Sex-Related Differences in Long-Term Outcomes After Early-Onset Myocardial Infarction.

Importance: There is growing awareness of sex-related differences in cardiovascular risk profiles, but less is known about whether these extend to pre-menopausal females experiencing an early-onset myocardial infarction (MI), who may benefit from the protective effects of estrogen exposure. Methods: A nationwide study involving 125 Italian Coronary Care Units recruited 2,000 patients between 1998 and 2002 hospitalized for a type I myocardial infarction before the age of 45 years (male, n = 1,778 (88.9%). Patients were followed up for a median of 19.9 years (IQR 18.1-22.6). The primary composite endpoint was the occurrence of cardiovascular death, non-fatal myocardial re-infarction or non-fatal stroke, and the secondary endpoint of hospitalization for revascularisation by means of a percutaneous coronary intervention (PCI) or coronary artery bypass surgery (CABG). Results: ST-elevation MI was the most frequent presentation among both men and women (85.1 vs. 87.4%, p = ns), but the men had a greater baseline coronary atherosclerotic burden (median Duke Coronary Artery Disease Index: 48 vs. 23; median Syntax score 9 vs. 7; both p < 0.001). The primary composite endpoint occurred less frequently among women (25.7% vs. 37.0%; adjusted hazard ratio: 0.69, 95% CI 0.52-0.91; p = 0.01) despite being less likely to receive treatment with most secondary prevention medications during follow up. Conclusions: There are significant sex-related differences in baseline risk factors and outcomes among patients with early-onset MI: women present with a lower atherosclerotic disease burden and, although they are less frequently prescribed secondary prevention measures, experience better long-term outcomes. Trial Registration: 4272/98 Ospedale Niguarda, Ca' Granda 03/09/1998.

Long-term outcomes of early-onset myocardial infarction with non-obstructive coronary artery disease (MINOCA).

BACKGROUND: Acute myocardial infarction with non-obstructive coronary artery disease (MINOCA) is frequent in patients experiencing an early-onset MI, but data concerning its long-term prognosis are limited and conflicting. METHODS: The Italian Genetic Study on Early-onset MI enrolled 2000 patients experiencing a first MI before the age of 45 years, and had a median follow-up of 19.9 years. The composite primary endpoint was cardiovascular (CV) death, non-fatal MI, and non-fatal stroke (MACE); the secondary endpoint was rehospitalisation for coronary revascularisation. RESULTS: MINOCA occurred in 317 patients (15.9%) and, during the follow-up, there was no significant difference in MACE rates between them and the patients with obstructive coronary artery disease (MICAD: 27.8% vs 37.5%; adjusted hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.57-1.09;p = 0.15). The CV death rate was lower in the MINOCA group (4.2% vs 8.4%, HR 0.26, 95%CI 0.08-0.86;p = 0.03), whereas the rates of non-fatal reinfarction (17.3% vs 25.4%; HR 0.76, 95%CI 0.52-1.13;p = 0.18), non-fatal ischemic stroke (9.5% vs 3.7%; HR 1.79, 95%CI 0.87-3.70;p = 0.12), and all-cause mortality (14.1% vs 20.7%, HR 0.73, 95%CI 0.43-1.25;p = 0.26) were not significantly different in the two groups. The rate of rehospitalisation for coronary revascularisation was lower among the MINOCA patients (6.7% vs 27.7%; HR 0.27, 95% CI 0.15-0.47;p < 0.001). CONCLUSIONS: MINOCA is frequent and not benign in patients with early-onset MI. Although there is a lower likelihood of CV death,the long-term risk of MACE and overall mortality is not significantly different from that of MICAD patients.

ImpaCt of an Optimal Implantation Strategy on Absorb Long-Term Outcomes: The CIAO Registry.

AIM: To compare the long-term outcomes of patients implanted with Absorb bioresorbable scaffold (BRS) with optimal versus suboptimal technique. METHODS AND RESULTS: All patients who received an Absorb between March 2012 and January 2016 were selected from 19 Italian centers databases to assess the impact of an optimal implantation technique (CIAO criteria) on long-term device-oriented composite end-point (DOCE) - including cardiac death (CD), target-vessel myocardial infarction (TV-MI) and ischemia-driven target lesion revascularization (ID-TLR) - on its single components and on scaffold thrombosis (ScT). CIAO criteria consist of predilation (balloon/vessel ratio 1:1), correct sizing (BRS/proximal reference vessel diameter -RVD- ratio 0.8-1.2) and high-pressure postdilation with non-compliant (NC) balloon (≥20 atm for balloon/BRS ratio 1:1 or ≥16 atm for a 0.25-0.5 mm oversized balloon). Among the 1.434 patients analyzed, 464 (32.4%) fulfilled all CIAO criteria for every BRS implanted (CIAO 3 group), while 970 (67.6%) did not in at least one of the received BRS (CIAO 0-1-2 group). At 31.0 (interquartile range -IQR- 24.8-38.5) months follow-up, CIAO criteria did not impact on DOCE (8.2% vs. 8.0%, p = 0.92), ID-TLR (6.9% vs. 7.1%, p = 0.72) or ScT (1.9% vs. 1.8%, p = 0.80) in the overall population. At multivariate analysis overall BRS length (p = 0.001), severely calcified lesions (p = 0.03) and absence of CIAO criteria (CIAO 0, p = 0.005) were independent predictors of DOCE in long-term follow-up. CONCLUSION: Our data suggest that strict application of an optimal Absorb implantation technique doesn't improve long-term DOCE or ScT but may mitigate the worse outcome of patients with calcific lesions.

Treatment of coronary artery disease with a new-generation drug-coated balloon: final results of the Italian Elutax SV rEgistry-DCB-RISE.

AIMS: Drug-coated balloons (DCBs) are a recognized alternative to stents for the treatment of in-stent restenosis (ISR), and there is some initial clinical evidence about their efficacy for the treatment of small coronary vessels. Newer-generation DCBs were developed to overcome the reduced deliverability of the previous generation, also warranting a more effective drug delivery to vessel wall. However, the vast majority of new-generation DCBs still lack of reliability due to paucity of clinical data. METHODS: Between 2012 and 2015, all patients treated with Elutax SV DCB (Aachen Resonance, Germany) at nine Italian centers were enrolled in this retrospective registry. Primary outcome was the occurrence of target-lesion revascularization (TLR) at the longest available follow-up. Secondary endpoints were procedural success and occurrence of device-oriented adverse cardiovascular events including cardiac death, target-vessel myocardial infarction, stroke, and TLR. A minimum 6-month clinical follow-up was required. RESULTS: We enrolled 544 consecutive patients treated at 583 sites. Fifty-three per cent of the patients had ISR, and the rest native vessel coronary artery disease. Procedural success occurred in 97.5%. At the longest available clinical follow-up (average 13.3 ±â€Š7.4 months), 5.9% of the patients suffered a TLR and 7.1% a device-oriented adverse cardiovascular event. We did not register cases of target-vessel abrupt occlusion. At multivariate analysis, severe calcification at the lesion site was the first determinant for the occurrence of TLR. CONCLUSION: This registry on the performance of a new-generation DCB shows an adequate profile of safety and efficacy at mid-term clinical follow-up.

Influence of 9p21.3 genetic variants on clinical and angiographic outcomes in early-onset myocardial infarction.

OBJECTIVES: The purpose of this study was to test whether the 9p21.3 variant rs1333040 influences the occurrence of new cardiovascular events and coronary atherosclerosis progression after early-onset myocardial infarction. BACKGROUND: 9p21.3 genetic variants are associated with ischemic heart disease, but it is not known whether they influence prognosis after an acute coronary event. METHODS: Within the Italian Genetic Study of Early-onset Myocardial Infarction, we genotyped rs1333040 in 1,508 patients hospitalized for a first myocardial infarction before the age of 45 years who underwent coronary angiography without index event coronary revascularization. They were followed up for major cardiovascular events and angiographic coronary atherosclerosis progression. RESULTS: Over 16,599 person-years, there were 683 cardiovascular events and 492 primary endpoints: 77 cardiovascular deaths, 223 reoccurrences of myocardial infarction, and 383 coronary artery revascularizations. The rs1333040 genotype had a significant influence (p = 0.01) on the primary endpoint, with an adjusted hazard ratio of 1.19 (95% confidence interval [CI]: 1.08 to 1.37) for heterozygous carriers and 1.41 (95% CI: 1.06 to 1.87) for homozygous carriers. Analysis of the individual components of the primary endpoints provided no significant evidence that the rs1333040 genotype influenced the hazard of cardiovascular death (p = 0.24) or the reoccurrence of myocardial infarction (p = 0.57), but did provide significant evidence that it influenced on the hazard of coronary revascularization, with adjusted heterozygous and homozygous ratios of 1.38 (95% CI: 1.17 to 1.63) and 1.90 (95% CI: 1.36 to 2.65) (p = 0.00015), respectively. It also significantly influenced the angiographic endpoint of coronary atherosclerosis progression (p = 0.002). CONCLUSIONS: In early-onset myocardial infarction, the 9p21.3 variant rs1333040 affects the progression of coronary atherosclerosis and the probability of coronary artery revascularization during long-term follow-up.

Genome-wide association of early-onset myocardial infarction with single nucleotide polymorphisms and copy number variants.

We conducted a genome-wide association study testing single nucleotide polymorphisms (SNPs) and copy number variants (CNVs) for association with early-onset myocardial infarction in 2,967 cases and 3,075 controls. We carried out replication in an independent sample with an effective sample size of up to 19,492. SNPs at nine loci reached genome-wide significance: three are newly identified (21q22 near MRPS6-SLC5A3-KCNE2, 6p24 in PHACTR1 and 2q33 in WDR12) and six replicated prior observations (9p21, 1p13 near CELSR2-PSRC1-SORT1, 10q11 near CXCL12, 1q41 in MIA3, 19p13 near LDLR and 1p32 near PCSK9). We tested 554 common copy number polymorphisms (>1% allele frequency) and none met the pre-specified threshold for replication (P < 10(-3)). We identified 8,065 rare CNVs but did not detect a greater CNV burden in cases compared to controls, in genes compared to the genome as a whole, or at any individual locus. SNPs at nine loci were reproducibly associated with myocardial infarction, but tests of common and rare CNVs failed to identify additional associations with myocardial infarction risk.

Circulating CD34-positive cell number is related to effective myocardial reperfusion in acute myocardial infarction treated with primary coronary angioplasty.

OBJECTIVE: In patients with ST-segment elevation acute myocardial infarction (STEMI) treated with primary percutaneous coronary interventions (PCIs), we sought to correlate circulating CD34+ and CD34+ CD133+ cell levels with clinical and laboratory findings that are known to affect prognosis in such patients. BACKGROUND: Although recent studies have focused on circulating adult peripheral blood stem cells in those patients, the possible relations between their circulating number and the various factors that may influence STEMI outcome have never been reported. METHODS: In 74 patients with STEMI presenting within 12 h from symptoms onset and treated with successful primary PCI, blood samples were collected before PCI (baseline) and 5-8 days thereafter (post-PCI). Myocardial blush was used as an index of effective myocardial reperfusion. Left ventricular functional recovery was assessed with echocardiography at 4-6 months. RESULTS: In STEMI patients, baseline CD34+ cell as well as CD34+ CD133+ cell numbers were lower than that of age-matched participants without history of ischemic heart disease. Both cell populations however increased post-PCI (P < 0.0001). A significant inverse relation was found between both CD34+, CD34+ CD133+ cell numbers and age, whereas both cell populations were directly related to myocardial blush grade (CD34+ r = 0.39, P = 0.002; CD34+ CD133+ r = 0.37, P = 0.003). By multiple regression analysis, a significant myocardial blush (grade 2-3) was the only predictor of left ventricular functional recovery (OR 10.77, 95% CI 3.1-22.8). CONCLUSION: CD34+ and CD34+ CD133+ cell number rises 5-8 days after STEMI, such increase being hampered by old age and favoured by effective myocardial reperfusion after primary PCI.

Unplanned surgery after drug eluting stent implantation: a strategy for safe temporary withdrawal of dual oral antiplatelet therapy.

We describe four cases of patients with multiple coronary drug eluting stent implantation who underwent major surgery (cardiac and noncardiac) early after stent implantation and needed premature interruption of dual antiplatelet therapy. The transitory withdrawal of oral antiplatelet therapy was accomplished without complications with the use of an IIb/IIIa glycoprotein inhibitor (Tirofiban).

Significance of total and differential leucocyte count in patients with acute myocardial infarction treated with primary coronary angioplasty.

AIMS: The aim of this study was to correlate total and differential leucocyte (WBC) count with myocardial blush, peak CK levels, and left ventricular (LV) functional recovery at 6 months in 238 consecutive acute myocardial infarction (MI) patients treated with successful primary coronary angioplasty (PCI). METHODS AND RESULTS: Total and differential WBC counts were measured on admission and every 24 h for at least 4 days after PCI. ST-segment resolution and myocardial blush were evaluated immediately after successful primary PCI. LV functional recovery (defined as improvement involving at least two segments, or at least one segment, when only two were asynergic on the basal examination) was obtained through echocardiographic evaluation of LV wall motion at the baseline and at 6 months. Basal CK (P<0.001) and increased neutrophil levels (P<0.001) were the only independent factors related to peak CK, whereas neutrophils and monocytes peaks were related to ST-segment resolution as well as to myocardial blush grade (MBG) 2-3. MBG 2-3 and monocytes number (both as continuous values as well as percentile values) were the only variables independently associated with 6-month LV functional recovery. CONCLUSION: The present study shows that neutrophils and monocytes counts on the first days after acute MI treated with primary PCI are related to markers of effective myocardial reperfusion such as MBG 2-3 and ST-segment resolution. However, only monocytes and MBG are significantly and independently associated with contractile recovery of the infarcted area at 6 months.

Effect of a short antibiotic treatment with roxithromycin on circulating adhesion molecules after coronary stenting: a single-center pilot trial.

BACKGROUND: The aim of this study was to assess the effect of periprocedural antibiotic treatment with roxithromycin on circulating cell adhesion molecules and restenosis after coronary stent implantation. METHODS: Case-control study enrolling 25 consecutive patients submitted to coronary stenting for stable, single-vessel coronary artery disease, treated with 300 mg roxithromycin once daily for 5 days, starting 2 days before the procedure (group R). Twenty-five patients, matched for lesion site, length and diameter, as control group (group C). The serological status for Chlamydia pneumoniae (CP) infection (IgG, ELISA) was assessed in all patients. The plasma concentrations of soluble intercellular adhesion molecule-1 (sICAM-1), E-selectin and C-reactive protein at 1 month after coronary stenting were compared with baseline values. Binary restenosis (> or = 50%) was also evaluated at 6 months. RESULTS: sICAM-1 significantly decreased at 1 month in group R vs group C (371 +/- 181 vs 573 +/- 273 ng/ml, p = 0.005). This decrease was more evident in patients with a positive serology for CP (CP+) (group R 373 +/- 131 vs group C 597 +/- 255 ng/ml, p = 0.014). Antibiotic treatment had no effects on circulating E-selectin levels at 1 month (56.7 +/- 97 vs 49.8 +/- 62 ng/ml, p = 0.54). The restenosis rate (9/50, 18%) was similar in the two groups (group R 5/25 [20%], group C 4/25 [16%]). The restenosis rate was similar in the CP+ vs CP- group (6/35 [17%] vs 3/15 [20%]). CONCLUSIONS: A short course of treatment with roxithromycin at the time of coronary stenting induces a significant reduction in the sICAM-1 levels at 1 month but apparently does not influence the restenosis rate.

["Cure" and "tactics" interventional strategies in unstable angina/non-Q infarction]. / Strategia di "cure" e "tattiche" interventistiche nell'angina instabile/infarto non Q.

Early risk stratification and an invasive approach (coronary angiography and reperfusion if indicated) have recently emerged as the treatment of choice in non-ST elevation acute coronary syndromes. An aggressive pharmacologic therapy, i.e. glycoprotein IIb/IIIa antagonists, is also more effective in case of risk assessment at the time of the admission of the patient in the coronary care unit. Recent data have assessed the advantages of abciximab over tirofiban in unstable patients submitted to percutaneous coronary intervention (PCI), whereas non-anticorpal molecules (tirofiban, integrilin) are indicated for the medical treatment of high-risk patients in order to reduce myocardial necrosis during the acute phase. A good platelet inhibition with the oral tienopiridine derivative clopidogrel, resulted in a lower incidence of major cardiovascular events at follow-up both in patients treated conservatively as well as in patients submitted to PCI (CURE and PCI-CURE trials). The early risk of myocardial necrosis before coronary revascularization was also reduced by clopidogrel in patients submitted to PCI, an effect already demonstrated with tirofiban and integrilin ("small molecules like" effect). A new therapeutic scheme including, at the time of admission, oral clopidogrel for platelet inhibition, an early risk assessment and the subsequent use of abciximab in the cath lab, if indicated is proposed for the treatment of unstable angina. The advantages associated with the proposed treatment have to be validated by ad hoc studies.

Integrated analysis of myocardial blush and ST-segment elevation recovery after successful primary angioplasty: Real-time grading of microvascular reperfusion and prediction of early and late recovery of left ventricular function.

BACKGROUND: ST-segment elevation (SigmaSTe) recovery and the angiographic myocardial blush (MB) grade are useful markers of microvascular reperfusion after recanalization of the infarct-related artery. We investigated the ability of a combined analysis of MB grade and SigmaSTe changes to identify different patterns of myocardial reperfusion shortly after primary percutaneous coronary angioplasty (PTCA) and to predict 7-day and 6-month left ventricular (LV) functional recovery. METHODS AND RESULTS: MB grade and SigmaSTe recovery were evaluated shortly after successful primary PTCA (restoration of TIMI grade 3 flow) in 114 consecutive patients with SigmaSTe acute myocardial infarction. LV function was assessed by 2D echocardiograms before PTCA and at 7 days and 6 months thereafter. By combining MB and SigmaSTe changes, 3 main groups of patients were identified. Group 1 patients (n=60) had both significant MB (grade 2 to 3) and SigmaSTe recovery (>50% versus basal SigmaSTe) and a high rate of 7-day (65%) and 6-month (95%) LV functional recovery. In group 2 patients (n=21), who showed MB but persistent SigmaSTe, the prevalence of early LV functional recovery was low (24%) but increased up to 86% in the late phase. Group 3 patients (n=28), who had neither significant MB nor SigmaSTe resolution, had poor early (18%) and late (32%) LV functional recovery. CONCLUSIONS: After successful primary PTCA, integrated analysis of MB and SigmaSTe recovery allows a real-time grading of microvascular reperfusion of the infarct area and predicts the time-course and magnitude of LV functional recovery.

[Combination therapy for acute myocardial infarction with glycoprotein IIb/IIIa inhibitors and fibrinolysis]. / Infarto miocardico acuto ST sopra: associazione tra inibitori delle glicoproteine e trombolitico? Pareri a confronto.

Early achievement of TIMI 3 (normal) flow in the infarct-related artery is the goal of therapy of acute myocardial infarction (AMI) in order to reduce infarct size and improve clinical outcome. By the mid 1990s mechanical treatment (primary angioplasty) has been recognized as the best method to gain this goal but fibrinolysis still remains the standard of care because of logistic limitations of angioplasty. Benefit of aspirin in association with fibrinolytic drugs encouraged the use of antagonists of the glycoprotein IIb/IIIa receptor (abciximab, eptifibatide, tirofiban), which block the final common pathway of platelet aggregation in AMI therapy. In dose-finding and dose-confirmation studies the combination of a fibrinolytic agent with a glycoprotein IIb/IIIa receptor antagonist, such as abciximab, resulted in nearly 80% of patients achieving complete reperfusion at 90 min without a substantial increase in side effects. This combination was tested in the phase III GUSTO V study. Compared to full-dose reteplase alone, the association of half-dose of reteplase and abciximab significantly reduced most non-fatal complications of myocardial infarction such as reinfarction and need of urgent revascularization. Failure to show a reduction in mortality with "combo therapy" must be related to the low 30-day mortality observed in both arms of the study, the lowest ever found in fibrinolytic trials. Warning about an increase in non-intracranial bleeding is counterbalanced by similar rates of intracranial hemorrhages and non-fatal disabling strokes in the two groups. On the basis of the GUSTO V results it appears clear that future advances in the management of AMI will only be possible by combining different reperfusion modalities (lytics, IIb/IIIa antagonists and coronary angioplasty). Whichever is the best combination, mechanical reperfusion will play a central role in the management of AMI. A major challenge for cardiologists will be reinforcement of collaboration and synergy between institutions with different levels of resources.

Effect of Abciximab on prothrombin activation and thrombin generation in acute coronary syndromes without ST-segment elevation: Global Utilization of Strategies to Open Occluded Coronary Arteries Trial IV in Acute Coronary Syndromes (GUSTO IV ACS) Italian Hematologic Substudy.

BACKGROUND: Abciximab is very effective in reducing major cardiac events in patients undergoing interventional procedures. Its antithrombotic effect is primarily attributable to the blocking of platelet glycoprotein IIb/IIIa receptors, but recent evidence suggests that it may have a direct antithrombin effect. No data are available concerning the effect of abciximab on the in vivo markers of prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation. METHODS AND RESULTS: We measured the plasma levels of prothrombin fragment 1+2 (a marker of prothrombin activation) and the thrombin/antithrombin complex (a marker of thrombin generation) in 167 patients with acute coronary syndromes without ST elevation enrolled in the GUSTO IV ACS trial who were randomized to receive abciximab for 24 hours (52 patients), abciximab for 48 hours (59 patients), or placebo (56 patients) in addition to heparin. Blood samples were obtained at baseline (before any treatment), after 24 and 48 hours (before study drug discontinuation), and 1 month later. There was a significant increase in the plasma levels of prothrombin fragment 1+2 after 48 hours and after 1 month in all 3 groups, placebo (P=0.0001), 24-hour abciximab (P=0.0002), and 48-hour abciximab (P=0.0001). The plasma thrombin/antithrombin complex levels were similar in the 3 groups at all time points and did not change during the study drug infusions. CONCLUSIONS: Abciximab does not decrease prothrombin activation and thrombin generation in patients with acute coronary syndromes without ST elevation not undergoing interventional procedures.