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This study was done to evaluate changes of microvascular function under cold stimulation by measuring coronary flow velocities (CFVs) in vasospastic angina (VA) patients using transthoracic Doppler echocardiography (TTDE). 14 patients with VA and 15 healthy controls were included. CFVs were measured at the distal left anterior descending coronary artery by TTDE at baseline and under cold stimulation. Hyperemia was induced by intravenous adenosine infusion (140 µg/kg/min). At baseline, CFVs and coronary flow reserve (CFR) were not different between controls and VA patients. Under cold stimulation, the degree of increment of CFV with adenosine was lower in VA patients than in controls. Comparing baseline with cold stimulation, coronary flow reserve (CFR) increased (3.1±0.7 to 3.8±1.0, p=0.06) in controls. In contrast, in VA patients, CFR was decreased (2.8±0.9 to 2.6±0.7, p=0.05) and coronary vascular resistance index markedly increased (0.35 to 0.43, p=0.01). Throughout the study, no patient experienced chest pain or ECG changes. In VA patients, CFR was preserved at baseline, but coronary blood flow increase in response to cold stimulation was blunted and CFR was decreased. These findings suggest that endothelial dependent vasodilation is impaired at the coronary microvascular and the epicardial artery level in VA under cold stimulation.

Introduction

Although coronary microembolization (CME) is a frequent phenomenon in patients undergoing percutaneous coronary intervention, few data are available on the changes in left ventricular ejection fraction (LVEF) and coronary flow reserve (CFR) after CME.

Material and methods

In this study, six miniature swine of either sex (body weight 21-25 kg) were used to prepare a CME model. After coronary angiography, 1.2 × 105 microspheres (42 µm) were selectively infused into the left anterior descending artery via an infusion catheter. Left ventricular ejection fraction was evaluated using transthoracic echocardiography; myocardial blood flow was measured using coloured microspheres; and CFR and coronary pressure were measured using Doppler and a pressure wire.

Results

Left ventricular ejection fraction was 0.77 ±0.08 at baseline, 0.69 ±0.08 at 2 h, 0.68 ±0.08 at 6 h, and 0.76 ±0.06 at 1 week (2 h vs. baseline p < 0.05; 6 h vs. baseline p < 0.01). After CME, left ventricular end systolic volume (LVESV) and end diastolic volume (LVEDV) were significant larger 1 week later (p < 0.01 for both), while CFR was significantly reduced at 6 h (1.24 ±0.10 at 6 h vs. 1.77 ±0.30 at baseline, p < 0.01) and myocardial blood flow remained unchanged. Serum ET-1 level was significantly higher only at 6 h after CME (6 h vs. baseline p < 0.05).

Conclusions

Reduction of CFR and LVEF is significant at 6 h after CME and recovers 1 week later with left ventricular dilation.

Background

Older heart failure (HF) patients exhibit exercise intolerance during activities of daily living. We hypothesized that reduced lower extremity blood flow (LBF) due to reduced forward cardiac output would contribute to submaximal exercise intolerance in older HF patients.

Methods and Results

Twelve HF patients both with preserved and reduced left ventricular ejection fraction (LVEF) (aged 68 ± 10 years) without large (aorta) or medium sized (iliac or femoral artery) vessel atherosclerosis, and 13 age and gender matched healthy volunteers underwent a sophisticated battery of assessments including a) peak exercise oxygen consumption (peak VO2), b) physical function, c) cardiovascular magnetic resonance (CMR) submaximal exercise measures of aortic and femoral arterial blood flow, and d) determination of thigh muscle area. Peak VO2 was reduced in HF subjects (14 ± 3 ml/kg/min) compared to healthy elderly subjects (20 ± 6 ml/kg/min) (p = 0.01). Four-meter walk speed was 1.35 ± 0.24 m/sec in healthy elderly verses 0.98 ± 0.15 m/sec in HF subjects (p < 0.001). After submaximal exercise, the change in superficial femoral LBF was reduced in HF participants (79 ± 92 ml/min) compared to healthy elderly (222 ± 108 ml/min; p = 0.002). This occurred even though submaximal stress-induced measures of the flow in the descending aorta (5.0 ± 1.2 vs. 5.1 ± 1.3 L/min; p = 0.87), and the stress-resting baseline difference in aortic flow (1.6 ± 0.8 vs. 1.7 ± 0.8 L/min; p = 0.75) were similar between the 2 groups. Importantly, the difference in submaximal exercise induced superficial femoral LBF between the 2 groups persisted after accounting for age, gender, body surface area, LVEF, and thigh muscle area (p ≤ 0.03).

Conclusion

During CMR submaximal bike exercise in the elderly with heart failure, mechanisms other than low cardiac output are responsible for reduced lower extremity blood flow.

Background

The determination of coronary flow reserve (CFR) is an essential concept at the moment of decision-making in ischemic heart disease. There are several direct and indirect tests to evaluate this parameter. In this sense, dobutamine stress echocardiography is one of the pharmacological method most commonly used worldwide. It has been previously demonstrated that CFR can be determined by this technique. Despite our wide experience with dobutamine stress echocardiography, we ignored the necessary heart rate to consider sufficient the test for the analysis of CFR. For this reason, our main goal was to determine the velocity of coronary flow in each stage of dobutamine stress echocardiography and the heart rate value necessary to double the baseline values of coronary flow velocity in the territory of the left anterior descending (LAD) coronary artery.

Methods

A total of 33 consecutive patients were analyzed. The patients included had low risk for coronary artery disease. All the participants underwent dobutamine stress echocardiography and coronary artery flow velocity was evaluated in the distal segment of LAD coronary artery using transthoracic color-Doppler echocardiography.

Results

The feasibility of determining CFR in the territory of the LAD during dobutamine stress echocardiography was high: 31/33 patients (94%). Mean CFR was 2.67 at de end of dobutamine test.

There was an excellent concordance between delta HR (difference between baseline HR and maximum HR) and the increase in the CFR (correlation coefficient 0.84). In this sense, we found that when HR increased by 50 beats, CFR was ≥ 2 (CI 93-99.2%). In addition, 96.4% of patients reached a CFR ≥ 2 (IC 91.1 - 99%) at 75% of their predicted maximum heart rate.

Conclusions

We found that the feasibility of dobutamine stress echocardiography to determine CFR in the territory of the LAD coronary artery was high. In this study, it was necessary to achieve a difference of 50 bpm from baseline HR or at least 75% of the maximum predicted heart rate to consider sufficient the test for the analysis of CFR.

Background

Impaired coronary flow reserve (CFR) is a significant predictor of poor prognosis in patients with idiopathic dilated cardiomyopathy (IDC). Nebivolol reduces mortality and morbidity in patients with heart failure and left ventricular dysfunction, including cases caused by IDC.

Objective

To assess the effects of nebivolol on CFR in patients with IDC.

Methods

CFR was measured in 21 clinically stable patients with IDC (mean (SD) ejection fraction 35.7 (6.2)) at baseline and after 1 month of treatment with nebivolol once daily. A control group of apparently healthy subjects who were matched for age and sex was used for comparison. Resting and hyperaemic coronary flows were measured using transthoracic second‐harmonic Doppler echocardiography. None of the subjects had any systemic disease.

Results

After 1 month of treatment, heart rate was reduced significantly (p<0.001). The blood pressure was decreased significantly (p<0.001). The left ventricular end‐diastolic diameter and stroke volume were not changed significantly, but end‐systolic diameter was decreased significantly (p<0.05). Resting rate–pressure product was lower after treatment with nebivolol, but dipyridamole‐induced change was not influenced by the treatment. Nebivolol treatment reduced significantly coronary velocities at rest (p<0.02) and also caused a significant increase in coronary velocities after dipyridamole (p<0.02), leading to a greater CFR (2.02 (0.35) vs 2.61 (0.43), p<0.001). Nebivolol induced an absolute increase of 6% in the CFR in 17 of 21 patients (80.9%).

Conclusions

In patients with IDC, 1 month of treatment with nebivolol induces a marked increase in CFR.

Background

Y- graft (Y-G) is a graft formed by the Left Internal Mammary Artery (LIMA) connected to the Left Anterior Descending Artery (LAD) and by a free Right Internal Mammary Artery (RIMA) connected to LIMA and to a Marginal artery of Left Circumflex Artery (LCx). Aim of the work was to study the flow of this graft during a six months follow-up to assess whether the graft was able to meet the request of all the left coronary circulation, and to assess whether it could be done by evaluation of coronary flow reserve (CFR).

Methods

In 13 consecutive patients submitted to Y-G (13 men), CFR was measured in distal LAD and in distal LCx from 1 week after , every two months, up to six months after operation (a total of 8 tests for each patient) by means of transthoracic echocardiography (TTE) and Adenosine infusion (140 mcg/kg/min for 3-6 min). A Sequoia 256, Acuson-Siemens, was used. Contrast was used when necessary (Levovist 300 mg/ml solution at a rate of 0,5-1 ml/min). Max coronary flow diastolic velocity post-/pre-test ≥2 was considered normal CFR.

Results

Coronary arteriography revealed patency of both branches of Y-G after six months. Accuracy of TTE was 100% for LAD and 85% for LCx. Feasibility was 100% for LAD and 85% for LCx. CFR improved from baseline in LAD (2.21 ± 0.5 to 2.6 ± 0.5, p = 0.03) and in LCx (1.7 ± 1 to 2.12 ± 1, p = 0.05). CFR was under normal at baseline in 30% of patients vs 8% after six months in LAD (p = 0.027), and in 69% of patients vs 30% after six months in LCx (p = 0.066).

Conclusion

CFR in Y-G is sometimes reduced in both left territories postoperatively but it improves at six months follow-up. A follow-up can be done non-invasively by TTE and CFR evaluation.

Background and Objectives

The purpose of this study was to evaluate the relationship between myocardial strain and coronary flow reserve (CFR) in the prediction of myocardial functional recovery after acute myocardial infarction (AMI).

Subjects and Methods

Consecutive patients with anterior ST elevation AMI were analyzed. Left ventricular (LV) strain, determined by 2-dimensional speckle tracking imaging and CFR, determined by intracoronary flow measurement, were obtained on the same day, 3-5 days after primary percutaneous coronary intervention. A-strain was defined as the mean systolic longitudinal strain of 11 LV segments (out of 18) assumed to be supplied by the left anterior descending coronary artery (LAD). Functional recovery was defined as improved wall motion >1 grade seen in at least 2 contiguous dysfunctional segments by echocardiography at the 6-month follow-up.

Results

Of 20 patients, 8 patients had preserved CFR (>2.0) and 12 patients had impaired CFR (≤2.0). There were no differences between the 2 CFR groups in LV ejection fractions and wall motion score indices in the LAD territory. However, A-strain was greater in patients with preserved CFR than in patients with impaired CFR (-6.4±2.0% vs. -4.6±1.4%, p=0.03). A-strain and CFR correlated well with each other (r=-0.49, p=0.03). Ten of 20 patients showed functional recovery at 6 months. Of clinical and echocardiographic parameters, A-strain was the only predictor of recovery (odds ratio 2.02, 95% confidence interval=1.03-3.97, p=0.04). For predicting recovery, the sensitivity and specificity were 80.0% and 80.0%, respectively, for CFR (cutoff=1.60), and 60.0% and 90.0%, respectively, for A-strain (cutoff=-6.13%).

Conclusion

Myocardial strain correlates well with the extent of microvascular integrity and can be used as a noninvasive method for predicting recovery after AMI.

After percutaneous transluminal coronary angioplasty (PTCA), stress-echocardiography and gated single photon emission computerized tomography (g-SPECT) are usually performed but both tools have technical limitations. The present study evaluated results of PTCA of left anterior descending artery (LAD) six months after PTCA, by combining transthoracic Doppler coronary flow reserve (CFR) and color Tissue Doppler (C-TD) dobutamine stress.

Six months after PTCA of LAD, 24 men, free of angiographic evidence of restenosis, underwent standard Doppler-echocardiography, transthoracic CFR of distal LAD (hyperemic to basal diastolic coronary flow ratio) and C-TD at rest and during dobutamine stress to quantify myocardial systolic (Sm) and diastolic (Em and Am, Em/Am ratio) peak velocities in middle posterior septum. Patients with myocardial infarction, coronary stenosis of non-LAD territory and heart failure were excluded. According to dipyridamole g-SPECT, 13 patients had normal perfusion and 11 with perfusion defects. The 2 groups were comparable for age, wall motion score index (WMSI) and C-TD at rest. However, patients with perfusion defects had lower CFR (2.11 ± 0.4 versus 2.87 ± 0.6, p < 0.002) and septal Sm at high-dose dobutamine (p < 0.01), with higher WMSI (p < 0.05) and stress-echo positivity of LAD territory in 5/11 patients. In the overall population, CFR was related negatively to high-dobutamine WMSI (r = -0.50, p < 0.01) and positively to high-dobutamine Sm of middle septum (r = 0.55, p < 0.005).

In conclusion, even in absence of epicardial coronary restenosis, stress perfusion imaging reflects a physiologic impairment in coronary microcirculation function whose magnitude is associated with the degree of regional functional impairment detectable by C-TD.

Women exhibit a greater symptom burden, more functional disability, and a higher prevalence of no obstructive coronary artery disease (CAD) compared to men when evaluated for signs and symptoms of myocardial ischemia. Microvascular Coronary Dysfunction (MCD) defined as limited coronary flow reserve (CFR) and/or coronary endothelial dysfunction is the predominant etiological mechanism of ischemia in women with the triad of persistent chest pain, no obstructive CAD, and ischemia evidenced by stress testing. Evidence shows that approximately 50% of these patients have physiologic evidence of MCD. MCD is associated with a 2.5% annual major adverse event rate that includes death, nonfatal MI, nonfatal stroke and congestive heart failure. Although tests such as adenosine stress cardiac magnetic resonance imaging (CMRI) may be a useful non-invasive method to predict subendocardial ischemia, the gold standard test to diagnose MCD is an invasive Coronary Reactivity Testing (CRT). Early identification of MCD by CRT may be beneficial in prognostication and stratifying these patients for optimal medical therapy. Currently, understanding of MCD pathophysiology can be used to guide diagnosis and therapy. Continued research in MCD is needed to further advance our understanding.

Background

Coronary flow reserve (CFR) recording by means of transthoracic echocardiography (TTDE) in all the main distal coronary arteries is a challenge for advanced echocardiography. Validation studies of TTDE versus Doppler-wire (DW) recordings are available for Left Anterior Descending artery (LAD) and the Posterior Descending coronary artery (PD), but lacking for the more technically challenging Left Circumflex coronary artery (LCx).

Aim

To evaluate the reliability of TTDE in assessing CFR in LCx when compared to the intracoronary Doppler flow-wire gold standard.

Methods

we evaluated 5 patients (age = 60 ± 9 years, 5 males) on LCx by TTDE and invasive CFR assessment. TTDE recording was performed using a low-frequency probe, with a four-chamber as a guiding 2D view. The 2 tests were performed on different days and in random order within 48 hours in a blind fashion. Vasodilator stimulus was adenosine, intravenously (140 γ/kg/min × 3–6 min) for TTDE and intracoronary (40 γ bolus) for DW recordings.

Results

CFR values on LCx ranged from 1.9 to 2.8 for DW, and from 2.0 to 3.0 for TTDE, with an overall correlation of R = 0,85 (p = 0,06); normal (CFR > 2.5) or abnormal (CFR < 2.5) value was concordantly identified by the 2 techniques in 4 out 5 cases (80%).

Conclusion

CFR of LCx artery can be obtained noninvasively with TTDE.

Objectives

To investigate the relation between aortic stiffness and coronary flow reserve (CFR) in patients with coronary artery disease (CAD).

Design

Observational study.

Setting

Coronary care unit of a primary care hospital.

Patients

192 consecutive patients who underwent coronary angiography.

Main outcome measure

Brachial‐ankle pulse wave velocity (ba‐PWV), CFR, and severity of CAD.

Results

According to the angiographic findings, patients were divided into four subgroups: patients without significant stenosis (normal coronary artery (NCA) group, n  =  28) and those with one vessel disease (1VD group, n  =  92), two vessel disease (2VD group, n  =  50), or three vessel disease (3VD group, n  =  22). ba‐PWV increased with the number of diseased vessels and was significantly correlated with the number of diseased vessels (NCA group v 1VD group v 2VD group v 3VD group: 1481 (252) v 1505 (278) v 1577 (266) v 1727 (347) cm/s, p < 0.001). CFR had a significant negative correlation with ba‐PWV (r  =  −0.45, p < 0.0001). The diastolic to systolic velocity ratio obtained in 45 patients also was significantly correlated with ba‐PWV (r  =  −0.35, p < 0.05). Multiple regression analysis showed that ba‐PWV was an independent determinant of CFR (p < 0.01).

Conclusions

Coronary flow is altered with aortic stiffening in patients with CAD. These results suggest one possible mechanism for recent reports that aortic stiffness is a key cardiovascular risk factor.

This study was investigated the role that endothelial function and systemic vascular resistance (SVR) play in determining cardiac function reserve during exercise by a new ambulatory radionuclide monitoring system (VEST) in patients with heart disease. The study population consisted of 32 patients. The patients had cardiopulmonary stress testing using the treadmill Ramp protocol and the VEST. The anaerobic threshold (AT) was autodetermined using the V-slope method. The SVR was calculated by determining the mean blood pressure/cardiac output. Flow-mediated vasodilation (FMD) was measured in the brachial artery to evaluate endotheilial function. FMD and the percent change f'rom rest to AT in SVR correlated with those from rest to AT in ejection fraction and peak ejection ratio by VEST, respectively. Our findings suggest that FMD in the brachial artery and the SVR determined by VEST in patients with heart disease can possibly reflect cardiac function reserve during aerobic exercise.

Background

Quantitative stress echocardiography enables calculation of left-ventricular power-to-mass ratio (LVPMR) at peak exercise, a novel measure of cardiac performance per unit mass of myocardial tissue. We hypothesized that LVPMR at peak exercise provides prognostic information beyond established echocardiographic indices such as left-ventricular ejection fraction (LVEF) and left-ventricular mass index (LVMI).

Methods

LVPMR (watts/kilogram) at peak exercise was defined as (k × heart rate × mean arterial pressure × stroke volume)/LV mass. We measured LVPMR in 918 adults with stable ambulatory coronary artery disease recruited for the Heart and Soul Study. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for all-cause mortality, cardiovascular death, nonfatal myocardial infarction, heart failure hospitalization, and combined adverse cardiovascular events. Multivariate adjustments were made for established risk factors including LVEF and LVMI. The prognostic value of LVPMR was also compared with established exercise parameters using receiver-operating characteristic curve analysis.

Results

Compared with patients in the highest LVPMR quartile, those in the lowest quartile were at increased risk of all-cause mortality (adjusted HR 1.9; 95% CI 1.1–3.3), heart failure hospitalization (adjusted HR 2.9; 95% CI 1.2–6.9), and combined adverse cardiovascular events (adjusted HR 1.9; 95% CI 1.1–3.4). In comparison with the rate-pressure product and the Duke treadmill score, LVPMR did not add significant prognostic value (p > 0.1 for c-statistic comparisons).

Conclusions

In patients with stable ambulatory coronary artery disease, LVPMR at peak exercise predicts mortality, heart failure hospitalization, and adverse cardiovascular events. However, LVPMR does not add significant prognostic information beyond established exercise test parameters.

To evaluate whether the flow-mediated vasodilation and coronary flow reserve are impaired or not in patients with vasospastic angina (VA), we measured the changes of epicardial coronary artery diameter and flow reserve in spasm related-left anterior descending coronary artery (LAD). The flow mediated-response of epicardial coronary arteries in 15 VA were compared with 15 controls. Using quantitative coronary angiography, we measured the diameter of proximal (pLAD) and middle segment (mid-LAD) of LAD under baseline conditions, during increased blood flow after distal adenosine injection and after proximal administration of nitroglycerin. An increased fraction of average peak velocity after injection of adenosine was similar in both groups [control 340 (mean)+/-24 (SEM)%; VA 330+/-19%]. Flow-mediated vasodilation was preserved in all controls (pLAD 13.1+/-1.4%; mid-LAD 15.8+/-2.5%) but it was significantly impaired in patients with VA (pLAD -1.0+/-1.8%; mid-LAD 0.1+/-3.5%). The vasodilator response to nitroglycerin was comparable in controls (pLAD 25.8+/-2.8%; mid-LAD 27.2+/-2.8%) and VA (pLAD 26.2+/-5.2%; mid-LAD 26.7+/-3.5%). Coronary flow reserve is preserved in patients with VA. However, the flow-mediated response of spasm related-epicardial coronary artery is impaired. This may play an important role in the pathogenesis of coronary artery spasm.

Objective

To test whether preserved coronary flow reserve (CFR) two days after reperfused acute myocardial infarction (AMI) is associated with less microvascular dysfunction (“ no‐reflow” phenomenon) and is predictive of myocardial viability.

Design

24 patients with anterior AMI underwent CFR assessment in the left anterior descending coronary artery (LAD) with transthoracic echocardiography and myocardial contrast echocardiography (MCE) 48 h after primary angioplasty in the LAD (mean 4 (SD 2) and 3 (1) days, respectively). Low‐dose dobutamine echocardiography was performed 6 (3) days after AMI and follow‐up echocardiography at three months.

Results

No‐reflow extent was greater in patients with impaired CFR (< 2.5) than in those with preserved CFR (> 2.5) (55 (35)% v 11 (25)%, p < 0.001). MCE reflow was more common in patients with preserved CFR (8/12) than in those with reduced CFR (1/12, p < 0.05). Wall motion score index in the LAD territory (A‐WMSI) was similar at the first echocardiography (2.14 (0.39) v 2.32 (0.47), NS), although it was better in patients with preserved CFR at dobutamine (1.38 (0.45) v 1.97 (0.67), p < 0.05) and follow‐up echocardiography (1.36 (0.40) v 1.97 (0.64), p < 0.05). An inverse correlation was found between CFR and A‐WMSI at dobutamine and follow‐up echocardiography (r  =  −0.49, p  =  0.016 and r  =  −0.55, p  =  0.005) and between MCE and A‐WMSI at dobutamine and follow‐up echocardiography (r  =  −0.75, p < 0.001 and r  =  −0.75, p < 0.001). By multivariate analysis MCE reflow remained the only predictor of recovery at both dobutamine and follow‐up echocardiography (odds ratio 1.06, 95% CI 1 to 1.1, p  =  0.009).

Conclusion

CFR is inversely correlated with the extent of microvascular dysfunction at MCE two days after reperfused AMI. CFR and MCE reflow early after AMI are correlated with myocardial viability at follow up.

To evaluate the feasibility and usefulness of transthoracic Doppler echocardiography (TTDE) as a non-invasive method in recording distal anterior descending (LAD) coronary flow velocity, we compared coronary flow reserve (CFR) measured by TTDE with measurements by intracoronary Doppler wire (ICDW). Twenty-one patients without LAD stenosis were studied. ICDW performed at baseline and after intracoronary injection of 18 microg adenosine. TTDE was performed at baseline and after intravenous adenosine (140 microg/kgmin for 2 min). Adequate Doppler recordings of coronary flow velocities during systole were obtained in 14 of 21 study patients (67%) and during diastole in 17 (81%) patients. Baseline and hyperemic peak diastolic flow velocities measured by TTDE were significantly smaller than those obtained by ICDW (p<0.05). However, diminishing trends of diastolic and systolic velocity ratio after hyperemia were similarly observed in both methods. CFR obtained by TTDE (3.0+/-0.5), was higher than the value calculated by ICDW (2.5+/-0.4). There were significant correlations between the values obtained by the two methods (r=0.72, p<0.01). It is concluded that TTDE is a feasible method in measuring coronary flow velocity and appears to be a promising non-invasive method in evaluating CFR.

Objectives

To examine the relationship between inflammation and coronary microvascular function in asymptomatic individuals using positron emission tomography (PET) and assessment of coronary flow reserve (CFR).

Background

Coronary microvascular dysfunction is an early precursor of coronary artery disease (CAD) thought to result from endothelial cell activation and inflammation, but data are limited.

Methods

We examined 268 asymptomatic male monozygotic and dizygotic twins. Plasma biomarkers of inflammation and endothelial cell activation included C-reactive protein (CRP), interleukin-6 (IL-6), white blood cell count (WBC), vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Blood flow quantitation was obtained with [13N] ammonia PET at rest and after adenosine stress. CFR was measured as the ratio of maximum flow to baseline flow at rest; abnormal CFR was defined as a ratio <2.5. A summed stress score for visible perfusion defects was calculated.

Results

In within-pair analyses, all biomarkers, except VCAM-1, were higher in twins with lower CFR than their brothers with higher CFR (p<0.05). This was observed in the entire sample, as well as within pairs discordant for a CFR of <2.5. Associations persisted after adjusting for summed stress score and CAD risk factors. In contrast no biomarker, except IL-6, was related to the summed stress score of visible defects.

Conclusions

Even in asymptomatic subjects, a decrease in coronary microvascular function is accompanied by a systemic inflammatory response, independent of CAD risk factors. Our results, using a controlled twin design, highlight the importance of coronary microvascular function in the early phases of CAD.

This review focuses on transthoracic Doppler echocardiography as noninvasive method used to assess coronary flow reserve (CFR) in a wide spectrum of clinical settings. Transthoracic Doppler echocardiography is rapidly gaining appreciation as popular tool to measure CFR both in stenosed and normal epicardial coronary arteries (predominantly in left anterior descending coronary artery). Post-stenotic CFR measurement is helpful in: functional assessment of moderate stenosis, detection of significant or critical stenosis, monitoring of restenosis after revascularization. In the absence of stenosis in the epicardial coronary artery, decreased CFR enable to detect impaired microvascular vasodilatation in: reperfused myocardial infarct, arterial hypertension with or without left ventricular hypertrophy, diabetes mellitus, hypercholesterolemia, syndrome X, hypertrophic cardiomyopathy. In these diseases, noninvasive transthoracic Doppler echocardiography allows for serial CFR evaluations to explore the effect of various pharmacological therapies.

The relative prevalence of abnormalities of coronary flow reserve and oesophageal function was ascertained in 32 syndrome X patients with typical angina chest pain, a positive exercise test, and normal coronary arteries. Coronary flow reserve in response to a hyperaemic dose of papaverine was measured using an intracoronary Doppler catheter positioned in the left anterior descending coronary artery. An abnormal coronary flow reserve was defined as being < 3.0. Patients were investigated for oesophageal dysfunction by manometry and 24-hour pH monitoring. Thirteen patients had an impaired coronary flow reserve (group 1) and 19 patients had a normal flow reserve (group 2). Eight of the 13 group 1 patients (62%) and 13 of the 19 group 2 patients (68%, p = NS) had evidence of oesophageal dysfunction on either manometry or pH studies. Therefore, a total of 26 (81%) syndrome X patients had either an abnormality of coronary flow reserve or oesophageal dysfunction suggesting that chest pain in these patients may be due to myocardial ischaemia or oesophageal dysfunction, thus confirming the heterogeneous nature of this syndrome. The prevalence of oesophageal abnormalities was independent of any abnormalities of coronary flow reserve.

Background

In patients with advanced non-ischemic cardiomyopathy (NIC), right-sided cardiac disturbances has prognostic implications. Right coronary artery (RCA) flow pattern and flow reserve (CFR) are not well known in this setting. The purpose of this study was to assess, in human advanced NIC, the RCA phasic flow pattern and CFR, also under right-sided cardiac disturbances, and compare with left coronary circulation. As well as to investigate any correlation between the cardiac structural, mechanical and hemodynamic parameters with RCA phasic flow pattern or CFR.

Methods

Twenty four patients with dilated severe NIC were evaluated non-invasively, even by echocardiography, and also by cardiac catheterization, inclusive with Swan-Ganz catheter. Intracoronary Doppler (Flowire) data was obtained in RCA and left anterior descendent coronary artery (LAD) before and after adenosine. Resting RCA phasic pattern (diastolic/systolic) was compared between subgroups with and without pulmonary hypertension, and with and without right ventricular (RV) dysfunction; and also with LAD. RCA-CFR was compared with LAD, as well as in those subgroups. Pearson's correlation analysis was accomplished among echocardiographic (including LV fractional shortening, mass index, end systolic wall stress) more hemodynamic parameters with RCA phasic flow pattern or RCA-CFR.

Results

LV fractional shortening and end diastolic diameter were 15.3 ± 3.5 % and 69.4 ± 12.2 mm. Resting RCA phasic pattern had no difference comparing subgroups with vs. without pulmonary hypertension (1.45 vs. 1.29, p = NS) either with vs. without RV dysfunction (1.47 vs. 1.23, p = NS); RCA vs. LAD was 1.35 vs. 2.85 (p < 0.001). It had no significant correlation among any cardiac mechanical or hemodynamic parameter with RCA-CFR or RCA flow pattern. RCA-CFR had no difference compared with LAD (3.38 vs. 3.34, p = NS), as well as in pulmonary hypertension (3.09 vs. 3.10, p = NS) either in RV dysfunction (3.06 vs. 3.22, p = NS) subgroups.

Conclusion

In patients with chronic advanced NIC, RCA phasic flow pattern has a mild diastolic predominance, less marked than in LAD, with no effects from pulmonary artery hypertension or RV dysfunction. There is no significant correlation between any cardiac mechanical-structural or hemodynamic parameter with RCA-CFR or RCA phasic flow pattern. RCA flow reserve is still similar to LAD, independently of those right-sided cardiac disturbances.

Age may affect coronary flow reserve (CFR) especially in subjects with atherosclerotic risk factors (ARFs). The aim of this prospective, multicenter, observational study was to determine the effects of aging on CFR in patients with normal epicardial coronary arteries and ARFs. Three-hundred-thirty-five subjects (mean age = 61 years) with at least one ARF but normal coronary angiography underwent high-dose dipyridamole stress-echo with Doppler evaluation of left anterior descending artery. CFR was calculated as the ratio between hyperemic and resting coronary diastolic peak velocities. Patients were divided in age quartiles. CFR was progressively reduced with aging (1st quartile: 3.01 ± 0.69, 4th quartile: 2.39 ± 0.49, p < 0.001). This was mainly due to a gradual increase of resting velocities (1st quartile = 26.3 ± 6.1 cm/s, 4th quartile = 30.2 ± 6.4 cm/s, p < 0.001) while the reduction of hyperemic velocities remained unaffected (1st quartile = 77.7 ± 18.9 cm/s, 4th quartile = 70.9 ± 18.4 cm/s, NS). When age quartiles and ARFs were entered into a regression model, third and fourth age quartile (p < 0.0005 and p < 0.0001 respectively), left ventricular mass index (p < 0.0001), diastolic blood pressure (p < 0.001), total cholesterol (p < 0.002), fasting blood glucose (p < 0.01) and male gender (p < 0.05) were independent determinants of CFR in the whole population. Aging reduces coronary flow reserve in patients with angiographically normal coronary arteries due to a gradual increase of resting coronary flow velocity. CFR is also affected by atherosclerotic risk factors and left ventricular hypertrophy.

Objectives

To comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF).

Background

Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilatation, endothelial function and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF.

Methods

Subjects with HFpEF (n=21), hypertension without heart failure (n=19) and no cardiovascular disease (control, n=10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry and gas exchange.

Results

Exercise capacity and tolerance were reduced in HFpEF compared with hypertensives and controls, with lower VO2 and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensives as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve.

Conclusion

HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.

Background

Diabetics with erectile dysfunction have a high prevalence of microvascular disturbance of the coronary circuit as measured by coronary flow reserve (CFR).

Purpose

We aimed to evaluate the effects of the phosphodiesterase 5 inhibitor sildenafil on CFR in diabetics with erectile dysfunction.

Methods

Diabetics seeking diabetes refinement therapy were screened for vascular or neurogenic erectile dysfunction which was confirmed in 43 patients. No ischemic ECG changes were found in any of the ECG stress tests at the 100 W level. Cardiologic examinations raised suspicion of coronary artery disease in 16 patients; coronary angiography confirmed severe coronary artery lesions in 12, who were excluded from further analysis. CFR measurements were not possible in 10 participants. The 21 diabetics eligible for CFR measurements aged 60 years (50–69) had known diabetes for 11 years (3–30) and a BMI of 27 kg/m2 (24–36). CFR of the left anterior descending artery was assessed at baseline and 1 hour after 50 mg sildenafil, using transthoracic Doppler echocardiography.

Results

Baseline CFR was at the lower level of the normal range (median 245%, range 210 – 490%). After sildenafil administration, CFR decreased insignificantly (ΔCFR -10%, p = 0.3). Patients with a BMI > 25 kg/m2 and left ventricular hypertrophy exhibited the highest reduction of CFR after sildenafil. No decrease of CFR below 200 % was observed. Systemic blood pressure dropped from 130/80 mmHg to 120/72 mmHg (p < 0.002).

Conclusions

Diabetics with erectile dysfunction exhibit a CFR in the lower normal range indicating severe microvascular disturbance. Sildenafil did not alter CFR in those patients. A high prevalence of severe coronary macroangiopathy was identified in asymptomatic diabetic patients screened for contraindications for sildenafil.

Cyclic variations in coronary blood flow (CFVs) in dogs with experimental coronary artery stenosis and endothelial injury appear to result primarily from the aggregation of platelets at the site of stenosis followed by dislodgement and distal embolization. Using this canine model, we tested the hypotheses: (a) that thrombin is an important mediator of CFVs in dogs with coronary stenoses and endothelial injury; (b) that inhibition of thrombin with heparin, or MCI-9038, a selective thrombin inhibitor, abolishes CFVs in this model; and (c) that abolition of CFVs by thrombin inhibition is time dependent. CFVs, produced in open-chest dogs by placing a flow-reducing plastic constrictor around the left anterior coronary artery, were monitored for either 30 min (group I) or 3 h (group II) before treatment with either heparin or 4-methyl-1-(N2-[(3-methyl-1,2,3,4-tetrahydro-8-quinolinyl (MCI-9038). In group I, cyclic flow variations were abolished by heparin in 12 of 18 dogs and by MCI-9038 in 5 of 7 dogs. In group II, cyclic flow variations were not abolished by heparin in any of seven dogs and were abolished by MCI-9038 in only one of seven dogs. Thus, (a) thrombin appears to be an important mediator of cyclic flow variations in dogs with coronary artery stenosis and endothelial injury and (b) inhibition of thrombin abolishes CFVs after short but not prolonged periods of CFVs.

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Objective: To determine the effect of one or multiple co-morbid conditions on the diagnostic accuracy of coronary flow velocity reserve (CFVR) in a heterogeneous patient population.

Methods: CFVR was measured in the left anterior descending coronary artery (LAD) by transthoracic Doppler echocardiography (TTDE) in 318 consecutive patients before elective coronary angiography. CFVR was calculated as the average peak diastolic velocity during intravenous ATP infusion divided by baseline flow velocity. All patients underwent coronary angiography within 48 hours. Significant LAD stenosis was defined as > 50% luminal narrowing. Diagnostic accuracy of CFVR was analysed according to the type and number of risk factors that may adversely affect microvascular function.

Results: CFVR was measured in 309 patients, of whom 105 were found to have significant LAD stenosis based on coronary angiography. CFVR < 2.0 had a sensitivity of 86% and a specificity of 77% for predicting significant LAD stenosis. Left ventricular hypertrophy (LVH) was the only factor that significantly lowered diagnostic accuracy (61% with LVH v 84% without LVH, p < 0.001). Diagnostic accuracy was not affected by increasing number of risk factors.

Conclusions: The diagnostic accuracy of CFVR by TTDE for detecting significant LAD stenosis remains high in a more clinically relevant population with multiple cardiovascular co-morbidities. Only the presence of LVH adversely affected diagnostic accuracy.