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).

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.

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.

Prevalence of coronary artery calcium scores and silent myocardial ischaemia was similar in Indian Asians and European whites in a cross-sectional study of asymptomatic subjects from a U.K. population (LOLIPOP-IPC).

BACKGROUND: Coronary heart disease (CHD) mortality is 70% higher among Indian Asians (IA) than European whites (EW), the reasons for this excess remain unexplained. Coronary artery calcification (CAC) is highly correlated with coronary plaque burden and silent myocardial ischaemia in EW; but fails to identify excess risk in IA. We hypothesised that IA have a higher prevalence of silent myocardial ischaemia compared to EW, despite similar CAC, and this may explain their excess CHD mortality. METHODS: CAC was measured for 2,369 asymptomatic men and women, aged 35 to 75 years, as part of the London Life Sciences Population (LOLIPOP) study. 518 subjects had CAC scores >100 Agatston units and of these 256 (49%) patients underwent myocardial perfusion scintigraphy (MPS). RESULTS: CAC scores were similar among IA and EW, after adjustment for conventional risk factors. MPS abnormalities were seen in 56 (22%) subjects. Presence of diabetes (P = .03) and increasing CAC (P < .001) were independent predictors for severity of silent myocardial ischaemia. Ethnicity did not influence the prevalence or the extent of silent myocardial ischaemia. CONCLUSION: MPS did not identify greater ischaemia among IA compared with EW. This appears incongruent with almost 2-fold higher risk of CHD mortality observed in IA.

Evolving role of cardiac CT in the diagnosis of coronary artery disease.

Non-invasive assessment of coronary artery patency has been attempted with different imaging modalities over the last few decades. The continuous motion of the heart, the respiratory movement, together with the small and tortuous nature of the coronary arteries, made this a technically challenging task. Over the last decade, significant advances in computed tomography (CT) technology helped CT coronary angiography (CTCA) to evolve as a non-invasive alternative to conventional catheter based coronary angiography. Clinical experience with CTCA has since grown rapidly and led to its acceptance as a useful diagnostic technique for coronary artery disease in certain patient populations. Recently, there has been exponential growth in the availability and use of CTCA in several centres across the world. In order to appreciate the potential impact of CTCA on current clinical practice, it is important to understand its advantages and limitations and its clinical performance in comparison with established techniques.

Salivary cortisol responses to mental stress are associated with coronary artery calcification in healthy men and women.

AIMS: Psychosocial stress is a risk factor for coronary heart disease (CHD), although the mechanisms are incompletely understood. We examined the cross-sectional association between the cortisol response to laboratory-induced mental stress and a marker of sub-clinical coronary atherosclerosis. METHODS AND RESULTS: Participants were 514 healthy men and women (mean age = 62.9 +/- 5.7 years), without history or objective signs of CHD, drawn from the Whitehall II epidemiological cohort. Salivary cortisol was measured in response to mental stressors, consisting of a 5 min Stroop task and a 5 min mirror tracing task. Coronary artery calcification (CAC) was measured using electron beam computed tomography. Approximately 40% of the sample responded to the stress tasks with a notable (>or=1 nmol/L) increase in cortisol. Significant CAC (Agatston score >or= 100) was recorded in 23.9% of the sample. The cortisol response group demonstrated a higher risk of significant CAC (odds ratio = 2.20, 95% CI, 1.39-3.47) after adjustments for age, gender, baseline cortisol, employment grade, and conventional risk factors, although cortisol was unrelated to the presence of detectable CAC. Among participants with detectable CAC, the cortisol response group also demonstrated higher log Agatston scores compared with non-responders (age and sex adjusted scores; 4.51 +/- 0.15 vs. 3.94 +/- 0.13, P = 0.004). CONCLUSION: In healthy, older participants without history or objective signs of CHD, heightened cortisol reactivity is associated with a greater extent of CAC. These data support the notion that heightened hypothalamic pituitary adrenal activity is a risk factor for CHD.

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.

Etiology and pathophysiology of new-onset heart failure: evaluation by myocardial perfusion imaging.

OBJECTIVE: The IMAGING in Heart Failure study was a prospective, multi-national trial designed to explore the role of single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (MPI) as an initial investigative strategy in patients hospitalized with new-onset heart failure. METHODS: We recruited 201 patients (age 65.3 +/- 14.5 years, 43% women) hospitalized with their first episode of heart failure. Rest/stress gated SPECT Tc-99m sestamibi MPI was performed during or within 2 weeks of the index hospitalization, in addition to standard care. RESULTS: SPECT MPI revealed a broad range of ejection fractions with preserved systolic function in 36% of patients. Forty-one percent of patients had normal perfusion. In the remaining patients, perfusion abnormalities were predominantly due to prior myocardial infarction, with extensive ischemia seen only in 6%. Among patients who underwent coronary angiography, SPECT performance characteristics revealed excellent negative predictive value (96%) for extensive coronary artery disease (CAD). In multivariable analyses, the extent of perfusion abnormality and advancing age predicted the presence of extensive CAD. CONCLUSIONS: These preliminary data derived from a non-randomized observational cohort suggest potential diagnostic utility of MPI for ischemic LV dysfunction in new-onset HF, and sets the stage for a prospective randomized study to confirm these findings.

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.

Evaluation of graft patency by computed tomographic angiography in symptom-free post-coronary artery bypass surgery patients.

BACKGROUND: Accelerated atherosclerosis occurs in aortocoronary saphenous vein grafts, contributing to increased morbidity and mortality rates. We estimated the prevalence of asymptomatic graft failure in patients 5 years or more after coronary artery bypass grafting (CABG) using electron-beam computed tomographic angiography (EBA). METHODS AND RESULTS: EBA was performed in 45 symptom-free patients (mean age, 66 +/- 9 years; 87% male; mean time interval after CABG, 8 +/- 5 years). A total of 102 vein grafts and 37 internal mammary artery grafts were evaluated. Patients with graft stenosis or occlusion on EBA underwent myocardial perfusion scintigraphy and invasive angiography. Six grafts were unevaluable by EBA. Twenty patients had evidence of graft stenosis or occlusion on EBA. Of 20 asymptomatic patients with graft disease, 17 (85%) had abnormal myocardial perfusion, with moderate to severe reversible ischemia occurring in one third of subjects. Fourteen occluded and eleven stenosed vein grafts were correctly diagnosed by EBA. There were 2 false-positive EBA diagnoses of graft stenosis, resulting in a 100% positive predictive accuracy for detecting graft occlusion and 85% positive predictive accuracy for detecting graft stenosis. All occluded internal mammary artery grafts (n = 3) were accurately diagnosed. CONCLUSION: Computed tomographic coronary angiography permits reliable identification of bypass graft stenoses and occlusions in symptom-free patients more than 5 years after CABG. Future studies are needed to assess the prognostic benefit of early detection of graft disease and intervention in asymptomatic patients.

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.

Effect of intensive versus standard lipid-lowering treatment with atorvastatin on the progression of calcified coronary atherosclerosis over 12 months: a multicenter, randomized, double-blind trial.

BACKGROUND: Recent clinical trials have suggested that intensive versus standard lipid-lowering therapy provides for additional benefit. Electron-beam computed tomography provides the opportunity to quantify the progression of coronary artery calcification (CAC) in serial measurements. METHODS AND RESULTS: In a multicenter, randomized, double-blind trial, 471 patients (age 61+/-8 years) who had no history of coronary artery disease and no evidence of high-grade coronary stenoses (>50% diameter reduction) were randomized if they had > or =2 cardiovascular risk factors and moderate calcified coronary atherosclerosis as evidenced by a CAC score > or =30. Patients were assigned to receive 80 mg or 10 mg of atorvastatin per day over 12 months. Progression of CAC volume scores could be analyzed in 366 patients. After pretreatment with 10 mg of atorvastatin for 4 weeks, 12 months of study medication reduced LDL cholesterol from 106+/-22 to 87+/-33 mg/dL in the group randomized to receive 80 mg of atorvastatin (P<0.001), whereas levels remained stable in the group randomized to receive 10 mg (108+/-23 at baseline, 109+/-28 mg/dL at the end of the study, P=NS). The mean progression of CAC volume scores, corrected for the baseline CAC volume score, was 27% (95% CI 20.8% to 33.1%) in the 80-mg atorvastatin group and 25% (95% CI 19.1% to 30.8%) in the 10-mg atorvastatin group (P=0.65). CAC progression showed no relationship with on-treatment LDL cholesterol levels. CONCLUSIONS: We did not observe a relationship between on-treatment LDL cholesterol levels and the progression of calcified coronary atherosclerosis. Over a period of 12 months, intensive atorvastatin therapy was unable to attenuate CAC progression compared with standard atorvastatin therapy. The possibility remains that the time window was too short to demonstrate an effect.

A randomized trial of exercise treadmill ECG versus stress SPECT myocardial perfusion imaging as an initial diagnostic strategy in stable patients with chest pain and suspected CAD: cost analysis.

BACKGROUND: Exercise electrocardiography (ETT) is frequently used in patients with suspected coronary artery disease (CAD). Single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) improves diagnostic stratification. There are no randomized trials comparing ETT and MPI. We hypothesized that first-line MPI would be effective and cost-saving versus ETT. METHODS AND RESULTS: We randomized 457 outpatients with stable chest pain and suspected CAD to either treadmill electrocardiography or MPI. The post-test likelihood incorporated the pretest likelihood and the test result, with clinically driven testing. The primary endpoint was cost to diagnosis based on institutional and National Institute for Clinical Excellence costs. MPI significantly reduced the intermediate post-test likelihood of CAD (30% for ETT vs 3% for MPI, P < .0001) and further investigations (71% for ETT vs 16% for MPI, P < .0001). Despite the reduction in downstream resource utilization after MPI, mean costs were not different between the 2 initial strategies: 490.44 pounds sterling (95% confidence interval, 453.80-527.08) for ETT versus 512.41 pounds sterling (95% confidence interval, 481.41-543.41) for MPI. MPI cost was no different from ETT cost in patients with an intermediate or high pretest likelihood (P = not significant). ETT was less expensive in low-risk patients. CONCLUSIONS: In this study there was no difference in cost to diagnosis between initial ETT and MPI. In low-likelihood patients ETT was less costly, whereas there was no cost difference in intermediate- or high-likelihood patients.