Leonarda Galiuto

Myocardial No-Reflow in Humans

In a variable proportion of patients presenting with ST-segment elevation myocardial infarction, ranging from 5% to 50%, primary percutaneous coronary intervention achieves epicardial coronary artery reperfusion but not myocardial reperfusion, a condition known as no-reflow. Of note, no-reflow is associated with a worse prognosis at follow-up. The phenomenon has a multifactorial pathogenesis including: distal embolization, ischemia-reperfusion injury, and individual predisposition of coronary microcirculation to injury. Moreover, it is spontaneously reversible in some patients, thus suggesting that it might be amenable to treatment also when we fail to prevent it. Several recent studies have shown that biomarkers and other easily available clinical parameters can predict the risk of no-reflow and can help in the assessment of the multiple mechanisms of the phenomenon. Several therapeutic strategies have been tested for the prevention and treatment of no-reflow. In particular, thrombus aspiration before stent implantation prevents distal embolization and has been recently shown to improve myocardial perfusion and clinical outcome as compared with the standard procedure. However, it is conceivable that the relevance of each pathogenetic component of no-reflow is different in different patients, thus explaining the occurrence of no-reflow despite the use of mechanical thrombus aspiration. Thus, in this review article, for the first time, we propose a personalized management of no-reflow on the basis of the assessment of the prevailing mechanisms of no-reflow operating in each patient.

Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy

BACKGROUND The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood. METHODS The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome. RESULTS Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year. CONCLUSIONS Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).

The Extent of Microvascular Damage During Myocardial Contrast Echocardiography Is Superior to Other Known Indexes of Post-Infarct Reperfusion in Predicting Left Ventricular Remodeling: Results of the Multicenter AMICI Study

OBJECTIVES We sought to evaluate the value of the extent of microvascular damage as assessed with myocardial contrast echocardiography (MCE) in the prediction of left ventricular (LV) remodeling after ST-segment elevation myocardial infarction (STEMI) as compared with established clinical and angiographic parameters of reperfusion. BACKGROUND Early identification of post-percutaneous coronary intervention microvascular dysfunction may help in tailoring appropriate pharmacological interventions in high-risk patients. The ideal method to establish effective microvascular reperfusion after percutaneous coronary intervention remains to be determined. METHODS A total of 110 patients with first successfully reperfused STEMI were enrolled in the AMICI (Acute Myocardial Infarction Contrast Imaging) multicenter study. After reperfusion, peak creatine kinase, ST-segment reduction, and Thrombolysis In Myocardial Infarction (TIMI) and myocardial blush grade were calculated. We evaluated perfusion defects with MCE by using continuous infusion of Sonovue (Bracco, Milan, Italy) in real-time imaging. The endocardial length of contrast defect (CD) on day 1 after reperfusion was calculated. Wall motion score index, the extent of wall motion abnormalities, LV end-diastolic volume, and ejection fraction after reperfusion and at follow-up also were calculated. RESULTS Of 110 patients, 25% evolved in LV remodeling and 75% did not. Although peak creatine kinase, ST-segment reduction >70%, and myocardial blush grade were not different between groups, in patients exhibiting LV remodeling, TIMI flow grade 3 was less frequent (p < 0.001), wall motion score index was greater (p < 0.001), and CD was greater (p < 0.001). At multivariate analysis, only TIMI flow grade <3 and CD with a cutoff of >25% were independently associated with LV remodeling. Among patients with TIMI flow grade 3, CD was the only independent variable associated with LV remodeling. CONCLUSIONS Among patients with TIMI flow grade 3, the extent of microvascular damage, detected and quantitated by MCE, is the most powerful independent predictor of LV remodeling after STEMI as compared with persistent ST-segment elevation and myocardial blush grade.

Reversible coronary microvascular dysfunction: a common pathogenetic mechanism in Apical Ballooning or Tako-Tsubo Syndrome

AIMS To study coronary microvascular dysfunction as possible pathogenetic mechanism in Apical Ballooning Syndrome (ABS). METHODS AND RESULTS Fifteen ABS patients (all women, 68 +/- 14 years) underwent myocardial contrast echocardiography at baseline during adenosine infusion (140 microg/kg/min) and at 1-month follow-up and compared with a group of anterior ST-elevation myocardial infarction (STEMI) patients with similar clinical characteristics. Myocardial perfusion was assessed by contrast score index (CSI) and endocardial length of contrast defect (contrast defect length, CDL), whereas myocardial dysfunction by wall motion score index (WMSI), endocardial length of contractile dysfunction (wall motion defect length, WMDL), and LV ejection fraction (LVEF). At baseline, no difference in myocardial perfusion and dysfunction were present between the two groups. During adenosine challenge, while no changes were observed in STEMI group, in ABS patients CSI, CDL, WMSI, and WMDL significantly decreased compared with baseline (P < 0.001 vs. baseline for all parameters) and LVEF significantly increased (P = 0.01 vs. baseline). At 1-month follow-up, myocardial perfusion and dysfunction completely recovered in ABS patients (P < 0.001 vs. baseline for all parameters), whereas no significant changes were observed in STEMI group. CONCLUSION Our data strongly suggest that in ABS, irrespectively of its underlying aetiology, acute and reversible coronary microvascular vasoconstriction could represent a common pathophysiological mechanism.

Temporal evolution and functional outcome of no reflow: sustained and spontaneously reversible patterns following successful coronary recanalisation.

Objective: To identify in humans the temporal patterns of no reflow and their functional implications. Methods: 24 patients with first acute myocardial infarction and successful coronary recanalisation by recombinant tissue-type plasminogen activator (n = 15) or primary percutaneous transluminal coronary angioplasty (n = 9) were studied by myocardial contrast echocardiography within 24 hours of recanalisation and at one month’s follow up. Myocardial contrast echocardiography was performed by intermittent harmonic power Doppler and intravenous Levovist. The regional contrast score index (CSI) was calculated within dysfunctioning myocardium. Videointensity was measured (dB) within risk and control areas and their ratio was calculated. Results: In 8 patients reflow was observed at 24 hours and persisted at one month. Conversely in 16 patients areas of no reflow were detectable at 24 hours. At one month, no reflow was spontaneously reversible in 9 patients (mean (SD) CSI and videointensity ratio improved from 2.5 (0.5) to 1.4 (0.6) and from 0.6 (0.1) to 0.7 (0.1), respectively; p < 0.05) and was sustained in the remaining 7 patients (CSI and videointensity ratio remained unchanged from 2.6 (0.6) to 2.6 (0.5) and from 0.5 (0.2) to 0.5 (0.2), respectively; NS). Left ventricular function improved significantly in patients with reflow and reversible no reflow. Volumes were enlarged only in patients with sustained no reflow. Conclusions: No reflow detected at 24 hours may be sustained or spontaneously reversible at one month. Such reversibility of the phenomenon is associated with preserved left ventricular volumes and function. Clarification of the mechanisms of delayed reversibility may lead to tailored treatment of no reflow even in the subacute phase of myocardial infarction.

Ischemia-Reperfusion Injury at the Microvascular Level Treatment by Endothelin A–Selective Antagonist and Evaluation by Myocardial Contrast Echocardiography

Background—The purpose of this study was to verify whether endothelin A–antagonist administration at the time of coronary reperfusion preserves postischemic microvasculature and whether myocardial contrast echo (MCE) is able to detect pharmacologically induced changes in microvascular reflow. Methods and Results—Twenty dogs underwent 90 minutes of LAD occlusion (OCC) followed by 180 minutes of reperfusion (RP). Five minutes before LAD reopening, an intravenous bolus (5 mg/kg) of LU 135252 was given in 10 dogs and vehicle in the remaining 10. At baseline (BSL), OCC, and 90 and 180 minutes of RP, microvascular flow (BF) was assessed by microspheres, and MCE was performed with intravenous echo contrast. MCE videointensity and BF were expressed as risk area/control ratio. Myocardial thickness of the risk area was calculated by 2D echo. No differences in BF between the 2 groups were observed at BSL, OCC, and 90 minutes of RP. At 180 minutes of RP, BF was decreased in controls (70±7.4% of BSL;P <0.005 versus BSL) and preserved in LU 135252–treated animals (89±4% of BSL;P =NS versus BSL;P <0.05 versus controls). Videointensity at MCE closely followed the changes in BF observed in both groups throughout the protocol. Myocardial thickness at 180 minutes of RP increased to 138.6±9.9% of BSL in controls and remained at 108.9±7.4% of BSL in treated dogs (P <0.05). Conclusions—Endothelin A–antagonist treatment at the time of reperfusion significantly limited the progressive decrease in postischemic microvascular reflow and the increase in myocardial thickness. MCE allowed a reliable evaluation of pharmacologically induced changes in microvascular flow.

Effect of intensive vs standard statin therapy on endothelial progenitor cells and left ventricular function in patients with acute myocardial infarction: Statins for regeneration after acute myocardial infarction and PCI (STRAP) trial

BACKGROUND Intensive statin therapy can lower the risk of recurrence of major cardiac events in patients with acute coronary syndromes. This could be related to the ability of statins to increase levels of Endothelial Progenitor Cells (EPCs), which were demonstrated to be favorably associated with a better prognosis and post-infarction left ventricular remodeling in patients with ischemic heart disease. AIM OF THE STUDY First, to evaluate, in a randomized clinical trial, the effect of an intensive vs a standard treatment with statins on EPC mobilization in patients undergoing a successful primary or rescue percutaneous coronary intervention; secondary, to evaluate whether left ventricular remodeling could be influenced by statin therapy through EPC mobilization. METHODS Forty ST-segment elevation myocardial infarction (STEMI) patients undergoing a successful primary or rescue PCI were randomized to receive atorvastatin 80 mg immediately after the admission (Intensive Treatment, IT) or atorvastatin 20 mg from the day of the discharge (Standard Treatment, ST). CD34+/KDR+ EPC count by flow cytometry and left ventricular function by 2-D Echo were measured on admission, at discharge and at 4 months follow up. RESULTS We found that EPC count was similar in the two groups of patients both on admission and at discharge. At follow up, however, EPC count was higher in patients randomized to IT compared to patients randomized to ST (7.59+/-7.30 vs 3.04+/-3.93, p=0.04). However, LV volumes, ejection fraction and wall motion score index were similar in both groups. CONCLUSIONS An intensive statin treatment after primary or rescue PCI is associated with a higher EPC count at follow up as compared to standard treatment. This beneficial effect did not translate in an improvement of LV function.

Incidence, determinants, and prognostic value of reverse left ventricular remodelling after primary percutaneous coronary intervention: results of the Acute Myocardial Infarction Contrast Imaging (AMICI) multicenter study

Aims Few data are available on the extent and prognostic value of reverse left ventricular remodelling (r-LVR) after ST-elevation acute myocardial infarction (STEMI). We sought to evaluate incidence, major determinants, and long-term clinical significance of r-LVR in a group of STEMI patients treated with primary percutaneous coronary intervention (PPCI). In particular, the role of preserved microvascular flow within the infarct zone in inducing r-LVR has been investigated. Methods and results Serial echocardiograms (2DE) and myocardial contrast study were obtained within 24 h of coronary recanalization (T1) and at pre-discharge (T2) in 110 reperfused STEMI patients. Follow-up 2DE was scheduled after 6 months (T3). Two-year clinical follow-up was obtained. Reverse remodelling was defined as a reduction >10% in LV end-systolic volume (LVESV) at 6 months follow-up. r-LVR occurred in 39% of study population. At multivariable analysis, independent predictors of r-LVR were an effective microvascular reflow within the infarct zone, the in-hospital improvement of myocardial perfusion, an initial large LVESV, and a short time to reperfusion. Cox analysis identified r-LVR as the only independent predictor of 2-year event-free survival. Combined events rate was significantly higher among patients without compared to those with r-LVR (log-rank test P < 0.05). Conclusion r-LVR frequently occurs in STEMI patients treated with PPCI and it is an important predictor of favourable long-term outcome. A preserved microvascular perfusion within the infarct zone is the major determinant of r-LVR.

The No-Reflow Phenomenon

LACK OF INTRAMYOCARDIAL REPERFUSION after successful coronary recanalization has been defined as the “no-reflow” phenomenon. The phenomenon is not uncommon (39% with myocardial contrast echocardiography [MCE] and 43% using myocardial blush grade at coronary angiography) in humans after

Comparison of sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography with gated single-photon emission computed tomography for detection of significant coronary artery disease: a large European multicenter study

OBJECTIVES The purpose of this study was to compare sulfur hexafluoride microbubble (SonoVue)-enhanced myocardial contrast echocardiography (MCE) with single-photon emission computed tomography (SPECT) relative to coronary angiography (CA) for assessment of coronary artery disease (CAD). BACKGROUND Small-scale studies have shown that myocardial perfusion assessed by SonoVue-enhanced MCE is a viable alternative to SPECT for CAD assessment. However, large multicenter studies are lacking. METHODS Patients referred for myocardial ischemia testing at 34 centers underwent rest/vasodilator SonoVue-enhanced flash-replenishment MCE, standard (99m)Tc-labeled electrocardiography-gated SPECT, and quantitative CA within 1 month. Myocardial ischemia assessments by 3 independent, blinded readers for MCE and 3 readers for SPECT were collapsed into 1 diagnosis per patient per technique and were compared to CA (reference standard) read by 1 independent blinded reader. RESULTS Of 628 enrolled patients who received SonoVue (71% males; mean age: 64 years; >1 cardiovascular [CV] risk factor in 99% of patients) 516 patients underwent all 3 examinations, of whom 161 (31.2%) had ≥70% stenosis (131 had single-vessel disease [SVD]; 30 had multivessel disease), and 310 (60.1%) had ≥50% stenosis. Higher sensitivity was obtained with MCE than with SPECT (75.2% vs. 49.1%, respectively; p < 0.0001), although specificity was lower (52.4% vs. 80.6%, respectively; p < 0.0001) for ≥70% stenosis. Similar findings were obtained for patients with ≥50% stenosis. Sensitivity levels for detection of SVD and proximal disease for ≥70% stenosis were higher for MCE (72.5% vs. 42.7%, respectively; p < 0.0001; 80% vs. 58%, respectively; p = 0.005, respectively). CONCLUSIONS SonoVue-enhanced MCE demonstrated superior sensitivity but lower specificity for detection of CAD compared to SPECT in a population with a high incidence of CV risk factors and intermediate-high prevalence of CAD. (A phase III study to compare SonoVue® enhanced myocardial echocardiography [MCE] to single photon emission computerized tomography [ECG-GATED SPECT], at rest and at peak of low-dose Dipyridamole stress test, in the assessment of significant coronary artery disease [CAD] in patients with suspect or known CAD using Coronary Angiography as Gold Standard-SonoVue MCE vs SPECT; EUCTR2007-003492-39-GR).