Apparent Coronary Artery Disease Research Articles

Transient ischaemic dilation ratio thresholds in patients with zero coronary calcium score undergoing exercise or dipyridamole stress SPECT myocardial perfusion imaging using a cadmium-zinc-telluride camera.

Transient ischaemic dilation (TID) is a marker of underlying extensive coronary artery disease (CAD) during myocardial perfusion imaging (MPI). The cut-off for a normal TID ratio (TIDr) value is often derived from a cohort of individuals with no apparent CAD. Varying criteria have been used to define the absence of CAD. We aim to derive TIDr cut-offs using patients with normal MPI and coronary artery calcium (CAC) score of zero, and compare the TIDr obtained from different software packages. We studied 232 patients with zero CAC and normal MPI undergoing exercise or dipyridamole stress using either a 1- or 2-day protocol. All patients were scanned in the supine position with a cadmium-zinc-telluride camera. TIDr was automatically generated using quantitative perfusion SPECT (QPS) software initially, and subsequently using Myometrix for comparison. The TIDr cut-offs calculated using the mean + 2 standard deviation were 1.29 and 1.24 for the 1- and 2-day protocol groups, respectively. In patients undergoing a 2-day protocol, dipyridamole stress resulted in significantly higher mean TIDr when compared to exercise stress (1.07 ± 0.13 vs. 1.01 ± 0.12, P = 0.035). Myometrix-derived TIDr were also significantly lower compared to QPS-derived values for most protocols except for 2-day exercise stress. This study is the first to derive TIDr threshold values using a normal population defined by zero CAC and normal MPI. TIDr was found to vary depending on stress modality, protocol as well as the software used.

Impact of ramus coronary artery on computed tomography derived fractional flow reserve (FFRCT ) in no apparent coronary artery disease.

The ramus artery contributes to the development of turbulence, which may influence computed tomography (CT) derived fractional flow reserve (FFRCT ) even without coronary artery disease (CAD). The relationship between ramus-induced turbulence and FFRCT is unclear. A total of 120 patients with<20% coronary stenosis assessed by both FFRCT and invasive coronary angiography were evaluated. The patients were divided into three groups: absent-ramus (n=72), small-ramus that could not be analyzed by FFRCT (n=18), and large-ramus that could be analyzed by FFRCT (n=30). FFRCT measurements were performed at the proximal and distal segments of the left anterior descending (LAD), left circumflex (LCX), and ramus artery. With absent-ramus and small-absent ramus groups, FFRCT was measured at the distal end of the left main trunk at the same level for the proximal segments of the LAD and LCX. In absent-ramus group, proximal FFRCT showed no significant differences between three vessels (LAD=.96±.02; MID=.97±.02; LCX=.97±.02). However, in small and large-ramus groups, proximal FFRCT was significantly higher in the ramus artery than LAD and LCX (small-ramus, LAD=.95±.03, Ramus=.97±.02, LCX=.95±.03; large-ramus: LAD=.95±.03, Ramus=.98±.01; LCX=.96±.03; p<.05). A large ramus was associated with a higher prevalence of a distal FFRCT ≤.80 (odds ratio 7.0, 95% CI 1.2-40.1, p=.03). A proximal ramus diameter predicted distal FFRCT ≤.80 (cut-off 2.1mm, AUC .76, sensitivity 100%, specificity 52%, 95% CI .61-.90). The presence of a large-ramus artery may cause an FFRCT decline in no apparent CAD.

Impact of coronary bifurcation angle on computed tomography derived fractional flow reserve in coronary vessels with no apparent coronary artery disease

ObjectivesComputed tomography (CT) derived fractional flow reserve (FFRCT) decreases from the proximal to the distal part due to a variety of factors. The energy loss due to the bifurcation angle may potentially contribute to a progressive decline in FFRCT. However, the association of the bifurcation angle with FFRCT is still not entirely understood. This study aimed to investigate the impact of various bifurcation angles on FFRCT decline below the clinically crucial relevance of 0.80 in vessels with no apparent coronary artery disease (CAD).MethodsA total of 83 patients who underwent both CT angiography including FFRCT and invasive coronary angiography, exhibiting no apparent CAD were evaluated. ΔFFRCT was defined as the change in FFRCT from the proximal to the distal in the left anterior descending artery (LAD) and left circumflex artery (LCX). The bifurcation angle was calculated from three-dimensional volume rendered images. Vessel morphology and plaque characteristics were also assessed.ResultsΔFFRCT significantly correlated with the bifurcation angle (LAD angle, r = 0.35, p = 0.001; LCX angle, r = 0.26, p = 0.02) and vessel length (LAD angle, r = 0.30, p = 0.005; LCX angle, r = 0.49, p < 0.0001). In LAD, vessel length was the strongest predictor for distal FFRCT of ≤ 0.80 (β-coefficient = 0.55, p = 0.0003), immediately followed by the bifurcation angle (β-coefficient = 0.24, p = 0.02). The bifurcation angle was a good predictor for a distal FFRCT ≤ 0.80 (LAD angle, cut-off 31.0°, AUC 0.70, sensitivity 74%, specificity 68%; LCX angle, cut-off 52.6°, AUC 0.86, sensitivity 88%, specificity 85%).ConclusionsIn vessels with no apparent CAD, vessel length was the most influential factor on FFRCT, directly followed by the bifurcation angle.Key Points• Both LAD and LCX bifurcation angles are factors influencing FFRCT.• Bifurcation angle is one of the predictors of a distal FFRCTof ≤ 0.80 and an optimal cut-off value of 31.0° for the LAD and 52.6° for the LCX.• Bifurcation angle should be taken into consideration when interpreting numerical values of FFRCT.

Impact of vascular morphology and plaque characteristics on computed tomography derived fractional flow reserve in early stage coronary artery disease

Abstract Background FFRCT gradually decreases from the proximal to the distal part of a vessel and reach the pathological threshold for significant ischemia even in the absence of obstructive coronary artery disease (CAD). The exact mechanisms of such gradual FFRCT decline remain unknown. Purpose The aims of this study are (1) to clarify the mechanisms of the gradual decline of computed tomography (CT) derived fractional flow reserve (FFRCT); and (2) to identify the predictive factors of an FFRCT decline below the pathological value of 0.80 in no apparent CAD vessels. Methods A total of 1058 outpatients with suspected CAD and who underwent CT angiography (CTA) with FFRCT analysis between January 2017 and December 2019 were evaluated. Among them, 150 consecutive patients who had both a CTA coupled to an FFRCT analysis and an invasive angiogram showing &amp;lt;25% coronary stenosis were included for analysis. Vessels were divided into two groups according to FFRCT at the distal vessel: FFRCT &amp;gt;0.80 (n=317) and FFRCT ≤0.80 (n=114). ΔFFRCT was defined as the magnitude of the change in FFRCT from the proximal to the distal vessel. Plaque characterization and vessel morphology measurements were performed semi-automatically. Vessel constituents were characterized based on Hounsfield units (HU) into lumen volume (&amp;lt;−50 HU), non-calcified plaque (NCP) (−50–150 HU), and calcified plaque (&amp;gt;150 HU). Results FFRCT decreased continuously from the proximal to distal across the three major vessels in both FFRCT&amp;gt;0.80 and FFRCT ≤0.80 groups (Figure 1). Compared to FFRCT&amp;gt;0.80 group, NCP volume was significantly higher in all three major vessels in FFRCT ≤0.80 group (210.2±83.6 mm3 vs. 140.9±139.3 mm3 for the RCA, p=0.01; 177.5±150.2 mm3 vs. 133.2±112.2 mm3 for the LAD, p=0.04; 127.6±91.5 mm3 vs. 58.7±57.7 mm3 for the LCX, p&amp;lt;0.01). Next, we investigated the vessel parameters that correlated with ΔFFRCT. ΔFFRCT was correlated with lumen volume in FFRCT&amp;gt;0.80 group (r=−0.24, p&amp;lt;0.0001), whereas ΔFFRCT was correlated with NCP volume in FFRCT ≤0.80 group (r=0.42, p&amp;lt;0.001) (Figure 2). An NCP volume above 44.8 mm3 was the strongest predictor of distal FFRCT of ≤0.80 (area under the curve 0.69, p&amp;lt;0.0001, sensitivity 95%, specificity 39%). Conclusions FFRCT is affected by vascular morphology and plaque characteristics even in the early stage of coronary artery disease. Our study highlights that subclinical coronary artery disease strongly influences FFRCT by effects unrelated to coronary stenosis. The presence of NCP is a major predictor of the gradual decrease of FFRCT toward pathological values. Anatomical findings as vessel morphology and plaque characteristics should be taken into consideration when interpreting numerical values of FFRCT to avoid unnecessary referrals for invasive coronary angiography or percutaneous coronary intervention. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Impact of vascular morphology and plaque characteristics on computed tomography derived fractional flow reserve in early stage coronary artery disease

BackgroundComputed-tomography (CT) derived fractional-flow-reserve (FFRCT) gradually may decrease from proximal to distal vessels even without apparent coronary artery disease (CAD). It may be unclear whether the decrease in FFRCT at the distal coronal artery is physiological or due to stenosis. We decided to study predictive factors of an FFRCT decline below the pathological value of 0.80 in no-apparent CAD. MethodsA total of 150 consecutive patients who had both CT angiography coupled to FFRCT analysis and invasive angiogram showing < 20% coronary stenosis were included. Vessels were divided into two groups according to FFRCT at the distal vessel: FFRCT > 0.80 (n = 317) and FFRCT ≤ 0.80 (n = 114). ΔFFRCT was defined as the change in FFRCT from proximal to distal vessel. Vessel morphology (vessel length and lumen volume) and plaque characteristics [low-attenuation plaque volume, intermediate-attenuation (IAP) plaque volume, and calcified plaque volume] were evaluated. ResultsFFRCT decreased from proximal to distal for the three major vessels in both FFRCT > 0.80 and FFRCT ≤ 0.80. Compared to FFRCT > 0.80, IAP volume was significantly higher in all three major vessels in FFRCT ≤ 0.80. ΔFFRCT was correlated with vessel length and lumen volume in FFRCT > 0.80, whereas ΔFFRCT was correlated with IAP volume in FFRCT ≤ 0.80. IAP volume above 44.8 mm3 was the strongest predictor of distal FFRCT of ≤ 0.80. ConclusionsThe presence of IAP is a major predictor of gradual decrease of FFRCT below 0.80 in no-apparent CAD vessels. Vessel morphology and plaque characteristics should be considered when interpreting FFRCT.

Differential polarization and the expression of efferocytosis receptor MerTK on M1 and M2 macrophages isolated from coronary artery disease patients

BackgroundDifferential polarization of macrophage into M1 and M2 mediates atherosclerotic plaque clearance through efferocytosis. Higher expression of Mer proto-oncogene tyrosine kinase (MerTK) on M2 macrophage helps in maintaining macrophage efferocytic efficiency. In healthy individuals, macrophage polarization into M1 and M2 occurs in tissues in concomitance with the acquisition of functional phenotypes depending on specific microenvironment stimuli. However, whether the macrophage differential polarization and MerTK expression vary in coronary artery disease (CAD) patients remain unknown.ObjectiveThis study aimed to elucidate the polarization of M1 and M2 macrophage from CAD patients as well as to investigate the expression of MerTK in these macrophage phenotypes.MethodsA total of 14 (n) CAD patients were recruited and subsequently grouped into “no apparent CAD”, “non-obstructive CAD” and “obstructive CAD” according to the degree of stenosis. Thirty ml of venous blood was withdrawn to obtain monocyte from the patients. The M1 macrophage was generated by treating the monocyte with GMCSF, LPS and IFN-γ while MCSF, IL-4 and IL-13 were employed to differentiate monocyte into M2 macrophage. After 7 days of polarization, analysis of cell surface differentiation markers (CD86+/CD80+ for M1 and CD206+/CD200R+ for M2) and measurement of MerTK expression were performed using flow cytometry.ResultsBoth M1 and M2 macrophage expressed similar level of CD86, CD80 and CD206 in all groups of CAD patients. MerTK expression in no apparent CAD patients was significantly higher in M2 macrophage compared to M1 macrophage [12.58 ± 4.40 vs. 6.58 ± 1.37, p = 0.040].ConclusionDifferential polarization of macrophage into M1 and M2 was highly dynamic and can be varied due to the microenvironment stimuli in atherosclerotic plaque. Besides, higher expression of MerTK in patients with the least coronary obstructive suggest its vital involvement in efferocytosis.

Reproductive risk factors for angiographic obstructive coronary artery disease among postmenopausal women.

Reproductive factors are female-specific coronary artery disease (CAD) risk factors. However, the importance of reproductive factors in angiographic obstructive CAD in postmenopausal women remains uncertain. This study aimed to compare reproductive factors between postmenopausal women with no apparent CAD, nonobstructive CAD, and obstructive CAD and identify reproductive risk factors for obstructive CAD. In this hospital-based cross-sectional study, 1,474 postmenopausal women, admitted with chest pain and referred for invasive coronary angiography were enrolled between April 2013 and October 2018. Adjusted odds ratio (95% CI) for obstructive CAD were 1.81 (1.03-3.17) for multigravidity (three or more pregnancies), 1.77 (1.14-2.76) for early menopause (≤40 y old), and 1.72 (1.26-2.35) for short reproductive life span (≤30 y). Each additional year in age at menopause or reproductive life span was associated with a 4% reduction in obstructive CAD risk in postmenopausal women (odds ratio, 0.96; 95% CI, 0.94-0.99; P = 0.011). The other reproductive factors, including parity, age at first birth, spontaneous abortion, induced abortion, stillbirth, hypertensive disorders of pregnancy, gestational diabetes mellitus, and age at menarche, were not correlated with obstructive CAD risk in postmenopausal women. Multigravidity (three or more pregnancies), early menopause, and a shorter reproductive life span were independent risk factors of angiographic obstructive CAD among postmenopausal women, which suggested that pregnancy and ovarian function may be important for the early identification and prevention of increased risk of female angiographic obstructive CAD.

Cytochrome P450-derived epoxyeicosatrienoic acids and coronary artery disease in humans: a targeted metabolomics study

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.

Factors associated with no apparent coronary artery disease in patients with type 2 diabetes mellitus for more than 10 years of duration: a case control study.

BackgroundType 2 diabetes mellitus is an important risk factor in the development of coronary artery disease (CAD) and is often associated with severe disease. However, this risk is not uniform, some patients remain free of CAD even after many years of treatment for diabetes. The present study was aimed to identify the factors that are associated with a favorable CAD profile.MethodsA case–control study of 76 patients with type 2 diabetes mellitus who were on treatment for more than 10 years duration and undergoing a coronary angiogram for the evaluation of clinically suspected CAD at a tertiary care hospital were recruited for the study. The presence and absence of significant CAD was determined after a coronary angiogram. Clinical history, and anthropometric and biochemical parameters were analyzed. Insulin resistance was determined by the Homeostasis Model Assessment. Multiple logistic regressions were done to find out the factors associated for a favorable CAD profile.ResultsThe difference in HOMA-IR (2.37 ± 0.69 VS 3.77 ± 1.64, p < 0.001) and urine microalbumin (24.15 ± 32.16 VS 82.72 ± 117.70, p = 0.004) were found to be statistically significant among those who did not have CAD when compared to those who had CAD. The difference in lipid profile, HbA1C, fasting blood sugar, BMI, waist hip ratio, waist and hip circumference was not significant. The adjusted odds ratio for insulin resistance less than 2.5 (OR 9.09, 95 % CI 1.91–41.83, p = 0.005), females (OR 7.91, 95 % CI 1.55–40.38, p = 0.013) and microalbumin <20 mg/l (OR 4.57, 95 % CI 1.17–17.85, p = 0.029) were independently associated with normal coronaries. The adjusted odds ratio for lipid profile, BMI, blood pressure and HbA1C were not significant.ConclusionsHOMA-IR less than 2.5, microalbuminuria less than 20 mg/l and females are the factors appear to be associated with no apparent CAD.

Putting cardiovascular risk into perspective

The Framingham Risk Score (FRS) is the gold standard for assessing cardiovascular (CV) risk.1 Individuals are categorized as having 10-year risk for CV disease event (myocardial infarction, stroke, peripheral arterial disease, congestive heart failure) that is low (0%–10%), moderate (11%–19%) or high (≥20%) based on risk factors that include age, sex, total cholesterol, high-density lipoprotein cholesterol, smoking status and systolic blood pressure. Those with diagnosed coronary artery disease (CAD), cerebrovascular disease, peripheral arterial disease or heart failure (HF) are automatically deemed to have a high 10-year risk.1 While the FRS is a useful clinical tool, it should be noted that it underestimates risk in certain categories of patients: in younger individuals, women, individuals with metabolic syndrome and those with chronic kidney disease.1 In addition, family history (evidence of CV disease in a first-degree relative younger than 60 years) is associated with a 1.7- and 2-fold increased risk of CV disease for women and men, respectively, which is not taken into account in the FRS. This factor helps to explain why 10% to 15% of patients with CAD have no apparent major CAD risk factors.1 As such, family history must be considered when assessing CV disease risk. Health professionals and patients may be much less concerned about individuals with low or moderate risk compared with those at high risk, and therefore may be less likely to recommend healthy lifestyle changes or medications. Moreover, in this population of patients, diagnoses such as angina may not be considered as often when the most remarkable complaints are symptoms such as excessive shortness of breath on exertion. This autobiographical case underscores the importance of heeding symptoms that may be suggestive of CV disease, regardless of risk assessment estimates. In addition, patients should be educated to appreciate the fact that low to moderate CV risk estimates do not imply that healthy lifestyle strategies are any less desirable.

Insulin resistance and atherosclerosis: Is it time to measure homa-ir to predict coronary artery disease?

Atherothrombotic cardiovascular disease (CVD) is the leading cause of death worldwide, despite remarkable advances in detection and management. The American Heart Association estimates that by 2030 at least 40% of the US population will have some form of CVD. Well-established modifiable risk factors include dyslipidemia, hypertension, obesity, diabetes mellitus, the metabolic syndrome and physical inactivity. Of these, insulin resistance (IR) is common to metabolic syndrome, diabetes mellitus and obesity. In this issue of North American Journal of Medical Sciences, Srinivasan et al., have provided data that relates the severity of insulin resistance to the severity of coronary artery disease.[1] Insulin resistance is mediated by the interplay of a person's genetic substrate and acquired pathophysiologic insults. Molecular studies have established that insulin resistance has a key role in every stage of atherosclerosis from the initiation and progression of early atherosclerosis to the formation of clinically significant plaques. In the early stages, insulin resistance appears to affect various molecular pathways at the cellular level in endothelial cells, macrophages and vascular smooth muscle cells.[2] Despite a wealth of data linking insulin resistance and atherosclerosis at the molecular level, the relation between the two in clinical settings has remained uncertain. A multi-center study reported an association between IR and multi-vessel coronary artery disease (CAD) in non-diabetic post-myocardial infarction survivors that was independent of other metabolic risk factors.[3] Another cross-sectional study from Europe reported that IR mediates subclinical atherosclerosis by increasing abdominal adiposity.[4] In an analysis of NHANES population data, we were able to demonstrate that IR was a greater risk for CVD than diabetes itself and that IR was associated with a higher risk of CVD in non-diabetics than in diabetics.[5] In the current study, the authors have taken this a step further and examined the relationship between insulin resistance and the severity of clinically apparent coronary artery disease. HOMA-IR was used to indicate insulin resistance while the Gensini score denoted CAD severity. They found statistically significant correlations between the HOMA-IR and the Gensini scores in their population. Interestingly in their multivariate analysis they did not find statistically significant associations with other known risk factors for CAD. In this way the authors have demonstrated a significant correlation between the insulin resistance and CAD. Though this positive correlation was small in statistical terms, it is a significant addition to the growing knowledge of the key role of insulin resistance in atherosclerosis. They conclude that they might be able to predict severity of CAD by measuring HOMA-IR. This is in contrast to other studies that have questioned the relative contribution of IR to clinically significant atherosclerotic disease. For example, a multiethnic study concluded that determination of the HOMA-IR is unlikely to improve detection of sub-clinical atherosclerosis.[6] The question then remains: Are we approaching primary prevention of coronary artery disease correctly by just screening for and treating diabetes mellitus and hyperlipidemia, while ignoring insulin resistance?

Relation of red cell distribution width with the presence, severity, and complexity of coronary artery disease

Red cell distribution width (RDW) is a measure of the heterogeneity of cell size in the peripheral blood and has been shown to be an independent correlate of adverse outcomes in healthy participants and in some cardiac conditions. We examined the association between RDW and the complexity of coronary artery disease (CAD). The study population included 193 nonanemic patients who had undergone coronary angiography for stable angina pectoris. Baseline RDW was measured as part of the automated complete blood count. Patients were classified depending on whether the SYNTAX score was 0 (no angiographically apparent CAD) or at least 1 where CAD was present angiographically. Patients with angiographic CAD had significantly elevated RDW levels compared with the patients without CAD (14.4±1.3 vs. 12.5±0.9, P<0.001). There was a good correlation between RDW and the SYNTAX score (r=0.55, P<0.001). In a receiver operating characteristic curve analysis, an RDW value of 13.25 was identified as an effective cut-point in the segregation of the presence or absence of CAD [area under curve=0.87, 95% confidence interval (CI) 0.81-0.92]. An RDW value of more than 13.25 yielded a sensitivity of 84%, a specificity of 79%, a positive predictive value of 89%, and a negative predictive value of 71%. In multivariate analysis, RDW was observed to be an independent predictor for both angiographic CAD (odds ratio=4.80, 95% CI 2.41-9.57, P<0.001) and for a high (>32) SYNTAX score (odds ratio=2.28, 95% CI 1.45-3.60, P=0.01). RDW is a readily available clinical laboratory value that is associated with both the presence and the complexity of CAD.

Abstract 17540: The CC Variant of Locus 9p21 Increases Coronary Disease Risk with High Values of Hs-CRP

Recent genomic wide association studies have identified several loci associated with coronary artery disease (CAD) risk. Among them, SNP rs 1333049 in the locus 9p21 (variant CC) has demonstrated a solid association with CAD which has been replicated in several populations, namely ours. High sensibility C-reactive protein (hs-CRP) has also been associated with inflammatory activity and atherosclerosis. An eventual interaction among these two atherosclerotic markers is unknown. Aim: To explore the interaction between this homozygous genetic variant (CC) and hs-CRP plasmatic levels in the emergence of CAD. Methods: Case-control study with 1561 participants, 695 consecutive coronary patients (mean age 53.9±8.9 years, 78.8% male) and 838 controls without apparent CAD (mean age 52.0±11.4 years, 71% male) selected in order not to present significant differences in sex and age. The G/C variants were studied blindly using a combined technique of PCR and TaqMan. Hardy-Weinberg distribution was analyzed. The CAD risk was investigated by univariate analysis and the OR and 95% confidence intervals were calculated. hs-CRP values were distributed by quartiles and the highest one, considered as the risk, was evaluated. To determine the interaction between CC genotype and elevated hs-CRP values we used a 4x2 table approach, as well as synergy measurements in additive (SI) and multiplicative (SIM) models. Finally, the risk excess (RERI) and the attributable proportion (AP) due to the interaction were calculated. Results: The CC variant was significantly associated with CAD risk in the whole population (OR=1.32; p=0.011). The presence of this genetic variant with normal hs-CRP values presented a smaller risk (OR=1.28) when compared to the association with the elevated hs-CRP values in the highest quartile (OR=1.7; p=0.007; SI=1.63; SIM=1.15; RERI=0.27). Conclusion: The present study demonstrates that the CC variant of the 9p21 locus globally increases the risk of CAD. This risk can be further increased in the presence of elevated hs-CRP values, as shown by the addictive and multiplicative interaction. This concept allows us to foresee the possibility of genetic risk factors management through the control of associated conditions, whenever possible.

Long-term association of brachial artery flow-mediated vasodilation and cardiovascular events in middle-aged subjects with no apparent heart disease

Background Endothelial dysfunction is considered an important prognostic factor in atherosclerosis. The aim of this study was to detect the long-term association of peripheral vascular endothelial function and clinical outcome in healthy subjects without apparent coronary artery disease (CAD). Methods We prospectively assessed brachial flow-mediated dilation (FMD) in 435 consecutive healthy subjects: 281 (65%) men, mean age 54 ± 12 years and body mass index 28 ± 4 kg/m 2. After overnight fasting and discontinuation of all medications for ≥ 12 h, FMD and endothelium-independent nitroglycerin-mediated vasodilation were assessed using high resolution linear array ultrasound. Results Subjects were divided into 2 groups: below ( n = 221) and above ( n = 214) the median FMD of 10.7%, and were comparable regarding CAD risk factors, lipoproteins, fasting glucose, C-reactive protein, and concomitant medications, with a mean clinical follow-up of 32 ± 2 months. Composite cardiovascular endpoints (all-cause mortality, non-fatal myocardial infarction, heart failure or angina pectoris hospitalization, stroke, coronary artery bypass grafting and percutaneous coronary interventions) were significantly more common in subjects with below median FMD of 10.7%, than above (11.8% vs 4.7%, p = 0.007, respectively). Univariate analysis demonstrated that median FMD significantly predicted cardiovascular events [odds ratio (OR) of 2.78 and 95% CI 1.35 to 5.71 ( p = 0.003)]. After multivariate analysis including conventional CAD risk factors, median FMD was the best independent predictor of long-term cardiovascular adverse events [OR of 2.70 and 95% CI 1.16 to 6.32 ( p = 0.011)]. Conclusions Brachial artery median FMD independently predicts long-term adverse cardiovascular events in healthy subjects in addition to traditional risk factor assessment.

Abstract 1528: Gender Differences In The Effect Of Traditional Cardiac Risk Factors On Age At Presentation With Stemi

For coronary artery disease (CAD), female gender is ’protective’, so that women typically present with clinically apparent CAD a decade later than men. We examined the extent to which traditional cardiovascular risk factor influence the age at presentation with STEMI in men and women. The Cardiovascular Patient Outcomes Research Team (C-PORT) primary PCI registry includes 7197 patients (5070 males and 2109 females) who presented with STEMI at 33 participating hospitals. The table below depicts the average age at presentation with STEMI in males and females with and without diabetes, hypercholesterolemia, hypertension, a family history of coronary artery disease and smoking history (current or former). The effect of smoking, family history and hypertension on age at presentation remained significant in multivariate analysis in both men and women. In both males and females, a family history of CAD and a positive smoking history are associated with presentation with STEMI at a younger age. Both have a greater effect in females. This is particularly true of smoking with lowers the age of presentation by 9 years in women, compared with 3.8 years in men. Male and female patients with a history of hypertension are older at presentation with STEMI, perhaps because the anti-ischemic effects of anti-hypertensive medications. We conclude that while the effect of most traditional risk factors for CAD on age at presentation with STEMI are similar in men and women, smoking lowers the age at presentation to a much greater degree in women. In women who do not smoke, STEMI is delayed for a decade or more compared to men; for women who do, the protective effect of female gender is nearly obliterated.

Increased nitric oxide production by peripheral blood monocytes and selective elevation of serum IgE in patients with systemic lupus erythematosus (SLE). (101.13)

Abstract Prospective studies of patients with SLE have reported a prevalence of clinically apparent coronary artery disease (CAD) of up to 20%, a marked increase compared with the estimated CAD prevalence rate of 3.5% among healthy females 20–35 years (AHA 1997 Heart and Stroke Statistical Update). Nitric oxide is an important mediator of inflammation associated with vascular damage. We measured nitric oxide production by cultures of peripheral blood monocytes (N= 26) from patients with SLE and determined serum immunoglobulin concentrations (N=19). Elevated immunoglobulin concentrations were observed in sera from 8 patients (42%), and 4 individuals had a selective increase in IgE (&amp;gt;100 IU/ml), with other immunoglobulin isotypes in the normal range. Nitric oxide (NO) production by adherent monocyte cultures from patients with SLE was determined on day 7 using a modified colorimetric Griess reaction to measure nitrite, the stable NO metabolite. The results showed activation in 31% of the patients, with nitrite concentrations exceeding the baseline of 2.8μM more than threefold, reaching 8.8 μM. The mechanism of this in vivo activation of blood monocytes among some patients with SLE remains to be established. Activated monocyte-derived nitric oxide may contribute to the development of atherosclerosis and cardiovascular complications seen in many patients with SLE.

Oral Antiplatelet Therapy in Cerebrovascular Disease, Coronary Artery Disease, and Peripheral Arterial Disease

Atherothrombosis is a pathophysiologic process that results in clinical ischemic events affecting the cerebral, coronary, and peripheral arterial circulation. Antiplatelet agents, used alone or in combination, are effective in preventing recurrent vascular events among individuals with established vascular disease. To summarize the current state of evidence regarding oral antiplatelet treatment in patients with cerebrovascular disease, coronary artery disease (CAD), and peripheral arterial disease. Using the key terms acute coronary syndrome, atherothrombosis, ischemic stroke, myocardial infarction, MI, peripheral arterial disease, TIA, transient ischemic attack, unstable angina,aspirin,ticlopidine,dipyridamole, and clopidogrel, we searched the MEDLINE database as well as the trial register of the Cochrane Groups to identify studies published from 1960 to August 2004. We manually searched journals and abstract booklets; scrutinized reference lists of trials and review articles; and reviewed meta-analyses, scientific statements, and guidelines from official societies. Appropriate oral first-line antiplatelet therapy is aspirin for individuals with ST-segment elevation myocardial infarction; aspirin or clopidogrel for those with TIA or stroke, chronic stable angina, or peripheral arterial disease; and aspirin combined with clopidogrel for those with non-ST-segment elevation acute coronary syndrome. Aspirin combined with dipyridamole is a possible alternative for patients who experience a first episode of TIA or stroke in the absence of clinically apparent CAD. Although ticlopidine has been shown to be of benefit in various vascular conditions, its adverse-effect profile has limited its use. Aspirin, ticlopidine, clopidogrel, aspirin combined with clopidogrel, and aspirin combined with dipyridamole are effective in preventing recurrent vascular events among various subgroups of patients with vascular disease. Current clinical trial evidence favors the use of aspirin or clopidogrel as first-line agents for the majority of patients with vascular disease. Clinical trials evaluating combination antiplatelet therapies will direct future practice.

Yield of stress single-photon emission computed tomography in asymptomatic patients with diabetes

Background Patients with diabetes without clinically apparent coronary artery disease are at increased risk of cardiac death. The value of screening stress testing in these patients remains controversial. The goal of this study was to examine the yield of stress single-photon emission computed tomography (SPECT) in asymptomatic diabetic patients. Methods The results of stress SPECT in patients without prior myocardial infarction or coronary revascularization were compared in asymptomatic diabetics (n = 1738) versus symptomatic diabetic patients (n = 2998), asymptomatic nondiabetic patients (n = 6215), and symptomatic nondiabetic patients (n = 16,214). Results Abnormal scans were present in 58.6% of asymptomatic diabetic patients, approximately equal to the percentage in symptomatic diabetic (59.5%) ( P = not significant) and higher than in asymptomatic nondiabetic (46.2%) ( P < .001) and symptomatic nondiabetic (44.4%) ( P < .001) patients. The breakdown of high-risk scans followed a similar pattern in the 4 patient subsets: asymptomatic diabetic, 19.7% versus symptomatic diabetic, 22.2% ( P = .051); asymptomatic nondiabetic, 11.1% ( P < .001); and symptomatic nondiabetic, 12.5% ( P < .001). Patients with diabetes had more electrocardiographic and scan evidence for silent myocardial infarction versus those without diabetes. Conclusions Asymptomatic diabetic patients have a high prevalence of both abnormal and high-risk SPECT scans. The finding that approximately 1 in 5 of these individuals has a high-risk scan suggests a potentially more widespread application of screening stress SPECT in asymptomatic diabetic patients to identify those with severe coronary artery disease.

Metabolic Syndrome and Cardiovascular Disease

Insulin resistance is characterized by an impaired physiological response to insulin. The constellation of insulin resistance, and several other metabolic and vascular disorders, is known as the insulin resistance syndrome, or metabolic syndrome. The characteristic features of metabolic syndrome include；central obesity, hypertension, dyslipidemia and glucose intolerance, and abnormalities in both the endothelial cells and vascular function. Several studies have shown that insulin resistance is a predictor of coronary artery disease (CAD). Recent studies have described relationships between the entire constellation of components in metabolic syndrome and the risk of CAD. The increasing prevalence of the insulin resistance syndrome, and its strong association with risk of CAD, has highlighted the potential importance of its early diagnosis and aggressive treatment. The managements of metabolic syndrome include lifestyle interventions, aggressive treatment of the identified CAD risk factors, and the treatments of abnormal glucose tolerance and insulin resistance. The connection between insulin resistance, metabolic syndrome and coronary disease must be recognized, and it is important not only to manage the obviously apparent CAD risk factors, but also to identify and manage other sought factors. (Korean Circulation

Relationship between dobutamine-induced regional wall motion abnormalities and coronary flow reserve in heart transplant patients without angiographic coronary artery disease

Background: Regional wall motion abnormalities (RWMA) demonstrated by dobutamine stress echocardiography (DSE) are a sensitive predictor of coronary artery disease (CAD) in heart transplant recipients. However, RWMA have been shown to occur in patients with angiographically “normal” coronary arteries. The reasons for this are unknown. We sought to determine if abnormal responses to dobutamine in this setting can be explained by microvascular dysfunction in the coronary circulation as detected by decreased coronary flow reserve (CFR). Methods: Twenty-six consecutive heart transplant patients were evaluated prospectively. Five of 26 (19.2%) patients (seven coronary arteries) were excluded for poor acoustic windows on echocardiography. Another three patients were excluded for angiographically apparent CAD. CFR and wall motion score index (WMSI) derived from DSE were measured in the remaining 18 patients and formed the basis of this study. Patients were divided into two groups based on the absence (Group 1; n = 5) or presence (Group 2; n = 13) of RWMA on DSE. CFR was measured with the Doppler Flo-Wire in 34 coronary arteries (18 patients) and correlated with WMSI. Results: In Group 1 patients, CFR measured in eight coronary arteries was normal (2.6 ± 0.4). In Group 2 patients, CFR measured in 26 coronary arteries also was normal (2.2 ± 0.6; p = NS vs Group 1). In Group 2, CFR was measured in 20 of 24 vessels assigned to segments that developed RWMA. Only 6 of these 20 vessels (30%) had abnormal CFR. Overall, there was no correlation between decreased CFR and the presence of RWMA induced by dobutamine. Conclusions: These data suggest that, in cardiac transplant patients with angiographically “normal” coronary arteries, inducible wall motion abnormalities during DSE cannot be attributed to coronary microvascular dysfunction as manifested by decreased CFR.