Changes In Coronary Blood Flow Research Articles

A novel GWAS locus influences microvascular response to mental stress and predicts adverse cardiovascular events.

Excessive peripheral microvascular constriction during acute psychologicalstress reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. Among individuals with coronary artery disease (CAD), we sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. A total of 580 stable CAD individuals from two prospective cohort studies underwent mental stress testing. Digital pulse wave amplitude was continuously measured and the stress/rest (sPAT) ratio of pulse wave amplitude was calculated. Race stratified genome-wide association studies (GWAS) of sPAT-ratio were conducted using linear regression of additive genetic models. A trans-ethnic meta-analysis integrated the four sets of GWAS results. Participants were followed for the outcome of recurrent cardiovascular events (myocardial infarction, heart failure, revascularization, and CV death) for a median of 5years. We used Wei-Lin-Weissfeld (WLW) model to assess the association between sPAT-ratio with recurrent events. Mean age was 63 ± 9. We identified three SNPs in linkage disequilibrium, closely related to chr7:111,666,943T > C (rs6466396) that were associated with sPAT-ratio (p = 6.68E-09). Participants homozygous for the T allele had 80% higher risk of incident adverse events (HR 1.8, 95% CI, 1.4-2.2). Also, participants with a lower sPAT-ratio (< median) had a higher adverse event rate, hazard ratio (HR) = 1.3, [95%confidence interval (CI), 1.1-1.6]. However, adjustment for the genotypes did not substantially alter the impact of sPAT ratio on adverse outcome rate.In conclusion,we have identified a genetic basis for stress-induced vasomotion. The 3 linked variants modulate vasoconstriction during mental stress may have a prognostic importance.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.

Role of potassium as a coronary metabolic vasodilator

K+ release from the myocardium is associated with decreased coronary vascular resistance. Accumulation of extracellular K+ has been linked to mechanisms of vasodilation in the coronary circulation including activation of the electrogenic Na+-K+ pump in smooth muscle (Murray and Sparks, Circ. Res. 1977) and endothelial-mediated hyperpolarization via Kir2.1 channels (Zhao et al., PNAS 2020). Our objective was to examine K+ as a coronary metabolic vasodilator in vivo. Further, we addressed two potential shortcomings of previous studies: the short duration of the bolus K+ stimulus employed and the seemingly high concentrations required to produce vasodilation. We hypothesized that continuous, steady-state intracoronary infusions of K+ would produce sustained coronary vasodilation in a concentration-dependent manner. Our methods involved instrumenting anesthetized, open-chest Yorkshire swine (male and female, 60 kg) for measurements of coronary blood flow, as well as arterial and coronary venous blood sampling. The left anterior descending coronary artery was cannulated and perfused under the control of a pressure servo, allowing us to determine flow and infuse K+. Our results show small, but statistically significant (* represents p &lt; 0.05), effects of K+ on coronary hemodynamics. The coronary venous K+ concentration was 4.0 ± 0.1 mM at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary venous K+ to 4.9 ± 0.2*, 6.4 ± 0.2*, and 7.9 ± 0.2* mM. Higher K+ concentrations caused fatal arrhythmias. Coronary blood flow was 0.73 ± 0.14 ml/min/g at baseline. Infusing K+ into the coronary artery at increasing rates increased coronary blood flow to 0.78 ± 0.14*, 0.82 ± 0.15*, and 0.86 ± 0.16* ml/min/g. These small coronary blood flow changes were sustained during continuous K+ infusion. We conclude that K+ is a coronary vasodilator, as has been demonstrated previously. Importantly, however, we emphasize that the effects of K+ are extremely modest and the concentrations required to produce physiologically significant vasodilation are life-threatening. With the assumption that the venous K+ concentration is in equilibrium with that surrounding the smooth muscle and cardiac muscle of the working heart, we urge caution in interpreting isolated artery studies that routinely use 15-20 mM K+ to elicit hyperpolarization and vasodilation. Our data do not support the idea that K+ plays a major role in regulating coronary vascular resistance. This work was supported by National Institutes of Health grant R01 HL158723. 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.

Sex differences of sequential changes in coronary blood flow and microvascular function in patients with suspected angina.

This study evaluated the sex differences of sequential changes in coronary blood flows and microvascular function in patients with suspected angina but with no obstructed coronary arteries. A total of 202 consecutive patients who experienced chest pain but had no significant coronary artery stenosis and who underwent adenosine stress echocardiography were included in the study. Coronary blood flow (CBF) velocities were measured at 1, 2, and 3min after adenosine infusion. The mean age was 61years, and 138 (68%) were women. Approximately 40% of patients had coronary microvascular dysfunction (CMD, coronary flow velocity reserve < 2.3), with women exhibiting higher CMD prevalence. The left ventricular (LV) mass index was similar between men and women, while women exhibited higher baseline rate pressure products (RPP). At baseline, coronary blood flow velocities were similar between the sexes. However, CBF velocities in women gradually increased during the examination; and in men, the increase was abrupt and steep during the early stages of examination (p = 0.015 for interaction between time and sex), even with similar RPP in stress. Coronary flow velocity reserve was steadily lower in women compared to men (1min, 2.09 ± 0.86 vs 2.44 ± 0.87; 2min, 2.39 ± 0.72 vs 2.63 ± 0.85; 3min, 2.45 ± 0.70 vs 2.68 ± 0.73). In patients with suspected angina but with no obstructed coronary arteries, CMD was especially prevalent among women. Women exhibited higher oxygen consumption, while exhibiting slower and gradual increases in CBF velocities. Conversely, men exhibited faster and steeper increases in CBF velocities even with similar RPP in stress.

Prognostic value of changes in coronary blood flow in patients with preserved ejection fraction

BACKGROUND: The measurement of the left ventricular ejection fraction during at echocardiographic study evaluates global contractility. A decrease in this parameter indicates a poor prognosis. However, in the range of normal values, the left ventricular ejection fraction loses prognostic significance. This category of patients requires the development of other prognostic methods.&#x0D; AIM: To explore the effect of changes in coronary blood flow parameters measured using dopplerography in patients with preserved left ventricular ejection fraction in predicting adverse outcomes over the next year.&#x0D; MATERIALS AND METHODS: The prospective study included patients referred for echocardiography in 20192020 followed up at the Saint Petersburg Research Center of Cardiology Medika. The inclusion criterion was age over 18 years. A decrease in left ventricular ejection fraction of less than 53% was an exclusion critrion. In addition to standard echocardiography, dopplerography has been used to study the velocity parameters of blood flow in the coronary arteries. The observation period was 1 year.&#x0D; RESULTS: The control group included 453 patients. During the year of observation, 89 cases of spontaneous adverse events (death / myocardial infarction / progressive heart failure) occurred, including 19 deaths. The patients who died were older (76.6 8.6 vs. 59.3 15.5 years; р 0.000001), with lower global longitudinal function (13.8 4.3% vs. 18.3 3.6%, р 0.000001), with a large volume index of the left atrium (54.6 15.5 vs. 36.5 13.1 ml/m2; р 0.000000), high pressure in the pulmonary artery (39 14.7 vs. 29.5 8.1 mmHg; р 0.000000), high left ventricular myocardial mass index (108.7 37.2 vs. 88,1 24.1 g/m2, р 0.000000) and impaired diastolic function [the ratio of blood flow velocity through the mitral valve in the first (early) phase of left ventricular filling and the average velocity of the mitral valve fibrous ring 13.6 7.1 vs. 9.4 4.4; р 0.000000]. The blood flow velocity in the anterior interventricular artery was significantly higher (78.0 39.0 vs. 50.0 25.4 cm/s, р 0.000007). Only age and flow velocity in anterior interventricular artery were independent predictors of death / myocardial infarction (р 0.004).&#x0D; CONCLUSIONS: Velocity parameters in the anterior interventricular artery are a significant predictor of short-term spontaneous events, including death, in patients with preserved ejection fraction.

Molecular mechanisms of endothelial dysfunction in coronary microcirculation dysfunction.

Coronary microvascular endothelial cells (CMECs) react to changes in coronary blood flow and myocardial metabolites and regulate coronary blood flow by balancing vasoconstrictors-such as endothelin-1-and the vessel dilators prostaglandin, nitric oxide, and endothelium-dependent hyperpolarizing factor. Coronary microvascular endothelial cell dysfunction is caused by several cardiovascular risk factors and chronic rheumatic diseases that impact CMEC blood flow regulation, resulting in coronary microcirculation dysfunction (CMD). The mechanisms of CMEC dysfunction are not fully understood. However, the following could be important mechanisms: the overexpression and activation of nicotinamide adenine dinucleotide phosphate oxidase (Nox), and mineralocorticoid receptors; the involvement of reactive oxygen species (ROS) caused by a decreased expression of sirtuins (SIRT3/SIRT1); forkhead box O3; and a decreased SKCA/IKCA expression in the endothelium-dependent hyperpolarizing factor electrical signal pathway. In addition, p66Shc is an adapter protein that promotes oxidative stress; although there are no studies on its involvement with cardiac microvessels, it is possible it plays an important role in CMD.

Impact of TAVR on coronary artery hemodynamics using clinical measurements and image‐based patient‐specific in silico modeling

In recent years, transcatheter aortic valve replacement (TAVR) has become the leading method for treating aortic stenosis. While the procedure has improved dramatically in the past decade, there are still uncertainties about the impact of TAVR on coronary blood flow. Recent research has indicated that negative coronary events after TAVR may be partially driven by impaired coronary blood flow dynamics. Furthermore, the current technologies to rapidly obtain non-invasive coronary blood flow data are relatively limited. Herein, we present a lumped parameter computational model to simulate coronary blood flow in the main arteries as well as a series of cardiovascular hemodynamic metrics. The model was designed to only use a few inputs parameters from echocardiography, computed tomography and a sphygmomanometer. The novel computational model was then validated and applied to 19 patients undergoing TAVR to examine the impact of the procedure on coronary blood flow in the left anterior descending (LAD) artery, left circumflex (LCX) artery and right coronary artery (RCA) and various global hemodynamics metrics. Based on our findings, the changes in coronary blood flow after TAVR varied and were subject specific (37% had increased flow in all three coronary arteries, 32% had decreased flow in all coronary arteries, and 31% had both increased and decreased flow in different coronary arteries). Additionally, valvular pressure gradient, left ventricle (LV) workload and maximum LV pressure decreased by 61.5%, 4.5% and 13.0% respectively, while mean arterial pressure and cardiac output increased by 6.9% and 9.9% after TAVR. By applying this proof-of-concept computational model, a series of hemodynamic metrics were generated non-invasively which can help to better understand the individual relationships between TAVR and mean and peak coronary flow rates. In the future, tools such as these may play a vital role by providing clinicians with rapid insight into various cardiac and coronary metrics, rendering the planning for TAVR and other cardiovascular procedures more personalized.

Personalized computational estimation of relative change in coronary blood flow after percutaneous coronary intervention in short-term and long-term perspectives

Abstract Coronary artery disease is the leading cause of mortality worldwide, accounting for 12.8% of all deaths. Although the clinical benefits of treating stenosis with percutaneous coronary intervention (PCI) have been extensively demonstrated, residual myocardial ischemia remains in about 30–50% of patients even after a formally successful PCI. We apply previously developed and validated 1D model of haemodynamics, which distributes terminal hydraulic resistance based on the diameters of the parent vessels and Murray’s law by a recursive algorithm. In our new model the terminal resistance is decreased according to a transmural perfusion ratio increase. In contrast to our previous work we calculate the transmural perfusion ratio for personally defined zones. Thus, peripheral hydraulic resistance of myocardial perfusion is personalized based on patient data, whichwere extracted from computed tomography perfusion images. The model serves as a computational tool for simulating pre- to post-PCI changes in coronary haemodynamics of four patients. We simulate fractional flow reserve (FFR), coronary flow reserve (CFR), instantaneous wave-free ratio (iFR), average flow in selected arteries in hyperemic and rest conditions before PCI and after PCI immediately after the surgery (in a short-term) and in a long-term (several months) perspectives. We conclude that high FFR and iFR values in short-term and long-term perspectives are not necessary correlate with CFR improvement and long-term blood flow recovery in coronary arteries.

The Complementary Value of Absolute Coronary Flow in the Assessment of Patients with Ischaemic Heart Disease

Fractional flow reserve (FFR) is the current gold standard invasive assessment of coronary artery disease (CAD). FFR reports coronary blood flow (CBF) as a fraction of a hypothetical and unknown normal value. Although used routinely to diagnose CAD and guide treatment, how accurately FFR predicts actual CBF changes remains unknown. In this study, we compared fractional CBF with absolute CBF (aCBF, in ml min−1), measured with a computational method during standard angiography and pressure wire assessment, on 203 diseased arteries (143 patients). We found a substantial correlation between the two measurements (r = 0.89 and Cohen’s kappa = 0.71). Concordance between fractional and absolute CBF reduction was high when FFR was >0.80 (91%) but reduced when FFR was ≤0.80 (81%), 0.70–0.80 (68%) and, particularly, 0.75–0.80 (62%). Discordance was associated with coronary microvascular resistance, vessel diameter and mass of myocardium subtended, all factors to which FFR is agnostic. Assessment of aCBF complements FFR and may be valuable to assess CBF, particularly in cases within the FFR ‘gray zone’.

Abstract 13732: Left Ventricular End Diastolic Pressure in Women With Ischemia and No Obstructive Coronary Artery Disease: An Analysis From the Women's Ischemia Syndrome Evaluation - Coronary Vascular Dysfunction Study

Introduction: Coronary microvascular dysfunction (CMD) has been proposed as a pathophysiological mechanism in heart failure with preserved ejection fraction (HFpEF). Elevated left ventricular end-diastolic pressure (LVEDP) is often present in patients with CMD. Hypothesis: We hypothesized that CMD-mediated impairment in LV relaxation may contribute to elevated LVEDP. Methods: Women (n=253; age 53.6 ± 11.5) with signs and symptoms of ischemia and no obstructive coronary artery disease underwent invasive coronary functional testing (CFT) for measurement of resting LVEDP, coronary flow reserve to adenosine, change in coronary blood flow and coronary artery diameter to acetylcholine, and diameter change to nitroglycerin. A subset (n=208) had rest-stress CMR at mean 47 days from CFT. Two sample t-test, Fisher’s exact test and Spearman correlation were performed. Results: All women had normal LVEF and no significant valvular disease. Mean LVEDP was 14.4±5.0 mmHg, with 150 women (59%) having LVEDP &gt;12 mmHg. Comorbidities and medications were similar between groups ( Table ). LVEDP correlated with body mass index (BMI) (r=0.324, p&lt;0.001), systolic (r=0.176, p=0.01) and diastolic systemic blood pressure (r=0.13, p=0.059) at time of CFT, as well as with time to peak filling rate (r=0.13, p=0.050), a CMR measure of diastolic function. LVEDP did not relate to invasive CFT measures nor CMR myocardial perfusion reserve index. LVEDP also did not correlate with CMR measures of LV function or structure, adjusted for body-surface area. Conclusions: Among women with suspected CMD, elevated resting LVEDP is prevalent and associated with higher BMI and systemic blood pressure. There were no significant associations between LVEDP and measurements of CMD in this cross-sectional analysis. Further analyses are underway to evaluate whether raised LVEDP initially from hypertension and obesity may lead to CMD, myocardial ischemia, structural impairment and development of HFpEF.

Coronary endothelial dysfunction appears to be a manifestation of a systemic process: A report from the Women’s Ischemia Syndrome Evaluation – Coronary Vascular Dysfunction (WISE-CVD) study

BackgroundCoronary microvascular dysfunction (CMD) is prevalent in symptomatic women with ischemia but no obstructive coronary artery disease (INOCA). Urine albumin-creatinine ratio (UACR) is a measure of renal microvascular endothelial dysfunction. Both are predictors of adverse cardiovascular events. It is unknown if CMD could be a manifestation of a systemic process. We evaluated the relationship between renal microvascular dysfunction and CMD as measured by invasive coronary function testing (CFT).Methods and resultsWe measured urine albumin and creatinine to provide UACR in 152 women enrolled in the Women’s Ischemia Syndrome Evaluation–Coronary Vascular Dysfunction (WISE-CVD) study (2008–2015) with suspected INOCA who underwent CFT. Invasive CFT measures of endothelial and non-endothelial dependent coronary microvascular function were obtained. Subjects were divided into those with detectable (≥20 mg/g) and undetectable urine albumin (<20 mg/g). The group mean age was 54 ± 11 years, with a moderate cardiac risk factor burden including low diabetes prevalence, and a mean UACR of 12 ± 55 mg/g (range 9.5–322.7 mg/g). Overall, coronary endothelial-dependent variables (change in coronary blood flow and coronary diameter in response to cold pressor testing) had significant inverse correlations with log UACR (r = -0.17, p = 0.05; r = -0.18, p = 0.03, respectively).ConclusionsAmong women with INOCA and relatively low risk factor including diabetes burden, renal microvascular dysfunction, measured by UACR, is related to coronary endothelial-dependent CMD. These results suggest that coronary endothelial-dependent function may be a manifestation of a systemic process. Enhancing efferent arteriolar vasodilatation in both coronary endothelial-dependent function and renal microvascular dysfunction pose potential targets for investigation and treatment.Clinical trial registrationhttps://clinicaltrials.gov/ct2/show/NCT00832702.

Association of coronary microvascular dysfunction and cardiac bridge integrator 1, a cardiomyocyte dysfunction biomarker.

BackgroundCoronary microvascular dysfunction (CMD) is associated with heart failure with preserved ejection fraction (HFpEF); however, pathophysiology is not well described.HypothesisWe hypothesized that CMD in women with suspected ischemia with no obstructive coronary artery disease (INOCA) is associated with cardiomyocyte dysfunction reflected by plasma levels of a cardiomyocyte calcium handling protein, cardiac bridge integrator 1 (cBIN1).MethodsWomen with suspected INOCA undergoing coronary function testing were included. Coronary flow reserve, vasodilation to nitroglycerin, change in coronary blood flow (ΔCBF), and vasodilation to acetylcholine (ΔAch) were evaluated. cBIN1 score (CS) levels in these women (n = 39) were compared to women with HFpEF (n = 20), heart failure with reduced ejection fraction (HFrEF) (n = 36), and reference controls (RC) (n = 50). Higher CS indicates cardiomyocyte tubule dysfunction.ResultsINOCA, HFpEF, and HFrEF women were older than RC (p < .05). Higher CS was associated with vasoconstriction to acetylcholine (r = −0.43, p = .011) with a trend towards lower ΔCBF (r = 0.30, p = .086). Higher CS was specific for ΔAch and ΔCBF but had limited sensitivity. INOCA women had higher CS than RC, but lower CS than HFpEF/HFrEF groups (p < .001).ConclusionsCS, a plasma biomarker indicating poor cardiomyocyte health, was higher in women with suspected INOCA as compared to RC, but lower than in women with HFpEF. Elevated CS in suspected INOCA patients represents an intermediate group between health and disease, supporting the hypothesis that CMD may progress to HFpEF. Larger prospective cohort studies are needed to confirm the pathophysiological relationship between cBIN1, CMD, and HFpEF.

Impact of coronary artery bypass grafting (CABG) on coronary collaterals in patients with a chronic total occlusion (CTO).

Chronic total occlusions (CTO) are found commonly in patients with prior coronary artery bypass grafting (CABG). We sought to determine the effect of CABG on collateral robustness in patients with a CTO. Patients with a CTO diagnosed on coronary angiography between July 2010 and December 2019 were included in this study. Patients were classified as either CTO supplied by a functional graft, CTO supplied by collaterals from a non-grafted donor vessel (non-grafted) or a CTO supplied by collaterals from a grafted donor vessel (grafted). The degree of collateral robustness was determined by the Rentrop classification and collateral connection (CC) grade. Demographic, angiographic and clinical outcomes were recorded. A total of 2088 CTO lesions were identified, of which 878 (42.0%) were supplied by a functional graft, 994 (47.6%) CTOs were supplied by a non-grafted donor vessel and 216 (10.3%) CTOs were supplied by a grafted donor vessel. CTOs supplied by a grafted donor vessel had lower rates of robust collaterals (37.0% vs 83.0%, p < 0.0001) with less mature collaterals as determined by the Rentrop grade (p < 0.0001) and CC grade (p < 0.0001) as compared to CTOs supplied by a non-grafted donor vessel. In patients with a previous CABG, a grafted donor vessel results in less robust coronary collaterals with lower Rentrop and CC grade compared to an ungrafted donor vessel. This may be attributable to changes in coronary blood flow and shear stress, and may be a factor in the lower procedural success rates for CTO intervention in patients with prior CABG.

Coronary microvascular dysfunction pathophysiology in COVID-19.

Recently, accumulating evidence has highlighted the role of endothelial dysfunction in COVID‐19 progression. Coronary microvascular dysfunction (CMD) plays a pivotal role in cardiovascular disease (CVD) and CVD‐related risk factors (eg, age, gender, hypertension, diabetes mellitus, and obesity). Equally, these are also risk factors for COVID‐19. The purpose of this review was to explore CMD pathophysiology in COVID‐19, based on recent evidence. COVID‐19 mechanisms were reviewed in terms of imbalanced renin‐angiotensin‐aldosterone‐systems (RAAS), systemic inflammation and immune responses, endothelial dysfunction, and coagulatory disorders. Based on these mechanisms, we addressed CMD pathophysiology within the context of COVID‐19, from five perspectives. The first was the disarrangement of local RAAS and Kallikrein‐kinin‐systems attributable to SARS‐Cov‐2 entry, and the concomitant decrease in coronary microvascular endothelial angiotensin I converting enzyme 2 (ACE2) levels. The second was related to coronary microvascular obstruction, induced by COVID‐19‐associated systemic hyper‐inflammation and pro‐thrombotic state. The third was focused on how pneumonia/acute respiratory distress syndrome (ARDS)‐related systemic hypoxia elicited oxidative stress in coronary microvessels and cardiac sympathetic nerve activation. Fourthly, we discussed how autonomic nerve dysfunction mediated by COVID‐19‐associated mental, physical, or physiological factors could elicit changes in coronary blood flow, resulting in CMD in COVID‐19 patients. Finally, we analyzed reciprocity between the coronary microvascular endothelium and perivascular cellular structures due to viremia, SARS‐CoV‐2 dissemination, and systemic inflammation. These mechanisms may function either consecutively or intermittently, finally culminating in CMD‐mediated cardiovascular symptoms in COVID‐19 patients. However, the underlying molecular pathogenesis remains to be clarified.

A randomized, placebo-controlled, double-blinded clinical trial of colchicine to improve vascular health in people living with HIV.

People living with HIV (PWH) experience an increased burden of coronary artery disease (CAD) believed to be related, in part, to an interplay of chronically increased inflammation and traditional risk factors. Recent trials suggest cardiovascular benefits of the anti-inflammatory, colchicine, in HIV-seronegative CAD patients. However, the impact of colchicine on impaired vascular health, as measured by coronary endothelial function (CEF), an independent contributor to CAD, has not been studied in PWH. We tested the hypothesis that colchicine improves vascular health in PWH. This was a randomized, placebo-controlled, double-blinded trial in 81 PWH to test whether low-dose colchicine (0.6 mg daily) improves CEF over 8-24 weeks. Coronary and systemic endothelial function and serum inflammatory markers were measured at baseline, and at 8 and 24 weeks. The primary endpoint was CEF, measured as the change in coronary blood flow from rest to that during an isometric handgrip exercise, an endothelial-dependent stressor, measured with non-invasive MRI at 8 weeks. Colchicine was well tolerated and not associated with increased adverse events. However, there were no significant improvements in coronary or systemic endothelial function or reductions in serum inflammatory markers at 8 or 24 weeks with colchicine as compared to placebo. In PWH with no history of CAD, low-dose colchicine was well tolerated but did not improve impaired coronary endothelial function, a predictor of cardiovascular events. These findings suggest that this anti-inflammatory approach using colchicine in PWH does not improve vascular health, the central, early driver of coronary atherosclerosis.

The Protective Effect of Cx43 Protein-Mediated Phosphocreatine on Myocardial Ischemia/Reperfusion Injury.

Objectives To verify the protective effect of phosphocreatine on myocardium in an ischemic model and the possible mechanism of action. Methods The model of myocardial ischemia/reperfusion (I/R) was established by the ligation balloon method. 30 SD rats were randomly divided into three groups, n = 10 in each group. Sham operation group: the coronary artery was not blocked and observed for 120 minutes. The ischemia/reperfusion (I/R) group was given ischemia for 30 minutes and ischemia reperfusion for 90 minutes. Phosphocreatine (PCr) group: after 30 minutes of ischemia, the rats were intraperitoneally injected with PCr (200 mg/kg) for 90 minutes. The animal groups of myocardial ischemia/reperfusion model in vitro were the same as those in vivo. The heart was removed by thoracotomy and washed immediately in H-K buffer solution. Then, the heart was installed on the Langendorff instrument. The concentration of PCr perfusion fluid in the PCr group was 10 mmol/L. The changes in coronary blood flow in isolated myocardium were recorded. The heart rate and electrocardiogram were recorded by RM6240BT. At the end of the experiment, myocardial pathological sections and Cx43 immunofluorescence staining were made, and the contents of malondialdehyde (MDA) in myocardial tissue were detected. Results Phosphocreatinine treatment improved the myocardial ischemia model, performance in electrocardiogram (ECG) changes (ST segment apparent), and histological changes (decrease in necrotic myocardial cells, inflammatory cell infiltration, and a reduction in myocardial edema). At the same time, MDA decreased, while coronary blood flow and Cx43 expression significantly improved. Conclusions Phosphocreatine can improve the electrocardiogram and restore histologic changes in ischemic myocardium and coronary blood flow. The postulated mechanism is by inhibiting the generation of free oxygen radicals and restoring the expression of Cx43 protein.

Ventricular strain is compromised outside of the coronary autoregulatory range – assessment by cardiovascular magnetic resonance

Introduction Coronary autoregulation maintains near-constant myocardial blood flow in a range of approximately 60-140 mmHg of mean arterial pressure (MAP). Using oxygenation-sensitive (OS) cardiovascular magnetic resonance (CMR), we showed that myocardial oxygenation is compromised at MAP levels below the lower limit of this range. Above its upper limit we observed luxury perfusion and mild oxygen excess. There is a lack of data exploring the relationship between coronary autoregulation, myocardial oxygenation and ventricular function. CMR feature tracking software allows to quantify myocardial deformation and strain in OS images. Our aim was to explore our data from an animal study for associations between myocardial function, myocardial oxygenation and coronary blood flow (CBF) over a wide range of MAP levels. Methods In ten anaesthetized swine a flow probe was surgically attached to the proximal left anterior descending coronary artery before the animals were placed into a 3 Tesla MRI scanner. Starting from a baseline of 70 mmHg, MAP was varied in steps of 10-15 mmHg using phenylephrine and urapidil, respectively. At each MAP level, OS cine images and CBF readings of the anterior descending coronary artery were obtained, as well as arterial and coronary sinus blood gas samples to determine myocardial oxygen extraction ratio. Using feature tracking-software, strain data were acquired from images by tracing endo- and epicardial contours in end-diastole, from which peak global circumferential strain (GCS) was calculated for both ventricles. The relationships of peak GCS to MAP, CBF and myocardial oxygenation were established. Results We analysed 101 MAP levels, which ranged between 35 and 196 mmHg. Oxygenation as assessed by OS-CMR showed a curvi-linear relationship to MAP, with a steeper decrease below the lower limit of the autoregulatory range and an increase above its upper limit. Peak GCS of both ventricles became progressively impacted when MAP was forced from its baseline (70 mmHg) towards and beyond the lower and upper autoregulatory limit (dashed yellow lines in figure). There was no apparent association between changes of peak GCS and CBF. GCS of left ventricular myocardium decreased linearly with increasing myocardial oxygen extraction ratio (r=0.261, p=0.026), and in a non-linear fashion with decreasing myocardial tissue oxygenation. Discussion In a porcine model with non-diseased hearts, biventricular systolic function becomes compromised when MAP reaches levels either below or above coronary autoregulatory limits. Contractile dysfunction at pressures below the lower limit appears to be caused by myocardial deoxygenation. Conversely, hypertension-induced systolic dysfunction is associated with increased coronary flow and oxygen excess, which points to high afterload rather than O2 demand/supply imbalance as the most likely mechanism. We conclude that in hearts without coronary disease, global strain abnormalities elicited by hypotensive or hypertensive stress also differ in their underlying pathophysiological mechanisms.

Functional coronary angiography in symptomatic patients with no obstructive coronary artery disease.

Patients without obstructive coronary artery disease (CAD) may have epicardial or microvascular dysfunction. The purpose of this study was to characterize patterns of epicardial and microvascular dysfunction in men and women with stable and unstable angina undergoing functional coronary angiography to inform medical therapy. 163 symptomatic patients with ≤50% diameter stenosis and fractional flow reserve (FFR) > 0.8 underwent endothelium-dependent epicardial and microvascular function after intracoronary acetylcholine (10-4 M, 81 mcg over 3minutes). Endothelium-independent function was assessed using coronary flow reserve (CFR) and hyperemic microvascular resistance (HMR) after intravenous adenosine (140ug/kg/min). Coronary microvascular dysfunction (CMD) was defined as CFR < 2.5, HMR ≥2, or ≤50% change in coronary blood flow with acetylcholine (CBFACH ). Seventy-two percent had endothelial-dependent epicardial dysfunction (response to ACH: % ∆ in coronary artery diameter and ∆%CBFACH ) and 92% had CMD. Among CMD patients, 65% had CFR < 2.5, 35% had HMR ≥2, and 60% had CBFACH change ≤50%. CFR modestly correlated with HMR (r=-0.38, p < .0001). Among patients with normal CFR, 26% had abnormal epicardial and 20% had abnormal microvascular endothelial dysfunction. Women had a lower CFR (p=.02), higher FFR (p=.03) compared to men. There were no differences in epicardial and microvascular function between patients with stable and unstable angina. In patients with no obstructive CAD: CMD is prevalent, abnormal CFR does not correlate with epicardial or microvascular endothelial dysfunction, women have lower CFR, higher FFR but similar endothelial function compared to men.

Abstract P141: A Novel GWAS Locus Influences Microvascular Response to Acute Psychological Stress

Background: Excessive peripheral microvascular constriction during acute psychological stress, measured using peripheral arterial tonometry reflects similar changes in coronary blood flow and is a predictor of adverse cardiovascular outcomes. The ratio of digital pulse wave amplitude during stress compared to rest (sPAT) is used to estimate the degree of microvascular response to stress. We sought to determine if genetic factors contribute to the degree of microvascular constriction during mental stress. Methods: A total of 642 post-MI and stable CAD subjects from two prospective cohort studies underwent mental stress testing with a standardized public speaking stressor. Digital pulse wave amplitude was continuously measured using PAT and the stress/rest PAT ratio (sPAT) of pulse wave amplitude during mental stress/baseline was calculated. Genotyping was performed using Illumina’s Multi-Ethnic Genotyping Array (MEGA) platform and imputed to the 1000 Genome reference panel. Race stratified genome-wide association studies (GWAS) of sPAT were conducted using linear regression of additive genetic mode adjusted for age, sex and population stratification in the two cohorts. A trans-ethnic meta-analysis integrated the four sets GWAS results. Results: Mean age was 63±9; 65% male, 35% Black. We identified two SNPs in linkage disequilibrium on chr4:185503564 and chr4:185491706 rs13353812 (with 35% and 28% allele frequency, respectively) that were associated with greater sPAT ratio ( P = 1.42E-08). The mean sPAT ratio during mental stress for subjects with none, one and two AT insertion alleles of SNP chr4:185503564 were 0.67, 0.76 and 0.93, respectively, an average of 12% (P &lt; 0.001), per allele. Results were similar for G insertion alleles of SNP rs13353812. The nearest gene of the sPAT-associated locus is CASP3 which encodes caspase, an essential protein for apoptosis signaling and brain and hematopoietic stem cell development. Conclusion: We have identified a genetic basis for stress-induced vasomotion. Presence of the chr4:185503564 allele is associated with less vasoconstriction during mental stress, and thus may be protective against long term cardiovascular risk. These findings need further exploration.

Prevalence of myocardial bridging associated with coronary endothelial dysfunction in patients with chest pain and non-obstructive coronary artery disease.

Myocardial bridging (MB), characterised by the epicardial coronary vessel diving into the myocardium, is present in up to one third of adults and is associated with angina and acute coronary syndromes. MB is accompanied by altered blood flow mechanics and regional changes in wall sheer stress. The purpose of this study was to determine the association between myocardial bridging and coronary endothelial dysfunction. Patients presenting with chest pain and found to have non-obstructive CAD (stenosis <40%) on angiography underwent an invasive assessment of epicardial and microvascular endothelial function. Epicardial endothelial function was assessed by measuring the percent change in coronary artery diameter in response to intracoronary infusions of acetylcholine (%ΔCADAch). Epicardial endothelial dysfunction was defined as a %ΔCADAch of <-20%. Microvascular endothelial function was assessed by the percent change in coronary blood flow in response to intracoronary infusions of acetylcholine (%ΔCBFAch), and microvascular endothelial dysfunction was defined as a %ΔCBFAch of <50%. MB was diagnosed angiographically by identifying the characteristic reduction in minimal luminal diameter during systole. Patients were divided into those with and those without MB, and the frequency of epicardial endothelial dysfunction and microvascular endothelial dysfunction was compared between patients with versus those without MB. Between 1993 and 2012, 1,469 patients (mean age 50.4 years, 35% male) underwent coronary angiography and invasive testing of endothelial function. Two hundred and eight (14.2%) patients were found to have MB in the LAD. Patients with any MB had a significantly higher frequency of endothelial dysfunction within the mid and/or distal vessel segment compared to patients without MB (60.1% vs 50.4%, p=0.012). In multivariate analyses, mid and/or distal vessel MB was a significant predictor of mid and/or distal vessel epicardial endothelial dysfunction (OR 1.44, 95% CI: 1.04-2.00, p=0.029) and of microvascular endothelial dysfunction (OR 1.34, 95% CI: 1.00-1.82, p=0.050). MB co-localises with epicardial endothelial dysfunction and is significantly associated with microvascular endothelial dysfunction in symptomatic patients with non-obstructive CAD, supporting its potential role as a mechanism for angina in symptomatic patients with MB.