Coronary Vasodilator Capacity Research Articles

Coronary microvascular dysfunction and autoregulatory capacity interfere with resting Dicrotic notch morphology

Coronary microvascular vasodilator capacity is substantially associated with coronary pressure waveform and dicrotic notch morphology, with or without concomitant epicardial disease. A prominent dicrotic notch is associated with preserved microvascular vasodilatory capacity and adequate resting microvascular tonus without relative hyperaemic state, cumulatively indicating a better microcirculatory health.

Abstract 18474: Impact of the Endothelial Nucleotidase on Vascular Function

Introduction: Cardiovascular disease (CVD) is the leading cause of mortality and morbidity worldwide. Endothelial dysfunction—marked by poor endothelial-derived vasodilation—is a major prelude to atherosclerotic cardiovascular disease. Endothelial cells (EC) play a vital role in modulating thrombosis, atherosclerosis, and blood flow. One tool the endothelium uses to communicate with surrounding tissues is purinergic signaling. EC express both purinergic receptors to respond to stimuli and ectonucleotidases to facilitate this communication. CD39 is believed to be vital in maintaining homeostasis within the vasculature as it is an ectonucleotidase responsible for converting extracellular ATP and ADP into AMP. However, little is known about the role of endothelial expressed CD39 on vascular function. Hypothesis: We hypothesized that the absence of endothelial CD39 causes an elevation in extracellular adenine-nucleotides, thus causing an elevated endothelial-derived vasodilatory response. Methods: We generated a novel cre-lox endothelial cell-specific CD39 knockout mouse model ( Tie2cre+ CD39flox/flox ) to explore the enzyme’s role in vascular physiology. After validation via flow cytometry and enzyme activity assays, we assessed mouse blood pressure along with EC-derived vasodilatory capacity. Coronary vasodilatory capacity or coronary flow reserve (CFR) was measured via an isoflurane-induced-vasodilation coronary flow model and imaged using transthoracic ultrasound. Results: We noted that the EC specific CD39 knockout mice (EC-cKO) exhibited significantly lower systolic, diastolic, and mean arterial blood pressures at baseline, showing the EC-cKO mice having reduced pressures of over 10mmHg compared to wild-type (EC-WT) (p<0.05). This suggested fundamental differences in vascular function, prompting assessment of CFR. The EC-cKO mice showed a 75.9% increase in CFR (p<0.05) compared to wild-type (EC-WT). Conclusions: The loss of CD39 on EC leads to an overall protective phenotype—EC-cKO mice show drastically lower blood pressures, likely due to improved vasodilatory capacity under healthy conditions. This study shows CD39 inhibition’s potential as a therapeutic target in terms of improving vascular function.

Post COVID-19 syndrome with impairment of flow-mediated epicardial vasodilation and flow reserve.

AimsThe aim of this study is to evaluate whether post‐acute sequelae of COVID‐19 cardiovascular syndrome (PASC‐CVS) is associated with alterations in coronary circulatory function.Materials and MethodsIn individuals with PASC‐CVS but without known cardiovascular risk factors (n = 23) and in healthy controls (CON, n = 23), myocardial blood flow (MBF) was assessed with 13N‐ammonia and PET/CT in mL/g/min during regadenoson‐stimulated hyperemia, at rest, and the global myocardial flow reserve (MFR) was calculated. MBF was also measured in the mid and mid‐distal myocardium of the left ventricle (LV). The Δ longitudinal MBF gradient (hyperemia minus rest) as a reflection of an impairment of flow‐mediated epicardial vasodilation, was calculated.ResultsResting MBF was significantly higher in PASC‐CVS than in CON (1.29 ± 0.27 vs. 1.08 ± 0.20 ml/g/min, p ≤ .024), while hyperemic MBFs did not differ significantly among groups (2.46 ± 0.53 and 2.40 ± 0.34 ml/g/min, p = .621). The MFR was significantly less in PASC‐CVS than in CON (1.97 ± 0.54 vs. 2.27 ± 0.43, p ≤ .031). In addition, there was a Δ longitudinal MBF gradient in PASC‐CVS, not observed in CON (−0.17 ± 0.18 vs. 0.04 ± 0.11 ml/g/min, p < .0001).ConclusionsPost‐acute sequelae of COVID‐19 cardiovascular syndrome may be associated with an impairment of flow‐mediated epicardial vasodilation, while reductions in coronary vasodilator capacity appear predominantly related to increases in resting flow in women deserving further investigations.

Challenges in Diagnosis and Functional Assessment of Coronary Artery Disease in Patients With Severe Aortic Stenosis.

More than half of patients with severe aortic stenosis (AS) over 70 years old have coronary artery disease (CAD). Exertional angina is often present in AS-patients, even in the absence of significant CAD, as a result of oxygen supply/demand mismatch and exercise-induced myocardial ischemia. Moreover, persistent myocardial ischemia leads to extensive myocardial fibrosis and subsequent coronary microvascular dysfunction (CMD) which is defined as reduced coronary vasodilatory capacity below ischemic threshold. Therefore, angina, as well as noninvasive stress tests, have a low specificity and positive predictive value (PPV) for the assessment of epicardial coronary stenosis severity in AS-patients. Moreover, in symptomatic patients with severe AS exercise testing is even contraindicated. Given the limitations of noninvasive stress tests, coronary angiography remains the standard examination for determining the presence and severity of CAD in AS-patients, although angiography alone has poor accuracy in the evaluation of its functional severity. To overcome this limitation, the well-established invasive indices for the assessment of coronary stenosis severity, such as fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR), are now in focus, especially in the contemporary era with the rapid increment of transcatheter aortic valve replacement (TAVR) for the treatment of AS-patients. TAVR induces an immediate decrease in hyperemic microcirculatory resistance and a concomitant increase in hyperemic flow velocity, whereas resting coronary hemodynamics remain unaltered. These findings suggest that FFR may underestimate coronary stenosis severity in AS-patients, whereas iFR as the non-hyperemic index is independent of the AS severity. However, because resting coronary hemodynamics do not improve immediately after TAVR, the coronary vasodilatory capacity in AS-patients treated by TAVR remain impaired, and thus the iFR may overestimate coronary stenosis severity in these patients. The optimal method for evaluating myocardial ischemia in patients with AS and co-existing CAD has not yet been fully established, and this important issue is under further investigation. This review is focused on challenges, limitations, and future perspectives in the functional assessment of coronary stenosis severity in these patients, bearing in mind the complexity of coronary physiology in the presence of this valvular heart disease.

Role of Inflammation in Coronary Epicardial and Microvascular Dysfunction.

There is accumulating evidence highlighting a close relationship between inflammation and coronary microvascular dysfunction (CMD) in various experimental and clinical settings, with major clinical implications. Chronic low-grade vascular inflammation plays important roles in the underlying mechanisms behind CMD, especially in patients with coronary artery disease, obesity, heart failure with preserved ejection fraction and chronic inflammatory rheumatoid diseases. The central mechanisms of coronary vasomotion abnormalities comprise enhanced coronary vasoconstrictor reactivity, reduced endothelium-dependent and -independent coronary vasodilator capacity and increased coronary microvascular resistance, where inflammatory mediators and responses are substantially involved. How to modulate CMD to improve clinical outcomes of patients with the disorder and whether CMD management by targeting inflammatory responses can benefit patients remain challenging questions in need of further research. This review provides a concise overview of the current knowledge of the involvement of inflammation in the pathophysiology and molecular mechanisms of CMD from bench to bedside.

Abstract 13834: Low Coronary Microvascular Vasodilator Capacity Relative to Myocardial Mass Predicts Cardiovascular Risk in Hypertensive Heart Disease

Introduction: Increased left ventricular (LV) mass and coronary microvascular disease (CMD) have been independently associated with risk of heart failure (HF) and mortality in hypertensive heart disease. Inability to match increased LV mass and corresponding metabolic demand with adequate perfusion may be important in the development of HF. Hypothesis: PET-derived coronary microvascular vasodilator capacity indexed to LV mass (stress P/M) is associated with LV structure (end-diastolic volume index, EDVi, and end-systolic volume index, ESVi), LV function (LVEF) and identifies patients at elevated risk for HF hospitalization and death. Methods: We studied a retrospective cohort of consecutive symptomatic patients with hypertension presenting for rest/stress myocardial perfusion PET with LVEF ≥ 40%, normal perfusion (summed stress score &lt; 3), and no prior CAD, cardiomyopathy, or HF. Stress P/M was defined as stress myocardial blood flow (MBF) divided by LV mass. CMD was defined by myocardial flow reserve (MFR = stress/rest MBF) ≤ 1.8. Associations between stress P/M and LV structure and function were assessed, and prognostic value for HF hospitalization and all-cause mortality was evaluated. Results: We studied 358 patients: mean age 62.7±12.3y, 72.4% female. Global stress MBF was negatively associated with LV mass (β=-0.023, P&lt;0.001). Lower stress P/M was independently associated with greater EDVi (β=-0.557, p&lt;0.001), greater ESVi (β=-0.943, p&lt;0.001), and lower LVEF (β=0.819, p&lt;0.001). A below-median stress P/M conferred increased risk of mortality or incident HF hospitalization (adjusted HR=1.73 [95% CI: 1.10-2.73], p=0.02) (Figure 1A) and conferred comparable risk to CMD in those with preserved MFR (Figure 1B). Conclusions: Coronary microvascular vasodilator capacity relative to myocardial mass integrates microvascular physiology with LV structure and function and refines risk of HF and all-cause death in hypertensive heart disease.

Differences in coronary vasodilatory capacity and atherosclerosis in endurance athletes using coronary CTA and computational fluid dynamics (CFD): Comparison with a sedentary lifestyle

BackgroundThe aim was to assess the effect of endurance exercise on coronary vasodilatory capacity and atherosclerosis by coronary computed tomography angiography (CTA) and computational fluid dynamic (CFD) modelling. Methods100 subjects (age 56.2y±11, 29 females) who underwent coronary CTA were included into this retrospectively matched cohort study. Endurance athletes (≥1 h per unit and ≥3 times per week training) were compared to controls with a sedentary lifestyle, and within subgroups with and without sublingual nitroglycerin preparation. CTA image analysis included coronary stenosis severity (CADRADS), total (segment involvement score = SIS) and mixed plaque burden (G-score), high-risk plaque criteria, the coronary artery calcium score (CACS) and CFD analysis including Fractional Flow Reserve (FFRCT), myocardial mass (M), total vessel lumen volume (V) and volume-to-mass (V/M) ratio. ResultsThe prevalence of atherosclerosis by CTA was 65.4 % and >50 % coronary stenosis was found in 17.3 % of athletes. Coronary stenosis severity (CADRADS), total and mixed non-calcified plaque burden (SIS and G-score) were lower in athletes (p = 0.003 and p < 0.001) but not CACS (p = 0.055) and less high-risk plaques were found (p < 0.001). The G-score was correlated with distal FFRCT (p = 0.025). V/M-ratio was different between athletes who received nitroglycerin compared with those who did not (V/M: 21.1 vs. 14.8; p < 0.001), but these differences were not observed in the control subjects. ConclusionEndurance training improves coronary vasodilatory capacity and reduces high-risk plaque and mixed non-calcifed plaque burden as assessed by coronary CTA angiography. Our study may advocate coronary CTA with FFRCT for evaluation of coronary artery disease in endurance athletes.

Contribution of Age-Related Microvascular Dysfunction to Abnormal Coronary: Hemodynamics in Patients With Ischemic Heart Disease

ObjectivesThis study sought to investigate the contribution of age-related microcirculatory dysfunction to abnormal coronary hemodynamics in patients with coronary atherosclerosis. BackgroundImpairment in myocardial blood supply in patients with coronary atherosclerosis can be accentuated due to age-related changes in microcirculatory function. MethodsIntracoronary pressure and flow were measured with the Doppler technique in 299 vessels (228 patients), and the thermodilution technique in 120 vessels (99 patients). In 172 patients, Doppler measurements were also performed in unobstructed vessels. Associations of coronary hemodynamics with aging were studied in both the stenosed and unobstructed arteries. ResultsAging was associated with a progressive increase in minimal microvascular resistance and a progressive decrease in hyperemic flow in both obstructed and nonobstructed coronary arteries. As such, coronary flow reserve decreased with advancing age. Epicardial stenosis severity assessed by resting Pd/Pa, basal stenosis resistance index, and hyperemic stenosis resistance index was equivalent across age groups. By contrast, fractional flow reserve increased with advancing age. Consequently, the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of concomitant focal epicardial and diffuse or microvascular disease (relative risk: 1.6; 95% confidence interval: 1.1 to 2.3; p = 0.017) increased with advancing age, whilst the adjusted risk of a fractional flow reserve/coronary flow reserve pattern reflective of non–flow-limiting stenosis with a healthy microcirculation decreased (relative risk: 0.7; 95% CI: 0.5 to 1.0; p = 0.022). ConclusionsAging is associated with progressive pan-myocardial impairment of coronary vasodilatory capacity due to an increase in minimal microvascular resistance. Concomitant aging-related impairment in microvascular function impacts the pathophysiology of ischemic heart disease in the individual patient and is not adequately identified by hyperemic coronary pressure measurements alone.

Frequency and angiographic characteristics of coronary microvascular dysfunction in stable angina: a hybrid imaging study.

Coronary microvascular dysfunction (CMD) can cause angina in the absence of obstructive coronary artery disease (CAD). We studied the frequency and angiographic characteristics of CMD in symptomatic patients with suspected stable CAD and identified CMD as diffusely abnormal coronary vasodilator capacity by positron emission tomography (PET) perfusion imaging. We recruited prospectively 189 patients with intermediate pre-test probability of CAD who underwent coronary computed tomography angiography and quantitative 15O-water PET perfusion imaging followed by invasive coronary angiography, and assessment of fractional flow reserve when feasible. Prevalence of obstructive epicardial CAD was 37%. Absolute myocardial blood flow was diffusely reduced (<2.4 mL/g/min) within the left ventricle during adenosine stress in 32 (17%) patients. In 15 (8%) patients, this was explained by three-vessel obstructive CAD, whereas the remaining 17 (9%) were diagnosed with CMD. Of these, 2 (1% of all patients) had no coronary atherosclerosis, 5 (3% of all patients) had non-obstructive atherosclerosis, and in 10 (5% of all patients) CMD co-existed with obstructive CAD. Atypical angina or non-anginal chest pain (53%) was the most common presentation. Older age and male sex were associated with CMD, but other risk factors of CAD were equally common in patients with or without CMD. Coronary microvascular dysfunction exists in 9% of symptomatic stable patients with suspected CAD. However, the prevalence of microvascular dysfunction without any coronary atherosclerosis is low (1%) in this population.

Myocardial Blood Flow and Inflammatory Cardiac Sarcoidosis

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

Potential Role of Cardiovascular Imaging in Improving Cardiovascular Outcome in Coronary Artery Disease.

There is increasing interest in cardiovascular imaging modalities in the detection of subclinical and clinically-manifested coronary artery disease (CAD) to improve cardiovascular outcome in these patients. SPECT/CT and PET/CT can be applied for the assessment of myocardial perfusion and myocardial blood flow (MBF) quantification in CAD detection and characterization, while CT is predominantly used to identify coronary plaque burden and epicardial narrowing. In addition, PET/CT plays an increasing role in the detection of the "vulnerable" plaque in the epicardial artery. Imaging of myocardial perfusion with SPECT, SPECT/CT and PET/CT is a mainstay in clinical practice for the identification of flow-limiting epicardial lesions and risk stratification of patients with suspected or known CAD. In this direction, the concurrent ability of PET/CT to determine regional myocardial blood flow (MBF) in ml/g/min at rest and during pharmacologically- induced hyperemic flows allows the calculation of the myocardial flow reserve (MFR) that may unravel reductions in coronary vasodilator capacity, as functional precursor of the CAD process, monitor its response to preventive medical intervention, yield important prognostic information in subclinical - and clinically-manifested CAD, and contributes to identify the flow-limiting effect of single lesions in multivessel CAD. Adding noncontrast computed-tomography (CT) measurements of coronary artery calcifications has further improved the reclassification of cardiovascular risk in asymptomatic individuals with intermediate probability of the presence of CAD. With contrast CT, the non-invasive visualization of coronary vessels, CAD-related plaque burden and stenosis has become feasible. Yet, a definite identification of the &quot;vulnerable plaque&quot; is still a matter of ongoing research. PET/CT in conjunction with various positron-emitting radiotracer yields promise in the detection of the &quot;vulnerable plaque," that, however, needs further clinical evaluation in CAD patients. Multimodality imaging in cardiovascular disease is likely to further advances and refine the identification and characterization of cardiovascular pathology in the near future.

Stress myocardial blood flow correlates with ventricular function and synchrony better than myocardial perfusion reserve: A Nitrogen-13 ammonia PET study

BackgroundCardiac PET quantifies stress myocardial blood flow (MBF) and perfusion reserve (MPR), while ECG-gated datasets can measure components of ventricular function simultaneously. Stress MBF seems to outperform MPR in the detection of significant CAD. However, it is uncertain which perfusion measurement is more related to ventricular function. We hypothesized that stress MBF correlates with ventricular function better than MPR in patients studied for suspected myocardial ischemia. MethodsWe studied 248 patients referred to a rest and adenosine-stress Nitrogen-13 ammonia PET. We performed a multivariate analysis using systolic function (left ventricular ejection fraction, LVEF), diastolic function (mean filling rate in diastole, MFR/3), and synchrony (Entropy) as the outcome variables, and stress MBF, MPR, and relevant covariates as the predictors. Secondarily, we repeated the analysis for the subgroup of patients with and without a previous myocardial infarction (MI). Results166 male and 82 female patients (mean age 63 ± 11 and 67 ± 11 year, respectively) were included. 60% of the patients presented hypertension, 57% dyslipidemia, 21% type 2 diabetes mellitus, 45% smoking, and 34.7% a previous MI. Mean stress MBF was 1.99 ± 0.75 mL/g/min, MPR = 2.55 ± 0.89, LVEF = 61.6 ± 15%, MFR/3 = 1.12 ± 0.38 EDV/s, and Entropy = 45.6 ± 11.3%. There was a significant correlation between stress MBF (P < .001) and ventricular function. This was stronger than the one for MPR (P = .063). Sex, age, diabetes, and extent of previous MI were also significant predictors. Results were similar for the analyses of the 2 subgroups. ConclusionStress MBF is better correlated with ventricular function than MPR, as evaluated by Nitrogen-13 ammonia PET, independently from other relevant cardiovascular risk factors and clinical covariates. This relationship between coronary vasodilatory capacity and ventricular function is sustained across groups with and without a previous MI.

Left atrial enlargement increases the risk of major adverse cardiac events independent of coronary vasodilator capacity.

Longstanding uncontrolled atherogenic risk factors may contribute to left atrial (LA) hypertension, LA enlargement (LAE) and coronary vascular dysfunction. Together they may better identify risk of major adverse cardiac events (MACE). The aim of this study was to test the hypothesis that chronic LA hypertension as assessed by LAE modifies the relationship between coronary vascular function and MACE. In 508 unselected subjects with a normal clinical (82)Rb PET/CT, ejection fraction ≥40 %, no prior coronary artery disease, valve disease or atrial fibrillation, LAE was determined based on LA volumes estimated from the hybrid perfusion and CT transmission scan images and indexed to body surface area. Absolute myocardial blood flow and global coronary flow reserve (CFR) were calculated. Subjects were systematically followed-up for the primary end-point - MACE - a composite of all-cause death, myocardial infarction, hospitalization for heart failure, stroke, coronary artery disease progression or revascularization. During a median follow-up of 862 days, 65 of the subjects experienced a composite event. Compared with subjects with normal LA size, subjects with LAE showed significantly lower CFR (2.25 ± 0.83 vs. 1.95 ± 0.80, p = 0.01). LAE independently and incrementally predicted MACE even after accounting for clinical risk factors, medication use, stress left ventricular ejection fraction, stress left ventricular end-diastolic volume index and CFR (chi-squared statistic increased from 30.9 to 48.3; p = 0.001). Among subjects with normal CFR, those with LAE had significantly worse event-free survival (risk adjusted HR 5.4, 95 % CI 2.3 - 12.8, p < 0.0001). LAE and reduced CFR are related but distinct cardiovascular adaptations to atherogenic risk factors. LAE is a risk marker for MACE independent of clinical factors and left ventricular volumes; individuals with LAE may be at risk of MACE despite normal coronary vascular function.

Preservation of Coronary Vasodilator Responses to the Nitroxyl Donor Angeli's Salt after Ischemia/Reperfusion of the Rat Isolated Heart

We previously reported that Angeli's salt (AS) simultaneously increases cardiac contractility and coronary flow (CF) in normal rat hearts. In this study, we tested the hypothesis that the cardiac contractile and vasodilator actions of AS will be preserved after myocardial ischaemia‐reperfusion (I/R). Isolated hearts from male rats were Langendorff‐perfused for 90 min (sham) or subjected to 30 min equilibration followed by 30 min global ischaemia and 30 min reperfusion. Haemodynamic responses to AS (1 nmol ‐ 10 μmol), the nitric oxide donor, diethylamine NONOate (DEA/NO, 1 nmol – 1 μmol) and the clinically used inotrope for heart failure, dobutamine (DOB, 0.1 nmol – 0.1 μmol) were determined. I/R reduced the cardiac contractile action of AS [change (Δ) in left ventricular (LV) +dP/dt (% baseline) by 10 μmol: sham 77 ± 13%, I/R‐treated hearts 17 ± 5%, p&lt;0.0001] however, I/R had no effect on the AS‐induced increase in heart rate (HR) [Δ HR (% baseline) by 10 μmol: sham 11 ± 3%, I/R‐treated hearts 14 ± 6%] or CF [Δ CF (% baseline) by 1 μmol: sham 72 ± 13%, I/R‐treated hearts 76 ± 15%]. In contrast, the DEA/NO‐induced vasodilatation was reduced by I/R [Δ CF (% baseline) by 1 μmol: sham 78 ± 12%, I/R‐treated hearts 37 ± 8%, p&lt;0.05]. I/R also significantly reduced the DOB‐induced increase in contractility [Δ LV+dP/dt (% baseline) by 10 nmol: sham 71 ± 13%, I/R‐treated hearts 22 ± 4%, p&lt;0.0001] while I/R aggravated DOB‐induced tachycardia [Δ HR (% baseline) by 0.1 μmol: sham 11 ± 4%, I/R‐treated hearts 36 ± 8%, p&lt;0.01], which increases the risk of arrhythmias. These data suggest that AS has superior coronary vasodilator capacity after I/R.

18F]fluorodeoxyglucose uptake in atherosclerotic plaques is associated with reduced coronary flow reserve in mice.

Coronary microvascular dysfunction, observed as impaired coronary vasodilator capacity, is an early manifestation of coronary artery disease. Inflammation plays an important role in different stages of atherogenesis. To study the role of vessel wall inflammation in the development of coronary dysfunction, we compared [(18)F]fluorodeoxyglucose (FDG) uptake in the aorta and coronary flow reserve (CFR) in atherosclerotic mice. We studied healthy young C57BL/6 mice fed a normal diet (n = 7) as well as hypercholesterolemic low-density lipoprotein receptor-disrupted/apolipoprotein B100-expressing (LDLR(-/-)ApoB(100/100)) mice (n = 15) and hypercholesterolemic and diabetic LDLR(-/-)ApoB(100/100)insulinlike growth factor II-overexpressing mice (n = 14) fed a western-type diet, aged 4 to 6 months. Doppler sonography was used to measure CFR as the ratio of coronary flow velocity during isoflurane-induced hyperemia and at rest. Uptake of [(18)F]FDG into the aorta was measured by autoradiography of tissue sections. Histologic sections showed extensive atherosclerosis in the aorta, but coronary arteries were not obstructed. Both hyperemic coronary flow velocity and CFR were reduced (P < .05) in hypercholesterolemic mice with and without diabetes in comparison to healthy young C57BL/6 controls. Among hypercholesterolemic mice, both hyperemic flow velocity and CFR inversely correlated with atherosclerotic plaque [(18)F]FDG uptake in the aorta (r = -0.73; P < .001; r = -0.63; P = .001, respectively). In a multivariate analysis, including animal weight, aortic plaque burden, plasma glucose, plasma cholesterol, and [(18)F]FDG uptake in atherosclerotic plaques, only [(18)F]FDG uptake remained an independent predictor of reduced CFR (β = 0.736; P = .001). The inflammatory activity in atherosclerotic plaques of the aorta independently predicts reduced CFR in atherosclerotic mice without obstructive coronary artery disease. This finding suggests that atherosclerotic inflammation contributes to coronary dysfunction.

Relation of Albuminuria to Coronary Microvascular Function in Patients With Chronic Kidney Disease

The relation between albuminuria and coronary microvascular function in patients with chronic kidney disease (CKD) has not been fully investigated. Therefore, we sought to assess whether albuminuria is associated with coronary flow velocity reserve (CFVR) impairment in patients with CKD. Coronary flow study was prospectively performed in 175 patients with CKD. CFVR of the left anterior descending artery was measured to evaluate coronary microvascular function using transthoracic echocardiography. We divided the patients into 5 groups according to the stages of CKD and analyzed the effect of albuminuria. CFVR gradually decreased with an increase in CKD stages. CFVR in patients with albuminuria was lower than those without albuminuria. In groups with CKD stages 2 and 3, the patients with albuminuria showed lower CFVR than those without albuminuria. Multiple logistic regression analysis revealed that albuminuria, age, and gender were independently associated with CFVR impairment. Of these factors, albuminuria was the most powerful predictor with the risk ratio of 12.4 for CFVR impairment. In conclusion, the more the CKD stages progressed, the more severe CFVR was impaired. Albuminuria was associated with CFVR impairment in patients with CKD; even in mild-to-moderate CKD, patients with albuminuria showed further reduced coronary vasodilator capacity.

Matching between regional coronary vasodilator capacity and corresponding circumferential strain in individuals with normal and increasing body weight

BackgroundTo define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight, overweight, and obese individuals with normal global left-ventricular function. Methods and ResultsMyocardial blood flow at rest and during pharmacologic vasodilation was measured with 13N-ammonia PET/CT in mL/g/minute in normal weight control (CON, n = 12), overweight (OW, n = 10), and obese individuals (OB, n = 10). In addition, resting myocardial function was evaluated as circumferential strain (Єc, %) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98 ± 0.96 vs 2.70 ± 0.66, P = .290), whereas it declined significantly in OB (1.98 ± 1.04, P = .030). Further, global Єc (%) was comparable between CON, OW, and OB (−0.24 ± 0.03, −0.23 ± 0.02, and −0.23 ± 0.04) but it was lowest in OB when normalized to the rate-pressure product (NЄc: −0.31 ± 0.06, −0.32 ± 0.05, and −0.26 ± 0.08). When MFR of the three major coronary territories was correlated with corresponding Єc, a positive association was observed in CON (r = 0.36, P = .030), in OW (r = 0.54, P = .002), and also in OB when relating NЄc to coronary vascular resistance during pharmacologic vasodilation (r = −0.46, P = .010). ConclusionsHigher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non-obese individuals, while this is also observed for reduced MFR in obesity.

Abstract 016: Sugar-Sweetened Beverage Consumption is Inversely Associated with Coronary Flow Reserve among Male Middle-Aged Twins

Introduction: Several previous studies have reported a link between sugar-sweetened beverage (SSB) consumption and numerous cardiovascular disease (CVD) risk factors including hypertension, dyslipidemia, and obesity. However, our understanding of how SSB consumption affects cardiovascular function remains limited. We sought to investigate the association between SSB consumption and coronary flow reserve (CFR), a measure of overall coronary vasodilator capacity and microvascular function. Hypothesis: Increased SSB consumption is associated with lower CFR. Methods: A sample of 320 male middle-aged twins, including 128 monozygotic and dizygotic twin pairs and 64 unpaired twins, with no previous history of coronary heart disease (CHD) and diabetes, was recruited from the Vietnam Era Twin Registry. All twins underwent comprehensive cardiovascular assessments and completed the Willett food-frequency questionnaire. Reported intakes of fruit drinks, regular carbonated beverages with sugar, low-calorie carbonated beverages with sugar, and other SSBs were used to derive habitual daily SSB consumption for the previous 12 months. Positron emission tomography [N 13 ] ammonia with quantitation of myocardial blood flow at rest and after adenosine stress was used to measure CFR. Mixed-effect regression analysis was used to examine the association between SSB consumption and CFR both at the individual level and between and within twin pairs. Potential confounders included demographic characteristics, lifestyle factors (including physical activity), traditional CVD risk factors, total energy intake, and other nutritional factors such as intake of cholesterol, fiber, sodium, alcohol, and saturated, monounsaturated, and polyunsaturated fatty acids. Results: The mean age of the twins was 55 years (SD = 3.2) and 94.4% (302 out of 320) were white. Across quintiles of twins consuming less than 2 SSBs per day, 2 to less than 4, 4 to less than 6, 6 to less than 8, and 8 or more, adjusted geometric mean CFR measurements were, respectively, 2.49, 2.45, 2.43, 2.37, and 2.18 ( P = 0.032 for linear trend) with the top quintile having a 12.4% lower CFR than the bottom quintile. The inverse association observed at the individual level persisted between-pairs ( P = 0.042), but was substantially reduced and no longer significant within twin pairs. These associations did not differ by zygosity. Conclusions: SSB consumption is inversely associated with CFR, a measure of coronary microvascular function, independent of traditional CVD risk factors. However, shared familial factors, such as growing up in the same home environment and adopting parental behaviors throughout youth and adolescence, may mediate the association between SSB consumption and CFR. Our study supports the importance of early-life, family-level interventions to promote healthy eating and improve cardiovascular health.

Abstract MP002: Dietary Intake of Marine Omega-3 Fatty Acids is Directly Associated with Coronary Flow Reserve among Male Middle-Aged Twins

Introduction: Evidence from previous studies suggests that dietary marine omega-3 fatty acids have cardioprotective properties. However, our understanding of the mechanism for these beneficial effects remains limited. We sought to examine the association between marine omega-3 fatty acid intake and coronary flow reserve (CFR), a measure of overall coronary vasodilator capacity and microvascular function. Hypothesis: Increased dietary intake of marine omega-3 fatty acids is associated with higher CFR. Methods: A sample of 259 male middle-aged twins, including 115 monozygotic and dizygotic twin pairs and 29 unpaired twins, with no previous history of coronary heart disease (CHD), was recruited from the Vietnam Era Twin Registry. Prior to the study visit, all twins completed a 3-day food record detailing their diet for the previous three days. Dietary information was analyzed using specialized nutrition software and reported intakes of various types of fish were used to derive marine omega-3 fatty acid (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) intake. CFR was measured using positron emission tomography [N 13 ] ammonia with quantitation of myocardial blood flow at rest and after adenosine stress. Mixed-effect regression analysis was used to assess the association between marine omega-3 fatty acid intake and CFR both at the individual level and within twin pairs. Potential confounders included demographic characteristics, lifestyle factors (including physical activity), traditional cardiovascular disease (CVD) risk factors, use of omega-3 and multivitamin supplements, total energy intake, and other nutritional factors such as intake of cholesterol, sodium, alcohol, sugar-sweetened beverages, and saturated and monounsaturated fatty acids. Results: The twins’ mean age was 54 years (SD = 3.0) and 93.1% (241 out of 259) were white. An increase in dietary intake of marine omega-3 fatty acids of 1 g/d was associated with a 7.6% higher CFR (95% CI: 0.6, 15.2) after adjustment for potential confounders ( P = 0.033). This association also persisted within twin pairs: a 1 g/d within-pair difference in dietary intake of marine omega-3 fatty acids was associated with a 16.3% higher CFR in the twin with the greater dietary intake of marine omega-3 fatty acids than in the co-twin with the lower dietary intake ( P = 0.020). These associations did not differ by zygosity. Conclusions: Dietary intake of marine omega-3 fatty acids is directly associated with CFR, a measure of coronary microvascular function, independent of traditional CVD risk factors and shared familial and genetic factors. Our study suggests a potential novel mechanism for the protective effects of dietary marine omega-3 fatty acids on the cardiovascular system and supports the benefit of consuming marine omega-3 fatty acids to promote cardiovascular health.

Habitual dietary sodium intake is inversely associated with coronary flow reserve in middle-aged male twins

Evidence links dietary sodium to hypertension and cardiovascular disease (CVD), but investigation of its influence on cardiovascular function is limited. We examined the relation between habitual dietary sodium and coronary flow reserve (CFR), which is a measure of overall coronary vasodilator capacity and microvascular function. We hypothesized that increased sodium consumption is associated with lower CFR. Habitual daily sodium intake for the previous 12 mo was measured in 286 male middle-aged twins (133 monozygotic and dizygotic pairs and 20 unpaired twins) by using the Willett food-frequency questionnaire. CFR was measured by positron emission tomography [N(13)]-ammonia, with quantitation of myocardial blood flow at rest and after adenosine stress. Mixed-effects regression analysis was used to assess the association between dietary sodium and CFR. An increase in dietary sodium of 1000 mg/d was associated with a 10.0% lower CFR (95% CI: -17.0%, -2.5%) after adjustment for demographic, lifestyle, nutritional, and CVD risk factors (P = 0.01). Across quintiles of sodium consumption, dietary sodium was inversely associated with CFR (P-trend = 0.03), with the top quintile (>1456 mg/d) having a 20% lower CFR than the bottom quintile (<732 mg /d). This association also persisted within pairs: a 1000-mg/d difference in dietary sodium between brothers was associated with a 10.3% difference in CFR after adjustment for potential confounders (P = 0.02). Habitual dietary sodium is inversely associated with CFR independent of CVD risk factors and shared familial and genetic factors. Our study suggests a potential novel mechanism for the adverse effects of dietary sodium on the cardiovascular system. This trial was registered at clinicaltrials.gov as NCT00017836.