Circulating Hepatocyte Growth Factor Reflects Activation of Vascular Repair in Response to Stress.

Hepatocyte growth factor (HGF) is released by stressed human vascular cells and promotes vascular cell repair responses in both autocrine and paracrine ways. Subjects with a low capacity to express HGF in response to systemic stress have an increased cardiovascular risk. Human atherosclerotic plaques with a low content of HGF have a more unstable phenotype. The present study shows that subjects with a low ability to express HGF in response to metabolic stress have an increased risk to suffer myocardial infarction and stroke.

Post-infarction ventricular septal defect: percutaneous or surgical management in the UK national registry.

AIMS: Post-infarction ventricular septal defect (PIVSD) is a mechanical complication of acute myocardial infarction (AMI) with a poor prognosis. Surgical repair is the mainstay of treatment, although percutaneous closure is increasingly undertaken. METHODS AND RESUTS: Patients treated with surgical or percutaneous repair of PIVSD (2010-2021) were identified at 16 UK centres. Case note review was undertaken. The primary outcome was long-term mortality. Patient groups were allocated based upon initial management (percutaneous or surgical). Three-hundred sixty-two patients received 416 procedures (131 percutaneous, 231 surgery). 16.1% of percutaneous patients subsequently had surgery. 7.8% of surgical patients subsequently had percutaneous treatment. Times from AMI to treatment were similar [percutaneous 9 (6-14) vs. surgical 9 (4-22) days, P = 0.18]. Surgical patients were more likely to have cardiogenic shock (62.8% vs. 51.9%, P = 0.044). Percutaneous patients were substantially older [72 (64-77) vs. 67 (61-73) years, P < 0.001] and more likely to be discussed in a heart team setting. There was no difference in long-term mortality between patients (61.1% vs. 53.7%, P = 0.17). In-hospital mortality was lower in the surgical group (55.0% vs. 44.2%, P = 0.048) with no difference in mortality after hospital discharge (P = 0.65). Cardiogenic shock [adjusted hazard ratio (aHR) 1.97 (95% confidence interval 1.37-2.84), P < 0.001), percutaneous approach [aHR 1.44 (1.01-2.05), P = 0.042], and number of vessels with coronary artery disease [aHR 1.22 (1.01-1.47), P = 0.043] were independently associated with long-term mortality. CONCLUSION: Surgical and percutaneous repair are viable options for management of PIVSD. There was no difference in post-discharge long-term mortality between patients, although in-hospital mortality was lower for surgery.

Evidence for a protective role of placental growth factor in cardiovascular disease.

Placental growth factor (PlGF) is a mitogen for endothelial cells, but it can also act as a proinflammatory cytokine. Because it promotes early stages of plaque formation in experimental models of atherosclerosis and was implicated in epidemiological associations with risk of cardiovascular disease (CVD), PlGF has been attributed a pro-atherogenic role. Here, we investigated whether PlGF has a protective role in CVD and whether elevated PlGF reflects activation of repair processes in response to vascular stress. In a population cohort of 4742 individuals with 20 years of follow-up, high baseline plasma PlGF was associated with increased risk of cardiovascular death, myocardial infarction, and stroke, but these associations were lost or weakened when adjusting for cardiovascular risk factors known to cause vascular stress. Exposure of cultured endothelial cells to high glucose, oxidized low-density lipoprotein (LDL) or an inducer of apoptosis enhanced the release of PlGF. Smooth muscle cells and endothelial cells treated with PlGF small interference RNA demonstrated that autocrine PlGF stimulation plays an important role in vascular repair responses. High expression of PlGF in human carotid plaques removed at surgery was associated with a more stable plaque phenotype and a lower risk of future cardiovascular events. When adjusting associations of PlGF with cardiovascular risk in the population cohort for plasma soluble tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2, a biomarker of cellular stress, a high PlGF/TRAIL receptor-2 ratio was associated with a lower risk. Our findings provide evidence for a protective role of PlGF in CVD.

Duration of type 2 diabetes mellitus and systolic blood pressure as determinants of severity of coronary stenosis and adverse events in an asymptomatic diabetic population: PROCEED study.

BACKGROUND: Evidence from imaging studies suggests a high prevalence of coronary artery disease (CAD) in patients with type 2 diabetes mellitus (T2DM). However, there are no criteria for initiating screening for CAD in this population. The current study investigated whether clinical and demographic characteristics can be used to predict significant CAD in patients with T2DM. METHODS: Computed tomography coronary angiography (CTCA) and laboratory assessments were performed in 259 patients diagnosed with T2DM attending clinics in Northwest London, UK. Coronary artery calcium (CAC) was calculated during CTCA. Significant plaque was defined as one causing more than 50% luminal stenosis. Associations between groups and variables were evaluated using Student's t test, Chi-square tests and univariate and multivariate regression analysis. P < 0.05 was considered statistically significant. RESULTS: Among patients with a median duration of T2DM of 13 years and a mean age of 62.0 years, median CAC score was 105.91 Agatston Units. In a multivariate analyses, duration of diabetes, CAC score and the presence and number of coronary artery plaques and presence of significant plaque were significant predictors of cardiovascular adverse events. Systolic blood pressure (SBP) had borderline significance as a predictor of cardiovascular events (p = 0.05). In a receiver operating characteristic curve (ROC) analysis, duration of diabetes of > 10.5 years predicted significant CAD (sensitivity, 75.3%; specificity 48.2%). Area under the ROC curve was 0.67 when combining duration of T2DM > 10.5 years and SBP of > 139 mm Hg. Adverse cardiovascular events after a median follow-up of 22.8 months were also significantly higher in those with duration of T2DM > 10.5 years and SBP > 140 mm Hg (log rank p = 0.02 and 0.009, respectively). CONCLUSIONS: Routine screening for CAD using CTCA should be considered for patients with a diagnosis of T2DM for > 10.5 years and SBP > 140 mm Hg. Trial registration Clinicaltrials.gov identifier: NCT02109835, 10 April 2014 (retrospectively registered).

Diagnostic role of coronary calcium scoring in the rapid access chest pain clinic: prospective evaluation of NICE guidance.

BACKGROUND: Coronary artery calcium (CAC) imaging by unenhanced computed X-ray tomography (CT) is recommended as an initial diagnostic test for patients with stable chest pain symptoms but a low likelihood (10-29%) of underlying obstructive coronary artery disease (CAD) after clinical assessment. The recommendation has not previously been tested prospectively in a rapid access chest pain clinic (RACPC). METHODS: We recruited 300 consecutive patients presenting with stable chest pain to the RACPC of three hospitals. All patients underwent CAC imaging, followed by invasive coronary angiography (ICA) in patients with CAC ≥ 1000 Agatston units (Au) and CT coronary angiography (CTCA) in those with CAC <1000. Patients with 50-70% stenosis on CTCA underwent myocardial perfusion scintigraphy (MPS) while those with ≥ 70% stenosis underwent ICA. Obstructive CAD was defined as ≥ 70% stenosis on ICA or the presence of inducible ischaemia on MPS. Patients were followed up clinically for a mean of 17 (SD 6) months. RESULTS: The mean patient age was 60.6 (SD 9.6) years and 48% were males. Obstructive CAD was found in 56 (19%) patients, of whom 42 (14%) underwent revascularization. CAC was zero in 131 (44%) patients, of whom two (1.5%) had obstructive CAD and one (0.8%) underwent revascularization. The sensitivity, specificity, negative predictive value, and positive predictive value of CAC ≥ 1 for detection of obstructive CAD were 96, 53, 32, and 98%, respectively. None of the 57 patients with low pre-test probability of CAD and zero CAC had obstructive CAD or suffered a cardiovascular event during the follow-up. CONCLUSION: Patients with stable chest pain symptoms but a low likelihood of CAD can safely be diagnosed as not having obstructive CAD in the absence of detectable coronary calcification by unenhanced CT. Patients with CAC >400 Au have a high prevalence of obstructive CAD and further investigation with ICA or functional imaging may be warranted rather than CTCA. These findings support NICE guidance for the investigation of stable chest pain. ClinicalTrials gov identifier: NCT01464203.

Physical activity, sedentary time, and pericardial fat in healthy older adults.

Pericardial fat is emerging as a unique risk factor for coronary disease. We examined the relationship between objectively measured physical activity during free-living and pericardial fat. Participants were 446 healthy men and women (mean age = 66 ± 6 years), without history or objective signs of cardiovascular disease (CVD), drawn from the Whitehall II epidemiological cohort. Physical activity was objectively measured using accelerometers (Actigraph GT3X) worn around the hip during waking hours for 7 consecutive days (average daily wear time = 889 ± 68 min/day), and was classified as sedentary (<200 counts/min (cpm)), light (200-1,998 cpm), or moderate-vigorous physical activity (MVPA; ≥1,999 cpm). Pericardial fat volume was measured in each participant using electron beam computed tomography. Average daily cpm in men was 338.0 ± 145.0 and in women 303.8 ± 130.2. There was an inverse association between average cpm and pericardial fat (B = -0.070, 95% confidence interval (CI), -0.101, -0.040, P < 0.001), and this remained significant after adjusting for age, sex, registered wear time, BMI, lipids, glycemic control, blood pressure, smoking, statins, and social status. Both sedentary time (B = 0.081, 95% CI, 0.022, 0.14) and MVPA (B = -0.362, 95% CI, -0.527, -0.197) were also associated with pericardial fat, although associations for sedentary time did not remain significant after adjustment for MVPA. The inverse association between physical activity and pericardial fat was stronger among overweight and obese adults than in normal weight. Objectively assessed daily activity levels are related to pericardial fat in healthy participants, independently of BMI. This might be an important mechanism in explaining the association between physical activity and CVD prevention.

Cortisol responses to mental stress and the progression of coronary artery calcification in healthy men and women.

BACKGROUND: Psychosocial stress is a risk factor for coronary heart disease (CHD). The mechanisms are incompletely understood, although dysfunction of the hypothalamic pituitary adrenal (HPA) axis might be involved. We examined the association between cortisol responses to laboratory-induced mental stress and the progression of coronary artery calcification (CAC). METHODS AND RESULTS: Participants were 466 healthy men and women (mean age = 62.7±5.6 yrs), without history or objective signs of CHD, drawn from the Whitehall II epidemiological cohort. At the baseline assessment salivary cortisol was measured in response to mental stressors, consisting of a 5-min Stroop task and a 5-min mirror tracing task. CAC was measured at baseline and at 3 years follow up using electron beam computed tomography. CAC progression was defined as an increase >10 Agatston units between baseline and follow up. 38.2% of the sample demonstrated CAC progression over the 3 years follow up. There was considerable variation in the cortisol stress response, with approximately 40% of the sample responding to the stress tasks with an increase in cortisol of at least 1 mmol/l. There was an association between cortisol stress reactivity (per SD) and CAC progression (odds ratio = 1.27, 95% CI, 1.02-1.60) after adjustments for age, sex, pre-stress cortisol, employment grade, smoking, resting systolic BP, fibrinogen, body mass index, and use of statins. There was no association between systolic blood pressure reactivity and CAC progression (odds ratio per SD increase = 1.03, 95% CI, 0.85-1.24). Other independent predictors of CAC progression included age, male sex, smoking, resting systolic blood pressure, and fibrinogen. CONCLUSION: Results demonstrate an association between heightened cortisol reactivity to stress and CAC progression. These data support the notion that cortisol reactivity, an index of HPA function, is one of the possible mechanisms through which psychosocial stress may influence the risk of CHD.

Radiation dose of CT coronary angiography in clinical practice: objective evaluation of strategies for dose optimization.

BACKGROUND: CT coronary angiography (CTCA) is an evolving modality for the diagnosis of coronary artery disease. Radiation burden associated with CTCA has been a major concern in the wider application of this technique. It is important to reduce the radiation dose without compromising the image quality. OBJECTIVES: To estimate the radiation dose of CTCA in clinical practice and evaluate the effect of dose-saving algorithms on radiation dose and image quality. METHODS: Effective radiation dose was measured from the dose-length product in 616 consecutive patients (mean age 58 ± 12 years; 70% males) who underwent clinically indicated CTCA at our institution over 1 year. Image quality was assessed subjectively using a 4-point scale and objectively by measuring the signal- and contrast-to-noise ratios in the coronary arteries. Multivariate linear regression analysis was used to identify factors independently associated with radiation dose. RESULTS: Mean effective radiation dose of CTCA was 6.6 ± 3.3 mSv. Radiation dose was significantly reduced by dose saving algorithms such as 100 kV imaging (-47%; 95% CI, -44% to -50%), prospective gating (-35%; 95% CI, -29% to -40%) and ECG controlled tube current modulation (-23%; 95% CI, -9% to -34%). None of the dose saving algorithms were associated with a significant reduction in mean image quality or the frequency of diagnostic scans (P = non-significant for all comparisons). CONCLUSION: Careful application of radiation-dose saving algorithms in appropriately selected patients can reduce the radiation burden of CTCA significantly, without compromising the image quality.

Objectively assessed physical activity, sedentary time, and coronary artery calcification in healthy older adults.

OBJECTIVE: Physical activity is related to lower risk of cardiovascular disease, but data relating to coronary lesions have been conflicting. These inconsistencies may in part be due to unreliable assessment of physical activity and limitations imposed by self-reported data. The purpose of this study was to determine the relationship between objectively measured physical activity and coronary artery calcium (CAC). METHODS AND RESULTS: Participants were 443 healthy men and women (mean age=66±6 years), without history or objective signs of coronary heart disease, drawn from the Whitehall II epidemiological cohort. Physical activity was objectively measured using accelerometers worn during waking hours for 7 consecutive days (average daily wear time=889±68 minutes/day). CAC was measured in each participant using electron beam computed tomography and was quantified according to the Agatston scoring system. On average, 54.4% of the sample recorded at least 30 minutes/day of moderate to vigorous physical activity (MVPA). There was no association between MVPA and presence of detectable CAC. For the participants with detectable CAC (n=283) a weak inverse relationship between MVPA (minutes/day) and log Agatston score was observed (B=-0.008, 95% CI: -0.16 to 0.00, P=0.05), although the association was no longer present after adjustments for age, sex, and conventional risk factors. No associations were seen for light activity or sedentary time. CONCLUSIONS: Our results confirm no association between objectively assessed physical activity and CAC. Because CAC measures cannot identify more vulnerable lesions, additional studies are required to examine whether physical activity can promote plaque stability.

Osteoprotegerin as a predictor of coronary artery disease and cardiovascular mortality and morbidity.

Osteoprotegerin (OPG) is a glycoprotein that acts as a decoy receptor for receptor activator of nuclear factor kappaB ligand (RANKL) and tumor necrosis factor-related apoptosis-inducing ligand. The OPG/RANKL/receptor activator of nuclear factor kappaB axis plays an important regulatory role in the skeletal, immune, and vascular systems. The protective role of OPG, in animal models, against vascular calcification has not been replicated in human trials; moreover, increased OPG levels have been consistently associated with the incidence and prevalence of coronary artery disease. There seems to be some dichotomy in the role of OPG, RANKL, and tumor necrosis factor-related apoptosis-inducing ligand in atherosclerosis and plaque stability. In this review, we integrate the findings from some of the important studies and try to draw conclusions with a view to gaining some insight into the complex interactions of the OPG/RANKL/receptor activator of nuclear factor kappaB axis and tumor necrosis factor-related apoptosis-inducing ligand in the pathophysiology of atherosclerosis.

Socioeconomic status and subclinical coronary disease in the Whitehall II epidemiological study.

BACKGROUND: There are pronounced socioeconomic disparities in coronary heart disease, but the extent to which these primarily reflect gradients in underlying coronary artery disease severity or in the clinical manifestation of advanced disease is uncertain. We measured the relationship between socioeconomic status (SES) as indexed by grade of employment and coronary artery calcification (CAC) in the Whitehall II epidemiological cohort, and tested the contribution of lifestyle, biological and psychosocial factors in accounting for this association. METHODS AND FINDINGS: CAC was assessed in 528 asymptomatic men and women aged 53-76 years, stratified into higher, intermediate and lower by grade of employment groups. Lifestyle (smoking, body mass index, alcohol consumption, physical activity), biological (blood pressure, lipids, fasting glucose, inflammatory markers) and psychosocial factors (work stress, financial strain, social support, depression, hostility, optimism) were also measured. Detectable CAC was present in 293 participants (55.5%). The presence of calcification was related to lifestyle and biological risk factors, but not to grade of employment. But among individuals with detectable calcification, the severity of CAC was inversely associated with grade of employment (p = 0.010), and this relationship remained after controlling for demographic, lifestyle, biological and psychosocial factors. Compared with the higher grade group, there was a mean increase in log Agatston scores of 0.783 (95% C.I. 0.265-1.302, p = 0.003) in the intermediate and 0.941 (C.I. 0.226-1.657, p = 0.010) in the lower grade of employment groups, after adjustment for demographic, lifestyle, biological and psychosocial factors. CONCLUSIONS: Low grade of employment did not predict the presence of calcification in this cohort, but was related to the severity of CAC. These findings suggest that lower SES may be particularly relevant at advanced stages of subclinical coronary artery disease, when calcification has developed.