Antonio Maria Leone

From bone marrow to the arterial wall: the ongoing tale of endothelial progenitor cells

Several physiological and pathophysiological stimuli or drugs modulate endothelial progenitor cell (EPC) mobilization. Moreover, levels of circulating EPCs predict cardiovascular risk and left ventricular remodelling after myocardial infarction. Nevertheless, our understanding in this field is complicated by lack of an unequivocal definition of EPCs, thus limiting their clinical applications. This review summarizes current knowledge and uncertainties on EPC characterization and mobilization in the attempt to define their role in the management of cardiovascular diseases.

EuroSCORE as predictor of in-hospital mortality after percutaneous coronary intervention

Objective: To date, no common risk stratification system is available to predict the risk of surgical or percutaneous myocardial revascularisation in patients with coronary artery disease (CAD). Thus, we sought to assess the European System for Cardiac Operative Risk Evaluation (EuroSCORE) validity to predict in-hospital mortality after percutaneous coronary intervention (PCI). Design, setting and participants: EuroSCORE was prospectively and systematically assessed in 1173 consecutive patients undergoing PCI in a high-volume single centre between April 2005 and October 2006. Main outcome measure: The receiver-operating characteristics (ROC) curve was used to describe performance and accuracy of the EuroSCORE risk model for the prediction of in-hospital mortality after PCI. Results: The EuroSCORE model demonstrated an overall relation between EuroSCORE rank and the incidence of in-hospital mortality, showing consistency in predicting patient risk across many subgroups and levels of global risk. At multivariable logistic regression analysis the EuroSCORE value was an independent in-hospital mortality predictor (p = 0.002) together with left main disease (p = 0.005), procedural urgency (p = 0.001), ACC/AHA C type lesion (p = 0.02) and PCI failure (p = 0.01). The area under the ROC curve for the EuroSCORE system was 0.91 (95% CI 0.86 to 0.97), indicating a good ability of the model to discriminate patients at risk of dying during the index hospitalisation. Conclusion: The EuroSCORE risk model, already extensively validated for the prediction of early mortality following open-heart surgery, can also be efficiently utilised in the setting of PCI. The introduction of the EuroSCORE assessment in patients with documented CAD may help to improve the revascularisation strategy decision-making process.

Widespread Myocardial Inflammation and Infarct-Related Artery Patency

Background—Diffuse coronary vascular inflammation is associated with acute coronary syndromes. However, it is unknown whether inflammation also occurs within the myocardium. Therefore, this study was aimed at assessing the presence of activated cells in unaffected remote myocardium of patients with acute myocardial infarction (AMI), in comparison to the peri-infarct region from the same cases, and in comparison to myocardial specimens from control hearts. Methods and Results—Sixteen patients dying 1 to 12 weeks after AMI and 16 control subjects were selected at autopsy. Myocardial specimens were taken at remote unaffected viable regions and at peri-infarct regions in cases with AMI. Confocal microscopy was performed to measure the number of activated cells (DR+), T-lymphocytes (CD3+), and activated T-lymphocytes (CD3+/DR+). Activated cells and activated T-lymphocytes were found in remote unaffected regions in 11 of 16 cases (69%), in peri-infarct zone in all cases (100%), and in none of the control hearts (0%, P <0.001 versus others). A greater myocardial inflammatory burden in remote regions but not in peri-infarct regions was associated with persistent infarct-related artery occlusion (P <0.05). Conclusions—This study for the first time shows the presence of activated T-lymphocytes in remote unaffected myocardial regions in approximately two thirds of patients with recent AMI. Because these cells are associated with persistent infarct-related artery occlusion, our data may suggest that an antigenic stimulus present also in the myocardium triggers an immune response that may be critical to precipitate artery occlusion.

Plaque rupture and intact fibrous cap assessed by optical coherence tomography portend different outcomes in patients with acute coronary syndrome.

AIMS Patients presenting with acute coronary syndrome (ACS) may have different plaque morphologies at the culprit lesion. In particular, plaque rupture (PR) has been shown as the more frequent culprit plaque morphology in ACS. However, its prognostic value is still unknown. In this study, we evaluated the prognostic value of PR, compared with intact fibrous cap (IFC), in patients with ACS. METHODS AND RESULTS We enrolled consecutive patients admitted to our Coronary Care Unit for ACS and undergoing coronary angiography followed by interpretable optical coherence tomography (OCT) imaging. Culprit lesion was classified as PR and IFC by OCT criteria. Prognosis was assessed according to such culprit lesion classification. Major adverse cardiac events (MACEs) were defined as the composite of cardiac death, non-fatal myocardial infarction, unstable angina, and target lesion revascularization (follow-up mean time 31.58 ± 4.69 months). The study comprised 139 consecutive ACS patients (mean age 64.3 ± 12.0 years, male 73.4%, 92 patients with non-ST elevation ACS and 47 with ST-elevation ACS). Plaque rupture was detected in 82/139 (59%) patients. There were no differences in clinical, angiographic, or procedural data between patients with PR when compared with those having IFC. Major adverse cardiac events occurred more frequently in patients with PR when compared with those having IFC (39.0 vs. 14.0%, P = 0.001). Plaque rupture was an independent predictor of outcome at multivariable analysis (odds ratio 3.735, confidence interval 1.358-9.735). CONCLUSION Patients with ACS presenting with PR as culprit lesion by OCT have a worse prognosis compared with that of patients with IFC. This finding should be taken into account in risk stratification and management of patients with ACS.

Lumbar spondylolysis: a review

Spondylolysis is an osseous defect of the pars interarticularis, thought to be a developmental or acquired stress fracture secondary to chronic low-grade trauma. It is encountered most frequently in adolescents, most commonly involving the lower lumbar spine, with particularly high prevalence among athletes involved in certain sports or activities. Spondylolysis can be asymptomatic or can be a cause of spine instability, back pain, and radiculopathy. The biomechanics and pathophysiology of spondylolysis are complex and debated. Imaging is utilized to detect spondylolysis, distinguish acute and active lesions from chronic inactive non-union, help establish prognosis, guide treatment, and to assess bony healing. Radiography with satisfactory technical quality can often demonstrate a pars defect. Multislice CT with multiplanar reformats is the most accurate modality for detecting the bony defect and may also be used for assessment of osseous healing; however, as with radiographs, it is not sensitive for detection of the early edematous stress response without a fracture line and exposes the patient to ionizing radiation. Magnetic resonance (MR) imaging should be used as the primary investigation for adolescents with back pain and suspected stress reactions of the lumbar pars interarticularis. Several imaging pitfalls render MR imaging less sensitive than CT for directly visualizing the pars defects (regional degenerative changes and sclerosis). Nevertheless, the presence of bone marrow edema on fluid-sensitive images is an important early finding that may suggest stress response without a visible fracture line. Moreover, MR is the imaging modality of choice for identifying associated nerve root compression. Single-photon emission computed tomography (SPECT) use is limited by a high rate of false-positive and false-negative results and by considerable ionizing radiation exposure. In this article, we provide a review of the current concepts regarding spondylolysis, its epidemiology, pathogenesis, and general treatment guidelines, as well as a detailed review and discussion of the imaging principles for the diagnosis and follow-up of this condition.

Predictors of Periprocedural (Type IVa) Myocardial Infarction, as Assessed by Frequency-Domain Optical Coherence Tomography

Background— Frequency-domain optical coherence tomography (FD-OCT) is easily able to define both pre- and post-stenting features of the atherosclerotic plaque that can potentially be related to periprocedural complications. We sought to examine which FD-OCT-defined characteristics, assessed both before and after stent deployment, predicted periprocedural (type IVa) myocardial infarction (MI). Methods and Results— FD-OCT was performed before and after coronary stenting in 50 patients undergoing percutaneous coronary intervention (PCI) for either non-ST segment elevation MI (NSTEMI) or stable angina. All patients underwent single-vessel stenting, and only drug-eluting stents were implanted. Troponin T was analyzed on admission, before PCI, and at 12 and 24 hours after PCI, and type IVa MI was defined in stable angina as a rise of at least 3× upper reference limit and in NSTEMI as a pre-PCI troponin T fall, followed by post-PCI troponin T rise >20%. Type IVa MI was diagnosed in 21 patients, while the remaining 29 represented the control group. FD-OCT analysis showed that thin-cap fibroatheroma (76.2% versus 41.4%; P=0.017) prior to PCI, intrastent thrombus (61.9% versus 20.7%; P=0.04), and intrastent dissection (61.9% versus 31%; P=0.03) after PCI were significantly more frequent in type IVa MI than in the control group. Multivariate logistic regression analysis confirmed thin-cap fibroatheroma (OR 29.7, 95% CI 1.4 to 32.1), intrastent thrombus (OR 5.5, CI 1.2 to 24.9) and intrastent dissection (OR 5.3, CI 1.2 to 24.3) as independent predictors of type IVa MI. Conclusions— In conclusion, presence of thin-cap fibroatheroma at pre-PCI FD-OCT and of intrastent thrombus and intrastent dissection at post-PCI FD-OCT predict type IVa MI in a contemporary sample of patients treated with second-generation drug-eluting stents. Interestingly, 2 of the 3 predictors of type IVa MI were not apparent at pre-PCI FD-OCT.

Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study.

OBJECTIVES This study sought to compare increasing doses of intracoronary (i.c.) adenosine or i.c. sodium nitroprusside versus intravenous (i.v.) adenosine for fractional flow reserve (FFR) assessment. BACKGROUND Maximal hyperemia is the critical prerequisite for FFR assessment. Despite i.v. adenosine currently representing the recommended approach, i.c. administration of adenosine or other coronary vasodilators constitutes a valuable alternative in everyday practice. However, it is surprisingly unclear which i.c. strategy allows the achievement of FFR values comparable to i.v. adenosine. METHODS Fifty intermediate coronary stenoses (n = 45) undergoing FFR measurement were prospectively and consecutively enrolled. Hyperemia was sequentially induced by incremental boli of i.c. adenosine (ADN) (60 μg ADN60, 300 μg ADN300, 600 μg ADN600), by i.c. sodium nitroprusside (NTP) (0.6 μg/kg bolus) and by i.v. adenosine infusion (IVADN) (140 μg/kg/min). FFR values, symptoms, and development of atrioventricular block were recorded. RESULTS Incremental doses of i.c. adenosine and NTP were well tolerated and associated with fewer symptoms than IVADN. Intracoronary adenosine doses (0.881 ± 0.067, 0.871 ± 0.068, and 0.868 ± 0.070 with ADN60, ADN300, and ADN600, respectively) and NTP (0.892 ± 0.072) induced a significant decrease of FFR compared with baseline levels (p < 0.001). Notably, ADN600 only was associated with FFR values similar to IVADN (0.867 ± 0.072, p = 0.28). Among the 10 patients with FFR values ≤0.80 with IVADN, 5 were correctly identified also by ADN60, 6 by ADN300, 7 by ADN600, and 6 by NTP. CONCLUSIONS Intracoronary adenosine, at doses higher than currently suggested, allows obtaining FFR values similar to i.v. adenosine. Intravenous adenosine, which remains the gold standard, might thus be reserved for those lesions with equivocal FFR values after high (up to 600 μg) i.c. adenosine doses.

Continuum of Vasodilator Stress From Rest to Contrast Medium to Adenosine Hyperemia for Fractional Flow Reserve Assessment

OBJECTIVES This study compared the diagnostic performance with adenosine-derived fractional flow reserve (FFR) ≤0.8 of contrast-based FFR (cFFR), resting distal pressure (Pd)/aortic pressure (Pa), and the instantaneous wave-free ratio (iFR). BACKGROUND FFR objectively identifies lesions that benefit from medical therapy versus revascularization. However, FFR requires maximal vasodilation, usually achieved with adenosine. Radiographic contrast injection causes submaximal coronary hyperemia. Therefore, intracoronary contrast could provide an easy and inexpensive tool for predicting FFR. METHODS We recruited patients undergoing routine FFR assessment and made paired, repeated measurements of all physiology metrics (Pd/Pa, iFR, cFFR, and FFR). Contrast medium and dose were per local practice, as was the dose of intracoronary adenosine. Operators were encouraged to perform both intracoronary and intravenous adenosine assessments and a final drift check to assess wire calibration. A central core lab analyzed blinded pressure tracings in a standardized fashion. RESULTS A total of 763 subjects were enrolled from 12 international centers. Contrast volume was 8 ± 2 ml per measurement, and 8 different contrast media were used. Repeated measurements of each metric showed a bias <0.005, but a lower SD (less variability) for cFFR than resting indexes. Although Pd/Pa and iFR demonstrated equivalent performance against FFR ≤0.8 (78.5% vs. 79.9% accuracy; p = 0.78; area under the receiver-operating characteristic curve: 0.875 vs. 0.881; p = 0.35), cFFR improved both metrics (85.8% accuracy and 0.930 area; p < 0.001 for each) with an optimal binary threshold of 0.83. A hybrid decision-making strategy using cFFR required adenosine less often than when based on either Pd/Pa or iFR. CONCLUSIONS cFFR provides diagnostic performance superior to that of Pd/Pa or iFR for predicting FFR. For clinical scenarios or health care systems in which adenosine is contraindicated or prohibitively expensive, cFFR offers a universal technique to simplify invasive coronary physiological assessments. Yet FFR remains the reference standard for diagnostic certainty as even cFFR reached only ∼85% agreement.

Prospective Randomized Comparison of Sirolimus- or Everolimus-Eluting Stent to Treat Bifurcated Lesions by Provisional Approach

OBJECTIVES This study sought to compare the procedural performance and the acute angiographic result on side-branch ostium obtained using 2 different drug-eluting stents (DES) to treat patients with bifurcated coronary lesions. BACKGROUND Drug-eluting stents are routinely used in percutaneous coronary interventions (PCI) of bifurcated coronary lesions. Different DES types have major technical differences that may influence the procedural and clinical performance in bifurcation PCI. METHODS Consecutive patients with bifurcated lesions undergoing DES implantation using a systematic provisional-stenting strategy were randomized to sirolimus-eluting stent (SES) or everolimus-eluting stent (EES) before intervention. The procedural details for PCI were prospectively recorded to assess the occurrence of any trouble in the side-branch (SB) management (primary end point). Post-PCI angiographic result (primary end point: minimal lumen diameter at SB ostium) was evaluated offline by 3-dimensional reconstruction and quantitative coronary analysis. Clinical outcome was prospectively recorded up to 18 months to assess the occurrence of target bifurcation failure. RESULTS A total of 150 patients were enrolled in the study (29% diabetics, 17% unprotected left main). The stent was successfully implanted according to randomization in all cases. Procedural performance was not significantly different between the 2 kinds of DES. Three-dimensional reconstruction and quantitative coronary analysis showed similar post-PCI results in the main vessel and better results in the SB with EES than with SES (minimal lumen diameter at SB ostium: 1.94 ± 0.72 mm vs. 1.64 ± 0.62 mm; p = 0.013). At 18 months, target bifurcation failure occurred in 7 (9.0%) of SES-treated patients versus 8 (10.7%) of EES patients (p = 0.57). CONCLUSIONS In patients with bifurcated lesions treated by provisional stenting technique, EES compared with SES is associated with similar procedural performance and better 3-dimensional reconstruction and quantitative coronary analysis result in the SB. Both DES are associated with low rates of major adverse events and angiographic failure. (Sirolimus Versus Everolimus-Eluting Stent Randomized Assessment in Bifurcated Lesions and Clinical Significance of Residual Side-Branch Stenosis [SEA-SIDE]; NCT00697372).

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.