Early short-term doxycycline therapy in patients with acute myocardial infarction and left ventricular dysfunction to prevent the ominous progression to adverse remodelling: the TIPTOP trial.

AIMS: Experimental studies suggest that doxycycline attenuates post-infarction remodelling and exerts protective effects on myocardial ischaemia/reperfusion injury. However, the effects of the drug in the clinical setting are unknown. The aim of this study was to examine the effect of doxycycline on left ventricular (LV) remodelling in patients with acute ST-segment elevation myocardial infarction (STEMI) and LV dysfunction. METHODS AND RESULTS: Open-label, randomized, phase II trial. Immediately after primary percutaneous coronary intervention, patients with STEMI and LV ejection fraction < 40% were randomly assigned to doxycycline (100 mg b.i.d. for 7 days) in addition to standard therapy, or to standard care. The echo LV end-diastolic volumes index (LVEDVi) was determined at baseline and 6 months. (99m)Tc-Sestamibi-single-photon emission computed tomography infarct size and severity were assessed at 6 months. We calculated a sample size of 110 patients, assuming that doxycycline may reduce the increase in the LVEDVi from baseline to 6 months > 50% compared with the standard therapy (statistical power > 80% with a type I error = 0.05). The 6-month changes in %LVEDVi were significant smaller in the doxycycline group than in the control group [0.4% (IQR: -16.0 to 14.2%) vs.13.4% (IQR: -7.9 to 29.3%); P = 0.012], as well as infarct size [5.5% (IQR: 0 to 18.8%) vs. 10.4% (IQR: 0.3 to 29.9%) P = 0.052], and infarct severity [0.53 (IQR: 0.43-0.62) vs. 0.44 (IQR: 0.29-0.60), P = 0.014], respectively. CONCLUSION: In patients with acute STEMI and LV dysfunction, doxycycline reduces the adverse LV remodelling for comparable definite myocardial infarct size (NCT00469261).

Effects of a timely therapy with doxycycline on the left ventricular remodeling according to the pre-procedural TIMI flow grade in patients with ST-elevation acute myocardial infarction.

Doxycycline has been demonstrated to reduced left ventricular (LV) remodeling, but its effect in patients with ST-elevation myocardial infarction (STEMI) and a baseline occluded [thrombolysis in myocardial infarction (TIMI) flow grade ≤1] infarct-related artery (IRA) is unknown. According to the baseline TIMI flow grade, 110 patients with a first STEMI were divided into 2 groups. Group 1: 77 patients with TIMI flow ≤1 (40 patients treated with doxycycline and 37 with standard therapy, respectively), and a Group 2: 33 patients with TIMI flow 2-3 (15 patients treated with doxycycline and 18 with standard therapy, respectively). The two randomized groups were well matched in baseline characteristics. A 2D-Echo was performed at baseline and at 6 months, together with a coronary angiography, for the remodeling and IRA patency assessment, respectively. The LV end-diastolic volume index (LVEDVi) decreased in Group 2 [-3 mL/m(2) (IQR: -12 to 4 mL/m(2))], and increased in Group 1 [6 mL/m(2) (IQR: -2 to 14 mL/m(2))], (p = 0.001). In Group 2, LVEDVi reduction was similar regardless of drug therapy, while in Group 1 the LVEDVi was smaller in patients treated with doxycycline as compared to control [3 mL/m(2) (IQR: -3 to 8 mL/m(2)) vs. 10 mL/m(2) (IQR: 1-27 mL/m(2)), p = 0.006]. A similar pattern was observed also for LV end-systolic volume and ejection fraction. In STEMI patients at higher risk, as those with a baseline TIMI flow grade ≤1, doxycycline reduces LV remodeling.

Relationship between infarct size and severity measured by gated SPECT and long-term left ventricular remodelling after acute myocardial infarction.

PURPOSE: After acute myocardial infarction (AMI), left ventricular (LV) remodelling may occur despite successful reperfusion. This study aimed to investigate by gated single photon emission computed tomography (SPECT) the long-term evolution of myocardial perfusion and LV function after AMI and to identify the predictors of LV remodelling. METHODS: Sixty-eight AMI patients successfully treated by primary percutaneous coronary intervention underwent (99m)Tc-sestamibi gated SPECT at 1 month (baseline) and over 6-month follow-up after the acute event. LV remodelling was defined as 20% increase in LV end-diastolic volume at follow-up. RESULTS: At baseline, patients with remodelling (n = 14) showed larger (infarct size 29.3 ± 7.8%) and more transmural (infarct severity 0.28 ± 0.10) infarctions, and reduced LV ejection fraction (35.4 ± 5.6%), but similar LV volume indexes, compared to patients without remodelling (n = 54) (infarct size 20.8 ± 14.4%, p < 0.05, infarct severity 0.40 ± 0.11, p < 0.001, ejection fraction 44.5 ± 9.2, p < 0.001). At stepwise multivariate regression analysis, infarct severity showed the best predictive value for predicting LV remodelling (F = 5.54, p < 0.05). Using the thresholds identified by receiver-operating characteristic curve analysis, infarct size and severity detected patients with remodelling with 75% accuracy and 95% negative predictive value. Infarct resorption (defined as the defect size difference between follow-up and baseline) was comparable between patients with (-4.4 ± 8.4%) and without remodelling (-6.8 ± 9.4%) (p = NS). CONCLUSION: Perfusion parameters assessed by gated SPECT in the subacute phase after successfully treated AMI correlate with changes in functional parameters at long-term follow-up. Infarct severity is more effective than infarct size, but both are helpful for predicting LV remodelling.

High residual platelet reactivity after clopidogrel loading and long-term clinical outcome after drug-eluting stenting for unprotected left main coronary disease.

BACKGROUND: No data exist about the impact of high residual platelet reactivity (HRPR) after clopidogrel loading on long-term clinical outcome in patients undergoing drug-eluting stent (DES) implantation for unprotected left main disease (ULMD). METHODS AND RESULTS: Consecutive patients who underwent percutaneous coronary intervention for ULMD had prospective platelet reactivity assessment by light transmittance aggregometry after a loading dose of 600 mg of clopidogrel. The primary end point of the study was cardiac mortality, and the secondary end point was stent thrombosis. From January 2005 to September 2008, 215 consecutive patients were treated with DES for ULMD. The incidence of HRPR after clopidogrel loading was 18.6%. The median follow-up was 19.3 months. The overall estimated 1-, 2- and 3-year cardiac mortality rate was 3.9+/-1.3%, 7.5+/-2.2%, and 12.2+/-3.4%, respectively. The 3-year cardiac mortality rate was 8.0+/-3.1% in the low residual platelet reactivity (LRPR) group and 28.3+/-10.4% in the HRPR group (P=0.005). The 3-year stent thrombosis rate was 4.2+/-1.8% in the low residual platelet reactivity group and 16.0+/-7.3% in the HRPR group (P=0.021). By forward stepwise regression analysis, HRPR after clopidogrel loading was the only independent predictor of cardiac death (hazard ratio, 3.82; 95% confidence interval,1.38 to 10.54; P=0.010) and stent thrombosis (hazard ratio, 3.69; 95% confidence interval, 1.12 to 12.09; P=0.031). CONCLUSIONS: HRPR after 600-mg clopidogrel loading is a strong marker of increased risk of cardiac death and DES thrombosis in patients receiving DES stenting for ULMD. Routine assessment of in vitro residual platelet reactivity after clopidogrel loading in patients with ULMD potentially suitable for DES-supported percutaneous coronary intervention should be considered to guide patient care decisions.

Predictor of stent thrombosis in patients treated with turbostratic carbon-coated stent implantation for acute myocardial infarction.

BACKGROUND: Stent thrombosis is a major complication after percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction (AMI) and is associated with reinfarction and increased risk of death. METHODS: Patients treated with the turbostratic carbon-coated stent (CID, Saluggia, Italy) for AMI were identified from a prospective primary PCI database. Primary end-point was stent thrombosis within 6 months. Forward stepwise Cox proportional hazards analysis was used to identify independent predictors of stent thrombosis. RESULTS: Between 2001 and 2008, 746 patients underwent turbostratic carbon-coated stent implantation for AMI. Patients had a mean age of 65 ± 12 years, 9% had cardiogenic shock on admission, 48% had multivessel coronary disease, 78% had baseline target vessel TIMI grade 0-1. Multiple stent implantation was performed in 26% of patients. The majority of patients (78%) received abciximab treatment and a postprocedural TIMI grade 3 flow was achieved in 98% patients. Definite stent thrombosis occurred in 10 patients (1.3%), while three patients (0.4%) had possible stent thrombosis. No probable stent thrombosis occurred. There were no procedural stent thromboses. In patients who received abciximab stent thrombosis the rate was 1%, while it was 4.3% in patients not receiving abciximab treatment. After adjusting for all clinical, angiographic, and procedural variables, abciximab treatment (HR 0.17; 95% CI 0.05-0.56, P = 0.003) and major bleedings (HR 14.2; 85% CI 2.79-72.44, P = 0.001) were the only two predictors related to stent thrombosis. CONCLUSIONS: Patients with AMI treated with turbostratic carbon-coated stent implantation and abciximab treatment have a low incidence of stent thrombosis. Abciximab treatment along with major bleeding complications are the only predictors related to stent thrombosis.

Impact of complete revascularization with percutaneous coronary intervention on survival in patients with at least one chronic total occlusion.

AIMS: This study sought to determine the impact on survival of successful drug-eluting stent-supported percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). METHODS AND RESULTS: Comparison of long-term cardiac survival of consecutive patients who underwent PCI for at least one CTO and who were stratified into successful and failure procedures. From 2003 to 2006, 486 patients underwent PCI for 527 CTO. CTO-PCI was successful in 344 patients (71%) and 361 lesions (68%). Multivessel PCI was performed in 62% in the CTO-PCI failure group and in 71% in the CTO-PCI success group (P = 0.062). Cardiac survival rate was higher in the CTO-PCI success group compared with CTO-PCI failure group (91.6 +/- 2.0 vs. 87.4 +/- 2.9%; P = 0.025), in patients with multivessel disease and CTO-PCI success compared with CTO-PCI failure (91.4 +/- 2.2 vs. 86.6 +/- 3.1%; P = 0.021), and in patients with complete revascularization when compared to patients with incomplete revascularization (94.0 +/- 1.7 vs. 83.8 +/- 3.6%; P < 0.001). CONCLUSION: Successful CTO-PCI confers a long-term survival benefit. Improvement in survival is driven by the differences in the outcome of patients with multivessel disease and who were completely revascularized.

Relationship of sustained brain natriuretic peptide release after reperfused acute myocardial infarction with gated SPECT infarct measurements and its connection with collagen turnover and left ventricular remodeling.

BACKGROUND: The relationship among plasma brain natriuretic peptide (BNP), markers of extracellular matrix (ECM) remodeling, and left ventricular (LV) dilation after reperfused acute myocardial infarction is poorly known. METHODS AND RESULTS: Echocardiogram, plasma BNP, and ECM degradation markers (serum amino-terminal telopeptide of type I procollagen and type III procollagen and carboxy-terminal telopeptide of type I procollagen [ICTP]) were evaluated in 34 patients at days 1, 3, and 30 after first reperfused acute myocardial infarction. At 1 month, infarct size and severity and LV volume were measured by sestamibi gated single photon emission computed tomography. Patients were stratified according to day 3 BNP levels into 2 groups: group 1 (n = 17) had BNP values over the median value, and group 2 (n = 17) had BNP values under the median value. Infarct size and severity were similar in the 2 groups. LV volumes increased in group 1 but decreased in group 2 (P < .01). BNP values, LV volume/mass index, and infarct size were independent predictors of 1-month LV dilation (beta = .58 [P = .001], beta = .41 [P = .01], and beta = .32 [P = .03], respectively). Levels of serum amino-terminal propeptide of type I procollagen and type III procollagen were similar in both groups. The level of ICTP increased significantly in group 1 only, and after 3 days, it was higher (P < .01) than in group 2. In group 1 ICTP significantly interacted with the relationship between BNP release and serial changes in LV volumes (F = 4.87, P = .03). CONCLUSIONS: ICTP is related to elevated BNP level independently of infarct size and severity and interacts with the relationship between BNP and LV dilation. BNP levels could play a role in LV remodeling by favoring ECM degradation.

Relation between plasma brain natriuretic peptide, serum indexes of collagen type I turnover, and left ventricular remodeling after reperfused acute myocardial infarction.

The aim of the study is to investigate the relation between plasma brain natriuretic peptide (BNP), collagen type I turnover, and left ventricular (LV) remodeling after primary angioplasty. Echo-Doppler, BNP, carboxy-terminal telopeptide of procollagen type I (ICTP), C-terminal propeptide of procollagen type I (PICP), and their ratio PICP/ICTP (as an index of coupling between the synthesis and degradation of collagen type I) were evaluated at days 1 and 3 and months 1 and 6 after primary angioplasty in 56 consecutive patients with a first large acute myocardial infarction (AMI). During the 6 months after AMI, a direct relation was shown between BNP and ICTP (day 1, r = 0.54, p = 0.000; day 3, r = 0.64, p = 0.000; month 1, r = 0.64, p = 0.000; month 6, r = 0.41, p = 0.005) and BNP and PICP/ICTP (day 1, r = -0.54, p = 0.003; day 3, r = -0.58, p = 0.000; month 1, r = -0.50, p = 0.000; month 6, r = -0.30, p = 0.043), but not between BNP and PICP. Using analysis of covariance, relations between BNP and ICTP and PICP/ICTP were independent from infarct size. Patients with LV remodeling had significantly higher plasma ICTP and BNP levels and lower PICP/ICTP than patients without LV remodeling. Day-1 ICTP independently predicted 6-month remodeling (exp beta = 2.14, 95% confidence interval 1,120 to 3,550, p = 0.01). In conclusion, a relation exists between plasma BNP collagen type I turnover and LV remodeling after reperfused AMI.

Prevalence, predictors, time course, and long-term clinical implications of left ventricular functional recovery after mechanical reperfusion for acute myocardial infarction.

This study prospectively evaluated the prevalence, predictors, time course, and prognostic impact of left ventricular (LV) functional recovery after successful primary percutaneous coronary intervention in 228 consecutive patients with acute myocardial infarctions (AMIs) and LV dysfunction. Serial echocardiographic exams were performed within 24 hours (time 1) and at 1 month (time 2) and 6 months (time 3) after AMI. Overall, 133 patients (58%) showed significant LV functional recovery (> or =10% ejection fraction increase compared with time 1 or ejection fraction > or =50%) at time 3. Early (from time 1 to time 2) and late (from time 2 to time 3) functional recovery patterns were detected in 102 patients (45%) and 31 patients (14%), respectively. Independent predictors of LV functional recovery were enzymatic infarct size (p = 0.0001), time from symptom onset to reperfusion (p = 0.022), extent and severity of baseline LV wall motion abnormalities (p = 0.007), and female gender (p = 0.031). Six-month LV remodeling rates were 36% and 64% in patients with and without LV functional recovery (p = 0.0001). The five-year cardiac death rate was significantly lower in patients with LV functional recovery than in those without (8% vs 18%, respectively, p = 0.024). The time course of LV functional recovery during 6 months did not significantly affect long-term survival. In conclusion, after successful mechanical reperfusion of AMIs, nearly half of patients showed poor LV functional recovery. The presence of significant LV functional recovery 6 months after reperfused AMI, but not the specific time course of recovery, is clearly associated with a better long-term clinical outcome. Simple baseline variables can predict the improvement of cardiac function after reperfused AMI.

A New Risk Score to Predict Long-Term Cardiac Mortality in Patients With Acute Myocardial Infarction Complicated by Cardiogenic Shock and Treated With Primary Percutaneous Intervention.

Poor data exist about predictors of long-term cardiac mortality in patients presenting acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) treated with primary percutaneous coronary intervention (p-PCI), and current risk-adjustment models in this setting are not adequate. We retrospectively analyzed our registry of patients with AMI treated with p-PCI. The aim of this study was to identify the independent predictors of 2-year cardiac mortality in patients presenting CS. A Risk Score was created assigning at any independent variable a value directly correlated with its power to increase mortality. From 1995 to 2013, 4,078 consecutive patients underwent primary PCI for AMI. Of these, 388 patients (10.5%) had CS on admission. The p-PCI procedural success was 85%. At 2-year follow-up, the overall cardiac mortality rate was 48%. The independent predictors related with mortality were: out of hospital cardiac arrest (OHCA) (hazard ratio [HR] 1.51; p = 0.04), age >75 years (HR 2.09; p ≤0.001), and failure p-PCI (HR 2.30; p <0.001). On the basis of the HR obtained, we assigned an incremental value to each independent variable identified (OHCA: 0.5 points, age>75 years: 1 point, failed p-PCI: 1.5 points). The mortality rates among different score risk level were highly significant (p <0.001): 32% score risk 1 (points 0), 58% score risk 2 (points 0.5-2), and 83% score risk 3 (points >2), respectively. In conclusion, OHCA, age >75 years, and failed p-PCI are strong predictors of 2-year cardiac mortality. On the basis of this, a rapid score tool could be useful to identify patients at major risk of death.

Early changes of left ventricular filling pattern after reperfused ST-elevation myocardial infarction and doxycycline therapy: Insights from the TIPTOP trial.

AIM: Metalloproteinases inhibition by doxycycline reduces cardiac protein degradation at extracellular and intracellular level in the experimental model ischemia/reperfusion injury. Since both extracellular cardiac matrix and titin filaments inside the cardiomyocyte are responsible for the myocardial stiffness, we hypothesized that doxycycline could favorably act on left ventricular (LV) filling pressures in patients after reperfused acute ST-elevation myocardial infarction (STEMI). METHODS AND RESULTS: Seventy-three of 110 patients of the TIPTOP trial underwent a 2D-Echo-Doppler on admission, and at pre-discharge and at 6-month after a primary PCI for STEMI and LV dysfunction. From admission to pre-discharge, LV filling changed from a high filling pressure (HFP) to a normal filling pressure (NFP) pattern in 91% of the doxycycline-group, and in 67% of the control-group. Conversely, 1% of the doxycycline-group, and 37% of the control-group changed the LV filling from NFP to HFP pattern. Overall, a pre-discharge HFP pattern was present in 4 patients (11%) of the doxycycline-group and in 13 patients (36%) of the control-group (p=0.025). The evaluation of metalloproteinases and their tissue inhibitors plasma concentrations provide possible favorable action of doxycycline. On the multivariate analyses, troponine I peak (p=0.026), doxycycline (p=0.033), and on admission to pre-discharge LVEF changes (p=0.044) were found to be associated with pre-discharge HFP pattern. Independently of their baseline LV filling behavior, the 6-month remodeling was less in patients with pre-discharge NFP pattern than in patients with HFP pattern. CONCLUSIONS: In patients with STEMI and LV dysfunction doxycycline can favorably modulate the LV filling pattern early after primary PCI.

Data on administration of cyclosporine, nicorandil, metoprolol on reperfusion related outcomes in ST-segment Elevation Myocardial Infarction treated with percutaneous coronary intervention.

Mortality and morbidity in patients with ST elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PCI) are still high [1]. A huge amount of the myocardial damage is related to the mitochondrial events happening during reperfusion [2]. Several drugs directly and indirectly targeting mitochondria have been administered at the time of the PCI and their effect on fatal (all-cause mortality, cardiovascular (CV) death) and non fatal (hospital readmission for heart failure (HF)) outcomes have been tested showing conflicting results [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. Data from 15 trials have been pooled with the aim to analyze the effect of drug administration versus placebo on outcome [17]. Subgroup analysis are here analyzed: considering only randomized clinical trial (RCT) on cyclosporine or nicorandil [3], [4], [5], [9], [10], [11], excluding a trial on metoprolol [12] and comparing trial with follow-up length <12 months versus those with longer follow-up [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16]. This article describes data related article titled "Clinical Benefit of Drugs Targeting Mitochondrial Function as an Adjunct to Reperfusion in ST-segment Elevation Myocardial Infarction: a Meta-Analysis of Randomized Clinical Trials" [17].

Clinical benefit of drugs targeting mitochondrial function as an adjunct to reperfusion in ST-segment elevation myocardial infarction: A meta-analysis of randomized clinical trials.

AIMS: To perform a systematic review and meta-analysis of randomized clinical trials (RCT) comparing the effectiveness of drugs targeting mitochondrial function vs. placebo in patients with ST-segment elevation myocardial infarction (STEMI) undergoing mechanical coronary reperfusion. METHODS: Inclusion criteria: RCTs enrolling STEMI patients treated with primary percutaneous coronary intervention (PCI) and comparing drugs targeting mitochondrial function vs. placebo. Odds ratios (OR) were computed from individual studies and pooled with random-effect meta-analysis. RESULTS: Fifteen studies were identified involving 5680 patients. When compared with placebo, drugs targeting mitochondrial component/pathway were not associated with significant reduction of cardiovascular and all-cause mortality (OR 0.9, 95% CI 0.7-1.17 and OR 0.92, 95% CI 0.69-1.23, respectively). However, these agents significantly reduced hospital admission for heart failure (HF) (OR 0.64; 95% CI 0.45-0.92) and increased left ventricular ejection fraction (LVEF) (OR 1.44; 95% CI 1.15-1.82). After analysis for subgroups according to the mechanism of action, drugs with direct/selective action did not reduce any outcome. Conversely, those with indirect/unspecific action showed a significant effect on cardiovascular mortality (0.65, 95% CI 0.46-0.92), all-cause mortality (OR 0.69, 95% CI 0.52-0.92), hospital readmission for HF (OR 0.41, 95% CI 0.28-0.6) and LVEF (OR 1.49, 95% CI 1.09-2.05). CONCLUSIONS: Administration of drugs targeting mitochondrial function in STEMI patients undergoing primary PCI appear to have no effect on mortality, but may reduce hospital readmission for HF. The drugs with a broad-spectrum mechanism of action seem to be more effective in reducing adverse events.

Angiographic and Clinical Outcomes After Everolimus-Eluting Stenting for Unprotected Left Main Disease and High Anatomic Coronary Complexity.

OBJECTIVES: This study determined angiographic and clinical outcomes after everolimus-eluting stent (EES)-supported percutaneous coronary intervention for unprotected left main disease (ULMD) and high SYNTAX (SYNergy between PCI with TAXus and Cardiac Surgery) trial score (≥33). BACKGROUND: The SYNTAX trial has shown the superiority of coronary surgery over percutaneous coronary intervention (PCI) in patients with ULMD and complex coronary anatomy. It has been hypothesized that, if newer generation drug-eluting stents had been used in the SYNTAX trial, there would have been a significant reduction in clinical events. METHODS: Patients had angiograms scored according to the SYNTAX score algorithm and were divided into 2 groups: those with SYNTAX score of ≥33 and those with <33. The main endpoints were ULMD restenosis and 3-year cardiac mortality. RESULTS: From May 2008 to July 2014, 393 patients underwent EES implantation for ULMD (181 patients had a SYNTAX score ≥33, whereas 212 patients had a SYNTAX score <33). Overall, the restenosis rate was 4.9% (6% in SYNTAX patients scoring ≥33 and 4.1% in SYNTAX patients scoring <33; p = 0.399). On multivariate analysis, the only variable related to restenosis was stent length (odds ratio [OR]: 1.06; 95% confidence interval [CI]: 1.02 to 1.09; p = 0.002). Three-year cardiac survival rates were 99 ± 1% and 98 ± 2% in patients with European system for cardiac operative risk evaluation (EuroSCORE) <6 and SYNTAX <33 and ≥33, respectively, and 90 ± 3% and 87 ± 3% in patients with a EuroSCORE >6 and SYNTAX score <33 and ≥33, respectively. EuroSCORE was strongly related to cardiac mortality, while the SYNTAX score ≥33 was not both in patients with a EuroSCORE <6 or ≥6, and there were no interactions between EuroSCORE and SYNTAX score ≥33. CONCLUSIONS: For ULMD patients, high anatomical complexity as defined by a SYNTAX score ≥33 is not predictive of clinical outcome after PCI. (TAXUS Drug-Eluting Stent Versus Coronary Artery Bypass Surgery for the Treatment of Narrowed Arteries [SYNTAX]; NCT00114972).

Impact of microvascular dysfunction on left ventricular remodeling and long-term clinical outcome after primary coronary angioplasty for acute myocardial infarction.

BACKGROUND: We hypothesized that preserved microvascular integrity in the area at risk would favorably influence left ventricular (LV) remodeling and long-term outcome after acute myocardial infarction. METHODS AND RESULTS: Before and after successful primary angioplasty (percutaneous transluminal coronary angioplasty [PTCA]), 124 patients with acute myocardial infarction underwent intracoronary myocardial contrast echo (MCE). An MCE score index (MCESI) was derived by averaging the single-segment score (0=not visible, 1=patchy, 2=homogeneous contrast effect) within the area at risk. An MCESI > or =1 was considered adequate reperfusion. Mean follow-up was 46+/-32 months. After PTCA, 100 patients showed adequate reperfusion (no microvascular dysfunction, NoMD), whereas 24 did not (MD). MD patients had a higher mean creatine kinase (4153+/-2422 versus 2743+/-1774 U/L; P=0.002) and baseline wall-motion score index (2.61+/-0.31 versus 2.25+/-0.42; P<0.001) and a lower baseline ejection fraction (33+/-8% versus 40+/-7%; P<0.001). From day 1 on, LV volumes progressively increased in the MD patients (n=19) and were larger than those of NoMD patients (n=85) at 6 months (end-diastolic volume 170+/-55 versus 115+/-29 mL; P<0.001). MCESI was the most important independent predictor of LV dilation (OR 0.61, 95% CI 0.52 to 0.71, P<0.000001). By Cox analysis, MD represented the only predictor of cardiac death (OR 0.26, 95% CI 0.09 to 0.72, P=0.010) and combined events (cardiac death, reinfarction, and heart failure; OR 0.44, 95% CI 0.23 to 0.85, P=0.014). MD patients showed worse survival in terms of cardiac death (P<0.0001) and combined events (P<0.0001). CONCLUSIONS: In reperfused acute myocardial infarction, MD within the risk area is an important predictor of both LV remodeling and unfavorable long-term outcome.

Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications.

BACKGROUND: We prospectively evaluated the prevalence, pattern, and prognostic impact of left ventricular (LV) remodeling after acute myocardial infarction (AMI) successfully treated with primary PTCA. The prevalence, course, and prognostic value of LV remodeling after primary PTCA are still to be clarified. METHODS AND RESULTS: In 284 consecutive patients with AMI treated with primary PTCA, serial echocardiographic and angiographic studies, within 24 hours (T1), at 1 (T2) and 6 months (T3) after AMI were performed. Long-term (61+/-14 months) clinical follow-up data were collected for 98.6% patients enrolled in the study. Overall, 85 (30%) patients showed LV dilation (>20% end-diastolic volume increase) at T3 as compared with T1. Early (from T1 to T2), late (from T2 to T3), and progressive dilation patterns (from T1 to T2 to T3) were detected in 42 (15%), 41 (14%), and 36 (13%) patients, respectively. Cardiac death and combined events rate was significantly higher among patients with than among those without LV dilation (P=0.005 and P=0.025, respectively). The pattern of LV dilation during 6 months did not significantly affect survival. Cox survival analysis identified end-systolic volume at T1 and age as baseline predictors and end-systolic volume at T3 and age as 6-month predictors of cardiac death, respectively. CONCLUSIONS: LV remodeling after successful PTCA occurs despite sustained patency of the infarct-related artery and preservation of regional and global LV function. LV dilation at 6 months after AMI but not the specific pattern of LV dilation is clearly associated with worse long-term clinical outcome.

Comparison of the usefulness of Doppler-derived deceleration time versus plasma brain natriuretic peptide to predict left ventricular remodeling after mechanical revascularization in patients with ST-elevation acute myocardial infarction and left ventricular systolic dysfunction.

The correlation between Doppler deceleration time (DT) and brain natriuretic peptide (BNP) and their predictive value for detecting left ventricular (LV) remodeling in patients who are treated with primary percutaneous intervention for infarction and LV dysfunction are unknown. Fifty-six patients (64 +/- 12 years of age; 11 women) who had a first ST-segment elevation myocardial infarction and systolic dysfunction that was successfully treated with direct primary coronary intervention underwent 2-dimensional Doppler echocardiographic and plasma BNP evaluation at days 1 and 3 and 1 and 6 months after the index infarction. Repeat coronary angiograms were obtained at 1 and 6 months. Because of previous consistent evidence, 3 days after the index infarction was the time point of comparison between BNP and DT values. Echocardiographic LV remodeling was defined as an increase in end-diastolic volume index above baseline values of 2 x SD. Ventricular remodeling occurred in 20 patients (36%). Multivariate analyses that included BNP level, Doppler DT, echocardiographic measurements of systolic function, peak creatine kinase, and anterior infarct location showed Doppler DT to be the only predictor of LV remodeling (odds ratio 0.963, 95% confidence interval 0.936 to 0.990, p = 0.008). The optimal cutoff for DT in the prediction of 6-month LV remodeling was <136 ms (sensitivity 75%, specificity 97%, accuracy 81%, area under receiver-operating characteristic curve 0.90). Thus, in patients who have a first ST-segment elevation myocardial infarction and LV systolic dysfunction that is successfully treated with primary percutaneous coronary intervention, Doppler-derived DT 3 days after index infarction is more effective than BNP level in detecting patients who are at higher risk for 6-month LV remodeling.

Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial.

BACKGROUND: The TIPTOP (Early Short-term Doxycycline Therapy In Patients with Acute Myocardial Infarction and Left Ventricular Dysfunction to Prevent The Ominous Progression to Adverse Remodelling) trial demonstrated that a timely, short-term therapy with doxycycline is able to reduce LV dilation, and both infarct size and severity in patients treated with primary percutaneous intervention (pPCI) for a first ST-elevation myocardial infarction (STEMI) and left ventricular (LV) dysfunction. In this secondary, pre-defined analysis of the TIPTOP trial we evaluated the relationship between doxycycline and plasma levels of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs). METHODS: In 106 of the 110 (96%) patients enrolled in the TIPTOP trial, plasma MMPs and TIMPs were measured at baseline, and at post-STEMI days 1, 7, 30 and 180. To evaluate the remodeling process, 2D-Echo studies were performed at baseline and at 6months. A (99m)Tc-SPECT was performed to evaluate the 6-month infarct size and severity. RESULTS: Doxycycline therapy was independently related to higher plasma TIMP-2 levels at day 7 (p<0.05). Plasma TIMP-2 levels above the median value at day 7 were correlated with the 6-month smaller infarct size (3% [0%-16%] vs. 12% [0%-30%], p=0.002) and severity (0.55 [0.44-0.64] vs. 0.45 [0.29-0.60], p=0.002), and LV dilation (-1ml/m(2) [from -7ml/m(2) to 9ml/m(2)] vs. 3ml/m(2) [from -2ml/m(2) to 19ml/m(2)], p=0.04), compared to their counterpart. CONCLUSIONS: In this clinical setting, doxycycline therapy results in higher plasma levels of TIMP-2 which, in turn, inversely correlate with 6month infarct size and severity as well as LV dilation.

Prognostic impact of high residual platelet reactivity after chronic total occlusion percutaneous coronary intervention in patients with diabetes mellitus.

BACKGROUND: The study sought to determine the impact of high residual platelet reactivity (HRPR) on long-term cardiac mortality in diabetic patients treated with PCI for CTO. No data exist about the impact of HRPR after 600 mg clopidogrel loading on long-term clinical outcome in patients with diabetes mellitus and treated with percutaneous coronary angioplasty (PCI) for chronic total occlusion (CTO). METHODS: From the Florence CTO-PCI registry, we identified consecutive diabetic patients with available in vitro platelet reactivity assessment by light transmittance aggregometry after a loading dose of 600 mg of clopidogrel. HRPR was defined as residual platelet aggregation by 10 µmol/L ADP test ≥70%. The primary end point of the study was long-term cardiac mortality. RESULTS: Two-hundred and three diabetic patients underwent CTO-PCI. The incidence of HRPR was 23%. The 3-year cardiac survival was lower in the HRPR group than the low residual platelet reactivity (LRPR) group (70 ± 7% and 92 ± 3%, respectively; p=0.001). Within the oral antidiabetic patients there were no significant differences in long-term survival between HRPR and LRPR groups. Conversely, the association of insulin therapy and HRPR was related to a dramatic decrease in survival compared to the LRPR group (34 ± 14% vs. 89 ± 4%; p<0.001). At multivariable analysis insulin therapy (HR 4.31; p=0.001) and HRPR (HR 3.26; p=0.004) were significantly related to long-term mortality, while completeness of revascularization was inversely related to cardiac mortality (HR 0.40; p=0.029). CONCLUSION: HRPR is a strong marker of increased risk of cardiac death in patients with DM who underwent PCI for CTO.

Abciximab therapy improves 1-month survival rate in unselected patients with acute myocardial infarction undergoing routine infarct artery stent implantation.

BACKGROUND: The impact of abciximab therapy on mortality in unselected patients with acute myocardial infarction (AMI) undergoing routine primary infarct-related artery (IRA) stent implantation is not yet defined, and previous randomized studies have produced conflicting results. METHODS: A strategy of IRA stenting alone as opposed to IRA stenting plus abciximab was compared in a series of 561 consecutive unselected patients with AMI. Abciximab treatment was strongly encouraged for all patients. The contraindication for abciximab therapy was a high risk of major bleeding as assessed by the operator before mechanical intervention. RESULTS: Of 561 patients, 348 patients underwent abciximab therapy and 213 underwent primary IRA stenting alone. The 1-month overall mortality rate was 2.9% in the abciximab group and 10.8% in the stent alone group (P <.001). The relative reduction in mortality rate was 73% for patients overall, 77% in the subset of patients aged < or =70 years (mortality rate, 1.2% vs 5.2%, P =.020), 57% in patients aged >70 years (7.7% vs 18%, P =.043), 63% in patients with cardiogenic shock (17% vs 46%, P =.022), and 77% in patients without cardiogenic shock (1.3% vs 5.6%, P =.002). Multivariate analyses on the basis of all patients, and on the subset of patients aged < or =70 years, showed that abciximab therapy was independently related to the risk of death at 1 month. No differences were seen between groups in the procedural success rate (99.1% vs 98.1%) or in the incidence rates of nonfatal reinfarction (0.3% vs 1.9%) or repeat target vessel revascularization (1.7% vs 1.9%). CONCLUSION: The results of this study strongly support the use of abciximab therapy in nonselected patients with AMI undergoing routine IRA stent implantation. The mechanism of the clinical benefit of abciximab was not related to the patency of the IRA.