Yuhei Kobayashi

Effect of Sex Differences on Invasive Measures of Coronary Microvascular Dysfunction in Patients With Angina in the Absence of Obstructive Coronary Artery Disease

OBJECTIVES This study investigated sex differences in coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) in patients with angina in the absence of obstructive coronary artery disease. BACKGROUND Coronary microvascular dysfunction is associated with worse long-term outcomes, especially in women. Coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR) are 2 methods of assessing the coronary microcirculation. METHODS We prospectively enrolled 117 women and 40 men with angina in the absence of obstructive coronary artery disease. We performed CFR, IMR, fractional flow reserve, and quantitative coronary angiography in the left anterior descending artery. Coronary flow was assessed with a thermodilution method by obtaining mean transit time (Tmn) (an inverse correlate to absolute flow) at rest and hyperemia. RESULTS All patients had minimal atherosclerosis by quantitative coronary angiography (% diameter stenosis: 23.2 ± 12.3%), and epicardial disease was milder in women (fractional flow reserve: 0.88 ± 0.04 vs. 0.87 ± 0.04; p = 0.04). IMR was similar between the sexes (20.7 ± 9.8 vs. 19.1 ± 8.0; p = 0.45), but CFR was lower in women (3.8 ± 1.6 vs. 4.8 ± 1.9; p = 0.004). This was primarily due to a shorter resting Tmn in women (p = 0.005), suggesting increased resting coronary flow, whereas hyperemic Tmn was identical (p = 0.79). In multivariable analysis, female sex was an independent predictor of lower CFR and shorter resting Tmn. CONCLUSIONS Despite similar microvascular function in women and men by IMR, CFR is lower in women. This discrepancy appears to be due to differences in resting coronary flow between the sexes. The effect of sex differences should be considered in interpretation of physiological indexes using resting coronary flow.

Four-year clinical outcomes of the OLIVUS-Ex (impact of Olmesartan on progression of coronary atherosclerosis: Evaluation by intravascular ultrasound) extension trial

BACKGROUND The previous OLIVUS trial reported a positive role in achieving a lower rate of coronary atheroma progression through the administration of olmesartan, an angiotension-II receptor blocking agent (ARB), for stable angina pectoris (SAP) patients requiring percutaneous coronary intervention (PCI). However, the benefits between ARB administration on long-term clinical outcomes and serial atheroma changes by IVUS remain unclear. Thus, we examined the 4-year clinical outcomes from OLIVUS according to treatment strategy with olmesartan. METHODS Serial volumetric IVUS examinations (baseline and 14 months) were performed in 247 patients with hypertension and SAP. When these patients underwent PCI for culprit lesions, IVUS was performed in their non-culprit vessels. Patients were randomly assigned to receive 20-40mg of olmesartan or control, and treated with a combination of β-blockers, calcium channel blockers, glycemic control agents and/or statins per physicians guidance. Four-year clinical outcomes and annual progression rate of atherosclerosis, assessed by serial IVUS, were compared with major adverse cardio- and cerebrovascular events (MACCE). RESULTS Cumulative event-free survival was significantly higher in the olmesartan group than in the control group (p=0.04; log-rank test). By adjusting for validated prognosticators, olmesartan administration was identified as a good predictor of MACCE (p=0.041). On the other hand, patients with adverse events (n=31) had larger annual atheroma progression than the rest of the population (23.8% vs. 2.1%, p<0.001). CONCLUSIONS Olmesartan therapy appears to confer improved long-term clinical outcomes. Atheroma volume changes, assessed by IVUS, seem to be a reliable surrogate for future major adverse cardio- and cerebrovascular events in this study cohort.

Invasive Assessment of Coronary Physiology Predicts Late Mortality After Heart Transplantation

Background— The aim of this study is to determine the prognostic value of invasively assessing coronary physiology early after heart transplantation. Methods and Results— Seventy-four cardiac transplant recipients had fractional flow reserve, coronary flow reserve, index of microcirculatory resistance (IMR), and intravascular ultrasound performed down the left anterior descending coronary artery soon after (baseline) and 1 year after heart transplantation. The primary end point was the cumulative survival free of death or retransplantation at a mean follow-up of 4.5±3.5 years. The cumulative event-free survival was significantly lower in patients with a fractional flow reserve <0.90 at baseline (42% versus 79%; P=0.01) or an IMR ≥20 measured 1 year after heart transplantation (39% versus 69%; P=0.03). Patients in whom IMR decreased or did not change from baseline to 1 year had higher event-free survival compared with patients with an increase in IMR (66% versus 36%; P=0.03). Fractional flow reserve <0.90 at baseline (hazard ratio, 0.13; 95% confidence interval, 0.02–0.81; P=0.03), IMR ≥20 at 1 year (hazard ratio, 3.93; 95% confidence interval, 1.08–14.27; P=0.04), and rejection during the first year (hazard ratio, 6.00; 95% confidence interval, 1.56–23.09; P=0.009) were independent predictors of death/retransplantation, whereas intravascular ultrasound parameters were not. Conclusions— Invasive measures of coronary physiology (fractional flow reserve and IMR) determined early after heart transplantation are significant predictors of late death or retransplantation.

Nicorandil prevents microvascular dysfunction resulting from PCI in patients with stable angina pectoris: a randomised study

AIMS Nicorandil, an ATP sensitive potassium channel opener, may reduce the incidence of microvascular dysfunction after percutaneous coronary intervention (PCI) by dilating coronary resistance vessels. The aim of the study was evaluation of the impact of the administration of intravenous nicorandil on measuring the index of microcirculatory resistance (IMR) in PCI to patients with stable angina pectoris (SAP). METHODS AND RESULTS Intravascular ultrasound (IVUS), fractional flow reserve (FFR), IMR and blood examination (CK-MB), cardiac troponin I (cTnI) immediately post-PCI (and 24 hours later) were performed in 62 consecutive patients with SAP undergoing PCI. FFR and IMR were measured simultaneously with a single coronary pressure wire. IMR was defined as Pd/coronary flow (or Pd* mean transit time) at peak hyperaemia. Patients were randomised to the control (n=29), or nicorandil group (n=33). In the nicorandil group, nicorandil was intravenously administered as a 6 mg bolus injection just before PCI and as a constant infusion at 6 mg/hour for 24 hours thereafter. All volumetric IVUS parameters and FFR were similar between the two groups both pre- and post-PCI. However, IMR immediately post-PCI and cTnI 24 hours post-PCI were significantly higher in the control group compared to the nicorandil group (IMR: 25.4±12.1 vs. 17.9±9.1 units, and cTnI: 0.21±0.13 vs. 0.12±0.08 ng/mL, for control vs. nicorandil). The incidence for cTnI elevation more than fivefold the normal range (>0.20 ng/mL) was significantly larger in the control group than in the nicorandil group (41% vs. 12%, p<0.01). Additionally, the control group showed a closer correlation between plaque volume reduction during stenting as assessed by volumetric IVUS, and cTnI elevation than the nicorandil group (r=0.55 vs. 0.42, p<0.001 for control vs. nicorandil). CONCLUSIONS In patients undergoing successful coronary stenting for stable angina, administration of nicorandil is associated with reduced microvascular dysfunction induced by PCI.

Functional Versus Anatomic Assessment of Myocardial Bridging by Intravascular Ultrasound: Impact of Arterial Compression on Proximal Atherosclerotic Plaque

Background The presence of a myocardial bridge (MB) has been shown to promote atherosclerotic plaque formation proximal to the MB, presumably because of hemodynamic disturbances provoked by retrograde blood flow toward this segment in cardiac systole. We aimed to determine the anatomic and functional properties of an MB related to the extent of atherosclerosis assessed by intravascular ultrasound. Methods and Results We enrolled 100 patients with angina but no significant obstructive coronary artery disease who had an intravascular ultrasound–detected MB in the left anterior descending artery (median age 54 years, 36% male). The MB was identified with intravascular ultrasound by the presence of an echolucent band (halo). Anatomically, the MB length was 22±13 mm, and halo thickness was 0.7±0.6 mm. Functionally, systolic arterial compression was 23±12%. The maximum plaque burden up to 20 mm proximal to the MB entrance was significantly greater than the maximum plaque burden within the MB segment. Among the intravascular ultrasound–defined MB properties, arterial compression was the sole MB parameter that demonstrated a significant positive correlation with maximum plaque burden up to 20 mm proximal to the MB entrance (r=0.254, P=0.011 overall; r=0.545, P<0.001 low coronary risk). In multivariate analysis, adjusting for clinical characteristics and coronary risk factors, arterial compression was independently associated with maximum plaque burden up to 20 mm proximal to the MB entrance. Conclusions In patients with an MB in the left anterior descending artery, the percentage of arterial compression is related directly to the burden of atherosclerotic plaque located proximally to the MB, particularly in patients who otherwise have low coronary risk. This may prove helpful in identifying high‐risk MB patients.

The impact of left ventricular ejection fraction on fractional flow reserve: Insights from the FAME (Fractional flow reserve versus Angiography for Multivessel Evaluation) trial

BACKGROUND Fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) significantly improves outcomes compared with angio-guided PCI in patients with multivessel coronary artery disease. However, there is a theoretical concern that in patients with reduced left ventricular ejection fraction (EF) FFR may be less accurate and FFR-guided PCI less beneficial. METHODS From the FAME (Fractional flow reserve versus Angiography for Multivessel Evaluation) trial database, we compared FFR values between patients with reduced EF (both ≤ 40%, n = 90 and ≤ 50%, n = 252) and preserved EF (> 40%, n = 825 and > 50%, n = 663) according to the angiographic stenosis severity. We also compared differences in 1 year outcomes between FFR- vs. angio-guided PCI in patients with reduced and preserved EF. RESULTS Both groups had similar FFR values in lesions with 50-70% stenosis (p = 0.49) and with 71-90% stenosis (p = 0.89). The reduced EF group had a higher mean FFR compared to the preserved EF group across lesions with 91-99% stenosis (0.55 vs. 0.50, p = 0.02), although the vast majority of FFR values remained ≤ 0.80. There was a similar reduction in the composite end point of death, nonfatal myocardial infarction, and repeat revascularization with FFR-guided compared to angio-guided PCI for both the reduced (14.5% vs. 19.0%, relative risk = 0.76, p = 0.34) and the preserved EF group (13.8 vs. 17.0%, relative risk = 0.81, p = 0.25). The results were similar with an EF cutoff of 40%. CONCLUSION Reduced EF has no influence on the FFR value unless the stenosis is very tight, in which case a theoretically explainable, but clinically irrelevant overestimation might occur. As a result, FFR-guided PCI remains beneficial regardless of EF.

Exercise Strain Echocardiography in Patients With a Hemodynamically Significant Myocardial Bridge Assessed by Physiological Study

Background Although a myocardial bridge (MB) is often regarded as a benign coronary variant, recent studies have associated MB with focal myocardial ischemia. The physiological consequences of MB on ventricular function during stress have not been well established. Methods and Results We enrolled 58 patients with MB of the left anterior descending artery, diagnosed by intravascular ultrasound. Patients underwent invasive physiological evaluation of the MB by diastolic fractional flow reserve during dobutamine challenge and exercise echocardiography. Septal and lateral longitudinal strain (LS) were assessed at rest and immediately after exercise and compared with strain of matched controls. Absolute and relative changes in strain were also calculated. The mean age was 42.5±16.0 years. Fifty‐five patients had a diastolic fractional flow reserve ≤0.76. At rest, there was no significant difference between the 2 groups in septal LS (19.0±1.8% for patients with MB versus 19.2±1.5% for control, P=0.53) and lateral LS (20.1±2.0% versus 20.0±1.6%, P=0.83). With stress, compared with controls, patients with MB had a lower peak septal LS (18.9±2.6% versus 21.7±1.6%, P<0.001) and lower absolute (−0.1±2.1% versus 2.5±1.3%, P<0.001) and relative change (−0.6±11.2% versus 13.1±7.8%, P<0.001) in septal LS, whereas there was no significant difference in lateral LS. In multivariate analysis, diastolic fractional flow reserve and length were independent determinants of lower changes in septal LS. Conclusions Patients with a hemodynamically significant MB, determined by invasive diastolic fractional flow reserve, have significantly lower change in septal LS on exercise echocardiography, suggesting that septal LS may be useful for noninvasively assessing the hemodynamic significance of an MB.

Additive value of nicorandil on ATP for further inducing hyperemia in patients with an intermediate coronary artery stenosis.

Background The induction of hyperemia is of importance to precisely assess the functional significance of coronary artery lesions with fractional flow reserve (FFR). Adenosine or ATP alone is used widely in this setting; however, little is known about the additive value of nicorandil, which acts as a nitrate and a K+-ATP channel opener, to induce further hyperemia. Patients and methods A total of 183 intermediate native coronary artery lesions from 112 patients were prospectively enrolled into this study. FFR was measured using a coronary pressure wire during an intravenous ATP infusion alone (150 mcg/kg/min) (FFRATP) and repeated after an adjunctive intracoronary nicorandil injection (2.0 mg) (FFRATP+Nico). Results Physiologic measurements were completed without any severe adverse effects from ATP and nicorandil in all patients. FFRATP and FFRATP+Nico had a strong linear correlation (R2=0.79, P<0.001). The FFR value became significantly lower with an adjunctive intracoronary nicorandil injection compared with ATP alone [FFRATP vs. FFRATP+Nico, 0.87 (interquartile range: 0.81–0.92) vs. 0.85 (0.79–0.90), P<0.001]. A total of 18 lesions out of 183 (9.8%) were reclassified after a nicorandil injection (12 from FFR>0.80 to ⩽0.80 vs. six from FFR⩽0.80 to >0.80, P=0.26). The adjunctive effect of nicorandil was accentuated with each increment of FFRATP strata (per 0.05 increase, P for trend<0.001), but with minimal effect around the borderline FFR zone. Conclusion An adjunctive intracoronary nicorandil injection is safe, but appears to have little effect in inducing further hyperemia. Therefore, its effect on the clinical scenario is limited.

Coronary Endothelial Dysfunction and the Index of Microcirculatory Resistance as a Marker of Subsequent Development of Cardiac Allograft Vasculopathy

Cardiac allograft vasculopathy (CAV) is a leading cause of long-term morbidity and mortality after heart transplantation.1 Conventional methods for monitoring for CAV detect CAV after it has developed, which may be too late to modify its course. Endothelial dysfunction and the index of microcirculatory resistance (IMR) assessed soon after transplantation have both been shown in separate studies to predict development of CAV and long-term adverse outcome.2,3 The purpose of this study (URL: http://clinicaltrials.gov. Unique identifier: NCT01078363) is to quantify the combined impact of early endothelial dysfunction and elevated microvascular resistance as a marker of subsequent development of CAV at 1 year after cardiac transplantation. Forty-four heart transplant recipients underwent intracoronary acetylcholine injection (50–100 µg over 30 seconds), coronary physiology assessment, and volumetric intravascular ultrasound analysis performed in the left anterior descending coronary artery within 8 weeks after transplantation (baseline) and at 1 year. Endothelial dysfunction was defined as ≥20% change in diameter of the left anterior descending coronary artery as measured by quantitative angiography after acetylcholine and in comparison with baseline angiography.2 Elevated microvascular resistance was defined as an IMR≥20.3 IMR was assessed with a coronary pressure/thermistor-tipped wire …

Invasive Assessment of the Coronary Microcirculation.

Despite successful restoration of epicardial coronary artery flow after treating ST-segment elevation myocardial infarction (STEMI) with primary percutaneous coronary intervention (PCI), a range of microvascular damage occurs, which correlates with both short- and long term outcomes. A number of