Function Of Coronary Circulation Research Articles

Coronary circulatory function with increasing obesity: A complex U-turn.

The aim of this investigation was to explore and characterize alterations in coronary circulatory function in function of increasing body weight with medically controlled cardiovascular risk factors and, thus, "metabolically" unhealthy obesity. We prospectively enrolled 106 patients with suspected CAD but with normal stress-rest myocardial perfusion on 13 N-ammonia PET/CT and with medically controlled or no cardiovascular risk factors. 13 N-ammonia PET/CT concurrently determined myocardial blood flow (MBF) during pharmacologically induced hyperaemia and at rest. Based on body mass index (BMI), patients were grouped into normal weight (BMI: 20.0-24.9kg/m2 , n=22), overweight (BMI: 25.0-29.9kg/m2 , n=27), obese (BMI: 30.0-39.9kg/m2 , n=31), and morbidly obese (BMI≥40kg/m2 , n=26). Resting MBF was comparable among groups (1.09±0.18 vs. 1.00±0.15 vs. 0.96±0.18 vs.. 1.06±0.31ml/g/min; p=.279 by ANOVA). Compared to normal weight individuals, the hyperaemic MBF progressively decreased in in overweight and obese groups, respectively (2.54±0.48 vs. 2.02±0.27 and 1.75±0.39ml/g/min; p<.0001), while it increased again in the group of morbidly obese individuals comparable to normal weight (2.44±0.41 vs. 2.54±0.48ml/g/min, p=.192). The BMI of the study population correlated with the hyperaemic MBF in a quadratic or U-turn fashion (r=.34, SEE=0.46; p≤.002). The U-turn of hyperaemic MBF from obesity to morbid obesity is likely to reflect contrasting effects of abdominal versus subcutaneous adipose tissue on coronary circulatory function indicative of two different disease entities, but needing further investigations.

Endocannabinoid 2-arachidonoylglycerol is elevated in the coronary circulation during acute coronary syndrome.

ObjectivesThe endocannabinoid system modulates coronary circulatory function and atherogenesis. The two major endocannabinoids (eCB), 2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamide (AEA), are increased in venous blood from patients with coronary artery disease (CAD). However, given their short half-life and their autocrine/paracrine mechanism of action, eCB levels in venous blood samples might not reflect arterial or coronary eCB concentrations. The aim of this cross-sectional study was to identify the local concentration profile of eCB and to detect whether and how this concentration profile changes in CAD and NSTEMI versus patients without CAD.Methods and results83 patients undergoing coronary angiography were included in this study. Patients were divided into three groups based on their definite diagnosis of a) no CAD, b) stable CAD, or c) non-ST-segment elevation myocardial infarction (NSTEMI). Blood was drawn from the arterial sheath and the aorta in all patients and additionally distal to the culprit coronary lesion in CAD- and NSTEMI patients. 2-AG levels varied significantly between patient groups and between the sites of blood extraction. The lowest levels were detected in patients without CAD; the highest 2-AG concentrations were detected in NSTEMI patients and in the coronary arteries. Peripheral 2-AG levels were significantly higher in NSTEMI patients (107.4 ± 28.4 pmol/ml) than in CAD- (17.4 ± 5.4 pmol/ml; p < 0.001), or no-CAD patients (23.9 ± 7.1 pmol/ml; p < 0.001). Moreover, coronary 2-AG levels were significantly higher in NSTEMI patients than in CAD patients (369.3 ± 57.2 pmol/ml vs. 240.1 ± 25.3 pmol/ml; p = 0.024).Conclusions2-AG showed significant variability in arterial blood samples drawn from distinct locations. Possibly, lesional macrophages synthesise 2-AG locally, which thereby contributes to endothelial dysfunction and local inflammation.

Physiologic Characteristics and Clinical Outcomes of Patients With Discordance Between FFR and iFR

ObjectivesThis study evaluated the physiologic characteristics of discordant lesions between instantaneous wave-free ratio (iFR) and fractional flow reserve (FFR) and the prognosis at 5 years. BackgroundFFR or iFR have been standard methods for assessing the functional significance of coronary artery stenosis. However, limited data exist about the physiologic characteristics of discordant lesions and the prognostic implications resulting from these lesions. MethodsA total of 840 vessels from 596 patients were classified according to iFR and FFR; high iFR–high FFR (n = 580), low iFR–high FFR (n = 40), high iFR–low FFR (n = 69), and low iFR–low FFR (n = 128) groups, which were compared with a control group (n = 23). The differences in coronary circulatory indices including the coronary flow reserve (CFR), index of microcirculatory resistance (IMR), and resistance reserve ratio (RRR) (resting distal arterial pressure × mean transit time / hyperemic distal arterial pressure × hyperemic mean transit time), which reflect the vasodilatory capacity of coronary microcirculation, were compared. Patient-oriented composite outcomes (POCO) at 5 years including all-cause death, any myocardial infarction, and any revascularization were compared among patients with deferred lesions. ResultsIn the low iFR–high FFR group, CFR, RRR, and IMR measurements were similar to the low iFR–low FFR group: CFR 2.71 versus 2.43 (p = 0.144), RRR 3.36 versus 3.68 (p = 0.241), and IMR 18.51 versus 17.38 (p = 0.476). In the high iFR–low FFR group, the CFR, RRR, and IMR measurements were similar to the control group: CFR 2.95 versus 3.29 (p = 0.160), RRR 4.28 versus 4.00 (p = 0.414), and IMR 17.44 versus 17.06 (p = 0.818). Among the 4 groups, classified by iFR and FFR, CFR and RRR were all significantly different, except for IMR. However, there were no significant differences in the rates of POCO, regardless of discordance between the iFR and FFR. Only the low iFR–low FFR group had a higher POCO rate compared with the high iFR–high FFR group (adjusted hazard ratio: 2.46; 95% confidence interval: 1.17 to 5.16; p = 0.018). ConclusionsDifferences in coronary circulatory function were found, especially in the vasodilatory capacity between the low iFR–high FFR and high iFR–low FFR groups. FFR–iFR discordance was not related to an increased risk of POCO among patients with deferred lesions at 5 years. (Clinical, Physiological and Prognostic Implication of Microvascular Status;NCT02186093; Physiologic Assessment of Microvascular Function in Heart Transplant Patients; NCT02798731)

Plasma endothelin-1 and adrenomedullin are associated with coronary artery function and cardiovascular outcomes in humans

BackgroundEndothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE). MethodsThirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years. ResultsPlasma ET-1 levels correlated with IMR (r = 0.57; p < 0.01) and ADM levels correlated with CFR (r = 0.50; p = 0.04) and cFMD (r = 0.62; p = 0.01). After adjustment for age, gender and cardiovascular risk factors, the association between ADM and cFMD (β = 0.79; p < 0.01) and between ET-1 and IMR (β = 5.7; p = 0.01) remained significant. IMR was higher, although not statistically significant, in patients with long-term MACE (17.9 ± 5.3 vs. 13.1 ± 6.0 units; p = 0.14). In patients free of MACE, cFMD (9.3 ± 7.6 vs. 2.8 ± 5.0%; p = 0.01) and plasma ADM levels (7.6 ± 5.3 vs. 4.0 ± 1.9 pmol/L; p = 0.07) were higher. ConclusionsPlasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Plasma Endothelin-1 and Adrenomedullin are Associated with Coronary Artery Function and Cardiovascular Outcomes in Humans

Abstract Background Endothelin-1 (ET-1) is a vasoconstrictor associated with cardiovascular disease, whereas adrenomedullin (ADM) is a vasorelaxant with cardioprotective properties. We sought to determine the relationship between plasma ET-1 and ADM with coronary circulatory function and long-term major adverse cardiovascular events (MACE). Methods Thirty-two patients undergoing coronary angiography for chest pain were recruited. Baseline plasma ET-1 and ADM levels were measured. The index of microcirculatory resistance (IMR), coronary flow mediated dilatation (cFMD) and coronary flow reserve (CFR) were measured in a non-obstructed coronary artery. Patients were assessed for MACE over a median period of 8.8 years. Results Plasma ET-1 levels correlated with IMR (r = 0.57; p Conclusions Plasma ET-1 and ADM were associated with measures of coronary microvascular and coronary conduit vessel function, respectively. Increased cFMD and elevated plasma ADM were associated with a cardioprotective effect.

Integrated Noninvasive Physiological Assessment of Coronary Circulatory Function and Impact on Cardiovascular Mortality in Patients With Stable Coronary Artery Disease.

It is suggested that the integration of maximal myocardial blood flow (MBF) and coronary flow reserve (CFR), termed coronary flow capacity, allows for comprehensive evaluation of patients with known or suspected stable coronary artery disease. Because management decisions are predicated on clinical risk, we sought to determine the independent and integrated value of maximal MBF and CFR for predicting cardiovascular death. MBF and CFR were quantified in 4029 consecutive patients (median age 66 years, 50.5% women) referred for rest/stress myocardial perfusion positron emission tomography scans from January 2006 to December 2013. The primary outcome was cardiovascular mortality. Maximal MBF <1.8 mL·g-1·min-1 and CFR<2 were considered impaired. Four patient groups were identified based on the concordant or discordant impairment of maximal MBF or CFR. Association of maximal MBF and CFR with cardiovascular death was assessed using Cox and Poisson regression analyses. A total of 392 (9.7%) cardiovascular deaths occurred over a median follow-up of 5.6 years. CFR was a stronger predictor of cardiovascular mortality than maximal MBF beyond traditional cardiovascular risk factors, left ventricular ejection fraction, myocardial scar and ischemia, rate-pressure product, type of radiotracer or stress agent used, and revascularization after scan (adjusted hazard ratio, 1.79; 95% confidence interval [CI], 1.38-2.31; P<0.001 per unit decrease in CFR after adjustment for maximal MBF and clinical covariates; and adjusted hazard ratio, 1.03; 95% CI, 0.84-1.27; P=0.8 per unit decrease in maximal MBF after adjustment for CFR and clinical covariates). In univariable analyses, patients with concordant impairment of CFR and maximal MBF had high cardiovascular mortality of 3.3% (95% CI, 2.9-3.7) per year. Patients with impaired CFR but preserved maximal MBF had an intermediate cardiovascular mortality of 1.7% (95% CI, 1.3-2.1) per year. These patients were predominantly women (70%). Patients with preserved CFR but impaired maximal MBF had low cardiovascular mortality of 0.9% (95% CI, 0.6-1.6) per year. Patients with concordantly preserved CFR and maximal MBF had the lowest cardiovascular mortality of 0.4% (95 CI, 0.3-0.6) per year. In multivariable analysis, the cardiovascular mortality risk gradient across the 4 concordant or discordant categories was independently driven by impaired CFR irrespective of impairment in maximal MBF. CFR is a stronger predictor of cardiovascular mortality than maximal MBF. Concordant and discordant categories based on integrating CFR and maximal MBF identify unique prognostic phenotypes of patients with known or suspected coronary artery disease.

Myocardial Blood Flow and Inflammatory Cardiac Sarcoidosis

ObjectivesThis study sought to evaluate the effects of inflammatory sarcoid disease on coronary circulatory function and the response to immune-suppressive treatment. BackgroundAlthough positron emission tomography assessment of myocardial inflammation is increasingly applied to identify active cardiac sarcoidosis, its effect on coronary flow and immune-suppressive treatment remains to be characterized. MethodsThirty-two individuals, who were referred for positron emission tomography/computed tomography, were evaluated for known or suspected cardiac sarcoidosis applying 18F-fluorodeoxyglucose to determine inflammation and 13N-ammonia to assess for perfusion deficits following a high-fat/low-carbohydrate diet and fasting state >12 h to suppress myocardial glucose uptake. Inflammation was quantified with standardized uptake value and regional myocardial blood flow at rest and during regadenoson-stimulated hyperemia was determined in ml/g/min. Positron emission tomography studies were repeated in 18 cases with a median follow-up of 2.5 years (interquartile range [IQR]:1.3 to 3.4 years). ResultsTwenty-five exams had normal perfusion but evidence of regional inflammation (group 1), and 21 exams presented a regional perfusion deficit associated with inflammation (group 2). Median myocardial blood flow did not differ between inflamed and noninflamed myocardium in both groups (0.86 ml/g/min [IQR: 0.66 to 1.11 ml/g/min] vs. 0.83 ml/g/min [IQR: 0.64 to 1.12 ml/g/min] and 0.74 ml/g/min [IQR: 0.60 to 0.93 ml/g/min] vs. 0.77 ml/g/min [IQR: 0.59 to 0.95 ml/g/min], respectively). As regards median hyperemic myocardial blood flows, they were significantly lower in the inflamed than in the remote regions in group 1 and 2 (2.31 ml/g/min [IQR: 1.81 to 2.95 ml/g/min] vs. 2.70 ml/g/min [IQR: 2.07 to 3.30 ml/g/min] and 1.61 ml/g/min [IQR: 1.17 to 2.18 ml/g/min] vs. 1.94 ml/g/min [IQR: 1.49 to 2.39 ml/g/min]; p < 0.001, respectively). Immune-suppression–mediated decrease in inflammation was associated with preserved myocardial flow reserve (MFR) at follow-up, whereas MFR significantly worsened in regions without changes or even increases in inflammation (median ΔMFR: 0.07 [IQR: –0.29 to 0.45] vs. –0.24 [IQR: –0.84 to 0.21]; p < 0.001). There was an inverse correlation between pronounced alterations in myocardial inflammation (Δ regional myocardial volume with standardized uptake value >4.1) and ΔMFR (r = –0.47; p = 0.048). ConclusionsSarcoid-mediated myocardial inflammation is associated with a regional impairment of coronary circulatory function. The association between immune-suppressive treatment-related alterations in myocardial inflammation and changes in coronary vasodilator capacity suggests direct adverse effect of inflammation on coronary circulatory function in cardiac sarcoidosis.

Exercise capacity and cardiac hemodynamic response in female ApoE/LDLR(-/-) mice: a paradox of preserved V'O2max and exercise capacity despite coronary atherosclerosis.

We assessed exercise performance, coronary blood flow and cardiac reserve of female ApoE/LDLR−/− mice with advanced atherosclerosis compared with age-matched, wild-type C57BL6/J mice. Exercise capacity was assessed as whole body maximal oxygen consumption (V’O2max), maximum running velocity (vmax) and maximum distance (DISTmax) during treadmill exercise. Cardiac systolic and diastolic function in basal conditions and in response to dobutamine (mimicking exercise-induced cardiac stress) were assessed by Magnetic Resonance Imaging (MRI) in vivo. Function of coronary circulation was assessed in isolated perfused hearts. In female ApoE/LDLR−/− mice V’O2max, vmax and DISTmax were not impaired as compared with C57BL6/J mice. Cardiac function at rest and systolic and diastolic cardiac reserve were also preserved in female ApoE/LDLR−/− mice as evidenced by preserved fractional area change and similar fall in systolic and end diastolic area after dobutamine. Moreover, endothelium-dependent responses of coronary circulation induced by bradykinin (Bk) and acetylcholine (ACh) were preserved, while endothelium-independent responses induced by NO-donors were augmented in female ApoE/LDLR−/− mice. Basal COX-2-dependent production of 6-keto-PGF1α was increased. Concluding, we suggest that robust compensatory mechanisms in coronary circulation involving PGI2- and NO-pathways may efficiently counterbalance coronary atherosclerosis-induced impairment in V’O2max and exercise capacity.

Effect of Roux-en-Y gastric bypass surgery on ventricular function and cardiac risk factors in obese patients: a systematic review

Introduction: Weight gain and obesity are two important public health problems, which are associated with many diseases such as cardiovascular disorders. Various policies such as bariatric surgery have been proposed for the treatment of morbid obesity. Methods: PubMed and Scopus were searched thoroughly with the following search terms (roux-en-y gastric bypass surgery) AND (ventricular function, OR cardiac risk factors OR heart)) AND (BMI OR body mass index) to find the articles in which the effect of roux-en-Y gastric bypass (RYGB) surgery had been evaluated in severely obese patients.Result: Out of 120 articles which were found in PubMed, and 28 records which were found in Scopus, only 18 articles fully met the inclusion criteria. Out of 2740 participants in the included studied, 1706 were patients with body mass index (BMI) over 40 kg/m2 who had undergone RYGB surgery, and 1034 were control participants. Results of the studies showed that RYGB surgery could reduce BMI, and cardiac risk factors, and improve diastolic function, systolic and diastolic blood pressures, and aortic function, postoperatively.Discussion: Obesity is associated with increased risk of cardiovascular diseases, impaired cardiac function, and hypertension. It is shown that RYGB surgery reduces the serum level of biochemical markers of cardiac diseases. Cardiac structure, parasympathetic indices of autonomic function, coronary circulatory function, hypertension, epicardial fat thickness, and ventricular performance improve after bariatric surgery.Conclusions: It is concluded that RYGB surgery is an effective strategy to improve ventricular function and cardiac risk factors in morbid obese patients.

Impact of Obesity and Bariatric Surgery on Metabolism and Coronary Circulatory Function

Increases in intra-abdominal visceral adipose tissue have been widely appreciated as a risk factor for metabolic disorders such as dyslipidemia, hypertension, insulin resistance, and type 2 diabetes, whereas this is not the case for peripheral or subcutaneous obesity. While the underlying mechanisms that contribute to these differences in adipose tissue activity remain uncertain, increases in visceral fat commonly induce metabolic dysregulation, in part because of increased venous effluent of fatty acids and/or adipokines/cytokines to the liver. Increased body weight, paralleled by an increase in plasma markers of the insulin-resistance syndrome and chronic inflammation, is independently associated with coronary circulatory dysfunction. Recent data suggest that plasma proteins originating from the adipose tissue, such as endocannabinoids (EC), leptin, and adiponectin (termed adipocytes) play a central role in the regulation and control of coronary circulatory function in obesity. Positron emission tomography (PET) in concert with tracer kinetic modeling is a well established technique for quantifying regional myocardial blood flow at rest and in response to various forms of vasomotor stress. Myocardial flow reserve assessed by PET provides a noninvasive surrogate of coronary circulatory function. PET also enables the monitoring and characterization of coronary circulatory function in response to gastric bypass-induced weight loss in initially morbidly obese individuals, to medication and/or behavioral interventions related to weight, diet, and physical activity. Whether the observed improvement in coronary circulatory dysfunction via weight loss may translate to diminution in cardiovascular events awaits clinical confirmation.

Assessment of myocardial matrix expansion with cardiac magnetic resonance: entering a new area of cardiac risk stratification in type 2 diabetes mellitus?

This editorial refers to ‘Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in diabetes and associated with mortality and incident heart failure admission’[†][1], by T.C. Wong et al. , on page 657 Type 2 diabetes mellitus (DM) may lead not only to early development of accelerated coronary artery disease (CAD) but also to cardiomyopathy (CMP), both of which confer an excess morbidity and mortality in these patients.1–3 As there is a continuous increase in the prevalence of DM in industrialized nations, it raises a considerable public health concern. Subclinical markers of early functional and structural vasculopathy such as an impairment of coronary circulatory function,4 increased carotid intima-media thickeness (IMT),5 and coronary artery calcification6 have all been demonstrated independently to predict the initiation and/or progression of CAD and subsequent cardiovascular events. More recently, cardiovascular magnetic resonance (CMR) assessment of increased extracellular volume (ECV) fraction of the left ventricle, which can be assumed to probe features of adverse myocardial remodelling, predicted mortality and heart failure-related events in an independent fashion in a general cardiovascular risk cohort.7 It is important to consider that, despite the standard use of preventive antidiabetic medication, DM is still associated with a greater coronary atherosclerotic burden, accelerated CAD progression, and CMP manifestation than in those individuals with cardiovascular risk but without a hyperglycaemic state.3,8 This emphasizes the necessity for additional diagnostic and medical therapeutic strategies aiming to prevent or inhibit the progression of diabetes-induced vasculopathy and/or CMP and, thereby, to improve cardiovascular outcome. Nowadays, CMR has evolved as a unique imaging tool to identify and characterize subclinical and clinically manifest alterations of the myocardial tissue. CMR in concert with intravenous use of gadolinium is commonly applied for determining myocardial perfusion with the first-pass technique as well … [1]: #fn-2

Improvement in coronary circulatory function in morbidly obese individuals after gastric bypass-induced weight loss: relation to alterations in endocannabinoids and adipocytokines

To investigate the effect of surgical gastric bypass-induced weight loss and related alterations in endocannabinoids (ECs) and adipocytokine plasma levels on coronary circulatory dysfunction in morbidly obese (MOB) individuals. Myocardial blood flow (MBF) responses to cold pressor test (CPT) from rest (ΔMBF) and during pharmacologically induced hyperaemia were measured with ¹³N-ammonia PET/CT in 18 MOB individuals with a body mass index (BMI) > 40 kg/m² at baseline and after a median follow-up period of 22 months. Gastric bypass intervention decreased BMI from a median of 44.8 (inter-quartile range: 43.3, 48.2) to 30.8 (27.3, 34.7) kg/m² (P < 0.0001). This decrease in BMI was accompanied by a marked improvement in endothelium-related ΔMBF to CPT and hyperaemic MBFs, respectively [0.34 (0.18, 0.41) from 0.03 (-0.08, 0.15) mL/g/min, P = 0.002; and 2.51 (2.17, 2.64) from 1.53 (1.39, 2.18) mL/g/min, P < 0.001]. There was an inverse correlation between decreases in plasma concentrations of the EC anandamide and improvement in ΔMBF to CPT (r = -0.59, P = 0.009), while increases in adiponectin plasma levels correlated positively with hyperaemic MBFs (r = 0.60, P = 0.050). Conversely, decreases in leptin plasma concentrations were not observed to correlate with the improvement in coronary circulatory function (r = 0.22, P = 0.400, and r = -0.31, P = 0.250). Gastric bypass-related reduction of BMI in MOB individuals beneficially affects coronary circulatory dysfunction. The dysbalance between ECs and adipocytokines appears to be an important determinant of coronary circulatory function in obesity.

Quantitative PET/CT Measures of Myocardial Flow Reserve and Atherosclerosis for Cardiac Risk Assessment and Predicting Adverse Patient Outcomes

Conventional scintigraphic myocardial perfusion imaging with SPECT/CT or with PET/CT has evolved as an important clinical tool for the diagnostic assessment of flow-limiting epicardial lesions and risk stratification of patients with suspected CAD. By determining the relative distribution of radiotracer-uptake in the left-ventricular (LV) myocardium during stress, the presence of flow-limiting CAD lesions can be identified. While this approach successfully identifies epicardial coronary artery lesions, the presence of subclinical and non-obstructive CAD may go undetected. In this direction, the concurrent ability of PET/CT to assess absolute myocardial blood flow (MBF) in ml/g/min, rather that relative regional distribution of radiotracer-uptake, and myocardial flow reserve (MFR), expands the scope of conventional myocardial perfusion imaging from the identification of more advanced and flow-limiting epicardial lesions to (1) subclinical CAD, (2) an improved characterization of the extent and severity of CAD burden, and (3) the discovery of "balanced" reduction in myocardial blood flow as a consequence of 3 vessel CAD. Concurrent to the PET data, the CT component of the hybrid PET/CT allows the assessment of coronary artery calcification as an indirect surrogate for CAD burden, without contrast, or with contrast angiography to directly denote coronary stenosis and/or plaque morphology with CT. Hybrid PET/CT system, therefore, has the potential to not only identify and characterize flow-limiting epicardial lesions but also subclinical stages of functional and/or structural stages of CAD. Whether the application of PET/CT for an optimal assessment of coronary pathology, its downstream effects on myocardial perfusion, and coronary circulatory function will in effect lead to changes in clinical decision-making process, investiture in preventive health care, and improved long-term outcome, awaits scientific verification.

Coronary Vasomotor Control in Obesity and Morbid Obesity: Contrasting Flow Responses With Endocannabinoids, Leptin, and Inflammation

This study sought to investigate abnormalities in coronary circulatory function in 2 different disease entities of obese (OB) and morbidly obese (MOB) individuals and to evaluate whether these would differ in severity with different profiles of endocannabinoids, leptin, and C-reactive protein (CRP) plasma levels. There is increasing evidence that altered plasma levels of endocannabinoids, leptin, and CRP may affect coronary circulatory function in OB and MOB. Myocardial blood flow (MBF) responses to cold pressor test from rest and during pharmacologically induced hyperemia were measured with N-13 ammonia positron emission tomography/computed tomography. Study participants (n = 111) were divided into 4 groups based on their body mass index (BMI) (kg/m(2)): 1) control group (BMI: 20 to 24.9, n = 30); 2) overweight group (BMI: 25 to 29.9, n = 31), 3) OB group (BMI: 30 to 39.9, n = 25); and 4) MOB group (BMI ≥40, n = 25). The cold pressor test-induced change in endothelium-related MBF response (ΔMBF) progressively declined in overweight and OB groups when compared with the control group [median: 0.19 (interquartile range [IQR] 0.08, 0.27) and 0.11 (0.03, 0.17) vs. 0.27 (0.23, 0.38) ml/g/min; p ≤ 0.01, respectively], whereas it did not differ significantly between OB and MOB groups [median: 0.11 (IQR: 0.03, 0.17) and 0.09 (-0.01, 0.19) ml/g/min; p = 0.93]. Compared with control subjects, hyperemic MBF subjects comparably declined in the overweight, OB, and MOB groups [median: 2.40 (IQR 1.92, 2.63) vs. 1.94 (1.65, 2.30), 2.05 (1.67, 2.38), and 2.14 (1.78, 2.76) ml/g/min; p ≤ 0.05, respectively]. In OB individuals, ΔMBF was inversely correlated with increase in endocannabinoid anandamide (r = -0.45, p = 0.044), but not with leptin (r = -0.02, p = 0.946) or with CRP (r = -0.33, p = 0.168). Conversely, there was a significant and positive correlation among ΔMBF and elevated leptin (r = 0.43, p = 0.031) and CRP (r = 0.55, p = 0.006), respectively, in MOB individuals that was not observed for endocannabinoid anandamide (r = 0.07, p = 0.740). Contrasting associations of altered coronary endothelial function with increases in endocannabinoid anandamide, leptin, and CRP plasma levels identify and characterize OB and MOB as different disease entities affecting coronary circulatory function.

Lysosome fusion to the cell membrane is mediated by the dysferlin C2A domain in coronary arterial endothelial cells

Dysferlin has recently been reported to participate in cell membrane repair in muscle and other cells through lysosome fusion. Given that lysosome fusion is a crucial mechanism that leads to membrane raft clustering, the present study attempted to determine whether dysferlin is involved in this process and its related signalling, and explores the mechanism underlying dysferlin-mediated lysosome fusion in bovine coronary arterial endothelial cells (CAECs). We found that dysferlin is clustered in membrane raft macrodomains after Fas Ligand (FasL) stimulation as detected by confocal microscopy and membrane fraction flotation. Small-interfering RNA targeted to dysferlin prevented membrane raft clustering. Furthermore, the translocation of acid sphingomyelinase (ASMase) to membrane raft clusters, whereby local ASMase activation and ceramide production--an important step that mediates membrane raft clustering--was attenuated. Functionally, silencing of the dysferlin gene reversed FasL-induced impairment of endothelium-dependent vasodilation in isolated small coronary arteries. By monitoring fluorescence quenching or dequenching, silencing of the dysferlin gene was found to almost completely block lysosome fusion to plasma membrane upon FasL stimulation. Further studies to block C2A binding and silencing of AHNAK (a dysferlin C2A domain binding partner), showed that the dysferlin C2A domain is required for FasL-induced lysosome fusion to the cell membrane, ASMase translocation and membrane raft clustering. We conclude that dysferlin determines lysosome fusion to the plasma membrane through its C2A domain and it is therefore implicated in membrane-raft-mediated signaling and regulation of endothelial function in coronary circulation.

Coronary Circulatory Function in Patients with the Metabolic Syndrome

The metabolic syndrome affects 25% of the U.S. population and greatly increases the risk of diabetes and coronary artery disease (CAD). We tested the hypothesis that the metabolic syndrome is associated with impaired coronary vasodilator function, a marker of atherosclerotic disease activity. Four hundred sixty-two patients at risk for CAD, as defined by a low-density lipoprotein cholesterol ≥ 160 mg/dL with fewer than 2 coronary risk factors, a low-density lipoprotein cholesterol ≥ 130 mg/dL with 2 or more coronary risk factors, or with documented CAD were included. A subset of 234 individuals underwent repeated PET at 1 y. Myocardial blood flow (MBF) and vasodilator reserve were assessed by PET. Modified criteria of the National Cholesterol Education Program, Adult Treatment Panel III were used to characterize the metabolic syndrome. Adenosine- and cold-stimulated MBF were similar in patients with and without metabolic syndrome, whereas baseline MBF showed a stepwise increase with increasing features of the syndrome. Consequently, patients with metabolic syndrome showed a lower coronary flow reserve (CFR) (2.5 ± 1.0) than those without metabolic syndrome (3.0 ± 0.9, P = 0.004). Differences in CFR were no longer present after correcting rest flows for the rate-pressure product. Change in MBF and CFR at 1 y were not different across groups of patients with increasing features of the metabolic syndrome. Patients with metabolic syndrome demonstrate impaired CFR, which is related to the augmentation in resting coronary blood flow caused by hypertension. In high-risk individuals, peak adenosine- and cold-stimulated blood flows are impaired even in the absence of the metabolic syndrome.

Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity

Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with (13)N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m(2)): control group 20 ≤ BMI <25 (n = 21); overweight group, 25 ≤ BMI <30 (n = 26); and obese group, BMI ≥ 30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806)]. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperaemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), respectively. Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.

Anatomy and physiology of coronary blood flow

Regional myocardial blood flow can now be measured noninvasively in units of milliliters blood per minute per gram myocardium. These noninvasive measurements are not confined to a specific imaging modality but are available with MRI, CT, and PET, although, thus far, most investigations of the coronary circulation in humans have employed PET flow measurements. Flow estimates with these different imaging modalities were found in animal experiments to correlate well with invasive flow estimates by the arterial blood sampling-microsphere technique widely considered as the “gold standard” of flow measurements.1-11 In these comparison studies, noninvasively-derived estimates corresponded linearly with invasively-measured myocardial blood flows over a wide flow range, i.e., from as low as 0.3 mL/minute/g to as high as 5-6 mL/minute/g. When tested in the human heart, noninvasive flow estimates correlated well with those obtained through invasively-obtained indices of flow and its changes by well-established alternate measurement approaches.12-16 Development and commercial availability of user-friendly software programs have facilitated the use of these new measurement capabilities so that they are now readily available in the clinical environment for the study of patients with cardiovascular disease. As several investigations have indicated, measurements of myocardial blood flow at rest contain only limited diagnostic information. For example, even in patients with advanced cardiovascular disease such as nonischemic dilated or ischemic cardiomyopathy, hypertrophic cardiomyopathy, or coronary artery disease, resting myocardial blood flows frequently are similar to those in normal individuals.17-19 It is the response of myocardial blood flow to specifically-targeted pharmacological or physiological interventions that can uncover the presence of functional or structural disease-related alterations of the coronary circulation. This then underscores the need for closely examining these targets and how they relate to anatomical and functional determinants of coronary blood flow and, by inference, to myocardial blood flow and their alterations in cardiovascular disease. Local and systemic mechanisms regulate the complex interactions between flow and anatomy in order to meet the heart’s energy needs. A comprehensive description of the coronary circulatory function and its control exceeds the scope of this review so that the interested reader is referred to detailed reviews on this topic.20,21 This review then seeks to describe in broad strokes the major functional and anatomical determinants of coronary blood flow as they pertain to noninvasive measured myocardial blood flows.

Structural alterations of the coronary arterial wall are associated with myocardial flow heterogeneity in type 2 diabetes mellitus

To determine the relationship between carotid intima-media thickness (IMT), coronary artery calcification (CAC), and myocardial blood flow (MBF) at rest and during vasomotor stress in type 2 diabetes mellitus (DM). In 68 individuals, carotid IMT was measured using high-resolution vascular ultrasound, while the presence of CAC was determined with electron beam tomography (EBT). Global and regional MBF was determined in milliliters per gram per minute with (13)N-ammonia and positron emission tomography (PET) at rest, during cold pressor testing (CPT), and during adenosine (ADO) stimulation. There was neither a relationship between carotid IMT and CAC (r = 0.10, p = 0.32) nor between carotid IMT and coronary circulatory function in response to CPT and during ADO (r = -0.18, p = 0.25 and r = 0.10, p = 0.54, respectively). In 33 individuals, EBT detected CAC with a mean Agatston-derived calcium score of 44 +/- 18. There was a significant difference in regional MBFs between territories with and without CAC at rest and during ADO-stimulated hyperemia (0.69 +/- 0.24 vs. 0.74 +/- 0.23 and 1.82 +/- 0.50 vs. 1.95 +/- 0.51 ml/g/min; p < or = 0.05, respectively) and also during CPT in DM but less pronounced (0.81 +/- 0.24 vs. 0.83 +/- 0.23 ml/g/min; p = ns). The increase in CAC was paralleled with a progressive regional decrease in resting as well as in CPT- and ADO-related MBFs (r = -0.36, p < or = 0.014; r = -0.46, p < or = 0.007; and r = -0.33, p < or = 0.041, respectively). The absence of any correlation between carotid IMT and coronary circulatory function in type 2 DM suggests different features and stages of early atherosclerosis in the peripheral and coronary circulation. PET-measured MBF heterogeneity at rest and during vasomotor stress may reflect downstream fluid dynamic effects of coronary artery disease (CAD)-related early structural alterations of the arterial wall.

Abstract 2085: Increased Regional Coronary Vascular Resistance During Hyperemia in Hypertrophic Cardiomyopathy Is Associated with Reduced Myocardial Blood Volume

Introduction: In patients with hypertrophic cardiomyopathy ( HCM ), myocardial blood flow ( MBF ) is decreased during hyperemia because of high coronary vascular resistance. Recently myocardial blood volume ( MBV ) can be estimated in vivo using myocardial contrast echocardiography ( MCE ) with the compensation for acoustic field inhomogeneity. The relationship between MBV and coronary resistance, however, has not been investigated. We thus assessed the hypothesis that increased regional coronary vascular resistance during hyperemia in HCM is associated with reduced MBV. Methods: In 13 patients with HCM ( H , 53±16 years) with asymmetric septal hypertrophy and 9 normal volunteers ( N , 54±11 years), MCE was performed under infusion of Levovist at rest and during hyperemia induced by ATP. Apical 4-chamber views of intermittent harmonic power Doppler imaging were acquired at end-diastole of every sixth beat. MBV was calculated as 10 X/10 ×100%, where X was myocardial contrast intensity minus contrast intensity of the adjacent intracavity blood pool in dB. 15 O-water PET was performed to measure regional MBF. These parameters were measured in the interventricular septum ( IVS ) and LV posterolateral ( PL ) wall. Regional coronary vascular resistance was calculated as (mean blood pressure)/MBF. Results: Wall thickness was significantly greater in H than in N (IVS: 19±4 vs 10±1 mm, p&lt;0.0001; PL: 10±1 vs 9±1 mm, p&lt;0.05). MBV of IVS was lower in H than in N (rest: 2.1±0.7 vs 3.5±1.1%, p&lt;0.01; hyperemia: 2.1±1.3 vs 4.3±1.7%, p&lt;0.01), whereas MBV of PL wall did not differ between groups. Coronary resistance at rest did not differ between groups, but the resistance during hyperemia was significantly greater in H than in N (IVS: 59±16 vs 31±14 mmHg·min·g·ml −1 , p&lt;0.001; PL: 40±10 vs 30±11 mmHg·min·g·ml −1 , p&lt;0.05). Coronary resistance at rest did not correlate with MBV, whereas that during hyperemia inversely correlated with MBV during hyperemia (r=−0.77, p&lt;0.0001) as well as MBV at rest (r=−0.65, p&lt;0.0001). Conclusions: Increased coronary vascular resistance during hyperemia in HCM was significantly associated with reduced MBV. MCE is useful for assessing the dynamic function of coronary circulation in the clinical setting.