European Physician Survey Characterizing the Clinical Pathway and Treatment Patterns of Patients Post-Myocardial Infarction.

INTRODUCTION: The 2019 European Society of Cardiology and European Atherosclerosis Society (2019 ESC/EAS) guidelines stress the importance of managing low-density lipoprotein cholesterol (LDL-C) after myocardial infarction (MI) to reduce the risk of cardiovascular events. Information on guideline implementation is limited. The aim of this survey was to describe current clinical practice regarding LDL-C management in the first year post-MI across Europe, improving understanding of the role of ESC/EAS guidelines on clinical practice. METHODS: A qualitative web-based cross-sectional physician survey about the patient pathway and LDL-C management post-MI was conducted in 360 physicians from France, Italy, Germany, The Netherlands, Spain, and the UK (n = 60/country) between December 2019 and June 2020. Secondary and primary care physicians (SCPs/PCPs) described their experiences treating patients post-MI over the preceding 2 months. RESULTS: Physicians reported that on average 90.7% of patients not prescribed lipid-lowering therapy (LLT) before an MI initiated LLT as inpatients; for patients already taking LLT, treatment was intensified for 64.7% of inpatients post-MI. SCPs reported prescribing higher-intensity statins and/or ezetimibe for between 72.3% (Italy) and 88.6% (UK) of patients post-MI. More than 80.0% of SCPs and 51.2% of PCPs stated that they would initiate a change in LLT immediately if patients did not achieve their LDL-C treatment goal by 12 weeks post-MI; 82.0% of SCPs and 55.1% of PCPs reported referring to 2019 ESC/EAS guidelines for management of patients post-MI. Barriers to initiating PCSK9 inhibitors (PCSK9is) included prior prescription of a maximally tolerated dose of statin (49.4%) and/or ezetimibe (38.9%), requirement to reach threshold LDL-C levels (44.9%), and pre-authorization requirements (30.4%). CONCLUSION: Differences in clinical practice post-MI were reported across the countries surveyed, including divergence between 2019 ESC/EAS and local guidelines. Increased use of innovative medicines to achieve LDL-C goals should reduce risk of subsequent cardiovascular events in very high-risk patients post-MI.

Identification of Secondary Prevention Patients Eligible for PCSK9 Inhibitors Therapy According to the Routine Clinical Practice in Spain.

INTRODUCTION: Many patients at very high risk of cardiovascular (CV) events would benefit from lipid-lowering therapies (LLT) intensification to decrease their risk. This study aimed to identify the real-world secondary prevention patients potentially eligible for proprotein convertase subtilisin-kexin type 9 inhibitors (PCSK9i) in Spain. METHODS: This retrospective cohort study included adult patients registered in the IQVIA Spanish Electronic Medical Records outpatient database (2014-2020), diagnosed with myocardial infarction (MI), unstable angina (UA), ischaemic stroke (IS), transient ischaemic attack (TIA) or peripheral artery disease (PAD) and with ≥ 1 low-density lipoprotein cholesterol (LDL-C) or total cholesterol measurements. Longitudinal data were collected from the initial diagnosis to the end of the study period or follow-up loss. RESULTS: The study included 9516 patients, 63.9% male, mean (SD) age 67.7 (12.5) years and mean LDL-C 117.3 (38.8) mg/dL. MI, IS and PAD were the most severe events reported during the study period (28.5%, 18.7% and 29.3% of patients, respectively). At the time of last available LDL-C assessment (≥ 3 months post-event), 64.4% patients were on LLT. Of those, 45.4%, 46.9% and 7.7% were on high-, moderate- and low-intensity LLT. Overall, 9.6% patients achieved LDL-C < 55 mg/dL (24.2% LDL-C < 70 mg/dL). Furthermore, 17.9% patients receiving optimized oral LLT showed LDL-C > 100 mg/dL (LDL-C reimbursement threshold for PCSK9i in Spain). CONCLUSION: Up to 82% of patients with atherosclerotic CV disease do not achieve LDL-C levels recommended by the 2019 ESC/EAS guidelines despite being on optimized oral LLT therapy. In 17.9% of these patients LDL-C levels exceed 100 mg/dL, being eligible for PCSK9i in Spain.

Healthcare resource utilization and costs of cardiovascular events in patients with atherosclerotic cardiovascular disease in Germany - results of a claims database study.

OBJECTIVES: We assessed healthcare resource utilization (HCRU) and costs of cardiovascular (CV) events in patients with a history of atherosclerotic cardiovascular disease (ASCVD) in Germany. METHODS: We conducted a retrospective matched case-control study based on German claims data from 1 January 2012 to 31 December 2017 using the "Institute for Applied Health Research Berlin" (InGef) Research Database. Cases who had a myocardial infarction (MI), stroke and angina pectoris identified by ICD-10-GM codes between 1 January 2014 and 31 December 2016 were matched to event-free controls by an exact matching approach without replacement at a ratio of 1:2. Costs and HCRU were assessed in individual 1-year follow-up periods after the index event for the overall cohort and subgroups of MI cases and stroke cases. RESULTS: The overall cohort consisted of a total of 14,169 cases with a CV index event matched to 28,338 controls. The mean age of the overall cohort was 73.3 years, 34.1% of the patients were female, 3,717 (26.2%) had an MI, and 3,752 (26.5%) had stroke. Following the index events, 12.2% of cases in the overall cohort, 12.6% of MI cases, and 8.7% of stroke cases experienced a recurrent CV event. CV cases had on average 1.7 more all-cause hospitalizations (p <0.001) and 6.1 more outpatient visits (p <0.001) during the 1-year follow-up period than did controls. In the MI and stroke subgroups, cases had on average 1.8 and 1.6 more all-cause hospitalizations and 7.0 and 4.0 more outpatient visits, respectively (differences were statistically significant). Compared to controls, cases incurred on average higher total healthcare costs: by €11,898 for overall cases, by €16,349 for MI, and by €14,360 in stroke cases (overall: p <0.001; MI: p <0.001; stroke: p <0.001). CONCLUSION: CV events in ASCVD patients pose a considerable clinical burden on patients and cause significant costs for the German statutory healthcare system.

Longitudinal evaluation of treatment patterns, risk factors and outcomes in patients with cardiovascular disease treated with lipid-lowering therapy in the UK.

OBJECTIVES: To compare treatment patterns, risk factors and cardiovascular disease (CVD) event rates in the UK from 2008 to 2017. DESIGN: Retrospective cohort study using the Clinical Practice Research Datalink. SETTING: UK primary care. PARTICIPANTS: We selected 10 annual cohorts of patients with documented CVD receiving lipid-lowering therapy and the subsets with myocardial infarction (MI). Each cohort included patients ≥18 years old, with ≥1 year of medical history and ≥2 lipid-lowering therapy prescriptions in the prior year. PRIMARY AND SECONDARY OUTCOME MEASURES: For each annual cohort, we identified cardiovascular risk factors and lipid-lowering therapy and estimated the 1-year composite rate of fatal and non-fatal MI, ischaemic stroke (IS) or revascularisation. RESULTS: The documented CVD cohort mean age was 71.6 years in 2008 (N=173 424) and 72.5 (N=94 418) in 2017; in the MI subset, mean age was 70.1 years in 2008 (N=38 999) and 70.4 in 2017 (N=25 900). Both populations had larger proportions of men. In the documented CVD cohort, the proportion receiving high-intensity lipid-lowering therapy from 2008 to 2017 doubled from 16% to 32%; in the MI subset, the increase was 20% to 48%. In the documented CVD cohort, the proportion of patients with low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L increased from 28% to 38%; in the MI subset, the proportion with LDL-C <1.8 mmol/L increased from 32% to 42%. The composite event rate per 100 person-years declined over time, from 2.5 to 2.0 in the documented CVD cohort, and from 3.7 to 2.8 in the MI subset. After excluding revascularisation from the composite outcome, the decline in the event rate in both populations was substantially attenuated. CONCLUSIONS: Despite an increase in high-intensity therapy use and a decline in revascularisation, more than half of patients did not receive high-intensity lipid-lowering therapy by 2017 and incidence rates of MI and IS remained virtually unchanged.

Healthcare Resource Utilization, Cardiovascular Event Rate and Use of Lipid-Lowering Therapies in Secondary Prevention of ASCVD in Hospitalized Patients in Italy.

INTRODUCTION: Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of mortality in Italy, accounting for 22% of total deaths. Lowering low-density lipoprotein cholesterol (LDL-C) levels reduces the risk of cardiovascular (CV) events; thus, lipid-lowering therapy (LLT) is the first-line treatment for patients with ASCVD and hypercholesterolaemia. However, many patients with ASCVD fail to reach LDL-C treatment thresholds, leaving them at greater risk of CV events. Inpatient care accounts for 51% of total expenditure on cardiovascular disease in the European Union, but healthcare resource utilization (HCRU) data for ASCVD in Italy is limited. METHODS: The study analysed healthcare claims data for 17,881 patients with acute coronary syndrome, ischemic stroke or peripheral artery disease from the Umbria 2 and Marche regions of Italy. LLT treatment patterns and CV event rates were collected and HCRU estimated in the year before and after the index event. RESULTS: High-intensity LLTs were prescribed to 44.3% of patients and 49.6% received moderate-/low-intensity LLTs during the 6 months after the index event. The first year CV event rate was 18.0/100 patient-years for patients receiving high-intensity LLTs and 17.2/100 patient-years for those on moderate-/low-intensity LLTs. Higher costs were associated with patients untreated with LLT 6 months post-index event (€8323) than patients prescribed high-intensity (€6278) or moderate-/low-intensity LLTs (€6270). Hospitalization accounted for most of the total costs. CONCLUSIONS: This study found that CV events in secondary prevention Italian patients are associated with substantial HCRU and costs. More intensive LDL-C lowering can prevent CV events, easing the financial burden on the healthcare system.

Association of Treatment Intensity and Adherence to Lipid-Lowering Therapy with Major Adverse Cardiovascular Events Among Post-MI Patients in Germany.

INTRODUCTION: Patients with a history of myocardial infarction (MI) are at very high risk of subsequent cardiovascular events. This study evaluated the association of treatment intensity and adherence to lipid-lowering therapies (LLT) with major adverse cardiovascular events (MACE) among post-MI patients in Germany. METHODS: We carried out a retrospective cohort study using German health claims data (2010-2015). We included patients ≥ 18 years, with a history of MI and who started an LLT (statin and/or ezetimibe), between 2011 and 2013. The follow-up period started 1 year after the second LLT prescription and continued until MACE, all-cause death or December 31, 2015, whichever occurred first. Treatment intensity was classified based on expected low-density lipoprotein cholesterol reduction; adherence was measured by the proportion of days covered using prescription data. A combined adherence-adjusted intensity variable was created by multiplying intensity and adherence. We used Cox proportional hazards models to control for age, sex, Charlson Comorbidity Index and other cardiovascular risk factors at baseline. RESULTS: A total of 14,944 patients were included. Mean age was 66.7 (SD = 13.0) years; 68.7% of patients were men. Each 10% increase in treatment intensity, adherence, or adherence-adjusted intensity was associated with a decrease in the risk of MACE of 17% (HR = 0.83, 95% CI 0.79-0.87), 5% (HR = 0.95, 95% CI 0.94-0.97), and 14% (HR = 0.86, 95% CI 0.83-0.90), respectively. CONCLUSIONS: Higher treatment intensity and/or adherence of LLT was associated with significantly lower risk of MACE in post-MI patients. Strategies to tailor intensity to patient profiles and improve adherence could reduce the risk of cardiovascular events.

Patient and caregiver productivity loss and indirect costs associated with cardiovascular events in Portugal.

OBJECTIVES: To present the Portuguese results of a multi-country cross-sectional survey aiming to estimate productivity loss in the first year after an acute coronary syndrome (ACS) or stroke. METHODS: Patients previously hospitalized for ACS or stroke were enrolled during a routine cardiology/neurology visit 3-12 months after the index event and ≥4 weeks after returning to work. Productivity loss for the patient and the caregiver in the previous four weeks were reported by the patient using the validated iMTA Productivity Cost Questionnaire (iPCQ). Hours lost were converted into eight-hour work days and prorated to one year, combined with initial hospitalization and sick leave, and valued according to Portuguese labor costs. RESULTS: The analysis included 39 employed patients with ACS (mean age 51 years, 80% men, 95% with myocardial infarction, mean left ventricular ejection fraction 55%) and 31 with stroke (mean age 50 years, 80% men, all ischemic, 77% with modified Rankin Scale 0-1); 41% of ACS and 10% of stroke patients had a history of cardiovascular disease. Mean (SD) productivity loss for patients and caregivers was 47 (62) work days for ACS and 76 (101) work days for stroke. ACS patients lost 37 (39) and caregivers lost 10 (42) work days. Stroke patients and caregivers lost 65 (78) and 12 (38) work days, respectively. Total mean indirect cost per case was €5403 (€7095) and €8726 (€11558) for employed patients with ACS and stroke, respectively. CONCLUSIONS: The annual proportions of productive time lost by employed patients due to ACS and stroke in Portugal were 17% and 27%, respectively. Caregivers of these patients lost about 5% of their annual productive time.

Patient and caregiver productivity loss and indirect costs associated with cardiovascular events in Europe.

AIMS: The aim of this study was to estimate patient and caregiver productivity loss and indirect costs following an acute coronary syndrome (ACS) or a stroke in Europe. METHODS: A cross-sectional study was conducted in seven European countries. A validated questionnaire was used during a cardiologist/neurologist visit 3-12 months post event. We included patients who returned to work ( ≥ 4 weeks prior to recruitment), given specific interest in presenteeism. Patient absenteeism, presenteeism and caregiver loss in the past four weeks were pro-rated to one year and combined with time-off due to initial hospitalisation/sick-leave. Hours lost were valued according to country labour cost (2018 euros). RESULTS: The analysis included 196 ACS (86% myocardial infarction) and 198 stroke (99% ischaemic, 77% modified Rankin Scale 0-1) patients. Mean age in ACS and stroke patients was 53 years, 86% and 78% respectively were men, 28% and 25% had previous cardiovascular event or established cardiovascular disease. Mean (country range) total productivity time loss was 70 (47-91) workdays for ACS and 68 (45-88) workdays for stroke (25% of annual workdays). Particularly, ACS patient lost 59 (37-79) workdays, and caregivers lost 11 (0-16) workdays, with total mean indirect cost per case €13,953 (€6641-23,160). After stroke, 56 (42-70) workdays were lost by patient plus 12 (3-20) days by caregiver, amounting to €13,773 (€10,469-20,215). Patients with previous events or established cardiovascular disease lost 80 (ACS) and 73 (stroke) workdays, costing €16,061 and €14,942 respectively. CONCLUSIONS: Our results suggest that lost productive time and indirect costs following ACS/stroke are substantial, with indirect costs comparable to direct costs.

The prevalence, low-density lipoprotein cholesterol levels, and treatment of patients at very high risk of cardiovascular events in the United Kingdom: a cross-sectional study.

OBJECTIVE: To assess the prevalence of patients at very high risk of cardiovascular (CV) events in the United Kingdom (UK) and evaluate low-density lipoprotein cholesterol (LDL-C) values and treatment patterns in these patients. METHODS: This cross-sectional study used primary care data from UK electronic medical records in the Clinical Practice Research Datalink (CPRD) in 2013. Very high-risk patients were defined per European Society of Cardiology guidelines as those with hyperlipidemia (assessed by co-medication) and documented cardiovascular disease (CVD) or hyperlipidemia and type 2 diabetes (DM2) without CVD (DM2w/oCVD). All analyses were descriptive. RESULTS: Data from 4,940,226 patients were captured in the CPRD in 2013. Of these, 5% of patients had received ≥2 lipid-modifying therapy prescriptions and were at very high risk of CVD (3% [n = 138,536] had documented CVD, 2% [n = 98,743] had DM2w/oCVD). In documented CVD patients, coronary artery disease (73%) was the most frequent type of event (25% had myocardial infarction [MI]), followed by cerebrovascular disease (18%), and peripheral arterial disease (9%); 21% had experienced multiple CV events, 25% had DM2, and 3% had MI within 1 year. In documented CVD and DM2w/oCVD patients, >95% received statin treatment; 24% received high-intensity statin, and 1.5% statin plus ezetimibe. Across both populations, 64-66% had LDL-C levels ≥1.8 mmol/L, 27-28% ≥2.5 mmol/L, 6-7% ≥3.5 mmol/L, and 3% had levels ≥4.0 mmol/L, respectively. CONCLUSION: A well-defined proportion of patients remain at very high-risk of CVD. Statin therapy needs optimization, but, for some patients with high LDL-C levels, multiple CV events, MI within 1 year, or CVD and DM2, additional more intensive therapy may be needed.

Validity of a simple Internet-based outcome-prediction tool in patients with total hip replacement: a pilot study.

We developed a user-friendly Internet-based tool for patients undergoing total hip replacement (THR) due to osteoarthritis to predict their pain and function after surgery. In the first step, the key questions were identified by statistical modelling in a data set of 375 patients undergoing THR. Based on multiple regression, we identified the two most predictive WOMAC questions for pain and the three most predictive WOMAC questions for functional outcome, while controlling for comorbidity, body mass index, age, gender and specific comorbidities relevant to the outcome. In the second step, a pilot study was performed to validate the resulting tool against the full WOMAC questionnaire among 108 patients undergoing THR. The mean difference between observed (WOMAC) and model-predicted value was -1.1 points (95% confidence interval, CI -3.8, 1.5) for pain and -2.5 points (95% CI -5.3, 0.3) for function. The model-predicted value was within 20% of the observed value in 48% of cases for pain and in 57% of cases for function. The tool demonstrated moderate validity, but performed weakly for patients with extreme levels of pain and extreme functional limitations at 3 months post surgery. This may have been partly due to early complications after surgery. However, the outcome-prediction tool may be useful in helping patients to become better informed about the realistic outcome of their THR.

Effect of cardiovascular training on fitness and perceived disease activity in people with ankylosing spondylitis.

OBJECTIVE: Several studies suggest that patients with ankylosing spondylitis (AS) have an increased risk of cardiovascular disease. This study aimed to evaluate the effects of a 12-week, individually monitored, with moderate heart rate level intensity cardiovascular training on cardiovascular fitness and perceived disease activity in AS patients. METHODS: Patients diagnosed with AS according to the modified New York criteria were randomized to either cardiovascular training or attention control. The training group performed 3 cardiovascular training units per week. All participants attended 1 weekly usual care flexibility training session. Attention control contained regular discussion groups on coping strategies. Adherence was self-monitored. Assessments were performed at baseline and after the intervention period of 3 months. Physical fitness was the primary end point, measured in watts using a submaximal bicycle test following the physical work capacity 75% protocol. All analyses controlled for sex, age, body mass index,baseline fitness and physical activity levels, and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). RESULTS: Of 106 AS patients enrolled, 40% were women and the mean ± SD age was 49 ± 12 years. A total of 74.6% of the training group reported exercising at least 3 times a week. At the 3-month followup, the fitness level in the training group was significantly higher than in the control group (mean ± SE 90.32W ± 4.52W versus 109.84W ± 4.72W; P = 0.001), independent of other covariates. The mean BASDAI total score was 0.31 points lower (P = 0.31) in the training group, reaching significance for the peripheral pain subscore (1.19; P = 0.01) but not for back pain or fatigue. CONCLUSION: Cardiovascular training, in addition to flexibility exercise, increased fitness in AS patients and reduced their peripheral pain.

Active over 45: a step-up jogging programme for inactive female hospital staff members aged 45+.

BACKGROUND: Inactive individuals face motivational obstacles for becoming and remaining physically active. Therefore, sustainable physical activity promotion programmes tailored to reach inactive individuals are needed. The aim of this study was to test the role of motivation and the effect and feasibility of a training programme. METHODS: We enrolled physically inactive female hospital staff members aged 45 and older in an uncontrolled exercise trial. Follow-up assessments were at 3 and 12 months. The primary outcome was running distance (Cooper test). Secondary outcomes were level of physical activity (Freiburger Physical Activity Questionnaire) and body mass index. RESULTS: Out of 1249 female hospital staff, 275 classified themselves as inactive and 250 (91%) of them were interested in the exercise programme. Of these, 68 (27%; mean age 53.2 years) agreed to participate in our study and 47 (69%) completed the programme. Average running distance increased by 255.70 m [95% confidence interval (CI) 208.09-303.31] at 3-month follow-up with a sustained benefit at 12-month follow-up (194.02; 95% CI 143.75-244.47). Physical activity level increased by 1152.52 kcal week(-1) (95% CI 703.73-1601.32) at 3 months with a sustained benefit (1279.10 kcal week(-1), 95% CI 826.80-1731.40) after 12 months. Notably, baseline motivation to become physically active was not associated with change in physical performance or physical activity level during the programme. CONCLUSION: The 3-month step-up jogging programme is a feasible and effective exercise intervention for physically inactive, middle-aged female hospital staff members. The intervention leads to sustained benefits independently of motivation to become more physically active.

Oral supplementation with 25(OH)D3 versus vitamin D3: effects on 25(OH)D levels, lower extremity function, blood pressure, and markers of innate immunity.

To test the effect of 25(OH)D(3) (HyD) compared to vitamin D(3) on serum 25-hydroxyvitamin D levels (25(OH)D), lower extremity function, blood pressure, and markers of innate immunity. Twenty healthy postmenopausal women with an average 25(OH)D level of 13.2 ± 3.9 ng/mL (mean ± SD) and a mean age of 61.5 ± 7.2 years were randomized to either 20 µg of HyD or 20 µg (800 IU) of vitamin D(3) per day in a double-blind manner. We measured on 14 visits over 4 months, 25(OH)D serum levels, blood pressure, and seven markers of innate immunity (eotaxin, interleukin [IL]-8, IL-12, interferon gamma-induced protein 10 kDa [IP-10], monocyte chemotactic protein-1 [MCP-1], macrophage inflammatory protein beta [MIP-1ß], and "Regulated upon Activation, Normal T-cell Expressed, and Secreted" [RANTES]). At baseline and at 4 months, a test battery for lower extremity function (knee extensor and flexor strength, timed up and go, repeated sit-to-stand) was assessed. All analyses were adjusted for baseline measurement, age, and body mass index. Mean 25(OH)D levels increased to 69.5 ng/mL in the HyD group. This rise was immediate and sustained. Mean 25(OH)D levels increased to 31.0 ng/mL with a slow increase in the vitamin D(3) group. Women on HyD compared with vitamin D(3) had a 2.8-fold increased odds of maintained or improved lower extremity function (odds ratio [OR] = 2.79; 95% confidence interval [CI], 1.18-6.58), and a 5.7-mmHg decrease in systolic blood pressure (p = 0.0002). Both types of vitamin D contributed to a decrease in five out of seven markers of innate immunity, significantly more pronounced with HyD for eotaxin, IL-12, MCP-1, and MIP-1 ß. There were no cases of hypercalcemia at any time point. Twenty micrograms (20 µg) of HyD per day resulted in a safe, immediate, and sustained increase in 25(OH)D serum levels in all participants, which may explain its significant benefit on lower extremity function, systolic blood pressure, and innate immune response compared with vitamin D(3).

A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on markers of their metabolism in normal mucosa of colorectal adenoma patients.

In cancer cell lines and rodent models, calcium and vitamin D favorably modulate cell proliferation, differentiation, and apoptosis in colonic epithelia. These effects may be modulated by local expression of the calcium receptor (CaR), the vitamin D receptor (VDR), and the P450 cytochromes, CYP27B1 and CYP24A1; however, they have yet to be investigated in humans. To address this gap, we conducted a randomized, double-blinded, placebo-controlled 2×2 factorial clinical trial. Patients with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d elemental calcium and/or 800 IU/d vitamin D3 versus placebo over 6 months (n=92; 23 per group). CaR, VDR, CYP27B1, and CYP24A1 expression and distribution in biopsies of normal appearing rectal mucosa were detected by standardized, automated immunohistochemistry and quantified by image analysis. In the calcium-supplemented group, CaR expression increased 27% (P=0.03) and CYP24A1 expression decreased 21% (P=0.79). In the vitamin D3-supplemented group, CaR expression increased 39% (P=0.01) and CYP27B1 expression increased 159% (P=0.06). In patients supplemented with both calcium and vitamin D3, VDR expression increased 19% (P=0.13) and CaR expression increased 24% (P=0.05). These results provide mechanistic support for further investigation of calcium and vitamin D3 as chemopreventive agents against colorectal neoplasms, and CaR, VDR, CYP27B1, and CYP24A1 as modifiable, preneoplastic risk biomarkers for colorectal neoplasms.

Effects of calcium and vitamin D on MLH1 and MSH2 expression in rectal mucosa of sporadic colorectal adenoma patients.

To further clarify and develop calcium and vitamin D as chemopreventive agents against colorectal cancer in humans and develop modifiable biomarkers of risk for colorectal cancer, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3), alone and in combination, on key DNA mismatch repair proteins in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2.0 g/d calcium or 800 IU/d vitamin D(3), alone or in combination, versus placebo over 6 months. Colorectal crypt overall expression and distribution of MSH2 and MLH1 proteins in biopsies of normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, MSH2 expression along the full lengths of crypts increased by 61% (P = 0.11) and 30% (P = 0.36) in the vitamin D and calcium groups, respectively, relative to the placebo group. The estimated calcium and vitamin D treatment effects were more pronounced in the upper 40% of crypts (differentiation zone) in which MSH2 expression increased by 169% (P = 0.04) and 107% (P = 0.13) in the vitamin D and calcium groups, respectively. These findings suggest that higher calcium and vitamin D intakes may result in increased DNA MMR system activity in the normal colorectal mucosa of sporadic adenoma patients and that the strongest effects may be vitamin D related and in the differentiation zone of the colorectal crypt.

Effects of supplemental vitamin D and calcium on oxidative DNA damage marker in normal colorectal mucosa: a randomized clinical trial.

The exact antineoplastic effects of calcium and vitamin D(3) in the human colon are unclear. Animal and in vitro studies show that these two agents reduce oxidative stress; however, these findings have never been investigated in humans. To address this, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of calcium and vitamin D(3) on a marker of oxidative DNA damage, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), in the normal colorectal mucosa. Patients (N = 92) with at least one pathology-confirmed colorectal adenoma were treated with 2 g/d calcium and/or 800 IU/d vitamin D(3) versus placebo over 6 months. Overall labeling and colorectal crypt distribution of 8-OH-dG in biopsies of normal-appearing rectal mucosa were detected by standardized automated immunohistochemistry and quantified by image analysis. After 6 months of treatment, 8-OH-dG labeling along the full lengths of colorectal crypts decreased by 22% (P = 0.15) and 25% (P = 0.10) in the calcium and vitamin D(3) groups, respectively, but not in the calcium plus vitamin D(3) group. The estimated treatment effects were strongest among participants with higher baseline colon crypt vitamin D receptor expression (P = 0.05). Overall, these preliminary results indicate that calcium and vitamin D(3) may decrease oxidative DNA damage in the normal human colorectal mucosa, support the hypothesis that 8-OH-dG labeling in colorectal crypts is a treatable oxidative DNA damage biomarker of risk for colorectal neoplasms, and provide support for further investigation of calcium and vitamin D(3) as chemopreventive agents against colorectal neoplasms.

Effects of vitamin d and calcium on proliferation and differentiation in normal colon mucosa: a randomized clinical trial.

To investigate the potential efficacy of calcium and vitamin D in reducing risk for colorectal neoplasms and to develop "treatable" phenotypic biomarkers of risk for colorectal neoplasms, we conducted a pilot, randomized, double-blind, placebo-controlled, 2 x 2 factorial clinical trial to test the effects of these agents on cell cycle markers in the normal colorectal mucosa. Ninety-two men and women with at least one pathology-confirmed colorectal adenoma were treated with 2 g/day calcium and/or 800 IU/day vitamin D(3) versus placebo over 6 months. Overall expression and distributions of p21(waf1/cip1) (marker of differentiation), MIB-1 (marker of short-term proliferation), and hTERT (marker of long-term proliferation) in colorectal crypts in the normal-appearing rectal mucosa were detected by automated immunohistochemistry and quantified by image analysis. In the calcium, vitamin D, and calcium plus vitamin D groups relative to the placebo, p21 expression increased by 201% (P = 0.03), 242% (P = 0.005), and 25% (P = 0.47), respectively, along the full lengths of colorectal crypts after 6 months of treatment. There were no statistically significant changes in the expression of either MIB-1 or hTERT in the crypts overall; however, the proportion of hTERT, but not MIB-1, expression that extended into the upper 40% of the crypts was reduced by 15% (P = 0.02) in the vitamin D plus calcium group relative to the placebo. These results indicate that calcium and vitamin D promote colorectal epithelial cell differentiation and may "normalize" the colorectal crypt proliferative zone in sporadic adenoma patients, and support further investigation of calcium and vitamin D as chemopreventive agents against colorectal neoplasms.

Colorectal mucosal expression of MSH2 as a potential biomarker of risk for colorectal neoplasms.

To characterize the expression of the mismatch repair gene MSH2 in normal colorectal crypts in humans and assess parameters of its expression as a potential modifiable biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases and 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MSH2 protein, and analyzed using custom quantitative image analysis procedures. MSH2 expression in adenoma cases was lower than in controls by 49% (P = 0.01) and 23% (P = 0.06) in the ascending colon and rectum, respectively, but not in the sigmoid colon. MSH2 expression in the rectum was 39% (P = 0.04) higher in subjects who regularly took a nonsteroidal anti-inflammatory drug than in those who did not, and it tended to be lower in those with adenomas in the right colon and those who had an adenoma with more advanced characteristics. These preliminary data suggest that lower MSH2 expression in the normal colonic mucosa, at least in the ascending colon and rectum, may be associated with increased risk of incident, sporadic colorectal adenoma as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MSH2 expression as a potential modifiable biomarker of risk for colorectal neoplasms.

MutL-homolog 1 expression and risk of incident, sporadic colorectal adenoma: search for prospective biomarkers of risk for colorectal cancer.

To characterize the expression of the mismatch repair gene MutL-homolog 1 (MLH1) in normal colorectal crypts in humans, and assess parameters of its expression as a potential biomarker of risk for colorectal neoplasms, we conducted a pilot, colonoscopy-based case-control study (51 cases, 154 controls) of incident, sporadic colorectal adenoma. Biopsies of normal-appearing rectal, sigmoid, and ascending colon mucosa were procured, immunohistochemically processed for MLH1 protein, and analyzed using custom quantitative image analysis procedures. MLH1 expression in the ascending colon was, on average, 49% proportionally lower in cases than controls (P = 0.03), but there was little evidence for case-control differences in the rectum and sigmoid colon. In cases and controls, average MLH1 expression in the ascending colon tended to be lower with increased age [by 56% (P = 0.02) and 25% (P = 0.16), respectively, for those > or =55 years], and with a history of colorectal cancer in a first-degree relative (by 22% [P = 0.56] and 34% [P = 0.16], respectively). Among cases, but not controls, average MLH1 expression tended to be higher with current alcohol consumption, regular aspirin use, and higher total intakes of calcium, vitamin D, and folate. There was little indication of similar differences in the rectum. These preliminary data suggest that lower MLH1 expression in the normal colonic mucosa, at least in the ascending colon, may be associated with increased risk of incident, sporadic colorectal adenoma, as well as with modifiable risk factors for colorectal neoplasms, thus supporting further investigation of MLH1 expression as a potential "treatable" biomarker of risk for colorectal neoplasms.

TGF-alpha expression as a potential biomarker of risk within the normal-appearing colorectal mucosa of patients with and without incident sporadic adenoma.

BACKGROUND: Transforming growth factor-alpha (TGF-alpha), a stimulatory growth factor and member of the epidermal growth factor family, is a mediator of oncogenesis and malignant progression in colorectal carcinogenesis. Limited evidence suggests its utility as a growth-related biomarker of risk for colorectal cancer. METHODS: We measured expression of TGF-alpha in biopsies of normal-appearing colorectal mucosa using automated immunohistochemistry and quantitative image analysis in a subsample of 29 cases and 31 controls from a colonoscopy-based case-control study (n = 203) of biomarkers of risk for incident sporadic colorectal adenoma. Diet, lifestyle, and medical history were assessed with validated questionnaires. RESULTS: TGF-alpha expression in the rectum was 51% higher in cases compared with controls (P = 0.05) and statistically significantly associated with accepted risk factors for colorectal neoplasms (36% lower among nonsteroidal anti-inflammatory drug users, 49% lower among women using hormone replacement therapy, 79% higher among persons with a family history of colorectal cancer). CONCLUSIONS: TGF-alpha expression in the normal-appearing rectal mucosa shows promise as an early, potentially modifiable biomarker of risk for colorectal cancer.