2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Incident Stroke in Individuals with Peripartum Cardiomyopathy.

BACKGROUND: Peripartum cardiomyopathy (PPCM), a form of heart failure with reduced ejection fraction (HFrEF) that occurs during the final month of pregnancy through the first 5 months postpartum, is associated with heightened risk for maternal morbidity and mortality. Stroke is a common complication of HFrEF but there is limited data on the incidence of stroke in PPCM. METHODS: Using statewide, non-federal administrative data from 2000-2015, we analyzed age-adjusted risk of stroke within 3 years after PPCM-associated pregnancies. RESULTS: PPCM was associated with a greater than four-fold increased risk of pregnancy-related stroke (aHR 4.7, 95% CI: 3.0-7.5). This risk was highest at the time of PPCM diagnosis but remained elevated in the first postpartum year. CONCLUSION: Our findings confirm the strong association between PPCM and stroke, with risk that persists throughout and after the peripartum period.

Cognitive Impairment in Heart Failure: A Heart Failure Society of America Scientific Statement.

Cognitive impairment is common among adults with heart failure (HF), as both diseases are strongly related to advancing age and multimorbidity (including both cardiovascular and noncardiovascular conditions). Moreover, HF itself can contribute to alterations in the brain. Cognition is critical for a myriad of self-care activities that are necessary to manage HF, and it also has a major impact on prognosis; consequently, cognitive impairment has important implications for self-care, medication management, function and independence, and life expectancy. Attuned clinicians caring for patients with HF can identify clinical clues present at medical encounters that suggest cognitive impairment. When present, screening tests such as the Mini-Cog, and consideration of referral for comprehensive neurocognitive testing may be indicated. Management of cognitive impairment should focus on treatment of underlying causes of and contributors to cognitive impairment, medication management/optimization, and accommodation of deficiencies in self-care. Given its implications on care, it is important to integrate cognitive impairment into clinical decision making. Although gaps in knowledge and challenges to implementation exist, this scientific statement is intended to guide clinicians in caring for and meeting the needs of an increasingly complex and growing subpopulation of patients with HF.

Race-ethnicity, age, and heart failure in ischemic stroke.

OBJECTIVES: Race-ethnic disparities contribute to cardiovascular morbidity. Heart failure (HF) is highly prevalent in acute ischemic stroke (AIS) and associated with worse outcomes. We hypothesized race-ethnic differences exist in the prevalence of HF among patients with AIS, particularly in younger patients, and in a manner not fully explained by cardiovascular profiles. METHODS: Patients with AIS in the National Inpatient Sample (2016-2019) were categorized as young (<50 years), middle (50-64) and older (≥65) age. Interaction between age and race-ethnicity on the presence of comorbid HF was examined, adjusting for vascular risk factors. Effect modification on in-hospital mortality and prolonged hospitalization across race-ethnic groups and age was also examined. RESULTS: Of 398,470 AIS patients, 16.2 % had HF. HF patients were older (73.7 vs. 69.5 years, P < 0.001), had a lower proportion of White, Hispanic and Asian/PI individuals but a larger proportion of patients of Black race (21.0 vs. 16.4 %, P < 0.001). Race-ethnicity modified the relationship between HF and age (Pinteraction < 0.001). Stroke patients of Black race had the greatest odds of having HF across all age groups, however differences between Black and White patients were most pronounced in young adults (OR: 2.08, 95 % CI: 1.91-2.27) after adjusting for vascular risk factors. Among patients with HF, Black race was associated with reduced risk of in-hospital mortality but greater likelihood of prolonged hospitalization at middle and older age. CONCLUSION: HF is highly prevalent in stroke patients of Black race, particularly in younger cohorts, and in a manner not fully explained by cardiovascular profiles.

Management of Patients at Risk for and With Left Ventricular Thrombus: A Scientific Statement From the American Heart Association.

Despite the many advances in cardiovascular medicine, decisions concerning the diagnosis, prevention, and treatment of left ventricular (LV) thrombus often remain challenging. There are only limited organizational guideline recommendations with regard to LV thrombus. Furthermore, management issues in current practice are increasingly complex, including concerns about adding oral anticoagulant therapy to dual antiplatelet therapy, the availability of direct oral anticoagulants as a potential alternative option to traditional vitamin K antagonists, and the use of diagnostic modalities such as cardiac magnetic resonance imaging, which has greater sensitivity for LV thrombus detection than echocardiography. Therefore, this American Heart Association scientific statement was commissioned with the goals of addressing 8 key clinical management questions related to LV thrombus, including the prevention and treatment after myocardial infarction, prevention and treatment in dilated cardiomyopathy, management of mural (laminated) thrombus, imaging of LV thrombus, direct oral anticoagulants as an alternative to warfarin, treatments other than oral anticoagulants for LV thrombus (eg, dual antiplatelet therapy, fibrinolysis, surgical excision), and the approach to persistent LV thrombus despite anticoagulation therapy. Practical management suggestions in the form of text, tables, and flow diagrams based on careful and critical review of actual study data as formulated by this multidisciplinary writing committee are given.

Stroke and Mechanical Circulatory Support in Adults.

PURPOSE OF THE REVIEW: Short-term and durable mechanical circulatory support (MCS) devices represent life-saving interventions for patients with cardiogenic shock and end-stage heart failure. This review will cover the epidemiology, risk factors, and treatment of stroke in this patient population. RECENT FINDINGS: Short-term devices such as intra-aortic balloon pump, Impella, TandemHeart, and Venoatrial Extracorporal Membrane Oxygenation, as well as durable continuous-flow left ventricular assist devices (LVADs), improve cardiac output and blood flow to the vital organs. However, MCS use is associated with high rates of complications, including ischemic and hemorrhagic strokes which carry a high risk for death and disability. Improvements in MCS technology have reduced but not eliminated the risk of stroke. Mitigation strategies focus on careful management of anti-thrombotic therapies. While data on therapeutic options for stroke are limited, several case series reported favorable outcomes with thrombectomy for ischemic stroke patients with large vessel occlusions, as well as with reversal of anticoagulation for those with hemorrhagic stroke. Stroke in patients treated with MCS is associated with high morbidity and mortality. Preventive strategies are targeted based on the specific form of MCS. Improvements in the design of the newest generation device have reduced the risk of ischemic stroke, though hemorrhagic stroke remains a serious complication.

Impact of the COVID-19 Pandemic on Cardiovascular Science: Anticipating Problems and Potential Solutions: A Presidential Advisory From the American Heart Association.

The coronavirus disease 2019 (COVID-19) pandemic has had worldwide repercussions for health care and research. In spring 2020, most non-COVID-19 research was halted, hindering research across the spectrum from laboratory-based experimental science to clinical research. Through the second half of 2020 and the first half of 2021, biomedical research, including cardiovascular science, only gradually restarted, with many restrictions on onsite activities, limited clinical research participation, and the challenges associated with working from home and caregiver responsibilities. Compounding these impediments, much of the global biomedical research infrastructure was redirected toward vaccine testing and deployment. This redirection of supply chains, personnel, and equipment has additionally hampered restoration of normal research activity. Transition to virtual interactions offset some of these limitations but did not adequately replace the need for scientific exchange and collaboration. Here, we outline key steps to reinvigorate biomedical research, including a call for increased support from the National Institutes of Health. We also call on academic institutions, publishers, reviewers, and supervisors to consider the impact of COVID-19 when assessing productivity, recognizing that the pandemic did not affect all equally. We identify trainees and junior investigators, especially those with caregiving roles, as most at risk of being lost from the biomedical workforce and identify steps to reduce the loss of these key investigators. Although the global pandemic highlighted the power of biomedical science to define, treat, and protect against threats to human health, significant investment in the biomedical workforce is required to maintain and promote well-being.

Stroke epidemiology and outcomes in the modern era of left ventricular assist devices.

The care for the patients with end-stage heart failure has been revolutionized by the introduction of durable left ventricular assist devices, providing a substantial improvement in patient survival and quality of life and an alternative to heart transplantation. The newest devices have lower instances of mechanical dysfunction and associated pump thrombosis. Despite these improvements in complications, the use of continuous flow assist devices is still associated with high rates of thrombotic and hemorrhagic complications, most notably stroke in approximately 10% of continuous flow assist devices patients per year. With the newest HeartMate 3 devices, there have been lower observed rates of stroke, which has in part been achieved by both improvements in pump technology and knowledge of the risk factors for stroke and neurological complications. The therapeutic options available to clinicians to reduce the risk of stroke, including management of hypertension and antithrombotics, will be reviewed in this manuscript.

Stroke Prevention After Cryptogenic Stroke.

PURPOSE OF REVIEW: Cryptogenic stroke represents a heterogenous but clinically important collection of stroke etiologies for which our understanding continues to grow. Here, we review our current knowledge and most recent recommendations on secondary prevention for common causes of cryptogenic stroke including paroxysmal atrial fibrillation, atrial cardiopathy, patent foramen ovale, and substenotic atherosclerotic disease as well as the under-recognized mechanisms of occult malignancy, heart failure, and, most recently, infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). RECENT FINDINGS: The results from recent observational studies and randomized clinical trials have provided greater insight into the causal relationship and attributable risk of these suspected etiologies and have identified potential strategies to reduce the rates of recurrence. However, further clinical trials are needed to confirm the benefits of specific stroke prevention strategies, including the patient populations most likely to benefit from anticoagulation. There is ongoing research aimed at both reducing the proportion of ischemic strokes classified as cryptogenic and resolving much of the clinical equipoise that still exists. The results of these studies have the potential to provide us with a better understanding of these occult mechanisms and allow for more targeted interventions.

Medical and Surgical Management of Left Ventricular Assist Device-Associated Intracranial Hemorrhage.

OBJECTIVES: Management of left ventricular assist device (LVAD)-associated intracranial hemorrhage (ICH) is complicated by the competing concerns of hematoma expansion and the risk of thrombosis. Strategies include reversal or withholding of anticoagulation (AC) and neurosurgical (NSG) interventions. The consequences of these decisions can significantly impact both short- and long-term survival. Currently no guidelines exist. We reviewed medical and NSG practices following LVAD-associated ICH and analyzed outcomes. MATERIALS AND METHODS: Retrospective analysis of data collected between 2012-2018 was performed. Survival probability following ICH was calculated using the Kaplan-Meier method. RESULTS: Out of 283 patients, 32 (11%) had 34 ICHs: 16 intraparenchymal (IPH, 47%), 4 subdural (SDH, 12%), and 14 subarachnoid (SAH, 41%). IPH tended to occur sooner (median 138 [IQR 48 - 258] days post-LVAD placement) and be more neurologically devastating (mean GCS 11.4 [4.4]). Antithrombotics were reversed in 27 (79%); 1 thrombotic event occurred while off AC. Following resumption, re-hemorrhage occurred in 7 (25%), a median of 13 days (IQR 8-30) post-ICH. Five underwent NSG intervention and 6 (18%) went on to receive heart transplant. Overall, 30-day mortality was 26% (38% in IPH, 0% in SDH, and 29% in SAH), but rose to 44% at 6 months. CONCLUSION: ICH is a common post-LVAD complication with high short- and long-term mortality, though ICH subtypes may not be equally devastating. Despite this, some may benefit from neurosurgical intervention and do well following cardiac transplant. Anticoagulation is frequently reversed after ICH. Resumption however should be approached cautiously in patients with LVADs given their possible baseline coagulopathy.

Racial-Ethnic disparities in stroke prevalence among patients with heart failure.

Racial-ethnic disparities exist in the prevalence and outcomes of heart failure (HF) and are presumed to be related to differences in cardiovascular risk factor burden and control. There is little data on stroke disparities among patients with HF or the factors responsible. We hypothesized disparities in stroke prevalence exist among patients with HF in a manner not fully explained by burden of cardiovascular disease. We analyzed data from the National Health and Nutrition Examination Survey (1999-2014). Cardiovascular profiles were compared by race/ethnicity. Using survey-weighted models, effect modification of the relationship between HF and stroke by race/ethnicity was examined adjusting for cardiovascular profiles. Of 40,437 participants, 2.5 % had HF. The HF cohort had a greater proportion of White and Black participants (77 % vs 74 % and 15 % vs 12 %, respectively) and fewer participants of Hispanic ethnicity (8 % vs 14 %). Stroke was 8 times more prevalent in HF (19.6 % vs 2.3 %, <0.001). Among individuals with HF, race-ethnic differences were identified in the prevalence and mean values of vascular risk factors but were largely driven by higher rates in Black participants. There was significant interaction between HF and race/ethnicity; HF increased the odds of stroke over 7-fold in participants of Hispanic ethnicity (aOR: 7.84; 95 % CI: 4.11-15.0) but to a lesser extent in Black and White participants (Black aOR: 2.49; 95 % CI: 1.72-3.60; White aOR: 3.36; 95 % CI: 2.57-4.40). People of Hispanic ethnicity with HF have a disproportionately higher risk of stroke in a manner not fully explained by differences in vascular risk profiles.

Association of aortic valve calcium with dementia and stroke: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Calcific aortic valve disease is associated with increased thrombin formation, platelet activation, decreased fibrinolysis, and subclinical brain infarcts. We examined the long-term association of aortic valve calcification (AVC) with newly diagnosed dementia and incident stroke in the Multi-Ethnic Study of Atherosclerosis (MESA). METHODS: AVC was measured using non-contrast cardiac CT at Visit 1. We examined AVC as a continuous (log-transformed) and categorical variable (0, 1-99, 100-299, ≥300). Newly diagnosed dementia was adjudicated using International Classification of Disease codes. Stroke was adjudicated from medical records. We calculated absolute event rates (per 1000 person-years) and multivariable adjusted Cox proportional hazards ratios (HR). RESULTS: Overall, 6812 participants had AVC quantified with a mean age of 62.1 years old, 52.9 % were women, and the median 10-year estimated atherosclerotic cardiovascular disease (ASCVD) risk was 13.5 %. Participants with AVC >0 were older and less likely to be women compared to those with AVC=0. Over a median 16-year follow-up, there were 535 cases of dementia and 376 cases of stroke. The absolute risk of newly diagnosed dementia increased in a stepwise pattern with higher AVC scores, and stroke increased in a logarithmic pattern. In multivariable analyses, AVC was significantly associated with newly diagnosed dementia as a log-transformed continuous variable (HR 1.09; 95 % CI 1.04-1.14) and persons with AVC ≥300 had nearly a two-fold higher risk (HR 1.77; 95 % CI 1.14-2.76) compared to those with AVC=0. AVC was associated with an increased risk of stroke after adjustment for age, sex, and race/ethnicity, but not after adjustment for ASCVD risk factors. CONCLUSIONS: After multivariable adjustment, AVC >0 was significantly associated with an increased risk of newly diagnosed dementia, but not incident stroke. This suggests that AVC may be an important risk factor for the long-term risk of dementia beyond traditional ASCVD risk factors.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Patients With Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Mechanical thrombectomy after acute ischemic stroke in patients with left ventricular assist devices: A nationwide analysis.

INTRODUCTION: Left ventricular assist devices (LVADs) are an established, durable, and life-saving treatment option for patients with advanced heart failure. However, large vessel occlusions (LVOs) remain one of its most devastating embolic complications. Mechanical thrombectomy (MT) is safe and effective in the management of LVOs in the general population, but LVO trials largely excluded patients on mechanical circulatory support, and large-scale analyses of outcomes following these interventions in the LVAD population are lacking. METHODS: Using the National Inpatient Sample, we identified all adult patients hospitalized with acute ischemic stroke (AIS) from 2005 to 2018. Regression models adjusting for patient demographics, hospital factors, and clinical severity were used to compare outcomes following MT in patients with and without LVAD. Subgroup analyses were also performed in LVAD patients experiencing stroke in the post-operative setting and stroke in the setting of pre-existing devices. RESULTS: Of the 1,633,234 AIS hospitalizations identified, 794 occurred in patients with LVADs. Around 61% were post-operative. Post-stroke in-hospital mortality was higher among patients with LVADs (23.3% vs 7.23%, P < 0.001). Among those receiving MT, mortality was also higher in the LVAD population (31.0% vs 14.1%, P = 0.009), though this was largely driven by the post-operative LVAD subgroup. In multivariable analysis, only post-operative LVAD patients experienced greater odds of in-hospital death after MT (adjusted odds ratio (aOR): 8.66, confidence interval (CI):1.46-51.3); patients with pre-existing LVADs demonstrated no difference in post-MT mortality (aOR: 1.06; 95% CI: 0.29-3.91) or in odds of discharge home after MT (aOR 0.63, CI: 0.17-2.32). CONCLUSION: Our data suggest MT is not a futile treatment approach in patients with pre-existing LVADs and may result in similar rates of good outcomes. Additional research is needed to evaluate the long-term benefits of endovascular therapy after stroke in patients on LVAD support.

Historical Redlining, Social Determinants of Health, and Stroke Prevalence in Communities in New York City.

Importance: Historical redlining was a discriminatory housing policy that placed financial services beyond the reach of residents in inner-city communities. The extent of the impact of this discriminatory policy on contemporary health outcomes remains to be elucidated. Objective: To evaluate the associations among historical redlining, social determinants of health (SDOH), and contemporary community-level stroke prevalence in New York City. Design, Setting, and Participants: An ecological, retrospective, cross-sectional study was conducted using New York City data from January 1, 2014, to December 31, 2018. Data from the population-based sample were aggregated on the census tract level. Quantile regression analysis and a quantile regression forests machine learning model were used to determine the significance and overall weight of redlining in relation to other SDOH on stroke prevalence. Data were analyzed from November 5, 2021, to January 31, 2022. Exposures: Social determinants of health included race and ethnicity, median household income, poverty, low educational attainment, language barrier, uninsurance rate, social cohesion, and residence in an area with a shortage of health care professionals. Other covariates included median age and prevalence of diabetes, hypertension, smoking, and hyperlipidemia. Weighted scores for historical redlining (ie, the discriminatory housing policy in effect from 1934 to 1968) were computed using the mean proportion of original redlined territories overlapped on 2010 census tract boundaries in New York City. Main Outcomes and Measures: Stroke prevalence was collected from the Centers for Disease Control and Prevention 500 Cities Project for adults 18 years and older from 2014 to 2018. Results: A total of 2117 census tracts were included in the analysis. After adjusting for SDOH and other relevant covariates, the historical redlining score was independently associated with a higher community-level stroke prevalence (odds ratio [OR], 1.02 [95% CI, 1.02-1.05]; P < .001). Social determinants of health that were positively associated with stroke prevalence included educational attainment (OR, 1.01 [95% CI, 1.01-1.01]; P < .001), poverty (OR, 1.01 [95% CI, 1.01-1.01]; P < .001), language barrier (OR, 1.00 [95% CI, 1.00-1.00]; P < .001), and health care professionals shortage (OR, 1.02 [95% CI, 1.00-1.04]; P = .03). Conclusions and Relevance: This cross-sectional study found that historical redlining was associated with modern-day stroke prevalence in New York City independently of contemporary SDOH and community prevalence of some relevant cardiovascular risk factors.

Cognition predicts days-alive-out-of-hospital after LVAD implantation.

OBJECTIVE: Cognition influences hospitalization rates for a variety of patient groups but this association has not been examined in heart failure (HF) patients undergoing left ventricular assist device (LVAD) implantation. We used cognition to predict days-alive-out-of-hospital (DAOH) in patients after LVAD surgery. METHODS: We retrospectively identified 59 HF patients with cognitive assessment prior to LVAD. Cognitive tests of attention, memory, language, and visual motor speed were averaged into one score. DAOH was converted to a percentage based on total days from LVAD surgery to either heart transplant or 900 days post-LVAD. Variables significantly associated with DAOH in univariate analyses were included in a linear regression model to predict DAOH. RESULTS: A linear regression model including LVAD type (continuous or pulsatile flow) and cognition significantly predicted DAOH (F(2,54) = 6.44, p = 0.003, R2 = .19). Inspection of each variable revealed that cognition was a significant predictor in the model (ß = .11, SE = .04, p = 0.007) but LVAD type was not (p = 0.08). CONCLUSIONS: Cognitive performance assessed prior to LVAD implantation predicted how much time patients spent out of the hospital following surgery. Further studies are warranted to identify the impact of pre-LVAD cognition on post-LVAD hospitalization.

Comparison of Neurologic Event Rates Among HeartMate II, HeartMate 3, and HVAD.

Strokes remain a leading cause of morbidity and mortality in patients with ventricular assist devices (VADs). Varying study populations, event definitions, and reporting methods make direct comparison of neurologic event risk across clinical trials and registries challenging. We aim to highlight important differences among major VAD studies and standardize rates of neurologic events to facilitate a comprehensive and objective comparison. We systematically identified and analyzed key clinical trials and registries evaluating the HeartMate II (HMII), HeartMate 3 (HM3), and HVAD devices. Reported neurologic events were nonexclusively categorized into ischemic stroke, hemorrhagic stroke, disabling stroke, fatal stroke, and other neurologic events per the studies' definitions. Event rates were standardized to events per patient-year (EPPY) and freedom from event formats. Seven key clinical trials and registries were included in our analysis. There is significant variation and overlap in neurologic event rates for the three VAD platforms across clinical trials (all neurologic events [EPPY]: HM3 0.17-0.21; HMII 0.19-0.26; HVAD 0.16-0.28). None performs consistently better for all types of neurologic events. Furthermore, stroke rates among VAD trials correlated with baseline stroke risk factors including ischemic etiology, history of atrial fibrillation, and history of prior stroke.

Inhibition of growth and induction of differentiation of colon cancer cells by peach and plum phenolic compounds.

The action of extracts from anthocyanin-enriched plums and peaches on growth and differentiation was studied with human colon cancer cells. Growth inhibitory effects were observed in Caco-2, SW1116, HT29 and NCM460 cells. In Caco-2 cells but not in the other cells studied there was evidence for increased differentiation as judged by increased activity of alkaline phosphatase and dipeptidyl peptidase. A differentiating effect on Caco-2 cells was not seen with cyanidin or cyanidin-3-glucoside but the action of the fruit extracts was additive with the action of butyrate and with the MEK1/2 inhibitor U0126. Fractionation using C18 indicated activity resided within a fraction containing anthocyanins but further fractionation using LH-20 suggested that most of the activity was in a fraction containing polyphenols other than anthocyanins. It was concluded that several peach and plum phenolic molecules can influence growth and differentiation in human colon cancer cells.

Induction of differentiation of colon cancer cells by combined inhibition of kinases and histone deacetylase.

The MAP kinase pathway inhibitor U0126 in combination with butyrate promotes differentiation in some colon cancer cell lines. We examined several inhibitors of histone deacetylase (HDAC) in combination with U0126 and other protein kinase inhibitors to see if these effects are general properties of HDAC inhibitors or butyrate alone. Alkaline phosphatase and peptidase activities were examined as markers for cellular differentiation in the human colon cancer cell lines Caco-2 and HT29 and the minimally transformed NCM460. Several HDAC inhibitors caused greater increases of alkaline phosphatase in the cancer cells than in NCM460, in which butyrate was the only HDAC inhibitor that caused a consistent increase. Unlike the JNK and PKC inhibitors examined, the MEK 1/2 inhibitor U0126 induced alkaline phosphatase activity in Caco-2 as a single agent and caused additive effects with HDAC inhibitors. The PI-3 kinase inhibitor LY294002 had little effect alone but enhanced the response of most HDAC inhibitors as did the raf inhibitor GW5074. In addition to butyrate, several HDAC inhibitors can induce differentiation in colon cancer cells and the responses may be enhanced by U0126, GW5074 and LY294002.