Intracoronary Infusion Of Adenosine Research Articles

Coronary microvascular dysfunction in postmenopausal minipigs with multiple risk factors

Abstract Background Coronary microvascular angina occurs in both men and women, however, the majority of patients are postmenopausal women with multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia. No treatment is available for coronary microvascular dysfunction, requiring more in depth knowledge on the mechanisms underlying this syndrome in this expanding group of patients. Purpose Here we studied microvascular function in vivo and and in vitro in isolated small coronary arteries, in post-menopausal miniswine with multiple cardiovascular risk factors. Methods DM (streptozotocin), hypercholesterolemia (HC, high fat, high sugar diet), CKD (renal artery embolization) and menopause (ovariectomy, OVX) were induced in 5 adult female minipigs (1.5-2 years old, ~40kg, DM+HC+CKD+OVX) for 6 months, while 11 healthy age- and weight-matched female minipigs on normal pig chow served as controls (Normal). At sacrifice, coronary flow reserve (CFR) in response to intracoronary infusion of adenosine was measured under anesthesia. Isolated small coronary arteries were used to study the endothelium-dependent response to bradykinin in the presence and absence of eNOS blockade with LNAME, and cyclooxygenase inhibition by indomethacin, and endothelium-independent response to the nitric oxide (NO) donor, SNAP. Results 6 months of sustained hyperglycemia (17.5±1.0 in DM+HC+CKD+OVX vs 8.2±0.9 mmol/l in Normal, P<0.05 by t-test), hypercholesterolemia (15.4±2.0 vs 1.7±0.1 mmol/l, P<0.05), renal dysfunction (NGAL: 205±72 vs 67±5 ng/ml, P<0.05) and low progesterone levels (13.1±5.7 in DM+HC+CKD+OVX vs 92.0±30.0 nmol/l in Normal, P=0.1) were accompanied by systemic inflammation (TNFα: 62±7 vs 47±1 pg/ml, P<0.05). CFR was significantly reduced in DM+HC+CKD+OVX as compared to the healthy animals (panel A). Coronary small arteries from DM+HC+CKD+OVX animals showed impaired endothelium-dependent vasodilation to bradykinin (panel B), which was mediated by a loss of NO (panels C & D). The loss of NO was partly compensated for by activation of the cyclooxygenase pathway, as indomethacin blunted the dilation to bradykinin in the DM+HC+CKD+OVX animals, but had no effect on the dilation to bradykinin in Normals (panels C & D). Endothelium-independent dilation to SNAP was also impaired in DM+HC+CKD+OVX animals, indicating blunted vascular smooth muscle responsiveness to nitric oxide (panel E). Conclusion Postmenopausal minipigs with multiple risk factors, displayed severe coronary microvascular dysfunction as evidenced by a significantly reduced coronary flow reserve and both reduced NO sensitivity/ production, indicating endothelial and smooth muscle cell dysfunction. Loss of NO-mediated vasodilation was partially compensated by activation of cyclooxygenase pathway. Such perturbations may contribute to reduced myocardial perfusion that is often observed in post-menopausal women with multiple cardiovascular risk factors.

Oxidative stress: A driving force in CKD induced heart failure

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Coronary microvascular dysfunction in postmenopausal minipigs with multiple risk factors

Coronary microvascular angina occurs in both men and women, however, the majority of patients are postmenopausal women with multiple cardiovascular risk factors, such as diabetes mellitus (DM), chronic kidney disease (CKD) and dyslipidemia. No treatment is available for coronary microvascular dysfunction, requiring more in depth knowledge on the mechanisms underlying this syndrome in this expanding group of patients. Here we studied microvascular function in vivo and and in vitro in isolated small coronary arteries, in postmenopausal miniswine with multiple cardiovascular risk factors. DM (streptozotocin), hypercholesterolemia (HC, high fat, high sugar diet), CKD (renal artery embolization) and menopause (OVX) were induced in 5 adult female minipigs (1.5-2 years old, ±40kg, DM+HC+CKD+OVX) for 6 months, while 11 healthy female minipigs matched for age and weight, on normal pig chow served as controls (Control). At sacrifice, coronary flow reserve (CFR) in response to intracoronary infusion of adenosine was measured under anesthesia, and endothelium-dependent response to bradykinin in the presence and absence of eNOS blockade with LNAME, were studied in vitro in isolated small coronary arteries. 6 months of sustained hyperglycemia (17.5±1.0 in in DM+HC+CKD+OVX vs 8.2±0.9 mmol/l in Control), hypercholesterolemia (15.4±2.0 vs 1.7±0.1 mmol/l) and renal dysfunction (plasma total protein: 84±3 vs 72±1 g/l) were accompanied by systemic inflammation (TNFalpha: 62±7 vs 47±1 pg/ml, all p<0.05 by t-test). Coronary flow reserve was significantly reduced in animals with multiple risk factors (3.4±0.4 in DM+HC+CKD+OVX) as compared to the healthy animals (4.9±0.3 in Control, p<0.05). In vitro, coronary small arteries from DM+HC+CKD+OVX animals showed impaired endothelium-dependent vasodilation to bradykinin, which was mediated by a loss of nitric oxide. Conclusion: Postmenopausal minipigs with multiple risk factors, displayed severe coronary microvascular dysfunction as evidenced by a significantly reduced coronary flow reserve and endothelial dysfunction. The latter was characterized by a marked loss of nitric oxide. Such perturbations may contribute to reduced myocardial perfusion that is often observed in postmenopausal women with multiple cardiovascular risk factors. Funding: Grant 2020B008 RECONNEXT. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Diabetes and chronic kidney disease synergistically contribute to left ventricular diastolic dysfunction and coronary microvascular disease in swine

Abstract Background Chronic kidney disease (CKD) and diabetes (DM) are common causes of cardiovascular disease (CVD), and contribute to the development of left ventricular diastolic dysfunction (LVDD) and coronary microvascular dysfunction (CMD). Purpose To investigate if CKD and DM contribute synergistically to the development of CMD and LVDD by increasing myocardial interstitial fibrosis in a swine model. Methods CKD was induced by renal microembolization at 10-12 weeks of age in 8 wild type (WT) and 6 DM (INSC94Y) swine, while 6 WT and 5 DM swine served as control. LVDD was assessed using pressure volume loops and coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in the left anterior descending coronary artery. Afterwards, myocardium and kidney tissues were histologically examined for interstitial fibrosis. Results DM was confirmed by increased blood glucose values in the DM and DMCKD (figure 1-A). Renal embolization resulted in renal fibrosis in the WTCKD and DMCKD (figure 1-B), which was accompanied by a trend towards proteinuria, i.e., elevated protein/creatinine ratios (figure 1-C). LVDD was evidenced by an increase in the slope of the end-diastolic pressure volume relationship (EDPVR) in WTCKD, DM and DMCKD as compared to WT, with the largest increase in DMCKD (figure 1-D). WTCKD and DMCKD animals showed higher interstitial fibrosis levels in the LV (figure 1-E). CFR tended to be decreased in WTCKD, DM and DMCKD swine compared to WT (figure 1-F). Conclusions Renal embolization resulted in proteinuria and renal fibrosis, particularly in DM animals. DM and CKD also caused myocardial interstitial fibrosis, which impaired left ventricular diastolic function. The effects tended to be larger in DMCKD as compared to DM or WTCKD. Moreover, CFR tended to be decreased, suggestive of CMD, with the largest effect in DMCKD. In conclusion, DM and CKD contributed synergistically to LVDD and CMD.

Slow Coronary Flow: Pathophysiology, Clinical Implications, and Therapeutic Management.

Coronary slow flow (CSF) is an angiographic phenomenon with specific epidemiologic characteristics, associated clinical presentation, and prognosis. Although patients with CSF are diagnosed as having "normal coronary arteries," it seems appropriate to consider CSF as a distinct disease entity requiring specific treatment. The patient with CSF is usually male, smoker, obese, with a constellation of risk factors suggestive of metabolic syndrome. Unstable angina is the most common clinical presentation, with recurrent episodes of chest pain at rest associated with electrocardiographic changes often requiring readmission and reevaluation. Regarding definition and diagnosis, interventionists should first exclude possible "secondary" causes of CSF, use objective means for definition and then differentiate from other similar conditions such as microvascular angina. Although the phenomenon is generally benign, patients with CSF are severely symptomatic with recurrent episodes of chest pain and poor quality of life. Furthermore, acute presentation of the phenomenon is commonly life-threatening with ventricular tachyarrhythmias, conduction abnormalities, or cardiogenic shock. Acute treatment of CSF includes, but is not restricted to, intracoronary infusion of dipyridamole, adenosine, or atropine. Chronic management of patients with CSF encompasses dipyridamole, diltiazem, nebivolol, telmisartan, and/or atorvastatin associated with amelioration of angina symptoms, improved quality of life, and good prognosis.

Continuous intracoronary versus standard intravenous infusion of adenosine for fractional flow reserve assessment: the HYPEREMIC trial.

The aim of this study was to evaluate the accuracy of a continuous intracoronary (IC) adenosine infusion, administered through the novel HYPEREM™IC over-the-wire microcatheter, to measure fractional flow reserve (FFR). The HYPEREMIC trial was a randomised, non-inferiority, crossover study in which patients with intermediate coronary lesions were enrolled for sequential pressure wire studies. FFR was measured using intravenous (IV) (140-180 mcg/kg/min) versus continuous non-weight-adjusted IC (360 mcg/min) adenosine. Patients were randomised and blinded to the order in which they received the adenosine, separated by a washout period. The primary endpoint was the mean hyperaemic FFR. Forty-one patients were enrolled at three UK sites between June and November 2016. The mean (standard deviation) FFR was 0.82 (±0.09) after IC versus 0.84 (±0.09) after IV adenosine. The difference of -0.02 (95% confidence interval [CI]: -0.03 to -0.01) confirmed the non-inferiority (margin <0.05) of IC to IV adenosine. Intracoronary adenosine was associated with a shorter mean time to maximal hyperaemia (difference -44 [95% CI: -59 to -29] seconds; p<0.0001). Chest discomfort was reported in 32/41 (78.0%) patients during IV adenosine versus 12/41 (29.3%) patients during IC adenosine. Continuous IC adenosine was a reliable, faster and better tolerated method of achieving maximal hyperaemia compared to IV adenosine.

Assessment with intracoronary pressure and flow guidewire, at baseline and after intracoronary adenosine infusion, in a patient with Takotsubo syndrome

Assessment with intracoronary pressure and flow guidewire, at baseline and after intracoronary adenosine infusion, in a patient with Takotsubo syndrome

P5620Clinical and hemodynamic determinants of coronary flow reserve in non-obstructed coronary arteries - A patient level pooled analysis of the DEBATE and ILIAS studies

Abstract Aim Coronary Flow Reserve (CFR) is a valuable physiological index for the assessment of myocardial flow impairment due to focal or microcirculatory coronary artery disease (CAD). Coronary flow capacity (CFC) is another flow-based concept in diagnosing ischemic heart disease (IHD), based on hyperemic average peak velocity (hAPV) and CFR. We evaluated clinical and hemodynamic factors which potentially influence CFR and CFC in non-obstructed coronary arteries. Methods We analysed CFR and CFC of 396 non-obstructed vessels of patients from two large multi-center trials (DEBATE and ILIAS) with stable CAD who were scheduled for percutaneous coronary intervention (PCI). Doppler flow measurements were performed after inducing hyperemia with either intracoronary or intravenous infusion of adenosine. Results Akaike's Information Criterion (AIC) revealed the parameters age, female gender, a history of myocardial infarction, hypercholesterolemia, current or previous smoking and rate pressure product (RPP) as independent predictors in the best model of fit for CFR in an angiographically non-obstructed vessel. After multivariate regression analysis age, female gender and RPP remained as determinants of CFR in angiographically non-obstructed vessels. Subsequently, ordered logistic regression analysis revealed that age is associated with a worse CFC. Conclusion Clinical and hemodynamic parameters are associated with CFR and to a lesser extent CFC in an angiographically non-obstructed coronary artery. CFC is less sensitive to variations in clinical and hemodynamic parameters than CFR and therefore a promising tool in contemporary clinical decision making in the cardiac catheterization laboratory. Acknowledgement/Funding DEBATE: Cardiometrics INC. ILIAS: Dutch Health Insurance Board; RADI Medical Systems, Uppsala, Sweden; and Endosonics, Rancho Cordova, CA.

Peripheral Microvascular Function Reflects Coronary Vascular Function.

Objectives- Coronary endothelial dysfunction is a precursor of atherosclerosis and adverse outcomes. Whether endothelial dysfunction is a localized or generalized phenomenon in humans remains uncertain. We simultaneously measured femoral and coronary vascular function with the hypothesis that peripheral vascular endothelial function will be reflective of coronary endothelial function. Approach and Results- Eighty-five subjects underwent coronary angiography for evaluation of chest pain or abnormal stress tests. Endothelium-dependent and -independent vascular function were measured using intracoronary and intrafemoral infusions of acetylcholine and sodium nitroprusside, respectively. Coronary flow reserve was assessed using intracoronary adenosine infusion. Flow velocity was measured in each circulation using a Doppler wire (FloWire, EndoSonics). Coronary vascular resistance and femoral vascular resistance were calculated as mean arterial pressure (mm Hg)/coronary blood flow (mL/min) and mean arterial pressure (mm Hg)/femoral average peak velocity (cm/s), respectively. Mean age was 53±11 years, 37% were female, 44% had hypertension, 12% had diabetes mellitus, and 38% had obstructive coronary artery disease. There was a correlation between the change in femoral vascular resistance with acetylcholine and acetylcholine-mediated changes in both the coronary vascular resistance ( r=0.27; P=0.014) and in the epicardial coronary artery diameter ( r=-0.25; P=0.021), indicating that subjects with normal endothelial function in the femoral circulation had normal endothelial function in the coronary epicardial and microcirculation and vice versa. The coronary vasodilator response to adenosine also correlated with the femoral vasodilatation with acetylcholine ( r=0.4; P=0.0002). There was no correlation between the coronary and femoral responses to sodium nitroprusside. Conclusions- Endothelial functional changes in the peripheral and coronary circulations were modestly correlated. Thus, peripheral microvascular endothelial function reflects endothelium-dependent coronary epicardial and microvascular function and the coronary flow reserve. Visual Overview- An online visual overview is available for this article.

Coronary microvascular dysfunction is associated with poor glycemic control amongst female diabetics with chest pain and non-obstructive coronary artery disease

BackgroundPatients with type 2 diabetes mellitus are at an increased risk of adverse cardiovascular events compared to those without diabetes. The timing, relative to disease onset, and degree of glycemic control that reduces the risk of adverse cardiovascular events remains uncertain. Coronary microvascular dysfunction is prevalent in patients with type 2 diabetes mellitus and is linked to adverse cardiovascular events. We assessed the association between endothelial-dependent and endothelial-independent coronary microvascular dysfunction and glycemic control in patients presenting with chest pain and nonobstructive coronary disease at angiography.MethodsPatients presenting with chest pain and found to have non-obstructive CAD (stenosis < 40%) at angiography underwent an invasive assessment of endothelial-independent and endothelial –dependent microvascular function. Endothelial-independent microvascular function was assessed by comparing the coronary flow velocity, measured using a Doppler guidewire, in response to intracoronary infusion of adenosine to calculate the coronary flow reserve ratio in response to adenosine (CFRAdn Ratio). A CFRAdn Ratio ≤ 2.5 was considered abnormal. Endothelial-dependent microvascular function was assessed by measuring the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction defined as a %ΔCBFAch of ≤ 50%. Patients were classified by normal versus abnormal CFRAdn Ratio and %ΔCBFAch. Measurements of HbA1c and fasting serum glucose were obtained prior to catheterization and compared between groups.ResultsBetween 1993 and 2012, 1469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing for coronary microvascular dysfunction, of which 129 (8.8%) had type 2 diabetes. Fifty-one (39.5%) had an abnormal %ΔCBFAch and 49 (38.0%) had an abnormal CFRAdn Ratio. Conventional cardiovascular risk factors and cardiovascular or diabetic medication use did not vary significantly between groups. Females with an abnormal CFRAdn Ratio or abnormal %ΔCBFAch had a significantly higher HbA1c compared to patients with a normal CFRAdn Ratio or %ΔCBFAch respectively: HbA1c % (standard deviation) 7.4 (2.1) vs. 6.5 (1.1), p = 0.035 and 7.3 (1.9) vs. 6.4 (1.2), p = 0.022, respectively. Female patients with an abnormal CFRAdn Ratio had significantly higher fasting serum glucose concentrations compared to those with a normal CFRAdn Ratio: fasting serum glucose mg/dL (standard deviation) 144.4 (55.6) vs. 121.9 (28.1), p = 0.035. This was not observed in men. Amongst female diabetics, a higher HbA1c was significantly associated with any coronary microvascular dysfunction both in a univariate and multivariate analysis: odds ratio (95% confidence interval) 1.69 (1.01–2.86) p = 0.049; and a fasting serum glucose > 140 mg/dL was significantly associated with an abnormal CFRAdn Ratio, 4.28 (1.43–12.81).ConclusionPoor glycemic control is associated with coronary microvascular dysfunction amongst female diabetics presenting with chest pain and non-obstructive CAD. These findings highlight the importance of sex specific risk stratification models and treatment strategies when managing cardiovascular risk amongst diabetics. Further studies are required to identify additional risk prevention tools and therapies targeting microvascular dysfunction as an integrated index of cardiovascular risk.

Abstract 17128: Pathophysiology of Coronary Artery Disease in Hiv-infected Patients: Dissociation Between Anatomy and Function

Introduction: Numerous reports suggest, among HIV+ patients (pts), an increased rate of acute coronary syndrome and cardiac death. Several data suggest that endothelial dysfunction is a major mechanisms in the development of coronary atherosclerosis in non-HIV infected patients. Hypothesis: The aim of our study is to assess coronary microvascular function using Doppler-flow wire in HIV+ patients in therapy with HAART. Methods: Thirteen HIV-infected patients were enrolled from the Department of Cardiovascular, Respiratory, Nephrology, Anesthesiology and Geriatric Sciences of the “Sapienza” University of Rome (Italy). The main inclusion criteria were: Framingham risk score &lt;10%, absence of metabolic syndrome (according to the definition of Adult Treatment Panel III e ATPIII12), negative echocardiographic and ECG stress-test and negative for anti-HCV antibodies. Diagnostic coronary angiography was performed via percutaneous radial approach. Microvascular function was assessed by measuring coronary flow velocity reserve (CFR). Intracoronary functional tests were performed to evaluate both endothelium-dependent microvascular function [via intracoronary (IC) infusion of acetylcholine (2.5[[Unable to Display Character: &amp;#8211;]]10 μg)] and non-endothelium-dependent microvascular function [via IC infusion of adenosine (5 μg) ]. Results: All the patients presented a Framingham risk score &lt;10%. The medium age was 53.3±4.1 years. The mean duration of highly active antiretroviral therapy was 12.9±2.4 years. Thirteen patients presented 23 coronary atherosclerotic plaques; while endothelium and non endothelium-dependent microvascular function was quite normal in our population (CFR after adenosine 2.37±0.4; CFR after Achetylcholine 2.43±0.4). Conclusion: Microvascular function is not compromised in HIV + pts who presented coronary atherosclerotic plaque. Microvascular dysfunction, involved in pathophysiology of coronary artery disease in general population, seems to be not implicated in coronary atherosclerosis in HIV + pts. These data suggest a peculiar pathophysiological mechanisms for HIV related atherosclerosis.

Abstract 17138: Intravenous Regadenoson with Aminophylline Reversal is Safe and Equivalent to Intracoronary Adenosine Infusion for Fractional Flow Reserve Measurements

Background: Small studies have shown that Adenosine is equivalent to Regadenoson when obtaining Fractional Flow Reserve (FFR) measurements. A larger study that also evaluates time and safety of aminophylline reversal was yet to be presented. Methods: After IRB approved consent was obtained, 46 consecutive patients with clinically indicated FFRs were enrolled between 4/2012 and 5/2014. Each patient had FFR measured with adenosine 140 mcg/kg/min IV then allowed to return to baseline. FFR was repeated with Regadenoson 140 mcg IV bolus than reversed with aminophylline 150 mg IV and time to baseline hemodynamics were measured. Tests were compared using linear regression. Reversal time recorded in seconds. Results: As demonstrated in Figure1 FFR results were similar with both agents, R2 = 0.935, p&lt;0.0001. Also, using the 0.80 cutoff, there was no divergence regarding studies significance. After aminophylline, hemodynamics returned to baseline in 112+/- 72 secs. There were no side-effects reported. Conclusion: The use of regadenoson for FFR measurements provides results consistent with the ones obtained with adenosine infusion. Aminophilline reversal for regadenoson was fast, well tolerated and safe. Regadenoson with aminophylline reversal may be considered as an alternative for FFR measurements.

Cardioprotective effect of high‐dose intragraft adenosine infusion on microvascular function and prevention of no‐reflow during saphenous vein grafts intervention

Despite the use of embolic protection devices, no-reflow can still occur during saphenous vein grafts (SVGs) intervention. High-dose intracoronary adenosine infusion preconditions the myocardium, improves coronary flow, and prevents no-reflow. The role of high-dose intragraft adenosine infusion on protection of microvascular function and prevention of no-reflow has not been investigated We investigated the cardioprotective effect of high-dose intragraft adenosine infusion, compared with placebo, on microvascular function and prevention of no-reflow during SVGs intervention. We randomized 22 patients with SVGs stenoses to receive either a 10-min intragraft adenosine infusion (200 μg/min; total dose = 2,000 μg) or normal saline prior to stenting. Average peak velocity (APV), coronary flow velocity reserve (CVR), thrombolysis in myocardial infarction (TIMI) frame count (TFC), TIMI myocardial perfusion grade (TMPG), and the rate of no-reflow were compared between the two groups before adenosine or saline infusions and after stenting After stenting, hyperemic APV, CVR, and TMPG were significantly higher in the adenosine-treated group than in the control group (60 ± 18 vs. 35 ± 10 cm/sec; 2.6 ± 0.54 vs. 1.8 ± 0.47; and 2.8 ± 0.90 vs. 2.1 ± 0.80, respectively; P < 0.05. TFC was significantly lower in the adenosine-treated group than in the control group (14 ± 3.0 vs. 26 ± 13; P < 0.05). In the control group, four patients (36%) developed no-reflow compared to none in the adenosine-treated patient; P < 0.05 CONCLUSIONS: This study provides the first evidence that high-dose intragraft adenosine infusion compared with placebo protects microvascular function and prevents no-reflow during SVGs intervention.

Ranolazine as Treatment of Microvascular Coronary Dysfunction in a Woman With Signs and Symptoms of Ischemia but No Obstructive Coronary Artery Disease

Women often exhibit persistent symptoms, functional disability and a relatively high prevalence of microvascular coronary dysfunction (MCD) with no obstructive coronary artery disease (CAD) when evaluated for signs and symptoms of myocardial ischemia. A 27-year-old woman was referred by her treating cardiologist for symptoms of persistent chest pain for 10 years. Cardiac catheterization showed normal coronary arteries. Given the constellation of persistent chest pain and no obstructive CAD, a diagnosis of MCD was suspected, and she underwent coronary reactivity testing (CRT) with intracoronary infusions of adenosine, acetylcholine and nitroglycerin to test nonendothelial- and endothelial-dependent, micro- and macro-vascular coronary function. CRT results were consistent with a diagnosis of MCD. The patient was started on ranolazine, with significant improvement in symptoms. Cardiac magnetic resonance imaging (CMRI) after 3 months of treatment demonstrated improvement in perfusion compared to baseline. J Med Cases. 2014;5(1):23-25 doi: http://dx.doi.org/10.4021/jmc1522w

Ranolazine as Treatment of Microvascular Coronary Dysfunction in a Woman With Signs and Symptoms of Ischemia but No Obstructive Coronary Artery Disease

Women often exhibit persistent symptoms, functional disability and a relatively high prevalence of microvascular coronary dysfunction (MCD) with no obstructive coronary artery disease (CAD) when evaluated for signs and symptoms of myocardial ischemia. A 27-year-old woman was referred by her treating cardiologist for symptoms of persistent chest pain for 10 years. Cardiac catheterization showed normal coronary arteries. Given the constellation of persistent chest pain and no obstructive CAD, a diagnosis of MCD was suspected, and she underwent coronary reactivity testing (CRT) with intracoronary infusions of adenosine, acetylcholine and nitroglycerin to test nonendothelial- and endothelial-dependent, micro- and macro-vascular coronary function. CRT results were consistent with a diagnosis of MCD. The patient was started on ranolazine, with significant improvement in symptoms. Cardiac magnetic resonance imaging (CMRI) after 3 months of treatment demonstrated improvement in perfusion compared to baseline. J Med Cases. 2014;5(1):23-25 doi: http://dx.doi.org/10.4021/jmc1522w

Relationship between intravascular ultrasound parameters and fractional flow reserve in intermediate coronary artery stenosis of left anterior descending artery: Intravascular ultrasound volumetric analysis

The objective of this study was to assess the relationship between intravascular ultrasound (IVUS) parameters, including volumetric analysis, and fractional flow reserve (FFR). Although it is known that coronary atherosclerosis burden measured by IVUS volumetric analysis is related with clinical outcomes, its relationship with functional significance remains unknown. Both IVUS and FFR were performed in 206 cases of intermediate stenosis of the left anterior descending artery (LAD). Myocardial ischemia was assessed by FFR and maximal hyperemia was induced by continuous intracoronary adenosine infusion. FFR < 0.80 was considered as significant inducible myocardial ischemia. We performed standard IVUS parameter measurements and volumetric analyses. IVUS parameter comparison was performed in the presence (n = 90) or absence (n =116) of significant myocardial ischemia. Lesions with minimal lumen area (MLA) ≥ 4.0 mm2 had FFR ≥ 0.80 in 91.4% of cases, while 50.9% of lesions with MLA < 4.0 mm2 had FFR < 0.80. The independent predictors of FFR < 0.80 were IVUS lesion length (odds ratio [OR]: 1.1, 95% confidence interval [CI] = 1.06–1.18, P < 0.001) and MLA significance according to the lesion location (OR: 7.01, 95% CI = 3.09–15.92, P = 0.001). FFR correlated with plaque volume (r = −0.345, P < 0.001) and percent atheroma volume (PAV) (r = −0.398, P < 0.001). Lesions with significant ischemia (FFR < 0.80) as compared to those with FFR > 0.80 were associated with larger plaque volume (181.8 ± 82.3 vs. 125.9 ± 77.9 mm3, P < 0.001) and PAV (58.9 ± 5.6 vs. 53.8 ± 7.9%, P < 0.001). IVUS parameters representing severity and extent of atheromatous plaque correlated with functional significance in LAD lesions with intermediate stenosis.

Intracoronary infusion of adenosine reduces infarct size and no-reflow in ST-segment elevation myocardial infarction

Purpose: Adenosine exerts a variety of actions that may attenuate many of the proposed mechanisms of reperfusion-mediated injury, including inhibition of neutrophil-mediated microvascular obstruction. Yet, attempts to achieve cardioprotection with administration of adenosine at reperfusion have yielded conflicting results in both pre-clinical and clinical settings. We sought to determine the effects of adenosine on infarct size (IS) and no-reflow in an appropriate translational porcine model, taking into account the predicted terms for efficacious intervention (i.e., prolonged intracoronary infusion starting just prior to reperfusion). Methods: Thirty-six open-chest swine of either sex were subjected to a 45-min left anterior descending coronary artery occlusion followed by 2 h of reperfusion. Animals received either intracoronary adenosine (50 μg/kg/min; n=15) infused for 2 h starting 5 min prior to reperfusion or an equal volume of saline (controls; n=21). The area-at-risk was delineated with Evans Blue, IS was determined histochemically with triphenyltetrazolium staining and no-reflow measured with thioflavin S staining. Results: Adenosine infusion significantly increased coronary blood flow throughout the 2-h reperfusion period compared with controls (p<0.001), with a maximum fourfold increase relative to baseline at 30 min of reperfusion (397±62% vs. 217±18% in controls; p<0.001). In contrast, adenosine did not affect systemic hemodynamic variables. Area-at-risk was similar between groups (p=NS). Administration of adenosine resulted in a significant reduction in IS (% area-at-risk; 46±4%) compared with controls (59±3%; p=0.02). Likewise, no-reflow (% IS) was significantly reduced in the adenosine-treated group (26±6%) compared to controls (49±6%; p=0.03). Conclusion: High and prolonged intracoronary adenosine infusion during early reperfusion limits infarct size and no-reflow in a porcine preparation of ST-segment elevation myocardial infarction. Further studies are warranted to confirm this effect, especially, when considering that there is no successful clinical pharmacological treatment for prevention of reperfusion-mediated injury at present.

Microvascular Coronary Dysfunction in a Woman With Signs and Symptoms of Myocardial Ischemia but No Obstructive Coronary Artery Disease

Women with signs and symptoms of myocardial ischemia often have no obstructive coronary artery disease by invasive coronary angiography when compared to men. Microvascular coronary dysfunction (MCD) is thought to be a key contributory mechanism for myocardial ischemia in women with chest pain and no obstructive CAD. We report a case of a 53-year-old post-menopausal female with hyperlipidemia evaluated for persistent chest pain following a non-ST elevation myocardial infarction (NSTEMI) and no obstructive CAD by coronary angiography. Vital signs and physical examination were within normal limits. Prior EKG showed diffuse abnormal T wave inversion and flattening in anterior and inferior leads. Echocardiography demonstrated an ejection fraction of 72% with no regional wall motion abnormalities. Laboratory values revealed a positive heterozygote factor V Leiden mutation. Given the constellation of persistent chest pain, no obstructive CAD, and prior NSTEMI, a diagnosis of MCD was suspected and she underwent coronary reactivity testing (CRT) with intracoronary infusions of adenosine, acetylcholine, and nitroglycerin to test non-endothelial and endothelial dependent, micro- and macrovascular coronary function. CRT results were consistent with a diagnosis of MCD. A statin and angiotensin converting enzyme inhibitor was added to her existing treatment of beta-blocker and nitrates. Additionally, she was started on warfarin therapy due to a positive factor V Leiden in the setting of prior NSTEMI. Her symptoms improved at one-month follow-up and she is currently asymptomatic by self- report. In women with signs and symptoms of myocardial ischemia and no obstructive CAD, it is important to identify and diagnose MCD, as inadequate diagnosis is associated with an increased risk of adverse cardiovascular events including myocardial infarction, congestive heart failure, and sudden cardiac death. Identification of MCD and clinical awareness are vital for optimal medical therapy and reduced CVD risk. Clinical trials testing efficacy of traditional and novel interventions are needed in MCD populations. doi: http://dx.doi.org/10.4021/jmc1048w

EFFECT OF MYOCARDIAL PROTECTION OF INTRACORONARY ADENOSINE IN PATIENTS WITH ACUTE CORONARY SYNDROME DURING ELECTIVE PERCUTANEOUS CORONARY INTERVENTION

ObjectivesTo investigate the myocardial protective effects of intracoronary adenosine infusion in patients with acute coronary syndrome during elective percutaneous coronary intervention.MethodsWe enrolled 100 consecutive patients with acute coronary syndrome who...

Ticagrelor Inhibits Adenosine Uptake In Vitro and Enhances Adenosine-Mediated Hyperemia Responses in a Canine Model

A routine secondary pharmacology screen indicated that reversibly binding oral P2Y(12) receptor antagonist ticagrelor could inhibit adenosine uptake in human erythrocytes, suggesting that ticagrelor may potentiate adenosine-mediated responses in vivo. The aim of this study was to further characterize the adenosine uptake inhibition in vitro and study possible physiological consequences of adenosine uptake inhibition by ticagrelor in an anesthetized dog model of coronary blood flow compared to dipyridamole. We measured [2-3H]adenosine uptake in purified human erythrocytes and several cell lines in the presence of ticagrelor or the known uptake inhibitor dipyridamole as a comparator. Using an open-chest dog model (beagles), we measured the left anterior descending (LAD) coronary artery blood flow during reactive hyperemia after 1 minute occlusion or intracoronary infusion of adenosine before and after administration of vehicle, ticagrelor, or dipyridamole (each n = 8). Ticagrelor concentration-dependently inhibited adenosine uptake in human erythrocytes and in cell lines of rat, canine, or human origin. In the dog model, ticagrelor and dipyridamole dose-dependently augmented reactive hyperemia after LAD occlusion, as assessed by percentage repayment of flow debt relative to control (both Ps < .05). Ticagrelor and dipyridamole also dose-dependently augmented intracoronary adenosine-induced increases in LAD blood flow relative to control (both Ps < .05). Ticagrelor inhibits adenosine uptake in vitro and subsequently augments cardiac blood flow in a canine model of reactive hypoxia- or adenosine-induced blood flow increases. These findings suggest that ticagrelor may have additional benefits in patients with acute coronary syndrome beyond inhibition of platelet aggregation.