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.

Association of Epicardial Fat Volume With the Extent of Coronary Atherosclerosis and Cardiovascular Adverse Events in Asymptomatic Patients With Diabetes.

Epicardial adipose tissue has a paracrine effect, enhancing coronary artery atherosclerotic plaque development. This study evaluated epicardial fat volume (EFV), adipokines, coronary atherosclerosis, and adverse cardiovascular events in a cohort of asymptomatic patients with type 2 diabetes mellitus (T2DM). Epicardial fat volume was calculated using data from computed tomography coronary angiograms. Adipokines and inflammatory cytokines were also assayed and correlated with EFV. Epicardial fat volume was also assessed as a predictor of coronary artery calcium (CAC) score, number of coronary artery plaques, and significant plaque (>50% luminal stenosis). Data from the EFV analysis were available for 221 (85.7%) participants. Median EFV was 97.4 cm3, mean body mass index was 28.1 kg/m2, and mean duration of T2DM was 13 years. Statistically significant, but weak, correlations were observed between several adipokines, inflammatory cytokines, and EFV. Epicardial fat volume was a significant univariate (P = .01), but not multivariate, predictor of the number of coronary plaques, but not of CAC score or significant plaque. After a mean follow-up of 22.8 months, 12 adverse cardiovascular events were reported, exclusively in participants with EFV >97.4 cm3. Epicardial fat volume has limited utility as a marker of coronary artery plaque in patients with T2DM and is weakly correlated with adipokine expression.

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).

Predicting Severity of Coronary Artery Disease in Patients With Diabetes Using Endothelial Function Measured With Peripheral Arterial Tonometry: PROCEED Study.

Endothelial dysfunction is common in patients with type 2 diabetes mellitus (T2DM) and is associated with atherosclerotic disease. This study aimed to determine prognostic factors for endothelial dysfunction and identify relationships between reactive hyperemia index (RHI) score, clinically relevant coronary artery disease (>50% stenosis), and major adverse cardiovascular events (MACEs) in patients with T2DM. Endothelial function was assessed using peripheral arterial tonometry and correlated with patient characteristics and cardiovascular outcomes during a median follow-up of 22.8 months. Among 235 patients with a median duration of T2DM of 13 years, mean (standard deviation) RHI score was 2.00 (0.76). Serum low- and high-density lipoprotein cholesterol levels positively (P = .004) and negatively (P = .02) predicted RHI score, respectively. Median coronary artery calcium (CAC) score was 109 Agatston units, but no correlation between CAC and RHI scores was observed. The RHI score did not predict the number or severity of coronary plaques identified using computed tomography coronary angiography. Additionally, there was no association between RHI score and the risk of an MACE during follow-up. Overall, endothelial function was not predictive of CAC score, extent, and severity of coronary plaque or MACEs and did not demonstrate utility in cardiovascular risk stratifying patients with T2DM.

Usefulness of Carotid Plaques as Predictors of Obstructive Coronary Artery Disease and Cardiovascular Events in Asymptomatic Individuals With Diabetes Mellitus.

Carotid intima-media thickness (CIMT) measurement and carotid plaque detection by B-mode ultrasound are frequently used as surrogates to predict coronary artery disease (CAD). However, their systematic use in routine clinical management of asymptomatic patients with diabetes mellitus (DM) has not been studied. The aim of the study was to identify carotid parameters that predict cardiovascular events in patients with asymptomatic type 2 DM by evaluating the relation between carotid disease and CAD. This multicenter, observational, prospective study included 259 asymptomatic patients with type 2 DM followed-up for 34 months after measurement of CIMT and carotid plaque with carotid ultrasound, and CAD assessment with computed tomography coronary angiography. Statistically significant differences between patients with and without carotid plaque were found for coronary plaque >50% stenosis (59 vs 36, p = 0.02). Greater maximal CIMT was associated with an increased risk of coronary plaque >50% (odds ratio 1.21 [1.02, 1.44], p = 0.03) and >70% stenosis (odds ratio 1.23 [1.01, 1.50], p = 0.04) after adjusting for traditional risk factors. At 34-month follow-up, the occurrence of total major adverse cardiovascular event was estimated to be 7.1% (mean age 68 years, 6% male and 1.1% female) in the whole study population. The subgroup of patients with carotid plaque showed increased incidence of major adverse cardiovascular event compared with patients with no carotid plaque (p = 0.005). In conclusion, carotid plaque was a strong predictor of future cardiovascular events and may be a prognostic marker in asymptomatic patients with type 2 DM. Carotid plaque and maximal intima-media thickness were independently associated with obstructive CAD.

Relationship between carotid atherosclerosis and coronary artery calcification in asymptomatic diabetic patients: A prospective multicenter study.

BACKGROUND: The value of screening sub-clinical atherosclerosis in asymptomatic patients with type 2 diabetes mellitus (T2DM) remains controversial. HYPOTHESIS: An integrated model incorporating carotid intima-media thickness (CIMT) and carotid plaque with traditional risk factors can be used to predict prevalence and severity of coronary artery calcification in asymptomatic T2DM patients. METHODS: A cohort of 262 asymptomatic T2DM patients were prospectively studied with carotid ultrasound to evaluate CIMT and carotid plaque and also a computed tomography coronary artery calcium (CT-CAC) scan. RESULTS: Carotid plaque was detected in 124 (47%) patients and mean CIMT was 0.75±0.14 mm. Two hundred (76%) patients had a CAC score >0, of whom 57 (22%) had severe coronary atherosclerosis (>400 Au). In this group, carotid plaque was present in 40 (70%) patients (p<0.001). Univariable analysis revealed significant associations between non-zero CAC score and age (p<0.001), hypertension (p=0.01), gender (p=0.003) and duration of diabetes (p=0.004). Carotid plaque and mean CIMT were also significantly associated with non-zero CAC score (odds ratios [95% CI], 3.12 [1.66 -5.85] and 2.98 [0.24 -7.17], respectively). After adjusting for traditional risk factors, carotid plaque continued to be predictive of non-zero CAC score (2.59 [1.17 -5.74]) and CIMT was borderline significant (p=0.05). When analysed with binary logistical regression, the prevalence of carotid plaque significantly predicted severe CAC burden (CAC >400 Au; 3.26 [2.05 -5.19]). Upper CIMT quartiles showed a similar association (2.55 [1.33 -4.87]). CONCLUSION: Carotid plaque is more predictive of underlying silent coronary atherosclerosis prevalence, severity and extent in asymptomatic T2DM patients.

Carotid intimal thickness and plaque predict prevalence and severity of coronary atherosclerosis: a pilot study.

We determined whether increased carotid intima-media thickness (cIMT) and prevalence of carotid plaque (CP) are predictive of prevalence and severity of coronary atherosclerosis. Consecutive patients (n = 150) with no history of coronary artery disease (CAD), who underwent both carotid ultrasound and computed tomographic coronary angiography, were included in the analysis. The mean cIMT was higher in patients with CAD than in those without CAD (0.76 vs 0.66 mm, P < .003). In a logistic regression analysis, diabetes (P = .03) and CP (P = .02) were associated with significant coronary plaque. Backward selection analysis (after removing nonsignificant variables) showed higher mean cIMT measurement correlated well with prevalence of any coronary plaque (P = .03) and obstructive coronary plaque disease (P = .05), whereas presence of CP was a good predictor of both obstructive (>50% stenosis P = .003) and any coronary plaque (P = .003). In conclusion, CP and cIMT can be useful predictors of prevalence of CAD and its severity.

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.

Myocardial Scar Detection by Standard CT Coronary Angiography.

We have described a myocardial infarct scar identified by a standard dual source CT coronary angiography (CTCA). We were able to detect the scar during the routine coronary assessment without contrast late enhancement and without additional radiation exposure. It is therefore feasible to assess chronic scar using a standard CTCA technique.

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.

Psychological distress, cortisol stress response and subclinical coronary calcification.

OBJECTIVES: Poor mental health has been associated with coronary heart disease (CHD). One hypothesized underlying mechanism is hypothalamus pituitary adrenal axis dysfunction. We examined the associations between psychological distress, cortisol response to laboratory-induced mental stress and subclinical coronary artery calcification (CAC). PARTICIPANTS: 527 volunteers free of CHD (mean age=63.0 ± 5.7 years), drawn from the Whitehall II cohort. MEASURES: CAC was measured using electron beam computed tomography. Current distress at time of the heart scan was indicated by a Short Form-36 mental health score, whereas long-term distress was based on the averaged scores of six assessments over the 15 preceding years. Salivary cortisol was measured in response to mental stressors (Stroop, mirror tracing). RESULTS: Detectable CAC was found in 56.4% (mild/moderate: 46.9%; severe: 9.5%) of the sample. After adjustment for sociodemographics and conventional risk factors, long-term but not current psychological distress was associated with a higher risk of severe CAC (OR per SD increase=1.49, 95%CI=1.03-2.16). Psychological distress was not significantly associated with cortisol stress response. A trend for interaction (p=.09) indicated that individuals with long-term poor mental health and high cortisol reactivity showed the highest odds for severe CAC. CONCLUSIONS: Long-term but not current psychological distress is associated with severe CAC in healthy older subjects. Although psychological distress generally was not associated with cortisol stress responses, participants with both long-term distress and increased cortisol response were especially at risk for severe calcification.

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.