Takashi Muro

Physiologic assessment of coronary artery stenosis by coronary flow reserve measurements with transthoracic doppler echocardiography: comparison with exercise thallium-201 single-photon emission computed tomography

OBJECTIVES We evaluated the value of coronary flow reserve (CFR), as determined by transthoracic Doppler echocardiography (TTDE), for physiologic assessment of coronary artery stenosis severity, and we compared TTDE measurements with those obtained by exercise thallium-201 (Tl-201) single-photon emission computed tomography (SPECT). BACKGROUND Coronary flow reserve measurements by TTDE have been reported to be useful for assessing angiographic left anterior descending coronary artery (LAD) stenosis. However, discrepancies exist between angiographic and physiologic estimates of coronary lesion severity. METHODS We studied 36 patients suspected of having coronary artery disease. The flow velocity in the distal LAD was measured by TTDE both at rest and during intravenous infusion of adenosine. Coronary flow reserve was calculated as the ratio of hyperemic to basal peak (peak CFR) and mean (mean CFR) diastolic flow velocities. The CFR measurements by TTDE were compared with the results of Tl-201-SPECT. RESULTS Complete TTDE data were acquired for 33 of 36 study patients. Of these 33 patients, Tl-201-SPECT confirmed reversible perfusion defects in the LAD territories in 12 patients (group A). Twenty-one patients had normal perfusion in the LAD territories (group B). Peak CFR and mean CFR (mean value +/- SD) were 1.5 +/- 0.6 and 1.5 +/- 0.7 in group A and 2.8 +/- 0.8 and 2.7 +/- 0.7 in group B, respectively. Both peak and mean CFR < or = 2.0 predicted reversible perfusion defects, with a sensitivity and specificity of 92% and 90%, respectively. CONCLUSIONS Noninvasive measurement of CFR by TTDE provides data equivalent to those obtained by Tl-201-SPECT for physiologic estimation of the severity of LAD stenosis.

Modulation of coronary flow velocity reserve by gender, menstrual cycle and hormone replacement therapy

OBJECTIVES The purpose of this study was twofold: 1) to examine the relationship between menstrual cycle and coronary flow velocity reserve (CFVR) in young healthy women, and 2) to evaluate the effect of hormone replacement therapy by estrogen on CFVR in postmenopausal women, using transthoracic color Doppler echocardiography (TTCDE). BACKGROUND Although the incidence of cardiovascular disease is lower in women before menopause compared with men, postmenopausal women have an incidence of coronary artery disease similar to that of men of the same age. This is mainly dependent upon estrogen deficiency. However, no clinical report has yet examined the effect of estrogen on CFVR, which is one index of coronary microcirculation. METHODS We examined 15 male and both 15 premenopausal and 10 postmenopausal female healthy volunteers. We measured coronary flow velocity of the left anterior descending coronary artery at baseline and hyperemic conditions during adenosine triphosphate infusion by TTCDE and determined CFVR. Each premenopausal woman was studied two times (menstrual [M] and follicular [F] phases) in one menstrual cycle. Fifteen men were also studied at a time corresponding to womens menstrual cycle. The postmenopausal women were studied before and two hours after oral administration of conjugated estrogen (CE). RESULTS Serum 17beta-estradiol level in premenopausal women increased in the F phase and decreased to the same levels as in men, as in the M phase and as in postmenopausal women (123 +/- 9 pg/ml vs. 28 +/- 6 pg/ml, 25 +/- 9 pg/ml and 19 +/- 11 pg/ml; p < 0.0001, respectively). The CFVR increased in the F phase compared with that in the M phase (4.8 +/- 0.4 vs. 3.7 +/- 0.8, p < 0.0001). We found that CFVR in men remained unchanged (3.7 +/- 0.6 vs. 3.8 +/- 0.5). After CE administration, CFVR increased compared with baseline in postmenopausal women (4.1 +/- 0.8 vs. 3.4 +/- 0.8, p < 0.005). CONCLUSIONS In premenopausal women, CFVR determined by TTCDE varied during the menstrual cycle, and in postmenopausal women, CFVR increased after acute estrogen replacement.

Direct Measurement of Multiple Vena Contracta Areas for Assessing the Severity of Mitral Regurgitation Using 3D TEE

OBJECTIVES The aim of this study was to determine whether direct measurement of multiple-jet vena contracta (VC) areas by real-time 3-dimensional (3D) transesophageal echocardiography is an accurate method for measuring the severity of mitral regurgitation (MR) in patients with multiple MR jets. BACKGROUND Because of the conflicting requirements of Doppler and imaging physics, measuring VC using 2-dimensional (2D) echocardiography is a difficult procedure for assessing MR severity. A real-time 3D echocardiographic measurement of the VC area has been validated in a single jet of MR, but the applicability of this method for multiple jets is unknown. METHODS Two-dimensional and 3D transesophageal echocardiography was performed in 60 patients with multiple functional MR jets. MR severity was assessed quantitatively using the effective regurgitant orifice area derived from 3D left ventricular volume and thermodilution data (EROAstd). Manual tracings of multiple 3D VC areas in a cross-sectional plane through the VC were obtained, and the sum of the areas was compared using EROAstd. Similarly, 2D measurement of VC diameter was obtained from a 2D transesophageal echocardiographic view to optimize the largest legion size in each jet. All VC diameters were summed and compared with EROAstd. RESULTS The correlation of the sum of the multiple 3D VC areas with EROAstd (r = 0.90, p < 0.01) was higher than that of the sum of the multiple 2D VC diameters (r = 0.56, p < 0.01), particularly with MR degrees greater than mild (r = 0.80, p < 0.01 vs. r = 0.05, p = 0.81) and in cases of 3 or more regurgitant jets (r = 0.91, p < 0.01 vs. r = 0.46, p = 0.05). CONCLUSIONS Direct measurement of multiple VC areas using 3D transesophageal echocardiography allows for assessing MR severity in patients with multiple jets, particularly for MR degrees greater than mild and in cases of more than 2 jets, for which geometric assumptions may be challenging.

Quantitative myocardial contrast echocardiography during pharmacological stress for diagnosis of coronary artery disease: a systematic review and meta-analysis of diagnostic accuracy studies.

AIMS We conducted a meta-analysis to evaluate the accuracy of quantitative stress myocardial contrast echocardiography (MCE) in coronary artery disease (CAD). METHODS AND RESULTS Database search was performed through January 2008. We included studies evaluating accuracy of quantitative stress MCE for detection of CAD compared with coronary angiography or single-photon emission computed tomography (SPECT) and measuring reserve parameters of A, beta, and Abeta. Data from studies were verified and supplemented by the authors of each study. Using random effects meta-analysis, we estimated weighted mean difference (WMD), likelihood ratios (LRs), diagnostic odds ratios (DORs), and summary area under curve (AUC), all with 95% confidence interval (CI). Of 1443 studies, 13 including 627 patients (age range, 38-75 years) and comparing MCE with angiography (n = 10), SPECT (n = 1), or both (n = 2) were eligible. WMD (95% CI) were significantly less in CAD group than no-CAD group: 0.12 (0.06-0.18) (P < 0.001), 1.38 (1.28-1.52) (P < 0.001), and 1.47 (1.18-1.76) (P < 0.001) for A, beta, and Abeta reserves, respectively. Pooled LRs for positive test were 1.33 (1.13-1.57), 3.76 (2.43-5.80), and 3.64 (2.87-4.78) and LRs for negative test were 0.68 (0.55-0.83), 0.30 (0.24-0.38), and 0.27 (0.22-0.34) for A, beta, and Abeta reserves, respectively. Pooled DORs were 2.09 (1.42-3.07), 15.11 (7.90-28.91), and 14.73 (9.61-22.57) and AUCs were 0.637 (0.594-0.677), 0.851 (0.828-0.872), and 0.859 (0.842-0.750) for A, beta, and Abeta reserves, respectively. CONCLUSION Evidence supports the use of quantitative MCE as a non-invasive test for detection of CAD. Standardizing MCE quantification analysis and adherence to reporting standards for diagnostic tests could enhance the quality of evidence in this field.

Early detection of cardiac involvement in patients with sarcoidosis by a non-invasive method with ultrasonic tissue characterisation

Objectives: To clarify the value of cycle dependent variation of myocardial integrated backscatter (CV-IB) analysis, which non-invasively measures acoustic properties of the myocardium, for early detection of cardiac involvement in patients with sarcoidosis. Methods: The study population consisted of 22 consecutive patients with biopsy proven sarcoidosis who did not have any abnormal findings on conventional two dimensional echocardiogram. Cardiac sarcoidosis was diagnosed by radionuclide testing including thallium-201 scintigraphy, gallium-67 scintigraphy, and cardiac fluorine-18-deoxyglucose positron emission tomography. The magnitude and delay of the CV-IB were analysed in the basal mid septum and the basal mid posterior wall of the left ventricle of all patients. Results: The patients were divided into two groups: 8 patients with cardiac involvement and 14 patients without cardiac involvement. In the basal septum, a major reduction in the magnitude (mean (SD) 1.8 (4.4) v 6.6 (1.3), p  =  0.012) and an increase in the time delay (1.3 (0.5) v 1.0 (0.1), p  =  0.038) of CV-IB were observed in patients with cardiac sarcoidosis even in the absence of two dimensional echocardiographic abnormalities. The sensitivity for detecting cardiac involvement was such that the magnitude of CV-IB in the basal septum discriminated 75% of patients with cardiac sarcoidosis from those with non-cardiac sarcoidosis, whereas two dimensional echocardiographic parameters did not discriminate between these two groups. Conclusions: The CV-IB is decreased in the basal septum in patients with cardiac sarcoidosis even in the absence of two dimensional echocardiographic abnormalities. Analysis of CV-IB may be a useful method to detect early myocardial involvement in patients with sarcoidosis.

Pravastatin accelerates ischemia-induced angiogenesis through AMP-activated protein kinase.

Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. In this study, we examined the role of pravastatin in ischemia-induced angiogenesis. Unilateral hindlimb ischemia was surgically induced in C57BL/6J mice. Phosphorylation of AMP-activated protein kinase (AMPK), acetyl-CoA carboxylase (ACC) and endothelial NO synthase (eNOS) was increased in ischemic tissues. Furthermore, mice treated with pravastatin showed higher increases in phosphorylation than did untreated mice. Laser Doppler analysis has shown that pravastatin treatment accelerates the development of collateral vessels and angiogenesis in response to hindlimb ischemia. Capillary density in the ischemic hindlimb was also increased by pravastatin treatment. An in vitro study on human umbilical vein endothelial cells (HUVECs) revealed that pravastatin increased the phosphorylation of AMPK. Pravastatin-induced phosphorylation of eNOS, one of the downstreams of AMPK, was inhibited by compound C, an AMPK antagonist. The increased migration and tube formation of HUVECs by pravastatin were significantly blocked by compound C treatment. The accelerated angiogenesis by pravastatin after hindlimb ischemia was significantly reduced after treatment with compound C. Thus, ischemia induced AMPK phosphorylation in vivo. Furthermore, pravastatin could also activate AMPK in vivo and in vitro. Such phosphorylation results in eNOS activation and angiogenesis, which provide a novel explanation for one of the pleiotropic effects of statins that is beneficial for angiogenesis.

The antifibrotic agent pirfenidone inhibits angiotensin II-induced cardiac hypertrophy in mice.

Pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) is an effective drug for idiopathic interstitial pneumonia that can prevent and reverse tissue fibrosis in several organs. Therefore, we investigated whether pirfenidone has a potential role in preventing angiotensin II (Ang II)-induced cardiac hypertrophy. A cardiac hypertrophic mouse model was created using an Ang II infusion (200 ng kg−1 min−1) in wild-type mice for 2 weeks. Mice were divided into the following three groups: a saline-infused (control) group, an Ang II infusion (vehicle) group and an Ang II infusion+pirfenidone-treated (PFD) group, which received pirfenidone (300 mg kg−1 per day) by gastric gavage during the Ang II infusion. At 2 weeks, we assessed hemodynamics and cardiac function and investigated tissue fibrosis of the myocardium histologically and genetically. Blood pressure in the vehicle group was significantly increased compared to the control group. Although blood pressure was not different between the vehicle and PFD groups, heart weight was significantly decreased in the PFD group. Echocardiography revealed that left ventricular hypertrophy was significantly increased in the vehicle group vs. the control group. Interestingly, pirfenidone significantly inhibited this effect. Continuous infusion of Ang II increased the perivascular and interstitial tissue fibrosis, and pirfenidone inhibited these fibrotic changes. Pirfenidone also inhibited Ang II-induced hypertrophy. In the vehicle group, the mRNA expressions of atrial natriuretic peptide, brain natriuretic peptide and transforming growth factor-β1 were increased, which was significantly inhibited by pirfenidone. Furthermore, the expression of mineralocorticoid receptors was attenuated by pirfenidone. These results indicate that pirfenidone might be effective as an antifibrotic drug in the treatment of cardiac hypertrophy induced by hypertension.

Prognostic Value of Aortic Valve Area Index in Asymptomatic Patients With Severe Aortic Stenosis

Recently, an aortic valve area (AVA) index (AVAI) <0.6 cm(2)/m(2) was proposed as an indicator of severe aortic stenosis. The purpose of the present study was to clarify the prognostic value of the AVAI. We identified 103 consecutive asymptomatic patients (mean age 72 ± 11 years) with severe aortic stenosis, defined by an AVA of <1.0 cm(2), who had not undergone aortic valve replacement on initial evaluation. During follow-up (median 36 ± 27 months), 31 aortic valve replacements and 20 cardiac deaths occurred. Multivariate analysis revealed that an AVAI <0.6 cm(2)/m(2) (hazard ratio 2.6, 95% confidence interval 1.1 to 6.3; p = 0.03) and peak aortic jet velocity (Vp) >4.0 m/s (hazard ratio 2.6, 95% confidence interval 1.2 to 5.8; p = 0.02) were associated with cardiac events but that an AVA <0.75 cm(2) was not. The event-free survival of patients with an AVAI of ≥0.6 cm(2)/m(2) was better than that for those with an AVAI <0.6 cm(2)/m(2) (86% vs 41% at 3 years, p <0.01). Furthermore, patients with an AVAI of ≥0.6 cm(2)/m(2) and Vp of ≤4.0 m/s showed an excellent prognosis, but those without these findings had poorer outcomes. In conclusion, AVAI is a powerful predictor of adverse events in asymptomatic patients with severe aortic stenosis. Furthermore, the combination of AVAI and Vp provides additional prognostic information. Watchful observations are required for timely aortic valve replacement in patients with an AVAI of <0.6 cm(2)/m(2) or a Vp >4.0 m/s.

Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low-dose dobutamine stress echocardiography

Objective: To assess the role of intravenous myocardial contrast echocardiography (MCE) in predicting functional recovery and regional or global left ventricular (LV) remodelling after acute myocardial infarction (AMI) compared with low dose dobutamine stress echocardiography (LDSE). Methods: 21 patients with anterior AMI and successful primary angioplasty underwent MCE and LDSE during the subacute stage (2–4 weeks after AMI). Myocardial perfusion and contractile reserve were assessed in each segment (12 segment model) with MCE and LDSE. The 118 dyssynergic segments in the subacute stage were classified as recovered, unchanged, or remodelled according to wall motion at six months’ follow up. Percentage increase in LV end diastolic volume (%ΔEDV) was also calculated. Results: The presence of perfusion was less accurate than the presence of contractile reserve in predicting regional recovery (55% v 81%, p < 0.0001). However, the absence of perfusion was more accurate than the absence of contractile reserve in predicting regional remodelling (83% v 48%, p < 0.0001). The number of segments without perfusion was an independent predictor of %ΔEDV, whereas the number of segments without contractile reserve was not. The area under the receiver operating characteristic curve showed that the number of segments without perfusion predicted substantial LV dilatation (%ΔEDV > 20%) more accurately than did the number of segments without contractile reserve (0.88 v 0.72). Conclusion: In successfully revascularised patients with AMI, myocardial perfusion assessed by MCE is predictive of regional and global LV remodelling rather than of functional recovery, whereas contractile reserve assessed by LDSE is predictive of functional recovery rather than of LV remodelling.

Noninvasive coronary flow velocity reserve measurement in the posterior descending coronary artery for detecting coronary stenosis in the right coronary artery using contrast-enhanced transthoracic Doppler echocardiography.

Background: Coronary flow velocity reserve (CFVR) measurement by transthoracic Doppler echocardiography (TTDE) has been found to be useful for assessing left anterior descending coronary artery (LAD) stenosis. However, this method has been restricted only for the LAD. The purpose of this study was to detect severe right coronary artery (RCA) stenosis by CFVR measurement using contrast‐enhanced TTDE. Methods: In 60 consecutive patients with angina pectoris (mean (SD) age: 60 (11), 18 women), coronary flow velocities in the RCA were recorded in the postero‐descending coronary artery by contrast‐enhanced TTDE at rest and during hyperemia induced by intravenous infusion of adenosine triphosphate (140 mcg/ml/kg). CFVR was calculated as the ratio of hyperemic to basal peak and mean diastolic flow velocity. CFVR measurements by TTDE were compared with the results of coronary angiography performed within 1 week. Results: Coronary flow velocity was successfully recorded in 49 (82%) of the 60 patients with contrast agent. CFVR (mean (SD)) was 1.4 (0.4) in patients with, and 2.6 (0.6) in patients without significant stenosis in the RCA (%diameter stenosis > 75%, P < 0.001). Using the cutoff value 2.0 for CFVR in the RCA, its sensitivity and specificity in detecting significant stenosis in the RCA were 88% and 91%, respectively. Conclusion: CFVR measurement in the postero‐descending coronary artery by contrast enhanced TTDE is a new, noninvasive method to detect significant stenosis in the RCA. (ECHOCARDIOGRAPHY, Volume 21, April 2004)