trust in these communities . MedicalMisgendering patients can have profound effects on patients’ health and safety and can damage the patient-provider relationship . As ideaRobust methodologies exist to eliminate subjectivity and maximize data accuracy and utility. Current approaches to distinguishing gender identity and biological sex are inadequate and threaten the applicability of research findings to many patients. Conflating sex and gender neglects the unique dermatologic health impacts of these attributes and contributes to the underrepresentation of gender minority populations in medical literature. While more research is needed to address these issues, communication training for physicians and other health care providers could be improved. The language used must respect patients’ identities while maintaining objectivity in clinical research.


Major educational goals of Infectious Diseases (ID) are to recruit more trainees into ID and promote good antimicrobial decision-making. National survey research  revealed that ID curricula that deemphasize memorization are associated with greater odds of trainees entering the field of ID. As ID electives are not required during medical school, preclinical ID courses could represent the last dedicated opportunity for students to gain exposure to the field and acquire key clinical skills for antimicrobial selection. Yet little is known about how students experience preclinical ID courses. We aimed to explore how students experience and engage with these courses to better understand how best to augment their learning and interest in ID.We conducted individual interviews with a purposeful sample of medical students who took the preclinical ID course during three curricular years (2019-2021). Our semi-structured interviews explored students' challenges in learning ID, as well as the motivations, learning principles, and strategies guiding that learning. We generated a codebook through an iterative, inductive process using Dedoose to code interviews and facilitate analysis. We confirmed and refined major themes over 19 interviews.Establishing Relevance, Organized Study, Relating Ideas, Multi-Modal Learning, Socially Constructed Learning, and Active Engagement with Material) that support student learning, deployed through four main strategies  .Students face unique challenges learning ID but are motivated to succeed by both intrinsic and extrinsic factors (Table 1). We identified six core learning principles (Our results build on prior research indicating that students learning ID benefit from incorporation of educational principles and strategies that move beyond rote memorization to encourage active engagement and self-reflection. We found that students preference deep, strategic learning methods propelled by intrinsic motivation, despite external pressures. Our findings have implications for optimizing ID education and ultimately increasing interest in the field.All Authors: No reported disclosures


A perceived increase in weekly quality control (QC) failures prompted the development of an electronic monitoring system for quality assurance of antibiotic susceptibility testing.Antibiotic susceptibility testing (AST) procedures are sensitive to variations in testing conditions. Our diagnostic laboratory is compliant with recommendations set out in Clinical and Laboratory Standards Institute (CLSI) M100 . The trends in cefepime zone sizes against P. aeruginosa ATCC 27853 also prompted an internal review and these improved when antibiotic disk dispensers were consolidated to improve disk utilization .Persistent recurrent borderline results reflected on the monitoring system sparked the implementation of systematic investigations into QC failures; a replacement program for QC strains; and standardization of incubation timings and desiccant usage. Using new American Type Culture Collection (ATCC) reference strains reduced the percentage of QC antibiotic-organism data which failed or were borderline, and led to greater consistency in testing . Visual presentation of QC data triggered greater reflection. For instance, recurrent failures of ertapenem disks against Systemic monitoring of QC trends is low cost and highlights issues which were previously not apparent. Standardization of practices and a systematic troubleshooting process have improved the quality of our disk diffusion susceptibility testing.All Authors: No reported disclosures


Coronary vasospasm is a known complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. We report the case of a 51-year-old male with nonischemic cardiomyopathy and paroxysmal atrial fibrillation. He presented with severe mitral and tricuspid regurgitation and was taken for mitral valve replacement, tricuspid valve repair, and Maze procedure. Postoperative emergent coronary angiography demonstrated diffuse coronary vasospasm. Injection of intracoronary nitroglycerin led to clinical and angiographic improvement. This demonstrates the possibility of coronary vasospasm following mitral valve replacement and effective treatment with intracoronary administration of vasodilating agents. Coronary vasospasm is a known and feared complication following coronary artery bypass grafting surgery that has rarely been described in non-coronary cardiac operations . IatrogeWe describe herein the case of a 51-year-old African American male with hypertension, paroxysmal atrial fibrillation, stage III chronic kidney disease, and nonischemic cardiomyopathy presenting with progressive shortness of breath and bilateral lower extremity edema. Echocardiogram demonstrated severe mitral regurgitation with asymmetric systolic restriction (Carpentier Type IIIc) and moderate-to-severe tricuspid regurgitation Figure . Right hCardiopulmonary bypass (CPB) was initiated with Del Nido cardioplegia. The mitral valve was replaced with 33mm St. Jude Biocor Porcine bioprosthetic, tricuspid valve repair was performed with Edwards MC3 30mm annuloplasty ring, LAA was ligated with AtriCure 50mm AtriClip, and Cox-Maze IV was completed with a cryoprobe. The transesophageal echocardiogram showed a well-seated mitral valve prosthesis with a peak gradient of 5 mmHg, a mean gradient of 2 mmHg, and no paravalvular leak Figure . IntraveCoronary vasospasm is a known and feared complication after coronary artery bypass grafting surgery but has rarely been described in non-coronary cardiac operations. Iatrogenic causes of ST-segment changes, hemodynamic instability, or difficulty weaning from CPB must be considered after valvular surgery and anti-arrhythmia procedures. Left circumflex artery injury or occlusion during mitral valve surgery and right coronary artery injuries during tricuspid valve operations are well described ,3. HowevH Shafei et al.  reportedUnlike most of the cases above, our patient developed ST segment changes while still in the operating room. The decision to pursue coronary angiography rather than reopening and performing a bypass graft is not trivial, but neither is the exercise of attempting a graft to the obtuse marginal branches. We must also consider the potential injury from cryoablation used during the CMP. Direct ablation of the coronary arteries may lead to significant obstruction or total occlusion. There is also a theoretical risk of indirect injury from cryolesions penetrating too deeply or pericoronary edema following the procedure. If technical considerations have been ruled out as a source of coronary injury, systemic administration of vasodilators is an appropriate next step. If this fails to address the issue, then in the appropriate patient, transportation to the coronary catheterization laboratory can provide further information via emergent coronary angiography with the potential to deliver intracoronary vasodilators and perform other advanced interventions. This capability does require a close working relationship between the surgical, anesthesia, and interventional teams within the hospital system. The availability of interventional cardiology allowed us to avoid a bypass graft that likely would have failed in the short term and not addressed the underlying pathology. Diffuse coronary vasospasm is a rare and potentially devastating complication following noncoronary cardiac surgery that should be considered in the setting of ECG changes and hemodynamic instability. As demonstrated by this case and the others cited, coronary spasms may present intraoperatively, shortly after the patient arrival to the intensive care unit, or in the first days after noncoronary surgery. Consideration of this pathology in the event of new ECG changes and hemodynamic changes will allow for timely diagnosis and treatment.


Neurotrauma and Repair: from Peripheral to Central Nerve Injury” brought together a diverse group of 58 authors, fostering interdisciplinary collaboration and offering new insights into the multifaceted landscape of neurotrauma research.Neurotrauma, encompassing traumatic brain injury (TBI), peripheral nerve injury (PNI), and spinal cord injury (SCI), continues to be a major global public health concern. The complex pathophysiological mechanisms and lifelong neurological deficits associated with neurotrauma emphasize the urgent need for effective clinical interventions. The Research Topic “This collaborative effort yielded a body of work that has garnered significant attention within the scientific community, underscoring the importance of the research contributions and the demand for advances in neurotrauma understanding and treatment.Effects of a Neurokinin-1 Receptor Antagonist in the Acute Phase after Thoracic Spinal Cord Injury in a Rat Model” delves into the potential therapeutic effects of neurokinin-1 receptor antagonists on neuroinflammation and edema following SCI . While the study suggests limited impact on reducing edema, it demonstrates a notable reduction in T-lymphocyte invasion and apoptotic cell numbers with the treatment. Additionally, it suggests a trend toward reduced fibrinogen leakage, endothelial and microglial activation, chondroitin sulfate glycosaminoglycan deposition, and astrogliosis. Although general locomotion recovery remained modest, CatWalk gait analysis revealed early improvements in several parameters. This research showcases the intricate and multifaceted nature of SCI and the potential of neurokinin-1 receptor antagonists in mitigating some aspects of neurogenic inflammation.“Muscle-Derived Stem Cell Exosomes with Overexpressed miR-214 Promote the Regeneration and Repair of Rat Sciatic Nerve after Crush Injury,” researchers explore the regenerative potential of muscle-derived stem cell exosomes enriched with miR-214 . The study demonstrates the ability of these exosomes to promote the proliferation and migration of Schwann cells, enhance the expression of neurotrophic factors, and facilitate axon extension in dorsal root ganglion neurons. By targeting PTEN and activating the JAK2/STAT3 pathway, these exosomes hold promise for promoting nerve regeneration in the context of sciatic nerve crush injuries. This research not only contributes to our understanding of neural repair mechanisms but also offers a potential avenue for therapeutic intervention.In “Partially Brain Effects of Injection of Human Umbilical Cord Mesenchymal Stem Cells at Injury Sites in a Mouse Model of Thoracic Spinal Cord Contusion” takes an intriguing angle, investigating the consequences of SCI on the brain . This study explores the potential therapeutic mechanisms of human umbilical cord mesenchymal stem cell injection at the injury site. It highlights the intricate interactions between the spinal cord and the brain, underscoring the interconnectedness of neural systems. This research raises important questions about the broader neurological effects of spinal cord injuries and offers insights into potential therapeutic interventions that could extend beyond the immediate injury site.“A Closed-Body Preclinical Model to Investigate Blast-Induced Spinal Cord Injury” introduces an innovative preclinical model for studying blast-induced spinal cord injuries . These injuries are particularly relevant in military contexts, where exposure to blast overpressure can result in significant spinal trauma. This research enhances our understanding of blast dynamics and their effects on the spinal cord, providing valuable insights into the complexities of these injuries. By investigating markers of traumatic axonal injury and neuroinflammation, this study sets the stage for future research into minimally invasive treatment approaches.“Huntingtin-Associated Protein 1 Ameliorates Neurological Function Rehabilitation by Facilitating Neurite Elongation,” researchers explore the role of Huntingtin-associated protein 1 (HAP1) in promoting neurological function recovery . By activating the TrkA-MAPK signaling pathway, HAP1 demonstrates its potential to enhance neurite elongation and improve outcomes in SCI. This study not only advances our understanding of the molecular mechanisms underlying neural repair but also suggests a promising avenue for therapeutic intervention.In “Differential Effects on TDP-43, Piezo-2, Tight-Junction Proteins in Various Brain Regions Following Repetitive Low-Intensity Blast Overpressure” delves into the often-overlooked issue of mild traumatic brain injuries caused by repetitive low-intensity blast overpressure . This research highlights the varied effects of such exposures on critical proteins in different brain regions, underscoring the structural and anatomical heterogeneity of the brain. The findings emphasize the need for a comprehensive understanding of neurotrauma's diverse impacts, especially in military and combat-related contexts.“A Cutting-Edge Strategy for Spinal Cord Injury Treatment: Resident Cellular Transdifferentiation,” the authors explore a cutting-edge strategy for SCI treatment—resident cellular transdifferentiation . This innovative approach involves reprogramming mature somatic cells into functional neurons, offering new hope for post-traumatic spinal cord repair and functional improvement. While the mechanisms and induced neuronal subtypes are not yet fully understood, this review provides a comprehensive analysis of the current state of research in this exciting field.In the review article “These contributions collectively advance our understanding of neurotrauma and offer new insights into potential pathways for treatment. While challenges remain, this collaborative effort signifies progress in the field, underscoring our shared commitment to alleviating the burden of neurotrauma for individuals worldwide. As we reflect on these achievements, we acknowledge the road ahead, filled with challenges and opportunities. Neurotrauma research continues to evolve, driven by a global community of researchers dedicated to translating insights into tangible treatments. Together, we embark on a journey that promises to bring healing and recovery to those affected by neurotrauma, one breakthrough at a time.AY: Writing—original draft.


The mesentery is a broad fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Although primary neoplasms arising in the mesentery are rare, the mesentery is a major avenue for the dissemination of tumours, which can spread through hematogenous, lymphatic, direct or peritoneal seeding. Imaging helps in the diagnosis of these tumours and aids in directing appropriate treatment by assessing their size, extent and relationship with adjacent structures. The aim of this article is to describe the spectrum of imaging findings of the various mesenteric lesions using ultrasound and CT.Evaluation of the mesentery is often neglected during routine ultrasound (US) because of inadequate training and unfamiliarity with the common US features encountered with mesenteric disease. CT plays an essential role in the diagnosis of mesenteric disease. Knowledge of imaging characteristics of various mesenteric lesions helps in timely diagnosis and management. The mesentery is a broad, fan-shaped fold of peritoneum that suspends the loops of small intestine from the posterior abdominal wall. Secondary involvement of the mesentery from tumours elsewhere is much more common than primary mesenteric neoplasms such as desmoid tumour, inflammatory myofibroblastic tumour (IMFT), and others. Most patients with mesenteric lesions present with non-specific symptoms of abdominal pain, tenderness, palpable abdominal swelling, abdominal distension and weight loss. These symptoms are shared by pathologies of other abdominal organs and it is therefore very difficult to identify mesenteric lesions clinically.Some mesenteric diseases present with distinctive imaging findings while others have similar findings, thereby complicating their differential diagnosis. Understanding the characteristic radiological patterns on ultrasound (USG) and CT offers valuable insights for differential diagnoses of mesenteric lesions and their treatment.Primary mesenteric solid neoplasms are rare and the majority of them are benign.1 On USG, this tumour appears as a well-defined or ill-defined mass with heterogenous echotexture and internal vascularity. On CT, it appears as a well-defined or ill-defined mass showing heterogenous enhancement usually in the portal venous phase and it may infiltrate the adjacent organs.2 The MRI appearance of desmoid tumours depends on the relative proportion of cellular, myxoid and fibrous components.The most common soft tissue lesion in the mesentery is a desmoid tumour. It usually occurs in patients with familial adenomatous polyposis (FAP) or Gardner syndrome. Trauma or surgery serves as a predisposing factor for the development of desmoid tumours.3 Inflammatory myofibroblastic tumour appears as a hypo or iso-attenuating mass compared with skeletal muscle depending on the amount of myxoid or collagenous stroma, respectively. Dense central calcification may be noticed. They demonstrate various contrast enhancement patterns including early peripheral enhancement because of vascular tissue , associated soft tissue component and thick irregular septations. Liposarcomas are rare malignant tumours of the mesentery. Liposarcomas are divided into five types histopathologically: well-differentiated, myxoid, pleomorphic, round cell and de-differentiated liposarcoma. Well-differentiated liposarcomas have mixed fatty and soft tissue components while de-differentiated liposarcomas have clearly separated soft tissue and fatty components. Myxoid liposarcomas have fluid density on CT with mixed soft tissue and fatty components. Pleomorphic and round cell liposarcomas have soft tissue components only, with no identifiable fatty component on imaging.5Three patterns of mesenteric involvement have been described for Castleman disease, namely a solitary non-invasive mass (most common), a dominant infiltrative mass with associated lymphadenopathy and matted lymphadenopathy without a dominant mass. These tumours show early, homogenous and intense enhancement . Tumours6  is seen as one or more irregular fibrotic soft tissue mesenteric masses10 They show variable attenuation depending on their contents  and may insinuate between the mesenteric vessels  on USG and as a unilocular or multilocular cyst with enhancement of the wall or septations on contrast enhanced CT. vessels .11These appear as thin-walled anechoic unilocular cysts with posterior acoustic enhancement on USG and unilocular fluid attenuation lesions with no discernible wall on CT.2 They occur because of entrapment of fluid (secreted by the ovaries during ovulation) between peritoneal adhesions.7 They are seen as a fluid attenuation multilocular cystic lesion, multiple unilocular thin-walled cysts or unilocular cystic mass on CT with enhancing but non-calcified septa, which often surround the ovaries. On USG, they appear as unilocular or multilocular cystic lesions, which may be anechoic or may display contents of variable echogenicity  and demonstrate homogeneous enhancement following contrast administration . Other findings observed in cases of abdominal tuberculosis include mesenteric nodularity, fat stranding, peritoneal thickening, localised collections, free fluid, clumping of bowel loops, bowel wall thickening and solid organ involvement in the form of hepatomegaly, splenomegaly, liver and splenic granulomas.Tropheryma whipplei. On imaging, small bowel wall thickening associated with enlarged mesenteric lymph nodes demonstrating hypoattenuating centres because of fat deposition can be seen. Diagnosis is made by small intestinal mucosal biopsy.16It is an infectious condition caused by Gram-positive bacterium, Actinomyces israelii is an anaerobic Gram-positive bacterium and is a normal inhabitant of the oral cavity, gastrointestinal tract and female genital tract. It spreads to involve the mesentery when a mucosal breach is present such as inflammation, surgery, trauma or intrauterine contraceptive device (IUCD) use.17 On imaging, an ill-defined heterogeneously enhancing soft tissue mass infiltrating the mesentery and adjacent organs can be seen. Septic embolism leading to hepatic, renal and splenic abscesses can occur.2 Diagnosis is made based on aggressive imaging features and subtle clinical symptoms in predisposed individuals. Biopsy should be performed in indeterminate imaging findings, which reveal sulphur granules representing bacterial colonies.18These usually occur because of intraperitoneal rupture of liver or splenic hydatid cysts . HydatidMesenteric changes in inflammatory bowel disease include mesenteric fibrofatty proliferation, mesenteric lymphadenopathy, fat stranding , abscess19 (Findings in acute mesenteric ischaemia related to superior mesenteric artery (SMA) thrombosis include dilated bowel loops with paper-thin walls, pneumatosis intestinalis, air within mesenteric vessels, mesenteric fat stranding and free fluid on CECT19 .On USG, tangled serpentine vessels can be seen, which show pulsatile waveforms on spectral doppler while on CECT, tangled serpentine vessels can be seen with early opacification of venous channels in the arterial phase. Direct communication between branches of the SMA and superior mesenteric vein (SMV) can be visualised on volume rendering technique (VRT) images.20 Evaluation of lesions is limited on USG because of operator-dependence, obscuration of the mass in the presence of a gaseous abdomen and obese patients, and inadequate visualisation of the extent of large mesenteric lesions. Contrast enhanced CT is the primary workhorse for evaluation of mesenteric lesions. It helps in determining the origin of the lesions, providing thoughtful differential diagnosis of masses, for selecting the site of biopsy, determining the extent of pathology and accessibility for resectability of lesion. CT, however, has several limitations including poor soft tissue contrast resolution, exposure to ionising radiation and contrast reactions. MRI can be used as the next step in characterising mesenteric lesions. It has higher soft tissue contrast resolution and helps in characterising fluid content of cysts as serous, mucinous, chylous or haemorrhagic and the soft tissue component of solid lesions. Fluoro-deoxyglucose (FDG) positron emission tomography (PET) CT is presently used to detect lymph nodes and distant metastases in mesenteric tumours and also for response assessment to chemotherapy.Ultrasound is the primary imaging modality in the evaluation of mesenteric lesions. It helps in characterising mesenteric lesions as solid or cystic. Ultrasound guided percutaneous biopsy offers real time assessment of the needle tract to avoid vascular injury while performing biopsy.21Management of mesenteric lesions depends on symptoms and imaging findings. Mesenteric lesions detected incidentally on imaging need classification as benign or malignant. Definite diagnosis of a few pathologies such as mesenteric panniculitis, lymphoma, desmoid tumour in patients with FAP and benign cystic lesions can be made on imaging. However, lesions with indeterminate imaging findings need to be biopsied to rule out malignancy. Imaging helps in determining the site for percutaneous biopsy in such tumours. Lesions that are inaccessible to percutaneous biopsy or show indeterminate histopathology findings on percutaneous biopsy require surgical biopsy to confirm the diagnosis.Once confirmed by biopsy, management of the mesenteric lesions depends on the histopathology. Lymphomas and desmoid tumours are managed conservatively with chemotherapy and hormonal therapy or imatinib, respectively. Well-circumscribed lesions located in the periphery of the mesentery can be resected completely, without sacrificing significant bowel length or major mesenteric vessels. Infiltrative mesenteric lesions, located in the root of mesentery are usually managed conservatively because of involvement of major vessels and the need for sacrificing a major portion of bowel, which may lead to small bowel syndrome. Well-defined malignant tumours and symptomatic benign tumours are treated surgically. The goal of surgery is R0 resection , while R1 resection followed by adjuvant chemoradiotherapy can also be performed. Well-defined asymptomatic benign lesions can be followed up and resection is performed when they become large or cause symptoms. Symptomatic infiltrative benign or malignant lesions can be managed by debulking surgery to reduce tumour load and prevent complications such as bowel obstruction or mesenteric ischemia.Although histopathology is the gold standard for diagnosis of mesenteric lesions, imaging plays an important role in diagnosis of mesenteric neoplasms, detection of complications and in deciding appropriate treatment options. Ultrasound is inadequate for optimal visualisation of mesenteric neoplasms and in detecting their relation with other structures because of shadowing from bowel gas, calcification or inadequate penetration of sound beams in obese patients. CT is an excellent imaging modality in the characterisation of mesenteric lesions, detecting their extent and relations with surrounding structures, which is useful for surgical planning. However, CT too has several limitations and other imaging modalities such as MRI and FDG-PET can be helpful in further characterisation of mesenteric lesions.


This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old woman had difficulty extending her left-thumb interphalangeal joint several weeks after a palpation-guided local corticosteroid injection. Passive motions remained intact without sensory abnormalities. Ultrasound examination showed hyperechoic tissues at the site of the extensor pollicis longus (EPL) tendon at the wrist level and an atrophic EPL muscle stump at the forearm level. Dynamic imaging demonstrated no motion in the EPL muscle during passive thumb flexion/extension. The diagnosis of complete EPL rupture, possibly due to inadvertent intratendinous corticosteroid injection, was therefore confirmed. This report aimed to present a case of wrist-tendon rupture and to discuss a rare complication after corticosteroid injection. A 67-year-old female complained of difficulty in extending the left thumb for several months. The medical history comprised radial wrist pain after a contusion injury one year ago, for which corticosteroid injection under palpation guidance had also been performed, with gradual symptom relief. The physical examination revealed loss of the active extension of the left-thumb interphalangeal joint with normal passive motions . Other fThe posterior interosseous nerve (PIN) remained bilaterally intact based on dynamic tracking from the level of the supinator tunnel to the dorsal wrist . Moving Finger drop can ensue due to neurological and orthopedic causes . In caseStatic ultrasound examination can serve as a helpful tool for scrutinizing tendon injury, whereas dynamic imaging can be employed to validate motion problems. The most common sonographic finding of tendon rupture is loss of fiber continuity with the formation of a retracted stump. The absence of normal tendon gliding during passive motion further confirms the diagnosis . In chroOne of the important etiologies of spontaneous EPL tendon rupture is intratendinous corticosteroid injection. Other causes include distal radial fracture, repetitive friction against metal implants, and contusions . Local cNeedless to say, ultrasound is a preferred tool for guiding the needle, in order to avoid unwanted intratendinous corticosteroid injection ,17. Peri


This case highlights the importance of having constrictive pericarditis (CP) as a differential diagnosis in unexplained sign and symptoms of right-sided heart failure. This case portrays challenges in diagnosing CP caused by certain rheumatologic diseases despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis. Constrictive pericarditis (CP) is a rare condition that often presents with non-specific symptoms and is often misdiagnosed. CP is characterized by a rigid pericardium that restricts the heart, resulting in signs and symptoms of diastolic heart failure. It occurs as a late sequela of pericardial inflammation caused by prior infection or radiation, inflammatory diseases and rarely, connective tissue disorders. We present a case of new-onset right-sided heart failure caused by constrictive pericarditis in a patient with diffuse systemic sclerosis (SSc). This case highlights the importance of having CP in our differential diagnosis in patients with unexplained sign and symptoms of right-sided heart failure and increased systemic venous pressure. This is crucial since CP secondary to SSc is largely curable and failure to diagnosis has devastating consequences. This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.A 27-year-old female with a seven-year history of diffuse systemic scleroderma complicated by recurrent pericarditis and severe Raynaud’s disease resulting in gangrene and amputation of the upper and lower extremity digits presented to the hospital with two weeks of progressive shortness of breath, early satiety, fatigue, abdominal distention, and lower extremity pain and edema. The physical examination was notable for the presence of jugular vein distention with positive hepatojugular reflux, right upper quadrant tenderness, ascites and 3+ lower extremity edema to the thighs. Her heart rate was 108 beats per minute; other vital signs were within normal limits. EKG showed sinus tachycardia with nonspecific ST-T wave changes. Chest x-ray showed a moderate right-sided pleural effusion with right basilar airspace opacity and a cardio mediastinal silhouette. Transthoracic echocardiogram demonstrated a normal left ventricular ejection fraction, mildly reduced right ventricular function, mild pulmonary hypertension with an estimated mean pulmonary artery pressure of 40 mmHg, and no significant valvular abnormalities. Abdominal ultrasound redemonstrated ascites and was also notable for hepatomegaly and a hyperechoic pancreatic mass.Initially the patient’s ascites was attributed to intrinsic hepatic disease and she was started on diuretics. However, her renal function deteriorated, halting diuresis while further diagnostic evaluation was pursued. The patient continued to have abdominal distension and shortness of breath which prompted a cardiovascular evaluation with a right heart catheterization. Mild pulmonary arterial hypertension was noted with elevated mean pulmonary arterial pressure (mPAP) of 28 mmHg. Due to the discrepancy between the mildly elevated cardiac filling pressures and significant anasarca on physical examination, a repeat hemodynamic assessment was pursued. The patient underwent right and left heart catheterization which discovered near equalization of the diastolic filling pressures, raising suspicion for pericardial tamponade constrictive physiology . In addiAs most diagnostic imaging studies were contraindicated due to the patient’s impaired renal function, a cardiac MRI without contrast was obtained to evaluate for possible pericardial disease. Cardiac MRI showed an abnormally thick pericardium (4–5 mm) and evidence of significant pericardial adhesion with a small dependent pericardial effusion. The ventricles were cone shaped and a septal bounce was seen during diastole. In addition, free breathing CINE imaging demonstrated ventricular interdependence. These findings were consistent with pericardial constriction.After extensive discussion between cardiology, rheumatology, nephrology and cardiothoracic surgery, the primary team agreed that surgical intervention was the best option to improve this patient’s quality of life and disease prognosis. Subsequently, she underwent successful pericardiectomy with complete resolution of her symptoms. The pathology report revealed extensive dense fibrosis in the pericardium that was likely secondary to patient’s known collagen vascular disease.Cardiac involvement in both limited and diffuse SSc has been recognized over the years as one of the most rare and feared complications due to poor prognosis . CardiacThe noteworthy pathophysiology involved in presentation of this condition is unique in that there is recurrent coronary microvascular ischemia and myocardial inflammation which leads to ischemic necrosis, reperfusion damage, and myocardial fibrosis . This adHowever, constrictive physiology can complicate virtually any condition associated with pericardial effusion . The nonCertain serologic tests for patients with systemic sclerosis can provide useful information about specific organ involvement, including cardiac manifestations. Studies have shown that patients with SSc with myocarditis had cytoplasmic antineutrophil cytoplasmic antibody (c-ANCA) and antiproteinase 3 (PR3) antibody positivity . FurtherOverall, due to the high prevalence of cardiac involvement in patients with SSc, it becomes imperative to do a thorough history taking and examination of this population. Prompt recognition and management of constrictive pericarditis can alleviate symptoms such as volume overload, drastically transform these patients’ quality of life, improve prognosis, and decrease mortality.This case portrays the challenges in diagnosing pericardial diseases caused by certain rheumatologic diseases and that despite advances in diagnostic modalities, clinical suspicion remains the most important tool for this diagnosis.To be able to recognize rare but very specific findings of a constrictive pericarditis physiology.To understand the role of Multidisciplinary approach to benefit the patient’s quality of life.A patient presenting with an odd case of Constrictive Pericarditis due to Systemic Sclerosis.


A hallmark of retroviral replication is stable integration of the viral genome in the host cell DNA. This characteristic makes retroviral-derived vector particles attractive vehicles for gene therapy. However, retroviral integration is not a random process. Lentiviruses preferentially integrate in the body of active transcription units, while gammaretroviruses, including Moloney Murine Leukemia Virus (MLV), favour transcription start sites and CpG islands. In clinical trials using gammaretroviral vectors for gene therapy, leukemogenesis has been associated with integration of vectors near oncogene transcription start sites. We found that the bromodomain and extra-terminal (BET) proteins  interact with MLV integrase and direct integration towards transcription start regions. BET proteins specifically bind and co-localize with the gammaretrovirus integrase protein in the nucleus of the cell. The interaction is gammaretroviral-specific and mediated by the integrase C-terminal domain and the BET extraterminal (ET) domain as determined by co-immunoprecipitation assays and in an Alphascreen assay using recombinant proteins. Interfering with chromatin interaction of BET proteins via specific bromodomain inhibitors JQ1 and l-BET decreases MLV virus replication and MLV vector transduction 5-to 10-fold, while HIV vector transduction is not affected. Analysis of viral DNA intermediates by quantitative PCR revealed a block at the integration step. In addition, bromodomain inhibitors do not have an effect on the late steps of viral replication. MLV integration site distribution analysis revealed a strong correlation with the BET protein chromatin binding profile. Finally, expression of an artificial fusion protein that merges the BET integrase binding domain with the chromatin interaction domain of the lentiviral targeting factor LEDGF/p75, retargets MLV integration into the body of actively transcribed genes, paralleling the Human Immunodeficiency Virus (HIV) integration pattern. Our results explain the molecular mechanism behind gammaretroviral integration site targeting and suggest methods for engineering gammaretroviral vectors with a safer integration site profile.


Next-generation DNA sequencing has dramatically affected cancer genomics efforts in several important ways. Although whole genome sequencing remains an analytical challenge, such efforts are yielding data that elucidate the myriad ways in which a genome can be influenced by single point mutations, focused insertions or deletions, and large structural alterations. In addition to cataloguing somatic alterations, various correlation analyses are indicating the genes whose alterations most profoundly determine patient outcomes, patient responses to therapeutics and other important aspects of disease biology. We have recently begun exploring how the digital nature of next-generation sequencing reads allows important information about tumor cell genomic heterogeneity to be inferred, revealing the earliest mutations and how the composition of the tumor cell mass changes over time under the influence of stressors such as chemotherapy.