Gerald P. McCann

Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: The Randomized Double-Blind Reminder Study

AIMS We aimed to assess the impact of eplerenone on cardiovascular (CV) outcomes in STEMI without known heart failure, when initiated within 24 h of symptom onset. METHODS AND RESULTS In this randomized, placebo-controlled, double-blind trial, we assigned 1012 patients with acute STEMI and without a history of heart failure to receive either eplerenone (25-50 mg once daily) or placebo in addition to standard therapy. The primary endpoint was the composite of CV mortality, re-hospitalization, or, extended initial hospital stay, due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, ejection fraction ≤40%, or elevated BNP/NT-proBNP at 1 month or more after randomization. BNP elevation was defined as BNP levels or values above 200 pg/mL or NT-proBNP values above 450 pg/mL (in patients aged below 50); above 900 pg/mL (age 50-75 years) or above 1800 pg/mL (patients older than 75). After a mean follow-up of 10.5 months, the primary endpoint occurred in 92 patients (18.2%) in the eplerenone group and in 149 patients (29.4%) in the placebo group [adjusted hazard ratio (HR), 0.58; 95% confidence interval (CI), 0.45-0.76; P < 0.0001]. The primary endpoint was driven by a high BNP/NT-proBNP level (adjusted HR, 0.60; 95% CI, 0.45-0.79; P < 0.0003). Adverse event rates were similar in both groups. Serum potassium levels exceeded 5.5 mmol/L in 5.6 vs. 3.2% (P = 0.09) and were below 3.5 mmol/L in 1.4 vs. 5.6% of patients (P = 0.0002), in the eplerenone and placebo groups, respectively. CONCLUSION The addition of eplerenone during the acute phase of STEMI was safe and well tolerated. It reduced the primary endpoint over a mean 13 months follow-up mostly because of significantly lower BNP/NT-proBNP levels. Additional studies are needed to clarify the role of early use of MRAs in STEMI patients without heart failure. CLINICAL TRIAL REGISTRATION NCT01176968.

Semi-quantitative assessment of right ventricular function in comparison to a 3D volumetric approach: A cardiovascular magnetic resonance study

Right ventricular (RV) volume measurements with cardiovascular magnetic resonance (CMR) is considered the gold standard, but acquisition and analysis remain time-consuming. The aim of our study was therefore to investigate the accuracy and performance of a semi-quantitative assessment of RV function in CMR, compared to the standard quantitative approach. Seventy-five subjects with pulmonary hypertension (15), anterior myocardial infarction (15), inferior myocardial infarction (15), Brugada syndrome (15) and normal subjects (15) underwent cine CMR. RV end-systolic and end-diastolic volumes were determined to calculate RV ejection fraction (EF). Four-chamber cine images were used to measure tricuspid annular plane systolic excursion (TAPSE). RV fractional shortening (RVFS) was calculated by dividing TAPSE by the RV end-diastolic length. RV EF correlated significantly with TAPSE (r = 0.62, p < 0.01) and RVFS (r = 0.67, p < 0.01). Sensitivity to predict RV dysfunction was comparable between TAPSE and RVFS, with higher specificity for RVFS, but comparable areas under the ROC curve. Intra- and inter-observer variability of RV EF was better than TAPSE (3%/4% versus 7%/15%, respectively). For routine screening in clinical practice, TAPSE and RVFS seem reliable and easy methods to identify patients with RV dysfunction. The 3D volumetric approach is preferred to assess RV function for research purposes or to evaluate treatment response.

Functional Outcome after Revascularization in Patients with Chronic Ischemic Heart Disease: A Quantitative Late Gadolinium Enhancement CMR Study Evaluating Transmural Scar Extent, Wall Thickness and Periprocedural Necrosis

In patients with chronic ischemic myocardial dysfunction, late gadolinium enhancement CMR (LGE-CMR) accurately depicts the regional extent of fibrosis and predicts functional recovery after revascularization. We hypothesized that the predictive accuracy of LGE-CMR could be optimized by not only taking into account the transmural extent of hyperenhancement but also the amount of residual, non-enhanced viable myocardium, and procedure related necrosis. We studied 45 patients with chronic ischemic left ventricular dysfunction, who underwent cine and LGE-CMR 1 month before and 3 months after surgical or percutaneous revascularization. Segmental and global function, scar, presence of a significant residual viable rim (defined as >or=4.5 mm), and procedure related necrosis were fully quantified using standardized methods and objective thresholds. Sixty percent of segments without hyperenhancement showed functional improvement at follow-up. No improvement was observed in segments with >75% segmental extent of hyperenhancement (SEH), while segments with 1-25%, 26-50%, and 51-75% SEH were 4, 8, and 20 times less likely to improve (multilevel analysis, p<0.001). Thickness of the viable rim largely paralleled total wall thickness; therefore, the presence of a significant viable rim did not provide additional diagnostic value beyond SEH. Procedure related necrosis was found in 12 (27%) patients. The presence of procedure related necrosis was the only (negative) predictor of changes in left ventricular volumes and ejection fraction. In conclusion, we found that functional outcome after revascularization was influenced by both transmural extent of hyperenhancement and procedure related necrosis. However, the presence of a significant residual, viable rim was of no additional diagnostic value.

Global myocardial strain assessment by different imaging modalities to predict outcomes after ST-elevation myocardial infarction: A systematic review.

AIM To conduct a systematic review relating myocardial strain assessed by different imaging modalities for prognostication following ST-elevation myocardial infarction (STEMI). METHODS An online literature search was performed in PubMed and OVID(®) electronic databases to identify any studies that assessed global myocardial strain parameters using speckle-tracking echocardiography (STE) and/or cardiac magnetic resonance imaging (CMR) techniques [either myocardial tagging or feature tracking (FT) software] in an acute STEMI cohort (days 0-14 post-event) to predict prognosis [either development of major adverse cardiac events (MACE)] or adverse left ventricular (LV) remodelling at follow-up (≥ 6 mo for MACE, ≥ 3 mo for remodelling). Search was restricted to studies within the last 20 years. All studies that matched the pre-defined search criteria were reviewed and their results interpreted. Due to considerable heterogeneity between studies, meta-analysis was not performed. RESULTS A total of seven studies (n = 7) were identified that matched the search criteria. All studies used STE to evaluate strain parameters - five (n = 5) assessed global longitudinal strain (GLS) (n = 5), one assessed GLS rate (GLS-R) (n = 1) and one assessed both (n = 1). Three studies showed that GLS independently predicted the development of adverse LV remodelling by multivariate analysis - odds ratio between 1.19 (CI: 1.04-1.37, P < 0.05) and 10 (CI: 6.7-14, P < 0.001) depending on the study. Four studies showed that GLS predicted the development of MACE - hazard ratio (HR) between 1.1 (CI: 1-1.1, P = 0.006) and 2.34 (1.10-4.97, P < 0.05). One paper found that GLS-R could significantly predict MACE - HR 18 (10-35, P < 0.001) - whilst another showed it did not. GLS < -10.85% had sensitivity/specificity of 89.7%/91% respectively for predicting the development of remodelling whilst GLS < -13% could predict the development of MACE with sensitivity/specificity of 100%/89% respectively. No suitable studies were identified that assessed global strain by CMR tagging or FT techniques. CONCLUSION GLS measured acutely post-STEMI by STE is a predictor of poor prognosis. Further research is needed to show that this is true for CMR-based techniques.

Combination Therapy Is Superior to Sequential Monotherapy for the Initial Treatment of Hypertension: A Double‐Blind Randomized Controlled Trial

Background Guidelines for hypertension vary in their preference for initial combination therapy or initial monotherapy, stratified by patient profile; therefore, we compared the efficacy and tolerability of these approaches. Methods and Results We performed a 1‐year, double‐blind, randomized controlled trial in 605 untreated patients aged 18 to 79 years with systolic blood pressure (BP) ≥150 mm Hg or diastolic BP ≥95 mm Hg. In phase 1 (weeks 0–16), patients were randomly assigned to initial monotherapy (losartan 50–100 mg or hydrochlorothiazide 12.5–25 mg crossing over at 8 weeks), or initial combination (losartan 50–100 mg plus hydrochlorothiazide 12.5–25 mg). In phase 2 (weeks 17–32), all patients received losartan 100 mg and hydrochlorothiazide 12.5 to 25 mg. In phase 3 (weeks 33–52), amlodipine with or without doxazosin could be added to achieve target BP. Hierarchical primary outcomes were the difference from baseline in home systolic BP, averaged over phases 1 and 2 and, if significant, at 32 weeks. Secondary outcomes included adverse events, and difference in home systolic BP responses between tertiles of plasma renin. Home systolic BP after initial monotherapy fell 4.9 mm Hg (range: 3.7–6.0 mm Hg) less over 32 weeks (P<0.001) than after initial combination but caught up at 32 weeks (difference 1.2 mm Hg [range: −0.4 to 2.8 mm Hg], P=0.13). In phase 1, home systolic BP response to each monotherapy differed substantially between renin tertiles, whereas response to combination therapy was uniform and at least 5 mm Hg more than to monotherapy. There were no differences in withdrawals due to adverse events. Conclusions Initial combination therapy can be recommended for patients with BP >150/95 mm Hg. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifier: NCT00994617.

Right ventricular function following surgical aortic valve replacement and transcatheter aortic valve implantation: A cardiovascular MR study

OBJECTIVE The response of the RV following treatment of aortic stenosis is poorly defined, reflecting the challenge of accurate RV assessment. Cardiovascular magnetic resonance (CMR) is the established reference for imaging of RV volumes, mass and function. We sought to define the impact of transcatheter aortic valve implantation (TAVI) and surgical aortic valve replacement (SAVR) upon RV function in patients treated for severe aortic stenosis using CMR. METHODS A 1.5T CMR scan was performed preoperatively and 6months postoperatively in 112 (56 TAVI, 56 SAVR; 76±8years) high-risk severe symptomatic aortic stenosis patients across two UK cardiothoracic centres. RESULTS TAVI patients were older (80.4±6.7 vs. 72.8±7.2years, p<0.05) with a higher STS score (2.13±0.73 vs. 5.54±3.41%, p<0.001). At 6months, SAVR was associated with a significant increase in RV end systolic volume (33±10 vs. 37±10ml/m2, p=0.008), and decrease in RV ejection fraction (58±8 vs. 53±8%, p=0.005) and tricuspid annular plane systolic excursion (22±5 vs. 14±3mm, p<0.001). Only 4 (7%) SAVR patients had new RV late gadolinium hyper-enhancement with no new cases seen in the TAVI patients at 6months. Longer surgical cross-clamp time was the only predictor of increased RV end systolic volume at 6months. Post-TAVI, there was no observed change in RV volumes or function. Over a maximum 6.3year follow-up, 18(32%) of TAVI patients and 1(1.7%) of SAVR patients had died (p=0.001). On multivariable Cox analysis, the RV mass at 6m post-TAVI was independently associated with all-cause mortality (HR 1.359, 95% CI 1.108-1.666, p=0.003). CONCLUSIONS SAVR results in a deterioration in RV systolic volumes and function associated with longer cross-clamp times and is not fully explained by suboptimal RV protection during cardiopulmonary bypass. TAVI had no adverse impact upon RV volumes or function.

Reply: Culprit Artery Only or Multivessel Primary PCI: The Debate Continues

The CvLPRIT (Complete versus Lesion-only Primary PCI Trial) [(1)][1] investigators welcome the comments of Dr. Agarwal. CvLPRIT was designed as a pragmatic trial of treatment strategies in real-world patients: randomization was carried out therefore on the basis of angiographic assessment of

038 LARGER INFARCT SIZE ASSOCIATED WITH DYSGLYCEMIA AT THE TIME OF ST-ELEVATION MYOCARDIAL INFARCTION IS RELATED TO LATER PRESENTATION

Introduction Patients with dysglycaemia at the time of ST-elevation myocardial infarction (STEMI) have a worse prognosis. The reasons for this are not entirely clear. Admission hyperglycaemia has been associated with larger infarct size. Table 1 Age (years) 60.77±11.75 (89% male sex) Reperfusion therapy PPCI: 45 (80%)/thrombolysis 11 (20%) Time to reperfusion (minutes) 194.16±121.12 Multivessel disease 22/56 (39%) LAD culprit 25/56 (45%) Percentage ECG resolution 62%±34% (median 67%) Glucose (mmol/l) 7.97±2.54 (median 7.7, IQR 2.10) HbA1c (%) 6.67±1.07 (median 5.9, IQR 0.4) Infarct size % 23.08±12.97 Myocardial Salvage Index % 53.71±26.41 The aims of this study were to examine the relation of acute and chronic glycaemic state to myocardial scar and salvage characteristics in patients with reperfused ST-elevation myocardial infarction. Methods Fifty-six patients treated for first ST-elevation myocardial infarction (STEMI) without a pre-existing diagnosis of Diabetes mellitus were prospectively enrolled between January and December 2010. Glycosylated haemoglobin (HbA1c) and glucose levels were sampled on admission to the emergency cardiac ward. Patients underwent cardiac magnetic resonance (CMR) examination during the index admission (median day 2 for CMR, IQR 2 days), with assessment of area-at-risk (STIRs), Infarct size (IS%), late microvascular obstruction (MVO%), and left ventricular function. Population characteristics are presented in table 1. There were no significant differences between patients receiving Primary Percutaneous Coronary Intervention (PPCI) or thrombolysis, so these were grouped for analysis. Patients were dichotomised into groups above and below the median both for admission glucose level and separately for HbA1c level before comparison between groups using Independent samples t test. Spearmans rank correlation was used to compare non-parametric data. Correlations with a p<0.1 were entered into a multivariate linear regression model. Results When patients were dichotomised into glucose levels below (<7.8 mmol/l) and above the median (¡Ý7.8 mmol/l), the supra-median group were significantly older (64.7 years vs 57.1 years, p=0.018) and had greater Infarct size (28.33% vs 18.46%, p=0.007). Dichotomising patients by HbA1c into levels below the median (<5.9%) and above the median (¡Ý5.9%), the supra-median group had significantly greater glucose levels (8.8 mmol/l vs 7.1 mmol/l, p=0.011), less ST-segment resolution (51.6% vs 75.5%, p=0.007), greater MVO% (2.77% vs 1.11%, p=0.049), greater intra-myocardial haemorrhage (IMH%) (1.96% vs 0.61%, p=−0.015), and lower myocardial salvage index (MSI%) (43.30% vs 65.15%, p=0.003). Correlations between infarct characteristics and admission glucose and HbA1c are shown in table 2. Admission glucose correlated significantly with age and IS%, while HbA1c correlated significantly with time to reperfusion and MSI%. On multivariate linear regression analysis however, glucose was not a predictor of IS% (R=0.549, R2=0.302, Age t=3.441, p=0.001, time to reperfusion t=2.708, p=0.009, glucose- not significant), and HbA1c was not a predictor of MSI% (R=0.453, R2=0.206, age t=−2.529, p=0.015, time to reperfusion t=−2.237, p=0.030, HbA1c-not significant). Table 2 Admission glucose HbA1c Percentage ECG resolution R=−0.393, p=0.003 R=−0.352, p=0.010 Time to reperfusion R=0.185, p=0.177 R=0.334, p=0.015 Age R=0.361, p=0.007 R=0.184, p=0.188 Infarct size % R=0.296, p=0.028 R=0.152, p=0.277 Microvascular obstruction % R=0.259, p=0.056 R=0.199, p=0.152 Intramyocardial haemorrhage % R=0.187, p=0.176 R=0.292, p=0.036 Area-at-risk (oedema) % R=0.128, p=0.358 R=−0.176, p=0.213 Myocardial Salvage Index % R=−0.187, p=0.176 R=−0.399, p=0.003 Conclusions/implications Admission Glucose levels are associated with larger infarct size, and HbA1c levels are associated with reduced myocardial salvage. However, glycaemic status is not an independent predictor of infarct size or salvage when time to reperfusion is taken in to consideration.

039 PREVALENCE AND EXTENT OF INFARCT AND MICROVASCULAR OBSTRUCTION FOLLOWING A RANGE OF REPERFUSION TECHNIQUES IN ST-ELEVATION MYOCARDIAL INFARCTION (STEMI)

Introduction Cardiac MRI (CMR) provides unique characterisation of myocardial injury post acute STEMI. It is the gold standard for non-invasive measurement of Infarct Size (IS) and tissue perfusion during STEMI. Microvascular obstruction (MVO) describes suboptimal tissue perfusion despite restoration of flow in the infarct-related artery (IRA). IS and MVO are independent predictors of adverse remodelling and prognosis post STEMI. MVO is generally assumed to be related primarily to reperfusion. CMR extent of IS and MVO decreases after 48 h post STEMI. There is a dearth of data on the prevalence and extent of MVO in clinical practice using different reperfusion methods, in particular in those without reperfusion. We hypothesise that the extent and presence of MVO are primarily related to the extent of ischaemic injury rather than reperfusion injury. Table 1 Key demographics and CMR analyses in the early reperfused and non-reperfused patients Variable Total study group (n=94) Early reperfused (PPCI+lysis, n=59) Non-reperfused (n=21) P Value Age (years) 61.01±13.1 60.24±11.90 65.57±16.18 0.114 Male sex (%) 82 (87.2) 53 (89.8) 16 (76.2) 0.121 Diabetes mellitus (n, %) 9 (9.6) 3 (5.1) 6 (28.6) 0.004 Time from admission-CMR (days) 2.22 (1.24–3.79) 1.91 (1.16–2.58) 6.59 (4.77–10.97) <0.001 LVEDVI (ml/m2) 94.21 (85.55–110.98) 90.68 (82.38–102.72) 98.04 (88.12–124.97) 0.013 LVESVI (ml/m2) 55.56 (48.08–69.93) 51.35 (45.37–62.62) 61.09 (53.97–83.64) 0.004 EF (%) 39.85±9.39 42.30±7.80 35.02±11.30 0.002 IS (% LV mass) 25.41±18.37 18.85±12.65 23.07±11.37 0.181 MVO (% LV mass) 0.60 (0.00–3.10) 0.44 (0.00–2.92) 1.34 (0.00–2.79) 0.364 Mean±SD where normally distributed. Method 94 acute STEMI subjects were studied. 75 were prospectively recruited into a study of ventricular remodelling post STEMI. 19 subjects were routine clinical CMR examinations undertaken in non-reperfused, late-presenting patients (>12 h symptoms) to assess viability. Subjects were assessed on a Siemens Avanto 1.5T system. LV function and volumes were assessed using SSFP. Ten minutes after intravenous injection of gadolinium contrast (0.2 mmol/kg), delayed contrast-enhanced images were acquired using a segmented inversion-recovery gradient-echo sequence. IS was defined as areas of hyperenhancement with signal intensity (SI) >50% of peak SI in the infarct core (Full-Width Half-Maximum technique). MVO was defined as hypointensity within areas of infarct. Independent T Test and Mann-Whitney U Test analyses were used for normally and non-parametrically distributed data respectively. Statistical significance was taken at p<0.05. Results There was no significant difference in age, sex, prevalence of angina, proportion of STEMI with left anterior descending artery IRA, TIMI score or Rentrop (degree of collateralization) score in early reperfused (PCI or Thrombolysis <12 h of symptoms, n=59) and non-reperfused patients (n=21) (table 1, below). Diabetes mellitus was more prevalent in non-reperfused patients (p=0.004). LV volumes were significantly greater and ejection fraction (LVEF) was significantly lower in non-reperfused patients. Despite a longer time from admission to CMR (p<0.001), there was a trend towards greater IS and extent of MVO in non-reperfused patients. Of the 15 non-reperfused patients who had angiography, the absence of spontaneous reperfusion was confirmed in 67% (TIMI flow 0–1). χ2 Analysis showed a trend towards higher prevalence of MVO in non-reperfused STEMI (71.4% vs 55.2%). Late PCI patients (n=6) demonstrated a trend towards higher volumes and greater extent of IS and MVO compared with non-reperfused and rescue PCI (n=8) patients. No differences were seen between rescue PCI and non-reperfused patients. Conclusions The prevalence and extent of myocardial and microvascular injury (IS, MVO) on CMR in non-reperfused STEMI is at least as much as that occurring in those undergoing early reperfusion therapy. This is despite a significantly longer time to CMR in non-reperfused patients, which would be expected to result in a reduction in IS and MVO. MVO is not exclusive to reperfusion and may represent the degree of ischaemic injury. Median (25th–75th quartiles) where non-normally distributed. Total study group (n=94) consists of early reperfused, non-reperfused, late PCI and rescue PCI patients.

013 RELATION OF MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO LEFT VENTRICULAR REMODELLING FOLLOWING FIRST ST-ELEVATION MYOCARDIAL INFARCTION

Introduction Adverse Left ventricular (LV) remodelling with increase in LV volumes and reduction in ejection fraction (EF) can occur following ST-elevation myocardial infarction (STEMI) and confers worse prognosis. LV remodelling is mediated in part by degradation of the extra-cellular matrix, through the activity of Matrix Metalloproteinase (MMP) enzymes and their intrinsic inhibitors, the tissue inhibitors of matrix metalloproteinases (TIMPs). Table 1 Age (years) 59.2±10.9 (93% male gender) Reperfusion therapy: PPCI (58%), thrombolysis (16%), rescue PCI (12%), completed/late presenting infarct (13%) LVESVI at STEMI 58.0±17.67 LVESVI at 4 months 53.2±18.35 LVEDVI at STEMI 95.84±18.15 LVEDVI at 4 months 97.29±22.25 EF at STEMI 41.17±8.35 EF at 4 months 47.21±8.39 We examined the relationships of NTproBNP, MMP and TIMP biomarkers measured at index admission with infarct characteristics, and relations to subsequent changes in LV volumes and mass. Methods Seventy-five patients with first STEMI presenting between January and December 2010 were prospectively enrolled. Pre-discharge serum samples were collected (median 45 h, IQR 40 h) before analysis via in-house chemiluminescent assay. Patients underwent Cardiac Magnetic Resonance (CMR) examination (1.5 T Seimens Avanto) during admission (median day 2, IQR 2 days) incorporating volume assessment (cine-SSFP) with further follow-up volume assessment at 4 months (median 120 days, IQR 8 days) completed in 67 patients. Percentage LV remodelling was determined by the following index for changes in end-systolic and end-diastolic volumes and masses: (Volume at 4 months−Volume at STEMI)÷Volume at STEMI×100% Patient demographics are shown in table 1. Where required, data was log transformed to normalise distribution. Biomarkers were correlated to volume and mass changes using Pearsons correlation to compare continuous variables and Spearmans rank correlation to compare non-parametric data. Correlations with p<0.1 were entered into multivariate linear regression model to predict subsequent remodelling. Results TIMP-4 levels sampled at the time of STEMI correlated with a relative change in LV end-systolic volume index (LVESVI) (R=0.315, p=0.009). Microvascular obstruction (MVO) and intra-myocardial haemorrhage (IMH) also correlated with LVESVI. There were no biomarker correlates with a relative change in LV End-diastolic volume index (LVEDVI). Percentage MVO and IMH positively correlated with LVEDVI. EF at 4 months correlated significantly with MMP3 (R=−0.346, p=0.004), NTproBNP (R=−0.450, p<0.001), time to reperfusion, Infarct size, MVO, IMH, and myocardial salvage index (MSI). There were no significant biomarker correlates with LV mass index. On univariate linear regression analysis, TIMP4 was an independent predictor of relative change in LVESVI (R=0.294, t=2.483, p=0.016). TIMP4 remained the only significant predictor of ESVI change on multivariate linear regression analysis incorporating IS%, MVO%, IMH% (R-0.390, TIMP4 t=2.131, p=0.037). Figure 1 NTproBNP remained the only independent predictor of EF at 4 months on multivariate linear regression (R=0.738, t=2.162, p=0.036). NTproBNP was also the only significant predictor of Infarct size at STEMI (R=0.733, t=4.852, p<0.001). Conclusions/implications TIMP4 is an independent predictor of a change in LVESVI in patients with STEMI. Early TIMP4 measurement might select patients at risk of subsequent LV remodelling. NTproBNP is an independent predictor of EF% and IS%.