Relation between Baseline Coronary Atherosclerotic Status, Cardiovascular Events, and Malignancies in Type 2 Diabetics: A Long-Term Prospective Cohort Study.

INTRODUCTION: Coronary artery disease and malignancy occur more frequently in patients with type 2 diabetes. They may share inflammation as a possible common pathogenetic mechanism, but it is unclear whether a clinical correlation exists between them. METHODS: This prospective cohort study followed 735 asymptomatic diabetics, aged 63.4 ± 5.3 years (mean ± standard deviation) for 12.2 ± 0.6 years after baseline coronary artery calcium scoring and cardiac computed tomography angiography. We examined extent and nature of coronary atherosclerosis and incidence of clinical cardiovascular (CV) events (death or myocardial infarction) and sought a relation to incidence of malignancy and malignancy mortality. RESULTS: Total mortality was 16.5% (121/735 patients): malignancy was cause of death in 48/121 (39.7%) of these and CV events in 44/121 (36.3%). There was no relation between extent of coronary atherosclerosis and incident malignancy (plaque volume 127 [21, 427] mm3 (median [interquartile range]) for incident malignancy versus 153 [24, 427] mm3 no malignancy, p = 0.71) or death from malignancy (plaque volume 176 [26, 646] versus 144 [22, 411] mm3, p = 0.32). There was also no relation between presence of high-risk plaque and incident malignancy (high-risk plaque in 27.1% with malignancy vs. 21.6% without, p = 0.18) or fatal malignancy (p = 0.16). Incident and fatal malignancy were not related to clinical CV events. Independent predictors of incident and fatal malignancy were age, smoking at baseline, and elevated C-reactive protein. CONCLUSION: This study found no relation between extent of coronary atherosclerosis or incidence of CV events and malignancy. Malignancy surpassed CV disease as the commonest long-term cause of mortality in middle-aged and older diabetics.

Cardiac Computed Tomography Angiographic Findings as Predictors of Late Heart Failure in an Asymptomatic Diabetic Cohort: An 8-Year Prospective Follow-Up Study.

OBJECTIVES: Predictive models for heart failure (HF) in heterogeneous populations have had limited success. We examined cardiac computed tomography angiography (CTA) predictors of HF or cardiovascular death (HF-CVD) in a prospective study of asymptomatic diabetics undergoing baseline assessment by CTA. METHODS: The subjects (n = 735, aged 55-74 years, 51.2% women) had no clinical history of cardiovascular disease at study entry. Coronary artery calcium (CAC) score, CTA-defined coronary atherosclerosis, cardiac chamber volumes, and clinical data were collected and late outcome events recorded over 8.4 ± 0.6 years (range 7.3-9.3). RESULTS: HF-CVD occurred in 41 (5.6%) subjects, with HF occurring mostly (19/23, 82.6%) in subjects without preceding myocardial infarction. Baseline univariate clinical outcome predictors of HF-CVD included older age (p = 0.027), the duration of diabetes (p = 0.004), HbA1c (p < 0.0001), microvascular disease (retinopathy, microalbuminuria) (p < 0.0001), and systolic blood pressure (p = 0.035). Baseline univariate CTA predictors included CAC score (p = 0.004), coronary stenosis (p = 0.047), and a CTA-defined left/right atrial (LA/RA) volume ratio >1 (p < 0.0001). Independent predictors were an LA/RA volume ratio >1, microvascular disease, and systolic blood pressure (model C-statistic 0.792, 95% CI 0.758-0.824). Measures of the extent of coronary artery disease (CAD) were not independent predictors of HF-CVD. CONCLUSIONS: In a low- to moderate-risk asymptomatic diabetic population, CTA LA enlargement (LA/RA volume ratio) but not the extent of CAD had independent prognostic value for HF-CVD in addition to the clinical variables.

Plaque Morphology as Predictor of Late Plaque Events in Patients With Asymptomatic Type 2 Diabetes: A Long-Term Observational Study.

OBJECTIVES: The authors used coronary computed tomography angiography (CTA) to determine plaque characteristics predicting individual late plaque events precipitating acute coronary syndromes (ACS) in a cohort of asymptomatic type 2 diabetic patients. BACKGROUND: In patients with coronary artery disease, CTA plaque characteristics may predict mid-term patient events. METHODS: Asymptomatic patients with diabetes 55 to 74 years of age with no history of coronary artery disease (N = 630) underwent baseline 64-slice CTA and detailed plaque level analysis. All subsequent clinical events were recorded and adjudicated. In patients who developed ACS, culprit plaque was identified at invasive angiography and its precursor located on the baseline CTA. Plaque characteristics predicting an ACS-associated culprit plaque event were analyzed by time to event accounting for inpatient clustering of plaques and competing events. RESULTS: Among 2,242 plaques in 499 subjects, 24 ACS culprit plaques were identified in 24 subjects during median follow-up of 9.2 years (interquartile range: 8.4 to 9.8 years). Plaque volume (upper vs. lower quartile hazard ratio [HR]: 6.9; 95% confidence interval [CI]: 1.6 to 30.8; p = 0.011), percentage of low-density plaque content <50 Hounsfield units (HR: 14.2; 95% CI: 1.9 to 108; p = 0.010), and mild plaque calcification (HR vs. all other plaques 3.3 [95% CI: 1.5 to 7.3]; p = 0.004) predicted plaque events univariately and after adjustment by clinical risk score. A culprit plaque event occurred in 13 of 376 (3.5%) high-risk plaques (HRP) (plaques with ≥2 risk predictors) versus 11 of 1,866 (0.6%) in non-HRPs (p < 0.0001), at 12 of 343 (3.5%) stenotic sites (≥50%) versus 12 of 1,899 (0.6%) nonstenotic sites (p < 0.0001) and in 7 of 131 (5.3%) HRP with stenosis (p < 0.0001 vs. all others). In 130 (20.6%) subjects, no coronary plaque was present on baseline CTA. CONCLUSIONS: In asymptomatic patients with type 2 diabetes, CTA plaque volume, percent low-density plaque content, and mild calcification predicted late plaque events. The additional presence of luminal stenosis increased the probability of an acute event.

Resting heart rate and measures of effort-related cardiac autonomic dysfunction predict cardiovascular events in asymptomatic type 2 diabetes.

BACKGROUND: Autonomic control of the cardiovascular system may be impaired in type 2 diabetes and is associated with increased morbidity and mortality. Parameters obtained during stress testing may reflect early stages of cardiac autonomic dysfunction and provide prognostic information in asymptomatic type 2 diabetes. METHODS: We performed maximal exercise treadmill testing in 594 patients with type 2 diabetes without known coronary heart disease. The prognostic significance of physiological parameters associated with autonomic dysfunction was assessed, including chronotropic incompetence (<80% heart rate reserve), abnormal heart rate recovery at 1 minute <18 beats/minute, and resting tachycardia >100 beats/minute. Cox proportional hazards analysis was used to determine the association of exercise parameters with a composite outcome of all-cause mortality, myocardial infarction or stroke. RESULTS: Resting heart rate >100 beats/minute was observed in 18% of patients, chronotropic incompetence in 30% and heart rate recovery at 1 minute <18 beats/minute in 35%. Over 79 ± 16 months, there were 72 (12%) events. Each parameter was significantly associated with event risk in an adjusted multivariate analysis: chronotropic incompetence (hazard ratio 1.89, 95% confidence interval 1.18-3.01; P = 0.008), resting heart rate ≥100 beats/minute (hazard ratio 1.97, 95% confidence interval 1.19-3.26; P = 0.008) and heart rate recovery at 1 minute <18 beats (hazard ratio 1.77, 95% confidence interval 1.12-2.81; P = 0.015). A progressive relationship between the number of abnormal parameters and event risk was observed (log rank P < 0.001). CONCLUSIONS: Chronotropic incompetence, resting tachycardia and reduced heart rate recovery are independently and additively associated with long-term mortality, myocardial infarction or stroke in type 2 diabetes without known coronary heart disease.

Coronary Computed Tomography (CT) Angiography as a Predictor of Cardiac and Noncardiac Vascular Events in Asymptomatic Type 2 Diabetics: A 7-Year Population-Based Cohort Study.

BACKGROUND: Type 2 diabetics are at increased risk for vascular events, but the value of further risk stratification for coronary heart disease (CHD) in asymptomatic subjects is unclear. We examined the added value of coronary computed tomography angiography over clinical risk scores (United Kingdom Prospective Diabetes Study), and coronary artery calcium in a population-based cohort of asymptomatic type 2 diabetics. METHODS AND RESULTS: Subjects (n=630) underwent baseline clinical assessment and computed tomography angiography (64-slice scanner). Plaque site, volume, calcific content, and arterial remodeling were recorded using dedicated software. Coronary, macrovascular, and microvascular-related events were assessed over 6.6±0.6 (mean±SD) (range 5.4-7.5) years and all CHD events were adjudicated. Discrimination of CHD events (cardiovascular death, myocardial infarction, unstable angina, or new-onset angina requiring intervention) (n=41) was improved by addition of total plaque burden to the clinical risk and coronary artery calcium scores combined (C=0.789 versus 0.763, P=0.034) and further improved by addition of an angiographic score (C=0.824, P=0.021). Independent predictors of a CHD event were United Kingdom Prospective Diabetes Study risk score (hazard ratio 1.3 per 10% 10-year risk, P=0.003) and the angiographic score (hazard ratio 3.2 per quartile, P<0.0001). Classification was improved over that by United Kingdom Prospective Diabetes Study and coronary artery calcium scores alone (overall net reclassification improvement 0.24). In subjects with coronary plaque (N=500), mild plaque calcification independently predicted a CHD event (hazard ratio 3.0, P=0.02). Computed tomography angiography predicted combined macrovascular but not microvascular-related events. CONCLUSIONS: Computed tomography angiography provides additional prognostic information in asymptomatic type 2 diabetics not obtainable from clinical risk assessment and coronary artery calcium alone.

Prognostic impact of abdominal fat distribution and cardiorespiratory fitness in asymptomatic type 2 diabetics.

BACKGROUND: Impaired cardiorespiratory fitness (CRF) is a potent risk factor for mortality in diabetes, and may modify the relation between adiposity and mortality. We evaluated the interaction between CRF and abdominal adiposity distribution with all-cause mortality, myocardial infarction or stroke in patients with diabetes. METHODS: We studied 294 type 2 diabetics without known coronary artery disease. CRF was quantified in metabolic equivalents by maximal treadmill testing, and categorized as low CRF (first tertile) or high CRF (second and third tertiles). Abdominal fat was quantified as subcutaneous or visceral adipose tissue from non-enhanced computed tomography scans. Association of CRF, adiposity distribution and their interaction with all-cause mortality, myocardial infarction or stroke was assessed by Cox proportional-hazard models. RESULTS: There were 31 (11%) events during 62 ± 12 months. Low CRF was significantly associated with event risk before and after adjustment for each measure of adiposity (hazard ratio 3.79, 95% confidence interval 1.79-8.01, p < 0.001). CRF level was inversely correlated with subcutaneous (r = -0.44, p < 0.001) but not visceral adipose tissue (r = -0.06, p = 0.31). Absolute event rates increased progressively across visceral adipose tissue tertiles, but decreased across subcutaneous tertiles. However, within each tertile of both adiposity measures, increased events were observed in the low compared with the high CRF group; this trend was also observed in an adjusted multivariate proportional hazards model. CONCLUSIONS: Although subcutaneous and visceral adipose tissues differed in their association with CRF levels and absolute event rates, lower baseline CRF in type 2 diabetics was significantly associated with higher risk of all-cause mortality, myocardial infarction or stroke, regardless of abdominal adiposity pattern.

Low cardiorespiratory fitness and coronary artery calcification: Complementary cardiovascular risk predictors in asymptomatic type 2 diabetics.

BACKGROUND: Despite its well-established prognostic value, cardiorespiratory fitness (CRF) is not incorporated routinely in risk assessment tools. Whether low CRF provides additional predictive information in asymptomatic type 2 diabetics beyond conventional risk scores and coronary artery calcification (CAC) is unclear. METHODS: We studied 600 type 2 diabetics aged 55-74 years without known coronary heart disease. CRF was quantified in metabolic equivalents (METs) by maximal treadmill testing and categorized as tertiles of percent predicted METs (ppMETs) achieved. CAC was calculated by non-enhanced computed tomography scans. The individual and joint association of both measures with an outcome event of all-cause mortality, myocardial infarction or stroke, was determined over a mean follow-up period of 80 ± 16 months. RESULTS: There were 72 (12%) events during follow-up. Low CRF was independently associated with event risk after adjustment for traditional risk factors and CAC (HR 2.25, 95% CI 1.41-3.57, p = 0.001). CRF (unfit/fit) allowed further outcome discrimination both amongst diabetics with low CAC scores (9.5% versus 2.0% event rate), and amongst diabetics with high CAC scores (23.5% versus 12.4% event rate), p < 0.001. The addition of CRF to a model comprising UKPDS and CAC scores improved the area under the curve for event prediction from 0.66 to 0.71, p = 0.03, with a positive continuous net reclassification improvement (NRI) of 0.451, p = 0.002. CONCLUSIONS: CRF, quantified by ppMETs, provided independent prognostic information which was additive to CAC. Low CRF may identify asymptomatic diabetic subjects at higher risk for all-cause mortality, myocardial infarction or stroke, despite low CAC.

Visceral abdominal adipose tissue and coronary atherosclerosis in asymptomatic diabetics.

BACKGROUND: Visceral abdominal adipose tissue (VAT) may play an active role in the progression of coronary atherosclerosis. We examined the relation between VAT, non-alcoholic fatty liver disease and extent of coronary atheroma in patients with type 2 diabetes mellitus but no known coronary artery disease. METHODS: Coronary artery calcium and area, distribution and thickness of upper abdominal fat were measured in selected axial cross-sections from non-enhanced computed tomography (CT) scans of the chest. Coronary atheroma was assessed visually on a per vessel basis from 64 slice CT angiography using axial views and multi-format reconstructions. Fatty liver was diagnosed when liver density was <40 Hounsfield units (HU) or ≥10 HU below spleen density. RESULTS: The area of VAT was increased in patients with versus without multi-vessel coronary artery plaque (237.0 ± 101.4 vs 179.2 ± 79.4 mm(2), p<0.001). Waist circumference (101.6 ± 12.3 versus 95.3 ± 13.8 cm) and internal abdominal diameter (218.7 ± 33.0 vs 194.6 ± 25.7 mm) (both p<0.001) were increased in patients with multi-vessel plaque whereas subcutaneous fat was unrelated to coronary plaque. Presence of fatty liver (93/318 patients, 29.2%) did not correlate with presence or extent of coronary plaque. The correlation of VAT with multi-vessel plaque although nominally independent of the metabolic syndrome (p=0.04) was not independent of waist circumference. CONCLUSION: In asymptomatic subjects with DM and no history of CAD area of VAT correlated with the presence and extent of coronary atheroma but as a risk predictor added little independent information to that obtained by more readily obtainable measures of adiposity-waist circumference and internal abdominal diameter.

Pulse pressure and coronary atherosclerosis in asymptomatic type 2 diabetes mellitus: a 64 channel cardiac computed tomography analysis.

BACKGROUND: Identification of high risk sub-groups for early initiation of preventive medical therapy requires widespread population screening using simple, inexpensive tests. High pulse pressure has been shown to predict adverse coronary events. We examined if this correlation was related to a greater coronary plaque burden in patients with high pulse pressure using 64 channel coronary computed tomographic angiography (CCTA) in patients with type 2 diabetes mellitus. METHODS: The study included 427 consecutive asymptomatic diabetic patients with no history of coronary disease, (age 55-74 years, 58% women), undergoing CCTA as part of a prospective outcomes study. RESULTS: Coronary atheroma was present in 76.6% of patients, multivessel coronary atheroma in 55.1% and luminal stenosis (>or=50% of diameter) in 22.9%. Pulse pressure (adjusted for age, gender, mean blood pressure and heart rate) correlated with number of coronary arteries with atheroma (p=0.005) and with multivessel coronary atheroma (odds ratio 1.24 95%CI 1.06-1.43 for each 10 mm Hg pulse pressure, p=0.009). The correlation was independent of Framingham and United Kingdom Prospective Diabetic Study risk scores (p=0.027 and p=0.036 respectively). Adjusted pulse pressure also correlated with quartiles of coronary artery calcium score (p=0.009). CONCLUSION: Elevated pulse pressure was a useful independent marker of presence and extent of pre-clinical coronary artery disease in an asymptomatic diabetic population.

Heart rate recovery after exercise and coronary atheroma in asymptomatic individuals with type 2 diabetes mellitus: a study using 64-slice coronary CT angiography.

Impaired heart rate recovery after exercise (HRR) is a marker of autonomic dysfunction and a predictor of long-term mortality either directly or due to associated cardiovascular disease. In a cohort of 552 asymptomatic type 2 diabetics (age 63.2 ± 5.4 yr, 54.9% women) participating in a long-term prospective outcomes study, we examined the hypothesis that cardiac autonomic dysfunction, as demonstrated by HRR in the first minute after exercise, is an independent correlate of multivessel coronary artery atheroma. HRR1 was reduced in patients with any coronary plaque (p = 0.012), multivessel coronary plaque (p = 0.006), and coronary stenosis (p = 0.027). However, the association was not independent of the United Kingdom Prospective Diabetes Study risk score thus it appears to be related to the adverse risk profile of these patients.