Giovanni Luigi De Maria

Intracoronary microparticles and microvascular obstruction in patients with ST elevation myocardial infarction undergoing primary percutaneous intervention

AIMS Microparticles (MP) are cell-derived fragments known to be increased in the blood of patients with acute coronary syndromes. We aimed to assess, in ST elevation myocardial infarction (STEMI), the systemic and local (in the culprit coronary artery) levels of platelet-derived MP (PMP, CD42+CD31+) and endothelial-derived MP (EMP, CD42-CD31+) and their relation to indexes of microvascular obstruction (MVO). METHODS AND RESULTS In 78 STEMI patients undergoing successful primary percutaneous coronary intervention, blood samples were sequentially drawn from the aorta and the culprit coronary artery for cytofluorimetric MP detection. Thrombolysis in myocardial infarction (TIMI) flow, thrombus score (TS), corrected TIMI frame count (cTFC), myocardial blush grade (MBG), quantitative blush evaluator (QuBE) score, and 90 min ST resolution (ΣSTR) were calculated. Both PMP and EMP levels were significantly higher in the intracoronary than in the aortic blood samples. Intracoronary PMP and EMP levels were positively related to TS and cTFC and inversely related to MBG and QuBE. Aortic PMP (but not EMP) levels were related to TS and cTFC and, inversely, to QuBE. Intracoronary PMP were independently related to angiographic and electrocardiographic MVO in a multivariate model. CONCLUSION The correlations of intracoronary EMP and of both systemic and intracoronary PMP levels with TS support the role of MP as markers of ongoing thrombosis. Moreover, the correlation of intracoronary MP with indexes of microvascular dysfunction suggests, for the first time, a possible direct role of MP in the pathogenesis of MVO.

Efficacy of contrast medium induced Pd/Pa ratio in predicting functional significance of intermediate coronary artery stenosis assessed by fractional flow reserve: insights from the RINASCI study.

AIMS The need of adenosine administration for the achievement of maximal hyperaemia limits the widespread application of fractional flow reserve (FFR) in the real world. We hypothesised that Pd/Pa ratio registered during submaximal reactive hyperaemia induced by conventional non-ionic radiographic contrast medium (contrast medium induced Pd/Pa ratio: CMR) can be sufficient for the assessment of physiological severity of stenosis in the vast majority of cases. The aim of the present study was to test the accuracy of CMR in comparison to FFR. METHODS AND RESULTS Eighty patients with 104 intermediate coronary stenoses were prospectively and consecutively enrolled. CMR was obtained after intracoronary injection of 6 ml of radiographic contrast medium, while FFR was measured after administration of adenosine. Despite the fact that CMR values were significantly higher than FFR values (0.88 [IR 0.80-0.92] vs. 0.87 [IR 0.83-0.94], p<0.001), a strong correlation between CMR and FFR values was observed (r=0.94, p<0.001) with a close agreement at Bland-Altman analysis (95% CI of disagreement: -0.029 to 0.072). ROC curve analysis showed an excellent accuracy of CMR cut-off of ≤0.83 in predicting FFR value ≤0.80 (AUC 0.97 [95% CI: 0.91-0.99, specificity 96.1, sensitivity 85.7]). Moreover, no FFR value ≤0.80 corresponded to a CMR ≥0.88. CONCLUSIONS CMR is accurate in predicting the functional significance of coronary stenosis. This could allow limiting the use of adenosine to obtain FFR to doubtful cases. In particular, we suggest considering a CMR value ≤0.83 to be significant, a CMR value ≥0.88 as not significant, and inducing maximal hyperaemia using adenosine for FFR assessment when CMR is between 0.84 and 0.87.

How does coronary stent implantation impact on the status of the microcirculation during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction?

Aims Primary percutaneous coronary intervention (PPCI) is the optimal treatment for patients presenting with ST-elevation myocardial infarction (STEMI). An elevated index of microcirculatory resistance (IMR) reflects microvascular function and when measured after PPCI, it can predict an adverse clinical outcome. We measured coronary microvascular function in STEMI patients and compared sequential changes before and after stent implantation. Methods and results In 85 STEMI patients, fractional flow reserve, coronary flow reserve, and IMR were measured using a pressure wire (Certus, St Jude Medical, St Paul, MN, USA) immediately before and after stent implantation. Stenting significantly improved all of the measured parameters of coronary physiology including IMR from 67.7 [interquartile range (IQR): 56.2–95.8] to 36.7 (IQR: 22.7–59.5), P < 0.001. However, after stenting, IMR remained elevated (>40) in 28 (32.9%) patients. In 15 of these patients (17.6% of the cohort), only a partial reduction in IMR occurred and these patients were more likely to be late presenters (pain to wire time >6 h). The extent of jeopardized myocardium [standardized beta: −0.26 (IMR unit/Bypass Angioplasty Revascularization Investigation score unit), P: 0.009] and pre-stenting IMR [standardized beta: −0.34 (IMR unit), P: 0.001] predicted a reduction in IMR after stenting (ΔIMR = post-stenting IMR − pre-stenting IMR), whereas thrombotic burden [standardized beta: 0.24 (IMR unit/thrombus score unit), P: 0.01] and deployed stent volume [standardized beta: 0.26 (IMR unit/mm3 of stent), P: 0.01] were associated with a potentially deleterious increase in IMR. Conclusion Improved perfusion of the myocardium by stent deployment during PPCI is not universal. The causes of impaired microvascular function at the completion of PPCI treatment are heterogeneous, but can reflect a later clinical presentation and/or the location and extent of the thrombotic burden.

Are endothelial progenitor cells mobilized by myocardial ischemia or myocardial necrosis? A cardiac magnetic resonance study

BACKGROUND In ST-elevation myocardial infarction (STEMI) patients, the main stimuli involved in endothelial progenitor cells (EPCs) mobilization are not fully understood. We aimed to assess by cardiac magnetic resonance (CMR) whether the extent of ischemic myocardium (area at risk (AAR)) or of necrotic myocardium (infarct size (IS)) can be correlated to levels of circulating EPCs. METHODS Peripheral EPCs were measured in fifteen STEMI patients at 24h after successful primary percutaneous coronary intervention (pPCI). Between two and four days after pPCI all patients underwent CMR assessment of myocardial AAR, IS, myocardial salvage (MS) and microvascular obstruction at late gadolinium enhancement CMR (LG-MVO). RESULTS CD34+/KDR+, CD34+/KDR+/CD45dim, CD34+/KDR+/CD45-, EPCs were related to extent of AAR (rho=0.51, p=0.05; rho=0.55, p=0.03; rho=0.72, p=0.002, respectively), while no relationships were detected with IS, MS or LG-MVO. CONCLUSIONS Our data show that EPCs were strongly correlated to extent of myocardial AAR, thus suggesting that progenitor cells mobilization in STEMI develops in response to myocardial ischemia and not to myocardial necrosis.

Comparison of the effects of ramipril versus telmisartan on high-sensitivity C-reactive protein and endothelial progenitor cells after acute coronary syndrome.

To compare the anti-inflammatory and endothelial progenitor cell mobilizing effects of ramipril and telmisartan in patients presenting with acute coronary syndrome (ACS), 42 patients with ACS were randomized after successful percutaneous coronary intervention to ramipril 5 mg/day (22 patients) or telmisartan 80 mg/day (20 patients). Peripheral blood samples were drawn at baseline and at 20 days to measure high-sensitivity C-reactive protein and to assess 4 populations of progenitor cells by flow cytometry, namely CD34+/KDR+, CD34+/CD133+, CD34+/CD133+/CD45-, and CD34+/KDR+/CD45- cells. High-sensitivity C-reactive protein levels, similar in the 2 groups at baseline, were significantly more decreased by telmisartan than by ramipril at follow up (p = 0.013 for time-by-drug interaction). The main effect for time was also significant (p <0.001). CD34+/KDR+ and CD34+/CD133+ cells were similar at baseline and did not change over time (p = 0.2 and p = 0.1, respectively). In contrast, for CD34+/KDR+/CD45- and CD34+/CD133+/CD45- cells, a significant increase with time was seen (p = 0.02 and p = 0.002, respectively) and no differential effect of either drug was seen. In conclusion, telmisartan shows a more potent anti-inflammatory effect than ramipril after an ACS. The 2 drugs do not show a differential effect on endothelial progenitor cell mobilization.

Frequency domain optical coherence tomography to assess non-ostial left main coronary artery

AIMS The aim of this study was to assess the feasibility of unprotected non-ostial left main (LM) imaging by frequency domain optical coherence tomography (FD-OCT). METHODS AND RESULTS We conducted a retrospective analysis of OCT studies performed to image lesions located in the non-ostial LM. OCT studies were analysed off-line to detect the number of artefact frames in the different LM/bifurcation segments. OCT cross-sectional images were used to assess area measures. OCT longitudinal reconstructions were used to obtain the LM length. Standard quantitative coronary angiography (QCA) was used as the reference methodology. A total of 54 patients with non-ostial LM disease entered the study. The mean number of LM artefact frames was 8±10, corresponding to 19% of the total number of LM frames analysed. The percentages of artefact frames differed significantly according to the segment analysed: 43.3% proximal LM, 11.4% mid LM and 2.1% distal LM, 2.0% ostial left anterior descending artery and 0% ostial left circumflex artery (p<0.0001). All LM OCT measurements were significantly correlated with QCA measurements. CONCLUSIONS The results of the present study show that FD-OCT assessment of non-ostial LM disease is feasible and may provide high-quality imaging. OCT assessment of distal LM is more efficient than that of the proximal LM segment.

Frequency-domain optical coherence tomography findings in patients with bifurcated lesions undergoing provisional stenting

AIMS Bifurcations represent challenging lesions which may benefit from improved understanding of stent-related vessel complications. Since optical coherence tomography (OCT) allows us to detect post-stenting vessel injuries, we sought to assess the geographic pattern of stent-related complications occurring during provisional stenting of bifurcated lesions. METHODS AND RESULTS Fifty-one patients with bifurcated lesions treated by provisional stenting and undergoing intra-procedural OCT assessment were enrolled. OCT images were acquired with the aim of guiding the percutaneous coronary intervention but were re-analysed off-line for the present study. The stented bifurcation was divided into four segments [three in the main vessel (MV) and one in the side branch (SB)]. The following acute post-stenting vessel injuries/complications at the different bifurcation segments were evaluated: (i) stent under-expansion, (ii) stent malapposition, (iii) stent edge dissection, (iv) side-branch ostium dissection, (v) tissue prolapse, (vi) intracoronary thrombus, and (vii) in-stent dissection. A total of 55 bifurcation lesions undergoing provisional stenting were analysed. At least one OCT complication was detectable in all cases. Across different bifurcation sites, significant differences in the occurrence of stent complications were observed. In particular, stent malapposition was more common at the proximal MV segment (P < 0.001), while tissue prolapse was more common at the distal MV segment (P < 0.001). CONCLUSION In bifurcated interventions, OCT often detects vessel injuries/stent complications, which tend to have a specific geographical distribution. In particular, stent malapposition is more common at the proximal MV and tissue prolapse at the distal MV segment.

Platelet P2Y12 receptor inhibition by thienopyridines: status and future

Thienopyridines have a well-established role in the treatment of coronary artery disease, especially in the setting of acute coronary syndromes and percutaneous coronary interventions. Ticlopidine, the first FDA-approved thienopyridine, was shown to be effective in reducing coronary events in high risk patients, but the original enthusiasm was hampered by concerns about its serious bone marrow toxicity. Clopidogrel a second generation thienopyridine with lesser side effects, is not only at least as effective as ticlopidine, but in combination with a low dose of aspirin, has been demonstrated to reduce the risk of major cardiovascular events in acute coronary syndrome patients in large-scale, randomised trials. Recent studies have highlighted major flaws in clopidogrel pharmacokinetics due to its delayed onset of action, and much attention has been devoted to the phenomenon of clopidogrel ‘resistance’. Among the novel, third generation thienopyridines, prasugrel as compared to clopidogrel has demonstrated lower inter-patient response variability and a reduced incidence of ischaemic events, but at an increased risk of major bleeding. Currently, several studies are continuing to test new direct P2Y12 receptor antagonists, such as cangrelor and AZD6140, characterised by a faster reversal of platelet inhibition.

CMR Native T1 Mapping Allows Differentiation of Reversible Versus Irreversible Myocardial Damage in ST-Segment-Elevation Myocardial Infarction: An OxAMI Study (Oxford Acute Myocardial Infarction).

Background— CMR T1 mapping is a quantitative imaging technique allowing the assessment of myocardial injury early after ST-segment–elevation myocardial infarction. We sought to investigate the ability of acute native T1 mapping to differentiate reversible and irreversible myocardial injury and its predictive value for left ventricular remodeling. Methods and Results— Sixty ST-segment–elevation myocardial infarction patients underwent acute and 6-month 3T CMR, including cine, T2-weighted (T2W) imaging, native shortened modified look-locker inversion recovery T1 mapping, rest first pass perfusion, and late gadolinium enhancement. T1 cutoff values for oedematous versus necrotic myocardium were identified as 1251 ms and 1400 ms, respectively, with prediction accuracy of 96.7% (95% confidence interval, 82.8% to 99.9%). Using the proposed threshold of 1400 ms, the volume of irreversibly damaged tissue was in good agreement with the 6-month late gadolinium enhancement volume (r=0.99) and correlated strongly with the log area under the curve troponin (r=0.80) and strongly with 6-month ejection fraction (r=−0.73). Acute T1 values were a strong predictor of 6-month wall thickening compared with late gadolinium enhancement. Conclusions— Acute native shortened modified look-locker inversion recovery T1 mapping differentiates reversible and irreversible myocardial injury, and it is a strong predictor of left ventricular remodeling in ST-segment–elevation myocardial infarction. A single CMR acquisition of native T1 mapping could potentially represent a fast, safe, and accurate method for early stratification of acute patients in need of more aggressive treatment. Further confirmatory studies will be needed.

Endothelial progenitor cells, microvascular obstruction, and left ventricular remodeling in patients with ST elevation myocardial infarction undergoing primary percutaneous coronary intervention.

Endothelial progenitor cells (EPCs) are released from the bone marrow during cardiac ischemic events, potentially influencing vascular and myocardial repair. We assessed the clinical and angiographic correlates of EPC mobilization at the time of primary percutaneous coronary intervention in 78 patients with ST elevation myocardial infarction and the impact of both baseline and follow-up EPC levels on left ventricular (LV) remodeling. Blood samples were drawn from the aorta and the culprit coronary artery for cytofluorimetric EPC detection (CD34+CD45dimKDR+ cells, in percentage of cytofluorimetric counts). Area at risk was assessed by Bypass Angioplasty Revascularization Investigation myocardial jeopardy index, thrombotic burden as thrombus score and microvascular obstruction (MVO) as a combination of ST segment resolution and myocardial blush grade. Echocardiographic evaluation of LV remodeling was performed at 1-year follow-up in 54 patients, whereas peripheral EPC levels were reassessed in 40 patients. EPC levels during primary percutaneous coronary intervention were significantly higher in intracoronary than in aortic blood (0.043% vs 0.0006%, p <0.001). Both intracoronary and aortic EPC were related to area at risk extent, to intracoronary thrombus score (p <0.001), and inversely to MVO (p = 0.001). Peripheral EPC levels at 1-year follow-up were lower in patients with LV remodeling than in those without (0.001% [0.001 to 0.002] vs 0.003% [0.002 to 0.010]; p = 0.01) and independently predicted absence of remodeling at multivariate analysis. In conclusion, a rapid intracoronary EPC recruitment takes place in the early phases of ST elevation myocardial infarction, possibly reflecting an attempted reparative response. The extent of this mobilization seems to be correlated to the area at risk and to the amount of MVO. Persistently low levels of EPC are associated to LV remodeling.