Decrease In Coronary Flow Reserve Research Articles

The role of markers of endothelial dysfunction in the pathogenesis of coronary microvascular dysfunction in patients with non-obstructive coronary artery disease

Aim. To study the potential of non-invasive biomarkers in the diagnosis of coronary microvascular dysfunction (CMD) and prediction of the course of heart failure with preserved ejection fraction (HFpEF) in non-obstructive coronary artery disease.Materials and methods. The 12-month observational study included 118 consecutive patients (6 patients dropped out of the study due to contact loss) with non-obstructive coronary artery disease (CAD) and HFpEF (62 [59; 64]%). At the beginning of the study, serum levels of several biomarkers were assessed using the enzyme immunoassay: N-terminal pro-B-type natriuretic peptide (NT-proBNP), vascular endothelial growth factor (VEGF), and endothelin-1. Coronary flow reserve (CFR) was examined using dynamic single photon emission computed tomography. In the absence of obstructive CAD, CMD was defined as a global decrease in CFR ≤ 2. Echocardiography was used to determine parameters of hemodynamics, LV diastolic dysfunction, and myocardial stress. LV global longitudinal strain (GLS) was assessed using 2D speckle tracking.Results. The patients were divided into groups depending on the presence of CMD: group 1 included patients with CMD (n = 43), group 2 included those without it (n = 75). In patients in group 1, serum levels of endothelin-1 were 1.9 times higher (p = 0.012), levels of VEGF were 2.16 times higher (p = 0.008), and the concentration of NT-proBNP was 2.6 times higher (p = 0.004) than in patients in group 2. According to the ROC analysis, the concentrations of endothelin-1 ≥ 6.9 pg / ml (AUC = 0.711; p = 0.040) and VEGF ≥ 346.7 pg / ml (AUC = 0.756; p = 0.002) were considered as markers associated with the presence of CMD in patients with non-obstructive CAD. The multivariate regression analysis showed that only the presence of CMD (odds ratio (OR) 2.42; 95% confidence interval (95% CI) 1.26–5.85; p < 0.001) and an increase in NT-proBNP ≥ 760.5 pg / ml (OR 1.33; 95% CI 1.08–3.19; p = 0.023) were factors associated with adverse events, and their combination increased the risk of HFpEF progression by more than 3 times (OR 3.18; 95% CI 2.76–7.98; p < 0.001), whereas markers of endothelial dysfunction were not independent predictors. Conclusion. Endothelin-1 ≥ 6.9 pg / ml and VEGF ≥ 346.7 pg / ml can be used as non-invasive markers for the diagnosis of CMD. However, markers of endothelial dysfunction were not independent predictors of HFpEF progression in patients with non-obstructive CAD during 12-month follow-up.

Relationship between peri-coronary inflammation and coronary vascular function in patients with suspected coronary artery disease.

In this study, we aim to investigate the relationship between the attenuation of peri-coronary adipose tissue (PCAT) in patients with suspected coronary artery disease (CAD) and the assessment of coronary vascular functions using coronary flow reserve (CFR). We included 364 patients who underwent 13N-NH3 positron emission tomography/computed tomography and coronary computed tomography angiography (CCTA). We determined the relationship between fat attenuation index (FAI), PCAT volume, and other qualitative CT-derived anatomic parameters with CFR. We detected a decrease in CFR (<2.5) in 206 (57%) patients. At the patient level, those with reduced CFR showed a significantly higher prevalence of diffused atherosclerosis (41% vs. 23%; P < 0.001) and higher FAI (-75.5 HU vs. -77.1 HU; P = 0.014). In patients without obstructive CAD, FAI was significantly higher in those with reduced CFR (-75.5 HU vs. -77.7 HU, P = 0.026). On the vessel level, 1,092 vessels were analyzed, and 642 (59%) exhibited reduced CFR. The vessels with reduced CFR presented a significantly higher prevalence of obstructive CAD (37% vs. 26%; P < 0.001), diffused atherosclerosis (22% vs. 11%; P < 0.001), low-attenuation plaque (6% vs. 3%; P = 0.030), and positive remodeling (7% vs. 2%; P = 0.001). FAI was higher in vessels with reduced CFR (-80.8 HU vs. -81.8 HU; P = 0.045) than in normal CFR. In the patient-level analysis, obstructive CAD, diffused atherosclerosis, and FAI were independently linked with CFR. FAI was still associated with global CFR after adjusting for traditional risk factors (age, hypertension, diabetes, hyperlipidemia, and smoking). FAI remained independently associated with reduced CFR in patients without obstructive CAD. Coronary perivascular inflammation evaluated by CCTA was independently associated with coronary vascular function. In patients without obstructive CAD, FAI was higher in the presence of reduced CFR. Altogether, FAI can help reveal microcirculatory damage in patients who do not exhibit epicardial artery stenosis.

Functional Assessment of Long-Term Microvascular Cardiac Allograft Vasculopathy.

Cardiac allograft vasculopathy (CAV) is a leading cause of death and retransplantation following heart transplantation (HTX). Surveillance angiography performed yearly is indicated for the early detection of the disease, but it remains of limited sensitivity. We performed bolus thermodilution-based coronary flow reserve (CFR) and index of microcirculatory resistance (IMR) and fractional flow reserve (FFR) measurements in HTX patients undergoing yearly surveillance coronary angiography without overt CAV. In total, 27 HTX patients were included who had 52 CFR, IMR, and FFR measurements at a mean of 43 months after HTX. Only five measurements were performed in the first year. CFR decreased significantly by 0.13 every year (p = 0.04) and IMR tended to increase by 0.98 every year (p = 0.051), whereas FFR did not change (p = 0.161) and remained well above 0.80 over time. After one year, CFR decreased significantly (p = 0.022) and IMR increased significantly (p = 0.015), whereas FFR remained unchanged (p = 0.72). The functional status of the epicardial coronary arteries of transplanted hearts did not deteriorate over time. On the contrary, a significant decrease in CFR was noted. In view of the increasing IMR, this is caused by the deterioration of the function of microvasculature. CFR and IMR measurements may provide an early opportunity to diagnose CAV.

Malperfusion in dilated cardiomyopathy: One more link in the pathologic chain?

Dilated cardiomyopathy (DCM) is considered the primary non-ischemic heart disease, but there are controversial data regarding the microcirculatory disturbance in these patients. While the major epicardial vessels are always intact in these patients, the malperfusion of the myocardium of the left ventricle (LV) may be present, and the role of this malperfusion in the progression of the disease is not clear. The non-invasive echocardiographic assessment of the coronary blood flow reveals that it may be increased at rest and decreased during pharmacological stress, leading to a decreased coronary flow reserve.1 Beyond echocardiographic studies, microvascular dysfunction in DCM has been previously investigated with various imaging modalities. Bietenbeck M. et al. performed the quantitative myocardial first-pass perfusion cardiovascular magnetic resonance (CMR) imaging and coronary sinus flow measurements at rest and during maximal vasodilatation which is a well-validated approach for the quantification of global myocardial blood flow in CMR. The blood flow parameters were reduced at rest and during stress in both groups of patients with DCM and hypertrophic cardiomyopathy.2 Interestingly, in another study, it was shown that myocardial blood flow assessed by the CMR in DCM could be elevated at rest with a substantial decrease during the stress-test with adenosine. This corresponds well with the previous echocardiographic findings and also can reflect the possible stress-induced stunning instead of chronic hypoperfusion in DCM.3 Another promising in microcirculation evaluation, though not a fully available modality, is PET. In a study by Yamaguchi et al., the authors observed the regional 18-fluorodesoxiglucose uptake in all patients with ischemic cardiomyopathy in the fasting state, while patients with DCM showed variable patterns of uptake. Nevertheless, when going to glucose loading state, the DCM patients demonstrated mostly non-reversing patterns of uptake, which allows PET to distinguish DCM from ischemic cardiomyopathy.4 (99 m)Tc-methoxy-isobutyl-isonitrile and (123)I-15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid dual single photon emission computed tomography also provides valuable data on perfusion-metabolism mismatches, which carry the prognostic role in DCM.5 Myocardial contrast echocardiography (MCE) being a more simple, bedside method has been previously found to be helpful in differentiating the DCM and ischemic heart disease in patients with acute onset of heart failure.6 However, another group of authors has the confronting results: the contrast replenishment rate was similar in patients with coronary artery disease and without it.7 In this issue of the Journal of Clinical Ultrasound Sha Tang et al, for the first time the MCE was combined with speckle tracking strain analysis in a layer-specific manner in patients with DCM and compared with the same parameters in healthy volunteers.8 While the poor global and regional LV systolic function assessed by speckle tracking strain in DCM patients in comparison to healthy subjects is awaited, the authors performed the comprehensive analysis of the interaction between segmental parameters by dividing the myocardium into standard segments plus three layers in each segment. Therefore, the data on gradients in strain and perfusion parameters becomes the mainstay of this study. The idea of layer-specific strain analysis is not new, but still can be regarded as a pure experimental method with no clinical implication. For example, in the work by Nagata Y et al. the authors offer Endo/Epi strain ratio for gradient assessment.9 Therefore, the authors demonstrated an interesting correlation between MCE perfusion and longitudinal function at rest in DCM patients with the diffuse pattern of impairment in all segments and layers. Considering the aforementioned CMR-based and PET-based studies, which showed a substantial decrease in coronary flow reserve between rest and stress, the MCE with pharmacological stress could be the rational development of basic ideas, presented in this study. Moreover, the dynamic nature of MCE can give the opportunity for dynamic malperfusion assessment in patients with DCM during stress. In addition, new insights into the pathophysiology of DCM may provide the basis for new clinical trials of various agents, intended to restore the damaged microcirculatory link in the chain of global LV deterioration. The authors have nothing to disclosure. Open Access funding enabled and organized by Projekt DEAL. Not applicable.

Endothelial dysfunction due to decreased nitric oxide bioavailability in dysglycaemic subjects and first-degree relatives of type 2 diabetic patients

Abstract Background/Introduction Oxidative stress plays an important role in the pathogenesis of type 2 diabetes mellitus. Purpose We aimed to investigate oxidative stress and nitrites/nitrates concentrations at baseline and during postprandial hyperglycaemia in 40 first-degree relatives (FDR) of type 2 diabetic patients with normal oral glucose test (OGTT), 40 subjects with abnormal OGTT (dysglycaemic) and 20 subjects with normal OGTT without parental history of diabetes (normoglycaemic). Methods Perfused boundary region (PBR) of the sublingual microvessels with a diameter 5–25μm (Microscan, Glycocheck), a marker of endothelial glycocalyx integrity, coronary flow reserve (CFR) in the distal left anterior descending coronary artery, left ventricular global longitudinal strain (GLS), malondialdehyde (MDA), protein carbonyls (PC) and nitrites/nitrates plasma levels were assessed at 0 and 120 min of a 2-hour OGTT. Insulin sensitivity was evaluated using Matsuda and insulin sensitivity index (ISI). Results In all subjects, there were no significant changes in MDA and PC at 120 min after OGTT (p&amp;gt;0.05). Compared with normoglycaemic subjects, in FDR and dysglycaemic subjects, nitrites/nitrates levels were significantly decreased at 120 min (−24% versus −30% versus −3%, respectively) with a parallel increase in PBR (+7% versus +10% versus −3%) and a reduction in CFR (−11% versus −14% versus −6%) and GLS (−4% versus −4% versus +0.1%) (p&amp;lt;0.05 for all comparisons). The percent reduction of nitrites/nitrates levels was associated with abnormal values of Matsuda and ISI, reversely related with the percent increase of PBR (r=−0.60, p=0.001) and positively related with the percent decrease of CFR (r=0.39, p=0.038) and GLS (r=0.48, p=0.008). Conclusion Insulin resistance determines acute endothelial responses during OGTT leading to reduced nitric oxide production with resultant coronary and myocardial dysfunction in FDR and dysglycaemic subjects. Funding Acknowledgement Type of funding sources: None.

Endothelial Dysfunction Is Associated with Decreased Nitric Oxide Bioavailability in Dysglycaemic Subjects and First-Degree Relatives of Type 2 Diabetic Patients.

Oxidative stress plays an important role in the pathogenesis of diabetes. We investigated oxidative stress and nitrite/nitrate concentrations at baseline and during postprandial hyperglycaemia in 40 first-degree relatives (FDRs) of diabetic patients with normal oral glucose tolerance test (OGTT) results, 40 subjects with abnormal OGTT results (dysglycaemic) and 20 subjects with normal OGTT results (normoglycaemic). Malondialdehyde (MDA), protein carbonyls (PCs), nitrite/nitrate plasma levels, the perfused boundary region (PBR—Glycocheck) of the sublingual microvessels, a marker of glycocalyx integrity, coronary flow reserve (CFR) and left ventricular global longitudinal strain (GLS) were assessed at 0 and 120 min of the OGTT. Insulin sensitivity was evaluated using Matsuda and the insulin sensitivity index (ISI). In all subjects, there were no significant changes in MDA or PC after the OGTT (p > 0.05). Compared with normoglycaemic subjects, FDRs and dysglycaemic subjects had significantly decreased nitrite/nitrate levels (−3% vs. −24% vs. −30%, respectively), an increased PBR and reduced CFR and GLS at 120 min (p < 0.05). The percent reduction in nitrite/nitrate was associated with abnormal Matsuda and ISI results, reversely related with the percent increase in PBR (r = −0.60) and positively related with the percent decrease in CFR (r = 0.39) and GLS (r = 0.48) (p < 0.05). Insulin resistance is associated with reduced nitric oxide bioavailability and coronary and myocardial dysfunction in FDRs and dysglycaemic subjects.

Examining the role of Drp1 in age‐related microvascular dysfunction

IntroductionAdvanced age is a well‐documented risk factor for coronary microvascular dysfunction. Recent evidence has underscored that advanced age is associated with a shift toward greater mitochondrial fission rather than mitochondrial fusion. Therefore, understanding key regulators of the balance of mitochondrial fission/fusion may help to identify the contribution of mitochondrial dynamics on microvascular endothelial function. DRP1 is a pro‐fission factor that has been linked to several disease manifestations including advanced age and cardiovascular disease (CVD).MethodsCoronary arteries were obtained from young control rats (YC, 15‐20 weeks) and old control rats (OC, 95‐100 weeks) and expression of DRP1 was assessed by immunofluorescence (IF). A novel rat model crossing flox‐stop DRP1‐GFP rats and VECAD‐Cre expressing rats was generated to assess the vascular and cardiac effects of endothelial‐specific DRP1 overexpression. Endothelial vascular function was determined by endothelial‐dependent flow‐mediated dilation while cardiac function was determined by echocardiography at 20 weeks old and compared to wildtype control group.ResultsData from IF comparing coronary arteries from YC and OC show that OC had higher DRP1 expression compared to YC (1.42 to 1.00, p=0.01). Max dilation measurements, taken at 20‐weeks of age, showed that DRP1‐overexpressing rats was decreased when compared to wildtype (WT) control rats (31.4 to 60.1, p=0.009). Echocardiography revealed that DRP1‐overexpressing rats showed a trend towards a decrease in coronary flow reserve and increased HR in response to a dobutamine stressor when compared to WT. Ejection fraction between the two groups remained largely preserved.ConclusionOur data demonstrate that there may be a critical role for DRP1 within in vitro vasodilation that mimics a CVD pro‐fission phenotype. Future studies will be performed to further evaluate the role of DRP1 in response to other stressors well‐established in age‐dependent CVD such as hypertension.

Coronary flow reserve in patients with heart failure with preserved ejection fraction

Aim. To study the parameters of myocardial blood flow (MBF) and coronary flow reserve (CFR) in patients with heart failure (HF) with preserved ejection fraction and evaluate their relationship with the severity of HF.Material and methods. The study included 47 patients (men, 68,7%) aged 65,0 (58,0; 72,0) years with left ventricular ejection fraction of 62 (56; 67)% and coronary artery stenosis &lt;50%. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) were assessed by enzyme immunoassay. MBF and CFR values were assessed using cardiac single photon emission computed tomography.Results. Depending on NT-proBNP levels, the patients were divided into 2 groups (p&lt;0,001): the 1st group included (n=15) patients with NT-proBNP &lt;125 pg/ml (58,2 [41,6; 70,7] pg/ml), while in the 2nd group (n=32) — with NT-proBNP ≥125 pg/ml (511,4 [249,8; 1578,1] pg/ml). The group of patients with high NTproBNP levels was characterized by higher values (by 33,8%, p=0,0001) of resting MBF and reduced CFR (by 14,7%, p=0,001) compared with patients with normal NT-proBNP level: resting MBF — 0,65 (0,44; 0,79) vs 0,43 (0,30; 0,58) ml/min/g; CFR — 2,21 (1,52; 2,83) vs 2,59 (2,47; 3,05), respectively. At the same time, MBF at stress did not differ between the groups. The relationship of NTproBNP levels with global CFR (p=0,012; r=-0,339) and MBF at rest (p=0,012; r=0,322) was established. A stepwise decrease in global CFR was revealed depending on the NYHA class as follows (p&lt;0,001): 2,79 (2,52; 2,93); 1,8 (1,55; 2,08); 1,31 (1,23; 1,49) — for class I, II, and III, respectively.Conclusion. A decrease in CFR in patients with HF with preserved ejection fraction indicates impaired myocardial blood supply, which, in this group of patients, is associated with microcirculatory changes. At the same time, the severity of MBF alterations is closely related to HF severity.

Cardiac microcirculation assessment of diabetic patients according to the presence of peripheral microangiopathy, by MRI myocardial perfusion

Coronary flow reserve (CFR), ratio of maximal myocardial blood flow (MBF) during pharmacologically induced coronary vasodilation to resting MBF, is an integrated measure of flow through both the large epicardial coronary arteries and the microcirculation. CFR has been proposed as an indirect parameter to evaluate the function of the coronary microcirculation, and its impairment is a strong predictor of cardiovascular mortality. Rubidium PET-computed tomography scanner, the gold standard method to evaluate CFR is not available in France. We aimed to assess cardiac microcirculation using MRI myocardial perfusion in diabetic patients. Using semi-quantitative analysis by MRI, we estimated CFR by the Myocardial Perfusion Reserve Index (MPRI), ratio between perfusion signal (maximal upslope) with adenosine stress and rest of myocardial segments in 27 diabetic patients without coronary artery disease perfectly phenotype for microangiopathy (eye, kidney, nerve). MPRI was analyzed according to the presence of extra cardiac microangiopathy. This technique is feasible with routine MRI protocols. Reproducibility was very good: 99 myocardial segments analyzed by 2 independent observers: MPRI 2.2 ± 0.76 vs. 2.24 ± 0.8; mean of differences: − 0.033 IC95% [−0.13; 0.07]. MPRI was lower in the group of diabetic patients with extra-cardiac microangiopathy ( n = 11) as compared to the group without ( n = 16): 2.01 ± 0.78 vs. 2.31 ± 0.7, P = 0.51, not statistically significant because of the modest number of patients. CFR was significantly altered in myocardial segments analyzed in diabetics with microangiopathy ( n = 150) as compared to myocardial segments from diabetics without microangiopathy ( n = 192): 1,99 ± 0.83 vs. 2.35 ± 0.98 P < 0.002. Semi quantitative analysis of CFR is feasible in a daily routine after stress MRI. Preliminary result in diabetic patients suggests a strong link between microangiopathy and a decrease in CFR.

Model-based analysis of the sensitivities and diagnostic implications of FFR and CFR under various pathological conditions.

Although fractional flow reserve (FFR) and coronary flow reserve (CFR) are both frequently used to assess the functional severity of coronary artery stenosis, discordant results of diagnosis between FFR and CFR in some patient cohorts have been reported. In the present study, a computational model was employed to quantify the impacts of various pathophysiological factors on FFR and CFR. In addition, a hyperemic myocardial ischemic index (HMIx) was proposed as a reference for comparing the diagnostic performances of FFR and CFR. Obtained results showed that CFR was more susceptible than FFR to the influence of many pathophysiological factors unrelated to coronary artery stenosis. In particular, the numerical study proved that increasing hyperemic coronary microvascular resistance significantly elevated FFR while reducing CFR despite fixed severity of coronary artery stenosis, whereas introducing aortic valve disease only caused a significant decrease in CFR with little influence on FFR. These results provided theoretical evidence for explaining some clinical observations, such as the increased risk of discordant diagnostic results between FFR and CFR in patients with increased hyperemic microvascular resistance, and significant increase in CFR after surgical relief of severe aortic valve disease. When evaluated with respect to the predictive value for hyperemic myocardial ischemia, the performance of FFR was found to be considerably compromised in the presence of severe coronary vasodilation dysfunction or aortic valve disease, whereas the relationship between CFR and HMIx remained relatively stable, suggesting that CFR may be a more reliable indicator of myocardial ischemia under complex pathophysiological conditions.

Coronary Microvascular Dysfunction and Cardiovascular Risk in Obese Patients

BackgroundBesides body mass index (BMI), other discriminators of cardiovascular risk are needed in obese patients, who may or may not undergo consideration for bariatric surgery. Coronary microvascular dysfunction (CMD), defined as impaired coronary flow reserve (CFR) in the absence of flow-limiting coronary artery disease, identifies patients at risk for adverse events independently of traditional risk factors. ObjectivesThe study sought to investigate the relationship among obesity, CMD, and adverse outcomes. MethodsConsecutive patients undergoing evaluation for coronary artery disease with cardiac stress positron emission tomography demonstrating normal perfusion (N = 827) were followed for median 5.6 years for events, including death and hospitalization for myocardial infarction or heart failure. ResultsAn inverted independent J-shaped relationship was observed between BMI and CFR, such that in obese patients CFR decreased linearly with increasing BMI (adjusted p < 0.0001). In adjusted analyses, CFR but not BMI remained independently associated with events (for a 1-U decrease in CFR, adjusted hazard ratio: 1.95; 95% confidence interval: 1.41 to 2.69; p < 0.001; for a 10-U increase in BMI, adjusted hazard ratio: 1.20; 95% confidence interval: 0.95 to 1.50; p = 0.125) and improved model discrimination (C-index 0.71 to 0.74). In obese patients, individuals with impaired CFR demonstrated a higher adjusted rate of events (5.7% vs. 2.6%; p = 0.002), even in those not currently meeting indications for bariatric surgery (6.4% vs. 2.6%; p = 0.04). ConclusionsIn patients referred for testing, CMD was independently associated with elevated BMI and adverse outcomes, and was a better discriminator of risk than BMI and traditional risk factors. CFR may facilitate management of obese patients beyond currently used markers of risk.

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.

Abstract 13679: Excess Cardiovascular Risk in Women Relative to Men Referred for Coronary Angiography is Associated With Impaired Coronary Flow Reserve From Diffuse versus Obstructive Coronary Artery Disease

Introduction: Case fatality rates for cardiovascular disease (CVD) are higher for women of all ages as compared with men, yet obstructive coronary artery disease (CAD) is less prevalent in women. Coronary flow reserve (CFR) is an integrated measure of large and small vessel CAD and myocardial ischemia, and identifies patients at risk for CVD death, independently of angiographic disease severity. Methods: Consecutive patients (N=329, 43% women) referred for invasive coronary angiography after stress testing with myocardial perfusion PET and with LV ejection fraction &gt;40% were followed (median 3.0 years) for CVD death, nonfatal MI, or heart failure admission. The extent/severity of angiographic CAD was estimated using the CAD prognostic index (CADPI), and CFR quantified using PET. Results: Although women relative to men had lower pretest clinical scores, rates of prior MI, and burden of angiographic CAD (p&lt;0.001), they demonstrated greater risk of CVD events (adjusted HR 2.05, 95%CI 1.05-4.02, p=0.03), even after adjustment for clinical risk factors, LV ejection fraction and ischemia, angiographic disease and time-dependent early revascularization. Impaired CFR was similarly present among women and men, but in patients with low CFR (&lt;1.6, n=163), women showed higher frequency of nonobstructive CAD, while men showed higher frequency of severely obstructive CAD (p=0.002). After also adjusting for CFR (adjusted HR for unit decrease in CFR, 1.69; 95%CI 1.04-2.76, p=0.03), the effect of sex on outcomes was no longer significant (p=0.10). When stratified by sex and CFR (Figure), only women with impaired CFR demonstrated significantly increased adjusted risk of CVD events (p&lt;0.0001, model p for interaction=0.04). Conclusions: Although women referred for coronary angiography had significantly lower burden of obstructive epicardial CAD relative to men, they were not protected from CVD events. Impaired CFR from diffuse CAD may represent a target for CVD risk reduction.

Bone Marrow-Derived Mesenchymal Stem Cells Have Innate Procoagulant Activity and Cause Microvascular Obstruction Following Intracoronary Delivery: Amelioration by Antithrombin Therapy.

Mesenchymal stem cells (MSCs) are currently under investigation as tools to preserve cardiac structure and function following acute myocardial infarction (AMI). However, concerns have emerged regarding safety of acute intracoronary (IC) MSC delivery. This study aimed to characterize innate prothrombotic activity of MSC and identify means of its mitigation toward safe and efficacious therapeutic IC MSC delivery post-AMI. Expression of the initiator of the coagulation cascade tissue factor (TF) on MSC was detected and quantified by immunofluorescence, FACS, and immunoblotting. MSC-derived TF antigen was catalytically active and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet thrombus deposition on collagen at arterial shear, an effect abolished by heparin coadministration. In a porcine AMI model, IC infusion of 25 × 10(6) MSC during reperfusion was associated with a decrease in coronary flow reserve but not when coadministered with an antithrombin agent (heparin). Heparin reduced MSC-associated thrombosis incorporating platelets and VWF within the microvasculature. Heparin-assisted therapeutic MSC delivery also reduced apoptosis in the infarct border zone at 24 hours, significantly improved infarct size, left ventricular (LV) ejection fraction, LV volumes, wall motion, and attenuated histologic evidence of scar formation at 6 weeks post-AMI. Heparin alone or heparin-assisted fibroblast control cell delivery had no such effect. Procoagulant TF activity of therapeutic MSCs is associated with reductions in myocardial perfusion when delivered IC may be successfully managed by heparin coadministration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic IC MSC delivery for AMI.

Assessment of Coronary Flow Reserve by Adenosine Stress Myocardial Perfusion Imaging in Patients with Hypertension.

In this study, our aim was to assess the coronary flow reserve (CFR) by performing the adenosine stress (99m)Tc-MIBI single-photon computed tomographic (SPECT) myocardial perfusion imaging in patients with hypertension. 47 hypertensive patients with normal coronary angiography were divided into 2 groups, defined by the presence (LVH, n=22) and absence (non-LVH, n=25) of left ventricular hypertrophy with 17 normal cases as controls. All patients were administered the adenosine stress-rest (99m)Tc-MIBI scintigraphy. 0.14mg/kg/min adenosine was administered by continuous infusion for 6min. We found that adenosine-induced myocardial ischemia was present in 26 cases (55.3%) with 87 segments (20.6%) showing abnormal distribution in the hypertensive group versus a single case (5.9%) (χ (2)=31.12, P<0.001) and segment (0.7%) (χ (2)=32.90, P<0.001) in the control group by SPECT perfusion. In the LVH group, 17 cases (77.3%) and 67 segments (33.8%) of myocardial ischemia were present. In the non-LVH group, there were 9 cases (36.0%) (χ (2)=8.06, P<0.001), 20 segments (8.9%) (χ (2)=40.13, P<0.001). There was a significant decrease in coronary reserve in the hypertensive groups following adenosine infusion with a fourfold decrease in cases and a sixfold decrease in segments (P<0.001). Our study suggests that assessing CFR by the (99m)Tc-MIBI adenosine stress by SPECT imaging is a relatively easy, safe, and non-invasive test in patients with hypertension. We noted a decrease in CFR in patients with hypertension. This decrease was especially remarkable for hypertensive patients with LVH. This study shows that administering the (99m)Tc-MIBI adenosine stress by SPECT imaging is a safe, simple, and non-invasive test for detecting CFR in patients with hypertension.

Renal function and coronary microvascular dysfunction in women with symptoms/signs of ischemia.

ObjectivesChronic kidney disease (CKD) is more prevalent among women and is associated with adverse cardiovascular events. Among women with symptoms and signs of ischemia enrolled in the Women’s Ischemia Syndrome Evaluation (WISE), a relatively high mortality rate was observed in those with no obstructive coronary artery disease. Coronary microvascular dysfunction or reduced coronary flow reserve (CFR) was a strong and independent predictor of adverse outcomes. The objective of this analysis was to determine if renal function was associated with coronary microvascular dysfunction in women with signs and symptoms of ischemia.MethodsThe WISE was a multicenter, prospective, cohort study of women undergoing coronary angiography for suspected ischemia. Among 198 women with additional measurements of CFR, we determined the estimated glomerular filtration rate (eGFR) with the CKD-EPI equation. We tested the association between eGFR and CFR with regression analysis.ResultsThe median eGFR was 89 ml/min. The eGFR correlated with CFR (r = 0.22; P = 0.002). This association persisted even after covariate adjustment. Each 10-unit decrease in eGFR was associated with a 0.04-unit decrease in CFR (P = 0.04).There was a strong interaction between eGFR and age (P = 0.006): in those ≥60 years old, GFR was strongly correlated with CFR (r = 0.55; P<0.0001). No significant correlation was noted in those <60 years old.ConclusionsReduced renal function was significantly associated with lower CFR in women with symptoms and signs of ischemia. Coronary microvascular dysfunction warrants additional study as a mechanism contributing to increased risk of cardiovascular events in CKD.

Global coronary flow reserve is associated with adverse cardiovascular events independently of luminal angiographic severity and modifies the effect of early revascularization.

Coronary flow reserve (CFR), an integrated measure of focal, diffuse, and small-vessel coronary artery disease (CAD), identifies patients at risk for cardiac death. We sought to determine the association between CFR, angiographic CAD, and cardiovascular outcomes. Consecutive patients (n=329) referred for invasive coronary angiography after stress testing with myocardial perfusion positron emission tomography were followed (median 3.1 years) for cardiovascular death and heart failure admission. The extent and severity of angiographic disease were estimated with the use of the CAD prognostic index, and CFR was measured noninvasively by positron emission tomography. A modest inverse correlation was seen between CFR and CAD prognostic index (r=-0.26; P<0.0001). After adjustment for clinical risk score, ejection fraction, global ischemia, and early revascularization, CFR and CAD prognostic index were independently associated with events (hazard ratio for unit decrease in CFR, 2.02; 95% confidence interval, 1.20-3.40; P=0.008; hazard ratio for 10-U increase in CAD prognostic index, 1.17; 95% confidence interval, 1.01-1.34; P=0.032). Subjects with low CFR experienced rates of events similar to those of subjects with high angiographic scores, and those with low CFR or high CAD prognostic index showed the highest risk of events (P=0.001). There was a significant interaction (P=0.039) between CFR and early revascularization by coronary artery bypass grafting, such that patients with low CFR who underwent coronary artery bypass grafting, but not percutaneous coronary intervention, experienced event rates comparable to those with preserved CFR, independently of revascularization. CFR was associated with outcomes independently of angiographic CAD and modified the effect of early revascularization. Diffuse atherosclerosis and associated microvascular dysfunction may contribute to the pathophysiology of cardiovascular death and heart failure, and impact the outcomes of revascularization.

Does Mild Renal Failure Affect Coronary Flow Reserve after Coronary Artery Bypass Graft Surgery?

There are only a limited number of studies on the link between mild renal failure and coronary artery disease. The purpose of this study is to investigate the effects of mild renal failure on the distal vascular bed by measuring the coronary flow reserve (CFR) in transthoracic echocardiography after coronary artery bypass grafting (CABG). The study included 52 consecutive patients (12 women and 40 men) who had undergone uncomplicated CABG. The patients were divided into 2 groups. Group 1 included patients with a preoperative glomerular filtration rate (GFR) of 60-90 (mild renal failure), and group 2 included those with a GFR >90. The CFR measurements were carried out through a second harmonic transthoracic Doppler echocardiography. The mean age was 60.08 ± 1.56 years in group 1 and 60.33 ± 1.19 in group 2. The mean preoperative CFR was 1.79 ± 0.06 in group 1 and 2.05 ± 0.09 in group 2. The mean postoperative CFR was 2.09 ± 0.08 in group 1 and 2.37 ± 0.06 in group 2. There was a statistically significant difference between the 2 groups as to preoperative creatinine clearance, preoperative estimated GFR, postoperative day 7 creatinine clearance, postoperative month 6 creatinine clearance, postoperative day 7 estimated GFR, postoperative month 6 estimated GFR, preoperative CFR, and postoperative CFR (P < .05). CFR was found to be unaffected by the choice of on-pump or off-pump technique (P = .907). After bypass surgery, there was a significant increase in the mean postoperative CFR, when compared with the mean preoperative CFR (P = .001). In our study, we detected a decrease in CFR in patients with mild renal failure. We believe that in patients undergoing CABG for coronary artery disease, mild renal failure can produce adverse effects due to deterioration of the microvascular bed.

Abstract 19260: Prothrombotic Activity and Reduction in Coronary Flow Reserve Associated With Therapeutic Intracoronary Delivery of Bone Marrow-Derived Mesenchymal Stem Cells is Ameliorated by Heparin Co-Administration in a Porcine Myocardial Infarction Model

Cell therapy remains an evolving therapeutic option for cardiac repair in the case of acute myocardial infarction (AMI) associated with significant cardiomyocyte death. Mesenchymal stem cells (MSCs) are promising candidates for promoting myocardial salvage post AMI, but concerns regarding the safety of intracoronary MSC delivery remain. Surface expression of tissue factor (TF), a key initiator of the soluble coagulation cascade, has recently been implicated as a possible cause of MSC procoagulant activity. This study aimed to characterize the prothrombotic activity of MSC and identify means of managing any thrombotic side effects during therapeutic intracoronary delivery post AMI. Expression of TF on MSC was detected by immunoflourescence, flow cytometry and immunoblotting. TF antigen was catalytically active (252.4 ± 8.3 pM/2 x 105 MSC) and capable of supporting thrombin generation in vitro. Addition of MSCs to whole citrated blood enhanced platelet-driven thrombus deposition on collagen at arterial shear flow (12.67 ± 1.0% untreated vs 18.9 ± 0.9% surface coverage with MSC, p&gt;0.001), an effect abolished by heparin co-administration (p&lt;0.01 vs MSC alone). Infusion of 25 x 106 MSC via an intracoronary route in a porcine AMI model was associated with a decrease in coronary flow reserve when delivered during reperfusion (-0.7 ± 0.05) but not when coadministered with heparin (0.1 ± 0.02, p&lt;0.01). Heparin also reduced MSC-associated thrombosis incorporating platelets and vWF in the microvasculature (p&lt;0.05). Therapeutic MSC delivery was able to reduce apoptosis in the infarct border zone 24 post AMI (p&lt;0.01). Procoagulant activity associated with therapeutic MSCs is independently associated with reduction in myocardial perfusion when delivered I.C. which may be successfully managed with heparin co-administration. This study highlights an important mechanistic insight into safety concerns associated with therapeutic intracoronary MSC delivery for AMI.

Coronary Flow Reserve and Myocardial Performance Index in Newly Diagnosed Diabetic Patients

Patients with diabetes mellitus (DM) are at high risk of left ventricular (LV) dysfunction. A reduction of coronary flow reserve (CFR) has been demonstrated in diabetic patients without coronary artery stenosis. In this study, we investigated the association between LV myocardial diastolic and systolic functions and the CFR in newly diagnosed diabetic patients in the absence of coronary artery disease. We studied 88 patients (mean age 49±10years) with newly diagnosed DM and 40 healthy control subjects (mean age 50±9years). All subjects underwent transthoracic echocardiography. The myocardial performance index (MPI) was determined by using pulsed-wave Doppler. The CFR was calculated as the hyperemic to resting coronary diastolic peak velocities ratio. Patients with diabetes had significantly longer mitral E-wave deceleration time and higher MPI value than control group (P=0.023 and P<0.001, respectively). The mean CFR was lower in diabetic patients compared with controls (P=0.001). The MPI was significantly correlated with CFR (r=-0.371, P<0.001), LV ejection fraction (r=-0.274, P=0.018) E/A ratio (r=-0.244, P=0.024), and glycosylated hemoglobin (HbA1c) (r=0.476, P<0.001). Multivariate regression analysis showed that MPI was independently associated with CFR (β=-0.292, P<0.0001) and HbA1c level (β=0.372, P<0.0001). The MPI was independently associated with CFR in newly diagnosed diabetic patients. The decrease in CFR may cause LV systolic and diastolic dysfunction in asymptomatic diabetic patients.