Cancer Treatment-Related Cardiovascular Toxicity in Gynecologic Malignancies: JACC: CardioOncology State-of-the-Art Review.

Improvements in early detection and treatment of gynecologic malignancies have led to an increasing number of survivors who are at risk of long-term cardiac complications from cancer treatment. Multimodality therapies for gynecologic malignancies, including conventional chemotherapy, targeted therapeutics, and hormonal agents, place patients at risk of cancer therapy-related cardiovascular toxicity during and following treatment. Although the cardiotoxicity associated with some female predominant cancers (eg, breast cancer) have been well recognized, there has been less recognition of the potential adverse cardiovascular effects of anticancer therapies used to treat gynecologic malignancies. In this review, the authors provide a comprehensive overview of the cancer therapeutic agents used in gynecologic malignancies, associated cardiovascular toxicities, risk factors for cardiotoxicity, cardiac imaging, and prevention strategies.

Interconnected Clinical and Social Risk Factors in Breast Cancer and Heart Failure.

Breast cancer and heart failure share several known clinical cardiovascular risk factors, including age, obesity, glucose dysregulation, cholesterol dysregulation, hypertension, atrial fibrillation and inflammation. However, to fully comprehend the complex interplay between risk of breast cancer and heart failure, factors attributed to both biological and social determinants of health must be explored in risk-assessment. There are several social factors that impede implementation of prevention strategies and treatment for breast cancer and heart failure prevention, including socioeconomic status, neighborhood disadvantage, food insecurity, access to healthcare, and social isolation. A comprehensive approach to prevention of both breast cancer and heart failure must include assessment for both traditional clinical risk factors and social determinants of health in patients to address root causes of lifestyle and modifiable risk factors. In this review, we examine clinical and social determinants of health in breast cancer and heart failure that are necessary to consider in the design and implementation of effective prevention strategies that altogether reduce the risk of both chronic diseases.

Breast Cancer and Heart Failure.

Heart failure and breast cancer have shared risks and morbidities. Multimodality therapies for breast cancer, including conventional chemotherapy, targeted therapeutics, radiation therapy, and hormonal agents, may make patients more susceptible to asymptomatic left ventricular dysfunction and clinical heart failure during and after treatment. New or preexisting left ventricular dysfunction may lead to interruptions in cancer treatment and limit options of breast cancer systemic therapy, leading to adverse outcomes. Early recognition and management of cardiovascular risk factors before, during, and after cancer treatment are of utmost importance. This review presents advances, challenges, and opportunities for cardiovascular care in contemporary breast cancer treatment.

SMARTWOMAN™: Feasibility assessment of a smartphone app to control cardiovascular risk factors in vulnerable diabetic women.

BACKGROUND/HYPOTHESIS: SMARTWOMAN™ was designed to develop and assess the feasibility of a smartphone app to control cardiovascular risk factors in vulnerable diabetic women. METHODS: Fourteen African-American women with diabetes and without known cardiovascular disease were enrolled. A weight-scale, glucometer, sphygmomanometer, and FitBit were synchronized to the smartphone, and text messaging was provided. Follow-up was 6 months. RESULTS: Patients were able to follow instructions for app use and device prompts. Weekly device reporting was 85% for blood glucose, 82.5% for daily steps, and 77% for systolic blood pressure. Patient engagement levels were 85% to 100% at 1 month and 50% to 78% at month 6. The majority reported text messages to be useful, easy to understand, and appropriate in frequency. The women indicated on the exit questionnaire that study participation increased their motivation and ability to take charge of their health. CONCLUSIONS: Use of a smartphone app to control cardiovascular risk factors appears feasible in a population of vulnerable indigent African-American diabetic women, resulted in increased patient satisfaction and positive reinforcement to healthy behaviors, and warrants a larger clinical outcome trial.

Depression Treatment and 1-Year Mortality After Acute Myocardial Infarction: Insights From the TRIUMPH Registry (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status).

BACKGROUND: Depression among patients with acute myocardial infarction (AMI) is prevalent and associated with an adverse quality of life and prognosis. Despite recommendations from some national organizations to screen for depression, it is unclear whether treatment of depression in patients with AMI is associated with better outcomes. We aimed to determine whether the prognosis of patients with treated versus untreated depression differs. METHODS: The TRIUMPH study (Translational Research Investigating Underlying Disparities in Acute Myocardial Infarction Patients' Health Status) is an observational multicenter cohort study that enrolled 4062 patients aged ≥18 years with AMI between April 11, 2005, and December 31, 2008, from 24 US hospitals. Research coordinators administered the Patient Health Questionnaire-9 (PHQ-9) during the index AMI admission. Depression was defined by a PHQ-9 score of ≥10. Depression was categorized as treated if there was documentation of a discharge diagnosis, medication prescribed for depression, or referral for counseling, and as untreated if none of these 3 criteria was documented in the medical records despite a PHQ score ≥10. One-year mortality was compared between patients with AMI having: (1) no depression (PHQ-9<10; reference); (2) treated depression; and (3) untreated depression adjusting for demographics, AMI severity, and clinical factors. RESULTS: Overall, 759 (18.7%) patients met PHQ-9 criteria for depression and 231 (30.4%) were treated. In comparison with 3303 patients without depression, the 231 patients with treated depression had 1-year mortality rates that were not different (6.1% versus 6.7%; adjusted hazard ratio, 1.12; 95% confidence interval, 0.63-1.99). In contrast, the 528 patients with untreated depression had higher 1-year mortality in comparison with patients without depression (10.8% versus 6.1%; adjusted hazard ratio, 1.91; 95% confidence interval, 1.39-2.62). CONCLUSIONS: Although depression in patients with AMI is associated with increased long-term mortality, this association may be confined to patients with untreated depression.

Subclinical Cardiovascular Disease in Lymphoma Survivors by Sex.

OBJECTIVE: To describe the prevalence of cardiovascular disease in lymphoma survivors by sex. DESIGN: Cross-sectional, correlation. SETTING: Large cancer institute in Southeastern United States. PARTICIPANTS: Participants (N = 31) had a mean age ± standard deviation of 47.6 ± 11.4 years; 55% were male and 84% were White. Participants averaged 5 years since lymphoma treatment. METHODS: During one research visit, routine laboratory tests and fasting lipid levels, coronary artery calcification computed tomography, echocardiography, comprehensive questionnaires, survivorship clinic, and cardiology consultation were measured. Analysis consisted of nonparametric Mann Whitney, t, chi-square, and Fisher's exact tests. MAIN OUTCOMES MEASURES: Comparison of the presence of subclinical cardiovascular disease, calculated cardiovascular disease risk, cardiovascular health knowledge, lifestyle behaviors, symptomatology, and health related quality of life between men and women. RESULTS: Subclinical disease and/or significant cardiovascular disease risk were found in 42%. Women tended to be slightly older (p = .07), had slightly lower but nonsignificant 10-year calculated risk, and slightly higher vascular age. Subclinical disease was detected in 35% of our sample; 28.6% of the women had diastolic dysfunction. Women scored less than men in health-related quality of life based on results of the Short Form Health Survey Physical Functioning (p = .03) and the EQ-5D Index (p = .04). Women had more symptoms (bloating and diarrhea; p < .05). Those with subclinical disease reported other pain (p < .01), numbness in hands or feet (p < .05), and shortness of breath (p < .05). CONCLUSION: Compared with men, more women than expected had subclinical disease, specifically diastolic dysfunction; less reported functioning and health-related quality of life, and greater symptoms. Of clinical relevance is the need for assessment of symptoms that could herald subclinical disease with timely referral.

Pattern of cardiac surveillance among patients with lymphoma receiving anthracycline-based chemotherapy.

OBJECTIVE: Anthracyclines are potent antineoplastic agents in the treatment of lymphoid malignancies, but their therapeutic benefit is limited by cardiotoxicity. The American Heart Association (AHA) recommends routine surveillance, early diagnosis and treatment of anthracycline-based chemotherapy (AC) induced cardiomyopathy (AC-CMP). We aimed to assess the prevalence of AC-CMP in patients with lymphoma, surveillance patterns of left ventricular ejection fraction (LVEF) in those receiving AC and management of patients with AC-CMP at an academic medical centre prior to the development of a comprehensive cardio-oncology programme. METHODS: We performed a retrospective cohort study examining 218 patients with aggressive B cell non-Hodgkin's lymphomas (B-NHL) who received AC 1992-2012 and had serial follow-up. AC-CMP was defined as LVEF decrease ≥10% with final LVEF≤50% or LVEF reduction ≥15% regardless of final LVEF. RESULTS: Of 218 patients treated with AC, 73 (34%) had LVEF assessment both prior to and after receiving AC. Of these 73 patients, 24 developed AC-CMP and had higher cumulative all-cause mortality than those without AC-CMP (HR 2.35, p=0.03). Coronary artery disease (CAD) was an independent predictor of AC-CMP (p=0.048). Mean post-AC LVEF was lower in patients with CAD compared with those without CAD when their baseline LVEF was 45% (p=0.0009) or 55% (p=0.001) but was similar at 65% (p=0.33). Less than half of patients with AC-CMP received recommended heart failure medication therapy. CONCLUSIONS: Historically, one-third of patients with B-NHL treated with AC underwent surveillance according to AHA guidelines. There is substantial opportunity for collaboration between oncologists and cardiologists to improve the care of patients with lymphoma receiving AC.

Longitudinal persistence with secondary prevention therapies relative to patient risk after myocardial infarction.

BACKGROUND: Prior studies have demonstrated that patients with high-risk acute myocardial infarction (AMI) are less likely to receive guideline-directed medications during hospitalisation. It is unknown if this paradox persists following discharge. We aimed to assess if persistence with guideline-directed medications post discharge varies by patients' risk following AMI. METHODS: Data were analysed from two prospective, multicentre US AMI registries. The primary outcome was persistence with all prescribed guideline-directed medications (aspirin, ß-blockers, statins, angiotensin-antagonists) at 1, 6 and 12 months post discharge. The association between risk and medication persistence post discharge was assessed using multivariable mixed-effect models. RESULTS: Among 6434 patients with AMI discharged home, 2824 were considered low-risk, 2014 intermediate-risk and 1596 high-risk for death based upon their Global Registry of Acute Coronary Event (GRACE) 6-month risk score. High-risk was associated with a lower likelihood of receiving all appropriate therapies at discharge compared with low-risk patients (relative risk (RR) 0.90; 95% CI 0.87 to 0.94). At 12 months, the rate of persistence with all prescribed therapies was 61.5%, 57.9% and 45.9% among low-risk, intermediate-risk and high-risk patients, respectively. After multivariable adjustment, high-risk was associated with lower persistence with all prescribed medications (RR 0.87; 95% CI 0.82 to 0.92) over follow-up. Similar associations were seen for individual medications. Over the 5 years of the study, persistence with prescribed therapies post discharge improved modestly among high-risk patients (RR 1.05; 95% CI 1.03 to 1.08 per year). CONCLUSIONS: High-risk patients with AMI have a lower likelihood of persistently taking prescribed medications post discharge as compared with low-risk patients. Continued efforts are needed to improve the use of guideline-directed medications in high-risk patients.

Angina Frequency After Acute Myocardial Infarction In Patients Without Obstructive Coronary Artery Disease.

BACKGROUND: Myocardial infarction (MI) patients without obstructive coronary artery disease (CAD) are at increased risk for recurrent ischemic events, but angina frequency post-MI has not been described. METHODS AND RESULTS: Among MI patients who underwent angiography, we assessed angina at baseline, 1, 6, and 12 months using the Seattle Angina Questionnaire (SAQ). A hierarchical repeated measures modified Poisson model assessed the association between the absence of obstructive CAD (defined as epicardial stenoses >70% or left main >50%) and angina. Among 5539 MI patients from 31 US hospitals (mean age 60, 68% male), 6.9% had no angiographic obstructive CAD. More patients without obstructive CAD (vs. obstructive CAD) were female (57% vs 30%), non-white (51% vs 24%) and had NSTEMI (87% vs 51%). In unadjusted analyses, patients without obstructive CAD had less angina prior to MI but more angina and worse health status post-discharge. After adjustment for socio-demographic and clinical factors, the risk of post-MI angina was similar in patients without vs. with obstructive CAD (IRR=0.89, 95% CI 0.77-1.02). Among patients without obstructive CAD, depression and self-reported avoidance of care due to cost were independently associated with angina (IRR=1.28 per 5 points on PHQ, 95% CI 1.17-1.41; IRR=1.34, 95% 1.02-1.1.74). CONCLUSIONS: Following MI, patients without obstructive CAD experience an angina burden at least as high as those with obstructive CAD, affecting 1 in 4 patients at 12 months. As these patients are not candidates for revascularization, other anti-anginal strategies are needed to improve their health status and quality of life.

New-onset atrial fibrillation after acute myocardial infarction and its relation to admission biomarkers (from the TRIUMPH registry).

Atrial fibrillation (AF) is an independent predictor of mortality after acute myocardial infarction (AMI). We analyzed the relation between biomarkers linked to myocardial stretch (NT-pro-brain natriuretic peptide [NT-proBNP]), myocardial damage (Troponin-T [TnT]), and inflammation (high-sensitivity C-reactive protein [hs-CRP]) and new-onset AF during AMI to identify patients at high risk for AF. In a prospective multicenter registry of AMI patients (from the Translational Research Investigating Underlying disparities in recovery from acute Myocardial infarction: Patients' Health status registry), we measured NT-proBNP, TnT, and hs-CRP in patients without a history of AF (n = 2,370). New-onset AF was defined as AF that occurred during the index hospitalization. Hierarchical multivariate logistic regression models were used to determine the association of biomarkers with new-onset AF, after adjusting for other covariates. New-onset AF was documented in 114 patients with AMI (4.8%; mean age 58 years; 32% women). For each twofold increase in NT-proBNP, there was an 18% increase in the rate of AF (odds ratio [OR] 1.18, 95% confidence interval [CI] 1.03 to 1.35; p <0.02). Similarly, for every twofold increase in hs-CRP, there was a 15% increase in the rate of AF (OR 1.15, 95% CI 1.02 to 1.30; p = 0.02). TnT was not independently associated with new-onset AF (OR 0.96, 95% CI 0.85 to 1.07; p = 0.3). NT-proBNP and hs-CRP were independently associated with new in-hospital AF after MI, in both men and women, irrespective of race. Our study suggests that markers of myocardial stretch and inflammation, but not the amount of myocardial necrosis, are important determinants of AF in the setting of AMI.

Predictors of early and late enrollment in cardiac rehabilitation, among those referred, after acute myocardial infarction.

BACKGROUND: Cardiac rehabilitation (CR) after acute myocardial infarction (AMI) is a Class I recommendation. Although referral to CR after an AMI has recently become a performance measure, many patients may not participate. To illuminate potential barriers to participation, we examined the prevalence of, and patient-related factors associated with, CR participation within 1 and 6 months after an AMI. METHODS AND RESULTS: We studied 2096 AMI patients enrolled from 19 US sites in the Prospective Registry Evaluating outcomes after Myocardial Infarction: Events and Recovery (PREMIER) registry. Analyses were limited to those patients referred for CR at the time of AMI hospitalization. A multivariable, conditional logistic regression model, stratified by hospital, was used to identify sociodemographic, comorbidity, and clinical factors independently associated with CR participation within 1 and 6 months of AMI hospital discharge. Only 29% (419/1450) and 48.25% (650/1347) of AMI patients who received referral for CR participated within 1 and 6 months after discharge, respectively. Women (odds ratio [OR], 0.61; 95% confidence interval [CI], 0.44-0.86), uninsured (OR, 0.39; 95% CI, 0.21-0.71), and patients with hypertension (OR, 0.58; 95% CI, 0.43-0.78) and peripheral arterial disease (OR, 0.43; 95% CI, 0.22-0.85) were less likely to participate at 1 month. At 6 months after AMI, older patients (OR, 0.85 for each 10-year increment; 95% CI, 0.74-0.97), smokers (OR, 0.59; 95% CI, 0.44-0.80), and patients with economic burden (OR, 0.56; 95% CI, 0.38-0.81) were less likely to participate. Caucasians (OR, 1.73; 95% CI, 1.16-2.58) and educated patients (OR, 1.81; 95% CI, 1.42-2.30) were more likely to participate at 6 months. Patients with previous percutaneous interventions were less likely to participate at both 1 and 6 months post-AMI. CONCLUSIONS: Among patients referred for CR post-AMI, participation remains low both at 1 and 6 months after AMI. Because CR is associated with beneficial changes in cardiovascular risk factors and better outcomes after AMI, more aggressive efforts are needed to increase CR participation after referral.

Changes in social support within the early recovery period and outcomes after acute myocardial infarction.

OBJECTIVE: To examine changes in social support during early recovery after acute myocardial infarction (AMI) and determine whether these changes influence outcomes within the first year. METHODS: Among 1951 AMI patients enrolled in a 19-center prospective study, we examined changes in social support between baseline (index hospitalization) and 1 month post-AMI to longitudinally assess their association with health status and depressive symptoms within the first year. We further examined whether 1-month support predicted outcomes independent of baseline support. Hierarchical repeated-measures regression evaluated associations, adjusting for site, baseline outcome level, baseline depressive symptoms, sociodemographic characteristics, and clinical factors. RESULTS: During the first month of recovery, 5.6% of patients had persistently low support, 6.4% had worsened support, 8.1% had improved support, and 80.0% had persistently high support. In risk-adjusted analyses, patients with worsened support (vs. persistently high) had greater risk of angina (relative risk=1.46), lower disease-specific quality of life (ß=7.44), lower general mental functioning (ß=4.82), and more depressive symptoms (ß=1.94) (all p≤.01). Conversely, patients with improved support (vs. persistently low) had better outcomes, including higher disease-specific quality of life (ß=6.78), higher general mental functioning (ß=4.09), and fewer depressive symptoms (ß=1.48) (all p≤.002). In separate analyses, low support at 1 month was significantly associated with poorer outcomes, independent of baseline support level (all p≤.002). CONCLUSION: Changes in social support during early AMI recovery were not uncommon and were important for predicting outcomes. Intervening on low support during early recovery may provide a means of improving outcomes.

Relationships between cardiovascular disease risk factors and depressive symptoms as predictors of cardiovascular disease events in women.

BACKGROUND: Modifiable risk factors for cardiovascular disease (CVD) account for much of the variability in CVD outcomes and are also related to psychosocial variables. There is evidence that depression can undermine the treatment and advance the progression of CVD risk factors, suggesting that CVD risk factor relationships with CVD events may differ among those with depression. METHODS: This study tracked CVD events and mortality over a median of 5.9 years among a prospective cohort of 620 women (mean age 59.6 years [11.6]) completing a diagnostic protocol including coronary angiography and CVD risk factor assessment. Depressive symptoms were assessed using the Beck Depression Inventory (BDI). The study outcome was combined cardiovascular mortality and events. RESULTS: Over the follow-up interval, 16.1% of the sample experienced one or more of the cardiovascular outcomes. In separate Cox regression models adjusting for age, education history, ethnicity, and coronary angiogram scores, we observed statistically significant CVD risk factor × BDI score interactions for diabetes, smoking, and waist-hip ratio factors. Simple effect analyses indicated that diabetes and smoking status were more strongly associated with cardiovascular outcomes among participants with lower BDI scores, whereas waist-hip ratio values predicted outcomes only among those with higher BDI scores. CONCLUSIONS: These results suggest that the relationship between modifiable CVD risk factors and CVD outcomes may vary with depression status in clinical samples of women. This evidence augments prior research by demonstrating that depression may influence CVD risk jointly with or independent of CVD risk factors. It also provides further support for the inclusion of depression assessment in cardiovascular clinic settings.

Early menopause predicts angina after myocardial infarction.

OBJECTIVE: Population studies have shown that age at menopause (AAM) predicts coronary heart disease. It is unknown, however, whether early menopause predicts post-myocardial infarction (MI) angina. We examined whether younger AAM increases risk of post-MI angina. METHODS: In a prospective multicenter MI registry, 493 postmenopausal women were enrolled (mean +/- SD age, 65.4 +/- 11.3 y, and mean +/- SD AAM, 45.2 ± 7.8 y). We categorized AAM into 40 years or younger, 41 to 49 years, and 50 years or older. In the multivariable analysis, we examined whether AAM predicted 1-year post-MI angina and severity of angina after adjusting for angina before MI, demographics, comorbidities, MI severity, and quality of care (QOC). RESULTS: Women with early AAM (> or =40 y; n = 132, 26.8%) were younger and more often smokers but were as likely to have comorbidities as were women with an AAM of 50 years or older. Although there were no differences in pre-MI angina, MI severity, obstructive coronary disease, and QOC based on AAM, the rate of 1-year angina was higher in women with an AAM of 40 years or younger (32.4%) than in women with an AAM of 50 years or older (12.2%). In the multivariable analysis, women with an AAM of 40 years or younger had more than twice the risk of angina (relative risk, 2.09; 95% CI, 1.38-3.17) and a higher severity of angina (odds ratio, 2.65; 95% CI, 1.34-5.22 for a higher severity level) compared with women with an AAM of 50 years or older. CONCLUSIONS: Women with early menopause are at higher risk of angina after MI, independent of comorbidities, severity of MI, and QOC. The use of a simple question regarding AAM may help in the identification of women who need closer follow-up, careful evaluation, and intervention to improve their symptoms and quality of life after MI.

The role of social support in health status and depressive symptoms after acute myocardial infarction: evidence for a stronger relationship among women.

BACKGROUND: Prior studies have associated low social support (SS) with increased rehospitalization and mortality after acute myocardial infarction. However, relatively little is known about whether similar patterns exist for other outcomes, such as health status and depressive symptoms, and whether these patterns vary by sex. METHODS AND RESULTS: Using data from 2411 English- or Spanish-speaking patients with acute myocardial infarction enrolled in a 19-center prospective study, we examined the association of SS (low, moderate, high) with health status (angina, disease-specific quality of life, general physical and mental functioning) and depressive symptoms over the first year of recovery. Overall and sex-stratified associations were evaluated using mixed-effects Poisson and linear regression, adjusting for site, baseline health status, baseline depressive symptoms, and demographic and clinical factors. Patients with the lowest SS (relative to those with the highest) had increased risk of angina (relative risk, 1.27; 95% confidence interval [CI], 1.10, 1.48); lower disease-specific quality of life (mean difference [beta]=-3.33; 95% CI, -5.25, -1.41), lower mental functioning (beta=-1.72; 95% CI, -2.65, -0.79), and more depressive symptoms (beta=0.94; 95% CI, 0.51, 1.38). A nonsignificant trend toward lower physical functioning (beta=-0.87; 95% CI, -1.95, 0.20) was observed. In sex-stratified analyses, the relationship between SS and outcomes was stronger for women than for men, with a significant SS-by-sex interaction for disease-specific quality of life, physical functioning, and depressive symptoms (all P<0.02). CONCLUSIONS: Lower SS is associated with worse health status and more depressive symptoms over the first year of acute myocardial infarction recovery, particularly for women.

Hip fractures and heart failure: findings from the Cardiovascular Health Study.

AIMS: The aim of the study was to find the epidemiology of hip fractures in heart failure. The increasing survival rate for patients with heart failure places them at risk for other diseases of ageing, including osteoporosis. METHODS AND RESULTS: We included 5613 persons from the Cardiovascular Health Study (CHS) with an average of 11.5 year follow-up. We determined incidence rates and hazard ratios (HRs) in persons with heart failure compared with persons without heart failure and mortality hazards following these fractures. Annualized incidence rates for hip fractures were 14 per 1000 person-years in heart failure and 6.8 per 1000 person-years without heart failure. Unadjusted and multivariable adjusted HRs for hip fracture associated with heart failure in men were 1.87 (95% CI 1.2-2.93) and 1.59 (95% CI 0.93-2.72), respectively. Respective HRs for women were 1.75 (95% CI 1.27-2.4) and 1.41 (95% CI 0.98-2.03). Mortality hazard was approximately 2-fold greater in patients with heart failure and hip fracture compared with those having heart failure alone. CONCLUSION: Persons with heart failure are at high risk for hip fractures. However, much of the association between hip fractures and heart failure is explained by shared risk factors. Hip fractures are a substantial contributor to mortality in men and women with heart failure.

Insufficient deactivation of the protein tyrosine kinase lck amplifies T-cell responsiveness in acute coronary syndrome.

RATIONALE: In the vulnerable atherosclerotic plaque, T cells may destabilize the tissue structure through direct cell-injurious effector functions. T cells transmit environmental signals, such as recognition of antigen, into cellular responses through regulated phosphorylation of cytoplasmic proteins, with the Src family kinase Lck (lymphocyte-specific protein tyrosine kinase) in critical membrane-proximal position of the T-cell receptor (TCR) signaling cascade. The balance between protein phosphorylation and dephosphorylation defines the signal transduction threshold and determines appropriate T-cell responses. OBJECTIVE: We have examined whether abnormal calibration of intracellular signaling pathways renders acute coronary syndrome (ACS) patients susceptible to disproportionate T-cell responses. METHODS AND RESULTS: Intracellular signaling cascades were quantified in CD4 T cells from ACS patients and control individuals after stimulation with major histocompatibility complex class II-superantigen complexes. ACS T cells mobilized more intracellular calcium and accumulated higher levels of phosphotyrosine than control T cells. Proximal steps in TCR signaling, such as recruitment of ZAP-70 and clustering of TCR complexes in the immune synapse, were abnormally enhanced in ACS T cells. Acceleration of the signaling cascade derived from a proximal defect in ACS T cells, which failed to phosphorylate Lck at Tyr505, extending activation of the Src kinase. Abnormalities in TCR signaling did not correlate with systemic inflammation as measured by C-reactive protein. CONCLUSIONS: An intrinsic abnormality in the signaling machinery of ACS T cells resulting in the accumulation of active Lck lowers the TCR threshold and renders lymphocytes hyperreactive and capable of unwanted immune responses.